Claims
- 1. A pyridine derivative or a 1,2,3,4-tetrahydropyridine derivative represented by formulae (I) or (II), respectively, or salts thereof: ##STR83## wherein A represents a sulfur atom or an oxygen atom; R.sub.1 represents an amino group substituted with a 3- to 7-membered cycloalkyl group; R.sub.2 and R.sub.3 each represents a halogen atom, an alkyl group, an aryl group, an alkenyl group, an acyl group, an arylcarbonyl group, or those having on the carbon atom(s) thereof a substituent selected from the group consisting of a halogen atom, an amino group, a nitro group, an alkoxy group having from 1 to 6 carbon atoms and a phenyl group; and m and n each represents an integer of from 0 to 4, with the proviso that when m and n are 2 or more, said R.sub.2 groups or said R.sub.3 groups may be the same or different.
- 2. The pyridine derivative or a 1,2,3,4-tetrahydropyridine derivative represented by formulae (I) or (II), respectively, or salts thereof, as in claim 1, wherein A is a sulfur atom.
- 3. The pyridine derivative or a 1,2,3,4-tetrahydropyridine derivative represented by formulae (I) or (II), respectively, or salts thereof, as in claim 2, wherein said m and n are 0.
Priority Claims (2)
| Number |
Date |
Country |
Kind |
| 61-241226 |
Oct 1986 |
JPX |
|
| 61-242164 |
Oct 1986 |
JPX |
|
CROSS-REFERENCE TO RELATED APPLICATIONS
This is a continuation-in-part application of the parent application Ser. No. 07/219,540 filed Jun. 13, 1988 now abandoned.
This invention relates to pyridine derivatives or 1,2,3,4-tetrahydropyridine derivatives represented by general formulae (I) and (II) or the salts thereof which act on the central nervous system and are useful as psychotropic drugs having antianxiety effects, learning improvement effects and psychic activation effects.
It is known that .beta.-carboline-3-carboxylic acid derivatives shown by the following general formula ##STR2## are useful as a psychotic medicament having a sedative activity (U.S. Pat. No. 4,371,536). Also, it is known that 1,2,3,4-tetrahydrobenzo[b]thieno[2,3-c]pyridine derivatives shown by the following general formula ##STR3## are useful as a sedative and a hypotensive drug (U.S. Pat. No. 3,651,068). Furthermore, methods for synthesizing 1,2,3,4-tetrahydrobenzo[b]thieno[2,3-c]pyridine and derivatives thereof as well as the biochemical activities of these compounds are described in Arch. der Pham., 309, 279 (1976) and Journal of Pharmacology and Experimental Therapeutics, 235(3), 696-708 (1985). However, the pyridine derivatives or 1,2,3,4-tetrahydropyridine derivatives of the present invention represented by general formula (I) and (II) have not yet been known and also the medical effects thereof are not known.
The present inventors have intensively investigated the pyridine derivatives and 1,2,3,4-tetrahydropyridine derivatives having general formulae (I) and (II), respectively. Accordingly, one object of this invention is to provide novel pyridine derivatives and 1,2,3,4-tetrahydropyridine derivatives useful as medicaments having an antianxiety activity, a learning improvement activity and a psychic activation activity, represented by the following general formulae (I) and (II): ##STR4## wherein A represents a sulfur atom or an oxygen atom; R.sub.1 represents an alkoxy group, an amino group, a hydrazino group, a 6- or 7-membered heterocyclic group having one or two nitrogen atoms, or those having on the carbon or nitrogen atom(s) thereof a substituent selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, a 3- to 7-membered cycloalkyl group, a phenyl group and a 5- to 7-membered heterocyclic group having a nitrogen atom, which may be substituted by an amino, carboxy or ester group for the hydrogen atom(s) bonded to carbon atom(s) in the substituent, with the proviso that R.sub.1 is not an alkoxy group in formula (I); R.sub.2 and R.sub.3 each represents a halogen atom, an alkyl group, an aryl group, an alkenyl group, an acyl group, an arylcarbonyl group, or those having on the carbon atom(s) thereof a substituent selected from the group consisting of a halogen atom, an amino group, a nitro group, an alkoxy group having from 1 to 6 carbon atoms and a phenyl group; and m and n each represents an integer of from 0 to 4, with the proviso that when m and n are 2 or more, said R.sub.2 s or R.sub.3 s may be the same or different.
