US3678052A - Benzamide derivatives - Google Patents

Benzamide derivatives Download PDF

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US3678052A
US3678052A US48841A US3678052DA US3678052A US 3678052 A US3678052 A US 3678052A US 48841 A US48841 A US 48841A US 3678052D A US3678052D A US 3678052DA US 3678052 A US3678052 A US 3678052A
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benzyl
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carbons
methyl
benzamide
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John Krapcho
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ER Squibb and Sons LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain

Definitions

  • T is selected from the group consisting of and NB;
  • Ar is phenyl: R is hydrogen or alkyl of from one to three carbons; R is selected from the group consisting of hydrogen, lower alkyl, monohalo-lower alkyl and butoxybenzyl; X is identically selected from the group consisting of hydrogen, alkoxy, halo, or trifluoromethyl; n is one to four; Y is selected from the group consisting of thia, sulfone, sulfoxide and oxa; Z is selected from the group consisting of nitro, amino and diloweralkylamino; A is ethylene or propylene and mono NB is an N containing, saturated heterocyclic, dilower alkylamino or N methyl N phene ethyl, bis NB is dilower alkylamino and non-toxic mono acid-addition salts, and methyl quaternary salts thereof are
  • X may be hydrogen, alkoxy of from one to seven carbons, trifluoromethyl or halo; n may be 1 or 2; Ar may be phenyl; 2 may be nitro, amino or diloweralkylamino; T may be wherein the alkyl has less than eight carbons, and non-toxic mono acid-addition salts, and methyl quaternary salts thereof.
  • This invention relates to new chemical compounds having valuable therapeutic properties and processes for the preparation thereof,
  • T is selected from the group consisting of and NB;
  • R is selected from the group consisting of hydrogen and lower alkyl, R is selected from the group consisting of hydrogen, lower alkyl, halo lower alkyl, aryl, aralkyl, X-substituted aralkyl, allyl, propargyl, cinnamyl and cycloalkylalkylene',
  • X is hydrogen, lower alkyl, lower alkoxy, amino, dialkylamino, halo, lower alkylthio (e.g., CH CH CH S), hydroxy, cyano, nitro or trifluoromethyl;
  • n is one to four;
  • Y is selected from the group consisting of thia (S sulfone SO sulfoxide (SO) and oxa Z is selected from the group consisting of nitro (NO and amino NH,) and dialkylamino (eg, dimethylamino);
  • suitable radicals represented by the symbol NB are: amino; (lower alkyl)amino; di(lower alkyl)amino; (hydroxylower alkyl)amino; di(hydroxylower alkyl)amino; phenyl-(lower a1kyl)amino; N-(lower alkyl)phenyl (lower alkyl)amino; and saturated to 7-membered monocyclic heterocyclic radicals of less than twelve carbon atoms, as exemplified by piperidino; (lower alkyl)piperidino; di(lower alkyl)piperidino; (lower alkoxy)- piperidino; homopiperidino; 2,3- or 4-piperidyl; 2,3- or 4- (N-lower alkylpiperidyl); pyrrolidino; (lower alkyl)pyrrolidino; di(lower alkyl)pyrrolidino; (lower alkoxy)
  • lower alkyl, lower alkoxy and lower alkylene, as employed herein, include both straight and branched chain radicals of less than eight carbon atoms.
  • the particularly preferred compounds are those wherein X is hydrogen, Y is sulfur, Ar is phenyl, R is hydrogen, Z is nitro or amino, T is wherein A is ethylene, B is dimethylamino and R is lower alkyl.
  • acids useful for preparing these acid-addition salts include, inter alia, inorganic acids, such as the hydrohalic acids (e.g., hydrochloric and hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid, and organic acids such as maleic, tartaric, citric, acetic, salicylic succinic acid, theophylline, 8-chl0r0theophylline, maleic, benzoic, nicotinic, methanesulfonic or cyclohexanesulfamic.
  • hydrohalic acids e.g., hydrochloric and hydrobromic acid
  • sulfuric acid e.g., sulfuric acid, nitric acid, and phosphoric acid
  • organic acids such as maleic, tartaric, citric, acetic, salicylic succinic acid, theophylline, 8-chl0r0theophylline, maleic, benzoic, nicotinic, methane
  • the quaternary ammonium salts include those formed with alkyl halides (e.g., methyl chloride, isobutyl bromide, dodecyl chloride and cetyl iodide), benzyl halides (e.g., benzyl chloride) and dilower alkyl sulfates (e.g., dimethyl sulfate).
  • alkyl halides e.g., methyl chloride, isobutyl bromide, dodecyl chloride and cetyl iodide
  • benzyl halides e.g., benzyl chloride
  • dilower alkyl sulfates e.g., dimethyl sulfate
  • Compounds of this invention and the salts thereof possess central nervous system modifying activity, particularly as depressants and are therefore useful as tranquilizers. They may be administered orally or parenterally in the form of tablets. capsules, elixirs, injectables, or the like, by incorporating the appropriate dosage of the compound of formula I or a physiologically acceptable salt thereof in a dosage range similar to that used with chlordiazepoxide.
  • the compounds of this invention also have been found to possess antibacterial activity.
  • the compounds of this invention may be prepared by the following novel process.
  • Thiosalicylic acid, salicylic acid or (X),,-substituted derivatives thereof is condensed with a nitrocompound having a formula wherein Ar and R are as defined hereinabove. This condensation yields a product having formula COOH III
  • the product formed by this treatment has the formula COHal wherein X, M, Ar, Rand n are as hereinabove described and Hal is halogen.
  • the acid-addition salts are treated with alkali, e.g., sodium hydroxide, to give a free base.
  • alkali e.g., sodium hydroxide
  • This free base may be interacted with at least one equivalent of a quaternizing reagent such as: methyl chloride, isobutyl bromide, dodecyl chloride and cetyl iodide, and the like.
  • thiosalicylic and salicylic acid derivatives that may be utilized in the practice of this invention are: 3-butyl-2- mercaptobenzoic acid; 4octyl-2-mercapto-benzoic acid; 3- methyl-5-butyl-2-mercaptobenzoic acid; 3-isobutoxy-2-mercaptobenzoic acid; 6-methyl-2-mercaptobenzoic acid; 5- amino-3-heptyl-2-mercaptobenzoic acid; 3,5-dichloro-2-mercaptobenzoic acid; 3,4,5,6-tetrafluoro2-mercaptobenzoic acid; 4-pentylthio-2-mercaptobenzoic acid; S-trifluoromethyl- Z-mercaptobenzoic acid; 4-isopropyl-Z-hydroxybenzoic acid; 3,4,5,6-tetramethyl-2-hydroxybenzoic acid; 3-methyl-5-butyl- 2-hydroxybenzoic acid; 4-isobutoxyl-2-hydroxybenzoic acid;
  • the reactants of formula Il may be prepared by the reacting of an aldehyde having the formula ArCHO with a nitroalkane of the formula R-CH NO wherein Ar and R are defined above.
  • Examples of compound II are l-(3,4- dichlorophenyl)-2-nitr0ethene; l-(2,3,4,5,6-pentafluorophenyl)-2-nitroethene; l-(2,6-dichloro-3-methoxyphenyl)-2- nitrobutene; l-(2-furyl)-2-nitroethene; l-(5 -nitro-2furyl)-2- nitroethene; l-(2-thiophene)-2-niiroethene; l-(2-pyridyl)-2- nitroethene; l-(3,4-dimethylphenyl)-2-nitroethene; l-(2,5- dioctylphen
  • the amino derivatives of the invention i.e., wherein Z is NH are prepared by reducing the nitro compounds of formula l, i.e., wherein Z is N This reduction may be carried out by known means as for example by the utilization of stannous chloride or by hydrogen in the presence of platinum or nickel.
  • the dialkyl amino derivatives of formula I i.e., wherein Z is a dialkylamino radical, may be prepared as by reacting the amino compound of formula I with formic acid and formaldehyde to yield the corresponding dialkyl derivative, i.e., dimethyl amino.
  • nitro-derivatives of the instant invention i.e., wherein X is nitro
  • the product recovered may then be reduced to form an amino derivative.
  • the hydroxy derivative of compound I may be formed by reacting a compound wherein X is alkoxy with concentrated hydrochloric acid or with pyridine hydrochloride.
  • Final product I may be converted to its corresponding sulfone and sulfoxide derivatives by oxidation.
  • Compound I may be reacted with potassium permanganate to yield the sulfoxides while if it is reacted with hydrogen peroxide, the sulfones will be produced.
  • compounds of general formula I can be prepared by interaction of ooml with T to give oo'r then reacting the latter with wherein T, X, M, Hal, Ar, R and n are as defined herein.
  • EXAMPLE 8 salicylic N-[2-(Diethylamino)ethyl ]-o-[ [at-(nitromethyl )benzyllo xy]benzamide, hydrochloride Following the procedure of Example 1 but utilizing N,N- diethylethylenediamine in lieu of N,N,N- trimethylethylenediamine the product recovered is N-[2- (diethylamino)ethyl]-o-[[a-(nitromethyl)benzyl]oxy]benzamide, hydrochloride.
  • EXAMPLE 9 EXAMPLE l N,N-Bis [2-(diethylamino)ethyl]-o-[ [a- (nitromethyl)benzyl]oxy]-benzarnide, hydrochloride Following the procedure of Example I but utilizing l,l,7,7- tetraethyldiethylenetriamine in lieu of N ,N ,N trimethylethylenediamine the product recovered is N,N-Bis- [2-(diethylamino)ethyl ]-o-[ [oz-(nitromethyl )benzyl ]oxy]- benzamide, hydrochloride.
  • T is selected from the group consisting of and NB;
  • Ar is phenyl;
  • R is hydrogen or alkyl of from one to three carbons;
  • R is selected from the group consisting of hydrogen, lower alkyl having less than eight carbons, monohalolower alkyl having less than eight carbons, and butoxybenzyl;
  • X is identically selected from the group consisting of hydrogen, alkoxy of from one to seven carbons, halo, or trifluoromethyl;
  • n is one or two;
  • Y is selected from the group consisting of thia, sulfone, sulfoxide and oxa;
  • Z is selected from the group consisting of nitro, amino and diloweralkylamino wherein the alkyl has less than eight carbons;
  • A is ethylene or propylene and mono NB is pyrroliding N lower alkyl piperazino wherein the alkyl has less than eight carbons.
  • dilower alkylamino wherein the alkyl has less than eight carbons, or NmethyLN-phenethyl, bis NB is dilower alkylamino wherein the alkyl has less than eight carbons and non-toxic mono acid-addition salts, and methyl quaternary salts thereof.
  • aryl as employed herein includes mononuclear and dinuclear radicals such as X-subsituted phenyl (erg, phenyl-3 ,4methylenedioxyphenyl and 3,4-ethylenedioxyphenyl) furyl, thienyl, naphthyl or pyridyl,
  • aryl as employed herein includes mononuclear and dinuclear radicals such as X-subsituted: phenyl (e.g. phenyl-3,4-methylenedioxyphenyl and 3,4-ethylenedioxyphenyl) furyl, thienyl, naphthyl or pyridyl.
  • phenyl e.g. phenyl-3,4-methylenedioxyphenyl and 3,4-ethylenedioxyphenyl
  • furyl e.g. phenyl-3,4-methylenedioxyphenyl and 3,4-ethylenedioxyphenyl

