GB2129424A - Basic acetanilides - Google Patents

Basic acetanilides Download PDF

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Publication number
GB2129424A
GB2129424A GB08321953A GB8321953A GB2129424A GB 2129424 A GB2129424 A GB 2129424A GB 08321953 A GB08321953 A GB 08321953A GB 8321953 A GB8321953 A GB 8321953A GB 2129424 A GB2129424 A GB 2129424A
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Prior art keywords
acetanilide
methyl
useful salt
basic
pharmacologically useful
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Granted
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GB08321953A
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GB2129424B (en
GB8321953D0 (en
Inventor
Edith Rudinger
Xavier Perlia
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Pharmaton SA
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Pharmaton SA
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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
    • C07D295/04—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
    • C07D295/14—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 carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—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 carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/15—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 carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated

Abstract

A basic acetanilide of the general formula III <IMAGE> wherein R1 is hydrogen or optionally substituted alkyl, and R4 is halogen, optionally substituted alkoxy, an optionally substituted alkylthio, nitro, amino or optionally substituted alkylamino, propionyl or trihalogenmethyl, and R5 is a basic group, or a pharmacologically useful salt thereof. Preferably R is halogen or methyl, R4 is chlorine, bromine, trihalogen- methyl, ethoxy, nitro, amino, or propionyl and R5 is diethylamine, piperidino, pyrrolidino, cyclopropyl, amino or cyclopentylamino.

