1-(3-Hydroxyalk-1-yl)-5-(carboxyalkyl)hydantoin derivatives

This invention relates to novel compounds having pharmacological activity, to a process for their preparation, to intermediates useful in that process and to pharmaceutical compositions containing them.
Offenlegungsschrift No. 2323193 discloses that pyrazolidine derivatives of the formula (I)': ##STR2## wherein A is CH.dbd.CH or C.tbd.C; R is H, an alkali metal, an amine salt, or an .notgreaterthan.12C hydrocarbon or chlorhydrocarbon residue; m is 0 or 1; n is 0-6; p is 0-6; and Y and Z are O or H.sub.2 except that Y and Z are not both O; have similar biological properties to the prostaglandins or are antagonists of prostaglandins.
French Patent Application No. 2258376 discloses that 10-aza prostaglandins of formula (II)": ##STR3## wherein R.dbd.H or lower alkyl; R' and R".dbd.CH.sub.3 or C.sub.2 H.sub.5 ; R.sup.o .dbd.H or lower alkyl; Y.dbd.--CH.sub.2 CH.sub.2 --, or --CH.dbd.CH--; Z.dbd.--CO or --CH(.about.OH)--; are useful in the treatment of blood pressure and gastro-intestinal disorders, and in the preparation for confinement.
Belgian Patent No. 835989 discloses that compounds of the formula (III)": ##STR4## wherein: X is CO, protected CO, CROH in which R is hydrogen or C.sub.1-4 alkyl and in which the OH moiety may be protected; Y is CH.sub.2 CH.sub.2 or CH.dbd.CH; Z is CO or CH.sub.2 ; n is 1 to 8; m is 1, 2 or 3; R.sub.1 is hydrogen, CH.sub.2 OH, CH.sub.2 OH in which the OH moiety is protected, CO.sub.2 W wherein W is hydrogen or CO.sub.2 W represents an ester group in which the ester moiety contains from 1 to 12 carbon atoms, or CONH.sub.2 ; R.sub.2 is hydrogen, C.sub.1-4 alkyl, or taken together with R.sub.3 and the carbon atom to which it is attached represents a carbonyl group; R.sub.3 is hydrogen, hydroxy or protected hydroxy; R.sub.4 is hydrogen or C.sub.1-9 alkyl; and salts thereof; have useful pharmacological activity.
A novel class of compounds also having useful pharmacological activity has now been discovered, which compounds are structurally distinct from the prior art referred to above.
Accordingly the present invention provides a compound of the formula (I): ##STR5## wherein: X is O or S;
n is 1 to 8;
R.sub.1 is hydrogen, or CO.sub.2 R.sub.1 represents an ester group in which the R.sub.1 moiety contains from 1-12 carbon atoms;
R.sub.2 is hydrogen, C.sub.1-4 alkyl, or phenyl;
R.sub.3 is hydroxy or protected hydroxy;
R.sub.4 is hydrogen, C.sub.1-9 alkyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkyl-C.sub.1-6 alkyl, phenyl, phenyl C.sub.1-6 alkyl, naphthyl, naphthyl-C.sub.1-6 -alkyl, any of which phenyl or naphthyl moieties may be substituted by one or more halogen, trifluoromethyl, C.sub.1-6 alkyl, hydroxy, C.sub.1-6 alkoxy, phenyl C.sub.1-6 alkoxy or nitro groups; or
R.sub.2 and R.sub.4 taken with the carbon atom to which they are joined represent a C.sub.5-8 cycloalkyl group;
R.sub.5 is C.sub.1-6 alkyl, C.sub.1-6 alkyl substituted by a nitro, hydroxy, C.sub.1-6 alkoxy, CO.sub.2 A, (CO.sub.2 A).sub.2, CN or halogen group, C.sub.5-8 cycloalkyl, phenyl, phenyl-C.sub.1-6 alkyl, phenyl-C.sub.3-6 cycloalkyl, any of which phenyl moieties may be substituted by one or more halogen, trifluoromethyl, C.sub.1-6 alkyl, C.sub.1-6 alkoxy or nitro groups; or a group CO.sub.2 A; in R.sub.5 when present A is hydrogen or CO.sub.2 A represents an ester group in which the A moiety contains from 1 to 12 carbon atoms; and salts thereof.
A group of compounds within formula (I) include those wherein:
X is O or S;
n is 4 to 8;
R.sub.1 is hydrogen, or CO.sub.2 R.sub.1 represents an ester group in which the R.sub.1 moiety contains from 1 to 12 carbon atoms;
R.sub.2 is hydrogen, C.sub.1-4 alkyl, or phenyl;
R.sub.3 is hydroxy or protected hydroxy;
R.sub.4 is hydrogen, C.sub.1-9 alkyl, C.sub.5-8 cycloalkyl, C.sub.5-8 cycloalkyl-C.sub.1-6 alkyl, phenyl, phenyl C.sub.1-6, alkyl, napthyl, napthyl-C.sub.1-6 -alkyl, any of which phenyl or naphthyl moieties may be substituted by one or more halogen, trifluoromethyl, C.sub.1-6 alkyl, C.sub.1-6 alkoxy or nitro groups;
R.sub.5 is C.sub.1-6 alkyl, phenyl, phenyl-C.sub.1-6 alkyl, or a group CO.sub.2 A wherein A is hydrogen or CO.sub.2 A represents an ester group in which the A moiety contains from 1 to 12 carbon atoms; and salts thereof.
Particularly suitable compounds within formula (I) include those where X is O.
Suitably n is 5, 6 or 7, preferably 6.
R.sub.1 is hydrogen or CO.sub.2 R.sub.1 represents an ester group in which the R.sub.1 moiety contains from 1 to 12 carbon atoms. Examples of R.sub.1 include hydrogen, methyl, ethyl, n- and iso-propyl, n-, sec- and tert-butyl, phenyl, benzyl, toluyl and the like, while normally hydrogen or C.sub.1-6 alkyl groups are preferred.
Suitable examples of R.sub.2 include hydrogen, methyl, ethyl and phenyl. More suitably R.sub.2 is hydrogen, methyl or ethyl, preferably methyl.
Suitable protected hydroxyl groups R.sub.3 include readily hydrolysable groups such as acylated hydroxy groups in which the acyl moiety contains 1 to 4 carbon atoms, for example the acetoxy group; and hydroxy groups etherified by readily removable inert groups such as the benzyl group or like groups. Preferably R.sub.3 is hydroxyl.
Suitable groups R.sub.4 when R.sub.4 is an alkyl group include C.sub.4-9 alkyl groups. Such C.sub.4-9 alkyl groups may be straight chain alkyl groups, such n-butyl, n-pentyl, n-hexyl and n-heptyl, or may be alkyl groups branched by one or two methyl groups (at the same or different carbon atoms). Thus for example, R.sub.4 may be a group CH.sub.2 R.sub.7, CH(CH.sub.3)R.sub.7 or C(CH.sub.3).sub.2 R.sub.7, wherein R.sub.7 is a straight chain alkyl group such that the carbon content of the resultant group R.sub.4 is 4 to 9.
In general preferred groups R.sub.4 when R.sub.4 is an alkyl group include straight chain pentyl, hexyl and heptyl groups. Of these, straight chain hexyl is often the most useful. Other preferred groups R.sub.4 include groups CH(CH.sub.3)R.sub.7 and C(CH.sub.3).sub.2 R.sub.7 wherein R.sub.7 is straight chain butyl, pentyl and hexyl.
Other suitable examples of R.sub.4 when R.sub.4 is an alkyl group include the lower alkyl groups, that is when R.sub.4 is a C.sub.1-4 alkyl group.
When R.sub.4 is or contains a C.sub.3-8 cycloalkyl moiety, the moiety may be cyclopropyl. The moiety may also be a C.sub.5-8 cycloalkyl moiety such as a cyclohexyl moiety. Examples of suitable C.sub.1-6 alkyl moieties when R.sub.4 is a C.sub.3-8 cycloalkyl-C.sub.1-6 alkyl group include methyl, ethyl, propyl, butyl and amyl.
When R.sub.4 is an aryl group as previously defined, suitable groups R.sub.4 include phenyl, phenylmethyl, phenylethyl, phenyl n-propyl, phenyl n-butyl, naphthyl, naphthyl-methyl, naphthyl-ethyl, naphthyl n-propyl and naphthyl n-butyl, and such groups branched in the alkyl moiety by one or two methyl groups (at the same or different carbon atoms). These groups may be substituted in the phenyl or naphthyl moiety by normally one, two or three groups selected from those substituent groups listed hereinbefore. Examples of suitable substituent groups include fluorine, chlorine and bromine atoms and CF.sub.3, methyl, ethyl, n- and iso-propyl, methoxy and ethoxy, n- and iso-propoxy and nitro groups. Other examples of such groups include hydroxy and benzyloxy. Preferably the aryl moieties when substituted by such groups will be mono or di-substituted.
