CH620431A5 - Process for the preparation of novel isoindole derivatives - Google Patents

Description

45 The present invention relates to a process for the preparation of new isoindole derivatives of the general formula

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II

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wherein Z, Ri, R2, R3 and R4 have the meaning 60 given above,

with a diamine of the general formula

RB

N-A-N

Rt

H2N-A-N;

Rn wherein A, R5 and R6 have the meaning given above, reductively aminated, and, if desired, a compound obtained

jjj wherein A is alkylene of 2-10 carbon atoms and Z is the 65-group OR or

Rt

-N:

Ra

3rd

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mean R is alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, allyl or aralkyl, Rx, R2, R3 and R4 each independently represent hydrogen, alkyl, alkoxy, halogen or trifluoromethyl and R5 and Re each independently represent hydrogen, alkyl, cycloalkyl, cycloalkylalkyl , Hydroxyalkyl, alkoxyalkyl, aryl, aralkyl or together the group - (CH2) n-, where n is an integer from 2-7, or together with the nitrogen atom connecting them together a 5- or 6-membered heterocyclic ring with an oxygen " or a further nitrogen atom optionally substituted with alkyl or hydroxyalkyl and R7 and R8 each independently represent hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl or aralkyl, at least one of the radicals R7 and R8 being different from hydrogen,

and their pharmaceutically acceptable acid addition salts.

The term "alkyl" used in this description

- alone or in combination as «alkoxy» - refers to straight-chain and branched saturated hydrocarbon residues with up to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl and the like. The term «alkylene» similarly refers to straight-chain and branched alkylene groups, such as Ethylene, methyl ethylene, trimethylene, tetramethylene and the like. The term "cycloalkyl" - alone or in combination - includes C3-C6 cycloalkyl residues, i.e. Cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The 5- or 6-membered heterocyclic ring is derived from a saturated heterocycle containing two nitrogen atoms or one nitrogen atom and one oxygen atom, e.g. Morpholino, N-methylpiperazino, piperazino and the like. The term “halogen” includes the four halogens fluorine, chlorine, bromine and iodine. The term "aryl" refers to mono- or polynuclear aromatic radicals in which one or more hydrogen atoms can be replaced by alkyl, alkoxy or halogen, such as e.g. Phenyl, halophenyl, methoxyphenyl and the like.

In a preferred embodiment, R1 means; R2, R3 and R4 each represent hydrogen, halogen or trifluoromethyl. R4 particularly preferably denotes hydrogen and Rt chlorine,

Fluorine or trifluoromethyl. R2 and R3 are particularly preferably hydrogen, chlorine or fluorine. Furthermore, compounds of the formula I are preferred in which R5 and R0 are alkyl, in particular ethyl or isopropyl. In a further preferred embodiment, A means ethylene or trimethylene. Furthermore, compounds of the formula I are preferred in which Z denotes the group -OR or -NHR7. R and R7 are preferably alkyl, particularly preferably ethyl or isopropyl.

As can be seen from the previous, in compounds of the formula IR4, hydrogen, Rt chlorine, fluorine or trifluoromethyl, R2 and R3 are particularly preferably hydrogen, chlorine or fluorine, R6 and R6 ethyl or isopropyl, A ethylene or trimethylene, Z the group -OR or -NHR7 and R and R7 ethyl or isopropyl.

Very particularly preferred compounds of the formula I are:

5-chloro-2- [2- (diethylamino) ethyl] -3-phenylisoindol-1-carboxylic acid ethyl ester,

5-chloro-2- [3- (diethylamino) propyl] -3-phenylisoindole-l - ethyl carboxylate,

5-chloro-3- (p-chlorophenyl) -2- [2- (diethylamino) ethyl] iso-indole-1-carboxylic acid ethyl ester,

5,7-dichloro-2- [2- (diethylamino) ethyl] -3-phenylisoindole-

- 1-carboxylic acid ethyl ester and

5-chloro-2- [2- (diethylamino) ethyl] -3-phenylisoindole-1-carboxylic acid ethyl amide.

