| CORP. SALE | HO-C6H4-CONH-C6H4-N(Me)2 |
| PATENT ASSIGNEE'S COUNTRY | Japan |
| UPDATE | 07.00 |
| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | 04.07.00 |
| PATENT TITLE |
Phenylenediamine derivative, radical scavenger, brain-infarction depressant, and brain-edema depressant |
| PATENT ABSTRACT |
A phenylenediamine derivative or a salt thereof in accordance with the present invention is expressed by the following formula 1: ##STR1## wherein A represents a group expressed by --CO--, --CH.sub.2 CO--, --CS--, or --SO.sub.2 --; Y represents a carbon atom or nitrogen atom; R.sub.1 represents a lower alkyl group; R.sub.2 represents a hydrogen, lower alkyl, alkenyl, benzyl, or benzoyl group; and each of R.sub.3 and R.sub.4 represents an alkyl group having 1-10 carbon atoms. The phenylenediamine derivative above mentioned, as a radical scavenger, has antioxidant effect and lipid peroxidation inhibitory activity so as to be available for inhibiting brain infarction or brain edema. |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | 02.06.98 |
| PATENT REFERENCES CITED |
Klosa, J. Praket. Chem. 19(4), 45-55(1963) (With Chemical Abstract 11349), German language, 1963. Gupta,, Gupta, Search for New Local Anaesthetics. Part IV, English Language, J. Indian Chem. Soc. 34.528-530(1957). Hassner et al., , Synthetic Methods. Part 23 Rearrangement of Some Hydroxamic Acids Into Amides. A Self-Condensation Leading to Disproportionation English Language, J. Chem. Soc. Perkin. Trans. 733-737(1988). Shiseido Co., Ltd., Abstract, Jap. Patent Application 07344947, Jun. 17, 1997. |
| PATENT CLAIMS |
What is claimed is: 1. A phenylenediamine derivative or a pharmacologically acceptable salt thereof expressed by the following formula 1: ##STR23## wherein A represents a group expressed by --CO--, --CH.sub.2 CO--, --CS--, or --SO.sub.2 --; Y represents a carbon atom; R.sub.1 represents a lower alkyl group; R.sub.2 represents a hydrogen atom, or a lower alkyl, benzyl, or benzoyl group; and each of R.sub.3 and R.sub.4 represents an alkyl group having 1-10 carbon atoms. 2. A phenylenediamine derivative or a pharmacologically acceptable salt thereof according to claim 1, wherein A is a group expressed by --CO--. 3. A phenylenediamine derivative or a pharmacologically acceptable salt thereof according to claim 1, wherein R.sub.3 and R.sub.4 are methyl group. 4. A phenylenediamine derivative or a pharmacologically acceptable salt thereof according to claim 1, wherein R.sub.1 is isobutyl group. 5. A phenylenediamine derivative or a pharmacologically acceptable salt thereof according to claim 1, as expressed by the following formula 2: ##STR24## wherein Y represents a carbon atom; R.sub.1 represents a lower alkyl group; and each of R.sub.3 and R.sub.4 represents an alkyl group having 1-10 carbon atoms. 6. A phenylenediamine derivative or a pharmacologically acceptable salt thereof according to claim 5, wherein R.sub.3 and R.sub.4 are methyl group. 7. A phenylenediamine derivative or a pharmacologically acceptable salt thereof according to claim 5, wherein R.sub.1 is isobutyl group. 8. A phenylenediamine derivative or a pharmacologically acceptable salt thereof according to claim 1, as expressed by the following formula 3: ##STR25## wherein Y represents a carbon atom; R.sub.1 represents a lower alkyl group; R.sub.2 represents a lower alkyl, benzyl, or benzoyl group; and each of R.sub.3 and R.sub.4 represents an alkyl group having 1-10 carbon atoms. 9. A phenylenediamine derivative or a pharmacologically acceptable salt thereof according to claim 8, wherein R.sub.3 and R.sub.4 are methyl group. 10. A phenylenediamine derivative or a pharmacologically acceptable salt thereof according to claim 8, wherein R.sub.1 is isobutyl group. 11. A phenylenediamine derivative or a pharmacologically acceptable salt thereof according to claim 1, as expressed by the following formula 4: ##STR26## wherein Y represents a carbon atom; A represents a group expressed by --CH.sub.2 CO--, --CS--, or --SO.sub.2 ; R.sub.1 represents a lower alkyl group; R.sub.2 represents a hydrogen, a lower alkyl, benzyl, or benzoyl group; and each of R.sub.3 and R.sub.4 represents an alkyl group having 1-10 carbon atoms. 12. A phenylenediamine derivative or a pharmacologically acceptable salt thereof according to claim 11, wherein R.sub.3 and R.sub.4 are methyl group. 13. A phenylenediamine derivative or a pharmacologically acceptable salt thereof according to claim 11, wherein R.sub.1 is isobutyl group. 14. A radical scavenger composition comprising, as an effective ingredient, a phenylenediamine derivative or a pharmacologically acceptable salt thereof according to claim 1, together with a pharmaceutically acceptable carrier and/or adjuvant. 15. A brain infarction depressant composition comprising, as an effective ingredient, a phenylenediamine derivative or a pharmacologically acceptable salt thereof according to claim 1, together with a pharmaceutically acceptable carrier and/or adjuvant. 16. A brain edema depressant composition comprising, as an effective ingredient, a phenylenediamine derivative or a pharmacologically acceptable salt thereof according to claim 1, together with a pharmaceutically acceptable carrier and/or adjuvant. 17. A method for inhibiting a brain infarction in man or mammals, which comprises administering an effective amount of a phenylenediamine derivative or a pharmacologically acceptable salt thereof according to claim 1 to a host in need of said treatment. 18. A method for inhibiting a brain edema in man or mammals, which comprises administering an effective amount of a phenylenediamine derivative or a pharmacologically acceptable salt thereof according to claim 1 to a host in need of said treatment. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