Description

SPECIFICATION Basic acetanilides processes for their preparation and pharmacological compositions containing these acetanilides The present invention is directed to novel basic acetanilides, to processes for their preparation and to pharmaceutical or veterinary compositions containing these novel acetanilides.
There is a continuing need for novel compounds which eg. may be used as local anaesthesia and antiarrhythmic active agents, and which show a lower toxicity and an improved effectiveness over the compounds known in the art and which may be prepared by processes which are easy to carry out and which are economical.
The present invention provides basic acetanilides having the formula Ill
wherein R, is hydrogen or an occasionally substituted alkyl, and R4 is halogen, an occasionally substituted alkoxy, an occasionally substituted alkylthio, nitro, amino or an occasionally substituted alkylamino, propionyl or trifluoromethyl, and R5 is a basic group, and their pharmacologically useful salts.The invention includes a process for preparing a basic acetanilide of the formula Ill
wherein R1, R4 and R5 are defined above, or a pharmacologically useful salt thereof, wherein an aniline of the formula I
wherein R, and R4 are defined above, is reacted under cooling or at room temperature in a solvent and in the presence of a base with a halogen compound of formula II X-COH2-Hal II wherein X is a hydroxyl group, an ester group, a halide, an amide group or an anhydride group or any other suitable leaving group, and Hal is a halogen atom or any other suitable leaving group, to yield a compound of formula IV
wherein R,, R4 and Hal are defined above, and then the compound of formula IV is reacted in an inert solvent at elevated temperature with an amine delivering the group R5, and the obtained compound optionally is transformed into a pharmacologically useful salt thereof.
The intermediates of formula IV may be prepared in such a way that halogen fatty acids or other suitable derivatives, such as esters, halides (eg acid chloride or bromide), amides or anhydrides, are contacted with an aniline under cooling or at room temperature in a solvent, eg acetone, acetic acid, acetic acid ethylester, or chloroform, in the presence of a base, such as sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate, sodium acetate, or in an aqueous sodium acetate buffer. The halogen acetanilides of the general formula IV may be reacted with an amine in an inert solvent, preferably benzene, at an elevated temperature.
The acetanilides of the general formula Ill may also be prepared without isolation of the intermediate of the formula IV, in that after the halogen alkanoylization the corresponding amine may be added to the reaction mixture in a higher boiling inert solvent, eg toluene or xylene, followed by heating this mixture.
The compounds of the general formula Ill, wherein R4 is amino, may be prepared from the corresponding acetanilides of the formula Ill, wherein R4 is nitro, by reduction.
The acetanilides of formula Ill, wherein R4 is halogen, may be prepared either from the corresponding aniline, as described above, or from the acetanilides, wherein R4 is amino, with the Sandmeyer reaction.
According to this invention a basic group is any group having at least one basic nitrogen atom.
Occasionally, the process of this invention may also be realized in the presence of catalysts. A person skilled in the art may easily determine the suitable reaction temperatures and reaction times.
Usually one works at standard pressure, but the use of higher pressure or lower pressure (vacuum) is not excluded.
The administration of the novel compounds of formula Ill according to this invention may be realized in a conventional way, as this is known in the prior art for the known compounds.
Preferred embodiments are illustrated in the set of examples, wherein also some novel starting materials and intermediates are described.
A. With isolation of the intermediate of the formula IV Example 1 To a mixture of 53 g (0.35 mol) 2-ethoxy-6-methylaniline in 525 ml absolute acetone and 70 g sodium bicarbonate is added drop by drop under cooling with ice during one hour 46 g (0.4 mol) chloroacetyl chloride, and then this mixture is stirred for one hour at room temperature. The inorganic salt is filtered with suction and washed with acetone. The filtrate is evaporated in the vacuum of a water jet pump, to the residue water is added, and the precipitated crystals of 2-chloro-2'-ethoxy-6'methyl-acetanilide, mp. 1 48--1 49 0, are filtered with suction.