Also, R.sub.2 and R.sub.4 taken with the carbon atom to which they are joined can represent a C.sub.5-8 cycloalkyl group, such as the cyclohexyl group.
Suitable examples of R.sub.5 include methyl, ethyl, n- and iso-propyl, n-, sec- and tert-butyl; phenyl; phenylmethyl, phenylethyl, phenyl-n-propyl, phenyl-n-butyl, and such phenylalkyl groups branched in their alkyl moities by one or two methyl groups (at the same or different carbon atoms). More suitably R.sub.5 is C.sub.1-6 alkyl such as methyl and ethyl.
R.sub.5 may also be a phenyl-C.sub.3-6 cycloalkyl group, in which case suitable examples of R.sub.5 include phenylcyclopropyl.
When R.sub.5 is or includes a phenyl moiety, it can optionally be substituted as described above for R.sub.4 aryl groups.
When R.sub.5 is C.sub.5-8 cycloalkyl, it is suitably cyclohexyl.
When R.sub.5 is, or contains, a group CO.sub.2 A, suitable examples of A include hydrogen, methyl, ethyl, n- and iso-propyl, n-, sec- and tert-butyl, phenyl, benzyl, toluyl and the like, while normally for A hydrogen or C.sub.1-6 alkyl are preferred.
R.sub.5 may also be a C.sub.1-6 alkyl group substituted by a nitro, hydroxy, C.sub.1-6 alkoxy (such as methoxy), CO.sub.2 A, (CO.sub.2 A).sub.2, CN or halogen group. In such cases often R.sub.5 will be a methylene group substituted by one of these groups.
The compounds of the formula (I) may form conventional salts. Such salts include those with alkali and alkaline earth metals, suitably sodium and potassium, and ammonium and substituted ammonium salts.
From the aforesaid it will be seen that one particularly suitable group of compounds within formula (I) is of formula (II): ##STR6## wherein: X and R.sub.1 are as defined in formula (I);
n.sup.1 is 5, 6 or 7;
R.sup.1.sub.2 is hydrogen, methyl, ethyl or phenyl;
R.sup.1.sub.4 is hydrogen or C.sub.1-9 alkyl;
R.sup.1.sub.5 is C.sub.1-6 alkyl, phenyl, phenyl-C.sub.1-6 alkyl, or a group CO.sub.2 A wherein A is hydrogen or CO.sub.2 A represents an ester group in which the A moiety contains from 1 to 12 carbon atoms; and salts thereof.
In formula (II) n.sup.1 is preferably 6. Also suitably X is O.
R.sup.1.sub.2 is more suitably hydrogen, methyl or ethyl, preferably methyl.
While R.sup.1.sub.4 may be hydrogen or a C.sub.1-9 alkyl group, it is normally a C.sub.4-9 alkyl group. In such cases suitable and preferred straight chain and branched groups R.sup.1.sub.4 include those previously described as suitable and preferred for the groups R.sub.4 when R.sub.4 is a C.sub.4-9 alkyl group. Such preferred groups R.sup.1.sub.4 include straight chain pentyl, hexyl and heptyl, and of these normally the most useful is straight chain hexyl. Other preferred groups R.sup.1.sub.4 include CH(CH.sub.3)R.sup.1.sub.7 and C(CH.sub.3).sub.2 R.sup.1.sub.7 wherein R.sup.1.sub.7 is straight chain butyl, pentyl or hexyl.
Suitably R.sup.1.sub.5 is C.sub.1-6 alkyl such as methyl and ethyl.
A second group of compounds within formula (I) of particular interest are those of formula (III): ##STR7## wherein: X and R.sub.1 are as defined in formula (I);
n.sup.1 is 5, 6 or 7;
R.sup.1.sub.2 is hydrogen, methyl, ethyl or phenyl;
R.sup.2.sub.4 is a group of formula (IV): ##STR8## wherein T is a bond, or a C.sub.1-6 alkylene group which may be straight chain or branched by one or two methyl groups at the same or different carbon atoms; and W, Y and Z are each hydrogen or fluorine, chlorine or bromine atoms, or CF.sub.3, methyl, ethyl, n- or iso-propyl, methoxy, ethoxy, n- or iso-propoxy or nitro groups;
R.sup.1.sub.5 is C.sub.1-6 alkyl, phenyl, phenyl-C.sub.1-6 alkyl, or a group CO.sub.2 A wherein A is hydrogen or CO.sub.2 A represents an ester group in which the A moiety contains from 1 to 12 carbon atoms; and salts thereof.
In formula (III) n.sup.1 is preferably 6. Also suitably X is O.
R.sup.1.sub.2 is more suitably hydrogen, methyl or ethyl, preferably methyl.
In formula (IV) often T will be a group --(CH.sub.2).sub.q -- wherein q is 0 to 4. Also suitably W and Y are hydrogen.
Suitably R.sup.1.sub.5 is C.sub.1-6 alkyl such as methyl and ethyl.
Another group of compounds within formula (I) of particular interest is of formula (V): ##STR9## wherein: X and R.sub.1 are as defined in formula (I);
n.sup.1 is 5, 6 or 7;
R.sup.1.sub.2 is hydrogen, methyl, ethyl or phenyl;
R.sup.3.sub.4 is a group of formula (VI): ##STR10## wherein T, W, Y and Z are as defined in formula (IV);
R.sup.1.sub.5 is C.sub.1-6 alkyl, phenyl, phenyl-C.sub.1-6 alkyl, or a group CO.sub.2 A wherein A is hydrogen or CO.sub.2 A represents an ester group in which the A moiety contains from 1 to 12 carbon atoms; and salts thereof.
In formula (V) n.sup.1 is preferably 6. Also suitably X is O.
R.sup.1.sub.2 is more suitably hydrogen, methyl or ethyl, preferably methyl.
In formula (V) often T will be a group --(CH.sub.2).sub.q -- wherein q is 0 to 4. Also suitably W and Y are hydrogen.
Suitably R.sup.1.sub.5 is C.sub.1-6 alkyl such as methyl and ethyl.
A further group of compounds within formula (I) of interest are of formula (VII): ##STR11## wherein: X and R.sub.1 are as defined in formula (I);
n.sup.1 is 5, 6 or 7;
R.sup.1.sub.2 is hydrogen, methyl, ethyl or phenyl;
R.sup.4.sub.4 is a group of formula (VIII): ##STR12## wherein T is as defined in formula (IV) and
r is 0 to 3;
R.sup.1.sub.5 is C.sub.1-6 alkyl, phenyl, phenyl-C.sub.1-6 alkyl, or a group CO.sub.2 A wherein A is hydrogen or CO.sub.2 A represents an ester group in which the A moiety contains from 1 to 12 carbon atoms; and salts thereof.
In formula (VII) n.sup.1 is preferably 6. Also suitably X is O.
R.sup.1.sub.2 is more suitably hydrogen, methyl, or ethyl, preferably methyl.
In formula (VIII) often T will be a group --(CH.sub.2).sub.q -- wherein q is 0 to 4. Also suitably r is 1.
Suitably R.sup.1.sub.5 is C.sub.1-6 alkyl such as methyl and ethyl.
One compound of the invention that is particularly preferred for its useful activity is 1-(3'-hydroxy-3'-methyl-n-nonyl)-3-methyl-5-(6"-carboxy-n-hexyl)hydantoin.
The present invention further provides a process for the preparation of the compounds of the formula (I), which process comprises the cyclisation of a compound of formula (IX): ##STR13## wherein the variable groups are as defined; and thereafter if desired or necessary converting R.sub.1 and/or R.sub.3 in the thus formed compound into other variables R.sub.1 and R.sub.3.
Compounds of the formula (IX) are conveniently prepared in situ during the reaction of a compound of the formula: ##STR14## wherein n, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are as defined, with R.sub.5 NCX, a preferred process of the invention. This process is suitably carried out under reflux in an inert solvent such as benzene and the like. It should be stated that when in this reaction R.sub.5 is a sterically hindered group then this reaction may proceed only as far as the uncyclised compound of formula (IX), in which case the necessary cyclisation of the compound (IX) can be achieved with a strong base, such as sodium hydride or sodium ethoxide, in a dry organic solvent. Sodium ethoxide in benzene, or potassium t-butoxide in toluene, benzene or hexamethyl phosphoramide are suitable reagents.
