CA1161844A - Aniline derivatives, pharmaceutical formulations thereof, and processes for the preparation thereof - Google Patents
Aniline derivatives, pharmaceutical formulations thereof, and processes for the preparation thereofInfo
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- CA1161844A CA1161844A CA000368140A CA368140A CA1161844A CA 1161844 A CA1161844 A CA 1161844A CA 000368140 A CA000368140 A CA 000368140A CA 368140 A CA368140 A CA 368140A CA 1161844 A CA1161844 A CA 1161844A
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- methyl
- phenyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
- C07D317/66—Nitrogen atoms not forming part of a nitro radical
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
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- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
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- Life Sciences & Earth Sciences (AREA)
- Neurology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Psychiatry (AREA)
- Pharmacology & Pharmacy (AREA)
- Biomedical Technology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pain & Pain Management (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Hydrogenated Pyridines (AREA)
- Polymers With Sulfur, Phosphorus Or Metals In The Main Chain (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE:
Aniline derivatives of the formula Ar-N(CH3)-R
wherein Ar is phenyl or phenyl substituted by F, Cl, alkoxy of up to 4 C atoms, methylenedioxy, OH, tri-methylene or CF3; R is -CH(C6H5)-CH2CH2-N(CH3)-Z or 2-(1-methyl-2-piperidyl)-ethyl; and Z is H or methyl, or a physiologically acceptable acid addition salt thereof, have valuable pharmacological properties.
Aniline derivatives of the formula Ar-N(CH3)-R
wherein Ar is phenyl or phenyl substituted by F, Cl, alkoxy of up to 4 C atoms, methylenedioxy, OH, tri-methylene or CF3; R is -CH(C6H5)-CH2CH2-N(CH3)-Z or 2-(1-methyl-2-piperidyl)-ethyl; and Z is H or methyl, or a physiologically acceptable acid addition salt thereof, have valuable pharmacological properties.
Description
The present invention relates to aniline derivatives having pharmacological activity.
It is an object of the present invention to provide new compounds which can be used for the preparation of medicaments.
The present invention relates to new aniline derivatives oE Formula I
Ar-N(cH3)-R
wherein Ar is phenyl or phenyl substituted by F, Cl, alkoxy of up to 4 C atoms, methylenedioxy, OH, tri-methylene or CF3; R is -CH(C6H5)-CH2CH2-NtCH3)-Z or
It is an object of the present invention to provide new compounds which can be used for the preparation of medicaments.
The present invention relates to new aniline derivatives oE Formula I
Ar-N(cH3)-R
wherein Ar is phenyl or phenyl substituted by F, Cl, alkoxy of up to 4 C atoms, methylenedioxy, OH, tri-methylene or CF3; R is -CH(C6H5)-CH2CH2-NtCH3)-Z or
2-~1-methyl-2-piperidyl)-eth,yl; and Z is H or methyl, and physiologically acceptable acid addition salts thereof.
The present invention relates to the aniline derivatives of Formula I and their physiologically acceptable acid addition salts.
--1--.
8~
For Ar, alkoxy is preferably methoxy, and also ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.-butoxy or tert.-butoxy.
More specifically, the radical Ar is preferably fluorophenyl, chlorophenyl, methoxyphenyl, hydroxy-phenyl, 4- or 5-indanyl or ~rifluoromethylphenyl, in particular p-fluorophenyl, p-chlorophenyl, o- or p methoxyphenyl, 5-indanyl or p-trifluoromethylphenyl.
Ar can also be phenyl, o- or m-fluorophenyl, o- or m-chlorophenyl, m-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-n-propoxyphenyl, o-, m- or p-isopropoxy-phenyl, o-, m- or p-n butoxyphenyl, o-, m- or p-isobutoxyphenyl, o-, m-or p- sec.-butox~phenyl, o-, m- or p tert.-butoxyphenyl, 2,3- or 3,4-methy:Lenedioxyphenyl, o-, m- or p-hydroxyphenyl, 4-indany:l or o- or m-trifluoro-methylphenyl.
The radical R is preferably l-phenyl-3-dimethyl-amino-propyl.
! The present invention, accordinyly, relates, in particular, to those compounds of ~ormula I in which at least one of the radicals has one of the above-mentioned meaninys, in particular one of the above-mentioned preferred meaninys.
The compounds of Formula I can have one or more asymmetric carbon atoms. They can thus exist in the form of racemates; if several asymmetric carbon atoms are present, in the form of mixtures of several racemates; and in various optically active forms.
`
4~
The invention furthermore relates to a process for preparing the compounds of Formula I and their physiologically acceptable acid addition salts, comprising reacting an amine of Formula II
Ar-NHCH3 II
wherein Ar is as defined above, or one of its salts, with an amine of formula III
X R III
wherein X is Cl, Br, I or OH and R is as defined above, or with one of its reactive derivatives, or methylating an amine of Formula IV
Ar-Y IV
wherein Y is -NH-R, N-methyl-N-(l-phenyl-3-aminopropyl)-amino or N-methyl-N-~2-(2-piper.idyl)-ethyl]-amino and : Ar and R are as defined above, or reacting an amine of Formula V
Ar-N(cH3)-cH(c6Hs)-cH2-cH2-x V
wherein Ar and X are as defined above, or one of its reactive derivatives, with an amine of the Formula VI
H-N(CH3)-Z VI
wherein Z is as defined above, or treating a compound which corresponds to Formula I, but contains one or more reducible groups and/or one or more C-C and~or C-N multiple bonds instead of hydrogen atoms, with a reducing agent, or
The present invention relates to the aniline derivatives of Formula I and their physiologically acceptable acid addition salts.
--1--.
8~
For Ar, alkoxy is preferably methoxy, and also ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.-butoxy or tert.-butoxy.
More specifically, the radical Ar is preferably fluorophenyl, chlorophenyl, methoxyphenyl, hydroxy-phenyl, 4- or 5-indanyl or ~rifluoromethylphenyl, in particular p-fluorophenyl, p-chlorophenyl, o- or p methoxyphenyl, 5-indanyl or p-trifluoromethylphenyl.
Ar can also be phenyl, o- or m-fluorophenyl, o- or m-chlorophenyl, m-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-n-propoxyphenyl, o-, m- or p-isopropoxy-phenyl, o-, m- or p-n butoxyphenyl, o-, m- or p-isobutoxyphenyl, o-, m-or p- sec.-butox~phenyl, o-, m- or p tert.-butoxyphenyl, 2,3- or 3,4-methy:Lenedioxyphenyl, o-, m- or p-hydroxyphenyl, 4-indany:l or o- or m-trifluoro-methylphenyl.
The radical R is preferably l-phenyl-3-dimethyl-amino-propyl.
! The present invention, accordinyly, relates, in particular, to those compounds of ~ormula I in which at least one of the radicals has one of the above-mentioned meaninys, in particular one of the above-mentioned preferred meaninys.
The compounds of Formula I can have one or more asymmetric carbon atoms. They can thus exist in the form of racemates; if several asymmetric carbon atoms are present, in the form of mixtures of several racemates; and in various optically active forms.
`
4~
The invention furthermore relates to a process for preparing the compounds of Formula I and their physiologically acceptable acid addition salts, comprising reacting an amine of Formula II
Ar-NHCH3 II
wherein Ar is as defined above, or one of its salts, with an amine of formula III
X R III
wherein X is Cl, Br, I or OH and R is as defined above, or with one of its reactive derivatives, or methylating an amine of Formula IV
Ar-Y IV
wherein Y is -NH-R, N-methyl-N-(l-phenyl-3-aminopropyl)-amino or N-methyl-N-~2-(2-piper.idyl)-ethyl]-amino and : Ar and R are as defined above, or reacting an amine of Formula V
Ar-N(cH3)-cH(c6Hs)-cH2-cH2-x V
wherein Ar and X are as defined above, or one of its reactive derivatives, with an amine of the Formula VI
H-N(CH3)-Z VI
wherein Z is as defined above, or treating a compound which corresponds to Formula I, but contains one or more reducible groups and/or one or more C-C and~or C-N multiple bonds instead of hydrogen atoms, with a reducing agent, or
3~
treating a compound o~ Formula VII
Ar N(CH3) CH~C6H5)-CH2-CH2-N(C~3)-W VII
wherein W is an amino-protecting group and Ar is as defined above, with a solvolyzing agent and/or in a compound o~ Formula I, if appropriate, methylating an NH group to yield an N(CH3) yroup, and/or converting a hydroxyl group, by treatment with an alkylating agent, into the corresponding alkoxy group, and/or splitting an alkoxy group to form a hydroxyl group, and/or converting a resulting base of Formula I
into one of its physiologically acceptable acld addition salts by treatment with an acid.
The preparation of the compounds of Formula I
; is in other respects carried out by methods which are known per se, e.g., which are described in the literature (~or example in the standard wo:rks, such as Houben-Weyl, Methoden der Org~nischen Chemie (Methods of Organic Chemistry), Georg-Thieme-Verlag, Stuttgart; and Organic Reactions, John Wiley & Sons, Inc., New York), and, in particular, under reaction conditions which are known and suitable ~or the mentioned reactio~s. It is also possible to utilize variants which are known per se but a.re not mentioned here in more detailO
I~ desired, the starting materials can also be 25 ~ormed in situ, in a manner whereby that they are not ! isolated ~rom the reaction mixture but are immediately reacted ~urther to give the compounds o~ Formula I.
treating a compound o~ Formula VII
Ar N(CH3) CH~C6H5)-CH2-CH2-N(C~3)-W VII
wherein W is an amino-protecting group and Ar is as defined above, with a solvolyzing agent and/or in a compound o~ Formula I, if appropriate, methylating an NH group to yield an N(CH3) yroup, and/or converting a hydroxyl group, by treatment with an alkylating agent, into the corresponding alkoxy group, and/or splitting an alkoxy group to form a hydroxyl group, and/or converting a resulting base of Formula I
into one of its physiologically acceptable acld addition salts by treatment with an acid.
The preparation of the compounds of Formula I
; is in other respects carried out by methods which are known per se, e.g., which are described in the literature (~or example in the standard wo:rks, such as Houben-Weyl, Methoden der Org~nischen Chemie (Methods of Organic Chemistry), Georg-Thieme-Verlag, Stuttgart; and Organic Reactions, John Wiley & Sons, Inc., New York), and, in particular, under reaction conditions which are known and suitable ~or the mentioned reactio~s. It is also possible to utilize variants which are known per se but a.re not mentioned here in more detailO
I~ desired, the starting materials can also be 25 ~ormed in situ, in a manner whereby that they are not ! isolated ~rom the reaction mixture but are immediately reacted ~urther to give the compounds o~ Formula I.
4~L
The compounds of Foxmula I can be obtained by reacting the amines of Formula II or their salts with the compounds of Formula III.
Most of the amines of Formula II are known, and they can be prepared by methods which are known per se, for example by methylation of the anilines of the formula Ar-NH2.
In the compounds of Formulae III and V, the radical X is preferably Cl or Br. Reactive derivatives of these compounds include, in particular, the reactive esters of the alcohols of Formulae III and V (X = OH), preferably the corresponding alkylsulfonates (with alkyl of 1-6 C atoms) and the corresponding arylsulfonates (with aryl of 6-10 C atoms), for example the corres-pondiny methane-, benzene-, p-toluene- or naphthalene-l-or -2-sulfonates.
Most of the compounds of Formula III are known, and they can be prepared by methods which are known per se. Thus, 3-dimethylamino-1-phenyl-propan-1-ol 20 . can be obtained, for example, by a Mannich reaction from acetophenone, formaldehyde and dimethylamine and by subsequent reduction of the resulting ketone; 1-methyl-2-(2-hydroxyethyl)-piperidine can be obtained, for example, by N-methylation of 2-(2-hydroxy-ethyl)-piperidine; the compounds of formula III (X = Cl, Br orI) can be obtained from the alcohols with inorganic - ` ~
halides, such as SOC12, P~r3 or HI; and the sulfonates can be obtained by esterification of the alcohols with the corresponding sulfonyl chlorides.
The compounds of Formulae II and III are pre-
The compounds of Foxmula I can be obtained by reacting the amines of Formula II or their salts with the compounds of Formula III.
Most of the amines of Formula II are known, and they can be prepared by methods which are known per se, for example by methylation of the anilines of the formula Ar-NH2.
In the compounds of Formulae III and V, the radical X is preferably Cl or Br. Reactive derivatives of these compounds include, in particular, the reactive esters of the alcohols of Formulae III and V (X = OH), preferably the corresponding alkylsulfonates (with alkyl of 1-6 C atoms) and the corresponding arylsulfonates (with aryl of 6-10 C atoms), for example the corres-pondiny methane-, benzene-, p-toluene- or naphthalene-l-or -2-sulfonates.
Most of the compounds of Formula III are known, and they can be prepared by methods which are known per se. Thus, 3-dimethylamino-1-phenyl-propan-1-ol 20 . can be obtained, for example, by a Mannich reaction from acetophenone, formaldehyde and dimethylamine and by subsequent reduction of the resulting ketone; 1-methyl-2-(2-hydroxyethyl)-piperidine can be obtained, for example, by N-methylation of 2-(2-hydroxy-ethyl)-piperidine; the compounds of formula III (X = Cl, Br orI) can be obtained from the alcohols with inorganic - ` ~
halides, such as SOC12, P~r3 or HI; and the sulfonates can be obtained by esterification of the alcohols with the corresponding sulfonyl chlorides.
The compounds of Formulae II and III are pre-
5 ferably reacted under N-alkylation conditions in the t presence or absence of an inert solvent, at temperatures of about 0 to about 250C, preferably of about 60 to i 180C, and under pressures of about 1 to 50 atmospheres.
