Anti-ulcer pyridyloxy derivatives, their preparation and uses

BACKGROUND TO THE INVENTION
The present invention relates to a series of new pyridyloxy derivatives which have the ability to inhibit the secretion of gastric juices and which may thus be used for the treatment and prevention of ulcers. The invention also provides methods and compositions using these new compounds for such treatment and prevention and processes for the preparation of these compounds.
Peptic ulcers are said to occur when there is an imbalance between factors which attack the gastro-intestinal mucosa and factors which defend the gastrointestinal mucosa. The gastric juice is among the attacking factors. Accordingly, if its secretion could be inhibited, this would be useful for the prevention and therapy of ulcers.
Among the drugs so far proposed for the inhibition of gastric juice secretion, anticholinergic agents and histamine-H.sub.2 receptor antagonists (such as cimetidine) have been widely used clinically and have had considerable success, although they are not free from disadvantages. For example, anticholinergic agents have exhibited a range of side effects, including inhibition of movement of the gastrointestinal tract, thirst, mydriasis and inhibition of sweating. Some of the histamine-H.sub.2 receptor antagonists also have undesirable side effects on the central nervous system, and may also have an antagonistic effect on androgens. Moreover, it is thought that the histamine-H.sub.2 receptor antagonists may weaken mucosal protecting factors after long-term administration, and recurrence of ulcers after withdrawal of these drugs has also been observed. Since recurrence is thought to be caused by a decrease in the protecting factors, a drug having the ability both to inhibit gastric juice secretion and to potentiate protecting factor activity would be highly desirable.
We have now discovered that a series of pyridyloxy derivatives having a certain specific and limited class of substituents has the desired combination of gastric juice secretion inhibitory activity, anti-ulcer activity and defense factor potentiating activity, and may therefore be used in the treatment and prevention of gastric ulcers.
A number of compounds having anti-ulcer activity and similar structures to the pyridyloxy derivatives of the present invention is known. Examples include Compound A (disclosed, for example, in European Patent Publication No. 404 949 or WO90/00544), Compound B (disclosed, for example, in Japanese Patent Kokai Application No. Hei-1-193247, Japanese Patent Kokai Application No. Sho-63-225371 and European Patent Publication No. 282 077) and Compound C (disclosed, for example, in Japanese Patent Kokai Application No. Hei-4-257581): ##STR2##
Compound C was disclosed after the priority dates hereof. The compounds of the present invention surprisingly have substantially better activities than these structurally similar and have a combination of gastric juice secretion inhibitory, anti-ulcer and defense factor potentiating activities which these prior compounds do not possess.
BRIEF SUMMARY OF INVENTION
It is, therefore, an object of the present invention to provide a series of new pyridyloxy derivatives.
It is a further, and more specific object of the invention to provide such compounds which may be useful for the treatment and/or prevention of gastric ulcers.
Other objects and advantages of the invention will become apparent as the description proceeds.
The compounds of the present invention are those compounds of formula (I): ##STR3## wherein: R.sup.1 represents
a cyclic amino group having from 3 to 7 ring atoms, of which from 1 to 3 are nitrogen atoms, 0 or 1 is an oxygen atom or a sulfur atom, and the remainder are carbon atoms, or
a dialkylamino group in which each alkyl group is independently selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms;
R.sup.2 represents
a group of formula --NHCHR.sup.3 R.sup.4, wherein
R.sup.3 and R.sup.4 are independently selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, aryl groups as defined below and aralkyl groups as defined below, or
R.sup.3 and R.sup.4 together with the carbon atom to which they are attached, represent a cycloalkyl group having from 3 to 8 ring carbon atoms, which group is unsubstituted or is substituted by at least one substituent selected from the group consisting of substituents .alpha.,
an aromatic heterocyclic, group having 5 ring atoms, of which from 1 to 3 are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur hetero-atoms, said group being unsubstituted or having at least one substituent selected, in the case of substituents on carbon atoms, from the group consisting of substituents .alpha. and, in the case of substituents on nitrogen atoms, from the group consisting of substituents .beta.,
or a group of formula --B--S(O).sub.m --R.sup.5, wherein
R.sup.5 represents: a substituted alkyl group which has from 1 to 4 carbon atoms and which is substituted by at least one substituent selected from the group consisting of substituents .gamma.; or an aromatic heterocyclic group which has 5 or 6 ring atoms of which from 1 to 4 are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur hetero-atoms, said group being unsubstituted or having at least one substituent selected, in the case of substituents on carbon atoms, from the group consisting of substituents .alpha. and, in the case of substituents on nitrogen atoms, from the group consisting of substituents .epsilon.,
B represents an alkylene or alkylidene group having from 1 to 6 carbon atoms,
and m is 0, 1 or 2;
A represents a group of formula --CH.dbd.CH-- or --(CH.sub.2).sub.n --, where n is 1, 2 or 3;
said aryl groups are carbocyclic aromatic groups having from 6 to 10 ring carbon atoms which are unsubstituted or which are substituted by at least one substituent selected from the group consisting of substituents .zeta.;
said aralkyl groups are alkyl groups which have from 1 to 4 carbon atoms and which are substituted by from 3 aryl groups as defined above;
said substituents .alpha. are selected from the group consisting of: alkyl groups having from 1 to 4 carbon atoms; alkoxy groups having from 1 to 4 carbon atoms; hydroxy groups; halogen atoms; amino groups; monoalkylamino groups in which the alkyl part has from 1 to 4 carbon atoms; dialkylamino groups in which each alkyl part is independently selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms; alkanoylamino groups having from 1 to 5 carbon atoms; arylcarbonylamino groups in which the aryl part is as defined above; and aryl groups as defined above;
said substituents .beta. are selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms;
said substituents y are selected from the group consisting of: hydroxy groups; alkanoyloxy groups having from 1 to 5 carbon atoms; substituted alkanoyloxy groups which have from 2 to 5 carbon atoms and which are substituted by at least one substituent selected from the group consisting of substituents .delta.; arylcarbonyloxy groups in which the aryl part is as defined above; and cycloalkylcarbonyloxy groups in which the cycloalkyl part has from 3 to 6 ring carbon atoms and is unsubstituted or is substituted by at least one substituent selected from the group consisting of substituents .alpha.;
said substituents .delta. are selected from the group consisting of: carboxy groups; alkoxycarbonyl groups in which the alkoxy part has from 1 to 4 carbon atoms; aryloxycarbonyl groups in which the aryl part is as defined above; and aryl groups as defined above;
said substituents .epsilon. are selected from the group consisting of: alkyl groups having from 1 to 4 carbon atoms; and hydroxyalkyl groups having from 2 to 4 carbon atoms;
said substituents .zeta. are selected from the group consisting of substituents .alpha., provided that any aryl group in said substituents .alpha. is not further substituted by an aryl group;
PROVIDED THAT, when m is 1, R.sup.5 represents: said substituted alkyl group having from 1 to 4 carbon atoms; an aromatic heterocyclic group which has 5 ring atoms of which from 2 to 4 are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur hetero-atoms, said group being unsubstituted as defined above or an aromatic heterocyclic group which has 6 ring atoms of which from 1 to 4 are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur hetero-atoms, said group being unsubstituted as defined above;
and pharmaceutically acceptable salts thereof.
The invention also provides a pharmaceutical composition for the treatment and prophylaxis of ulcerous conditions, which comprises an anti-ulcer compound in admixture with a pharmaceutically acceptable carrier or diluent, wherein the anti-ulcer compound is selected from the group consisting of compounds of formula (I) and pharmaceutically acceptable salts thereof.
The invention still further provides a method for the treatment and prophylaxis of ulcerous conditions, which comprises administering an effective amount of an anti-ulcer compound to a mammal, wherein the anti-ulcer compound is selected from the group consisting of compounds of formula (I) and pharmaceutically acceptable salts thereof.
The present invention also provides processes for preparing these compounds, which are described in greater detail hereafter.
DETAILED DESCRIPTION OF INVENTION
In the compounds of the present invention, where R.sup.1 represents a cyclic amino group, this has from 3 to 7 ring atoms, including at least one nitrogen atom. In addition, there may be another 1 or 2 nitrogen atoms and/or an oxygen or sulfur atom. The group is attached to the methylene group forming part of the remainder of the molecule by means of a nitrogen atom. The group preferably has a single nitrogen atom, the remainder of the ring atoms being carbon. Examples of such groups include the 1-aziridinyl, 1-azetidinyl, 1-pyrrolidinyl, piperidino and 1-hexahydroazepinyl groups. Of these we prefer the 1-pyrrolidinyl and piperidino groups, more preferably the piperidino group.
Where R.sup.1 represents a dialkylamino group or substituent .alpha., .beta., .epsilon. or .zeta. represents an alkyl group, this alkyl group may be a straight or branched chain alkyl group having from 1 to 4 carbon atoms, and examples include the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and t-butyl groups, preferably the methyl, ethyl, propyl, isopropyl, butyl and sec-butyl groups, and most preferably the methyl or ethyl group.
In the case of the dialkylamino group represented by R.sup.1, the two alkyl groups may be the same or different although they are preferably the same. Specific examples of dialkylamino groups include the dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, dipentylamino, dihexylamino, methylethylamino and methylpropylamino, of which we prefer the dimethylamino, diethylamino and dipropylamino groups, especially the dimethylamino group.
Where R.sup.2 represents a group of formula --NHCHR.sup.3 R.sup.4 and R.sup.3 and/or R.sup.4 represents an alkyl group having from 1 to 6 carbon atoms, this may be a straight or branched chain group having from 1 to 6, preferably from 1 to 4, carbon atoms, and examples include the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, 2-methylbutyl, 1-ethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, hexyl and isohexyl groups. Of these, we prefer the methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, pentyl and hexyl groups, and most prefer the methyl and ethyl groups.
Where R.sup.2 represents a group of formula --NHCHR.sup.3 R.sup.4 and R.sup.3 and/or R.sup.4 represents an aryl group, this has from 6 to 10, preferably 6 or 10, ring carbon atoms and may be unsubstituted or it may be substituted by one or more of substituents .zeta., defined above and exemplified below. Specific examples of the unsubstituted aryl groups include the phenyl and naphthyl (1- or 2- naphthyl) groups, of which the phenyl group is preferred. The aryl ring may optionally have one or more substituents (preferably from 1 to 3 substituents, and more preferably 1 substituent). Examples of such substituents are given in more detail below, but the preferred substituents are alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, and halogen atoms (such as the fluorine, chlorine, bromine or iodine atoms). Preferred substituents are the methyl group, the methoxy group, the fluorine atom and the chlorine atom. The substituents are, in the case of substituted phenyl groups, preferably on the 4-position. Examples of preferred substituted phenyl groups include the 4-methylphenyl, 4-methoxyphenyl, 4-chlorophenyl and 4-fluorophenyl groups.
Where R.sup.2 represents a group of formula --NHCHR.sup.3 R.sup.4, and R.sup.3 and/or R.sup.4 represents an aralkyl group, the aryl part may be as exemplified above and the alkyl part may be any one of those alkyl groups having from 1 to 4 carbon atoms exemplified above. Preferably the aryl and alkyl parts of the aralkyl group together have from 7 to 11 carbon atoms. The aryl part of the aralkyl group may be substituted or unsubstituted, and, if substituted, the substituents are selected from the group consisting of substituents .zeta. defined above and exemplified below. However, the group is preferably unsubstituted. Examples of such aralkyl groups include the benzyl, phenethyl, 1-phenylethyl, 2-phenylpropyl, 3-phenylpropyl, 4-phenylbutyl and 1- and 2- naphthylmethyl groups, of which the benzyl, phenethyl and 1- and 2- naphthylmethyl groups are preferred, the benzyl group being most preferred.
Where R.sup.2 represents a group of formula --NHCHR.sup.3 R.sup.4 and R.sup.3 and R.sup.4 together with the carbon atom to which they are attached, represent a cycloalkyl group, this has from 3 to 8 ring carbon atoms, and examples include the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups, of which the cyclopropyl, cyclobutyl and cyclopentyl groups are preferred, and the cyclopropyl and cyclobutyl groups are most preferred. The cycloalkyl ring may be substituted or unsubstituted, and, if substituted, it preferably has from 1 to 3, more preferably 1, substituents selected from the group consisting of substituents .alpha.. Examples of such substituents are given in more detail below, but the preferred substituents are alkyl groups having from 1 to 4 carbon atoms and alkoxy groups having from 1 to 4 carbon atoms. Of these, we prefer the methyl or ethyl group, but the cycloalkyl group is preferably unsubstituted.
Where R.sup.2 represents an aromatic heterocyclic group, this has 5 ring atoms, of which from 1 to 3 are hetero-atoms selected from oxygen, nitrogen and sulfur atoms. Where there is one hetero-atom, this may be any of the oxygen, nitrogen and sulfur atoms. Where there are two or three hetero-atoms, we prefer that all three or two should be nitrogen atoms and none or one should be an oxygen or sulfur atom. Examples of such groups include the furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, 1,2,3-, 1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl, 1,2,3-, 1,2,4-, 1,2,5- or 1,3,4thiadiazolyl, and 1,2,3- or 1,2,4-triazolyl groups. Of these, the furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, imidazolyl and 1,2,3-thiadiazolyl groups are preferred, and the thienyl, thiazolyl, pyrrolyl, pyrazolyl and 1,2,3-thiadiazolyl groups are more preferred. We particularly prefer the thienyl, pyrrolyl and pyrazolyl groups. These groups may be unsubstituted or they may be substituted by one or more substituents. Where the substituent is on a carbon atom, it may be selected from the group consisting of substituents .alpha., defined above and exemplified below. Where the substituent is on a nitrogen atom, it may be selected from the group consisting of substituents .beta., defined above and exemplified below. There is no particular limitation on the number of such substituents, except that the number of substitutable positions on 5-membered aromatic heterocyclic groups is 4, and from 1 to 4 such substituents are possible, from 1 to 3 being preferred and 1 or 2 being most preferred.
Examples of substituents .alpha. include:
alkyl groups having from 1 to 4 carbon atoms, as exemplified above;
alkoxy groups having from 1 to 4 carbon atoms, such as the methoxy, ethoxy, propoxy, isopropoxy, butoxy and isobutoxy groups, of which the methoxy and ethoxy groups are preferred;
hydroxy groups;
halogen atoms, such as the fluorine, chlorine, bromine and iodine atoms, of which the fluorine and chlorine atoms are preferred;
amino groups;
monoalkylamino groups in which the alkyl part has from 1 to 4 carbon atoms, such as the methylamino, ethylamino, propylamino, isopropylamino, butylamino and isobutylamino groups, preferably the methylamino and ethylamino groups;
dialkylamino groups in which each alkyl part is independently selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, such as those exemplified above in relation to the dialkylamino groups which may be represented by R.sup.1 ;
alkanoylamino groups having from 1 to 5 carbon atoms, such as the formamido, acetamido, propionamido, butyramido, valerylamino and isovalerylamino groups, preferably the acetamido or propionamido group;
arylcarbonylamino groups in which the aryl part is as defined and exemplified above in relation to the aryl groups which may be represented by R.sup.3 and R.sup.4 particularly the benzamido group;
and aryl groups as defined and exemplified above in relation to the aryl groups which may be represented by R.sup.3 and R.sup.4, particularly the phenyl group.
Examples of substituents .beta. are straight or branched chain alkyl groups having from 1 to 4 carbon atoms, and examples include the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and t-butyl groups, preferably the methyl, ethyl, propyl, isopropyl, butyl and sec-butyl groups, and most preferably the methyl or ethyl group.
Specific examples of such substituted and unsubstituted groups which may be represented by R.sup.2 are given hereafter.
Where R.sup.5 represents a substituted alkyl group, the alkyl moiety may be a straight or branched chain alkyl group having from 1 to 4 carbon atoms, and examples include the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and t-butyl groups, preferably the methyl, ethyl, propyl, isopropyl, butyl and sec-butyl groups, more preferably the ethyl or propyl group having a substituent at the 2-position, and most preferably the ethyl group having a substituent at the 2-position. The group is substituted by at least one, and preferably from 1 to 3, more preferably 1, substituent selected from the group consisting of substituents .gamma..
Examples of substituents .gamma. include:
hydroxy groups;
alkanoyloxy groups having from 1 to 5 carbon atoms, such as the formoxy, acetoxy, propionyloxy, butyryloxy, valeryloxy and isovaleryloxy groups, preferably the acetoxy or propionyloxy group;
substituted alkanoyloxy groups which have from 2 to 5 carbon atoms and which are substituted by at least one substituent selected from the group consisting of substituents .delta., such as the acetoxy, propionyloxy, butyryloxy, valeryloxy and isovaleryloxy groups, preferably the acetoxy or propionyloxy group; examples of substituents .delta. are:
carboxy groups;
alkoxycarbonyl groups in which the alkoxy part has from 1 to 4 carbon atoms, such as the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl and isobutoxycarbonyl groups, of which the methoxycarbonyl and ethoxycarbonyl groups are preferred;
aryloxycarbonyl groups in which the aryl part is as defined and exemplified above in relation to the aryl groups which may be represented by R.sup.3 and R.sup.4, particularly the phenoxycarbonyl group; and
aryl groups as defined and exemplified above in relation to the aryl groups which may be represented by R.sup.3 and R.sup.4, particularly the phenyl group;
especially, propionyloxy groups substituted at the 3-position by a carboxy, alkoxycarbonyl or aryloxycarbonyl group and acetoxy groups substituted by an aryl group;
arylcarbonyloxy groups in which the aryl part is as defined and exemplified above in relation to the aryl groups which may be represented by R.sup.3 and R.sup.4 particularly the benzoyloxy group;
and cycloalkylcarbonyloxy groups in which the cycloalkyl part has from 3 to 6 ring carbon atoms,, such as the cyclopropylcarbonyloxy, cyclobutylcarbonyloxy, cyclopentylcarbonyloxy and cyclohexylcarbonyloxy groups, which may be substituted or unsubstituted (preferably unsubstituted) and, if substituted, have one or more substituents selected from the group consisting of substituents .alpha., preferably alkyl groups or alkoxy groups, as exemplified above, and more preferably methyl or ethyl groups; the cycloalkylcarbonyloxy group is preferably a cyclopentylcarbonyloxy or cyclohexylcarbonyloxy group.
Where R.sup.5 represents an aromatic heterocyclic group, this has 5 or 6 ring atoms, of which from 1 to 4 are hetero-atoms selected from the group consisting of oxygen, nitrogen and sulfur atoms. Where there is only one hetero-atom, this may be any of the oxygen, nitrogen and sulfur atoms. However, where there are two, three or four hetero-atoms, it is preferred that 0 or 1 is an oxygen or sulfur atom and, where there are no oxygen or sulfur atoms, 1, 2, 3 or 4 are nitrogen atoms, or, where there is 1 oxygen or sulfur atom, 0, 1, 2 or 3 are nitrogen atoms. Examples of such groups include the furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, 1,2,3-, 1,2,4-, 1,2,5- or 1,3,4-oxadiazolyl, 1,2,3-, 1,2,4-, 1,2,5- or 1,3,4-thiadiazolyl, 1,2,3- or 1,2,4-triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and 1,2,3-, 1,2,4- or 1,3,5-triazinyl groups. Of these, we prefer the imidazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl and pyrimidinyl groups, more preferably the 1,3,4-oxadiazolyl, 1,2,4-triazolyl, tetrazolyl and pyrimidinyl groups and most preferably the 1,3,4-oxadiazolyl, 1,2,4-triazolyl and pyrimidinyl groups. Such groups may be unsubstituted or they may have one or more (preferably from 1 to 3) substituents selected from the group consisting of substituents .alpha., in the case of substituents on carbon atoms, or substituents .epsilon., in the case of substituents on nitrogen atoms. Examples of substituents .alpha. have been given above. Examples of substituents .epsilon. are as follows:
alkyl groups having from 1 to 4 carbon atoms, such as those exemplified above in relation to substituents .beta.; and
hydroxyalkyl groups having from 2 to 4 carbon atoms, such as the 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxybutyl, 3-hydroxybutyl and 4-hydroxybutyl groups; preferably a 2-hydroxyethyl or 3-hydroxypropyl group.
Specific examples of such substituted and unsubstituted groups which may be represented by R.sup.5 are given hereafter.
B can represent an alkylene or alkylidene group having from 1 to 6 carbon atoms. Examples include the methylene, ethylene, trimethylene, propylene, tetramethylene, 2-methyltrimethylene, pentamethylene and hexamethylene groups. Of these, we prefer the methylene, ethylene or trimethylene group, more preferably a methylene or trimethylene group.
Preferably m is 0 or 1, and most preferably m is 0.
Preferably A is a group of formula --CH.dbd.CH-- or --CH.sub.2 CH.sub.2 --, and most preferably A is a group of formula --CH.dbd.CH--.
Specific examples of preferred optionally substituted 5-membered aromatic heterocyclic groups containing from 1 to 3 hetero-atoms selected from the group consisting of oxygen, nitrogen and sulfur atoms, which may be represented by R.sup.2 include the 2-furyl, 3-furyl, 3-methyl-2-furyl, 4-methyl-2-furyl, 5-methyl-2-furyl, 2-methyl-3-furyl, 4-methyl-3-furyl, 5-methyl-3-furyl, 5-chloro-2ofuryl, 5-chloro-3-furyl, 3-amino-2furyl, 5-amino-2-furyl, 3-acetamido-2-furyl, 5-acetamido-2-furyl, 5-phenyl-2-furyl, 5-(4-methylphenyl)-2furyl, 5-(4-chlorophenyl)-2-furyl, 2,4-dimethyl-3-furyl, 2,5-dimethyl-3-furyl, 3-methyl-5-amino-2-furyl, 2-thienyl, 3-thienyl, 3-methyl-2-thienyl, 4-methyl-2-thienyl, 5-methyl-2-thienyl, 2-methyl-3-thienyl, 4-methyl-3-thienyl, 5-methyl-3-thienyl, 5-ethyl-2-thienyl, 4-methoxy-2-thienyl, 4-methoxy-3-thienyl, 4-hydroxy-2-thienyl, 4-hydroxy-3-thienyl, 5-chloro-2-thienyl, 5-chloro-3 -thienyl, 5-bromo-3-thienyl, 3-amino-2-thienyl, 5-amino- 2-thienyl, 2-amino-3-thienyl, 4-amino-3-thienyl, 3-acetamido-2-thienyl, 5-acetamido-2-thienyl, 2-acetamido-3-thienyl, 4-acetamido-3-thienyl, 5-phenyl-2-thienyl, 5-(4-methylphenyl)-2-thienyl, 5-(4-chlorophenyl)-2-thienyl, 3,4-dimethyl-2-thienyl, 3,5-dimethyl-2-thienyl, 4,5-dimethyl-2-thienyl, 2,4-dimethyl-3-thienyl, 2,5-dimethyl-3-thienyl, 4,5-dimethyl-3-thienyl, 5-methyl-2-amino-3-thienyl, 4-methyl-5-chloro-3-thienyl, 4,5-dichloro-2-thienyl, 2-amino-5-phenyl-3-thienyl, 2,4,5-trimethyl-3-thienyl, 2,5-dimethyl-4-amino-3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 1-methyl-2-pyrrolyl, 3-methyl-2-pyrrolyl, 4-methyl-2-pyrrolyl, 5-methyl-2-pyrrolyl, 1-methyl-3-pyrrolyl, 2-methyl-3-pyrrolyl, 4-methyl-3-pyrrolyl, 5-methyl-3-pyrrolyl, 4-methoxy-3-pyrrolyl, 4-hydroxy-3-pyrrolyl, 5-chloro-2-pyrrolyl, 5-chloro-3-pyrrolyl, 3-amino-2-pyrrolyl, 4-amino-2-pyrrolyl, 3-acetamido-2-pyrrolyl, 4-acetamido-2-pyrrolyl, 4-phenyl-2-pyrrolyl, 5-phenyl-2-pyrrolyl, 5-phenyl-3-pyrrolyl, 4-(4-methylphenyl)-2-pyrrolyl, 5-(4-methylphenyl)-2-pyrrolyl, 4-(4-methoxy-phenyl)-2-pyrrolyl, 5-(4-methoxyphenyl)-2-pyrrolyl, 4-(4-fluorophenyl)-2-pyrrolyl, 5-(4-fluorophenyl)-2pyrrolyl, 4-(4-chlorophenyl)-2-pyrrolyl, 5-(4-chlorophenyl)-2-pyrrolyl, 5-(4-methylphenyl)-3-pyrrolyl, 5-(4-methoxyphenyl)-3-pyrrolyl, 5-(4-fluorophenyl)-3-pyrrolyl, 5-(4-chlorophenyI)-3-pyrrolyl, 1,3-dimethyl-2-pyrrolyl, 1,4-dimethyl-2-pyrrolyl, 1,5-dimethyl-2-pyrrolyl, 3,4-dimethyl-2-pyrrolyl, 3,5-dimethyl-2-pyrrolyl, 4,5-dimethyl-2-pyrrolyl, 1,5-dimethyl-3-pyrrolyl, 2,4-dimethyl-3-pyrrolyl, 2,5-dimethyl-3-pyrrolyl, 1-methyl-4-hydroxy-3-pyrrolyl, 1-methyl-4-methoxy-3-pyrrolyl, 1-methyl-2-chloro-3-pyrrolyl, 4-methyl-5-chloro-3-pyrrolyl, 1-methyl-5-amino-2-pyrrolyl, 3,4,5-trimethyl-2-pyrrolyl, 1,2,4-trimethyl-3-pyrrolyl, 1,4-dimethyl-5-chloro-3-pyrrolyl, 1,4-dimethyl-5-bromo-3 -pyrrolyl, 3,5-dimethyl-4-amino-2-pyrrolyl, 2-oxazolyl , 4-oxazolyl, 5-oxazolyl, 2-methyl-4-oxazolyl, 5-methyl-2-oxazolyl, 2-methoxy-4-oxazolyl, 2-hydroxy-4-oxazolyl, 2-phenyl-4-oxazolyl, 5-phenyl-2-oxazolyl, 2,5-dimethyl-4-oxazolyl, 2,4-dimethyl-5-oxazolyl, 5-methyl-2-phenyl-4-oxazolyl, 4-methyl-2-phenyl-5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 3-methyl-4-isoxazolyl, 4-methyl-3-isoxazolyl, 5-methyl-3-isoxazolyl, 3-methoxy-4-isoxazolyl, 4-methoxy-3-isoxazolyl, 3-hydroxy-4-isoxazolyl, 3-hydroxy-5-isoxazolyl, 4-hydroxy-3-isoxazolyl, 5-amino-4-isoxazolyl, 4-amino-3-isoxazolyl, 4-phenyl-3-isoxazolyl, 5-phenyl-3-isoxazolyl, 4-(4-methylphenyl)-3-isoxazolyl, 5-(4-methylphenyl)-3-isoxazolyl, 4,5-dimethyl-3-isoxazolyl, 5-methyl-4-hydroxy-3-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 4-methyl-2-thiazolyl, 5-methyl-2-thiazolyl, 2-methyl-4-thiazolyl, 5-methyl-4-thiazolyl, 2-methyl-5-thiazolyl, 4-methyl-5-thiazolyl, 2-methoxy-4-thiazolyl, 2-methoxy-5-thiazolyl, 2-hydroxy-4-thiazolyl, 2-hydroxy-5-thiazolyl, 5-chloro-2-thiazolyl, 2-chloro-4-thiazolyl, 5-chloro-4-thiazolyl, 2-chloro-5-thiazolyl, 4-chloro-5thiazolyl, 2-amino-4-thiazolyl, 5-amino-4-thiazolyl, 2-amino-5-thiazolyl, 2-acetamido-4-thiazolyl, 5-acetamido-4-thiazolyl, 2-acetamido-5-thiazolyl, 2-phenyl-4-thiazolyl, 2-phenyl-5-thiazolyl, 4,5-dimethyl-2-thiazolyl, 2,5-dimethyl-4-thiazolyl, 2,4-dimethyl-5-thiazolyl, 5-methyl-2-hydroxy-4-thiazolyl, 4-methyl-2-hydroxy-5-thiazolyl, 5-methyl-2-chloro-4-thiazolyl, 4-methyl-2-chloro-5-thiazolyl, 2-methyl-4-chloro-5-thiazolyl, 5-methyl-2-amino-4-thiazolyl, 2-methyl-5-amino-4-thiazolyl, 4-methyl-2-amino-5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 3-pyrazolyl, 4-pyrazolyl, 1-methyl-4-pyrazolyl, 3-methyl-4-pyrazolyl, 1-methyl-3-pyrazolyl, 4-methyl-3-pyrazolyl, 5-methyl-3-pyrazolyl, 1-methyl-5-pyrazolyl, 1-ethyl-4-pyrazolyl, 1-ethyl-3-pyrazolyl, 5-ethyl-3-pyrazolyl, 1-propyl-4-pyrazolyl, 1-propyl-3-pyrazolyl, 5-propyl-3-pyrazolyl, 1-butyl-4-pyrazolyl, 4-methoxy-3-pyrazolyl, 4-propoxy-3-pyrazolyl, 4-hydroxy-3-pyrazolyl, 4-chloro-3pyrazolyl, 3-chloro-4-pyrazolyl, 4-bromo-3-pyrazolyl, 4-amino-3-pyrazolyl, 5-amino-3-pyrazolyl, 3-amino-4-pyrazolyl, 3-acetamido-4-pyrazolyl, 3-propionylamino-4-pyrazolyl, 4-acetamido-3-pyrazolyl, 5-acetamido-3-pyrazolyl, 5-phenyl-3-pyrazolyl, 1,3-dimethyl-4-pyrazolyl, 1,5-dimethyl-4-pyrazolyl, 3,5-dimethyl-4-pyrazolyl, 1,4-dimethyl-3-pyrazolyl, 1,5-dimethyl-3-pyrazolyl, 4,5-dimethyl-3-pyrazolyl, 1,3-dimethyl-5-pyrazolyl, 1,4-dimethyl-5-pyrazolyl, 1-methyl-4-methoxy-3-pyrazolyl, 5-methyl-4-hydroxy-3-pyrazolyl, 1-methyl-3-chloro-4-pyrazolyl, 1-methyl-5-chloro-4-pyrazolyl, 5-methyl-3-chloro-4-pyrazolyl, 1-methyl-4-chloro-3-pyrazolyl, 5-methyl-4-chloro-3-pyrazolyl, 1-methyl-4-chloro-5-pyrazolyl, 1-methyl-3-amino-4-pyrazolyl, 1-methyl-5-amino-4-pyrazolyl, 5-methyl-3-amino-4-pyrazolyl, 1-methyl-3-acetamido-4-pyrazolyl, 1-methyl-5-acetamido-4-pyrazolyl, 3-methyl-5-acetamido-4-pyrazolyl, 1-methyl-5-amino-3-pyrazolyl, 5-methyl-4-amino-3-pyrazolyl, 4-methyl-5-amino-3-pyrazolyl, 1,3,5-trimethyl-4-pyrazolyl, 1,4,5-trimethyl-3-pyrazolyl, 1,3,4-trimethyl-5-pyrazolyl, 1,3-dimethyl-4-chloro-5-pyrazolyl, 2-imidazolyl, 4-imidazolyl, 1-methyl-2-imidazolyl, 5-methyl-2-imidazolyl, 1-methyl-4-imidazolyl, 2-methyl-4-imidazolyl, 5-methyl-4-imidazolyl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 5-methyl-1,2,3-oxadiazol-4-yl, 4-methyl-1,2,3-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-oxodiazol-3-yl, 4-methyl-1,2,5-oxadiazol-3-yl, 4-phenyl-1,2,5-oxadiazol-3-yl, 4-(4-methylphenyl)-1,2,5-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 5-methyl-1,2,3-thiadiazol-4-yl, 5-phenyl-1,2,3-thiadiazol-4-yl, 5-(4-methyl-phenyl)-1,2,3-thiadiazol-4-yl, 4-methyl-1,2,3-thiadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,5-thiadiazol-3-yl, 4-methyl-1,2,5-thiadiazol-3-yl, 1,3,4-thiadiazol-2-yl, 1,2,3-triazol-4-yl, 1-methyl-1,2,3-triazol-4-yl, 5-methyl-1,2,3-triazol-4-yl, 1,5-dimethyl-1,2,3-triazol-4-yl, 1,2,4-triazol-5-yl, 1-methyl-1,2,4-triazol-3-yl and 2-ethyl-4-methyl-1,2,3-triazol-5-yl groups.
Examples of more preferred such groups include: the 2-furyl, 3-furyl, 3-methyl-2-furyl, 4-methyl-2-furyl, 5-methyl-2-furyl, 2- methyl-3-furyl, 4-methyl-3-furyl, 5-methyl-3-furyl, 2- thienyl, 3-thienyl, 3-methyl-2-thienyl, 4-methyl-2- thienyl, 5-methyl-2-thienyl, 2-methyl-3-thienyl, 4-methyl-3-thienyl, 5-methyl-3-thienyl, 5-chloro-2-thienyl, 5-chloro-3-thienyl, 3-amino-2-thienyl, 5-amino-2-thienyl, 2-amino-3-thienyl, 4-amino-3-thienyl, 3-acetamido-2-thienyl, 5-acetamido-2-thienyl, 2-acetamido-3-thienyl, 4-acetamido-3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 1-methyl-2-pyrrolyl, 3-methyl-2-pyrrolyl, 4-methyl-2-pyrrolyl, 5-methyl-2-pyrrolyl, 1-methyl-3-pyrrolyl, 2-methyl-3-pyrrolyl, 4-methyl-3-pyrrolyl, 5-methyl-3-pyrrolyl, 4-methoxy-3-pyrrolyl, 5-chloro-2-pyrrolyl, 5-chloro-3-pyrrolyl, 3-amino-2-pyrrolyl, 4-amino-2-pyrrolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-methyl-4-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 3-methyl-4-isoxazolyl, 4-methyl-3-isoxazolyl, 5-methyl-3-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 4-methyl-2-thiazolyl, 5-methyl-2-thiazolyl, 2-methyl-4-thiazolyl, 5-methyl-4-thiazolyl, 2-methyl-5-thiazolyl, 4-methyl-5-thiazolyl, 2-chloro-4-thiazolyl, 5-chloro-4-thiazolyl, 2-chloro-5-thiazolyl, 4-chloro-5-thiazolyl, 2-amino-4-thiazolyl, 5-amino-4-thiazolyl, 3-pyrazolyl, 4-pyrazolyl, 1-methyl-4-pyrazolyl, 3-methyl-4-pyrazolyl, 1-methyl-3-pyrazolyl, 4-methyl-3-pyrazolyl, 5-methyl-3-pyrazolyl, 1-methyl-5-pyrazolyl, 1-ethyl-4-pyrazolyl, 4-methoxy-3-pyrazolyl, 4-chloro-3-pyrazolyl, 3-chloro-4-pyrazolyl, 4-amino-3-pyrazolyl, 5-amino-3-pyrazolyl, 3-amino-4-pyrazolyl, 3-acetamido-4-pyrazolyl, 2-imidazolyl, 4-imidazolyl, 1-methyl-2-imidazolyl, 5-methyl-2-imidazolyl, 1-methyl-4-imidazolyl, 2-methyl-4-imidazolyl, 5-methyl-4-imidazolyl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 5-methyl-1,2,3-thiadiazol-4-yl, 4-methyl-1,2,3-thiadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,5-thiadiazol-3-yl, 4-methyl-1,2,5-thiadiazol-3-yl and 1,3,4-thiadiazol-2-yl groups.
Examples of still more preferred such groups include: the 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 3-methyl-2-thienyl, 4-methyl-2-thienyl, 5-methyl-2-thienyl, 2-methyl-3-thienyl, 4-methyl-3-thienyl, 5-methyl-3-thienyl, 5-chloro-2-thienyl, 5-chloro-3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 1-methyl-2-pyrrolyl, 3-methyl-2-pyrrolyl, 4-methyl-2-pyrrolyl, 5-methyl-2-pyrrolyl, 1-methyl-3-pyrrolyl, 2-methyl-3-pyrrolyl, 4-methyl-3-pyrrolyl, 5-methyl-3-pyrrolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-methyl-4-thiazolyl, 5-methyl-4-thiazolyl, 2-methyl-5-thiazolyl, 4-methyl-5-thiazolyl, 3-pyrazolyl, 4-pyrazolyl, 1-methyl-4-pyrazolyl, 3-methyl-4-pyrazolyl, 1-methyl-3-pyrazolyl, 4-methyl -3-pyrazolyl, 5-methyl-3-pyrazolyl, 1-methyl-5-pyrazolyl, 3-chloro-4-pyrazolyl, 4-amino-3-pyrazolyl, 5-amino-3-pyrazolyl, 3-amino-4-pyrazolyl, 2-imidazolyl, 4-imidazolyl, 1,2,3-thiadiazol-4-yl 1,2,3-thiadiazol-5-yl, 1,2,4-thiadiazol-3-yl and 1,2,4-thiadiazol-5-yl.
Examples of the most preferred such groups which may be represented by R.sup.2 include: the 2-thienyl, 3-thienyl, 5-methyl-2-thienyl, 5-chloro-3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 1-methyl-2-pyrrolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-pyrazolyl, 4-pyrazolyl, 1-methyl-4-pyrazolyl, 3-methyl-4-pyrazolyl, 5-methyl-3-pyrazolyl, 3-amino-4-pyrazolyl, 1,2,3-thiadiazol-4-yl groups and 1,2,3-thiadiazol-5-yl groups.
Specific examples of optionally substituted 5- or 6-membered aromatic heterocyclic groups having from 1 to 4 hetero-atoms selected from the group consisting of oxygen, nitrogen and sulfur atoms, which may be represented by R.sup.5 include: the 2-furyl, 3-furyl, 3-methyl-2-furyl, 4-methyl-2-furyl, 5-methyl-2-furyl, 2-methyl-3-furyl, 4-methyl-3-furyl, 5-methyl-3-furyl, 5-chloro-2-furyl, 5-chloro-3-furyl, 3-amino-2-furyl, 5-amino-2-furyl, 3-acetamido-2-furyl, 5-acetamido-2-furyl, 5-phenyl-2-furyl, 5-(4-methylphenyl)-2-furyl, 5-(4-chlorophenyl)-2-furyl, 2,4-dimethyl-3-furyl, 2,5-dimethyl-3-furyl, 3-methyl-5-amino-2-furyl, 2-thienyl, 3-thienyl, 3-methyl-2-thienyl, 4-methyl-2-thienyl, 5-methyl-2-thienyl, 2-methyl-3-thienyl, 4-methyl-3-thienyl, 5-methyl-3-thienyl, 5-ethyl-2-thienyl, 4-methoxy-2-thienyl, 4-methoxy-3-thienyl, 4-hydroxy-2-thienyl, 4-hydroxy-3-thienyl, 5-chloro-2-thienyl, 5-chloro-3-thienyl, 5-bromo-3-thienyl, 3-amino-thienyl, 5-amino-2-thienyl, 2-amino-3-thienyl, 4-amino-3-thienyl, 3-acetamido-2-thienyl, 5-acetamido-2-thienyl, 2-acetamido-3-thienyl, 4-acetamido-3-thienyl, 5-phenyl-2-thienyl, 5-(4-methylphenyl)-2-thienyl, 5-(4-chlorophenyl)-2-thienyl, 3,4-dimethyl-2-thienyl, 3,5-dimethyl-2-thienyl, 4,5-dimethyl-2-thienyl, 2,4-dimethyl-3-thienyl, 2,5-dimethyl-3-thienyl, 4,5-dimethyl-3-thienyl, 5-methyl-2-amino-3-thienyl, 4-methyl-5-chloro-3-thienyl, 4,5-dichloro-2-thienyl, 2-amino-5-phenyl-3-thienyl, 2,4,5-trimethyl-3-thienyl, 2,5-dimethyl-4-amino-3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 1-methyl-2-pyrrolyl, 3-methyl-2-pyrrolyl, 4-methyl-2-pyrrolyl, 5-methyl-2-pyrrolyl, 1-methyl-3-pyrrolyl, 2-methyl-3-pyrrolyl, 4-methyl-3-pyrrolyl, 5-methyl-3-pyrrolyl, 4-methoxy-3-pyrrolyl, 4-hydroxy-3-pyrrolyl, 5-chloro-2-pyrrolyl, 5-chloro-3-pyrrolyl, 3-amino-2-pyrrolyl, 4-amino-2-pyrrolyl, 3-acetamido-2-pyrrolyl, 4-acetamido-2-pyrrolyl, 4-phenyl-2-pyrrolyl, 5-phenyl-2-pyrrolyl, 5-phenyl-3-pyrrolyl, 4-(4-methylphenyl)-2-pyrrolyl, 5-(4-methylphenyl)-2-pyrrolyl, 4-(4-methoxyphenyl)-2-pyrrolyl, 5-(4-methoxyphenyl)-2-pyrrolyl, 4-(4-fluorophenyl)-2-pyrrolyl, 5-(4-fluorophenyl)-2-pyrrolyl, 4-(4-chlorophenyl)-2-pyrrolyl, 5-(4-chlorophenyl)-2-pyrrolyl, 5-(4-methylphenyl)-3-pyrrolyl, 5-(4-methoxyphenyl)-3-pyrrolyl, 5-(4-fluorophenyl)-3-pyrrolyl, 5-(4-chlorophenyl)-3-pyrrolyl, 1-(2-hydroxyethyl)-2-pyrrolyl, 1-(3-hydroxypropyl)-2-pyrrolyl, 1-(2-hydroxyethyl)-3-pyrrolyl, 1-(3-hydroxypropyl)-3-pyrrolyl, 1,3-dimethyl-2-pyrrolyl, 1,4-dimethyl-2-pyrrolyl, pyrrolyl, 1,5-dimethyl-2-pyrrolyl, 3,4-dimethyl-2-pyrrolyl, 3,5-dimethyl-2-pyrrolyl, 4,5-dimethyl-2-pyrrolyl, 1,5-dimethyl-3-pyrrolyl, 2,4-dimethyl-3-pyrrolyl, 2,5-dimethyl-3-pyrrolyl, 1-methyl-4-hydroxy-3-pyrrolyl, 1-methyl-4-methoxy-3-pyrrolyl, 1-methyl-2-chloro-3-pyrrolyl, 4-methyl-5-chloro-3-pyrrolyl, 1-methyl-5-amino-2-pyrrolyl, 3,4,5-trimethyl-2-pyrrolyl, 1,2,4-trimethyl-3-pyrrolyl, 1,4-dimethyl-5-chloro-3-pyrrolyl, 1,4-dimethyl-5-bromo-3-pyrrolyl, 3,5-dimethyl-4-amino-2-pyrrolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-methyl-4-oxazolyl, 5-methyl-2-oxazolyl, 2-methoxy-4-oxazolyl, 2-hydroxy-4-oxazolyl, 2-phenyl-4-oxazolyl, 5-phenyl-2-oxazolyl, 2,5-dimethyl-4-oxazolyl, 2,4-dimethyl-5-oxazolyl, 5-methyl-2-phenyl-4-oxazolyl, 4-methyl-2-phenyl-5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 3-methyl-4-isoxazolyl, 4-methyl-3-isoxazolyl, 5-methyl-3-isoxazolyl, 3-methoxy-4-isoxazolyl, 4-methoxy-3-isoxazolyl, 3-hydroxy-4-isoxazolyl, 3-hydroxy-5-isoxazolyl, 4-hydroxy-3-isoxazolyl, 5-amino-4-isoxazolyl, 4-amino-3-isoxazolyl, 4-phenyl-3-isoxazolyl, 5-phenyl-3-isoxazolyl, 4-(4-methylphenyl)-3-isoxazolyl, 5-(4-methylphenyl)-3-isoxazolyl, 4,5-dimethyl-3-isoxazolyl, 5-methyl-4-hydroxy-3-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 4-methyl-2-thiazolyl, 5-methyl-2-thiazolyl, 2-methyl-4-thiazolyl, 5-methyl-4-thiazolyl, 2-methyl-5-thiazolyl, 4-methyl-5-thiazolyl, 2-methoxy-4-thiazolyl, 2-methoxy-5-thiazolyl, 2-hydroxy-4-thiazolyl, 2-hydroxy-5-thiazolyl, 5-chloro-2-thiazolyl, 2-chloro-4-thiazolyl, 5-chloro-4-thiazolyl, 2-chloro-5-thiazolyl, 4-chloro-5-thiazolyl, 2-amino-4-thiazolyl, 5-amino-4-thiazolyl, 2-amino-5-thiazolyl, 2-acetamido-4-thiazolyl, 5-acetamido-4-thiazolyl, 2-acetamido-5-thiazolyl, 2-phenyl-4-thiazolyl, 2-phenyl-5-thiazolyl, 4,5-dimethyl-2-thiazolyl, 2,5-dimethyl-4-thiazolyl, 2,4-dimethyl-5-thiazolyl, 5-methyl-2-hydroxy-4-thiazolyl, 4-methyl-2-hydroxy-5-thiazolyl, 5-methyl-2-chloro-4-thiazolyl, 4-methyl-2-chloro-5-thiazolyl, 2-methyl-4-chloro-5-thiazolyl, 5-methyl-2-amino-4-thiazolyl, 2-methyl-5-amino-4-thiazolyl, 4-methyl-2-amino-5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 3-pyrazolyl, 4-pyrazolyl, 1-methyl-4-pyrazolyl, 3-methyl-4-pyrazolyl, 1-methyl-3-pyrazolyl, 4-methyl-3-pyrazolyl, 5-methyl-3-pyrazolyl, 1-methyl-5-pyrazolyl, 1-ethyl-4-pyrazolyl, 1-ethyl-3-pyrazolyl, 5-ethyl-3-pyrazolyl, 1-propyl-4-pyrazolyl, 1-propyl-3-pyrazolyl, 5-propyl-3-pyrazolyl, 1-butyl-4-pyrazolyl, 4-methoxy-3-pyrazolyl, 4-propoxy-3-pyrazolyl, 4-hydroxy-3-pyrazolyl, 4-chloro-3-pyrazolyl, 3-chloro-4-pyrazolyl, 4-bromo-3-pyrazolyl, 4-amino-3-pyrazolyl, 5-amino-3-pyrazolyl, 3-amino-4-pyrazolyl, 3-acetamido-4-pyrazolyl, 3-propionylamino-4-pyrazolyl, 4-acetamido-3-pyrazo lyl, 5-acetamido-3-pyrazolyl, 5-phenyl-3-pyrazolyl , 1-(2-hydroxyethyl)-3-pyrazolyl, 1-(3-hydroxypropyl)- 3-pyrazolyl, 1-(2-hydroxyethyl)-4-pyrazolyl, 1-(3-hydroxypropyl)-4-pyrazolyl, 1-(2-hydroxyethyl)-5-pyrazolyl, 1-(3-hydroxypropyl)-5-pyrazolyl, 1,3-dimethyl-4-pyrazolyl, 1,5-dimethyl-4-pyrazolyl, 3,5-dimethyl-4-pyrazolyl, 1,4-dimethyl-3-pyrazolyl, 1,5-dimethyl-3-pyrazolyl, 4,5-dimethyl-3-pyrazolyl, 1,3-dimethyl-5-pyrazolyl, 1,4-dimethyl-5-pyrazolyl, 1-methyl-4-methoxy-3-pyrazolyl, 5-methyl-4-hydroxy-3-pyrazolyl, 1-methyl-3-chloro-4-pyrazolyl, 1-methyl-5-chloro-4-pyrazolyl, 5-methyl-3-chloro-4-pyrazolyl, 1-methyl-4-chloro-3-pyrazolyl, 5-methyl-4-chloro-3-pyrazolyl, 1-methyl-4-chloro-5-pyrazolyl, 1-methyl-3-amino-4-pyrazolyl, 1-methyl-5-amino-4-pyrazolyl, 5-methyl-3-amino-4-pyrazolyl, 1-methyl-3-acetamido-4-pyrazolyl, 1-methyl-5-acetamido-4-pyrazolyl, 3-methyl-5-acetamido-4-pyrazolyl, 1-methyl-5-amino-3-pyrazolyl, 5-methyl-4-amino-3-pyrazolyl, 4-methyl-5-amino-3-pyrazolyl, 1,3,5-trimethyl-4-pyrazolyl, 1,4,5-trimethyl-3-pyrazolyl, 1,3,4-trimethyl-5-pyrazolyl, 1,3-dimethyl-4-chloro-5-pyrazolyl, 2-imidazolyl, 4-imidazolyl, 1-methyl-2-imidazolyl, 5-methyl-2-imidazolyl, 1-methyl-4-imidazolyl, 2-methyl-4-imidazolyl, 5-methyl-4-imidazolyl, 1-ethyl-2-imidazolyl, 4-ethyl-2-imidazolyl, 1-(2-hydroxyethyl)-2-imidazolyl, 1-(3-hydroxypropyl)-2-imidazolyl, 4-amino-2-imidazolyl, 2-amino-4-imidazolyl, 5-amino-4-imidazolyl, 4-chloro-2-imidazolyl, 2-chloro-4-imidazolyl, 5-chloro-4-imidazolyl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 5-methyl-1,2,3-oxadiazol-4-yl, 4-methyl-1,2,3-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 4-methyl-1,2,5-oxadiazol-3-yl, 4-phenyl-1,2,5-oxadiazol-3-yl, 4-(4-methylphenyl)-1,2,5-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazol-2-yl, 5-ethyl-1,3,4-oxadiazol-2-yl, 5-phenyl-1,3,4-oxadiazol-2-yl, 5-chloro-1,3,4-oxadiazol-2-yl, 5-amino-1,3,4-oxadiazol-2-yl, 5-acetamido-1,3,4-oxadiazol-2-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 5-methyl-1,2,3-thiadiazol-4-yl, 5-phenyl-1,2,3-thiadiazol-4-yl, 5-(4-methylphenyl)-1,2,3-thiadiazol-4-yl, 4-methyl-1,2,3-thiadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,5-thiadiazol-3-yl, 4-methyl-1,2,5-thiadiazol-3-yl, 1,3,4-thiadiazol-2-yl, 5-methyl-1,3,4-thiadiazol-2-yl, 5-ethyl-1,3,4-thiadiazol-2-yl, 5-phenyl-1,3,4-thiadiazol-2-yl, 5-chloro-1,3,4-thiadiazol-2-yl, 5-amino-1,3,4-thiadiazol-2-yl, 5-acetamido-1,3,4-thiadiazol-2-yl, 1,2,3-triazol-4-yl, 1-methyl-1,2,3-triazol-4-yl, 5-methyl-1,2,3-triazol-4-yl, 1,5-dimethyl-1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1-methyl-1,2,4-triazol-3-yl, 1-methyl-1,2,4-triazol-5-yl, 5-methyl-1,2,4-triazol-3-yl, 5-ethyl-1,2,4-triazol-3-yl, 5-phenyl-1,2,4-triazol-3-yl, 1-(2-hydroxyethyl)-1,2,4-triazol-3-yl, 1-(3-hydroxypropyl)-1,2,4-triazol-3-yl, 1-(2-hydroxyethyl)-1,2,4-triazol-5-yl, 1-(3-hydroxypropyl)-1,2,4-triazol-5-yl, 5-chloro-1,2,4-triazol-3-yl, 5-amino-1,2,4-triazol-3-yl, 5-acetamido-1,2,4-triazol-3-yl, 1,3-dimethyl-1,2,4-triazol-5-yl, 1,5-dimethyl-1,2,4-triazol-3-yl, 2-ethyl-4-methyl-1,2,3-triazol-5-yl, tetrazol-5-yl, 1-methyltetrazol-5-yl, 2-methyltetrazol-5-yl, 1-ethyltetrazol-5-yl, 2-ethyltetrazol-5-yl, 1-phenyltetrazol-5-yl, 2-phenyltetrazol-5-yl, 1-(2-hydroxyethyl)tetrazol-5-yl, 2-(2-hydroxyethyl)-tetrazol-5-yl, 1-(2-hydroxypropyl) tetrazol-5-yl, 2-(2-hydroxypropyl) tetrazol- 5-yl, 1-(3 -hydroxypropyl)-tetrazol-5-yl, 2-(3-hydroxypropyl)tetrazol-5-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-methyl-2-pyridyl, 4-methyl-2-pyridyl, 5-methyl-2-pyridyl, 6-methyl-2-pyridyl, 2-methyl-4-pyridyl, 3-methyl-4-pyridyl, 3-chloro-2-pyridyl, 4-chloro-2-pyridyl, 5-chloro-2-pyridyl, 6-chloro-2-pyridyl, 2-chloro-3-pyridyl, 4-chloro-3-pyridyl, 5-chloro-3-pyridyl, 6-chloro-3-pyridyl, 2-chloro-4-pyridyl, 3-chloro-4-pyridyl, 3-amino-2-pyridyl, 4-amino-2-pyridyl, 5-amino-2-pyridyl, 6-amino-2-pyridyl, 2-amino-3-pyridyl, 4-amino-3-pyridyl, 5-amino-3-pyridyl, 6-amino-3-pyridyl, 2-amino-4-pyridyl, 3-amino-4-pyridyl, 3-hydroxy-2-pyridyl, 4-hydroxy-2-pyridyl, 5-hydroxy-2-pyridyl, 6-hydroxy-2-pyridyl, 2-hydroxy-4-pyridyl, 3-hydroxy-4-pyridyl, 3-phenyl-2-pyridyl, 4-phenyl-2-pyridyl, 5-phenyl-2-pyridyl, 6-phenyl-2-pyridyl, 2-phenyl-4-pyridyl, 3-phenyl-4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 4-methyl-2-pyrimidinyl, 5-methyl-2-pyrimidinyl, 2-methyl-4-pyrimidinyl, 5-methyl-4-pyrimidinyl, 6-methyl-4-pyrimidinyl, 2-methyl-5-pyrimidinyl, 4-methyl-5-pyrimidinyl, 4-phenyl-2-pyrimidinyl, 5-phenyl-2-pyrimidinyl, 2-phenyl-4-pyrimidinyl, 5-phenyl-4-pyrimidinyl, 6-phenyl-4-pyrimidinyl, 2-phenyl-5-pyrimidinyl, 4-phenyl-5-pyrimidinyl, 4-chloro-2-pyrimidinyl, 5-chloro-2-pyrimidinyl, 2-chloro-4-pyrimidinyl, 5-chloro-4-pyrimidinyl, 6-chloro-4-pyrimidinyl, 2-chloro-5-pyrimidinyl, 4-chloro-5-pyrimidinyl, 4-amino-2-pyrimidinyl, 5-amino-2-pyrimidinyl, 2-amino-4-pyrimidinyl, 5-amino-4-pyrimidinyl, 6-amino-4-pyrimidinyl, 2-amino-5-pyrimidinyl, 4-amino-5-pyrimidinyl, 4-acetamido-2-pyrimidinyl, 5-acetamido-2-pyrimidinyl, 2-acetamido-4-pyrimidinyl, 5-acetamido-4-pyrimidinyl, 6-acetamido-4-pyrimidinyl, 2-acetamido-5-pyrimidinyl, 4-acetamido-5-pyrimidinyl, 4,5-dimethyl-2-pyrimidinyl, 4,6-dimethyl-2-pyrimidinyl, 2,5-dimethyl-4-pyrimidinyl, 2,6-dimethyl-4-pyrimidinyl, 2,4-dimethyl-5-pyrimidinyl, 2,6-dimethyl-5-pyrimidinyl, 4-amino-5-hydroxy-2-pyrimidinyl, 4-amino-6-hydroxy-2-pyrimidinyl, 2-amino-5-hydroxy-4-pyrimidinyl, 2-amino-6-hydroxy-4-pyrimidinyl, 2-amino-4-hydroxy-5-pyrimidinyl, 5-amino-2-hydroxy-4-pyrimidinyl, 6-amino-2-hydroxy-4-pyrimidinyl, 4-amino-2-hydroxy-5-pyrimidinyl, 4,5-diamino-2-pyrimidinyl, 4,6-diamino-2-pyrimidinyl, 5-diamino-4-pyrimidinyl, 2,6-diamino-4-pyrimidinyl, 4-diamino-5-pyrimidinyl, 2,6-diamino-5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 4-methyl-3-pyridazinyl, 5-methyl-3-pyridazinyl, 6-methyl-3-pyridazinyl, 3-methyl-4 -pyridazinyl, 5-methyl-4-pyridazinyl, 6-methyl-4 -pyridazinyl, 4-chloro-3-pyridazinyl, 5-chloro-3 -pyridazinyl, 6-chloro-3-pyridazinyl, 3-chloro-4 -pyridazinyl, 5-chloro-4-pyridazinyl, 6-chloro-4 -pyridazinyl, 4-hydroxy-3-pyridazinyl, 5-hydroxy-3-pyridazinyl, 6-hydroxy-3-pyridazinyl, 3-hydroxy-4-pyridazinyl, 5-hydroxy-4-pyridazinyl, 6-hydroxy-4-pyridazinyl, 4-amino-3-pyridazinyl, 5-amino-3-pyridazinyl, 6-amino-3-pyridazinyl, 3-amino-4-pyridazinyl, 5-amino-4-pyridazinyl, 6-amino-4-pyridazinyl, 2-pyrazinyl, 3-amino-2-pyrazinyl, 5-amino-2-pyrazinyl, 6-amino-2-pyrazinyl, 3-hydroxy-2-pyrazinyl, 5-hydroxy-2-pyrazinyl, 6-hydroxy-2-pyrazinyl, 3,5-dihydroxy-2-pyrazinyl, 3,6-dihydroxy-2-pyrazinyl, 1,2,3-triazin-4-yl, 1,2,3-triazin-5-yl, 5-methyl-1,2,3-triazin-4-yl, 6-methyl-1,2,3-triazin-4-yl, 4-methyl-1,2,3-triazin-5-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl, 5-methyl-1,2,4triazin-3-yl, 6-methyl-1,2,4-triazin-3-yl, 3-methyl-1,2,4-triazin-5-yl, 6-methyl-1,2,4-triazin-5-yl, 3-methyl-1,2,4-triazin-6-yl, 5-methyl-1,2,4-triazin-6-yl, 1,3,5-triazin-2-yl and 4-methyl-1,3,5-triazin-2-yl groups.
Examples of preferred such groups include: the 2-furyl, 3 -furyl, 3-methyl-2-furyl, 4-methyl-2-furyl, 5-methyl-2 -furyl, 2-methyl-3-furyl, 4-methyl-3-furyl, 5-methyl-3 -furyl, 2-thienyl, 3-thienyl, 3-methyl-2-thienyl, 4 -methyl-2-thienyl, 5-methyl-2-thienyl, 2-methyl-3 -thienyl, 4-methyl-3-thienyl, 5-methyl-3-thienyl, 5 -ethyl-2-thienyl, 4-methoxy-2-thienyl, 4-methoxy- 3-thienyl, 3-amino-2-thienyl, 5-amino-2-thienyl, 2-amino-3-thienyl, 4-amino-3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 1-methyl-2-pyrrolyl, 3-methyl-2-pyrrolyl, 4-methyl-2-pyrrolyl, 5-methyl-2-pyrrolyl, 1-methyl-3-pyrrolyl, 2-methyl-3-pyrrolyl, 4-methyl-3-pyrrolyl, 5-methyl-3-pyrrolyl, 4-methoxy-3-pyrrolyl, 4-hydroxy-3-pyrrolyl, 5-chloro-2-pyrrolyl, 5-chloro-3-pyrrolyl, 3-amino-2-pyrrolyl, 4-amino-2-pyrrolyl, 3-acetamido-2-pyrrolyl, 4-acetamido-2-pyrrolyl, 4-phenyl-2-pyrrolyl, 5-phenyl-2-pyrrolyl, 5-phenyl-3-pyrrolyl, 4-(4-methylphenyl)-2-pyrrolyl, 5-(4-methylphenyl)-2-pyrrolyl, 4-(4-methoxyphenyl)-2-pyrrolyl, 5-(4-methoxyphenyl)-2-pyrrolyl, 4-(4-chlorophenyl)-2-pyrrolyl, 5-(4-chlorophenyl)-2-pyrrolyl, 5-(4-methylphenyl)-3-pyrrolyl, 1-(2-hydroxyethyl)-2-pyrrolyl, 1-(3-hydroxypropyl)-2-pyrrolyl, 1-(2-hydroxyethyl)-3-pyrrolyl, 1-(3-hydroxypropyl)-3-pyrrolyl, 1,3-dimethyl-2-pyrrolyl, 1,4-dimethyl-2-pyrrolyl, 1,5-dimethyl-2-pyrrolyl, 3,4-dimethyl-2-pyrrolyl, 4,5-dimethyl-2-pyrrolyl, 1,5-dimethyl-3-pyrrolyl, 2,4-dimethyl-3-pyrrolyl, 2,5-dimethyl-3-pyrrolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-methyl-4-oxazolyl, 5-methyl-2-oxazolyl, 2-methoxy-4-oxazolyl, 2-hydroxy-4-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 3-methyl-4-isoxazolyl, 4-methyl-3-isoxazolyl, 5-methyl-3-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5othiazolyl, 4-methyl-2-thiazolyl, 5-methyl-2-thiazolyl, 2-methyl-4-thiazolyl, 5-methyl-4-thiazolyl, 2-methyl-5-thiazolyl, 4-methyl-5-thiazolyl, 2-methoxy-4-thiazolyl, 2-methoxy-5-thiazolyl, 2-hydroxy-4-thiazolyl, 2-hydroxy-5-thiazolyl, 5-chloro-2-thiazolyl, 2-chloro-4-thiazolyl, 5-chloro-4-thiazolyl, 2-chloro-5-thiazolyl, 4-chloro-5-thiazolyl, 2-amino-4-thiazolyl, 5-amino-4-thiazolyl, 2-amino-5-thiazolyl, 2-acetamido-4-thiazolyl, 5-acetamido-4-thiazolyl, 2-acetamido-5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 3-pyrazolyl, 4-pyrazolyl, 1-methyl-4-pyrazolyl, 3-methyl-4-pyrazolyl, 1-methyl-3-pyrazolyl, 4-methyl-3-pyrazolyl, 5-methyl-3-pyrazolyl, 1-methyl-5-pyrazolyl, 1-ethyl-4-pyrazolyl, 1-ethyl-3-pyrazolyl, 5-ethyl-3-pyrazolyl, 1-propyl-4-pyrazolyl, 1-propyl-3-pyrazolyl, 5-propyl-3-pyrazolyl, 1-butyl-4-pyrazolyl, 4-methoxy-3-pyrazolyl, 4-chloro-3-pyrazolyl, 3-chloro-4-pyrazolyl, 4-bromo-3-pyrazolyl, 4-amino-3-pyrazolyl, 5-amino-3-pyrazolyl, 3-amino-4-pyrazolyl, 3-acetamido-4-pyrazolyl, 3-propionylamino-4-pyrazolyl, 4-acetamido-3-pyrazolyl, 5oacetamido-3-pyrazolyl, 5-phenyl-3-pyrazolyl, 1-(2-hydroxyethyl)-3-pyrazolyl, 1-(3-hydroxypropyl)-3-pyrazolyl, 1-(2-hydroxyethyl)-4-pyrazolyl, 1-(3-hydroxypropyl)-4-pyrazolyl, 1-(2-hydroxyethyl)-5-pyrazolyl, 1-(3-hydroxypropyl)-5-pyrazolyl, 1,3-dimethyl-4-pyrazolyl, 1,5-dimethyl -4-pyrazolyl, 3,5-dimethyl-4-pyrazolyl, 1,4-dimethyl -3-pyrazolyl, 1,5-dimethyl-3-pyrazolyl, 4,5-dimethyl -3-pyrazolyl, 1,3-dimethyl-5-pyrazolyl, 1,4-dimethyl -5-pyrazolyl, 1-methyl-3-amino-4-pyrazolyl, 1-methyl-5-amino-4-pyrazolyl, 5-methyl-3-amino-4-pyrazolyl, 1-methyl-3-acetamido-4-pyrazolyl, 1-methyl-5-acetamido-4-pyrazolyl, 3-methyl-5-acetamido-4-pyrazolyl, 1-methyl-5-amino-3-pyrazolyl, 5-methyl-4-amino-3-pyrazolyl, 4-methyl-5-amino-3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, 1-methyl-2-imidazolyl, 5-methyl-2-imidazolyl, 1-methyl-4-imidazolyl, 2-methyl-4-imidazolyl, 5-methyl-4-imidazolyl, 1-ethyl-2-imidazolyl, 4-ethyl-2-imidazolyl, 1-(2-hydroxyethyl)-2-imidazolyl, 1-(3-hydroxypropyl)-2-imidazolyl, 4-amino-2-imidazolyl, 2-amino-4-imidazolyl, 5-amino-4-imidazolyl, 4-chloro-2-imidazoly, 2-chloro-4-imidazolyl, 5-chloro-4-imidazolyl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 5-methyl-1,2,3-oxadiazol-4-yl, 4-methyl-1,2,3-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 4-methyl-1,2,5-oxadiazol-3-yl, 4-phenyl-1,2,5-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazol-2-yl, 5-ethyl-1,3,4-oxadiazol-2-yl, 5-phenyl-1,3,4-oxadiazol-2-yl, 5-chloro-1,3,4-oxadiazol-2-yl, 5-amino-1,3,4-oxadiazol-2-yl, 5-acetamido-1,3,4-oxadiazol-2-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 5-methyl-1,2,3-thiadiazol-4-yl, 5-phenyl-1,2,3-thiadiazol-4-yl, 4-methyl-1,2,3-thiadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,5-thiadiazol-3-yl, 4-methyl-1,2,5-thiadiazol-3-yl, 1,3,4-thiadiazol-2-yl, 5-methyl-1,3,4-thiadiazol-2-yl, 5-ethyl-1,3,4-thiadiazol-2-yl, 5-phenyl-1,3,4-thiadiazol-2-yl, 5-chloro-1,3,4-thiadiazol-2-yl, 5-amino-1,3,4-thiadiazol-2-yl, 5-acetamido-1,3,4-thiadiazol-2-yl, 1,2,3-triazol-4-yl, 1-methyl-1,2,3-triazol-4-yl, 5-methyl-1,2,3-triazol-4-yl, 1,5-dimethyl-1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1-methyl-1,2,4-triazol-3-yl, 1-methyl-1,2,4-triazol-5-yl, 5-methyl-1,2,4-triazol-3-yl, 5-ethyl-1,2,4-triazol-3-yl, 5-phenyl-1,2,4-triazol-3-yl, 1-(2-hydroxyethyl)-1,2,4-triazol-3-yl, 1-(3-hydroxypropyl)-1,2,4-triazol-3-yl, 1-(2-hydroxyethyl)-1,2,4-triazol-5-yl, 1-(3-hydroxypropyl)-1,2,4-triazol-5-yl, 5-chloro-1,2,4-triazol-3-yl, 5-amino-1,2,4-triazol-3-yl, 5-acetamido-1,2,4-triazol-3-yl, 1,3-dimethyl-1,2,4-triazol-5-yl, 1,5-dimethyl-1,2,4-triazol-3-yl, tetrazol-5-yl, 1-methyltetrazol-5-yl, 2-methyltetrazol-5-yl, 1-ethyltetrazol-5-yl, 2-ethyltetrazol-5-yl, 1-phenyltetrazol-5-yl, 2-phenyltetrazol-5-yl, 1- (2-hydroxyethyl)tetrazol-5-yl, 2-(2-hydroxyethyl) tetrazol -5 -yl, 1-(2-hydroxypropyl) tetrazol-5 -yl, 2- ( 2 - hydroxypropyl ) tet razol - 5 - yl, 1 - ( 3 - hydroxypropyl)- tetrazol-5 -yl, 2- (3 -hydroxypropyl ) tetrazol - 5 -yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-methyl-2-pyridyl, 4-methyl-2-pyridyl, 5-methyl-2-pyridyl, 6-methyl-2-pyridyl, 2-methyl-4-pyridyl, 3-methyl-4-pyridyl, 3-chloro-2-pyridyl, 4-chloro-2-pyridyl, 5-chloro-2-pyridyl, 6-chloro-2-pyridyl, 2-chloro-4-pyridyl, 3-chloro-4-pyridyl, 3-amino-2-pyridyl, 4-amino-2-pyridyl, 5-amino-2-pyridyl, 6-amino-2-pyridyl, 2-amino4-pyridyl, 3-amino-4-pyridyl, 3-hydroxy-2-pyridyl, 4-hydroxy-2-pyridyl, 5-hydroxy-2-pyridyl, 6-hydroxy2-pyridyl, 2-hydroxy-4-pyridyl, 3-hydroxy-4-pyridyl, 3-phenyl-2-pyridyl, 4-phenyl-2-pyridyl, 5-phenyl-2pyridyl, 6-phenyl-2-pyridyl, 2-phenyl-4-pyridyl, 3-phenyl-4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 4-methyl-2-pyrimidinyl, 5-methyl-2pyrimidinyl, 2-methyl-4-pyrimidinyl, 5 -methyl-4-pyrimidinyl, 6-methyl-4-pyrimidinyl, 4 -phenyl-2-pyrimidinyl, 5-phenyl-2-pyrimidinyl, 2 -phenyl-4-pyrimidinyl, 5-phenyl-4-pyrimidinyl, 6 -phenyl-4-pyrimidinyl, 4-chloro-2-pyrimidinyl, 5 -chloro-2-pyrimidinyl, 2-chloro-4-pyrimidinyl, 5 -chloro-4-pyrimidinyl, 6-chloro-4-pyrimidinyl, 4-amino-2-pyrimidinyl, 5-amino-2-pyrimidinyt, 2-amino-4-pyrimidinyl, 5-amino-4-pyrimidinyl, 6-amino-4-pyrimidinyl, 4-acetamido-2-pyrimidinyl, 5-acetamido-2-pyrimidinyl, 2-acetamido-4-pyrimidinyl, 5-acetamido-4-pyrimidinyl, 6-acetamido-4-pyrimidinyl, 4,5-dimethyl-2-pyrimidinyl, 4,6-dimethyl-2-pyrimidinyl, 2,5-dimethyl-4-pyrimidinyl, 2,6-dimethyl-4-pyrimidinyl, 4-amino-5-hydroxy-2-pyrimidinyl, 4-amino-6-hydroxy-2-pyrimidinyl, 2-amino-5-hydroxy-4-pyrimidinyl, 2-amino-6-hydroxypyrimidinyl, 5-amino-2-hydroxy-4-pyrimidinyl, 6-amino-2-hydroxy-4-pyrimidinyl, 4,5-diamino-2-pyrimidinyl, 4,6-diamino-2-pyrimidinyl, 2,5-diamino-4-pyrimidinyl, 2,6-diamino-4-pyrimidinyl , 3-pyridazinyl, 4-pyridazinyl, 4-methyl-3-pyridazinyl, 5 -methyl-3-pyridazinyl, 6-methyl-3-pyridazinyl, 3 -methyl-4-pyridazinyl, 5-methyl-4-pyridazinyl, 6 -methyl-4-pyridazinyl, 4-chloro-3-pyridazinyl, 5 -chloro-3-pyridazinyl, 6-chloro-3-pyridazinyl, 3 -chloro-4-pyridazinyl, 5-chloro-4-pyridazinyl, 6 -chloro-4-pyridazinyl, 4-hydroxy-3-pyridazinyl, 5-hydroxy-3-pyridazinyl, 6- hydroxy-3-pyridazinyl, 3-hydroxy-4-pyridazinyl, 5- hydroxy-4-pyridazinyl, 6-hydroxy-4-pyridazinyl, 4- amino-3-pyridazinyl, 5-amino-3-pyridazinyl, 6-amino-3-pyridazinyl, 3-amino-4-pyridazinyl, 5-amino-4-pyridazinyl, 6-amino-4-pyridazinyl, 2-pyrazinyl, 3-methyl-2-pyrazinyl, 5-methyl-2-pyrazinyl, 6-methyl-2-pyrazinyl, 3-amino-2-pyrazinyl, 5-amino-2-pyrazinyl, 6-amino-2-pyrazinyl, 3-hydroxy-2-pyrazinyl, 5-hydroxy-2-pyrazinyl, 6-hydroxy-2-pyrazinyl, 3,5-dihydroxy-2-pyrazinyl, 3,6-dihydroxy-2-pyrazinyl, 1,2,3-triazin-4-yl, 1,2,3-triazin-5-yl, 5-methyl-1,2,3-triazin-4-yl, 6-methyl-1,2,3-triazin-4-yl, 4-methyl-1,2,3-triazin-5-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl, 5-methyl-1,2,4-triazin-3-yl, 6-methyl-1,2,4-triazin-3-yl, 3-methyl-1,2,4-triazin-5-yl, 6-methyl-1,2,4-triazin-5-yl, 3-methyl-1,2,4-triazin-6-yl, 5-methyl-1,2,4-triazin-6-yl, 1,3,5-triazin-2-yl and 4-methyl-1,3,5-triazin-2-yl groups.
