CH636341A5 - Process for preparing novel N-(2-aminocycloheptyl)-N-alkanoyl anilides or their 2-N-oxides - Google Patents

Description

The invention relates to a process for the preparation of new amino-cycloaliphatic amides with pharmaceutical activity on the central nervous system. These compounds can be used as such or in the form of pharmacologically acceptable salts as drugs. It has been shown that the connections mentioned are strong,

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have antidepressant properties which act on the central nervous system and which, after conversion into suitable pharmaceutically consumable forms of preparation and administration in suitable doses, enable them to be used as antidepressants.

By W.G. Stoll and co-workers are reported in “Helvetica Chemica Acta”, volume 34, pages 1937 to 1043 (1951) about N- [2- (dimethylamino) cyclohexyl] aniline and processes for its preparation from N- (2-hydroxycyclohexyl) aniline. The authors also report that such compounds are pharmacologically active as antihistamines. However, there is no reference in the cited literature reference to the compounds according to the invention or their use as antidepressants.

J.W. Lewis and co-workers report in “The Reactions of Aromatic Nitroso-compounds with Enamines. Part I. The Reaction of Nitrosobenzene with 1-morpholine-1-cyclohexene »titled article in« J. Chem. Soc. (London) (1972) », Perkins Transactions I, Part III, pages 2521 to 2524, inter alia on N- (2-morpholin-1-ylcylo-hexyl) phenylhydroxylamine and its hydrochloride. However, there is no reference in the cited reference to the alkanoylanilides according to the invention or their antidepressant properties.

Furthermore, J.W. Lewis and co-workers in an article entitled “Chemistry and Biological Activity of N-Substituted Hydroxylamines” in “J. Pharmaceutical Sciences », December 1974, Volume 63, No. 12, pages 1951 to 1953 about some N-arylhydroxylamines, such as N- [2- (N-pyrrolidinyl) cyclohexyl] -N-phenylhydroxylamine; however, these compounds have no central nervous system properties. For example, for the alcohols, e.g. [2- (N-Piperidinyl) cyclohexyl] - (4-methoxy-phenyl) methanol, a diuretic activity reported. It is also said that when the alcohol is acetylated, depressive activity occurs on the central nervous system. Furthermore, the reaction of propionyl chloride with N- [2- (N-piperidinyl) -1,1-dimethylethyl] -N-phenyl-hydroxylamine to form the N-chloro compound and subsequent conversion thereof into a mixture of chlorinated aniline derivatives is reported. However, the cited literature reference lacks any reference to the compounds according to the invention, to their preparation or to their antidepressant properties.

US Pat. No. 3,510,492 discloses some 2-anilino- and 2-anilinomethyl-cycloalkylamines which are suitable as antidiabetics (when administered in low doses to lower the blood sugar). The structural formula IV given in column 2 of US Pat. No. 3,510,492 generally includes some of the compounds of the formula I according to the invention, but the compounds in question represent chemical intermediates on the way to their 2-anilino-cycloalkylamines. In the US patent mentioned there is no indication of the practical utility of compounds of structural formula IV as end products.

The invention had for its object to provide new and promising antidepressants, namely N- (2-aminocyclo-heptyl) alkanoylanilides, in particular the preferred types of which should have a better therapeutic ratio or a better therapeutic index than imipramines and further should have a longer duration of effectiveness with regard to longer periods between the individual administrations.

The new eis and trans-N- (2-aminocycloheptyl) -N-al-kanoylanilides have the following formula

R

in which the wavy line (~) in the 1-position of the cycloheptyl ring indicates an ic or trans configuration of the substituents in the I and 2 positions of the cycloheptyl ring and in which:

R is a Cj-Ca-alkyl, a C3 to C6-cycloalkyl, vinyl, ethoxy or methoxymethyl radical;

Rj alone is a Q to C3 alkyl group;

R2 alone is a Cj to C3 alkyl radical or in the event that R! represents a Q to C3 alkyl radical, a radical of the formulas:

-CH2CH2N (CH3) 2,

-CH2CH2CH2N (CH3) 2,

-CH2C6Hs,

-CH2CH2C6H5 or

C3 to C6 alkenyl or

R! and R2, together with the nitrogen atom to which they are attached, an N-pyrrolidinyl or N-piperidinyl ring;

Y and Z, which may be the same or different, are a hydrogen atom, a halogen atom with an atomic number from 9 to 35, a trifluoromethyl radical, a Cj to C2 alkyl radical, an azido radical or a Q to C2 alkyloxy radical, or Z in the case, that Y represents a trifluoromethyl radical or azidorest, a hydrogen atom, and it is true that in the event that Y represents a Q to C2 alkyloxy radical and Z represents a hydrogen atom, the Q to C2 alkyloxy radical is in the 3-position , and in the event that Y and Z both represent halogen atoms or Q- to C2-alkyloxy radicals, these radicals are in 3- and 4- or 3- and 5-positions.

The compounds mentioned have antidepressant properties directed at the central nervous system. They can be used, optionally together with a pharmaceutical carrier, in the treatment or control of depressive conditions in mammals or humans. A preferred example of an antidepressant is trans-3,4-dichloro-N- [2- (dimethylamino) cyclo-heptylj-propionanilide. The compounds in question are suitable in the form of suitable pharmaceutical dosage units or unit doses for administration to humans in doses of 4 up to 400 mg per day as part of therapy for the treatment of depressive conditions. In the case of conventional laboratory test animals which were used to determine these properties, the compounds mentioned suggest that the antidepressant properties (of the respective medicament) respond quickly or come to bear quickly. The preferred compounds also have a lower toxicity in standard laboratory tests than the usual standard antidepressant imipramine, and a longer duration of activity of the test compound in the test animal. These properties enable the new compounds to be administered as antidepressants in a smaller amount and / or after a longer period between the individual administrations, for example once a day, by one

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to achieve the desired antidepressant effect.