Further preferred compounds of the formula I are: 5-chloro-2- [2- (dibutylamino) ethyl] -3-phenylisoindole-1-car-bonic acid ethyl ester

5-Chloro-2- [2- (diethylamino) ethyl] -3-phenylisoindole-1-carbenic acid benzyl ester

5-Chloro-2- [2- (diethylamino) ethyl] -3-phenylisoindoI-1-car-bonic acid isobutyl ester

5-Chloro-2- [2- (diethylamino) ethyl] -3-phenylisoindole-1-car-boxylic acid allyl ester

5-Chloro-2- [2- (diisopropylamino) ethyl] -3-phenylisoindole-1 - carboxylic acid ethyl ester

5-Chloro-2- [2- (diethylamino) ethyl] -3-phenylisoindole-1-car-bonic acid isopropyl ester

6-Chloro-2- [2- (diethylamino) ethyl] -3-phenylisoindole-1-carbonic acid ethyl ester

5-Chloro-2- [2- (diethylamino) ethyl] -3- (o-fluorophenyl) iso-indole-1-carboxylic acid ethyl ester

3- (p-Chlorophenyl) -2- [2- (diethylamino) ethyl] isoindole-1-carboxylic acid ethyl ester

5-chloro-2- [2- (diethylamino) ethyl] -3-phenylisoindole-1-car-bonic acid methylamide

2- [3- (Butylmethylamino) propyl] -5-chloro-3-phenylisoindole-- 1-carboxylic acid ethyl ester

2- {3- [bis (2-hydroxyethyl) amino] propyl} -5-chloro-3-pheny-lisoindole-1-carboxylic acid ethyl ester

5-chloro-2- [2- (diethylamino) ethyl] -3-phenylisoindole-1-carboxylic acid dimethylamide

5-chloro-3- (3,4-dichlorophenyl) -2- [2- (diethylamino) ethyl] - isoindole-1-carboxylic acid ethyl ester

2- [2- (diethylamino) ethyl] -3-phenyl-5- (trifluoromethyl) isoindole-1-carboxylic acid ethyl ester

Ethyl 2- [5- (butylmethylamino) -3,3-dimethylpentyl] -5-chloro-3-phenylisoindole-1-carboxylate

5-Chloro-2- [4- (isopropylamino) pentyl] -3-phenylisoindole-1-carboxylic acid ethyl ester

5-Chloro-2- {3- [bis (methoxyethyl) amino] propyl} -3-phenyl-isoindole-1-carboxylic acid ethyl ester

2- [3- (Cyclohexylamino) propyl] -5-chloro-3-phenylIisoindoI - 1-carboxylic acid ethyl ester

5-Chloro-2- [3- (N-methylanilino) propyl] -3-phenylisoindole-1-carboxylic acid ethyl ester.

The compounds of formula I and their pharmaceutically acceptable acid addition salts can be prepared according to the invention in such a way that a compound of the general formula coz

I.

wherein Z, Rl9 R2, Rs and R4 have the meaning given above,

with a diamine of the general formula Rs

H2N-A-Nd III

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wherein A, RB and Rß are as defined above, reductively aminated, and if desired, a compound obtained is converted into a pharmaceutically acceptable acid addition salt.

The reductive amination of a compound of the formula II with a diamine of the formula III is carried out by various methods known per se by reacting a dicarbonyl compound of the formula II with a diamine of the formula III in the presence of a suitable reducing agent. For example, the reaction can be carried out in the presence of catalytically excited hydrogen, preferably in the presence of Raney nickel, in an organic solvent such as an alcohol, preferably in ethanol, at temperatures between room temperature and about 100 ° C. and at a pressure of 1-100 Atm. be performed. Formic acid, sodium cyanoborohydride, sodium borohydride and the borane-dimethylamine complex can also be mentioned as reducing agents. The choice of solvent as well as the other reaction conditions, e.g. the reaction temperature depends primarily on the reducing agent used. Thus, the reaction in the presence of sodium cyanoborohydride is preferably carried out in methanol at room temperature at a pH between 6 and 8 and the reaction in the presence of the borane-dimethylamine complex in glacial acetic acid at a temperature between room temperature and the reflux temperature of the reaction mixture . If formic acid is used as the reducing agent, it is preferably used as a solvent at the same time. Formic acid is preferably used at a temperature between about 100 ° and 150 ° C. The reductive amination using sodium borohydride is carried out in a suitable organic solvent such as an alcohol, preferably at room temperature. Since transesterification can occur in the case of compounds of the formula II in which the group -COZ represents an ester group when sodium borohydride is used, the choice of solvent in this case depends largely on the starting material of the formula II used.