The conversion of a compound of the formula (I) to another compound of the formula (I) wherein R.sub.1 and/or R.sub.3 are altered when desired or necessary, may be achieved in conventional manner.
For example, if desired the group R.sub.1 in the compound may be varied by conventional esterification and/or de-esterification reactions. Similarly protected R.sub.3 hydroxy moieties may be deprotected in conventional manner. For example when R.sub.3 is a benzyloxy group, the benzyl group may readily be removed by hydrogenolysis. Thus it may be seen that `protected hydroxy` compounds of the formula (I) are useful intermediates in the preparation of the corresponding `free hydroxy` compounds of the formula (I). Also when a compound of the formula (I) contains an acidic hydrogen atom, salts thereof may be prepared in conventional manner for example by reacting the compound of the formula (I) with the required base.
Also intermediates of the formula (I) which however are unsubstituted in the 3-position may be converted to the corresponding compounds of this invention wherein R.sub.5 is as defined above by conventional substitution reactions with R.sub.5 X wherein X is a displaceable group such as a halide or other good leaving group. In such reactions it may be necessary to first convert the unsubstituted compound to an alkali metal salt.
The skilled man will realise that in some such cases substitutions will also substitute a R.sub.1 hydrogen. Thus if a compound is desired wherein R.sub.1 is hydrogen, in such cases it will be preferred to esterify the R.sub.1 hydrogen before the substitution reaction, and then de-esterify after the substitution reaction, to give the desired R.sub.1 hydrogen compound.
Intermediates of formula (I) which are unsubstituted in the 3-position can be obtained through the reaction of a compound of formula (X) with an isocyanate or isothiocyanate.
When R.sub.1 is hydrogen, this cyclisation may suitably be carried out by reacting a salt M.sup.+ C.sup.- NX, wherein M.sup.+ is a metal ion and X is O or S as defined, with a compound of formula (X). The metal salt of a compound of formula (IX) thus obtained can be converted to the acid of formula (IX) with mineral acid, and then the cyclisation completed in aqueous conditions at acid pH, for example in 25% aqueous acid. Suitably M.sup.+ is a sodium or potassium ion, preferably a potassium ion.
When R.sub.1 is other than hydrogen a compound of formula (X) is cyclised by reaction with M.sup.+ C.sup.- NX. This conversion may suitably be achieved using a hydrochloride salt of the compound of the formula (X) and reacting that salt in aqueous solution at reflux, or in aqueous dichloromethane with a phase transfer catalyst.
It is believed that the compounds of formula (IX) are novel, and thus they form an important part of this invention as intermediates.
The compounds of the formula (X) may be prepared by the method disclosed in Belgian Pat. No. 835989, or by analogous methods thereto.
It will of course be realised that the compounds of the formula (I) have asymmetric centres, and thus are capable of existing in a number of stereoisomeric forms. The invention extends to each of these stereoisomeric forms, and to mixtures thereof. The different stereoisomeric forms may be separated one from the other by the usual methods.
Compounds within the formula (I) have useful pharmacological activity. For example compounds within the formula (I) have anti-gastric secretion activity e.g. anti-ulcer activity, cardiovascular activity e.g. anti-hypertensive activity, platelet aggregration inhibition activity, affect the respiratory tract e.g. bronchodilator activity, and have anti-fertility, smooth muscle and anti-arrythmic activity.
In general it may be said that compounds within the formula (I) have a range of pharmacological activities similar to those shown by the natural prostaglandins, but that these activities tend to be rather more selective.
The invention therefore also provides a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable carrier.
Clearly the formulation of the said pharmaceutical composition will depend on the nature of the activity shown by the chosen compound of the formula (I), and on other factors such as a preference in a particular area of therapy for a particular mode of administration.
The compositions may be in the form of tablets, capsules, powders, granules, lozenges or liquid preparations, such as oral or sterile parenteral solutions of suspensions.
Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, fillers, tabletting lubricants, disintegrants, and acceptable wetting agents and the like. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and if desired conventional flavouring or colouring agents, and the like.
For parenteral administration, fluid unit dosage forms are prepared utilizing the compound of the formula (I) and a sterile vehicle. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved for injection and filter sterilized before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents can be dissolved in the vehicle. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
When appropriate, the compositions of this invention may be presented as an aerosol for oral administration, or as a microfine powder for insufflation.
As is common practice, the compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.
It will of course be realised that the precise dosage used in the treatment of any of the hereinbefore described disorders will depend on the actual compound of the formula (I) used, and also on other factors such as the seriousness of the disorder being treated.
The invention also provides a method of treatment and/or propylaxis of disorders in human beings or animals which comprises the administration to the sufferer of an effective amount of a compound of the formula (I).
Normally however the compounds will be used in the therapy of human disorders.
The following Examples illustrate the preparation of compounds of the formula (I) and their pharmacological properties.

EXAMPLE 1 ##STR15##
Dimethyl 2-[N-3'-hydroxy-3'-methyl-n-decyl]aminoazelate (9.6 g) was refluxed with methyl iso-cyanate (1.365 g) for 3 hours in dry benzene (80 mls). The benzene was evaporated in vacuo to give a pale yellow gum (10.2 g). This was chromatographed on kieselgel (packing ratio 30:1), using chloroform as eluant to give 1-(3'-hydroxy-3'-methyl-n-decyl)-3-methyl-5-(6"-methoxycarbonyl-n-hexyl)hydantoin as a clear oil (6 g).
The compounds shown in Table 1 were prepared in a similar manner.
Table I______________________________________ ##STR16##Compoundnumber R.sub.1 R.sub.2 R.sub.4 R.sub.5 n______________________________________2 C.sub.2 H.sub.5 CH.sub.3 C.sub.6 H.sub.13 C.sub.2 H.sub.5 63 C.sub.2 H.sub.5 CH.sub.3 C.sub.6 H.sub.13 CH.sub.3 64 CH.sub.3 ##STR17## CH.sub.3 65 CH.sub.3 CH.sub.3 (CH.sub.2).sub.2 Ph CH.sub.3 66 CH.sub.3 CH.sub.3 C.sub.6 H.sub.13 CH.sub.3 67 CH.sub.3 CH.sub.3 CH(CH.sub.3)C.sub.4 H.sub.9 CH.sub.3 68 CH.sub.3 CH.sub.3 Ph CH.sub.3 69 CH.sub.3 CH.sub.3 C.sub.6 H.sub.13 Ph 610 CH.sub.3 CH.sub.3 ##STR18## CH.sub.3 611 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 612 CH.sub.3 CH.sub.3 C.sub.6 H.sub.13 ##STR19## 635 CH.sub.3 CH.sub.3 C.sub.6 H.sub.13 ##STR20## 636 C.sub.2 H.sub.5 CH.sub.3 C.sub.6 H.sub.13 CH.sub.3 737 C.sub.2 H.sub.5 CH.sub.3 C.sub.6 H.sub.13 CH.sub.3 538 CH.sub.3 CH.sub.3 C.sub.6 H.sub.13 CH.sub.3 1______________________________________
example 2 ##STR21##
Dimethyl 2-[N-(3'-hydroxy-3'-methyl)-n-nonyl]aminoazelate (20 g) was refluxed with t-butyl isocyanate (5.12 g) in dry benzene (200 ml) for 3 hours. The benzene was evaporated in vacuo to give a pale yellow gum (20 g). The gum was chromatographed on kieselgel (600 g) using chlorogorm as eluant to give dimethyl 2-[N-(3'-hydroxy-3'-methyl-n-nonyl)-N-(N'-t-butylformamido)]aminoazelate (11.6 g) as a clear gum.
EXAMPLE 3 ##STR22##
Dimethyl 2-[N-(3'-hydroxy-3'-methyl-n-nonyl)-N-(N'-t-butylformamido)]aminoazelate (10 g) was refluxed with potassium t-butoxide (2.5 g) in dry toluene (150 ml) for 3 hours. The toluene was evaporated in vacuo and the resulting gum was partitioned between ether and very dilute hydrochloric acid. The ether solution was washed with brine then dried (MgSO.sub.4) and evaporated in vacuo to give a yellow gum (8.4 g). The gum was chromatographed on kieselgel (250 g) using chloroform as eluant to give 1-(3'-hydroxy-3'-methyl-n-nonyl)-3-t-butyl-5-(6"-methoxycarbonyl-n-hexyl)hydantoin (5.2) as a clear gum.
