CH652595A5 - Medicament with antidepressant effect and corresponding active substances - Google Patents

Description

The invention relates to a pharmaceutical agent with an antidepressant effect, namely new pharmaceutical preparations or drugs with ice and trans-N- (aminocyclopentyl) -N-acylanilide compounds or their pharmacologically acceptable salts.

It has been shown that the compounds in question have strong antidepression properties which act on the central nervous system and which, after conversion into pharmaceutically acceptable formulations, enable them to be used as antidepressants.

The invention further relates to new compounds which are useful as active ingredients in the pharmaceutical compositions mentioned; these compounds are defined in independent claim 3.

In "Helvetica Chimica Acta", Vol. 34, 1937 to 1943 (1951), W. G. Stoll u. Employee on N- [2-dimethylamino) cyclohexyl] aniline and process for its preparation from N- (2-hydroxycyclohexyl) aniline and state 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 »article titled in« J. Chem. Soc. (London) (1972) », Perkins Transactions I, Part III, pages 2521 to 2524, inter alia on N- (2-morpholin-l-yl-cyclohexyl) phenylhydroxylamine and its hydrochloride. However, there is no reference in the cited literature reference to the acylanilides 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 Hydroxyl-amines” in “J. Pharceutical Sciences », December 1974, Volume 63, No. 12, pages 1951 to 1953 on some N-arylhydroxylamines, such as N- [2- (n-pyrrolidinyl) cyclohexyl] - N-phenylhydroxylamine; however, these compounds have no properties affecting the central nervous system. However, it is used for the alcohols, e.g. [2- (N-piperidinyl) cyclo-hexyl] - (4-methoxyphenyl) 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, l-dimethylethyl] -N-phenyl-hydroxylamine to form or 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-anilinomethylcycloalkylamines which are suitable as antidiabetic agents (when administered in low doses to lower blood sugar). The structural formula IV given in column 2 of US Pat. No. 3,510,492 quite 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-anilinocycloalkylamines. In the US patent mentioned there is no indication of the practical utility of compounds of structural formula IV as end products.

One of the ideas of the invention is to provide new drugs with promising antidepressant properties.

Furthermore, the invention is intended to make new N- (2-aminocyclopentyl) acylanilides available as active compounds, the preferred compounds showing better therapeutic activity and longer-lasting activity than imipramine. This allows longer intervals between two administrations.

The invention first relates to a medicament with an antidepressant effect, characterized in that it contains an antidepressant, non-toxic amount of a compound of the formula

R

C = Q

N

or their pharmacologically acceptable salts in addition to a pharmaceutical diluent, wherein in formula I the wavy line in the 1-position of the cyclopentyl ring indicates the eis or trans configuration of the substituents in the 1- and 2-positions and the symbols have the following meanings:

p zero or 1,

Q oxygen or sulfur,

R Ci to C3 alkyl, vinyl, C3 to Q cycloalkyl, ethoxy or

Methoxymethyl,

Ri is hydrogen or Q to C3 alkyl,

R2 is hydrogen, Ci to C3 alkyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, benzyl, phenethyl or C3 to Cc-Al-kenyl with an allylic double bond, where Ri and R2 are not both Ci-C3-alkyl, and Y and Z are each hydrogen, halogen with an atomic number from 9 to 35, trifluoromethyl, methyl, ethyl, methoxy or ethoxy, with the following requirements:

Z = hydrogen when Y = trifluoromethyl; if Z = hydrogen and Y = methoxy or ethoxy, Y is in the 3-position of the benzene nucleus; and when Y and Z are both halogen or methoxy and ethoxy, respectively, they are in the 3,4 or 3,5 positions of the benzene ring.

The invention further relates to compounds of the formula

R

C = Q

• Y

-NO

(0)

R

and the pharmacologically acceptable salts, wherein in formula I 'the wavy line in the 1-position of the cyclopentane ring indicates the cis or trans configuration of the substituents in the 1- and 2-positions and the symbols have the following meanings:

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p zero or 1,

Q oxygen or sulfur,

R vinyl, C3 to Cfi cycloalkyl, ethoxy or methoxymethyl,

Ri is hydrogen or Ci to C3 alkyl,

R2 is hydrogen, Cr to c3-alkyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, benzyl, phenethyl or c3- to C6-alkenyl with an allylic double bond, where not both Ri and R2 are Cr to c3-alkyl, and Y and Z is hydrogen, a halogen with atomic numbers 9 to 35, trifluoromethyl, methyl, ethyl, methoxy or ethoxy, with the following requirements:

Z is hydrogen when Y is trifluoromethyl; when Y is methoxy or ethoxy and Z is hydrogen, Y is in the 3-position of the benzene ring; and when Y and Z are both halogen, methoxy or ethoxy, these residues take the 3,4 or 3,5 position of the benzene ring. The agents defined above have an antidepressant effect on the central nervous system. A preferred example of such a use is trans-3,4-dichloro-N- [2- (N-methylamino) cyclopentyl] cyclohexane carboxanilide. In the form of suitable pharmaceutical dosage units, the agents according to the invention are suitable for administration to humans in doses of 1 to 100 mg of active ingredient per day as part of a therapy for the treatment of depressive states. In the case of conventional laboratory animals used to determine these properties, the compounds in question suggest a quick response or a rapid reappearance of the antidepressant properties (of the respective medicament). The preferred agents also have a higher therapeutic ratio in standard laboratory tests, i.e. a higher therapeutic index (higher activity and / or lower toxicity) than the usual standard antidepressant imipramine, and a longer duration of activity of the test compound in the test animal. These properties enable the compositions according to the invention to be administered as antidepressants in a smaller amount and / or after a longer period between individual administrations, for example once a day, in order to achieve a desired given antidepressant effect.

In formulas I and I ', R 1 and R 2 are not simultaneously Cr to c3 alkyl. This restriction serves to distinguish it from older law from CH-A 636 340 and possibly also CH-A 636 342.

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

In the formulas I and I 'the expression “Cr to c3-alkyl” stands for a methyl, ethyl, n-propyl or isopropyl radical. The term “c3 to Cg cycloalkyl” stands for a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radical. The term "c3 to Cö alkenyl with allyl double bond" includes e.g. Allyl, 2-butenyl, 2-methyl-2-butenyl, 2-pentenyl, 3-methyl-2-pentenyl and 2-hexenyl radicals. “Halogen atoms with atomic numbers from 9 to 35” are fluorine, chlorine and bromine atoms.

Compounds preferred according to the invention show a trans configuration.

Examples of acid addition salts, including pharmacologically acceptable salts of the above Formula I compounds, are those of the salt, methanesulfone, hydrogen bromide, sulfur, vinegar, cyclohexanesulfamine, para-toluenesulfone, amber, beta-naphthalenesulfone -, Maleic, fumaric, citric, lactic and oxalic acid.

In order to be able to use these new compounds I 'as pharmaceutical, antidepressant drugs, they are processed or formulated in the usual pharmaceutical compositions, e.g. in oral dosage units such as tablets, powders, capsules and solutions or suspensions in a suitable solvent or suspending medium, and in parenteral dosage units such as dry powder in a sterile sealed container which can be mixed with a sterile solvent shortly before administration, sterile solutions or Suspensions in water or other suitable solvents or suspending agents. In this way daily doses of about 1 mg to about 100 mg, preferably 10 mg to 90 mg, of a compound of formula I or its pharmacologically acceptable salt can be administered. The dosage depends on the effectiveness of the formula I compound, on the condition of treatment and the weight of the patient, and on his physical condition.