Suitable solvents include J for example, hydrocarbons (e.g., hexane, benzene, toluene or xylene), ethers (e.g., diethyl ether, diisopropyl ether, tetrahydro-furan (THF), dioxane or diethylene glycol dimethyl i ether), amides, e.g., dimethylformamide (DMF), sul-foxides, e.g., dimethylsulfoxide, and alcohols (e.g., methanol, ethanol, isopropanol or n-butanol). If desired, a catalyst can be present. IE starting materials of Formula III (X = Cl, Br or I) are used, it is advisable to add a base, such as NaOH, KOH, Na2CO3, NaHCO3, triethylamine or pyridine. An excess of the aniline derivative of Formula II can also serve as the base and/or solvent.
The aniline derivatives of Formula I can also be obtained by reacting compounds of Formula IV with methylating agents.
The starting substances of Formula IV tY =
-NE~-R) can be obtained, for example, by reacting anilines of the formula Ar-NH2 with compounds of the formula X-R
(III); those of the Formula IV [Y = N-methyl-N-(l-phenyl-3-amino-propyl)-amino] can be obtained by adding methylaniline derivatives of the formula Ar-NH-CE3 onto cinnamic acid nitrile and then reducing the product;
and those of the Formula IV [Y = `l~-methyl-N-[2-(2-piperidyl~ethyl~mino] can be obtained by hydrogenolysis of corresponding l-benzyl-2-piperidyl derivatives.
Methylation of the compounds of Formula IV is in general carried out at temperatures of about 0 to about 150C, preferably using formaldehyde/formic acid, and especially using about 37~ aqueous formaldehyde solution in the presence of excess formic acid at about 90 - 110C. Reductive alkylation with formaldehyde/
sodium cyanoborohydride, preferably in the presence of an inert solvent, such as THF, in a weakly acid medium at temperatures of about 0 to 40C, is equally possible; the corresponding aldehyde-ammonia, which does not need to be isolated, is probably formed as an intermediate product. Reactions with methyl chloride, bromide, iodide or ~toluenesulfon~te~ prefexabl~ unde~
the conditions mentioned above`for the N-al~ylation~ axe also suitable.
Primary amines of the formula N(CH3) CHCC6H5~ CH2 CH2 NH2 can be methylated with met~anol in the presence oE R~ney ' ~
nickel at elevated temperatures to yield the corres-ponding monomethylamines of the formula Ar-N(CH3)-CH(C6E5)-CH2CH2-NH-CH3-Those compounds of Formula I in which R is -CH(C6H5)-CH2CH2-N~CH3)-Z are furthermore accessible by reacting amines of Formula V or their reactive de-rivatives with amines of Formula ~I (methylamine or dimethylamine).
~ The starting materials of Formula V (X = OH) can be obtained, for example, from the aniline deri-vatives of the formula Ar-NH-CH3 (II) and 3-phenyl-3-chloro-propan-l-ol; compounds of Formula V (X = Cl, Br or I) can be obtained from compounds of the Formula V
(X = OH) by reaction with inorganic halides, such as SOC12, PBr3 or HI; and the corresponding sulfonates can be obtained by esteri~ication of the alcohols V (X = O~) with sulfonyl chlorides.
~ The reaction of thecompounds of Formula V with compounds of Formula VI is carried out under alkylating conditions, preferably in the presence of one of the inert solvents mentioned above, at temperature of about 20 to 140C, preerably 80 to 120C, advantageously under pressure (up to about 100 atmospheres).
The aniline derivatives of Formula I can further-more be prepared by reducing corresponding starting substances which additionally contain reducible groups and/or C-C and/or C/N double or triple bonds.
- \ ~
Among the reducible starting substances t those of Formula VII are preferred:
Ar-N(cH3)-Q VIII
' wherein Q is -CH(C6H5)-CH=CH-N(CH3)-Z, -CH(C6H5)-CH2-¦ 5 CO-N(CH3)-Z, -CH(C6H5)-CH2-CH~-N(CHO)-z~ 2-(1-methyl-
Suitable solvents include J for example, hydrocarbons (e.g., hexane, benzene, toluene or xylene), ethers (e.g., diethyl ether, diisopropyl ether, tetrahydro-furan (THF), dioxane or diethylene glycol dimethyl i ether), amides, e.g., dimethylformamide (DMF), sul-foxides, e.g., dimethylsulfoxide, and alcohols (e.g., methanol, ethanol, isopropanol or n-butanol). If desired, a catalyst can be present. IE starting materials of Formula III (X = Cl, Br or I) are used, it is advisable to add a base, such as NaOH, KOH, Na2CO3, NaHCO3, triethylamine or pyridine. An excess of the aniline derivative of Formula II can also serve as the base and/or solvent.
The aniline derivatives of Formula I can also be obtained by reacting compounds of Formula IV with methylating agents.
The starting substances of Formula IV tY =
-NE~-R) can be obtained, for example, by reacting anilines of the formula Ar-NH2 with compounds of the formula X-R
(III); those of the Formula IV [Y = N-methyl-N-(l-phenyl-3-amino-propyl)-amino] can be obtained by adding methylaniline derivatives of the formula Ar-NH-CE3 onto cinnamic acid nitrile and then reducing the product;
and those of the Formula IV [Y = `l~-methyl-N-[2-(2-piperidyl~ethyl~mino] can be obtained by hydrogenolysis of corresponding l-benzyl-2-piperidyl derivatives.
Methylation of the compounds of Formula IV is in general carried out at temperatures of about 0 to about 150C, preferably using formaldehyde/formic acid, and especially using about 37~ aqueous formaldehyde solution in the presence of excess formic acid at about 90 - 110C. Reductive alkylation with formaldehyde/
sodium cyanoborohydride, preferably in the presence of an inert solvent, such as THF, in a weakly acid medium at temperatures of about 0 to 40C, is equally possible; the corresponding aldehyde-ammonia, which does not need to be isolated, is probably formed as an intermediate product. Reactions with methyl chloride, bromide, iodide or ~toluenesulfon~te~ prefexabl~ unde~
the conditions mentioned above`for the N-al~ylation~ axe also suitable.
Primary amines of the formula N(CH3) CHCC6H5~ CH2 CH2 NH2 can be methylated with met~anol in the presence oE R~ney ' ~
nickel at elevated temperatures to yield the corres-ponding monomethylamines of the formula Ar-N(CH3)-CH(C6E5)-CH2CH2-NH-CH3-Those compounds of Formula I in which R is -CH(C6H5)-CH2CH2-N~CH3)-Z are furthermore accessible by reacting amines of Formula V or their reactive de-rivatives with amines of Formula ~I (methylamine or dimethylamine).
~ The starting materials of Formula V (X = OH) can be obtained, for example, from the aniline deri-vatives of the formula Ar-NH-CH3 (II) and 3-phenyl-3-chloro-propan-l-ol; compounds of Formula V (X = Cl, Br or I) can be obtained from compounds of the Formula V
(X = OH) by reaction with inorganic halides, such as SOC12, PBr3 or HI; and the corresponding sulfonates can be obtained by esteri~ication of the alcohols V (X = O~) with sulfonyl chlorides.
~ The reaction of thecompounds of Formula V with compounds of Formula VI is carried out under alkylating conditions, preferably in the presence of one of the inert solvents mentioned above, at temperature of about 20 to 140C, preerably 80 to 120C, advantageously under pressure (up to about 100 atmospheres).
The aniline derivatives of Formula I can further-more be prepared by reducing corresponding starting substances which additionally contain reducible groups and/or C-C and/or C/N double or triple bonds.
- \ ~
Among the reducible starting substances t those of Formula VII are preferred:
Ar-N(cH3)-Q VIII
' wherein Q is -CH(C6H5)-CH=CH-N(CH3)-Z, -CH(C6H5)-CH2-¦ 5 CO-N(CH3)-Z, -CH(C6H5)-CH2-CH~-N(CHO)-z~ 2-(1-methyl-
6-oxo-2-piperidyl)-ethyl or the group -CH~-CH2 ~ An ~ , wherein CH
An is an anion of a strong acid and Ar is as defined above.
The compounds of Formula VIII can be obtained, for example, by reacting anilines of the formula Ar-NH-CH3 (II) with compounds of the formula Q-X (wherein X and Q
are as defined above). Amides of the formula Ar-N(~CH3)-CH~¢6H5)-CH2-CO-N(CH3)-Z can also be obtained by amida-tion of corresponding carboxylic acid esters of the for-mula Ar-N(CH3)-CH(C6H5)-CH2-COOAlkyl (wherein alkyl is of 1 - 4 C atoms). N-formyl compounds of the formula Ar-N(CH3)-CH(C6H5)-C~2-CH2-N(CHO)-Z can also be obtained by formylation of the corresponding NH-compounds of the formula Ar-N(cH3)~cH~c6H5)-cH2-cH2-NH-z-Furthermore, for example, starting substances which correspond to Formula I but carry a benzylQxy group instead of an OH group in the radical Ar are suitable.
_9_ r The starting substances of Formula VIII and the other reducible starting substances can, for example, be converted into the compoun~s of Formula I by catalytic hydrogenation with nascent hydrogen, with complex metal hydrides or with use of other chemical reducing agents.
The reducing methods suitable for the individual starting substances in general depend on the nature of the group, those skilled in the art being familiar with them from statements in the literature. Thus, for example, it is particularly advantageous to catalytically hydrogenate quaternary pyridinium salts and olefinic compounds. In contrast, the acid amides are particularly advantageously reduced with complex metal hydrides or with diborane.
Catalysts which are suitable for catalytic hydro-genations include, for example, noble metal catalysts, nickel catalysts or cobalt catalysts, and also mixed catalysts, such as copper/chromium oxide. Suitable noble metals are, above all, platinum and palladium, which can be present on supports (for example on charcoal, calcium carbonate or strontium carbonate), in the form of o~ides tfor e~ample platinum oxide) or in finely divided form.
Nickel catalysts and cobalt catalysts are preferabl~
employed as Raney metals. Hydrogenation can preferably be carried out under pressures of about 1 to 20a atmos-25 pheres and at temperatures of about -80 to ~150~C. The hydrogenation is carried out in the presence of an inert solvent, for example an alcohol, such as methanol, ethanol or isopropanol, a carboxylic acid, such as acetic acid, an ester, such as ethyl acetate, or an ether, such as tetrahydrofuran or dioxane. It is also possible to use solvent mixtures, for example also mixtures which contain water. Hydrogenation under mild conditions, for example at temperatures of 0 to 30C and under normal pressure, is preferred.
Complex metal hydrides, such as LiAlH4, NaBH4 of 10 NaAl(OCH2CH2OCH332H2 as well as diborane can also be employed as the reducing agents, if desired with the ! addition of catalysts, such as BF3, AlC13 or LiBr.
Suitable solvents in this case are, in particular, ethers, such as diethyl ether, llHF, dioxane, 1,2~dimethoxy-ethane or diglyme, and hydrocarbons, such as benzene.
Alcohols, such as methanol or et:hanol, are above all suitable as the solvent for reductions with NaBH4. A
reduction by this method is preferably carried out at temperatures of about -80 to +150C, in particular of 20 about 20 to 120C.
Reaction with nascent hydrogen is also a suitable method of reduction. The nascent hydrogen can be pro-i duced, for example,~ by treating metals with acids or bases. Thus, for example, the systems zinc/acid, zinc/
alkali metal hydroxide solution, iron/acid or tin/acid can be used. Suitable acids include, for exa~ple, I
1, --11--~6~
h~drochloric acid or acetic acid. The reducing agent used can also be an alkali metal, e.g., sodium, in an alcohol, e.g., ethanol, isopropanol, n-butanol, amyl alcohol or isoamyl alcohol, or in phenol, and furhtermore, for example, an aluminum/nickel alloy in alkaline-aqueous or alkaline-aqueous-alcoholic solution, as well as sodium amalgam or aluminum amalgam in aqueous-alcoholic or aqueous solution. In these methods, the reaction tem-peratures are about 0 to about 150C, preferably about 20 to 120C.
Aniline derivatives of the formula Ar-N(CH3)-CH(C6H5) CH2-CH2-NH-CH3 are obtainable particularly favorably by solvolytic, preferably hydrolytic removal cf an amino-protecting group from corresponding protected compounds of Formula VII.
The expression "amino-protecting group" is quite conventional and refers to groups which are suitable for protecting, i.e~, blocking, a secondary amino group from chemical reactions, but which can be removed easily after the desired chemical reaction has been completed at other positions of the molecule. Since the amino-protecting group is removed during solvolysis, its nature and size are not critical. Preferred amino-protecting groups are acyl groups o~ preferably 1 - 20, in particular, 1 - 8 carbon atoms. The expression "acyl group" in connection with the present process is to be interpreted in the broadest sense. It encompasses acyl groups derived from aliphatic, araliphaticr aromatic, or heterocyclic car-boxylic acids or sulfonic acids, furthermore, for example, alkoxycarbonyl, aryloxycarbonyl and aralkyloxycarbonyl groups. Specific preferred amino-protecting groups are formyl, acetyl, trifluoroacetyl and benzoyl.
The starting compounds of Formula VII can be ob-tained, for example, by reaction of methylanilines of the formula Ar-NH-C~3 with compounds of the formula X-CH(C6H5)CH2-CH2-N(CH3)-W, wherein Ar, X and W are as defined above or their reactive derivatives.
The solvolytic cleavage of the compounds of Formula VII is favorably effected by reaction with a solvent such as water (hydrolys,is) or an alcohol of preferably 1 - 4 carbon atoms (alcoholysis) at temperatures~
of about O to about 120C in the presence of an acidic or`a basic catalyst, for example, a mineral acid, e.g., sulfuric or hydrochloric acidf a metal hydroxide, e.g., sodium, potassium, calcium, barium, lead or silver hydroxide, or à metal or ammonium salt, e.g., sodium or potassium carbonate or ammonium chloride. As alcohols, methanol, ethanol or isopropanol are preferably suited;
one can also use mixtures owater with one of these al-cohols. In order to solvolyze the preferred N-formyl derivatives of Formula VII (W - CHO~, a boiling aqueous-ethanolic KOH solution is preferably used.