This invention relates to pyridine derivatives, 1,2,3,4-tetrahydropyridine derivatives shown by general formulae (I) and (II) and salts thereof: ##STR5##
In formulae (I) and (II), A is a sulfur atom or an oxygen atom.
R.sub.1 is an alkoxy group preferably having from 1 to 6 carbon atoms, an amino group, a hydrazino group or a 6- or 7-membered heterocyclic group having one or two nitrogen atoms with the proviso that in compounds of formula (I), R.sub.1 is not an alkoxy group. The hydrogen atom bonded to a carbon or nitrogen atom in any of these groups represented by R.sub.1 may be substituted by another group, if desired. Examples of suitable substituents are an alkyl group having 1 to 6 carbon atoms, a 3- to 7-membered cycloalkyl group, a phenyl group, a 5- to 7-membered heterocyclic group having a nitrogen atom, etc., which may be unsubstituted or a hydrogen atom bonded to carbon atom of which may be substituted by an amino group, a carboxy group, an ester group, etc. Examples of R.sub.1 are a methoxy group, an ethoxy group, a propyloxy group, a hexyloxy group, a benzyloxy group, an amino group, a hydrazino group, a 2-aminoethylamino group, a 3-aminopropylamino group, an N-dimethylaminoethylamino group, a methylamino group, an ethylamino group, a propylamino group, a hexylamino group, a cyclohexylamino group, a 4-aminobutyric acid group, a 4-aminobutyric acid ethyl ester group, a piperizino group, a 2,6-dimethylpiperidino group, a piperazinyl group, a 3-methylpiperazinyl group, a 4-methylpiperazinyl group, a hexahydro-1H-1,4-diazepinyl group, a hexahydro-1H-4-methyldiazepinyl group, a morpholino group, etc.
R.sub.2 and R.sub.3 are a halogen atom, an alkyl group, an aryl group, an alkenyl group, an acyl group or an arylcarbonyl group, each of said groups being optionally substituted. The total carbon atom number of these groups is from 1 to 20 and preferably from 1 to 8, and a hydrogen atom bonded to a carbon atom in any of these groups may be substituted by another group, if desired. Suitably substituents include, for example, a halogen atom, an amino group, a nitro group, an alkoxy group having 1 to 6 carbon atoms, a phenyl group, etc. Examples of R.sub.2 and R.sub.3 are a chlorine atom, a methyl group, a phenyl group, an allyl group, a 2-chlorobenzoyl group, a 4-methoxybenzoyl group, a benzyl group, a 4-nitrobenzyl group, an acetyl group, etc.
Also, m and n are an integer of from 0 to 4. When m and n are 2 or more, R.sub.2 s and R.sub.3 s may be the same or different.
Examples of the pyridine derivatives and 1,2,3,4-tetrahydropyridine derivatives of this invention are given below:
c]pyridine-3-carbonyl)-morpholine
The pyridine derivatives of this invention represented by general formula (I) described above can be obtained by the following synthesis methods.
1) Method 1: ##STR6##
In the above formulae (III) to (VIII), A, R.sub.1, R.sub.2, R.sub.3, m and n have the same meaning as described above for formulae (I) and (II); R.sub.4 and R'.sub.4 each represents a hydrogen atom or a group represented by said R.sub.2 ; and X.sub.1 is a group which becomes an acid by combining with hydrogen atom (such as a halogen atom, a methanesulfonyl group, a 4,6-dimethylpyridinylmercapto group, etc.), or a group which is excellent as a releasable group.
A method of obtaining compound (IV) from compound (III) is described by H. R. Snyder and Donal S. Matterson in Journal of Americal Chemical Society, 79, 2217 (1957).
A suitable solvent used in the method of synthesizing compound (IV) from compound (III) is a mixed solvent of a polar solvent such as acetic acid, dimethylformamide, etc., and a non-polar solvent such as benzene, toluene, etc. In this case, it is preferred that a benzene solution of an alkyldeneisopropylamine is added dropwise to a solution of compound (III) dissolved in acetic acid. The alkyldeneisopropylamine is used in an amount of from 1 to 3 equivalents, and preferably from 1.1 to 1.5 equivalents. Also, in place of the alkyldeneisopropylamine, an alkyldene tert-butylamine or the like may be used. As a reaction catalyst, hydrochloric acid, sulfuric acid, etc., may be added. The reaction is performed at temperature of from -20.degree. C. to 50.degree. C., and preferably from 0.degree. C. to 10.degree. C. The reaction is generally completed after 10 to 70 hours.