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Abstract

Compounds having the formula: WHEREIN T is selected from the group consisting of AND NB; Ar is phenyl: R is hydrogen or alkyl of from one to three carbons; R'' is selected from the group consisting of hydrogen, lower alkyl, monohalo-lower alkyl and butoxy-benzyl; X is identically selected from the group consisting of hydrogen, alkoxy, halo, or trifluoromethyl; n is one to four; Y is selected from the group consisting of thia, sulfone, sulfoxide and oxa; Z is selected from the group consisting of nitro, amino and diloweralkylamino; A is ethylene or propylene and mono NB is an N containing, saturated heterocyclic, dilower alkylamino or N methyl N phene ethyl, bis NB is dilower alkylamino and non-toxic mono acid-addition salts, and methyl quaternary salts thereof are disclosed as having CNS modifying activity. The compounds have the formula WHEREIN X may be hydrogen, alkoxy of from one to seven carbons, trifluoromethyl or halo; n may be 1 or 2; Ar may be phenyl; Z may be nitro, amino or diloweralkylamino; T may be OR NB; R'' may be hydrogen, alkyl or monohalolower alkyl of from one to seven carbons or butoxybenzyl; A may be ethylene or propylene and mono NB may be pyrrolidino, N-lower alkyl piperazino wherein the alkyl radical has less than eight carbons and diloweralkylamino wherein the alkyl radical has less than eight carbons, bis NB may be dilower alkylamino wherein the alkyl has less than eight carbons, and non-toxic mono acid-addition salts, and methyl quaternary salts thereof.