The compounds of formula I where Q is oxygen and p 0 can be prepared by (a) a mixture of a compound of the formula

Y

wherein R 1, R 2, Y and Z have the meaning defined above, and an anhydride of an organic carboxylic acid of the formula R-COOH is heated on a steam bath or at an equivalent temperature for a time sufficient to obtain the N-acylated product of the formula I. to form wherein R is as defined above, Q is oxygen and p 0, (b) adding to the reaction mixture from step (a) an aqueous medium sufficient to decompose excess anhydride present, (c) an alkali metal hydroxide or another base in an amount sufficient to neutralize excess acid present and to make the mixture basic to the reaction mixture from step (b), (d) the N-acylated product of the formula I with a water- miscible, organic solvents, e.g. extracting ethereal solvents such as diethyl ether, tetrahydrofuran or dioxane, or chloroform, carbon tetrachloride, methylene chloride, ethylene dichloride or the like, (e) separating the organic liquid phase which contains the N-acylated product of the formula I from the aqueous phase and (f) recovering the corresponding N-acylated compound of formula I from the organic liquid phase, generally after washing the organic liquid phase one or more times with aqueous media, such as sodium chloride solutions, sodium bicarbonate solutions or water, in order to extract components soluble in these aqueous media , the aqueous phase is separated off, the washed organic phase is dried with drying agents such as magnesium sulfate or sodium or calcium sulfate, and then the organic solvent is removed. Further purification is possible by forming an acid addition salt from the N-acylated amide product of formula I and then recrystallizing the amide salt from a suitable solvent or a mixture of solvents.

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These compounds of formula I can also be prepared by (a) dissolving a solution of a suitable carboxylic acid halide RC (0) -X, wherein R is as defined above and X is chloride or bromide, at a cooled (-5 ° C to + 10 ° C) mixture of diamine of the formula II and a tertiary amine which can form a tertiary amine chloride or amine bromide salt in the mixture, for example a Cr to c4 trialkylamine, such as tri-methylamine, triethylamine, tributylamine or pyridine, lutidine, N, N-dimethylaniline or the like, in an organic liquid solvent suitable for the mixture, e.g. an ethereal solvent such as diethyl ether, tetrahydrofuran, dioxane or the like, while stirring the mixture until the corresponding N-acylated compound of formula I is formed, (b) an aqueous alkali metal bicarbonate solution to the reaction mixture from step (a) adds, (c) separating the aqueous phase from the organic liquid phase, (d) washing the organic liquid phase with aqueous washing solutions as described above, (e) drying the organic phase and (f) the N-acylated compound of the formula I recovered from the resulting organic liquid mixture. The N-acylated amide compound of formula I can be further purified by forming its acid addition salts, e.g. the acid addition salt of hydrochloric acid or maleic acid, and by recrystallizing the amide salt from a suitable solvent or mixture of solvents.

The compounds of the formula I which do not contain a reactive aliphatic carbon-carbon double bond in the molecule and in which Q is oxygen and p is zero can be converted by the reaction of such an amlnoamide of the formula I or its salt with a percarboxylic acid by known processes, to obtain the corresponding compound of formula I, where p is 1.

The corresponding N-thioacylaminoanilide compounds can be prepared by reacting the corresponding compounds of formula I, wherein Q = oxygen, with a sulfur introducing agent, e.g. Phosphorus pentasulfide or diethyldithiophosphate [P (S) SH (oc2h5) 2], in a suitable solvent such as pyridine, boils at reflux for a sufficient time to replace the acyl oxygen atom with sulfur, and then the N-thioacylanilide compound by known ones Process recovers and cleans. If the N-oxides of the compounds in which Q = sulfur are to be produced, the N-oxide is first prepared and then the N-oxide obtained is thiolated as described above to form the compound of formula I, wherein Q = Is sulfur and p = 1.

Further explanations of these manufacturing processes appear in the detailed examples.

The trans-diamine starting material of the formula

Y

wherein Ri, Cr to C3-alkyl; R2 is -ch2ch2N- (CH3) 2, -CH2CH2-CH2N (CH3) 2, -CH2C6Hj, -ch2ch2qh5 or C3- to C6- (allylic) alkenyl; and Y and Z are as defined above (Ri and R2 are not both alkyl) can be prepared by reacting 1,2-cyclopentene oxide of the formula with the selected hnrir2 amine in water to give the trans-2-aminocyclopentanoï of the formula

OH

to manufacture. This amino alcohol (Illb) is first reacted with sodium hydride and then with methanesulfonyl chloride, the non-isolated mesylate of the formula

^ 2

where Ms represents the CH3S02 group. This reaction mixture is further selected with the substituted aniline of the formula

Y

implemented to form the diamine of formula II. Examples of this method are given in detail below.

Examples of carboxylic anhydrides which can be used for reaction with compounds of the formula II

are acetic anhydride, propionic anhydride, iso-butter acid anhydride, n-butyric acid anhydride, cyclopropane carboxylic acid anhydride, acrylic acid anhydride and the like. The preferred anhydride is propionic anhydride. The carboxylic acid halides are replaced by acetyl chloride or bromide, propionyl chloride or bromide, acryloyl chloride or bromide, cyclohexane carbonyl chloride or bromide, n- and isobutanoyl chloride or bromide, cyclopropane carbonyl chloride or bromide, ethyl formate or methoxyacetate bromide and the like are illustrated. It has generally been found that the most antidepressant compounds are those which have an N-propionyl moiety, so that in the compound of the formula I R is preferably ethyl.

If the compound of formula I is desired to have an allyl group in the r2 position, another method can also be used: the amino amide is prepared as described above using an alkylbenzylamine to produce the amino alcohol of the formula Illb form. This amino alcohol is then converted into the diamine by means of the intermediate reactions of the formulas IV and V. The diamine obtained is then catalytically reduced, preferably in the presence of a palladium-on-carbon catalyst, to the

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Remove the benzyl group in the r2 position and form the trans-diamine of the formula. The trans diamine (VI) is then reacted with the alkenyl with alkyl double bond chloride or bromide, the diamine having the formula

(VII)

Approx

(Allylic) alkenyl is formed, which is used as an intermediate in a reaction, as described above, with the selected carboxylic anhydride or acid chloride or bromide to give the N-acylated product of the formula

R

(VIII)

to form (allylic) alkenyl. In the formulas Ia, Illb, IV, V, VI, VII and VIII, R, Ri, Y and Z are defined as described above.

Preparation of the cis-amino compound:

The method of JW Lewis et al., J. Pharm. Sei., 63, 1951 (1974), which uses one of the 1-tertiary aminocyclopentenes (enamines) and nitrosoaryl defined above as the starting material, can be used to obtain cis-1 To obtain 2-tertiary amino-cyclopentane, which is then reacted as described above with carboxylic acid anhydride or carboxylic acid halide to give the amino-amide product.

A preferred method is the reaction of cycloptenoxide with an aniline in the presence of a strong acid to give the compound of formula

OH

to surrender. This is then reacted with carboxylic acid anhydride and then with base, and you can the compound of formula

OH

isolate. The oxidation of this alcohol leads to the compound of the formula

If this is reacted with a primary or secondary amine and a reducing agent such as sodium cyanoborohydride and the like, a compound of the formula is obtained

R - C = 0

wherein R2 is not c3-C6- (allylic) alkenyl.

Cis compounds in which R2 is c3-c6- (allylic) alkenyl can be prepared analogously to the trans compounds. In this case, a primary amine is used together with the reducing agent, followed by the reaction with the allylalkenyl chloride or bromide.

The sulfur analogs of such cis-amino amides can be prepared as described earlier in this specification.

Examples of further compounds of formula I include the following compounds, preferably in their trans configuration:

3,4-dichloro-N- {2- [N-methyl-N- (2-dimethylaminoethyl) amino] cyclopentyl} propionanilide,

3,4-dichloro-N- {2- [N-methyl-N- (3-dimethylaminopröpyI) amino] cyclopentyl} propionanilide,

3-trifhiormethyl-N- [2- (N-methyl-N-benzylamino) cyclopentyl] propionanilide,

3,4-dibromo-N- {2- [N-ethyl-N- (2-phenylethyl) amino] cyclopentyl} propionanilide,

3-chloro-4-methyl-N- [2- (N-methyl-N-allylamino) cyclopentylpropionanilide,

3,4-difluoro-N- {2- [N-methyl-N- (2-dimethylaminoethyl) amino] cyclopentyl} propionanilide,

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

3.5-dibromo-N- [2- (N-methyl-N-2-phenylethylamino) cyclopentylpropionanilide,

3,4-dichloro-N- [2- (N-methyl-N-dimethylaminoethyl) amino-cyclopentyljmethoxyacetanilide,

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3-trifluoromethyl-N- [2- (N-methyl-N-2-butenyl) aminocyclopentyljcyclohexane carboxanilide,

and the like, the 2-N-oxides of the above compounds containing no aliphatic unsaturated parts and their acid addition salts.