A method of obtaining compound (V) and compound (VI) from compound (IV) is described by D. A. Little and D. I. Wesblat in Journal of American Chemical Society, 69, 2118 (1947).
A suitable solvent used in the method of synthesizing compound (V) from compound (IV) is xylene, toluene, etc., and is preferably xylene. The reaction temperature is from 50.degree. C. to 150.degree. C., and preferably from 90.degree. C. and 100.degree. C. The reaction is generally completed after 1 to 12 hours. An alkyl nitroacetate is used in an amount of from 1 to 3 equivalents.
A suitable solvent used in the method of synthesizing compound (VI) from compound (V) is preferably a mixed solvent of a polar .solvent such as methanol, ethanol, etc., and water. The reaction temperature is from 10.degree. C. to 120.degree. C., and preferably from 60.degree. C. to 80.degree. C. The reaction is generally completed after 10 to 120 minutes. Iron powder is used in an amount of from 1 to 10 equivalents and hydrogen chloride is used in an amount of from 1 to 20 equivalents. Also, in place of iron powder, a metal such as zinc or the like may be used or the reduction by hydrogen may be performed in the presence of a catalyst such as Raney nickel, palladium-active carbon, etc.
A method of synthesizing compounds (VII) and (VIII) from compound (VI) is described by Gerhard Wolf and Felix Zymalkowsiki in Arch. Pharm., 309, 279 (1976).
A suitable solvent used in the method of synthesizing compound (VII) from compound (VI) is an organic solvent such as ethanol, benzene, etc. The reaction temperature is from 50.degree. C. to 150.degree. C. and the reaction is generally completed after 1 to 12 hours.
A suitable solvent used in the method of synthesizing compound (VIII) from compound (VII) is methanol, ethanol, water, etc., and is preferably water. The reaction temperature is from 50.degree. C. to 120.degree. C. and the reaction is generally completed after 10 minutes to 2 hours. As the reaction catalyst, an acid such as hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, etc., is used in an amount of from 10 to 100 equivalents.
A suitable method for obtaining compound (I) from compound (VIII) (but not disclosing the present novel compounds) is described by Michael Cainet et al. in Journal of Medical Chemistry, 25, 1081 (1982).
A suitable solvent used in the method of synthesizing compound (I) from compound (VIII) is an organic solvent such as benzene, toluene, xylene, dioxane, tetrahydrofuran, etc. Elementary sulfur is used in an amount of from 1 to 30 equivalents, preferably from 15 to 25 equivalents. The reaction temperature is from 50.degree. C. to 150.degree. C., and preferably from 100.degree. C. to 120.degree. C. The reaction is generally completed after 1 to 7 days.
Also, in other similar synthesis methods, dichlorodicyanobenzoquinone, chloroanisole, tetraacetic acid salts, palladium-black, or palladium-active carbon may be used.
2) Method 2:
The following method may be used by using the material of aforesaid formula (IV) as a starting material. ##STR7##
In the above formulae (IX) to (XVI), A, R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R'.sub.4 have the same meaning as described above in formulae (I) to (VIII). Further, R.sub.5 is an alkyl group having from 1 to 6 carbon atoms, such as a methyl group, an ethyl group, etc. R.sup.11 and R.sup.12 each is a hydrogen atom, an unsubstituted or substituted alkyl group, an unsubstituted or substituted amino group, or an unsubstituted or substituted 5- to 7-membered heterocyclic group containing a nitrogen atom, or R.sup.11 and R.sup.12 may together form a 6- to 7-membered heterocyclic group with an adjacent nitrogen atom. Boc is a tertiary butoxycarbonyl group and X.sub.1, X.sub.2, and X.sub.3 each represents a group which becomes an acid by combining with a hydrogen atom (such as a halogen atom, a methanesulfone group, a 4,6-dimethylpyrimidinylmercapto group, etc.), or a group which is excellent as a releasable group.
A method of obtaining compounds (IX) and (X) from compound (IV) is described by D. A. Little and D. I. Wesblat in Journal of American Chemical Society, 69, 2118 (1947).
A suitable solvent used in the method of synthesizing compound (IX) from compound (IV) is xylene, toluene, etc., and preferably xylene. The reaction temperature is from 50.degree. C. to 150.degree. C. and preferably from 90.degree. C. to 100.degree. C. The reaction is generally completed after 1 to 12 hours. An alkyl nitroacetate is used in an amount of from 1 to 3 equivalents.