RELATED APPLICATIONS None. FIELD OF THE INVENTION The present invention relates to a phenylenediamine derivative and, in particular, to a derivative effective as a radical scavenger in organisms. BACKGROUND OF THE INVENTION In recent years, attention has been paid to influences of active oxygen and free radical upon organisms. Active oxygen and free radical are always generated and eliminated within an organism as long as the organism continues to live while using oxygen. In general, they act advantageously to the organism as a part of organism protection. However, when they are generated in an amount exceeding the protecting ability of the organism against the radical, they may attack the components of the organism constituting membranes and tissues of thereof, thereby causing various pathologies and malignancies. At present, the pathologies and diseases which may be attributable to active oxygen and free radical are numerous and their examples include cerebral nerves diseases such as brain infarction, brain edema, and parkinsonism; lung diseases such as lung oxygen intoxication and adult respiratory distress syndrome; circulation system diseases such as ischemic heart diseases (e.g., myocardial infarction and arrhythmia), and arteriosclerosis; and digestive organs diseases such as peptic ulcer, ulcerative colitis, and Crohn's disease. Under these circumstances, consequently, there have been attempts to apply scavengers of active oxygen and free radical to medicaments for the above-mentioned diseases. For example, with respect to brain edema, mannitol, which is a mild radical scavenger, has been clinically used, though it is necessary continuous administration for two weeks. Recently, radical scavengers such as AVS (currently being applied) and MCI186 (currently being clinically tested in the third phase) have been developed recently. The sole target disease of these compounds is, however, brain edema. There has been no medical drug in which a radical scavenger is used for suppressing brain infarction. On the other hand, a recombinant of SOD has become available and has been administered to patients so as to study its tissue-protecting effect. Acute myocardial infarction is one of its target diseases. By contrast, no radical scavenger other than SOD has been known as a medicament for this disease. With respect to arrhythmia, on the other hand, only lidocaine, which is a local anesthetic, has been clinically used. SUMMARY OF THE INVENTION In view of the foregoing prior art, an object of the present invention is to provide a low-molecular compound which is, as a radical scavenger, effective against brain edema and brain infarction. Another object of the present invention is to provide a low-molecular compound which is effective against various diseases which are attributable to active oxygen and free radical. As a result of diligent studies of the inventors for attaining the above mentioned objects, it has been found that a specific phenylenediamine derivative and its pharmacologically acceptable salts are effective, as a radical scavenger, against brain edema and brain infarction, thereby accomplishing the present invention. Namely, a phenylenediamine derivative in accordance with the present invention is expressed by the following formula 1: ##STR2## wherein A represents a group expressed by --CO--, --CH.sub.2 CO--, --CS--, or --SO.sub.2 --; Y represents a carbon atom or nitrogen atom; R.sub.1 represents a lower alkyl group; R.sub.2 represents a hydrogen, lower alkyl, alkenyl, benzyl, or benzoyl group and each of R.sub.3 and R.sub.4 represents an alkyl group having 1 to 10 carbon atoms. A radical scavenger in accordance with the present invention is characterized by comprising, as an effective ingredient, said phenylenediamine derivative or the pharmacologically acceptable salt thereof, together with a pharmaceutically acceptable carrier and/or adjuvant. A brain infarction depressant in accordance with the present invention is characterized by comprising, as an effective ingredient, said phenylenediamine derivative or the pharmacologically acceptable salt thereof together with a pharmaceutically acceptable carrier and/or adjuvant. A brain edema depressant in accordance with the present invention is characterized by comprising, as an effective ingredient, said phenylenediamine derivative or the pharmacologically acceptable salt thereof, together with a pharmaceutically acceptable carrier and/or adjuvant. A method for inhibiting a brain infarction in man or manmals in accordance with the present invention is characterized by administering an effective amount of said phenylenediamine derivative or the pharmacologically acceptable salt thereof to a host. A method for inhibiting a brain edema in man or manmals in accordance with the present invention is characterized by administering an effective amount of said phenylenediamine derivative or the pharmacologically acceptable salt thereof to a host. BRIEF DESCRIPTION OF THE DRAWINGS FIGS. 1 to 5 show examples of steps for manufacturing the phenylenediamine derivative in accordance with the present invention and FIGS. 6 to 11 show examples of steps for manufacturing material compounds for synthesizing the phenylenediamine derivative in accordance with the present invention. DETAILED DESCRIPTION OF THE INVENTION In the above-mentioned formula 1 which represents a phenylenediamine derivative in accordance with the present invention, A represents a group expressed by --CO--, --CH.sub.2 CO--, --CS--, or --SO.sub.2 -- and is preferably a group expressed by --CO--. Further, Y represent a carbon atom or nitrogen atom. In each