Examples of more preferred such groups include: the 2-imidazolyl, 4-imidazolyl, 1-methyl-2-imidazolyl, 5-methyl-2-imidazolyl, 1-methyl-4-imidazolyl, 2-methyl-4-imidazolyl, 5-methyl-4-imidazolyl, 4-chloro-2-imidazolyl, 2-chloro-4-imidazolyl, 5-chloro-4-imidazolyl, 1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazol-2-yl, 5-ethyl-1,3,4-oxadiazol-2-yl, 5-chloro-1,3,4-oxadiazol-2-yl, 5-amino-1,3,4-oxadiazol-2-yl, 5-acetamido-1,3,4-oxadiazol-2-yl, 1,3,4-thiadiazol-2-yl, 5-methyl-1,3,4-thiadiazol-2-yl, 5-ethyl-1,3,4-thiadiazol-2-yl, 5-chloro-1,3,4-thiadiazol-2-yl, 5-amino-1,3,4-thiadiazol-2-yl, 5-acetamido-1,3,4-thiadiazol-2-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1-methyl-1,2,4-triazol-3-yl, 1-methyl-1,2,4-triazol-5-yl, 5-methyl-1,2,4-triazol-3-yl, 5-ethyl-1,2,4-triazol-3-yl, 5-phenyl-1,2,4-triazol-3-yl, 5-chloro-1,2,4-triazol-3-yl, 5-amino-1,2,4-triazol-3-yl, 5-acetamido-1,2,4triazol-3-yl, tetrazol-5-yl, 1-methyltetrazol-5-yl, 1-ethyltetrazol-5-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-methyl-2-pyridyl, 4-methyl-2-pyridyl, 5-methyl-2-pyridyl, 6-methyl-2-pyridyl, 2-methyl-4-pyridyl, 3-methyl-4-pyridyl, 3-chloro-2-pyridyl, 4-chloro-2-pyridyl, 5-chloro-2-pyridyl, 6-chloro-2-pyridyl, 2-chloro-4-pyridyl, 3-chloro-4-pyridyl, 3-amino-2-pyridyl, 4-amino-2-pyridyl, 5-amino-2-pyridyl, 6-amino-2-pyridyl, 2-amino-4-pyridyl, 3-amino-4-pyridyl, 3-hydroxy-2-pyridyl, 4-hydroxy-2-pyridyl, 5-hydroxy-2-pyridyl, 6-hydroxy-2-pyridyl, 2-hydroxy-4-pyridyl, 3-hydroxy-4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 4-methyl-2-pyrimidinyl, 5-methyl-2-pyrimidinyl, 2-methyl-4-pyrimidinyl, 5-methyl-4-pyrimidinyl, 6-methyl-4-pyrimidinyl, 4-chloro-2-pyrimidinyl, 5-chloro-2-pyrimidinyl, 2-chloro-4-pyrimidinyl, 5-chloro-4-pyrimidinyl, 6-chloro-4-pyrimidinyl, 4-amino-2-pyrimidinyl, 5-amino-2-pyrimidinyl, 2-amino-4-pyrimidinyl, 5-amino-4-pyrimidinyl, 6-amino-4-pyrimidinyl, 4-acetamido-2-pyrimidinyl, 5-acetamido-2-pyrimidinyl, 2-acetamido-4-pyrimidinyl, 5-acetamido-4-pyrimidinyl, 6-acetamido-4-pyrimidinyl, 4-amino-5-hydroxy-2-pyrimidinyl, 4-amino-6-hydroxy-2-pyrimidinyl, 2-amino-5-hydroxy-4-pyrimidinyl, 2-amino-6-hydroxy-4-pyrimidinyl, 5-amino-2-hydroxy-4-pyrimidinyl, 6-amino-2-hydroxy-4-pyrimidinyl, 4,5-diamino-2-pyrimidinyl, 4,6-diamino-2-pyrimidinyl, 2,5-diamino-4-pyrimidinyl and 2,6-diamino-4-pyrimidinyl groups.
Examples of still more preferred such groups include: the 2-imidazolyl, 4-imidazolyl, 1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazol-2-yl, 1,3,4-thiadiazol-2-yl, 5-methyl-1,3,4-thiadiazol-2-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1-methyl-1,2,4-triazol-3-yl, 1-methyl-1,2,4-triazol-5-yl, 5-methyl-1,2,4-triazol-3-yl, tetrazol-5-yl, 1-methyltetrazol-5-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-methyl-2-pyridyl, 4-methyl-2-pyridyl, 5-methyl-2-pyridyl, 6-methyl-2-pyridyl, 2-methyl-4-pyridyl, 3-methyl-4-pyridyl, 3-amino-2-pyridyl, 4-amino-2-pyridyl, 5-amino-2-pyridyl, 6-amino-2-pyridyl, 2-amino-4-pyridyl, 3-amino-4-pyridyl, 3-hydroxy-2-pyridyl, 4-hydroxy-2-pyridyl, 5-hydroxy-2-pyridyl, 6-hydroxy-2-pyridyl, 2-hydroxy-4opyridyl, 3-hydroxy-4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 4-methyl-2-pyrimidinyl, 5-methyl-2-pyrimidinyl, 2-methyl-4-pyrimidinyl, 5-methyl-4-pyrimidinyl, 6-methyl-4-pyrimidinyl, 4-amin-2-pyrimidinyl, 5-amino-2-pyrimidinyl, 2-amino-4-pyrimidinyl, 5-amino-4-pyrimidinyl, 6-amino-4-pyrimidinyl, 4-amino-5-hydroxy-2-pyrimidinyl, 4-amino-6-hydroxy-2-pyrimidinyl, 2-amino-5-hydroxy-4-pyrimidinyl 2-amino-6-hydroxy-4opyrimidinyl, 5-amino-2ohydroxy-4-pyrimidinyl and 6-amino-2-hydroxy-4-pyrimidinyl groups.
Examples of the most preferred such groups include: the 1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazol-2-yl, 1,3,4-thiadiazol-2-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1-methyl-1,2,4-triazol-3-yl, 1-methyl-1,2,4-triazol-5-yl, 5-methyl-1,2,4-triazol-3-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 4-methyl-2-pyrimidinyl, 5-methyl-2-pyrimidinyl, 2-methyl-4-pyrimidinyl, 5-methyl-4-pyrimidinyl and 6-methyl-4-pyrimidinyl groups.
The compounds of the present invention can form salts. Where the compound contains a carboxy group, it can form a salt with a cation. Examples of such salts include: salts with an alkali metal, such as sodium, potassium or lithium; salts with an alkaline earth metal, such as barium or calcium; salts with another metal, such as magnesium or aluminum; ammonium salts; organic base salts, such as a salt with triethylamine, diisopropylamine, cyclohexylamine or dicyclohexylamine; and salts with a basic amino acid, such as lysine or arginine. Also, since the compounds of the present invention necessarily contain basic groups in their molecules, they can form acid addition salts. Examples of such acid addition salts include: salts with mineral acids, especially hydrohalic acids (such as hydrofluoric acid, hydrobromic acid, hydroiodic acid or hydrochloric acid), nitric acid, perchloric acid, carbonic acid, sulfuric acid or phosphoric acid; salts with lower alkylsulfonic acids, such as methanesulfonic acid, trifluoromethanesulfonic acid or ethanesulfonic acid; salts with arylsulfonic acids, such as benzenesulfonic acid or p-toluenesulfonic acid; salts with organic carboxylic acids, such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid, benzoic acid, mandelic acid, ascorbic acid, lactic acid, gluconic acid, citric acid or 2-(4-hydroxybenzoyl)benzoic acid; and salts with amino acids, such as glutamic acid or aspartic acid.
The compounds of the present invention may contain several asymmetric carbon atoms in their molecules, and can thus form optical isomers. Although these are all represented herein by a single molecular formula, the present invention includes both the individual, isolated isomers and mixtures, including racemates thereof. Where stereospecific synthesis techniques are employed or optically active compounds are employed as starting materials, individual isomers may be prepared directly; on the other hand, if a mixture of isomers is prepared, the individual isomers may be obtained by conventional resolution techniques.
Of the compounds of the present invention, we prefer those wherein R.sup.1 represents a cyclic amino group having from 3 to 7 ring atoms, of which 1 is a nitrogen atom and the remainder are carbon atoms, or said dialkylamino group, more preferably those wherein R.sup.1 represents a cyclic amino group having 5 or 6 ring atoms, of which 1 is a nitrogen atom and the remainder are carbon atoms, or said dialkylamino group, especially those wherein R.sup.1 represents a 1-pyrrolidinyl, piperidino, dimethylamino or diethylamino group.
Another preferred class of compounds of the present invention are those wherein R.sup.2 represents a group of formula --NHCHR.sup.3 R.sup.4 wherein R.sup.3 and R.sup.4 are independently selected from the group consisting of:
alkyl groups having from 1 to 4 carbon atoms,
phenyl groups which are unsubstituted or have at least one substituent selected from the group consisting of substituents .zeta., defined above, and
benzyl and phenethyl groups; or
R.sup.3 and R.sup.4 together with the carbon atom to which they are attached, represent a cycloalkyl group having from 3 to 6 ring carbon atoms,
An alternative preferred class of compounds of the present invention are those wherein R.sup.2 represents an aromatic heterocyclic group having 5 ring atoms, of which 1 is a hetero-atom selected from the group consisting of nitrogen, oxygen and sulfur hetero-atoms, there are 0, 1 or 2 additional nitrogen hetero-atoms, and the remaining ring atoms are carbon atoms, said group being unsubstituted or having at least one substituent selected, in the case of substituents on carbon atoms, from the group consisting of substituents .alpha. and, in the case of substituents on nitrogen atoms, from the group consisting of substituents .beta., as defined above, and particularly those wherein said aromatic heterocyclic group is selected from the group consisting of furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl and thiadiazolyl groups, which are unsubstituted or are substituted as defined above.
A further alternative preferred class of compounds of the present invention are those wherein R.sup.2 represents a group of formula --B--S(O).sub.m --R.sup.5, wherein:
B represents an alkylene or alkylidene group having from 1 to 3 carbon atoms;
m is 0, 1 or 2; and
R.sup.5 represents: a substituted alkyl group which has from 2 to 4 carbon atoms and which is substituted at its 2-position by at least one substituent selected from the group consisting of substituents .gamma.; or an aromatic heterocyclic group which has 5 or 6 ring atoms of which 1 is a hetero-atom selected from the group consisting of nitrogen, oxygen and sulfur hetero-atoms, there are 0, 1, 2 or 3 additional nitrogen hetero-atoms, and the remaining ring atoms are carbon atoms, said group being unsubstituted or having at least one substituent selected, in the case of substituents on carbon atoms, from the group consisting of substituents .alpha. and, in the case of substituents on nitrogen atoms, from the group consisting of substituents .epsilon., as defined above.
We also especially prefer those compounds of the present invention wherein A represents a group of formula --CH.dbd.CH-- or --(CH.sub.2).sub.n --, where n is 1 or 2.
A more preferred class of compounds of the present invention are those wherein:
R.sup.1 represents a 1-pyrrolidinyl, piperidino, dimethylamino or diethylamino group;
R.sup.2 represents
a group of formula --NHCHR.sup.3 R.sup.4 wherein
R.sup.3 and R.sup.4 are independently selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, benzyl groups, phenethyl groups and phenyl groups which are unsubstituted or which are substituted by at least one substituent selected from the group consisting of methyl, methoxy, fluorine atoms and chlorine atoms, or
R.sup.3 and R.sup.4 together with the carbon atom to which they are attached, represent a cycloalkyl group having from 3 to 6 ring carbon atoms,
a furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, imidazolyl or thiadiazolyl group, which is unsubstituted or is substituted by at least one substituent selected, in the case of substituents on carbon atoms, from the group consisting of substituents .alpha..sup.1 and, in the case of substituents on nitrogen atoms, from the group consisting of methyl and ethyl groups,
or a group of formula --B--S(O).sub.m --R.sup.5, wherein
R.sup.5 represents: a substituted ethyl or propyl group which is substituted at its 2-position by at least one substituent selected from the group consisting of substituents .gamma..sup.1 ; or an imidazolyl, 1,2,4-triazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, pyridyl or pyrimidinyl group which is unsubstituted or has at least one substituent selected, in the case of substituents on carbon atoms, from the group consisting of substituents .alpha..sup.1 and, in the case of substituents on nitrogen atoms, from the group consisting of substituents .epsilon..sup.1,
B represents an alkylene or alkylidene group having from 1 to 3 carbon atoms,
and m is 0, 1 or 2;
A represents a group of formula --CH.dbd.CH-- or --(CH.sub.2).sub.n --, where n is 1 or 2;
said substituents .alpha..sup.1 are selected from the group consisting of: methyl groups, ethyl groups, methoxy groups, ethoxy groups, hydroxy groups, chlorine atoms, amino groups; methylamino groups, ethylamino groups, dimethylamino groups, diethylamino groups, alkanoylamino groups having from 1 to 3 carbon atoms, phenyl groups, and substituted phenyl groups in which the substituent is selected from the group consisting of methyl groups, methoxy groups, chlorine atoms and fluorine atoms;
said substituents .gamma..sup.1 are selected from the group consisting of: hydroxy groups; alkanoyloxy groups having from 1 to 5 carbon atoms; substituted alkanoyloxy groups which have 3 or 4 carbon atoms and which are substituted by at least one substituent selected from the group consisting of carboxy, methoxycarbonyl and ethoxycarbonyl groups; phenylacetoxy groups; benzoyloxy groups; and cycloalkylcarbonyloxy groups in which the cycloalkyl part has from 3 to 6 ring carbon atoms;
said substituents .epsilon..sup.1 are selected from the group consisting of: methyl groups, ethyl groups, and hydroxyalkyl groups having from 2 to 4 carbon atoms.
Still more preferred compounds of the present invention are those compounds of formula (I) and salts thereof, wherein:
R.sup.1 represents a 1-pyrrolidinyl or piperidino group;
R.sup.2 represents
a group of formula --NHCHR.sup.3 R.sup.4 wherein
R.sup.3 and R.sup.4 are independently selected from the group consisting of methyl, ethyl, phenyl and benzyl groups, or
R.sup.3 and R.sup.4, together with the carbon atom to which they are attached, represent a cycloalkyl group having from 3 to 5 ring carbon atoms,
a furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl or 1,2,3-thiadiazolyl group, which is unsubstituted or is substituted by at least one substituent selected, in the case of substituents on carbon atoms, from the group consisting of substituents .alpha..sup.2 and, in the case of substituents on nitrogen atoms, from the group consisting of methyl and ethyl groups,
or a group of formula --B--S(O).sub.m --R.sup.5, wherein
R.sup.5 represents: a substituted ethyl or propyl group which is substituted at its 2-position by at least one substituent selected from the group consisting of substituents .gamma..sup.2 ; or a 1,2,4-triazolyl, 1,3,4-oxadiazolyl or pyrimidinyl group which is unsubstituted or has at least one substituent selected, in the case of substituents on carbon atoms, from the group consisting of substituents .alpha..sup.3 and, in the case of substituents on nitrogen atoms, from the group consisting of methyl and ethyl groups,
B represents an alkylene or alkylidene group having from 1 to 3 carbon atoms,
and m is 0 or 1;
A represents a group of formula --CH.dbd.CH-- or --(CH.sub.2).sub.2 --;
said substituents .alpha..sup.2 are selected from the group consisting of: methyl groups, ethyl groups, methoxy groups, ethoxy groups, hydroxy groups, chlorine atoms, amino groups, acetamido groups and phenyl groups;
said substituents .alpha..sup.3 are selected from the group consisting of: methyl groups, ethyl groups, methoxy groups, ethoxy groups, hydroxy groups, chlorine atoms, amino groups, and acetamido groups;
said substituents .gamma..sup.2 are selected from the group consisting of: hydroxy groups; acetoxy groups; propionyloxy groups; substituted alkanoyloxy groups which have 3 or 4 carbon atoms and which are substituted by at least one substituent selected from the group consisting of carboxy, methoxycarbonyl and ethoxycarbonyl groups; phenylacetoxy groups; benzoyloxy groups; and cycloalkylcarbonyloxy groups in which the cycloalkyl part has from 3 to 6 ring carbon atoms.
Yet more preferred compounds of the present invention are those compounds of formula (I) and salts thereof, wherein:
R.sup.1 represents a piperidino group;
R.sup.2 represents
a group of formula --NHCHR.sup.3 R.sup.4 wherein
R.sup.3 and R.sup.4 are independently selected from the group consisting of methyl, ethyl, phenyl and benzyl groups, or
R.sup.3 and R.sup.4 together with the carbon atom to which they are attached, represent a cycloalkyl group having 3 or 4 ring carbon atoms,
a thienyl, pyrrolyl, thiazolyl, pyrazolyl or 1,2,3-thiadiazolyl group, which is unsubstituted or is substituted by at least one substituent selected, in the case of substituents on carbon atoms, from the group consisting of substituents .alpha..sup.4 and, in the case of substituents on nitrogen atoms, from methyl groups,
or a group of formula --B--S(O).sub.m --R.sup.5, wherein
B represents a methylene group and R.sup.5 represents: a substituted ethyl or propyl group which is substituted at its 2-position by at least one substituent selected from the group consisting of substituents .gamma..sup.3 ; or
B represents a trimethylene group and R.sup.5 represents: a 1,2,4-triazolyl, 1,3,4-oxadiazolyl or pyrimidinyl group which is unsubstituted or has at least one substituent selected, in the case of substituents on carbon atoms, from the group consisting of methyl, hydroxy and amino groups, and, in the case of substituents on nitrogen atoms, from methyl groups,
and m is 0;
A represents a group of formula --CH=CH--;
said substituents .alpha..sup.4 are selected from the group consisting of: methyl.groups, methoxy groups, hydroxy groups, chlorine atoms and amino groups; said substituents .gamma..sup.3 are selected from the group consisting of: hydroxy groups; acetoxy groups; propionyloxy groups; substituted propionoyloxy groups which are substituted by at least one substituent selected from the group consisting of carboxy, methoxycarbonyl and ethoxycarbonyl groups; benzoyloxy groups; and cycloalkylcarbonyloxy groups in which the cycloalkyl part has 5 or 6 ring carbon atoms.
The most preferred compounds of the present invention are those compounds of formula (I) and salts thereof, wherein:
R.sup.1 represents a piperidino group;
R.sup.2 represents:
a pyrazolyl group, which is unsubstituted or is substituted on a carbon atom by at least one amino substituent,
or a group of formula --B--S(O).sub.m --R.sup.5, wherein
B represents a methylene group and R.sup.5 represents: a substituted ethyl group which is substituted at its 2-position by at least one substituent selected from the group consisting of substituents hydroxy, acetoxy, propionyloxy, benzoyloxy, cyclopentylcarbonyloxy and cyclohexylcarbonyloxy groups; or
B represents a trimethylene group and R.sup.5 represents: a 2-pyrimidinyl group;
and m is 0;
A represents a group of formula --CH.dbd.CH--.
Examples of specific preferred compounds of the present invention are those compounds of formula (I-1), in which the substituents are as defined in Table 1, and those compounds of formula (I-1), in which the substituents are as defined in Tables 2 and 3. ##STR4##
In the Tables, the following abbreviations are used:
______________________________________Ac acetylAze azetidinoAzi aziridinoBoz benzoylBu butylcBu cyclobutyliBu isobutylsBu sec-butylByr butyryliByr isobutyrylBz benzylEt ethylEtc ethoxycarbonylFo formylFur furylHp heptylcHp cycloheptylHx hexylcHx cyclohexyliHx isohexylImidazo imidazolylIsoxazo isoxazolylIsothiazo isothiazolylMe methylMec methoxycarbonylNaph naphthylcOc cyclooctylOxazo oxazolylOxadiazo oxadiazolylPh phenylPhc phenoxycarbonylPip piperidinoPiv pivaloylPn pentylcPn cyclopentyliPn isopentylnPn neopentylPr propylcPr cyclopropyliPr isopropylPrc propoxycarbonylPrn propionylPyl pyrrolylPymz pyrimidinylPyr 1-pyrrolidinylPyrazo pyrazolylPyz pyridylTetrazo tetrazolylThi thienylThiazo thiazolylThiadiazo thiadiazolylTriazo triazolylVal valeryliVal isovaleryl.______________________________________
TABLE 1______________________________________Cpd.No. R.sup.1 A R.sup.2______________________________________1-1 Pip CH.dbd.CH 2-Fur1-2 Pip CH.dbd.CH 3-Fur1-3 Pip CH.dbd.CH 4-Me-2-Fur1-4 Pip CH.dbd.CH 5-Me-2-Fur1-5 Pip CH.dbd.CH 2-Me-3-Fur1-6 Pip CH.dbd.CH 5-Me-3-Fur1-7 Pip CH.dbd.CH 5-Cl-2-Fur1-8 Pip CH.dbd.CH 5-Cl-3-Fur1-9 Pip CH.dbd.CH 5-NH.sub.2 -2-Fur1-10 Pip CH.dbd.CH 5-AcNH-2-Fur1-11 Pip CH.dbd.CH 5-Ph-2-Fur1-12 Pip CH.dbd.CH 5-(4-MePh)-2-Fur1-13 Pip CH.dbd.CH 5-(4-ClPh)-2-Fur1-14 Pip CH.dbd.CH 3-Me-5-NH.sub.2 -2-Fur1-15 Pip CH.dbd.CH 2,4-diMe-3-Fur1-16 Pip CH.dbd.CH 2-Thi1-17 Pip CH.dbd.CH 3-Thi1-18 Pip CH.dbd.CH 3-Me-2-Thi1-19 Pip CH.dbd.CH 5-Me-2-Thi1-20 Pip CH.dbd.CH 2-Me-3-Thi1-21 Pip CH.dbd.CH 4-Me-3-Thi1-22 Pip CH.dbd.CH 5-Me-3-Thi1-23 Pip CH.dbd.CH 4-MeO-2-Thi1-24 Pip CH.dbd.CH 4-MeO-3-Thi1-25 Pip CH.dbd.CH 4-HO-2-Thi1-26 Pip CH.dbd.CH 4-HO-3-Thi1-27 Pip CH.dbd.CH 5-Et-2-Thi1-28 Pip CH.dbd.CH 5-Cl-2-Thi1-29 Pip CH.dbd.CH 5-Cl-3-Thi1-30 Pip CH.dbd.CH 5-Br-3-Thi1-31 Pip CH.dbd.CH 3-NH.sub.2 -2-Thi1-32 Pip CH.dbd.CH 5-NH.sub.2 -2-Thi1-33 Pip CH.dbd.CH 2-NH.sub.2 -3-Thi1-34 Pip CH.dbd.CH 4-NH.sub.2 -3-Thi1-35 Pip CH.dbd.CH 3-AcNH-2-Thi1-36 Pip CH.dbd.CH 4-AcNH-3-Thi1-37 Pip CH.dbd.CH 5-Ph-2-Thi1-38 Pip CH.dbd.CH 4,5-diMe-2-Thi1-39 Pip CH.dbd.CH 3,5-diMe-2-Thi1-40 Pip CH.dbd.CH 2,5-diMe-3-Thi1-41 Pip CH.dbd.CH 4,5-diMe-3-Thi1-42 Pip CH.dbd.CH 4,5-diCl-2-Thi1-43 Pip CH.dbd.CH 2-NH.sub.2 -5-Ph-3-Thi1-44 Pip CH.dbd.CH 4-NH.sub.2 -2,5-diMe-3-Thi1-45 Pip CH.dbd.CH 2-Pyl1-46 Pip CH.dbd.CH 3-Pyl1-47 Pip CH.dbd.CH 1-Me-2-Pyl1-48 Pip CH.dbd.CH 3-Me-2-Pyl1-49 Pip CH.dbd.CH 4-Me-2-Pyl1-50 Pip CH.dbd.CH 2-Me-3-Pyl1-51 Pip CH.dbd.CH 5-Me-3-Pyl1-52 Pip CH.dbd.CH 3-NH.sub.2 -2-Pyl1-53 Pip CH.dbd.CH 4-NH.sub.2 -2-Pyl1-54 Pip CH.dbd.CH 3-AcNH-2-Pyl1-55 Pip CH.dbd.CH 5-Cl-2-Pyl1-56 Pip CH.dbd.CH 5-Cl-3-Pyl1-57 Pip CH.dbd.CH 4-Ph-2-Pyl1-58 Pip CH.dbd.CH 5-Ph-3-Pyl1-59 Pip CH.dbd.CH 1-Me-4-MeO-3-Pyl1-60 Pip CH.dbd.CH 1-Me-4-HO-3-Pyl1-61 Pip CH.dbd.CH 3,5-diMe-2-Pyl1-62 Pip CH.dbd.CH 4,5-diMe-2-Pyl1-63 Pip CH.dbd.CH 1,3-diMe-2-Pyl1-64 Pip CH.dbd.CH 5-NH.sub.2 -1-Me-2-Pyl1-65 Pip CH.dbd.CH 4-NH.sub.2 -3,5-diMe-2-Pyl1-66 Pip CH.dbd.CH 5-Br-1,4-diMe-3-Pyl1-67 Pip CH.dbd.CH 4-Oxazo1-68 Pip CH.dbd.CH 5-Oxazo1-69 Pip CH.dbd.CH 2-Oxazo1-70 Pip CH.dbd.CH 2-Me-4-Oxazo1-71 Pip CH.dbd.CH 2-Ph-4-Oxazo1-72 Pip CH.dbd.CH 5-Ph-2-Oxazo1-73 Pip CH.dbd.CH 2-HO-4-Oxazo1-74 Pip CH.dbd.CH 2,5-diMe-4-Oxazo1-75 Pip CH.dbd.CH 4-Me-2-Ph-5-Oxazo1-76 Pip CH.dbd.CH 3-Isoxazo1-77 Pip CH.dbd.CH 4-Isoxazo1-78 Pip CH.dbd.CH 4-Me-3-Isoxazo1-79 Pip CH.dbd.CH 5-Me-3-Isoxazo1-80 Pip CH.dbd.CH 3-Me-4-Isoxazo1-81 Pip CH.dbd.CH 4-MeO-3-Isoxazo1-82 Pip CH.dbd.CH 4-HO-3-Isoxazo1-83 Pip CH.dbd.CH 3-HO-4-Isoxazo1-84 Pip CH.dbd.CH 3-HO-5-Isoxazo1-85 Pip CH.dbd.CH 4-NH.sub.2 -3-Isoxazo1-86 Pip CH.dbd.CH 5-NH.sub.2 -4-Isoxazo1-87 Pip CH.dbd.CH 5-Ph-3-Isoxazo1-88 Pip CH.dbd.CH 4-Ph-3-Isoxazo1-89 Pip CH.dbd.CH 4,5-diMe-3-Isoxazo1-90 Pip CH.dbd.CH 4-HO-5-Me-3-Isoxazo1-91 Pip CH.dbd.CH 2-Thiazo1-92 Pip CH.dbd.CH 4-Thiazo1-93 Pip CH.dbd.CH 5-Thiazo1-94 Pip CH.dbd.CH 4-Me-2-Thiazo1-95 Pip CH.dbd.CH 2-Me-4-Thiazo1-96 Pip CH.dbd.CH 2-Me-5-Thiazo1-97 Pip CH.dbd.CH 2-MeO-4-Thiazo1-98 Pip CH.dbd.CH 2-MeO-5-Thiazo1-99 Pip CH.dbd.CH 2-HO-4-Thiazo1-100 Pip CH.dbd.CH 2-HO-5-Thiazo1-101 Pip CH.dbd.CH 2-Cl-5-Thiazo1-102 Pip CH.dbd.CH 5-Cl-2-Thiazo1-103 Pip CH.dbd.CH 2-NH.sub.2 -4-Thiazo1-104 Pip CH.dbd.CH 2-NH.sub.2 -5-Thiazo1-105 Pip CH.dbd.CH 5-NH.sub.2 -4-Thiazo1-106 Pip CH.dbd.CH 2-AcNH-4-Thiazo1-107 Pip CH.dbd.CH 5-AcNH-4-Thiazo1-108 Pip CH.dbd.CH 2-Ph-4-Thiazo1-109 Pip CH.dbd.CH 4,5-diMe-2-Thiazo1-110 Pip CH.dbd.CH 2-HO-5-Me-4-Thiazo1-111 Pip CH.dbd.CH 5-NH.sub.2 -2-Me-4-Thiazo1-112 Pip CH.dbd.CH 2-Cl-4-Me-5-Thiazo1-113 Pip CH.dbd.CH 3-Isothiazo1-114 Pip CH.dbd.CH 4-Isothiazo1-115 Pip CH.dbd.CH 3-Pyrazo1-116 Pip CH.dbd.CH 4-Pyrazo1-117 Pip CH.dbd.CH 1-Me-3-Pyrazo1-118 Pip CH.dbd.CH 1-Et-3-Pyrazo1-119 Pip CH.dbd.CH 1-Pr-3-Pyrazo1-120 Pip CH.dbd.CH 1-Me-4-Pyrazo1-121 Pip CH.dbd.CH 1-Et-4-Pyrazo1-122 Pip CH.dbd.CH 1-Pr-4-Pyrazo1-123 Pip CH.dbd.CH 1-Bu-4-Pyrazo1-124 Pip CH.dbd.CH 4-Me-3-Pyrazo1-125 Pip CH.dbd.CH 5-Me-3-Pyrazo1-126 Pip CH.dbd.CH 5-Et-3-Pyrazo1-127 Pip CH.dbd.CH 5-Pr-3-Pyrazo1-128 Pip CH.dbd.CH 5-Me-4-Pyrazo1-129 Pip CH.dbd.CH 4-MeO-3-Pyrazo1-130 Pip CH.dbd.CH 4-PrO-3-Pyrazo1-131 Pip CH.dbd.CH 4-HO-3-Pyrazo1-132 Pip CH.dbd.CH 4-Cl-3-Pyrazo1-133 Pip CH.dbd.CH 4-Br-3-Pyrazo1-134 Pip CH.dbd.CH 3-Cl-4-Pyrazo1-135 Pip CH.dbd.CH 4-NH.sub.2 -3-Pyrazo1-136 Pip CH.dbd.CH 5-NH.sub.2 -3-Pyrazo1-137 Pip CH.dbd.CH 3-NH.sub.2 -4-Pyrazo1-138 Pip CH.dbd.CH 4-AcNH-3-Pyrazo1-139 Pip CH.dbd.CH 5-AcNH-3-Pyrazo1-140 Pip CH.dbd.CH 3-AcNH-4-Pyrazo1-141 Pip CH.dbd.CH 3-EtCONH-4-Pyrazo1-142 Pip CH.dbd.CH 5-Ph-3-Pyrazo1-143 Pip CH.dbd.CH 1,5-diMe-3-Pyrazo1-144 Pip CH.dbd.CH 1,4-diMe-3-Pyrazo1-145 Pip CH.dbd.CH 4,5-diMe-3-Pyrazo1-146 Pip CH.dbd.CH 3-Me-4-Pyrazo1-147 Pip CH.dbd.CH 3,5-diMe-4-Pyrazo1-148 Pip CH.dbd.CH 1,5-diMe-4-Pyrazo1-149 Pip CH.dbd.CH 1,3-diMe-4-Pyrazo1-150 Pip CH.dbd.CH 1,3-diMe-5-Pyrazo1-151 Pip CH.dbd.CH 3-Cl-5-Me-4-Pyrazo1-152 Pip CH.dbd.CH 3-Cl-1-Me-4-Pyrazo1-153 Pip CH.dbd.CH 5-Cl-1-Me-4-Pyrazo1-154 Pip CH.dbd.CH 4-Cl-1-Me-3-Pyrazo1-155 Pip CH.dbd.CH 4-Cl-5-Me-3-Pyrazo1-156 Pip CH.dbd.CH 4-Cl-1-Me-3-Pyrazo1-157 Pip CH.dbd.CH 3-NH.sub.2 -5-Me-4-Pyrazo1-158 Pip CH.dbd.CH 3-NH.sub.2 -1-Me-4-Pyrazo1-159 Pip CH.dbd.CH 5-NH.sub.2 -1-Me-4-Pyrazo1-160 Pip CH.dbd.CH 5-NH.sub.2 -4-Me-3-Pyrazo1-161 Pip CH.dbd.CH 5-NH.sub.2 -1-Me-3-Pyrazo1-162 Pip CH.dbd.CH 5-AcNH-1-Me-4-Pyrazo1-163 Pip CH.dbd.CH 4-NH.sub.2 -5-Me-3-Pyrazo1-164 Pip CH.dbd.CH 4-HO-5-Me-3-Pyrazo1-165 Pip CH.dbd.CH 5-AcNH-3-Me-4-Pyrazo1-166 Pip CH.dbd.CH 1,3,5-triMe-4-Pyrazo1-167 Pip CH.dbd.CH 1,3,4-triMe-5-Pyrazo1-168 Pip CH.dbd.CH 4-Cl-1,3-diMe-5-Pyrazo1-169 Pip CH.dbd.CH 2-Imidazo1-170 Pip CH.dbd.CH 4-Imidazo1-171 Pip CH.dbd.CH 2-Me-4-Imidazo1-172 Pip CH.dbd.CH 1-Me-4-Imidazo1-173 Pip CH.dbd.CH 5-Me-4-Imidazo1-174 Pip CH.dbd.CH 5-Me-2-Imidazo1-175 Pip CH.dbd.CH 1-Me-2-Imidazo1-176 Pip CH.dbd.CH 1,2,3-Oxadiazo-5-yl1-177 Pip CH.dbd.CH 1,3,4-Oxadiazo-2-yl1-178 Pip CH.dbd.CH 1,2,3-Oxadiazo-4-yl1-179 Pip CH.dbd.CH 1,2,4-Oxadiazo-5-yl1-180 Pip CH.dbd.CH 1,2,4-Oxadiazo-3-yl1-181 Pip CH.dbd.CH 1,2,5-Oxadiazo-3-yl1-182 Pip CH.dbd.CH 5-Me-1,2,3-Oxadiazo-4-yl1-183 Pip CH.dbd.CH 4-Me-1,2,5-Oxadiazo-3-yl1-184 Pip CH.dbd.CH 4-Ph-1,2,5-Oxadiazo-3-yl1-185 Pip CH.dbd.CH 1,2,3-Thiadiazo-4-yl1-186 Pip CH.dbd.CH 1,2,3-Thiadiazo-5-yl1-187 Pip CH.dbd.CH 1,3,4-Thiadiazo-2-yl1-188 Pip CH.dbd.CH 1,2,4-Thiadiazo-3-yl1-189 Pip CH.dbd.CH 1,2,4-Thiadiazo-5-yl1-190 Pip CH.dbd.CH 1,2,5-Thiadiazo-3-yl1-191 Pip CH.dbd.CH 4-Me-1,2,3-Thiadiazo-5-yl1-192 Pip CH.dbd.CH 5-Me-1,2,3-Thiadiazo-4-yl1-193 Pip CH.dbd.CH 4-Me-1,2,5-Thiadiazo-3-yl1-194 Pip CH.dbd.CH 5-Ph-1,2,3-Thiadiazo-4-yl1-195 Pyr CH.dbd.CH 2-Fur1-196 Pyr CH.dbd.CH 3-Fur1-197 Pyr CH.dbd.CH 4-Me-2-Fur1-198 Pyr CH.dbd.CH 2-Me-3-Fur1-199 Pyr CH.dbd.CH 2,4-diMe-3-Fur1-200 Pyr CH.dbd.CH 2-Thi1-201 Pyr CH.dbd.CH 3-Thi1-202 Pyr CH.dbd.CH 3-Me-2-Thi1-203 Pyr CH.dbd.CH 2-Me-3-Thi1-204 Pyr CH.dbd.CH 4-Me-3-Thi1-205 Pyr CH.dbd.CH 4-MeO-3-Thi1-206 Pyr CH.dbd.CH 4-HO-2-Thi1-207 Pyr CH.dbd.CH 5-Cl-3-Thi1-208 Pyr CH.dbd.CH 3-NH.sub.2 -2-Thi1-209 Pyr CH.dbd.CH 2-NH.sub.2 -3-Thi1-210 Pyr CH.dbd.CH 3-AcNH-2-Thi1-211 Pyr CH.dbd.CH 5-Ph-2-Thi1-212 Pyr CH.dbd.CH 4,5-diMe-2-Thi1-213 Pyr CH.dbd.CH 2,5-diMe-3-Thi1-214 Pyr CH.dbd.CH 4,5-diCl-2-Thi1-215 Pyr CH.dbd.CH 4-NH.sub.2 -2,5-diMe-3-Thi1-216 Pyr CH.dbd.CH 2-Pyl1-217 Pyr CH.dbd.CH 3-Pyl1-218 Pyr CH.dbd.CH 1-Me-2-Pyl1-219 Pyr CH.dbd.CH 3-Me-2-Pyl1-220 Pyr CH.dbd.CH 4-Me-2-Pyl1-221 Pyr CH.dbd.CH 2-Me-3-Pyl1-222 Pyr CH.dbd.CH 1-Me-4-MeO-3-Pyl1-223 Pyr CH.dbd.CH 3,5-diMe-2-Pyl1-224 Pyr CH.dbd.CH 1,3-diMe-2-Pyl1-225 Pyr CH.dbd.CH 4-Oxazo1-226 Pyr CH.dbd.CH 5-Oxazo1-227 Pyr CH.dbd.CH 2-Oxazo1-228 Pyr CH.dbd.CH 2-Me-4-Oxazo1-229 Pyr CH.dbd.CH 5-Ph-2-Oxazo1-230 Pyr CH.dbd.CH 2,5-diMe-4-Oxazo1-231 Pyr CH.dbd.CH 3-Isoxazo1-232 Pyr CH.dbd.CH 4-Isoxazo1-233 Pyr CH.dbd.CH 5-Me-3-Isoxazo1-234 Pyr CH.dbd.CH 3-Me-4-Isoxazo1-235 Pyr CH.dbd.CH 4-MeO-3-Isoxazo1-236 Pyr CH.dbd.CH 4-HO-3-Isoxazo1-237 Pyr CH.dbd.CH 3-HO-5-Isoxazo1-238 Pyr CH.dbd.CH 5-HO-4-Isoxazo1-239 Pyr CH.dbd.CH 4-NH.sub.2 -3-Isoxazo1-240 Pyr CH.dbd.CH 5-Ph-3-Isoxazo1-241 Pyr CH.dbd.CH 4,5-diMe-3-Isoxazo1-242 Pyr CH.dbd.CH 4-HO-5-Me-3-Isoxazo1-243 Pyr CH.dbd.CH 2-Thiazo1-244 Pyr CH.dbd.CH 4-Thiazo1-245 Pyr CH.dbd.CH 5-Thiazo1-246 Pyr CH.dbd.CH 4-Me-2-Thiazo1-247 Pyr CH.dbd.CH 2-Me-5-Thiazo1-248 Pyr CH.dbd.CH 2-MeO-4-Thiazo1-249 Pyr CH.dbd.CH 2-MeO-5-Thiazo1-250 Pyr CH.dbd.CH 2-HO-5-Thiazo1-251 Pyr CH.dbd.CH 5-Cl-2-Thiazo1-252 Pyr CH.dbd.CH 2-NH.sub.2 -4-Thiazo1-253 Pyr CH.dbd.CH 2-AcNH-4-Thiazo1-254 Pyr CH.dbd.CH 4,5-diMe-2-Thiazo1-255 Pyr CH.dbd.CH 2-HO-5-Me-4-Thiazo1-256 Pyr CH.dbd.CH 5-NH.sub.2 -2-Me-4-Thiazo1-257 Pyr CH.dbd.CH 3-Isothiazo1-258 Pyr CH.dbd.CH 4-Isothiazo1-259 Pyr CH.dbd.CH 3-Pyrazo1-260 Pyr CH.dbd.CH 4-Pyrazo1-261 Pyr CH.dbd.CH 1-Me-3-Pyrazo1-262 Pyr CH.dbd.CH 1-Et-3-Pyrazo1-263 Pyr CH.dbd.CH 1-Me-4-Pyrazo1-264 Pyr CH.dbd.CH 1-Et-4-Pyrazo1-265 Pyr CH.dbd.CH 4-Me-3-Pyrazo1-266 Pyr CH.dbd.CH 5-Me-3-Pyrazo1-267 Pyr CH.dbd.CH 5-Me-4-Pyrazo1-268 Pyr CH.dbd.CH 4-MeO-3-Pyrazo1-269 Pyr CH.dbd.CH 4-HO-3-Pyrazo1-270 Pyr CH.dbd.CH 4-Cl-3-Pyrazo1-271 Pyr CH.dbd.CH 4-NH.sub.2 -3-Pyrazo1-272 Pyr CH.dbd.CH 5-NH.sub.2 -3-Pyrazo1-273 Pyr CH.dbd.CH 3-NH.sub.2 -4-Pyrazo1-274 Pyr CH.dbd.CH 4-AcNH-3-Pyrazo1-275 Pyr CH.dbd.CH 5-Ph-3-Pyrazo1-276 Pyr CH.dbd.CH 1,5-diMe-3-Pyrazo1-277 Pyr CH.dbd.CH 1,4-diMe-3-Pyrazo1-278 Pyr CH.dbd.CH 3,5-diMe-4-Pyrazo1-279 Pyr CH.dbd.CH 1,5-diMe-4-Pyrazo1-280 Pyr CH.dbd.CH 1,3-diMe-4-Pyrazo1-281 Pyr CH.dbd.CH 1,3-diMe-5-Pyrazo1-282 Pyr CH.dbd.CH 3-Cl-5-Me-4-Pyrazo1-283 Pyr CH.dbd.CH 3-Cl-1-Me-4-Pyrazo1-284 Pyr CH.dbd.CH 4-Cl-5-Me-3-Pyrazo1-285 Pyr CH.dbd.CH 4-Cl-1-Me-3-Pyrazo1-286 Pyr CH.dbd.CH 3-NH.sub.2 -5-Me-4-Pyrazo1-287 Pyr CH.dbd.CH 3-NH.sub.2 -1-Me-4-Pyrazo1-288 Pyr CH.dbd.CH 5-NH.sub.2 -1-Me-4-Pyrazo1-289 Pyr CH.dbd.CH 5-NH.sub.2 -4-Me-3-Pyrazo1-290 Pyr CH.dbd.CH 5-NH.sub.2 -1-Me-3-Pyrazo1-291 Pyr CH.dbd.CH 5-NH.sub.2 -3-Me-3-Pyrazo1-292 Pyr CH.dbd.CH 4-NH.sub.2 -5-Me-3-Pyrazo1-293 Pyr CH.dbd.CH 4-HO-5-Me-3-Pyrazo1-294 Pyr CH.dbd.CH 1,3,5-triMe-4-Pyrazo1-295 Pyr CH.dbd.CH 1,3,4-triMe-5-Pyrazo1-296 Pyr CH.dbd.CH 4-Cl-1,3-diMe-5-Pyrazo1-297 Pyr CH.dbd.CH 2-Imidazo1-298 Pyr CH.dbd.CH 4-Imidazo1-299 Pyr CH.dbd.CH 1-Me-4-Imidazo1-300 Pyr CH.dbd.CH 5-Me-4-Imidazo1-301 Pyr CH.dbd.CH 5-Me-2-Imidazo1-302 Pyr CH.dbd.CH 1-Me-2-Imidazo1-303 Pyr CH.dbd.CH 1,2,3-Oxadiazo-5-yl1-304 Pyr CH.dbd.CH 1,2,4-Oxadiazo-5-yl1-305 Pyr CH.dbd.CH 1,2,5-Oxadiazo-3-yl1-306 Pyr CH.dbd.CH 5-Me-1,2,3-Oxadiazo-4-yl1-307 Pyr CH.dbd.CH 1,2,3-Thiadiazo-4-yl1-308 Pyr CH.dbd.CH 1,2,4-Thiadiazo-2-yl1-309 Pyr CH.dbd.CH 1,2,5-Thiadiazo-3-yl1-310 Pyr CH.dbd.CH 4-Me-1,2,3-Thiadiazo-5-yl1-311 Pyr CH.dbd.CH 5-Ph-1,2,3-Thiadiazo-4-yl1-312 NMe.sub.2 CH.dbd.CH 2-Fur1-313 NMe.sub.2 CH.dbd.CH 3-Fur1-314 NMe.sub.2 CH.dbd.CH 4-Me-2-Fur1-315 NMe.sub.2 CH.dbd.CH 2,4-diMe-3-Fur1-316 NMe.sub.2 CH.dbd.CH 2-Thi1-317 NMe.sub.2 CH.dbd.CH 3-Thi1-318 NMe.sub.2 CH.dbd.CH 3-Me-2-Thi1-319 NMe.sub.2 CH.dbd.CH 2-Me-3-Thi1-320 NMe.sub.2 CH.dbd.CH 4,5-diMe-2-Thi1-321 NMe.sub.2 CH.dbd.CH 2-Pyl1-322 NMe.sub.2 CH.dbd.CH 3-Pyl1-323 NMe.sub.2 CH.dbd.CH 1-Me-2-Pyl1-324 NMe.sub.2 CH.dbd.CH 4-Me-2-Pyl1-325 NMe.sub.2 CH.dbd.CH 2-Me-3-Pyl1-326 NMe.sub.2 CH.dbd.CH 3,5-diMe-2-Pyl1-327 NMe.sub.2 CH.dbd.CH 1,3-diMe-2-Pyl1-328 NMe.sub.2 CH.dbd.CH 4-Oxazo1-329 NMe.sub.2 CH.dbd.CH 5-Oxazo1-330 NMe.sub.2 CH.dbd.CH 2-Oxazo1-331 NMe.sub.2 CH.dbd.CH 2-Me-4-Oxazo1-332 NMe.sub.2 CH.dbd.CH 2,5-diMe-4-Oxazo1-333 NMe.sub.2 CH.dbd.CH 3-Isoxazo1-334 NMe.sub.2 CH.dbd.CH 4-Isoxazo1-335 NMe.sub.2 CH.dbd.CH 5-Me-3-Isoxazo1-336 NMe.sub.2 CH.dbd.CH 4-MeO-3-Isoxazo1-337 NMe.sub.2 CH.dbd.CH 4-HO-3-Isoxazo1-338 NMe.sub.2 CH.dbd.CH 4,5-diMe-3-Isoxazo1-339 NMe.sub.2 CH.dbd.CH 4-HO-5-Me-3-Isoxzo1-340 NMe.sub.2 CH.dbd.CH 2-Thiazo1-341 NMe.sub.2 CH.dbd.CH 4-Thiazo1-342 NMe.sub.2 CH.dbd.CH 5-Thiazo1-343 NMe.sub.2 CH.dbd.CH 4-Me-2-Thiazo1-344 NMe.sub.2 CH.dbd.CH 2-Me-5-Thiazo1-345 NMe.sub.2 CH.dbd.CH 2-MeO-4-Thiazo1-346 NMe.sub.2 CH.dbd.CH 4,5-diMe-2-Thiazo1-347 NMe.sub.2 CH.dbd.CH 3-Isothiazo1-348 NMe.sub.2 CH.dbd.CH 4-Isothiazo1-349 NMe.sub.2 CH.dbd.CH 3-Pyrazo1-350 NMe.sub.2 CH.dbd.CH 4-Pyrazo1-351 NMe.sub.2 CH.dbd.CH 1-Me-3-Pyrazo1-352 NMe.sub.2 CH.dbd.CH 1-Me-4-Pyrazo1-353 NMe.sub.2 CH.dbd.CH 4-Me-3-Pyrazo1-354 NMe.sub.2 CH.dbd.CH 5-Me-3-Pyrazo1-355 NMe.sub.2 CH.dbd.CH 5-Me-4-Pyrazo1-356 NMe.sub.2 CH.dbd.CH 4-MeO-3-Pyrazo1-357 NMe.sub.2 CH.dbd.CH 4-HO-3-Pyrazo1-358 NMe.sub.2 CH.dbd.CH 3,5-diMe-4-Pyrazo1-359 NMe.sub.2 CH.dbd.CH 1,3,5-triMe-4-Pyrazo1-360 NMe.sub.2 CH.dbd.CH 1,3,4-triMe-5-Pyrazo1-361 NMe.sub.2 CH.dbd.CH 2-Imidazo1-362 NMe.sub.2 CH.dbd.CH 4-Imidazo1-363 NMe.sub.2 CH.dbd.CH 5-Me-4-Imidazo1-364 Azi CH.dbd.CH 2-Fur1-365 Azi CH.dbd.CH 3-Fur1-366 Azi CH.dbd.CH 4-Me-2-Fur1-367 Azi CH.dbd.CH 2-Thi1-368 Azi CH.dbd.CH 3-Thi1-369 Azi CH.dbd.CH 5-Me-2-Thi1-370 Azi CH.dbd.CH 2-Pyl1-371 Azi CH.dbd.CH 3-Pyl1-372 Azi CH.dbd.CH 1-Me-2-Pyl1-373 Azi CH.dbd.CH 4-Me-2-Pyl1-374 Azi CH.dbd.CH 4-Oxazo1-375 Azi CH.dbd.CH 5-Oxazo1-376 Azi CH.dbd.CH 2-Oxazo1-377 Azi CH.dbd.CH 3-Isoxazo1-378 Azi CH.dbd.CH 4-Isoxazo1-379 Azi CH.dbd.CH 4-HO-3-Isoxazo1-380 Azi CH.dbd.CH 2-Thiazo1-381 Azi CH.dbd.CH 4-Thiazo1-382 Azi CH.dbd.CH 5-Thiazo1-383 Azi CH.dbd.CH 2-Me-5-Thiazo1-384 Azi CH.dbd.CH 3-Pyrazo1-385 Azi CH.dbd.CH 4-Pyrazo1-386 Azi CH.dbd.CH 1-Me-3-Pyrazo1-387 Azi CH.dbd.CH 4-Me-3-Pyrazo1-388 Azi CH.dbd.CH 5-Me-4-Pyrazo1-389 Azi CH.dbd.CH 4-NH.sub.2 -3-Pyrazo1-390 Azi CH.dbd.CH 3-NH.sub.2 -4-Pyrazo1-391 Azi CH.dbd.CH 3,5-diMe-4-Pyrazo1-392 Azi CH.dbd.CH 1,3,5-triMe-4-Pyrazo1-393 Azi CH.dbd.CH 2-Imidazo1-394 Azi CH.dbd.CH 4-Imidazo1-395 Azi CH.dbd.CH 5-Me-4-Imidazo1-396 Aze CH.dbd.CH 2-Fur1-397 Aze CH.dbd.CH 3-Fur1-398 Aze CH.dbd.CH 4-Me-2-Fur1-399 Aze CH.dbd.CH 2-Thi1-400 Aze CH.dbd.CH 3-Thi1-401 Aze CH.dbd.CH 5-Me-2-Thi1-402 Aze CH.dbd.CH 2-Pyl1-403 Aze CH.dbd.CH 3-Pyl1-404 Aze CH.dbd.CH 1-Me-2-Pyl1-405 Aze CH.dbd.CH 4-Me-2-Pyl1-406 Aze CH.dbd.CH 4-Oxazo1-407 Aze CH.dbd.CH 5-Oxazo1-408 Aze CH.dbd.CH 2-Oxazo1-409 Aze CH.dbd.CH 3-Isoxazo1-410 Aze CH.dbd.CH 4-Isoxazo1-411 Aze CH.dbd.CH 4-HO-3-Isoxazo1-412 Aze CH.dbd.CH 2-Thiazo1-413 Aze CH.dbd.CH 4-Thiazo1-414 Aze CH.dbd.CH 5-Thiazo1-415 Aze CH.dbd.CH 2-Me-5-Thiazo1-416 Aze CH.dbd.CH 3-Pyrazo1-417 Aze CH.dbd.CH 4-Pyrazo1-418 Aze CH.dbd.CH 1-Me-3-Pyrazo1-419 Aze CH.dbd.CH 4-Me-3-Pyrazo1-420 Aze CH.dbd.CH 5-Me-4-Pyrazo1-421 Aze CH.dbd.CH 4-NH2 -3-Pyrazo1-422 Aze CH.dbd.CH 3-NH2 -4-Pyrazo1-423 Aze CH.dbd.CH 3,5-diMe-4-Pyrazo1-424 Aze CH.dbd.CH 1,3,5-triMe-4-Pyrazo1-425 Aze CH.dbd.CH 2-Imidazo1-426 Aze CH.dbd.CH 4-Imidazo1-427 Aze CH.dbd.CH 5-Me-4-Imidazo1-428 Pip CH.dbd.CH 1,2,3-Triazo-4-yl1-429 Pip CH.dbd.CH 1-Me-1,2,3-Triazo-4-yl1-430 Pip CH.dbd.CH 5-Me-1,2,3-Triazo-4-yl1-431 Pip CH.dbd.CH 1,5-diMe-1,2,3-Triazo-4-yl1-432 Pip CH.dbd.CH 1,2,4-Triazo-5-yl1-433 Pip CH.dbd.CH 1-Me-1,2,5-Triazo-3-yl1-434 Pyr CH.dbd.CH 1,2,3-Triazo-4-yl1-435 Pyr CH.dbd.CH 1,2,4-Triazo-5-yl1-436 NMe.sub.2 CH.dbd.CH 1,2,3-Triazo-4-yl1-437 NMe.sub.2 CH.dbd.CH 1,2,4-Triazo-5-yl1-438 Pip (CH.sub.2).sub.3 2-Fur1-439 Pip (CH.sub.2).sub.3 3-Fur1-440 Pip (CH.sub.2).sub.3 4-Me-2-Fur1-441 Pip (CH.sub.2).sub.3 2-Thi1-442 Pip (CH.sub.2).sub.3 3-Thi1-443 Pip (CH.sub.2).sub.3 5-Me-2-Thi1-444 Pip (CH.sub.2).sub.3 2-Pyl1-445 Pip (CH.sub.2).sub.3 3-Pyl1-446 Pip (CH.sub.2).sub.3 1-Me-2-Pyl1-447 Pip (CH.sub.2).sub.3 4-Me-2-Pyl1-448 Pip (CH.sub.2).sub.3 3,5-diMe-2-Pyl1-449 Pip (CH.sub.2).sub.3 4-Oxazo1-450 Pip (CH.sub.2).sub.3 5-Oxazo1-451 Pip (CH.sub.2).sub.3 2-Oxazo1-452 Pip (CH.sub.2).sub.3 2-Me-4-Oxazo1-453 Pip (CH.sub.2).sub.3 3-Isoxazo1-454 Pip (CH.sub.2).sub.3 4-Isoxazo1-455 Pip (CH.sub.2).sub.3 5-Me-3-Isoxazo1-456 Pip (CH.sub.2).sub.3 4-HO-3-Isoxazo1-457 Pip (CH.sub.2).sub.3 2-Thiazo1-458 Pip (CH.sub.2).sub.3 4-Thiazo1-459 Pip (CH.sub.2).sub.3 5-Thiazo1-460 Pip (CH.sub.2).sub.3 2-Me-5-Thiazo1-461 Pip (CH.sub.2).sub.3 3-Pyrazo1-462 Pip (CH.sub.2).sub.3 4-Pyrazo1-463 Pip (CH.sub.2).sub.3 1-M.e-3-Pyrazo1-464 Pip (CH.sub.2).sub.3 1-Me-4-Pyrazo1-465 Pip (CH.sub.2).sub.3 4-Me-3-Pyrazo1-466 Pip (CH.sub.2).sub.3 5-Me-3-Pyrazo1-467 Pip (CH.sub.2).sub.3 5-Me-4-Pyrazo1-468 Pip (CH.sub.2).sub.3 4-NH.sub.2 -3-Pyrazo1-469 Pip (CH.sub.2).sub.3 5-NH.sub.2 -3-Pyrazo1-470 Pip (CH.sub.2).sub.3 3-NH.sub.2 -4-Pyrazo1-471 Pip (CH.sub.2).sub.3 3,5-diMe-4-Pyrazo1-472 Pip (CH.sub.2).sub.3 1,3,5-triMe-4-Pyrazo1-473 Pip (CH.sub.2).sub.3 2-Imidazo1-474 Pip (CH.sub.2).sub.3 4-Imidazo1-475 Pip (CH.sub.2).sub.3 5-Me-4-Imidazo1-476 Pip CH.sub.2 CH.sub.2 2-Fur1-477 Pip CH.sub.2 CH.sub.2 3-Fur1-478 Pip CH.sub.2 CH.sub.2 4-Me-2-Fur1-479 Pip CH.sub.2 CH.sub.2 5-Me-2-Fur1-480 Pip CH.sub.2 CH.sub.2 2-Me-3-Fur1-481 Pip CH.sub.2 CH.sub.2 5-Me-3-Fur1-482 Pip CH.sub.2 CH.sub.2 5-Cl-2-Fur1-483 Pip CH.sub.2 CH.sub.2 5-Cl-3-Fur1-484 Pip CH.sub.2 CH.sub.2 5-NH.sub.2 -2-Fur1-485 Pip CH.sub.2 CH.sub.2 5-AcNH-2-Fur1-486 Pip CH.sub.2 CH.sub.2 5-Ph-2-Fur1-487 Pip CH.sub.2 CH.sub.2 5-(4-MePh)-2-Fur1-488 Pip CH.sub.2 CH.sub.2 5-(4-ClPh)-2-Fur1-489 Pip CH.sub.2 CH.sub.2 3-Me-5-NH.sub.2 -2-Fur1-490 Pip CH.sub.2 CH.sub.2 2,4-diMe-3-Fur1-491 Pip CH.sub.2 CH.sub.2 2-Thi1-492 Pip CH.sub.2 CH.sub.2 3-Thi1-493 Pip CH.sub.2 CH.sub.2 3-Me-2-Thi1-494 Pip CH.sub.2 CH.sub.2 5-Me-2-Thi1-495 Pip CH.sub.2 CH.sub.2 2-Me-3-Thi1-496 Pip CH.sub.2 CH.sub.2 4-Me-3-Thi1-497 Pip CH.sub.2 CH.sub.2 5-Me-3-Thi1-498 Pip CH.sub.2 CH.sub.2 4-MeO-2-Thi1-499 Pip CH.sub.2 CH.sub.2 4-MeO-3-Thi1-500 Pip CH.sub.2 CH.sub.2 4-HO-2-Thi1-501 Pip CH.sub.2 CH.sub.2 4-HO-3-Thi1-502 Pip CH.sub.2 CH.sub.2 5-Et-2-Thi1-503 Pip CH.sub.2 CH.sub.2 5-Cl-2-Thi1-504 Pip CH.sub.2 CH.sub.2 5-Cl-3-Thi1-505 Pip CH.sub.2 CH.sub.2 5-Br-3-Thi1-506 Pip CH.sub.2 CH.sub.2 3-NH.sub.2 -2-Thi1-507 Pip CH.sub.2 CH.sub.2 5-NH.sub.2 -2-Thi1-508 Pip CH.sub.2 CH.sub.2 2-NH.sub.2 -3-Thi1-509 Pip CH.sub.2 CH.sub.2 4-NH.sub.2 -3-Thi1-510 Pip CH.sub.2 CH.sub.2 3-AcNH-2-Thi1-511 Pip CH.sub.2 CH.sub.2 4-AcNH-3-Thi1-512 Pip CH.sub.2 CH.sub.2 5-Ph-2-Thi1-513 Pip CH.sub.2 CH.sub.2 4,5-diMe-2-Thi1-514 Pip CH.sub.2 CH.sub.2 3,5-diMe-2-Thi1-515 Pip CH.sub.2 CH.sub.2 2,5-diMe-3-Thi1-516 Pip CH.sub.2 CH.sub.2 4,5-diMe-3-Thi1-517 Pip CH.sub.2 CH.sub.2 4,5-diCl-2-Thi1-518 Pip CH.sub.2 CH.sub.2 2-NH.sub.2 -5-Ph-3-Thi1-519 Pip CH.sub.2 CH.sub.2 4-NH.sub.2 -2,5-diMe-3-Thi1-520 Pip CH.sub.2 CH.sub.2 2-Pyl1-521 Pip CH.sub.2 CH.sub.2 3-Pyl1-522 Pip CH.sub.2 CH.sub.2 1-Me-2-Pyl1-523 Pip CH.sub.2 CH.sub.2 3-Me-2-Pyl1-524 Pip CH.sub.2 CH.sub.2 4-Me-2-Pyl1-525 Pip CH.sub.2 CH.sub.2 2-Me-3-Pyl1-526 Pip CH.sub.2 CH.sub.2 5-Me-3-Pyl1-527 Pip CH.sub.2 CH.sub.2 3-NH.sub.2 -2-Pyl1-528 Pip CH.sub.2 CH.sub.2 4-NH.sub.2 -2-Pyl1-529 Pip CH.sub.2 CH.sub.2 3-AcNH-2-Pyl1-530 Pip CH.sub.2 CH.sub.2 5-Cl-2-Pyl1-531 Pip CH.sub.2 CH.sub.2 5-Cl-3-Pyl1-532 Pip CH.sub.2 CH.sub.2 4-Ph-2-Pyl1-533 Pip CH.sub.2 CH.sub.2 5-Ph-3-Pyl1-534 Pip CH.sub.2 CH.sub.2 1-Me-4-MeO-3-pyl1-535 Pip CH.sub.2 CH.sub.2 1-Me-4-HO-3-Pyl1-536 Pip CH.sub.2 CH.sub.2 3,5-diMe-2-Pyl1-537 Pip CH.sub.2 CH.sub.2 4,5-diMe-2-Pyl1-538 Pip CH.sub.2 CH.sub.2 1,3-diMe-2-Pyl1-539 Pip CH.sub.2 CH.sub.2 5-NH.sub.2 -1-Me-2-Pyl1-540 Pip CH.sub.2 CH.sub.2 4-NH.sub.2 -3,5-diMe-2-Pyl1-541 Pip CH.sub.2 CH.sub.2 5-Br-1,4-diMe-3-Pyl1-542 Pip CH.sub.2 CH.sub.2 4-Oxazo1-543 Pip CH.sub.2 CH.sub.2 5-Oxazo1-544 Pip CH.sub.2 CH.sub.2 2-Oxazo1-545 Pip CH.sub.2 CH.sub.2 2-Me-4-Oxazo1-546 Pip CH.sub.2 CH.sub.2 2-Ph-4-Oxazo1-547 Pip CH.sub.2 CH.sub.2 5-Ph-2-Oxazo1-548 Pip CH.sub.2 CH.sub.2 2-HO-4-Oxazo1-549 Pip CH.sub.2 CH.sub.2 2,5-diMe-4-Oxazo1-550 Pip CH.sub.2 CH.sub.2 4-Me-2-Ph-5-Oxazo1-551 Pip CH.sub.2 CH.sub.2 3-Isoxazo1-552 Pip CH.sub.2 CH.sub.2 4-Isoxazo1-553 Pip CH.sub.2 CH.sub.2 4-Me-3-Isoxazo1-554 Pip CH.sub.2 CH.sub.2 5-Me-3-Isoxazo1-555 Pip CH.sub.2 CH.sub.2 3-Me-4-Isoxazo1-556 Pip CH.sub.2 CH.sub.2 4-MeO-3-Isoxazo1-557 Pip CH.sub.2 CH.sub.2 4-HO-3-Isoxazo1-558 Pip CH.sub.2 CH.sub.2 3-HO-4-Isoxazo1-559 Pip CH.sub.2 CH.sub.2 3-HO-5-Isoxazo1-560 Pip CH.sub.2 CH.sub.2 4-NH.sub.2 -3-Isoxazo1-561 Pip CH.sub.2 CH.sub.2 5-NH.sub.2 -4-Isoxazo1-562 Pip CH.sub.2 CH.sub.2 5-Ph-3-Isoxazo1-563 Pip CH.sub.2 CH.sub.2 4-Ph-3-Isoxazo1-564 Pip CH.sub.2 CH.sub.2 4,5-diMe-3-Isoxazo1-565 Pip CH.sub.2 CH.sub.2 4-HO-5-Me-3-Isoxazo1-566 Pip CH.sub.2 CH.sub.2 2-Thiazo1-567 Pip CH.sub.2 CH.sub.2 4-Thiazo1-568 Pip CH.sub.2 CH.sub.2 5-Thiazo1-569 Pip CH.sub.2 CH.sub.2 4-Me-2-Thiazo1-570 Pip CH.sub.2 CH.sub.2 2-Me-4-Thiazo1-571 Pip CH.sub.2 CH.sub.2 2-Me-5-Thiazo1-572 Pip CH.sub.2 CH.sub.2 2-MeO-4-Thiazo1-573 Pip CH.sub.2 CH.sub.2 2-MeO-5-Thiazo1-574 Pip CH.sub.2 CH.sub.2 2-HO-4-Thiazo1-575 Pip CH.sub.2 CH.sub.2 2-HO-5-Thiazo1-576 Pip CH.sub.2 CH.sub.2 2-Cl-5-Thiazo1-577 Pip CH.sub.2 CH.sub.2 5-Cl-2-Thiazo1-578 Pip CH.sub.2 CH.sub.2 2-NH 4-Thiazo1-579 Pip CH.sub.2 CH.sub.2 2-NH.sub.2 -5-Thiazo1-580 Pip CH.sub.2 CH.sub.2 5-NH.sub.2 -4-Thiazo1-581 Pip CH.sub.2 CH.sub.2 2-AcNH-4-Thiazo1-582 Pip CH.sub.2 CH.sub.2 5-AcNH-4-Thiazo1-583 Pip CH.sub.2 CH.sub.2 2-Ph-4-Thiazo1-584 Pip CH.sub.2 CH.sub.2 4,5-diMe-2-Thiazo1-585 Pip CH.sub.2 CH.sub.2 2-HO-5-Me-4-Thiazo1-586 Pip CH.sub.2 CH.sub.2 5-NH.sub.2 -2-Me-4-Thiazo1-587 Pip CH.sub.2 CH.sub.2 2-Cl-4-Me-5-Thiazo1-588 Pip CH.sub.2 CH.sub.2 3-Isothiazo1-589 Pip CH.sub.2 CH.sub.2 4-Isothiazo1-590 Pip CH.sub.2 CH.sub.2 3-Pyrazo1-591 Pip CH.sub.2 CH.sub.2 4-Pyrazo1-592 Pip CH.sub.2 CH.sub.2 1-Me-3-Pyrazo1-593 Pip CH.sub.2 CH.sub.2 1-Et-3-Pyrazo1-594 Pip CH.sub.2 CH.sub.2 1-Pr-3-Pyrazo1-595 Pip CH.sub.2 CH.sub.2 1-Me-4-Pyrazo1-596 Pip CH.sub.2 CH.sub.2 1-Et-4-Pyrazo1-597 Pip CH.sub.2 CH.sub.2 1-Pr-4-Pyrazo1-598 Pip CH.sub.2 CH.sub.2 1-Bu-4-Pyrazo1-599 Pip CH.sub.2 CH.sub.2 4-Me-3-Pyrazo1-600 Pip CH.sub.2 CH.sub.2 5-Me-3-Pyrazo1-601 Pip CH.sub.2 CH.sub.2 5-Et-3-Pyrazo1-602 Pip CH.sub.2 CH.sub.2 5-Pr-3-Pyrazo1-603 Pip CH.sub.2 CH.sub.2 5-Me-4-Pyrazo1-604 Pip CH.sub.2 CH.sub.2 4-MeO-3-Pyrazo1-605 Pip CH.sub.2 CH.sub.2 4-PrO-3-Pyrazo1-606 Pip CH.sub.2 CH.sub.2 4-HO-3-Pyrazo1-607 Pip CH.sub.2 CH.sub.2 4-Cl-3-Pyrazo1-608 Pip CH.sub.2 CH.sub.2 4-Br-3-Pyrazo1-609 Pip CH.sub.2 CH.sub.2 3-Cl-4-Pyrazo1-610 Pip CH.sub.2 CH.sub.2 4-NH.sub.2 -3-Pyrazo1-611 Pip CH.sub.2 CH.sub.2 5-NH.sub.2 -3-Pyrazo1-612 Pip CH.sub.2 CH.sub.2 3-NH.sub.2 -4-Pyrazo1-613 Pip CH.sub.2 CH.sub.2 4-AcNH-3-Pyrazo1-614 Pip CH.sub.2 CH.sub.2 5-AcNH-3-Pyrazo1-615 Pip CH.sub.2 CH.sub.2 3-AcNH-4-Pyrazo1-616 Pip CH.sub.2 CH.sub.2 3-EtCONH-4-Pyrazo1-617 Pip CH.sub.2 CH.sub.2 5-Ph-3-Pyrazo1-618 Pip CH.sub.2 CH.sub.2 1,5-diMe-3-Pyrazo1-619 Pip CH.sub.2 CH.sub.2 1,4-diMe-3-Pyrazo1-620 Pip CH.sub.2 CH.sub.2 4,5-diMe-3-Pyrazo1-621 Pip CH.sub.2 CH.sub.2 3-Me-4-Pyrazo1-622 Pip CH.sub.2 CH.sub.2 3,5-diMe-4-Pyrazo1-623 Pip CH.sub.2 CH.sub.2 1,5-diMe-4-Pyrazo1-624 Pip CH.sub.2 CH.sub.2 1,3-diMe-4-Pyrazo1-625 Pip CH.sub.2 CH.sub.2 1,3-diMe-5-Pyrazo1-626 Pip CH.sub.2 CH.sub.2 3-Cl-5-Me-4-Pyrazo1-627 Pip CH.sub.2 CH.sub.2 3-Cl-1-Me-4-Pyrazo1-628 Pip CH.sub.2 CH.sub.2 5-Cl-1-Me-4-Pyrazo1-629 Pip CH.sub.2 CH.sub.2 4-Cl-1-Me-3-Pyrazo1-630 Pip CH.sub.2 CH.sub.2 4-Cl-5-Me-3-Pyrazo1-631 Pip CH.sub.2 CH.sub.2 4-Cl-1-Me-3-Pyrazo1-632 Pip CH.sub.2 CH.sub.2 3-NH.sub.2 -5-Me-4-Pyrazo1-633 Pip CH.sub.2 CH.sub.2 3-NH.sub.2 -1-Me-4-Pyrazo1-634 Pip CH.sub.2 CH.sub.2 5-NH.sub.2 -1-Me-4-Pyrazo1-635 Pip CH.sub.2 CH.sub.2 5-NH.sub.2 -4-Me-3-Pyrazo1-636 Pip CH.sub.2 CH.sub.2 5-NH.sub.2 -1-Me-3-Pyrazo1-637 Pip CH.sub.2 CH.sub.2 5-AcNH-1-Me-4-Pyrazo1-638 Pip CH.sub.2 CH.sub.2 4-NH.sub.2 -5-Me-3-Pyrazo1-639 Pip CH.sub.2 CH.sub.2 4-HO-5-Me-3-Pyrazo1-640 Pip CH.sub.2 CH.sub.2 5-AcNH-3-Me-4-Pyrazo1-641 Pip CH.sub.2 CH.sub.2 1,3,5-triMe-4-Pyrazo1-642 Pip CH.sub.2 CH.sub.2 1,3,4-triMe-5-Pyrazo1-643 Pip CH.sub.2 CH.sub.2 4-Cl-1,3-diMe-5-Pyrazo1-644 Pip CH.sub.2 CH.sub.2 2-Imidazo1-645 Pip CH.sub.2 CH.sub.2 4-Imidazo1-646 Pip CH.sub.2 CH.sub.2 2-Me-4-Imidazo1-647 Pip CH.sub.2 CH.sub.2 1-Me-4-Imidazo1-648 Pip CH.sub.2 CH.sub.2 5-Me-4-Imidazo1-649 Pip CH.sub.2 CH.sub.2 5-Me-2-Imidazo1-650 Pip CH.sub.2 CH.sub.2 1-Me-2-Imidazo1-651 Pip CH.sub.2 CH.sub.2 1,2,3-Oxadiazo-5-yl1-652 Pip CH.sub.2 CH.sub.2 1,3,4-Oxadiazo-2-yl1-653 Pip CH.sub.2 CH.sub.2 1,2,3-Oxadiazo-4-yl1-654 Pip CH.sub.2 CH.sub.2 1,2,4-Oxadiazo-5-yl1-655 Pip CH.sub.2 CH.sub.2 1,2,4-Oxadiazo-3-yl1-656 Pip CH.sub.2 CH.sub.2 1,2,5-Oxadiazo-3-yl1-657 Pip CH.sub.2 CH.sub.2 5-Me-1,2,3-Oxadiazo-4-yl1-658 Pip CH.sub.2 CH.sub.2 4-Me-1,2,5-Oxadiazo-3-yl1-659 Pip CH.sub.2 CH.sub.2 4-Ph-1,2,5-Oxadiazo-3-yl1-660 Pip CH.sub.2 CH.sub.2 1,2,3-Thiadiazo-4-yl1-661 Pip CH.sub.2 CH.sub.2 1,2,3-Thiadiazo-5-yl1-662 Pip CH.sub.2 CH.sub.2 1,3,4-Thiadiazo-2-yl1-663 Pip CH.sub.2 CH.sub.2 1,2,4-Thiadiazo-3-yl1-664 Pip CH.sub.2 CH.sub.2 1,2,4-Thiadiazo-5-yl1-665 Pip CH.sub.2 CH.sub.2 1,2,5-Thiadiazo-3-yl1-666 Pip CH.sub.2 CH.sub.2 4-Me-1,2,3-Thiadiazo-5-yl1-667 Pip CH.sub.2 CH.sub.2 5-Me-1,2,3-Thiadiazo-4-yl1-668 Pip CH.sub.2 CH.sub.2 4-Me-1,2,5-Thiadiazo-3-yl1-669 Pip CH.sub.2 CH.sub.2 5-Ph-1,2,3-Thiadiazo-4-yl1-670 Pyr CH.sub.2 CH.sub.2 2-Fur1-671 Pyr CH.sub.2 CH.sub.2 3-Fur1-672 Pyr CH.sub.2 CH.sub.2 4-Me-2-Fur1-673 Pyr CH.sub.2 CH.sub.2 2-Me-3-Fur1-674 Pyr CH.sub.2 CH.sub.2 2,4-diMe-3-Fur1-675 Pyr CH.sub.2 CH.sub.2 2-Thi1-676 Pyr CH.sub.2 CH.sub.2 3-Thi1-677 Pyr CH.sub.2 CH.sub.2 3-Me-2-Thi1-678 Pyr CH.sub.2 CH.sub.2 2-Me-3-Thi1-679 Pyr CH.sub.2 CH.sub.2 4-Me-3-Thi1-680 Pyr CH.sub.2 CH.sub.2 4-MeO-3-Thi1-681 Pyr CH.sub.2 CH.sub.2 4-HO-2-Thi1-682 Pyr CH.sub.2 CH.sub.2 5-Cl-3-Thi1-683 Pyr CH.sub.2 CH.sub.2 3-NH.sub.2 -2-Thi1-684 Pyr CH.sub.2 CH.sub.2 2-NH.sub.2 -3-Thi1-685 Pyr CH.sub.2 CH.sub.2 3-AcNH-2-Thi1-686 Pyr CH.sub.2 CH.sub.2 5-Ph-2-Thi1-687 Pyr CH.sub.2 CH.sub.2 4,5-diMe-2-Thi1-688 Pyr CH.sub.2 CH.sub.2 2,5-diMe-3-Thi1-689 Pyr CH.sub.2 CH.sub.2 4,5-diCl-2-Thi1-690 Pyr CH.sub.2 CH.sub.2 4-NH.sub.2 -2,5-diMe-3-Thi1-691 Pyr CH.sub.2 CH.sub.2 2-Pyl1-692 Pyr CH.sub.2 CH.sub.2 3-Pyl1-693 Pyr CH.sub.2 CH.sub.2 1-Me-2-Pyl1-694 Pyr CH.sub.2 CH.sub.2 3-Me-2-Pyl1-695 Pyr CH.sub.2 CH.sub.2 4-Me-2-Pyl1-696 Pyr CH.sub.2 CH.sub.2 2-Me-3-Pyl1-697 Pyr CH.sub.2 CH.sub.2 1-Me-4-MeO-3-Pyl1-698 Pyr CH.sub.2 CH.sub.2 1-Me-4-HO-3-Pyl1-699 Pyr CH.sub.2 CH.sub.2 3,5-diMe-2-Pyl1-700 Pyr CH.sub.2 CH.sub.2 1,3-diMe-2-Pyl1-701 Pyr CH.sub.2 CH.sub.2 4-Oxazo1-702 Pyr CH.sub.2 CH.sub.2 5-Oxazo1-703 Pyr CH.sub.2 CH.sub.2 2-Oxazo1-704 Pyr CH.sub.2 CH.sub.2 2-Me-4-Oxazo1-705 Pyr CH.sub.2 CH.sub.2 5-Ph-2-Oxazo1-706 Pyr CH.sub.2 CH.sub.2 2,5-d.iMe-4-Oxazo1-707 Pyr CH.sub.2 CH.sub.2 3-Isoxazo1-708 Pyr CH.sub.2 CH.sub.2 4-Isoxazo1-709 Pyr CH.sub.2 CH.sub.2 5-Me-3-Isoxazo1-710 Pyr CH.sub.2 CH.sub.2 3-Me-4-Isoxazo1-711 Pyr CH.sub.2 CH.sub.2 4-MeO-3-Isoxazo1-712 Pyr CH.sub.2 CH.sub.2 4-HO-3-Isoxazo1-713 Pyr CH.sub.2 CH.sub.2 3-HO-5-Isoxazo1-714 Pyr CH.sub.2 CH.sub.2 5-HO-4-Isoxazo1-715 Pyr CH.sub.2 CH.sub.2 4-NH.sub.2 -3-Isoxazo1-716 Pyr CH.sub.2 CH.sub.2 5-Ph-3-Isoxazo1-717 Pyr CH.sub.2 CH.sub.2 4,5-diMe-3-Isoxazo1-718 Pyr CH.sub.2 CH.sub.2 4-HO-5-Me-3-Isoxazo1-719 Pyr CH.sub.2 CH.sub.2 2-Thiazo1-720 Pyr CH.sub.2 CH.sub.2 4-Thiazo1-721 Pyr CH.sub.2 CH.sub.2 5-Thiazo1-722 Pyr CH.sub.2 CH.sub.2 4-Me-2-Thiazo1-723 Pyr CH.sub.2 CH.sub.2 2-Me-5-Thiazo1-724 Pyr CH.sub.2 CH.sub.2 2-MeO-4-Thiazo1-725 Pyr CH.sub.2 CH.sub.2 2-MeO-5-Thiazo1-726 Pyr CH.sub.2 CH.sub.2 2-HO-5-Thiazo1-727 Pyr CH.sub.2 CH.sub.2 5-Cl-2-Thiazo1-728 Pyr CH.sub.2 CH.sub.2 2-NH.sub.2 -4-Thiazo1-729 Pyr CH.sub.2 CH.sub.2 2-AcNH-4-Thiazo1-730 Pyr CH.sub.2 CH.sub.2 4,5-diMe-2-Thiazo1-731 Pyr CH.sub.2 CH.sub.2 2-HO-5-Me-4-Thiazo1-732 Pyr CH.sub.2 CH.sub.2 5-NH.sub.2 -2-Me-4-Thiazo1-733 Pyr CH.sub.2 CH.sub.2 3-Isothiazo1-734 Pyr CH.sub.2 CH.sub.2 4-Isothiazo1-735 Pyr CH.sub.2 CH.sub.2 3-Pyrazo1-736 Pyr CH.sub.2 CH.sub.2 4-Pyrazo1-737 Pyr CH.sub.2 CH.sub.2 1-Me-3-Pyrazo1-738 Pyr CH.sub.2 CH.sub.2 1-Et-3-Pyrazo1-739 Pyr CH.sub.2 CH.sub.2 1-Me-4-Pyrazo1-740 Pyr CH.sub.2 CH.sub.2 1-Et-4-Pyrazo1-741 Pyr CH.sub.2 CH.sub.2 4-Me-3-Pyrazo1-742 Pyr CH.sub.2 CH.sub.2 5-Me-3-Pyrazo1-743 Pyr CH.sub.2 CH.sub.2 5-Me-4-Pyrazo1-744 Pyr CH.sub.2 CH.sub.2 4-MeO-3-Pyrazo1-745 Pyr CH.sub.2 CH.sub.2 4-HO-3-Pyrazo1-746 Pyr CH.sub.2 CH.sub.2 4-Cl-3-Pyrazo1-747 Pyr CH.sub.2 CH.sub.2 4-NH.sub.2 -3-Pyrazo1-748 Pyr CH.sub.2 CH.sub.2 5-NH.sub.2 -3-Pyrazo1-749 Pyr CH.sub.2 CH.sub.2 3-NH.sub.2 -4-Pyrazo1-750 Pyr CH.sub.2 CH.sub.2 4-AcNH-3-Pyrazo1-751 Pyr CH.sub.2 CH.sub.2 5-Ph-3-Pyrazo1-752 Pyr CH.sub.2 CH.sub.2 1,5-diMe-3-Pyrazo1-753 Pyr CH.sub.2 CH.sub.2 1,4-diMe-3-Pyrazo1-754 Pyr CH.sub.2 CH.sub.2 3,5-diMe-4-Pyrazo1-755 Pyr CH.sub.2 CH.sub.2 1,5-diMe-4-Pyrazo1-756 Pyr CH.sub.2 CH.sub.2 1,3-diMe-4-Pyrazo1-757 Pyr CH.sub.2 CH.sub.2 1,3-diMe-5-Pyrazo1-758 Pyr CH.sub.2 CH.sub.2 3-Cl-5-Me-4-Pyrazo1-759 Pyr CH.sub.2 CH.sub.2 3-Cl-1-Me-4-Pyrazo1-760 Pyr CH.sub.2 CH.sub.2 4-Cl-5-Me-3-Pyrazo1-761 Pyr CH.sub.2 CH.sub.2 4-Cl-1-Me-3-Pyrazo1-762 Pyr CH.sub.2 CH.sub.2 3-NH.sub.2 -5-Me-4-Pyrazo1-763 Pyr CH.sub.2 CH.sub.2 3-NH.sub.2 -1-Me-4-Pyrazo1-764 Pyr CH.sub.2 CH.sub.2 5-NH.sub.2 -1-Me-4-Pyrazo1-765 Pyr CH.sub.2 CH.sub.2 5-NH.sub.2 -4-Me-3-Pyrazo1-766 Pyr CH.sub.2 CH.sub.2 5-NH.sub.2 -1-Me-3-Pyrazo1-767 Pyr CH.sub.2 CH.sub.2 5-NH.sub.2 -3-Me-4-Pyrazo1-768 Pyr CH.sub.2 CH.sub.2 4-NH.sub.2 -5-Me-3-Pyrazo1-769 Pyr CH.sub.2 CH.sub.2 4-HO-5-Me-3-Pyrazo1-770 Pyr CH.sub.2 CH.sub.2 1,3,5-triMe-4-Pyrazo1-771 Pyr CH.sub.2 CH.sub.2 1,3,4-triMe-5-Pyrazo1-772 Pyr