The compounds of formula I are basic in nature and can be converted into pharmaceutically acceptable acid addition salts. Such salts are, for example, those with organic acids such as oxalic acid, citric acid, acetic acid, lactic acid, maleic acid, fumaric acid, ascorbic acid, salicylic acid and tartaric acid, or with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid.

Processes for the preparation of compounds of the formula II are described in German Offenlegungsschrift 2,553,595.

The isoindole derivatives of the general formula I and their pharmaceutically usable acid addition salts can be used as medicaments. For example, they have a pronounced anorectic effect, which suggests that they can be used as appetite suppressants, especially since, in contrast to other appetite suppressants, they have practically no central stimulating effect. The anorectic effectiveness is demonstrated when groups of 6 male rats each, which receive ad libitum in the experiment for 48 hours, are administered the preparation to be tested in four doses of 300 (xMol / kg or less in 5% gum arabic po). 24 and 48 hours after the first application, feed consumption is determined by weighing the feed vessels and compared with the feed consumption of untreated control animals (100%) EDC5 is the dose in mg / kg at which the preparation reduces the feed consumption to 65% of the Controls reduced, for example, the compound 5-chloro-2- [2- (diethylamino) ethyl] -3-phenylisoindole-1-carboxylic acid

ethyl ester (compound A) an EDe5 of 42 mg / kg, the compound 5-chloro-2- [3- (diethylamino) propyl] -3-phenylisoindole-1-carboxylic acid ethyl ester (compound B) one of 35 mg / kg and the Compound 5-chloro-3- (p-chlorophenyl) -2 - [2- (diethylamino) ethyl] -isoindole-1-carboxylic acid ethyl ester (compound C) was 27 mg / kg. The toxicity values (LD50) were determined using standard mouse methods and are 1250 mg / kg for compounds A and B and 2500 mg / kg for compound C.

The process products can be used as healing agents e.g. in the form of pharmaceutical preparations which they or their pharmaceutically applicable acid addition salts are used in admixture with a pharmaceutical, organic or inorganic inert carrier material suitable for enteral or parenteral administration, such as e.g. Contain water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly, etc. The pharmaceutical preparations can be in solid form, e.g. as tablets, dragées, suppositories, capsules or in liquid form, e.g. as solutions, suspensions or emulsions. If necessary, they are sterilized and / or contain auxiliaries such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffers. They can also contain other therapeutically valuable substances.

Appropriate pharmaceutical dosage forms contain about 1 to 30 mg of a compound of formula I. Appropriate oral dosage ranges are from about 0.1 mg / kg per day to about 0.5 mg / kg per day. The range mentioned can, however, be extended upwards or downwards, depending on the individual requirements and instructions of the person skilled in the art.

The following examples illustrate the invention. All temperatures are given in ° C.

example 1

A mixture of 0.83 g (18 mmol) of formic acid and 1.05 g (9 mmol) of 2-diethylaminoethylamine is mixed with 0.95 g (3 mmol) of [o- (p-chlorobenzoyl) phenyl] -glyoxylic acid ethyl ester at room temperature added and then stirred at 140 ° for 2 hours. After cooling, the solution obtained is made alkaline with the addition of ice with 2N ammonium hydroxide and extracted with ether. The extract, which is protected from daylight, is washed with water, dried over sodium sulfate, concentrated and chromatographed on 70 g of silica gel with ether as the eluent. The homogeneous fractions are combined, concentrated to a volume of 15-20 ml and mixed with ethereal hydrochloric acid. The crystallized hydrochloride is filtered off and washed with ether. This gives 3- (p-chlorophenyl) -2- [2- (diethyIamino) ethyI] iso-indole-1-carboxylic acid ethyl ester hydrochloride, melting point 202-204 ° (dec.). Recrystallization from methylene chloride / ether does not raise the melting point.

