Claims
- 1. A benzodioxole derivative having the formula (I) or a pharmaceutically acceptable salt thereof: ##STR362## wherein T is hydrogen, U is hydrogen, V is R.sup.3 and W is ##STR363## wherein R.sup.1 and R.sup.2 may be the same or different and each represents a hydrogen atom, an alkyl, benzyl, phenethyl or a heteroarylalkyl group wherein the heteroaryl group is a five or six membered ring containing nitrogen, R.sup.3 represents a hydrogen atom or a lower alkyl, benzyl orphenethyl, or heteroarylalkyl group wherein the heteroaryl group is a five or six membered ring containing nitrogen, R.sup.4 represents a hydrogen atom or a lower alkyl group, or R.sup.2 and R.sup.3 may join together to form a 4 to 6-membered ring and X represents a group of the formula: ##STR364## with the proviso that R.sup.1 is an alkyl, benzyl, phenethyl, or heteroarylalkyl group having at least 3 carbon atoms when X is --S-- group and R.sup.3 and R.sup.2 are each a hydrogen atom.
- 2. The benzodioxole derivative according to claim 1, wherein X is --S-- and R.sup.3 is a hydrogen atom.
- 3. The benzodioxole derivative according to claim 1, wherein W is --CH(n--CH.sub.3 H.sub.7)--S--CH.sub.2 COOH.
- 4. The benzodioxole derivative according to claim 1, wherein W is --C(CH.sub.3).sub.2 --S--CH.sub.2 COOH.
Priority Claims (6)
| Number |
Date |
Country |
Kind |
| 62-49141 |
Mar 1987 |
JPX |
|
| 62-82258 |
Apr 1987 |
JPX |
|
| 62-103724 |
Apr 1987 |
JPX |
|
| 62-105508 |
Apr 1987 |
JPX |
|
| 62-105509 |
Apr 1987 |
JPX |
|
| 62-243492 |
Sep 1987 |
JPX |
|
STATEMENT OF PRIOR ARTS
This application is a continuation of application Ser. No. 07/160,333 filed on Feb. 25, 1988, now abandoned.
The invention relates to a benzodioxole derivative, a pharmacologically acceptable salt thereof, a pharmaceutical composition containing the same, a process for preparing the same and the medical treatment of liver troubles therewith. The invention compound exhibits an excellent activity as a medicine for liver troubles such as liver diseases of the human being and liver injury of animals.
The development of a liver trouble remedy is very difficult, because the cause, figure and pathophysiology of liver troubles are various and mostly unobvious.
Representative medicines which are widely used in the treatment and prevention of liver troubles and evaluated to be clinically effective include glycyrrhizin preparations. Although the glycyrrhizin preparations are generally believed to be effective in the treatment of a liver affection, cirrhosis and hepatitis and in the protection of a liver after a surgical operation, however, none of the preparations exhibit a sufficient effect and they are further problematic in that they cause a steroidal adverse reaction. Further, the glycyrrhizin preparations are disadvantageous in that the oral administration thereof is ineffective, though they can be administered as intravenous injections to give an effect.
Under these circumstances, it is strongly desired to develop an excellent medicine which is excellent in safety and can be orally administered to exhibit an excellent effect.
Under these circumstances, the inventors of the present invention have eagerly studied to develop a new liver trouble remedy.
The inventors of the present invention have long studied plants which have been used as folk medicines and have found 2-[(phenylmethyl)trithiojethanol (A) and cubebin (B) which are represented by the general formulas: ##STR1## and are active compounds effective as liver trouble remedies, from Petiveria alliacea L. and Cinnamonum porrectum (Roxb.) Kosterm.
Thereafter, the inventors of the present invention have synthesized various compounds by using the above compounds as basic compounds and have examined the obtained compounds for pharmacological activity. As a result of the examination, they have found that benzodioxole derivatives represented by the general formula (I) or pharmacologically acceptable salts thereof exhibit higher safety and are useful as a more excellent liver trouble remedy. The present invention has been accomplished on the basis of this finding.
The following two patent publications show liver trouble remedies which are different from the benzodioxole derivatives of the present invention in chemical structure.
More precisely, the compounds disclosed in Japanese Patent Laid-Open No. 29522/1987 have each a structure comprising a benzodioxole ring and a saturated alkyl group bonded to the phenyl ring of the benzodioxole ring and most of them have already been known.
Further, Japanese Patent Laid-Open No. 39583/1987 discloses (1,3-benzodioxol-5-yl)methylthio derivatives. However, the group bonded to the S atom of these derivatives is a heterocyclic group such as pyridine, pyrimidine or thiadiazole, so that the derivatives are clearly different from the compounds of the present invention in structure.
As described above, the present invention has been accomplished on the basis of a hint taken from the compounds (A) and (B) found by the inventors of the present invention themselves from plant components and therefore is different from the inventions of the above two Laid-Open, Patents in conception. Accordingly, the compounds of the present invention are different from those of the above two Laid-Open Patents in chemical structure.
The invention provides a novel benzodioxole derivative having the formula [I] and a pharmacologically acceptable salt thereof: ##STR2## in which T, U, V and W are each defined according to the below shown respective six groups (a) to (f):
(a) T is hydrogen, U is hydrogen, V is R3 and W is ##STR3## wherein R.sup.1 and R.sup.2 may be the same or different from each other and each represents a hydrogen atom or an alkyl, arylalkyl or heteroarylalkyl group, R.sup.3 represents a hydrogen atom or a lower alkyl, arylalkyl or hetercarylalkyl group, R.sup.4 represents a hydrogen atom or a lower alkyl group, or R.sup.2 and R.sup.3 may form together an at least 4-membered ring and X represents a group of the formula: ##STR4## with the proviso that R.sup.1 is an alkyl, arylalkyl or heteroarylalkyl group having at least 3 carbon atoms when X is a --S-- group and R.sup.3 and R.sup.2 are each a hydrogen atom;
(b) T is hydrogen, U is hydrogen, V is hydrogen and
W is .sub.--(CH2)2--X--R
R represents:
(1) a hydrogen atom or a lower alkyl group,
(2) a group of the formula: --(CH.sub.2).sub.n --COOR.sup.1 in which n represents an integer of 1 to 5 and R.sup.1 represents a hydrogen atom or a lower alkyl group,
(3) a group of the formula: --(CH.sub.2).sub.n --OR.sup.2 in which n represents an integer of 1 to 5 and R.sup.2 represents a hydrogen atom, a lower alkyl group or an acyl group,
(4) a group of the formula: ##STR6## in which n represents an integer of 1 to 5, and R.sup.3 and R.sup.4, which may be the same or different from each other, each represents a hydrogen atom, a lower alkyl or carboxymethyl group,
(5) a group of the formula: ##STR7## in which n represents an integer of 1 to 5, and R.sup.5 and R.sup.6, which may be the same or different from each other, each represents a hydrogen atom or a lower alkyl group,
(6) a group of the formula: ##STR8## in which n represents an integer of 1 to 5 and R.sup.7 represents a hydrogen atom or a lower alkyl group,
(7) a group of the formula shown in the above item (2) but wherein one or more carbon atoms of the alkylene chain having n carbon atoms are bonded with a lower alkyl group or a group of the formula: --COOR.sup.8 in which R.sup.8 represents a hydrogen atom or a lower alkyl group, in place of hydrogen atom,
(8) a group of the formula shown in the above item (3) but wherein one or more carbon atoms of the alkylene chain having n carbon atoms are bonded with a hydroxyl group in place of hydrogen atom, or