A suitable solvent used in the method of synthesizing compound (X) from compound (IX) is preferably a mixed solvent of a polar solvent such as methanol, ethanol, etc., and water. The reaction temperature is from 10.degree. C. to 120.degree. C., and preferably from 60.degree. C. to 80.degree. C. The reaction is generally completed after 10 to 120 minutes. Iron powder is used in an amount of from 1 to 10 equivalents and hydrogen chloride is used in an amount of from 1 to 20 equivalents. Also, in place of iron powder, a metal such as zinc, etc., may be used and the reduction by hydrogen may be performed in the presence of a catalyst such as .Raney nickel, palladium-active carbon, etc.
A method of synthesizing compound (XI) and (XII) from compound (X) is described by Gerhard Wolf and Felix Zymalkowski in Arch. Pham., 309, 279 (1976).
A suitable solvent used in the method of synthesizing compound (XI) from compound (X) is an organic solvent such as ethanol, benzene, etc. The reaction temperature is from 50.degree. C. to 150.degree. C. and the reaction is generally completed after 1 to 12 hours.
A suitable solvent used in the method of synthesizing compound (XII) from compound (XI) is methanol, ethanol, water, etc., and is preferably water. The reaction temperature is from 50.degree. C. to 120.degree. C. The reaction is generally completed after 10 minutes to 2 hours. Also, as a reaction catalyst, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, etc., is used in an amount of from 1 to 10 equivalents.
A method of obtaining compound (XIII) from compound (XII) is described by T. Nakagawa, L. Kuroiwa, K. Narita, and Y. Isowa in Bulletin of the Chemical Society of Japan, 46, 1269 (1973).
A suitable solvent used in the method of synthesizing compound (XIII) from compound (XII) is an organic solvent such as chloroform, methylene chloride, tetrahydrofuran, dimethylformamide, etc.. The reaction temperature is from 0.degree. C. to 100.degree. C. and the reaction is generally completed after 1 to 48 hours. For neutralizing HX.sub.1 of compound (XII), a tertiary amine such as triethylamine, N-methylmorpholine, etc., is used. Also, as a method of introducing a tertiary butoxycarbonyl group (Boc group), a tertiary butoxycarbonylating agent such as Boc-azide, etc., may be used. Alternatively, in place of a Boc group, other amino protective groups such as benzyloxycarbonyl, etc., may be used.
A method of obtaining compound (XIV) from compound (XIII) is described by E. Brand, B. F. Erlanger, H. Sacks, and J. Polathick in Journal of American Chemical Society, 73, 3510 (1951).
A suitable solvent used in the method of synthesizing compound (XIV) from compound (XIII) is an alcohol such as methanol, ethanol, etc., or water. The reaction temperature is from 0.degree. C. to 80.degree. C. and the reaction is generally completed after 1 to 48 hours. Sodium hydroxide is used in an amount of from 1 to 3 equivalents and potassium hydroxide may be used instead. As an acid for neutralizing the alkali, citric acid or acetic acid is used.
A method of obtaining compound (XV) from compound (XIV) is described by G. W. Anderson, E. Zimmermann, and F. Callahan in Journal of American Chemical Society, 85 3039 (1963).
A suitable solvent used in the method of synthesizing compound (XV) from compound (XIV) is an organic solvent such as chloroform, methylene chloride, dioxane, tetrahydrofuran, dimethylformamide, etc. The reaction temperature is from -20.degree. C. to 100.degree. C. The reaction is usually completed after 10 minutes to 48 hours. As a method for the amido bond-forming reaction, an active ester method by N-hydroxysuccinimide is employed. N-hydroxysuccinimide is generally used in an amount of from 1 to 3 equivalents. Sodium hydroxide is used in an amount of from 1 to 3 equivalents. Also, other suitable methods include an acid chloride method, a dicyclohexylcarbodiimide method, a mixed acid anhydride method, etc.
A method of obtaining compound (XVI) from compound (XV) is described by G. W. Anderson and A. C. Mcgregor in Journal of American Chemical Society, 79, 6180 (1957).