If the compounds which can be prepared according to the invention or their acid addition salts are e.g. in crystalline form as solvates, i.e. can be isolated with a very specific amount of solvent, for example water, ethanol and the like, in physical combination, the solvent can be removed per se without effective change in the chemical unit, so that solvates of this type are also intended to fall under the invention.

In formula I, the expression “Cr to C3-alkyl radical” stands for a methyl, ethyl, n-propyl or isopropyl radical.

The expression “C3 to C6 cycloalkyl radical” stands for a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radical. The expression “C3 to C6 alkenyl radical” encompasses radicals which have non-adjacent double bonds, for example allyl, 2-butenyl and 2-methyl-2-butenyl, 2-pentenyl and 3-methyl-2-pentenyl and the various

2-hexenyl residues. “Halogen atoms with atomic numbers from 9 to 35” are fluorine, chlorine and bromine atoms.

The preferred compounds obtainable according to the invention are in trans configuration.

Preferred new compounds are those of the formula given, in which:

R is a Ct to C3 alkyl radical, preferably an ethyl radical;

Ri and R2 each have a Ct to C3 alkyl radical and at least one of the radicals Y and Z has a halogen atom with an atomic number of 9 to 35, preferably in the 3- or 4-position, a Cj - to C2-alkyloxy or trifluoromethyl radical in 3- Position or a methyl radical in the 3- or 4-position in combination with one of the halogen atoms mentioned in the neighboring

3- or 4-position.

In the same way, their pharmacologically acceptable salts are preferred.

Examples of such compounds are: 3,4-dichloro-N- [2- (dimethylamino) cycloheptyl] propionanilide,

3-trifluoromethyl-N- [2- (dimethylamino) cycloheptyl] propionanilide,

3,4-dichloro-N- [2- (diethylamino) cycloheptyl] propionanilide,

3-chloro-4-methyl-N- [2- (dimethylamino) cycloheptyl] propionanilide,

4-chloro-3-methyl-N- [2- (diethylamino) cycloheptyl] propionanilide,

3-chloro-N- [2- (dimethylamino) cycloheptyl] propionanilide,

4-chloro-N- [2- (dimethylamino) cycloheptyl] propionanilide, 3-methoxy-4-chloro-N- [2- (dimethylamino) cycloheptyl] -

propionanilide,

3-methoxy-N- [2- (dimethylamino) cycloheptyl] propionanilide, 3-bromo-N- [2- (dimethylamino) cycloheptyl] propionanilide, 3-fluoro-N- [2- (dimethylamino) cycloheptyl] propionanilide, especially in trans configuration, as well as their pharmacologically acceptable salts.

Another preferred subgroup of the compounds which can be prepared according to the invention comprises those of the formula given, in which:

R is a Q to C3 alkyl radical, preferably an ethyl radical;

R! and R2 together with the nitrogen atom to which they are attached, an N-pyrrolidinyl or N-piperidinyl ring and at least one of the radicals Y and Z is a halogen atom with an atomic number from 9 to 35 in the 3- or 4-position.

Examples of such compounds are: 3-fluoro-N- [2- (N-pyrrolidinyl) cycloheptyl] propionanilide, 3,4-dichloro-N- [2- (N-piperidinyl) cycloheptyl] propionanilide,

3-bromo-N- [2- (N-pyrrolidinyl) cycloheptyl] propionanilide,

4-chloro-N- [2- (N-pyrrolidinyl) cycloheptyl] propionanilide,

3,4-dichloro-N- [2- (N-pyrrolidinyl) cycloheptyl] propionanilide, 3,4-difluoro-N- [2- (N-pyrrolidinyl) cycloheptyl] propionanilide and

3,4-dibromo-N- [2- (N-pyrrolidinyl) cycloheptyl] propionanilide, especially in the trans configuration, and their pharmacologically acceptable salts.

A further preferred subgroup of the new compounds mentioned comprises those of the formula given, in which:

R is a C3 to C6 cycloalkyl radical;

Rx and R2 are a Ct to C3 alkyl radical and at least one of the radicals Y and Z is a halogen atom with an atomic number from 9 to 35 in the 3 or 4 position, a trifluoromethyl radical in the 3 position or a methyl radical in the 3 or 4 position in combination with one of the halogen atoms mentioned in the adjacent 3- or 4-position, and their pharmacologically acceptable salts.

Examples of such compounds are: 3,4-dichloro-N- [2-dimethylaminocycloheptyl] cyclobutane carboxanilide,

3,4-dichloro-N- [2-dimethylaminocycloheptyl] cyclohexane carboxanilide,

3-bromo-4-methyl-N- [2-dimethylaminocycloheptyl] cyclo-

butane carboxanilide, 3,4-dichloro-N- [2-dimethylaminocycloheptyl] cyclopropane carboxanilide,

3-trifluoromethyl-N- [2-diethylaminocycloheptyl] cyclo-

propane carboxanilide, 3,4-dibromo-N- [2-diethylaminocycloheptyl] cyclopropane carboxanilide,

3-chloro-4-methyl-N- [2-dimethylaminocycloheptyl] cyclo-

propanecarboxanilide, 3-bromo-4-methyl-N- [2-dimethylaminocycloheptyl] cyclo-

hexane carboxanilide and 3-trifluoromethyl-N- [2-dimethylaminocycloheptyl] cyclo-

hexane carboxanilide,

and their pharmacologically acceptable salts.

Examples of acid addition salts, including pharmacologically acceptable salts, of compounds of the formulas I and IA, are the salts of hydrogen chloride, methanesulfone, pamoe, hydrogen bromide, sulfur, vinegar, cyclohexanesulfame, p-toluenesulfone and amber. , ß-naphthalenesulfonic, maleic, fumaric, citric, lactic and oxalic acid.