formula that represents a compound in accordance with the present invention, lower alkyl group found at R.sub.1 refers to a straight or branched alkyl group having 1 to 6 carbon atoms. Examples thereof include methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl, 1-ethylpropyl, isoamyl, and n-hexyl groups. Preferable example of the lower alkyl group is isobutyl groups. R.sub.2 represents a hydrogen atom, a lower alkyl, alkenyl, benzyl, or benzoyl group. Also, the definition of lower alkyl group in R.sub.2 is the identical with the above-mentioned R.sub.1. Alkenyl group found at R.sub.2 refers to a straight or branched alkenyl group, which has 2 to 20 carbon atoms. It is preferably a branched alkenyl group and, more preferably, geranyl group. While the double bond has two kinds of configurations, namely, cis and trans, each double bond in alkenyl group may have either configuration. When R.sub.2 is benzyl or benzoyl group, it may be have a substituent R.sub.3 and R.sub.4 represent alkyl group having 1 to 10 carbon atoms and may be identical to or different from each other. In R.sub.3 and R.sub.4, alkyl group may be a straight or branched chain and is preferably methyl group. The phenylenediamine derivative and its pharmacologically acceptable salts expressed by formula 1 that are preferable as a main ingredient of the radical scavenger, brain-infarction depressant, and brain-edema depressant in accordance with the present invention, as a radical scavenger, have antioxidant effect and lipid peroxidation suppressing effect as well as a high safety. Accordingly, they are effective as medicaments for preventing and curing various damages attributable to radicals generated by ischemic reperfusion or the like such as brain infarction and brain edema. Also, they are expected to be effective against the other ischemic reperfusion damages. Further, unlike the conventional radical scavengers, some kinds of the compound of the present invention has effective, by one drug, against both brain edema and brain infarction. As similar compounds of a phenylenediamine derivative in accordance with the present invention, there have been known a phenylenediamine derivative having anti-thrombocyte aggregation effect in DE 3,830,054, a phenylenediamine derivative having anti-hypnotic effect anti-tumor effect and sedative effect in U.S. Pat. No. 2,870,146, a phenylenediamine derivative in J. Prakt. Chem. 19(4), 45(1963). And a phenylenediamine derivative having local anesthesia effect in J. Indian. Chem. Soc. 34, 528(1957). However, these phenylenediamine derivatives have no relation to pharmacological effect of the present invention. Further, the derivative of the resent invention is characterized in that has a substituent expressed as R.sub.1 and R.sub.2 --O-- on benzene ring as shown in the above-mentioned formula 1. Such compound was not shown in the above. Thus, the phenylenedi amine of the present invention shown in the formula 1 is a novel compound. A preferable example of a phenylenediamine derivative in accordance with the present invention is expressed by the following formula 2: ##STR3## wherein R.sub.1, R.sub.3, R.sub.4, and Y are defined as those in formula 1. Also, a preferable example of a phenylenediamine derivative in accordance with the resent invention is expressed by the following formula 3: ##STR4## wherein R.sub.2 represents a lower alkyl, alkenyl, benzyl, or benzoyl group and R.sub.1, R.sub.3, R.sub.4, and Y are defined as those in formula 1. Further, a preferable example of a phenylenediamine derivative in accordance with the present invention is expressed by the following formula 4: ##STR5## wherein A represents a group expressed by --CH.sub.2 CO--, --CS--, or --SO.sub.2 -- and R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are defined as those in formula 1. In formula 1-4, each of R.sub.3 and R.sub.4 is preferably methyl group and R.sub.1 is preferably isobutyl group. The compound (I), which is expressed by formula 1, can be made by reaction formulas A to E shown in FIGS. 1 to 5. As its manufacturing method, a general method disclosed in "New Experimental Chemistry Course" (Maruzen Co.) or "Peptide Synthesis" (Maruzen Co.), for example, can be used. First, in reaction formula A shown in FIG. 1, A.sub.1 represents --CO-- or --CH.sub.2 CO--, while R.sub.1, R.sub.2, R.sub.3, R.sub.4 and Y are defined as those in formula (I). In reaction formula A, from the carboxylic acid(II) and the amine(III), the amide(I-a) in accordance with the present invention can be obtained. In this reaction, known amide-bond forming reactions such as a method proceeding by way of a mixed anhydride, a method proceeding by way of an acid chloride, a method using a condensing agent, a method using a carbonyl diimidazole, and a method using with an azide can be used. In the mixed anhydride method, an activator such as diphenylphosphinic chloride, phosphorus oxychloride, ethyl chloroformate, isobutyl chloroformate, or pivaloyl chloride is used to convert the carboxylic acid (II) into its corresponding acid anhydride and then the latter is reacted with the amine (III). As an additive, for example, an organic base such as triethylamine, pyridine, or N-methylmorpholine can be used. As a solvent, for example, a halogenated hydrocarbon such as dichloromethane or chloroform; an aromatic compound such as benzene, toluene, xylene, or pyridine; an ether such as tetrahydrofuran or dioxane; an amide such as dimethylformamide or dimethylacetamide; or dimethylsulfoxide can be used. While the reaction temperature and reaction time may be changed according to the material compounds used, the reaction is usually effected at a temperature within the range of -15.degree. C. to