Amination To 10.25 g (0.045 mol) 2-chloro-2'-ethoxy-6'-methyl-acetanilide in 100 ml benzene are added 10 g (0.136 mol) diethylamine and this mixture is refluxed for 6 hours. After cooling the precipitated diethylamine hydrochloride is filtered with suction, washed with benzene, and the filtrate is evaporated in the vacuum of the water jet pump. To the residue is added water and ether, the base is extracted from the ether layer with 5% hydrochloric acid, the aqueous acidic solution is rendered alkaline and extracted with ether. After drying and evaporating the ether the residue is dissolved in ethanol, and under cooling etheric hydrochloric acid is added drop by drop, and the hydrochloride of 2-diethylamino-2'-ethoxy-6'-methyl-acetanilide, mp. 107--1090, is obtained.
Example 2 By the amination method described in example 1 2-piperidino-2'-ethoxy-6'-methyl-acetanilide, mp. 79--800, is obtained, and the base is reacted to the hydrochloride, mp. 192--193", when piperidine is used instead of diethylamine.
Example 3 When pyrrolidine is used instead of diethylamine, as described in example 1.2-pyrrolidino-2'- ethoxy-6'-methylacetanilide, mp. 60.5--620 is obtained, which is reacted to the hydrochloride, mp.
180--181.50.
Example 4 By the method described in example 1 2-chloro-2'-methyl-6'-nitro-acetanilide is obtained, mp.
14O141.50 when 2-methyl-6-nitro-aniline is used instead of 2-ethoxy-6-methyl-aniline.
By the amination method described in example 1 2-diethylamino-2'-methyl-6'-nitro-acetanilide, mp. 60-61 , is obtained from the 2-chloro-2'-methyl-6'-nitro-acetanilide and diethyl-amine, as well as its hydrochloride, mp. 1 66-1 680.
Example 5 When piperidine is used instead of diethylamine, using the amination method described in example 1, 2-piperidino-2'-methyl-6'-nitro-acetanilide, mp. 72--730, and its hydrochloride, mp.
1 92-1 940, is obtained.
Example 6 Using the amination method described in example 1, the hydrochloride of 2-diethylamino-2'-trifluoromethylacetanilide, mp. 1 60.1 0, is prepared, when 2-chloro-2'-trifluoromethyl-acetanilide and diethylamine are used.
Example 7 When pyrrolidine is used instead of diethylamine, using the amination method described in examples 1 and 6, the hydrochloride of 2-pyrrolidino-2'-trifluoromethyl-acetanilide, mp. 229.40, is obtained.
Example 8 Using the amination method described in example 1 , the hydrochloride of 2-pyrrolidino-2'propionyl-acetanilide is prepared, when 2-chloro-2'-propionyl-acetanilide and pyrrolidine are used.
Example 9 Using the amination method in example 1 , the hydrochloride of 2-pyrrolidino-2'-methyl-6'propionyl-acetanilide, mp. 192.60, is prepared from 2-chloro-2'-methyl-6"-propionyl-acetanil and pyrrolidine are used.
The 2-methyl-6-propionyl-aniline, which is used as starting material, is prepared as follows from 2-amino-3-methyl-benzonitrile: From 6.3 g (0.26 mol) magnesium and 25.5 g ethylbromide in 130 ml absolute ether the ethyl magnesium-bromide is prepared which is heated for 30 minutes on the water bath. A solution of 6.65 (0.05 mol) 2-amino-3-methyl-benzonitrile in 100 ml absolute ether is then added slowly drop by drop, and the mixture is refluxed under stirring for 1 5 hours. After cooling the mixture is poured on 110 g ice and the solution of 1 5.6 g ammonium-chloride in 67 ml water is added. The ether layer is separated, and the aqueous layer is extracted with ether. From the combined ether layer the ether is distilled off, and the residue is refluxed with 9.5 ml water and 11.2 ml concentrated hydrochloric acid for 30 minutes.After cooling the mixture is extracted with ether, the aqueous layer is rendered alkaline and extracted with ether. After drying and evaporating the ether the 2-methyl-6-propionyl-aniline is obtained, which was characterized as hydrochloride, mp. 191.20.
Example 10 To 10.9 g (0.05 mol) 2-chloro-2'-chloro-6'-methyl-acetanilide in 30 ml absolute toluene are added 12.75 g (0.1 5 mol) cyclopentylamine in 50 ml toluene, and this mixture is refluxed for 6 hours.