Further compounds which can be prepared according to the invention have the following formula

R

: = o where the substituents are defined above. These compounds do not contain any reactive aliphatic C-C double bonds.

To use the new compounds in antidepressant drugs, the compounds in question can be in suitable pharmaceutical preparation forms, for example

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wise oral forms of administration, such as tablets, powders, capsules and solutions or suspensions, in suitable solvents or suspending agents, or parenteral forms of administration, e.g. dry powders in sterile, tightly closed containers, which are mixed with a sterile solvent immediately prior to administration, sterile solutions or suspensions in water or other suitable solvents or suspending agents, optionally together with a pharmaceutical carrier, excipient or diluent, for convenient administration to patients be transferred or packaged in an amount effective to relieve depressive conditions. As a rule, the dose of compounds of the formulas I or IA or their pharmacologically acceptable salt is about 4 to about 400, preferably 50 to 200 mg. The dose depends on the strength of the new compound, the condition to be treated, the weight of the patient and other factors relevant to the decision.

The process according to the invention for the preparation of the new compounds of the formula I is characterized in that a compound of the formula

Y

wherein R 1, R 2, Y and Z are as defined above, either heated with the anhydride of an organic carboxylic acid of the formula R-COOH, or with a carboxylic acid halide of the formula R-C (0) -X, wherein

X represents chlorine or bromine, at -5 ° to +10 ° C in the presence of a tertiary amine in an organic liquid solvent to react and optionally convert the compounds obtained into the corresponding salts.

The preferred procedure is as follows:

a) heating a mixture of a compound of the formula II with an anhydride of a corresponding organic carboxylic acid of the formula R-COOH, in which R has the meaning given, on a steam bath or to an equivalent temperature to form the N-acylated product of the formula I, in which R, Rls R2, Y and Z have the meaning given, for a sufficient time,

b) adding an amount of an aqueous medium sufficient to decompose the excess anhydride to the reaction mixture of step a),

c) adding a sufficient amount of alkali metal hydroxide or an equivalent to neutralize the excess acid and adjust the pH to a value in the basic range to the reaction mixture of step b),

d) extracting the N-acylated product of formula I into a water-immiscible organic liquid solvent, e.g. an ether such as diethyl ether, tetrahydrofuran or dioxane or chloroform, carbon tetrachloride, methylene chloride, ethylene dichloride and the like,

e) separating the organic liquid phase containing the N-acylated product of the formula I from the aqueous phase and f) recovering the respective N-acylated compound s of the formula I from the organic liquid phase, as a rule after washing them one or more times with an aqueous medium, e.g. a sodium chloride or sodium bicarbonate solution or water, for extracting the components soluble in the aqueous medium, separating io the aqueous phase, drying the washed organic phase with drying agents such as magnesium sulfate or sodium or calcium sulfate, and finally evaporating the organic solvent.

Further purification can be carried out by forming an acid addition salt of the N-acylated amide product of the formula I and then recrystallizing the amide salt from a suitable solvent or solvent mixture.

The compounds of For-2o mei I mentioned immediately above are preferably obtained by a) adding a solution of a suitable carboxylic acid halide RC (0) -X, in which R has the meaning given and X represents a chlorine or bromine atom, to one cooled to a temperature of -5 ° to +10 ° C mixture 25 of a diamine of formula II and a tertiary amine, which forms a tertiary amine chloride or bromide salt in the mixture, for example a Ct to C4 trialkylamine such as tri-methylamine , Triethylamine, tributylamine or pyridine, lutidine, N, N-dimethylaniline and the like, see in an organic liquid solvent for the mixture, for example an ether solvent, such as diethyl ether, tetrahydrofuran, dioxane and the like, while stirring the mixture until the corresponding N-acylated compound of the formula I is formed,

35 b) adding an aqueous alkali metal bicarbonate solution to the reaction mixture of step a),

c) separating the aqueous phase from the organic liquid phase,

d) washing the organic liquid phase with an aqueous washing liquid of the type described,

e) drying the organic phase and f) recovering the N-acylated compound of formula I from the organic liquid mixture obtained.

The N-acylated amide compound of the formula I can be further purified by forming an acid addition salt thereof, for example the hydrochloric acid or maleic acid addition salt, and recrystallizing the amide salt from a suitable solvent or solvent mixture.

Those compounds of the formula I which do not contain a reactive aliphatic carbon-carbon double bond in their molecule are converted according to the invention into their N-55 oxides by reacting corresponding aminoamides of the formula I or their salts with a percarboxylic acid.

The trans-diamine starting materials of the formula used in the process according to the invention:

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where R], R2, Y and Z have the meaning given, is preferably obtained by reacting 1,2-cyclo-heptenoxide of the formula:

(M la)

with a suitable amine HNRXR2 in water to form the trans-2-aminocycloheptanol of the formula:

OH

(Mlb)

^ Ra

The amino alcohol of the formula Illb can then with sodium hydride and finally with methanesulfonyl chloride to form the non-isolated mesylate of the formula:

OC

OMs \.

(IV)

be implemented, in which Ms represents the remainder CH3S02-. The reaction mixture obtained in this way is usually treated with a suitably substituted aniline of the formula:

h2n

(V)

converted to the diamine of formula II. Examples of this procedure can be found later.

Examples of carboxylic acid anhydrides which can be used to prepare the new compounds are acetic acid, propionic acid, isobutyric acid, n-butyric acid, cyclopropanecarboxylic acid and acrylic acid anhydride, preferably propionic acid anhydride. Usable carboxylic acid halides are, for example, acetyl chloride or bromide, propionyl chloride or bromide, acryloyl chloride or bromide, cyclohexane carbonyl chloride or bromide, n-butter acid and isobutyric acid chloride or bromide, cyclo-propane carbonyl chloride or bromide, ethyl formate or methoxyacetate bromide and the like. It has generally been shown that the strongest antidepressants can be prepared from compounds with the N-propionyl unit, the radical R in the compounds of the formula I preferably being an ethyl radical.