Description

Unite tates aent Krapcho 51 July 18,1972
[54] BENZAMIDE DERIVATIVES John Krapcho, Somerset, NJ.
E. R. Squibb & Sons, Inc., New York, NY.
[22] Filed: June 11, 1970 [21] Appl.No.: 48,841
[72] Inventor:
[73] Assignee:
Related U.S. Application Data [63] Continuation of Ser. No. 802,650, Feb. 26, 1969, abandoned, which is a continuation-in-part of Ser. No. 546,179, April 29, 1966, abandoned.
[52] U.S. Cl. ..260/268 R, 260/239 B, 260/239 BC, 260/243 B, 260/247.1, 260/247.7 H, 260/256,
260/268 C, 2601268 CN, 260/290 R, 260/293.72, 260/293.73, 260/293.75, 260/296 R, 260/326.8,
260/326.85, 260/329 R, 260/329 AM, 260/346.1 R, 260/347.7, 260/465 D, 260/515 A, 260/516,
260/52] R, 260/521 A, 260/558 S, 260/646,
Moffett ..260/268 3,254,120 3,268,526 3,297,726 3,318,882 3,342,859
Dorfman et al ..260/559 Primary Examiner-Donald G. Daus Attorney-Lawrence S. Levinson and Merle J. Smith [5 7] ABSTRACT Compounds having the formula:
Ar 1]! YJJHC H- Z XI wherein T is selected from the group consisting of and NB; Ar is phenyl: R is hydrogen or alkyl of from one to three carbons; R is selected from the group consisting of hydrogen, lower alkyl, monohalo-lower alkyl and butoxybenzyl; X is identically selected from the group consisting of hydrogen, alkoxy, halo, or trifluoromethyl; n is one to four; Y is selected from the group consisting of thia, sulfone, sulfoxide and oxa; Z is selected from the group consisting of nitro, amino and diloweralkylamino; A is ethylene or propylene and mono NB is an N containing, saturated heterocyclic, dilower alkylamino or N methyl N phene ethyl, bis NB is dilower alkylamino and non-toxic mono acid-addition salts, and methyl quaternary salts thereof are disclosed as having CNS modifying activity. The compounds have the formula wherein X may be hydrogen, alkoxy of from one to seven carbons, trifluoromethyl or halo; n may be 1 or 2; Ar may be phenyl; 2 may be nitro, amino or diloweralkylamino; T may be wherein the alkyl has less than eight carbons, and non-toxic mono acid-addition salts, and methyl quaternary salts thereof.
7 Claims, No Drawings BENZAMIDE DERIVATIVES The present application is a continuation of copending application Ser. No. 802,650, filed 26 Feb. 1969, now abandoned, which in turn is a continuation-in-part application of my U. S. application, Ser. No. 546,179, filed Apr. 29, 1966 now abandoned.
This invention relates to new chemical compounds having valuable therapeutic properties and processes for the preparation thereof,
The therapeutically active compounds of this invention are of the general formula wherein T is selected from the group consisting of and NB; R is selected from the group consisting of hydrogen and lower alkyl, R is selected from the group consisting of hydrogen, lower alkyl, halo lower alkyl, aryl, aralkyl, X-substituted aralkyl, allyl, propargyl, cinnamyl and cycloalkylalkylene', X is hydrogen, lower alkyl, lower alkoxy, amino, dialkylamino, halo, lower alkylthio (e.g., CH CH CH S), hydroxy, cyano, nitro or trifluoromethyl; n is one to four; Y is selected from the group consisting of thia (S sulfone SO sulfoxide (SO) and oxa Z is selected from the group consisting of nitro (NO and amino NH,) and dialkylamino (eg, dimethylamino); A is alkylene of from two to four carbons and NB is a basic nitrogen containing radical having less than twelve carbons and salts thereof.
Among the suitable radicals represented by the symbol NB are: amino; (lower alkyl)amino; di(lower alkyl)amino; (hydroxylower alkyl)amino; di(hydroxylower alkyl)amino; phenyl-(lower a1kyl)amino; N-(lower alkyl)phenyl (lower alkyl)amino; and saturated to 7-membered monocyclic heterocyclic radicals of less than twelve carbon atoms, as exemplified by piperidino; (lower alkyl)piperidino; di(lower alkyl)piperidino; (lower alkoxy)- piperidino; homopiperidino; 2,3- or 4-piperidyl; 2,3- or 4- (N-lower alkylpiperidyl); pyrrolidino; (lower alkyl)pyrrolidino; di(lower alkyl)pyrrolidino; (lower alkoxy)pyrrolidino; 2- or 3-pyrr0lidyl; 2- or 3-(N-lower alkyl pyrrolidyl); morpholino; (lower alkyl)morpholino; di(lower alkyl)morpholino; (lower alkoxy)-morpholino; thiamorpholino; (lower alkyl)thiamorpholino; di(lower alkyl)thiamorpholino; (lower alkoxy)thiamorpholino; piperazino; 4-R -substituted piperazino (e.g., N-ethylpiperazino; N-phenyl-piperazino, and so forth); [hydroxy (lower alkyl)]piperazino [e.g., N-(2-hydroxyethyl)piperazino]; (lower alkyl)piperazino (e.g., N-methylpiperazino); di(lower alkyl)piperazino; (lower alkoxy)- piperazino; homopiperazino; and 4-R'-substituted homopiperazino (e.g., N-benzylhomopiperazino). The terms lower alkyl, lower alkoxy," and lower alkylene, as employed herein, include both straight and branched chain radicals of less than eight carbon atoms. The particularly preferred compounds are those wherein X is hydrogen, Y is sulfur, Ar is phenyl, R is hydrogen, Z is nitro or amino, T is wherein A is ethylene, B is dimethylamino and R is lower alkyl.
As to the salts, those coming within the purview of this invention include the acid-addition salts of those compounds containing a basic group particularly the non-toxic acid-addition and quaternary ammonium salts. Acids useful for preparing these acid-addition salts include, inter alia, inorganic acids, such as the hydrohalic acids (e.g., hydrochloric and hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid, and organic acids such as maleic, tartaric, citric, acetic, salicylic succinic acid, theophylline, 8-chl0r0theophylline, maleic, benzoic, nicotinic, methanesulfonic or cyclohexanesulfamic. The quaternary ammonium salts include those formed with alkyl halides (e.g., methyl chloride, isobutyl bromide, dodecyl chloride and cetyl iodide), benzyl halides (e.g., benzyl chloride) and dilower alkyl sulfates (e.g., dimethyl sulfate).