The starting material can be produced as follows:

A suspension of 4.9 g (0.02 mol) of o- (p-chlorobenzoyl) benzaldehyde in 28 ml of water is mixed with 7.6 g (0.04 mol) of sodium pyrosulfite and heated to 80 ° until a clear solution is obtained (2-4 minutes). It is immediately cooled in an ice bath and a solution of 5.2 g (0.08 mol) of potassium cyanide in 8 ml of water is added dropwise at 10-15 °, a thick oil separating out. After stirring at 0-5 ° for 15 minutes, the aqueous phase is separated off by decanting and the honey-like residue is digested twice with ice water. The crude cyanohydrin of o- (p-chlorobenzoyl) benzaldehyde thus obtained is immediately mixed with 15 ml of concentrated hydrochloric acid in an ice bath and well rubbed with a glass rod. The mass turns orange and solidifies

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short time. The mixture is then stirred for 3 hours at room temperature, water is added to twice the volume, the mixture is stirred for a further half hour at room temperature and then extracted with methylene chloride. The organic phase is washed successively with water, a sodium bicarbonate solution and a saturated solution of sodium chloride in water. After drying over sodium sulfate and concentration under reduced pressure, a yellow residue is obtained which is chromatographed on 150 g of silica gel with methylene chloride as the eluent. The homogeneous fractions are combined and triturated with a little hexane. 3- (p-Chlorophenyl) -l-cyan-iso-benzofuran is obtained in the form of yellow crystals, melting point 128-130 °. Crystallization from ethanol does not raise the melting point.

A suspension of 5 g (0.02 mol) of 3- (p-chlorophenyl) -1-cyanoisobenzofuran in 135 ml of ether is treated with 50 ml of a 20% solution of hydrochloric acid in ethanol and stirred for 48 hours at room temperature. The crystallized orange imino ether hydrochloride is filtered off, washed with ether and hydrolyzed by boiling for 90 minutes with 300 ml of water. After cooling, the oil which has separated out is extracted with methylene chloride, the extract is washed with a sodium bicarbonate solution and dried over sodium sulfate. Concentration in vacuo gives a yellow oil which is chromatographed on 150 g of silica gel with methylene chloride as the eluent. The homogeneous fractions are combined, concentrated and the solid residue is recrystallized from ether / hexane, giving ethyl 3- (p-chlorophenyl) isobenzofuran-1-carboxylate in the form of felt-like crystals of melting point 99-101 °.

11.5 g (0.02 mol) of cerium (IV) ammonium nitrate are dissolved in 20 ml of water and 20 ml of glacial acetic acid. 3.0 g (0.01 mol) of 3- (p-chlorophenyl) isobenzofuran-1-carboxylic acid - ethyl ester are added and the mixture is boiled for 2-3 minutes until the color of the solution obtained changes from orange to light yellow. After cooling, 150 ml of ice water are added and the mixture is stirred for 1 hour in an ice bath, during which the product, which is oily first, solidifies. This is separated off by decanting the aqueous solution and dissolved in ether. The ethereal solution is washed with 2N sodium carbonate and water, dried over sodium sulfate and evaporated. After the residue has been crystallized from ethanol, ethyl [o- (p-chlorobenzoyl) phenyl] glyoxylate is obtained in the form of colorless crystals, melting point 79 ° to 81 °.

Example 2

In a manner analogous to that described in Example 1, 0.95 g (3 mmol) of ethyl o-benzoyl-p-chlorophenylglyoxylate, 1.05 g (9 mmol) of 2-diethylaminoethylamine and 0.83 g are obtained (18 mmol) formic acid 5-chloro-2- [2- (diethylamino) ethyl] -3-phenylisoindole-1-carboxylic acid ethyl ester hydrochloride, melting point 248-250 ° (dec.).