(9) a group of the formula: ##STR9## in which n represents an integer of 1 to 5 and
m represents an integer of 3 or 4, with the proviso that when X represents a group of the formula: --S--and R represents a lower alkyl group, the lower alkyl group cannot be a methyl group;
(c) T is hydrogen, U is hydrogen, V is R1 and W is ##STR10## wherein R.sup.1 represents a hydrogen atom or a lower alkyl or lower alkoxy-lower alkyl group, R.sup.2 represents a hydrogen atom or a lower alkyl or lower alkoxy group, R.sup.3 represents a hydrogen atom or a lower alkyl group and R.sup.4 represents a hydrogen atom or a lower alkyl group, or R.sup.1 and R.sup.2 or R.sup.1 and R.sup.3 may form together a 5- to 7-membered ring, with the proviso that all of R.sup.1, R.sup.2 and R.sup.3 cannot be hydrogen atoms at the same time;
(d) T is R4, U is R5, V is R.sup.3 and W is ##STR11## wherein R.sup.1 and R.sup.2 may be the same or different from each other and each represents a hydrogen atom or a lower alkyl group,
R.sup.3 represents a hydrogen atom, a lower alkyl group or a group of the formula: --(CH.sub.2).sub.n COOH in which n represents an integer of 1 to 3,
R.sup.4 and R.sup.5 may be the same or different from each other and each represents a hydrogen atom or a lower alkyl group, X represents a group of the ##STR12##
A represents a lower alkyl group, a group of the formula: --(CH.sub.2).sub.n '--Het in which n' represents an integer of 1 to 3 and Het represents a substituted or unsubstituted heterocyclic ring, a group of the formula: ##STR13## a group of the formula: ##STR14## a group of the formula: ##STR15## in which R.sup.6 and R.sup.7 may be the same or different from each other and each represents a hydrogen atom or a lower alkyl group, a group of the formula: --CH.sub.2 --CN, a group of the formula: ##STR16## in which R.sup.8 represents a lower alkyl group or a group of the formula:
(e) T is hydrogen, U is hydrogen, V is hydrogen and W is ##STR17## wherein X is a group of the formula: --CH.sub.2 --, --CH.sub.2 --CH.sub.2 --, --CH.sub. --CH.sub.2 --CH.sub.2 --or ##STR18## R.sup.1 is a hydrogen atom or a lower alkyl group and Y is hydrogen atom or an alkyl, hydroxyl, carboxyl, aryl or heteroarylcarbonyloxy group, and
(f) T is hydrogen, U is hydrogen, V is R.sup.3 and W is ##STR19## wherein R.sup.1 and R.sup.2 may be the same or different from each other and each represents a hydrogen atom or a lower alkyl, aryl or arylalkyl group; n represents an integer of 0 or 1; Y represents a group of the formula: --COOH or ##STR20## wherein R.sup.4 and R.sup.5 may be the same as or different from each other and each represents a hydrogen atom or a lower alkyl or carboxymethyl group and R.sup.3 represents a hydrogen atom or a lower alkyl cr arylalkyl group.
In addition, the invention provides a process for preparing the above shown benzodioxole derivative and a pharmaceutical composition containing it and a pharmacologically acceptable carrier.
The invention compound [I]consists of six compound groups (I-a), (I-b), (I-c), (I-d), (I-e) and (I-f). Each group is defined below, corresponding to the six group definitions (a), (h), (c), (d), (e) and (f) of T, U, V and W of the formula [I], respectively.
The compound group (I-a) has the formula (I-a): ##STR21## wherein R.sup.1 and R.sup.2 may be the same or different from each other and each represents a hydrogen atom or an alkyl, arylalkyl or heteroarylalkyl group, R.sup.3 represents a hydrogen atom or a lower alkyl, arylalkyl or heteroarylalkyl group, R.sup.4 represents a hydrogen atom or a lower alkyl group, or R.sup.2 and R.sup.3 may form together an at least 4-membered ring and X represents a group of the formula: ##STR22## with the proviso that R.sup.1 is an alkyl, arylalkyl or heteroarylalkyl group having at least 3 carbon atoms when X is a --S-- group and R.sup.3 and R.sup.2 are each a hydrogen atom.
In the formula (I-a), the alkyl for R1 and R2 includes a straight or branched alkyl, such as methyl, ethyl, n-propyl, n-butyl, iso-propyl, iso-butyl, 1-methylpropyl, tert-butyl, n-pentyl, 1-ethylpropyl, isoamyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl. Methyl, ethyl, n-propyl, iso-propyl and n-butyl are preferable. The lower for R.sup.3 and R.sup.4 includes a straight or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, n-butyl, iso-propyl, iso-butyl, 1-methylpropyl, tert-butyl, n-pentyl, 1-ethylpropyl, iso-amyl and n-hexyl. Methyl, ethyl and n-propyl are preferable. The arylalkyl for R1, R.sup.2 and R.sup.3 includes benzyl and phenethyl. The heteroarylalkyl for the same includes a heterocyclic ring connected with an alkyl such as methyl, ethyl and propyl. The heteroaryl includes a five- or six-membered ring having nitrogen such as pyridine, pyrimidine, pyrrole, pyrazole and imidazole, thiazole, oxazole. A preferable hetero-arylalkyl is pyridylmethyl, pyrimidylmethyl or furylmethyl, the alkyl being connected with the hetero-cyclic ring at any position. R2 and R3 may form a 4- or more membered cyclic ring together in combination. This is supported by Examples 15 and 17.
The compound group (I-b) has the formula (I-b): ##STR23## wherein X represents a group of the formula: ##STR24##
R represents:
(1) a hydrogen atom or a lower alkyl group,
(2) a group of the formula: --(CH.sub.2).sub.n --COOR.sup.1 in which n represents an integer of 1 to 5 and R.sup.1 represents a hydrogen atom or a lower alkyl group,
(3) a group of the formula: --(CH.sub.2).sub.n --OR.sup.2 in which n represents an integer of 1 to 5 and R.sup.2 represents a hydrogen atom, a lower alkyl group or an acyl group,
(4) a group of the formula: ##STR25## in which n represents an integer of 1 to 5, and R.sup.3 and R.sup.4, which may be the same or different from each other, each represents a hydrogen atom, a lower alkyl or carboxymethyl group,
(5) a group of the formula: ##STR26## in which n represents an integer of 1 to 5, and R.sup.5 and R.sup.6, which may be the same or different from each other, each represents a hydrogen atom or a lower alkyl group,
(6) a group of the formula: ##STR27## in which n represents an integer of 1 to 5 and R.sup.7 represents a hydrogen atom or a lower alkyl group,
(7) a group of the formula shown in the above item (2) but wherein one or more carbon atoms of the alkylene chain having n carbon atoms are bonded with a lower alkyl group or a group of the formula: --COOR.sup.8 in which R.sup.8 represents a hydrogen atom or a lower alkyl group, in place of hydrogen atom,
(8) a group of the formula shown in the above item (3) but wherein one or more carbon atoms of the alkylene chain having n carbon atoms are bonded with a hydroxyl group in place of hydrogen atom, or
(9) a group of the formula: ##STR28## in which n represents an integer of 1 to 5 and m represents an integer of 3 or 4, with the proviso that when X represents a group of the formula: --S--and R represents a lower alkyl group, the lower alkyl group cannot be a methyl group.
In the formula (I-b), the lower alkyl for R1, R2, R3, R4, R5, R6, R7 and R8 includes a straight or branched alkyl having 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, iso-propyl, iso-butyl, 1-methylpropyl, tert-butyl, n-pentyl, 1-ethylpropyl, iso-amyl and n-hexyl. Methyl and ethyl are preferable. The acyl for R2 includes a residue of an organic acid such as an aliphatic saturated carboxylic acid, an aliphatic unsaturated carboxylic acid, a carbocyclic carboxylic acid and a hetero-cyclic carboxylic acid. It includes in particular a lower alkanoyl such as formyl, acetyl, propionyl, butyryl, iso-butyryl, valeryl, iso-valeryl and pivaloyl, an aroyl such as benzoyl, toluoyl and naphthoyl and a hetro-aroyl such as furoyl, nicbtinoyl and iso-nicotinoyl.