EXAMPLE 4 ##STR23##
Dimethyl 2-[N-3'-benzyloxy-n-nonyl]aminoazelate (20 g) was refluxed with methyl iso-cyanate (2.46 g) in dry benzene (200 ml) for 3 hours. The benzene was evaporated in vacuo to give a deep yellow oil which was chromatographed on kieselgel (30:1 packing ratio), using chloroform as eluant, to give 1-(3'-benzyloxy-n-nonyl)3-methyl-5-(6"-methoxycarbonyl-n-hexyl)hydantoin (9 g) as a colourless gum.
EXAMPLE 5 ##STR24##
1-(3'-hydroxy-3'-methyl-n-nonyl)-3-ethyl-5-(6"-ethoxycarbonyl-n-hexyl)hydantoin (1.1 g) was refluxed overnight with 10% aqueous potassium carbonate solution (7.5 ml) and ethanol (30 ml). The solution was cooled and acidified with concentrated hydrochloric acid. The product was extracted into ether (3 .times. 100 ml). The ether solution was extracted with 5% sodium bicarbonate solution. The resulting aqueous phase was back-washed with ether then was acidified with dilute hydrochloric acid. The product was extracted into ether and the ether solution was washed with brine, dried (MgSO.sub.4) and evaporated in vacuo to give 1-(3'-hydroxy-3'-methyl-n-nonyl)-3-ethyl-5-(6"-carboxy-n-hexyl)hydantoin as a colourless gum (770 mg).
The compounds shown in Table 2 were prepared in a similar manner.
Table 2______________________________________ ##STR25##Compoundnumber R.sub.2 R.sub.4 R.sub.5 n______________________________________17 CH.sub.3 C.sub.7 H.sub.15 CH.sub.3 618 CH.sub.3 C.sub.2 H.sub.5 CH.sub.3 619 ##STR26## CH.sub.3 620 CH.sub.3 (CH.sub.2).sub.2 Ph CH.sub.3 621 CH.sub.3 C.sub.6 H.sub.13 CH.sub.3 622 CH.sub.3 CH(CH.sub.3)C.sub.4 H.sub.9 CH.sub.3 623 CH.sub.3 Ph CH.sub.3 624 H C.sub.6 H.sub.13 CH.sub.3 625 CH.sub.3 C.sub.6 H.sub.13 C(CH.sub.3).sub.3 626 CH.sub.3 C.sub.6 H.sub.13 Ph 627 CH.sub.3 ##STR27## CH.sub.3 628 CH.sub.3 CH.sub.3 CH.sub.3 629 CH.sub.3 C.sub.6 H.sub.13 ##STR28## 639 CH.sub.3 C.sub.6 H.sub.13 ##STR29## 640 CH.sub.3 C.sub.6 H.sub.13 CH.sub.3 741 CH.sub.3 C.sub.6 H.sub.13 CH.sub.3 542 CH.sub.3 C.sub.6 H.sub.13 CH.sub.3 148 CH.sub.3 C.sub.6 H.sub.13 CH.sub.2 OCH.sub.3 649 CH.sub.3 C.sub.6 H.sub.13 CH.sub.2 CO.sub.2 H 6______________________________________
example 6 ##STR30##
Dimethyl 2-[N-3'-hydroxy-3'-methyl-n-nonyl]aminoazelate (10 g) was refluxed with methyl iso-thiocyanate (1.89 g) in dry toluene (100 ml) for 3 hours. The toluene was evaporated in vacuo to give a yellow oil (11.1 g). The oil was chromatographed on kieselgel (330 g) using chloroform as eluant to give 1-(3'-hydroxy-3'-methyl-n-nonyl)-3-methyl-5-(6"-methoxycarbonyl-n-hexyl)-2-thiohydantoin (9.49 g) as a pale yellow oil.
The compounds shown in Table 3 were prepared in a similar manner:
Table 3______________________________________ ##STR31##Compound No. R.sub.1 R.sub.2 R.sub. 4 R.sub.5______________________________________31 C.sub.2 H.sub.5 CH.sub.3 C.sub.6 H.sub.13 CH.sub.332 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3______________________________________
example 8 ##STR32##
1-(3'-Benzyloxy-n-nonyl)-3-methyl-5-(6"-methoxycarbonyl-n-hexyl)hydantoin (5g) was hydrogenolysed over 10% palladium/charcoal, in dry dimethoxyethane (50 mls), at room temperature and atmospheric pressure. The reaction mixture was then filtered through kieselguhr and the dimethoxyethane was evaporated in vacuo to give a colourless oil (3.8g). The oil was chromatographed on silica gel (110g) using chloroform as eluant to give 1-(3'-hydroxy-n-nonyl)-3-methyl-5-(6"-methoxycarbonyl-n-hexyl)hydantoin as a colourless oil (2.48g).
EXAMPLE 9 ##STR33##
Dry hydrogen chloride gas was passed into an ice-cold solution of dimethyl 2-[N-(3'-hydroxy-3'-methyl)-n-nonyl] aminoazelate (40 g) in dry ether (1 l). The ether was evaporated in vacuo and the resulting hydrochloride was stirred with water (300 ml). A solution of potassium cyanate (8.2 g; 1.01 eq) in water (20 ml) was added and the resulting suspension was stirred at room temperature for 1.5 hours then at reflux for 1.5 hours. The mixture was allowed to cool and the product was extracted into dichloromethane. The dichloromethane solution was washed with brine until the washings were neutral then was dried and evaporated to give a yellow gum (38 g). A sample was purified via column chromatography (silica gel; 30:1) using chloroform, and chloroform methanol mixtures as eluants to give 1-(3'-hydroxy-3'-methyl-n-nonyl)-5-(6"-methoxycarbonyl-n-hexyl) hydantoin as a pale yellow gum.
EXAMPLE 9 ##STR34##
1-(3'-Hydroxy-3'-methyl-n-nonyl)-5-(6"-methoxycarbonyl-n-hexyl) hydantoin (5g) in dry dimethylformamide (10 ml) was added to a stirred suspension of sodium hydride (376 mg; 80% oil dispersion) in dry dimethyl-formamide (20 ml), under nitrogen, at room temperature. The mixture was stirred overnight. Chloromethyl methyl ether (1.01 g) in dry dimethylformamide (10 ml) was added dropwise and the mixture was stirred for 24 hours at room temperature. The product was partitioned between very dilute hydrochloric acid and ether. The ether solution was washed with 5% aqueous sodium hydroxide solution, and with brine until the washings were neutral, then was dried and evaporated in vacuo to give a yellow oil (4.1 g). The oil was chromatographed on silica gel (30:1) using chloroform, 1% methanol/chloroform and 2% methanol/chloroform as eluants to give 1-(3'-hydroxy-3'-methyl-n-nonyl)-3-methoxymethyl-5-(6"-methoxycarbonyl-n-hexyl) hydantoin (2.5 g) as a pale yellow gum.
The compounds prepared in Table 7 were prepared in a similar manner.
Table 7______________________________________ ##STR35##Compoundnumber R.sub.5 X R.sub.5______________________________________45 BrCH.sub.2 CO.sub.2 CH.sub.3 CH.sub.2 CO.sub.2 CH.sub.346 BrCH.sub.2 CN CH.sub.2 CN 47* BrCH(CO.sub.2 CH.sub.3).sub.2 CH(CO.sub.2 CH.sub.3).sub.251 BrCH.sub.2 Ph CH.sub.2 Ph______________________________________ *The alkali extraction procedure was eliminated.
EXAMPLE 10 ##STR36##
A 1% solution of sodium hydroxide in dry methanol (1 equivalent) was added to a solution of 1-(3'-hydroxy-3'-methyl-n-nonyl)-3-methyl-5-(6"-carboxy-n-hexyl) hydantoin in dry methanol at room temperature. The methanol was evaporated in vacuo at 30.degree. C. and the product was triturated with 40/60 petroleum ether. The product was collected and dried over sodium hydroxide in a vacuum desiccator then was ground to a fine, pale yellow powder.
In similar manner was prepared the corresponding lithium salt.