If you want to prepare compounds of formula II with a C3-C6 alkenyl radical in the R2 position as starting compounds, an alternative process can be used. The aminoamide is obtained e.g. in the manner described using an alkylbenzylamine to form the amino alcohol of the formula Illb. This amino alcohol can be converted into the diamine via intermediates IV and V. The diamine obtained is then preferably catalytically hydrogenated in the presence of a palladium-on-carbon catalyst, the benzyl radical being removed in the R2 position and the trans-diamine having the formula:

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(VI)

is formed. The trans-diamine of the formula VI can then be used with a C3 to C6 alkenyl chloride or bromide to give a diamine of the formula:

H

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/ r *

X

C3 ~ Cß

(vi 1)

Alkenyl are allowed to react. The diamine of the formula VTI serves as an intermediate in the reaction according to the invention already described with the respective carboxylic anhydride or acid chloride or bromide to form the N-acylated product of the formula:

so

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(VI II)

Alkenyl

In the formulas Ia, Illb, IV, V, VI, VII and VIII, the radicals R, R1; Y and Z have the meaning given.

Preferred preparation of the new cis-aminoamide 65 compounds:

The J.W. Lewis and co-workers in «J. Pharm. Be. » 63, 1951 (1974) and with 1-dialkylamino-cyclopentene (enamine) and nitrosoaryl as starting materials.

The process can also be carried out with the corresponding cycloheptenenamines for the production of ice-1,2-diaminocycloheptanes. These are then reacted with a carboxylic acid anhydride or halide to form the desired amino amides.

Examples of further preferred compounds of the formula I (preferably in trans configuration) are: N- [2- (dimethylamino) cycloheptyl] propionanilide, 3-methyl-N- [2- (dimethylamino) cycloheptyl] propionanilide, 3-methoxy-N - [2- (dimethylamino) cycloheptyl] propionanilide, 3,4-dichloro-N- {2- [N-methyl-N- (2-dimethylamino-

ethyl) amino] -cycloheptyl} propionanilide, 3,4-dichloro-N- {2- [N-methyl-N- (3-dimethylaminopro-

pyl) amino] -cycloheptyl} propionanilide, N- [2- (dimethylamino) cycloheptyl] acetanilide, N- [2- (dimethylamino) cycloheptyl] butyranilide, 3-trifluoromethyl-N- [2- (N-methyl-N-benzylamino ) cyclo-

heptylpropionanilide, 3,4-dibromo-N- {2- [N-ethyI-N- (2-phenylethyl) amino] cyclo-heptyl} propionanilide,

3-chloro-4-methyl-N- [2- (N-methyl-N-allylamino) cyclo-heptyl] propionanilide,

4-bromo-3-methyl-N- [2- (N-pyrrolidinyl) cycloheptyl] propionanilide,

3,4-difluoro-N- {2- [N-methyl-N- (2-dimethylaminoethyl) -

amino] cyc! oheptyl} propionanilide, 3-chloro-4-fluoro-N- [2- (dimethylamino) cycloheptyl] propionanilide,

3,4-dibromo-N- [2- (dimethylamino) cycloheptyl] propionanilide,

3,4-dimethyl-N- [2- (dimethylamino) cycloheptyl] propionanilide,

3,4-dichloro-N- [2- (dimethylamino) cycloheptyl] butyranilide, 3,4-dichloro-N- [2- (dimethylamino) cycloheptyl] -N-cyclo-

propane carboxanilide, 3,4-dichloro-N- [2- (dimethylamino) cycloheptyl] -N-acrylic anilide,

3,4-dichloro-N- [2- (dimethylamino) cycloheptyl] iso-butyranilide,

3-bromo-N- [2- (N-methyl-N-benzylamino) cycloheptyl] butyranilide,

3-chloro-4-fluoro-N- [2- (N-pyrrolidinyl) cycloheptyl] cyclo-propane carboxanilide,

3.5-dibromo-N- [2- (N-methyl-N-2-phenylethylamino) cyclo-heptylpropionanilide,

3,4-dichloro-N- [2-dimethylaminocycloheptyl] methoxyacetanilide,

3,4-dichloro-N- [2-dimethylaminocycloheptyl] carbethoxy anilide,

3-methyl-4-chloro-N- [2-diethylaminocycloheptyl] propionanilide,

3-trifluoromethyl-N- {2- [N-methyl-N-2-butenyl] aminocyclo-heptyl} cyclohexane carboxanilide,

3-ethoxy-4-bromo-N- [2-dimethylaminocycloheptyl] propionanilide,

4-Azido-N- [2- (dimethylamino) cycloheptyl] propionanilide, and the like, as well as their 2-N-oxides of the formula IA without aliphatic unsaturated bonds and their acid addition salts.

If appropriate, the compounds of the formulas I and IA obtained according to the invention can be separated or dissolved in their d- and 1-optical isomers in a customary known manner. In such a case, the optical resolution or separation can take place according to at least two process variants. The separating or dissolving agents in both process variants are known, e.g. optically active combat sulfonic acid, bis-p-toluoyl tartaric acid, tartaric acid and diacetyl tartaric acid. These connections are in

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Commercially available and are usually used for the separation or dissolution of amines (bases) (cf. “Organic Syntheses”, volume V, page 932 (1973), dissolution or separation of R - (+) and S - (-) -a-phenylethylamine with (+) - 'tartaric acid).