the reflux temperature of the solvent. In the acid chloride method, for example, phosphorus pentachloride, phosphorus trichloride, or thionyl chloride is used to convert the carboxylic acid (II) into its corresponding acid chloride and then the latter is reacted with the amine (III). As an additive, for example, an organic base such as triethylamine, pyridine, or N-methylmorpholine; an inorganic base such as sodium hydroxide; or a salt such as sodium acetate or potassium carbonate can be used. As a solvent, for example, a halogenated hydrocarbon such as dichloromethane or chloroform; an aromatic compound such as benzene, toluene, xylene, or pyridine; an ether such as diethyl ether, tetrahydrofuran, or dioxane; an amide such as dimethylformamide or dimethylacetamide; dimethylsulfoxide; water; or the mixture thereof can be used. While the reaction temperature and reaction time may be changed according to the material compounds used, the reaction is usually effected at a temperature within the range of 0.degree. C. to the reflux temperature of the solvent. In the method using a condensing agent, for example, a carbodiimide such as N, N'-dicyclohexylcarbodiimide (DCC) or 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCI) or a chloride such as titanium tetrachloride or silicon tetrachloride can be used. As a solvent, for example, a halogenated hydrocarbon such as dichloromethane or chloroform; an aromatic compound such as benzene, toluene, xylene, or pyridine; an ether such as tetrahydrofuran or dioxane; an amide such as dimethylformamide or dimethylacetamide; or dimethylsulfoxide can be used. If necessary, this reaction may be effected while 1-hydroxy benzotriazole (HOBt) or N-hydroxysuccinimide (HOSu) is added thereto. While the reaction temperature and reaction time may be changed according to the material compounds used, the reaction is usually effected at a temperature within the range of -78.degree. C. to the reflux temperature of the solvent. In the method using carbonyl diimidazole (CDI), 1,1'-carbonyldiimidazole is used to convert the carboxylic acid (II) into its N-acyl derivative and then the latter is reacted with the amine (III). As a solvent, for example, a halogenated hydrocarbon such as dichloromethane or chloroform; an aromatic compound such as benzene, toluene, or xylene; an ether such as tetrahydrofuran or dioxane; an amide such as dimethylformamide or dimethylacetamide; or dimethylsulfoxide can be used. While the reaction temperature and reaction time may be changed according to the material compounds used, the reaction is usually effected at a temperature within the range of 0.degree. C. to the reflux temperature of the solvent. In the azide method, an activator such as diphenylphosphorylazide is used to convert the carboxylic acid (II) into its corresponding azide and then the latter is reacted with the amine (III). As an additive, for example, an organic base such as triethylamine, pyridine, or N-methylmorpholine can be used. As a solvent, for example, a halogenated hydrocarbon such as dichloromethane or chloroform; an aromatic compound such as benzene, toluene, xylene, or pyridine; an ether such as tetrahydrofuran or dioxane; an amide such as dimethylformamide or dimethylacetamide; or dimethylsulfoxide can be used. While the reaction temperature and reaction time may be changed according to the material compounds used, the reaction is usually effected at a temperature within the range of 0.degree. C. to the reflux temperature of the solvent. In the ester-bond formation by the dehydrating condensation, for example, methods using, as a catalyst, a mineral acid such as sulfuric acid or hydrochloric acid, an organic acid such as p-toluene sulfonic acid, or a Lewis acid such as boron trifluoride etherate or methods using a coexisting desiccating agent such as magnesium sulfate anhydride or molecular sieve can be used. Also, a condensing agent such as trifluoroacetic anhydride or N,N'-dicyclohexylcarbodiimide (DCC) can be used. In this case, pyridine, 4-dimethylaminopyridine, or the like can be used therewith. Further, in the presence of triphenylphosphine, diethyl diazocarboxylate can be used. As a solvent, for example, a halogenated hydrocarbon such as dichloromethane or chloroform; an aromatic compound such as benzene, toluene, xylene, or pyridine; an ether such as tetrahydrofuran or dioxane; or an amide such as N,N-dimethylformamide or N,N-dimethylacetamide can be used. While the reaction temperature and reaction time can be changed according to the material compounds used, the reaction is usually effected at a temperature within the range of 0.degree. C. to the reflux temperature of the solvent. Specifically, for example, in the method using the condensing agent, the carboxylic acid (II) is dissolved in dichloromethane, N,N-dimethylformamide, or the like and, after a condensing agent such as DCC or WSCI is added thereto, in or without the presence of HOBt or HOSu as an additive, and the resulting mixture is stirred, the amine (III) is added thereto and the reaction is effected at a temperature within the range of 0.degree. C. to room temperature, thereby attaining the aimed object. In the mixed acid anhydride method, the reaction is effected at a temperature within the range of 0.degree. C. to room temperature in the solvent such as chloroform by using diphenylphosphinic chloride as an activating agent and triethylamine as an additive, thereby attaining the aimed object. Also, the compound in accordance with the present invention can be obtained by reaction formula B shown in FIG. 2. In reaction formula B, A.sub.1 represents --CO-- or --CH.sub.2 CO--, while R.sub.1, R.sub.3, R.sub.4, and Y are defined as those of