If desired, the compounds of the formula I and I 'can be separated into the optical isomers d and / or by known processes. In the present case, the optical resolution can take place in at least two different ways. The separating agents in both processes can be known separating agents such as optically active camphorsulfonic acid, bis-para-toluoyl tartaric acid, tartaric acid and diacetyl tartaric acid, which are commercially available and which are generally used for the dissolution of amines (bases), e.g. in “Organic Syntheses”, Coll. Vol. V., page 932 (1973), separation of R - (+) and S - (-) -a-phenylethylamine with (+) - tartaric acid.

In the first process for the separation of the above compounds e.g. one of the amino-amide compounds can be converted into their optically active diastereomeric salt by reacting them with an optically active acid as mentioned above in the standard methods for the separation into the isomers.

These diastereomeric salts can then be separated by conventional methods such as stepwise crystallization. Diastereomeric salts have different crystallization properties. This advantage can be used for the separation. The corresponding optically active, free amino amides can be obtained by neutralizing the diastereomeric salts in question with aqueous base, each of which can subsequently and individually, as previously described in the examples, be converted into the desired acid addition salts.

In the second process, which is preferred for some of these compounds, the compound of the formula I or I 'can be made the d- or / isomer by first the di- or trans-1,2-cycloaliphatic unsymmetrically substituted diamine separated into its d- or / -isomers by treatment with the resolving agent, crystallization, separation and recovery of the trans-d-diamine, or trans - / - diamine or the cis-d-diamine or the cis - / - diamine . The correspondingly separated diamines are then reacted with the desired carboxylic acid anhydride or halide, the corresponding cis or trans-d or / compounds of the formula I or I 'being formed, which are then pharmaceutically employed in the desired processes using the processes illustrated above acceptable acid addition salt can be converted.

If the acid addition salt with which the compound of formula I (F) is extracted from its reaction mixture is not itself pharmacologically acceptable, the free amino amide base I (F) can be prepared from the acid salt and then converted into a pharmacologically acceptable salt a known method can be converted.

When using the compounds of the formula I as antidepressants, the compound of the formula I to be used in each case as an active ingredient is processed with a suitable pharmaceutical diluent or carrier to give a pharmaceutical preparation or a medicament for oral, parenteral or rectal administration. Such preparations 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 composition of the preparations differ from compounds of the formula I to compounds of the formula I, they depend in particular on the physical properties of the compound of the formula I or its pharmacologically acceptable salt, weight and age of the particular patient and the effect to be achieved . The pharmaceutical dosage unit for these compounds is based on the general description given above, with about 1 to about 100 mg of compound of the formula I or its pharmacologically acceptable salt being (are) generally contained per dosage unit. The dosage regimen relating to the amount of compound of the formula I should be sufficient to enable the patient in question to be relieved or relieved of the depression or conditions when a non-toxic amount is administered.

The following detailed procedures and examples further describe and illustrate how to prepare and use the starting amine and the compounds of the invention. Unless otherwise noted, all temperatures are given in degrees Celsius. For brevity, the term THF means tetrahydrofuran, NMR means nuclear magnetic resonance spectrum, IR means infrared spectrum, UV means ultraviolet spectrum, ether means diethyl ether, NaOH means sodium hydroxide, MgSÛ4 means anhydrous magnesium sulfate and MeOH means methanol.

I. General procedure for the preparation of trans-2-aminocycloalkanols:

The process is illustrated by the preparation of trans-2-dimethylaminocyclopentanol. Analogous connections are listed in Table 1. All tabulated compounds have NMR, IR, UV and mass spectra that match the corresponding structures. .

A mixture of cyclopentene oxide (188 g, 2.24 moles) and aqueous dimethylamine (40%, 750 ml, 6.67 moles) is stirred overnight (the temperature rises to 45 ° C. after 1 hour and then drops again). The solution (750 ml) is extracted several times with ether. The extract is dried (anhydrous MgSO4) and concentrated by distillation. The remaining oil is distilled in vacuo and gives 276 g (90%) of the trans-2-dimethylaminocyclopentanol, bp 98 to 100 ° / 14 mm; UV (EtOH): final absorption; IR: OH 3370, 3200, M-alkyl 2780, CO 1045 cm "1; mass spectrum M + 129; NMR (CDC13): S var (br, 1H exchanged with D2O, OH), 3.9-4.3 (m, 1H, CH), 2.3-2.6 (m, IH, CH), 2.28 [s, 6H, N (CH3) 2], 1.2-2.0 (m, 6H, ring hydrogen atoms) .The analysis (Fumaric acid salt) is shown in Table 1.

Table 1 below summarizes the physical and analytical data for some 2-aminocyclopentanols produced. The individual 2-amino part for each of these compounds is represented by the group in the -NRiR2 column.

The process used to prepare the trans-cyclopentanediamine intermediates is unique and appears to be new. In any case, there is at least an improvement, since previous attempts to produce cyclopentanediamines by a method analogous to cyclohexanediamine chemistry have been very ineffective. More specifically, e.g.

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the reaction of thionyl chloride with cyclohexane-2-amino alcohols is very smooth and gives the cyclohexane-2-amino halides, which then react further with the selected amine to give the cyclo-hexane-1,2-diamines. In the case of the cyclopentane compounds, the reaction of the thioiiyl chloride with the amino alcohol followed by the reaction with the selected amine gives only a small yield of the desired cyclopentanediamine. The main product of such a reaction is compound IX, as the following example 5 shows:

+

IX

In contrast, the use of methanesulfonyl chloride, as shown above in the description, gives a good leaving group (mesylate) and results in considerable yields of the desired 1,2-cyclopendanediamine precursor of the compounds according to the invention. This process cannot be taken for granted on the basis of the corresponding cyclohexane ring chemistry.

Table 1 trans-2-aminocyclopentanols

.OH

NR tRz

Starting material

No.

No, R2

Kp (° C)

Mp (° C)

formula

Analysis calculated found

A

N (CH3) CH2C6H5

134-40 ° / 0.3 mm

95.7o5, a

CI3H19NO.

c4h4o4

C 63.53 H 7.21 N 3.36

C 63.45 H 7.31 N 4.32

B

N (CH3) CH2CH2C6H5

134-40 ° / 0.3 mm

139-41 o5'a

CmH2INO.

1/204-H404

C 69.28 H 8.36 N 5.05

C 69.25 H 7.31 N 5.12

C.

N (CH3) CH2CH = CH2

108-9 ° / 13 mm

-

c9h17no

-

-

D

N (CH3) CH2CH2N-

98 ° / 0.2mm

135-6o4, a

CIOH22N20

..CIHI04

C 51.55 H 7.23 N 6.70

C 51.63 H 7.39 N 6.71

E

N (CH3) CH2CH2CH2-N (CH3) 2

115-8 ° / .0.2 mm

137-8 ° 2, a

CIIH24N20

. c4h4o4

C 52.76 H 7.46 N 6.48

C 53.00 H 7.8 N 6.43

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Table 1 (continued)

Recrystallization solvent

Derivatives a. Methanol ether

I. free base b. Ethanol ether

2. hydrochloride c. Petroleum ether

3. Hydrobromide d. ether

4. Maleate e. Petroleum ether

5. Fumarate f. benzene

6. Oxalate

7. 2-naphthalene sulfonate

8. p-toluenesulfonate

9. Methanesulfonate

II. General procedure for the preparation of trans-1,2-diaminocycloalkanes:

The process is illustrated by the preparation of trans-N, N-dimethyl-N '- (3,4-dichlorophenyl) -1,2-cyclopentanediamine; however, this connection is not in accordance with the invention. Analogous compounds are listed in Table 2. All of the compounds listed have NMR, IR, UV and mass spectra which correspond to those expected due to the structures.