In the first process variant for dissolving or separating the compounds mentioned, for example one of the amino amide compounds is converted into its optically active diastereomeric salts by reaction with an optically active acid of the type mentioned in the conventional isomer separation of the type described. These diastereomeric salts can be separated from one another in a conventional manner, for example by fractional crystallization. Diastereomeric salts have different crystallization properties which are used in this separation. The neutralization of each diastereomeric salt with an aqueous base usually gives the corresponding optically active free aminoamide. Each optically active free aminoamide can then be converted into the desired acid addition salt separately and in the manner described above.

In the second process variant, which is preferred for some of the compounds mentioned, the compounds of the formula I or IA are converted into their corresponding d- and 1-isomers by first of all the cis or trans-1,2-cycloaliphatic, asymmetrically substituted diamine converted into their corresponding d- and 1-isomers by treatment with a separating or dissolving agent, crystallization, separation and recovery of the corresponding trans-d-diamine, trans-l-diamine or the cis-d-diamine or cis-l-diamine and then allowing the separate diamine starting material to react with the desired carboxylic acid anhydride or halide to form the corresponding cis or trans-d- or -1-compound of the formulas I and IA. The latter can then be converted into any pharmaceutically acceptable acid addition salt in the manner already described.

If the acid addition salt used to extract the new compound mentioned from its reaction mixture is not pharmacologically acceptable as such, the corresponding free aminoamide base can be prepared therefrom and then converted into a pharmacologically acceptable salt in the usual known manner.

When using the new compounds as antidepressants, the compound to be used in each case from the active ingredient can be processed with a suitable pharmaceutical diluent or carrier to give a pharmaceutical preparation or a medicament for oral, parenteral or rectal administration in the form of a unit dose or unit dose. Such unit doses or dosage units are, for example, tablets, powder sachets, wafer capsules, dragees, capsules, solutions, suspensions, sterile injectable forms of administration, suppositories, bougies and the like. Suitable diluents or carriers are, for example, carbohydrates (lactose), proteins, lipids, calcium phosphate, corn starch, stearic acid, methyl cellulose and the like. These substances can be used as carriers or for the production of coatings on suitable administration forms. Water and oils, for example coconut, sesame, safflower, cottonseed or peanut oil, are suitable for the preparation of solutions or suspensions of the active ingredient. If necessary, sweeteners, colors and flavors can be added. The regulations for the dosing units or unit doses differ from new compound to new compound, they depend in particular on the physical properties of the compound mentioned or its pharmacologically acceptable

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acceptable salt, weight and age of the respective patient and the effect to be achieved. The pharmaceutical unit dose or dosage unit for these compounds is based on the general description given above, with about 4 to 400 mg of compound of the formula I or IA or their pharmacologically acceptable salt generally being contained per unit dose or dosage unit. The dosage regimen regarding the amount of compound of the formula I or IA should be sufficient to enable the respective patient to be relieved or relieved of depression states when a non-toxic amount is administered.

The following examples illustrate the production and processing of the starting amines and the preparation of the new compounds. Unless otherwise stated, all temperature data are given in ° C.

example 1

Preparation of trans-3,4-dichloro-N- [2- (dimethylamino) cycloheptyl] propionanilide and its maleate salt:

A. Preparation of trans-2-dimethylaminocyclo-heptanol and its fumarate salt:

A mixture of 89.0 g (0.80 mol) of cycloheptenoxide and 275 ml (2.4 mol) of a 40% aqueous dimethylamine solution is shaken for 24 hours at a temperature of about 125 ° C. in a shake bomb, whereby receives a brown solution. The reaction solution is then saturated with about 50 g of potassium carbonate, two layers being formed. After adding 1 ml of a 40% aqueous potassium hydroxide solution, the mixture obtained is extracted 3 times with ether. The ether extracts obtained are combined, dried with anhydrous magnesium sulfate and then concentrated by evaporating the ether. Distillation of the evaporation residue gives 114.6 g of trans-2-dimethylaminocyclo-heptanol with a bp of 98 ° to 100 ° C. in a yield of 91% with a 10 mm Hg column. The nuclear magnetic resonance spectrum, IR spectrum and mass spectrum confirm the structure ascribed to the reaction product.

A crystalline fumarate salt is now produced from the cycloheptanol obtained. After recrystallization from ethanol / ether, this has an mp of 136 ° to 137 ° C.

The elemental analysis of the amino alcohol C9H19NO gives the following values:

Calculated: C 68.74 H 12.18 N 8.91

Found: C 68.48 H 12.39 N 8.53.

B. Preparation of trans-N- [2-dimethylamino) cycloheptyl] -3,4-dichloroaniline and its oxalic acid salt:

A mixture of 15.7 g (0.10 mol) of 2-dimethylamino-cycloheptan-l-ol and 4.8 g (0.10 mol) of sodium hydride (50% dispersion) in 50 ml of tetrahydrofuran is placed on a for 1 hour Steam bath heated and then cooled in ice. 11.5 g (0.10 mol) of methanesulfonyl chloride in 25 ml of tetrahydrofuran are then added over the course of 30 minutes. Then 32.4 g (0.20 mol) of 3,4-dichlorani-lin are added all at once. After the tetrahydrofuran solvent has been distilled off, the reaction mixture is heated on a steam bath overnight. 200 ml of a 20% aqueous sodium hydroxide solution are then added and the mixture is heated for 1 hour. After extracting the reaction mixture with 10% aqueous hydrochloric acid, the aqueous acid layer is washed with ether, made basic with 40% aqueous sodium hydroxide solution and then extracted with 250 ml ether. The ether layer is washed with a saturated aqueous sodium chloride solution, dried with magnesium sulfate and freed from the ether by evaporation. The oily evaporation residue obtained in this way is distilled, 17.3 g of trans-N- [2-dimethylamino) cycloheptyl] -3,4-dichloroaniline having a bp of 170 ° to 180 ° C. at 0. 3 mm Hg column.