formula (I). Also, R.sub.5 represents a protective group of phenolic hydroxyl group and can use benzyl group, various substituted benzyl groups, benzyloxycarbonyl group, or tert-butyloxycarbonyl group, as long as no problem has occurred in the subsequent reaction. In the first step of reaction formula B, the compound (I-b) can be obtained from carboxylic acid (II-a) and amine (III) by using condensation method described in formula A. In the second step of reaction formula B, the compound (I-c) can be obtained by putting the compound (I-b) into deprotection. The deprotection can use various known methods according to the types of protective group R.sub.5. For example, a reductive removal method or a method by treating with acid can be used in the case where R.sub.5 is benzyl group. Specifically, for example, palladium-carbon is used as catalyst under the catalytic reduction condition and the reaction is effected in the solvent such as ethanol and at a temperature within the range of room temperature to the reflux temperature of the solvent, thereby attaining the aimed object. Also, the compound in accordance with the present invention can be obtained by reaction formula C shown in FIG. 3. In reaction formula C, R.sub.2 represents a lower alkyl, alkenyl, benzyl, or benzoyl group, while R.sub.1, R.sub.3, R.sub.4, and Y are defined as those of formula (I). Also, X represents a halogen atom. In the first step of reaction formula C, sulfonyl amide compound (V) in accordance with the present invention can be obtained from sulfonyl halide (IV) and amine (III). In this reaction, for example, sodium hydroxide, potassium hydroxide, or organic base such as triethylamine, pyridine, or N-methylmorpholine can be used as an additive. As a solvent, for example, water; acetone; a halogenated hydrocarbon such as dichloromethane or chloroform; an aromatic compound such as benzene, toluene, xylene, or pyridine; an ether such as tetrahydrofuran or dioxane; or an amide such as dimethylformamide or dimethylacetamide can be used. While the reaction temperature and reaction time may be changed according to the material compounds used, the reaction is usually effected at a temperature within the range of -15.degree. C. to the reflux temperature of the solvent. Specifically, for example, sulfonyl halide (IV) is dissolved in tetrahydrofuran, chloroform, or the like, amine (III) is added to the solution in the presence of triethylamine, sodium hydroxide, or the like. The reaction is effected at a temperature within the range of -15.degree. C. to the reflux temperature of the solvent, thereby attaining the aimed object. In the second step of reaction formula C, the compound (V-a) can be obtained by deprotection of the compound (V). This deprotection can be conducted by the same condition with the second step in reaction formula B. The compound in accordance with the present invention can be obtained by reaction formula D shown in FIG. 4. In reaction formula D, A.sub.1 represents --CO-- or --CH.sub.2 CO--, while X represents a halogen atom. R.sub.2 represents a lower alkyl, alkenyl, benzyl, or benzoyl group, while R.sub.1, R.sub.3, R.sub.4, Y, and n are defined as those of formula (I). In reaction formula D, when a halide (VI) is reacted with the compound (I-c), the compound (I-a) of the present invention can be synthesized. This reaction can be effected in the presence of a base. Sodium amide, triethylamine, sodium hydride, sodium hydroxide, potassium carbonate, barium oxide, silver oxide, or the like can be used therefor. Also, a catalytic amount of potassium iodide can be added thereto. As a solvent, for example, an alcohol such as methanol, ethanol, or butanol; an aromatic compounds such as benzene, toluene, xylene, or pyridine; an ether such as diethylether, tetrahydrofuran, or dioxane; an amide such as N,N-dimethylformamide or N,N-dimethylacetamide; a sulfoxide such as dimethylsulfoxide; or a ketone such as acetone can be used. While the reaction temperature and reaction time may be changed according to the material compounds used, the reaction is usually effected at a temperature within the range of 0.degree. C. to the reflux temperature of the solvent. Specifically, for example, the compound (I-c) is dissolved in the solvent such as tetrahydrofuran, N,N-dimethylformamide, or the like and, after sodium hydride is added thereto and the resulting mixture is stirred, the halide (VI) is added thereto. The reaction is effected at a temperature within the range of room temperature to the reflux temperature of the solvent, thereby attaining the aimed object. Also, the compound of the present invention can be obtained by reaction formula E shown in FIG. 5. In reaction formula E, A.sub.1 represents --CO-- or --CH.sub.2 CO--, while A.sub.2 represents --CS-- or --CH.sub.2 CS--. R.sub.1, R.sub.2, R.sub.3, R.sub.4, and Y are defined as those of formula (I). In reaction formula E, the amide (I-a) is converted into the thioamide compound (I-d). Examples of the reagents used for this reaction include Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetan-2,4-disulfide) and phosphorus pentasulfide. Also, imidoyl chloride obtained by the reaction of the amide compound (I-a) with phosgene can be reacted with hydrogen sulfide to synthesize the thioamide compound (I-d). As a solvent, for example, a halogenated hydrocarbon such as dichloromethane or chloroform; an aromatic compounds such as benzene, toluene, xylene, or pyridine; an ether such as tetrahydrofuran or dioxane; an amide such as N,N-dimethylformamide or N,N-dimethylacetamide; or dimethylsulfoxide can be used. While the reaction temperature and reaction time may be changed according to the material compounds used, the reaction is