"~
Secondary amines of the formula Ar-N(CH3)-CH(C6H5)-CH2-CH2-NH-CH3 can be methylated according to one of the above methods to yield the corresponding tertiary amines of the formula Ar-N(CH3)-CH(C6H5)-CH2-CH2-N(CH3)2, if desired.
Moreover, if desired, a phenol of Formula I (Ar =
a phenyl group substituted by an OH group) can be alkylated, a compound of Formula I (Ar = a phenyl group substituted by an alkoxy group) being obtained. Suitable alkylating agents include, for example, alkyl halides, e.g., methyl chloride, bromide or iodide, dialkyl sulfates, e.g., dimethyl sulfate, and sulfonic acid alkyl esters, e.g., methyl p-toluenesulfonate. The O alkylation is preferably carr~ed out at temperatures of about 0 to about 150C, and especially of 20 to 100C, in an inert solvent, for example, an alcohol, such as methanol or ethanol, a hydrocarbon, such as benzene, an amide, such as DMF, an ether, such as THF, or an amine, such as pyridine. If halides are used, the reaction is preferably carried out in the presence of a base, such as NaOH, KOH, triethylamine or pyridine, in which case an excess of this base can serve as the solvent.
Ethers of Formula I (Ar = a phenyl group s~bsti-tuted by an alkoxy group) can be split by methods which are known from the literature. The corresponding phenols of Formula I (Ar = a phenyl gxoup substituted by an OH
group) are thereby formed. The ether can be split, for example, by treatment with HBr or HI in a~ueous or acetic acid solution, by heating with Lewis acids, such as AlC13 or boron trihalides, or fusing the pyridine hydrohalides or aniline hydrohalides, preferably pyridine hydrochloride, at about 150 - 250C.
A resulting base of Formula I can be converted into an associated acid addition salt with an acid.
Acids which produce physiologically acceptable salts are suitable for the reaction. Thus, it is possible to use inorganic acids, for-example, sulfuric acid, hydrogen halide acids, phosphoric acids, e.g., orthophosphoric acid, nitric acid and sulfamic acid, and also organic acids, for example, aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monobasic or polybasic carboyxlic, sulfonic or suluric acids, e.g., formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, mal~ic acid, benzoic acid, salicylic acid, 2-phenylpropionic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethane-sulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene-mono- and -di-sulfonic acids and laurylsulfuric acid~ If desired, thefree bases of Formula I can be liberated from their ' ' !
6~
salts by treatment with strong bases r such as sodium hydroxide or potassium hydroxide, sodium carbonate or potassium carbonate.
It has been found that the compounds of Formula I and their physiologically acceptable acid addition salts have valuable pharmacological properties. Thus, in particular, they display actions on the central nervous system, above all antidepressant actions. In detail, it is possible to demonstrate a reserpine-antagonistic action (which can be detected, for example, towards reserpine in mice in accordance with the method of Askew, hife Science, volume 10 (1963), pages 725-730);
an anticataleptic action (which can be detected, for example, towards tetrabenazine in rats in accordance with the method of Giurgea et al, Medicina Experimentalis, volume 9, (1963), pages 249-262); and an antipto~ic action (which can be detected, for example, towards reserpine in accordance with the method of Domenjoz and Theobald, Arch. Int. Pharmacodyn., volume 120 (1959), pages 450 et seq., with evaluation in accordance with the method of Rubin et al, J. Pharmaco~. Exp. Therap., volume 12~ (1957), pages 125-136). Furthermore, the action of 5-hydroxy-tryptophan in mice can be potentiated (method: similar to that of Ross et al, Acta Pharmacol. et Toxicol., volume 39 (1976), pages 152-166), and the effects, on the central nervous system, of excitation and increase in temperature which D-amphetamine sulfate (for example, 1.5 mg/kg administered subcutaneously 1 hour after the test substance, which is ]ikewise administered subcuta-neously) and aggregation ~placing 5 rats together in one glass) trigger off (method in accordance with M~ller-Calgan et al in Zippel, H. P.,(Ed.): Memory and Transferof Information, Plenum Pr~ss, New York-London, 1973, pages 87-125), can be increased and/or prolonged. The substances influence the biogenic amines of the central nervous system~ Thus, for example, they lead to an inhibition of the absorption of noradrenaline, 5-hydroxy-tryptamine and dopamine (method: Kannengiesser et al, Biochem. Pharmacol., volume 22 (1973), pages 73-84) in synaptosornes in vitro and, in vivo, they inhibit the release of catecholamine and serotonin induced in the brain by tyramine derivatives (method: Carlsson et al, Europ. J. Pharmacol., volume 5 (:L969), pages 357-366;
and 367-373). Furthermore, when a~ninistered orally to rats, the compounds antagonize the lowering in the level of serotonin caused by p-chloramphetamine (method: Fuller 20 et al, Biochem. Pharmacol. volume 27 (1978), pages 193-198~.
Spasmolytic actions which can be detected by the methocls conventional for such actions also occur.
Compounds of Formula I and their physiolo~ically acceptable acid addition salts can, therefore, be used as active compounds for medicaments and also as intermediate products for the preparation of other active compounds for medicaments.
The present invention, thus, also relates to the use of the compounds of Formula I and of their physiologi-cally acceptable salts for the preparation of pharma~
ceutical formulations, in particular by a non-chemical route.
For this, they can be brought into a suitable dosage form together with at least one excipient or auxiliary and, if appropriate, in combination with one or more other active compound(s).
This invention furthermore relates to agents, in particular pharmaceutical formulations, containing a compound of Formula I and/or one of its physiologically acceptable acid addition salts. These formulations can be employed as medicaments in human medicine or veterinary medicine. Suitable carrier substances include organic ox inorganic substances which are suitable for enteral tfor example oral) or parenteral administration or topical application and which do not react with the new compounds, or example water, vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, carbohydrates, such as 2n lactose or starch, magnesium stearate, talc and petroleum jelly. Tablets, dragees, capsules, syrups, elixirs, drops or suppositories are used, in par~icular, for enteral administration; solutions, preferably oily or aqueous solutions, and also suspensions, emulsions or ~5 implants are used for parenteral administration; and ointments, creams or powders are used for topical appli-cation. The new compounds can also be lyophilized, and the resulting lyophilizates can be used, for example, for producing injection preparations. The formulations mentioned can be sterilized and/or can contain auxiliaries, such as lubricants, preservati~es, stabilizers and/or wetting agents, emulsifiers, salts for in~luencing the osmotic pressure, buffer substances, colorants, flavoring agents and/or aroma generating substances. If desired, they can also contain one or more other active compounds, for example one or more vitamins.
The present invention also relates to the use of the compounds of Formula I and oE their physiologically acceptable acid addition salts in combating illnesses, in particular depressions of various etiology and symp-tomatology, and to their use in t:he therapeutic treatment of the human or animal hody.
The substances of this invention are as a rule administered analogously to known commercially available psychopharmaceuticals (for example, imipramine), preferably in dosages of about 2 to 500 mg~ in particular of 10 to 50 mg per dosage unit. The daily dosage is pre~erably about 0.05 to 10 mg/kg of body wei~ht. However, the speciic dose for each particular patient depends on the most diverse factors, for example on the activity of the specific compound employed, on the age, body weight, general state of health, sex, diet, time and method of administration, rate oE elimination, medicament combina~
tion and the severity of the particular illness to which the therapy applies. Oral administration is preferred.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative.
In the following examples, all temperatures are set forth uncorrectecl in degrees Celsius; unless otherwise indicated, all parts and percentages are by weight.
In the following examples, the term "customary working up" means:
Sodium hydroxide solution is added; the mixture is extracted with an organic solvent; e.g., benzene, chloroform or methylene chloride; the organic phase is separa-ted off, dried over sodium sulfate and filtered;
the filtrate is evaporated; and the residue is purified by chromatography and/or crystallization.
The Rf values were obtained on silica gel with toluene~triethylamine 8:2 as the solvent.
A mixture of 14.2 g of p-chloro-N-methyl-aniline, 23.4 g of 1-phenyl-3-dimethylamino-propyl chloride hydro-chloride (or 32.3 g of 1-phenyl-3-dimethylamino-propyl bromide hydrobromide), 27.6 g of K2C03 and 250 ml of DMF
is boiled for 12 hours. After cooling and customary working ùp, p-chloro-N-methyl-N~ phenyl-3-dimethyl-844~
aminopropyl)-aniline is obtained. Dihydrochloride, m.p.
164.
EXAM2LES 2 to 20 ,! -_, , . ..... ~ . . .. ... _ . . .
The following compounds are obtained analogously5 to Exampie 1, from the corresponding N-methyl-anilines:
20 N-Methyl-N-(l-phenyl-3-dimethylaminopropyl)-aniline~
3. o-Fluoro-N-methyl-N-(l-phenyl-3-dimethylamino-propyl)-aniline. 0 4. m- Fluoro-N-methyl-N-(l-phenyl-3-dimethylamino-propyl)-aniline.
5. p-Fluoro-N-methyl-N-(l-phenyl-3-dimethylamino-propyl)-aniline, dihydrochloride, m.p. 204.
6, o-Chloro-N-methyl-N~ phenyl-3-climethylamino-propyl)-aniline.
An is an anion of a strong acid and Ar is as defined above.
The compounds of Formula VIII can be obtained, for example, by reacting anilines of the formula Ar-NH-CH3 (II) with compounds of the formula Q-X (wherein X and Q
are as defined above). Amides of the formula Ar-N(~CH3)-CH~¢6H5)-CH2-CO-N(CH3)-Z can also be obtained by amida-tion of corresponding carboxylic acid esters of the for-mula Ar-N(CH3)-CH(C6H5)-CH2-COOAlkyl (wherein alkyl is of 1 - 4 C atoms). N-formyl compounds of the formula Ar-N(CH3)-CH(C6H5)-C~2-CH2-N(CHO)-Z can also be obtained by formylation of the corresponding NH-compounds of the formula Ar-N(cH3)~cH~c6H5)-cH2-cH2-NH-z-Furthermore, for example, starting substances which correspond to Formula I but carry a benzylQxy group instead of an OH group in the radical Ar are suitable.
_9_ r The starting substances of Formula VIII and the other reducible starting substances can, for example, be converted into the compoun~s of Formula I by catalytic hydrogenation with nascent hydrogen, with complex metal hydrides or with use of other chemical reducing agents.
The reducing methods suitable for the individual starting substances in general depend on the nature of the group, those skilled in the art being familiar with them from statements in the literature. Thus, for example, it is particularly advantageous to catalytically hydrogenate quaternary pyridinium salts and olefinic compounds. In contrast, the acid amides are particularly advantageously reduced with complex metal hydrides or with diborane.
Catalysts which are suitable for catalytic hydro-genations include, for example, noble metal catalysts, nickel catalysts or cobalt catalysts, and also mixed catalysts, such as copper/chromium oxide. Suitable noble metals are, above all, platinum and palladium, which can be present on supports (for example on charcoal, calcium carbonate or strontium carbonate), in the form of o~ides tfor e~ample platinum oxide) or in finely divided form.
Nickel catalysts and cobalt catalysts are preferabl~
employed as Raney metals. Hydrogenation can preferably be carried out under pressures of about 1 to 20a atmos-25 pheres and at temperatures of about -80 to ~150~C. The hydrogenation is carried out in the presence of an inert solvent, for example an alcohol, such as methanol, ethanol or isopropanol, a carboxylic acid, such as acetic acid, an ester, such as ethyl acetate, or an ether, such as tetrahydrofuran or dioxane. It is also possible to use solvent mixtures, for example also mixtures which contain water. Hydrogenation under mild conditions, for example at temperatures of 0 to 30C and under normal pressure, is preferred.
Complex metal hydrides, such as LiAlH4, NaBH4 of 10 NaAl(OCH2CH2OCH332H2 as well as diborane can also be employed as the reducing agents, if desired with the ! addition of catalysts, such as BF3, AlC13 or LiBr.
Suitable solvents in this case are, in particular, ethers, such as diethyl ether, llHF, dioxane, 1,2~dimethoxy-ethane or diglyme, and hydrocarbons, such as benzene.
Alcohols, such as methanol or et:hanol, are above all suitable as the solvent for reductions with NaBH4. A
reduction by this method is preferably carried out at temperatures of about -80 to +150C, in particular of 20 about 20 to 120C.
Reaction with nascent hydrogen is also a suitable method of reduction. The nascent hydrogen can be pro-i duced, for example,~ by treating metals with acids or bases. Thus, for example, the systems zinc/acid, zinc/
alkali metal hydroxide solution, iron/acid or tin/acid can be used. Suitable acids include, for exa~ple, I
1, --11--~6~
h~drochloric acid or acetic acid. The reducing agent used can also be an alkali metal, e.g., sodium, in an alcohol, e.g., ethanol, isopropanol, n-butanol, amyl alcohol or isoamyl alcohol, or in phenol, and furhtermore, for example, an aluminum/nickel alloy in alkaline-aqueous or alkaline-aqueous-alcoholic solution, as well as sodium amalgam or aluminum amalgam in aqueous-alcoholic or aqueous solution. In these methods, the reaction tem-peratures are about 0 to about 150C, preferably about 20 to 120C.
Aniline derivatives of the formula Ar-N(CH3)-CH(C6H5) CH2-CH2-NH-CH3 are obtainable particularly favorably by solvolytic, preferably hydrolytic removal cf an amino-protecting group from corresponding protected compounds of Formula VII.