A suitable solvent used in the method of synthesizing compound (XVI) from compound (XV) is ethyl acetate or dioxane. The reaction temperature is from -20.degree. C. to 100.degree. C. The reaction is generally completed after 10 minutes to 5 hours. Hydrochloric acid is used in an amount of from 1 to 20 equivalents. Also, in place of hydrochloric acid, trifluoroacetic acid, hydrogen bromide, hydrogen fluoride, methanesulfonic acid, etc., may be used.
A method of obtaining compound (I) from compound (XVI) (but not disclosing the novel compounds of formula (I)) is referred to Michael Cain et al. in Journal of Medical Chemistry, 25, 1081 (1982).
A suitable solvent used in the method of synthesizing compound (I) from compound (XVI) is an organic solvent such as benzene, toluene, xylene, dioxane, tetrahydrofuran, etc. Elementary sulfur is used in an amount of from 1 to 30 equivalents, and preferably from 15 to 25 equivalents. The reaction temperature is from 50.degree. C. to 150.degree. C., and preferably from 100.degree. C. to 120.degree. C. The reaction is generally completed within 1 day to 7 days.
Also, in other suitable methods dichlorodicyanobenzoquinone, chloroanisole, lead tetraacetate, palladium-black, or palladium-active carbon may be used.
As a method of obtaining compound (I), the synthesis may be performed by the following route from the compound of aforesaid formula (X):
3) Method 3: ##STR8##
Also, in another suitable amidation method, the amide is directly formed from the ester.
4) Method 4: ##STR9##
In this case, a catalyst such as phenyllithium, etc., may be used.
The 1,2,3,4-tetrahydropyridine derivatives represented by formula (II) described above can be obtained by the following synthesis method from the compounds represented by aforesaid formula (VIII).
5) Method 5: ##STR10## wherein A, R.sub.1, R.sub.2, R.sub.3, R'.sub.4, X.sub.1, and X.sub.2 have the same meaning as described in the above various formulae and R".sub.4 has the same meaning as R'.sub.4.
A suitable method for obtaining compound (II) from compound (VIII) (but not disclosing the novel compounds of formula (II)), is described by B. Bortnick, et al. in Journal of American Chemical Society, 78, 4039 (1956).
A suitable solvent used in the method of synthesizing compound (II) from compound (VIII) is an organic solvent such as chloroform, ethanol, etc., and is preferably chloroform. The reaction temperature is from 0.degree. C. to 100.degree. C., and preferably from 30.degree. C. to 60.degree. C. The reaction is generally completed after 1 to 12 hours. For neutralizing HX.sub.1 of compound (XIII), a tertiary amine such as triethylamine, N-methylmorpholine, 1,8-diazabicyclo[5,4,0]-7-undecene, etc., is used.
Also, the synthesis may be performed by the following method using the compound of aforesaid formula (XVI) as the starting material.
6) Method 6: ##STR11##
A suitable solvent used in the method of synthesizing compound (II) from compound (XVI) is an organic solvent such as chloroform, dioxane, ethanol, etc., and is preferably chloroform. The reaction temperature is from 0.degree. C. to 150.degree. C., and preferably from 0.degree. C. to 60.degree. C. The reaction is generally completed after to 24 hours. General formula R".sub.4 X.sub.4 represents methyl bromide, chlorinated acetyl, etc., and is usually used in an amount of from 1 to 3 equivalents. For neutralizing HX.sub.3 and by-produced HX.sub.4, a tertiary amine such as triethylamine, N-methylmorpholine, 1,8-diazabicyclo[5,4,0]-7-undecene, etc., is used.
As a method of obtaining compound (II), the synthesis may be performed by the following route from the compound of aforesaid formula (X):
7) Method 7: ##STR12##
8) Method 8:
Also, in a similar amidation method, the amide may be directly formed by the ester. In this case, a catalyst such as phenyllithium, etc., may be used: ##STR13##
Also, the compounds represented by general formulae (I) and (II) described above can be converted into their pharmaceutically acceptable acid- or base-addition salts. Suitable pharmaceutically acceptable acid-addition salts include, for example, the acid-addition salts with an inorganic acid such as a hydrochloric acid, sulfuric acid, phosphoric acid, etc., or an organic acid such as acetic acid, p-toluenesulfonic acid, maleic acid, etc. Also, suitable base-addition salts include the base-addition salts with an inorganic base such as sodium hydroxide, calcium hydroxide, etc., or an organic base such as ammonia, triethylamine, etc.
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Continuation in Parts (1)
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Number |
Date |
Country |
| Parent |
219540 |
Jun 1988 |
|
Patent Grant
5126448