CH.sub.2 CH.sub.2 4-Cl-1,3-diMe-5-Pyrazo1-773 Pyr CH.sub.2 CH.sub.2 2-Imidazo1-774 Pyr CH.sub.2 CH.sub.2 4-Imidazo1-775 Pyr CH.sub.2 CH.sub.2 1-Me-4-Imidazo1-776 Pyr CH.sub.2 CH.sub.2 5-Me-4-Imidazo1-777 Pyr CH.sub.2 CH.sub.2 5-Me-2-Imidazo1-778 Pyr CH.sub.2 CH.sub.2 1-Me-2-Imidazo1-779 Pyr CH.sub.2 CH.sub.2 1,2,3-Oxadiazo-5-yl1-780 Pyr CH.sub.2 CH.sub.2 1,2,4-Oxadiazo-5-yl1-781 Pyr CH.sub.2 CH.sub.2 1,2,5-Oxadiazo-3-yl1-782 Pyr CH.sub.2 CH.sub.2 5-Me-1,2,3-Oxadiazo-4-yl1-783 Pyr CH.sub.2 CH.sub.2 1,2,3-Thiadiazo-4-yl1-784 Pyr CH.sub.2 CH.sub.2 1,2,4-Thiadiazo-3-yl1-785 Pyr CH.sub.2 CH.sub.2 1,2,5-Thiadiazo-3-yl1-786 Pyr CH.sub.2 CH.sub.2 4-Me-1,2,3-Thiadiazo-5-yl1-787 Pyr CH.sub.2 CH.sub.2 5-Ph-1,2,3-Thiadiaio-4-yl1-788 NMe.sub.2 CH.sub.2 CH.sub.2 2-Fur1-789 NMe.sub.2 CH.sub.2 CH.sub.2 3-Fur1-790 NMe.sub.2 CH.sub.2 CH.sub.2 4-Me-2-Fur1-791 NMe.sub.2 CH.sub.2 CH.sub.2 2,4-diMe-3-Fur1-792 NMe.sub.2 CH.sub.2 CH.sub.2 2-Thi1-793 NMe.sub.2 CH.sub.2 CH.sub.2 3-Thi1-794 NMe.sub.2 CH.sub.2 CH.sub.2 3-Me-2-Thi1-795 NMe.sub.2 CH.sub.2 CH.sub.2 2-Me-3-Thi1-796 NMe.sub.2 CH.sub.2 CH.sub.2 4-MeO-3-Thi1-797 NMe.sub.2 CH.sub.2 CH.sub.2 4,5-diMe-2-Thi1-798 NMe.sub.2 CH.sub.2 CH.sub.2 2-Pyl1-799 NMe.sub.2 CH.sub.2 CH.sub.2 3-Pyl1-800 NMe.sub.2 CH.sub.2 CH.sub.2 1-Me-2-Pyl1-801 NMe.sub.2 CH.sub.2 CH.sub.2 4-Me-2-Pyl1-802 NMe.sub.2 CH.sub.2 CH.sub.2 2-Me-3-Pyl1-803 NMe.sub.2 CH.sub.2 CH.sub.2 3,5-diMe-2-Pyl1-804 NMe.sub.2 CH.sub.2 CH.sub.2 1,3-diMe-2-Pyl1-805 NMe.sub.2 CH.sub.2 CH.sub.2 4-Oxazo1-806 NMe.sub.2 CH.sub.2 CH.sub.2 5-Oxazo1-807 NMe.sub.2 CH.sub.2 CH.sub.2 2-Oxazo1-808 NMe.sub.2 CH.sub.2 CH.sub.2 2-Me-4-Oxazo1-809 NMe.sub.2 CH.sub.2 CH.sub.2 2,5-diMe-4-Oxazo1-810 NMe.sub.2 CH.sub.2 CH.sub.2 3-Isoxazo1-811 NMe.sub.2 CH.sub.2 CH.sub.2 4-Isoxazo1-812 NMe.sub.2 CH.sub.2 CH.sub.2 5-Me-3-Isoxazo1-813 NMe.sub.2 CH.sub.2 CH.sub.2 4-MeO-3-Isoxazo1-814 NMe.sub.2 CH.sub.2 CH.sub.2 4-HO-3-Isoxazo1-815 NMe.sub.2 CH.sub.2 CH.sub.2 4,5-diMe-3-Isoxazo1-816 NMe.sub.2 CH.sub.2 CH.sub.2 4-HO-5-Me-3-Isoxazo1-817 NMe.sub.2 CH.sub.2 CH.sub.2 2-Thiazo1-818 NMe.sub.2 CH.sub.2 CH.sub.2 4-Thiazo1-819 NMe.sub.2 CH.sub.2 CH.sub.2 5-Thiazo1-820 NMe.sub.2 CH.sub.2 CH.sub.2 4-Me-2-Thiazo1-821 NMe.sub.2 CH.sub.2 CH.sub.2 2-Me-5-Thiazo1-822 NMe.sub.2 CH.sub.2 CH.sub.2 2-MeO-4-Thiazo1-823 NMe.sub.2 CH.sub.2 CH.sub.2 4,5-diMe-2-Thiazo1-824 NMe.sub.2 CH.sub.2 CH.sub.2 3-Isothiazo1-825 NMe.sub.2 CH.sub.2 CH.sub.2 4-Isothiazo1-826 NMe.sub.2 CH.sub.2 CH.sub.2 3-Pyrazo1-827 NMe.sub.2 CH.sub.2 CH.sub.2 4-Pyrazo1-828 NMe.sub.2 CH.sub.2 CH.sub.2 1-Me-3-Pyrazo1-829 NMe.sub.2 CH.sub.2 CH.sub.2 1-Me-4-Pyrazo1-830 NMe.sub.2 CH.sub.2 CH.sub.2 4-Me-3-Pyrazo1-831 NMe.sub.2 CH.sub.2 CH.sub.2 5-Me-3-Pyrazo1-832 NMe.sub.2 CH.sub.2 CH.sub.2 5-Me-4-Pyrazo1-833 NMe.sub.2 CH.sub.2 CH.sub.2 4-MeO-3-Pyrazo1-834 NMe.sub.2 CH.sub.2 CH.sub.2 4-HO-3-Pyrazo1-835 NMe.sub.2 CH.sub.2 CH.sub.2 3,5-diMe-4-Pyrazo1-836 NMe.sub.2 CH.sub.2 CH.sub.2 1,3,5-triMe-4-Pyrazo1-837 NMe.sub.2 CH.sub.2 CH.sub.2 1,3,4-triMe-5-Pyrazo1-838 NMe.sub.2 CH.sub.2 CH.sub.2 2-Imidazo1-839 NMe.sub.2 CH.sub.2 CH.sub.2 4-Imidazo1-840 NMe CH.sub.2 CH.sub.2 5-Me-4-Imidazo1-841 Azi CH.sub.2 CH.sub.2 2-Fur1-842 Azi CH.sub.2 CH.sub.2 3-Fur1-843 Azi CH.sub.2 CH.sub.2 4-Me-2-Fur1-844 Azi CH.sub.2 CH.sub.2 2-Thi1-845 Azi CH.sub.2 CH.sub.2 3-Thi1-846 Azi CH.sub.2 CH.sub.2 5-Me-2-Thi1-847 Azi CH.sub.2 CH.sub.2 2-Pyl1-848 Azi CH.sub.2 CH.sub.2 3-Pyl1-849 Azi CH.sub.2 CH.sub.2 1-Me-2-Pyl1-850 Azi CH.sub.2 CH.sub.2 4-Me-2-Pyl1-851 Azi CH.sub.2 CH.sub.2 4-Oxazo1-852 Azi CH.sub.2 CH.sub.2 5-Oxazo1-853 Azi CH.sub.2 CH.sub.2 2-Oxazo1-854 Azi CH.sub.2 CH.sub.2 3-Isoxazo1-855 Azi CH.sub.2 CH.sub.2 4-Isoxazo1-856 Azi CH.sub.2 CH.sub.2 4-HO-3-Isoxazo1-857 Azi CH.sub.2 CH.sub.2 2-Thiazo1-858 Azi CH.sub.2 CH.sub.2 4-Thiazo1-859 Azi CH.sub.2 CH.sub.2 5-Thiazo1-860 Azi CH.sub.2 CH.sub.2 2-Me-5-Thiazo1-861 Azi CH.sub.2 CH.sub.2 3-Pyrazo1-862 Azi CH.sub.2 CH.sub.2 4-Pyrazo1-863 Azi CH.sub.2 CH.sub.2 1-Me-3-Pyrazo1-864 Azi CH.sub.2 CH.sub.2 4-Me-3-Pyrazo1-865 Azi CH.sub.2 CH.sub.2 5-Me-4-Pyrazo1-866 Azi CH.sub.2 CH.sub.2 4-NH.sub.2 -3-Pyrazo1-867 Azi CH.sub.2 CH.sub.2 3-NH.sub.2 -4-Pyrazo1-868 Azi CH.sub.2 CH.sub.2 3,5-diMe-4-Pyrazo1-869 Azi CH.sub.2 CH.sub.2 1,3,5-triMe-4-Pyrazo1-870 Azi CH.sub.2 CH.sub.2 2-Imidazo1-871 Azi CH.sub.2 CH.sub.2 4-Imidazo1-872 Azi CH.sub.2 CH.sub.2 5-Me-4-Imidazo1-873 Aze CH.sub.2 CH.sub.2 2-Fur1-874 Aze CH.sub.2 CH.sub.2 3-Fur1-875 Aze CH.sub.2 CH.sub.2 4-Me-2-Fur1-876 Aze CH.sub.2 CH.sub.2 2-Thi1-877 Aze CH.sub.2 CH.sub.2 3-Thi1-878 Aze CH.sub.2 CH.sub.2 5-Me-2-Thi1-879 Aze CH.sub.2 CH.sub.2 2-Pyl1-880 Aze CH.sub.2 CH.sub.2 3-Pyl1-881 Aze CH.sub.2 CH.sub.2 1-Me-2-Pyl1-882 Aze CH.sub.2 CH.sub.2 4-Me-2-Pyl1-883 Aze CH.sub.2 CH.sub.2 4-Oxazo1-884 Aze CH.sub.2 CH.sub.2 5-Oxazo1-885 Aze CH.sub.2 CH.sub.2 2-Oxazo1-886 Aze CH.sub.2 CH.sub.2 3-Isoxazo1-887 Aze CH.sub.2 CH.sub.2 4-Isoxazo1-888 Aze CH.sub.2 CH.sub.2 4-HO-3-Isoxazo1-889 Aze CH.sub.2 CH.sub.2 2-Thiazo1-890 Aze CH.sub.2 CH.sub.2 4-Thiazo1-891 Aze CH.sub.2 CH.sub.2 5-Thiazo1-892 Aze CH.sub.2 CH.sub.2 2-Me-5-Thiazo1-893 Aze CH.sub.2 CH.sub.2 3-Pyrazo1-894 Aze CH.sub.2 CH.sub.2 4-Pyrazo1-895 Aze CH.sub.2 CH.sub.2 1-Me-3-Pyrazo1-896 Aze CH.sub.2 CH.sub.2 4-Me-3-Pyrazo1-897 Aze CH.sub.2 CH.sub.2 5-Me-4-Pyrazo1-898 Aze CH.sub.2 CH.sub.2 4-NH.sub.2 -3-Pyrazo1-899 Aze CH.sub.2 CH.sub.2 3-NH.sub.2 -4-Pyrazo1-900 Aze CH.sub.2 CH.sub.2 3,5-diMe-4-Pyrazo1-901 Aze CH.sub.2 CH.sub.2 1,3,5-triMe-4-Pyrazo1-902 Aze CH.sub.2 CH.sub.2 2-Imidazo1-903 Aze CH.sub.2 CH.sub.2 4-Imidazo1-904 Aze CH.sub.2 CH.sub.2 5-Me-4-Imidazo1-905 Pip CH.sub.2 CH.sub.2 1,2,3-Triazo-4-yl1-906 Pip CH.sub.2 CH.sub.2 1-Me-1,2,3-Triazo-4-yl1-907 Pip CH.sub.2 CH.sub.2 5-Me-1,2,3-Triazo-4-yl1-908 Pip CH.sub.2 CH.sub.2 1,5-diMe-1,2,3-Triazo-4-yl1-909 Pip CH.sub.2 CH.sub.2 1,2,4-Triazo-5-yl1-910 Pip CH.sub.2 CH.sub.2 1-Me-1,2,5-Triazo-3-yl1-911 Pyr CH.sub.2 CH.sub.2 1,2,3-Triazo-4-yl1-912 Pyr CH.sub.2 CH.sub.2 1,2,4-Triazo-5-yl1-913 NMe.sub.2 CH.sub.2 CH.sub.2 1,2,3-Triazo-4-yl1-914 NMe.sub.2 CH.sub.2 CH.sub.2 1,2,4-Triazo-5-yl1-915 Pip CH.sub.2 1,2,3-Triazo-4-yl1-916 Pip CH.sub.2 2-Fur1-917 Pip CH.sub.2 3-Fur1-918 Pip CH.sub.2 4-Me-2-Fur1-919 Pip CH.sub.2 2,4-diMe-3-Fur1-920 Pip CH.sub.2 2-Thi1-921 Pip CH.sub.2 3-Thi1-922 Pip CH.sub.2 3-Me-2-Thi1-923 Pip CH.sub.2 2-Me-3-Thi1-924 Pip CH.sub.2 4-MeO-3-Thi1-925 Pip CH.sub.2 4,5-diMe-2-Thi1-926 Pip CH.sub.2 2-Pyl1-927 Pip CH.sub.2 3-Pyl1-928 Pip CH.sub.2 1-Me-2-Pyl1-929 Pip CH.sub.2 4-Me-2-Pyl1-930 Pip CH.sub.2 2-Me-3-Pyl1-931 Pip CH.sub.2 3,5-diMe-2-Pyl1-932 Pip CH.sub.2 1,3-diMe-2-Pyl1-933 Pip CH.sub.2 5-NH.sub.2 -1-Me-2-Pyl1-934 Pip CH.sub.2 4-Oxazo1-935 Pip CH.sub.2 5-Oxazo1-936 Pip CH.sub.2 2-Oxazo1-937 Pip CH.sub.2 2-Me-4-Oxazo1-938 Pip CH.sub.2 2,5-diMe-4-Oxazo1-939 Pip CH.sub.2 3-Isoxazo1-940 Pip CH.sub.2 4-Isoxazo1-941 Pip CH.sub.2 5-Me-3-Isoxazo1-942 Pip CH.sub.2 4,5-diMe-3-Isoxazo1-943 Pip CH.sub.2 2-Thiazo1-944 Pip CH.sub.2 4-Thiazo1-945 Pip CH.sub.2 5-Thiazo1-946 Pip CH.sub.2 2-Me-5-Thiazo1-947 Pip CH.sub.2 4,5-diMe-2-Thiazo1-948 Pip CH.sub.2 3-Isothiazo1-949 Pip CH.sub.2 4-Isothiazo1-950 Pip CH.sub.2 3-Pyrazo1-951 Pip CH.sub.2 4-Pyrazo1-952 Pip CH.sub.2 1-Me-3-Pyrazo1-953 Pip CH.sub.2 1-Me-4-Pyrazo1-954 Pip CH.sub.2 4-Me-3-Pyrazo1-955 Pip CH.sub.2 5-Me-3-Pyrazo1-956 Pip CH.sub.2 5-Me-4-Pyrazo1-957 Pip CH.sub.2 4-MeO-3-Pyrazo1-958 Pip CH.sub.2 4-HO-3-Pyrazo1-959 Pip CH.sub.2 4-Cl-3-Pyrazo1-960 Pip CH.sub.2 4-NH.sub.2 -3-Pyrazo1-961 Pip CH.sub.2 5-NH.sub.2 -3-Pyrazo1-962 Pip CH.sub.2 3-NH.sub.2 -4-Pyrazo1-963 Pip CH.sub.2 5-Ph-3-Pyrazo1-964 Pip CH.sub.2 3,5-diMe-4-Pyrazo1-965 Pip CH.sub.2 3-NH.sub.2 -5-Me-4-Pyrazo1-966 Pip CH.sub.2 5-NH.sub.2 -4-Me-3-Pyrazo1-967 Pip CH.sub.2 5-NH.sub.2 -3-Me-3-Pyrazo1-968 Pip CH.sub.2 4-NH.sub.2 -5-Me-3-Pyrazo1-969 Pip CH.sub.2 1,3,5-triMe-4-Pyrazo1-970 Pip CH.sub.2 1,3,4-triMe-5-Pyrazo1-971 Pip CH.sub.2 2-Imidazo1-972 Pip CH.sub.2 4-Imidazo1-973 Pip CH.sub.2 5-Me-4-Imidazo1-974 Pip CH.dbd.CH NHiPr1-975 Pip CH.dbd.CH NHsBu1-976 Pip CH.dbd.CH NH(1-MeBu)1-977 Pip CH.dbd.CH NH(1,2-diMePr)1-978 Pip CH.dbd.CH NH(1-MePn)1-979 Pip CH.dbd.CH NH(1,3-diMeBu)1-980 Pip CH.dbd.CH NH(1,2-diMeBu)1-981 Pip CH.dbd.CH NH(1-MeHx)1-982 Pip CH.dbd.CH NH(1,4-diMePn)1-983 Pip CH.dbd.CH NH(1-MeHp)1-984 Pip CH.dbd.CH NH(1,5-diMeHx)1-985 Pip CH.dbd.CH NH(1-EtPr)1-986 Pip CH.dbd.CH NH(1-EtBu)1-987 Pip CH.dbd.CH NH(1-Et-2-MePr)1-988 Pip CH.dbd.CH NH(1-EtPn)1-989 Pip CH.dbd.CH NH(1-Et-3-MeBu)1-990 Pip CH.dbd.CH NH(1-EtHx)1-991 Pip CH.dbd.CH NH(1-EtHp)1-992 Pip CH.dbd.CH NH(1-PrBu)1-993 Pip CH.dbd.CH NH(1-iPrBu)1-994 Pip CH.dbd.CH NH(1-PrPn)1-995 Pip CH.dbd.CH NH(1-PrHx)1-996 Pip CH.dbd.CH NH(1-PrHp)1-997 Pip CH.dbd.CH NH(1-BuPn)1-998 Pip CH.dbd.CH NH(1-PnHx)1-999 Pip CH.dbd.CH NH(1-HxHp)1-1000 Pip CH.dbd.CH NH(1-PhEt)1-1001 Pip CH.dbd.CH NH(1-NaPhEt)1-1002 Pip CH.dbd.CH NH(1-PhPr)1-1003 Pip CH.dbd.CH NH(1-PhBu)1-1004 Pip CH.dbd.CH NHCHPh.sub.21-1005 Pip CH.dbd.CH NHCHPh(4-MePh)1-1006 Pip CH.dbd.CH NHCHPh(4-MeOPh)1-1007 Pip CH.dbd.CH NHCHPh(4-FPh)1-1008 Pip CH.dbd.CH NHCHPh(4-ClPh)1-1009 Pip CH.dbd.CH NH(1-Me-2-PhEt)1-1010 Pip CH.dbd.CH NH(1-Me-3-PhPr)1-1011 Pip CH.dbd.CH NH(1-Et-2-PhEt)1-1012 Pip CH.dbd.CH NH[1-Me-2-(4-MePh)Et]1-1013 Pip CH.dbd.CH NH[1-Me-2-(4-MeOPh)Et]1-1014 Pip CH.dbd.CH NH[1-Me-2-(4-FPh)Et]1-1015 Pip CH.dbd.CH NH[1-Me-2-(4-ClPh)Et]1-1016 Pip CH.dbd.CH NH(1,2-diPhEt)1-1017 Pip CH.dbd.CH NH(1-Bz-2-PhEt)1-1018 Pip CH.dbd.CH NHcPr1-1019 Pip CH.dbd.CH NHcBu1-1020 Pip CH.dbd.CH NHcPn1-1021 Pip CH.dbd.CH NHcHx1-1022 Pip CH.dbd.CH NHcHp1-1023 Pip CH.dbd.CH NHcOc1-1024 Pyr CH.dbd.CH NHiPr1-1025 Pyr CH.dbd.CH NHsBu1-1026 Pyr CH.dbd.CH NH(1-MeBu)1-1027 Pyr CH.dbd.CH NH(1-MePn)1-1028 Pyr CH.dbd.CH NH(1-MeHx)1-1029 Pyr CH.dbd.CH NH(1-MeHp)1-1030 Pyr CH.dbd.CH NH(1-EtPr)1-1031 Pyr CH.dbd.CH NH(1-EtBu)1-1032 Pyr CH.dbd.CH NH(1-EtPn)1-1033 Pyr CH.dbd.CH NH(1-PrBu)1-1034 Pyr CH.dbd.CH NH(1-BuPn)1-1035 Pyr CH.dbd.CH NH(1-PhEt)1-1036 Pyr CH.dbd.CH NH(1-NaPhEt)1-1037 Pyr CH.dbd.CH NH(1-PhPr)1-1038 Pyr CH.dbd.CH NHCHPh.sub.21-1039 Pyr CH.dbd.CH NHCHPh(4-MePh)1-1040 Pyr CH.dbd.CH NHCHPh(4-MeoPh)1-1041 Pyr CH.dbd.CH NHCHPh(4-FPh)1-1042 Pyr CH.dbd.CH NHCHPh(4-ClPh)1-1043 Pyr CH.dbd.CH NH(1-Me-2-PhEt)1-1044 Pyr CH.dbd.CH NH[1-Me-2-(4-MePh)Et]1-1045 Pyr CH.dbd.CH NH[1-Me-2-(4-MeOPh)Et]1-1046 Pyr CH.dbd.CH NH[1-Me-2-(4-FPh)Et]1-1047 Pyr CH.dbd.CH NH(1-Bz-2-PhEt)1-1048 Pyr CH.dbd.CH NHcPr1-1049 Pyr CH.dbd.CH NHcBu1-1050 Pyr CH.dbd.CH NHcPn1-1051 Pyr CH.dbd.CH NHcHx1-1052 Pyr CH.dbd.CH NHcHp1-1053 Pyr CH.dbd.CH NHcOc1-1054 NMe.sub.2 CH.dbd.CH NHiPr1-1055 NMe.sub.2 CH.dbd.CH NHsBu1-1056 NMe.sub.2 CH.dbd.CH NH(1-MeBu)1-1057 NMe.sub.2 CH.dbd.CH NH(1-MePn)1-1058 NMe.sub.2 CH.dbd.CH NH(1-MeHx)1-1059 NMe.sub.2 CH.dbd.CH NH(1-MeHp)1-1060 NMe.sub.2 CH.dbd.CH NH(1-EtPr)1-1061 NMe.sub.2 CH.dbd.CH NH(1-EtBu)1-1062 NMe.sub.2 CH.dbd.CH NH(1-EtPn)1-1063 NMe.sub.2 CH.dbd.CH NH(1-PrBu)1-1064 NMe.sub.2 CH.dbd.CH NH(1-BuPn)1-1065 NMe.sub.2 CH.dbd.CH NH(1-PhEt)1-1066 NMe.sub.2 CH.dbd.CH NH(1-NaPhEt)1-1067 NMe.sub.2 CH.dbd.CH NH(1-PhPr)1-1068 NMe.sub.2 CH.dbd.CH NHCHPh.sub.21-1069 NMe.sub.2 CH.dbd.CH NHCHPh(4-MePh)1-1070 NMe.sub.2 CH.dbd.CH NHCHPh(4-MeOPh)1-1071 NMe.sub.2 CH.dbd.CH NHCHPh(4-FPh)1-1072 NMe.sub.2 CH.dbd.CH NHCHPh(4-ClPh)1-1073 NMe.sub.2 CH.dbd.CH NH(1-Me-2-PhEt)1-1074 NMe.sub.2 CH.dbd.CH NH[1-Me-2-(4-MePh)Et]1-1075 NMe.sub.2 CH.dbd.CH NH[1-Me-2-(4-MeOPh)Et]1-1076 NMe.sub.2 CH.dbd.CH NH[1-Me-2-(4-FPh)Et]1-1077 NMe.sub.2 CH.dbd.CH NH(1-Bz-2-PhEt)1-1078 NMe.sub.2 CH.dbd.CH NHcPr1-1079 NMe.sub.2 CH.dbd.CH NHcBu1-1080 NMe.sub.2 CH.dbd.CH NHcPn1-1081 NMe.sub.2 CH.dbd.CH NHcHx1-1082 NMe.sub.2 CH.dbd.CH NHcHp1-1083 NMe.sub.2 CH.dbd.CH NHcOc1-1084 Aze CH.dbd.CH NHiPr1-1085 Aze CH.dbd.CH NHsBu1-1086 Aze CH.dbd.CH NH(1-MeBu)1-1087 Aze CH.dbd.CH NH(1-MePn)1-1088 Aze CH.dbd.CH NH(1-MeHx)1-1089 Aze CH.dbd.CH NH(1-MeHp)1-1090 Aze CH.dbd.CH NH(1-EtPr)1-1091 Aze CH.dbd.CH NH(1-EtBu)1-1092 Aze CH.dbd.CH NH(1-EtPn)1-1093 Aze CH.dbd.CH NH(1,2-diMePr)1-1094 Aze CH.dbd.CH NH(1-PhEt)1-1095 Aze CH.dbd.CH NHCHPh.sub.21-1096 Aze CH.dbd.CH NH(1-Me-2-PhEt)1-1097 Aze CH.dbd.CH NH(1,2-diPhEt)1-1098 Aze CH.dbd.CH NHcPr1-1099 Aze CH.dbd.CH NHcBu1-1100 Aze CH.dbd.CH NHcPn1-1101 Aze CH.dbd.CH NHcHx1-1102 Aze CH.dbd.CH NHcHp1-1103 Aze CH.dbd.CH NHcOc1-1104 Azi CH.dbd.CH NHiPr1-1105 Azi CH.dbd.CH NHsBu1-1106 Azi CH.dbd.CH NH(1-MeBu)1-1107 Azi CH.dbd.CH NH(1-MePn)1-1108 Azi CH.dbd.CH NH(1-MeHx)1-1109 Azi CH.dbd.CH NH(1-MeHp)1-1110 Azi CH.dbd.CH NH(1-EtPr)1-1111 Azi CH.dbd.CH NH(1-EtBu)1-1112 Azi CH.dbd.CH NH(1-EtPn)1-1113 Azi CH.dbd.CH NH(1,2-diMePr)1-1114 Azi CH.dbd.CH NH(1-PhEt)1-1115 Azi CH.dbd.CH NHCHPh 21-1116 Azi CH.dbd.CH NH(1-Me-2-PhEt)1-1117 Azi CH.dbd.CH NH(1,2-diPhEt)1-1118 Azi CH.dbd.CH NHcPr1-1119 Azi CH.dbd.CH NHcBu1-1120 Azi CH.dbd.CH NHcPn1-1121 Azi CH.dbd.CH NHcHx1-1122 Azi CH.dbd.CH NHcHp1-1123 Azi CH.dbd.CH NHcOc1-1124 Pip CH.sub.2 CH.sub.2 NHiPr1-1125 Pip CH.sub.2 CH.sub.2 NHsBu1-1126 Pip CH.sub.2 CH.sub.2 NH(1-MeBu)1-1127 Pip CH.sub.2 CH.sub.2 NH(1,2-diMePr)1-1128 Pip CH.sub.2 CH.sub.2 NH(1-MePn)1-1129 Pip CH.sub.2 CH.sub.2 NH(1,3-diMeBu)1-1130 Pip CH.sub.2 CH.sub.2 NH(1,2-diMeBu)1-1131 Pip CH.sub.2 CH.sub.2 NH(1-MeHx)1-1132 Pip CH.sub.2 CH.sub.2 NH(1,4-diMePn)1-1133 Pip CH.sub.2 CH.sub.2 NH(1-MeHp)1-1134 Pip CH.sub.2 CH.sub.2 NH(1,5-diMeHx)1-1135 Pip CH.sub.2 CH.sub.2 NH(1-EtPr)1-1136 Pip CH.sub.2 CH.sub.2 NH(1-EtBu)1-1137 Pip CH.sub.2 CH.sub.2 NH(1-Et-2-MePr)1-1138 Pip CH.sub.2 CH.sub.2 NH(1-EtPn)1-1139 Pip CH.sub.2 CH.sub.2 NH(1-Et-3-MeBu)1-1140 Pip CH.sub.2 CH.sub.2 NH(1-EtHx)1-1141 Pip CH.sub.2 CH.sub.2 NH(1-EtHp)1-1142 Pip CH.sub.2 CH.sub.2 NH(1-PrBu)1-1143 Pip CH.sub.2 CH.sub.2 NH(1-iPrBu)1-1144 Pip CH.sub.2 CH.sub.2 NH(1-PrPn)1-1145 Pip CH.sub.2 CH.sub.2 NH(1-PrHx)1-1146 Pip CH.sub.2 CH.sub.2 NH(1-PrHp)1-1147 Pip CH.sub.2 CH.sub.2 NH(1-BuPn)1-1148 Pip CH.sub.2 CH.sub.2 NH(1-PnHx)1-1149 Pip CH.sub.2 CH.sub.2 NH(1-HxHp)1-1150 Pip CH.sub.2 CH.sub.2 NH(1-PhEt)1-1151 Pip CH.sub.2 CH.sub.2 NH(1-NaPhEt)1-1152 Pip CH.sub.2 CH.sub.2 NH(1-PhPr)1-1153 Pip CH.sub.2 CH.sub.2 NH(1-PhBu)1-1154 Pip CH.sub.2 CH.sub.2 NHCHPh.sub.21-1155 Pip CH.sub.2 CH.sub.2 NHCHPh(4-MePh)1-1156 Pip CH.sub.2 CH.sub.2 NHCHPh(4-MeOPh)1-1157 Pip CH.sub.2 CH.sub.2 NHCHPh(4-FPh)1-1158 Pip CH.sub.2 CH.sub.2 NHCHPh(4-ClPh)1-1159 Pip CH.sub.2 CH.sub.2 NH(1-Me-2-PhEt)1-1160 Pip CH.sub.2 CH.sub.2 NH(1-Me-3-PhPr)1-1161 Pip CH.sub.2 CH.sub.2 NH(1-Et-2-PhEt)1-1162 Pip CH.sub.2 CH.sub.2 NH[1-Me-2-(4-MePh)Et]1-1163 Pip CH.sub.2 CH.sub.2 NH[1-Me-2-(4-MeOPh)Et]1-1164 Pip CH.sub.2 CH.sub.2 NH[1-Me-2-(4-FPh)Et]1-1165 Pip CH.sub.2 CH.sub.2 NH[1-Me-2-(4-ClPh)Et]1-1166 Pip CH.sub.2 CH.sub.2 NH(1,2-diPhEt)1-1167 Pip CH.sub.2 CH.sub.2 NH(1-Bz-2-PhEt)1-1168 Pip CH.sub.2 CH.sub.2 NHcPr1-1169 Pip CH.sub.2 CH.sub.2 NHcBu1-1170 Pip CH.sub.2 CH.sub.2 NHcPn1-1171 Pip CH.sub.2 CH.sub.2 NHcHx1-1172 Pip CH.sub.2 CH.sub.2 NHcHp1-1173 Pip CH.sub.2 CH.sub.2 NHcOc1-1174 Pyr CH.sub.2 CH.sub.2 NHiPr1-1175 Pyr CH.sub.2 CH.sub.2 NHsBu1-1176 Pyr CH.sub.2 CH.sub.2 NH(1-MeBu)1-1177 Pyr CH.sub.2 CH.sub.2 NH(1-MePn)1-1178 Pyr CH.sub.2 CH.sub.2 NH(1-MeHx)1-1179 Pyr CH.sub.2 CH.sub.2 NH(1-MeHp)1-1180 Pyr CH.sub.2 CH.sub.2 NH(1-EtPr)1-1181 Pyr CH.sub.2 CH.sub.2 NH(1-EtBu)1-1182 Pyr CH.sub.2 CH.sub.2 NH(1-EtPn)1-1183 Pyr CH.sub.2 CH.sub.2 NH(1-PrBu)1-1184 Pyr CH.sub.2 CH.sub.2 NH(1-BuPn)1-1185 Pyr CH.sub.2 CH.sub.2 NH(1-PhEt)1-1186 Pyr CH.sub.2 CH.sub.2 NH(1-NaPhEt)1-1187 Pyr CH.sub.2 CH.sub.2 NH(1-PhPr)1-1188 Pyr CH.sub.2 CH.sub.2 NHCHPh.sub.21-1189 Pyr CH.sub.2 CH.sub.2 NHCHPh(4-MePh)1-1190 Pyr CH.sub.2 CH.sub.2 NHCHPh(4-MeOPh)1-1191 Pyr CH.sub.2 CH.sub.2 NHCHPh(4-FPh)1-1192 Pyr CH.sub.2 CH.sub.2 NHCHPh(4-ClPh)1-1193 Pyr CH.sub.2 CH.sub.2 NH(1-Me-2-PhEt)1-1194 Pyr CH.sub.2 CH.sub.2 NH[1-Me-2-(4-MePh)Et]1-1195 Pyr CH.sub.2 CH.sub.2 NH[1-Me-2-(4-MeOPh)Et]1-1196 Pyr CH.sub.2 CH.sub.2 NH[1-Me-2-(4-FPh)Et]1-1197 Pyr CH.sub.2 CH.sub.2 NH(1-Bz-2-PhEt)1-1198 Pyr CH.sub.2 CH.sub.2 NHcPr1-1199 Pyr CH.sub.2 CH.sub.2 NHcBu1-1200 Pyr CH.sub.2 CH.sub.2 NHcPn1-1201 Pyr CH.sub.2 CH.sub.2 NHcHx1-1202 Pyr CH.sub.2 CH.sub.2 NHcHp1-1203 Pyr CH.sub.2 CH.sub.2 NHcOc1-1204 NMe.sub.2 CH.sub.2 CH.sub.2 NHiPr1-1205 NMe.sub.2 CH.sub.2 CH.sub.2 NHsBu1-1206 NMe.sub.2 CH.sub.2 CH.sub.2 NH(1-MeBu)1-1207 NMe.sub.2 CH.sub.2 CH.sub.2 NH(1-MePn)1-1208 NMe.sub.2 CH.sub.2 CH.sub.2 NH(1-MeHx)1-1209 NMe.sub.2 CH.sub.2 CH.sub.2 NH(1-MeHp)1-1210 NMe.sub.2 CH.sub.2 CH.sub.2 NH(1-EtPr)1-1211 NMe.sub.2 CH.sub.2 CH.sub.2 NH(1-EtBu)1-1212 NMe.sub.2 CH.sub.2 CH.sub.2 NH(1-EtPn)1-1213 NMe.sub.2 CH.sub.2 CH.sub.2 NH(1-PrBu)1-1214 NMe.sub.2 CH.sub.2 CH.sub.2 NH(1-BuPn)1-1215 NMe.sub.2 CH.sub.2 CH.sub.2 NH(1-PhEt)1-1216 NMe.sub.2 CH.sub.2 CH.sub.2 NH(1-NaPhEt)1-1217 NMe.sub.2 CH.sub.2 CH.sub.2 NH(1-PhPr)1-1218 NMe.sub.2 CH.sub.2 CH.sub.2 NHCHPh.sub.21-1219 NMe.sub.2 CH.sub.2 CH.sub.2 NHCHPh(4-MePh)1-1220 NMe.sub.2 CH.sub.2 CH.sub.2 NHCHPh(4-MeOPh)1-1221 NMe.sub.2 CH.sub.2 CH.sub.2 NHCHPh(4-FPh)1-1222 NMe.sub.2 CH.sub.2 CH.sub.2 NHCHPh(4-ClPh)1-1223 NMe.sub.2 CH.sub.2 CH.sub.2 NH(1-Me-2-PhEt)1-1224 NMe.sub.2 CH.sub.2 CH.sub.2 NH[1-Me-2-(4-MePh)Et]1-1225 NMe.sub.2 CH.sub.2 CH.sub.2 NH[1-Me-2-(4-MeOPh)Et]1-1226 NMe.sub.2 CH.sub.2 CH.sub.2 NH[1-Me-2-(4-FPh)Et]1-1227 NMe.sub.2 CH.sub.2 CH.sub.2 NH(1-Bz-2-PhEt)1-1228 NMe.sub.2 CH.sub.2 CH.sub.2 NHcPr1-1229 NMe.sub.2 CH.sub.2 CH.sub.2 NHcBu1-1230 NMe.sub.2 CH.sub.2 CH.sub.2 NHcPn1-1231 NMe.sub.2 CH.sub.2 CH.sub.2 NHcHx1-1232 NMe.sub.2 CH.sub.2 CH.sub.2 NHcHp1-1233 NMe.sub.2 CH.sub.2 CH.sub.2 NHcOc1-1234 Aze CH.sub.2 CH.sub.2 NHiPr1-1235 Aze CH.sub.2 CH.sub.2 NHsBu1-1236 Aze CH.sub.2 CH.sub.2 NH(1-MeBu)1-1237 Aze CH.sub.2 CH.sub.2 NH(1-MePn)1-1238 Aze CH.sub.2 CH.sub.2 NH(1-MeHx)1-1239 Aze CH.sub.2 CH.sub.2 NH(1-MeHp)1-1240 Aze CH.sub.2 CH.sub.2 NH(1-EtPr)1-1241 Aze CH.sub.2 CH.sub.2 NH(1-EtBu)1-1242 Aze CH.sub.2 CH.sub.2 NH(1-EtPn)1-1243 Aze CH.sub.2 CH.sub.2 NH(1,2-diMePr)1-1244 Aze CH.sub.2 CH.sub.2 NH(1-PhEt)1-1245 Aze CH.sub.2 CH.sub.2 NHCHPh.sub.21-1246 Aze CH.sub.2 CH.sub.2 NH(1-Me-2-PhEt)1-1247 Aze CH.sub.2 CH.sub.2 NH(1,2-diPhEt)1-1248 Aze CH.sub.2 CH.sub.2 NHcPr1-1249 Aze CH.sub.2 CH.sub.2 NHcBu1-1250 Aze CH.sub.2 CH.sub.2 NHcPn1-1251 Aze CH.sub.2 CH.sub.2 NHcHx1-1252 Aze CH.sub.2 CH.sub.2 NHcHp1-1253 Aze CH.sub.2 CH.sub.2 NHcOc1-1254 Azi CH.sub.2 CH.sub.2 NHiPr1-1255 Azi CH.sub.2 CH.sub.2 NHsBu1-1256 Azi CH.sub.2 CH.sub.2 NH(1-MeBu)1-1257 Azi CH.sub.2 CH.sub.2 NH(1-MePn)1-1258 Azi CH.sub.2 CH.sub.2 NH(1-MeHx)1-1259 Azi CH.sub.2 CH.sub.2 NH(1-MeHp)1-1260 Azi CH.sub.2 CH.sub.2 NH(1-EtPr)1-1261 Azi CH.sub.2 CH.sub.2 NH(1-EtBu)1-1262 Azi CH.sub.2 CH.sub.2 NH(1-EtPn)1-1263 Azi CH.sub.2 CH.sub.2 NH(1,2-diMePr)1-1264 Azi CH.sub.2 CH.sub.2 NH(1-PhEt)1-1265 Azi CH.sub.2 CH.sub.2 NHCHPh.sub.21-1266 Azi CH.sub.2 CH.sub.2 NH(1-Me-2-PhEt)1-1267 Azi CH.sub.2 CH.sub.2 NH(1,2-diPhEt)1-1268 Azi CH.sub.2 CH.sub.2 NHcPr1-1269 Azi CH.sub.2 CH.sub.2 NHcBu1-1270 Azi CH.sub.2 CH.sub.2 NHcPn1-1271 Azi CH.sub.2 CH.sub.2 NHcHx1-1272 Azi CH.sub.2 CH.sub.2 NHcHp1-1273 Azi CH.sub.2 CH.sub.2 NHcOc1-1274 Pip CH.sub.2 NHiPr1-1275 Pip CH.sub.2 NHsBu1-1276 Pip CH.sub.2 NH(1-MeBu)1-1277 Pip CH.sub.2 NH(1,2-diMePr)1-1278 Pip CH.sub.2 NH(1-MePn)1-1279 Pip CH.sub.2 NH(1,3-diMeBu)1-1280 Pip CH.sub.2 NH(1,2-diMeBu)1-1281 Pip CH.sub.2 NH(1-MeHx)1-1282 Pip CH.sub.2 NH(1,4-diMePn)1-1283 Pip CH.sub.2 NH(1-MeHp)1-1284 Pip CH.sub.2 NH(1,5-diMeHx)1-1285 Pip CH.sub.2 NH(1-EtPr)1-1286 Pip CH.sub.2 NH(1-EtBu)1-1287 Pip CH.sub.2 NH.(1-Et-2-MePr)1-1288 Pip CH.sub.2 NH(1-EtPn)1-1289 Pip CH.sub.2 NH(1-Et-3-MeBu)1-1290 Pip CH.sub.2 NH(1-EtHx)1-1291 Pip CH.sub.2 NH(1-EtHp)1-1292 Pip CH.sub.2 NH(1-PrBu)1-1293 Pip CH.sub.2 NH(1-iPrBu)1-1294 Pip CH.sub.2 NH(1-PrPn)1-1295 Pip CH.sub.2 NH(1-PrHx)1-1296 Pip CH.sub.2 NH(1-PrHp)1-1297 Pip CH.sub.2 NH(1-BuPn)1-1298 Pip CH.sub.2 NH(1-PnHx)1-1299 Pip CH.sub.2 NH(1-HxHp)1-1300 Pip CH.sub.2 NH(1-PhEt)1-1301 Pip CH.sub.2 NH(1-NaPhEt)1-1302 Pip CH.sub.2 NH(1-PhPr)1-1303 Pip CH.sub.2 NH(1-PhBu)1-1304 Pip CH.sub.2 NHCHPh.sub.21-1305 Pip CH.sub.2 NHCHPh(4-MePh)1-1306 Pip CH.sub.2 NHCHPh(4-MeOPh)1-1307 Pip CH.sub.2 NHCHPh(4-FPh)1-1308 Pip CH.sub.2 NHCHPh(4-ClPh)1-1309 Pip CH.sub.2 NH(1-Me-2-PhEt)1-1310 Pip CH.sub.2 NH(1-Me-3-PhPr)1-1311 Pip CH.sub.2 NH(1-Et-2-PhEt)1-1312 Pip CH.sub.2 NH[1-Me-2-(4-MePh)Et]1-1313 Pip CH.sub.2 NH[1-Me-2-(4-MeOPh)Et]1-1314 Pip CH.sub.2 NH[1-Me-2-(4-FPh)Et]1-1315 Pip CH.sub.2 NH[1-Me-2-(4-ClPh)Et]1-1316 Pip CH.sub.2 NH(1,2-diPhEt)1-1317 Pip CH.sub.2 NH(1-Bz-2-PhEt)1-1318 Pip CH.sub.2 NHcPr1-1319 Pip CH.sub.2 NHcBu1-1320 Pip CH.sub.2 NHcPn1-1321 Pip CH.sub.2 NHcHx1-1322 Pip CH.sub.2 NHcHp1-1323 Pip CH.sub.2 NHcOc1-1324 Pip (CH.sub.2).sub.3 NHiPr1-1325 Pip (CH.sub.2).sub.3 NHsBu1-1326 Pip (CH.sub.2).sub.3 NH(1-MeBu)1-1327 Pip (CH.sub.2).sub.3 NH(1-MePn)1-1328 Pip (CH.sub.2).sub.3 NH(1-MeHx)1-1329 Pip (CH.sub.2).sub.3 NH(1-MeHp)1-1330 Pip (CH.sub.2).sub.3 NH(1-EtPr)1-1331 Pip (CH.sub.2).sub.3 NH(1-EtBu)1-1332 Pip (CH.sub.2).sub.3 NH(1-EtPn)1-1333 Pip (CH.sub.2).sub.3 NH(1-PrBu)1-1334 Pip (CH.sub.2).sub.3 NH(1-BuPn)1-1335 Pip (CH.sub.2).sub.3 NH(1-PhEt)1-1336 Pip (CH.sub.2).sub.3 NH(1-NaPhEt)1-1337 Pip (CH.sub.2).sub.3 NH(1-PhPr)1-1338 Pip (CH.sub.2).sub.3 NHCHPh.sub.21-1339 Pip (CH.sub.2).sub.3 NHCHPh(4-MePh)1-1340 Pip (CH.sub.2).sub.3 NHCHPh(4-MeOPh)1-1341 Pip (CH.sub.2).sub.3 NHCHPh(4-FPh)1-1342 Pip (CH.sub.2).sub.3 NHCHPh(4-ClPh)1-1343 Pip (CH.sub.2).sub.3 NH(1-Me-2-PhEt)1-1344 Pip (CH.sub.2).sub.3 NH[1-Me-2-(4-MePh)Et]1-1345 Pip (CH.sub.2).sub.3 NH[1-Me-2-(4-MeOPh)Et]1-1346 Pip (CH.sub.2).sub.3 NH[1-Me-2-(4-FPh)Et]1-1347 Pip (CH.sub.2).sub.3 NH(1-Bz-2-PhEt)1-1348 Pip (CH.sub.2).sub.3 NHcPr1-1349 Pip (CH.sub.2).sub.3 NHcBu1-1350 Pip (CH.sub.2).sub.3 NHcPn1-1351 Pip (CH.sub.2).sub.3 NHcHx1-1352 Pip (CH.sub.2).sub.3 NHcHp1-1353 Pip (CH.sub.2).sub.3 NHcOc______________________________________
TABLE 2__________________________________________________________________________Cpd.No. R.sup.1 A B m R.sup.5__________________________________________________________________________2-1 Pip CH.dbd.CH CH.sub.2 0 CH.sub.2 OH2-2 Pip CH.dbd.CH CH.sub.2 0 2-HOEt2-3 Pip CH.dbd.CH CH.sub.2 0 2-FoOEt2-4 Pip CH.dbd.CH CH.sub.2 0 2-AcOEt2-5 Pip CH.dbd.CH CH.sub.2 0 2-PrnOEt2-6 Pip CH.dbd.CH CH.sub.2 0 2-ByrOEt2-7 Pip CH.dbd.CH CH.sub.2 0 2-iByrOEt2-8 Pip CH.dbd.CH CH.sub.2 0 2-ValOEt2-9 Pip CH.dbd.CH CH.sub.2 0 2-iValOEt2-10 Pip CH.dbd.CH CH.sub.2 0 2-(PhAcO)Et2-11 Pip CH.dbd.CH CH.sub.2 0 2-(HOOC.AcO)Et2-12 Pip CH.dbd.CH CH.sub.2 0 2-(3-HOOC.Prno)Et2-13 Pip CH.dbd.CH CH.sub.2 0 2-(3-Mec.PrnO)Et2-14 Pip CH.dbd.CH CH.sub.2 0 2-(3-Etc.PrnO)Et2-15 Pip CH.dbd.CH CH.sub.2 0 2-(3-Prc.PrnO)Et2-16 Pip CH.dbd.CH CH.sub.2 0 2-(3-Phc.PrnO)Et2-17 Pip CH.dbd.CH CH.sub.2 0 2-[3-(4-MePhcO)PrnO]Et2-18 Pip CH.dbd.CH CH.sub.2 0 2-(3-PhPrnO)Et2-19 Pip CH.dbd.CH CH.sub.2 0 2-(3-PhPrnO)Et2-20 Pip CH.dbd.CH CH.sub.2 0 2-BozOEt2-21 Pip CH.dbd.CH CH.sub.2 0 2-(4-MeBozO)Et2-22 Pip CH.dbd.CH CH.sub.2 0 2-(4-MeOBozO)Et2-23 Pip CH.dbd.CH CH.sub.2 0 2-(4-FBozO)Et2-24 Pip CH.dbd.CH CH.sub.2 0 2-(4-ClBozO)Et2-25 Pip CH.dbd.CH CH.sub.2 0 2-(cPrCOO)Et2-26 Pip CH.dbd.CH CH.sub.2 0 2-(cBuCOO)Et2-27 Pip CH.dbd.CH CH.sub.2 0 2-(cPnCOO)Et2-28 Pip CH.dbd.CH CH.sub.2 0 2-(cHxCOO)Et2-29 Pip CH.dbd.CH CH.sub.2 0 2-HOPr2-30 Pip CH.dbd.CH CH.sub.2 0 2-FoOPr2-31 Pip CH.dbd.CH CH.sub.2 0 2-AcOPr2-32 Pip CH.dbd.CH CH.sub.2 0 2-PrnOPr2-33 Pip CH.dbd.CH CH.sub.2 0 2-(3-HOOC.PrnO)Pr2-34 Pip CH.dbd.CH CH.sub.2 0 2-(3-Mec.PrnO)Pr2-35 Pip CH.dbd.CH CH.sub.2 0 2-(3-Etc.PrnO)Pr2-36 Pip CH.dbd.CH CH.sub.2 0 2-(3-Phc.PrnO)Et2-37 Pip CH.dbd.CH CH.sub.2 0 2-[3-(4-MePhcO)PrnO]Et2-38 Pip CH.dbd.CH CH.sub.2 0 2-(PhAcO)Pr2-39 Pip CH.dbd.CH CH.sub.2 0 2-BozOPr2-40 Pip CH.dbd.CH CH.sub.2 0 2-(cPnCOO)Pr2-41 Pip CH.dbd.CH CH.sub.2 0 2-(cHxCOO)Pr2-42 Pip CH.dbd.CH CH.sub.2 0 3-HOPr2-43 Pip CH.dbd.CH CH.sub.2 0 3-FoOPr2-44 Pip CH.dbd.CH CH.sub.2 0 3-AcOPr2-45 Pip CH.dbd.CH CH.sub.2 0 3-PrnOPr2-46 Pip CH.dbd.CH CH.sub.2 0 3-(3-HOOC.PrnO)Pr2-47 Pip CH.dbd.CH CH.sub.2 0 3-(3-Mec.PrnO)Pr2-48 Pip CH.dbd.CH CH.sub.2 0 3-(3-Etc.PrnO)Pr2-49 Pip CH.dbd.CH CH.sub.2 0 3-BozOPr2-50 Pip CH.dbd.CH CH.sub.2 0 3-(cPnCOO)Pr2-51 Pip CH.dbd.CH CH.sub.2 0 3-(cHxCOO)Pr2-52 Pip CH.dbd.CH CH.sub.2 0 2-HOBu2-53 Pip CH.dbd.CH CH.sub.2 0 2-AcOBu2-54 Pip CH.dbd.CH CH.sub.2 0 2-(3-HOOC.PrnO)Bu2-55 Pip CH.dbd.CH CH.sub.2 0 2-BozOBu2-56 Pip CH.dbd.CH CH.sub.2 0 2-(cHxCOO)Bu2-57 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 2-HOEt2-58 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 2-FoOEt2-59 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 2-AcOEt2-60 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 2-PrnOEt2-61 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 2-ValOEt2-62 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 2-(PhAcO)Et2-63 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 2-(3-HOOC.PrnO)Et2-64 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 2-(3-Mec.Prno)Et2-65 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 2-(3-Etc.PrnO)Et2-66 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 2-(3-PhPrnO)Et2-67 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 2-BozOEt2-68 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 2-(4-MeBozO)Et2-69 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 2-(4-FBozO)Et2-70 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 2-(4-ClBozO)Et2-71 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 2-(cPrCOO)Et2-72 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 2-(cBuCOO)Et2-73 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 2-(cPnCOO)Et2-74 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 2-(cHxCOO)Et2-75 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 2-HOPr2-76 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 2-FoOPr2-77 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 2-AcOPr2-78 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 2-PrnOPr2-79 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 2-(3-HOOC.PrnO)Pr2-80 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 2-(3-Mec.Prno)Pr2-81 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 2-BozOPr2-82 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 2-(cPnCOO)Pr2-83 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 2-(cHxCOO)Pr2-84 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 3-HOPr2-85 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 3-AcOPr2-86 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 3-PrnOPr2-87 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 3-(3-HOOC.PrnO)Pr2-88 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 3-BozOPr2-89 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 3-(cPnCOO)Pr2-90 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 3-(cHxCOO)Pr2-91 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 2-HOBu2-92 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 2-AcOBu2-93 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 2-(3-HOOC.PrnO)Bu2-94 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 2-BozOBu2-95 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 2-(cHxCOO)Bu2-96 Pip CH.dbd.CH (CH.sub.2).sub.3 0 2-HOEt2-97 Pip CH.dbd.CH (CH.sub.2).sub.3 0 2-FoOEt2-98 Pip CH.dbd.CH (CH.sub.2).sub.3 0 2-AcOEt2-99 Pip CH.dbd.CH (CH.sub.2).sub.3 0 2-PrnOEt2-100 Pip CH.dbd.CH (CH.sub.2).sub.3 0 2-ByrOEt2-101 Pip CH.dbd.CH (CH.sub.2).sub.3 0 2-iByrOEt2-102 Pip CH.dbd.CH (CH.sub.2).sub.3 0 2-ValOEt2-103 Pip CH.dbd.CH (CH.sub.2).sub.3 0 2-(3-HOOC.PrnO)Et2-104 Pip CH.dbd.CH (CH.sub.2).sub.3 0 2-(3-Mec.PrnO)Et2-105 Pip CH.dbd.CH (CH.sub.2).sub.3 0 2-(3-Etc.PrnO)Et2-106 Pip CH.dbd.CH (CH.sub.2).sub.3 0 2-(PhAcO)Et2-107 Pip CH.dbd.CH (CH.sub.2).sub.3 0 2-BozOEt2-108 Pip CH.dbd.CH (CH.sub.2).sub.3 0 2-(4-MeBozO)Et2-109 Pip CH.dbd.CH (CH.sub.2).sub.3 0 2-(4-MeOBozO)Et2-110 Pip CH.dbd.CH (CH.sub.2).sub.3 0 2-(4-FBozO)Et2-111 Pip CH.dbd.CH (CH.sub.2).sub.3 0 2-(4-ClBozO)Et2-112 Pip CH.dbd.CH (CH.sub.2).sub.3 0 2-(cPrCOO)Et2-113 Pip CH.dbd.CH (CH.sub.2).sub.3 0 2-(cBuCOO)Et2-114 Pip CH.dbd.CH (CH.sub.2).sub.3 0 2-(cPnCOO)Et2-115 Pip CH.dbd.CH (CH.sub.2).sub.3 0 2-(cHxCOO)Et2-116 Pip CH.dbd.CH (CH.sub.2).sub.3 0 2-HOPr2-117 Pip CH.dbd.CH (CH.sub.2).sub.3 0 2-AcOPr2-118 Pip CH.dbd.CH (CH.sub.2).sub.3 0 2-PrnOPr2-119 Pip CH.dbd.CH (CH.sub.2).sub.3 0 2-(3-HOOC.PrnO)Pr2-120 Pip CH.dbd.CH (CH.sub.2).sub.3 0 2-(3-Etc.PrnO)Pr2-121 Pip CH.dbd.CH (CH.sub.2).sub.3 0 2-BozOPr2-122 Pip CH.dbd.CH (CH.sub.2).sub.3 0 2-(cHxCOO)Pr2-123 Pip CH.dbd.CH (CH.sub.2).sub.3 0 3-HOPr2-124 Pip CH.dbd.CH (CH.sub.2).sub.3 0 3-AcOPr2-125 Pip CH.dbd.CH (CH.sub.2).sub.3 0 3-(3-HOOC.PrnO)Pr2-126 Pip CH.dbd.CH (CH.sub.2).sub.3 0 3-(3-Mec.PrnO)Pr2-127 Pip CH.dbd.CH (CH.sub.2).sub.3 0 3-BozOPr2-128 Pip CH.dbd.CH (CH.sub.2).sub.3 0 3-(cHxCOO)Pr2-129 Pip CH.dbd.CH (CH.sub.2).sub.3 0 2-HOBu2-130 Pip CH.dbd.CH (CH.sub.2).sub.3 0 2-AcOBu2-131 Pip CH.dbd.CH (CH.sub.2).sub.3 0 2-(3-HOOC.PrnO)Bu2-132 Pip CH.dbd.CH (CH.sub.2).sub.3 0 2-BozOBu2-133 Pip CH.dbd.CH (CH.sub.2).sub.3 0 2-(cHxCOO)Bu2-134 Pip CH.dbd.CH (CH.sub.2).sub.4 0 2-HOEt2-135 Pip CH.dbd.CH (CH.sub.2).sub.4 0 2-FoOEt2-136 Pip CH.dbd.CH (CH.sub.2).sub.4 0 2-AcOEt2-137 Pip CH.dbd.CH (CH.sub.2).sub.4 0 2-PrnOEt2-138 Pip CH.dbd.CH (CH.sub.2).sub.4 0 2-(3-HOOC.PrnO)Et2-139 Pip CH.dbd.CH (CH.sub.2).sub.4 0 2-(3-Mec.PrnO)Et2-140 Pip CH.dbd.CH (CH.sub.2).sub.4 0 2-BozOEt2-141 Pip CH.dbd.CH (CH.sub.2).sub.4 0 2-(cHxCOO)Et2-142 Pip CH.dbd.CH (CH.sub.2).sub.4 0 2-HOPr2-143 Pip CH.dbd.CH (CH.sub.2).sub.4 0 2-AcOPr2-144 Pip CH.dbd.CH (CH.sub.2).sub.4 0 2-(3-HOOC.PrnO)Pr2-145 Pip CH.dbd.CH (CH.sub.2).sub.4 0 2-BozOPr2-146 Pip CH.dbd.CH (CH.sub.2).sub.4 0 2-(cHxCOO)Pr2-147 Pip CH.dbd.CH (CH.sub.2).sub.4 0 3-HOPr2-148 Pip CH.dbd.CH (CH.sub.2).sub.4 0 3-AcOPr2-149 Pip CH.dbd.CH (CH.sub.2).sub.4 0 3-(3-HOOC.PrnO)Pr2-150 Pip CH.dbd.CH (CH.sub.2).sub.4 0 3-BozOPr2-151 Pip CH.dbd.CH (CH.sub.2).sub.4 0 3-(cHxCOO)Pr2-152 Pip CH.dbd.CH (CH.sub.2).sub.4 0 2-HOBu2-153 Pip CH.dbd.CH (CH.sub.2).sub.4 0 2-AcOBu2-154 Pip CH.dbd.CH (CH.sub.2).sub.4 0 2-(3-HOOC.PrnO)Bu2-155 Pip CH.dbd.CH (CH.sub.2).sub.4 0 2-(cHxCOO)Bu2-156 Pip CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 2-HOEt2-157 Pip CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 2-AcOEt2-158 Pip CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 2-(3-HOOC.PrnO)Et2-159 Pip CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 2-BozOEt2-160 Pip CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 2-(cHxCOO)Et2-161 Pip CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 2-HOPr2-162 Pip CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 2-AcOPr2-163 Pip CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 2-BozOPr2-164 Pip CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 2-(cHxCOO)Pr2-165 Pip CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 3-HOPr2-166 Pip CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 3-AcOPr2-167 Pip CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 3-(3-HOOC.PrnO)Pr2-168 Pip CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 3-BozOPr2-169 Pip CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 3-(cHxCOO)Pr2-170 Pip CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 2-HOBu2-171 Pip CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 2-AcOBu2-172 Pip CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 2-(3-Etc.PrnO)Bu2-173 Pip CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 2-(cHxCOO)Bu2-174 Pip CH.dbd.CH (CH.sub.2).sub.5 0 2-HOEt2-175 Pip CH.dbd.CH (CH.sub.2).sub.5 0 2-AcOEt2-176 Pip CH.dbd.CH (CH.sub.2).sub.5 0 2-(3-HOOC.PrnO)Et2-177 Pip CH.dbd.CH (CH.sub.2).sub.5 0 2-BozOEt2-178 Pip CH.dbd.CH (CH.sub.2).sub.5 0 2-(cHxCOO)Et2-179 Pip CH.dbd.CH (CH.sub.2).sub.5 0 2-HOPr2-180 Pip CH.dbd.CH (CH.sub.2).sub.5 0 2-AcOPr2-181 Pip CH.dbd.CH (CH.sub.2).sub.5 0 2-(3-HOOC.PrnO)Pr2-182 Pip CH.dbd.CH (CH.sub.2).sub.5 0 2-BozOPr2-183 Pip CH.dbd.CH (CH.sub.2).sub.5 0 2-(cHxCOO)Pr2-184 Pip CH.dbd.CH (CH.sub.2).sub.5 0 3-HOPr2-185 Pip CH.dbd.CH (CH.sub.2).sub.5 0 3-AcOPr2-186 Pip CH.dbd.CH (CH.sub.2).sub.5 0 3-(3-HOOC.PrnO)Pr2-187 Pip CH.dbd.CH (CH.sub.2).sub.5 0 3-BozOPr2-188 Pip CH.dbd.CH (CH.sub.2).sub.5 0 3-(cHxCOO)Pr2-189 Pip CH.dbd.CH (CH.sub.2).sub.5 0 2-HOBu2-190 Pip CH.dbd.CH (CH.sub.2).sub.5 0 2-AcOBu2-191 Pip CH.dbd.CH (CH.sub.2).sub.5 0 2-(3-HOOC.PrnO)Bu2-192 Pip CH.dbd.CH (CH.sub.2).sub.5 0 2-(cHxCOO)Bu2-193 Pip CH.dbd.CH (CH.sub.2).sub.6 0 2-HOEt2-194 Pip CH.dbd.CH (CH.sub.2).sub.6 0 2-AcOEt2-195 Pip CH.dbd.CH (CH.sub.2).sub.6 0 2-(3-HOOC.PrnO)Et2-196 Pip CH.dbd.CH (CH.sub.2).sub.6 0 2-(cHxCOO)Et2-197 Pip CH.dbd.CH (CH.sub.2).sub.6 0 2-HOPr2-198 Pip CH.dbd.CH (CH.sub.2).sub.6 0 2-AcOPr2-199 Pip CH.dbd.CH (CH.sub.2).sub.6 0 2-(3-HOOC.PrnO)Pr2-200 Pip CH.dbd.CH (CH.sub.2).sub.6 0 2-(cHxCOO)Pr2-201 Pip CH.dbd.CH (CH.sub.2).sub.6 0 3-HOPr2-202 Pip CH.dbd.CH (CH.sub.2).sub.6 0 3-AcOPr2-203 Pip CH.dbd.CH (CH.sub.2).sub.6 0 3-(3-HOOC.PrnO)Pr2-204 Pip CH.dbd.CH (CH.sub.2).sub.6 0 3-(cHxCOO)Pr2-205 Pip CH.dbd.CH (CH.sub.2).sub.6 0 2-HOBu2-206 Pip CH.dbd.CH (CH.sub.2).sub.6 0 2-AcOBu2-207 Pip CH.dbd.CH (CH.sub.2).sub.6 0 2-(3-HOOC.PrnO)Bu2-208 Pip CH.dbd.CH (CH.sub.2).sub.6 0 2-(cHxCOO)Bu2-209 Pyr CH.dbd.CH CH.sub.2 0 2-HOEt2-210 Pyr CH.dbd.CH CH.sub.2 0 2-FoOEt2-211 Pyr CH.dbd.CH CH.sub.2 0 2-AcOEt2-212 Pyr CH.dbd.CH CH.sub.2 0 2-PrnOEt2-213 Pyr CH.dbd.CH CH.sub.2 0 2-(3-HOOC.PrnO)Et2-214 Pyr CH.dbd.CH CH.sub.2 0 2-(3-Mec.PrnO)Et2-215 Pyr CH.dbd.CH CH.sub.2 0 2-(3-Etc.PrnO)Et2-216 Pyr CH.dbd.CH CH.sub.2 0 2-BozOEt2-217 Pyr CH.dbd.CH CH.sub.2 0 2-(cPnCOO)Et2-218 Pyr CH.dbd.CH CH.sub.2 0 2-(cHxCOO)Et2-219 Pyr CH.dbd.CH CH.sub.2 0 2-HOPr2-220 Pyr CH.dbd.CH CH.sub.2 0 2-AcOPr2-221 Pyr CH.dbd.CH CH.sub.2 0 2-(3-HOOC.PrnO)Pr2-222 Pyr CH.dbd.CH CH.sub.2 0 2-BozOPr2-223 Pyr CH.dbd.CH CH.sub.2 0 2-(cHxCOO)Pr2-224 Pyr CH.dbd.CH CH.sub.2 0 3-HOPr2-225 Pyr CH.dbd.CH CH.sub.2 0 3-FoOPr2-226 Pyr CH.dbd.CH CH.sub.2 0 3-AcOPr2-227 Pyr CH.dbd.CH CH.sub.2 0 3-(3-HOOC.PrnO)Pr2-228 Pyr CH.dbd.CH CH.sub.2 0 3-(3-Mec.PrnO)Pr2-229 Pyr CH.dbd.CH CH.sub.2 0 3-BozOPr2-230 Pyr CH.dbd.CH CH.sub.2 0 3-(cHxCOO)Pr2-231 Pyr CH.dbd.CH CH.sub.2 0 2-HOBu2-232 Pyr CH.dbd.CH CH.sub.2 0 2-AcOBu2-233 Pyr CH.dbd.CH CH.sub.2 CH.sub.2 0 2-HOEt2-234 Pyr CH.dbd.CH CH.sub.2 CH.sub.2 0 2-AcOEt2-235 Pyr CH.dbd.CH CH.sub.2 CH.sub.2 0 2-(3-HOOC.PrnO)Et2-236 Pyr CH.dbd.CH CH.sub.2 CH.sub.2 0 2-(3-Mec.PrnO)Et2-237 Pyr CH.dbd.CH CH.sub.2 CH.sub.2 0 2-BozOEt2-238 Pyr CH.dbd.CH CH.sub.2 CH.sub.2 0 2-(cPnCOO)Et2-239 Pyr CH.dbd.CH CH.sub.2 CH.sub.2 0 2-(cHxCOO)Et2-240 Pyr CH.dbd.CH CH.sub.2 CH.sub.2 0 2-HOPr2-241 Pyr CH.dbd.CH CH.sub.2 CH.sub.2 0 2-AcOPr2-242 Pyr CH.dbd.CH CH.sub.2 CH.sub.2 0 2-(3-HOOC.PrnO)Pr2-243 Pyr CH.dbd.CH CH.sub.2 CH.sub.2 0 2-(cHxCOO)Pr2-244 Pyr CH.dbd.CH CH.sub.2 CH.sub.2 0 3-HOPr2-245 Pyr CH.dbd.CH CH.sub.2 CH.sub.2 0 3-AcOPr2-246 Pyr CH.dbd.CH CH.sub.2 CH.sub.2 0 3-(cHxCOO)Pr2-247 Pyr CH.dbd.CH CH.sub.2 CH.sub.2 0 2-HOBu2-248 Pyr CH.dbd.CH CH.sub.2 CH.sub.2 0 2-AcOBu2-249 Pyr CH.dbd.CH (CH.sub.2).sub.3 0 2-HOEt2-250 Pyr CH.dbd.CH (CH.sub.2).sub.3 0 2-AcOEt2-251 Pyr CH.dbd.CH (CH.sub.2).sub.3 0 2-PrnOEt2-252 Pyr CH.dbd.CH (CH.sub.2).sub.3 0 2-(3-HOOC.PrnO)Et2-253 Pyr CH.dbd.CH (CH.sub.2).sub.3 0 2-BozOEt2-254 Pyr CH.dbd.CH (CH.sub.2).sub.3 0 2-(cPnCOO)Et2-255 Pyr CH.dbd.CH (CH.sub.2).sub.3 0 2-(cHxCOO)Et2-256 Pyr CH.dbd.CH (CH.sub.2).sub.3 0 2-HOPr2-257 Pyr CH.dbd.CH (CH.sub.2).sub.3 0 2-AcOPr2-258 Pyr CH.dbd.CH (CH.sub.2).sub.3 0 2-BozOPr2-259 Pyr CH.dbd.CH (CH.sub.2).sub.3 0 3-HOPr2-260 Pyr CH.dbd.CH (CH.sub.2).sub.3 0 3-AcOPr2-261 Pyr CH.dbd.CH (CH.sub.2).sub.3 0 3-(3-HOOC.PrnO)Pr2-262 Pyr CH.dbd.CH (CH.sub.2).sub.3 0 2-HOBu2-263 Pyr CH.dbd.CH (CH.sub.2).sub.3 0 2-AcOBu2-264 Pyr CH.dbd.CH (CH.sub.2).sub.4 0 2-HOEt2-265 Pyr CH.dbd.CH (CH.sub.2).sub.4 0 2-AcOEt2-266 Pyr CH.dbd.CH (CH.sub.2).sub.4 0 2-(3-HOOC.PrnO)Et2-267 Pyr CH.dbd.CH (CH.sub.2).sub.4 0 2-(cHxCOO)Et2-268 Pyr CH.dbd.CH (CH.sub.2).sub.4 0 2-HOPr2-269 Pyr CH.dbd.CH (CH.sub.2).sub.4 0 2-AcOPr2-270 Pyr CH.dbd.CH (CH.sub.2).sub.4 0 3-HOPr2-271 Pyr CH.dbd.CH (CH.sub.2).sub.4 0 3-AcOPr2-272 Pyr CH.dbd.CH (CH.sub.2).sub.4 0 2-HOBu2-273 Pyr CH.dbd.CH (CH.sub.2).sub.4 0 2-AcOBu2-274 Pyr CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 2-HOEt2-275 Pyr CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 2-AcOEt2-276 Pyr CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 2-HOPr2-277 Pye CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 2-AcOPr2-278 Pyr CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 3-HOPr2-279 Pyr CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 3-AcOPr2-280 Pyr CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 2-HOBu2-281 Pyr CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 2-AcOBu2-282 Pyr CH.dbd.CH (CH.sub.2).sub.5 0 2-HOEt2-283 Pyr CH.dbd.CH (CH.sub.2).sub.5 0 2-AcOEt2-284 Pyr CH.dbd.CH (CH.sub.2).sub.5 0 2-HOPr2-285 Pyr CH.dbd.CH (CH.sub.2).sub.5 0 2-AcOPr2-286 Pyr CH.dbd.CH (CH.sub.2).sub.5 0 2-(cHxCOO)Pr2-287 Pyr CH.dbd.CH (CH.sub.2).sub.5 0 3-HOPr2-288 Pyr CH.dbd.CH (CH.sub.2).sub.5 0 3-AcOPr2-289 Pyr CH.dbd.CH (CH.sub.2).sub.5 0 2-AcOBu2-290 Pyr CH.dbd.CH (CH.sub.2).sub.6 0 2-HOEt2-291 Pyr CH.dbd.CH (CH.sub.2).sub.6 0 2-AcOEt2-292 Pyr CH.dbd.CH (CH.sub.2).sub.6 0 2-HOPr2-293 Pyr CH.dbd.CH (CH.sub.2).sub.6 0 2-AcOPr2-294 Pyr CH.dbd.CH (CH.sub.2).sub.6 0 3-HOPr2-295 Pyr CH.dbd.CH (CH.sub.2).sub.6 0 3-AcOPr2-296 Pyr CH.dbd.CH (CH.sub.2).sub.6 0 2-AcOBu2-297 NMe.sub.2 CH.dbd.CH CH.sub.2 0 2-HOEt2-298 NMe.sub.2 CH.dbd.CH CH.sub.2 0 2-AcOEt2-299 NMe.sub.2 CH.dbd.CH CH.sub.2 0 2-PrnOEt2-300 NMe.sub.2 CH.dbd.CH CH.sub.2 0 2-(3-HOOC.PrnO)Et2-301 NMe.sub.2 CH.dbd.CH CH.sub.2 0 2-(3-Mec.PrnO)Et2-302 NMe.sub.2 CH.dbd.CH CH.sub.2 0 2-BozOEt2-303 NMe.sub.2 CH.dbd.CH CH.sub.2 0 2-(cHxCOO)Et2-304 NMe.sub.2 CH.dbd.CH CH.sub.2 0 2-HOPr2-305 NMe.sub.2 CH.dbd.CH CH.sub.2 0 2-(cHxCOO)Pr2-306 NMe.sub.2 CH.dbd.CH CH.sub.2 0 3-HOPr2-307 NMe.sub.2 CH.dbd.CH CH.sub.2 0 3-AcOPr2-308 NMe.sub.2 CH.dbd.CH CH.sub.2 0 2-HOBu2-309 NMe.sub.2 CH.dbd.CH CH.sub.2 0 2-AcOBu2-310 NMe.sub.2 CH.dbd.CH CH.sub.2 CH.sub.2 0 2-HOEt2-311 NMe.sub.2 CH.dbd.CH CH.sub.2 CH.sub.2 0 2-AcOEt2-312 NMe.sub.2 CH.dbd.CH CH.sub.2 CH.sub.2 0 3-HOPr2-313 NMe.sub.2 CH.dbd.CH CH.sub.2 CH.sub.2 0 3-AcOPr2-314 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.3 0 2-HOEt2-315 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.3 0 2-AcOEt2-316 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.3 0 2-PrnOEt2-317 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.3 0 2-(3-HOOC.PrnO)Et2-318 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.3 0 2-BozOEt2-319 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.3 0 2-(cHxCOO)Et2-320 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.3 0 2-(cPnCOO)Pr2-321 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.3 0 2-(cHxCOO)Pr2-322 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.3 0 3-HOPr2-323 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.3 0 3-AcOPr2-324 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.3 0 2-HOBu2-325 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.3 0 2-AcOBu2-326 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.4 0 2-HOEt2-327 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.4 0 2-AcOEt2-328 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.4 0 3-HOPr2-329 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.4 0 3-AcOPr2-330 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.4 0 2-AcOBu2-331 NMe.sub.2 CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 2-HOEt2-332 NMe.sub.2 CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 2-AcOEt2-333 NMe.sub.2 CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 2-HOPr2-334 NMe.sub.2 CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 2-AcOPr2-335 NMe.sub.2 CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 3-AcOPr2-336 NMe.sub.2 CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 2-AcOBu2-337 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.5 0 2-HOEt2-338 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.5 0 2-AcOEt2-339 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.5 0 3-HOPr2-340 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.5 0 3-AcOPr2-341 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.6 0 2-HOEt2-342 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.6 0 2-AcOEt2-343 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.6 0 3-HOPr2-344 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.6 0 3-AcOPr2-345 NEt.sub.2 CH.dbd.CH CH.sub.2 0 2-HOEt2-346 NEt.sub.2 CH.dbd.CH CH.sub.2 0 2-AcOEt2-347 NEt.sub.2 CH.dbd.CH CH.sub.2 0 2-PrnOEt2-348 NEt.sub.2 CH.dbd.CH CH.sub.2 0 2-(3-HOOC.PrnO)Et2-349 NEt.sub.2 CH.dbd.CH CH.sub.2 0 2-BozOEt2-350 NEt.sub.2 CH.dbd.CH CH.sub.2 0 2-(cHxCOO)Et2-351 NEt.sub.2 CH.dbd.CH CH.sub.2 0 3-HOPr2-352 NEt.sub.2 CH.dbd.CH CH.sub.2 0 3-AcOPr2-353 NEt.sub.2 CH.dbd.CH CH.sub.2 0 3-(3-HOOC.PrnO)Pr2-354 NEt.sub.2 CH.dbd.CH CH.sub.2 0 3-BozOPr2-355 NEt.sub.2 CH.dbd.CH CH.sub.2 0 3-(cHxCOO)Pr2-356 NEt.sub.2 CH.dbd.CH CH.sub.2 0 2-AcOBu2-357 NEt.sub.2 CH.dbd.CH CH.sub.2 CH.sub.2 0 2-HOEt2-358 NEt.sub.2 CH.dbd.CH CH.sub.2 CH.sub.2 0 2-AcOEt2-359 NEt.sub.2 CH.dbd.CH CH.sub.2 CH.sub.2 0 3-AcOPr2-360 NEt.sub.2 CH.dbd.CH CH.sub.2 CH.sub.2 0 3-BozOPr2-361 NEt.sub.2 CH.dbd.CH CH.sub.2 CH.sub.2 0 2-AcOBu2-362 NEt.sub.2 CH.dbd.CH (CH.sub.2).sub.3 0 2-HOEt2-363 NEt.sub.2 CH.dbd.CH (CH.sub.2).sub.3 0 2-AcOEt2-364 NEt.sub.2 CH.dbd.CH (CH.sub.2).sub.3 0 3-HOPr2-365 NEt.sub.2 CH.dbd.CH (CH.sub.2).sub.3 0 3-AcOPr2-366 NEt.sub.2 CH.dbd.CH (CH.sub.2).sub.3 0 2-AcOBu2-367 NEt.sub.2 CH.dbd.CH (CH.sub.2).sub.4 0 2-HOEt2-368 NEt.sub.2 CH.dbd.CH (CH.sub.2).sub.4 0 2-AcOEt2-369 NEt.sub.2 CH.dbd.CH (CH.sub.2).sub.4 0 3-HOPr2-370 NEt.sub.2 CH.dbd.CH (CH.sub.2).sub.4 0 3-AcOPr2-371 NEt.sub.2 CH.dbd.CH (CH.sub.2).sub.4 0 2-AcOBu2-372 NEt.sub.2 CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 2-HOEt2-373 NEt.sub.2 CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 2-AcOEt2-374 NEt.sub.2 CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 2-HOPr2-375 NEt.sub.2 CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 2-AcOPr2-376 NEt.sub.2 CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 3-HOPr2-377 NEt.sub.2 CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 3-AcOPr2-378 NEt.sub.2 CH.dbd.CH (CH.sub.2).sub.5 0 2-HOEt2-379 NEt.sub.2 CH.dbd.CH (CH.sub.2).sub.5 0 2-AcOEt2-380 NEt.sub.2 CH.dbd.CH (CH.sub.2).sub.5 0 3-HOPr2-381 NEt.sub.2 CH.dbd.CH (CH.sub.2).sub.5 0 3-AcOPr2-382 NEt.sub.2 CH.dbd.CH (CH.sub.2).sub.5 0 2-AcOBu2-383 NEt.sub.2 CH.dbd.CH (CH.sub.2).sub.6 0 2-HOEt2-384 NEt.sub.2 CH.dbd.CH (CH.sub.2).sub.6 0 2-AcOEt2-385 NEt.sub.2 CH.dbd.CH (HC2).sub.6 0 3-HOPr2-386 NEt.sub.2 CH.dbd.CH (CH.sub.2).sub.6 0 3-AcOPr2-387 NEt.sub.2 CH.dbd.CH (CH.sub.2).sub.6 0 2-AcOBu2-388 Azi CH.dbd.CH CH.sub.2 0 2-AcOEt2-389 Aze CH.dbd.CH CH.sub.2 0 2-AcOEt2-390 Pip CH.dbd.CH CH.sub.2 1 2-HOEt2-391 Pip CH.dbd.CH CH.sub.2 1 2-AcOEt2-392 Pip CH.dbd.CH CH.sub.2 1 2-PrnOEt2-393 Pip CH.dbd.CH CH.sub.2 1 2-(3-HOOC.PrnO)Et2-394 Pip CH.dbd.CH CH.sub.2 1 2-(3-Mec.PrnO)Et2-395 Pip CH.dbd.CH CH.sub.2 1 2-BozOEt2-396 Pip CH.dbd.CH CH.sub.2 1 2-(cHxCOO)Et2-397 Pip CH.dbd.CH CH.sub.2 1 2-HOPr2-398 Pip CH.dbd.CH CH.sub.2 1 2-FoOPr2-399 Pip CH.dbd.CH CH.sub.2 1 2-AcOPr2-400 Pip CH.dbd.CH CH.sub.2 1 2-(3-HOOC.PrnO)Pr2-401 Pip CH.dbd.CH CH.sub.2 1 2-(cHxCOO)Pr2-402 Pip CH.dbd.CH CH.sub.2 1 3-HOPr2-403 Pip CH.dbd.CH CH.sub.2 1 3-AcOPr2-404 Pip CH.dbd.CH CH.sub.2 1 3-(3-HOOC.PrnO)Pr2-405 Pip CH.dbd.CH CH.sub.2 1 3-BozOPr2-406 Pip CH.dbd.CH CH.sub.2 1 3-(cHxCOO)Pr2-407 Pip CH.dbd.CH CH.sub.2 1 2-HOBu2-408 Pip CH.dbd.CH CH.sub.2 1 2-AcOBu2-409 Pip CH.dbd.CH CH.sub.2 CH.sub.2 1 2-HOEt2-410 Pip CH.dbd.CH CH.sub.2 CH.sub.2 1 2-AcOEt2-411 Pip CH.dbd.CH CH.sub.2 CH.sub.2 1 2-(3-HOOC.PrnO)Et2-412 Pip CH.dbd.CH CH.sub.2 CH.sub.2 1 2-BozOEt2-413 Pip CH.dbd.CH CH.sub.2 CH.sub.2 1 2-(cHxCOO)Et2-414 Pip CH.dbd.CH CH.sub.2 CH.sub.2 1 3-HOPr2-415 Pip CH.dbd.CH CH.sub.2 CH.sub.2 1 3-AcOPr2-416 Pip CH.dbd.CH CH.sub.2 CH.sub.2 1 2-HOBu2-417 Pip CH.dbd.CH CH.sub.2 CH.sub.2 1 2-AcOBu2-418 Pip CH.dbd.CH (CH.sub.2).sub.3 1 2-HOEt2-419 Pip CH.dbd.CH (CH.sub.2).sub.3 1 2-AcOEt2-420 Pip CH.dbd.CH (CH.sub.2).sub.3 1 2-PrnOE.t2-421 Pip CH.dbd.CH (CH.sub.2).sub.3 1 2-(3-HOOC.PrnO)Et2-422 Pip CH.dbd.CH (CH.sub.2).sub.3 1 2-BozOEt2-423 Pip CH.dbd.CH (CH.sub.2).sub.3 I 2-(cHxCOO)Et2-424 Pip CH.dbd.CH (CH.sub.2).sub.3 1 2-HOPr2-425 Pip CH.dbd.CH (CH.sub.2).sub.3 1 2-AcOPr2-426 Pip CH.dbd.CH (CH.sub.2).sub.3 1 2-(3-HOOC.PrnO)Pr2-427 Pip CH.dbd.CH (CH.sub.2).sub.3 1 2-(cPnCOO)Pr2-428 Pip CH.dbd.CH (CH.sub.2).sub.3 1 2-(cHxCOO)Pr2-429 Pip CH.dbd.CH (CH.sub.2).sub.3 1 3-HOPr2-430 Pip CH.dbd.CH (CH.sub.2).sub.3 1 3-AcOPr2-431 Pip CH.dbd.CH (CH.sub.2).sub.3 1 2-HOBu2-432 Pip CH.dbd.CH (CH.sub.2).sub.3 1 2-AcOBu2-433 Pip CH.dbd.CH (CH.sub.2).sub.4 1 2-HOEt2-434 Pip CH.dbd.CH (CH.sub.2).sub.4 1 2-AcOEt2-435 Pip CH.dbd.CH (CH.sub.2).sub.4 1 2-(cHxCOO)Et2-436 Pip CH.dbd.CH (CH.sub.2).sub.4 1 2-HOPr2-437 Pip CH.dbd.CH (CH.sub.2).sub.4 1 2-AcOPr2-438 Pip CH.dbd.CH (CH.sub.2).sub.4 1 3-HOPr2-439 Pip CH.dbd.CH (CH.sub.2).sub.4 1 3-AcOPr2-440 Pip CH.dbd.CH (CH.sub.2).sub.4 1 2-AcOBu2-441 Pip CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 1 2-HOEt2-442 Pip CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 1 2-AcOEt2-443 Pip CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 1 2-HOPr2-444 Pip CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 1 2-AcOPr2-445 Pip CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 1 3-AcOPr2-446 Pip CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 1 2-AcOBu2-447 Pip CH.dbd.CH (CH.sub.2).sub.5 1 2-HOEt2-448 Pip CH.dbd.CH (CH.sub.2).sub.5 1 2-AcOEt2-449 Pip CH.dbd.CH (CH.sub.2).sub.5 1 2-HOPr2-450 Pip CH.dbd.CH (CH.sub.2).sub.5 1 2-AcOPr2-451 Pip CH.dbd.CH (CH.sub.2).sub.5 1 3-HOPr2-452 Pip CH.dbd.CH (CH.sub.2).sub.5 1 3-AcOPr2-453 Pip CH.dbd.CH (CH.sub.2).sub.5 1 2-AcOBu2-454 Pip CH.dbd.CH (CH.sub.2).sub.6 1 2-HOEt2-455 Pip CH.dbd.CH (CH.sub.2).sub.6 1 2-AcOEt2-456 Pip CH.dbd.CH (CH.sub.2).sub.6 1 2-HOPr2-457 Pip CH.dbd.CH (CH.sub.2).sub.6 1 2-AcOPr2-458 Pip CH.dbd.CH (CH.sub.2).sub.6 1 3-HOPr2-459 Pip CH.dbd.CH (CH.sub.2).sub.6 1 3-AcOPr2-460 Pip CH.dbd.CH CH.sub.2 2 2-HOEt2-461 Pip CH.dbd.CH CH.sub.2 2 2-AcOEt2-462 Pip CH.dbd.CH CH.sub.2 2 2-PrnOEt2-463 Pip CH.dbd.CH CH.sub.2 2 2-(3-HOOC.PrnO)Et2-464 Pip CH.dbd.CH CH.sub.2 2 2-BozOEt2-465 Pip CH.dbd.CH CH.sub.2 2 2-(cHxCOO)Et2-466 Pip CH.dbd.CH CH.sub.2 2 3-HOPr2-467 Pip CH.dbd.CH CH.sub.2 2 3-AcOPr2-468 Pip CH.dbd.CH CH.sub.2 2 3-(3-HOOC.PrnO)Pr2-469 Pip CH.dbd.CH CH.sub.2 2 3-BozOPr2-470 Pip CH.dbd.CH CH.sub.2 2 3-(cHxCOO)Pr2-471 Pip CH.dbd.CH CH.sub.2 2 2-AcOBu2-472 Pip CH.dbd.CH CH.sub.2 CH.sub.2 2 2-HOEt2-473 Pip CH.dbd.CH CH.sub.2 CH.sub.2 2 2-AcOEt2-474 Pip CH.dbd.CH CH.sub.2 CH.sub.2 2 3-AcOPr2-475 Pip CH.dbd.CH CH.sub.2 CH.sub.2 2 3-BozOPr2-476 Pip CH.dbd.CH CH.sub.2 CH.sub.2 2 2-AcOBu2-477 Pip CH.dbd.CH (CH.sub.2).sub.3 2 2-HOEt2-478 Pip CH.dbd.CH (CH.sub.2).sub.3 2 2-AcOEt2-479 Pip CH.dbd.CH (CH.sub.2).sub.3 2 3-HOPr2-480 Pip CH.dbd.CH (CH.sub.2).sub.3 2 3-AcOPr2-481 Pip CH.dbd.CH (CH.sub.2).sub.3 2 2-AcOBu2-482 Pip CH.dbd.CH (CH.sub.2).sub.4 2 2-HOEt2-483 Pip CH.dbd.CH (CH.sub.2).sub.4 2 2-AcOEt2-484 Pip CH.dbd.CH (CH.sub.2).sub.4 2 3-HOPr2-485 Pip CH.dbd.CH (CH.sub.2).sub.4 2 3-AcOPr2-486 Pip CH.dbd.CH (CH.sub.2).sub.4 2 2-AcOBu2-487 Pip CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 2 2-HOEt2-488 Pip CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 2 2-AcOEt2-489 Pip CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 2 2-HOPr2-490 Pip CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 2 2-AcOPr2-491 Pip CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 2 3-HOPr2-492 Pip CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 2 3-AcOPr2-493 Pip CH.dbd.CH (CH.sub.2).sub.5 2 2-HOEt2-494 Pip CH.dbd.CH (CH.sub.2).sub.5 2 2-AcOEt2-495 Pip CH.dbd.CH (CH.sub.2).sub.5 2 3-HOPr2-496 Pip CH.dbd.CH (CH.sub.2).sub.5 2 3-AcOPr2-497 Pip CH.dbd.CH (CH.sub.2).sub.5 2 2-AcOBu2-498 Pip CH.dbd.CH (CH.sub.2).sub.6 2 2-HOEt2-499 Pip CH.dbd.CH (CH.sub.2).sub.6 2 2-AcOEt2-500 Pip CH.dbd.CH (CH.sub.2).sub.6 2 3-HOPr2-501 Pip CH.dbd.CH (CH.sub.2).sub.6 2 3-AcOPr2-502 Pip CH.dbd.CH (CH.sub.2).sub.6 2 2-AcOBu2-503 Pyr CH.dbd.CH (CH.sub.2).sub.6 1 2-AcOEt2-504 