The expression "amino-protecting group" is quite conventional and refers to groups which are suitable for protecting, i.e~, blocking, a secondary amino group from chemical reactions, but which can be removed easily after the desired chemical reaction has been completed at other positions of the molecule. Since the amino-protecting group is removed during solvolysis, its nature and size are not critical. Preferred amino-protecting groups are acyl groups o~ preferably 1 - 20, in particular, 1 - 8 carbon atoms. The expression "acyl group" in connection with the present process is to be interpreted in the broadest sense. It encompasses acyl groups derived from aliphatic, araliphaticr aromatic, or heterocyclic car-boxylic acids or sulfonic acids, furthermore, for example, alkoxycarbonyl, aryloxycarbonyl and aralkyloxycarbonyl groups. Specific preferred amino-protecting groups are formyl, acetyl, trifluoroacetyl and benzoyl.
The starting compounds of Formula VII can be ob-tained, for example, by reaction of methylanilines of the formula Ar-NH-C~3 with compounds of the formula X-CH(C6H5)CH2-CH2-N(CH3)-W, wherein Ar, X and W are as defined above or their reactive derivatives.
The solvolytic cleavage of the compounds of Formula VII is favorably effected by reaction with a solvent such as water (hydrolys,is) or an alcohol of preferably 1 - 4 carbon atoms (alcoholysis) at temperatures~
of about O to about 120C in the presence of an acidic or`a basic catalyst, for example, a mineral acid, e.g., sulfuric or hydrochloric acidf a metal hydroxide, e.g., sodium, potassium, calcium, barium, lead or silver hydroxide, or à metal or ammonium salt, e.g., sodium or potassium carbonate or ammonium chloride. As alcohols, methanol, ethanol or isopropanol are preferably suited;
one can also use mixtures owater with one of these al-cohols. In order to solvolyze the preferred N-formyl derivatives of Formula VII (W - CHO~, a boiling aqueous-ethanolic KOH solution is preferably used.
"~
Secondary amines of the formula Ar-N(CH3)-CH(C6H5)-CH2-CH2-NH-CH3 can be methylated according to one of the above methods to yield the corresponding tertiary amines of the formula Ar-N(CH3)-CH(C6H5)-CH2-CH2-N(CH3)2, if desired.
Moreover, if desired, a phenol of Formula I (Ar =
a phenyl group substituted by an OH group) can be alkylated, a compound of Formula I (Ar = a phenyl group substituted by an alkoxy group) being obtained. Suitable alkylating agents include, for example, alkyl halides, e.g., methyl chloride, bromide or iodide, dialkyl sulfates, e.g., dimethyl sulfate, and sulfonic acid alkyl esters, e.g., methyl p-toluenesulfonate. The O alkylation is preferably carr~ed out at temperatures of about 0 to about 150C, and especially of 20 to 100C, in an inert solvent, for example, an alcohol, such as methanol or ethanol, a hydrocarbon, such as benzene, an amide, such as DMF, an ether, such as THF, or an amine, such as pyridine. If halides are used, the reaction is preferably carried out in the presence of a base, such as NaOH, KOH, triethylamine or pyridine, in which case an excess of this base can serve as the solvent.
Ethers of Formula I (Ar = a phenyl group s~bsti-tuted by an alkoxy group) can be split by methods which are known from the literature. The corresponding phenols of Formula I (Ar = a phenyl gxoup substituted by an OH
group) are thereby formed. The ether can be split, for example, by treatment with HBr or HI in a~ueous or acetic acid solution, by heating with Lewis acids, such as AlC13 or boron trihalides, or fusing the pyridine hydrohalides or aniline hydrohalides, preferably pyridine hydrochloride, at about 150 - 250C.
A resulting base of Formula I can be converted into an associated acid addition salt with an acid.
Acids which produce physiologically acceptable salts are suitable for the reaction. Thus, it is possible to use inorganic acids, for-example, sulfuric acid, hydrogen halide acids, phosphoric acids, e.g., orthophosphoric acid, nitric acid and sulfamic acid, and also organic acids, for example, aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monobasic or polybasic carboyxlic, sulfonic or suluric acids, e.g., formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, mal~ic acid, benzoic acid, salicylic acid, 2-phenylpropionic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethane-sulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene-mono- and -di-sulfonic acids and laurylsulfuric acid~ If desired, thefree bases of Formula I can be liberated from their ' ' !
6~
salts by treatment with strong bases r such as sodium hydroxide or potassium hydroxide, sodium carbonate or potassium carbonate.
It has been found that the compounds of Formula I and their physiologically acceptable acid addition salts have valuable pharmacological properties. Thus, in particular, they display actions on the central nervous system, above all antidepressant actions. In detail, it is possible to demonstrate a reserpine-antagonistic action (which can be detected, for example, towards reserpine in mice in accordance with the method of Askew, hife Science, volume 10 (1963), pages 725-730);
an anticataleptic action (which can be detected, for example, towards tetrabenazine in rats in accordance with the method of Giurgea et al, Medicina Experimentalis, volume 9, (1963), pages 249-262); and an antipto~ic action (which can be detected, for example, towards reserpine in accordance with the method of Domenjoz and Theobald, Arch. Int. Pharmacodyn., volume 120 (1959), pages 450 et seq., with evaluation in accordance with the method of Rubin et al, J. Pharmaco~. Exp. Therap., volume 12~ (1957), pages 125-136). Furthermore, the action of 5-hydroxy-tryptophan in mice can be potentiated (method: similar to that of Ross et al, Acta Pharmacol. et Toxicol., volume 39 (1976), pages 152-166), and the effects, on the central nervous system, of excitation and increase in temperature which D-amphetamine sulfate (for example, 1.5 mg/kg administered subcutaneously 1 hour after the test substance, which is ]ikewise administered subcuta-neously) and aggregation ~placing 5 rats together in one glass) trigger off (method in accordance with M~ller-Calgan et al in Zippel, H. P.,(Ed.): Memory and Transferof Information, Plenum Pr~ss, New York-London, 1973, pages 87-125), can be increased and/or prolonged. The substances influence the biogenic amines of the central nervous system~ Thus, for example, they lead to an inhibition of the absorption of noradrenaline, 5-hydroxy-tryptamine and dopamine (method: Kannengiesser et al, Biochem. Pharmacol., volume 22 (1973), pages 73-84) in synaptosornes in vitro and, in vivo, they inhibit the release of catecholamine and serotonin induced in the brain by tyramine derivatives (method: Carlsson et al, Europ. J. Pharmacol., volume 5 (:L969), pages 357-366;
and 367-373). Furthermore, when a~ninistered orally to rats, the compounds antagonize the lowering in the level of serotonin caused by p-chloramphetamine (method: Fuller 20 et al, Biochem. Pharmacol. volume 27 (1978), pages 193-198~.
Spasmolytic actions which can be detected by the methocls conventional for such actions also occur.
Compounds of Formula I and their physiolo~ically acceptable acid addition salts can, therefore, be used as active compounds for medicaments and also as intermediate products for the preparation of other active compounds for medicaments.
The present invention, thus, also relates to the use of the compounds of Formula I and of their physiologi-cally acceptable salts for the preparation of pharma~
ceutical formulations, in particular by a non-chemical route.
For this, they can be brought into a suitable dosage form together with at least one excipient or auxiliary and, if appropriate, in combination with one or more other active compound(s).
This invention furthermore relates to agents, in particular pharmaceutical formulations, containing a compound of Formula I and/or one of its physiologically acceptable acid addition salts. These formulations can be employed as medicaments in human medicine or veterinary medicine. Suitable carrier substances include organic ox inorganic substances which are suitable for enteral tfor example oral) or parenteral administration or topical application and which do not react with the new compounds, or example water, vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, carbohydrates, such as 2n lactose or starch, magnesium stearate, talc and petroleum jelly. Tablets, dragees, capsules, syrups, elixirs, drops or suppositories are used, in par~icular, for enteral administration; solutions, preferably oily or aqueous solutions, and also suspensions, emulsions or ~5 implants are used for parenteral administration; and ointments, creams or powders are used for topical appli-cation. The new compounds can also be lyophilized, and the resulting lyophilizates can be used, for example, for producing injection preparations. The formulations mentioned can be sterilized and/or can contain auxiliaries, such as lubricants, preservati~es, stabilizers and/or wetting agents, emulsifiers, salts for in~luencing the osmotic pressure, buffer substances, colorants, flavoring agents and/or aroma generating substances. If desired, they can also contain one or more other active compounds, for example one or more vitamins.
The present invention also relates to the use of the compounds of Formula I and oE their physiologically acceptable acid addition salts in combating illnesses, in particular depressions of various etiology and symp-tomatology, and to their use in t:he therapeutic treatment of the human or animal hody.
The substances of this invention are as a rule administered analogously to known commercially available psychopharmaceuticals (for example, imipramine), preferably in dosages of about 2 to 500 mg~ in particular of 10 to 50 mg per dosage unit. The daily dosage is pre~erably about 0.05 to 10 mg/kg of body wei~ht. However, the speciic dose for each particular patient depends on the most diverse factors, for example on the activity of the specific compound employed, on the age, body weight, general state of health, sex, diet, time and method of administration, rate oE elimination, medicament combina~
tion and the severity of the particular illness to which the therapy applies. Oral administration is preferred.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative.
In the following examples, all temperatures are set forth uncorrectecl in degrees Celsius; unless otherwise indicated, all parts and percentages are by weight.
In the following examples, the term "customary working up" means:
Sodium hydroxide solution is added; the mixture is extracted with an organic solvent; e.g., benzene, chloroform or methylene chloride; the organic phase is separa-ted off, dried over sodium sulfate and filtered;
the filtrate is evaporated; and the residue is purified by chromatography and/or crystallization.
The Rf values were obtained on silica gel with toluene~triethylamine 8:2 as the solvent.
A mixture of 14.2 g of p-chloro-N-methyl-aniline, 23.4 g of 1-phenyl-3-dimethylamino-propyl chloride hydro-chloride (or 32.3 g of 1-phenyl-3-dimethylamino-propyl bromide hydrobromide), 27.6 g of K2C03 and 250 ml of DMF
is boiled for 12 hours. After cooling and customary working ùp, p-chloro-N-methyl-N~ phenyl-3-dimethyl-844~
aminopropyl)-aniline is obtained. Dihydrochloride, m.p.
164.
EXAM2LES 2 to 20 ,! -_, , . ..... ~ . . .. ... _ . . .
The following compounds are obtained analogously5 to Exampie 1, from the corresponding N-methyl-anilines:
20 N-Methyl-N-(l-phenyl-3-dimethylaminopropyl)-aniline~
3. o-Fluoro-N-methyl-N-(l-phenyl-3-dimethylamino-propyl)-aniline. 0 4. m- Fluoro-N-methyl-N-(l-phenyl-3-dimethylamino-propyl)-aniline.
5. p-Fluoro-N-methyl-N-(l-phenyl-3-dimethylamino-propyl)-aniline, dihydrochloride, m.p. 204.
6, o-Chloro-N-methyl-N~ phenyl-3-climethylamino-propyl)-aniline.
7. m-Chloro-N-methyl-N-(l-phenyl-3-dimethylamino-propyl)-aniline.
8. o-Methoxy-N-methyl-N-(l-phenyl-3-dimethylamino-propyl)-aniline. Oxaiate, m.~. 139 . Fumarate, m.p. 119.
9. m-Methoxy N-methyl-N-(l-phenyl-3-dimethylamino-propyl)-aniline.
10. p-Methoxy-N-methyl-N-(l-phenyl-3-dimethylamino-propyl~-aniline, dihydrochloride, m.p. 194;
11. p-n-But~xy-N-methyl-N-(l-phenyl-3-dimethylamino-propyl)~aniline.
12. 3,4-Methylene~ioxy-N-methyl-N~ Fhenyl-3-dimethyl-aminopro~yl)-aniline, dihydr~chloride, m.p. 218-220.
13. o-Hydroxy-N-methyl-N-(l-phenyl-3-dimethylamino-propyl)-aniline.
14. m-Hydroxy-N-methyl-N-(l-phenyl-3-dimethylamino--propyl)-aniline.
15. p-Hydroxy-N-methyl-N-(l-phenyl-3-dimethylamino-~--~ prop~ niline,.''`' ''~''~'''''~~'
16. o-Trifluoromethyl-N-methyl-N-(l-phenyl-3-dimethyl-aminopropyl)-aniline.
i7. m-~rifluoromethyl-N-methyl-N-(l-phenyl-3-dimethyl-aminopropyl)-aniline.
1'8. p-Trifluoromethyl-N-methyl-N-(l-phenyl-3-dimethyl-aminopropyl)-aniline.
19. 4-(N-Methyl-N-l-phenyl-3-dimethylamin'o-propylamino~
indane, .~o. 5-(N-Methyl-N-l-phenyl-3--dimethylamino-propylamino~
indane, ~ihydrochloride, m.p. 184. Oxalate, m.p.18~-186.
EXAMPLES 21 to 40 .:
.. .. ..... . . .
The following compounds are obtained analogously to Examples 1 to 2~, using 1-methyl-2-(2-chloroethyl)-piperidine: ' -21. N-Methyl-N-[2-(1-methyl-2-piperidyl)-ethyl]-aniline.
22.,o-Fluoro-N-methyl-N-[2-(1-methyl-2-piperidyl)-ethyl~-anlline .
23. m-~luoro-N-methyl-N-[2-(1-methyl-2-piperidyl)-e-thyl]-aniline, ~.6~
2~. p-Fluoro-N-methyl-N-[2-(1-methyl-2-piperidyl)-et`hyl]-aniline.
--25. o-Chloro-N-methyl-N-~2-(1-methyl-2-piperidyl)-ethyl]-aniline~
-26. m-Chloro-N-methyl-N-~2-(1-methyl-2-piperidyl)-ethyl]-aniline.