usually effected at a temperature within the range of 0.degree. C. to the reflux temperature of the solvent. Specifically, for example, the compound (I-a) is dissolved in the solvent such as toluene or the like, Lawesson's reagent is added thereto, and the reaction is effected at a temperature within the range of room temperature to the reflux temperature of the solvent, thereby attaining the aimed object. The material compounds (II), (II-a), (III), and (IV), which are used in the above-mentioned reaction formulas, are commercially available or can be easily synthesized by known methods. As examples of the known methods, the methods of reaction formulas F-K shown in FIGS. 6-11 can be listed. These methods are explained in the following. First, in the compound of formula (II), the compounds (II-b) and (XI) in which R.sub.1 is a lower alkyl group, as shown in reaction formula G in FIG. 7, can be synthesized by the compounds (X) and (XII) having an alkenyl group correspond to R.sub.1. The compounds (X) and (XII) can be synthesized by reaction formula F shown in FIG. 6. In formulas F and G, A.sub.1 represents --CO-- or --CH.sub.2 CO--, while R.sub.7, R.sub.8, R.sub.9, R.sub.10, and R.sub.11 represent a hydrocarbon atom or lower alkyl group. X represents a halogen atom. Also, R.sub.6 represents a carboxyl protecting group and can use a lower alkyl group such as methyl, ethyl, isopropyl, t-butyl; phenacyl group; or trichloroethyl group, as long as no problem has occurred in the subsequent reaction. R.sub.2 represents a lower alkyl, alkenyl, benzyl, or benzoyl group, while Y is defined as that in Formula (I). In reaction formula F, the compound (X) can be obtained by alkenylation and Claisen rearrangement reaction with respect to the compound (VII). Further, the compound (XII) can be obtained by alkylation of the compound (X). Alkenylation reaction in formula F and alkylation reaction with respect to the compound (X) is effected by the same conditions with the reaction condition in reaction formula D. Claisen rearrangement reaction in the second step of reaction formula F is conducted in the high boiling point solvent or without the presence of the solvent, under the ordinary pressure or application of pressure. As a solvent, for example, phenyl ether, N,N-dimethylaniline, or the like can be used. While the reaction temperature and reaction time may be changed according to the material compounds used, the reaction is usually effected at a temperature within the range between 100.degree. C. and 200.degree. C. The compound (X) or (XII) obtained by formula F can be formed to the compounds (XI) and (II-b), by hydrogenation and deprotection of carboxyl protecting group as shown in reaction formula G. Hydrogenation at the first step in reaction formula G can use the known method. When the reaction is conducted under the catalytic reduction condition, for example, palladium, platinum, nickel, rhodium, ruthenium, or the like can be used as a catalyst. Specifically, for example, palladium-carbon is used under hydrogen gas atmosphere and the reaction is effected in the solvent such as ethanol ethyl acetate, tetrahydrofuran, or the like and at a temperature within the range of room temperature to the reflux temperature of the solvent, thereby attaining the aimed object. Deprotection at the final step of reaction formula G can use the known ester hydrolysis method according to the types of protecting group R.sub.6. For example, when R.sub.6 is methyl or ethyl group, an inorganic base such as sodium hydroxide, or potassium hydroxide is used and the reaction is effected in the solvent such as water, ethanol containing water or methanol containing water and at a temperature within the range of room temperature to the reflux temperature of the solvent, thereby attaining the aimed object. Also, the material compound (II-c) that R.sub.1 is a lower alkyl group in formula (II) also can be synthesized by reaction formula H shown in FIG. 8. In reaction formula H, A.sub.1 represents --CO-- or --CH.sub.2 CO--, while R.sub.12 represents a lower alkyl group such as methyl, ethyl, isopropyl, or t-butyl group. X represents a halogen atom, while Z represents a chlorine atom or R.sub.12 COO-group. R.sub.6 represents a carboxyl protecting group and can use a lower alkyl group such as methyl, ethyl, isopropyl, or t-butyl; phenacyl group; or trichloroethyl group, as long as no problem has occurred in the subsequent reaction. R.sub.2 represents a lower alkyl, alkenyl, benzyl, or benzoyl group, while Y is defined as that in Formula (I). In reaction formula H, the objective compound (II-c) can be obtained by conducting set of reaction of Friedel-Crafts acylation, alkylation of hydroxyl group, reduction of ketone, and deprotection with respect to the compound (VII). Friedel-Crafts acylation of the first step in the present reaction can be conducted by acting acid chloride or acid anhydride represented by formula (XIII) on the compound represented by formula (VII) in the presence of Lewis acid as a activating agent. As an activating agent, for example, Lewis acid such as aluminium chloride, antimony pentachloride, titanium tetrachloride, stannic tetrachloride, or boron trifluoride; trifluoroacetate anhydride; trimethylsilyl triflate; or the like can be used. As a solvent, for example, an aromatic compound such as nitrobenzene, a halogenated hydrocarbon such as dichloromethane, or 1,2-dichloroethane, carbon bisulfide, or the like can be used. While the reaction temperature and reaction time may be changed according to the material compounds used, the reaction is usually effected at a temperature within the range of -78.degree. C. to the reflux temperature of the solvent. Specifically, for