Pyr CH.dbd.CH CH.sub.2 1 2-AcOEt2-505 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 CH.sub.2 OH2-506 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-HOEt2-507 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-FoOEt2-508 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-AcOEt2-509 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-PrnOEt2-510 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-ByrOEt2-511 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-iByrOEt2-512 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-ValOEt2-513 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-iValOEt2-514 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-(PhAcO)Et2-515 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-(HOOC.AcO)Et2-516 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-(3-HOOC.PrnO)Et2-517 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-(3-Mec.PrnO)Et2-518 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-(3-Etc.PrnO)Et2-519 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-(3-Prc.PrnO)Et2-520 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-(3-Phc.PrnO)Et2-521 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-[3-(4-MePhcO)PrnO]Et2-522 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-(3-PhPrnO)Et2-523 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-(3-PhPrnO)Et2-524 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-BozOEt2-525 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-(4-MeBozO)Et2-526 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-(4-MeOBozO)Et2-527 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-(4-FBozO)Et2-528 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-(4-ClBozo)Et2-529 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-(cPrCOO)Et2-530 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-(cBuCOO)Et2-531 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-(cPnCOO)Et2-532 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-(cHxCOO)Et2-533 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-HOPr2-534 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-FoOPr2-535 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-AcOPr2-536 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-PrnOPr2-537 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-(3-HOOC.PrnO)Pr2-538 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-(3-Mec.PrnO)Pr2-539 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-(3-Etc.PrnO)Pr2-540 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-(3-Phc.PrnO)Et2-541 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-[3-(4-MePhcO)PrnO]Et2-542 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-(PhAcO)Pr2-543 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-BozOPr2-544 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-(cPnCOO)Pr2-545 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-(cHxCOO)Pr2-546 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 3-HOPr2-547 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 3-FoOPr2-548 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 3-AcOPr2-549 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 3-PrnOPr2-550 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 3-(3-HOOC.PrnO)Pr2-551 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 3-(3-Mec.PrnO)Pr2-552 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 3-(3-Etc.PrnO)Pr2-553 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 3-BozOPr2-554 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 3-(cPnCOO)Pr2-555 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 3-(cHxCOO)Pr2-556 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-HOBu2-557 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-AcOBu2-558 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-(3-HOOC.PrnO)Bu2-559 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-BozOBu2-560 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-(cHxCOO)Bu2-561 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-HOEt2-562 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-FoOEt2-563 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-AcOEt2-564 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-PrnOEt2-565 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-ValOEt2-566 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-(PhAcO)Et2-567 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-(3-HOOC.PrnO)Et2-568 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-(3-Mec.PrnO)Et2-569 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-(3-Etc.PrnO)Et2-570 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-(3-PhPrnO)Et2-571 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-BozOEt2-572 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-(4-MeBozO)Et2-573 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-(4-FBozO)Et2-574 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-(4-ClBozO)Et2-575 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-(cPrCOO)Et2-576 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-(cBuCOO)Et2-577 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-(cPnCOO)Et2-578 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-(cHxCOO)Et2-579 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-HOPr2-580 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-FoOPr2-581 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-AcOPr2-582 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-PrnOPr2-583 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-(3-HOOC.PrnO)Pr2-584 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-(3-Mec.PrnO)Pr2-585 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-BozOPr2-586 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-(cPnCOO)Pr2-587 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-(cHxCOO)Pr2-588 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 3-HOPr2-589 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 3-AcOPr2-590 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 3-PrnOPr2-591 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 3-(3-HOOC.PrnO)Pr2-592 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 3-BozOPr2-593 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 3-(cPnCOO)Pr2-594 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 3-(cHxCOO)Pr2-595 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-HOBu2-596 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-AcOBu2-597 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-(3-HOOC.PrnO)Bu2-598 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-BozOBu2-599 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-(cHxCOO)Bu2-600 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-HOEt2-601 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-FoOEt2-602 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-AcOEt2-603 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-PrnOEt2-604 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-ByrOEt2-605 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-iByrOEt2-606 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-ValOEt2-607 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-(3-HOOC.PrnO)Et2-608 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-(3-Mec.PrnO)Et2-609 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-(3-Etc.PrnO)Et2-610 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-(PhAcO)Et2-611 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-BozOEt2-612 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-(4-MeBozO)Et2-613 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-(4-MeOBozO)Et2-614 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-(4-FBozO)Et2-615 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-(4-ClBozO)Et2-616 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-(cPrCOO)Et2-617 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-(cBuCOO)Et2-618 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-(cPnCOO)Et2-619 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-(cHxCOO)Et2-620 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-HOPr2-621 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-AcOPr2-622 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-PrnOPr2-623 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-(3-HOOC.PrnO)Pr2-624 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-(3-Etc.PrnO)Pr2-625 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-BozOPr2-626 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-(cHxCOO)Pr2-627 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 3-HOPr2-628 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 3-AcOPr2-629 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 3-(3-HOOC.PrnO)Pr2-630 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 3-(3-Mec.PrnO)Pr2-631 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 3-BozOPr2-632 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 3-(cHxCOO)Pr2-633 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-HOBu2-634 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-AcOBu2-635 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-(3-HOOC.PrnO)Bu2-636 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-BozOBu2-637 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-(cHxCOO)Bu2-638 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 2-HOEt2-639 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 2-FoOEt2-640 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 2-ACOEt2-641 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 2-PrnOEt2-642 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 2-(3-HOOC.PrnO)Et2-643 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 2-(3-Mec.PrnO)Et2-644 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 2-BozOEt2-645 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 2-(cHxCOO)Et2-646 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 2-HOPr2-647 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 2-AcOPr2-648 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 2-(3-HOOC.PrnO)Pr2-649 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 2-BozOPr2-650 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 2-(cHxCOO)Pr2-651 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 3-HOPr2-652 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 3-AcOPr2-653 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 3-(3-HOOC.PrnO)Pr2-654 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 3-BozOPr2-655 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 3-(cHxCOO)Pr2-656 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 2-HOBu2-657 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 2-AcOBu2-658 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 2-(3-HOOC.PrnO)Bu2-659 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 2-(cHxCOO)Bu2-660 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 2-HOEt2-661 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 2-AcOEt2-662 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 2-(3-HOOC.PrnO)Et2-663 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 2-BozOEt2-664 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 2-(cHxCOO)Et2-665 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 2-HOPr2-666 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 2-AcOPr2-667 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 2-BozOPr2-668 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 2-(cHxCOO)Pr2-669 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 3-HOPr2-670 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 3-AcOPr2-671 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 3-(3-HOOC.PrnO)Pr2-672 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 3-BozOPr2-673 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 3-(cHxCOO)Pr2-674 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 2-HOBu2-675 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 2-AcOBu2-676 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 2-(3-Etc.PrnO)Bu2-677 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 2-(cHxCOO)Bu2-678 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 2-HOEt2-679 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 2-AcOEt2-680 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 2-(3-HOOC.PrnO)Et2-681 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 2-BozOEt2-682 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 2-(cHxCOO)Et2-683 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 2-HOPr2-684 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 2-AcOPr2-685 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 2-(3-HOOC.PrnO)Pr2-686 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 2-BozOPr2-687 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 2-(cHxCOO)Pr2-688 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 3-HOPr2-689 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 3-AcOPr2-690 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 3-(3-HOOC.PrnO)pr2-691 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 3-BozOPr2-692 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 3-(cHxCOO)Pr2-693 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 2-HOBu2-694 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 2-AcOBu2-695 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 2-(3-HOOC.PrnO)Bu2-696 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 2-(cHxCOO)Bu2-697 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 2-HOEt2-698 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 2-AcOEt2-699 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 2-(3-HOOC.PrnO)Et2-700 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 2-(cHxCOO)Et2-701 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 2-HOPr2-702 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 2-AcOPr2-703 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 2-(3-HOOC.PrnO)Pr2-704 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 2-(cHxCOO)Pr2-705 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 3-HOPr2-706 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 3-AcOPr2-707 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 3-(3-HOOC.PrnO)Pr2-708 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 3-(cHxCOO)Pr2-709 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 2-HOBu2-710 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 2-AcOBu2-711 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 2-(3-HOOC.PrnO)Bu2-712 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 2-(cHxCOO)Bu2-713 Pyr CH.sub.2 CH.sub.2 CH.sub.2 0 2-HOEt2-714 Pyr CH.sub.2 CH.sub.2 CH.sub.2 0 2-FoOEt2-715 Pyr CH.sub.2 CH.sub.2 CH.sub.2 0 2-AcOEt2-716 Pyr CH.sub.2 CH.sub.2 CH.sub.2 0 2-PrnOEt2-717 Pyr CH.sub.2 CH.sub.2 CH.sub.2 0 2-(3-HOOC.PrnO)Et2-718 Pyr CH.sub.2 CH.sub.2 CH.sub.2 0 2-(3-Mec.PrnO)Et2-719 Pyr CH.sub.2 CH.sub.2 CH.sub.2 0 2-(3-Etc.PrnO)Et2-720 Pyr CH.sub.2 CH.sub.2 CH.sub.2 0 2-BozOEt2-721 Pyr CH.sub.2 CH.sub.2 CH.sub.2 0 2-(cPnCOO)Et2-722 Pyr CH.sub.2 CH.sub.2 CH.sub.2 0 2-(cHxCOO)Et2-723 Pyr CH.sub.2 CH.sub.2 CH.sub.2 0 2-HOPr2-724 Pyr CH.sub.2 CH.sub.2 CH.sub.2 0 2-AcOPr2-725 Pyr CH.sub.2 CH.sub.2 CH.sub.2 0 2-(3-HOOC.PrnO)Pr2-726 Pyr CH.sub.2 CH.sub.2 CH.sub.2 0 2-BozOPr2-727 Pyr CH.sub.2 CH.sub.2 CH.sub.2 0 2-(cHxCOO)Pr2-728 Pyr CH.sub.2 CH.sub.2 CH.sub.2 0 3-HOPr2-729 Pyr CH.sub.2 CH.sub.2 CH.sub.2 0 3-FoOPr2-730 Pyr CH.sub.2 CH.sub.2 CH.sub.2 0 3-AcOPr2-731 Pyr CH.sub.2 CH.sub.2 CH.sub.2 0 3-(3-HOOC.PrnO)Pr2-732 Pyr CH.sub.2 CH.sub.2 CH.sub.2 0 3-(3-Mec.PrnO)Pr2-733 Pyr CH.sub.2 CH.sub.2 CH.sub.2 0 3-BozOPr2-734 Pyr CH.sub.2 CH.sub.2 CH.sub.2 0 3-(cHxCOO)Pr2-735 Pyr CH.sub.2 CH.sub.2 CH.sub.2 0 2-HOBu2-736 Pyr CH.sub.2 CH.sub.2 CH.sub.2 0 2-AcOBu2-737 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-HOEt2-738 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-AcOEt2-739 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-(3-HOOC.PrnO)Et2-740 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-(3-Mec.PrnO)Et2-741 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-BozOEt2-742 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-(cPnCOO)Et2-743 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-(cHxCOO)Et2-744 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-HOPr2-745 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-AcOPr2-746 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-(3-HOOC.PrnO)Pr2-747 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-(cHxCOO)Pr2-748 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 3-HOPr2-749 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 3-AcOPr2-750 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 3-(cHxCOO)Pr2-751 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-HOBu2-752 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-AcOBu2-753 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-HOEt2-754 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-AcOEt2-755 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-PrnOEt2-756 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-(3-HOOC.PrnO)Et2-757 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-BozOEt2-758 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-(cPnCOO)Et2-759 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-(cHxCOO)Et2-760 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-HOPr2-761 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-AcOPr2-762 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-BozOPr2-763 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 3-HOPr2-764 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 3-AcOPr2-765 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 3-(3-HOOC.PrnO)Pr2-766 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-HOBu2-767 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-AcOBu2-768 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 2-HOEt2-769 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 2-AcOEt2-770 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 2-(3-HOOC.PrnO)Et2-771 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 2-(cHxCOO)Et2-772 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 2-HOPr2-773 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 2-AcOPr2-774 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 3-HOPr2-775 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 3-AcOPr2-776 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 2-HOBu2-777 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 2-AcOBu2-778 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 2-HOEt2-779 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 2-AcOEt2-780 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 2-HOPr2-781 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 2-AcOPr2-782 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 3-HOPr2-783 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 3-AcOPr2-784 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 2-HOBu2-785 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 2-AcOBu2-786 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 2-HOEt2-787 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 2-AcOEt2-788 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 2-HOPr2-789 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 2-AcOPr2-790 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 2-(cHxCOO)Pr2-791 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 3-HOPr2-792 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 3-AcOPr2-793 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 2-AcOBu2-794 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 2-HOEt2-795 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 2-AcOEt2-796 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 2-HOPr2-797 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 2-AcOPr2-798 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 3-HOPr2-799 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 3-AcOPr2-800 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 2-AcOBu2-801 NMe.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-HOEt2-802 NMe.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-AcOEt2-803 NMe.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-PrnOEt2-804 NMe.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-(3-HOOC.PrnO)Et2-805 NMe.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-(3-Mec.PrnO)Et2-806 NMe.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-BozOEt2-807 NMe.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-(cHxCOO)Et2-808 NMe.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-HOPr2-809 NMe.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-(cHxCOO)Pr2-810 NMe.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 3-HOPr2-811 NMe.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 3-AcOPr2-812 NMe.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-HOBu2-813 NMe.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-AcOBu2-814 NMe.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-HOEt2-815 NMe.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-AcOEt2-816 NMe.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 3-HOPr2-817 NMe.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 3-AcOPr2-818 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-HOEt2-819 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-AcOEt2-820 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-PrnOEt2-821 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-(3-HOOC.PrnO)Et2-822 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-BozOEt2-823 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-(cHxCOO)Et2-824 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-(cPnCOO)Pr2-825 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-(cHxCOO)Pr2-826 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 3-HOPr2-827 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 3-AcOPr2-828 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-HOBu2-829 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-AcOBu2-830 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 2-HOEt2-831 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 2-AcOEt2-832 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 3-HOPr2-833 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 3-AcOPr2-834 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 2-AcOBu2-835 NMe.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 2-HOEt2-836 NMe.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 2-AcOEt2-837 NMe.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 2-HOPr2-838 NMe.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 2-AcOPr2-839 NMe.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 3-AcOPr2-840 NMe.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 2-AcOBu2-841 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 2-HOEt2-842 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 2-AcOPr2-843 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 3-HOPr2-844 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 3-AcOPr2-845 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 2-HOEt2-846 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 2-AcOEt2-847 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 3-HOPr2-848 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 3-AcOPr2-849 Azi CH.sub.2 CH.sub.2 CH.sub.2 0 2-AcOEt2-850 Aze CH.sub.2 CH.sub.2 CH.sub.2 0 2-AcOEt2-851 Pip (CH.sub.2).sub.3 CH.sub.2 0 CH.sub.2 OH2-852 Pip (CH.sub.2).sub.3 CH.sub.2 0 2-HOEt2-853 Pip (CH.sub.2).sub.3 CH.sub.2 0 2-FoOEt2-854 Pip (CH.sub.2).sub.3 CH.sub.2 0 2-AcOEt2-855 Pip (CH.sub.2).sub.3 CH.sub.2 0 2-PrnOEt2-856 Pip (CH.sub.2).sub.3 CH.sub.2 0 2-ByrOEt2-857 Pip (CH.sub.2).sub.3 CH.sub.2 0 2-iByrOEt2-858 Pip (CH.sub.2).sub.3 CH.sub.2 0 2-ValOEt2-859 Pip (CH.sub.2).sub.3 CH.sub.2 0 2-iValOEt2-860 Pip (CH.sub.2).sub.3 CH.sub.2 0 2-(PhAcO)Et2-861 Pip (CH.sub.2).sub.3 CH.sub.2 0 2-(HOOC.AcO)Et2-862 Pip (CH.sub.2).sub.3 CH.sub.2 0 2-(3-Hooc.prnO)Et2-863 Pip (CH.sub.2).sub.3 CH.sub.2 0 2-(3-Mec.PrnO)Et2-864 Pip (CH.sub.2).sub.3 CH.sub.2 0 2-(3-Etc.PrnO)Et2-865 Pip (CH.sub.2).sub.3 CH.sub.2 0 2-(3-Prc.PrnO)Et2-866 Pip (CH.sub.2).sub.3 CH.sub.2 0 2-(3-Phc.PrnO)Et2-867 Pip (CH.sub.2).sub.3 CH.sub.2 0 2-[3-(4-MePhcO)PrnO]Et2-868 Pip (CH.sub.2).sub.3 CH.sub.2 0 2-(3-PhPrnO)Et2-869 Pip (CH.sub.2).sub.3 CH.sub.2 0 2-(3-PhPrnO)Et2-870 Pip (CH.sub.2).sub.3 CH.sub.2 0 2-BozOEt2-871 Pip (CH.sub.2).sub.3 CH.sub.2 0 2-(4-MeBozO)Et2-872 Pip (CH.sub.2).sub.3 CH.sub.2 0 2-(4-MeOBozo)Et2-873 Pip (CH.sub.2).sub.3 CH.sub.2 0 2-(4-FBozO)Et2-874 Pip (CH.sub.2).sub.3 CH.sub.2 0 2-(4-ClBozO)Et2-875 Pip (CH.sub.2).sub.3 CH.sub.2 0 2-(cPrCOO)Et2-876 Pip (CH.sub.2).sub.3 CH.sub.2 0 2-(cBuCOO)Et2-877 Pip (CH.sub.2).sub.3 CH.sub.2 0 2-(cPnCOO)Et2-878 Pip (CH.sub.2).sub.3 CH.sub.2 0 2-(cHxCoo)Et2-879 Pip (CH.sub.2).sub.3 CH.sub.2 0 2-HOPr2-880 Pip (CH.sub.2).sub.3 CH.sub.2 0 2-FoOPr2-881 Pip (CH.sub.2).sub.3 CH.sub.2 0 2-AcOPr2-882 Pip (CH.sub.2).sub.3 CH.sub.2 0 2-PrnOPr2-883 Pip (CH.sub.2).sub.3 CH.sub.2 0 2-(3-HOOC.PrnO)Pr2-884 Pip (CH.sub.2).sub.3 CH.sub.2 0 2-(3-Mec.PrnO)Pr2-885 Pip (CH.sub.2).sub.3 CH.sub.2 0 2-(3-Etc.PrnO)Pr2-886 Pip (CH.sub.2).sub.3 CH.sub.2 0 2-(3-Phc.PrnO)Et2-887 Pip (CH.sub.2).sub.3 CH.sub.2 0 2-[3-(4-MePhcO)PrnO]Et2-888 Pip (CH.sub.2).sub.3 CH.sub.2 0 2-(PhAcO)Pr2-889 Pip (CH.sub.2).sub.3 CH.sub.2 0 2-BozOPr2-890 Pip (CH.sub.2).sub.3 CH.sub.2 0 2-(cPnCOO)Pr2-891 Pip (CH.sub.2).sub.3 CH.sub.2 0 2-(cHxCOO)Pr2-892 Pip (CH.sub.2).sub.3 CH.sub.2 0 3-HOPr2-893 Pip (CH.sub.2).sub.3 CH.sub.2 0 3-FoOPr2-894 Pip (CH.sub.2).sub.3 CH.sub.2 0 3-AcOPr2-895 Pip (CH.sub.2).sub.3 CH.sub.2 0 3-PrnOPr2-896 Pip (CH.sub.2).sub.3 CH.sub.2 0 3-(3-HOOC.PrnO)Pr2-897 Pip (CH.sub.2).sub.3 CH.sub.2 0 3-(3-Mec.PrnO)Pr2-898 Pip (CH.sub.2).sub.3 CH.sub.2 0 3-(3-Etc.PrnO)Pr2-899 Pip (CH.sub.2).sub.3 CH.sub.2 0 3-BozOPr2-900 Pip (CH.sub.2).sub.3 CH.sub.2 0 3-(cPnCOO)Pr2-901 Pip (CH.sub.2).sub.3 CH.sub.2 0 3-(cHxCOO)Pr2-902 Pip (CH.sub.2).sub.3 CH.sub.2 0 2-HOBu2-903 Pip (CH.sub.2).sub.3 CH.sub.2 0 2-AcOBu2-904 Pip (CH.sub.2).sub.3 CH.sub.2 0 2-(3-HOOC.PrnO)Bu2-905 Pip (CH.sub.2).sub.3 CH.sub.2 0 2-BozOBu2-906 Pip (CH.sub.2).sub.3 CH.sub.2 0 2-(cHxCOO)Bu2-907 Pip (CH.sub.2).sub.3 CH.sub.2 CH.sub.2 0 2-HOEt2-908 Pip (CH.sub.2).sub.3 CH.sub.2 CH.sub.2 0 2-FoOEt2-909 Pip (CH.sub.2).sub.3 CH.sub.2 CH.sub.2 0 2-AcOEt2-910 Pip (CH.sub.2).sub.3 CH.sub.2 CH.sub.2 0 2-PrnOEt2-911 Pip (CH.sub.2).sub.3 CH.sub.2 CH.sub.2 0 2-ValOEt2-912 Pip (CH.sub.2).sub.3 CH.sub.2 CH.sub.2 0 2-(PhAcO)Et2-913 Pip (CH.sub.2).sub.3 CH.sub.2 CH.sub.2 0 2-(3-HOOC.PrnO)Et2-914 Pip (CH.sub.2).sub.3 CH.sub.2 CH.sub.2 0 2-(3-Mec.PrnO)Et2-915 Pip (CH.sub.2).sub.3 CH.sub.2 CH.sub.2 0 2-(3-Etc.PrnO)Et2-916 Pip (CH.sub.2).sub.3 CH.sub.2 CH.sub.2 0 2-(3-PhPrnO)Et2-917 Pip (CH.sub.2).sub.3 CH.sub.2 CH.sub.2 0 2-BozOEt2-918 Pip (CH.sub.2).sub.3 CH.sub.2 CH.sub.2 0 2-(4-MeBozO)Et2-919 Pip (CH.sub.2).sub.3 CH.sub.2 CH.sub.2 0 2-(4-FBozO)Et2-920 Pip (CH.sub.2).sub.3 CH.sub.2 CH.sub.2 0 2-(4-ClBozO)Et2-921 Pip (CH.sub.2).sub.3 CH.sub.2 CH.sub.2 0 2-(cPrCOO)Et2-922 Pip (CH.sub.2).sub.3 CH.sub.2 CH.sub.2 0 2-(cBuCOO)Et2-923 Pip (CH.sub.2).sub.3 CH.sub.2 CH.sub.2 0 2-(cPnCOO)Et2-924 Pip (CH.sub.2).sub.3 CH.sub.2 CH.sub.2 0 2-(cHxCOO)Et2-925 Pip (CH.sub.2).sub.3 CH.sub.2 CH.sub.2 0 2-HOPr2-926 Pip (CH.sub.2).sub.3 CH.sub.2 CH.sub.2 0 2-FoOPr2-927 Pip (CH.sub.2).sub.3 CH.sub.2 CH.sub.2 0 2-AcOPr2-928 Pip (CH.sub.2).sub.3 CH.sub.2 CH.sub.2 0 2-PrnOPr2-929 Pip (CH.sub.2).sub.3 CH.sub.2 CH.sub.2 0 2-(3-HOOC.PrnO)Pr2-930 Pip (CH.sub.2).sub.3 CH.sub.2 CH.sub.2 0 2-(3-Mec.PrnO)Pr2-931 Pip (CH.sub.2).sub.3 CH.sub.2 CH.sub.2 0 2-BozOPr2-932 Pip (CH.sub.2).sub.3 CH.sub.2 CH.sub.2 0 2-(cPnCOO)Pr2-933 Pip (CH.sub.2).sub.3 CH.sub.2 CH.sub.2 0 2-(cHxCOO)Pr2-934 Pip (CH.sub.2).sub.3 CH.sub.2 CH.sub.2 0 3-HOPr2-935 Pip (CH.sub.2).sub.3 CH.sub.2 CH.sub.2 0 3-AcOPr2-936 Pip (CH.sub.2).sub.3 CH.sub.2 CH.sub.2 0 3-PrnOPr2-937 Pip (CH.sub.2).sub.3 CH.sub.2 CH.sub.2 0 3-(3-HOOC.PrnO)Pr2-938 Pip (CH.sub.2).sub.3 CH.sub.2 CH.sub.2 0 3-BozOPr2-939 Pip (CH.sub.2).sub.3 CH.sub.2 CH.sub.2 0 3-(cPnCOO)Pr2-940 Pip (CH.sub.2).sub.3 CH.sub.2 CH.sub.2 0 3-(cHxCOO)Pr2-941 Pip (CH.sub.2).sub.3 CH.sub.2 CH.sub.2 0 2-HOBu2-942 Pip (CH.sub.2).sub.3 CH.sub.2 CH.sub.2 0 2-AcOBu2-943 Pip (CH.sub.2).sub.3 CH.sub.2 CH.sub.2 0 2-(3-HOOC.PrnO)Bu2-944 Pip (CH.sub.2).sub.3 CH.sub.2 CH.sub.2 0 2-BozOBu2-945 Pip (CH.sub.2).sub.3 CH.sub.2 CH.sub.2 0 2-(cHxCOO)Bu2-946 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.3 0 2-HOEt2-947 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.3 0 2-FoOEt2-948 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.3 0 2-AcOEt2-949 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.3 0 2-PrnOEt2-950 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.3 0 2-ByrOEt2-951 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.3 0 2-iByrOEt2-952 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.3 0 2-ValOEt2-953 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.3 0 2-(3-HOOC.PrnO)Et2-954 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.3 0 2-(3-Mec.PrnO)Et2-955 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.3 0 2-(3-Etc.PrnO)Et2-956 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.3 0 2-(PhAcO)Et2-957 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.3 0 2-BozOEt2-958 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.3 0 2-(4-MeBozo)Et2-959 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.3 0 2-(4-MeOBozO)Et2-960 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.3 0 2-(4-FBozO)Et2-961 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.3 0 2-(4-ClBozO)Et2-962 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.3 0 2-(cPrCOO)Et2-963 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.3 0 2-(cBuCOO)Et2-964 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.3 0 2-(cPnCOO)Et2-965 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.3 0 2-(cHxCOO)Et2-966 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.3 0 2-HOPr2-967 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.3 0 2-AcOPr2-968 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.3 0 2-PrnOPr2-969 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.3 0 2-(3-HOOC.PrnO)Pr2-970 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.3 0 2-(3-Etc.PrnO)Pr2-971 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.3 0 2-BozOPr2-972 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.3 0 2-(cHxCOO)Pr2-973 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.3 0 3-HOPr2-974 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.3 0 3-AcOPr2-975 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.3 0 3-(3-HOOC.PrnO)Pr2-976 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.3 0 3-(3-Mec.PrnO)Pr2-977 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.3 0 3-BozOPr2-978 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.3 0 3-(cHxCOO)Pr2-979 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.3 0 2-HOBu2-980 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.3 0 2-AcOBu2-981 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.3 0 2-(3-HOOC.PrnO)Bu2-982 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.3 0 2-BozOBu2-983 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.3 0 2-(cHxCOO)Bu2-984 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.4 0 2-HOEt2-985 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.4 0 2-FoOEt2-986 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.4 0 2-AcOEt2-987 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.4 0 2-PrnOEt2-988 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.4 0 2-(3-HOOC.PrnO)Et2-989 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.4 0 2-(3-Mec.PrnO)Et2-990 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.4 0 2-BozOEt2-991 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.4 0 2-(cHxCOO)Et2-992 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.4 0 2-HOPr2-993 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.4 0 2-AcOPr2-994 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.4 0 2-(3-HOOC.PrnO)Pr2-995 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.4 0 2-BozOPr2-996 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.4 0 2-(cHxCOO)Pr2-997 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.4 0 3-HOPr2-998 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.4 0 3-AcOPr2-999 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.4 0 3-(3-HOOC.PrnO)Pr2-1000 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.4 0 3-BozOPr2-1001 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.4 0 3-(cHxCOO)Pr2-1002 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.4 0 2-HOBu2-1003 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.4 0 2-AcOBu2-1004 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.4 0 2-(3-HOOC.PrnO)Bu2-1005 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.4 0 2-(cHxCOO)Bu2-1006 Pip (CH.sub.2).sub.3 CH.sub.2 CH(Me)CH.sub.2 0 2-HOEt2-1007 Pip (CH.sub.2).sub.3 CH.sub.2 CH(Me)CH.sub.2 0 2-AcOEt2-1008 Pip (CH.sub.2).sub.3 CH.sub.2 CH(Me)CH.sub.2 0 2-(3-HOOC.PrnO)Et2-1009 Pip (CH.sub.2).sub.3 CH.sub.2 CH(Me)CH.sub.2 0 2-BozOEt2-1010 Pip (CH.sub.2).sub.3 CH.sub.2 CH(Me)CH.sub.2 0 2-(cHxCOO)Et2-1011 Pip (CH.sub.2).sub.3 CH.sub.2 CH(Me)CH.sub.2 0 2-HOPr2-1012 Pip (CH.sub.2).sub.3 CH.sub.2 CH(Me)CH.sub.2 0 2-AcOPr2-1013 Pip (CH.sub.2).sub.3 CH.sub.2 CH(Me)CH.sub.2 0 2-BozOPr2-1014 Pip (CH.sub.2).sub.3 CH.sub.2 CH(Me)CH.sub.2 0 2-(cHxCOO)Pr2-1015 Pip (CH.sub.2).sub.3 CH.sub.2 CH(Me)CH.sub.2 0 3-HOPr2-1016 Pip (CH.sub.2).sub.3 CH.sub.2 CH(Me)CH.sub.2 0 3-AcOPr2-1017 Pip (CH.sub.2).sub.3 CH.sub.2 CH(Me)CH.sub.2 0 3-(3-HOOC.PrnO)Pr2-1018 Pip (CH.sub.2).sub.3 CH.sub.2 CH(Me)CH.sub.2 0 3-BozOPr2-1019 Pip (CH.sub.2).sub.3 CH.sub.2 CH(Me)CH.sub.2 0 3-(cHxCOO)Pr2-1020 Pip (CH.sub.2).sub.3 CH.sub.2 CH(Me)CH.sub.2 0 2-HOBu2-1021 Pip (CH.sub.2).sub.3 CH.sub.2 CH(Me)CH.sub.2 0 2-AcOBu2-1022 Pip (CH.sub.2).sub.3 CH.sub.2 CH(Me)CH.sub.2 0 2-(3-Etc.PrnO)Bu2-1023 Pip (CH.sub.2).sub.3 CH.sub.2 CH(Me)CH.sub.2 0 2-(cHxCOO)Bu2-1024 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.5 0 2-HOEt2-1025 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.5 0 2-AcOEt2-1026 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.5 0 2-(3-HOOC.PrnO)Et2-1027 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.5 0 2-BozOEt2-1028 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.5 0 2-(cHxCOO)Et2-1029 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.5 0 2-HOPr2-1030 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.5 0 2-AcOPr2-1031 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.5 0 2-(3-HOOC.PrnO)Pr2-1032 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.5 0 2-BozOPr2-1033 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.5 0 2-(cHxCOO)Pr2-1034 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.5 0 3-HOPr2-1035 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.5 0 3-AcOPr2-1036 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.5 0 3-(3-HOOC.PrnO)Pr2-1037 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.5 0 3-BozOPr2-1038 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.5 0 3-(cHxCOO)Pr2-1039 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.5 0 2-HOBu2-1040 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.5 0 2-AcOBu2-1041 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.5 0 2-(3-HOOC.PrnO)Bu2-1042 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.5 0 2-(cHxCOO)Bu2-1043 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.6 0 2-HOEt2-1044 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.6 0 2-AcOEt2-1045 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.6 0 2-(3-HOOC.PrnO)Et2-1046 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.6 0 2-(cHxCOO)Et2-1047 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.6 0 2-HOPr2-1048 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.6 0 2-AcOPr2-1049 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.6 0 2-(3-HOOC.PrnO)Pr2-1050 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.6 0 2-(cHxCOO)Pr2-1051 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.6 0 3-HOPr2-1052 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.6 0 3-AcOPr2-1053 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.6 0 3-(3-HOOC.PrnO)Pr2-1054 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.6 0 3-(cHxCOO)Pr2-1055 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.6 0 2-HOBu2-1056 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.6 0 2-AcOBu2-1057 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.6 0 2-(3-HOOC.PrnO)Bu2-1058 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.6 0 2-(cHxCOO)Bu2-1059 Pip CH.sub.2 CH.sub.2 0 2-HOEt2-1060 Pip CH.sub.2 CH.sub.2 0 2-FoOEt2-1061 Pip CH.sub.2 CH.sub.2 0 2-AcOEt2-1062 Pip CH.sub.2 CH.sub.2 0 2-PrnOEt2-1063 Pip CH.sub.2 CH.sub.2 0 2-(3-HOOC.PrnO)Et2-1064 Pip CH.sub.2 CH.sub.2 0 2-(3-Mec.PrnO)Et2-1065 Pip CH.sub.2 CH.sub.2 0 2-(3-Etc.PrnO)Et2-1066 Pip CH.sub.2 CH.sub.2 0 2-BozOEt2-1067 Pip CH.sub.2 CH.sub.2 0 2-(cPnCOO)Et2-1068 Pip CH.sub.2 CH.sub.2 0 2-(cHxCOO)Et2-1069 Pip CH.sub.2 CH.sub.2 0 2-HOPr2-1070 Pip CH.sub.2 CH.sub.2 0 2-AcOPr2-1071 Pip CH.sub.2 CH.sub.2 0 2-(3-HOOC.PrnO)Pr2-1072 Pip CH.sub.2 CH.sub.2 0 2-BozOPr2-1073 Pip CH.sub.2 CH.sub.2 0 2-(cHxCOO)Pr2-1074 Pip CH.sub.2 CH.sub.2 0 3-HOPr2-1075 Pip CH.sub.2 CH.sub.2 0 3-FoOPr2-1076 Pip CH.sub.2 CH.sub.2 0 3-AcOPr2-1077 Pip CH.sub.2 CH.sub.2 0 3-(3-HOOC.PrnO)Pr2-1078 Pip CH.sub.2 CH.sub.2 0 3-(3-Mec.PrnO)Pr2-1079 Pip CH.sub.2 CH.sub.2 0 3-BozOPr2-1080 Pip CH.sub.2 CH.sub.2 0 3-(cHxCOO)Pr2-1081 Pip CH.sub.2 CH.sub.2 0 2-HOBu2-1082 Pip CH.sub.2 CH.sub.2 0 2-AcOBu2-1083 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-HOEt2-1084 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-AcOEt2-1085 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-(3-HOOC.PrnO)Et2-1086 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-(3-Mec.Prn.O)Et2-1087 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-BozOEt2-1088 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-(cPnCOO)Et2-1089 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-(cHxCOO)Et2-1090 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-HOPr2-1091 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-AcOPr2-1092 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-(3-HOOC.PrnO)Pr2-1093 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-(cHxCOO)Pr2-1094 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 3-HOPr2-1095 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 3-AcOPr2-1096 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 3-(cHxCOO)Pr2-1097 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-HOBu2-1098 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-AcOBu2-1099 Pip CH.sub.2 (CH.sub.2).sub.3 0 2-HOEt2-1100 Pip CH.sub.2 (CH.sub.2).sub.3 0 2-AcOEt2-1101 Pip CH.sub.2 (CH.sub.2).sub.3 0 2-PrnOEt2-1102 Pip CH.sub.2 (CH.sub.2).sub.3 0 2-(3-HOOC.PrnO)Et2-1103 Pip CH.sub.2 (CH.sub.2).sub.3 0 2-BozOEt2-1104 Pip CH.sub.2 (CH.sub.2).sub.3 0 2-(cPnCOO)Et2-1105 Pip CH.sub.2 (CH.sub.2).sub.3 0 2-(cHxCOO)Et2-1106 Pip CH.sub.2 (CH.sub.2).sub.3 0 2-HOPr2-1107 Pip CH.sub.2 (CH.sub.2).sub.3 0 2-AcOPr2-1108 Pip CH.sub.2 (CH.sub.2).sub.3 0 2-BozOPr2-1109 Pip CH.sub.2 (CH.sub.2).sub.3 0 3-HOPr2-1110 Pip CH.sub.2 (CH.sub.2).sub.3 0 3-AcOPr2-1111 Pip CH.sub.2 (CH.sub.2).sub.3 0 3-(3-HOOC.PrnO)Pr2-1112 Pip CH.sub.2 (CH.sub.2).sub.3 0 2-HOBu2-1113 Pip CH.sub.2 (CH.sub.2).sub.3 0 2-AcOBu2-1114 Pip CH.sub.2 (CH.sub.2).sub.4 0 2-HOEt2-1115 Pip CH.sub.2 (CH.sub.2).sub.4 0 2-AcOEt2-1116 Pip CH.sub.2 (CH.sub.2).sub.4 0 2-(3-HOOC.PrnO)Et2-1117 Pip CH.sub.2 (CH.sub.2).sub.4 0 2-(cHxCOO)Et2-1118 Pip CH.sub.2 (CH.sub.2).sub.4 0 2-HOPr2-1119 Pip CH.sub.2 (CH.sub.2).sub.4 0 2-AcOPr2-1120 Pip CH.sub.2 (CH.sub.2).sub.4 0 3-HOPr2-1121 Pip CH.sub.2 (CH.sub.2).sub.4 0 3-AcOPr2-1122 Pip CH.sub.2 (CH.sub.2).sub.4 0 2-HOBu2-1123 Pip CH.sub.2 (CH.sub.2).sub.4 0 2-AcOBu2-1124 Pip CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 2-HOEt2-1125 Pip CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 2-AcOEt2-1126 Pip CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 2-HOPr2-1127 Pip CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 2-AcOPr2-1128 Pip CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 3-HOPr2-1129 Pip CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 3-AcOPr2-1130 Pip CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 2-HOBu2-1131 Pip CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 2-AcOBu2-1132 Pip CH.sub.2 (CH.sub.2).sub.5 0 2-HOEt2-1133 Pip CH.sub.2 (CH.sub.2).sub.5 0 2-AcOEt2-1134 Pip CH.sub.2 (CH.sub.2).sub.5 0 2-HOPr2-1135 Pip CH.sub.2 (CH.sub.2).sub.5 0 2-AcOPr2-1136 Pip CH.sub.2 (CH.sub.2).sub.5 0 2-(cHxCOO)Pr2-1137 Pip CH.sub.2 (CH.sub.2).sub.5 0 3-HOPr2-1138 Pip CH.sub.2 (CH.sub.2).sub.5 0 3-AcOPr2-1139 Pip CH.sub.2 (CH.sub.2).sub.5 0 2-AcOBu2-1140 Pip CH.sub.2 (CH.sub.2).sub.6 0 2-HOEt2-1141 Pip CH.sub.2 (CH.sub.2).sub.6 0 2-AcOEt2-1142 Pip CH.sub.2 (CH.sub.2).sub.6 0 2-HOPr2-1143 Pip CH.sub.2 (CH.sub.2).sub.6 0 2-AcOPr2-1144 Pip CH.sub.2 (CH.sub.2).sub.6 0 3-HOPr2-1145 Pip CH.sub.2 (CH.sub.2).sub.6 0 3-AcOPr2-1146 Pip CH.sub.2 (CH.sub.2).sub.6 0 2-AcOBu2-1147 Pip CH.dbd.CH CH.sub.2 0 2-(nPnCOO)Et2-1148 Pip CH.dbd.CH CH.sub.2 0 2-PivOEt2-1149 Pip CH.sub.2 CH.sub.2 0 2-(nPnCOO)Et2-1150 Pip CH.sub.2 CH.sub.2 0 2-PivOEt2-1151 Pyr CH.dbd.CH CH.sub.2 0 2-(nPnCOO)Et2-1152 Pyr CH.dbd.CH CH.sub.2 0 2-PivOEt__________________________________________________________________________