27.p-Chloro-N-methyl-N-~2-(1-methyl-2-piperidyl)-ethyl]-aniline, Rf: 0.38.
-28. o-Methoxy-N-methyl-N-[2-(1-methyl-2-piperidyl)-ethy~]-aniline.
29. m-Methoxy-N-methyl-N-L2-(1-methyl-2-piperidyl)-ethyl]-aniline.
30. p-Methoxy-N-methyl-N-L2-(1-methyl-2-piperidyl)-ethyl]-aniline, hydrochloricle, m p. 138.
31. ~-n-Butoxy-N-methyl-N-/2-(1-methyl-2-~i~eridyl)-ethyl7-aniline.
32. 3,4-~5ethylenedioxy-N-methyl-N-/2-(l-methyl-2-piperidyl)-ethyl7-aniline.
33. o-Hydroxy-N-methyl-N-~2~ methyl-2-piperidyl)-ethyl]-aniline.
34. m-Hydroxy-N-methyl-N-[2-(1-methyl-2-piperidyl)-ethyl]-aniline.
35. p-Hydroxy-N-methyl-N-[2-(1-methyl-2-piperidyl)-ethyl]-aniline.
36. o-Trifluorome~thyl-N-methyl-N-[2-(1-methyl-2-piperidyl)-ethyl]-aniline.
37. m-Trifluoromethyl-N-methyl-N-[2-(1-methyl-2-piperidyl)-e-thyl~-aniline.
38. p-Trifluoromethyl-N-methyl-N-[2-(1-methyl-2-piperidyl)-ethyl~-aniline, Rf: 0.42.
39. 4-[N-Methyl-N-(2-(1-methyl-2-piperidyl)-ethyl)-amino]-indane 540. 5-[N-Methyl-N-(2-(1-methyl-2 piperidyl)-ethyl)-amino]-indane.
.. . ..
.. , . ,.. . . ~ .. ... . .. . . . . . ..... . . . .. . . . .
In analogy to Examples 1 to 20, the following compounds are obtained using l-phenyl-3-methylamino-propyl chloride;
41. N-Methyl-N~l-phenyl-3-methylamino-propyl)-2niline.
42. o-Fluoro-N-methyl-N-(l-phenyl-3-methylaminopropyl)-aniline.
43. m-Fluoro-N-methyl-N-(l-phenyl-3-methylaminopropyl)-aniline.
44. p-Fluoro-N-methyl-N-(1-phenyl-3-methylaminopro~yl)-aniline.
45. o-Chloro-N-methyl-N-(l-phenyl-3-methylaminoprop~
aniline.
0 46. m-Chloro-N-methyl-N-(l-phenyl-3-methylaminopropyl)-aniline.
47. p-Chloro-N-methyl-N-(1-phenyl-3-methylaminopropyl)-aniline.
48. o-Methoxy-N-methyl-N-(l-phenyl-3-methyla~ino~ropyl)-aniline.
49. m-Methoxy-~-methyl-N-(l-phenyl-3-methyla~inopropyl)-anilin.
-2~-LB~9~
50. p-Methoxy-N-methyl-N-(l-phenyl-3--methylaminopropyl)-aniline.
51. p-n-Butoxy-N-methyl-N-(l-phenyl-3-methylaminopropyl) aniline, 52. 3,4-~Sethylenedioxy-N-methyl-N-~l-phenyl-3-methyl--aminopropyl)-aniline.
53. o-Hydroxy-N-methyl-N-(l-phenyl-3-methylamino-propyl)-aniline.
54. m-Hydroxy-N-methyl-N-(l-phenyl-3-methylamino-propyl)-aniline.
55. p-Hydroxy-N-methyl-N-~l-phenyl-3-methylamino-propyl)-aniline.
56. o-Trifluoromethyl-N-methyl-N-(l-phenyl-3-methylamino-propyl)-aniline.
57. m-Trifluoromethyl-N-methyl-N-(l-phenyl-3-methylamino-propyl)-aniline.
58. p-Trifluoromethyl-N-methyl'N-(l-phenyl-3-methylamino-propyl~-aniline.
59. 4-(n-Methyl-N-l-phenyl-3-methylaminopropyl-amino)-indane.
6~. 5-lN-Methyl-N-l-phenyl-3-methylaminopropyl-amino)-indane~
-~L~1~34~
EX~MPLE 61 23 g of 85% formic acid and then 9.9 g of 37~
aqueous formaldehyde solution are added to 29 g of p-chloro-N-(l-phenyl-3-dimethylamino-propyl)-aniline [obtainable from p-chloroaniline and 1-phenyl-3-dimethyl-amino-propyl chloride] while cooling with ice. The mixture is heated to 100 for 5 hours, acidified and concentrated and the residue is worked up in the customary manner.
p-Chloro-N-methyl-N-(l-phenyl-3-dimethylamino-propyl)-aniline is obtained. Dihydrochloride, m.p. 164.
EX~MPLES 62 to 100 The tertiary aniline derivatives given in Examples2 to 40 are obtained analogously to Example 61 by methy-lation of the correspo~ding secondary aniline derivatives.
25.1 g of p-chloro-N-~2-(1-methyl-2-piperidyl)-ethyl]-aniline is dissolved in 200 ml of THF and 100 ml of water; hydrochloric acid is added until the pH is 5;
and 120 ml of 37% aqueous formaldehyde solution is added.
After stirring the mixture ~or 15 minutes, a solution of ~8O9 g of Na(CN)BH3 in 120 ml of THF is added dropwise.
During this addition, the pH is kept at 6 by adding HCl.
The mixture is stirred for a further 2 hours at 20, acidified with concentrated hydrochloric acid, washed with ether, rendered alkaline and worked up in the custo-mary manner to give p-chloro-N-methyl-N-[2-(1-methyl-2-piperidyl)-ethyl]-aniline, Rf: 0.38.
EXAMPLES 102 to 140 The tertiary aniline derivatives mentioned in Examples 1 to 26 and 28 to 40 are obtained analogously to Example 101, by reaction of the corresponding secondary aniline derivatives with formaldehyde/Na(CN)BH3.
E ~MPLE 141 A mixture of 31.1 g of 1-amino-3-phenyl-(p-chloro-N-methylanilino)-propane hydrochloride ~obtainable by adding p-chloro-N-methylaniline onto cinnamaldehyde, reacting the resulting 3-phenyl-3-(p-chloro-N-methyl-anilino)-propanal with NH3 to give the imine and hydro-genating the imine~, 50 ml of formic acid, 7 g o~ sodium ~ormate and 40 ml of 40% formaldehyde solution is heated to 60 for 3 hours and then to 100 for 12 hours. A~ter customary working up, p-chloro-N-methyl-N-~l-phenyl-3-dimethylaminopropyl)-aniline is obtained~ Dihydrochloride, m.p. 164.
EXAMPLES 142 to 160 The compounds described in Examples 2 to 20 are obtained analogously to Example 141 from the corresponding l-amino-3-phenyl-3-N-methylanilino-propanes and formic acid/sodium formate/formaldehyde.
A solution of 27.5 g of 1-amino-3-phenyl-3-(p-chloro-N-methylanilino)-propane in 500 ml of methanol is shaken with 5 g of Raney nickel for 15 hours at 160 in a sealed tube. After cooling, filtration and evapora-tion of the solvent, the mixture is worked up in the customary manner to yield p-chloro-N-methyl-N-(l-phenyl-3-methyl-aminopropyl)-aniline.
EXAMPLES 162 to 180 The secondary amines mentioned in Examplés 41 to 46 and 48 to 60 are obtained by methylation of the cor-responding primary amines analogously to Example 161.
p-Chloro-N-methyl-N-[2~(1-methyl-2-piperidyl)-ethyl]-aniline, Rf: 0.38, is obtained analogously to Example 141 from p-chloro-N-methyl-N-[2-(2-piperidyl)-ethyl]-aniline and formic acid/sodium formate/formaldehyde.
EXAMPLES 182 to 200 The compounds described in Examples 20 to 26 and 28 to 40 are obtained analogously to Example 181 from the corresponding M-methyl-N-[2-(2-piperidyl)-ethyl]
anilines and formic acid/sodium formate/formaldehyde.
A solution of 4.30 g of l-p-toluenesulfonyloxy-3-phenyl-2-(p-chloro-N-methyl-anilino)-propane lobtainable by reacting p-chloro-N-methyl-aniline with 3-chloro-3-phenyl-propanol and tosylating the product~ and 30 g of dimethylamine in lO0 ml of methanol is heated to 120 in an autoclave for 2 hours. After cooling and customary working up-, p-chloro-N-methyl-N-(l-phenyl-3-dimethylamino propyl)-aniline is obtained, Dihydrochloride, m.p. 164.
EX~IPLES 202 to 240 The compounds mentioned in Examples 20 and41 to 60 are obtained analogously to Example 201.by reacting the corresponding l-p-toluenesulfonyloxy-, l-chloro- or l-bromo-3-phenyl-3-N-methyl-anilino-propanes with di-methylamine or methylamine, respectively.
A mixture of 27.9 g of 3-phenyl-3-~N-methyl-N-5-indanylamino)-propanal lobtainable from 5-methylamino-indane and cinnamaldehyde~, lO0 g of dimethylamine and 300 ml of ethanol is hydrogenated in the presence of 2 g of 5% Pd-on-charcoal at 100 and under 5 atmospheres for 12 hours. 1-Dîmethylamino-3-phenyl-3-N-methyl-N-t5-indanyl)-amino-propene is probably formed as an inter-mediate product, which is not isolated. After evapoaration and customary working up, 5-(n-methyl-N-1-phe~yl-3-dimethylamino-propyl-amino)-indane is obtained. Dihydro-chloride, m.p. 184.
EX~PLES 242 to 260 The compounds-mentioned in Examples 2 to 20 are obtained analogously to Example 241 by reacting the corresponding 3-phenyl-3-N methylanilino-propanals with dimethylamine and hydroyen.
A solu~ion of 30 g of 3-phenyl-3-(p-fluoro-N-methyl-anilino)-propanoic acid N,N-dimethylamide ~ob*
tainable by adding p-fluoro-N-methyl-aniline onto cinnamic acid ethyl ester and reacting the resulting 3-phenyl-3-(p-fluoro-N-methyl-anilino)~propanoic acid ethyl ester with dimethylamine] in 500 ml of THF i.s added dropwise to a suspension of 7.6 g of LiAlH4 in 250 ml of absolute THF, while stirring; the mixture is boiled for 16 hours;
ethyl acetate is added, while cooling, and 32% sodium hydroxide solution is then added; and the mixture is worked up in the customary manner to give p-fluoro-N-methyl-N-(l-phenyl-3-dimethylaminopropyl)-aniline.
Dihydrochloride~ m. p. 204.
EXA~LES 262 to 300 -The compounds mentioned in Examples 1 to 4, 6 to 20 and 41 to 60 are obtained analogously to Example 261 by reducing the corresponding 3-phenyl-3-N-methylanilino-~6~4D~
propanoic acid N,N-dimethylamides or N-methylamides, respectively.
p-Trifluoromethyl-N-methyl-N-[2-(1-methyl-2-piperidyl)-ethyl]-aniline is obtained analogously to Example 261 from p-trifluoromethyl-N-methyl-N-[2-(1-methyl-6-oxo-2-piperidyl)-ethyl]aniline [obtainable from p-trifluoromethyl-N-methyl-aniline and 2--(1-methyl-6-oxo-2-piperidyl)-ethyl chloride analogously to Example 1]
and LiAlH4. Rf: 0.42.
EX~MPLES 302 to 320 ~ he compounds mentioned in Examples 21 to 37, 39 and 40 are obtained analogously to Example 301 from the corresponding piperidone derivatives o LiAlH4.
EX~MPLE 321 A solution of 31.7 g of p-chloro-N-methyl-N-(l-phenyl-3-N-methyl-formamido-propyl)-aniline (obtainable by 2 hours refluxing of p-chloro-N-methyl-N-(l-phenyl-3-methylamino-propyl)-aniline with ethyl formate) in 600 ml of THF is added dropwise with stirring to a solution of 3.8 g of LiAlH~ in 100 ml of THF . The mixture is stirred for 2 hours at 20. Saturated Na2SO4 solution is added, the precipitate is filtered, and the filtrate is concen-trated and worked up in the customary manner. p-Chloro-N-methyl-N-(l-phenyl-3-dimethylaminopropyl)-aniline is obtained. Dihydrochloride, m. p. 164.
EXAMPLES 322 to 360 The compounds mentioned in Examples 2 to 20 and 41 to 60 are obtained analogously to Example 321 by reduc-tion of the corresponding N-methyl-N-(l-phenyl-3-formamido-propyl)-anilines~
1 g of l-methyl-2-[2-(p-methoxy-N-methylanilino)-ethyl]-pyridinium chloride [obtainable by reacting p-methoxy-N-methylaniline with l-methyl-2-(2-chloroethyl)-pyridinium chloride] is dissolved in 25 ml of methanol;
hydrogenation is carried out on 0.1 g of platinum at 25 and under 1 atmosphere until the reaction ceases; the mixture is filtered; the filtrate is evaporated; and, after customary working up of the residue, p-methoxy-N-methyl-N-~2-(1-methyl-2-piperidyl)-ethyl]-aniline is obtained.
Hydrochloride, m. p. 138.
EX~MPLES 362 to 380 The compounds mentioned in Examples 21 to 29 and 31 to 40 are obtained analogously to Example 361 from the corresponding pyridinium chlorides by hydrogenation.