Compounds of this invention and the salts thereof possess central nervous system modifying activity, particularly as depressants and are therefore useful as tranquilizers. They may be administered orally or parenterally in the form of tablets. capsules, elixirs, injectables, or the like, by incorporating the appropriate dosage of the compound of formula I or a physiologically acceptable salt thereof in a dosage range similar to that used with chlordiazepoxide. The compounds of this invention also have been found to possess antibacterial activity.
The compounds of this invention may be prepared by the following novel process. Thiosalicylic acid, salicylic acid or (X),,-substituted derivatives thereof is condensed with a nitrocompound having a formula wherein Ar and R are as defined hereinabove. This condensation yields a product having formula COOH III
wherein M is oxa or thia and Ar -(a-nitromethyl)-benzyl]R are as defined above. The acid group of the product having formula III is converted to its acid halide by treatment with thionyl halide, e.g., thionyl bromide or thionyl chloride.
The product formed by this treatment has the formula COHal wherein X, M, Ar, Rand n are as hereinabove described and Hal is halogen.
Reacting the compound of formula IV with an amine of the formula or H-B yields a compound of formula I, generally in the form of its hydrohalide salt.
To form quaternary ammonium salts of the compounds of formula I, the acid-addition salts are treated with alkali, e.g., sodium hydroxide, to give a free base. This free base may be interacted with at least one equivalent of a quaternizing reagent such as: methyl chloride, isobutyl bromide, dodecyl chloride and cetyl iodide, and the like.
Examples of thiosalicylic and salicylic acid derivatives that may be utilized in the practice of this invention are: 3-butyl-2- mercaptobenzoic acid; 4octyl-2-mercapto-benzoic acid; 3- methyl-5-butyl-2-mercaptobenzoic acid; 3-isobutoxy-2-mercaptobenzoic acid; 6-methyl-2-mercaptobenzoic acid; 5- amino-3-heptyl-2-mercaptobenzoic acid; 3,5-dichloro-2-mercaptobenzoic acid; 3,4,5,6-tetrafluoro2-mercaptobenzoic acid; 4-pentylthio-2-mercaptobenzoic acid; S-trifluoromethyl- Z-mercaptobenzoic acid; 4-isopropyl-Z-hydroxybenzoic acid; 3,4,5,6-tetramethyl-2-hydroxybenzoic acid; 3-methyl-5-butyl- 2-hydroxybenzoic acid; 4-isobutoxyl-2-hydroxybenzoic acid; 4-cyano-2-hydroxybenzoic acid; 6-pentoxy-2-hydroxybenzoic acid; 3-bromo-2-hydroxybenzoic acid.
The reactants of formula Il may be prepared by the reacting of an aldehyde having the formula ArCHO with a nitroalkane of the formula R-CH NO wherein Ar and R are defined above. Examples of compound II are l-(3,4- dichlorophenyl)-2-nitr0ethene; l-(2,3,4,5,6-pentafluorophenyl)-2-nitroethene; l-(2,6-dichloro-3-methoxyphenyl)-2- nitrobutene; l-(2-furyl)-2-nitroethene; l-(5 -nitro-2furyl)-2- nitroethene; l-(2-thiophene)-2-niiroethene; l-(2-pyridyl)-2- nitroethene; l-(3,4-dimethylphenyl)-2-nitroethene; l-(2,5- dioctylphenyl)-2-nitrobutene; l-( 2-hydroxyphenyl )-2- nitrobutene; l-(4-isopropoxyphenyl)-2-nitrobutene; and so forth.
The amino derivatives of the invention, i.e., wherein Z is NH are prepared by reducing the nitro compounds of formula l, i.e., wherein Z is N This reduction may be carried out by known means as for example by the utilization of stannous chloride or by hydrogen in the presence of platinum or nickel. The dialkyl amino derivatives of formula I, i.e., wherein Z is a dialkylamino radical, may be prepared as by reacting the amino compound of formula I with formic acid and formaldehyde to yield the corresponding dialkyl derivative, i.e., dimethyl amino.
The nitro-derivatives of the instant invention, i.e., wherein X is nitro, may be prepared by reacting compound I with fuming nitric acid. The product recovered may then be reduced to form an amino derivative. The hydroxy derivative of compound I may be formed by reacting a compound wherein X is alkoxy with concentrated hydrochloric acid or with pyridine hydrochloride. Final product I may be converted to its corresponding sulfone and sulfoxide derivatives by oxidation. Compound I may be reacted with potassium permanganate to yield the sulfoxides while if it is reacted with hydrogen peroxide, the sulfones will be produced.
Alternately, compounds of general formula I can be prepared by interaction of ooml with T to give oo'r then reacting the latter with wherein T, X, M, Hal, Ar, R and n are as defined herein.
The following examples illustrate the invention, all temperatures are in degrees Centigrade unless otherwise stated:
EXAMPLE I N-[ 2-( Dimethylamino)ethyl l-N-methyl-o-l a- (nitromethyl )benzyl l-thio ]benzamide, hydrochloride A solution of 42.0 g. of 2-[[a-nitromethyl)benzyl]thio] benzoyl chloride (prepared in accordance with the teachings in copending application, Ser. No. 533,264, filed Mar. 10, 1966) in 200 ml. of chloroform is cooled to 15 and treated with a solution of 13.4 g. of N,N,N'-trimethylethylenediamine in ml. of chloroform. This solution is refluxed for 1 hour, cooled to room temperature and diluted to 800 ml. with ether to give 46 g. of pale yellow solid, m.p. about 1 l5-l2l. The material is dissolved in 200 ml. of chloroform, filtered the small quantity of insoluble material, and the filtrate diluted with 800 ml. of ether. The semi-solid which separates is digested with 70 ml. of warm butanone to give a granular product weighing 37.3 g., m.p. about 1 l7-l22. After crystallization from 100 ml. of butanone, the nearly colorless solid weighs 28.6 g., m.p. about l20122.