The compound group (I-c) has the formula (I-c): ##STR29## wherein R.sup.1 represents a hydrogen atom or a lower alkyl or lower alkoxy-lower alkyl group, R.sup.2 represents a hydrogen atom or a lower alkyl or lower alkoxy group, R.sup.3 represents a hydrogen atom or a lower alkyl group and R.sup.4 represents a hydrogen atom or a lower alkyl group, or R.sup.1 and R.sup.2 or R.sup.1 and R.sup.3 may form together a 5- to 7-membered ring, with the proviso that all of R.sup.1, R.sup.2 and R.sup.3 cannot be hydrogen atoms at the same time.
In the formula (I-c), the lower alkyl for R1, R2, R3 and R4 includes an alkyl, straight or branched, having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl (amyl), iso-pentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, iso-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl. Methyl, ethyl, propyl and iso-propyl are preferable. The lower alkoxy for R.sup.2 includes an alkoxy, straight or branched, having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentyloxy, iso-pentyloxy, neopentyloxy, tert-pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 1,2-dimethylpropoxy and hexyloxy. Methoxy and ethoxy are preferable. The lower alkoxy-lower alkyl for R1 includes methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propoxymethyl, propoxyethyl and propoxypropyl. Methoxymethyl and ethoxymethyl are preferable. R1 and R2 may, together in combination, form a 5- to 7-membered ring. This is exemplified in Example 13. The 5- to 7-membered ring may contain oxygen atom, in addition to a ring consisting of carbon atoms. R1 and R.sup.3 also may, together in combination, form a 5-to 7-membered ring, exemplified in Example 11.
The compound group (I-d) has the formula (I-d): ##STR30## wherein R.sup.1 and R.sup.2 may be the same or different from each other and each represents a hydrogen atom or a lower alkyl group,
R.sup.3 represents a hydrogen atom, a lower alkyl group or a group of the formula: --(CH.sub.2).sub.n COOH in which n represents an integer of 1 to 3,
R.sup.4 and R.sup.5 may be the same or different from each other and each represents a hydrogen atom or a lower alkyl group, X represents a group of the formula: ##STR31##
A represents a lower alkyl group, a group of the formula: --(CH.sub.2).sub.n '-Het in which n' represents an integer of 1 to 3 and Het represents a substituted or unsubstituted heterocyclic ring, a group of the formula: ##STR32## a group of the formula: ##STR33## a group of the formula ##STR34## in which R.sup.6 and R.sup.7 may be the same or different from each other and each represents a hydrogen atom or a lower alkyl group, a group of the formula: --CH.sub.2 --CN, a group of the formula: ##STR35## in which R.sup.8 represents a lower alkyl group or a group of the formula: ##STR36## in which p represents an integer of 1 to 3 and R.sup.9 and R.sup.10 may be the same or different from each other and each represents a lower alkyl group.
In the formula (I-d), the lower alkyl for R1, R2, R3, R4, R5, R6, R7, R8, R9 and R.sup.10 includes a straight or branched alkyl having 1 to 6 carbon atoms such as methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl (amyl), iso-pentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, iso-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl. Methyl, ethyl, propyl and iso-propyl are preferable. The hetero-cyclic ring, called Het in the A, means a nitrogen-containing hetero-cyclic ring, such as pyridine, pyradine, pyrimidine, imidazole, pyrazole, oxazole, iso-oxazole, thiazole and iso-thiazole. The hetero-cyclic ring may have a substituent such as a lower alkyl, for example methyl, and hydroxyl. Pyridyl, imidazolyl and iso-oxazolyl are preferable.
The compound group (I-e) has the formula (I-e): ##STR37## wherein X is a group of the formula: --CH.sub.2 --, --CH.sub.2 --CH.sub.2 --, --CH.sub.2 --CH.sub.2 --CH.sub.2 --or ##STR38## R.sup.1 is a hydrogen atom or a lower alkyl group and Y is hydrogen atom or an alkyl, hydroxyl, carboxyl, aryl or heteroarylcarbonyloxy group.
In the formula (I-e), the lower alkyl for R1 includes an alkyl having 1 to 6 carbon atoms, straight or branched, such as methyl, ethyl, n-propyl, n-butyl, iso-propyl, iso-butyl, 1-methylpropyl, tert-butyl, n-pentyl, 1-ethylpropyl, iso-amyl and n-hexyl. Methyl, ethyl and n-propyl are preferable. The alkyl for Y includes an alkyl, straight or branched, such as methyl, ethyl, n-propyl, n-butyl, iso-propyl, iso-butyl, 1-methylpropyl, tert-butyl, n-pentyl, 1-ethylpropyl, iso-amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl. The aryl for R1 includes phenyl, tolyl, xylyl, biphenyl and naphthyl. Phenyl is preferable. The hetero-arylcarboxyloxy includes one derived from a nitrogen-containing, 5- or 6-membered cyclic ring such as pyridine, pyrimidine, pyrrole, pyrazole and imidazole, thiazole, oxazole or furane. Nicotinoyloxy is preferable.
The compound group (I-f) has the formula (I-f): ##STR39## wherein R.sup.1 and R.sup.2 may be the same or different from each other and each represents a hydrogen atom or a lower alkyl, aryl or arylalkyl group; n represents an integer of 0 or 1;
Y represents a group of the formula: --COOH or ##STR40## (wherein R.sup.4 and R.sup.5 may be the or different from each other and each represents a hydrogen atom or a lower alkyl or carboxymethyl group) and R.sup.3 represents a hydrogen atom or a lower alkyl or arylalkyl group.
The lower alkyl group in the above definition with respect to the groups R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 of the compound (I) according to the present invention is a straight-chain or branched alkyl group having 1 to 6 carbon atoms and examples thereof include methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl, 1-ethylpropyl, isoamyl and n-hexyl groups.
The aryl group in the definition with respect to the groups R.sup.1 and R.sup.2 includes phenyl, tolyl and naphthyl groups, among which a phenyl group is most preferred.
Preferred examples of the arylalkyl group in the definition with respect to the groups R.sup.1, R.sup.2 and R.sup.3 include groups derived from the above aryl groups, among which benzyl and phenethyl groups are most preferred.
In the compounds according to the invention, those having the formulae (I-a), (I-b) and (I-f), respectively, are preferable.
In the invention, a preferable group of the compounds has the formula (I) in which T is hydrogen, U is hydrogen, V is R.sup.3 and W is (a) or (f), in which R3, (a) and (f) are defined above, provided that the definition of (f) excludes the cases where n is zero, Y is --COOH, R1 and R2 are each hydrogen, a lower alkyl or an arylalkyl and R3 is hydrogen, a lower alkyl or an arylakyl.
It is more preferable in the formula (I-a) that X is --S--, R3 is hydrogen or a lower alkyl and R1 and R2 are each hydrogen or a lower alkyl. The compound having the formula (I-a) in which R3 is hydrogen, R1 is hydrogen, R2 is n-propyl, X is --S--and R4 is hydrogen and sodium salt thereof are most preferable.
Also the compound having the formula (I-f) in which R3 is hydrogen, R1 and R2 are hydrogen, n is one and Y is --COOH and sodium salt thereof are most preferable.
In the formula (I-b), X is preferred to be --S--. When this is the case, R is preferred to be --CH2--COOH, --(CH2)n--CH(NH2)--COOR7 or --CH --CH(NH.sub.2)COOH. In addition, it is preferred that X is --S--, R3 is hydrogen, R1 is hydrogen and R2 is --C3H8; X is --S--, R3 is hydrogen, R1 is --CH3 and R2 is --CH3; or X is --S--, R3 is --CH3 or --C2H5, R1 is hydrogen and R.sup.2 is --C2H5.
All the compounds employed in the pharmacological tests, shown below, are more important to the invention. In particular, the compounds 1 to 5 shown in Table 1 in view of the the compound group I-a) and the compounds 1, 2, 4, 7, 8, 10, 11, 12, 13 and 15 listed in Table 6 in view of the compound group (I-f) are most preferred.