The starting material can be prepared from o-benzoyl-p-chloro-benzaldehyde in a manner analogous to that given in Example 1. The following connections are obtained in succession:

5-chloro-l-cyan-3-phenyl-isobenzofuran, yellow crystals from ethanol, melting point 128-130 °.

5-Chloro-3-phenyl-isobenzofuran-1-carboxylic acid, ethyl ester, yellow crystals of ethanol, melting point 78-80 °.

Ethyl o-benzoyl-p-chlorophenylglyoxylate as a light yellow, thick oil after chromatography on silica gel with methylene chloride as the eluent.

Example 3

A solution of 3.5 g (30 mmol) of 2-diethylamino-ethyl amine in 10 ml of methanol is mixed with 2 ml (10 mmol) of 5N methanolic hydrochloric acid. A solution of 1.6 g (5 mmol) of ethyl o-benzoyl-p-chlorophenylglyoxylate in 5 ml of methanol and 0.2 g (3 mmol) of sodium cyanoborohydride is then added in succession under argon at 20-25 ° and the mixture is stirred at room temperature 7 hours further. While cooling with ice, the reaction mixture is acidified with concentrated hydrochloric acid, stirred for a further half hour at room temperature and evaporated to dryness under reduced pressure. The residue is made alkaline with the addition of ice with 1N sodium hydroxide solution and extracted with 50 ml of ether. The ethereal extract is mixed with 20 ml of 0.5N hydrochloric acid and the mixture is shaken well. After cooling in an ice bath, the crystallized hydrochloride is isolated and purified as in Example 1. This gives 5-chloro-2- [2- (diethylamino) ethyl] -3-phenylisoindole-1-carbonate, ethyl ester hydrochloride, melting point 248-250 ° (dec.).

Example 4

According to the procedure described in Example 3, 1.6 g (5 mmol) of o-benzoyl-p-chlorophenylglyoxylic acid - dimethylamide with 3.5 g (30 mmol) of 2-diethylaminoethylamine and 0.2 g ( 3 mmol) sodium cyanoborohydride reacted. The ether extract from the free base is evaporated to dryness and the oily residue is chromatographed on 80 g of aluminum oxide (neutral, Brockmann activity I) using methylene chloride / ethyl acetate (4: 1) as the eluent. The homogeneous fractions are combined and evaporated. The remaining oil is dissolved in 10 ml of acetone and mixed with 0.9 g (5 mmol) of N-cyclohexylsulfamic acid. After standing overnight in the refrigerator, the crystallized, almost colorless salt is filtered off, washed with a little ether and dried in a desiccator. 5-Chloro-2- [2- (diethylamino) ethyl] -3-phenylisoindole-1-carboxylic acid - dimethylamide cyclohexanesulfamate, melting point 107-109 ° is obtained.

The starting material can be produced as follows:

A suspension of 9.0 g (0.03 mol) of 5-chloro-2-methyl-3-phenylisoindole-1-carboxylic acid methylamide in 120 ml of dimethylformamide is treated under argon at 0 ° with 5.0 g (0.045 Mol) added potassium tert-butoxide and then stirred in an ice bath for 30 minutes. 8 ml (0.12 mol) of methyl iodide are added in one portion at 0-5 °, the mixture is then stirred for 2 hours at room temperature and poured onto 2 l of ice water. After adding 100 g of sodium chloride, the oil which has separated out is extracted with methylene chloride. The organic phase is washed with a solution of sodium chloride, dried over sodium sulfate and evaporated to dryness under reduced pressure. The oily residue is dissolved in 200 ml of hot hexane and the solution obtained is cooled in an ice bath, whereupon colorless crystals separate out. 5-Chloro-2-methyl-3-phenyIisoindol-1-carboxylic acid dimethylamide is obtained, melting point 86-88 °.