EXAMPLE 2 N-[ 2-( Diethylamino)ethyl ]-o-[ a-( nitromethyl )benzyl ]thio benzamide, hydrochloride Following the procedure of Example 1 but utilizing N,N- diethylethylenediamine in lieu of N,N,N'- trimethylethylenediamine the desired product is recovered.
EXAMPLE 3 N-[3-(4-Methyl-l-piperazinyl)propyl]-o-[[a- (nitromethyl)benzyll-thiolbenzamide, hydrochloride Following the procedure of Example 1 but utilizing 3-(N- methylpiperazino)propylamine in lieu of N,N,N'- trimethylethylene-diamine the desired product is recovered.
EXAMPLE 4 N,N-Bis [Z-(diethylamino)ethyl]-o[[a-(nitromethyl)benzyl]t hio]-benzamide, hydrochloride Following the procedure of Example 1 but utilizing 1,1 ,7,7- tetraethyldiethylenetriamine in lieu of N,N,N'- trimethylethylene-diamine the desired product is recovered.
EXAMPLE 5 N-cyclopropyl-N-[3-(4-ethyl-l-piperazinyl)propyl]-o-[[a- (nitro-methyl)benzyl]thio]benzamide, hydrochloride Following the procedure of Example 1 but utilizing l-[3- (cyclopropylmethylamino)propyl]-4 -ethylpiperazine in lieu of N,N,N-trimethylethylenediamine the desired product is recovered.
EXAMPLE 6 N-(m-Butoxybenzyl)-N-[(3-dimethylamino)propyl]-o-[[a- (nitro-methyl)benzyl]thio]benzamide, hydrochloride Following the procedure of Example 1 but utilizing N-(mbutoxybenzyl)-N',N'-dimethylpropylenediamine in lieu of N,N,N'-trimethylethylenediamine the desired product is recovered.
EXAMPLE 7 N-[Z-(Dimethylamino)ethyl]-N-methyl-o-[[a-Z-(anitromethyl)-benzyl]oxy]benzamide, hydrochloride 2[ [a-(Nitromethyl )benzyl]oxy]benzoyl chloride (prepared by reacting salicyclic acid with w-nitrostyrene and resulting acid treated with thionyl chloride) is reacted with N,N,N-trimethylethylenediamine in a manner set forth in Example to yield the product.
EXAMPLE 8 salicylic N-[2-(Diethylamino)ethyl ]-o-[ [at-(nitromethyl )benzyllo xy]benzamide, hydrochloride Following the procedure of Example 1 but utilizing N,N- diethylethylenediamine in lieu of N,N,N- trimethylethylenediamine the product recovered is N-[2- (diethylamino)ethyl]-o-[[a-(nitromethyl)benzyl]oxy]benzamide, hydrochloride.
EXAMPLE 9 EXAMPLE l N,N-Bis [2-(diethylamino)ethyl]-o-[ [a- (nitromethyl)benzyl]oxy]-benzarnide, hydrochloride Following the procedure of Example I but utilizing l,l,7,7- tetraethyldiethylenetriamine in lieu of N ,N ,N trimethylethylenediamine the product recovered is N,N-Bis- [2-(diethylamino)ethyl ]-o-[ [oz-(nitromethyl )benzyl ]oxy]- benzamide, hydrochloride.
EXAMPLE 11 N-( 3-chloropentyl )-N-[ 2-(4-ethyll -piperazinyl ]ethyl-o-[ [a- (nitromethyl)benzyl]oxy]benzamide, hydrochloride Following the procedure of Example 1 but utilizing 1-[2-[3- (chloropentyl)amino]ethyl]-4-ethylpiperazine in lieu of N,N,N'-trimethylethylenediamine the product recovered is N- (3-chloropentyl)-N-[2-(4-ethyll -piperazinyl )]ethyl-o-[ [a- (nitromethyl)benzyl]oxy]benzamide, hydrochloride.
EXAMPLE l2 N-(m-butoxybenzyl)-N-[(3-dimethylamino)propyl]-o-[ [a- (nitro-methyl)benzyl]oxylbenzamide, hydrochloride Following the procedure of Example 1 but utilizing N-(mbutoxybenzyl)-N,N-dimethylpropylenediamine in lieu of N,N,N'-trimethylethylenediamine the product recovered is N- (m-butoxybenzyl)-N-[(3-dimethylamino)propyl]-o-[[a- (nitromethyl)-benzyl]oxy]benzamide, hydrochloride.
EXAMPLE l3 N,N-Dimethyl-o-[ [a-(a-nitrobutyl )benzyl]thio]-benzamide 2-[[a-(a-Nitrobutyl)benzyl]thio]-benzoyl chloride (prepared by reacting thiosalicylic acid with l-phenyl-2- nitrobutene and treating the acid formed with thionyl chloride) is reacted with dimethylamine to give the desired product.
EXAMPLE l4 5-Cyano-N,N-dimethyl-2-[[a-(a-nitrobutyl)benzyl]thio]- benzamide 5-Cyano-2-[[a-(a-nitrobutyl)benzyl]thio]-benzoyl chloride is reacted with dimethylamine to give the desired product.
EXAMPLE l5 N-Pyrrolidinyl-o-[ [oz-(nitromethyl )benzyl]thio]-benzamide Following the procedure utilized in Example 1 but substituting an equivalent amount of pyrrolidine in lieu of N,N,N-
trimethylethylenediamine, the desired product is recovered.
EXAMPLE l6 N,N-Dipropyl-o-[[a(nitromethyl)benzyl]thio]-benzamide Following the procedure utilized in Example 1 but substituting an equivalent amount of dipropylamine in lieu of N,N,N'-
trimethylethylenediamine, the desired product is recovered.
EXAMPLE 17 bl-Methyl-N-phenethyl-o-[ a-nitromethyl)benzyl]thio benzamide Following the procedure utilized in Example 1 but substituting an equivalent amount of N-methyl-N-phenethylamine in lieu of N,N,N-trimethylethylenediamine, the desired product is recovered.
EXAMPLE 18 N-(2-Ethylmorpholinyl)-o-[[o-nitromethyl)benzyl]thio]- benzamide Following the procedure utilized in Example 1 but substituting an equivalent amount of 2-ethylmorpholine in lieu of N,N,N'-trimethylethylenediamine, the desired product is recovered.
EXAMPLE l9 N-[2-(Dimethylamino)ethyl]-N-methyl-o-[[a- (nitromethyl)benzyl]thio]-benzamide-S-oxide To a solution of potassium permangante, N-[Z-(dimethylamino)ethyl]-N-methyl-o-[[ct-(nitromethyl)benzyl]thiolbenzamide is added and the desired product is recovered.
EXAMPLE 20 N-[2-(Dimethylamino)ethyl]-N-methyl-o-[[or-(nitromethyl)- benzyl]thiol-benzamide-S-dioxide Repeating the procedure of Example 14 but utilizing hydrogen peroxide in lieu of permanganate the desired product is recovered.
EXAMPLE 21 N-[2-(Dimethylamino)ethyl]-N-methyl-o-[[a- (aminomethyl)benzyl]-thio]-benzamide The material from Example 1 (10.0 g.) is added to a solution of stannous chloride dihydrate (22 g.) in 70 ml. of ethanol-20 ml. of glacial acetic acid. The resulting mixture is refluxed for 3 hours and the major portion of the solvent being removed under reduced pressure. The residue is treated with ml. of water, followed by 50 g. of potassium carbonate (portionwise) and then extracted with a mixture of 300 ml. of ether and 100 ml. of chloroform. The organic phase is separated, dried over magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to give 7.6 g. of the product.