CT

"HMS;

NaH MeSOsC 1 ^

A solution of trans-2- (dimethylamino) cyclopentanol (32.3 g, 0.25 mole) in THF (50 ml) becomes all at once a stirred suspension of sodium hydride (10.5 g, 57 ° 7 oige dispersion in mineral oil , 0.25 mole) in THF (50 ml) and the

table

Mixture refluxed for one hour. To the mixture, which is cooled in an ice bath, methanesulfonyl chloride (28.6 g, 0.25 mole) is added dropwise over 30 minutes. When all of the methanesulfonyl chloride has been added, 5 3,4-dichloroaniline (81.0 g, 0.50 mole) is added all at once. The solvent is distilled off and the residue is heated on a steam bath overnight. Sodium hydroxide (200 ml, 20%) is added and heating is continued for 1 hour. The mixture is extracted with ether. The organic phase is washed with water and extracted with 10% hydrochloric acid. The aqueous phase is washed with ether, made basic with sodium hydroxide (40%) and extracted again with ether. The ether phase is washed with saturated sodium chloride solution, dried (anhydrous MgS (? 4) and concentrated in-i5. The remaining oil is distilled in vacuo and, after a preliminary run consisting mainly of 3,4-dichloroaniline (65, 7 g) consists of 36.2 g (53%) of 3,4-dichloro-N- [2- (dimethylamino-no) cyclopentyl] aniline, bp 160-70 ° / 0.3 mm Formation of the maleic acid salt purified and recrystallized from methanol ether 20. mp 128-29 °; UV (EtOH): A, max (e) 210, 45.450), 257 (19.400), 310 (2300) nm; IR: NH 3380, NH / Acid-OH 2600, 2520, 2400, Co2 / C = C / NH def 1600, 1580, 1480, CH / CCN / Co2 1430, 1350, 1330, other 985, 870, 865 cm "1 ; Mass spectrum: M + 272, 274, 25 (free base); NMR (D2O): 5 7.1 (m, 1H, aromatic), 6.7 (m, 1H, aromatic), 6.5 (m, 1H, aromatic), 6.1 (s, 2H, vinyl, maleic acid), 3.8 (m, 1H, CH), 3.35 (m, 1H, CH), 2.75 [s, 6H, N (CH3) 2], 1.2-2.3 (m, 6H, ring hydrogen atoms).

Analysis calculated for Ci3Hi8Cl2N2. C1H1O1:

Calculated: C 52.45 H 5.70 Cl 18.22 N 7.20 Found: C 52.48 H 5.80 Cl 18.41 N 7.07 Examples of other 2-tertiary aminocyclopentylanilines used in the preparation of the compounds according to the invention can be found in Table 35 below:

No.

Y Z

-No, R2

Kp (° C)

Mp (° C)

formula

Analysis calculated found

AA

H

N (CH3) CH2C6H3

160-75 ° / 0.25 m

109-10 ° 2'a

Ci9H24N2. C4H404

C 69.67 H 7.12 N 7.08

C 69.60 H 7.43 N 6.90

BB

3,4-diCl

N (CH3) CH2CH = CH2

170-80 ° / 0.3 mm

170-2 ° 2, a

Ci5H2ON2C12. 2HC1

C 48.40 H 5.96 N 7.53 Cl 38.11

C 48.36 H 6.15 N 7.54 Cl 38.36

CC

3,4-diCl

N (CH3) CH2CH2 N (CH3) 2

- *

161-2 °

c10h25ci2n3.

2C4H4O4

C 51.25 H 5.91 Cl 12.61 N 7.47

C 1.33 H 6.13 Cl 12.46 N 7.27

DD

3,4-diCl

N (CH3) CH2CH2-CH2N (CH3) 2

- *

155-704.3

C, 7H27CL2N3.

2C4H4Û4

C 52.09 H 6.12 Cl 12.30 N 7.28

C 51.91 H 6.26 Cl 12.53 N 7.23

* isolated with silica gel chromatography

Derivatives

1. free base

2. Hydrochloride

3. Hydrobromide

4. Maleate

5. Fumarate

6. Oxalate

7. 2-naphthalene sulfonate

8. p-toluenesulfonate

9. Methanesulfonate

Recrystallization solvent a. Methanol ether b. Ethanol-ether recrystallization solvent c. Petroleum ether d. Ether e. Petroleum ether f. benzene

652 595

10th

Manufacturing 1

III. General Procedure A for the preparation of trans-N- (2-aminocyclopentyl) anilides using alkanoic anhydrides.

The process is illustrated by the preparation of trans-N- [2 - dimethylamino) cyclopentyl] -3 ', 4'-dichloropropionanilide; however, this connection is not in accordance with the invention. Analogous compounds are listed in Table 3. All of the compounds listed have NMR, IR, UV and mass spectra which correspond to those expected on the basis of the structures attributed to them.

Cl

CH

KHtg i-Cl

'-CzHsCO) r.O heat'

"HMeg he

A solution of 3,4-dichloro-N- [2- (dimethylamino) cyclopentyljaniline (2.73 g, 10.0 moles) in propionic anhydride (10 ml) is heated on a steam bath overnight. Water (100 ml) is added and heating is continued for 1 hour to decompose excess anhydride. The solution is made basic with sodium hydroxide (25 ml, 20% aqueous) and extracted with ether. The extract is washed with saturated sodium chloride solution, dried (MgSO 4 and evaporated to a yellow oil. The crude amide product, 3,4-dichloro-N- [2- (dimethylamino) cyclopentyl] propionanilide is passed through the formation of the maleic acid salt was purified and recrystallized from methanol ether: 3.3 g, (74%), mp. 154-5 °; UV (EtOH): Xmax (e) final absorption, 203 (61.350), 264 (sh, 828 ), 272 (744), 281 (592) nm; IR: NH / acid-OH 2720, 2530, 2490, C = ö / CO2- / C = C 1665, 1620, 1560 C = O / CN / other 1355, 1265, 1030, 865 cm "1; mass spectrum: M + 328, 330, 332, (free base); NMR (d2o): 5 7.6 (m, 1H, aromatic), 7.5 (m, 1H, aromatic) , 7.3 (m, 1H, aromatic), 6.3 (s, 2H, maleic acid), 5.1 (m, 1H, CH), 3.8 (m, 1H, CH), 2.95 [s , 6H, N + (CHjM, 2.0 (q, 2H, ch3ch2co), 1.1-1.9 (m, 6H, ring hydrogen atoms), 0.9 (t, 3H, ch3ch2co).

Analysis calculated for C16H22CI2N2O. C1H1O4:

Calc .: C 53.94 H 5.89 Cl 15.95 N 6.29:

Found: C 53.91 H 5.82 Cl 15.82 N 6.33

Manufacturing 2

IV. General Procedure B for the preparation of trans-N- (2-aminocyclopentyl) anilides using alkanoyl halides.

The process is illustrated by the preparation of trans-N - [2- (dimethylamino) cyclopentyl] -4 '- (a, a, a-trifluoromethyl) propionanilide; however, this connection is not in accordance with the invention. Analogous compounds are listed in Table 3. All of the compounds listed have NMR, IR, UV and mass spectra which correspond to those expected on the basis of the structures attributed to them.

ÇaHs CO

'5 / r ~ ^ CFa _ H— ^ XFa

CsHsCOCl EtsN

20 A solution of propionyl chloride (2.11 g, 22.0 moles) in ether (50 ml) is cooled with ice over a period of 30 minutes to a solution of 4-trifluoromethyl-N- [2-dimethylamino) cyclopentyljaniline (3rd , 10 g, 11.0 moles) and triethylamine (2.30 g, 22.0 moles) in ether (100 ml) were added dropwise. The mixture is stirred at room temperature overnight and then saturated sodium bicarbonate solution (100 ml) is added. The organic layer is washed with water and saturated sodium chloride solution, dried (MgSÛ4) and evaporated to a yellow oil. The crude amide product, 4-trifhiormethyl-N- [2- (dimethylamino) cy-30 clopentyljpropionanilide, is purified by the formation of the hydrochloric acid salt and recrystallized from methanol ether: 3.20 g, (80%), mp. 184 -5 °; UV (EtOH): Xmax (s) final absorption, 231 (sh, 2950), 255 (sh, 1100), 262 (881), 268 (627) nm; IR: N + H2560, C = C 1660, C = C 1615, 1585, 1520, CF3 / ande-35 re 1325, 1320, 1175, 1140, 1115, 1075 cm "1; mass spectrum: M + 328 (free base); NMR (D20): 5 7.9 (m, 4H, aromatic), 2.9 [s, 6H, N + (CH3) 2], 1.4-2.3 (m, 8H, ring hydrogen atoms and ch3ch2co), 0 , 9 (t, 3H, CH3ch2co), other protons not observable due to the broadening.