5 The oxalic acid salt of the amine is prepared from 5.2 g (0.057 mol) of oxalic acid and the diamine obtained in a solvent mixture of 25 ml of methanol and 200 ml of ether. When recrystallizing from the same solvent mixture, 15.5 g of pure oxalic acid salt of the diamine mentioned, mp 153 ° to 154 ° C., are obtained in 69% yield. The structure ascribed to the compound is confirmed by the nuclear magnetic resonance spectrum, IR, UV and mass spectrum.

The elementary analysis of the compound i5 Cx SH22N2CI2 • C2H204 gives the following values:

Calculated: C 52.15 H 6.18 N 7.16 Cl 18.12 Found: C 52.25 H 6.34 N 6.98 Cl 18.23. C. Preparation of trans-3,4-dichloro-N- [2- (dimethylamino) cycloheptyl] propionanilide and its maleate salt: 20 An ice-cooled solution of 3.01 g (0.01 mol) of trans-N- (2- (Dimethylamino) cycloheptyl] -3,4-dichloroaniline and 2.02 g (0.02 mol) of triethylamine in 100 ml of ether are mixed with 1.85 g (0.02 mol) of propionyl chloride within 30 min the reaction mixture was stirred at room temperature overnight, 100 ml of a saturated aqueous sodium bicarbonate solution was added, the organic layer was washed with water and then with a saturated sodium chloride solution, then dried over anhydrous magnesium sulfate and finally borrowed the oily residue obtained is concentrated in a mixture of 10 ml of methanol and 75 ml of ether, and 1.16 g (0.01 mol) of maleic acid are added, giving a crystalline precipitate. This was produces 3.90 g of trans-3,4-dichloro-N- [2- (dimethylamino) cyclo-heptyl] propionanilide, maleate salt of mp 165 ° to 166 ° C. when recrystallizing from the same solvent mixture in 82% yield. The structure ascribed to the compound is confirmed by the nuclear magnetic resonance, IR, UV and mass 40 spectrum.

The elementary analysis of the connection C18H26N2C120 • C4H404 gives the following values:

Calculated: C 55.81 H 6.39 N 5.92 Cl 14.98 45 Found: C 56.05 H 6.46 N 6.07 Cl 15.16.

Example 2

Preparation of trans-3-trifluoromethyl-N- [2- (l-pyrrolodinyl) cycloheptyl] propionanilide:

50 According to Example 1, but replacing the dimethylamine in Part A with a stoichiometrically equivalent amount of pyrrolidine (to obtain trans-2- (N-pyrrolidinyl) cycloheptanol) and replacing the 3,4-dichloroaniline in Part B. a stoichiometrically equivalent amount of 3-trifluoromethylaniline is obtained trans-N- [2- (N-pyrrolidinyl) cycloheptyl] -3-trifluoromethylaniline. This can then be according to Example 1, Part C, in its propionanilide and, if desired, in its acid addition salt, e.g. the hydrochloride or maleate salt.

60

Example 3

Preparation of trans-3,4-dichloro-N- [2- (dimethylamino) cycloheptyl] propionanilide-2-N-oxide:

A stoichiometrically equivalent amount of 85% m-65 chloroperbenzoic acid in chloroform is added dropwise to an equimolar amount of trans-3,4-dichloro-N- [2- (dimethylamino) cycloheptyl] propionanilide (prepared according to Example 1) while cooling with ice registered. After that, the reak

tion mixture stirred overnight at room temperature and finally evaporated to dryness. After repeated washing and concentration, trans-3,4-dichloro-N- [2- (dimethylamino) cycloheptyl] propionanilide-2-N-oxide is obtained.

Example 4

According to Example 1, but with the replacement of the 3,4-di-chloroaniline in Part B by a stoichiometrically equivalent amount of one of the following substituted anilines:

(a) 3-fluoroaniline,

(b) 4-bromoaniline,

(c) 3-bromoaniline,

(d) 3,5-dichloroaniline,

(e) 3,4-dibromaniline,

(f) 3-trifluoromethylaniline,

(g) 3,4-dimethylaniline or

(h) 3-methoxyaniline is obtained:

(a) N- (2-dimethylaminocycloheptyl) -3-fluoroaniline,

(b) N- (2-dimethylaminocycloheptyl) -4-bromoaniline,

(c) N- (2-dimethylaminocycloheptyl) -3-bromoaniline,

(d) N- (2-dimethylaminocycloheptyl) -3,5-dichloroaniline,

(e) N- (2-dimethylaminocycloheptyl) -3,4-dibromaniline,

(f) N- (2-dimethylaminocycloheptyl) -3-trifluoromethyl-aniline,

(g) N- (2-dimethylaminocycloheptyl) -3,4-dimethylaniline or

(h) N- (2-Dimethylaminocycloheptyl) -3-methoxyaniline.

The subsequent reaction of these N- (2-dimethylaminocycloheptyl) -substituted anilines with propionyl chloride corresponding to Part C of Example 1 gives:

(a) 3-fluoro-N- (2-dimethylaminocycloheptyl) propionanilide,

(b) 4-bromo-N- (2-dimethylaminocycloheptyl) propionanilide,

(c) 3-bromo-N- (2-dimethylaminocycloheptyl) propionanilide,

(d) 3,5-dichloro-N- (2-dimethylaminocycloheptyl) propionanilide,

(e) 3,4-dibromo-N- (2-dimethylaminocycloheptyl) propionanilide,

(f) 3-trifluoromethyl-N- (2-dimethylaminocycloheptyl) propionanilide,

(g) 3,4-dimethyl-N- (2-dimethylaminocycloheptyl) propionanilide,

(h) 3-methoxy-N- (2-dimethylaminocycloheptyl) propionanilide.