The pharmacologically acceptable salts may be ordinary non-toxic salts and examples thereof include salts of alkali metals such as sodium and potassium; salts of alkaline earth metals such as calcium and magnesium; salts of organic amines such as trimethylamine, triethylamine, pyridine, picoline, dicyclohexylamine and N,N'-dibenzylethylenediamine and ammonium salts and additionally, depending upon the substituent, inorganic acid salts such as hydrochloride, hydrobromide, sulfate and phosphate; organic acid salts such as acetate, maleate, tartrate, methanesulfonate, benzenesulfonate and toluenesulfonate and salts of amino acids such as arginine and aspartic and glutamic acids. Further, these salts may form hydrates.
Although the compounds of the present invention may have an asymmetric carbon atom depending upon the substituents to be present as optical isomers, it is a matter of course that these isomers are included in the scope of the present invention.
It should be understood from the results of Experimental Examples 1 and 2 that the compounds of the present invention remarkably inhibit liver trouble due to D-galactosamine or carbon tetrachloride. Thus, the compounds of the present invention are very useful as liver trouble remedies.
Accordingly, the compounds of the present invention are useful as a therapeutic and preventive medicine for various liver troubles of animals including human beings. More precisely, they can be used in the treatment and prevention of chronic or acute hepatitis, liver affections due to drugs, viral hepatitis, alcoholic hepatitis and choloplania and even cirrhosis as a terminal symptom of these diseases.
Further, it should be understood from the results of Experimental Example 3 that the compounds of the present invention exhibit remarkably low toxicity and are excellent in safety. Therefore, the compounds of the present invention are highly valuable in this regard, because they are generally administered repeatedly for a prolonged period of time owing to the nature of the trouble.
When the compounds of the present invention are administered as a therapeutic and preventive medicine for liver troubles, they may be orally administered as a powder, granule, capsule, syrup or the like or may be parenterally administered as a suppository, injection, external preparation or drop. Although the dose thereof remarkably varies depending upon the symptom, the age or the kind of the liver trouble, it is generally about 0.1 to 1,000 mg, preferably 2 to 500 mg, still preferably 5 to 100 mg, per adult and per day, which may be administered at once or in several portions a day.
The preparation of a medicine containing the compound of the present invention is carried out by using conventional carriers according to an ordinary method.
More precisely, in the production of a solid preparation for oral administration, a filler and, if necessary, a binder, disintegrating agent, lubricant, coloring agent or corrigent are added to a principal agent and the obtained mixture is converted into a tablet, coated tablet, granule, powder or capsule according to an ordinary method.
Examples of the filler include lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose and silicon dioxide, while those of the binder include polyvinyl alcohol, polyvinyl ether, ethylcellulose, methylcellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropylcellulose, hydroxypropylmethylcellulose, calcium citrate, detrin and pectin. Examples of the lubricant include magnesium stearate, talc, polyethylene glycol, silica and hardened vegetable oils, while the coloring agent may be any one permitted as the additive to drugs. The corrigent include powdered cacao, mentha herb, aromatic powder, mentha oil, borneol and powdered cinnamon bark. Of course, these tablets and granules may be coated with sugar, gelatin or other material.
In preparing an injection containing the compound of the present invention, a principal agent is, if necessary, mixed with a pH adjusting agent, buffer, stabilizer, solubilizing agent or the like and converted into a subcutaneous, intramuscular or intravenous injection according to an ordinary method.
The above mentioned pharmacological effect of the invention compounds is supported by the pharmacological experiments procedures and results of which are described below according to the compound groups (I-a) to (I-f).
Experimental method:
300 mg/kg of D-galactosamine was administered to male Fischer (F.sub.344) rats weighing around 180 g by subcutaneous injection to induce liver injury. Each compound was dissolved in distilled water was given by oral administration in a dose of 50 mg/kg one hour after the injection of D-galactosamine.
The D-galactosamine was used in the form of a solution having a concentration of 200 mg/ml, obtained by dissolving D-galactosamine in a physiological saline solution to obtain a dilute D-galactosamine solution and adjusting the pH of the dilute solution to 7.0 with 10N aqueous potassium hydroxide.
Blood was collected from the rat's tail vein 48 h after the injection of D-galactosamine. The blood coagulation time was determined by the hepaplastin test (HPT) and GPT activity in the blood plasma was determined by an enzymatic method.
The inhibition (%) of liver injury by each compound is shown in Table 1a.
0.5 ml/kg of carbon tetrachloride was given to male Fischer (F.sub.344) rats weighing around 180 g by intraperitoneal injection to induce liver injury. In this test, carbon tetrachloride was diluted to a final concentration of 0.25 ml/ml with olive oil.
Each compound dissolved in distilled water was given by oral administration in a dose of 100 mg/kg one hour before the administration of carbon tetrachloride.
Blood was collected from the rat's tail vein 24 h after the injection of carbon tetrachloride. GPT activity in plasma as an index of the liver injury was determined by an enzymatic method. The inhibition (%) of the liver injury by each compound is shown in Table 2a.
The method was conducted in the same way as shown in Experimental Example 1a except that 400 mg/kg of D-galactosamine was used in its solution in physiological saline and each test compound was administered in a dose of 100 mg/kg in 0.5 % methylcellulose solution. Results are shown in Table 1b.
The test was conducted in the same manner as shown in Experimental Example 1b except that the test compound was orally administered to the rats in a dose of 100 mg/kg in 0.5% methylcellulose solution. Results are shown in Table 2b.
The tests were conducted in the same ways as shown in Experimental Examples 1a and 2a, respectively. Results are shown in Tables 1c and 2c, respectively.
The test was conducted in the same manner as shown in Experimental Example 1a except that each test compound was used in its solution in distilled water or a suspension in 0.5% methylcellulose solution. Results are shown in Table 1d.
The test was conducted in the same way as shown in Experimental Example 2a except that each test compound was used in a solution in distilled water. Results are shown in Table 2d.
The test was conducted in the same way as shown in Experimental Example 1a except that 400 mg/kg of D-galactosamine was administered and each test compound was used in a dose of 100 mg/kg in a suspension of 0.5 % aqueous methylcellulose solution. Results are shown in Table 1e.
The test was conducted in the same way as shown in Experimental Example 2a except that each test compound was used in a suspension of 0.5 % aqueous methylcellulose solution. Results are shown in Table 2e.
The test was conducted in the same way as shown in Experimental Example 1a except that 400 mg/kg of D-galactosamine was administered in its physiological saline solution and each test compound was used in an amount of 100 mg/kg in 0.5 % methylcellulose liquid. Results are shown in Table 1f.
The test was conducted in the same way as shown in Experimental Example 1a except that each test compound was used in an amount of 100 mg/kg in a suspension in 0.5% methylcellulose solution. Results are shown in Table 2f.
Male ddy mice being 7 weeks old and weighing around 30 g were used. 800 mg/kg of the respective compounds shown in Tables 1a, 1b, 1c, 1d and 1f and the respective compounds 1, 3, 6 and 7 of Table 1e were administered orally to the mice for 4 days. No mouse died.
A symbolic reference to * in Table 1b shows administration of 50 mg/kg.
The compounds of the invention can be prepared by various processes. Typical examples of the processes are described below according to the respective compound groups.
Preparation of compounds of the general formula (I) wherein X represents a group of the formula: --S-- ##STR127## wherein R.sup.1, R.sup.2 and R.sup.3 are as defined above and R.sup.4 represents H or a lower alkyl group.
In this process, an alcohol of the general formula (II) is reacted with a thiol of the general formula (III) to obtain an intended compound (IV). This reaction is conducted by an ordinary method without using any solvent or in an organic solvent inert to the reaction selected from the group consisting of aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as ethyl ether, isopropyl ether, tetrahydro-furan and dioxane, halogenated hydrocarbons such as dichloro-methane, chloroform and carbon tetrachloride, esters such as ethyl acetate, ketones, such as acetone and methyl ethyl ketone, as well as acetonitrile, dimethylformamide and acetic acid under cooling with ice, at room temperature or under heating for several hours. The reaction proceeds easily when an acid such as sulfuric, p-toluenesulfonic or D-10-camphorsulfonic acid is used as the catalyst.