EXAMPLE 22 N-[2-(Dimethylamino)ethyl]-N-methyl-o-[[a- (dimethylaminomethyl)-benzyl]thio]-benzamide A mixture of 32.0 g. of the material from Example 16 and 26 ml. of 88% formic acid is treated with 26 ml. of 37% formaldehyde solution. After the evolution of carbon dioxide subsided, the mixture is refluxed for 12 hours, cooled and treated with 10 ml. of concentrated hydrochloric acid. The major portion of the solvent is removed under reduced pressure. The residue is cooled, treated with 20 ml. of water and then with a solution of 10 g. of sodium hydroxide in 20 ml. of water. The mixture is extracted with 100 ml. of ether (three times), the organic phases combined, dried over magnesium sulfate, filtered and the filtrate concentrated to give the product.
EXAMPLE 23 N-[ 2-( Dimethylamino )ethyl ]-N-methyl-o-{ [anitromethyl )benzyl]-thio]-benzamide, methochloride A mixture of 10 g. of material from Example 1 in 50 ml. of water is treated with 10 ml. of 10% sodium hydroxide solution and the liberated base extracted with 200 ml. of ether. The organic phase is dried over magnesium sulfate, filtered and concentrated to remove the solvent. The residue is dissolved in 50 ml. of acetonitrile and treated with 20 g. of methyl chloride. After standing at room temperature for a day, the mixture is refluxed for 1 hour and the solvent removed under reduced pressure to give the product.
The invention may be variously otherwise embodied within the scope of the appended'claims.
l claim:
1. A compound having the fonnula:
wherein T is selected from the group consisting of and NB; Ar is phenyl; R is hydrogen or alkyl of from one to three carbons; R is selected from the group consisting of hydrogen, lower alkyl having less than eight carbons, monohalolower alkyl having less than eight carbons, and butoxybenzyl; X is identically selected from the group consisting of hydrogen, alkoxy of from one to seven carbons, halo, or trifluoromethyl; n is one or two; Y is selected from the group consisting of thia, sulfone, sulfoxide and oxa; Z is selected from the group consisting of nitro, amino and diloweralkylamino wherein the alkyl has less than eight carbons; A is ethylene or propylene and mono NB is pyrroliding N lower alkyl piperazino wherein the alkyl has less than eight carbons. dilower alkylamino wherein the alkyl has less than eight carbons, or NmethyLN-phenethyl, bis NB is dilower alkylamino wherein the alkyl has less than eight carbons and non-toxic mono acid-addition salts, and methyl quaternary salts thereof.
2. The compound in accordance with the formula of claim I having the name N-[2-(dimethylamino)ethyl]-N-methyl-o-[ [a -(nitromethyl)benzyl]thio]benzamide, hydrochloride.
3. The compound in accordance with the formula of claim 1 having the name N-[2-(diethylamino)ethyl]-o-[[a- (nitromethyl)benzyl]thio]benzamide, hydrochloride.
4. The compound in accordance with the formula of claim 1 having the name N-[3-(4-methyl-1-piperazinyl)propyl]-o-[[a- (nitromethyl)benzyl]thio]benzamide, hydrochloride.
5. The compound in accordance with the formula of claim 1 having the name N-[2-(dimethylamino)ethyl]-N-methyl-o[[a- (aminomethyl)benzyl]thio]benzamide.
6. The compound in accordance with the formula of claim 1 having the name N-[Z-(dimethylamino)ethyl]-N-methyl-o-[ [a -(dimethylaminomethyl)benzyl]thio]benzamide.
7. The compound in accordance with the formula of claim I having the name N-[2-(dimethylamino)ethyl]-N-methyl-o-[[a -(nitromethyl)benzyl]thio]benzamide, methochloride.
E Ag? UNlTED S'lrllffi PATENT @FFMIE QERTKJFZ GATE @l GQPRREQTMlN Patent No. 316787052 Dated July 18, 1972 Invent0r s John Krapcho It is certified that errer appears in the above iclentified patent and that said Letters Patent are hereby eerreeted as show below:
Column 1, line 67, after less than eight carbon atomsa" insert the following sentence:
The term "aryl" as employed herein includes mononuclear and dinuclear radicals such as X-subsituted phenyl (erg, phenyl-3 ,4methylenedioxyphenyl and 3,4-ethylenedioxyphenyl) furyl, thienyl, naphthyl or pyridyl,
Column 2, line 48 delete "-(d-nitromethyl) benzyl".
line 61, "Rand' should read R and Column 3, line 25, "niiroethene" should read nitroethene Column 4, line 72, after EXAMPLE 8, delete "salicylicH Column 8, line 1, pyrroliding should read pyrrolidino Signed and sealed this 23rd day of January 1973..
(SEAL) Attest EDWARD I T.PLETCHER,JR. ROBERT GOTTSCHALK Arresting Officer Commissioner of Patentgj Attesting Officer mg UNHED STATES PATENT @FFICE CER'HMQATE @i CRREUHN Patent No. 3,678,052 Dated July 18, 1972 Inventor(s) John KraPChO It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:
Column 1, line 67, after "less than eight carbon atoms."
insert the following sentence:
The term "aryl" as employed herein includes mononuclear and dinuclear radicals such as X-subsituted: phenyl (e.g. phenyl-3,4-methylenedioxyphenyl and 3,4-ethylenedioxyphenyl) furyl, thienyl, naphthyl or pyridyl.
Column 2, line 48, delete "-(oc-nitromethyl)benzyl".
line 61, "Rand" should read R and Column 3, line 25, "niiroethene" should read nitroethene Column 4, line 72, after EXAMPLE 8, delete "salicylic".
Column 8, line 1, "pyrroliding" should read pyrrolidino Signed and sealed this 23rd day of January 1973..
(SEAL) Attest- EDWARD M.FLETCHER,JR. ROBERT GOTTSCHALK Commissioner of Patent fi