A solution of 30.6 g of l~dimethylamino-3-phenyl 3-N-methyl-N-(5--!ndanyl)-amino-propene ~obtainable by reacting 5-methylaminoindane with cinnamaldehyde to ~ive 3-phenyl-3-N-methyl-N-(5-indanyl)-amino propanal and reacting this with dimethylamine) in 250 ml of dioxane is hydrogenated on 2 g of 2% Pd-on-C at 20 and under normal pressure until 1 mole of hydrogen has been taken up. The mixture is filtered and the iltrate is evaporated to give 5-(N-methyl-N-l-phenyl-3-dimetnylamino-propylamino)-indane. Dihydrochloride, m. p. 184.
EXAMPLES 382 to 420 The compounds mentioned in Examples 1 to 19 and 41 to 60 are obtained analogously to Example 381 by hydro-genating the corresponding 1-dimethylamino-3-phenyl-3-N-methylanilino-propenes.
. . .
A solution of 31.7 g of p-chloro-N-methyl-N-[l-phenyl-3-(N-formyl-N-methylamino)-propyl]-aniline [obtainable by reaction of N-methyl-N-(l-chloro-3-phenyl-propyl)-formamide with p-chloro-N-methyl-aniline in analogy to Example 1] in 320 ml of a 5% solution of KOH in 90%
ethanol is refluxed for 5 hours, evaporated and worked up in the customary manner. p-Chloro-N-methyl-N-(l-phenyl-3-methylaminopropyL)-aniline is obtained.
EXAMPLES 422 to 440 The compounds mentioned in Examples 41 to 46 and 48 to 60 are obtained analqgously to Example 421 by alkaline hydrolysis of the corresponding N-formyl compounds.
p-Fluoro-N-methyl-N-(l-phenyl-3-dimethylaminopropyl)-aniline is obtained analogously to Example 141 from 1-methylamino-3-phenyl-3-(p-fluoro-N-methylanilino)-propane hydrochloride and formic acid/sodium formate/formaldehyde.
Dihydrochloride, m. p. 204.
EXAMPLES 442 to 460 The compounds described in Examples 1 to 4 and 6 to 20 are obtained analogously to Example 441 from the corres-ponding 1-methylamino-3-phenyl-3-N-methyl-anilino-propene hydrochlorides and formic acid/sodium formate/formaldehyde.
A mixture of 1 g of p-methoxy-N-methyl-N-(l-phenyl-3-dimethylaminopropyl)-aniline hydrochloride and 1 g of pyridine hydrochloride is stirred at 160 for 3 hours. After customary working up, p-hydroxy-N-methyl-N-(l-phenyl-3-dimethylamino-propyl)-aniline is obtained.
A mixture of 24.8 g of p-hydroxy-N-methyl-N-12-(1-methyl-2-piperidyl)-ethyl]-aniline, 100 ml of absolute ethanol and 200 ml of 0.5 N ethanolic KOH is stirred at 20 for one hour and evaporated. The residue is dissolved in 250 ml of absolute DMF, and 12.6 g of dimethyl sulfate is added in portions, while stirrîng. The mixture is boiled for two hours, evaporated and worked up in the customary -3~-~ bi18~
manner to give p-methoxy-N-methyl-N-[2-(1-methyl-2-piperidyl)-ethyl]-aniline, hydrochloride, m. p. 138.
The following examples relate to pharmaceutical formulations which contain amines of Formula I or their acid addition salts.
EXAMPLE A: Tablets A mixture of 1 kg of p-chloro-N-methyl-N-(l-phenyl-3, 3-dimethylamino-propyl)-aniline hydrochloride, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is pressed to orm tablets in the customary manner, such that each tablet contains 10 mg of active compound.
EX~MPLE B: Dragees Tablets are pressed analogously to Example A and are then coated in the customary manner with a coating consisting of sucrose, potato starch, talc, tragacanth and colorant.
EXAMPLE C: Capsules 2 kg of p-chloro-N-methyl-N-(l-phenyl-3-dimethyl-~0 amino-propyl)-aniline hydrochloride is filled into hard gelatin capsules in the customary manner, such that each capsule contains 20 mg of the active compound.
EXAMPLE D: Ampoules A solution of 1 kg of p-chloro-N-methyl-(l-phenyl-3-dimethylamino-propyl)-aniline hydrochloride in 30 1 of doubly distilled water is filtered under sterile conditions, filled into ampoules and lyophilized under sterile condi-tions and the ampoules are sealed unaer sterile conditions.
Each ampoule contains 10 mg of active compound.
Tablets, dragees, capsules and ampoules which contain one or more of the other active compounds of the Formula I
and/or of their physiologically acceptable acid addition salts can be obtained analogously.
The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention ~or those used in the preceding examples.
i7. m-~rifluoromethyl-N-methyl-N-(l-phenyl-3-dimethyl-aminopropyl)-aniline.
1'8. p-Trifluoromethyl-N-methyl-N-(l-phenyl-3-dimethyl-aminopropyl)-aniline.
19. 4-(N-Methyl-N-l-phenyl-3-dimethylamin'o-propylamino~
indane, .~o. 5-(N-Methyl-N-l-phenyl-3--dimethylamino-propylamino~
indane, ~ihydrochloride, m.p. 184. Oxalate, m.p.18~-186.
EXAMPLES 21 to 40 .:
.. .. ..... . . .
The following compounds are obtained analogously to Examples 1 to 2~, using 1-methyl-2-(2-chloroethyl)-piperidine: ' -21. N-Methyl-N-[2-(1-methyl-2-piperidyl)-ethyl]-aniline.
22.,o-Fluoro-N-methyl-N-[2-(1-methyl-2-piperidyl)-ethyl~-anlline .
23. m-~luoro-N-methyl-N-[2-(1-methyl-2-piperidyl)-e-thyl]-aniline, ~.6~
2~. p-Fluoro-N-methyl-N-[2-(1-methyl-2-piperidyl)-et`hyl]-aniline.
--25. o-Chloro-N-methyl-N-~2-(1-methyl-2-piperidyl)-ethyl]-aniline~
-26. m-Chloro-N-methyl-N-~2-(1-methyl-2-piperidyl)-ethyl]-aniline.
27.p-Chloro-N-methyl-N-~2-(1-methyl-2-piperidyl)-ethyl]-aniline, Rf: 0.38.
-28. o-Methoxy-N-methyl-N-[2-(1-methyl-2-piperidyl)-ethy~]-aniline.
29. m-Methoxy-N-methyl-N-L2-(1-methyl-2-piperidyl)-ethyl]-aniline.
30. p-Methoxy-N-methyl-N-L2-(1-methyl-2-piperidyl)-ethyl]-aniline, hydrochloricle, m p. 138.
31. ~-n-Butoxy-N-methyl-N-/2-(1-methyl-2-~i~eridyl)-ethyl7-aniline.
32. 3,4-~5ethylenedioxy-N-methyl-N-/2-(l-methyl-2-piperidyl)-ethyl7-aniline.
33. o-Hydroxy-N-methyl-N-~2~ methyl-2-piperidyl)-ethyl]-aniline.
34. m-Hydroxy-N-methyl-N-[2-(1-methyl-2-piperidyl)-ethyl]-aniline.
35. p-Hydroxy-N-methyl-N-[2-(1-methyl-2-piperidyl)-ethyl]-aniline.
36. o-Trifluorome~thyl-N-methyl-N-[2-(1-methyl-2-piperidyl)-ethyl]-aniline.
37. m-Trifluoromethyl-N-methyl-N-[2-(1-methyl-2-piperidyl)-e-thyl~-aniline.
38. p-Trifluoromethyl-N-methyl-N-[2-(1-methyl-2-piperidyl)-ethyl~-aniline, Rf: 0.42.
39. 4-[N-Methyl-N-(2-(1-methyl-2-piperidyl)-ethyl)-amino]-indane 540. 5-[N-Methyl-N-(2-(1-methyl-2 piperidyl)-ethyl)-amino]-indane.
.. . ..
.. , . ,.. . . ~ .. ... . .. . . . . . ..... . . . .. . . . .
In analogy to Examples 1 to 20, the following compounds are obtained using l-phenyl-3-methylamino-propyl chloride;
41. N-Methyl-N~l-phenyl-3-methylamino-propyl)-2niline.
42. o-Fluoro-N-methyl-N-(l-phenyl-3-methylaminopropyl)-aniline.
43. m-Fluoro-N-methyl-N-(l-phenyl-3-methylaminopropyl)-aniline.
44. p-Fluoro-N-methyl-N-(1-phenyl-3-methylaminopro~yl)-aniline.
45. o-Chloro-N-methyl-N-(l-phenyl-3-methylaminoprop~
aniline.
0 46. m-Chloro-N-methyl-N-(l-phenyl-3-methylaminopropyl)-aniline.
47. p-Chloro-N-methyl-N-(1-phenyl-3-methylaminopropyl)-aniline.
48. o-Methoxy-N-methyl-N-(l-phenyl-3-methyla~ino~ropyl)-aniline.
49. m-Methoxy-~-methyl-N-(l-phenyl-3-methyla~inopropyl)-anilin.
-2~-LB~9~
50. p-Methoxy-N-methyl-N-(l-phenyl-3--methylaminopropyl)-aniline.
51. p-n-Butoxy-N-methyl-N-(l-phenyl-3-methylaminopropyl) aniline, 52. 3,4-~Sethylenedioxy-N-methyl-N-~l-phenyl-3-methyl--aminopropyl)-aniline.
53. o-Hydroxy-N-methyl-N-(l-phenyl-3-methylamino-propyl)-aniline.
54. m-Hydroxy-N-methyl-N-(l-phenyl-3-methylamino-propyl)-aniline.
55. p-Hydroxy-N-methyl-N-~l-phenyl-3-methylamino-propyl)-aniline.
56. o-Trifluoromethyl-N-methyl-N-(l-phenyl-3-methylamino-propyl)-aniline.
57. m-Trifluoromethyl-N-methyl-N-(l-phenyl-3-methylamino-propyl)-aniline.
58. p-Trifluoromethyl-N-methyl'N-(l-phenyl-3-methylamino-propyl~-aniline.
59. 4-(n-Methyl-N-l-phenyl-3-methylaminopropyl-amino)-indane.
6~. 5-lN-Methyl-N-l-phenyl-3-methylaminopropyl-amino)-indane~
-~L~1~34~
EX~MPLE 61 23 g of 85% formic acid and then 9.9 g of 37~
aqueous formaldehyde solution are added to 29 g of p-chloro-N-(l-phenyl-3-dimethylamino-propyl)-aniline [obtainable from p-chloroaniline and 1-phenyl-3-dimethyl-amino-propyl chloride] while cooling with ice. The mixture is heated to 100 for 5 hours, acidified and concentrated and the residue is worked up in the customary manner.
p-Chloro-N-methyl-N-(l-phenyl-3-dimethylamino-propyl)-aniline is obtained. Dihydrochloride, m.p. 164.
EX~MPLES 62 to 100 The tertiary aniline derivatives given in Examples2 to 40 are obtained analogously to Example 61 by methy-lation of the correspo~ding secondary aniline derivatives.
25.1 g of p-chloro-N-~2-(1-methyl-2-piperidyl)-ethyl]-aniline is dissolved in 200 ml of THF and 100 ml of water; hydrochloric acid is added until the pH is 5;
and 120 ml of 37% aqueous formaldehyde solution is added.
After stirring the mixture ~or 15 minutes, a solution of ~8O9 g of Na(CN)BH3 in 120 ml of THF is added dropwise.
During this addition, the pH is kept at 6 by adding HCl.
The mixture is stirred for a further 2 hours at 20, acidified with concentrated hydrochloric acid, washed with ether, rendered alkaline and worked up in the custo-mary manner to give p-chloro-N-methyl-N-[2-(1-methyl-2-piperidyl)-ethyl]-aniline, Rf: 0.38.
EXAMPLES 102 to 140 The tertiary aniline derivatives mentioned in Examples 1 to 26 and 28 to 40 are obtained analogously to Example 101, by reaction of the corresponding secondary aniline derivatives with formaldehyde/Na(CN)BH3.
E ~MPLE 141 A mixture of 31.1 g of 1-amino-3-phenyl-(p-chloro-N-methylanilino)-propane hydrochloride ~obtainable by adding p-chloro-N-methylaniline onto cinnamaldehyde, reacting the resulting 3-phenyl-3-(p-chloro-N-methyl-anilino)-propanal with NH3 to give the imine and hydro-genating the imine~, 50 ml of formic acid, 7 g o~ sodium ~ormate and 40 ml of 40% formaldehyde solution is heated to 60 for 3 hours and then to 100 for 12 hours. A~ter customary working up, p-chloro-N-methyl-N-~l-phenyl-3-dimethylaminopropyl)-aniline is obtained~ Dihydrochloride, m.p. 164.
EXAMPLES 142 to 160 The compounds described in Examples 2 to 20 are obtained analogously to Example 141 from the corresponding l-amino-3-phenyl-3-N-methylanilino-propanes and formic acid/sodium formate/formaldehyde.
A solution of 27.5 g of 1-amino-3-phenyl-3-(p-chloro-N-methylanilino)-propane in 500 ml of methanol is shaken with 5 g of Raney nickel for 15 hours at 160 in a sealed tube. After cooling, filtration and evapora-tion of the solvent, the mixture is worked up in the customary manner to yield p-chloro-N-methyl-N-(l-phenyl-3-methyl-aminopropyl)-aniline.
EXAMPLES 162 to 180 The secondary amines mentioned in Examplés 41 to 46 and 48 to 60 are obtained by methylation of the cor-responding primary amines analogously to Example 161.
p-Chloro-N-methyl-N-[2~(1-methyl-2-piperidyl)-ethyl]-aniline, Rf: 0.38, is obtained analogously to Example 141 from p-chloro-N-methyl-N-[2-(2-piperidyl)-ethyl]-aniline and formic acid/sodium formate/formaldehyde.