23 g (0.04 mol) of cerium (IV) ammonium nitrate are dissolved in 80 ml of glacial acetic acid / water (1: 1), 6.25 g (0.02 mol) of 5-chloro-2-methyl-3- phenylisoindole-l-carboxylic acid dimethylamide and heated under reflux for 2 minutes. After cooling in an ice bath, 200 ml of ice water are added and the mixture is stirred at 0-5 ° for 1 hour. The greasy precipitate is separated off by decanting the aqueous solution and taken up in methylene chloride. The organic solution is washed with 2N sodium carbonate solution and with water, dried over sodium sulfate and evaporated. The residue is purified by chromatography on 300 g of silica gel with methylene chloride / ethyl acetate (4: 1) as the eluent. After crystallization from hexane, the homogeneous fractions provide o-benzoyl-p-chlorophenylglyoxylic acid dimethylamide, melting point 88-90 °.

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Claims (10)

620431 2. The method according to claim 1, characterized in that a compound of formula II, wherein Z is the group -OR or R7 -NC Rs means R has the meaning given in claim 1 with the exception of allyl and R, and Rs have the meanings given in claim 1, but one of the substituents R7 and Rs being hydrogen. 2nd PATENT CLAIMS 1. Process for the preparation of new isoindole derivatives of the general formula coz wherein A is alkylene with 2-10 carbon atoms and Z is the group -OR or R7 -NC Rs are R, alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, allyl or aralkyl, Rl5 R2, Rs and R4 independently of one another are each hydrogen, alkyl, alkoxy, halogen or trifluoromethyl and R5 and R0 are each independently of one another hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, Hydroxyalkyl, alkoxyalkyl, aryl, aralkyl or together the group - (CH2) n-, where n is an integer from 2-7, or together with the nitrogen atom connecting them together a 5- or 6-membered heterocyclic ring with an oxygen - Or mean a nitrogen atom optionally substituted with alkyl or hydroxyalkyl and R7 and Rg independently of one another each represent hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl or aralkyl, at least one of the radicals R7 and Rs being different from hydrogen, and of their pharmaceutically acceptable acid addition salts , characterized in that a compound of the general formula 10th 15 20th 25th 30th 35 40 binding converted into a pharmaceutically acceptable acid addition salt. 3. The method according to claim 1 or 2, characterized in that R1} R2, R3 and R4 each hydrogen, halogen or trifluoromethyl, Z the group -OR or -NHR7, A ethylene or trimethylene and R, R5, Re and R7 each alkyl mean. 4. The method according to any one of claims 1-3, characterized in that R4 is hydrogen, Rx chlorine, fluorine or trifluoromethyl, R2 and R3 each hydrogen, chlorine or fluorine, R5 and Re each ethyl or isopropyl, A ethylene or trimethylene, Z the Grappe -OR or -NHRT and R and R7 each represent ethyl or isopropyl. 5. The method according to claim 1 or 2, characterized in that 5-chloro-2- [2- (diethylamino) ethyl] -3-phenyl-isoindole-1-carboxylic acid ethyl ester is prepared. 6. The method according to claim 1 or 2, characterized in that 5-chloro-2- [2- (dibutylamino) ethyl] -3-phenyl-isoindole-1-carboxylic acid ethyl ester is prepared. 7. The method according to claim 1 or 2, characterized in that 5-chloro-2- [3- (diethylamino) propyl] -3-phe-nylisoindole-1-carboxylic acid ethyl ester is prepared. 8. The method according to claim 1 or 2, characterized in that 5-chloro-2- | 2- (diisopropylamino) ethyl] -3 - phenylisoindole-1-carboxylic acid ethyl ester is produced. 9. The method according to claim 1 or 2, characterized in that 5-chloro-2- [3- (diethylamino) ethyl] -3-phe-nylisoindole-1-carboxylic acid isopropyl ester is prepared. 10. The method according to claim 1 or 2, characterized in that 5-chloro-3- (p-chlorophenyl) -2- [2- (diethylamino) ethyl] -isoindole-l-carboxylic acid ethyl ester is produced.