TABLE 3__________________________________________________________________________Cpd.No. R.sup.1 A B m R.sup.5__________________________________________________________________________3-1 Pip CH.dbd.CH CH.sub.2 0 Imdazo-2-yl3-2 Pip CH.dbd.CH CH.sub.2 0 Imdazo-4-yl3-3 Pip CH.dbd.CH CH.sub.2 0 1-Me-Imdazo-2-yl3-4 Pip CH.dbd.CH CH.sub.2 0 1,3,4-Oxadiazo-2-yl3-5 Pip CH.dbd.CH CH.sub.2 0 5-Me-1,3,4-Oxadiazo-2-yl3-6 Pip CH.dbd.CH CH.sub.2 0 1,3,4-Thiadiazo-2-yl3-7 Pip CH.dbd.CH CH.sub.2 0 5-Me-1,3,4-Thiadiazo-2-yl3-8 Pip CH.dbd.CH CH.sub.2 0 1,2,4-Triazo-3-yl3-9 Pip CH.dbd.CH CH.sub.2 0 1,2,4-Triazo-5-yl3-10 Pip CH.dbd.CH CH.sub.2 0 1-Me-1,2,4-Triazo-3-yl3-11 Pip CH.dbd.CH CH.sub.2 0 1-Me-1,2,4-Triazo-5-yl3-12 Pip CH.dbd.CH CH.sub.2 0 5-Me-1,2,4-Triazo-3-yl3-13 Pip CH.dbd.CH CH.sub.2 0 Tetrazo-5-yl3-14 Pip CH.dbd.CH CH.sub.2 0 1-Me-Tetrazo-5-yl3-15 Pip CH.dbd.CH CH.sub.2 0 Pyz-2-yl3-16 Pip CH.dbd.CH CH.sub.2 0 Pyz-3-yl3-17 Pip CH.dbd.CH CH.sub.2 0 Pyz-4-yl3-18 Pip CH.dbd.CH CH.sub.2 0 3-Me-Pyz-2-yl3-19 Pip CH.dbd.CH CH.sub.2 0 2-Me-Pyz-4-yl3-20 Pip CH.dbd.CH CH.sub.2 0 3-NHz-Pyz-2-yl3-21 Pip CH.dbd.CH CH.sub.2 0 4-NH.sub.2 -Pyz-3-yl3-22 Pip CH.dbd.CH CH.sub.2 0 3-NH.sub.2 -Pyz-4-yl3-23 Pip CH.dbd.CH CH.sub.2 0 3-HO-Pyz-2-yl3-24 Pip CH.dbd.CH CH.sub.2 0 2-HO-Pyz-4-yl3-25 Pip CH.dbd.CH CH.sub.2 0 Pymz-2-yl3-26 Pip CH.dbd.CH CH.sub.2 0 Pymz-4-yl3-27 Pip CH.dbd.CH CH.sub.2 0 4-Me-Pymz-2-yl3-28 Pip CH.dbd.CH CH.sub.2 0 5-Me-Pymz-2-yl3-29 Pip CH.dbd.CH CH.sub.2 0 2-Me-Pymz-4-yl3-30 Pip CH.dbd.CH CH.sub.2 0 5-Me-Pymz-4-yl3-31 Pip CH.dbd.CH CH.sub.2 0 6-Me-Pymz-4-yl3-32 Pip CH.dbd.CH CH.sub.2 0 2-Me-Pymz-5-yl3-33 Pip CH.dbd.CH CH.sub.2 0 4-NH.sub.2 -Pymz-2-yl3-34 Pip CH.dbd.CH CH.sub.2 0 5-NH.sub.2 -Pymz-2-yl3-35 Pip CH.dbd.CH CH.sub.2 0 2-NH.sub.2 -Pymz-4-yl3-36 Pip CH.dbd.CH CH.sub.2 0 4-NH.sub.2 -5-HO-Pymz-2-yl3-37 Pip CH.dbd.CH CH.sub.2 0 2-NH.sub.2 -5-HO-Pymz-4-yl3-38 Pip CH.dbd.CH CH.sub.2 0 5-NH.sub.2 -2-HO-Pymz-4-yl3-39 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 Imdazo-2-yl3-40 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 Imdazo-4-yl3-41 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 1-Me-Imdazo-2-yl3-42 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 1,3,4-Oxadiazo-2-yl3-43 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 5-Me-1,3,4-Oxadiazo-2-yl3-44 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 1,3,4-Thiadiazo-2-yl3-45 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 5-Me-1,3,4-Thiadiazo-2-yl3-46 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 1,2,4-Triazo-3-yl3-47 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 1,2,4-Triazo-5-yl3-48 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 1-Me-1,2,4-Triazo-3-yl3-49 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 1-Me-1,2,4-Triazo-5-yl3-50 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 5-Me-1,2,4-Triazo-3-yl3-51 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 Tetrazo-5-yl3-52 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 1-Me-Tetrazo-5-yl3-53 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 Pyz-2-yl3-54 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 Pyz-3-yl3-55 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 Pyz-4-yl3-56 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 4-Me-Pyz-2-yl3-57 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 2-Me-Pyz-4-yl3-58 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 3-NH.sub.2 -Pyz-2-yl3-59 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 3-NH.sub.2 -Pyz-4-yl3-60 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 3-HO-Pyz-2-yl3-61 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 2-HO-Pyz-4-yl3-62 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 Pymz-2-yl3-63 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 Pymz-4-yl3-64 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 Pymz-5-yl3-65 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 4-Me-Pymz-2-yl3-66 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 5-Me-Pymz-2-yl3-67 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 2-Me-Pymz-4-yl3-68 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 5-Me-Pymz-4-yl3-69 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 6-Me-Pymz-4-yl3-70 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 4-NH.sub.2 -Pymz-2-yl3-71 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 5-NH.sub.2 -Pymz-2-yl3-72 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 2-NH.sub.2 -Pymz-4-yl3-73 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 4-HO-Pymz-5-yl3-74 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 4-NH.sub.2 -5-HO-Pymz-2-yl3-75 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 2-NH.sub.2 -5-HO-Pymz-4-yl3-76 Pip CH.dbd.CH CH.sub.2 CH.sub.2 0 5-NH.sub.2 -2-HO-Pymz-4-yl3-77 Pip CH.dbd.CH (CH.sub.2).sub.3 0 Imdazo-2-yl3-78 Pip CH.dbd.CH (CH.sub.2).sub.3 0 Imdazo-4-yl3-79 Pip CH.dbd.CH (CH.sub.2).sub.3 0 1-Me-Imdazo-2-yl3-80 Pip CH.dbd.CH (CH.sub.2).sub.3 0 2-Me-Imdazo-4-yl3-81 Pip CH.dbd.CH (CH.sub.2).sub.3 0 1,3,4-Oxadiazo-2-yl3-82 Pip CH.dbd.CH (CH.sub.2).sub.3 0 5-Me-1,3,4-Oxadiazo-2-yl3-83 Pip CH.dbd.CH (CH.sub.2).sub.3 0 5-Et-1,3,4-Oxadiazo-2-yl3-84 Pip CH.dbd.CH (CH.sub.2).sub.3 0 5-NH.sub.2 -1,3,4-Oxadiazo-2-yl3-85 Pip CH.dbd.CH (CH.sub.2).sub.3 0 5-AcNH-1,3,4-Oxadiazo-2-yl3-86 Pip CH.dbd.CH (CH.sub.2).sub.3 0 1,3,4-Thiadiazo-2-yl3-87 Pip CH.dbd.CH (CH.sub.2).sub.3 0 5-Me-1,3,4-Thiadiazo-2-yl3-88 Pip CH.dbd.CH (CH.sub.2).sub.3 0 5-NH.sub.2 -1,3,4-Thiadiazo-2-yl3-89 Pip CH.dbd.CH (CH.sub.2).sub.3 0 1,2,4-Triazo-3-yl3-90 Pip CH.dbd.CH (CH.sub.2).sub.3 0 1,2,4-Triazo-5-yl3-91 Pip CH.dbd.CH (CH.sub.2).sub.3 0 1-Me-1,2,4-Triazo-3-yl3-92 Pip CH.dbd.CH (CH.sub.2).sub.3 0 1-Me-1,2,4-Triazo-5-yl3-93 Pip CH.dbd.CH (CH.sub.2).sub.3 0 5-Me-1,2,4-Triazo-3-yl3-94 Pip CH.dbd.CH (CH.sub.2).sub.3 0 5-Cl-1,2,4-Triazo-3-yl3-95 Pip CH.dbd.CH (CH.sub.2).sub.3 0 5-NH.sub.2 -1,2,4-Triazo-3-yl3-96 Pip CH.dbd.CH (CH.sub.2).sub.3 0 5-AcNH-1,2,4-Triazo-3-yl3-97 Pip CH.dbd.CH (CH.sub.2).sub.3 0 Tetrazo-5-yl3-98 Pip CH.dbd.CH (CH.sub.2).sub.3 0 1-Me-Tetrazo-5-yl3-99 Pip CH.dbd.CH (CH.sub.2).sub.3 0 1-Et-Tetrazo-5-yl3-100 Pip CH.dbd.CH (CH.sub.2).sub.3 0 1-(2-HOEt)-Tetrazo-5-yl3-101 Pip CH.dbd.CH (CH.sub.2).sub.3 0 Pyz-2-yl3-102 Pip CH.dbd.CH (CH.sub.2).sub.3 0 Pyz-3-yl3-103 Pip CH.dbd.CH (CH.sub.2).sub.3 0 Pyz-4-yl3-104 Pip CH.dbd.CH (CH.sub.2).sub.3 0 3-Me-Pyz-2-yl3-105 Pip CH.dbd.CH (CH.sub.2).sub.3 0 5-Me-Pyz-2-yl3-106 Pip CH.dbd.CH (CH.sub.2).sub.3 0 2-Me-Pyz-4-yl3-107 Pip CH.dbd.CH (CH.sub.2).sub.3 0 3-Me-Pyz-4-yl3-108 Pip CH.dbd.CH (CH.sub.2).sub.3 0 3-Cl-Pyz-2-yl3-109 Pip CH.dbd.CH (CH.sub.2).sub.3 0 3-Cl-Pyz-4-yl3-110 Pip CH.dbd.CH (CH.sub.2).sub.3 0 3-NH.sub.2 -Pyz-2-yl3-111 Pip CH.dbd.CH (CH.sub.2).sub.3 0 5-NH.sub.2 -Pyz-2-yl3-112 Pip CH.dbd.CH (CH.sub.2).sub.3 0 4-NH.sub.2 -Pyz-3-yl3-113 Pip CH.dbd.CH (CH.sub.2).sub.3 0 3-NH.sub.2 -Pyz-4-yl3-114 Pip CH.dbd.CH (CH.sub.2).sub.3 0 3-HO-Pyz-2-yl3-115 Pip CH.dbd.CH (CH.sub.2).sub.3 0 5-HO-Pyz-2-yl3-116 Pip CH.dbd.CH (CH.sub.2).sub.3 0 2-HO-Pyz-4-yl3-117 Pip CH.dbd.CH (CH.sub.2).sub.3 0 3-HO-Pyz-4-yl3-118 Pip CH.dbd.CH (CH.sub.2).sub.3 0 Pymz-2-yl3-119 Pip CH.dbd.CH (CH.sub.2).sub.3 0 Pymz-4-yl3-120 Pip CH.dbd.CH (CH.sub.2).sub.3 0 Pymz-5-yl3-121 Pip CH.dbd.CH (CH.sub.2).sub.3 0 4-Me-Pymz-2-yl3-122 Pip CH.dbd.CH (CH.sub.2).sub.3 0 5-Me-Pymz-2-yl3-123 Pip CH.dbd.CH (CH.sub.2).sub.3 0 2-Me-Pymz-4-yl3-124 Pip CH.dbd.CH (CH.sub.2).sub.3 0 5-Me-Pymz-4-yl3-125 Pip CH.dbd.CH (CH.sub.2).sub.3 0 6-Me-Pymz-4-yl3-126 Pip CH.dbd.CH (CH.sub.2).sub.3 0 4-Cl-Pymz-2-yl3-127 Pip CH.dbd.CH (CH.sub.2).sub.3 0 2-Me-Pymz-4-yl3-128 Pip CH.dbd.CH (CH.sub.2).sub.3 0 4-NH.sub.2 -Pymz-2-yl3-129 Pip CH.dbd.CH (CH.sub.2).sub.3 0 5-NH.sub.2 -Pymz-2-yl3-130 Pip CH.dbd.CH (CH.sub.2).sub.3 0 2-NH.sub.2 -Pymz-4-yl3-131 Pip CH.dbd.CH (CH.sub.2).sub.3 0 5-NH.sub.2 -Pymz-4-yl3-132 Pip CH.dbd.CH (CH.sub.2).sub.3 0 4-AcNH-Pymz-2-yl3-133 Pip CH.dbd.CH (CH.sub.2).sub.3 0 2-AcNH-Pymz-4-yl3-134 Pip CH.dbd.CH (CH.sub.2).sub.3 0 4-NH.sub.2 -5-HO-Pymz-2-yl3-135 Pip CH.dbd.CH (CH.sub.2).sub.3 0 2-NH.sub.2 -5-HO-Pymz-4-yl3-136 Pip CH.dbd.CH (CH.sub.2).sub.3 0 4,6-diNH.sub.2 -Pymz-2-yl3-137 Pip CH.dbd.CH (CH.sub.2).sub.3 0 2,5-diNH.sub.2 -Pymz-4-yl3-138 Pip CH.dbd.CH (CH.sub.2).sub.4 0 Imdazo-2-yl3-139 Pip CH.dbd.CH (CH.sub.2).sub.4 0 1,3,4-Oxadiazo-2-yl3-140 Pip CH.dbd.CH (CH.sub.2).sub.4 0 1,3,4-thiadiazo-2-yl3-141 Pip CH.dbd.CH (CH.sub.2).sub.4 0 1,2,4-Triazo-3-yl3-142 Pip CH.dbd.CH (CH.sub.2).sub.4 0 1,2,4-Triazo-5-yl3-143 Pip CH.dbd.CH (CH.sub.2).sub.4 0 Tetrazo-5-yl3-144 Pip CH.dbd.CH (CH.sub.2).sub.4 0 Pyz-2-yl3-145 Pip CH.dbd.CH (CH.sub.2).sub.4 0 Pyz-3-yl3-146 Pip CH.dbd.CH (CH.sub.2).sub.4 0 Pyz-4-yl3-147 Pip CH.dbd.CH (CH.sub.2).sub.4 0 Pymz-2-yl3-148 Pip CH.dbd.CH (CH.sub.2).sub.4 0 Pymz-4-yl3-149 Pip CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 Imdazo-2-yl3-150 Pip CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 1,3,4-Oxadiazo-2-yl3-151 Pip CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 1,3,4-Thiadiazo-2-yl3-152 Pip CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 1,2,4-Triazo-3-yl3-153 Pip CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 1,2,4-Triazo-5-yl3-154 Pip CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 Tetrazo-5-yl3-155 Pip CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 Pyz-2-yl3-156 Pip CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 Pyz-4-yl3-157 Pip CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 Pymz-2-yl3-158 Pip CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 Pymz-4-yl3-159 Pip CH.dbd.CH (CH.sub.2).sub.5 0 Imdazo-2-yl3-160 Pip CH.dbd.CH (CH.sub.2).sub.5 0 1,3,4-Oxadiazo-2-yl3-161 Pip CH.dbd.CH (CH.sub.2).sub.5 0 1,3,4-Thiadiazo-2-yl3-162 Pip CH.dbd.CH (CH.sub.2).sub.5 0 1,2,4-Triazo-3-yl3-163 Pip CH.dbd.CH (CH.sub.2).sub.5 0 1,2,4-Triazo-5-yl3-164 Pip CH.dbd.CH (CH.sub.2).sub.5 0 Tetrazo-5-yl3-165 Pip CH.dbd.CH (CH.sub.2).sub.5 0 Pyz-2-yl3-166 Pip CH.dbd.CH (CH.sub.2).sub.5 0 Pyz-4-yl3-167 Pip CH.dbd.CH (CH.sub.2).sub.5 0 Pymz-2-yl3-168 Pip CH.dbd.CH (CH.sub.2).sub.5 0 Pymz-4-yl3-169 Pip CH.dbd.CH (CH.sub.2).sub.6 0 Imdazo-2-yl3-170 Pip CH.dbd.CH (CH.sub.2).sub.6 0 1,3,4-Oxadiazo,-2-yl3-171 Pip CH.dbd.CH (CH.sub.2).sub.6 0 1,3,4-Thiadiazo-2-yl3-172 Pip CH.dbd.CH (CH.sub.2).sub.6 0 1,2,4-Triazo-3-yl3-173 Pip CH.dbd.CH (CH.sub.2).sub.6 0 1,2,4-Triazo-5-yl3-174 Pip CH.dbd.CH (CH.sub.2).sub.6 0 Tetrazo-5-yl3-175 Pip CH.dbd.CH (CH.sub.2).sub.6 0 Pyz-3-yl3-176 Pip CH.dbd.CH (CH.sub.2).sub.6 0 Pyz-4-yl3-177 Pip CH.dbd.CH (CH.sub.2).sub.6 0 Pymz-2-yl3-178 Pip CH.dbd.CH (CH.sub.2).sub.6 0 Pymz-4-yl3-179 Pyr CH.dbd.CH CH.sub.2 0 Imdazo-2-yl3-180 Pyr CH.dbd.CH CH.sub.2 0 Imdazo-4-yl3-181 Pyr CH.dbd.CH CH.sub.2 0 1,3,4-Oxadiazo-2-yl3-182 Pyr CH.dbd.CH CH.sub.2 0 1,3,4-Thiadiazo-2-yl3-183 Pyr CH.dbd.CH CH.sub.2 0 1,2,4-Triazo-3-yl3-184 Pyr CH.dbd.CH CH.sub.2 0 1,2,4-Triazo-5-yl3-185 Pyr CH.dbd.CH CH.sub.2 0 Tetrazo-5-yl3-186 Pye CH.dbd.CH CH.sub.2 0 Pyz-2-yl3-187 Pyr CH.dbd.CH CH.sub.2 0 Pyz-4-yl3-188 Pyr CH.dbd.CH CH.sub.2 0 3-Me-Pyz-2-yl3-189 Pyr CH.dbd.CH CH.sub.2 0 2-Me-Pyz-3-yl3-190 Pyr CH.dbd.CH CH.sub.2 0 3-NH.sub.2 -Pyz-2-yl3-191 Pyr CH.dbd.CH CH.sub.2 0 2-HO-Pyz-3-yl3-192 Pyr CH.dbd.CH CH.sub.2 0 Pymz-2-yl3-193 Pyr CH.dbd.CH CH.sub.2 0 Pymz-4-yl3-194 Pyr CH.dbd.CH CH.sub.2 0 4-Me-Pymz-2-yl3-195 Pyr CH.dbd.CH CH.sub.2 0 5-Me-Pymz-2-yl3-196 Pyr CH.dbd.CH CH.sub.2 0 2-Me-Pymz-4-yl3-197 Pyr CH.dbd.CH CH.sub.2 0 6-Me-Pymz-4-yl3-198 Pyr CH.dbd.CH CH.sub.2 0 4-NH.sub.2 -Pymz-2-yl3-199 Pyr CH.dbd.CH CH.sub.2 0 4-HO-Pymz-2-yl3-200 Pyr CH.dbd.CH CH.sub.2 0 4-NH.sub.2 -5-HO-Pymz-2-yl3-201 Pyr CH.dbd.CH CH.sub.2 CH.sub.2 0 Imdazo-2-yl3-202 Pyr CH.dbd.CH CH.sub.2 CH.sub.2 0 Imdazo-4-yl3-203 Pyr CH.dbd.CH CH.sub.2 CH.sub.2 0 1,3,4-Oxadiazo-2-yl3-204 Pyr CH.dbd.CH CH.sub.2 CH.sub.2 0 1,3,4-Thiadiazo-2-yl3-205 Pyr CH.dbd.CH CH.sub.2 CH.sub.2 0 1,2,4-Triazo-3-yl3-206 Pyr CH.dbd.CH CH.sub.2 CH.sub.2 0 1,2,4-Triazo-5-yl3-207 Pyr CH.dbd.CH CH.sub.2 CH.sub.2 0 Tetrazo-5-yl3-208 Pyr CH.dbd.CH CH.sub.2 CH.sub.2 0 Pyz-2-yl3-209 Pyr CH.dbd.CH CH.sub.2 CH.sub.2 0 Pyz-4-yl3-210 Pyr CH.dbd.CH CH.sub.2 CH.sub.2 0 3-Me-Pyz-2-yl3-211 Pyr CH.dbd.CH CH.sub.2 CH.sub.2 0 3-NH.sub.2 -Pyz-2-yl3-212 Pyr CH.dbd.CH CH.sub.2 CH.sub.2 0 3-HO-Pyz-2-yl3-213 Pyr CH.dbd.CH CH.sub.2 CH.sub.2 0 Pymz-2-yl3-214 Pyr CH.dbd.CH CH.sub.2 CH.sub.2 0 Pymz-4-yl3-215 Pyr CH.dbd.CH CH.sub.2 CH.sub.2 0 Pymz-5-yl3-216 Pyr CH.dbd.CH CH.sub.2 CH.sub.2 0 4-Me-Pymz-2-yl3-217 Pyr CH.dbd.CH CH.sub.2 CH.sub.2 0 5-Me-Pymz-2-yl3-218 Pyr CH.dbd.CH CH.sub.2 CH.sub.2 0 2-Me-Pymz-4-yl3-219 Pyr CH.dbd.CH CH.sub.2 CH.sub.2 0 5-Me-Pymz-4-yl3-220 Pyr CH.dbd.CH CH.sub.2 CH.sub.2 0 4-NH.sub.2 -Pymz-2-yl3-221 Pyr CH.dbd.CH CH.sub.2 CH.sub.2 0 2-HO-Pymz-2-yl3-222 Pyr CH.dbd.CH (CH.sub.2).sub.3 0 Imdazo-2-yl3-223 Pyr CH.dbd.CH (CH.sub.2).sub.3 0 Imdazo-4-yl3-224 Pyr CH.dbd.CH (CH.sub.2).sub.3 0 1,3,4-Oxadiazo-2-yl3-225 Pyr CH.dbd.CH (CH.sub.2).sub.3 0 1,3,4-Thiadiazo-2-yl3-226 Pyr CH.dbd.CH (CH.sub.2).sub.3 0 1,2,4-Triazo-3-yl3-227 Pyr CH.dbd.CH (CH.sub.2).sub.3 0 1,2,4,-Triazo-5-yl3-228 Pyr CH.dbd.CH (CH.sub.2).sub.3 0 Tetrazo-5-yl3-229 Pyr CH.dbd.CH (CH.sub.2).sub.3 0 Pyz-2-yl3-230 Pyr CH.dbd.CH (CH.sub.2).sub.3 0 Pyz-3-yl3-231 Pyr CH.dbd.CH (CH.sub.2).sub.3 0 Pyz-4-yl3-232 Pyr CH.dbd.CH (CH.sub.2).sub.3 0 3-Me-Pyz-2-yl3-233 Pyr CH.dbd.CH (CH.sub.2).sub.3 0 2-Me-Pyz-4-yl3-234 Pyr CH.dbd.CH (CH.sub.2).sub.3 0 2-Cl-Pyz-3-yl3-235 Pyr CH.dbd.CH (CH.sub.2).sub.3 0 3-NH.sub.2 -Pyz-2-yl3-236 Pyr CH.dbd.CH (CH.sub.2).sub.3 0 3-NH.sub.2 -Pyz-4-yl3-237 Pyr CH.dbd.CH (CH.sub.2).sub.3 0 3-HO-Pyz-2-yl3-238 Pyr CH.dbd.CH (CH.sub.2).sub.3 0 Pymz-2-yl3-239 Pyr CH.dbd.CH (CH.sub.2).sub.3 0 Pymz-4-yl3-240 Pyr CH.dbd.CH (CH.sub.2).sub.3 0 4-Me-Pymz-2-yl3-241 Pyr CH.dbd.CH (CH.sub.2).sub.3 0 2-Me-Pymz-4-yl3-242 Pyr CH.dbd.CH (CH.sub.2).sub.3 0 5-Me-Pymz-4-yl3-243 Pyr CH.dbd.CH (CH.sub.2).sub.3 0 4-Me-Pymz-5-yl3-244 Pyr CH.dbd.CH (CH.sub.2).sub.3 0 5-NH.sub.2 -Pymz-2-yl3-245 Pyr CH.dbd.CH (CH.sub.2).sub.3 0 2-NH.sub.2 -Pymz-4-yl3-246 Pyr CH.dbd.CH (CH.sub.2).sub.3 0 2-HO-Pymz-4-yl3-247 Pyr CH.dbd.CH (CH.sub.2).sub.3 0 4-NH.sub.2 -5-HO-Pymz-2-yl3-248 Pyr CH.dbd.CH (CH.sub.2).sub.3 0 2-NH.sub.2 -5-HO-Pymz-4-yl3-249 Pyr CH.dbd.CH (CH.sub.2).sub.3 0 4,6-diNH.sub.2 -Pymz-2-yl3-250 Pyr CH.dbd.CH (CH.sub.2).sub.4 0 Imdazo-2-yl3-251 Pyr CH.dbd.CH (CH.sub.2).sub.4 0 1,3,4-Oxadiazo-2-yl3-252 Pyr CH.dbd.CH (CH.sub.2).sub.4 0 1,3,4-Thiadiazo-2-yl3-253 Pyr CH.dbd.CH (CH.sub.2).sub.4 0 1,2,4-Triazo-3-yl3-254 Pyr CH.dbd.CH (CH.sub.2).sub.4 0 1,2,4-Triazo-5-yl3-255 Pyr CH.dbd.CH (CH.sub.2).sub.4 0 Tetrazo-5-yl3-256 Pyr CH.dbd.CH (CH.sub.2).sub.4 0 Pyz-2-yl3-257 Pyr CH.dbd.CH (CH.sub.2).sub.4 0 Pyz-3-yl3-258 Pyr CH.dbd.CH (CH.sub.2).sub.4 0 Pyz-4-yl3-259 Pyr CH.dbd.CH (CH.sub.2).sub.4 0 Pymz-2-yl3-260 Pyr CH.dbd.CH (CH.sub.2).sub.4 0 Pymz-4-yl3-261 Pyr CH.dbd.CH (CH.sub.2).sub.4 0 Pymz-5-yl3-262 Pyr CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 Imdazo-2-yl3-263 Pyr CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 1,3,4-Oxadiazo-2-yl3-264 Pyr CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 1,3,4-Thiadiazo-2-yl3-265 Pyr CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 1,2,4-Triazo-3-yl3-266 Pyr CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 1,2,4-Triazo-5-yl3-267 Pyr CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 Tetrazo-5-yl3-268 Pyr CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 Pyz-2-yl3-269 Pyr CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 Pyz-3-yl3-270 Pyr CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 Pymz-2-yl3-271 Pyr CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 Pymz-4-yl3-272 Pyr CH.dbd.CH (CH.sub.2).sub.5 0 Imdazo-2-yl3-273 Pyr CH.dbd.CH (CH.sub.2).sub.5 0 1,3,4-Oxadiazo-2-yl3-274 Pyr CH.dbd.CH (CH.sub.2).sub.5 0 1,3,4-Thiadiazo-2-yl3-275 Pyr CH.dbd.CH (CH.sub.2).sub.5 0 1,2,4-Triazo-3-yl3-276 Pyr CH.dbd.CH (CH.sub.2).sub.5 0 1,2,4-Triazo-5-yl3-277 Pyr CH.dbd.CH (CH.sub.2).sub.5 0 Tetrazo-5-yl3-278 Pyr CH.dbd.CH (CH.sub.2).sub.5 0 Pyz-2-yl3-279 Pyr CH.dbd.CH (CH.sub.2).sub.5 0 Pyz-3-yl3-280 Pyr CH.dbd.CH (CH.sub.2).sub.5 0 Pymz-2-yl3-281 Pyr CH.dbd.CH (CH.sub.2).sub.5 0 Pymz-4-yl3-282 Pyr CH.dbd.CH (CH.sub.2).sub.6 0 Imdazo-2-yl3-283 Pyr CH.dbd.CH (CH.sub.2).sub.6 0 1,3,4-Oxadiazo-2-yl3-284 Pyr CH.dbd.CH (CH.sub.2).sub.6 0 1,3,4-Thiadiazo-2-yl3-285 Pyr CH.dbd.CH (CH.sub.2).sub.6 0 1,2,4-Triazo-3-yl3-286 Pyr CH.dbd.CH (CH.sub.2).sub.6 0 1,2,4-Triazo-5-yl3-287 Pyr CH.dbd.CH (CH.sub.2).sub.6 0 Tetrazo-5-yl3-288 Pyr CH.dbd.CH (CH.sub.2).sub.6 0 Pyz-2-yl3-289 Pyr CH.dbd.CH (CH.sub.2).sub.6 0 Pyz-3-yl3-290 Pyr CH.dbd.CH (CH.sub.2).sub.6 0 Pymz-2-yl3-291 Pyr CH.dbd.CH (CH.sub.2).sub.6 0 Pymz-4-yl3-292 NMe.sub.2 CH.dbd.CH CH.sub.2 0 Imdazo-2-yl3-293 NMe.sub.2 CH.dbd.CH CH.sub.2 0 1,3,4-Oxadiazo-2-yl3-294 NMe.sub.2 CH.dbd.CH CH.sub.2 0 1,3,4-Thiadiazo-2-yl3-295 NMe.sub.2 CH.dbd.CH CH.sub.2 0 1,2,4-Triazo-3-yl3-296 NMe.sub.2 CH.dbd.CH CH.sub.2 0 1,2,4-Triazo-5-yl3-297 NMe.sub.2 CH.dbd.CH CH.sub.2 0 Tetrazo-5-yl3-298 NMe.sub.2 CH.dbd.CH CH.sub.2 0 Pyz-2-yl3-299 NMe.sub.2 CH.dbd.CH CH.sub.2 0 3-Me-Pyz-2-yl3-300 NMe.sub.2 CH.dbd.CH CH.sub.2 0 Pymz-2-yl3-301 NMe.sub.2 CH.dbd.CH CH.sub.2 0 4-Me-Pymz-2-yl3-302 NMe.sub.2 CH.dbd.CH CH.sub.2 0 6-Me-Pymz-4-yl3-303 NMe.sub.2 CH.dbd.CH CH.sub.2 CH.sub.2 0 1,3,4-Oxadiazo-2-yl3-304 NMe.sub.2 CH.dbd.CH CH.sub.2 CH.sub.2 0 1,2,4-Triazo-3-yl3-305 NMe.sub.2 CH.dbd.CH CH.sub.2 CH.sub.2 0 1,2,4-Triazo-5-yl3-306 NMe.sub.2 CH.dbd.CH CH.sub.2 CH.sub.2 0 Pyz-2-yl3-307 NMe.sub.2 CH.dbd.CH CH.sub.2 CH.sub.2 0 3-Me-Pyz-2-yl3-308 NMe.sub.2 CH.dbd.CH CH.sub.2 CH.sub.2 0 Pymz-2-yl3-309 NMe.sub.2 CH.dbd.CH CH.sub.2 CH.sub.2 0 Pymz-4-yl3-310 NMe.sub.2 CH.dbd.CH CH.sub.2 CH.sub.2 0 4-Me-Pymz-2-yl3-311 NMe.sub.2 CH.dbd.CH CH.sub.2 CH.sub.2 0 2-Me-Pymz-4-yl3-312 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.3 0 Imdazo-2-yl3-313 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.3 0 Imdazo-4-yl3-314 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.3 0 1,3,4-Oxadiazo-2-yl3-315 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.3 0 1,3,4-Thiadiazo-2-yl3-316 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.3 0 1,2,4-Triazo-3-yl3-317 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.3 0 1,2,4-Triazo-5-yl3-318 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.3 0 Tetrazo-5-yl3-319 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.3 0 Pyz-2-yl3-320 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.3 0 Pymz-2-yl3-321 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.3 0 Pymz-4-yl3-322 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.4 0 1,3,4-Oxadiazo-2-yl3-323 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.4 0 1,2,4-Triazol-3-yl3-324 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.4 0 1,2,4-Triazo-5-yl3-325 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.4 0 Tetrazo-5-yl3-326 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.4 0 Pyz-2-yl3-327 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.4 0 Pymz-2-yl3-328 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.4 0 Pymz-4-yl3-329 NMe.sub.2 CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 1,3,4-Oxadiazo-2-yl3-330 NMe.sub.2 CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 1,2,4-Triazo-3-yl3-331 NMe.sub.2 CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 1,2,4-Triazo-5-yl3-332 NMe.sub.2 CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 Pymz-2-yl3-333 NMe.sub.2 CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 0 Pymz-4-yl3-334 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.5 0 1,3,4-Oxadiazo-2-yl3-335 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.5 0 1,2,4-Triazo-3-yl3-336 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.5 0 1,2,4-Triazo-5-yl3-337 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.5 0 Pymz-2-yl3-338 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.5 0 Pymz-4-yl3-339 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.6 0 1,3,4-Oxadiazo-2-yl3-340 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.6 0 1,2,4-Triazo-3-yl3-341 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.6 0 1,2,4-Triazo-5-yl3-342 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.6 0 Pymz-2-yl3-343 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.6 0 Pymz-4-yl3-344 NEt.sub.2 CH.dbd.CH CH.sub.2 0 1,3,4-Oxadiazo-2-yl3-345 NEt.sub.2 CH.dbd.CH CH.sub.2 0 1,2,4-Triazo-3-yl3-346 NEt.sub.2 CH.dbd.CH CH.sub.2 0 Pymz-2-yl3-347 NEt.sub.2 CH.dbd.CH CH.sub.2 CH.sub.2 0 1,3,4-Oxadiazo-2-yl3-348 NEt.sub.2 CH.dbd.CH CH.sub.2 CH.sub.2 0 1,2,4-Triazo-3-yl3-349 NEt.sub.2 CH.dbd.CH CH.sub.2 CH.sub.2 0 Pymz-2-yl3-350 NEt.sub.2 CH.dbd.CH CH.sub.2 CH.sub.2 0 Pymz-4-yl3-351 NEt.sub.2 CH.dbd.CH (CH.sub.2).sub.3 0 Imdazo-2-yl3-352 NEt.sub.2 CH.dbd.CH (CH.sub.2).sub.3 0 Imdazo-4-yl3-353 NEt.sub.2 CH.dbd.CH (CH.sub.2).sub.3 0 1,3,4-Oxadiazo-2-yl3-354 NEt.sub.2 CH.dbd.CH (CH.sub.2).sub.3 0 1,3,4-Thiadiazo-2-yl3-355 NEt.sub.2 CH.dbd.CH (CH.sub.2).sub.3 0 1,2,4-Triazo-3-yl3-356 NEt.sub.2 CH.dbd.CH (CH.sub.2).sub.3 0 1,2,4-Triazo-5-yl3-357 NEt.sub.2 CH.dbd.CH (CH.sub.2).sub.3 0 Tetrazo-5-yl3-358 NEt.sub.2 CH.dbd.CH (CH.sub.2).sub.3 0 Pyz-2-yl3-359 NEt.sub.2 CH.dbd.CH (CH.sub.2).sub.3 0 Pymz-2-yl3-360 NEt.sub.2 CH.dbd.CH (CH.sub.2).sub.3 0 Pymz-4-yl3-361 NEt.sub.2 CH.dbd.CH (CH.sub.2).sub.4 0 1,3,4-Oxadiazo-2-yl3-362 NEt.sub.2 CH.dbd.CH (CH.sub.2).sub.4 0 1,2,4-Triazo-3-yl3-363 NEt.sub.2 CH.dbd.CH (CH.sub.2).sub.4 0 Pymz-2-yl3-364 NEt.sub.2 CH.dbd.CH (CH.sub.2).sub.4 0 Pymz-4-yl3-365 NEt.sub.2 CH.dbd.CH (CH.sub.2).sub.5 0 1,3,4-Oxadiazo-2-yl3-366 NEt.sub.2 CH.dbd.CH (CH.sub.2).sub.5 0 1,2,4-Triazo-3-yl3-367 NEt.sub.2 CH.dbd.CH (CH.sub.2).sub.5 0 Pymz-2-yl3-368 NEt.sub.2 CH.dbd.CH (CH.sub.2).sub.5 0 Pymz-4-yl3-369 NEt.sub.2 CH.dbd.CH (CH.sub.2).sub.6 0 1,3,4-Oxadiazo-2-yl3-370 NEt.sub.2 CH.dbd.CH (CH.sub.2).sub.6 0 1,2,4-Triazo-5-yl3-371 NEt.sub.2 CH.dbd.CH (CH.sub.2).sub.6 0 Pymz-2-yl3-372 NEt.sub.2 CH.dbd.CH (CH.sub.2).sub.6 0 Pymz-4-yl3-373 Azi CH.dbd.CH (CH.sub.2).sub.3 0 1,2,4-Triazo-3-yl3-374 Azi CH.dbd.CH (CH.sub.2).sub.3 0 Pymz-2-yl3-375 Aze CH.dbd.CH (CH.sub.2).sub.3 0 1,2,4-Triazo-3-yl3-376 Aze CH.dbd.CH (CH.sub.2).sub.3 0 Pymz-2-yl3-377 Pip CH.dbd.CH CH.sub.2 1 Imdazo-2-yl3-378 Pip CH.dbd.CH CH.sub.2 1 1,3,4-Oxadiazo-2-yl3-379 Pip CH.dbd.CH CH.sub.2 1 1,3,4-Thiadiazo-2-yl3-380 Pip CH.dbd.CH CH.sub.2 1 1,2,4-Triazo-3-yl3-381 Pip CH.dbd.CH CH.sub.2 1 1,2,4-Triazo-5-yl3-382 Pip CH.dbd.CH CH.sub.2 1 Tetrazo-5-yl3-383 Pip CH.dbd.CH CH.sub.2 1 Pyz-2-yl3-384 Pip CH.dbd.CH CH.sub.2 1 3-Me-Pyz-2-yl3-385 Pip CH.dbd.CH CH.sub.2 1 Pymz-2-yl3-386 Pip CH.dbd.CH CH.sub.2 1 4-Me-Pymz-2-yl3-387 Pip CH.dbd.CH CH.sub.2 1 6-Me-Pymz-4-yl3-388 Pip CH.dbd.CH CH.sub.2 CH.sub.2 1 1,3,4-Oxadiazo-2-yl3-389 Pip CH.dbd.CH CH.sub.2 CH.sub.2 1 1,2,4-Triazo-3-yl3-390 Pip CH.dbd.CH CH.sub.2 CH.sub.2 1 1,2,4-Triazo-5-yl3-391 Pip CH.dbd.CH CH.sub.2 CH.sub.2 1 Pyz-2-yl3-392 Pip CH.dbd.CH CH.sub.2 CH.sub.2 1 3-Me-Pyz-2-yl3-393 Pip CH.dbd.CH CH.sub.2 CH.sub.2 1 Pymz-2-yl3-394 Pip CH.dbd.CH CH.sub.2 CH.sub.2 1 Pymz-4-yl3-395 Pip CH.dbd.CH CH.sub.2 CH.sub.2 1 4-Me-Pymz-2-yl3-396 Pip CH.dbd.CH CH.sub.2 CH.sub.2 1 2-Me-Pymz-4-yl3-397 Pip CH.dbd.CH (CH.sub.2).sub.3 1 Imdazo-2-yl3-398 Pip CH.dbd.CH (CH.sub.2).sub.3 1 Imdazo-4-yl3-399 Pip CH.dbd.CH (CH.sub.2).sub.3 1 1,3,4-Oxadiazo-2-yl3-400 Pip CH.dbd.CH (CH.sub.2).sub.3 1 1,3,4-Thiadiazo-2-yl3-401 Pip CH.dbd.CH (CH.sub.2).sub.3 1 1,2,4-Triazo-3-yl3-402 Pip CH.dbd.CH (CH.sub.2).sub.3 1 1,2,4-Triazo-5-yl3-403 Pip CH.dbd.CH (CH.sub.2).sub.3 1 Tetrazo-5-yl3-404 Pip CH.dbd.CH (CH.sub.2).sub.3 1 Pyz-2-yl3-405 Pip CH.dbd.CH (CH.sub.2).sub.3 1 Pymz-2-yl3-406 Pip CH.dbd.CH (CH.sub.2).sub.3 1 Pymz-4-yl3-407 Pip CH.dbd.CH (CH.sub.2).sub.4 1 1,3,4-Oxadiazo-2-yl3-408 Pip CH.dbd.CH (CH.sub.2).sub.4 1 1,2,4-Triazo-3-yl3-409 Pip CH.dbd.CH (CH.sub.2).sub.4 1 1,2,4-Triazo-5-yl3-410 Pip CH.dbd.CH (CH.sub.2).sub.4 1 Tetrazo-5-yl3-411 Pip CH.dbd.CH (CH.sub.2).sub.4 1 Pyz-2-yl3-412 Pip CH.dbd.CH (CH.sub.2).sub.4 1 Pymz-2-yl3-413 Pip CH.dbd.CH (CH.sub.2).sub.4 1 Pymz-4-yl3-414 Pip CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 1 1,3,4-Oxadiazo-2-yl3-415 Pip CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 1 1,2,4-Triazo-3-yl3-416 Pip CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 1 1,2,4-Triazo-5-yl3-417 Pip CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 1 Pymz-2-yl3-418 Pip CH.dbd.CH CH.sub.2 CH(Me)CH.sub.2 1 Pymz-4-yl3-419 Pip CH.dbd.CH (CH.sub.2).sub.5 1 1,3,4-Oxadiazo-2-yl3-420 Pip CH.dbd.CH (CH.sub.2).sub.5 1 1,2,4-Triazo-3-yl3-421 Pip CH.dbd.CH (CH.sub.2).sub.5 1 1,2,4-Triazo-5-yl3-422 Pip CH.dbd.CH (CH.sub.2).sub.5 1 Pymz-2-yl3-423 Pip CH.dbd.CH (CH.sub.2).sub.5 1 Pymz-4-yl3-424 Pip CH.dbd.CH (CH.sub.2).sub.6 1 1,3,4-Oxadiazo-2-yl3-425 Pip CH.dbd.CH (CH.sub.2).sub.6 1 1,2,4-Triazo-3-yl3-426 Pip CH.dbd.CH (CH.sub.2).sub.6 1 1,2,4-Triazo-5-yl3-427 Pip CH.dbd.CH (CH.sub.2).sub.6 1 Pymz-2-yl3-428 Pip CH.dbd.CH (CH.sub.2).sub.6 1 Pymz-4-yl3-429 Pip CH.dbd.CH CH.sub.2 2 1,3,4-Oxadiazo-2-yl3-430 Pip CH.dbd.CH CH.sub.2 2 1,2,4-Triazo-3-yl3-431 Pip CH.dbd.CH CH.sub.2 2 Pymz-2-yl3-432 Pip CH.dbd.CH CH.sub.2 CH.sub.2 2 1,3,4-Oxadiazo-2-yl3-433 Pip CH.dbd.CH CH.sub.2 CH.sub.2 2 1,2,4-Triazo-3-yl3-434 Pip CH.dbd.CH CH.sub.2 CH.sub.2 2 Pymz-2-yl3-435 Pip CH.dbd.CH CH.sub.2 CH.sub.2 2 Pymz-4-yl3-436 Pip CH.dbd.CH (CH.sub.2).sub.3 2 Imdazo-2-yl3-437 Pip CH.dbd.CH (CH.sub.2).sub.3 2 Imdazo-4-yl3-438 Pip CH.dbd.CH (CH.sub.2).sub.3 2 1,3,4-Oxadiazo-2-yl3-439 Pip CH.dbd.CH (CH.sub.2).sub.3 2 1,3,4-Thiadiazo-2-yl3-440 Pip CH.dbd.CH (CH.sub.2).sub.3 2 1,2,4-Triazo-3-yl3-441 Pip CH.dbd.CH (CH.sub.2).sub.3 2 1,2,4-Triazo-5-yl3-442 Pip CH.dbd.CH (CH.sub.2).sub.3 2 Tetrazo-5-yl3-443 Pip CH.dbd.CH (CH.sub.2).sub.3 2 Pyz-2-yl3-444 Pip CH.dbd.CH (CH.sub.2).sub.3 2 Pymz-2-yl3-445 Pip CH.dbd.CH (CH.sub.2).sub.3 2 Pymz-4-yl3-446 Pip CH.dbd.CH (CH.sub.2).sub.4 2 1,3,4-Oxadiazo-2-yl3-447 Pip CH.dbd.CH (CH.sub.2).sub.4 2 1,2,4-Triazo-3-yl3-448 Pip CH.dbd.CH (CH.sub.2).sub.4 2 Pymz-2-yl3-449 Pip CH.dbd.CH (CH.sub.2).sub.4 2 Pymz-4-yl3-450 Pip CH.dbd.CH (CH.sub.2).sub.5 2 1,3,4-Oxadiazo-2-yl3-451 Pip CH.dbd.CH (CH.sub.2).sub.5 2 1,2,4-Triazo-3-yl3-452 Pip CH.dbd.CH (CH.sub.2).sub.5 2 Pymz-2-yl3-453 Pip CH.dbd.CH (CH.sub.2).sub.5 2 Pymz-4-yl3-454 Pip CH.dbd.CH (CH.sub.2).sub.6 2 1,3,4-Oxadiazo-2-yl3-455 Pip CH.dbd.CH (CH.sub.2).sub.6 2 1,2,4-Triazo-5-yl3-456 Pip CH.dbd.CH (CH.sub.2).sub.6 2 Pymz-2-yl3-457 Pip CH.dbd.CH (CH.sub.2).sub.6 2 Pymz-4-yl3-458 Azi CH.dbd.CH (CH.sub.2).sub.3 1 1,2,4-Triazo-3-yl3-459 Azi CH.dbd.CH (CH.sub.2).sub.3 1 Pymz-2-yl3-460 Aze CH.dbd.CH (CH.sub.2).sub.3 1 1,2,4-Triazo-3-yl3-461 Aze CH.dbd.CH (CH.sub.2).sub.3 1 Pymz-2-yl3-462 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 Imdazo-2-yl3-463 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 Imdazo-4-yl3-464 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 1-Me-Imdazo-2-yl3-465 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 1,3,4-Oxadiazo-2-yl3-466 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 5-Me-1,3,4-Oxadiazo-2-yl3-467 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 1,3,4-Thiadiazo-2-yl3-468 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 5-Me-1,3,4-Thiadiazo-2-yl3-469 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 1,2,4-Triazo-3-yl3-470 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 1,2,4-Triazo-5-yl3-471 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 1-Me-1,2,4-Triazo-3-yl3-472 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 1-Me-1,2,4-Triazo-5-yl3-473 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 5-Me-1,2,4-Triazo-3-yl3-474 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 Tetrazo-5-yl3-475 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 1-Me-Tetrazo-5-yl3-476 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 Pyz-2-yl3-477 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 Pyz-3-yl3-478 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 Pyz-4-yl3-479 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 3-Me-Pyz-2-yl3-480 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-Me-Pyz-4-yl3-481 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 3-NH.sub.2 -Pyz-2-yl3-482 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 4-NH.sub.2 -Pyz-3-yl3-483 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 3-NH.sub.2 -Pyz-4-yl3-484 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 3-HO-Pyz-2-yl3-485 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-HO-Pyz-4-yl3-486 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 Pymz-2-yl3-487 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 Pymz-4-yl3-488 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 4-Me-Pymz-2-yl3-489 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 5-Me-Pymz-2-yl3-490 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-Me-Pymz-4-yl3-491 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 5-Me-Pymz-4-yl3-492 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 6-Me-Pymz-4-yl3-493 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-Me-Pymz-5-yl3-494 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 4-NH.sub.2 -Pymz-2-yl3-495 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 5-NH.sub.2 -Pymz-2-yl3-496 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-NH.sub.2 -Pymz-4-yl3-497 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 4-NH.sub.2 -5-HO-Pymz-2-yl3-498 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-NH.sub.2 -5-HO-Pymz-4-yl3-499 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 5-NH.sub.2 -2-HO-Pymz-4-yl3-500 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 Imdazo-2-yl3-501 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 Imdazo-4-yl3-502 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 1-Me-Imdazo-2-yl3-503 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 1,3,4-Oxadiazo-2-yl3-504 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 5-Me-1,3,4-Oxadiazo-2-yl3-505 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 1,3,4-Thiadiazo-2-yl3-506 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 5-Me-1,3,4-Thiadiazo-2-yl3-507 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 1,2,4-Triazo-3-yl3-508 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 1,2,4-Triazo-5-yl3-509 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 1-Me-1,2,4-Triazo-3-yl3-510 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 1-Me-1,2,4-Triazo-5-yl3-511 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 5-Me-1,2,4-Triazo-3-yl3-512 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 Tetrazo-5-yl3-513 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 1-Me-Tetrazo-5-yl3-514 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 Pyz-2-yl3-515 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 Pyz-3-yl3-516 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 Pyz-4-yl3-517 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 4-Me-Pyz-2-yl3-518 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-Me-Pyz-4-yl3-519 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 3-NH.sub.2 -Pyz-2-yl3-520 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 3-NH.sub.2 -Pyz-4-yl3-521 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 3-HO-Pyz-2-yl3-522 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-HO-Pyz-4-yl3-523 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 Pymz-2-yl3-524 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 Pymz-4-yl3-525 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 Pymz-5-yl3-526 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 4-Me-Pymz-2-yl3-527 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 5-Me-Pymz-2-yl3-528 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-Me-Pymz-4-yl3-529 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 5-Me-Pymz-4-yl3-530 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 6-Me-Pymz-4-yl3-531 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 4-NH.sub.2 -Pymz-2-yl3-532 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 5-NH.sub.2 -Pymz-2-yl3-533 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-NH.sub.2 -Pymz-4-yl3-534 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 4-HO-Pymz-5-yl3-535 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 4-NH.sub.2 -5-HO-Pymz-2-yl3-536 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-NH.sub.2 -5-HO-Pymz-4-yl3-537 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 5-NH.sub.2 -2-HO-Pymz-4-yl3-538 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 Imdazo-2-yl3-539 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 Imdazo-4-yl3-540 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 1-Me-Imdazo-2-yl3-541 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-Me-Imdazo-4-yl3-542 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 1,3,4-Oxadiazo-2-yl3-543 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 5-Me-1,3,4-Oxadiazo-2-yl3-544 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 5-Et-1,3,4-Oxadiazo-2-yl3-545 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 5-NH.sub.2 -1,3,4-Oxadiazo-2-yl3-546 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 5-AcNH-1,3,4-Oxadiazo-2-yl3-547 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 1,3,4-Thiadiazo-2-yl3-548 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 5-Me-1,3,4-Thiadiazo-2-yl3-549 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 5-NH.sub.2 -1,3,4-Thiadiazo-2-yl3-550 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 1,2,4-Triazo-3-yl3-551 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 1,2,4-Triazo-5-yl3-552 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 1-Me-1,2,4-Triazo-3-yl3-553 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 1-Me-1,2,4-Triazo-5-yl3-554 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 5-Me-1,2,4-Triazo-3-yl3-555 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 5-Cl-1,2,4-Triazo-3-yl3-556 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 5-NH.sub.2 -1,2,4-Triazo-3-yl3-557 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 5-AcNH-1,2,4-Triazo-3-yl3-558 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 Tetrazo-5-yl3-559 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 1-Me-Tetrazo-5-yl3-560 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 1-Et-Tetrazo-5-yl3-561 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 1-(2-HOEt)-Tetrazo-5-yl3-562 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 Pyz-2-yl3-563 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 Pyz-3-yl3-564 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 Pyz-4-yl3-565 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 3-Me-Pyz-2-yl3-566 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 5-Me-Pyz-2-yl3-567 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-Me-Pyz-4-yl3-568 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 3-Me-Pyz-4-yl3-569 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 3-Cl-Pyz-2-yl3-570 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 3-Cl-Pyz-4-yl3-571 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 3-NH.sub.2 -Pyz-2-yl3-572 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 5-NH.sub.2 -Pyz-2-yl3-573 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 4-NH.sub.2 -Pyz-3-yl3-574 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 3-NH.sub.2 -Pyz-4-yl3-575 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 3-HO-Pyz-2-yl3-576 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 5-HO-Pyz-2-yl3-577 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-HO-Pyz-4-yl3-578 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 3-HO-Pyz-4-yl3-579 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 Pymz-2-yl3-580 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 Pymz-4-yl3-581 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 Pymz-5-yl3-582 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 4-Me-Pymz-2-yl3-583 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 5-Me-Pymz-2-yl3-584 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-Me-Pymz-4-yl3-585 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 5-Me-Pymz-4-yl3-586 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 6-Me-Pymz-4-yl3-587 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 4-Cl-Pymz-2-yl3-588 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-Me-Pymz-4-yl3-589 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 4-NH.sub.2 -Pymz-2-yl3-590 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 5-NH.sub.2 -Pymz-2-yl3-591 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-NH.sub.2 -Pymz-4-yl3-592 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 5-NH.sub.2 -Pymz-4-yl3-593 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 4-AcNH-Pymz-2-yl3-594 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-AcNH-Pymz-4-yl3-595 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 4-NH.sub.2 -5-HO-Pymz-2-yl3-596 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-NH.sub.2 -5-HO-Pymz-4-yl3-597 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 4,6-diNH.sub.2 -Pymz-2-yl3-598 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2,5-diNH.sub.2 -Pymz-4-yl3-599 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 Imdazo-2-yl3-600 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 1,3,4-Oxadiazo-2-yl3-601 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 1,3,4-Thiadiazo-2-yl3-602 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 1,2,4-Triazo-3-yl3-603 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 1,2,4-Triazo-5-yl3-604 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 Tetrazo-5-yl3-605 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 Pyz-2-yl3-606 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 Pyz-3-yl3-607 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 Pyz-4-yl3-608 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 Pymz-2-yl3-609 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 Pymz-4-yl3-610 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 Imdazo-2-yl3-611 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 1,3,4-Oxadiazo-2-yl3-612 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 1,3,4-Thiadiazo-2-yl3-613 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 1,2,4-Triazo-3-yl3-614 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 1,2,4-Triazo-5-yl3-615 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 Tetrazo-5-yl3-616 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 Pyz-2-yl3-617 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 Pyz-4-yl3-618 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 Pymz-2-yl3-619 Pip CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 Pymz-4-yl3-620 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 Imdazo-2-yl3-621 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 1,3,4-Oxadiazo-2-yl3-622 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 1,3,4-Thiadiazo-2-yl3-623 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 1,2,4-Triazo-3-yl3-624 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 1,2,4-Triazo-5-yl3-625 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 Tetrazo-5-yl3-626 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 Pyz-2-yl3-627 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 Pyz-4-yl3-628 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 Pymz-2-yl3-629 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 Pymz-4-yl3-630 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 Imdazo-2-yl3-631 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 1,3,4-Oxadiazo-2-yl3-632 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 1,3,4-Thiadiazo-2-yl3-633 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 1,2,4-Triazo-3-yl3-634 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 1,2,4-Triazo-5-yl3-635 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 Tetrazo-5-yl3-636 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 Pyz-3-yl3-637 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 Pyz-4-yl3-638 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 Pymz-2-yl3-639 Pip CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 Pymz-4-yl3-640 Pyr CH.sub.2 CH.sub.2 CH.sub.2 0 Imdazo-2-yl3-641 Pyr CH.sub.2 CH.sub.2 CH.sub.2 0 Imdazo-4-yl3-642 Pyr CH.sub.2 CH.sub.2 CH.sub.2 0 1,3,4-Oxadiazo-2-yl3-643 Pyr CH.sub.2 CH.sub.2 CH.sub.2 0 1,3,4-Thiadiazo-2-yl3-644 Pyr CH.sub.2 CH.sub.2 CH.sub.2 0 1,2,4-Triazo-3-yl3-645 Pyr CH.sub.2 CH.sub.2 CH.sub.2 0 1,2,4-Triazo-5-yl3-646 Pyr CH.sub.2 CH.sub.2 CH.sub.2 0 Tetrazo-5-yl3-647 Pyr CH.sub.2 CH.sub.2 CH.sub.2 0 Pyz-2-yl3-648 Pyr CH.sub.2 CH.sub.2 CH.sub.2 0 Pyz-4-yl3-649 Pyr CH.sub.2 CH.sub.2 CH.sub.2 0 3-Me-Pyz-2-yl3-650 Pyr CH.sub.2 CH.sub.2 CH.sub.2 0 2-Me-Pyz-3-yl3-651 Pyr CH.sub.2 CH.sub.2 CH.sub.2 0 3-NH.sub.2 -Pyz-2-yl3-652 Pyr CH.sub.2 CH.sub.2 CH.sub.2 0 2-HO-Pyz-3-yl3-653 Pyr CH.sub.2 CH.sub.2 CH.sub.2 0 Pymz-2-yl3-654 Pyr CH.sub.2 CH.sub.2 CH.sub.2 0 Pymz-4-yl3-655 Pyr CH.sub.2 CH.sub.2 CH.sub.2 0 4-Me-Pymz-2-yl3-656 Pyr CH.sub.2 CH.sub.2 CH.sub.2 0 5-Me-Pymz-2-yl3-657 Pyr CH.sub.2 CH.sub.2 CH.sub.2 0 2-Me-Pymz-4-yl3-658 Pyr CH.sub.2 CH.sub.2 CH.sub.2 0 6-Me-Pymz-4-yl3-659 Pyr CH.sub.2 CH.sub.2 CH.sub.2 0 4-NH.sub.2 -Pymz-2-yl3-660 Pyr CH.sub.2 CH.sub.2 CH.sub.2 0 4-HO-Pymz-2-yl3-661 Pyr CH.sub.2 CH.sub.2 CH.sub.2 0 4-NH.sub.2 -5-HO-Pymz-2-yl3-662 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 Imdazo-2-yl3-663 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 Imdazo-4-yl3-664 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 1,3,4-Oxadiazo-2-yl3-665 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 1,3,4-Thiadiazo-2-yl3-666 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 1,2,4-Triazo-3-yl3-667 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 1,2,4-Triazo-5-yl3-668 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 Tetrazo-5-yl3-669 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 Pyz-2-yl3-670 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 Pyz-4-yl3-671 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 3-Me-Pyz-2-yl3-672 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 3-NH.sub.2 -Pyz-2-yl3-673 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 3-HO-Pyz-2-yl3-674 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 Pymz-2-yl3-675 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 Pymz-4-yl3-676 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 Pymz-5-yl3-677 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 4-Me-Pymz-2-yl3-678 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 5-Me-Pymz-2-yl3-679 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-Me-Pymz-4-yl3-680 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 5-Me-Pymz-4-yl3-681 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 4-NH.sub.2 -Pymz-2-yl3-682 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-HO-Pymz-2-yl3-683 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 Imdazo-2-yl3-684 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 Imdazo-4-yl3-685 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 1,3,4-Oxadiazo-2-yl3-686 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 1,3,4-Thiadiazo-2-yl3-687 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 1,2,4-Triazo-3-yl3-688 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 1,2,4-Triazo-5-yl3-689 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 Tetrazo-5-yl3-690 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 Pyz-2-yl3-691 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 Pyz-3-yl3-692 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 Pyz-4-yl3-693 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 3-Me-Pyz-2-yl3-694 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-Me-Pyz-4-yl3-695 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-Cl-Pyz-3-yl3-696 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 3-NH.sub.2 -Pyz-2-yl3-697 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 3-NH.sub.2 -Pyz-4-yl3-698 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 3-HO-Pyz-2-yl3-699 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 Pymz-2-yl3-700 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 Pymz-4-yl3-701 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 4-Me-Pymz-2-yl3-702 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-Me-Pymz-4-yl3-703 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 5-Me-Pymz-4-yl3-704 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 4-Me-Pymz-5-yl3-705 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 5-NH.sub.2 -Pymz-2-yl3-706 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-NH.sub.2 -Pymz-4-yl3-707 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-HO-Pymz-4-yl3-708 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 4-NH.sub.2 -5-HO-Pymz-2-yl3-709 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 2-NH.sub.2 -5-HO-Pymz-4-yl3-710 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 4,6-diNH.sub.2 -Pymz-2-yl3-711 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 Imdazo-2-yl3-712 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 1,3,4-Oxadiazo-2-yl3-713 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 1,3,4-Thiadiazo-2-yl3-714 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 1,2,4-Triazo-3-yl3-715 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 1,2,4-Triazo-5-yl3-716 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 Tetrazo-5-yl3-717 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 Pyz-2-yl3-718 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 Pyz-3-yl3-719 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 Pyz-4-yl3-720 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 Pymz-2-yl3-721 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 Pymz-4-yl3-722 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 Pymz-5-yl3-723 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 Imdazo-2-yl3-724 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 1,3,4-Oxadiazo-2-yl3-725 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 1,3,4-Thiadiazo-2-yl3-726 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 1,2,4-Triazo-3-yl3-727 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 1,2,4-Triazo-5-yl3-728 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 Tetrazo-5-yl3-729 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 Pyz-2-yl3-730 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 Pyz-3-yl3-731 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 Pymz-2-yl3-732 Pyr CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 Pymz-4-yl3-733 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 Imdazo-2-yl3-734 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 1,3,4-Oxadiazo-2-yl3-735 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 1,3,4-Thiadiazo-2-yl3-736 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 1,2,4-Triazo-3-yl3-737 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 1,2,4-Triazo-5-yl3-738 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 Tetrazo-5-yl3-739 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 Pyz-2-yl3-740 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 Pyz-3-yl3-741 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 Pymz-2-yl3-742 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 Pymz-4-yl3-743 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 Imdazo-2-yl3-744 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 1,3,4-Oxadiazo-2-yl3-745 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 1,3,4-Thiadiazo-2-yl3-746 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 1,2,4-Triazo-3-yl3-747 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 1,2,4-Triazo-5-yl3-748 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 Tetrazo-5-yl3-749 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 Pyz-2-yl3-750 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 Pyz-3-yl3-751 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 Pymz-2-yl3-752 Pyr CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 Pymz-4-yl3-753 NMe.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 Imdazo-2-yl3-754 NMe.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 1,3,4-Oxadiazo-2-yl3-755 NMe.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 1,3,4-Thiadiazo-2-yl3-756 NMe.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 1,2,4-Triazo-3-yl3-757 NMe.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 1,2,4-Triazo-5-yl3-758 NMe.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 Tetrazo-5-yl3-759 NMe.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 Pyz-2-yl3-760 NMe.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 3-Me-Pyz-2-yl3-761 NMe.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 Pymz-2-yl3-762 NMe.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 4-Me-Pymz-2-yl3-763 NMe.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 6-Me-Pymz-4-yl3-764 NMe.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 1,3,4-Oxadiazo-2-yl3-765 NMe.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 1,2,4-Triazo-3-yl3-766 NMe.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 1,2,4-Triazo-5-yl3-767 NMe.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 Pyz-2-yl3-768 NMe.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 3-Me-Pyz-2-yl3-769 NMe.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 Pymz-2-yl3-770 NMe.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 Pymz-4-yl3-771 NMe.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 4-Me-Pymz-2-yl3-772 NMe.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 0 2-Me-Pymz-4-yl3-773 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 Imdazo-2-yl3-774 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 Imdazo-4-yl3-775 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 1,3,4-Oxadiazo-2-yl3-776 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 1,3,4-Thiadiazo-2-yl3-777 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 1,2,4-Triazo-3-yl3-778 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 1,2,4-Triazo-5-yl3-779 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 Tetrazo-5-yl3-780 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 Pyz-2-yl3-781 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 Pymz-2-yl3-782 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 Pymz-4-yl3-783 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 1,3,4-Oxadiazo-2-yl3-784 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 1,2,4-Triazo-3-yl3-785 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 1,2,4-Triazo-5-yl3-786 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 Tetrazo-5-yl3-787 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 Pyz-2-yl3-788 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 Pymz-2-yl3-789 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.4 0 Pymz-4-yl3-790 NMe.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 1,3,4-Oxadiazo-2-yl3-791 NMe.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 1,2,4-Triazo-3-yl3-792 NMe.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 1,2,4-Triazo-5-yl3-793 NMe.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 Pymz-2-yl3-794 NMe.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 Pymz-4-yl3-795 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 1,3,4-Oxadiazo-2-yl3-796 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 1,2,4-Triazo-3-yl3-797 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 1,2,4-Triazo-5-yl3-798 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 Pymz-2-yl3-799 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.5 0 Pymz-4-yl3-800 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 1,3,4-Oxadiazo-2-yl3-801 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 1,2,4-Triazo-3-yl3-802 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 1,2,4-Triazo-5-yl3-803 NMe.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.6 0 Pymz-2-yl3-804 NMe.sub.2 CH.dbd.CH (CH.sub.2).sub.6 0 Pymz-4-yl3-805 Azi CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 1,2,4-Triazo-3-yl3-806 Azi CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 Pymz-2-yl3-807 Aze CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 1,2,4-Triazo-3-yl3-808 Aze CH.sub.2 CH.sub.2 (CH.sub.2).sub.3 0 Pymz-2-yl3-809 Pip CH.sub.2 CH.sub.2 0 Imdazo-2-yl3-810 Pip CH.sub.2 CH.sub.2 0 1,3,4-Oxadiazo-2-yl3-811 Pip CH.sub.2 CH.sub.2 0 1,3,4-Thiadiazo-2-yl3-812 Pip CH.sub.2 CH.sub.2 0 1,2,4-Triazo-3-yl3-813 Pip CH.sub.2 CH.sub.2 0 1,2,4-Triazo-5-yl3-814 Pip CH.sub.2 CH.sub.2 0 Tetrazo-5-yl3-815 Pip CH.sub.2 CH.sub.2 0 Pyz-2-yl3-816 Pip CH.sub.2 CH.sub.2 0 3-Me-Pyz-2-yl3-817 Pip CH.sub.2 CH.sub.2 0 Pymz-2-yl3-818 Pip CH.sub.2 CH.sub.2 0 4-Me-Pymz-2-yl3-819 Pip CH.sub.2 CH.sub.2 0 6-Me-Pymz-4-yl3-820 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 1,3,4-Oxadiazo-2-yl3-821 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 1,2,4-Triazo-3-yl3-822 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 1,2,4-Triazo-5-yl3-823 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 Pyz-2-yl3-824 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 3-Me-Pyz-2-yl3-825 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 Pymz-2-yl3-826 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 Pymz-4-yl3-827 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 4-Me-Pymz-2-yl3-828 Pip CH.sub.2 CH.sub.2 CH.sub.2 0 2-Me-Pymz-4-yl3-829 Pip CH.sub.2 (CH.sub.2).sub.3 0 Imdazo-2-yl3-830 Pip CH.sub.2 (CH.sub.2).sub.3 0 Imdazo-4-yl3-831 Pip CH.sub.2 (CH.sub.2).sub.3 0 1,3,4-Oxadiazo-2-yl3-832 Pip CH.sub.2 (CH.sub.2).sub.3 0 1,3,4-Thiadiazo-2-yl3-833 Pip CH.sub.2 (CH.sub.2).sub.3 0 1,2,4-Triazo-3-yl3-834 Pip CH.sub.2 (CH.sub.2).sub.3 0 1,2,4-Triazo-5-yl3-835 Pip CH.sub.2 (CH.sub.2).sub.3 0 Tetrazo-5-yl3-836 Pip CH.sub.2 (CH.sub.2).sub.3 0 Pyz-2-yl3-837 Pip CH.sub.2 (CH.sub.2).sub.3 0 Pymz-2-yl3-838 Pip CH.sub.2 (CH.sub.2).sub.3 .0 Pymz-4-yl3-839 Pip CH.sub.2 (CH.sub.2).sub.4 0 1,3,4-Oxadiazo-2-yl3-840 Pip CH.sub.2 (CH.sub.2).sub.4 0 1,2,4-Triazo-3-yl3-841 Pip CH.sub.2 (CH.sub.2).sub.4 0 1,2,4-Triazo-5-yl3-842 Pip CH.sub.2 (CH.sub.2).sub.4 0 Tetrazo-5-yl3-843 Pip CH.sub.2 (CH.sub.2).sub.4 0 Pyz-2-yl3-844 Pip CH.sub.2 (CH.sub.2).sub.4 0 Pymz-2-yl3-845 Pip CH.sub.2 (CH.sub.2).sub.4 0 Pymz-4-yl3-846 Pip CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 1,3,4-Oxadiazo-2-yl3-847 Pip CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 1,2,4-Triazo-3-yl3-848 Pip CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 1,2,4-Triazo-5-yl3-849 Pip CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 Pymz-2-yl3-850 Pip CH.sub.2 CH.sub.2 CH(Me)CH.sub.2 0 Pymz-4-yl3-851 Pip CH.sub.2 (CH.sub.2).sub.5 0 1,3,4-Oxadiazo-2-yl3-852 Pip CH.sub.2 (CH.sub.2).sub.5 0 1,2,4-Triazo-3-yl3-853 Pip CH.sub.2 (CH.sub.2).sub.5 0 1,2,4-Triazo-5-yl3-854 Pip CH.sub.2 (CH.sub.2).sub.5 0 Pymz-2-yl3-855 Pip CH.sub.2 (CH.sub.2).sub.5 0 Pymz-4-yl3-856 Pip CH.sub.2 (CH.sub.2).sub.6 0 1,3,4-Oxadiazo-2-yl3-857 Pip CH.sub.2 (CH.sub.2).sub.6 0 1,2,4-Triazo-3-yl3-858 Pip CH.sub.2 (CH.sub.2).sub.6 0 1,2,4-Triazo-5-yl3-859 Pip CH.sub.2 (CH.sub.2).sub.6 0 Pymz-2-yl3-860 Pip CH.sub.2 (CH.sub.2).sub.6 0 Pymz-4-yl3-861 Pip (CH.sub.2).sub.3 CH.sub.2 0 1,3,4-Oxadiazo-2-yl3-862 Pip (CH.sub.2).sub.3 CH.sub.2 0 1,2,4-Triazo-3-yl3-863 Pip (CH.sub.2).sub.3 CH.sub.2 0 Pymz-2-yl3-864 Pip (CH.sub.2).sub.3 CH.sub.2 CH.sub.2 0 1,3,4-Oxadiazo-2-yl3-865 Pip (CH.sub.2).sub.3 CH.sub.2 CH.sub.2 0 1,2,4-Triazo-3-yl3-866 Pip (CH.sub.2).sub.3 CH.sub.2 CH.sub.2 0 Pymz-2-yl3-867 Pip (CH.sub.2).sub.3 CH.sub.2 CH.sub.2 0 Pymz-4-yl3-868 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.3 0 Imdazo-2-yl3-869 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.3 0 Imdazo-4-yl3-870 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.3 0 1,3,4-Oxadiazo-2-yl3-871 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.3 0 1,3,4-Thiadiazo-2-yl3-872 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.3 0 1,2,4-Triazo-3-yl3-873 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.3 0 1,2,4-Triazo-5-yl3-874 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.3 0 Tetrazo-5-yl3-875 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.3 0 Pyz-2-yl3-876 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.3 0 Pymz-2-yl3-877 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.3 0 Pymz-4-yl3-878 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.4 0 1,3,4-Oxadiazo-2-yl3-879 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.4 0 1,2,4-Triazo-3-yl3-880 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.4 0 Pymz-2-yl3-881 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.4 0 Pymz-4-yl3-882 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.5 0 1,3,4-Oxadiazo-2-yl3-883 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.5 0 1,2,4-Triazo-3-yl3-884 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.5 0 Pymz-2-yl3-885 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.5 0 Pymz-4-yl3-886 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.6 0 1,3,4-Oxadiazo-2-yl3-887 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.6 0 1,2,4-Triazo-5-yl3-888 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.6 0 Pymz-2-yl3-889 Pip (CH.sub.2).sub.3 (CH.sub.2).sub.6 0 Pymz-4-yl3-890 Pyr CH.sub.2 (CH.sub.2).sub.3 0 1,2,4-Triazo-3-yl3-891 Pyr CH.sub.2 (CH.sub.2).sub.3 0 Pymz-2-yl3-892 Azi CH.sub.2 (CH.sub.2).sub.3 0 1,2,4-Triazo-3-yl3-893 Aze CH.sub.2 (CH.sub.2).sub.3 0 Pymz-2-yl__________________________________________________________________________