In this process, a halogen compound of the general formula (V) is reacted with a thiol of the general formula (III) to obtain an intended compound (IV).
This reaction is conducted by an ordinary method without using any solvent or in an organic solvent inert to the reaction selected from the group consisting of aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as tetrahydro-furan and dioxane, ketones such as acetone and methyl ethyl ketone, alcohols such as methanol and ethanol, halogenated hydrocarbons such as chloroform and carbon tetrachloride, as well as acetonitrile, dimethylformamide and dimethyl sulfoxide under cooling with ice, at room temperature or under heating for several hours. The reaction proceeds easily when an alkali metal carbonate or hydrogencarbonate such as sodium hydrogen-carbonate, potassium carbonate or sodium carbonate, an alkali hydroxide such as sodium hydroxide or potassium hydroxide, an organic base such as triethylamine, pyridine or diethylaniline, or sodium hydride is used as a dehydrohalogenating agent.
In this process, a compound of the general formula (VI) is reacted with a thiol of the general formula (III) to obtain an intended compound (VII). This reaction is conducted by an ordinary method without using any solvent or in an organic solvent selected from the group consisting of aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as tetrahydrofuran and dioxane, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride, ketones such as acetone and methyl ethyl ketone, esters such as ethyl acetate, as well as acetonitrile and dimethylformamide under cooling with ice, at room temperature or by heating under reflux. When the reaction proceeds only slowly, an acid such as sulfuric, p-toluenesulfonic or D-10-camphorsulfonic acid can be used as the catalyst.
The compound (VII) thus obtained is an intended one of the present invention represented by the above general formula (I) wherein X represents --S--and R.sup.2 represents ##STR130##
Preparation of compounds of the general formula (I) wherein X represents of a group of the formula: --S-- ##STR131## wherein Hal represents a halogen atom and R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined above.
In this process, a thiol of the general formula (VIII) is reacted with a halogen compound of the general formula (IX) under the same conditions as those of the preparation process B to obtain an intended compound (IV). Preferred results are obtained when the base shown with reference to the preparation process (B) is used.
The halogen atoms used in the preparation processes B and D include bromine, chlorine and iodine. Usually bromine or chlorine is used.
Preparation of compounds of the general formula (I) wherein X represents a group of the formula: --S--and R.sup.4 represents a hydrogen atom ##STR132## wherein R.sup.1, R.sup.2 and R.sup.3 are as defined above and R.sup.4' is the same as R.sup.4 but excluding the hydrogen atom, namely, R.sup.4' represents a lower alkyl group.
An ester of the general formula (X) which is one of the intended compounds can be hydrolyzed by an ordinary method to obtain an intended carboxylic acid of the general formula (IV)'. In particular, the hydrolysis is conducted by an ordinary method in the presence of a base or acid in a solvent suitably selected from the group consisting of water, methanol, ethanol, hydrous methanol, hydrous ethanol, hydrous tetrahydrofuran, hydrous acetonitrile and hydrous acetone. The bases include alkali metal carbonates such as sodium and potassium carbonates and alkali hydroxides such as sodium and potassium hydroxides. The acids include, for example, hydrochloric and sulfuric acids.
Preparation of compounds of the general formula (I) wherein X represents a group of the formula: ##STR133## wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined above.
In this process, an intended compound (XI) is prepared by oxidizing, for example, an intended compound (IV) prepared by the above-described process. In particular, the compound (IV) is dissolved in a solvent selected from the group consisting of aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride, water, alcohols such as methanol and ethanol, ethyl acetate, acetone and acetic acid, and an equimolar amount of an oxidizing agent such as hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid or sodium hypochlorite is added thereto under cooling with dry ice/alcohol or ice/water to conduct the reaction in an ordinary manner and to produce an intended sulfoxide compound (XI).
Preparation of compounds of the general formula (I) wherein X represents a group of the formula: ##STR134## wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined above.
In this process, an intended compound (XII) is prepared by oxidizing, an intended compound (IV) prepared by, for example, the above-described process. More particularly, the compound (IV) is dissolved in a solvent selected from the group consisting of aromatic hydrocarbons such as benzene, toluene and xylene, halggenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride, water, alcohols such as methanol and ethanol, ethyl acetate, acetone and acetic acid, and at least two equivalents of an oxidizing agent such as hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid, sodium hypochlorite or sodium m-periodate is added thereto under cooling with ice or at room temperature to conduct the reaction and thereby to obtain an intended sulfone compound (XII).
In another preparation process, a sulfoxide compound (XI) prepared by, for example, the preparation process F is dissolved in a solvent such as chloroform and then an oxidizing agent such as m-chloroperbenzoic acid is added thereto to conduct the reaction.
Pharmacologically acceptable salts of the intended compounds (I) which are also intended in the present invention can be produced by, for example, reacting a carboxylic acid compound of the general formula (I) wherein R.sup.4 represents a hydrogen atom with an alkali hydrogencarbonate such as NaHCO.sub.3 or KHCO.sub.3, an alkali carbonate such as Na.sub.2 CO.sub.3 or K.sub.2 CO.sub.3 or an alkali hydroxide such as NaOH or KOH to obtain a pharmacologically acceptable salt such as sodium or potassium salt thereof.
Preparation of compounds of the general formula (I) wherein X represents a group of the formula: --S-- ##STR135## wherein Hal represents a halogen atom and R is as defined above.
In this process, 5-(2-halogenoethyl)-1,3-benzodioxole of the general formula (II) is reacted with a thiol of the general formula (III) to obtain an intended compound (IV).
This reaction is conducted by an ordinary method without using any solvent or in an organic solvent inert to the reaction selected from the group consisting of benzene, ethanol, xylene, tetrahydrofuran, chloroform, carbon tetrachloride, N,N-dimethylformamide, etc. under cooling with ice, at room temperature or under heating for several hours. The reaction is facilitated by using an inorganic base such as sodium hydrogencarbonate, potassium carbonate, sodium carbonate or sodium hydroxide or an organic base such as triethylamine, pyridine, pyrimidine or N,N-diethylaniline as the dehydrohalogenating agent.
Preparation of compounds of the general formula (I) wherein X represents a group of the formula: --S-- ##STR136## wherein Hal represents a halogen atom and R is as defined above.
In this process, 2-(1,3-benzodioxol-5-yl)ethanethiol (V) is reacted with a halogenating agent of the general formula (VI) under the same conditions as those of the preparation process A to obtain an intended compound (IV). Also in this process, preferred results are obtained when the base as described above with reference to the preparation process A is used. The halogen atoms used in the preparation processes A and B include bromine, chlorine and iodine. Usually bromine or chlorine is used.
In this process, a thiol (V) is reacted with an unsaturated compound of the general formula (VII) by an ordinary method without using any solvent or in a solvent selected from the group consisting of, for example, benzene, dichloromethane, tetrahydrofuran, N,N-dimethylformamide and ethanol under cooling with ice, at room temperature or by heating under reflux to obtain an intended compound (VIII). When the reaction proceeds only slowly, a catalyst such as piperidine, triethylamine, sodium methylate, Triton B, sulfur or sulfuric acid can be used as the catalyst.
The compound (VIII) thus obtained is an intended one of the present invention represented by the above general formula (I) wherein X represents --S--and R represents ##STR138##
Preparation of compounds of the general formula (I) wherein X represents a group of the formula: --S-- ##STR139## wherein R is as defined above.