According to Example 1, Part A, but replacing the dimethylamine with a stoichiometrically equivalent amount of pyrrolidine, diethylamine or N-methyl-N ', N'-dimethylaminoethylamine, the following is obtained:

N- [2- (N-pyrrolidinyl] cycloheptanediamine,

N- [2- (diethylamino)] cycloheptanediamine and

N- [2- (N-methyl-N ', N'-dimethylaminoethyl)] cyclo-

heptane diamine.

If the cycloheptanediamines obtained are reacted with 3,4-dichloroaniline in the manner described in Example 1, part B and then with propionyl chloride in accordance with Example 1, part C, the following are obtained:

3,4-dichloro-N- [2- (N-pyrrolidinyl) cycloheptyl] propionanilide,

3,4-dichloro-N- [2- (diethylaminocycloheptyl)] propion anilide and

3,4-dichloro-N- [2- (N-methyl-N ', N'-dimethylamino-ethyl) cycloheptyl] propionanilide.

636341

Corresponding to Example 1, Part C, but replacing the propionyl chloride with a stoichiometrically equivalent amount of:

(a) cyclopropanecarbonyl chloride,

(b) cyclobutane carbonyl chloride,

(c) cyclopentane carbonyl chloride,

(d) cyclohexane carbonyl chloride,

(e) Methoxyacetyl chloride is obtained:

(a) 3,4-dichloro-N- (2-dimethylaminocycloheptyl) cyclo-propane carboxanilide,

(b) 3,4-dichloro-N- (2-dimethylaminocycloheptyl) butane carboxanilide,

(c) 3,4-dichloro-N- (2-dimethyaminocycloheptyl) cyclopentanecarboxanilide,

(d) 3,4-dichloro-N- (2-dimethylaminocycloheptyl) cyclo-hexane carboxanilide,

(e) 3,4-dichloro-N- (2-dimethylaminocyclo-heptyl) methoxyacetanilide.

For oral administration, either solid or liquid dosage units or unit doses of the respective alkanoylanilide can be prepared. For the manufacture of solid forms of administration, e.g. of tablets, the compounds of formula I are mixed or blended with customary components, such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, acacia, methyl cellulose and substances which function functionally similarly as pharmaceutical diluents or carriers. Wafer capsules are obtained in a similar way to tablets, the only difference being the different form and the addition of cane sugar or other sweeteners and flavors. In its simplest embodiment, capsules similar to tablets are obtained by mixing the compounds with inert pharmaceutical diluents and filling the mixture obtained in each case into hard gelatin capsules of a suitable size. Soft gelatin capsules are obtained by mechanically encapsulating a slurry of the compound in an acceptable vegetable oil, light liquid petroleum jelly, or other inert

Oil.

Flowable unit doses or dosage units for oral administration, such as syrups, elixirs and suspensions, can also be prepared. The water-soluble forms can be dissolved in aqueous carriers together with sugar, aromatic flavors and preservatives to form a syrup. An elixir is obtained using an aqueous alcoholic (e.g. aqueous-ethanolic) carrier and suitable sweeteners such as sugar and the sodium salt of benzoic acid sulfimide, along with aromatic flavors or ingredients.

Suspensions are obtained with aqueous carriers with the addition of suspending agents, such as acacia, traanthanth, methyl cellulose and the like.

Flowable unit doses or dosage units suitable for parenteral administration are obtained from the compounds in question and a sterile carrier, preferably water; depending on the carrier and the concentration required, the compound in question can either be suspended or dissolved in the carrier. When preparing solutions, the compounds in question are dissolved in water suitable for injection purposes and then sterilized by filtration before filling into suitable vials or ampoules and closing them. Appropriately, aids such. B. Local anesthetics, preservatives and buffers with dissolved. To improve stability, the respective mass can be filled into the vial and the water removed.

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636341

be frozen under vacuum. The dry lyophilized powder is then sealed in the vial, and a vial filled with water for injection is added to this vial to reprocess the liquid before use. Parenteral suspensions are obtained in practically the same manner, except that the compound is suspended therein instead of being dissolved in the carrier. In this case, too, no filtration sterilization can take place. Rather, the compound in question is sterilized by exposure to ethylene oxide before being suspended in the sterile carrier. A wetting agent or surface-active agent is expediently incorporated into the respective composition in order to better and more evenly distribute the compound.

Rectal suppositories here and below mean solid bodies for insertion into the rectum, which melt or become soft at body temperature and release at least one pharmacologically or therapeutically active component.

Pharmaceutically acceptable substances for the production of rectal suppositories are the basis or carrier and means for increasing the melting point.

Examples of bases or carriers are cocoa butter (theobroma oil), glycerin / gelatin, carbowax (polyoxyethylene glycol) and suitable mixtures of mono-, di- and triglycerides of fatty acids. Combinations of the different basics can also be used. Means for increasing the melting point of suppositories are, for example, spermaceti and wax. Rectal suppositories can be prepared either by pressing or by other shaping processes. The usual weight of rectal suppositories is approximately 2.0 g.

Tablets and capsules for rectal administration are obtained using the same pharmaceutically acceptable substances and according to the same methods as are used or carried out in the preparation of tablets and capsules for oral administration.

Rectal suppositories, tablets or capsules are packaged either individually in the form of unit doses or dosage units or in multiples thereof, for example in amounts of 2, 6 or 12.

The term “dosage unit” or “unit dose” refers to physically removable units, suitable as dosage units or unit doses for humans and animals, each of which a given amount of active material, which are aimed at producing the desired therapeutic effect, diluents, carriers

10th

or contains extenders. The regulations for such dosage units or unit doses are determined and are directly dependent on (a) the characteristics of the active material and the desired success and 5 (b) the restrictions inherent in the art of packaging an active material by administration to humans and animals.