______________________________________Analytical DataCompound 1______________________________________I.R. (cm.sup.-1) : ##STR37## 1730, [CO.sub.2 CH.sub.3 ],NMR, (.tau.) : 7.15, (s), [OH]; ##STR38## ##STR39## 6.35, (s). [CO.sub.2 CH.sub.3 ]; ##STR40##______________________________________
analysis: C.sub.23 H.sub.42 N.sub.2 O.sub.5
requires: C, 64.76; H, 9.92; N, 6.57%.
found: C, 64.44; H, 9.92; N, 6.71%.
mass Spec: C.sub.23 H.sub.42 N.sub.2 O.sub.5
requires: 426.3093
found: 426.3065
______________________________________Compound 2______________________________________I.R. (cm.sup.-1) : ##STR41## 1730, [CO.sub.2 Et]NMR (.tau.) : 7.2, (s) [OH]; 6.2 to 6.8, (m),(CCl.sub.4) ##STR42## ##STR43##______________________________________
______________________________________compound 3______________________________________I.R. (cm.sup.-1) : ##STR44## 1730, [CO.sub.2 Et]NMR (.tau.) : ##STR45## ##STR46## ##STR47##______________________________________
______________________________________compound 4______________________________________I.R. (cm.sup.-1) : 3500, [OH]; 1700, 1760, ##STR48## 1720, [CO.sub.2CH.sub.3 ].NMR (.tau.) : ##STR49## ##STR50## 6.35, (s), [CO.sub.2 CH.sub.3 ] ##STR51##______________________________________
analysis: C.sub.20 H.sub.34 N.sub.2 O.sub.5
requires: C, 62.80; H, 8.96; N, 7.32%
found: C, 62.61; H, 8.95; N, 7.19%
mass Spec: C.sub.20 H.sub.34 N.sub.2 O.sub.5
requires: 382.2468
found: 382.2466
______________________________________Compound 5______________________________________I.R. (cm.sup.-1) : 3500, [OH]; 1700, 1760, ##STR52## 1730, [CO.sub.2 CH.sub.3 ].NMR (.tau.) : 7.75, (t), [CH.sub.2 CO.sub.2 CH.sub.3 ]; 7.3, (m), [CH.sub.2 Ph]; 7.1, (s), [OH]; ##STR53## ##STR54## 6.5, (s), [CO.sub.2 CH.sub.3 ]; ##STR55##______________________________________
mass Spec: C.sub.24 H.sub.34 N.sub.2 O.sub.4 [m*-H.sub.2 O]
requires: 414.2518
found: 414.2523
______________________________________Compound 6______________________________________I.R. (cm.sup.-1) : ##STR56## 1730, [CO.sub.2 CH.sub.3 ].NMR (.tau.) : 7.3, (s), [OH]; ##STR57## ##STR58## 6.35, (s), [CO.sub.2 CH.sub.3 ]; ##STR59##______________________________________
analysis: C.sub.22 H.sub.40 N.sub.2 O.sub.5
requires: C, 64.05; H, 9.77; N, 6.79%
found: C, 64.14; H, 9.68; N, 6.62%
mass Spec: C.sub.22 H.sub.38 N.sub.2 O.sub.4 [m*-H.sub.2 O]
requires: 394.2832
found: 394.2848
______________________________________Compound 7______________________________________I.R. (cm.sup.-1) : ##STR60## 1730, [CO.sub.2 CH.sub.3 ].NMR (.tau.) : 7.75, (m), [CH.sub.2 CO.sub.2 CH.sub.3 ]; 7.2, (s), [OH]; ##STR61## ##STR62## 6.35, (s), [CO.sub.2 CH.sub.3 ]; ##STR63##______________________________________
mass Spec: C.sub.22 H.sub.38 N.sub.2 O.sub.4 [m*-H.sub.2 O]
requires: 394.2831
found: 394.2794
______________________________________Compound 8I.R. (cm.sup.-1) : 3500, [OH]; 1700, 1760, ##STR64## 1730, [CO.sub.2 CH.sub.3 ].Compound 9I.R. (cm.sup.-1) : 3500 cm.sup.-1, [OH]; 1710, 1770, ##STR65## 1730, [CO.sub.2 CH.sub.3 ].NMR (.tau.) : 7.75, (t), [CH.sub.2 CO.sub.2 CH.sub.3 ]; 7.45, (s), [OH]; ##STR66## 6.37, (s), [CO.sub.2 CH.sub.3 ]; ##STR67## 2.65, (s), [C.sub.6 H.sub.5 ].______________________________________
mass Spec: C.sub.27 H.sub.42 N.sub.2 O.sub.5
requires: 474.3094
found: 474.3083
______________________________________ Compound 10______________________________________I.R. (cm.sup.-1) : ##STR68## 1730, [CO.sub.2 CH.sub.3 ].NMR (.tau.) : 7.8, (t), [CH.sub.2 CO.sub.2 CH.sub.3 ]; 7.3, (m), [CH.sub.2Ar]; ##STR69## ##STR70## 6.45, (s), [CO.sub.2 CH.sub.3 ]; ##STR71## 2.65, (broad s), [Ar].______________________________________
Mass Spec: C.sub.25 H.sub.33 N.sub.2 O.sub.4 F.sub.3 [m*-H.sub.2 O]
requires: 482.2392
found: 482.2415
______________________________________ Compound 11______________________________________I.R. (cm.sup.-1) : ##STR72## 1730, [CO.sub.2 CH.sub.3 ].NMR (.tau.) : 7.75, (t), [CH.sub.2CO.sub.2 CH.sub.3 ]; 7.15, (s), [OH]; ##STR73## ##STR74## 6.4, (s), [CO.sub.2 CH.sub.3 ]; 6.05, (m), [NCH].______________________________________
mass Spec: C.sub.17 H.sub.30 N.sub.2 O.sub.5
requires: 342.2154
found: 342.2144
Mass Spec: C.sub.17 H.sub.28 N.sub.2 O.sub.4 [m*-H.sub.2 O]
requires: 324.2049
found: 324.2050
______________________________________Compound 12______________________________________I.R. (cm.sup.-1): ##STR75## 1740, [CO.sub.2 CH.sub.3 ].NMR (.tau.): 7.75, (t), [CH.sub.2 CO.sub.2 CH.sub.3 ]; 7.1, (s), [OH]; ##STR76## 6.4, (s), [CO.sub.2 CH.sub.3 ]; ##STR77##______________________________________
mass Spec: C.sub.27 H.sub.48 N.sub.2 O.sub.5
requires: 480.3564
found: 480.3536
______________________________________Compound 13______________________________________I.R. (cm.sup.-1): 3400, [OH]; 1740, [CO.sub.2 CH.sub.3 ]; ##STR78##______________________________________
analysis: C.sub.26 H.sub.50 N.sub.2 O.sub.6
requires: C, 64.16; H, 10.36; N, 5.76%
found: C, 64.22; H, 10.69; N, 5.43%
mass Spec: C.sub.25 H.sub.44 N.sub.2 O.sub.4 [m*-H.sub.2 O-CH.sub.3 OH]
requires: 436.3301
found: 436.3293
______________________________________Compound 14______________________________________I.R. (cm.sup.-1): 3500, [OH]; ##STR79## 1735, [CO.sub.2 CH.sub.3 ].NMR (.tau.): 7.2, (s), [OH]; ##STR80## 6.3, (s), [CO.sub.2 CH.sub.3 ]; ##STR81##______________________________________
analysis: C.sub.25 H.sub.46 N.sub.2 O.sub.5
requires: C, 66.05; H, 10.20; N, 6.16%
found: C, 65.89; H, 10.30; N, 6.13%
mass Spec: C.sub.25 H.sub.46 N.sub.2 O.sub.5
requires: 454.3406
found: 454.3451
Mass Spec: C.sub.25 H.sub.44 N.sub.2 O.sub.4 [m*-H.sub.2 O]
requires: 436.3301
found: 436.3317
______________________________________Compound 15______________________________________I.R. (cm.sup.-1): ##STR82## 1730, [CO.sub.2 CH.sub.3 ].NMR (.tau.): ##STR83## ##STR84## 6.35, (s), [CO.sub.2 CH.sub.3 ]; ##STR85## 5.5, (s, with shoulder), [OCH.sub.2 Ph]; 2.75, (s), [OCH.sub.2 Ph].______________________________________
Analysis: C.sub.28 H.sub.44 N.sub.2 O.sub.5
requires: C, 68.82; H, 9.08; N, 5.73%
found: C, 68.62; H, 9.21; N, 5.66%
mass Spec: C.sub.28 H.sub.44 N.sub.2 O.sub.5