In this process, 5-ethenyl-1,3-benzodioxole (IX) is reacted with a thiol of the general formula (III) by an ordinary method without using any solvent or in a solvent such as tetrahydrofuran under cooling with ice, at room temperature or by heating under reflux to obtain an intended compound (IV). When the reaction proceeds only slowly, a peroxide such as benzoyl peroxide, or azobisisobutyronitrile can be used as the catalyst.
Preparation of compounds of the general formula (I) wherein X represents a group of the formula: ##STR140## wherein R is as defined above.
In this process, an intended compound (X) is prepared by oxidizing, for example, an intended compound (IV) prepared by the above-described process. Particularly, the compound (IV) is dissolved in a solvent selected from the group consisting of aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride, water, alcohols such as methanol and ethanol, ethyl acetate, acetone and acetic acid, and an equimolar amount of an oxidizing agent such as hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid or sodium hypochlorite is added thereto under cooling with dry ice/alcohol or ice/water to conduct the reaction in an ordinary manner and thereby to produce an intended sulfoxide compound (X).
Preparation of compounds of the general formula (I) wherein X represents a group of the formula: ##STR141## wherein R is as defined above.
In this process, an intended compound (XI) is prepared by oxidizing an intended compound (IV) prepared by the above-described process. More particularly, the compound (IV) is dissolved in a solvent selected from the group consisting of aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride, water, alcohols such as methanol and ethanol, ethyl acetate, acetone and acetic acid, and two equivalents of an oxidizing agent such as hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid, sodium hypochlorite or sodium m-periodate is added thereto under cooling with ice or at room temperature to conduct the reaction and thereby to obtain an intended sulfone compound (XI).
In another preparation process, for example, a sulfoxide compound (X) prepared by the preparation process E is dissolved in a solvent such as chloroform and an oxidizing agent such as m-chloroperbenzoic acid is added thereto to conduct the reaction.
Preparation of compounds of the general formula (I) wherein X represents a group of the formula: --S-- ##STR142## wherein n represents an integer of 1 to 5 and R.sup.11 represents a lower alkyl, aryl, or heteroaryl group.
In this process, [2-(1,3-benzodioxol-5-yl)ethyl]thio derivative of the general formula (XI) as it is or in the form of a solution in, for example, benzene, dichloromethane, chloroform, tetrahydrofuran or N,N-dimethylformamide is mixed with a base such as pyridine, triethylamine, N,N-dimethylaniline or sodium carbonate as the dehydrohalogenating agent. An acid halide of the general formula: (XII) is added to the mixture to conduct the reaction and thereby to obtain an intended compound (XIII). Pyridine can be used as both the solvent and the dehydrohalogenating agent. The reaction is conducted by cooling with water or by heating under reflux.
Preparation of compounds of the general formula (I) wherein X represents a group of the formula: --S-- ##STR143## wherein n represents an integer of 1 to 5.
A [2-(1,3-benzodioxol-5-yl)ethyl]thio derivative (XIV) produced by, for example, the above-described process A, B or D is dissolved in a solvent such as benzene, chloroform or dimethylformamide. A chlorinating agent such as thionyl chloride, oxalyl chloride, phosphorus oxychloride or phosphorus pentachloride is added to the solution to conduct the reaction under cooling with ice, at room temperature or by heating under reflux to obtain an acid chloride derived from the compound (XIV). A solution of glycine (XV) in, for example, an aqueous sodium hydrogencarbonate solution, aqueous sodium carbonate solution or aqueous sodium hydroxide solution under stirring under cooling with ice/water to conduct the reaction and thereby to obtain an intended glycinamide (XVI).
The compound (XVI) prepared by this process is an intended compound of the general formula (I) wherein X represents --S--and R.sup.2 represents --(CH.sub.2).sub.n --CONHCH.sub.2 COOH.
Preparation of compounds of the general formula (I) wherein X represents a group of the formula: --S-- ##STR144## wherein Hal represents a halogen atom.
A 5-(2-halogenoethyl)-1,3-benzodioxole of the general formula (II) and thiourea of the formula (XVII) are dissolved in a solvent such as methanol or ethanol to conduct the reaction at room temperature or by heating under reflux to obtain a thiuronium salt (XVIII), which is then hydrolyzed in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitably selected solvent such as water, methanol, ethanol, hydrous methanol or hydrous ethanol at room temperature or by heating under reflux to obtain intended 2-(1,3-bnezodioxol-5-yl)ethanethiol (V). The halogen atoms include bromine, chlorine and iodine. Usually bromine or chlorine is used.
Preparation of compounds of the general formula (I) wherein X represents a group of the formula: --S-- ##STR145## wherein n represents an integer of 1 to 5 and R.sup.3 and R.sup.4 may be the same or different from each other and each represent a hydrogen atom or a lower alkyl group,
The carboxylic acid prepared by the preparation process A, B or D or its reactive derivative is reacted with an amino compound of the general formula (XIX) to form an amide which is an intended compound of the formula (XX).
The reactive derivatives of the compound (XIV) include acid halides such as acid chlorides and acid bromides; acid azides; active esters thereof with N-hydroxybenzotriazole and N-hydroxysuccinimides; symmetric acid anhydrides; and mixed acid ahydrides with alkylcarbonic acids and p-toluenesulfonic acid.
When a free carboxylic acid is used as the compound (XIV), the reaction is conducted preferably in the presence of a condensation agent such as dicyclohexylcarbodiimide or 1,1'-carbonyldiimidazole.
The reaction is conducted by using a compound (XIV) or its reactive derivative and a compound (XIX) in equimolar amounts or, alternatively, by using one of them in a small excess amount, in an organic solvent inert to the reaction such as pyridine, tetrahydrofuran, dioxane, ether, benzene, toluene, xylene, methylene chloride, dichloroethane, chloroform, dimethylformamide, ethyl acetate or acetonitrile.
Depending on the kind of the reactive derivative, it is advantageous for conducting the reaction smoothly to add a base such as triethylamine, pyridine, picoline, lutidine, N,N-dimethylaniline, potassium carbonate or sodium hydroxide.
The reaction temperature is not particularly limited, since it varies depending on the kind of the reactive derivative.
Pharmacologically acceptable salts of the intended compounds (I) which are also intended products of the present invention can be prepared by, for example, reacting a carboxylic acid compound of the general formula (I) wherein R represents --(CH.sub.2).sub.n --COOH, an amino acid compound of the general formula (I) wherein R represents ##STR146## or a glycinamide compound (XVI) wherein R represents --(CH.sub.2).sub.n --CONHCH.sub.2 COOH with an alkali hydrogencarbonate such as sodium hydrogen-carbonate or potassium hydrogencarbonate, an alkali carbonate such as sodium carbonate or potassium carbonate or an alkali hydroxide such as sodium hydroxide or potassium hydroxide to obtain a pharmacologically acceptable salt such as the above-mentioned sodium or potassium salt.
preparation of compounds of the general formula (I) wherein R.sup.4 represents a hydrogen atom ##STR147## wherein R.sup.1, R.sup.2 and R.sup.3 are as defined above.
In this process, a dicarboxylic acid of the general formula (II) is heated to a temperature of 150.degree. C. or higher in the absence of any solvent to obtain an intended carboxylic acid (I)'.
Preparation of compounds of the general formula (I) wherein R.sup.4 represents a hydrogen atom ##STR148## wherein R.sup.1, R.sup.2 and R.sup.3 are as defined above.
In this process, a nitrile of the general formula (III) is hydrolyzed in an ordinary manner to obtain an intended carboxylic acid (I)'.
Particularly, the hydrolysis is conducted by an ordinary method in the presence of a base in a solvent suitably selected from the group consisting of water, alcohols such as methanol, ethanol and ethylene glycol, hydrous alcohols such as hydrous methanol, hydrous ethanol, hydrous ethylene glycol, hydrous diethylene glycol and hydrous ethylene glycol, monoethyl ether, etc. The bases used herein include, for example, potassium hydroxide, sodium hydroxide, and barium hydroxide.