40

Analysis calculated for Ci7H23F3N20. HCl:

Calc .: C 55.96 H 6.63 Cl 9.72 F 15.62 N 7.68

Found: C 55.97 H 6.85 Cl 9.72 F 15.48 N 7.60

Table 3 below summarizes the physical and analytical data for some compounds of Formula I and indicates the method (A-over the acid anhydride or S-over the acyl halide) used to prepare the compound.

11

652 595

Table 3

By

analysis

Connected raw material

from Table 2

method

Y Z

-nr1r2

Mp (° C)

calculated found

No.

a or B

1 GG

B-l

3,4-diCl

N (CH3)

165-6 ° 2-a

C 47.81

C 47.52

1

H 6.97

H 6.64

CH2CH2

Cl 29.72

Cl 28.98

1

N 8.80

N 8.86

N (CH3) 2

2 HH

B-l

3,4-diCl

N (CH3)

259-60 ° 2'a

C 50.27

C 50.30

1

H 7.07

H 6.99

CH2CH2CH2

Cl 29.68

Cl 29.57

1

N 8.79

N 8.52

N (CH3) 2

3 FF

A-l

3,4-diCl

N (CH3) CH2-

104-6 ° s'a

C 53.94

C 54.14

ch = ch2

H 5.87

H 5.88

N 6.29

N 6.47

CI 15.92

Cl 15.91

4 EE

A-l

3,4-diCl

N (CH3) CH2-

120-1 ° 6'a

C 56.14

C 56.10

c6h5

H 5.89

H 6.23

N 5.46

N 5.21

Cl 13.81

Cl 13.26

90-1 ° 6'a C 57.67 C 57.52

H 6.32 H 6.23

N 5.17 N 4.98

Cl 13.09 Cl 12.62

Procedure A

1. Propionic anhydride

2. Acetic anhydride

3. Butyric anhydride

Procedure b

1. Propionyl chloride

2. Cyclopropanecarbonyl chloride

3. Acryloyl chloride

4. Cyclobutane carbonylchloride

5. Cyclohexane carbonyl chloride

6. Isobutyryl chloride

7. Ethyl chloroformate

8. Methoxyacetyl chloride

I.

ch2ck2c «h.

A-l

3,4-diCl N (CH3)

I.

CH2CH2C6H5

Footnotes to Table 3

Derivatives

1. free base

2. Hydrochloride

3. Hydrobromide

4. Maleate

5. Fumarate

6. Oxalate

7. 2-naphthalene sulfonate

8. p-toluenesulfonate

9. Methanesulfonate

Recrystallization solvent a. Methanol ether b. Ethanol ether c. Petroleum ether d. Ether e. Petroleum ether f. Benzene g. Dioxane

Preparation C: Preparation of trans-3,4-dichloro-N- [2- (N-me-

thyl-N- (dimethylaminopropylamino) cyclopentyl] propionanilide-

-2-N-oxide

3.5 g (0.015 mol) of 85% m-chloroperbenzoic acid in 50 ml of chci3 are added dropwise with ice cooling over the period of 30 minutes to 3.29 g (0.01 mol) of trans-3,4-dichloro - N- [ 2- (N-methyl-N-dimethylaminopropylamino) cyclopentyl] propionanilide (see compound 1). The mixture is stirred at room temperature overnight and then evaporated to dryness. A viscous oil is obtained. This oil is treated with 50 ml ether, creating a two-phase system. This mixture is mixed with 100 g of silica gel (glass

frit) filtered and eluted with 1500 ml ether, followed by 500 ml MeOH. The methanol is evaporated off, leaving a residue which is dissolved in warm dioxane. The solution is filtered to remove foreign material and then diluted with ether to the point of flocculation. Crystals form and these are recrystallized from dioxane ether at room temperature.

65 Preparation D: Preparation of cis-3,4-dichloro-N- [2- (N-methyl-N-phenethylamino) cyclopentyl] propionanilide

Part A: A solution of 3,4-dichloroaniline (220 g, 1.23

652 595

12

Mol), cyclopentene oxide (400 ml) and conc. HCl (2 ml) is heated under reflux for 7 days. The unreacted epoxy is evaporated at 60 ° and the residue is treated with excess ethereal hydrochloric acid to form a syrup. This is washed with 1000 ml ether. The crystalline residue is recrystallized from methanol ether (1 / 5.5, v / v), and gives 170.0 g (49% yield) of 3,4-dichloro-N- [2-hydroxycyclopentyl] aniline - hydrochloric acid salt.

Part B: Proponic anhydride (208 g, 1.6 mol) and the free io base of Part A (113.2 g, 0.40 mol base) are mixed and heated on a steam bath overnight. 350 ml of water are added and heating is continued for 1 hour. After cooling in ice, the reaction mixture is neutralized with 240 ml of 40% sodium hydroxide solution (2.4 mol) and extracted with ether. The ether extract is extracted in succession with saturated NaHCC> 3,

Washed water, 10% HCl, water and saturated NaCl, dried the organic layer over MgSO4 and then evaporated to a brown oil. This oil is then dissolved in 500 ml of 95% EtOH and 26.4 g (0.4 mol) of 85% KOH are added. With gentle heating, the solution is stirred for 3 hours. The ethanol is removed by evaporation. The residue is treated with 800 ml of ether and 250 ml of water. The organic layer is washed successively with water, 10% hydrochloric acid and saturated sodium chloride solution and dried (MgS04). The solution is concentrated by distillation. The subsequent treatment with petroleum ether gives 87.7 g (72% yield) of 3,4-dichloro-N- [2-hydroxycyclopentyl] propionanilide.

30th

Part C: 75 ml of Jones reagent (oxidizing) are added dropwise to an ice-cold solution of 60.4 g (0.20 mol) of the product from Part B in 1000 ml of acetone. The reaction mixture is stirred for 30 minutes at room temperature and then filtered. The filtrate is concentrated under reduced pressure. The residue is taken up in 500 ml of ether and this solution is washed 3 times first with water and then with saturated sodium chloride solution, dried over MgSO4 and the solvent is evaporated off. A yellow oil remains, which solidifies when left to stand. 44.4 g (74% yield) of 3,4-dichloro-N- [2-oxocyclopentyl] propionanilide are obtained as a sticky solid.

Part D: A solution of N-methyl-N-phenethylamine (0.24 mol) and its ethylamine hydrochloride (9.8 g, 0.12 mol) in 250 ml of MeOH is prepared and 18.0 g (0 , 06 mol) of the ke-clay from part C in 1 time. 2.65 g (0.042 mol) of sodium cyanoborohydride and 3A molecular sieve (25 g) are also added to this mixture all at once. The whole mixture is stirred for 8 days at room temperature. After this time, 10% hydrochloric acid is added to the solution until no more gas escapes. It is filtered through a filter aid (Celite®) to remove the molecular sieves and a small amount of insoluble material. The methanol is evaporated off, and the remaining aqueous layer, after having been washed with ether, is made basic with 50 ml of 40% sodium hydroxide solution and amorphous solid residues are filtered off. The residue is washed with ether and the filtrate extracted with ether. The ether extracts are washed with saturated sodium chloride solution, dried (MgSO4) and evaporated to a tan oil (6.1 g). Chromatography on 150 g of silica gel (2% MeOH in chci3) gives several 20 ml fractions. The fractions which are homogeneous on the basis of thin-layer chromatography are combined, concentrated and give an oil which is converted to the oxalic acid salt in MeOH / ether (1: 5, v / v). A solid is created. This solid is the cis-3,4-dichloro-N- [2- (N-methyl-N-phenethylamino) cyclopentyl] propionanilide oxalic acid salt.