requires: 488.3250
found: 488.3287
______________________________________Compound 16______________________________________I.R. (cm.sup.-1): 3700, to 2500, [CO.sub.2 H; OH]; ##STR86##NMR (.tau.): ##STR87## 4.4 (broad s), [CO.sub.2 H; OH].______________________________________
mass Spec: C.sub.22 H.sub.40 N.sub.2 O.sub.5
requires: 412.2937
found: 412.2917
______________________________________Compound 17______________________________________I.R. (cm.sup.-1): 3700 to 2400, ##STR88## ##STR89##NMR (.tau.): ##STR90## ##STR91## ##STR92## 3.15, (broad s), [CO.sub.2 H; OH].______________________________________
analysis: C.sub.22 H.sub.40 N.sub.2 O.sub.5
requires: C, 64.05; H, 9.77; N, 6.79%
found: C, 64.36; H, 9.99; N, 6.99%
mass Spec: C.sub.22 H.sub.38 N.sub.2 O.sub.4 [m*-H.sub.2 O]
requires: 394.2831
found: 394.2848
______________________________________Compound 18______________________________________I.R. (cm.sup.-1): 3700 to 2500, [CO.sub.2 H; OH]; ##STR93##NMR (.tau.): ##STR94##(CD.sub.3).sub.2 CO ##STR95## ##STR96##______________________________________
mass Spec: C.sub.17 H.sub.30 N.sub.2 O.sub.5
requires: 342.2155
found: 342.2174
______________________________________Compound 19______________________________________I.R. (cm.sup.-1): 3700 to 2400, [CO.sub.2 H; OH] ##STR97##NMR (.tau.): ##STR98## ##STR99## 6.05, (broad s), [CO.sub.2 H; OH]; ##STR100##______________________________________
analysis: C.sub.19 H.sub.32 N.sub.2 O.sub.5
requires: C, 61.93; H, 8.75; N, 7.60%
found: C, 61.99; H, 8.97; N, 7.64%
mass Spec: C.sub.19 H.sub.32 N.sub.2 O.sub.5
requires: 368.2311
found: 368.2313
______________________________________Compound 20______________________________________I.R. (cm.sup.-1): 3700 to 2400, [CO.sub.2 H; OH]; ##STR101##NMR (.tau.): 7.3, (m), [CH.sub.2 Ph]; ##STR102## ##STR103## 6.15, (s), [CO.sub.2 H; OH]; ##STR104##______________________________________
analysis: C.sub.23 H.sub.34 N.sub.2 O.sub.5
requires: C, 66.01; H, 8.19; N, 6.69%
found: C, 65.82; H, 8.38; N, 6.37%
mass Spec: C.sub.23 H.sub.32 N.sub.2 O.sub.4 [m*-H.sub.2 O]
requires: 400.2362
found: 400.2323
______________________________________Compound 21______________________________________I.R. (cm.sup.-1) : 3700 to 2400, [CO.sub.2 H; OH]; ##STR105##NMR (.tau.) : ##STR106## ##STR107## 6.1, (s), [CO.sub.2 H; OH]; ##STR108##______________________________________
mass Spec: C.sub.21 H.sub.36 N.sub.2 O.sub.4 [m*-H.sub.2 O]
requires: 380.2675
found: 380.2672
______________________________________Compound 22______________________________________I.R. (cm.sup.-1) : 3700 to 2500, [CO.sub.2 H; OH]; ##STR109##NMR (.tau.) : ##STR110##(CD.sub.3).sub.2 CO ##STR111## ##STR112## 5 to 3, (broad hump), [CO.sub.2 H; OH].______________________________________
analysis: C.sub.21 H.sub.38 N.sub.2 O.sub.5
requires: C, 63.29; H, 9.61; N, 7.03%
found: C, 62.94; H, 9.79; N, 6.65%
mass Spec: C.sub.21 H.sub.36 N.sub.2 O.sub.4 [m*-H.sub.2 O]
requires: 380.2675
found: 380.2641
______________________________________Compound 23______________________________________I.R. (cm.sup.-1) : 3700 to 2500, [CO.sub.2 H, OH]; ##STR113##NMR (.tau.) : ##STR114## ##STR115## 5.6, (broad s), [CO.sub.2 H; OH]; 2.65, (m), [Ph].______________________________________
Analysis: C.sub.21 H.sub.30 N.sub.2 O.sub.5
requires: C, 64.60; H, 7.74; N, 7.17%
found: C, 64.83; H, 7.96; N, 6.91%
mass Spec: C.sub.21 H.sub.28 N.sub.2 O.sub.4 [m*-H.sub.2 O]
requires: 372.2049
found: 372.2037
______________________________________Compound 24______________________________________I.R. (cm.sup.-1) : 3700 to 2500, [CO.sub.2 H; OH]; ##STR116##NMR (.tau.) : ##STR117## ##STR118## ##STR119## 4.5, (broad), [CO.sub.2 H; OH].______________________________________
analysis: C.sub.20 H.sub.36 N.sub.2 O.sub.5
requires: C, 62.47; H, 9.44; N, 7.29%
found: C, 62.40; H, 9.59; N, 7.04%
mass Spec: C.sub.20 H.sub.36 N.sub.2 O.sub.5
requires: 384.2624
found: 384.2640
______________________________________Compound 25______________________________________I.R. (cm.sup.-1) : 3700 to 2400, [CO.sub.2 H; OH]; ##STR120##NMR (.tau.) : 6.7, (s), [CO.sub.2 H; OH]; ##STR121## ##STR122##______________________________________
analysis: C.sub.24 H.sub.44 N.sub.2 O.sub.5
requires: C, 65.42; H, 10.07; N, 6.36%
found: C, 65.21; H, 10.29; N, 6.08%
mass Spec: C.sub.24 H.sub.44 N.sub.2 O.sub.5
requires: 440.3250
found: 440.3280
______________________________________Compound 25______________________________________I.R. (cm.sup.-1) : 3200 to 2600, [CO.sub.2 H; OH]; ##STR123##NMR (.tau.) : ##STR124## 5.95, (broad), [CO.sub.2 H; OH]; ##STR125## 2.6, (d), [Ph].______________________________________
Mass Spec: C.sub.26 H.sub.38 N.sub.2 O.sub.4 [m*-H.sub.2 O]
requires: 442.2832
found: 442.2841
______________________________________Compound 27______________________________________I.R. (cm.sup.-1) : 3200 to 2400, [CO.sub.2 H; OH]; ##STR126##NMR (.tau.) : 7.8, (t), [CH.sub.2CO.sub.2 H];D.sub.6 DMSO 7.4, (m), [CH.sub.2Ar]; ##STR127## ##STR128## ##STR129##______________________________________
analysis: C.sub.24 H.sub.33 N.sub.2 O.sub.5 F.sub.3
requires: C, 59.25; H, 6.83; N, 5.76%
found: C, 59.29; H, 7.13; N, 5.82%
mass Spec: C.sub.24 H.sub.31 N.sub.2 O.sub.4 F.sub.3 [m*-H.sub.2 O]
requires: 468.2236
found: 468.2245
______________________________________Compound 28______________________________________I.R. (cm.sup.-1) : 3200 to 2400, [CO.sub.2 H; OH]; ##STR130##NMR (.tau.) : 7.75, (t), [CH.sub.2CO.sub.2 H];(D.sub.6 DMSO) ##STR131## ##STR132## ##STR133##______________________________________
analysis: C.sub.16 H.sub.28 N.sub.2 O.sub.5
requires: C, 58.52; H, 8.59; N, 8.53%
found: C, 58.59; H, 8.71; N, 8.70%
mass Spec: C.sub.16 H.sub.28 N.sub.2 O.sub.5
requires: 328.1998
found: 328.1995
______________________________________Compound 29______________________________________I.R. (cm.sup.-1) : 3200 to 2400, [CO.sub.2 H; OH]; ##STR134##NMR (.tau.) : ##STR135##(CD.sub.3).sub.2 CO 6.1, (broad s), [CO.sub.2 H; OH]; ##STR136## ##STR137##______________________________________
analysis: C.sub.26 H.sub.46 N.sub.2 O.sub.5