EXAMPLES 182 to 200 The compounds described in Examples 20 to 26 and 28 to 40 are obtained analogously to Example 181 from the corresponding M-methyl-N-[2-(2-piperidyl)-ethyl]
anilines and formic acid/sodium formate/formaldehyde.
A solution of 4.30 g of l-p-toluenesulfonyloxy-3-phenyl-2-(p-chloro-N-methyl-anilino)-propane lobtainable by reacting p-chloro-N-methyl-aniline with 3-chloro-3-phenyl-propanol and tosylating the product~ and 30 g of dimethylamine in lO0 ml of methanol is heated to 120 in an autoclave for 2 hours. After cooling and customary working up-, p-chloro-N-methyl-N-(l-phenyl-3-dimethylamino propyl)-aniline is obtained, Dihydrochloride, m.p. 164.
EX~IPLES 202 to 240 The compounds mentioned in Examples 20 and41 to 60 are obtained analogously to Example 201.by reacting the corresponding l-p-toluenesulfonyloxy-, l-chloro- or l-bromo-3-phenyl-3-N-methyl-anilino-propanes with di-methylamine or methylamine, respectively.
A mixture of 27.9 g of 3-phenyl-3-~N-methyl-N-5-indanylamino)-propanal lobtainable from 5-methylamino-indane and cinnamaldehyde~, lO0 g of dimethylamine and 300 ml of ethanol is hydrogenated in the presence of 2 g of 5% Pd-on-charcoal at 100 and under 5 atmospheres for 12 hours. 1-Dîmethylamino-3-phenyl-3-N-methyl-N-t5-indanyl)-amino-propene is probably formed as an inter-mediate product, which is not isolated. After evapoaration and customary working up, 5-(n-methyl-N-1-phe~yl-3-dimethylamino-propyl-amino)-indane is obtained. Dihydro-chloride, m.p. 184.
EX~PLES 242 to 260 The compounds-mentioned in Examples 2 to 20 are obtained analogously to Example 241 by reacting the corresponding 3-phenyl-3-N methylanilino-propanals with dimethylamine and hydroyen.
A solu~ion of 30 g of 3-phenyl-3-(p-fluoro-N-methyl-anilino)-propanoic acid N,N-dimethylamide ~ob*
tainable by adding p-fluoro-N-methyl-aniline onto cinnamic acid ethyl ester and reacting the resulting 3-phenyl-3-(p-fluoro-N-methyl-anilino)~propanoic acid ethyl ester with dimethylamine] in 500 ml of THF i.s added dropwise to a suspension of 7.6 g of LiAlH4 in 250 ml of absolute THF, while stirring; the mixture is boiled for 16 hours;
ethyl acetate is added, while cooling, and 32% sodium hydroxide solution is then added; and the mixture is worked up in the customary manner to give p-fluoro-N-methyl-N-(l-phenyl-3-dimethylaminopropyl)-aniline.
Dihydrochloride~ m. p. 204.
EXA~LES 262 to 300 -The compounds mentioned in Examples 1 to 4, 6 to 20 and 41 to 60 are obtained analogously to Example 261 by reducing the corresponding 3-phenyl-3-N-methylanilino-~6~4D~
propanoic acid N,N-dimethylamides or N-methylamides, respectively.
p-Trifluoromethyl-N-methyl-N-[2-(1-methyl-2-piperidyl)-ethyl]-aniline is obtained analogously to Example 261 from p-trifluoromethyl-N-methyl-N-[2-(1-methyl-6-oxo-2-piperidyl)-ethyl]aniline [obtainable from p-trifluoromethyl-N-methyl-aniline and 2--(1-methyl-6-oxo-2-piperidyl)-ethyl chloride analogously to Example 1]
and LiAlH4. Rf: 0.42.
EX~MPLES 302 to 320 ~ he compounds mentioned in Examples 21 to 37, 39 and 40 are obtained analogously to Example 301 from the corresponding piperidone derivatives o LiAlH4.
EX~MPLE 321 A solution of 31.7 g of p-chloro-N-methyl-N-(l-phenyl-3-N-methyl-formamido-propyl)-aniline (obtainable by 2 hours refluxing of p-chloro-N-methyl-N-(l-phenyl-3-methylamino-propyl)-aniline with ethyl formate) in 600 ml of THF is added dropwise with stirring to a solution of 3.8 g of LiAlH~ in 100 ml of THF . The mixture is stirred for 2 hours at 20. Saturated Na2SO4 solution is added, the precipitate is filtered, and the filtrate is concen-trated and worked up in the customary manner. p-Chloro-N-methyl-N-(l-phenyl-3-dimethylaminopropyl)-aniline is obtained. Dihydrochloride, m. p. 164.
EXAMPLES 322 to 360 The compounds mentioned in Examples 2 to 20 and 41 to 60 are obtained analogously to Example 321 by reduc-tion of the corresponding N-methyl-N-(l-phenyl-3-formamido-propyl)-anilines~
1 g of l-methyl-2-[2-(p-methoxy-N-methylanilino)-ethyl]-pyridinium chloride [obtainable by reacting p-methoxy-N-methylaniline with l-methyl-2-(2-chloroethyl)-pyridinium chloride] is dissolved in 25 ml of methanol;
hydrogenation is carried out on 0.1 g of platinum at 25 and under 1 atmosphere until the reaction ceases; the mixture is filtered; the filtrate is evaporated; and, after customary working up of the residue, p-methoxy-N-methyl-N-~2-(1-methyl-2-piperidyl)-ethyl]-aniline is obtained.
Hydrochloride, m. p. 138.
EX~MPLES 362 to 380 The compounds mentioned in Examples 21 to 29 and 31 to 40 are obtained analogously to Example 361 from the corresponding pyridinium chlorides by hydrogenation.
A solution of 30.6 g of l~dimethylamino-3-phenyl 3-N-methyl-N-(5--!ndanyl)-amino-propene ~obtainable by reacting 5-methylaminoindane with cinnamaldehyde to ~ive 3-phenyl-3-N-methyl-N-(5-indanyl)-amino propanal and reacting this with dimethylamine) in 250 ml of dioxane is hydrogenated on 2 g of 2% Pd-on-C at 20 and under normal pressure until 1 mole of hydrogen has been taken up. The mixture is filtered and the iltrate is evaporated to give 5-(N-methyl-N-l-phenyl-3-dimetnylamino-propylamino)-indane. Dihydrochloride, m. p. 184.
EXAMPLES 382 to 420 The compounds mentioned in Examples 1 to 19 and 41 to 60 are obtained analogously to Example 381 by hydro-genating the corresponding 1-dimethylamino-3-phenyl-3-N-methylanilino-propenes.
. . .
A solution of 31.7 g of p-chloro-N-methyl-N-[l-phenyl-3-(N-formyl-N-methylamino)-propyl]-aniline [obtainable by reaction of N-methyl-N-(l-chloro-3-phenyl-propyl)-formamide with p-chloro-N-methyl-aniline in analogy to Example 1] in 320 ml of a 5% solution of KOH in 90%
ethanol is refluxed for 5 hours, evaporated and worked up in the customary manner. p-Chloro-N-methyl-N-(l-phenyl-3-methylaminopropyL)-aniline is obtained.
EXAMPLES 422 to 440 The compounds mentioned in Examples 41 to 46 and 48 to 60 are obtained analqgously to Example 421 by alkaline hydrolysis of the corresponding N-formyl compounds.
p-Fluoro-N-methyl-N-(l-phenyl-3-dimethylaminopropyl)-aniline is obtained analogously to Example 141 from 1-methylamino-3-phenyl-3-(p-fluoro-N-methylanilino)-propane hydrochloride and formic acid/sodium formate/formaldehyde.
Dihydrochloride, m. p. 204.
EXAMPLES 442 to 460 The compounds described in Examples 1 to 4 and 6 to 20 are obtained analogously to Example 441 from the corres-ponding 1-methylamino-3-phenyl-3-N-methyl-anilino-propene hydrochlorides and formic acid/sodium formate/formaldehyde.
A mixture of 1 g of p-methoxy-N-methyl-N-(l-phenyl-3-dimethylaminopropyl)-aniline hydrochloride and 1 g of pyridine hydrochloride is stirred at 160 for 3 hours. After customary working up, p-hydroxy-N-methyl-N-(l-phenyl-3-dimethylamino-propyl)-aniline is obtained.
A mixture of 24.8 g of p-hydroxy-N-methyl-N-12-(1-methyl-2-piperidyl)-ethyl]-aniline, 100 ml of absolute ethanol and 200 ml of 0.5 N ethanolic KOH is stirred at 20 for one hour and evaporated. The residue is dissolved in 250 ml of absolute DMF, and 12.6 g of dimethyl sulfate is added in portions, while stirrîng. The mixture is boiled for two hours, evaporated and worked up in the customary -3~-~ bi18~
manner to give p-methoxy-N-methyl-N-[2-(1-methyl-2-piperidyl)-ethyl]-aniline, hydrochloride, m. p. 138.
The following examples relate to pharmaceutical formulations which contain amines of Formula I or their acid addition salts.
EXAMPLE A: Tablets A mixture of 1 kg of p-chloro-N-methyl-N-(l-phenyl-3, 3-dimethylamino-propyl)-aniline hydrochloride, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is pressed to orm tablets in the customary manner, such that each tablet contains 10 mg of active compound.
EX~MPLE B: Dragees Tablets are pressed analogously to Example A and are then coated in the customary manner with a coating consisting of sucrose, potato starch, talc, tragacanth and colorant.
EXAMPLE C: Capsules 2 kg of p-chloro-N-methyl-N-(l-phenyl-3-dimethyl-~0 amino-propyl)-aniline hydrochloride is filled into hard gelatin capsules in the customary manner, such that each capsule contains 20 mg of the active compound.
EXAMPLE D: Ampoules A solution of 1 kg of p-chloro-N-methyl-(l-phenyl-3-dimethylamino-propyl)-aniline hydrochloride in 30 1 of doubly distilled water is filtered under sterile conditions, filled into ampoules and lyophilized under sterile condi-tions and the ampoules are sealed unaer sterile conditions.
Each ampoule contains 10 mg of active compound.
Tablets, dragees, capsules and ampoules which contain one or more of the other active compounds of the Formula I
and/or of their physiologically acceptable acid addition salts can be obtained analogously.
The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention ~or those used in the preceding examples.
Claims (8)
1. A process for preparing an aniline derivative of the formula Ar-N(CH3)-R
wherein Ar is phenyl or phenyl substituted by F, C1, al-koxy of up to 4 C atoms, methylenedioxy, OH, trimethylene or CF3; R is -CH(C6H5)-CH2CH2-N(CH3)-Z or 2-(1-methyl-2-piperidyl)-ethyl; and Z is H or methyl, or a physiologi-cally acceptable acid addition salt thereof; comprising reacting an amine of Formula II
Ar-NHCH3 II
wherein Ar is as defined above, or one of its salts, with an amine of Formula III
X-R III
wherein X is Cl, Br, I or OH and R is as defined above, or with one of its reactive derivatives, or methylating an amine of Formula IV
Ar-Y IV
wherein Y is -NH-R, N-methyl-N-(1-phenyl-3-aminopropyl)-amino or N-methyl-N-[2-(2-piperidyl)-ethyl]-amino and Ar and R are as defined above, or reacting an amine of Formula V
Ar-N(CH3)-CH(C6H5)-CH2-CH2-X V
wherein Ar and X are as defined above, or one of its reactive derivatives, with an amine of the Formula VI
H-N(CH3)-Z VI
wherein Z is as defined above, or treating a compound which corresponds to Formula I, but contains one or more reducible groups and/or one or more C-C and/or C-N mul-tiple bonds instead of hydrogen atoms, with a reducing agent, or treating a compound of Formula VII
Ar-N(CH3)-CH(C6H5)-CH2-CH2-N(CH3)-W VII
wherein W is an amino-protecting group and Ar is as de-fined above, with a solvolyzing agent and/or in a compound of Formula I, if appropriate, methylating an NH group to yield an N(CH3) group, and/or converting a hydroxyl group, by treatment with an alkylating agent, into the corres-ponding alkoxy group, and/or splitting an alkoxy group to form a hydroxyl group, and/or converting a resulting base of Formula I into one of its physiologically acceptable acid addition salts by treatment with an acid.
wherein Ar is phenyl or phenyl substituted by F, C1, al-koxy of up to 4 C atoms, methylenedioxy, OH, trimethylene or CF3; R is -CH(C6H5)-CH2CH2-N(CH3)-Z or 2-(1-methyl-2-piperidyl)-ethyl; and Z is H or methyl, or a physiologi-cally acceptable acid addition salt thereof; comprising reacting an amine of Formula II
Ar-NHCH3 II
wherein Ar is as defined above, or one of its salts, with an amine of Formula III
X-R III
wherein X is Cl, Br, I or OH and R is as defined above, or with one of its reactive derivatives, or methylating an amine of Formula IV
Ar-Y IV
wherein Y is -NH-R, N-methyl-N-(1-phenyl-3-aminopropyl)-amino or N-methyl-N-[2-(2-piperidyl)-ethyl]-amino and Ar and R are as defined above, or reacting an amine of Formula V
Ar-N(CH3)-CH(C6H5)-CH2-CH2-X V
wherein Ar and X are as defined above, or one of its reactive derivatives, with an amine of the Formula VI
H-N(CH3)-Z VI
wherein Z is as defined above, or treating a compound which corresponds to Formula I, but contains one or more reducible groups and/or one or more C-C and/or C-N mul-tiple bonds instead of hydrogen atoms, with a reducing agent, or treating a compound of Formula VII
Ar-N(CH3)-CH(C6H5)-CH2-CH2-N(CH3)-W VII
wherein W is an amino-protecting group and Ar is as de-fined above, with a solvolyzing agent and/or in a compound of Formula I, if appropriate, methylating an NH group to yield an N(CH3) group, and/or converting a hydroxyl group, by treatment with an alkylating agent, into the corres-ponding alkoxy group, and/or splitting an alkoxy group to form a hydroxyl group, and/or converting a resulting base of Formula I into one of its physiologically acceptable acid addition salts by treatment with an acid.