Preparation of trans-3,4-dichloro-N- [2- (dimethylamino) -cyclopentyljthiocyclohexane carboxanilide:

A solution of 0.025 mol of 3 ', 4'-dichloro-N- [2- (dimethylamino) cyclopentyl] cyclohexane carboxanilide and phosphorus pentasulfide (6.1 g, 0.028 mol) in 250 ml of pyridine is heated under reflux overnight. The pyridine is then removed by distillation at about 100 ° in vacuo. The residue is treated with 250 ml of chci3 and 200 ml of saturated aqueous sodium bicarbonate solution and stirred for one hour. The organic layer is diluted with 250 ml of ether and washed successively with 200 ml of water and 250 ml of saturated sodium chloride solution, dried (anhydrous MgS04) and evaporated to a red-brown oil. This oil is mixed twice with hot petroleum ether. A yellow solution and a red solid form. The yellow solution is washed with water, dried (MgS04) and evaporated to an oil. The oxalic acid salt is prepared from the oil and 0.011 mol of the acid in 25 ml of methanol and 200 ml of ether. The oxalic acid addition salt of the title compound is obtained by recrystallization. This is not according to the invention because of Ri = r2 = ch3; the compounds described below (where R 1 and R 2 can be hydrogen atoms, either individually or simultaneously) can be used in the pharmaceutical formulation examples described above as the essential, active, anti-depressive component in a chemically equivalent amount. For example, the compounds 3,4-dichloro-N- [2- (N-methylamino) -cyclopentylIcy-clohexane carboxanilide, 3,4-dichloro-N- [2-aminocyclopentyl) acrylanilide, 3,4-dichloro-N- [2- (N-methlylamino) cyclopentyl] cyclopropane carboxanilide, 3,4-dimethyl-N- [2- (N-methylamino) cyclopentyl] carbäthoxyanilide or 3,4-dichloro-N- (2-amino-cyclopentyl) methoxyacetanilide or their pharmacologically acceptable addition salts can be used.

The trans compounds of the formula given, in which Ri and R2 represent hydrogen atoms or one of the radicals Ri and R2 represents a hydrogen atom and the other has the meaning indicated and in which p, Q, R. Y and Z also correspond to the definitions given, can be obtained as follows:

+ HaH

purple

<x

IX

i

1) cxsojii

2) R] NHZ or nu4oh

125 ° C, 48 h (autoclave)

rr "" 8

-N-COCHaCClj I

ß I

«

0

I!

CIC0CH2CC13

XI

NH— (

-NH I

Ri

0

(RC) 0

V

13

652 595

he

C = 0 y n-cochkcci3 i

Ri

XII

Zn

.Acetic acid

ROO v

• NH i

Ri

XIII

The reaction of the cyclopentene oxide of the formula lilac with an aniline under known conditions provides the N- (2- ■ -hydroxycyclopentyl) aniline of the formula IX, which, when reacted with chlorosulfonic acid in a non-polar organic solvent, for example methylene chloride, at one temperature from 20 ° to 30 ° C and then heating together with a suitable aqueous Cr to c3-monoalkylamine or aqueous ammonium hydroxide to a temperature of 100 ° to 150 ° C for 40 to 55 h at elevated pressure (2 to 10 atm) the diamine Formula X delivers. When the diamine of the formula X is reacted with 2,2,2-trichloroethyl chloroformate or an equivalent N-blocking compound or an equivalent N-blocker at a temperature of 20 ° to 30 ° C. for 1 to 5 h in the presence of an acid scavenger, e.g. Triethylamine, the 2- (N-blocked amino) compound of the formula XI is obtained. An acylation of the N-blocked compound of formula XI with the desired acid anhydride o

II

of the formula (rq2o by heating to a temperature of 90 ° to 120 ° C. for 12 to 30 hours provides the N-blocked anilide of the formula XII. Unblocking or removal of the protective part of the 2-amino function of the 2-N-blocked anilide of the Formula XII is achieved by reaction with an N-deblocking agent or N-deblocker, for example metal dust in an acid, such as zinc in acetic acid, in a polar organic solvent, for example in methanol at a temperature of 20 ° to 100 ° C. for 2 up to 6 hrs. For working up isolation and cleaning, standard organic processes are used in organic chemistry.

The cis isomeric compounds of the formula:

r.

\

c = 0

(XIV)

(XV)

10 with a known oxidizing agent, e.g. Jones reagent, to a ketone of the formula

(XVI)

that in the presence of an R2NH2 amine. a reducing agent, for example sodium cyanoborohydride, a mixture of isomeric aminoanilides of the formula:

(XVII)

is obtained by oxidation of a 2-hydroxycyclopentylanilide of the formula:

delivers. Chromatographic separation of the two isomers gives the cis-aminoanilide of the formula VIX, in which R2 corresponds to the general definition.

A preferred group of the above type of compounds, 40 including those where R2 is hydrogen, as well as their pharmaceutical preparation forms, are those in which R is ci- to c3-alkyl, preferably ethyl, Ri is hydrogen and R2 is N, N-dimethylaminoethyl or N, Is N-dimethylaminopropyl, and at least one of the radicals Y and Z is a halogen atom of 45 atomic numbers from 9 to 35 in the 3- or 4-position, Y is a trifluoromethyl radical in the 3-position and Z is a hydrogen or a methyl radical in 3- or 4-position in combination with one of the halogen atoms mentioned in the adjacent 3- or 4-position, or their pharmacologically acceptable salts. Examples of such connections include the following:

3,4-dichloro-N- [2- (N ', N'-dimethylaminoethylamino) cyclopentyl] propionanilide;

3-trifluoromethyl-N- [2- (N ', N'-dimethylaminopropylamino) cyclopentylcyclopropanecarboxanilide;

55 3,4-dichloro-N- [2- (N ', N'-dimethylaminoethylamino) cy.clopentyl] cyclobutane carboxanilide;

3-chloro-4-methyl-N- [2- (N ', N'-dimethylaminopropylamino) cyclopentyl] propionanilide;

4-chloro-3-methyl-N- [2- (N ', N'-dimethylaminoethylamino) -60 cyclopentyljcarbäthoxyanilid; .

3-chloro-N- [2- (N ', N'-dimethylaminopropylamino) cyclo-pentylj-propionanilide; "

4-chloro-N- [2- (N ', N'-dimethylaminoethylamino) cyclopentyl] methoxyacetanilide;

65 3,4-dichloro-N- [2- (N ', N'-dimethylaminopropylamino) cyclopentyl] propionanilide; and

3-fluoro-N- [2- (N ', N'-dimethylaminoethylamino) cyclopentyl acrylamide;

652 595

14

these compounds are preferably in the trans configuration, as well as their pharmacologically acceptable salts.

The latter preferred group of compounds with a mono-N, N-dimethylaminoethyl or N, N-dimethylamino-propyl substituted amino group in the 2-position of the cyclopentyl ring show anti-depressive properties in standard laboratory animal tests, such as e.g. in the standard yohimbine toxicity percentage and oxotremorine hyperthermia antagonism tests, which indicates quite effective anti-depressive properties of these compounds.

example 1

trans-3,4-dichloro-N- [2- (N, N-dimethylaminoethylamino) cyclopentyljcyclopropane carboxanilide and its p-toluenesulfonate salt.

A. trans-N- (2-hydroxycyclopentyl) -3,4-dichloroaniline and its hydrochloride salt

A solution of 3,4-dichloroaniline (200 g, 1.28 mol), cyclopentene oxide (400 ml) and concentrated HCl (2 ml) is heated to reflux temperature for 7 days. The unreacted epoxide is evaporated at 60 ° C and the residue is treated with excess ethereal HCl, creating a syrup. This is washed with 1000 ml ether. The residue is allowed to crystallize and recrystallized from methanol / ether (1: 5.5; v / v) to obtain 170.0 g (49% yield) of trans-3,4-dichloro-N- (2-hydroxycyclopentyl) ani-linhydrochloride salt.

B. trans-3,4-dichloro-N- (2-sulfonyloxycyclopentyl) aniline

To a stirred solution / suspension of 283 g (1.0 mol)

of the amino alcohol salt from part A, trans-3,4-dichloro-N- (2-hydroxycyclopentyl) aniline hydrochloride, in 2 liters of methylene chloride, 129 g (1.1 mol) of chlorosulfonic acid in 500 ml of methylene chloride are added over a period of 4 hours. A complete solution of the amino alcohol is achieved when half of the acid solution has been added. The mixture is heated overnight. The formed precipitate is collected, washed with methylene chloride and ethyl ether and dried in an oven at 45 ° C. The title product is obtained in 81% yield (263 g). A sample becomes dark at temperatures above 200 ° C and melts, with decomposition, at 217 to 218 ° C.