requires: C, 66.92; H, 9.94; N, 6.00%
found: C, 66.57; H, 10.06; N, 6.25%
mass Spec: C.sub.26 H.sub.46 N.sub.2 O.sub.5
requires: 466.3406
found: 466.3403
______________________________________Compound 30______________________________________I.R. (cm.sup.-1) : 3510, [OH]; 1750 to 1720, ##STR138##NMR (.tau.) : 7.75, (m), [OH; CH.sub.2CO.sub.2 CH.sub.3 ]; ##STR139## ##STR140## 6.35, (s), [CO.sub.2 CH.sub.3 ]; 5.9, (m), [NCH].______________________________________
analysis: C.sub.22 H.sub.40 N.sub.2 O.sub.4 S
requires: C, 61.64; H, 9.41; N, 6.53; S, 7.48%
found: C, 61.71; H, 9.51; N, 6.54; S, 7.34%
mass Spec: C.sub.22 H.sub.38 N.sub.2 O.sub.3 S [m*-H.sub.2 O]
requires: 410.2603
found: 410.2610
______________________________________Compound 31______________________________________I.R. (cm.sup.-1) : ##STR141##NMR (.tau.) : 7.7, (s), [OH]; ##STR142## ##STR143## ##STR144##______________________________________
analysis: C.sub.23 H.sub.42 N.sub.2 O.sub.4 S
requires: C, 62.41; H, 9.56; N, 6.33; S, 7.24%
found: C, 62.54; H, 9.85; N, 6.05; S, 7.35%
mass Spec: C.sub.23 H.sub.42 N.sub.2 O.sub.4 S
requires: 442.2865
found: 442.2866
______________________________________Compound 32______________________________________I.R. (cm.sup.-1) : 3500, [OH]; 1740, 1720, ##STR145##NMR (.tau.) : 7.45, (s), [OH]; ##STR146## ##STR147## 6.4, (s), [CO.sub.2 CH.sub.3 ]; ##STR148##______________________________________
mass Spec: C.sub.17 H.sub.30 N.sub.2 O.sub.4 S
requires: 358.1926
found: 358.1956
______________________________________Compound 34______________________________________I.R. (cm.sup.-1) : 3500, [OH]; 1760, 1710, ##STR149##NMR (.tau.) : ##STR150## ##STR151## 6.35, (s), [CO.sub.2 CH.sub.3 ]; ##STR152##______________________________________
analysis: C.sub.21 H.sub.38 N.sub.2 O.sub.5
requires: C, 63.29; H, 9.61; N, 7.03%
found: C, 63.61; H, 9.83; N, 7.34%
mass Spec: C.sub.21 H.sub.38 N.sub.2 O.sub.5
requires: 398.2780
found: 398.2769
______________________________________Compound 35______________________________________I.R. (cm.sup.-1) : 3550, [OH]; 1770, 1730 (broad) ##STR153##NMR (.tau.) : 7.75 (t), [CH.sub.2 CO.sub.2 CH.sub.3 ]; 7.35, (m), [Ph-CH]; 7.35, (s), [OH]; ##STR154## 6.4, (s), [CO.sub.2 CH.sub.3 ]; ##STR155## 2.7, (s), [Ph].______________________________________
Mass Spec: C.sub.30 H.sub.44 N.sub.2 O.sub.4 (m*-H.sub.2 O)
requires: 496.3301
found: 496.3303
______________________________________Compound 36______________________________________I.R. (cm.sup.-1) : ##STR156## 1730, [CO.sub.2 C.sub.2 H.sub.5 ].NMR (.tau.) : 7.7 (t), [CH.sub.2 CO.sub.2 C.sub.2 H.sub.5 ]; 7.5, (s), [OH]; ##STR157## ##STR158## ##STR159## ##STR160##______________________________________
mass Spec: C.sub.24 H.sub.42 N.sub.2 O.sub.4 (m*-H.sub.2 O)
requires: 422.3144
found: 422.3156
______________________________________Compound 37______________________________________I.R. (cm.sup.-1) : ##STR161## 1720, [CO.sub.2 C.sub.2 H.sub.5 ].NMR (.tau.) : 7.75, (t), [CH.sub.2 CO.sub.2 C.sub.2 H.sub.5 ]; 7.5, (s), [OH]; ##STR162## ##STR163## ##STR164## 5.9, (q), [CO.sub.2 CH.sub.2 CH.sub.3 ].______________________________________
mass Spec: C.sub.22 H.sub.38 N.sub.2 O.sub.4 (m*-H.sub.2 O)
requires: 394.2832
found: 394.2826
______________________________________Compound 38______________________________________I.R. (cm.sup.-1) : ##STR165## 1740, [CO.sub.2 CH.sub.3 ].NMR (.tau.) : 7.75, (s), [OH]; 7.1, (m), [CH.sub.2 CO.sub.2 CH.sub.3 ]; ##STR166## ##STR167## 6.25, (s), [CO.sub.2 CH.sub.3 ]; ##STR168##______________________________________
mass Spec: C.sub.17 H.sub.28 N.sub.2 O.sub.4 (m*-H.sub.2 O)
requires: 324.2048
found: 324.2056
______________________________________Compound 39______________________________________I.R. (cm.sup.-1) : 3700 to 2500, [CO.sub.2 H; OH]; ##STR169##NMR (.tau.) : 7.7, (m), [CH.sub.2 CO.sub.2 H]; 7.3 (m), (Ph-CH]; ##STR170## ##STR171## 5.7, (broad s), [CO.sub.2 H; OH]; 2.75, (s), [Ph].______________________________________
Mass Spec: C.sub.29 H.sub.42 N.sub.2 O.sub.4 (m*-H.sub.2 O)
requires: 482.3145
found: 482.3184
Analysis: C.sub.29 H.sub.44 N.sub.2 O.sub.5
requires: C, 69.57; H, 8.86; N, 5.60%.
found: C, 69.83; H, 9.05; N, 5.32%.
______________________________________Compound 40______________________________________I.R. (cm.sup.-1) : 3800 to 2500, [CO.sub.2 H; OH]; ##STR172##NMR (.tau.) : 7.7, (t), [CH.sub.2 CO.sub.2 H]; ##STR173## ##STR174## 6.2, (broad s), [CO.sub.2 H; OH]; ##STR175##______________________________________
mass Spec: C.sub.22 H.sub.38 N.sub.2 O.sub.4 (m*-H.sub.2 O)
requires: 394.2831
found: 394.2823
Analysis: C.sub.22 H.sub.40 N.sub.2 O.sub.5
requires: C, 64.05; H, 9.77; N, 6.79%.
found: C, 63.98; H, 9.97; N, 6.57%.
______________________________________Compound 41______________________________________I.R. (cm.sup.-1) : 3700 to 2500, [CO.sub.2 H; OH]; ##STR176##NMR (.tau.) : 7.8, (t), [CH.sub.2 CO.sub.2 H]; ##STR177## ##STR178## ##STR179## 4.6 to 3.3, (hump), [CO.sub.2 H; OH].______________________________________
mass Spec: C.sub.20 H.sub.34 N.sub.2 O.sub.4 (m*-H.sub.2 O)
requires: 366.2518
found: 366.2513
Compound 42
Mass Spec: C.sub.16 H.sub.26 N.sub.2 O.sub.4 (m*-H.sub.2 O)
requires: 310.1892
found: 310.1891
______________________________________Compound 43______________________________________I.R. (cm.sup.-1) : 3500, [OH]; 3300, [NH]; ##STR180## 1730, [CO.sub.2 CH.sub.3 ].NMR (.tau.) : 7.85, (m), [CH.sub.2 CO.sub.2 CH.sub.3 ]; ##STR181## 6.4, (s), [CO.sub.2 CH.sub.3 ]; ##STR182##______________________________________
mass Spec: C.sub.21 H.sub.36 N.sub.2 O.sub.4 (m*-H.sub.2 O)
requires: 380.2675
found: 380.2659
______________________________________Compound 44______________________________________I.R. (cm.sup.-1) : 3500, [OH]; 1770, 1720 (broad), ##STR183##NMR (.tau.) : 7.8, (t), [CH.sub.2 CO.sub.2 CH.sub.3 ]; 7.3, (s), [OH]; ##STR184## 6.6, (s), (OCH.sub.3 ]; 6.3, (s), [CO.sub.2 CH.sub.3 ]; ##STR185## 5.2, (s), [CH.sub.2 OCH.sub.3 ].______________________________________
mass Spec: C.sub.23 H.sub.40 N.sub.2 O.sub.5 (m*-H.sub.2 O)
requires: 424.2937
found: 424.2942.