2. A process for preparing an aniline derivative of the formula Ar-N(CH3)-R
wherein Ar is flourophenyl, chlorophenyl, methoxyphenyl, hydroxyphenyl, 4- or 5-indanyl or trifluoromethylphenyl, R is -CH(C6H5)-CH2CH2-N(CH3)-Z or 2-(1-methyl-2-piperidyl) -ethyl; and Z is H or methyl, or a physiologically accept-able acid addition salt thereof; comprising reacting an amine of Formula II
Ar-NHCH3 II
wherein Ar is as defined above, or one of its salts, with an amine of Formula III
X-R III
wherein X is Cl, Br, I or OH and R is as defined above, or with one of its reactive derivatives, or methylating an amine of Formula IV
Ar-Y IV
wherein Y is -NH-R, N-methyl-N-(1-phenyl-3-aminopropyl)-amino or N-methyl-N-[2-(2-piperidyl)-ethyl]-amino and Ar and R are as defined above, or reacting an amine of Formula V
Ar-N(CH3)-CH(C6H5)-CH2-CH2-X V
wherein Ar and X are as defined ahove, or one of its reactive derivatives, with an amine of the Formula VI
H-N(CH3)-Z VI
wherein Z is as defined above, or treating a compound which corresponds to Formula I, but contains one or more reducible groups and/or one or more C-C and/or C-N multi-ple bonds instead of hydrogen atoms, with a reducing agent, or treating a compound of Formula VII
AR-N(CH3)-CH(C6H5)-CH2-CH2-N(CH3)-W VII
wherein W is an amino-protecting group and Ar is as defined above, with a solvolyzing agent and/or in a compound of Formula I, if appropriate, methylating an NH group to yield an N(CH3) group, and/or converting a hydroxyl group, by treatment with an alkylating agent, into the correspond-ing alkoxy group, and/or splitting an alkoxy group to form a hydroxyl group, and/or converting a resulting base of Formula I into one of its physiologically acceptable acid addition salts by treatment with an acid.
wherein Ar is flourophenyl, chlorophenyl, methoxyphenyl, hydroxyphenyl, 4- or 5-indanyl or trifluoromethylphenyl, R is -CH(C6H5)-CH2CH2-N(CH3)-Z or 2-(1-methyl-2-piperidyl) -ethyl; and Z is H or methyl, or a physiologically accept-able acid addition salt thereof; comprising reacting an amine of Formula II
Ar-NHCH3 II
wherein Ar is as defined above, or one of its salts, with an amine of Formula III
X-R III
wherein X is Cl, Br, I or OH and R is as defined above, or with one of its reactive derivatives, or methylating an amine of Formula IV
Ar-Y IV
wherein Y is -NH-R, N-methyl-N-(1-phenyl-3-aminopropyl)-amino or N-methyl-N-[2-(2-piperidyl)-ethyl]-amino and Ar and R are as defined above, or reacting an amine of Formula V
Ar-N(CH3)-CH(C6H5)-CH2-CH2-X V
wherein Ar and X are as defined ahove, or one of its reactive derivatives, with an amine of the Formula VI
H-N(CH3)-Z VI
wherein Z is as defined above, or treating a compound which corresponds to Formula I, but contains one or more reducible groups and/or one or more C-C and/or C-N multi-ple bonds instead of hydrogen atoms, with a reducing agent, or treating a compound of Formula VII
AR-N(CH3)-CH(C6H5)-CH2-CH2-N(CH3)-W VII
wherein W is an amino-protecting group and Ar is as defined above, with a solvolyzing agent and/or in a compound of Formula I, if appropriate, methylating an NH group to yield an N(CH3) group, and/or converting a hydroxyl group, by treatment with an alkylating agent, into the correspond-ing alkoxy group, and/or splitting an alkoxy group to form a hydroxyl group, and/or converting a resulting base of Formula I into one of its physiologically acceptable acid addition salts by treatment with an acid.
3. A process for preparing an aniline derivative of the formula Ar-N(CN3)-CH(C6H5)-CH2CH2-N(CH3)2 wherein Ar is phenyl or phenyl substituted by F, Cl, alkoxy of up to 4 C-atoms, methylenedioxy, OH, trimethylene or CF3, or a physiologically acceptable acid addition salt thereof, comprising reacting an amine of Formula II
Ar-NHCH3 II
wherein Ar is as defined above, or one of its salts, with an amine of Formula III
X-CH(C6H5)-CH2CH2-N(CH3)2 III
wherein X is Cl, Br, I or OH or with one of its reactive derivatives, or methylating an amine of Formula IV
Ar-Y IV
wherein Y is -NH-CH(C6H5)-CH2CH2-N(CH3)2 or N-methyl-N-(1-phenyl-3-aminopropyl)-amino and Ar is as defined above, or reacting with an amine of Formula V
Ar-N(CH3)-CH(C6H5)-CH2-CH2-X V
wherein Ar and X are as defined above, or one of its re-active derivatives, with dimethylamine, or treating a com-pound which corresponds to formula I, but contains one or more reducible groups and/or one or more C-C and/or C-N
multiple bonds instead of hydrogen atoms, with a reducing agent, and/or in a compound of formula I, if appropriate, converting a hydroxyl group, by treatment with an alkylat-ing agent, into the corresponding alkoxy group, and/or splitting an alkoxy group to form a hydroxyl group, and/or converting a resulting base of formula I into one of its physiologically acceptable acid addition salts by treatment with an acid.
Ar-NHCH3 II
wherein Ar is as defined above, or one of its salts, with an amine of Formula III
X-CH(C6H5)-CH2CH2-N(CH3)2 III
wherein X is Cl, Br, I or OH or with one of its reactive derivatives, or methylating an amine of Formula IV
Ar-Y IV
wherein Y is -NH-CH(C6H5)-CH2CH2-N(CH3)2 or N-methyl-N-(1-phenyl-3-aminopropyl)-amino and Ar is as defined above, or reacting with an amine of Formula V
Ar-N(CH3)-CH(C6H5)-CH2-CH2-X V
wherein Ar and X are as defined above, or one of its re-active derivatives, with dimethylamine, or treating a com-pound which corresponds to formula I, but contains one or more reducible groups and/or one or more C-C and/or C-N
multiple bonds instead of hydrogen atoms, with a reducing agent, and/or in a compound of formula I, if appropriate, converting a hydroxyl group, by treatment with an alkylat-ing agent, into the corresponding alkoxy group, and/or splitting an alkoxy group to form a hydroxyl group, and/or converting a resulting base of formula I into one of its physiologically acceptable acid addition salts by treatment with an acid.
4. A process for preparing p-chloro-N-methyl-N-(1-phenyl-3-dimethylaminopropyl)-aniline or a physiologi-cally acceptable acid addition salt thereof comprising reacting p-chloro-M-methylaniline or one of its salts with an amine of formula X-CH(C6H5)-CH2CH2-N(CH3)2 wherein X is Cl, Br, I or OH or with one of its reactive derivatives, or methylating p-chloro-N-(1-phenyl-3-dimethyl-aminopropyl)-aniline or p-chloro-N-(1-phenyl-3-aminopropyl) -aniline or reacting an amine of formula p-Cl-C6H4-N(CH3)-CH(C6H5)-CH2CH2-X
wherein X is as defined above, or one of its reactive derivatives with dimethylamine, or treating a compound which corresponds to p-chloro-N-methyl-N-(1-phenyl)-3-dimethylaminopropyl)-aniline but contains one or more re-c1ucible groups and/or one or more C-C and/or C-N multiple bonds instead of hydrogen atoms, with a reducing agent, and/or, if desired, converting a resulting base into one of its physiologically acceptable acid addition salts by treatment with an acid.
wherein X is as defined above, or one of its reactive derivatives with dimethylamine, or treating a compound which corresponds to p-chloro-N-methyl-N-(1-phenyl)-3-dimethylaminopropyl)-aniline but contains one or more re-c1ucible groups and/or one or more C-C and/or C-N multiple bonds instead of hydrogen atoms, with a reducing agent, and/or, if desired, converting a resulting base into one of its physiologically acceptable acid addition salts by treatment with an acid.
5. An aniline derivative of Formula I
Ar-N(CH3)-R I
wherein Ar is phenyl or phenyl substituted by F, Cl, alkoxy of up to 4 C atoms, methylenedioxy, OH, trimethylene or CF3; R is -CH(C6H5)-CH2CH2-N(CH3)-Z or 2-(1-methyl-2-piperidyl)-ethyl; and Z is H or methyl, and physiologi-cally acceptable acid addition salts thereof, whenever prepared by the process of claim 1 or its obvious chemical equivalents.
Ar-N(CH3)-R I
wherein Ar is phenyl or phenyl substituted by F, Cl, alkoxy of up to 4 C atoms, methylenedioxy, OH, trimethylene or CF3; R is -CH(C6H5)-CH2CH2-N(CH3)-Z or 2-(1-methyl-2-piperidyl)-ethyl; and Z is H or methyl, and physiologi-cally acceptable acid addition salts thereof, whenever prepared by the process of claim 1 or its obvious chemical equivalents.
6. A compound of Claim 5, wherein Ar is fluoro-phenyl, chlorophenyl, methoxyphenyl, hydroxyphenyl, 4-or 5-indanyl or trifluoromethylphenyl, whenever prepared by the process of Claim 2 or its obvious chemical equiva-lents.
7. A compound of Claim 5, wherein R is 1-phenyl-3-dimethylaminopropyl, whenever prepared by the process of Claim 3 or its obvious chemical equivalents.
8. p-Chloro-N-methyl-N-(1-phenyl-3-dimethyl-aminopropyl)-aniline, a compound of Claim 5, whenever prepared by the process of Claim 4 or its obvious chemical equivalents.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3000441.2 | 1980-01-08 | ||
| DE19803000441 DE3000441A1 (en) | 1980-01-08 | 1980-01-08 | ANILINE DERIVATIVES, PHARMACEUTICAL PREPARATIONS CONTAINING THEM AND METHOD FOR THE PRODUCTION THEREOF |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1161844A true CA1161844A (en) | 1984-02-07 |
Family
ID=6091666
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000368140A Expired CA1161844A (en) | 1980-01-08 | 1981-01-08 | Aniline derivatives, pharmaceutical formulations thereof, and processes for the preparation thereof |
Country Status (11)
| Country | Link |
|---|---|
| EP (1) | EP0031910B1 (en) |
| JP (1) | JPS56100744A (en) |
| AT (1) | ATE3031T1 (en) |
| AU (1) | AU539617B2 (en) |
| CA (1) | CA1161844A (en) |
| DE (2) | DE3000441A1 (en) |
| ES (4) | ES8205191A1 (en) |
| HU (1) | HU183282B (en) |
| IL (1) | IL61868A (en) |
| YU (1) | YU326880A (en) |
| ZA (1) | ZA81100B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW198008B (en) * | 1991-04-08 | 1993-01-11 | Green Cross Corp |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2742174A1 (en) * | 1977-09-20 | 1979-03-29 | Bayer Ag | Process for the preparation of amines |
| ZA793568B (en) * | 1978-07-26 | 1981-02-25 | Duphar Int Res | Algicidal composition |
-
1980
- 1980-01-08 DE DE19803000441 patent/DE3000441A1/en not_active Withdrawn
- 1980-12-06 AT AT80107680T patent/ATE3031T1/en not_active IP Right Cessation
- 1980-12-06 DE DE8080107680T patent/DE3062786D1/en not_active Expired
- 1980-12-06 EP EP80107680A patent/EP0031910B1/en not_active Expired
- 1980-12-24 YU YU03268/80A patent/YU326880A/en unknown
- 1980-12-26 JP JP18421080A patent/JPS56100744A/en active Pending
-
1981
- 1981-01-06 IL IL61868A patent/IL61868A/en unknown
- 1981-01-07 ZA ZA00810100A patent/ZA81100B/en unknown
- 1981-01-07 AU AU66037/81A patent/AU539617B2/en not_active Ceased
- 1981-01-07 ES ES498351A patent/ES8205191A1/en not_active Expired
- 1981-01-08 CA CA000368140A patent/CA1161844A/en not_active Expired
- 1981-01-08 HU HU8141A patent/HU183282B/en unknown
-
1982
- 1982-01-29 ES ES509186A patent/ES509186A0/en active Granted
- 1982-01-29 ES ES509187A patent/ES8301880A1/en not_active Expired
- 1982-01-29 ES ES509188A patent/ES509188A0/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| YU326880A (en) | 1983-12-31 |
| ATE3031T1 (en) | 1983-04-15 |
| AU6603781A (en) | 1981-07-16 |
| DE3000441A1 (en) | 1981-07-09 |
| ZA81100B (en) | 1982-01-27 |
| DE3062786D1 (en) | 1983-05-19 |
| IL61868A (en) | 1983-11-30 |
| ES498351A0 (en) | 1982-06-01 |
| AU539617B2 (en) | 1984-10-11 |
| HU183282B (en) | 1984-04-28 |
| ES8205191A1 (en) | 1982-06-01 |
| JPS56100744A (en) | 1981-08-12 |
| EP0031910B1 (en) | 1983-04-13 |
| ES509187A0 (en) | 1982-12-16 |
| ES8306993A1 (en) | 1983-06-16 |
| EP0031910A1 (en) | 1981-07-15 |
| ES8306471A1 (en) | 1983-06-01 |
| ES509188A0 (en) | 1983-06-16 |
| ES509186A0 (en) | 1983-06-01 |
| ES8301880A1 (en) | 1982-12-16 |
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