Examples of suitable dosage units or unit doses are tablets, capsules, pills, suppositories, pul-lo sachets, wafers, wafer capsules, teaspoons, tablespoons, droppers, ampoules, vials, divided multiples of any of the administration forms mentioned and other administration forms.

The dosage of the compound in question for treatment depends on the route of administration and the age, weight and condition of the patient. A dosage regimen of about 4 to 400 mg, preferably 50 to 200 mg, per day, given as a single dose or in multiple doses, corresponds to the range of effectiveness of the medicaments or pharmaceutical preparations according to the invention intended to alleviate depression. The dose to be administered is calculated based on about 0.08 to about 6 mg / kg body weight of the patient. The respective compound is brought into the form of a dosage unit with a suitable pharmaceutical carrier for convenient and effective administration. Dosage units or unit doses of medicaments according to the invention preferably contain 5, 10, 25, 30, 50, 100 or 200 mg of the respective compound for systemic treatment. Sterile preparations of the active material advantageously contain 0.1 to 25% by weight of the compound in question for parenteral treatment. The dosage of at least one compound of formula I and at least one other active ingredient-containing medicament according to the invention is determined according to the actual dosage instructions for each such ingredient.

In addition to the administration of compounds of the formula I or IA alone or as the main constituent 40 drugs, the compounds of the formula I or IA can also be used with other active compounds, e.g. Analgesics such as acetylsalicylic acid, acetaminophen, PAC compound (phenacetin / acetylsalicylic acid / Kof-fein), anti-inflammatory or anti-inflammatory agents such as 45 ibuprofen and the like, anxiety-relieving agents such as perphenazines, amitriptylene hydrochloride, chlorodiazepoxides and alprazolamrochloride, alprazolamam, Alprazolamam, alprazolamam, alprazolamam, alprazolamam, alprazolamam, alprazolamam, alprazolamam, alprazolamam, alprazolamam, alprazolamam, alprazolamam, alprazolamam, Alprazolamam, Alprazolamam, Alprazolamam, Alprazolamam, Alprazin be combined.

Claims (2)

636 341 2nd PATENT CLAIMS 1. Process for the preparation of new compounds of formula (I) Y (II) of the formula R-C (0) -X, in which X is chlorine or bromine, is reacted at -5 ° to +10 = C in the presence of a tertiary amine in an organic liquid solvent and, if appropriate, compounds obtained are converted into the corresponding salts. 2. Process for the preparation of new compounds of the formula R in which the wavy line (~) in the 1-position of the cycloheptyl ring indicates an ic or trans configuration of the substituents in the 1 and 2 positions of the cycloheptyl ring and in which: R is a Cj to C3 alkyl, a C3 to C6 cycloalkyl, vinyl, ethoxy or methoxymethyl radical; Ri alone is a Cj to C3 alkyl radical; R2 alone is a Cj to C3 alkyl radical or, if Rj is a Cr to C3 alkyl radical, a radical of the formulas: -CH2CH2N (CH3) 2, -CH2CH2CH2N (CH3) 2, -CH2C6H5, -CH2CH2C6H5 or C3 to C6 alkenyl; or Rj and R2 together with the nitrogen atom to which they are attached form an N-pyrrolidinyl or N-piperidinyl ring; Y and Z, which may be the same or different, are a hydrogen atom, a halogen atom with an atomic number from 9 to 35, a trifluoromethyl radical, a Q to C2 alkyl radical, an azidor radical or a Cj to C2 alkyloxy radical, or Z in the case, that Y represents a trifluoromethyl radical or azidor radical, a hydrogen atom, and it is true that in the event that Y represents a Q to C2 alkyloxy radical and Z represents a hydrogen atom, the Q to C2 alkyloxy radical is in the 3-position , and in the event that Y and Z both represent halogen atoms or Ci to C2-alkyloxy radicals, these radicals are in 3- and 4- or 3- and 5-positions, and acid addition salts of the compounds mentioned, characterized in that to get a compound of formula 15 20th (IA) 35 in which the wavy line (~) in the 1-position of the cycloheptyl ring indicates an ic or trans configuration of the substituents in 1-25 and 2-positions of the cycloheptyl ring and in which: R is Q to C3 alkyl, C3 to C6 cycloalkyl, ethoxy or methoxymethyl; Rj alone is a Cr to C3 alkyl group; 30 R2 alone is a Ci to C3 alkyl radical or, in the case that Rx represents a Q to C3 alkyl radical, a radical of the formulas: -CH2CH2N (CH3) 2, -CH2CH2CH2N (CH3) 2, -CH2C6Hs or -CH2CH2C6H5 or Rj and R2 together with the nitrogen atom to which they are attached form an N-pyrrolidinyl or N-piperidinyl-40 ring; Y and Z, which may be the same or different, represent a hydrogen atom, a halogen atom with an atomic number of 9 to 35, a trifluoromethyl radical, a Q to C2 alkyl radical, an azido radical or a Ci to C2 alkyloxy radical, or Z 45 in the case that Y represents a trifluoromethyl radical or azidorest, a hydrogen atom, and it is true that in the event that Y represents a Cj - to C2-alkyloxy radical and Z represents a hydrogen atom, the C ^ to C2-alkyloxy radical is in the 3-position is, and in the event that Y and Z both represent halogen atoms or Cx to C2 alkyloxy radicals, these radicals are in the 3- and 4- or 3- and 5-positions, and acid addition salts of the compounds mentioned, characterized that a compound of the formula I is prepared 55 by the process according to claim 1 and this or a salt thereof is reacted with a percarboxylic acid and any compounds obtained are converted into the corresponding salts. 60 wherein Rt, R2, Y and Z are as defined above, either heated with the anhydride of an organic carboxylic acid of the formula R-COOH or with a carboxylic acid halide