Of the compounds listed above, the following are preferred, that is to say Compounds No. 1-1, 1-5, 1-16, 1-17, 1-19, 1-28, 1-31, 1-45, 1-46, 1-47, 1-61, 1-82, 1-87, 1-92, 1-115, 1-116, 1-125, 1-137, 1-166, 1-185, 1-216, 1-260, 1-350, 1-462, 1-591, 1-612, 1-951, 1-974, 1-975, 1-976, 1-977, 1-981, 1-985, 1-1004, 1-1016, 1-1018, 1-1019, 1-1020, 1-1021, 1-1022, 1-1023, 1-1065, 1-1124, 1-1168, 1-1169, 1-1274, 2-2, 2-4, 2-5, 2-6, 2-7, 2-8, 2-9, 2-10, 2-12, 2-20, 2-27, 2-28, 2-42, 2-44, 2-57, 2-59, 2-96, 2-98, 2-123, 2-209, 2-211, 2-212, 2-216, 2-217, 2-218, 2-297, 2-298, 2-390, 2-391, 2-392, 2-461, 2-482, 2-483, 2-493, 2-494, 2-506, 2-508, 2-509, 2-852, 2-854, 2-1059, 2-1061, 2-1147, 2-1148, 3-8, 3-14, 3-25, 3-79, 3-82, 3-86, 3-87, 3-89, 3-98, 3-100, 3-101, 3-103, 3-118, 3-119, 3-121, 3-136, 3-238, 3-405 and 3-579. More preferred compounds are Compounds No. 1-46, 1-116, 1-137, 1-591, 1-612, 1-974, 1-1019, 2-2, 2-4, 2-5, 2-6, 2-7, 2-9, 2-10, 2-12, 2-20, 2-27, 2-28, 2-209, 2-211, 2-212, 2-216, 2-217, 2-218, 2-390, 2-392, 2-1147, 2-1148, 3-118, 3-238 and 3-579.
The most preferred compounds of the present invention are Compounds No.:
1-116. N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]pyrazole -4-carboxamide;
1-137. 3-amino-N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]pyrazole-4-carboxamide;
2-2. N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-hydroxyethylthio)acetamide;
2-4. N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-acetoxyethylthio)acetamide;
2-5. N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-propionyloxyethylthio)acetamide;
2-6. N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-butyryloxyethylthio)acetamide;
2-7. N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-isobutyryloxyethylthio)acetamide;
2-9. N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-isovaleryloxyethylthio)acetamide;
2-10. N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-phenylacetoxyethylthio)acetamide;
2-12. 2-{-N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]carbamoylmethylthio}ethyl hydrogen succinate;
2-20. N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-benzoyloxyethylthio)acetamide;
2-27. N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-cyclopentylcarbonyloxyethylthio)acetamide;
2-28. N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-cyclohexylcarbonyloxyethylthio)acetamide;
2-390. N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-hydroxyethylsulfinyl)acetamide;
2-392. N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-propionyloxyethylsulfinyl)acetamide;
2-1147. -N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-[2-(3,3-dimethylbutyryloxy)ethylthio)acetamide;
2-1148. N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-[2-(2,2-dimethylpropionyloxy)ethylthio)acetamide;
3-118. N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-4-(2-pyrimidinylthio)butyramide;
and pharmaceutically acceptable salts thereof.
The compounds of the present invention may be prepared by a variety of methods well known in the art for the preparation of compounds of this type. For example, they may be prepared by the following Reactions A to G: ##STR5##
In the above formulae:
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, A, B and m are as defined above;
R.sup.2a represents any of the groups defined above for R.sup.2, except the groups of formula --NHCHR.sup.3 R.sup.4 (wherein R.sup.3 and R.sup.4 are as defined above) and provided that any hydroxy group in the group represented by R.sup.2 is protected;
R.sup.2b represents any of the groups defined above for R.sup.2, except the groups of formula --NHCHR.sup.3 R.sup.4 (wherein R.sup.3 and R.sup.4 are as defined above);
R.sup.5a represents a hydroxyalkyl group having from 2 to 4 carbon atoms (with the proviso that the group must include a moiety having the formula --CH.sub.2 OH);
R.sup.6 represents an alkyl group having from 1 to 3 carbon atoms and substituted with a carboxy or alkoxycarbonyl group having from 1 to 6 carbon atoms in the alkoxy moiety;
X represents a halogen atom, preferably a chlorine, bromine or iodine atom;
Y represents a hydrogen atom or an alkali metal atom, such as a lithium, sodium or potassium atom; and
p is an integer from 1 to 3.
Where a hydroxy-protecting group is present, there is no particular limitation upon the nature of this group, and any such group well known in the field of organic chemistry may equally be used here. Typical examples of such groups include: cyclic ether groups, such as the tetrahydropyranyl, tetrahydrofuranyl and tetrahydrothiopyranyl groups; tri(C.sub.1 -C.sub.4 alkyl)silyl or di(C.sub.1 -C.sub.4 alkyl)arylsilyl groups, such as the trimethylsilyl, triethylsilyl, t-butyldimethylsilyl and methyldiphenylsilyl groups; methyl groups substituted with a methoxy, methylthio or trihaloethoxy group, such as the methoxymethyl, methylthiomethyl and 2,2,2-trichloroethoxymethyl groups; and aralkyl groups, such as the benzyl and diphenylmethyl groups. Of these, we particularly prefer the cyclic ether groups (particularly a tetrahydropyranyl group), the substituted silyl groups (particularly a trimethylsilyl or t-butyldimethylsilyl group) and the methoxymethyl group.
In Reaction A, a compound of formula (Ia), i.e. a compound of formula (I) in which R.sup.2 represents a group of formula --NHCHR.sup.3 R.sup.4 (wherein R.sup.3 and R.sup.4 are as defined above) is prepared by reacting a compound of formula (II) with a compound of formula (III) in the presence of carbonyldiimidazole in an inert solvent.
The reaction is normally and preferably effected in the presence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: aromatic hydrocarbons, such as benzene, toluene or xylene; halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such as methylene chloride or chloroform; ethers, such as diethyl ether, tetrahydrofuran or dioxane; amides, such as dimethylformamide, diethylformamide or dimethylacetamide; nitriles, such as acetonitrile; and sulfoxides, such as dimethyl sulfoxide. Of these, we prefer the halogenated hydrocarbons.
The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of from -20.degree. C. to 100.degree. C. (more preferably from 0.degree. C. to 50.degree. C.). The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 30 minutes to 10 hours (more preferably from 1 to 5 hours) will usually suffice.
After completion of the reaction, the desired compound can be recovered from the reaction mixture by conventional means. For example, one such recovery method comprises: distilling off the solvent from the reaction mixture or pouring the reaction mixture into water; extracting the mixture with a water-immiscible organic solvent; and distilling off the organic solvent, to leave the desired product as a residue. If necessary, the resulting product can be further purified by conventional means, such as recrystallization, reprecipitation or the various chromatography techniques, notably column chromatography.
Reaction B comprises another method for preparing a compound of formula (Ia). In this reaction, a compound of formula (Ia) is prepared by reacting a compound of formula (II) with a compound of formula (IV) in an inert solvent.
The reaction is normally and preferably effected in the presence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: aromatic hydrocarbons, such as benzene, toluene or xylene; halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such as methylene chloride or chloroform; ethers, such as diethyl ether, tetrahydrofuran or dioxane; alcohols, such as methanol, ethanol or isopropanol; and nitriles, such as acetonitrile. Of these, we prefer the aromatic hydrocarbons or the halogenated hydrocarbons.
The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of from -20.degree. C. to 100.degree. C. (more preferably from 0.degree. C. to 50.degree. C.). The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 30 minutes to 10 hours (more preferably from 1 to 5 hours) will usually suffice.
After completion of the reaction, the desired compound can be recovered from the reaction mixture by conventional means. For example, one such recovery method comprises: distilling off the solvent from the reaction mixture or pouring the reaction mixture into water; extracting the mixture with a water-immiscible organic solvent; and distilling off the organic solvent, to leave the desired product as a residue. If necessary, the resulting product can be further purified by conventional means, such as recrystallization, reprecipitation or the various chromatography techniques, notably column chromatography.
In Reaction C, a compound of formula (Ib), that is a compound of formula (I) wherein R.sup.2 represents R.sup.2b (R.sup.2b is as defined above) is prepared by reacting an amine derivative of formula (II) with a carboxylic acid compound of formula (V) or with a reactive derivative of the carboxylic acid, and, if desired, removing any hydroxy-protecting group.
The reaction of the amine of formula (II) with the carboxylic acid of formula (V) may be carried out in the presence or absence of a base and preferably in the presence of a condensing agent and of in an inert solvent.
There is no particular limitation upon the nature of the condensing agent used for the reaction, and any reagent capable of producing an amide bond from a carboxylic acid and an amine may be used. Examples of the preferred condensing agents which may be used include: dicyclohexylcarbodiimide (DCC); diethyl cyanophosphonate (DEPC); carbonyldiimidazole; diphenylphosphoryl azide (DPPA); 1-hydroxybenzotriazole in admixture with dicyclohexylcarbodiimide; or diethyl azodicarboxylate in admixture with triphenyl phosphine, Of these, we prefer either 1-hydroxybenzotriazole in admixture with dicyclohexylcarbodiimide or diethyl cyanophosphonate.
Examples of preferred bases which may be used include organic amines, such as trimethylamine, triethylamine, pyridine, dimethylaniline, N-methylmorpholine or 4-(N,N-dimethylamino)pyridine. Of these, we prefer triethylamine or N-methylmorpholine.
The reaction is normally and preferably effected in the presence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: aromatic hydrocarbons, such as benzene, toluene or xylene; halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such as methylene chloride, dichloroethane or chloroform; ethers, such as diethyl ether, tetrahydrofuran or dioxane; esters, such as ethyl acetate or propyl acetate; amides, such as dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; and nitriles, such as acetonitrile. Of these, we prefer the ethers (particularly tetrahydrofuran), halogenated hydrocarbons (particularly methylene chloride), amides (particularly dimethylformamide) and esters (particularly ethyl acetate).
The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of from -10.degree. C. to 50.degree. C. (more preferably from 0.degree. C. to 30.degree. C.). The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 30 minutes to 24 hours (more preferably from 1 to 15 hours) will usually suffice.
Alternatively, the compound of formula (Ib) can be prepared by converting a carboxylic acid of formula (V) to a reactive derivative thereof, and reacting an amine of formula (II) with the reactive derivative.
Examples of reactive derivatives of the carboxylic acid compound include: acid halides, such as the acid chloride or acid bromide; acid azides; reactive esters, such as esters with N-hydroxybenzotriazole or N-hydroxysuccinimide; acid anhydrides of the carboxylic acid used; and mixed acid anhydrides comprising monoalkyl carbonates in which the alkyl group has from 1 to 4 carbon atoms (such as monomethyl carbonate, monoethyl carbonate or monoisobutyl carbonate) or monoaryl carbonates (such as monophenyl carbonate or monotolyl carbonate). Of these, we prefer the mixed acid anhydrides with an alkyl carbonate. The reactive derivative of the carboxylic acid, typically an acid halide or an acid anhydride, can be prepared by conventional means. For example, they may be prepared by reacting a carboxylic acid of formula (V) with an appropriate halide (for example, thionyl chloride, thionyl bromide, acid chloride or acid bromide of the desired carboxylic acid, methyl chloroformate, ethyl chloroformate, isobutyl chloroformate, phenyl chloroformate or tolyl chloroformate) in an inert solvent (for example, methylene chloride, benzene or tetrahydrofuran) and, if necessary, in the presence of a base (for example, pyridine, triethylamine or dimethylaniline) in the temperature range from 20.degree. C. to 100.degree. C. for a period of from 1 to 20 hours. Other reactive derivatives, such as the acid amide or the reactive ester, can be prepared by reacting the carboxylic acid of formula (V) with an appropriate compound (for example, hydrogen azide, N-hydroxybenzotriazole or N-hydroxysuccinimide) in the same manner as described above in Reaction C for producing an amide bond, using a carboxylic acid of formula (V) and an amine of formula (II).
The reaction of the amine of formula (II) and the reactive derivative of the carboxylic acid of formula (V) is preferably carried out in the presence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: aromatic hydrocarbons, such as benzene, toluene or xylene; halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such as methylene chloride, dichloroethane or chloroform; ethers, such as diethyl ether, tetrahydrofuran or dioxane; and esters, such as ethyl acetate. Of these, we prefer the aromatic hydrocarbons or ethers.
The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of from -10.degree. C. to 50.degree. C. (more preferably from 0.degree. C. to 25.degree. C.). The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 5 minutes to 20 hours (more preferably from 30 minutes to 10 hours) will usually suffice.
The reaction employed to remove the hydroxy-protecting group will, of course, vary depending upon the nature of the protecting group, but its removal may be achieved by conventional means well known in the field of organic chemistry.
For example, where the protecting group is a silyl group, it can be removed by reacting the corresponding compound with a base (for example, an alkali metal carbonate, such as sodium carbonate or potassium carbonate), an acid (for example, a mineral acid, such as hydrochloric acid or sulfuric acid, or an organic carboxylic acid, such as acetic acid or citric acid) or a fluoride (for example, an ammonium fluoride compound, such as tributylammonium fluoride) in an inert solvent. The reaction is normally and preferably effected in the presence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: ethers, such as diethyl ether, tetrahydrofuran or dioxane; and alcohols, such as methanol or ethanol. Of these, we prefer the alcohols.
The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of from -20.degree. C. to 50.degree. C. (preferably from 0.degree. C. to 30.degree. C.). The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 5 minutes to 2 hours (more preferably from 20 minutes to 1 hour) will usually suffice.
Where the protecting group is a cyclic ether or a substituted methyl group, it can be removed by reacting the corresponding compound with an acid in an inert solvent. Examples of acids which may be used for this reaction include: mineral acids, such as hydrochloric acid, hydrobromic acid or sulfuric acid; and organic sulfonic acids, such as methanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid. Of these, we prefer hydrochloric acid or toluenesulfonic acid.
The reaction is normally and preferably effected in the presence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: aromatic hydrocarbons, such as benzene, toluene or xylene; halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such as methylene chloride, dichloroethane or chloroform; ethers, such as diethyl ether, tetrahydrofuran or dioxane; alcohols, such as methanol or ethanol; esters, such as ethyl acetate or propyl acetate; amides, such as dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; and nitriles, such as acetonitrile. Of these, we prefer the halogenated hydrocarbons or esters.
The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of from -20.degree. C. to 100.degree. C. (more preferably from 20.degree. C. to 70.degree. C.). The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 15 minutes to 5 hours (more preferably from 30 minutes to 2 hours) will usually suffice.
Where the protecting group is an aralkyl group, it can be removed by reacting the corresponding compound with hydrogen in an inert solvent in the presence of a catalyst for reduction. Examples of catalysts which may be used for reduction include: platinum oxide, platinum black, palladium-on-charcoal, and rhodium-on-charcoal. Of these, we prefer palladium-on-charcoal.
The hydrogen pressure used is normally in the range of from atmospheric pressure to 3 atmospheres pressure.
The reaction is normally and preferably effected in the presence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: aromatic hydrocarbons, such as benzene, toluene or xylene; halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such as methylene chloride, dichloroethane or chloroform; ethers, such as diethyl ether, tetrahydrofuran or dioxane; alcohols, such as methanol or ethanol; esters, such as ethyl acetate or propyl acetate; amides, such as dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; and nitriles, such as acetonitrile. Of these, we prefer the alcohols.
The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of from -20.degree. C. to 100.degree. C. (more preferably from 10.degree. C. to 50.degree. C.). The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 15 minutes to 5 hours (more preferably from 30 minutes to 2 hours) will usually suffice.
After completion of the reaction, the desired compound from each reaction can be recovered from the reaction mixture by conventional means. For example, one such method comprises: neutralizing properly the reaction mixture; distilling off the solvent from the reaction mixture; or if necessary, after distilling off the solvent, pouring the reaction mixture into water; extracting the mixture with a water-immiscible organic solvent; and distilling off the solvent from the extract, to leave the desired product as a residue. If necessary, the resulting product can be further purified by conventional means, such as recrystallization, reprecipitation or the various chromatography techniques, notably column chromatography.
In Reaction D, a compound of formula (Ic), that is a compound of formula (I) wherein R.sup.2 represents a group of formula --B--S(O).sub.m --R.sup.5 (wherein R.sup.5, B and m are as defined above), is prepared by reacting a compound of formula (VI) with a compound of formula (VII), normally in an inert solvent in the presence of a base and then, if desired, oxidizing the resulting thioether compound.
There is no particular restriction on the nature of the base employed in this reaction, and any base may be used, provided that it has no adverse effect on any part of the molecule of the reagents. Examples of bases which may be used for the reaction include: alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide; alkali metal carbonates, such as sodium carbonate or potassium carbonate; alkali metal hydrogencarbonates, such as sodium hydrogencarbonate or potassium hydrogencarbonate; and organic amines, such as trimethylamine, triethylamine, pyridine, dimethylaniline, N-methylmorpholine or 4-(N,N-dimethylamino)pyridine. Of these, we prefer the alkali metal hydroxides.
The reaction is normally and preferably effected in the presence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: aromatic hydrocarbons, such as benzene, toluene or xylene; halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such as methylene chloride or chloroform; ethers, such as diethyl ether, tetrahydrofuran or dioxane; alcohols, such as methanol, ethanol or isopropanol; amides, such as dimethylformamide diethylformamide or dimethylacetamide; nitriles, such as acetonitrile; and sulfoxides, such as dimethyl sulfoxide. Of these, we prefer the alcohols.
The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of from -20.degree. C. to 100.degree. C. (more preferably from 0.degree. C. to 50.degree. C.). The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 10 minutes to 5 hours (more preferably from 30 minutes to 2 hours) will usually suffice.
Oxidation can be conducted by oxidizing the corresponding thioether compound with an oxidizing reagent in an inert solvent. Examples of oxidizing reagents which may be used for this reaction include: inorganic peroxides, such as hydrogen peroxide or periodic acid; peroxyaliphatic acids, such as peracetic acid or perpropionic acid; peroxyarylic acids, such as perbenzoic acid or m-chloroperbenzoic acid; and metal salts of peroxyphthalic acids, such as magnesium monoperoxyphthalate. Of these, we prefer the peroxyarylic acids.
The reaction is normally and preferably effected in the presence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: aromatic hydrocarbons, such as benzene, toluene or xylene; halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such as methylene chloride, dichloroethane or chloroform; and ethers, such as diethyl ether, tetrahydrofuran or dioxane. Of these, we prefer the halogenated hydrocarbons.
The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of from -30.degree. C. to 50.degree. C. (more preferably from -20.degree. C. to room temperature). The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 10 minutes to 5 hours (more preferably from 30 minutes to 2 hours) will usually suffice.
In this reaction, a sulfinyl compound may be obtained by using about an equimolar of the oxidizing reagent per mole of the thioether compound, and a sulfonyl compound may be obtained by using more than two moles of the oxidizing reagent per mole of the thioether compound.
The corresponding thioether compounds of formula (Ib), (Id) or (Ie) can be subjected to oxidation in a similar manner to that described above to afford the corresponding sulfinyl and sulfonyl compounds.
In the compounds of formula (Ic) where R.sup.5 represents a hydroxyalkyl group, if desired, the corresponding acyloxyalkyl compound can be prepared by acylating the hydroxy group.
Specifically, compounds of formula (Ic), wherein R.sup.5 represents: a C.sub.1 -C.sub.5 alkanoyloxy group; a C.sub.2 -C.sub.5 alkanoyloxy group substituted with a C.sub.2 -C.sub.5 alkoxycarbonyl, C.sub.7 -C.sub.11 aryloxycarbonyl or C.sub.6 -C.sub.10 aryl group; a C.sub.7 -C.sub.11 arylcarbonyloxy group; or an alkyl group substituted with a C.sub.3 -C.sub.6 cycloalkylcarbonyloxy group, can be prepared by reacting a hydroxy compound with the corresponding carboxylic acid compound or with a reactive derivative thereof.
The reaction conditions used in the reaction of the hydroxy compound with the carboxylic acid compound are similar to those used, in the presence of a condensing agent, in Reaction C, described above.
Reaction of the hydroxy compound with a reactive derivative of the carboxylic acid compound is preferably conducted in an inert solvent in the presence or absence of a base.
There is no particular limitation upon the nature of the reactive derivative of the carboxylic acid used, provided that it is a compound capable of producing an ester compound by reaction with an alcohol compound, and it will, of course, depend on the nature of the group which it is desired to introduce. Examples of reactive derivatives which may be used for the reaction include: acid halides, such as acetyl chloride, propionyl chloride, valeryl chloride, valeryl bromide, isovaleryl chloride, methyl chloroformylacetate, ethyl 3-chloroformylpropionate, ethyl 4-chloroformylbutyrate, ethyl 5-chloroformylvalerate, phenylacetyl chloride, phenylpropionyl chloride, benzoyl chloride, toluoyl chloride, naphthoyl chloride, cyclopropanecarbonyl chloride, cyclobutanecarbonyl chloride, cyclopentanecarbonyl chloride, and cyclohexanecarbonyl chloride; acid anhydrides, such as acetic formic anhydride, acetic anhydride, propionic anhydride or benzoic anhydride; and mixed acid anhydrides of monoalkyl carbonates (in which the alkyl part has from 1 to 4 carbon atoms), such as monomethyl carbonate, monoethyl carbonate or monoisobutyl carbonate, or monoaryl carbonates, such as monophenyl carbonate or mono(methylphenyl) carbonate, and of the corresponding acids, such as acetic acid, propionic acid, phenylacetic acid, benzoic acid, cyclopentanecarboxylic acid or cyclohexanecarbonylic acid. Of these, we prefer the acid chlorides, acid anhydrides or mixed acid anhydrides comprising alkyl carbonates. These reactive derivatives of carboxylic acids can be prepared in the same manner as those of carboxylic acids described in Reaction C, described above.
There is no particular restriction on the nature of the base employed in this reaction, and any base may be used, provided that it has no adverse effect on any part of the molecule of the reagents. Examples of preferred bases which may be used for this reaction include: organic amines, such as trimethylamine, triethylamine, pyridine, dimethylaniline, N-methylmorpholine or 4-(N,N-dimethylamino)pyridine; and particularly preferably triethylamine or N-methylmorpholine. An excess of the organic amine can also serve as a solvent.
The reaction is normally and preferably effected in the presence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: aromatic hydrocarbons, such as benzene, toluene or xylene; halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such as methylene chloride, dichloroethane or chloroform; ethers, such as diethyl ether, tetrahydrofuran or dioxane; esters, such as ethyl acetate or propyl acetate; amides, such as dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; and nitriles, such as acetonitrile. Of these, we prefer the ethers (particularly tetrahydrofuran) or esters (particularly ethyl acetate).
The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of from -10.degree. C. to 50.degree. C. (more preferably from 0.degree. C. to 30.degree. C.). The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 30 minutes to 24 hours will usually suffice.
Where R.sup.5 represents an alkyl group substituted with a carboxyl group, the corresponding compounds of formula (Ic) can be prepared by reacting a hydroxy compound with a cyclic carboxylic acid anhydride, such as succinic anhydride, glutaric anhydride or adipic anhydride (preferably succinic anhydride or glutaric anhydride).
The reaction is normally and preferably effected in the presence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: aromatic hydrocarbons, such as benzene, toluene or xylene; halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such as methylene chloride or chloroform; ethers, such as diethyl ether, tetrahydrofuran or dioxane; ketones, such as acetone or methyl ethyl ketone; amides, such as dimethylformamide, diethylformamide or dimethylacetamide; nitriles, such as acetonitrile; and sulfoxides, such as dimethyl sulfoxide. Of these, we prefer the ketones.
The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of from -20.degree. C. to 100.degree. C. (more preferably from 0.degree. C. to 50.degree. C.). The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 30 minutes to 8 hours (more preferably from 1 to 5 hours) will usually suffice.
The carboxylic acid compounds obtained above may be converted to the corresponding ester compounds by conventional esterification procedures, including reacting the carboxylic acid compound with a diazo compound, such as diazomethane, diazoethane, diazopropane, diazobutane or trimethylsilyldiazomethane in an inert solvent (preferably an ether, such as diethyl ether, tetrahydrofuran or dioxane), at about room temperature for a period of from 10 minutes to 2 hours.
After completion of the reaction, the desired compound prepared in this step can be recovered from the reaction mixture by conventional means. For example, one such technique comprises: neutralizing properly the reaction mixture; distilling off the solvent from the reaction mixture or, if necessary, after distilling off the solvent from the reaction mixture, pouring the reaction mixture into water; extracting the mixture with a water-immiscible organic solvent; and finally distilling off the solvent from the extract. Further, if necessary, the product can be purified by conventional means, for example, recrystallization, reprecipitation or the various chromatography techniques, notably column chromatography.
Reaction E comprises an alternative method for preparing a compound of formula (Ic). In this reaction, a compound of formula (Ic) is prepared by reacting a compound of formula (VIII) with a compound of formula (IX) and, if desired, oxidizing the thioether compound thus obtained. This step is carried out in a similar manner as those described above in Reactions C and D.
In Reaction F, a compound of formula (Id), that is, a compound of formula (I) wherein R.sup.2 represents a group of formula --CH.sub.2 S(O).sub.m (CH.sub.2).sub.p+1 OH (wherein m and p are as defined as above), is prepared by reacting a compound of formula (II) with a compound of formula (X), normally in an inert solvent.
The reaction is normally and preferably effected in the presence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: aromatic hydrocarbons, such as benzene, toluene or xylene; ethers, such as diethyl ether, tetrahydrofuran or dioxane; halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such as methylene chloride or chloroform; and alcohols, such as methanol, ethanol or isopropanol. The reaction may also be carried out in the absence of a solvent.
The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of from -20.degree. C. to 130.degree. C. (more preferably from 50.degree. C. to 100.degree. C.). The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 30 minutes to 5 hours (more preferably from 1 to 2 hours) will usually suffice.
After completion of the reaction, the desired compound prepared in this step can be recovered from the reaction mixture by conventional means. For example, one such technique comprises: neutralizing properly the reaction mixture; distilling off the solvent from the reaction mixture or, if necessary, after distilling off the solvent from the reaction mixture, pouring the reaction mixture into water; extracting the mixture with a water-immiscible organic solvent; and finally distilling off the solvent from the extract. Further, if necessary, the product can be purified by conventional means, for example, recrystallization, reprecipitation or the various chromatography techniques, notably column chromatography.
In Reaction G, a compound of formula (Ie), that is, a compound of formula (I) wherein R.sup.2 represents a group of formula --B--S(O).sub.m --R.sup.5a (wherein R.sup.5a, B and m are as defined above), can be prepared by reacting a compound of formula (XI) with a reducing reagent in an inert solvent.
Examples of reducing reagents which may be used include: borohydride compounds, such as lithium borohydride, sodium borohydride, calcium borohydride or sodium cyanoborohydride. Of these, we prefer sodium borohydride.
The reaction is normally and preferably effected in the presence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: ethers, such as diethyl ether, tetrahydrofuran or dioxane; alcohols, such as methanol or ethanol; water; or a mixture of any two or more of these solvents. Of these, we prefer a mixture of an alcohol and an ether.
The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of from -20.degree. C. to 100.degree. C. (more preferably from 0.degree. C. to 30.degree. C.). The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 1 to 24 hours (more preferably from 3 to 10 hours) will usually suffice.
After completion of the reaction, the desired compound prepared in this step can be recovered from the reaction mixture by conventional means. For example, one such technique comprises: neutralizing properly the reaction mixture; distilling off the solvent from the reaction mixture or, if necessary, after distilling off the solvent from the reaction mixture, pouring the reaction mixture into water; extracting the mixture with a water-immiscible organic solvent; and finally distilling off the solvent from the extract. Further, if necessary, the product can be purified by conventional means, for example, recrystallization, reprecipitation or the various chromatography techniques, notably column chromatography.
The starting materials of formula (II) are known or can be prepared by any of several known methods (for example, as described Japanese Patent Kokai Application No. Sho 61-85365 or in an analogous manner).
The starting compounds of formulae (VI), (VIII) and (XI) can be prepared by reacting a compound of formula (II) with a compound of formula HOCO--B--X, HOCO--B--SY' or HOCO--B--SR.sup.6, in which: R.sup.6, B and X are as defined above; and Y' represents a hydrogen atom, an alkali metal, a C.sub.2 -C.sub.5 alkanoyl group (such as an acetyl, propionyl, butyryl or valeryl group, preferably an acetyl or propionyl group) or an aromatic acyl group in which the aromatic part has from 6 to 10 ring carbon atoms (such as a benzoyl, toluoyl or naphthoyl group, preferably a benzoyl group). These reactions may be carried out in a similar manner to those described in Reaction C described above. Where Y' represents an acyl group, the compound produced may, if desired, be subjected to hydrolysis using a base (for example, an alkali metal alkoxide, such as sodium methoxide or sodium ethoxide, or an alkali metal hydroxide, such as sodium hydroxide or potassium hydroxide) at a temperature of from -20.degree. C. to 80.degree. C. (more preferably from 0.degree. C. to 50.degree. C.) in an inert solvent (for example, an alcohol, such as methanol or ethanol) for a suitable period, for example from 5 minutes to 10 hours (more preferably from 10 minutes to 5 hours) to give a compound in which Y' is a hydrogen atom.
The pyridyloxy derivatives of the present invention have excellent histamine-H.sub.2 receptor antagonist activity, and are therefore useful for the prevention and therapy of peptic diseases resulting from undesirable peptic secretion, such as gastric ulcers, duodenal ulcers, gastritis, esophagistis, gastric dispepsia and Zollinger-Ellison syndrome; they are also useful for the prophylaxis or treatment of gastric disease before surgery.
The compounds of the present invention may be administered in any conventional form known for use with compounds having this type of activity, the precise form depending on the patient and the preferred route of administration, as is well known in the art. For example, for oral administration they may be formulated as tablets, capsules, granules, powders or syrups; and for parentheral administration they may be formulated as injections. Depending on the formulation, the compounds of the present invention may be administered by themselves or in admixture with conventional additives, such as vehicles (for example lactose, mannitol, corn starch or crystalline cellulose), binders (for example cellulose derivatives, gum arabic or gelatin), disintegrating agents (for example calcium carboxymethylcelulose), lubricants (for example talc or magnesium stearate), stabilizers, corrigents, solvents for preparing injections (for example water, ethanol or glycerin). The dosage may vary depending on the age, condition and symptoms of the patient, as well as the nature and severity of the disorder being treated, however, the usual daily dosage for an adult human patient would be from 1 mg to 1000 mg (preferably from 10 mg to 500 mg), per day, which may be administered as a single dose or divided into several doses.
BIOLOGICAL ACTIVITY
The activity of the compounds of the present invention is illustrated by the following Test Examples. In these, the compounds of the invention are identified by the number of the subsequent Example in which its preparation is illustrated. The prior art compounds A, B and C are as identified in the introductory portion of this specification.
TEST EXAMPLE 1
Atrial Test in Guinea Pigs
The guinea pig right atrium in a spontaneous palpitation was excised, suspended in 40 ml of Krebs-Henselite solution, and a tension of 1 g was loaded between the atrium preparation and a transducer. The solution was aerated at a fixed rate at 37.degree. C. 10.sup.-5 M histamine was added, and the heart rate was recorded as control. A test compound was added to a concentration of 1 .mu.g/ml and then, after 3 minutes, 10.sup.-5 M histamine was added, and the heart rate was again recorded. The inhibitory rate (R %) compared to the control group was calculated according to the following equation:
R=(1-B/A).times.100
where:
A: The heart rate of the control group
B: The heart rate of the group to which the drug was administered
The results are shown in the following Table 4.
TABLE 4______________________________________Compound ofExample No. % Inhibition______________________________________ 1 86 2 90 6 8613 8417 8326 8034 9437 9941 8548 81A 68B 99C 45______________________________________
TEST EXAMPLE 2
Inhibition of Gastric Secretions
This test was carried out according to Shay's method [H. Shay: Gastroenterology 5, 43 (1945)] using male SD rats (5 weeks old). The rats were divided into groups, each group containing 5 rats. The animals were fasted for 24 hours before the beginning of the experiment. They were then anesthetized with ether, the abdominal region was opened, and the pylorus was ligated. A test compound suspended in a 0.5% w/v aqueous carboxymethylcellulose (CMC) solution was administered intraduodenally. After 4 hours, the rat was sacrificed by deep anesthesia with ether, and the stomach was excised. The gastric juice was removed, centrifuged for 15 minutes at 2500 rpm, and then 0.1 ml of the supernatant was taken out and titrated until the end point of neutralization with a 0.01N aqueous solution of sodium hydroxide, to determine the total gastric acidity. The amount of gastric acid secreted per hour (.mu.Eq/hr) was calculated, and the inhibition rate (R %) to the control group was calculated according to the following equation.
R=(1-B/A).times.100
where
A: The gastric acid output of the control group (.mu.Eq/hr)
B: The amount of gastric acid output of the drug administered group (.mu.Eq/hr)
The results are shown in Table 5.
TABLE 5______________________________________Compound of DoseExample No. (mg/kg) % Inhibition______________________________________ 1 50 63 2 50 52 6 50 73 7 25 63 7 12.5 5113 50 8013 25 6217 50 7117 25 7334 25 8634 12.5 6137 50 7441 50 7641 25 6148 50 7158 50 56A 50 -67B 50 -40C 50 56______________________________________
TEST EXAMPLE 3
HCl-Ethanol-Induced Ulcer Test in Rats
Male SD rats (6 to 8 weeks old) were fasted for 24 hours before the beginning of the experiment. Each was then administered orally with 1 ml of a 60% ethanol solution containing 150 mM of hydrogen chloride. After 1 hour, the stomach was excised. Into the stomach was injected 10 ml of a 0.5% formaldehyde solution, and the stomach was fixed for 20 minutes. The injured area (mm.sup.2) occuring on the surface of the gastric mucosa was measured, and the total injured area per rat was regarded as the injury index.
Test compounds and 0.5% CMC, as the control, were orally administered each at a dose of 0.1 ml/100 g, 60 minutes before treatment with the HCl-ethanol solution.
The ulcer formation inhibitory rate (R %) was calculated by the following equation.
R=(1-B/A).times.100
where
A: The injury index of the control group (mm.sup.2)
B: The injury index of the drug administered group (mm.sup.2)
The results are shown in the following Table 6.
TABLE 6______________________________________Compound ofExample No. % Inhibition*.sup.)______________________________________ 2 100 7 6113 8734 7948 78A 39B 97C 56______________________________________ .sup.*.sup.) Dose: 50 mg/kg.
From these results, it can be seen that the compounds of the present invention strongly inhibit ulcer formation in our HCl-ethanol-induced ulcer model, and have a defense factor potentiating activity.
The invention is further illustrated by the following Examples, which illustrate the preparation of certain of the compounds of the present invention, and the subsequent Preparations, which illustrate the preparation of certain starting materials used in these Examples.

EXAMPLE 1 -[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-hydroxyethylthio)acetamide
0.20 ml of 2-mercaptoethanol was added to a solution of 0.24 g of 85% potassium hydroxide (i.e. potassium hydroxide of 85% purity) and 0.94 g of N-[4-(4-piperidinomethyl -2-pyridyloxy)-cis-2-butenyl]-2-chloroacetamide (prepared as described in Preparation 1) in 20 ml of methanol, and the resulting mixture was stirred at room temperature for 1 hour. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure. The concentrate was diluted with water, after which it was extracted with chloroform. The extract was concentrated by evaporation under reduced pressure, and the residue thus obtained was purified by column chromatography through silica gel, using a 1:9 by volume mixture of ethanol and chloroform as the eluent, to give 0.95 g (yield 90%) of the title compound as an oil.
Nuclear Magnetic Resonance. Spectrum (CDCl.sub.3), .delta. ppm: 1.32-1.52 (2H, multiplet); 1.52-1.70 (4H, multiplet); 2.25-2.55 (4H, multiplet); 2.77 (2H, triplet, J=6.3 Hz); 3.25-3.50 (1H, broad); 3.27 (2H, singlet); 3.44 (2H, singlet); 3.80 (2H, triplet, J=6.3 Hz); 4.05 (2H, triplet, J=6.1 Hz); 4.93 (2H, doublet, J=6.8 Hz); 5.68-5.80 (1H, multiplet); 5.80-5.95 (1H, multiplet); 6.79 (1H, singlet); 6.90 (1H, doublet, J=5.4 Hz); 7.08-7.28 (1H, broad); 8.06 (1H, doublet, J=5.4 Hz).
Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3360, 2920, 1650, 1610, 1415, 1400, 1295, 1285, 1030.
EXAMPLE 2
N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-acetoxyethylthio)acetamide
0.50 g of N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-2-(2-hydroxyethylthio)acetamide (prepared as described in Example 1) was added to a mixture of 0.47 ml of acetic anhydride and 0.39 g of pyridine, and the resulting mixture was heated at 60.degree. C. for 2 hours. At the end of this time, the reaction mixture was poured into ice-water, after which a saturated aqueous solution of sodium hydrogencarbonate was added. The aqueous mixture was then extracted with chloroform. The extract was concentrated by evaporation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 1:19 by volume mixture of methanol and methylene chloride as the eluent, to give 0.51 g (yield 91%) of the title compound as an oil.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.38-1.50 (2H, multiplet); 1.50-1.70 (4H, multiplet); 2.06 (3H, singlet); 2.30-2.45 (4H, multiplet); 2.79 (2H, triplet, J=6.3 Hz); 3.28 (2H, singlet); 3.41 (2H, singlet); 4.08 (2H, triplet, J=6.3 Hz); 4.23 (2H, triplet, J=6.3 Hz); 4.94 (2H, doublet, J=6.8 Hz); 5.62-5.74 (1H, multiplet); 5.82-5.95 (1H, multiplet); 6.74 (1H, singlet); 6.88 (1H, doublet, J=5.4 Hz); 6.90-7.05 (1H, broad); 8.06 (1H, doublet, J=5.4 Hz).
Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3370, 2920, 1735, 1660, 1610, 1515, 1415, 1400, 1295, 1285, 1025.
The hydrochloride of the title compound, melting at 198.degree.-208.degree. C., was prepared by dissolving the compound obtained above in ethyl acetate, after which it was treated with an excess of a 4N ethyl acetate solution of hydrogen chloride.
The oxalate of the title compound, melting at 127.degree.-133.degree. C., was prepared by dissolving the title compound, obtained as described above, in acetone, after which an equimolar amount of oxalic acid was added, and crystals of the oxalate, which precipitated, were collected by filtration.
EXAMPLE 3
N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-4-(2-hydroxyethylthio)butyramide
Following a procedure similar to that described in Example 1, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-4-chlorobutyramide (prepared as described in Preparation 2) and 2-mercaptoethanol as starting materials, in relative proportions similar to those used in that Example, and carrying out the reaction at 80.degree. C. for 5 hours, the title compound was obtained in a 66% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm: 1.35-1.50 (2H, multiplet); 1.50-1.75 (4H, multiplet); 1.80-2.02 (2H, multiplet); 2.30-2.50 (4H, multiplet); 2.32 (2H, triplet, J=7.0 Hz); 2.50-2.65 (1H, singlet); 2.59 (2H, triplet, J=7.0 Hz); 2.72 (2H, triplet, J=6.7 Hz); 3.44 (2H, singlet); 3.68-3.80 (2H, multiplet); 4.03 (2H, triplet, J=6.8 Hz); 4.93 (2H, doublet, J=6.8 Hz); 5.60-5.75 (1H, multiplet); 5.75-5.90 (1H, multiplet); 6.10-6.30 (1H, broad); 6.76 (1H, singlet); 6.90 (1H, doublet, J=5.4 Hz); 8.05 (1H, doublet, J=5.4 Hz).
Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3440, 2930, 1660, 1610, 1415, 1400, 1295, 1285, 1030.
EXAMPLE 4
N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-hydroxypropylthio)acetamide
Following a procedure similar to that described in Example 1, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-2-chloroacetamide (prepared as described in Preparation 1) and 1-mercapto-2-propanol as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in an 89% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.25 (3H, doublet, J=6.4 Hz); 1.30-1.86 (1H, broad); 1.38-1.49 (2H, multiplet); 1.53-1.65 (4H, multiplet); 2.31-2.43 (4H, multiplet); 2.54 (1H, doublet of doublets, J=8.3 & 13.9 Hz); 2.74 (1H, doublet of doublets, J=3.4 & 13.9 Hz); 3.25 (1H, doublet, J=16.1 Hz); 3.29 (1H, doublet, J=16.1 Hz); 3.41 (2H, singlet); 3.87-4.01 (1H, multiplet); 4.06 (2H, doublet, J=6.1 Hz); 4.93 (2H, doublet, J=6.8 Hz); 5.65-5.77 (1H, multiplet); 5.83-5.93 (1H, multiplet); 6.75 (1H, singlet); 6.89 (1H, doublet, J=5.4 Hz); 7.03-7.21 (1H, broad); 8.05 (1H, doublet, J=5.4 Hz).
Infrared Absorption Spectrum (liquid film), .nu..sub.max cm.sup.-1 : 3293, 2935, 1648, 1613, 1560, 1421, 1403, 1301, 1290, 1039.
EXAMPLE 5
N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis -2-butenyl]-4-(2-hydroxypropylthio)butyramide
Following a procedure similar to that described in Example 1, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-4-chlorobutyramide (prepared as described in Preparation 2) and 1-mercapto-2-propanol as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a 58% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.24 (3H, doublet, J=6.6 Hz); 1.38-1.50 (2H, multiplet); 1.52-1.64 (4H, multiplet); 1.84-2.04 (2H, multiplet); 2.27-2.46 (6H, multiplet); 2.46 (1H, doublet of doublets, J=5.3 & 13.9 Hz); 2.59 (2H, triplet, J=6.9 Hz); 2.71 (1H, doublet of doublets, J=3.3 & 13.9 Hz); 3.41 (2H, singlet); 3.81-3.92 (1H, multiplet); 4.03 (2H, triplet, J=5.9 Hz); 4.93 (2H, doublet, J=6.6 Hz); 5.78-5.91 (1H, multiplet); 5.63-5.76 (1H, multiplet); 6.06-6.22 (1H, broad); 6.74 (1H, singlet); 6.89 (1H, doublet, J=5.3 Hz); 8.04 (1H, doublet, J=5.3 Hz).
Infrared Absorption Spectrum (liquid film), .nu..sub.max cm.sup.-1 : 3298, 2935, 1647, 1613, 1560, 1421, 1403, 1311, 1301, 1289, 1070.
EXAMPLE 6
N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-4-(2-acetoxyethylthio)butyramide
Following a procedure similar to that described in Example 2, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-4-(2-hydroxyethylthio)butyramide (prepared as described in Example 3) and acetic anhydride as starting materials, in relative proportions similar to those used in that Example, the title compound, melting at 36.degree.-40.degree. C., was obtained in an 80% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.30-1.60 (2H, multiplet); 1.60-1.80 (4H, multiplet); 1.80-2.02 (2H, multiplet); 2.06 (3H, singlet); 2.32 (2H, triplet, J=7.0 Hz); 2.30-2.55 (4H, multiplet); 2.62 (2H, triplet, J=7.0 Hz); 2.73 (2H, triplet, J=6.8 Hz); 3.46 (2H, singlet); 4.04 (2H, triplet, J=6.1 Hz); 4.20 (2H, triplet, J=6.8 Hz); 4.93 (2H, doublet, J=6.8 Hz); 5.60-5.75 (1H, multiplet); 5.77-5.90 (1H, multiplet); 6.00-6.20 (1H, broad); 6.75 (1H, singlet); 6.92 (1H, doublet, J=5.4 Hz); 8.06 (1H, doublet, J=5.4 Hz).
Infrared Absorption Spectrum (CHCl.sub.3) .nu..sub.max cm.sup.-1 : 3450, 2930, 1735, 1665, 1610, 1415, 1400, 1295, 1285, 1030.
EXAMPLE 7
N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-propionyloxyethylthio)acetamide
0.09 ml of propionyl chloride was added to a mixture of 0.40 g of N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-2-(2-hydroxyethylthio)acetamide (prepared as described in Example 1) and 1.02 ml of pyridine, and the resulting mixture was allowed to stand at room temperature for 2 hours. At the end of this time, the reaction mixture was poured into ice-water, and a saturated aqueous solution of sodium hydrogencarbonate was added to the resulting mixture, after which it was extracted with chloroform. The extract was concentrated by evaporation under reduced pressure and the residue was purified by column chromatography through silica gel, using a 1:19 by volume mixture of methanol and ethyl acetate as the eluent, to give 0.39 g (yield 85%) of the title compound as an oil.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.14 (3H, triplet, J=7.5 Hz); 1.35-1.75 (6H, multiplet); 2.30-2.60 (4H, multiplet); 2.34 (2H, quartet, J=7.5 Hz); 2.79 (2H, triplet, J=6.6 Hz); 3.28 (2H, singlet); 3.41 (2H, singlet); 4.08 (2H, triplet, J=6.6 Hz); 4.25 (2H, triplet, J=6.3 Hz); 4.93 (2H, doublet, J=6.6 Hz); 5.63-5.69 (1H, multiplet); 5.72-5.93 (1H, multiplet); 6.73 (1H, singlet); 6.88 (1H, doublet, J=5.3 Hz); 6.95-7.10 (1H, broad); 8.06 (1H, doublet, J=5.3 Hz).
Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3380, 2940, 1735, 1665, 1615, 1420, 1405, 1300, 1290, 1180.
The hydrochloride of the title compound, melting at 99.degree.-106.degree. C., was prepared by dissolving the title compound, prepared as described above, in diethyl ether, after which the resulting solution was treated with an equimolar amount of a 4N ethyl acetate solution of hydrogen chloride.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3 +CD.sub.3 OD), .delta. ppm: 1.10 (3H, triplet, J=7.6 Hz); 1.58-1.76 (2H, multiplet); 1.76-1.94 (4H, multiplet); 2.35 (2H, quartet, J=7.6 Hz); 2.84 (2H, triplet, J=6.6 Hz); 3.03-3.38 (4H, multiplet); 3.24 (2H, singlet); 3.99 (2H, triplet, J=6.6 Hz); 4.24 (2H, triplet, J=6.6 Hz); 4.26 (2H, singlet); 4.99 (2H, doublet, J=6.6 Hz); 5.59-5.70 (1H, multiplet); 5.76-5.86 (1H, multiplet); 7.00 (1H, singlet); 7.10 (1H, doublet, J=5.0 Hz); 8.25 (1H, doublet, J=5.0 Hz).
The dihydrochloride of the title compound, melting at 235.degree.-255.degree. C., was prepared by dissolving the title compound, prepared as described above, in ethyl acetate, after which the resulting solution was treated with a molar excess of a 4N ethyl acetate solution of hydrogen chloride.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3 +CD.sub.3 OD), .delta. ppm: 1.10 (3H, triplet, J=7.6 Hz); 1.44-1.69 (2H, multiplet); 1.75-2.05 (4H, multiplet); 2.35 (2H, quartet, J=7.6 Hz); 2.84 (2H, triplet, J=6.6 Hz); 2.98-3.19 (2H, multiplet); 4.00 (2H, triplet, J=5.9 Hz); 4.24 (2H, triplet, J=6.6 Hz); 4.49 (2H, singlet); 5.18 (2H, doublet, J=5.9 Hz); 5.66-5.88 (2H, multiplet); 7.48 (1H, doublet, J=5.3 Hz); 7.66 (1H, singlet); 8.39 (1H, doublet, J=5.3 Hz).
EXAMPLE 8
2-{N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]carbamoylmethylthio}ethyl hydrogen succinate
0.11 g of succinic anhydride was added to a solution of 0.4 g of N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-2-(2-hydroxyethylthio)acetamide (prepared as described in Example 1) in 10 ml of acetone, and the resulting mixture was stirred at room temperature for 3 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the concentrate was purified by column chromatography through silica gel, using a 100:5:2 by volume mixture of methylene chloride, triethylamine and methanol as the eluent, to give 0.49 g of the triethylamine salt of the title compound in an 80% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.18 (9H, triplet, J=7.3 Hz); 1.40-1.55 (2H, multiplet); 1.55-1.80 (4H, multiplet); 2.40-2.60 (2H, multiplet); 2.50-2.68 (4H, multiplet); 2.78 (2H, triplet, J=6.3 Hz); 2.82 (6H, quartet, J=7.3 Hz); 3.50 (2H, singlet); 4.08 (2H, triplet, J=6.3 Hz); 4.26 (2H, triplet, J=6.3 Hz); 4.40-5.10 (1H, broad); 4.93 (2H, doublet, J=7.2 Hz); 5.66-5.75 (1H, multiplet); 5.82-5.95 (1H, multiplet); 6.79 (1H, singlet); 6.87 (1H, doublet, J=5.2 Hz); 8.08 (1H, doublet, J=5.2 Hz).
Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3380, 1735, 1660, 1610, 1415, 1400, 1295, 1285, 1160, 1030.
EXAMPLE 9
N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-benzoyloxyethylthio)acetamide
0.24 ml of benzoyl chloride was added, whilst ice-cooling, to a mixture of 0.40 g of N-[4-(4-piperidinomethyl -2-pyridyloxy)-cis-2-butenyl]-2-(2-hydroxyethylthio)acetamide (prepared as described in Example 1) and 1.02 ml of pyridine, and the resulting mixture was stirred at room temperature for 2 hours. At the end of this time, the mixture was concentrated by evaporation under reduced pressure. The concentrate was diluted with water and made alkaline by the addition of an aqueous ammonia solution, after which it was extracted with ethyl acetate. The extract was concentrated by evaporation under reduced pressure, and the concentrate was purified by column chromatography through silica gel, using a 1:40 by volume mixture of methanol and ethyl acetate as the eluent, to give 0.31 g of the title compound in a 61% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.35-1.50 (2H, multiplet); 1.50-1.75 (4H, multiplet); 2.25-2.45 (4H, multiplet); 2.94 (2H, triplet, J=6.3 Hz); 3.40 (2H, singlet); 3.32 (2H, singlet); 4.07 (2H, triplet, J=6.3 Hz); 4.49 (2H, triplet, J=6.6 Hz); 4.92 (2H, doublet, J=6.6 Hz); 5.62-5.71 (1H, multiplet); 5.81-5.88 (1H, multiplet); 6.73 (1H, singlet); 6.87 (1H, doublet, J=5.3 Hz); 7.40-7.62 (4H, multiplet); 8.02-8.07 (3H, multiplet).
Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3390, 2940, 1720, 1665, 1615, 1275, 1170.
The dihydrochloride of the title compound, melting at 185.degree.-195.degree. C., was prepared by dissolving the compound obtained above in ethyl acetate, after which the resulting solution was treated with a molar excess of a 4N ethyl acetate solution of hydrogen chloride.
EXAMPLE 10
N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-cyclohexylcarbonyloxyethylthio)acetamide
0.10 ml of ethyl chloroformate was added, whilst ice-cooling, to a solution of 0.13 ml of cyclohexanecarboxylic acid in 18 ml of ethyl acetate, and the resulting mixture was stirred at room temperature for 1 hour. At the end of this time, a solution of 0.40 g of N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-hydroxyethylthio)acetamide (prepared as described in Example 1) in 4 ml of ethyl acetate was added to the reaction mixture, whilst ice-cooling. The reaction mixture was then stirred at room temperature for 1 hour, after which it was heated under reflux for 16 hours. At the end of this time, it was concentrated by evaporation under reduced pressure. The concentrate was purified by column chromatography through silica gel, using a 1:9 by volume mixture of methanol and ethyl acetate as the eluent, to give 0.18 g of the title compound in a 35% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.17-2.09 (16H, multiplet); 2.23-2.47 (5H, multiplet); 2.79 (2H, triplet, J=6.3 Hz); 3.28 (2H, singlet); 3.42 (2H, singlet); 4.08 (2H, triplet, J=6.3 Hz); 4.23 (2H, triplet, J=6.3 Hz); 4.94 (2H, doublet, J=6.6 Hz); 5.81-5.94 (1H, multiplet); 5.62-5.74 (1H, multiplet); 6.74 (1H, singlet); 6.85-7.05 (1H, broad); 6.89 (1H, doublet, J=5.3 Hz); 8.06 (1H, doublet, J=5.3 Hz).
Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3380, 2940, 1730, 1665, 1610, 1310, 1165.
EXAMPLE 11
N-[4-(4-Piperidinomethyl-2 -pyridyloxy)-cis-2 -butenyl]-3-(2-hydroxyethylthio)propionamide
105 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) were added, whilst ice-cooling and in an atmosphere of nitrogen, to a solution of 0.76 g of N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-3-mercaptopropionamide (prepared as described in Preparation 3) in 24 ml of dimethylformamide, and the resulting mixture was stirred at room temperature for 30 minutes. At the end of this time, 0.16 ml of ethylene chlorohydrin were added to the reaction mixture, whilst ice-cooling. The reaction mixture was stirred at room temperature for 15 minutes, after which it was poured into ice-water and extracted with ethyl acetate. The extract was concentrated by evaporation under reduced pressure, and the residue thus obtained was purified by column chromatography through silica gel, using a 1:9 by volume mixture of methanol and methylene chloride as the eluent, to give 0.56 g of the title compound as an oil in a 65% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.38-1.50 (2H, multiplet); 1.50-1.64 (4H, multiplet); 1.55-2.10 (1H, broad); 2.30-2.43 (4H, multiplet); 2.49 (2H, triplet, J=6.9 Hz); 2.74 (2H, triplet, J=5.9 Hz); 2.88 (2H, triplet, J=6.9 Hz); 3.41 (2H, singlet); 3.76 (2H, doublet of triplets, J=5.3 & 5.9 Hz); 4.05 (2H, triplet, J=6.3 Hz); 4.93 (2H, doublet, J=6.6 Hz); 5.63-5.78 (1H, multiplet); 5.78-5.90 (1H, multiplet); 6.75 (1H, singlet); 6.89 (1H, doublet, J=5.3 Hz); 8.04 (1H, doublet, J=5.3 Hz).
Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3450, 2930, 1665, 1612, 1418, 1400, 1300, 1290, 1035.
EXAMPLE 12
N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-3-(2-acetoxyethylthio)propionamide
Following a procedure similar to that described in Example 2, but using N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-3-(2-hydroxyethylthio)propionamide (prepared as described in Example 11) and acetic anhydride as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in an 87% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.36-1.50 (2H, multiplet); 1.50-1.63 (4H, multiplet); 2.07 (3H, singlet); 2.28-2.43 (4H, multiplet); 2.48 (3H, triplet, J=7.3 Hz); 2.77 (2H, triplet, J=6.9 Hz); 3.41 (2H, singlet); 4.05 (2H, triplet, J=6.3 Hz); 4.22 (2H, triplet, J=6.9 Hz); 4.93 (2H, doublet, J=6.6 Hz); 5.62-5.76 (1H, multiplet); 5.79-5.90 (1H, multiplet); 6.17-6.40 (1H, broad); 6.74 (1H, singlet); 6.89 (1H, doublet, J=5.3 Hz); 8.04 (1H, doublet, J=5.3 Hz).
Infrared Absorption Spectrum (CHCl.sub.3) .nu..sub.max cm.sup.-1 : 3450, 2930, 1735, 1665, 1610, 1415, 1400, 1298, 1288, 1028.
EXAMPLE 13
N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]pyrazole-4-carboxamide
A solution of 2.39 g of 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 1.08 g of 4-pyrazolecarboxylic acid in 40 ml of dry dimethylformamide was stirred for 5 minutes, whilst ice-cooling. 1.89 g of diethyl cyanophosphonate and 1.65 ml of triethylamine were added to the mixture, and the resulting mixture was stirred at room temperature for 3 hours. At the end of this time, the reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 1:9 by volume mixture of methanol and chloroform as the eluent, to give 1.65 g (yield 51%) of the title compound as a white powder, melting at 121.degree.-123.degree. C.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.38-1.52 (2H, multiplet); 1.52-1.66 (4H, multiplet); 2.32-2.48 (4H, multiplet); 3.42 (2H, singlet); 4.16 (2H, triplet, J=5.6 Hz); 4.95 (2H, doublet, J=5.9 Hz); 5.72-5.96 (2H, multiplet); 6.74 (1H, singlet); 6.81 (1H, broad triplet, J=5.6 Hz); 6.87 (1H, doublet, J=5.3 Hz); 7.99 (2H, singlet); 8.03 (1H, doublet, J=5.3 Hz).
Infrared Absorption Spectrum (KBr), .nu..sub.max cm.sup.-1 : 2933, 1629, 1611, 1566, 1530, 1408, 1342, 1299.
EXAMPLE 14
N-[4-(4-piperidinomethyl-2 -pyridyloxy)-cis-2-butenyl]thiophene-2-carboxamide
240 mg of 2-thiophenecarboxylic acid, 390 mg of N,N'-dicyclohexylcarbodiimide and 275 mg of 1-hydroxybenzotriazole were added to a solution of 485 mg of 4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenylamine in 10 ml of dry dimethylformamide, and the resulting mixture was stirred at room temperature for 17 hours. At the end of this time, the reaction mixture was mixed with ethyl acetate, and the urea which precipitated was removed by filtration. The filtrate was diluted with water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 1:19 by volume mixture of methanol and methylene chloride as the eluent, to give 499 mg (yield 73%) of the title compound as an oil.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.37-1.52 (2H, multiplet); 1.52-1.65 (4H, multiplet); 2.28-2.46 (4H, multiplet); 3.41 (2H, singlet); 4.22 (2H, triplet, J=6.3 Hz); 4.98 (2H, doublet, J=6.6 Hz); 5.73-5.85 (1H, multiplet); 5.85-5.97 (1H, multiplet); 6.56 (1H, broad singlet); 6.74 (1H, singlet); 6.89 (1H, doublet, J=5.3 Hz); 7.02-7.09 (1H, multiplet); 7.46 (1H, doublet, J=5.3 Hz); 7.51 (1H, doublet, J=4.0 Hz); 8.03 (1H, doublet, J=5.3 Hz).
Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 2920, 1665, 1640, 1610, 1565, 1530, 1500, 1415, 1400, 1295, 1285.
The hydrochloride of the title compound, melting at 180.degree.-183.degree. C., was prepared by dissolving the title compound obtained above in ethyl acetate, after which it was treated with an equimolar amount of an ethyl acetate solution of hydrogen chloride.
EXAMPLE 15
N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]pyrrole-2-carboxamide
Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenylamine and 2-pyrrolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as colorless prisms, melting at 136.degree.-137.degree. C., in an 80% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.39-1.51 (2H, multiplet); 1.51-1.65 (4H, multiplet); 2.33-2.48 (4H, multiplet); 3.42 (2H, singlet); 4.21 (2H, triplet, J=6.4 Hz); 4.98 (2H, doublet, J=6.3 Hz); 5.70-5.79 (1H, multiplet); 5.83-5.92 (1H, multiplet); 6.20-6.23 (1H, multiplet); 6.25-6.36 (1H, broad); 6.52-6.55 (1H, multiplet); 6.75 (1H, singlet); 6.88-6.93 (2H, multiplet); 8.06 (1H, doublet, J=4.9 Hz); 9.51-9.75 (1H, broad).
Infrared Absorption Spectrum (KBr), .nu..sub.max cm.sup.-1 : 3242, 1641, 1561, 1524.
EXAMPLE 16
1,3,5-Trimethyl-N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]pyrazole-4-carboxamide
Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 1,3,5-trimethyl-4-pyrazolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 75.degree.-77.degree. C., in a 69% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.37-1.52 (2H, multiplet); 1.52-1.69 (4H, multiplet); 2.36 (3H, singlet); 2.30-2.49 (4H, multiplet); 2.46 (3H, singlet); 3.44 (2H, singlet); 3.71 (3H, singlet); 4.19 (2H, triplet, J=6.1 Hz); 4.96 (2H, doublet, J=6.4 Hz); 5.75-5.91 (3H, multiplet); 6.74 (1H, singlet); 6.89 (1H, doublet, J=4.9 Hz); 8.00 (1H, doublet, J=4.9 Hz).
Infrared Absorption Spectrum (KBr), .nu..sub.max cm.sup.-1 : 3344, 2930, 1617, 1561, 1410.
EXAMPLE 17
3-Amino-N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]pyrazole-4-carboxamide
Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 3-amino-4-pyrazolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 172.degree.-174.degree. C., in a 38% yield.
Nuclear Magnetic Resonance Spectrum (hexadeuterated dimethyl sulfoxide), .delta. ppm: 1.32-1.45 (2H, multiplet); 1.45-1.57 (4H, multiplet); 2.26-2.44 (4H, multiplet); 3.42 (2H, singlet); 3.92 (2H, triplet, J=5.9 Hz); 4.92 (2H, doublet, J=5.9 Hz); 5.52-5.78 (2H, multiplet); 6.72 (1H, singlet); 6.92 (1H, doublet, J=5.4 Hz); 7.67-7.79 (1H, broad); 7.88 (1H, broad triplet, J=5.4 Hz); 8.08 (1H, doublet, J=5.4 Hz).
Infrared Absorption Spectrum (KBr), .nu..sub.max cm.sup.-1 : 3229, 2934, 1616, 1529, 1399.
EXAMPLE 18
N-[4-(4-Piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]pyrazole-3-carboxamide
Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 3-pyrazolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 57% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.38-1.52 (2H, multiplet); 1.52-1.65 (4H, multiplet); 2.31-2.50 (4H, multiplet); 3.43 (2H, singlet); 4.21 (2H, triplet, J=6.3 Hz); 4.96 (2H, doublet, J=6.6 Hz); 5.77-5.99 (2H, multiplet); 6.80-6.89 (3H, multiplet); 7.21-7.31 (1H, broad); 7.57 (1H, doublet, J=2.0 Hz); 8.08 (1H, doublet, J=5.3 Hz).
Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 2925, 1655, 1610, 1560 (shoulder), 1540.
EXAMPLE 19
5-Methyl-N-[4-(piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]pyrazole-3-carboxamide
Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 5-methyl-3-pyrazolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 93.degree.-95.degree. C., in a 52% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.38-1.52 (2H, multiplet); 1.52-1.66 (4H, multiplet); 2.33 (3H, singlet); 2.31-2.48 (4H, multiplet); 3.42 (2H, singlet); 4.20 (2H, triplet, J=6.4 Hz); 4.96 (2H, doublet, J=6.8 Hz); 5.72-5.81 (1H, multiplet); 5.83-5.93 (1H, multiplet); 6.55 (1H, singlet); 6.76 (1H, singlet); 6.87 (1H, doublet, J=5.4 Hz); 7.06-7.20 (1H, broad); 8.08 (1H, doublet, J=5.4 Hz); 10.37-10.93 (1H, broad).
Infrared Absorption Spectrum (KBr), .nu..sub.max cm.sup.-1 : 3195, 2931, 1645, 1612, 1558.
EXAMPLE 20
N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]furan-2-carboxamide
Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 2-furancarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in an 82% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.35-1.53 (2H, multiplet); 1.53-1.80 (4H, multiplet); 2.25-2.60 (4H, multiplet); 3.48 (2H, singlet); 4.22 (2H, triplet, J=6.4 Hz); 4.98 (2H, doublet, J=6.8 Hz); 5.70-5.82 (1H, multiplet); 5.84-5.96 (1H, multiplet); 6.49 (1H, doublet of doublets, J=3.4 & 2.0 Hz); 6.58-6.72 (1H, multiplet); 6.77 (1H, singlet); 6.85-7.03 (1H, multiplet); 7.11 (1H, doublet of doublets, J=3.4 & 1.0 Hz); 7.43 (1H, triplet, J=1.0 Hz); 8.10 (1H, doublet, J=5.3 Hz).
Infrared Absorption Spectrum (CHCl.sub.3) .nu..sub.max cm.sup.-1 : 3430, 2930, 1655, 1610, 1595, 1518, 1475, 1415, 1400, 1295, 1285.
EXAMPLE 21
5-Methyl-N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]thiophene-2-carboxamide
Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 5-methyl-2-thiophenecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound, melting at 71.degree.-73.degree. C., was obtained in a yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.45-1.55 (2H, multiplet); 1.55-1.80 (4H, multiplet); 2.30-2.60 (4H, multiplet); 3.48 (2H, singlet); 4.20 (2H, triplet, J=6.3 Hz); 4.97 (2H, doublet, J=6.3 Hz); 5.78-5.82 (1H, multiplet); 5.82-5.93 (1H, multiplet); 6.20-6.35 (1H, broad); 6.72 (1H, doublet, J=3.5 Hz); 6.78 (1H, singlet); 6.87-7.03 (1H, multiplet); 7.31 (1H, doublet, J=3.5 Hz); 8.07 (1H, doublet, J=5.4 Hz).
Infrared Absorption Spectrum (CHCl.sub.3) .nu..sub.max cm.sup.-1 : 3430, 2920, 1640, 1505, 1415, 1400, 1295, 1285, 1032.
EXAMPLE 22
3-Amino-N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]thiophene-2-carboxamide
Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 3-amino-2-thiophenecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as colorless needles, melting at 138.degree.-140.degree. C., in a 40% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.40-1.52 (2H, multiplet); 1.52-1.65 (4H, multiplet); 2.28-2.44 (4H, multiplet); 3.41 (2H, singlet); 4.17 (2H, triplet, J=5.9 Hz); 4.96 (2H, doublet, J=5.9 Hz); 5.60 (2H, broad singlet); 5.67-5.94 (3H, multiplet); 6.55 (1H, doublet, J=5.3 Hz); 6.74 (1H, singlet); 6.89 (1H, doublet, J=5.3 Hz); 7.12 (1H, doublet, J=5.3 Hz); 8.08 (1H, doublet, J=5.3 Hz).
Infrared Absorption Spectrum (KBr), .nu..sub.max cm.sup.-1 : 3300, 2935, 1617, 1560, 1525, 1402, 1313, 1299, 1291.
EXAMPLE 23
N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]thiophene-3-carboxamide
Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 3-thiophenecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 90% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.38-1.52 (2H, multiplet); 1.52-1.65 (4H, multiplet); 2.30-2.45 (4H, multiplet); 3.41 (1H, singlet); 4.22 (2H, triplet, J=6.1 Hz); 4.98 (2H, doublet, J=6.4 Hz); 5.73-5.93 (2H, multiplet); 6.40-6.60 (1H, broad); 6.74 (1H, singlet); 6.87 (1H, doublet, J=5.4 Hz); 7.32 (1H, doublet of doublets, J=5.2 & 2.9 Hz); 7.39 (1H, doublet, J=5.2 Hz); 7.85 (1H, doublet, J=2.9 Hz); 8.01 (1H, doublet, J=5.4 Hz).
Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 2930, 1655 (shoulder), 1645, 1610, 1560, 1535, 1500, 1415, 1400, 1285.
EXAMPLE 24
5-Chloro-N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]thiophene-2-carboxamide
Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 5-chloro-3-thiophenecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as colorless prisms, melting at 75.degree.-77.degree. C., in a 54% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.38-1.52 (2H, multiplet); 1.52-1.68 (4H, multiplet); 2.30-2.42 (4H, multiplet); 3.41 (2H, singlet); 4.19 (2H, triplet, J=6.1 Hz); 4.97 (2H, doublet, J=6.8 Hz); 5.70-5.84 (1H, multiplet); 5.84-5.95 (1H, multiplet); 6.41-6.53 (1H, broad); 6.74 (1H, singlet); 6.88 (1H, doublet, J=5.4 Hz); 7.19 (1H, doublet, J=2.0 Hz); 7.62 (1H, doublet, J=2.0 Hz); 7.99 (1H, doublet, J=5.4 Hz).
Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3450, 2930, 1655, 1610, 1415, 1400, 1298, 1285, 1032.
EXAMPLE 25
5-Phenyl-N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]isoxazole-3-carboxamide
Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 5-phenyl-3-isoxazolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound, melting at 105.degree.-106.degree. C., was obtained as colorless prisms in a 50% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.36-1.51 (2H, multiplet); 1.51-1.67 (4H, multiplet); 2.29-2.46 (4H, multiplet); 3.43 (2H, singlet); 4.27 (2H, triplet, J=6.3 Hz); 4.99 (2H, doublet, J=6.6 Hz); 5.72-5.82 (1H, multiplet); 5.88-5.97 (1H, multiplet); 6.75 (1H, singlet); 6.91 (1H, doublet, J=5.4 Hz); 6.97 (1H, singlet); 7.13-7.27 (1H, broad); 7.44-7.55 (3H, multiplet); 7.75-7.84 (2H, multiplet); 8.12 (1H, doublet, J=5.4 Hz).
Infrared Absorption Spectrum (KBr), .nu..sub.max cm.sup.-1 : 3322, 2936, 1668, 1613, 1561, 1448.
EXAMPLE 26
N-[4-(4-Piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]thiazole-4-carboxamide
Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 4-thiazolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 68% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.36-1.52 (2H, multiplet); 1.52-1.67 (4H, multiplet); 2.24-2.53 (4H, multiplet); 3.43 (2H, singlet); 4.26 (2H, triplet, J=6.4 Hz); 4.98 (2H, doublet, J=6.4 Hz); 5.72-5.81 (1H, multiplet); 5.86-5.96 (1H, multiplet); 6.75 (1H, singlet); 6.90 (1H, doublet, J=5.4 Hz); 7.40-7.58 (1H, broad); 8.11 (1H, doublet, J=5.4 Hz); 8.18 (1H, doublet, J=2.4 Hz); 8.75 (1H, doublet, J=2.4 Hz).
Infrared Absorption Spectrum (liquid film), .nu..sub.max cm.sup.-1 : 2936, 1664, 1611, 1560, 1540, 1481, 1420, 1403, 1313, 1288.
EXAMPLE 27
N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-1,2,3-thiadiazole-4-carboxamide
Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 1,2,3-thiadiazole-4-carboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as colorless needles, melting at 70.degree.-72.degree. C., in a 52% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.28-1.53 (2H, multiplet); 1.53-1.82 (4H, multiplet); 2.24-2.55 (4H, multiplet); 3.46 (2H, singlet); 4.35 (2H, triplet, J=6.3 Hz); 5.01 (2H, doublet, J=6.3 Hz); 5.75-5.87 (1H, multiplet); 5.87-6.00 (1H, multiplet); 6.77 (1H, singlet); 6.85-7.00 (1H, multiplet); 7.72-7.90 (1H, broad); 8.13 (1H, doublet, J=5.4 Hz); 9.23 (1H, singlet).
Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3425, 2940, 1675, 1612, 1540, 1420, 1402, 1300, 1290, 1260, 1035.
EXAMPLE 28
N-{4-[4-(1-Pyrrolidinylmethyl)-2-pyridyloxy]-cis-2-butenyl}pyrazole-4-carboxamide
Following a procedure similar to that described in Example 13, but using 4-[4-(1-pyrrolidinylmethyl)-2-pyridyloxy]-cis-2-butenylamine and 4-pyrazolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 57.degree.-61.degree. C., in a 34% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.75-1.90 (4H, multiplet); 2.50-2.67 (4H, multiplet); 3.61 (2H, singlet); 4.17 (2H, triplet, J=5.9 Hz); 4.95 (2H, doublet, J=6.4 Hz); 5.69-5.92 (2H, multiplet); 6.72 (1H, broad triplet, J=5.4 Hz); 6.77 (1H, singlet); 6.90 (1H, doublet, J=5.4 Hz); 7.96 (2H, singlet); 8.04 (1H, doublet, J=5.4 Hz).
Infrared Absorption Spectrum (KBr), .nu..sub.max cm.sup.-1 : 2962, 1626, 1610, 1568, 1539, 1421, 1410, 1400.
EXAMPLE 29
N-{4-[4-(1-Pyrrolidinylmethyl)-2-pyridyloxy]-cis-2-butenyl}pyrrole-2-carboxamide
Following a procedure similar to that described in Example 13, but using 4-[4-(1-pyrrolidinylmethyl)-2-pyridyloxy]-cis-2-butenylamine and 2-pyrrolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 124.degree.-127.degree. C., in a 64% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.71-1.88 (4H, multiplet); 2.43-2.61 (4H, multiplet); 3.57 (2H, singlet); 4.21 (2H, triplet, J=6.3 Hz); 4.97 (2H, doublet, J=6.6 Hz); 5.70-5.80 (1H, multiplet); 5.83-5.94 (1H, multiplet); 6.16-6.25 (1H, multiplet); 6.30-6.42 (1H, broad); 6.53-6.59 (1H, multiplet); 6.88-6.96 (2H, multiplet); 8.07 (1H, doublet, J=5.3 Hz); 9.67-9.92 (1H, broad).
Infrared Absorption Spectrum (KBr), .nu..sub.max cm.sup.-1 : 3252, 1637, 1617, 1561, 1528, 1428, 1423, 1401, 1307, 1029.
EXAMPLE 30
4-Hydroxy-N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]isoxazole-3-carboxamide
375 mg of ethyl 4-hydroxy-3-isoxazolecarboxylate (prepared as described in Preparation 4) were added to a solution of 520 mg of 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine in 10 ml of toluene, and the resulting mixture was heated under reflux for 6 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was dissolved in ethyl acetate. The resulting solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 1:19 by volume mixture of methanol and ethyl acetate as the eluent, to give 228 mg (yield 31%) of the title compound as an oil.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.33-1.50 (2H, multiplet); 1.50-1.65 (4H, multiplet); 2.25-2.46 (4H, multiplet); 3.42 (2H, singlet); 4.26 (2H, triplet, J=6.6 Hz); 4.98 (2H, doublet, J=6.6 Hz); 5.67-5.82 (1H, multiplet); 5.88-6.00 (1H, multiplet); 6.75 (1H, singlet); 6.90 (1H, doublet, J=5.3 Hz); 7.25-7.42 (1H, broad); 8.13 (1H, doublet, J=5.3 Hz); 8.22 (1H, singlet).
Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 2930, 1680, 1610, 1560 (shoulder), 1550.
EXAMPLE 31
1-Methyl-N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]pyrrole-2-carboxamide
Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 1-methyl-2-pyrrolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 76% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.38-1.51 (2H, multiplet); 1.51-1.65 (4H, multiplet); 2.33-2.43 (4H, multiplet); 3.42 (2H, singlet); 3.94 (3H, singlet); 4.16 (2H, triplet, J=6.1 Hz); 4.97 (2H, doublet, J=6.8 Hz); 5.71-5.83 (1H, multiplet); 5.83-5.94 (1H, multiplet); 6.06 (1H, doublet of doublets, J=3.9 & 2.2 Hz); 6.14-6.24 (1H, broad); 6.53 (1H, doublet of doublets, J=7.8 & 2.2 Hz); 6.69-6.73 (1H, multiplet); 6.74 (1H, singlet); 6.89 (1H, doublet, J=5.2 Hz); 8.04 (1H, doublet, J=5.2 Hz).
Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 2935, 1655 (shoulder), 1645, 1610, 1560, 1535, 1500, 1475, 1415, 1400.
The hydrochloride of the title compound, melting at 136.degree.-137.degree. C., was prepared by dissolving the title compound, obtained as described above, in ethyl acetate, after which an ethyl acetate solution containing an equimolar amount of hydrogen chloride was added to the resulting solution.
EXAMPLE 32
N-[4-(4-Piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]pyrrole-3-carboxamide
Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 3-pyrrolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 74% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.33-1.51 (2H, multiplet); 1.51-1.67 (4H, multiplet); 2.27-2.49 (4H, multiplet); 3.41 (2H, singlet); 4.18 (2H, triplet, J=6.3 Hz); 4.96 (2H, doublet, J=5.9 Hz); 5.69-5.94 (2H, multiplet); 6.17-6.33 (1H, broad); 6.42 (1H, broad singlet); 6.73 (2H, broad singlet); 6.87 (1H, doublet, J=4.9 Hz); 7.33 (1H, broad singlet); 8.05 (1H, doublet, J=4.9 Hz); 9.31-9.54 (1H, broad).
Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3470, 2930, 1635, 1610, 1560, 1510, 1415, 1400, 1310, 1295.
EXAMPLE 33
N-[4-(4-Piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-2-(2-pyrimidinylthio)acetamide
163 mg of 2-mercaptopyrimidine were added to a solution of 116 mg of 85% potassium hydroxide and 484 mg of N-[4-(4-piperidinomethyl-2-pyridyl-cis-2-butenyl]-2-chloroacetamide (prepared as described in Preparation 1) in 10 ml of methanol, and the resulting mixture was stirred at room temperature for 7 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the concentrate was mixed with water, after which it was extracted with ethyl acetate. The extract was freed from the solvent by distillation under reduced pressure. The residue thus obtained was recrystallized from ethyl acetate, to give 474 mg (yield 80%) of the title compound as a white powder, melting at 103.degree.-106.degree. C.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.37-1.50 (2H, multiplet); 1.52-1.64 (4H, multiplet); 2.30-2.43 (4H, multiplet); 3.40 (2H, singlet); 3.82 (2H, singlet); 4.29 (2H, triplet, J=6.3 Hz); 4.87 (2H, doublet, J=5.9 Hz); 5.52-5.65 (1H, multiplet); 5.75-5.86 (1H, multiplet); 6.70 (1H, singlet); 6.87 (1H, doublet, J=5.4 Hz); 7.00-7.11 (1H, broad); 7.02 (1H, doublet, J=4.9 Hz); 8.03 (1H, doublet, J=5.4 Hz); 8.53 (2H, doublet, J=4.9 Hz).
Infrared Absorption Spectrum (KBr), .nu..sub.max cm.sup.-1 : 3333, 2940, 2920, 1643, 1560, 1552, 1524, 1397, 1316.
EXAMPLE 34
N-[4-(4-Piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-4-(2-pyrimidinylthio) butyramide
2.78 g of 2-mercaptopyrimidine were added to a solution of 1.95 g of 85% potassium hydroxide and 9.03 g of N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-4-chlorobutyramide (prepared as described in Preparation 2) in 140 ml of methanol, and the resulting mixture was heated under reflux for 15 hours. At the end of this time, the reaction mixture was cooled, and the solvent was removed by distillation under reduced pressure. The resulting residue was mixed with water, and the aqueous mixture was extracted with ethyl acetate. The extract was concentrated by evaporation under reduced pressure, and the concentrate was purified by column chromatography through silica gel, using a 9:1 by volume mixture of ethyl acetate and methanol as the eluent, to give 10.1 g (yield 92%) of the title compound as an oil.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.38-1.50 (2H, multiplet); 1.53-1.67 (4H, multiplet); 2.11 (2H, quintet, J=7.2 Hz); 2.30-2.49 (6H, multiplet); 3.20 (2H, triplet, J=7.2 Hz); 3.41 (2H, singlet); 4.06 (2H, doublet, J=5.9 Hz); 4.93 (2H, doublet, J=6.3 Hz); 5.64-5.73 (1H, multiplet); 5.80-5.89 (1H, multiplet); 6.27-6.41 (1H, broad); 6.73 (1H, singlet); 6.88 (1H, doublet, J=5.1 Hz); 6.94 (1H, triplet, J=4.9 Hz); 8.03 (1H, doublet, J=5.1 Hz); 8.49 (2H, doublet, J=4.9 Hz).
Infrared Absorption Spectrum (liquid film), .nu..sub.max cm.sup.-1 : 3295, 2936, 1646, 1611, 1564, 1548, 1420, 1403, 1382, 1312, 1300, 1289.
The compound obtained as described above was dissolved in ethyl acetate, and an ethyl acetate solution containing an equimolar amount of hydrogen chloride was added to the resulting solution. The mixture was stirred at room temperature for 10 minutes, and then the solvent was removed by distillation under reduced pressure, to give the hydrochloride of the title compound, melting at 123.degree.-125.degree. C.
EXAMPLE 35
N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-4-(4-methyl-2-pyrimidinylthio)butyramide
Following a procedure similar to that described in Example 34, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-4-chlorobutyramide (prepared as described in Preparation 2) and 2-mercapto-4-methylpyrimidine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 70% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.40-1.56 (2H, multiplet); 1.60-1.81 (4H, multiplet); 2.10 (2H, quintet, J=7.1 Hz); 2.39 (2H, triplet, J=7.1 Hz); 2.44 (3H, singlet); 2.35-2.70 (4H, multiplet); 3.20 (2H, triplet, J=7.1 Hz); 3.55 (2H, singlet); 4.05 (2H, triplet, J=6.1 Hz); 4.93 (2H, doublet, J=6.3 Hz); 5.64-5.73 (1H, multiplet); 5.78-5.87 (1H, multiplet); 6.25-6.37 (1H, broad); 6.76-6.81 (2H, multiplet); 6.98 (1H, singlet); 8.08 (1H, triplet, J=5.4 Hz); 8.34 (1H, doublet, J=5.4 Hz).
Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 2930, 1660, 1610, 1570, 1560, 1540, 1415, 1325.
EXAMPLE 36
N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-4-(1-methylimidazol-2-ylthio)butyramide
Following a procedure similar to that described in Example 34, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-4-chlorobutyramide (prepared as described in Preparation 2) and 2-mercapto-1-methylimidazole as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 49% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.36-1.50 (2H, multiplet); 1.50-1.62 (4H, multiplet); 2.03 (2H, quintet, J=6.8 Hz); 2.30-2.46 (6H, multiplet); 3.08 (2H, triplet, J=6.8 Hz); 3.41 (2H, singlet); 3.60 (3H, singlet); 4.04 (2H, triplet, J=6.1 Hz); 4.93 (2H, doublet, J=5.9 Hz); 5.63-5.73 (1H, multiplet); 5.76-5.91 (1H, multiplet); 6.72 (1H, singlet); 6.89 (1H, doublet, J=5.4 Hz); 6.90 (1H, singlet); 7.01 (1H, singlet); 7.24-7.38 (1H, broad); 8.04 (1H, doublet, J=5.4 Hz).
Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3250, 2940, 1660, 1610, 1560, 1420, 1290.
EXAMPLE 37
N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-4-(5-methyl-1,3,4-oxadiazol-2-ylthio)butyramide
Following a procedure similar to that described in Example 34, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-4-chlorobutyramide (prepared as described in Preparation 2) and 2-mercapto-5-methyl -1,3,4-oxadiazole as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 79% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.37-1.50 (2H, multiplet); 1.50-1.65 (4H, multiplet); 2.17 (2H, quintet, J=7.3 Hz); 2.31-2.41 (6H, multiplet); 2.51 (3H, singlet); 3.28 (2H, triplet, J=7.3 Hz); 3.41 (2H, singlet); 4.04 (2H, triplet, J=5.9 Hz); 4.93 (2H, doublet, J=6.6 Hz); 5.64-5.75 (1H, multiplet); 5.79-5.90 (1H, multiplet); 6.39-6.54 (1H, broad); 6.73 (1H, singlet); 6.89 (1H, doublet, J=5.3 Hz); 8.04 (1H, doublet, J=5.3 Hz).
Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3440, 2930, 1660, 1610, 1560, 1510, 1480, 1420.
EXAMPLE 38
N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-4-(1,3,4-thiadiazol-2-ylthio)butyramide
Following a procedure similar to that described in Example 34, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-4-chlorobutyramide (prepared as described in Preparation 2) and 2-mercapto-1,3,4-thiadiazole as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in an 84% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.36-1.51 (2H, multiplet); 1.51-1.68 (4H, multiplet); 2.20 (2H, quintet, J=7.3 Hz); 2.27-2.45 (6H, multiplet); 3.41 (2H, singlet); 3.43 (2H, triplet, J=7.3 Hz); 5.63-5.73 (1H, multiplet); 5.78-5.89 (1H, multiplet); 6.34-6.51 (1H, broad); 6.73 (1H, singlet); 6.89 (1H, doublet, J=5.3 Hz); 8.04 (1H, doublet, J=5.3 Hz); 9.00 (1H, singlet).
Infrared Absorption Spectrum (CHCl.sub.3) .nu..sub.max cm.sup.-1 : 3350, 3300, 2940, 1660, 1610, 1560, 1510, 1420.
EXAMPLE 39
N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-4-(5-methyl-1,3,4-thiadiazol-2-ylthio)butyramide
Following a procedure similar to that described in Example 34, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-4-chlorobutyramide (prepared as described in Preparation 2) and 2-mercapto-5-methyl -1,3,4-thiadiazole as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 65.degree.-68.degree. C., in a 78% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.37-1.51 (2H, multiplet); 1.51-1.68 (4H, multiplet); 2.16 (2H, quintet, J=6.9 Hz); 2.31-2.44 (6H, multiplet); 2.71 (3H, singlet); 3.35 (2H, triplet, J=6.9 Hz); 3.41 (2H, singlet); 4.04 (2H, triplet, J=5.9 Hz); 4.94 (2H, doublet, J=6.6 Hz); 5.65-5.76 (1H, multiplet); 5.77-5.90 (1H, multiplet); 6.37-6.50 (1H, broad); 6.73 (1H, singlet); 6.89 (1H, doublet, J=5.3 Hz); 8.04 (1H, doublet, J=5.3 Hz).
Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3450, 3300, 2940, 1660, 1610, 1560, 1510, 1420, 1300.
EXAMPLE 40
N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(1,2,4-triazol-3-ylthio)acetamide
Following a procedure similar to that described in Example 33, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-2-chloroacetamide (prepared as described in Preparation 1) and 3-mercapto-1,2,4-triazole as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 65.degree.-67.degree. C., in a 91% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.41-1.55 (2H, multiplet); 1.55-1.67 (4H, multiplet); 2.42-2.55 (4H, multiplet); 3.47 (2H, singlet); 3.77 (2H, singlet); 4.00 (2H, triplet, J=6.3 Hz); 4.83 (2H, doublet, J=6.8 Hz); 5.71-5.80 (1H, multiplet); 5.85-5.94 (1H, multiplet); 6.73 (1H, singlet); 6.85 (1H, doublet, J=5.1 Hz); 7.32-7.44 (1H, broad); 8.06 (1H, doublet, J=5.1 Hz); 8.07 (1H, singlet).
Infrared Absorption Spectrum (liquid film), .nu..sub.max cm.sup.-1 : 2935, 1652, 1612, 1560, 1421, 1403, 1301, 1288.
EXAMPLE 41
N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-4-(1,2,4-triazol-3-ylthio)butyramide
Following a procedure similar to that described in Example 34, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-4-chlorobutyramide (prepared as described in Preparation 2) and 3-mercapto-1,2,4-triazole as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 87.degree.-89.degree. C., in a 56% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.39-1.51 (2H, multiplet); 1.54-1.65 (4H, multiplet); 2.09 (2H, quintet, J=7.0 Hz); 2.33-2.50 (6H, multiplet); 3.13 (2H, triplet, J=7.0 Hz); 3.44 (2H, singlet); 4.06 (2H, triplet, J=6.1 Hz); 4.93 (2H, doublet, J=6.4 Hz); 5.69-5.82 (1H, multiplet); 5.82-5.9 3 (1H, multiplet); 6.75 (1H, singlet); 6.89 (1H, doublet, J=5.4 Hz); 6.92-7.0 3 (1H, broad); 8.03 (1H, singlet); 8.04 (1H, doublet, J=5.4 Hz).
Infrared Absorption Spectrum (KBr), .nu..sub.max cm.sup.-1 : 2942, 2915, 1625, 1614, 1564, 1293, 1250, 1238.
EXAMPLE 42
N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(1-methyltetrazol-5-ylthio)acetamide
Following a procedure similar to that described in Example 33, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-2-chloroacetamide (prepared as described in Preparation 1) and 1-methyl-5-mercaptotetrazole as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 58.degree.-62.degree. C., in an 87% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.35-1.50 (2H, multiplet); 1.50-1.63 (4H, multiplet); 2.27-2.44 (4H, multiplet); 3.41 (2H, singlet); 3.95 (3H, singlet); 3.96 (2H, singlet); 4.04 (2H, triplet, J=5.9 Hz); 4.90 (2H, doublet, J=5.9 Hz); 5.54-5.68 (1H, multiplet); 5.78-5.89 (1H, multiplet); 6.73 (1H, singlet); 6.88 (1H, doublet, J=5.9 Hz); 8.05 (1H, doublet, J=5.9 Hz).
Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3300, 2950, 1730, 1670, 1610, 1560, 1400, 1290.
EXAMPLE 43
N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-4-(1-methyltetrazol-5-ylthio)butyramide
Following a procedure similar to that described in Example 34, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-4-chlorobutyramide (prepared as described in Preparation 2) and 1-methyl-5-mercaptotetrazole as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 70% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.38-1.50 (2H, multiplet); 1.50-1.63 (4H, multiplet); 2.13-2.24 (2H, quintet, J=7.3 Hz); 2.26-2.47 (6H, multiplet); 3.40 (2H, triplet, J=7.3 Hz); 3.41 (2H, singlet); 3.91 (3H, singlet); 4.05 (2H, triplet, J=5.3 Hz); 4.94 (2H, doublet, J=6.6 Hz); 5.66-5.75 (1H, multiplet); 5.80-5.89 (1H, multiplet); 6.39-6.50 (1H, broad); 6.73 (1H, singlet); 6.89 (1H, doublet, J=5.2 Hz); 8.03 (1H, doublet, J=5.2 Hz).
Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3450, 2925, 1660, 1610, 1560, 1510, 1410, 1290.
EXAMPLE 44
N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-4-[1-(2-hydroxyethyl)tetrazol-5-ylthio]butyramide
Following a procedure similar to that described in Example 34, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-4-chlorobutyramide (prepared as described in Preparation 2) and 1-(2-hydroxyethyl)-5-mercaptotetrazole as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 63% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.38-1.50 (2H, multiplet); 1.50-1.63 (4H, multiplet); 2.17 (2H, quintet, J=6.8 Hz); 2.33-2.60 (6H, multiplet); 3.38 (2H, triplet, J=6.8 Hz); 3.49 (2H, singlet); 4.01 (2H, triplet, J=6.1 Hz); 4.08-4.11 (2H, multiplet); 4.34-4.38 (2H, multiplet); 4.92 (2H, doublet, J=6.4 Hz); 5.67-5.87 (2H, multiplet); 6.49-6.65 (1H, broad); 6.79 (1H, singlet); 6.93 (1H, doublet, J=4.9 Hz); 8.05 (1H, doublet, J=4.9 Hz).
Infrared Absorption Spectrum (CHCl.sub.3) .nu..sub.max cm.sup.-1 : 3300, 2940, 1660, 1610, 1560, 1510, 1420, 1400.
EXAMPLE 45
N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-4-(2-pyridylthio)butyramide
Following a procedure similar to that described in Example 34, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-4-chlorobutyramide (prepared as described in Preparation 2) and 2-mercaptopyridine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 53% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.40-1.53 (2H, multiplet); 1.59-1.75 (4H, multiplet); 2.07 (2H, quintet, J=7.1 Hz); 2.39 (2H, triplet, J=7.1 Hz); 2.33-2.60 (4H, broad); 3.21 (2H, triplet, J=7.1 Hz); 3.51 (2H, singlet); 4.07 (2H, triplet, J=6.2 Hz); 4.94 (2H, doublet, J=6.3 Hz); 5.63-5.75 (1H, multiplet); 5.80-5.88 (1H, multiplet); 6.58-6.69 (1H, broad); 6.77 (1H, singlet); 6.92-7.00 (2H, multiplet); 7.17 (1H, triplet of doublets, J=8.3 & 1.0 Hz); 7.46 (1H, doublet of triplets, J=8.3 & 2.0 Hz); 8.07 (1H, doublet, J=5.4 Hz); 8.39 (1H, triplet of doublets, J=4.9 & 1.0 Hz).
Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 2945, 1660, 1655 (shoulder), 1610, 1580, 1560, 1415.
EXAMPLE 46
N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-4-(4-pyridylthio)butyramide
Following a procedure similar to that described in Example 34, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-4-chlorobutyramide (prepared as described in Preparation 2) and 4-mercaptopyridine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 33% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.37-1.48 (2H, multiplet); 1.54-1.63 (4H, multiplet); 2.07 (2H, quintet, J=7.2 Hz); 2.25-2.3 9 (6H, multiplet); 3.05 (2H, triplet, J=7.2 Hz); 3.41 (2H, singlet); 4.04 (2H, triplet, J=5.9 Hz); 4.92 (2H, doublet, J=6.6 Hz); 5.63-5.75 (1H, multiplet); 5.78-5.96 (1H, multiplet); 6.15-6.27 (1H, broad); 6.73 (1H, singlet); 6.88 (1H, doublet, J=5.3 Hz); 7.13 (2H, doublet, J=4.6 Hz); 8.02 (1H, doublet, J=5.3 Hz); 8.37 (2H, doublet, J=4.6 Hz).
Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 2945, 1660, 1655 (shoulder), 1610, 1580, 1560, 1415, 1405, 1310, 1300, 1290.
EXAMPLE 47
N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-4-(4,6-diamino-2-pyrimidinylthio)butyramide
Following a procedure similar to that described in Example 34, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-4-chlorobutyramide (prepared as described in Preparation 2) and 4,6-diamino-2-mercaptopyrimidine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 48% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.39-1.50 (2H, multiplet); 1.55-1.67 (4H, multiplet); 1.83-2.14 (4H, multiplet); 2.30-2.47 (6H, multiplet); 3.10 (2H, triplet, J=6.8 Hz); 3.45 (2H, singlet); 3.99-4.09 (2H, multiplet); 4.61 (2H, broad singlet); 4.92 (2H, doublet, J=6.8 Hz); 5.24 (1H, singlet); 5.63-5.72 (1H, multiplet); 5.78-5.87 (1H, multiplet); 6.12-6.23 (1H, broad); 6.72-6.79 (1H, multiplet); 6.91 (1H, doublet, J=4.4 Hz); 8.05 (1H, doublet, J=4.4 Hz).
Infrared Absorption Spectrum (CHCl.sub.3) .nu..sub.max cm.sup.-1 : 2940, 1655, 1610, 1580, 1555, 1310.
EXAMPLE 48
N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-N'-isopropylurea
A solution of 0.113 g of isopropylamine in 2 ml of methylene chloride was added to a solution of 0.31 g of carbonyldiimidazole in 5 ml of methylene chloride, and the resulting mixture was cooled with ice, after which a solution of 0.500 g of 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine in 5 ml of methylene chloride was added. The reaction mixture was stirred at room temperature for 2 hours, after which it was poured into ice-water and extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 1:20 by volume mixture of methanol and ethyl acetate as the eluent, to give 0.41 g (yield 62%) of the title compound as a white powder, melting at 90.degree.-92.degree. C.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.13 (6H, doublet, J=6.4 Hz); 1.40-1.55 (2H, multiplet); 1.55-1.90 (6H, multiplet); 2.30-2.57 (4H, multiplet); 3.49 (2H, singlet); 3.80-3.90 (1H, multiplet); 3.95 (2H, triplet, J=5.9 Hz); 4.10-4.30 (1H, broad); 4.52-4.67 (1H, broad); 4.91 (2H, doublet, J=6.3 Hz); 5.67-5.88 (2H, multiplet); 6.80 (1H, singlet); 6.92 (1H, doublet, J=5.9 Hz); 8.07 (1H, doublet, J=5.9 Hz).
Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3430, 2920, 1655, 1605, 1555, 1520, 1410.
EXAMPLE 49
N-Diphenylmethyl-N'-[4-(47piperidinomethyl)-2-pyridyloxy) -cis-2-butenyl]urea
Following a procedure similar to that described in Example 48, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and diphenylmethylamine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 69% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.37-1.42 (2H, multiplet); 1.42-1.70 (4H, multiplet); 2.28-2.57 (4H, multiplet); 3.44 (2H, singlet); 3.94 (2H, triplet, J=5.9 Hz); 4.86 (2H, doublet, J=6.3 Hz); 4.87 (1H, singlet); 5.10-5.24 (1H, broad); 5.58-5.70 (1H, multiplet); 5.72-5.83 (1H, multiplet); 5.97 (1H, doublet, J=7.3 Hz); 6.74 (1H, singlet); 6.87 (1H, doublet, J=5.4 Hz); 7.13-7.42 (10H, multiplet); 8.00 (1H, doublet, J=5.4 Hz).
Infrared Absorption Spectrum (CHCl.sub.3 .sup.), .nu..sub.max cm.sup.-1 : 3430, 2980, 2930, 1660, 1610, 1560, 1520, 1415, 1400, 1298, 1285.
EXAMPLE 50
N-(1-Methylpropyl)-N'-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]urea
Following a procedure similar to that described in Example 48, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 1-methylpropylamine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 72.degree.-74.degree. C., in an 80% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 0.90 (3H, triplet, J=7.5 Hz); 1.11 (3H, doublet, J=6.4 Hz); 1.35-1.80 (6H, multiplet); 2.33-2.60 (4H, multiplet); 3.51 (2H, singlet); 3.60-3.77 (1H, multiplet); 3.95 (2H, triplet, J=5.9 Hz); 4.13-4.28 (1H, broad); 4.54-4.69 (1H, broad); 4.92 (2H, doublet, J=6.5 Hz); 6.67-6.88 (2H, multiplet); 6.81 (1H, singlet); 6.93 (1H, doublet, J=5.4 Hz); 8.07 (1H, doublet, J=5.4 Hz).
Infrared Absorption Spectrum (CHCl.sub.3) .nu..sub.max cm.sup.-1 : 3430, 3350, 2920, 1655, 1610, 1558, 1525, 1415, 1400, 1340, 1298, 1285.
EXAMPLE 51
N-(1-Methylbutyl)-N'-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]urea
Following a procedure similar to that described in Example 48, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 1-methylbutylamine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 66% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 0.89 (3H, triplet, J=7.1 Hz); 1.10 (3H, doublet, J=6.4 Hz); 1.22-1.50 (6H, multiplet); 1.50-1.64 (4H, multiplet); 2.30-2.43 (4H, multiplet); 3.41 (2H, singlet); 3.67-3.82 (1H, multiplet); 3.95 (2H, triplet, J=5.9 Hz); 4.17 (1H, broad doublet, J=7.8 Hz); 4.58-4.68 (1H, broad); 4.91 (2H, doublet, J=6.8 Hz); 5.66-5.76 (1H, multiplet); 5.76-5.88 (1H, multiplet); 6.73 (1H, singlet); 6.80 (1H, doublet, J=5.9 Hz); 8.04 (1H, doublet, J=5.9 Hz).
Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3430, 3350, 2930, 1650, 1610, 1558, 1525, 1415, 1400, 1310, 1295, 1285.
EXAMPLE 52
N-(1-Methylhexyl)-N'-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]urea
Following a procedure similar to that described in Example 48, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 1-methylhexylamine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 65% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 0.87 (3H, triplet, J=6.6 Hz); 1.10 (3H, doublet, J=6.4 Hz); 1.20-1.50 (10H, multiplet); 1.50-1.67 (4H, multiplet); 2.30-2.47 (4H, multiplet); 3.42 (2H, singlet); 3.64-3.80 (1H, multiplet); 3.95 (2H, triplet, J=6.1 Hz); 4.07-4.20 (1H, broad doublet, J=7.7 Hz); 4.25-4.65 (1H, broad); 4.92 (2H, doublet, J=6.3 Hz); 5.63-5.88 (2H, multiplet); 6.74 (1H, singlet); 6.89 (1H, doublet, J=5.3 Hz); 8.05 (1H, doublet, J=5.3 Hz).
Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3430, 3350, 2930, 2850, 1655, 1610, 1560, 1528, 1415, 1400, 1310, 1298, 1285.
EXAMPLE 53
N-(1-Phenylethyl)-N'-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]urea
Following a procedure similar to that described in Example 48, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 1-phenylethylamine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 62% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.45 (3H, doublet, J=6.8 Hz); 1.50-1.74 (6H, multiplet); 2.30-2.43 (4H, multiplet); 3.41 (2H, singlet); 3.92 (2H, triplet, J=5.6 Hz); 4.50-4.70 (2H, broad); 4.86 (2H, doublet, J=6.3 Hz); 5.57-5.68 (1H, multiplet); 5.72-5.84 (1H, multiplet); 6.71 (1H, singlet); 6.86 (2H, doublet, J=5.4 Hz); 7.19-7.37 (5H, multiplet); 8.01 (1H, doublet, J=5.4 Hz).
Infrared Absorption Spectrum (CHCl.sub.3) .nu..sub.max cm.sup.-1 : 3440, 2980, 2930, 1660, 1610, 1558, 1525, 1415, 1400, 1298, 1285.
EXAMPLE 54
N-(1-Ethylpropyl)-N'-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]urea
Following a procedure similar to that described in Example 48, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 1-ethylpropylamine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 82.degree.-84.degree. C., in a 77% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 0.89 (6H, triplet, J=7.3 Hz); 1.22-1.78 (10H, multiplet); 2.30-2.56 (4H, multiplet); 3.49 (2H, singlet); 3.96 (2H, triplet, J=6.1 Hz); 4.05-4.20 (1H, broad); 4.57-4.68 (1H, broad); 4.92 (2H, doublet, J=6.3 Hz); 5.65-5.88 (2H, multiplet); 6.80 (1H, singlet); 6.92 (1H, doublet, J=5.3 Hz); 8.07 (1H, doublet, J=5.3 Hz).
Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3440, 3370, 2960, 2930, 1655, 1622, 1540, 1528, 1418, 1400, 1300, 1285.
EXAMPLE 55
N-(1,2-Dimethylpropyl)-N'-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]urea
Following a procedure similar to that described in Example 48, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 1,2-dimethylpropylamine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 73% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 0.87 (3H, triplet, J=6.8 Hz); 0.88 (3H, doublet, J=6.8 Hz); 1.05 (3H, doublet, J=5.8 Hz); 1.37-1.51 (2H, multiplet); 1.51-1.82 (5H, multiplet); 2.30-2.42 (4H, multiplet); 3.56 (2H, singlet); 3.56-3.71 (1H, multiplet); 3.95 (2H, triplet, J=6.1 Hz); 4.20 (1H, broad doublet, J=8.8 Hz); 4.58-4.70 (1H, broad); 4.92 (2H, doublet, J=6.3 Hz); 5.65-5.77 (1H, multiplet); 5.77-5.88 (1H, multiplet); 6.73 (1H, sin91et); 6.88 (1H, doublet, J=5.4 Hz); 8.04 (1H, doublet, J=5.4 Hz).
Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3440, 2930, 1660, 1610, 1560, 1525, 1415, 1400, 1308, 1300, 1285.
EXAMPLE 56
N-(1,2-Diphenylethyl)-N'-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]urea
Following a procedure similar to that described in Example 48, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 1,2-diphenylethylamine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in an 80% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.37-1.54 (2H, multiplet); 1.54-1.84 (4H, multiplet); 2.32-2.62 (4H, multiplet); 3.05 (2H, doublet, J=6.8 Hz); 3.52 (2H, singlet); 3.85 (2H, triplet, J=5.9 Hz); 4.63-4.78 (1H, broad); 4.83 (2H, doublet, J=6.8 Hz); 4.90-5.02 (1H, multiplet); 5.52-5.62 (1H, multiplet); 5.68-5.79 (1H, multiplet); 6.74-6.87 (1H, broad); 6.91 (1H, doublet, J=5.3 Hz); 7.00-7.08 (2H, multiplet); 7.12-7.39 (8H, multiplet); 8.02 (1H, doublet, J=5.3 Hz).
Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3450, 3010, 2950, 1668, 1615, 1560, 1528, 1420, 1408, 1300, 1290.
EXAMPLE 57
N-Cyclopropyl-N'-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]urea
Following a procedure similar to that described in Example 48, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and cyclopropylamine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 102.degree.-104.degree. C., in a 60% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.51-1.59 (2H, multiplet); 1.67-1.77 (2H, multiplet); 1.36-1.82 (6H, multiplet); 2.30-2.60 (4H, multiplet); 3.49 (2H, singlet); 4.04 (2H, triplet, J=6.1 Hz); 4.62-4.78 (1H, broad); 4.94 (2H, doublet, J=6.4 Hz); 5.02-5.17 (1H, broad); 5.67-5.90 (2H, multiplet); 6.78 (1H, singlet); 6.93 (1H, doublet, J=5.4 Hz); 8.07 (1H, doublet, J=5.4 Hz).
Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3430, 2990, 2930, 1642, 1610, 1560, 1528, 1415, 1400, 1298, 1285.
EXAMPLE 58
N-Cyclobutyl-N'-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]urea
Following a procedure similar to that described in Example 48, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and cyclobutylamine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 130.degree.-132.degree. C., in a 66% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.37-1.49 (2H, multiplet); 1.52-1.88 (8H, multiplet); 2.23-2.42 (6H, multiplet); 3.41 (2H, singlet); 3.95 (2H, triplet, J=5.8 Hz); 4.03-4.21 (1H, multiplet); 4.50-4.68 (2H, multiplet); 4.91 (2H, doublet, J=6.4 Hz); 5.62-5.74 (1H, multiplet); 5.76-5.89 (1H, multiplet); 6.74 (1H, singlet); 6.88 (1H, doublet, J=5.4 Hz); 8.05 (1H, doublet, J=5.4 Hz).
Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3440, 2980, 2940, 1660, 1612, 1560, 1528, 1415, 1400, 1300, 1288, 1248.