After cooling the precipitated cyclopentylamine-hydrochloride is filtered with suction, the filtrate is evaporated and to the residue is added water and ether. The ether is extracted with 5% hydrochloric acid solution, wherefrom the hydrochloride of 2-cyclopentylamino-2'-chloro-6'-methyi-acetanilide crystallizes, mp. 209.70.
From 1 g of the hydrochloride the base was prepared, mp. 76.80.
Example 11 When cyclopropylamine in benzene is added to 2-chloro-2'-chloro-6'-methyl-acetanilide and when this mixture is heated in an autoclave having a glass insertion for 10 hours at a temperature of 1000, and when after cooling the prescription of example 1 is followed, then the hydrochloride of 2cyclopropylamino-2'-chloro-6'-methyl-acetanilide, mp. 2570, is obtained.
B. Without isolation of the intermediate of formula IV Example 12 To 18.6 g (0.1 mol) 2-bromo-6-methyl-aniline in 150 ml absolute acetone and 20 g sodium bicarbonate are added drop by drop under cooling with ice during one hour 12 g (0.11 mol) chloroacetyl chloride and then this mixture is stirred at room temperature for 30 minutes. To the mixture are added 22 g (0.3 mol) diethylamine in 50 ml toluene, and this mixture is refluxed for 6 hours. The further treatment is the same as described in section A in example 1.
The hydrochloride of the 2-diethylamino-2'-bromo-6'-methyl-acetanilide, mp. 172--1 740, is obtained.
Example 13 The same 2-diethylamino-2'-bromo-6'-methyl-acetanilide can be prepared according to the Sandmeyer reaction from 2-diethylamino-2'-amino-6'-methyl-acetanilide as follows: 11.75 g (0.05 mol) 2-diethylamino-2'-amino-6'-methyl-acetanilide in 30 ml 48% hydrobromic acid are cooled in an ice bath, and at a temperature of --50 this mixture is diazotized with 3.45 g sodium nitrite in 20 ml water during 30 minutes (iodo-starch paper test) and then this mixture is stirred for 40 minutes at a temperature of 5. This suspension is added slowly to a mixture having a temperature of 700 of 4 g CuBr in 20 ml 48% hydrobromic acid, and this mixture is stirred for 2 hours at this temperature. After cooling this mixture is extracted with ether, the acidic solution is rendered alkaline and extracted with ether.After drying and evaporating the ether the residue is dissolved in ethanol and transformed into the hydrochloride with etheric hydrochloric acid, which is identical with the product, mp. 172--1740, described in example 1 2.
C. Reduction of the 2-diethylamino- and 2-piperidino-2'-methyl-6'-nitro-acetanilide.
Example 14 a) To 25 g (0.094 mol) 2-diethylamino-2'-methyl-6'-nitro-acetanilide in 500 ml concentrated hydrochloric acid are added under stirring during one hour 100 g tin (11)-chloride. The mixture is heated for 30 minutes on a boiling water bath, after cooling with ice this mixture is rendered alkaline with 35% sodium hydroxide solution, followed by an extraction with ether. After washing, drying and evaporating the ether the 2-diethylamino-2'-amino-6'-methyl-acetanilide, mp. 1 05--1 06.5 0, is obtained, which is transformed into its dihydrochloride, mp. 1 82-1 84C, with etheric hydrochloric acid.
b) The same 2-diethylamino-2'-amino-61-methyl-acetanilide is also obtained as follows: To a mixture of 300 ml Pd/C in 60 ml water under nitrogen are added 4.8 g sodium borohydride in 90 ml water. Then the solution of 1 5.9 g (0.06 mol) 2-diethylamino-2'-methyl-6'-nitro-acetanilide in 1 50 ml methanol is added drop by drop during 30 minutes, and this mixture is stirred for further 20 minutes. The mixture is filtrated, the filtrate is evaporated in the vacuum of a water jet pump, water is added and the precipitated crystals are filtered with suction. Mp. 105--106.50.
Example 15 As described in example 1 4b), 2-piperidino-2'-amino-6'-methylacetanilide, mp. 169-1 70C, is prepared with the difference, that the mixture is heated before the filtration, because the product is little soluble in cold methanol. The base is dissolved in ethanol and transformed with an etheric hydrochloric acid into the dihydrochloride. Mp. 259--2600.
While there are shown and described present preferred embodiments of the invention, it is to be distinctly understood that the invention is not limited thereto, but may be otherwise variously embodied and practiced within the scope of the following claims.