example, aluminium chloride is used as an activating agent and the reaction is effected in the solvent such as dichloromethane and at a temperature within the range of 0.degree. C. to the room temperature, thereby attaining the aimed object. Alkylation with respect to the compound (XIV) at the second step of reaction formula H can be conducted by the same condition with the reaction condition in reaction formula D. In the reaction at the third step of reaction formula H, by reduction of the ketone in the compound (XV) the compound (XVI) or (II-c) can be obtained. The known methods can be used in the present reaction. For example, a condition such as Wolff-Kishner reduction, Clemmensen reduction, or the like can be used. In the case where Wolff-Kishner reduction is adopted, hydrazine and a strong base such as potassium hydroxide, sodium methoxide are used. The reaction is effected in high boiling point solvent such as diethylene glycol or without the solvent in the sealed tube at a temperature within the range between 150.degree. C. and 200.degree. C., thereby attaining the aimed object. In the case where Clemmensen reduction is adopted, diethylether, acetic anhydride, or the like is used as a solvent and the reaction is effected by reacting zinc or zinc amalgam in the presence of hydrochloric acid, thereby attaining the aimed object. Specifically, an inorganic base such as sodium hydroxide and hydrazine are used and the reaction is effected in the solvent such as ethylene glycol at a temperature within the range of 100.degree. C. to the reflux temperature of the solvent, thereby attaining the aimed object. In the present reaction, the compound (II-c) may be obtained by deprotection of a carboxyl-protecting group R.sub.6, depending on the condition. However, when the compound (XVI) is obtained, deprotection under the same reaction condition with the final step of reaction formula G, is conducted, thereby attaining the aimed object. Also, as the examples of the other synthetic method of material compound (II), a method accompanying alkylation such as reaction formula I shown in FIG. 9 can be listed. In reaction formula I, A.sub.1 represents --CO-- or --CH.sub.2 CO--, while X represents a halogen atom. R.sub.6 represents a carboxyl protective group and can use a lower alkyl group such as methyl, ethyl, isopropyl, or t-butyl; phenacyl group; or trichloroethyl group, as long as no problem has occurred in the subsequent reaction. R.sub.2 represents a lower alkyl, alkenyl, benzyl, or benzoyl group, while R.sub.1 and Y are defined as those in Formula (I). In reaction formula I, hydroxy compounds (XVII) and (XIX) are alkylated by hilide (VI) and hydrolyzed, thereby the compound (II-d) can be synthesized. Alkylation at the first step in the present reaction can be conducted under the same condition with the reaction condition of reaction formula D. Also, hydrolysis reaction of the second step in the present reaction can be conducted by the same condition with reaction formula G. The material compound (IV) used in the above-mentioned reaction formula C can be synthesized by reaction formula J shown in FIG. 10. Also, in reaction formula J, R.sub.7, R.sub.8, R.sub.9, R.sub.10, and R.sub.11 represent a hydrogen atom or lower alkyl group, while X represents a halogen atom. R.sub.2 represents a lower alkyl, alkenyl, benzyl, or benzoyl group, while Y is defined as that in Formula (I). In reaction formula J, the compound (IV-a) can be obtained by conducting set of reactions of alkenylation, Claisen rearrangement, hydrogenation, alkylation, and introduction of halogenated sulfonyl group to the compound (XX). In formula J, alkenylation reaction of compound (XX), Claisen rearrangement of the compound (XXI), and alkylation reaction of the compound (XXII-a) can be conducted under the same condition with reaction formula F. Hydrogenation with respect to the compound (XXII) at the third step in reaction formula J can be conducted under the same condition with reaction formula G. In the reaction at the fifth step of formula J, the objective compound (IV-a) can be obtained by reacting a halogenated sulfuric acid such as chlorosulfuric acid on benzene ring of the compound expressed by formula (XXII-b). As a solvent, for example, carbon bisulfide, liquid sulfur dioxide, or a halogenated hydrocarbon such as dichloroethane, chloroform, dichloromethane, tetrachloroethane, or the like is used. While the reaction temperature and reaction time may be changed according to the material compounds used, the reaction is usually effected at a temperature within the range of 0.degree. C. to the reflux temperature of the solvent. Specifically, aromatic compound (XXII-b) is dissolved in chloroform, dichloroethane, or the like and the reaction is effected by reacting chlorosulfuric acid at a temperature within the range of 0.degree. C. to the reflux temperature of the solvent, thereby attaining the aimed object. Next, the material compound (III) can be synthesized as like reaction formula K shown in FIG. 11. In reaction formula K, R.sub.3 and R.sub.4 are defined as those in formula (I). In reaction formula K, the objective compound (III) can be obtained by successively alkylating the compound and by further reducing a nitro group. Alkylation at the first and second steps of the present reaction can be conducted under the same condition with reaction formula D. Reduction of the nitro group of the compound (XXV-b) at the third step in the present reaction can use the known reactions. For example, a condition such as Birch reduction, Benkesser reduction, or the reduction using metal hydride complex compound, and the like can be used. In the case where Birch reduction is adopted, metal