C. trans-3,4-dichloro-N- [2- (N ', N'-dimethylaminoethylamino) cyclopentyl] aniline and its dihydrochloride salt

A portion of 3,4-dichloro-N- (2-sulfonyloxycyclopentyl) aniline is reacted with an equimolar amount of N ', N'-dimethylaminoethylamine in water in an autoclave at 125 ° C. for 48 hours, during which trans-3, Forms 4-dichloro-N- [2- (N ', N' - dimethylaminoethylamino) cyclopentyl] aniline in solution.

The reaction product mixture is washed with a 1/1 v / v water / ethyl ether mixture. The organic layer is separated from the aqueous layer and the aqueous layer is extracted with ethyl ether. The combined ether layers are washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to an oil. This oil is chromatographed on ethyl acetate and methanol. The later fractions contain the amine product, trans-3,4-dichloro-N- [2- (N ', N'-dimethylaminoethylamino) cyclopentyl] aniline. After evaporation of the solvent, the amine fractions give an orange oil. This oily amine product is converted to its hydrochloride salt with an excess of ethyl ether / hydrochloric acid solution. The amine hydrochloride salt is recrystallized from methanol and ethyl ether.

A further attempt at this reaction, starting from amino alcohol and not isolating the intermediate 2-sulfonyloxy compound, is carried out as follows:

To a stirred solution of amino alcohol salt, trans - 3,4-dichloro-N- (2-hydroxycyclopentyl) aniline hydrochloride in chloroform is added chlorosulfonic acid in chloroform over a period of 15 minutes. The mixture is placed in a hot water bath to accelerate the evolution of hydrochloric acid gas by-product. The resulting reaction mixture solution is evaporated and the residue mixed with N ', N'-dimethylaminoethylamine. The resulting mixture is heated to 125 ° C. overnight in a bomb reactor. The resulting reaction mixture is cooled and extracted with ethyl ether. The ether extracts are washed with saturated sodium chloride solution, dried over magnesium sulfate and then evaporated to an oil. The oil is chromatographed on silica gel by eluting with ethyl acetate to remove the amino alcohol starting material. The oil in the chromatography column is then eluted with methanol and, after evaporation of the solvent, gives a crude oil product. This oily title amine product, trans-3,4-dichloro-N- [2- (N ', N'-dimethylaminoethylamino) cyclopentyl] aniline, is converted to its hydrochloride with an excess of ethyl ether / hydrochloric acid solution and then recrystallized from methanol in ethyl ether.

D. trans-3,4-dichloro-N- {2- [N- (N ', N, -dimethylaminoethyl) - N- (trichloroethoxycarbonyl) amino] cyclopentyl} aniline hydrochloride

To an equimolar mixture of triethylamine and free diamine, trans-3,4-dichloro-N- [2- (N ', N'-dimethylamino-ethylamino) cyclopentyl] aniline, which has been released from its hydrochloride salt with sodium hydroxide, in ethyl ether , you add an equimolar amount of 2,2,2-trichloroethyl chloroformate in ethyl ether. The mixture is stirred at room temperature for 2 hours. Then saturated sodium bicarbonate solution is added. The organic layer is dried over magnesium sulfate and concentrated to an oil. This oil is converted to its hydrochloride salt (title salt) by treatment with an excess of ethereal hydrochloric acid. This salt is recrystallized from a mixture of methanol and ethyl ether.

E. trans-3,4-dichloro-N- {2 - [(N ', N'-dimethylaminoethyl) (- N-trichloroethoxycarbonyl) amino] cyclopentyl} cyclopropane carboxanilide

A mixture of the aniline, prepared as in Part D above and converted to its free base, and an equimolar amount of cyclopropanecarboxylic anhydride is heated on the steam bath overnight. Then water is added and the mixture is further heated for 1 hour. The mixture is diluted with ethyl ether. The organic layer is washed with 15% sodium hydroxide solution and with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to an oil, the cyclopropanecarboxanilide named in the title.

In another experiment, in which two steps were performed without isolating the 2-N-blocked amine from part D, 2,2,2-trichloroethyl chloroformate in ethyl ether was added to a mixture over a period of half an hour while cooling with ice equimolar amounts of triethylamine and amine, trans-3,4-dichloro-N- [2- (N ', N'-dimethylaminoethylamino-no) cyclopentyl] aniline, released from its hydrochloride salt, in ethyl ether. After stirring at room temperature for 2 hours, aqueous sodium bicarbonate solution is added. The organic layer is washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to an oil. Then, cyclopropanecarboxylic acid is added to the oil and the solution is heated on a steam bath overnight. Water is then added and the mixture is heated with stirring. The mixture is made basic with 15% sodium hydroxide solution and with

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

15

652 595

Extracted ethyl ether. The ether extract is washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to an oily product, the cyclopropanecarboxanilide mentioned in the title.

F. trans-3,4-dichloro-N- [2- (N ', N'-dimethylaminoethylamino) cyclopentyl] cyclopropanecarboxanilide and its p-toluenesulfonate salt.

The N-blocked cyclopropanecarboxanilide from part E above and a large excess of zinc dust in 5% glacial acid in methanol are stirred at room temperature for 3 hours, refluxed for 1 hour and cooled again to room temperature. The mixture is filtered using a filter aid (Celite®), and washed with methanol. The solvent is evaporated and the residue is treated with 5N ammonium hydroxide and ethyl ether. The ether extract is washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to an oil, the cyclopropanecarboxanilide mentioned in the title. This cyclopropanecarboxanilide is converted to its para-toluenesulfonate salt by treating the oil with para-toluenesulfonic acid in methanol and ethyl ether.

The spectra correspond to those of an authentic sample.

Preparation E: trans-3,4-dichloro-N- [2- (N ', N'-dimethylaminopropylamino) cyclopentyl] propionanilide and its β-naphthylsulfonate salt

A. trans-3,4-dichloro-N- [2- (N ', N'-dimethylaminopropylamino) cyclopentyl] aniline and its hydrochloride.

A mixture of 3,4-dichloro-N- (2-sulfonyloxycyclopen-tyl) aniline (from Example 59, Part B) and an excess of N ', N'-dimethylaminopropylamine is in a sealed ampoule at 125 ° for 48 hours C. heated. The mixture is then cooled to room temperature. The contents of the ampoule are dissolved in a mixture of ethyl ether and water. The ether phase is washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated to an oil. This oil is chromatographed on silica gel by eluting with ethyl acetate and methanol. After most of the methanol has been evaporated from the amine, the residue is treated with an excess of ethyl ether / hydrochloric acid solution to form the amine hydrochloride salt. The salt is recrystallized from a mixture of methanol and ethyl ether to give the title amine hydrochloride salt.

B. trans-3,4-dichloro-N- {2- [N- (trichloroethoxycarbonyl) -N - (N ', N'-dimethylaminopropyl) amino] cyclopentyl} aniline and its hydrochloride salt.

To an amine mixture of part A above released from its hydrochloride salt and an equimolar amount of triethylamine in ethyl ether, cooled in ice, is added an equimolar amount of 2,2,2-trichloroethyl chloroformate in ethyl ether. The resulting mixture is stirred at room temperature for a weekend.

Then saturated sodium bicarbonate solution is added. The organic layer is washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated to an oil, the aniline mentioned in the title. The hydrochloride salt is obtained by treating the oily residue with excess ether / hydrochloric acid solution. The salt is recrystallized from a mixture of methanol and ethyl ether to give the title aniline salt.

C. trans-3,4-dichloro-N- {2- [N- (2,2,2-trichloroethoxycarbonyl) -N- (N ', N'-dimethylaminopropyl) amino] cyclopentyl} propionanilide.