When R.sup.1 in the general formula (I) is a lower alkoxy-lower alkyl group, the intended compound can be prepared also by the following process: ##STR149## wherein R.sup.2, R.sup.3 and R.sup.4 are as defined above, X represents a halogen atom, M represents an alkali metal atom, "Alkyl" represents a lower alkyl group which is a straight-chain or branched one having 1 to 6 carbon atoms as described above, and "Alkylene" represents an alkylene group derived from the above-mentioned alkyl group.
In this process, a halide of the general formula (IV) is reacted with an alcoholate of the general formula (V) by an ordinary method in an organic solvent selected from the group consisting of, for example, tetrahydrofuran, dimethylformamide, methanol, ethanol and 1-propanol under cooling with ice, at room temperature or under heating to obtain an intended compound (VI). The halogen atoms usable in this process include, for example, bromine, chlorine and iodine atoms. The alkali metal atoms include, for example, sodium and potassium.
The compound (VI) obtained by this process is an intended compound of the present invention which is represented by the general formula (I) wherein R.sup.1 represents --Alkylene-O-Alkyl.
An intended compound of the general formula (I) wherein R.sup.1 represents a lower alkoxy-lower alkyl group of the formula: --CH.sub.2 --O--Alkyl in which "Alkyl" represents a lower alkyl group having 1 to 6 carbon atoms can be produced also by the following process: ##STR150## wherein R.sup.2, R.sup.3, R.sup.4 and "Alkyl" are as defined above.
In this process, an acetoxymethyl compound of the general formula (VII) is reacted with a compound of the general formula (VIII) in the presence of an acid catalyst at room temperature or under heating to obtain an intended compound of the general formula (IX). This reaction is preferably conducted in the presence of a lower alcohol such as methanol, ethanol, 1-propanol or 2-propanol.
The acid catalysts include, for example, hydrochloric, sulfuric, p-toluenesulfonic and D-10-camphorsulfonic acids.
The compound (IX) prepared by this process is an intended compound of the present invention which is represented by the general formula (I) wherein R.sup.1 represents --CH.sub.2 --O--Alkyl.
A compound of the general formula (I) wherein R.sup.1 and R.sup.3 form together a ring can be prepared also by the following process: ##STR151## wherein R.sup.2, R.sup.3 and R.sup.4 are as defined above and n represents an integer of 1 to 3.
An acrylic acid derivative of the general formula (X) is subjected to an intramolecular cyclization to obtain an intended compound (XI) of the present invention. This reaction is conducted by an ordinary method without using any solvent or in an organic solvent such as benzene, ethanol, tetrahydrofuran or dimethylformamide under cooling with ice, at room temperature or under heating for several hours. The reaction proceeds easily in the presence of a base such as sodium ethylate, potassium t-butoxide or sodium hydride.
The compound (XI) obtained by the above-mentioned process is one of the intended compounds of the present invention.
Preparation of compounds of the general formula (I) wherein X represents a group of the formula: --S-- ##STR152## wherein Y represents a halogen atom or a methanesulfonyloxy or p-toluenesulfonyloxy group and A, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as defined above.
In this process, a thiol of the general formula (II) is reacted with a compound of the general formula (III) to form an intended compound (IV). This reaction is conducted by an ordinary method without using any solvent or in an organic solvent inert to the reaction selected from the group consisting of aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as tetrahydrofuran and dioxane, ketones such as acetone and methyl ethyl ketone, alcohols such as methanol and ethanol, halogenated hydrocarbons such as chloroform and carbon tetrachloride, acetonitrile, N,N-dimethylformamide and dimethyl sulfoxide under cooling with ice, at room temperature or under heating for several hours. The reaction proceeds easily when an alkali metal carbonate or hydrogencarbonate such as sodium hydrogencarbonate, potassium carbonate or sodium carbonate, an alkali hydroxide such as sodium hydroxide or potassium hydroxide, or an organic base such as triethylamine, pyridine or diethylaniline is used as the dehydrohalogenating agent, or an agent for removing methanesulfonic or p-toluenesulfonic acid.
Preparation of compounds of the general formula (I) wherein X represents a group of the formula: --S-- ##STR153## wherein Y represents a halogen atom or a methane-sulfonyloxy or p-toluenesulfonyloxy group and A, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as defined above.
In this process, a compound of the general formula (V) is reacted with a thiol of the general formula (VI) under the same conditions as those of preparation process A to obtain an intended compound (IV). Also in this process, preferred results are obtained when a base described above with reference to the preparation process A is used.
The halogen atom used in the preparation processes A and B include chlorine, bromine and iodine. Usually bromine or chlorine is used.
Preparation of compounds of the general formula (I) wherein X represents a group of the formula: --S-- ##STR154## wherein A, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as defined above.
A compound of the general formula (VII) is reacted with a thiol of the general formula (VI) to obtain an intended compound (IV). This reaction is conducted by an ordinary method without using any solvent or in a solvent selected from the group consisting of aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as tetrahydrofuran and dioxane, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride, ketones such as acetone and methyl ethyl ketone, esters such as ethyl acetate, acetonitrile and N,N-dimethylformamide under cooling with ice, at room temperature or by heating under reflux.
When the reaction proceeds only slowly, a peroxide such as benzoyl peroxide or a catalyst such as azobisisobutyronitrile can be added.
Preparation of compounds of the general formula (I) wherein X represents a group of the formula: --S-- ##STR155## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as defined above.
A cyano compound of the general formula (VIII) which is also an intended compound is reacted with carbon dioxide in the presence of a base to obtain an intended carboxylic acid of the general formula (IX). In this process, a compound (VIII) as it is or in the form of a solution in an anhydrous ether solvent such as anhydrous ethyl ether, anhydrous tetrahydrofuran or anhydrous ethylene glycol dimethyl ether is reacted with a strong base such as n-butyllithium, phenyllithium, lithium diisopropylamide or sodium amide under cooling with dry ice/alcohol or with ice, and the reaction product is further reacted with carbon dioxide under cooling with dry ice/alcohol or with ice to obtain the compound (IX).
The compound (IX) is an intended one of the present invention represented by the general formula (I) wherein X represents --S--and A represents ##STR156##
Preparation of compounds of the general formula (I) wherein X represents a group of the formula: --S-- ##STR157## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.9, R.sup.10 and p are as defined above.
A sodium sulfonate of the general formula (X) is suspended in, for example, benzene or chloroform. Then, thionyl chloride or the like is added thereto and the reaction is conducted by heating under reflux to obtain an acid chloride of the compound (X). This product is reacted with an amine (XI) in the presence of a base in the absence of any solvent or in a solvent such as water, methanol, ethanol, benzene, dichloromethane, tetrahydrofuran or N,N-dimethylformamide to obtain an intended compound (XII). The bases usable herein include, for example, the amine (XI) per se, pyridine, N,N-dimethylaniline or triethylamine.
The compound (XII) is an intended one of the present invention represented by the general formula (I) wherein X represents --S--and A represents ##STR158##
Preparation of compounds of the general formula (I) wherein X represents a group of the formula: ##STR159## wherein A, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as defined above.
A compound (IV) which also is an intended compound prepared by, for example, the above-described process is oxidized to obtain an intended compound (XIII). In this process, the compound (IV) is dissolved in a solvent selected from the group consisting of aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride, water, alcohols such as methanol and ethanol, ethyl acetate, acetone and acetic acid and then reacted with an equimolar amount of an oxidizing agent such as hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid or sodium hypochlorite by an ordinary method under cooling with dry ice/ alcohol or with ice/water to obtain the intended sulfoxide compound (XIII).
Preparation of compounds of the general formula (I) wherein X represents a group of the formula: ##STR160## wherein A, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as defined above.
In this process, an intended compound (IV) obtained by, for example, the above-described process is oxidized to obtain an intended compound (XIV). More particularly, the compound (IV) is dissolved in a solvent selected from the group consisting of aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride, water, alcohols such as methanol and ethanol, ethyl acetate, acetone and acetic acid. At least two equivalents of an oxidizing agent such as hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid, sodium hypochlorite or sodium m-periodate is added thereto under cooling with ice or at room temperature to conduct the reaction and thereby to obtain an intended sulfone compound (XIV).