EXAMPLE 59
N-Cyclopentyl-N'-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]urea
Following a procedure similar to that described in Example 48, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and cyclopentylamine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 121.degree.-124.degree. C., in a 77% yield.
Nuclear Magnetic Resonance Spectrum (hexadeuterated dimethyl sulfoxide), .delta. ppm: 1.14-1.67 (12H, multiplet); 1.67-1.82 (2H, multiplet); 2.20-2.43 (4H, multiplet); 3.45 (2H, singlet); 3.72 (2H, triplet, J=5.8 Hz); 3.75-3.91 (1H, multiplet); 4.86 (2H, doublet, J=6.4 Hz); 5.49-5.72 (2H, multiplet); 5.77 (1H, triplet, J=5.9 Hz); 5.84 (2H, doublet, J=7.3 Hz); 6.71 (1H, singlet); 6.92 (1H, doublet of doublets, J=5.4 & 1.0 Hz); 8.07 (1H, doublet, J=5.4 Hz).
Infrared Absorption Spectrum (KBr), .nu..sub.max cm.sup.-1 : 3318, 2935, 1618, 1584, 1561, 1426, 1409, 1301, 1041.
EXAMPLE 60
N-Cyclohexyl -N'-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]urea
Following a procedure similar to that described in Example 48, but using 4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenylamine and cyclohexylamine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 131.degree.-132.degree. C., in a 72% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm: 0.99-1.21 (2H, multiplet); 1.25-1.50 (4H, multiplet); 1.52-1.75 (8H, multiplet); 1.85-1.97 (2H, multiplet); 2.30-2.42 (4H, multiplet); 3.40 (2H, singlet); 3.42-3.58 (1H, multiplet); 3.95 (2H, triplet, J=5.8 Hz); 4.25 (1H, broad doublet, J=7.8 Hz); 4.61 (1H, broad triplet, J=5.9 Hz); 4.92 (2H, doublet, J=6.8 Hz); 5.64-5.76 (1H, multiplet); 5.76-5.87 (1H, multiplet); 6.73 (1H, singlet); 6.87 (1H, doublet, J=5.4 Hz); 8.04 (1H, doublet, J=5.4 Hz). Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3430, 3350, 2980, 2920, 2850, 1655, 1610, 1558, 1528, 1415, 1400, 1310, 1300, 1288.
EXAMPLE 61
N-Cycloheptyl-N'-[4-(4-iperidinomethyl-2-pyridyloxy)-cis-2-butenyl]urea
Following a procedure similar to that described in Example 48, but using 4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenylamine and cycloheptylamine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 89.degree.-91.degree. C., in a 60% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.32-1.80 (16H, multiplet); 1.82-2.00 (2H, multiplet); 2.25-2.50 (4H, multiplet); 3.43 (2H, singlet); 3.64-3.80 (1H, multiplet); 3.95 (2H, triplet, J=5.9 Hz); 4.29 (1H, broad doublet, J=7.3 Hz); 4.56 (1H, broad triplet, J=5.4 Hz); 4.92 (2H, doublet, J=6.3 Hz); 5.64-5.77 (1H, multiplet); 5.77-5.88 (1H, multiplet); 6.75 (1H, singlet); 6.88 (1H, doublet, J=5.4 Hz); 8.05 (1H, doublet, J=5.4 Hz). Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3430, 2920, 1655, 1610, 1558, 1520, 1413, 1400, 1308, 1298, 1285.
EXAMPLE 62
N-Cyclooctyl-N'-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]urea
Following a procedure similar to that described in Example 48, but using 4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenylamine and cyclooctylamine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 59% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.32-1.93 (20H, multiplet); 2.30-2.70 (4H, multiplet); 3.49 (2H, singlet); 3.68-3.86 (1H, multiplet); 3.94 (2H, triplet, J=5.9 Hz); 4.27-4.43 (1H, broad); 4.52-4.67 (1H, broad); 4.91 (2H, doublet, J=6.3 Hz); 5.65-5.88 (2H, multiplet); 6.80 (1H, singlet); 6.92 (1H, doublet, J=5.3 Hz); 8.07 (1H, doublet, J=5.3 Hz). Infrared Absorption Spectrum (CHCl.sub.3) .nu..sub.max cm.sup.-1 : 3440, 2930, 1655, 1610, 1560, 1525, 1415, 1400, 1310, 1300, 1288.
EXAMPLE 63
N-Isopropyl-N'-[3-(4-piperidinomethyl-2-pyridyloxy)propyl]urea
Following a procedure similar to that described in Example 48, but using 3-(4-piperidinomethyl-2-pyridyloxy)propylamine and isopropylamine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 58.degree.-60.degree. C., in a 50% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.14 (6H, doublet, J=6.3 Hz); 1.38-1.50 (2H, multiplet); 1.52-1.64 (4H, multiplet); 1.90-2.05 (2H, multiplet); 2.37 (4H, triplet, J=5.1 Hz); 3.34 (2H, triplet of doublets, J=6.3 & 5.8 Hz); 3.41 (2H, singlet); 3.74-3.92 (1H, multiplet); 4.19 (1H, broad doublet, J=7.8 Hz); 4.38 (2H, triplet, J=5.8 Hz); 4.70-4.82 (1H, broad); 6.72 (1H, singlet); 6.86 (1H, doublet, J=5.4 Hz); 8.04 (1H, doublet, J=5.4 Hz). Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3420, 3320, 2920, 1650, 1608, 1555, 1530, 1412.
EXAMPLE 64
N-[3-(4-Piperidinomethyl-2-pyridyloxy)propyl]-pyrazole-4-carboxamide
A solution of 1.0 g of 3-(4-piperidinomethyl-2-pyridyloxy)propylamine and 0.45 g of 4-pyrazolecarboxylic acid dissolved in 15 ml of dimethylformamide was stirred for 5 minutes, whilst ice-cooling, after which 734 mg of diethyl cyanophosphonate and 0.68 ml of triethylamine were added to the resulting mixture. The mixture was then stirred at room temperature for 3 hours, after which it was diluted with water, and the aqueous mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 1:9 by volume mixture of methanol and chloroform as the eluent, to give 1.2 g (yield 85%) of the title compound as a white powder, melting at 117.degree.-119.degree. C.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.39-1.47 (2H, multiplet); 1.50-1.62 (4H, multiplet); 1.99-2.11 (2H, multiplet); 2.34-2.44 (4H, multiplet); 3.41 (2H, singlet); 3.55 (2H, quartet, J=5.9 Hz); 4.42 (2H, triplet, J=5.9 Hz); 6.72 (1H, singlet); 6.88 (1H, doublet, J=5.3 Hz); 7.16 (2H, broad triplet, J=5.9 Hz); 7.99-8.05 (2H, multiplet); 8.05 (1H, doublet, J=5.3 Hz). Infrared Absorption Spectrum (KBr), .nu..sub.max cm.sup.-1 : 3250, 2935, 1631, 1607, 1566, 1421, 1386, 1302, 1212.
EXAMPLE 65
N-[4-(4-Piperidinomethyl-2-pyridyloxy)butyl]-pyrazole-4-carboxamide
Following a procedure similar to that described in Example 64, but using 4-(4-piperidinomethyl-2-pyridyloxy)butylamine and 4-pyrazolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 145.degree.-147.degree. C., in a 71% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm. 1.39-1.50 (2H, multiplet); 1.53-1.62 (4H, multiplet); 1.71-1.92 (4H, multiplet); 2.31-2.42 (4H, multiplet); 3.41 (2H, singlet); 3.49 (2H, doublet of doublets, J=12.5 & 6.6 Hz); 4.29 (2H, doublet of doublets, J=11.2 & 6.1 Hz); 6.36-6.42 (1H, broad); 6.71 (1H, singlet); 6.85 (1H, doublet, J=5.3 Hz); 7.96 (2H, singlet); 8.05 (1H, doublet, J=5.3 Hz). Infrared Absorption Spectrum (KBr), .nu..sub.max cm.sup.-1 : 3335, 2940, 1628, 1619, 1560, 1426, 1366, 1299, 992.
EXAMPLE 66
N-[5-(4-Piperidinomethyl-2-pyridyloxy)pentyl]pyrazole-4-carboxamide
Following a procedure similar to that described in Example 64, but using 5-(4-piperidinomethyl-2-pyridyloxy)pentylamine and 4-pyrazolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 105.degree.-106.degree. C., in a yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.42-1.60 (4H, multiplet); 1.60-1.74 (6H, multiplet); 1.76-1.88 (2H, multiplet); 2.40-2.63 (4H, multiplet); 3.43 (2H, quartet, J=6.7 Hz); 3.51 (2H, singlet); 4.27 (2H, triplet, J=6.3 Hz); 6.15-6.25 (1H, broad); 6.75 (1H, singlet); 6.88 (1H, doublet, J=5.3 Hz); 7.96 (2H, singlet); 8.07 (1H, doublet, J=5.3 Hz). Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3460, 2930, 1640, 1610, 1570, 1418, 1320.
EXAMPLE 67
N-[3-(4-Piperidinomethyl-2-pyridyloxy)propyl]-2-(2-acetoxyethylthio)acetamide
67(a) N-[3-(4-Piperidinomethyl-2-pyridyloxy)propyl]-2-chloroacetamide
1.68 ml of triethylamine were added to a solution of 3.00 g of 3-(4-piperidinomethyl-2-pyridyloxy)propylamine in 60 ml of ethyl acetate, and the resulting mixture was cooled with ice, after which 0.96 ml of 2-chloroacetyl chloride was added. The reaction mixture was then stirred at room temperature for 1 hour, after which it was mixed with water and the aqueous mixture was extracted with ethyl acetate. The extract was concentrated by evaporation under reduced pressure, and the concentrate was purified by column chromatography through silica gel, using a 1:9 by volume mixture of methanol and ethyl acetate as the eluent, to give 3.40 g (yield 87%) of the title compound as an oil.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.39-1.52 (2H, multiplet); 1.52-1.66 (4H, multiplet); 2.94-3.07 (2H, multiplet); 2.33-2.44 (4H, multiplet); 3.43 (2H, singlet); 3.48 (2H, triplet of doublets, J=6.6 & 5.9 Hz); 4.07 (2H, singlet); 4.44 (2H, triplet, J=5.9 Hz); 6.76 (1H, singlet); 6.89 (1H, doublet, J=5.3 Hz); 7.36-7.58 (1H, broad); 8.06 (1H, doublet, J=5.3 Hz). Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3425, 2925, 1730, 1660, 1610, 1530, 1420.
67(b) N-[3-(4-Piperidinomethyl-2-pyridyloxy)propyl]-2-(2-hydroxyethylthio)acetamide
0.12 ml of 2-mercaptoethanol was added to a solution of 0.13 g of 85% potassium hydroxide and 0.50 g of N-[3-(4-piperidinomethyl-2-pyridyloxy)propyl]-2-chloroacetamide [prepared as described in step (a) above] in 10 ml methanol, and the resulting mixture was stirred at room temperature for 1 hour. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, the concentrate was mixed with water, and the resulting aqueous mixture was extracted with chloroform. The extract was concentrated by evaporation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 1:9 by volume mixture of ethanol and chloroform as the eluent, to give 0.43 g (yield 77%) of the title compound as an oil.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.38-1.52 (2H, multiplet); 1.52-1.66 (4H, multiplet); 1.95-2.09 (2H, multiplet); 2.31-2.85 (4H, multiplet); 2.79 (2H, triplet, J=5.6 Hz); 3.30 (2H, singlet); 3.42 (2H, singlet); 3.49 (2H, triplet of doublets, J=6.6 & 5.9 Hz); 3.82 (2H, triplet, J=5.6 Hz); 4.42 (2H, triplet, J=5.9 Hz); 6.77 (1H, singlet); 6.88 (1H, doublet, J=5.3 Hz); 7.48-7.66 (1H, broad); 8.06 (1H, doublet, J=5.3 Hz). Infrared Absorption Spectrum (CHCl.sub.3) .nu..sub.max cm.sup.-1 : 3350, 2925, 1650, 1610, 1560, 1520, 1420.
67(c) N-[3-(4-Piperidinomethyl-2-pyridyloxy)propyl]-2-(2-acetoxyethylthio)acetamide
0.49 g of N-[3-(4-piperidinomethyl-2-pyridyloxy)propyl]-2-(2-hydroxyethylthio)acetamide [prepared as described in step (b) above] was added to a mixture of 0.48 ml of acetic anhydride and 0.43 ml of pyridine, and the resulting mixture was warmed at 60.degree. C. for 2 hours. At the end of this time, the reaction mixture was poured into ice-water and a saturated aqueous solution of sodium hydrogencarbonate was added to it. The resulting aqueous mixture was extracted with ethyl acetate. The extract was concentrated by evaporation under reduced pressure, and the concentrate was purified by column chromatography through silica gel, using a 1:9 by volume mixture of methanol and ethyl acetate as the eluent, to give 0.41 g (yield 75%) of the title compound as an oil.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.37-1.51 (2H, multiplet); 1.51-1.67 (4H, multiplet); 1.93-2.09 (2H, multiplet); 2.05 (3H, singlet); 2.31-2.43 (4H, multiplet); 2.80 (2H, triplet, J=5.9 Hz); 3.30 (2H, singlet); 3.42 (2H, singlet); 3.46 (2H, triplet of doublets, J=6.6 & 5.9 Hz); 4.24 (2H, triplet, J=6.6 Hz); 4.42 (2H, triplet, J=5.9 Hz); 6.77 (1H, singlet); 6.88 (1H, doublet, J=5.3 Hz); 7.38-7.54 (1H, broad); 8.06 (1H, doublet, J=5.3 Hz). Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3375, 2925, 1740, 1660, 1610, 1520, 1420, 1220.
The title compound, prepared as described above, was dissolved in ethyl acetate, and a 4N ethyl acetate solution of hydrogen chloride was added to the solution. The crystals which precipitated were collected by filtration, to give the hydrochloride of the title compound, melting at 121.degree.-128.degree. C.
EXAMPLE 68
N-[3-(4-Piperidinomethyl-2-pyridyloxy)propyl]-2-(2-hydroxyethylthio)acetamide
A mixture of 0.38 g of 3-(4-piperidinomethyl-2-pyridyloxy)propylamine and 0.18 g of 1,4-oxathian-2-one was added to 10 ml of ethanol, and the resulting mixture was heated under reflux for 2 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure. The concentrate was mixed with water, and the resulting aqueous mixture was extracted with ethyl acetate. The extract was concentrated by evaporation under reduced pressure, and the concentrate was purified by column chromatography through silica gel, using a 1:9 by volume mixture of methanol and methylene chloride as the eluent, to give 0.49 g (yield 88%) of the title compound as an oil.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.38-1.52 (2H, multiplet); 1.52-1.66 (4H, multiplet); 1.95-2.09 (2H, multiplet); 2.31-2.85 (4H, multiplet); 2.79 (2H, triplet, J=5.6 Hz); 3.30 (2H, singlet); 3.42 (2H, singlet); 3.49 (2H, triplet of doublets, J=6.6 & 5.9 Hz); 3.82 (2H, triplet, J=5.6 Hz); 4.42 (2H, triplet, J=5.9 Hz); 6.77 (1H, singlet); 6.88 (1H, doublet, J=5.3 Hz); 7.48-7.66 (1H, broad); 8.06 (1H, doublet, J=5.3 Hz). Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3350, 2925, 1650, 1610, 1560, 1520, 1420.
EXAMPLE 69
N-[4-(4-Piperidinomethyl-2-pyridyloxy)butyl]-2-(2-acetoxyethylthio)acetamide
69(a) N-[4-(4-Piperidinomethyl-2-pyridyloxy)butyl]-2-chloroacetamide
Following a procedure similar to that described in Example 67(a), but using 4-(4-piperidinomethyl-2-pyridyloxy)butylamine and 2-chloroacetyl chloride as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 59.degree.-63.degree. C., in an 80% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.39-1.51 (2H, multiplet); 1.51-1.66 (4H, multiplet); 1.66-1.91 (4H, multiplet); 2.31-2.44 (4H, multiplet); 3.35-3.47 (2H, multiplet); 3.41 (2H, singlet); 4.05 (2H, singlet); 4.31 (2H, triplet, J=5.9 Hz); 6.63-6.81 (1H, broad); 6.71 (1H, singlet); 6.87 (1H, triplet, J=5.3 Hz); 8.05 (1H, doublet, J=5.3 Hz). Infrared Absorption Spectrum (CHCl.sub.3) .nu..sub.max cm.sup.-1 : 3325, 2925, 1670, 1610, 1530, 1420.
69(b) N-[4-(4-Piperidinomethyl-2-pyridyloxy)butyl]-2-(2-hydroxyethylthio)acetamide
Following a procedure similar to that described in Example 67(b), but using 4-(4-piperidinomethyl-2-pyridyloxy)butyl-2-chloroacetamide [prepared as described in step (a) above] and 2-mercaptoethanol as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a quantitative yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.38-1.50 (2H, multiplet); 1.59-1.64 (4H, multiplet); 1.64-1.91 (5H, multiplet); 2.31-2.44 (4H, multiplet); 2.77 (2H, triplet, J=5.9 Hz); 3.27 (2H, singlet); 3.31-3.45 (2H, multiplet); 3.41 (2H, singlet); 3.81 (2H, triplet, J=5.9 Hz); 4.30 (2H, triplet, J=5.9 Hz); 6.74 (1H, singlet); 6.86 (1H, doublet, J=5.3 Hz); 6.86-7.14 (1H, broad); 8.04 (1H, doublet, J=5.3 Hz). Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3350, 2925, 1660, 1610, 1540, 1520, 1420, 1300.
69(c) N-[4-(4-Piperidinomethyl-2-pyridyloxy)butyl]-2-(2-acetoxyethylthio)acetamide
Following a procedure similar to that described in Example 67(c), but using N-[4-(4-piperidinomethyl-2-pyridyloxy)butyl]-2-(2-hydroxyethylthio)acetamide [prepared as described in step (b) above] and acetic anhydride as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in an 84% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.38-1.51 (2H, multiplet); 1.51-1.64 (4H, multiplet); 1.64-1.89 (4H, multiplet); 2.07 (3H, singlet); 2.31-2.44 (4H, multiplet); 2.79 (2H, triplet, J=6.6 Hz); 3.27 (2H, singlet); 3.32-3.43 (2H, multiplet); 3.41 (2H, singlet); 4.24 (2H, triplet, J=6.6 Hz); 4.31 (2H, triplet, J=5.9 Hz); 6.70 (1H, singlet); 6.81-6.94 (1H, broad); 6.87 (2H, doublet, J=5.3 Hz); 8.05 (1H, doublet, J=5.3 Hz). Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3375, 2925, 1740, 1660, 1610, 1560, 1520, 1420.
The title compound, prepared as described above, was dissolved in ethyl acetate, and a 4N ethyl acetate solution of hydrogen chloride was added to the solution. The crystals which precipitated were collected by filtration, to give the hydrochloride of the title compound, melting at 91.degree.-98.degree. C.
EXAMPLE 70
N-[5-(4-Piperidinomethyl-2-pyridyloxy)pentyl]-2-(2-acetoxyethylthio)acetamide
70(a) N-[5-(4-Piperidinomethyl-2-pyridyloxy)pentyl]-2-(2-hydroxyethylthio)acetamide
Following a procedure similar to that described in Example 68, but using 5-(4-piperidinomethyl-2-pyridyloxy)pentylamine and 1,4-oxathian-2-one as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 78% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.37-2.00 (13H, multiplet); 2.31-2.43 (4H, multiplet); 2.77 (2H, triplet, J=5.9 Hz); 3.26 (2H, singlet); 3.33 (2H, triplet of doublets, J=6.6 & 5.9 Hz); 3.40 (2H, singlet); 3.81 (2H, triplet, J=5.9 Hz); 4.26 (2H, triplet, J=5.9 Hz); 6.74 (1H, singlet); 6.78-6.95 (1H, broad); 6.84 (1H, triplet, J=5.3 Hz); 8.04 (1H, doublet, J=5.3 Hz). Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3375, 2925, 1660, 1610, 1560, 1520, 1420.
70(b) N-[5-(4-Piperidinomethyl-2-pyridyloxy)pentyl]-2-(2-acetoxyethylthio)acetamide
Following a procedure similar to that described in Example 67(c), but using N-[5-(4-piperidinomethyl-2-pyridyloxy)pentyl]-2-(2-hydroxyethylthio)acetamide [prepared as described in step (a) above] and acetic anhydride as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 90% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.36-1.64 (10H, multiplet); 1.72-1.86 (2H, multiplet); 2.07 (3H, singlet); 2.31-2.41 (4H, multiplet); 2.79 (2H, triplet, J=6.6 Hz); 3.27 (2H, singlet); 3.32 (2H, quartet, J=6.6 Hz); 4.19-4.31 (4H, multiplet); 6.69 (1H, singlet); 6.69-6.88 (1H, broad); 6.85 (1H, doublet, J=5.3 Hz); 8.05 (1H, doublet, J=5.3 Hz). Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3375, 2925, 1740, 1660, 1610, 1520, 1420.
EXAMPLE 71
N-[4-(4-Piperidinomethyl-2-pyridyloxy)butyl]-2-(2-propionyloxyethylthio)acetamide
Following a procedure similar to that described in Example 67(c), but using N-[4-(4-piperidinomethyl-2-pyridyloxy)butyl]-2-(2-hydroxyethylthio)acetamide [prepared as described in Example 69(b)] and propionic anhydride as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in an 80% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.14 (3H, triplet, J=7.3 Hz); 1.35-1.88 (10H, multiplet); 2.26-2.42 (4H, multiplet); 2.35 (2H, quartet, J=7.3 Hz); 2.79 (2H, triplet, J=6.3 Hz); 3.27 (2H, singlet); 3.32-3.43 (2H, multiplet); 3.41 (2H, singlet); 4.25 (2H, triplet, J=6.3 Hz); 4.30 (2H, triplet, J=6.6 Hz); 6.70 (1H, singlet); 6.75-6.98 (1H, broad); 6.86 (1H, doublet, J=5.3 Hz); 8.04 (1H, doublet, J=5.3 Hz). Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3375, 2925, 1730, 1660, 1610, 1560, 1520, 1420.
EXAMPLE 72
N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-5-(2-acetoxyethylthio)pentanamide
72(a) N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-5-chloropentanamide
Following a procedure similar to that described in Example 67(a), but using 4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenylamine and 5-chlorovaleryl chloride as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 93% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.36-1.50 (2H, multiplet); 1.50-1.63 (4H, multiplet); 1.74-1.86 (4H, multiplet); 2.18-2.28 (2H, multiplet); 2.28-2.42 (4H, multiplet); 3.41 (2H, singlet); 3.50-3.59 (2H, multiplet); 4.04 (2H, triplet, J=5.9 Hz); 4.93 (2H, doublet, J=6.6 Hz); 5.62-5.74 (1H, multiplet); 5.77-5.90 (1H, multiplet); 5.92-6.20 (1H, broad); 6.73 (1H, singlet); 6.89 (1H, doublet, J=5.3 Hz); 8.03 (1H, doublet, J=5.3 Hz). Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3450, 2950, 1660, 1610, 1560, 1510, 1400.
72(b) N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-5-(methoxycarbonylmethylthio)pentanamide
344 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) were added, whilst ice-cooling and in an atmosphere of nitrogen, to a solution of 0.35 ml of methyl thioglycolate in 90 ml of tetrahydrofuran, and the resulting mixute was stirred at room temperature for 30 minutes. At the end of this time, it was cooled with ice, and a solution of 2.94 g of N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-5-chloropentanamide [prepared as described in step (a) above] in 30 ml of tetrahydrofuran was added dropwise to the mixture. The reaction mixture was then stirred at room temperature for 2 hours, after which the solvent was removed by distillation under reduced pressure. The residue was mixed with water, and the resulting aqueous mixture was extracted with ethyl acetate. The extract was concentrated by evaporation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 1:19 by volume mixture of methanol and ethyl acetate as the eluent, to give 2.84 g (yield 89%) of the title compound as an oil.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.38-1.48 (2H, multiplet); 1.48-1.87 (8H, multiplet); 2.23 (2H, triplet, J=7.3 Hz); 2.32-2.46 (4H, multiplet); 2.66 (2H, triplet, J=7.3 Hz); 3.23 (2H, singlet); 3.42 (2H, singlet); 3.75 (3H, singlet); 4.05 (2H, triplet, J=5.9 Hz); 4.94 (2H, doublet, J=6.6 Hz); 5.63-5.76 (1H, multiplet); 5.79-5.92 (1H, multiplet); 5.95-6.18 (1H, broad); 6.75 (1H, singlet); 6.91 (1H, doublet, J=5.3 Hz); 8.05 (1H, doublet, J=5.3 Hz). Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3450, 2925, 1730, 1660, 1610, 1560, 1510, 1400.
72(c) N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2butenyl]-5-(2-hydroxyethylthio)pentanamide
0.21 g of sodium borohydride was added to a solution of 1.98 g of N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-5-(methoxycarbonylmethylthio)pentanamide [prepared as described in step (b) above] in 40 ml of tetrahydrofuran, and 8 ml of methanol were added dropwise to the mixture, whilst ice-cooling; it was then stirred at room temperature for 3 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was mixed with water. The resulting aqueous mixture was extracted with ethyl acetate, and the extract was freed from the solvent by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 1:9 by volume mixture of methanol and methylene chloride as the eluent, to give 1.51 g (yield 63%) of the title compound as an oil.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.38-2.09 (11H, multiplet); 2.22 (2H, triplet, J=7.3 Hz); 2.26-2.47 (4H, multiplet); 2.54 (2H, triplet, J=7.3 Hz); 2.72 (2H, triplet, J=5.9 Hz); 3.41 (2H, singlet); 3.72 (2H, triplet, J=5.9 Hz); 4.04 (2H, triplet, J=5.9 Hz); 4.93 (2H, doublet, J=6.6 Hz); 5.62-5.75 (1H, multiplet); 5.78-5.90 (1H, multiplet); 5.97-6.19 (1H, broad); 6.74 (1H, singlet); 6.90 (1H, doublet, J=5.3 Hz); 8.04 (1H, doublet, J=5.3 Hz). Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3450, 2925, 1660, 1610, 1560, 1510, 1420.
72(d) N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-5-(2-acetoxyethylthio)pentanamide
Following a procedure similar to that described in Example 67(c), but using N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-5-(2-hydroxyethylthio)pentanamide [prepared as described in step (c) above] and acetic anhydride as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 92% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.36-1.86 (10H, multiplet); 2.07 (3H, singlet); 2.21 (2H, triplet, J=7.3 Hz); 2.30-2.47 (4H, multiplet); 2.57 (2H, triplet, J=7.3 Hz); 2.73 (2H, doublet of doublets, J=7.3 & 6.6 Hz); 3.41 (2H, singlet); 4.03 (2H, triplet, J=5.8 Hz); 4.20 (2H, doublet of doublets, J=7.3 & 6.6 Hz); 4.93 (2H, doublet, J=6.6 Hz); 5.58-5.76 (1H, multiplet); 5.78-5.90 (1H, multiplet); 5.95-6.16 (1H, broad); 6.73 (1H, singlet); 6.89 (1H, doublet, J=5.3 Hz); 8.04 (1H, doublet, J=5.3 Hz). Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3375, 2950, 1660, 1610, 1560, 1520, 1420.
EXAMPLE 73
N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-6-(2-acetoxyethylthio)hexanamide
73(a) N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-6-bromohexanamide
Following a procedure similar to that described in Example 67(a), but using N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenylamine] and 6-bromohexanoyl bromide as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in an 86% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.37-1.77 (10H, multiplet); 1.82-1.95 (2H, multiplet); 2.20 (2H, triplet, J=7.3 Hz); 2.28-2.43 (4H, multiplet); 3.41 (2H, triplet, J=5.3 Hz); 4.04 (2H, triplet, J=5.9 Hz); 4.93 (2H, doublet, J=6.6 Hz); 5.62-5.76 (1H, multiplet); 5.78-5.90 (1H, multiplet); 5.92-6.11 (1H, broad); 6.73 (1H, singlet); 6.89 (1H, doublet, J=5.3 Hz); 8.03 (1H, doublet, J=5.3 Hz). Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3350, 2925, 1660, 1610, 1560, 1510, 1420, 1300.
73(b) N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-6-(2-hydroxyethylthio)hexanamide
Following a procedure similar to that described in Example 67(b), but using N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-6-bromohexanamide [prepared as described in step (a) above] and 2-mercaptoethanol as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a 94% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.36-1.74 (12H, multiplet); 1.63-2.19 (1H, broad); 2.19 (2H, triplet, J=7.3 Hz); 2.29-2.45 (4H, multiplet); 2.53 (2H, triplet, J=7.3 Hz); 2.71 (2H, triplet, J=5.9 Hz); 3.41 (2H, singlet); 3.72 (2H, triplet, J=5.9 Hz); 4.03 (2H, doublet of doublets, J=6.6 & 5.9 Hz); 4.92 (2H, doublet, J=6.6 Hz); 5.61-5.74 (1H, multiplet); 5.77-5.89 (1H, multiplet); 5.93-6.13 (1H, broad); 6.73 (1H, singlet); 6.89 (1H, doublet, J=5.3 Hz); 8.03 (1H, doublet, J=5.3 Hz). Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3450, 2925, 1660, 1610, 1560, 1510, 1420.
73(c) N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-6-(2-acetoxyethylthio)hexanamide
Following a procedure similar to that described in Example 67(c), but using N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-6-(2-hydroxyethylthio)hexanamide [prepared as described in step (b) above] and acetic anhydride as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in an 87% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.37-1.74 (12H, multiplet); 2.07 (3H, singlet); 2.19 (2H, triplet, J=7.3 Hz); 2.31-2.44 (4H, multiplet); 2.56 (2H, triplet, J=7.3 Hz); 2.72 (2H, triplet, J=7.3 Hz); 3.41 (2H, singlet); 4.03 (2H, doublet of doublets, J=6.6 & 5.9 Hz); 4.20 (2H, triplet, J=7.3 Hz); 4.92 (2H, doublet, J=6.6 Hz); 5.62-5.74 (1H, multiplet); 5.78-5.90 (1H, multiplet); 5.92-6.12 (1H, broad); 6.73 (1H, singlet); 6.89 (1H, doublet, J=5.3 Hz); 8.03 (1H, doublet, J=5.3 Hz). Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3450, 2925, 1740, 1660, 1610, 1560, 1510, 1420.
EXAMPLE 74
N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(3-acetoxyethylthio)acetamide
74 (a) N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-chloroacetamide
0.54 ml of triethylamine was added to a solution of 1.00 g of 4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenylamine in 20 ml of ethyl acetate, and the resulting mixture was cooled. 0.31 ml of 2-chloroacetyl chloride were then added to the mixture. The reaction mixture was then stirred at room temperature for 1 hour, after which it was mixed with water, and the aqueous mixture was extracted with ethyl acetate. The extract was concentrated by evaporation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 1:19 by volume mixture of methanol and ethyl acetate as the eluent, to give 0.94 g (yield 73%) of the title compound as an oil.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.37-1.50 (2H, multiplet); 1.50-1.64 (4H, multiplet); 2.30-2.43 (2H, multiplet); 2.30-2.43 (4H, multiplet); 3.41 (2H, singlet); 4.06 (2H, singlet); 4.11 (2H, triplet, J=6.6 Hz); 4.94 (2H, doublet, J=6.6 Hz); 5.62-5.75 (1H, multiplet); 5.84-5.97 (1H, multiplet); 6.69-6.92 (1H, broad); 6.74 (1H, singlet); 6.88 (1H, doublet, J=4.6 Hz); 8.06 (1H, doublet, J=4.6 Hz). Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3420, 2920, 1665, 1610, 1525, 1400, 1285.
74(b) N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(acetylthio)acetamide
A solution of 0.47 ml of thioacetic acid in 20 ml of tetrahydrofuran was added dropwise, whilst ice-cooling and in an atmosphere of nitrogen, to a suspension of 0.29 g of sodium hydride (as a 55% w/w dispersion in mineral oil) in 20 ml of tetrahydrofuran, and the resulting mixture was stirred at room temperature for 30 minutes. At the end of this time, a solution of 2.00 g of N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-chloroacetamide [prepared as described in step (a) above] in 20 ml of tetrahydrofuran was added dropwise to the mixture, whilst ice-cooling, after which it was stirred at room temperature for 30 minutes. The reaction mixture was then concentrated by evaporation under reduced pressure, the residue was mixed with water, and the resulting aqueous mixture was extracted with ethyl acetate. The extract was concentrated by evaporation under reduced pressure, and the concentrate was purified by column chromatography through silica gel, using a 1:19 by volume mixture of methanol and ethyl acetate as the eluent, to give 1.72 g (yield 77%) of the title compound as an oil.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.39-1.50 (2H, multiplet); 1.50-1.67 (4H, multiplet); 2.32-2.43 (4H, multiplet); 2.41 (3H, singlet); 3.42 (2H, singlet); 3.57 (2H, singlet); 4.04 (2H, triplet, J=5.9 Hz); 4.93 (2H, triplet, J=6.6 Hz); 5.57-5.71 (1H, multiplet); 5.81-5.91 (1H, multiplet); 6.35-6.66 (1H, broad); 6.75 (1H, singlet); 6.90 (1H, doublet, J=5.3 Hz); 8.08 (1H, doublet, J=5.3 Hz). Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3400, 2925, 1680, 1610, 1560, 1520, 1400.
74(c) N-[4-(4-Piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-2-(3-hydroxypropylthio)acetamide
5 ml of a methanolic solution containing 0.26 g of a 28% w/v sodium methoxide solution were added, whilst ice-cooling, to a solution of 0.50 g of N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(acetylthio)acetamide [prepared as described in step (b) above] in 5 ml of methanol, and the resulting solution was stirred for 20 minutes. At the end of this time, a solution of 0.11 ml of 3-chloro-1-propanol in 5 ml of methanol, was added, and the reaction mixture was heated under reflux for 5 hours. The solvent was then removed by distillation under reduced pressure. The residue thus obtained was mixed with water, and the aqueous mixture was extracted with ethyl acetate. The extract was concentrated by evaporation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 1:9 by volume mixture of methanol and methylene chloride as the eluent, to give 0.42 g (yield 81%) of the title compound as an oil.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.39-1.51 (2H, multiplet); 1.51-1.66 (4H, multiplet); 1.54-2.02 (4H, broad); 1.84 (2H, triplet of doublets, J=7.3 & 5.9 Hz); 2.32-2.45 (4H, multiplet); 2.68 (2H, triplet, J=7.3 Hz); 3.24 (2H, singlet); 3.41 (2H, singlet); 3.73 (2H, triplet, J=5.9 Hz); 4.07 (2H, doublet of doublets, J=6.6 & 5.9 Hz); 4.93 (2H, doublet, J=6.6 Hz); 5.61-5.78 (1H, multiplet); 5.82-5.94 (1H, multiplet); 6.76 (1H, singlet); 6.89 (1H, doublet, J=5.3 Hz); 7.70-7.25 (1H, broad); 8.06 (1H, doublet, J=5.3 Hz). Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3375, 2950, 1660, 1610, 1560, 1520, 1420.
74(d) N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(3-acetoxypropylthio)acetamide
Following a procedure similar to that described in Example 67(c), but using N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(3-hydroxypropylthio)acetamide [prepared as described in step (c) above] and acetic anhydride as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in an 87% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.38-1.51 (2H, multiplet); 1.51-1.66 (4H, multiplet); 1.91 (2H, triplet of doublets, J=7.3 & 5.9 Hz); 2.05 (3H, singlet); 2.31-2.43 (4H, multiplet); 2.61 (2H, triplet, J=7.3 Hz); 3.23 (2H, singlet); 3.41 (2H, singlet); 4.03-4.20 (4H, multiplet); 4.94 (2H, doublet, J=6.6 Hz); 5.60-5.77 (1H, multiplet); 5.81-5.94 (1H, multiplet); 6.74 (1H, singlet); 6.89 (1H, doublet, J=5.3 Hz); 6.92-7.10 (1H, broad); 8.06 (1H, doublet, J=5.3 Hz). Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3375, 2950, 1715, 1660, 1610, 1560, 1520, 1420.
The title compound, prepared as described above, was dissolved in ethyl acetate, and a 4N ethyl acetate solution of hydrogen chloride was added to the resulting solution. The crystals which precipitated were collected by filtration, to give the hydrochloride of the title compound, melting at 110.degree.-124.degree. C.
EXAMPLE 75
N-[4-(4-Dimethylaminomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-acetoxyethylthio)acetamide
75(a) N-[4-(4-Dimethylaminomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-hydroxyethylthio)acetamide
Following a procedure similar to that described in Example 68, but using 4-(4-dimethylaminomethyl-2-pyridyloxy)-cis-2-butenylamine and 1,4-oxathian-2-one as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a 53% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.61-2.27 (1H, broad singlet); 2.26 (6H, singlet); 2.77 (2H, triplet, J=5.9 Hz); 3.29 (2H, singlet); 3.40 (2H, singlet); 4.07 (2H, doublet of doublets, J=6.6 & 5.9 Hz); 4.95 (2H, doublet, J=6.6 Hz); 5.61-5.73 (1H, multiplet); 5.76-5.87 (1H, multiplet); 6.76 (1H, singlet); 6.89 (1H, doublet, J=5.3 Hz); 7.07-7.26 (1H, broad); 8.08 (1H, doublet, J=5.3 Hz). Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3400, 2975, 1660, 1610, 1560, 1520, 1420.
75(b) N-[4-(4-Dimethylaminomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-acetoxyethylthio)acetamide
Following a procedure similar to that described in Example 67(c), but using N-[4-(4-dimethylaminomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-hydroxyethylthio)acetamide [prepared as described in step (a) above] and acetic anhydride as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a 58% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 2.09 (3H, singlet); 2.26 (6H, singlet); 2.81 (2H, triplet, J=6.6 Hz); 3.30 (2H, singlet); 3.40 (2H, singlet); 4.10 (2H, doublet of doublets, J=6.6 & 5.9 Hz); 4.26 (2H, triplet, J=6.6 Hz); 4.96 (2H, doublet, J=6.6 Hz); 5.62-5.75 (1H, multiplet); 5.82-5.96 (1H, multiplet); 6.73 (1H, singlet); 6.89 (1H, doublet, J=5.3 Hz); 6.90-7.13 (1H, broad); 8.10 (1H, doublet, J=5.3 Hz). Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3375, 2950, 2800, 1740, 1660, 1610, 1560, 1510, 1400.
EXAMPLE 76
N-{4-[4-(1-Pyrrolidinylmethyl)-2-pyridyloxy]-cis-2-butenyl}-2-(2-acetoxyethylthio)acetamide
Following a procedure similar to that described in Example 68, but using 4-[4-(1-pyrrolidinylmethyl)-2-pyridyloxy]-cis-2-butenylamine and 1,4-oxathian-2-one as starting materials, in relative proportions similar to those used in that Example, N-{4-[4-(1-pyrrolidinylmethyl)-2-pyridyloxy]-cis-2-butenyl}-2-(2-hydroxyethylthio)acetamide was obtained. This product was reacted with acetic anhydride in the same manner and same relative proportions as described in Example 67(c), to give the title compound in a 42% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.71-1.84 (4H, multiplet); 2.07 (3H, singlet); 2.46-2.57 (4H, multiplet); 2.79 (2H, triplet, J=6.3 Hz); 3.28 (2H, singlet); 3.58 (2H, singlet); 4.08 (2H, triplet, J=6.6 Hz); 4.24 (2H, triplet, J=6.3 Hz); 4.94 (2H, doublet, J=6.6 Hz); 5.61-5.73 (1H, multiplet); 5.81-5.94 (1H, multiplet); 6.74 (1H, singlet); 6.90 (1H, doublet, J=5.3 Hz); 6.90-7.09 (1H, broad); 8.07 (1H, doublet, J=5.3 Hz). Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3400, 2950, 2800, 1740, 1660, 1610, 1560, 1520, 1420.
EXAMPLE 77
N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-acetoxyethylsulfinyl)acetamide
77 .mu.l of methanesulfonic acid was added to a solution of 0.50 g of N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-acetoxyethylthio)acetamide (prepared as described in Example 2) in 5.5 ml of 1,2-dichloroethane, and the resulting mixture was cooled to -10.degree. C. 0.28 g of 3-chloroperoxybenzoic acid (purity: 80%) was then added, and the reaction mixture was stirred, whilst keeping the temperature in the range from -10.degree. C. to -5.degree. C., for 2 hours. At the end of this time, it was washed with a 10% w/v aqueous solution of sodium hydrogensulfite, with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 1:9 by volume mixture of ethanol and chloroform as the eluent, to give 0.38 g (yield 73%) of the title compound as an oil.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.37-1.49 (2H, multiplet); 1.49-1.64 (4H, multiplet); 2.09 (3H, singlet); 2.31-2.42 (4H, multiplet); 3.12-3.18 (2H, multiplet); 3.39 (1H, doublet, J=13.2 Hz); 3.41 (2H, singlet); 3.73 (1H, doublet, J=13.2 Hz); 4.10 (2H, triplet, J=5.9 Hz); 4.38-4.60 (2H, multiplet); 4.93 (2H, doublet, J=5.3 Hz); 5.61-5.73 (1H, multiplet); 5.79-5.90 (1H, multiplet); 6.73 (1H, singlet); 6.88 (1H, doublet, J=5.3 Hz); 7.05-7.24 (1H, broad); 8.06 (1H, doublet, J=5.3 Hz). Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3400, 2950, 1740, 1670, 1610, 1560, 1410, 1310, 1220.
EXAMPLE 78
N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-acetoxyethylsulfonyl)acetamide
72 .mu.l of methanesulfonic acid were added to a solution of 0.47 g of N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-acetoxyethylthio)acetamide (prepared as described in Example 2) in 5.5 ml of 1,2-dichloroethane. The resulting mixture was cooled to -10.degree. C. 0.51 g of 3-chloroperoxybenzoic acid (purity: was added to the reaction mixture, which was then stirred at a temperature in the range from -10.degree. C. to -5.degree. C. for 2 hours. At the end of this time, the reaction mixture was washed with a 10% w/v aqueous solution of sodium hydrogensulfite, with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order, and then the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 1:9 by volume mixture of ethanol and chloroform as the eluent, to give 0.40 g (yield 40%) of the title compound as an oil.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.37-1.50 (2H, multiplet); 1.50-1.70 (4H, multiplet); 2.11 (3H, singlet); 2.30-2.41 (4H, multiplet); 3.41 (2H, singlet); 3.55 (2H, triplet, J=5.6 Hz); 3.93 (2H, singlet); 4.09 (2H, triplet, J=5,6 Hz); 4.93 (2H, doublet, J=5.9 Hz); 5.61-5.73 (1H, multiplet); 5.80-5.93 (1H, multiplet); 6.75 (1H, singlet); 6.90 (1H, doublet, J=5.3 Hz); 7.32-7.43 (1H, broad); 8.06 (1H, doublet, J=5.3 Hz). Infrared Absorption Spectrum (CHCl.sub.3) .nu..sub.max cm.sup.-1 : 3300, 2950, 1740, 1680, 1610, 1560, 1400, 1320.
EXAMPLE 79
N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-[2-(3,3-dimethylbutyryloxy)ethylthio)acetamide
Following a procedure similar to that described in Example 7, but using N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-hydroxyethylthio)acetamide (prepared as described in Example 1) and 3,3-dimethylbutyryl chloride as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in an 83% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.02 (9H, singlet); 1.37-1.50 (2H, multiplet); 1.50-1.65 (4H, multiplet); 2.21 (2H, singlet); 2.31-2.43 (4H, multiplet); 2.79 (2H, triplet, J=6.6 Hz); 3.28 (2H, singlet); 3.41 (2H, singlet); 4.08 (2H, triplet, J=5.9 Hz); 4.23 (2H, triplet, J=6.6 Hz); 4.94 (2H, doublet, J=5.9 Hz); 5.60-5.72 (1H, multiplet); 5.81-5.93 (1H, multiplet); 6.73 (1H, singlet); 6.88 (1H, doublet, J=5.3 Hz); 6.92-7.10 (1H, broad); 8.06 (1H, doublet, J=5.3 Hz). Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3375, 2925, 1730, 1660, 1610, 1560, 1520, 1400.
The title compound, prepared as described above, was dissolved in ethyl acetate and treated with an equivalent amount of a 4N solution of hydrogen chloride in ethyl acetate to give the hydrochloride of the title compound, melting at 106.degree.-109.degree. C.
EXAMPLE 80
N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-[2-(2-methylpropionyloxy)ethylthio]acetamide
Following a procedure similar to that described in Example 7, but using N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-hydroxyethylthio)acetamide (prepared as described in Example 1) and 2-methylpropionyl chloride as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a 73% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.17 (6H, doublet, J=7.3 Hz); 1.37-1.52 (2H, multiplet); 1.50-1.66 (4H, multiplet); 2.31-2.44 (4H, multiplet); 2.56 (1H, septet, J=7.3 Hz); 2.79 (2H, triplet, J=6.6 Hz); 3.28 (2H, singlet); 3.42 (2H, singlet); 4.08 (2H, triplet, J=6.3 Hz); 4.24 (2H, triplet, J=6.6 Hz); 4.94 (2H, doublet, J=6.6 Hz); 5.60-5.74 (1H, multiplet); 5.81-5.93 (1H, multiplet); 6.73 (1H, singlet); 6.88 (1H, doublet, J=5.3 Hz); 6.93-7.07 (1H, broad); 8.06 (1H, doublet, J=5.3 Hz). Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3375, 2925, 1730, 1660, 1610, 1560, 1520, 1400.
The title compound, prepared as described above, was dissolved in ethyl acetate and treated with an equimolar amount of a 4N solution of hydrogen chloride in ethyl acetate to give the hydrochloride of the title compound, melting at 93.degree.-96.degree. C.
EXAMPLE 81
N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-[2-(2,2-dimethylpropionyloxy)ethylthio]acetamide
Following a procedure similar to that described in Example 7, but using N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-hydroxyethylthio)acetamide (prepared as described in Example 1) and 2,2-dimethylpropionyl chloride as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a 63% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.20 (9H, singlet); 1.38-1.52 (2H, multiplet); 1.52-1.69 (4H, multiplet); 2.28-2.53 (4H, multiplet); 2.79 (2H, triplet, J=6.6 Hz); 3.28 (2H, singlet); 3.45 (2H, singlet); 4.09 (2H, triplet, J=6.6 Hz); 4.22 (2H, triplet, J=6.6 Hz); 4.94 (2H, doublet, J=6.6 Hz); 5.64-5.73 (1H, multiplet); 5.82-5.93 (1H, multiplet); 6.75 (1H, singlet); 6.91 (1H, doublet, J=5.1 Hz); 6.93-7.09 (1H, broad); 8.07 (1H, doublet, J=5.1 Hz). Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3375, 2925, 1720, 1660, 1610, 1540, 1520, 1480, 1400.
The title compound, prepared as described above, was dissolved in ethyl acetate and treated with an equimolar amount of a 4N solution of hydrogen chloride in ethyl acetate to give the hydrochloride of the title compound, melting at 93.degree.-97.degree. C.
EXAMPLE 82
N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-butyryloxyethylthio)acetamide
Following a procedure similar to that described in Example 7, but using N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-hydroxyethylthio)acetamide (prepared as described in Example 1) and butyryl chloride as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in an 88% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 0.94 (3H, triplet, J=7.3 Hz); 1.34-1.78 (8H, multiplet); 2.29-2.39 (4H, multiplet); 2.30 (2H, triplet, J=7.3 Hz); 2.79 (2H, triplet, J=6.6 Hz); 3.28 (2H, singlet); 3.41 (2H, singlet); 4.08 (2H, doublet of doublets, J=7.3 & 6.6 Hz); 4.24 (2H, triplet, J=6.6 Hz); 4.93 (2H, doublet, J=7.9 Hz); 5.60-5.78 (1H, multiplet); 5.81-5.94 (1H, multiplet); 6.73 (1H, singlet); 6.89 (1H, doublet, J=5.3 Hz); 6.92-7.10 (1H, broad); 8.07 (1H, doublet, J=5.3 Hz). Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3400, 2950, 1740, 1660, 1610, 1560, 1520, 1420.
EXAMPLE 83
N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-hydroxyethylsulfinyl)acetamide
Following a procedure similar to that described in Example 77, but using N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-hydroxyethylthio)acetamide (prepared as described in Example 1) as a starting material, in a relative proportion similar to that used in that Example, the title compound was obtained in a 63% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.34-1.50 (2H, multiplet); 1.50-1.64 (4H, multiplet); 1.76-1.98 (1H, broad); 2.28-2.45 (4H, multiplet); 3.10 (2H, triplet, J=5.9 Hz); 3.41 (2H, singlet); 3.52 (2H, doublet, J=13.9 Hz); 3.79 (1H, doublet, J=13.9 Hz); 4.04-4.16 (4H, multiplet); 4.92 (2H, doublet, J=6.6 Hz); 5.65-5.77 (1H, multiplet); 5.82-5.93 (1H, multiplet); 6.75 (1H, singlet); 6.88 (1H, doublet, J=5.3 Hz); 7.15-7.34 (1H, broad); 8.06 (1H, doublet, J=5.3 Hz). Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3300, 2925, 1730, 1670, 1610, 1560, 1420, 1400.
The title compound, prepared as described above, was dissolved in ethyl acetate and treated with an equimolar amount of a 4N solution of hydrogen chloride in ethyl acetate to give the hydrochloride of the title compound, melting at 111.degree.-114.degree. C.
EXAMPLE 84
N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-propionyloxyethylsulfinyl)acetamide
Following a procedure similar to that described in Example 77, but using N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-propionyloxyethylthio)acetamide (prepared as described in Example 7) as a starting material, in a relative proportion similar to that used in that Example, the title compound was obtained in a 73% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.15 (3H, triplet, J=7.3 Hz); 1.34-1.50 (2H, multiplet); 1.50-1.62 (4H, multiplet); 2.28-2.42 (4H, multiplet); 2.37 (2H, quartet, J=7.3 Hz); 3.15 (2H, triplet, J=6.6 Hz); 3.38 (1H, doublet, J=14.2 Hz); 3.41 (2H, singlet); 3.73 (1H, doublet, J=14.2 Hz); 4.10 (2H, triplet, J=6.6 Hz); 4.39-4.61 (2H, multiplet); 4.93 (2H, doublet, J=6.6 Hz); 5.60-5.72 (1H, multiplet); 5.78-5.91 (1H, multiplet); 6.73 (1H, singlet); 6.88 (1H, doublet, J=5.3 Hz); 7.04-7.23 (1H, broad); 8.06 (1H, doublet, J=5.3 Hz). Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3300, 2925, 1740, 1670, 1610, 1560, 1420, 1400.
The title compound, prepared as described above, was dissolved in ethyl acetate and treated with an equimolar amount of a 4N solution of hydrogen chloride in ethyl acetate to give the hydrochloride of the title compound, melting at 77.degree.-83.degree. C.
EXAMPLE 85
N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-4-(4-pyrimidinylthio)butyramide
85(a) N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-4-(acetylthio)butyramide
0.50 g of sodium hydride (as a 55% w/w dispersion in mineral oil) was added to 80 ml of dimethylformamide under an atmosphere of nitrogen gas, and then 10 ml of a dimethylformamide solution containing 0.81 ml of thioacetic acid was added to the resulting mixture. The mixture was then stirred at room temperature for 30 minutes. At the end of this time, 30 ml of a dimethylformamide solution containing 3.79 g of N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-4-chlorobutyramide (prepared as described in Preparation 2) were added to the mixture, and the mixture was stirred at room temperature for 2 hours. Ethyl acetate was then added to the reaction mixture, which was then washed with a saturated aqueous solution of sodium hydrogencarbonate and water. The solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 1:19 by volume mixture of methanol and ethyl acetate as the eluent, to give 5.04 g (a quantitative yield) of the title compound as an oil.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.37-1.50 (2H, multiplet); 1.50 1.63 (4H, multiplet); 1.93 (2H, quintet, J=7.3 Hz); 2.26 (2H, triplet, J=7.3 Hz); 2.29-2.42 (4H, multiplet); 2.91 (2H, triplet, J=7.3 Hz); 3.41 (2H, singlet); 4.03 (2H, triplet, J=5,9 Hz); 4.93 (2H, triplet, J=5.9 Hz); 5.61-5.75 (1H, multiplet); 5.78-5.89 (1H, multiplet); 6.09-6.34 (1H, broad); 6.73 (1H, singlet); 6.89 (1H, doublet, J=5.3 Hz); 8.04 (1H, doublet, J=5.3 Hz). Infrared Absorption Spectrum (CHCl.sub.3) .nu..sub.max cm.sup.-1 : 3450, 3350, 2925, 2800, 1670, 1610, 1560, 1520, 1480, 1420, 1400.
85(b) N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl ]-4-(4-pyrimidinylthio)butyramide
A solution of 1.00 g of N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-4-(acetylthio)butyramide [prepared as described in step (a) above] in 10 ml of methanol was added to a mixture of 0.48 g of 28% w/v methanolic sodium methoxide and 5 ml of methanol, whilst ice-cooling, and the mixture was stirred at the same temperature for 20 minutes. At the end of this time, 0.28 g of 4-chloropyrimidine was added to the mixture and the mixture was heated under reflux for 2 hours. The solvent was then removed by evaporation under reduced pressure, and water was added to the resulting residue, which was then extracted with ethyl acetate. The solvent was removed from the extract by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 1:9 by volume mixture of ethanol and chloroform as the eluent, to give 0.65 g (yield 60%) of the title compound as an oil.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.36-1.50 (2H, multiplet); 1.50-1.65 (4H, multiplet); 2.06 (2H, quintet, J=7.3 Hz); 2.29-2.43 (4H, multiplet); 2.37 (2H, triplet, J=7.3 Hz); 3.24 (2H, triplet, J=7.3 Hz); 3.41 (2H, singlet); 4.05 (2H, triplet, J=5,9 Hz); 4.93 (2H, doublet, J=6.6 Hz); 5.61-5.76 (1H, multiplet); 5.78-5.90 (1H, multiplet); 6.22-6.44 (1H, broad); 6.73 (1H, singlet); 6.88 (1H, doublet, J=5.3 Hz); 7.17 (2H, doublet, J=5.3 Hz); 8.03 (1H, doublet, J=5.3 Hz); 8.32 (1H, doublet, J=5.3 Hz); 8.91 (1H, singlet). Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.- : 3450, 3300, 2925, 1660, 1610, 1570, 1520, 1440, 1420, 1380.
EXAMPLE 86
N-[4-(4-Dimethylaminomethyl-2-pyridyloxy)-cis-2-butenyl]pyrazole-2-carboxamide
Following a procedure similar to that described in Example 13, but using 4-(4-dimethylaminomethyl-2-pyridyloxy)-cis-2-butenylamine and 4-pyrazolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 65% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 2.27 (6H, singlet); 3.40 (2H, singlet); 4.22 (2H, triplet, J=5.9 Hz); 4.99 (2H, doublet, J=6.6 Hz); 5.71-5.94 (2H, multiplet); 6.47 (1H, broad singlet); 6.74 (1H, singlet); 6.89 (1H, doublet, J=5.3 Hz); 7.97 (2H, singlet); 8.07 (1H, doublet, J=5.3 Hz). Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3450, 3170, 2980, 2940, 1640, 1615, 1565, 1510, 1415, 1400, 1290.
EXAMPLE 87
N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-3,5-dimethylpyrrole-2-carboxamide
Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenylamine and 3,5-dimethylpyrrole-2-carboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as crystals, melting 140.degree.-141.degree. C., in a 58% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.37-1.48 (2H, multiplet); 1.50-1.61 (4H, multiplet); 2.23 (3H, singlet); 2.26 (2H, singlet); 2.30-2.42 (4H, multiplet); 3.40 (2H, singlet); 4.22 (2H, triplet, J=5.6 Hz); 4.96 (2H, doublet, J=6.6 Hz); 5.66-5.79 (3H, multiplet); 5.82-5.92 (1H, multiplet); 6.73 (1H, singlet); 6.87 (1H, doublet, J=5.3 Hz); 8.04 (1H, doublet, J=5.3 Hz); 9.13-9.27 (1H, broad). Infrared Absorption Spectrum (KBr), .nu..sub.max cm.sup.-1 : 3249, 1612, 1525, 1410, 1272, 1035, 826.
EXAMPLE 88
N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-methylfuran-3-carboxamide
Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenylamine and 2-methylfuran-3-carboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 77% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.39-1.51 (2H, multiplet); 1.53-1.66 (4H, multiplet); 2.31-2.45 (4H, multiplet); 2.58 (3H, singlet); 3.42 (2H, singlet); 4.17 (2H, triplet, J=6.4 Hz); 4.97 (2H, doublet, J=6.4 Hz); 5.71-5.81 (1H, multiplet); 5.83-5.93 (1H, multiplet); 6.01-6.18 (1H, broad); 6.41 (1H, doublet, J=2.2 Hz); 6.75 (1H, singlet); 6.90 (1H, doublet, J=5.4 Hz); 7.23 (1H, doublet, J=2.2 Hz); 8.03 (1H, doublet, J=5.4 Hz). Infrared Absorption Spectrum (liquid film), .nu..sub.max cm.sup.-1 : 3325, 2936, 1636, 1611, 1561, 1523, 1420, 1402, 1301, 1290, 1039.
The title compound, prepared as described above, was dissolved in ethyl acetate and treated with an equimolar amount of a 4N solution of hydrogen chloride in ethyl acetate to give the hydrochloride of the title compound, melting at 258.degree.-261.degree. C. (with decomposition).
EXAMPLE 89
N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-4-(2-pyrimidinylsulfinyl)butyramide
Following a procedure similar to that described in Example 77, but using N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-4-(2-pyrimidinylthio)butyramide (prepared as described in Example 34) as a starting material, in a relative proportion similar to that used in that Example, the title compound was obtained as an oil in a 55% yield.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.37-1.50 (2H, multiplet); 1.52-1.63 (4H, multiplet); 1.99-2.12 (1H, multiplet); 2.20-2.45 (7H, multiplet); 3.10-3.32 (2H, multiplet); 3.41 (2H, singlet); 4.01 (2H, doublet, J=6.3 Hz); 4.91 (2H, doublet, J=6.6 Hz); 5.61-5.71 (1H, multiplet); 5.78-5.87 (1H, multiplet); 6.32 (1H, broad singlet); 6.73 (1H, singlet); 6.89 (1H, doublet, J=5.3 Hz); 7.41 (1H, triplet, J=4.6 Hz); 8.03 (1H, doublet, J=5.3 Hz); 8.89 (2H, doublet, J=4.6 Hz). Infrared Absorption Spectrum (liquid film), .nu..sub.max cm.sup.-1 : 3302, 2936, 1657, 1612, 1561, 1420, 1403, 1384, 1312, 1300, 1289, 1062, 1040, 753.
EXAMPLE 90
N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-propionyloxyethylthio)acetamide
Following a procedure similar to that described in Example 2, but using N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-hydroxyethylthio)acetamide (prepared as described in Example 1) and propionic anhydride as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a 90% yield.
The nuclear magnetic resonance spectrum and the infrared spectrum of the title compound are identical with those of the compound prepared as described in Example 7.
PREPARATION 1
N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-chloroacetamide
1.00 g of 4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenylamine was dissolved in 20 ml of ethyl acetate. 0.54 ml of triethylamine was added to the solution, and the resulting mixture was cooled in an ice bath. 0.31 ml of 2-chloroacetyl chloride was added, and the mixture was stirred for 1 hour at room temperature. At the end of this time, water was added, and the reaction mixture was extracted with ethyl acetate. The extract was condensed by evaporation under reduced pressure, and the residue was purified by silica gel chromatography, eluted with a 1:19 by volume mixture of methanol and ethyl acetate, to give 0.94 g (yield 73%) of the title compound as an oil.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.37-1.50 (2H, multiplet); 1.50-1.64 (4H, multiplet); 2.30-2.43 (2H, multiplet); 3.41 (2H, singlet); 4.06 (2H, singlet); 4.11 (2H, triplet, J=6.6 Hz); 4.94 (2H, doublet, J=6.6 Hz); 5.62-5.75 (1H, multiplet); 5.84-5.97 (1H, multiplet); 6.69-6.92 (1H, broad); 6.74 (1H, singlet); 6.88 (1H, doublet, J=4.6 Hz); 8.06 (1H, doublet, J=4.6 Hz). Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3420, 2920, 1665, 1610, 1525, 1400, 1285.
PREPARATION 2
N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-4-chlorobutyramide
Following a procedure similar to that described in Preparation 1, but using 4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenylamine and 4-chlorobutyryl chloride as starting materials, in relative proportions similar to those used in that Preparation, the title compound was obtained at a yield of 73%.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.35-1.53 (2H, multiplet); 1.53-1.78 (4H, multiplet); 2.06-2.17 (2H, multiplet); 2.33-2.41 (2H, multiplet); 2.41-2.52 (4H, multiplet); 3.50 (2H, singlet); 3.61 (2H, triplet, J=6.1 Hz); 4.04 (2H, triplet, J=6.1 Hz); 4.93 (2H, doublet, J=6.8 Hz); 5.62-5.73 (1H, multiplet); 5.77-5.89 (1H, multiplet); 6.07 (1H, doublet, J=4.9 Hz); 6.08-6.26 (1H, broad); 6.78 (1H, singlet); 6.95 (1H, doublet, J=4.9 Hz). Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3440, 2920, 1660, 1610, 1415, 1295.
PREPARATION 3
N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-3-mercaptopropionamide
3(a) N-[4-(4-Piperidinomethyl-2-pyridyloxy]-cis-2-butenyl]-3-(acetylthio)propionamide
1.00 g of 3-(acetylthio)propionic acid, 1.39 g of dicyclohexyl carbodiimide, 1.05 g of 1-hydroxybenzotriazole and 1.76 g of 4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenylamine were added to 45 ml of dimethylformamide, and the solution was stirred for 5 hours at room temperature. At the end of this time, ethyl acetate was added to the reaction mixture, insoluble matter was filtered off, and the filtrate was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with water. The reaction mixture was then condensed by evaporation under reduced pressure, and the resulting residue was subjected to silica gel chromatography, eluted with a 1:19 by volume mixture of methanol and ethyl acetate, to give 1.27 g (yield 48%) of the title compound as an oil.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.30-1.50 (2H, multiplet); 1.50-1.70 (4H, multiplet); 2.28-2.44 (4H, multiplet); 2.32 (3H, singlet); 2.50 (2H, triplet, J=6.9 Hz); 3.16 (2H, triplet, J=6.9 Hz); 3.41 (2H, singlet); 4.04 (2H, triplet, J=6.3 Hz); 4.93 (2H, doublet, J=6.6 Hz); 5.62-5.74 (1H, multiplet); 5.78-5.90 (1H, multiplet); 6.73 (1H, singlet); 6.89 (1H, doublet, J=5.3 Hz); 8.03 (1H, doublet, J=5.3 Hz). Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3440, 2930, 1675, 1610, 1415, 1400, 1310, 1295, 1285, 1140.
3(b) N-[4-(4-Piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]3-(mercapto)propionamide
1.0 g of N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-3-(acetylthio)propionamide [prepared as described in step (a) above] and 0.49 g of a 28% w/v methanolic solution of sodium methoxide were added to 20 ml of methanol, whilst ice-cooling, and the mixture was stirred at the same temperature for 20 minutes. At the end of this time, 0.15 ml of acetic acid was added, and the solvent was removed by distillation under reduced pressure. The residue was dissolved in ethyl acetate, washed with water and condensed by evaporation under reduced pressure, to obtain 0.76 g (yield 85%) of the title compound as an oil.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.37-1.50 (2H, multiplet); 1.46-1.96 (1H, broad); 1.50-1.65 (4H, multiplet); 2.27-2.43 (4H, multiplet); 2.51 (2H, triplet, J=6.9 Hz); 2.83 (2H, doublet of triplets, J=6.9 & 7.9 Hz); 3.41 (2H, singlet); 4.06 (2H, triplet, J=5.9 Hz); 4.94 (2H, doublet, J=6.6 Hz); 5.63-5.77 (1H, multiplet); 5.79-5.90 (1H, multiplet); 6.74 (1H, singlet); 6.89 (1H, doublet, J=5.3 Hz); 8.04 (1H, doublet, J=5.3 Hz). Infrared Absorption Spectrum (CHCl.sub.3), .nu..sub.max cm.sup.-1 : 3450, 2940, 1665, 1612, 1418, 1400, 1300, 1290.
PREPARATION 4
Ethyl 4-Hydroxy-3-isoxazolecarboxylate
144 g of urea were added to 1 liter of a dimethylformamide solution containing 72 g of ethyl 4-bromo-2-hydroxyimino-3-oxobutyrate. The reaction solution was heated for 15 minutes at 100.degree. C. and then cooled, after which water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with dilute aqueous hydrochloric acid and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and a 1:1 by volume mixture of ethyl acetate and hexane was added to the residue, to remove insoluble materials. The solution thus obtained was purified by silica gel chromatography, eluted with a 1:4 by volume mixture of ethyl acetate and hexane, to give 19 g of the title compound, melting at 59.degree.-60.degree. C. (after recrystallization from a mixture of ethyl acetate and hexane).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3), .delta. ppm: 1.42 (3H, triplet, J=8.0 Hz); 4.48 (2H, quartet, J=8.0 Hz); 6.72 (1H, broad); 8.32 (1H, singlet). Infrared Absorption Spectrum (KBr), .nu..sub.max cm.sup.-1 : 3420, 1718, 1140.

Number	Date	Country
4-65324	Mar 1992	JPX
4-101392	Apr 1992	JPX
4-175707	Jul 1992	JPX
4-349035	Dec 1992	JPX

Number	Date	Country
0023578	Feb 1981	EPX
0214823	Mar 1987	EPX
0282077	Sep 1988	EPX
0032422	Feb 1989	EPX
0404949	Jan 1991	EPX
1-93247	Aug 1989	JPX
4-257581	Sep 1992	JPX

Anti-ulcer pyridyloxy derivatives, their preparation and uses

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