such as lithium, sodium, or potassium is used and liquid ammonia is used as a solvent and then the reaction is conducted by coexisting methanol, ethanol, t-butanol, or the like as a proton source. While the reaction temperature and reaction time may be changed according to the material compounds used, the reaction is usually effected at a temperature within the range of -78.degree. C. to the reflux temperature of the solvent. In the case where Benkesser reduction is adopted, for example, methylamine, ethylamine, or ethylenediamine is used as a solvent and the reaction is effected at a temperature within the range of -78.degree. C. to the reflux temperature of the solvent, thereby attaining the aimed object. In the case where the reaction using metal hydride complex compound is adopted, sodium boron hydroxide is used. Water, methanol, ethanol, isopropanol, or the like is used as a solvent and then the reaction is conducted in the presence of 10% palladium/carbon, cyano nickel complex ion, or dichlorobis (triphenylphosphine) nickel (II) as a catalyst. While the reaction temperature and reaction time may be changed according to the material compounds used, the reaction is usually effected at a temperature within the range of 0.degree. C. to the reflux temperature of the solvent. Specifically, for example, dichlorobis (triphenylphosphine) nickel (II) of catalyst is dissolved in ethanol and, after sodium boron hydroxide and the compound (XXV-b) are added thereto, the reaction is effected at a temperature within the range of 0.degree. C. to the reflux temperature of the solvent, thereby attaining the aimed object. Here, in the material compounds used in the above mentioned reaction formulas, those not specified, for example, the compound (VI), (VII), (VIII), (XX), (XXV), or the like is commercially available or can be easily synthesized by known methods. The compound expressed by formula (I) in accordance with the present invention can be changed to acid-added salts if necessary. Examples of the acid-added salts include salts in conjunction with inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, or phosphoric acid and salts in conjunction with organic salts such as acetic acid, propionic acid, citric acid, lactic acid, oxalic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, or methanesulfonic acid. These salts can be easily manufactured by normal methods. When the phenylenediamine derivative in accordance with the present invention is used as a medicament for cerebral nerve diseases such as brain infarction and brain edema, it is generally used as a medicine for internal use or an injection. When the compound of the present invention is used as a medicine for internal use, it may be administered orally as tablet, powder, granule, capsule, syrup, or the like as well as parenterally as suppository or the like. While the amount of administration may be outside of the range mentioned below according to the degree of symptom, personal difference, age, kind of symptom, or the like, it should of course be adjusted so as to fit the individual circumstances in specific cases. Usually 0.01 to 200 mg/kg or, preferably, 0.05 to 50 mg/kg or, more preferably, 0.1 to 10 mg/kg is administered per day for an adult in a single dose or several doses. When formulating the medicament, a normal manufacturing method is used with a normal formulation carrier. If necessary, pharmacologically and pharmaceutically acceptable additives may be added thereto. Namely, when preparing an oral solid formulation, after an excipient and, if necessary, a binder, a decaying agent, a luster, a coloring agent, a correctives, and the like are added to the main medicament, a normal method is used to form tablet, coated tablet, granule, powder, capsule, or the like. Examples of the excipient include lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose, and silicon dioxide. Examples of the binder include polyvinylalcohol, polyvinylether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl cellulose, hydroxy propyl starch, and polyvinylpyrrolidone. Examples of the decaying agent include starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium hydrogencarbonate, calcium citrate, dextrin, and pectin. Examples of the luster include magnesium stearate, talc, polyethyleneglycol, silica, and hardened vegetable oil. As the coloring agent, those permitted to be added to medicines are used. Examples of the correctives include cocoa powder, menthol, aromatic acid, mentha oil, borneol, and cinnamon powder. If necessary, these tablet and granule can be coated with sugar-coating, gelatin-coating, and the like. When the compound of the present invention is used as an injection, while the amount of administration may differ according to the degree of symptom, personal difference, age, or the like, usually 0.05 to 10 mg/kg or, preferably, 0.1 to 3 mg/kg is administered per day for an adult in a single dose or several doses. The injection may be a sterile aqueous or non-aqueous solution, suspension, and emulsion. In such an injection, at least one active material is used as being mixed with at least one inactive aqueous diluent or inactive non-aqueous diluent. Further, if necessary, it may contain such adjuvants as antiseptic, wetting agent, emulsifier, dispersant, stabilizer, and dissolution adjuvant. In general, these are sterilized by filtration (e.g., by bacteria-blocking filter), compounding of sterilizer, or gamma-ray radiation or, after these treatments, turned into a solid composition by means of freeze-drying technique or the like and then sterile water or sterile injection diluent is added thereto immediately before use. |
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