Claims (6)

  1. 2. The compound in accordance with the formula of claim 1 having the name N-(2-(dimethylamino)ethyl)-N-methyl-o-(( Alpha -(nitromethyl)benzyl)thio)benzamide, hydrochloride.
  2. 3. The compound in accordance with the formula of claim 1 having the name N-(2-(diethylamino)ethyl)-o-(( Alpha -(nitromethyl)benzyl)thio)benzamide, hydrochloride.
  3. 4. The compound in accordance with the formula of claim 1 having the name N-(3-(4-methyl-1-piperazinyl)propyl)-o-(( Alpha -(nitromethyl)benzyl)thio)benzamide, hydrochloride.
  4. 5. The compound in accordance with the formula of claim 1 having the name N-(2-(dimethylamino)ethyl)-N-methyl-o(( Alpha -(aminomethyl)benzyl)thio)benzamide.
  5. 6. The compound in accordance with the formula of claim 1 having the name N-(2-(dimethylamino)ethyl)-N-methyl-o-(( Alpha -(dimethylaminomethyl)benzyl)thio)benzamide.
  6. 7. The compound in accordance with the formula of claim 1 having the name N-(2-(dimethylamino)ethyl)-N-methyl-o-(( Alpha -(nitromethyl)benzyl)thio)benzamide, methochloride.
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Cited By (1)