______________________________________Compound 45______________________________________I.R. (cm.sup.-1) : 3550, [OH]; 1760 to 1710, (broad), ##STR186##NMR (.tau.) : 7.75, (t), [CH.sub.2 CO.sub.2 CH.sub.3 ]; 7.4, (s), [OH]; ##STR187## 6.4, (s), [CO.sub.2 CH.sub.3 ]; 6.25, (s), [CO.sub.2 CH.sub.3 ]; ##STR188##______________________________________
mass Spec: C.sub.24 H.sub.40 N.sub.2 O.sub.6 (m*-H.sub.2 O)
requires: 452.2886
found: 452.2892
______________________________________Compound 46______________________________________I.R. (cm.sup.-1) : 3500, [OH]; 1765, 1720 (broad), ##STR189##NMR (.tau.) : 7.7, (t), [CH.sub.2 CO.sub.2 CH.sub.3 [; 7.3, (s), [OH]; ##STR190## 6.35, (s), [CO.sub.2 CH.sub.3 ]; ##STR191## 5.65, (s), [CH.sub.2 CN].______________________________________
mass Spec: C.sub.23 H.sub.37 N.sub.3 O.sub.4 (m*-H.sub.2 O)
requires: 419.2784
found: 419.2771
Analysis: C.sub.23 H.sub.39 N.sub.3 O.sub.5
requires: C, 63.13; H, 8.98; N, 9.60%.
found: C, 63.21; H, 9.13; N, 9.31%.
______________________________________Compound 47______________________________________I.R. (cm.sup.-1) : 3500, [OH]; 1730, (very broad), ##STR192##NMR (.tau.) : 7.75 (t), [CH.sub.2 CO.sub.2 CH.sub.3 ]; 7.6, (s), [OH]; ##STR193## 6.4, (s), [CO.sub.2 CH.sub.3 ]; ##STR194## ##STR195## ##STR196##______________________________________
mass Spec: C.sub.26 H.sub.42 N.sub.2 O.sub.8 (m*-H.sub.2 O)
requires: 510.2941
found: 510.2937
______________________________________Compound 48______________________________________I.R. (cm.sup.-1) : 3200 to 2600, [CO.sub.2 H; OH]; ##STR197##NMR (.tau.) : 7.7, (t), [CH.sub.2 CO.sub.2 H]; ##STR198## 6.65, (s), [OCH.sub.3 ]; ##STR199## ##STR200## 4.3, (broad s), [CO.sub.2 H; OH].______________________________________
mass Spec: C.sub.21 H.sub.34 N.sub.2 O.sub.4 (m*-H.sub.2 O-MeOH)
requires: 378.2519
found: 378.2507
______________________________________Compound 49______________________________________I.R. (cm.sup.-1) : 3600 to 2400, [CO.sub.2 H; OH]; ##STR201##______________________________________
compound 50
Analysis: C.sub.21 H.sub.37 N.sub.2 O.sub.5 Na
requires: C, 59.98; H, 8.87; N, 6.66; Na, 5.47%.
found: C, 60.15; H, 9.19; N, 6.71; Na, 5.52%.
______________________________________Compound 51______________________________________I.R. (cm.sup.-1) : ##STR202## 1730, [CO.sub.2 CH.sub.3 ].NMR (.gamma.) : 7.8, (t), [CH.sub.2 CO.sub.2 CH.sub.3 ]; 7.2, (hump), [OH]; 7 to 6.2 approx, (m), [NCH.sub.2]; 6.4, (s), [CO.sub.2 CH.sub.3 ]; 6.05, (t), [NCH]; 5.45, (s), [CH.sub.2 Ph]; 2.7, (broad s), [CH.sub.2 Ph].______________________________________
PHARMACOLOGICAL DATA
Bronchodilation activity
1. The compounds were examined for their ability to inhibit 5-hydroxytryptamine or histamine induced bronchoconstriction in the anaesthetised, artificially respired guinea pig (Konzett-Rossler preparation). The compounds were administered intravenously. The results are shown in Table A.
2. the compounds were also examined for their ability to protect conscious guinea pigs against bronchoconstriction induced by an histamine aerosol (Herxheimer test). In these experiments the compounds were administered by aerosol or by oral administration. The results are shown in Table B. The results are the mean of several experiments.
______________________________________Compound ID.sub.50 against 5-hydroxytryptamine-number induced constriction .mu.g/kg, i.v.______________________________________1 4.52 6.83 0.44 2206 1.57 3.316 5.817 8.519 >22021 0.622 3.223 6024 6.027 3031 4.2______________________________________
Similar results were obtained against histamine-induced bronchoconstriction; for example, compound 21 also had an ID.sub.50 of 0.6 .mu.g/kg, i.v., against histamine-induced constriction.
TABLE B______________________________________Compound Aerosol route Oral routenumber Activity; .mu.g/ml Activity; mg/kg______________________________________1 A ; 10 --2 A ; 10 --3 A ; 1.0 A ; 0.2516 A ; 10 --17 A ; 10 --21 A ; 0.25 A ; 0.25______________________________________ A = active
Anti-ulcer activity
Method
Anti-ulcer activity was assessed by the inhibition of indomethacin induced gastric damage in the rat according to the method of Eleghe (1974) Israeli J. Med. Sci. 10. 1451. Rats were starved overnight given 15 mg/kg indomethacin subcutaneously and sacrificed 4 hours later. Stomachs were reflated with n.saline, cut along the greater curvature pinned out and scored for gastric damage by the following system:
Score 1-3--according to degree of erythema and slight haemorrhage.
Score 4-6--according to degree of mucosal erosion.
Score 7-9--according to depth of gastric damage.
Groups of 7 rats were used for each treatment and the test compound or vehicle were administered 30 minutes prior to giving the indomethacin. Dose of test compound was 100 mg/kg orally and control groups receiving vehicle only were set up simultaneously. Mean values for each treatment were obtained using the above scoring system and the Mann Witney test applied for significance of difference between the values obtained with the treatments.
The results are shown in Table C.
TABLE C______________________________________ Vehicle Control TestCompound Mean Score + S.E. Mean Score + S.E.number of Mean of Mean______________________________________17 4.86 .+-. 0.77 0.43 .+-. 0.30 (P<0.01)22 2.29 .+-. 0.87 0.00 .+-. 0.00 (P<0.05)25 3.86 .+-. 0.74 1.14 .+-. 0.74 (P<0.05)30 2.86 .+-. 0.83 0.14 .+-. 0.14 (P<0.05)31 2.00 .+-. 0.79 0.00 .+-. 0.00______________________________________
Compared with vehicle only treatment, the compounds reduced the mean ulcer score and therefore have significant anti-ulcer activity.
Anti-secretory activity
The compounds were examined for their ability to inhibit pentagastrin-stimulated gastric acid secretion in the anaesthetised, perfused rat stomach preparation (Ghosh and Schild preparation). The compounds were administered intra-venously.
Compound 17 inhibited gastric acid secretion over the dose range 5-10 mg/kg, i.v.
Anti-platelet aggregation activity
The compounds were examined for their ability to inhibit platelet aggregation induced in vitro by collagen in human platelet rich plasma.
Compounds 18 and 17 inhibited aggregation by 100% and 34%, respectively, at a concentration of 100 .mu.M. The IC.sub.50 for Compound 18 against collagen-induced aggregation was 7 .mu.M.
Anti-arrythmic activity
The compounds were examined for anti-arrythmic activity by determining their ability to prevent heart fibrillation in mice exposed to chloroform.
Compound 17, when given intraperitoneally at 100 mg/kg, prevented fibrillation induced by chloroform in a group of 3 mice.
Toxicity
The compounds do not appear to be actualy toxic. For example, Compound 17 was not toxic in mice at doses up to 300 mg/kg, orally, or at doses up to 100 mg/kg, intraperitoneally, whereas Compound 21 was not toxic at doses up to 900 mg/kg, orally, in mice.

Number	Date	Country	Kind
52955/76	Dec 1976	GB
30369/77	Jul 1977	GB

Number	Name	Date
2290281	Henze	Jul 1942
2436851	Businger	Mar 1948
2955057	Gagliardi et al.	Oct 1960
3246002	Gagliardi et al.	Apr 1966
3256247	Gagliardi et al.	Jun 1966
3576858	Mizoguchi et al.	Apr 1971
3798233	Akiba et al.	Mar 1974
4089860	Merten et al.	May 1978

Number	Date	Country
2539730	Mar 1977	DE
1273868	Sep 1961	FR

1-(3-Hydroxyalk-1-yl)-5-(carboxyalkyl)hydantoin derivatives

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Abstract

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CROSS-REFERENCE TO RELATED APPLICATION

US Referenced Citations (8)

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Non-Patent Literature Citations (2)

Continuation in Parts (1)

Entry
Dakin, Amer. Chem. Journal, 1910, vol. 44, pp. 48-60.
Ware, Chem. Rev., 1950, vol. 46, pp. 406-407.