In another process, a sulfoxide compound (XIII) obtained by, for example, the preparation process F is dissolved in a solvent such as chloroform and then an oxidizing agent such as m-chloroperbenzoic acid is added to the solution to conduct the reaction.
Pharmacologically acceptable salts of the intended compounds (I) which are also intended products of the present invention can be prepared by, for example, reacting a compound of the general formula (I) wherein A represents ##STR161## R .sup.3 represents --(CH.sub.2).sub.n COOH or A represents ##STR162## with sodium hydrogencarbonate, potassium hydrogen-carbonate, sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide to obtain a pharmacologically acceptable salt such as sodium or potassium salt thereof.
That is, a thiol represented by the general formula (II) is reacted with a thiol represented by the general formula (III) to obtain a compound (I) which is one of the objective compounds according to the present invention.
More precisely, the reaction of a compound (II) with a compound (III) is carried out in the absence of any solvent or in the presence of a solvent inert to the reaction selected from among alcohols such as methanol, ethanol and propanol, acetic acid and an aqueous solution of potassium iodide or the like either under cooling with ice or heating or at a room temperature by using an oxidizing agent such as iodine, hydrogen peroxide, lead dioxide, oxygen, copper sulfate, ferric chloride, potassium permanganate, potassium ferricyanide, sulfuryl chloride, dimethyl sulfoxide, sulfur dioxide or phosphorus pentachloride according to an ordinary method to obtain a compound (I) which is one of the objective compounds.
More precisely, the reaction of an alcohol represented by the general formula (IV) with an acid halide represented by the general formula (V) is carried out in the absence of any solvent or in the presence of a solvent such as dichloromethane, chloroform, tetrahydrofuran or N,N-dimethylformamide by using a base such as pyridine, triethylamine, N,N-dimethylaniline, sodium carbonate or sodium hydrogencarbonate as a dehydrohalogenating agent to obtain a compound (VI) which is one of the objective compounds. In the reaction, pyridine can serve as both a solvent and a dehydrohalogenating agent. The reaction may be carried out either under cooling with water or under reflux by heating.
The preparation of pharmacologically acceptable salts of the compounds (I), which are also among the objective compounds according to the present invention, can be carried out by, for example, reacting a compound represented by the general formula (I) wherein Y is ##STR165## with hydrochloric, sulfuric or hydrobromic acid. Thus, the hydrochloride, sulfate or hydrobromide of the compound (I) is obtained.
That is, an alcohol represented by the general formula (II) is reacted with a mercaptoacetic acid represented by the general formula (III) to obtain a compound represented by the general formula (IV) which is one of the objective compounds according to the present invention. This reaction is carried out in the absence of any solvent or in the presence of an organic solvent inert to the reaction selected from among aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as ether, isopropyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride; esters such as ethyl acetate; ketones such as acetone and methyl ethyl ketone; acetonitrile; dimethylformamide and acetic acid either under cooling with ice or heating or at a room temperature for several hours according to an ordinary process. The progress of the reaction is facilitated by using an acid such as sulfonic, p-toluenesulfonic or D-10-camphorsulfonic acid as a catalyst.
That is, a compound represented by the general formula (V) is reacted with a mercaptoacetic acid represented by the formula (III) to obtain a compound represented by the general formula (VI) which is one of the objective compounds according to the present invention.
More precisely, the above reaction is carried out in the absence of any solvent or in the presence of an organic solvent inert to the reaction selected from among aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahydrofuran and dioxane; ketones such as acetone and methyl ethyl ketone; alcohols such as methanol and ethanol; halogenated hydrocarbons such as chloroform and carbon tetrachloride; acetonitrile, N,N-dimethylformamide and dimentyl sulfoxide either under cooling with ice or heating or at a room temperature for several hours according to an ordinary process. The progress of the reaction can be facilitated by using an alkali metal carbonate or hydrogencarbonate such as sodium hydrogencarbonate or potassium or sodium carbonate; an alkali hydroxide such as sodium or potassium hydroxide; an organic base such as triethylamine, pyridine or diethylaniline or sodium hydride as a dehydrohalogenating, demethanesulfonating or de-p-toluenesulfonating agent.
In the preparation processes A and B, the halogen atom includes chlorine, bromine, and iodine, among which bromine and iodine are generally used.
That is, a carboxylic acid represented by the general formula (VI) or a reactive derivative thereof, which can be prepared by, for example, the above preparation process A or B, is reacted with an amine represented by the general formula (VII) to obtain a compound represented by the general formula (VIII) which is one of the objective compounds according to the present invention.
The reactive derivative of the compound (VI) includes acid halides such as acid chloride and acid bromide; acid azide; reactive esters thereof with N-hydroxybenzotriazole, N-hydroxysuccinimide or the like; symmetric acid anhydride and mixed acid anhydride thereof with alkylcarbonic acid and p-toluenesulfonic acid.
When a compound (VI) having a free carboxyl group is used, it is preferred to carry out the reaction in the presence of a condensation agent such as dicyclohexylcarbodiimide or 1,1'-carbonyldiimidazole.
The reaction is carried out by using a compound (VI) or a reactive derivative thereof and a compound (VII) in equimolar amounts or in such amounts that either of then is in slight excess over the other in an organic solvent inert to the reaction selected from among pyridine, tetrahydrofuran, dioxane, ether, benzene, toluene, xylene, methylene chloride, dichloroethane, chloroform, dimethylformamide, ethyl acetate, acetonitrile and the like.
When some kinds of the reactive derivatives are used, the addition of a base such as triethylamine, pyridine, picoline, lutidine, N,N-dimethylaniline, potassium carbonate or sodium hydroxide advantageously serves to make the reaction proceed smoothly
The reaction temperature is not particularly limited and varies depending upon the kind of the reactive derivative used.
More precisely, a compound (VI), which can be prepared by the preparation process A or B, is dissolved in a solvent such as benzene, chloroform or dimethylfromamide, followed by the addition of thionyl chloride, oxalyl chloride, phosphorus oxychloride or phosphorus pentachloride. The obtained mixture was reacted either under cooling with ice or reflux by heating or at a room temperature to prepare an acid chloride of the compound (VI). A solution of glycine (IX) in an aqueous solution of sodium hydrogencarbonate, sodium carbonate or sodium hydroxide or the like is poured into the obtained reaction mixture under stirring and cooling with ice to carry out the reaction. Thus, a glycinamide (X) which is one of the objective compounds is obtained.
The glycinamide (X) obtained above corresponds to a compound represented by the general formula (I) wherein R.sup.4 or R.sup.5 is a carboxymethyl group and is thus one of the objective compounds according to the present invention.
The preparation of a pharmacologically acceptable salt of a compound (I), which is also one of the objective compounds according to the present invention, can be carried out by, for example, reacting a carboxylic acid (VI) corresponding to a compound represented by the general formula (I) wherein Y is --CO.sub.2 H or a glycinamide (X) corresponding to a compound represented by the general formula (I) wherein R.sup.4 or R.sup.5 is a carboxymethyl group with an alkali hydrogen-carbonate such as sodium or potassium hydrogen-carbonate, an alkali carbonate such as sodium or potassium carbonate or an alkali hydroxide such as sodium or potassium hydroxide.
US Referenced Citations (1)
| Number |
Name |
Date |
Kind |
| 3852439 |
Hennart et al. |
Dec 1974 |
|
Foreign Referenced Citations (2)
| Number |
Date |
Country |
| 62-29522 |
Feb 1987 |
JPX |
| 62-39583 |
Feb 1987 |
JPX |
Continuations (1)
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Number |
Date |
Country |
| Parent |
160333 |
Feb 1988 |
|
Patent Grant
5110956