* Cited by examiner, † Cited by third party
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US5011992A (en) * 1984-06-28 1991-04-30 Bristol-Myers Squibb Company Pharmacologically active substituted benzamides

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US3131188A (en) * 1958-08-29 1964-04-28 Upjohn Co Novel alkenyloxy-3, 5-dialkyl benzamides
US3254120A (en) * 1961-12-05 1966-05-31 Pharmazeutische Fabrik Montavit Gmbh N-(tertiaryaminoalkoxy-benzoyl) anilides
US3268526A (en) * 1962-09-12 1966-08-23 Monsanto Co Heterocyclic polyhalobenzamide derivatives
US3297726A (en) * 1962-05-30 1967-01-10 Bayer Ag Aromatic hindered isocyanates
US3318882A (en) * 1963-06-05 1967-05-09 Ciba Geigy Corp 2-amino-5-diloweralkyl sulfamoyl-n, n-disubstituted benzamides
US3342859A (en) * 1962-11-30 1967-09-19 Hooker Chemical Corp Tetrahalohydroxybenzamides

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Publication number Priority date Publication date Assignee Title
US3131188A (en) * 1958-08-29 1964-04-28 Upjohn Co Novel alkenyloxy-3, 5-dialkyl benzamides
US3254120A (en) * 1961-12-05 1966-05-31 Pharmazeutische Fabrik Montavit Gmbh N-(tertiaryaminoalkoxy-benzoyl) anilides
US3297726A (en) * 1962-05-30 1967-01-10 Bayer Ag Aromatic hindered isocyanates
US3268526A (en) * 1962-09-12 1966-08-23 Monsanto Co Heterocyclic polyhalobenzamide derivatives
US3342859A (en) * 1962-11-30 1967-09-19 Hooker Chemical Corp Tetrahalohydroxybenzamides
US3318882A (en) * 1963-06-05 1967-05-09 Ciba Geigy Corp 2-amino-5-diloweralkyl sulfamoyl-n, n-disubstituted benzamides

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5011992A (en) * 1984-06-28 1991-04-30 Bristol-Myers Squibb Company Pharmacologically active substituted benzamides

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