Claims (29)

Claims
1. A basic acetanilide of the general formula Ill
wherein R, is hydrogen or optionally substituted alkyl, and R4 is halogen, optionally substituted alkoxy, optionally substituted alkylthio, nitro, amino or optionally substituted alkylamino, propionyl or trifl uoromethyl, and Rs is a basic group, or a pharmacologically useful salt thereof.
2. A basic acetanilide as claimed in claim 1 wherein R, is hydrogen or methyl.
3. A basic acetanilide as claimed in claim 1 or claim 2 wherein R4 is chlorine, bromine, trihalogen methyl, preferably trifluoro methyl, ethoxy, nitro, amino or propionyl.
4. A basic acetanilide as claimed in any one of claims 1 to 3 wherein Rs is diethylamino, piperidino, pyrrolidino, cyclopropyiamino or cyclopentylamino.
5. A basic acetanilide as claimed in any one of claims 1 to 4 in the form of its hydrochloride, hydrobromide, fumarate, maleate, hydrogen fu ma rate or hydrogen maleate salt.
6. 2-diethyl-amino-2'-ethoxy-6'-methyl-acetanilide, or a pharmacologically useful salt thereof.
7. 2-piperidino-2'-ethoxy-6'-methyl-acetanilide, or a pharmacologically useful salt thereof.
8. 2-pyrrolidi no-2'-ethoxy-6'-methylacetanilide, or a pharmacologically useful salt thereof.
9. 2-diethylamino-2'-methyl-6'-nitro-acetanilide, or a pharmacologically useful salt thereof.
1 0. 2-piperidino-2'-methyl-6'-nitro-acetanilide, or a pharmacologically useful salt thereof.
11. 2-diethylamino-2'-trifluoromethyl-acetanilide, or a pharmacologically useful salt thereof.
12. 2-pyrrolidino-2'-trifluoromethyl-acetanilide, or a pharmacologically useful salt thereof.
1 3. 2-pyrrolidino-2'-propionyl-acetanilide, or a pharmacologically useful salt thereof.
1 4. 2-pyrrolidino-2'-methyl-6'-propionyl-acetanilide, or a pharmacologically useful salt thereof.
1 5. 2-cyclopentylamino-2'-ch loro-6'-methyl-acetanilide, or a pharmacologically useful salt thereof.
1 6. 2-cyclopropylamino-2'-ch loro-6'-methyl-acetanilide, or a pharmacologically useful salt thereof.
1 7. 2-diethylamino-2'-bromo-6'-methyl-acetanilide, or a pharmacologically useful salt thereof.
1 8. 2-diethylamino-2'-amino-6'-methyl-acetanilide, or a pharmacologically useful salt thereof.
19. A basic acetanilide of formula Ill as defined in claim 1 substantially as hereinbefore described in any one of the foregoing examples.
20. A process for preparing a basic acetanilide of the general formula Ill
wherein R,, R4 and Rs are defined in claim 1, or a pharmacologically useful salt thereof wherein an aniline of the formula I
wherein R1 and R4 are defined in claim 1, is reacted under cooling or at room temperature in a solvent and in the presence of a base with a halogen compound of formula II X-C0CH2-Hal II wherein X is a hydroxyl group, an ester group, a halide, an amide group or an anhydride group or any other suitable leaving group, and Hal is a halogen atom or any other suitable leaving group, to yield a compound of formula IV
wherein R,, R4 and Hal are defined above, and wherein the compound of formula IV is reacted in an inert solvent at elevated temperature with an amine delivering the group R,, and optionally the obtained compound is transformed into a pharmacologically useful salt thereof.
21. A process as claimed in claim 4, wherein the compounds oaf formula II is an acid chloride or an acid bromide.
22. A process for producing a basic acetanilide of formula Ill as defined in claim 1 substantially as hereinbefore described in any one of the foregoing examples.
23. A basic acetanilide of formula Ill as defined in claim 1 produced by a process as claimed in claim 22.
24. (101) A basic acetanilide as claimed in any one of claims 1 to 19 or claim 23 (103) for use in the treatment of the human or animal body by surgery or therapy-( 102).
25. (101)--(102) by use as a local anaesthetic or an antiarrythmic agent.
26. A pharmaceutical or veterinary formulation comprising (1 0 1 )-( 103) formulated for pharmaceutical or veterinary use.
27. A pharmacological composition, characterized in that it contains at least one compound of the formula Ill.
28. A pharmacological composition according to claim 27, characterized in that it is a local anaesthesic.
29. A pharmacological composition according to claim 27, characterized in that it is an antiarrhythmic.
GB08321953A 1982-08-27 1983-08-15 Basic acetanilides Expired GB2129424B (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CH5116/82A CH650768A5 (en) 1982-08-27 1982-08-27 BASIC ACETANILIDES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE ACETANILIDES.

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GB8321953D0 GB8321953D0 (en) 1983-09-14
GB2129424A true GB2129424A (en) 1984-05-16
GB2129424B GB2129424B (en) 1986-07-09

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JP (1) JPS59130250A (en)
CA (1) CA1214776A (en)
CH (1) CH650768A5 (en)
DE (1) DE3328186A1 (en)
FR (1) FR2532306B1 (en)
GB (1) GB2129424B (en)
IT (1) IT1168212B (en)
SE (1) SE8304456L (en)

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Publication number Publication date
FR2532306A1 (en) 1984-03-02
CA1214776A (en) 1986-12-02
GB2129424B (en) 1986-07-09
DE3328186A1 (en) 1984-03-01
JPS59130250A (en) 1984-07-26
SE8304456D0 (en) 1983-08-17
IT8348886A0 (en) 1983-08-26
FR2532306B1 (en) 1989-03-10
CH650768A5 (en) 1985-08-15
GB8321953D0 (en) 1983-09-14
SE8304456L (en) 1984-02-28
IT1168212B (en) 1987-05-20

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