A mixture of trans-3,4-dichloro-N- {2- [N- (2,2,2-tri-

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chloroethoxycarbonyl) -N- (N ', N'-dimethylaminopropyl) amino] -cyclopentytyaniline and from an equimolar amount of propionic anhydride is heated on a steam bath overnight. Then water is added and the mixture is heated for a further 5 hours. The mixture is diluted with ethyl ether. The organic layer that forms is separated from the aqueous layer, washed with 15% sodium hydroxide solution and with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to a solid - the N-blocking propion mentioned in the title -anilide compound.

D. trans-3,4-dichloro-N- [2- (N ', N'-dimethylaminopropylamino) cyclopentyl] propionanilide and its β-naphthylsulfonate salt.

15 A mixture of trans-3,4-dichloro-N- [2-N- (2,2,2-tri-chloroethoxycarbonyl) -N- (N ', N'-dimethylaminopropyl) amino-cyclopentyl] propionanilide from the above part C and a large molar excess of zinc dust in 15% acetic acid in methanol solution is stirred at room temperature overnight. This mixture is filtered through a filter aid (Celite®) and washed with methanol. The filtrate is concentrated and the residue is heated with 5N ammonium hydroxide and ethyl ether. The ether layer is washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to an oil. This is in its napsylate salt (ß-naphthylsulfonic acid) in methanol / ethyl. ether solution converted by using an equimolar amount of ß-naphthylsulfonic acid.

Preferred subgroups of the compounds of the formula I contained in the compositions for the treatment of depression in humans and for use in compositions according to the invention of pharmaceutical compositions for administration to patients to treat depression include the following:

(1) compounds where p is zero; Q oxygen; R Ci to C3 alkyl; R, Cr to C3 alkyl; R2 is -CH2CH2N (CH3) 2 or -CH2CH2ch2n (CH3) 2, and at least the radicals Y and Z

. a halogen atom with an atomic number of 9 to 35 in the 3- or 40 4-position, Y a trifluoromethyl radical in the 3-position and Z a hydrogen 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, or their pharmacologically acceptable salts. Examples of such compounds are 3,4-di-45 chloro-N- {2- [N-methyl-N- (N ', N'-dimethylaminoethyl) amino] cyclopentyl} propionanilide, 3,4-dichloro-N- { 2- [N-methyl-N - (N ', N'-dimethylaminopropyl) amino] cyclopentyl} propionanilide or their pharmacologically acceptable salts.

(2) compounds where p is zero; Q oxygen; R C3 to Q-50 cycloalkyl; Ri hydrogen; R2 -CH2Ch2N (CH3) 2 or -CH2-

CH2CH2N (CH3) 2 and at least one of the radicals Y and Z is a halogen atom with an atomic number of 9 to 35 in the 3- or 4-position, Y is a trifluoromethyl radical in the 3-position and Z is a hydrogen or a methyl radical in 3- or 4- Position in combination with one of the halogen atoms mentioned in the adjacent 3- or 4-position, or their pharmacologically acceptable salts. Examples of such compounds are 3,4-di-chloro-N- [2- (N ', N'-dimethylaminoethylamino) cyclopentyl] cyclo-propanecarboxanilide, 3-methyl-4-chloro-N- [2- (N', N '-dimethyl-60 aminopropylamino) cyclopentyl] cyclopentanecarboxanilide, or their pharmacologically acceptable salts.

(3) compounds where p is zero; Q oxygen; R is a methoxymethyl, ethoxy or vinyl radical; Ri is hydrogen, R2 -CH2-CH2N (CH3) 2 or -CH2CH2CH2N (CH3) 2, and at least one

65 of the radicals Y and Z are a halogen atom with an atomic number of 9 to 35 in the 3- or 4-position, Y is a trifluoromethyl radical in the 3-position and Z is hydrogen or a methyl radical in the 3- or 4-position in combination with one of the halogen atoms mentioned in the

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is adjacent 3- or 4-position, or their pharmacologically acceptable salts. An example of such a compound is 3,4-dichloro-N- {2- [N ', N'-dimethylaminopropyl) amino] cyclopentyljacrylanilide or its pharmacologically acceptable salts.

(4) compounds where p is zero; Q oxygen; R is a vinyl, ethoxy or methoxymethyl radical; Ri is a Cr to c3 alkyl radical; R2 -CH2CH2N (CH3) 2 or -CH2ch2ch2N (CH3) 2, 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, Y is a trifluoromethyl radical in

3-position and Z is a hydrogen or a methyl radical in 3- or

4-position in combination with one of the halogen atoms mentioned in the adjacent 3- or 4-position, or their pharmacologically acceptable salts. Examples of such compounds are 3,4-dichloro-N- {2- [N-methyl-N- (N ', N'-dimethylaminoethyl) amino] cyclopentyl] methoxyacetanilide, 3,4-dichloro-N- {2 - [N-methyl-N- (N ', N'-dimethylaminopropyl) amino] cyclopentyl} carbäthoxyanilid or their pharmacologically acceptable salts.

Another preferred sub-group of compounds which can be used in the anti-depressive pharmaceutical compositions according to the invention are those where: R is a vinyl, C3 to C0-cycloalkyl, ethoxy or methoxymethyl radical, Ri and R2 both hydrogen atoms or Ri or R2 a hydrogen atom and the other of R 1 and R 2 are a Q to C3 alkyl radical, preferably a methyl radical, and at least one of the radicals Y and Z is a halogen atom with an atomic number of 9 to 35, preferably in the 3 or 4 position, a 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 adjacent 3- or 4-position, or their pharmacologically acceptable salts. Examples of such connections include the following:

3,4-dichloro-N- [2- (N-methylamino) cyclopentyl] cyclopropane carboxanilide;

3-trifluoromethyl-N- [2- (N-methylamino) cyclopentyl] cyclo-hexane carboxanilide;

3,4-dichloro-N- [2- (N-ethylamino) cyclopentyl] acrylanilide;

3-chloro-4-methyl-N- [2-aminocyclopentyl] carbäthoxyanilid;

3,4-dichloro-N- (2-aminocyclopentyl) acrylanilide;

4-chloro-3-methyl-N- [2- (N-methylamino) cyclopentyl] meth-oxyacetanilide;

3-chloro-N- [2- (N-methylamino) cyclopentyl] cyclobutancar boxanilide;

4-chloro-N- [2-aminocyclopentyl] cyclopentane carboxanilide;

2-bromo-N- [2-aminocyclopentyl] acrylanilide; and

3-fluoro-N- [2- (N-methylamino) cyclopentyl] carbäthoxyanilid; the compounds in the trans configuration and their pharmacologically acceptable salts are preferred.

This latter preferred group of compounds with an unsubstituted amino group in the 2-position of the cyclopentyl ring shows strong anti-depressant properties in the standard laboratory animal tests, such as in the standard yohimbine toxicity potentiation and oxotremorine hyperthermia antagonism tests, which anti- indicates depressive properties.

Example 2

trans-3,4-dichloro-N- [2- (N-methylamino) cyclopentyl] -

cyclopropanecarboxanilide and its p-toluenesulfonate salt.

Procedure A.

trans-N- (2-hydroxycyclopentyl) -3,4-dichloroaniline and its hydrochloride salt.

A solution of 3,4-dichloroaniline (200 g, 1.23 mol), cyclopentene oxide (400 ml) and concentrated HCl (2 ml) is heated at the reflux temperature for 7 days. The unreacted epoxy is evaporated at 60 ° C and the residue is treated with excess ethereal hydrochloric acid solution, whereby a syrup is formed. This is washed with 1000 ml ether. The residue is allowed to crystallize and recrystallized from methanol / ether (1 / 5.5, v / v), which gives 170.0 g (49% yield) of trans-3,4-dichloro-N- (2-hydroxy- cyclopentyl) aniline hydrochloride salt.

B. trans-3,4-dichloro-N- (2-sulfonyloxycyclopentyl) aniün.

To a stirred solution / suspension of 283 g (1.0 mol)

of the amino alcohol salt from part A, trans-3,4-dichloro-N- (2-hydroxycyclopentyl) aniline hydrochloride salt, in 2 liters of methylene chloride, 129 g (1.1 mol) of chlorosulfonic acid in 500 ml of methylene chloride are added over a period of 4 Hours. A complete solution of the amino alcohol is achieved when the addition of the acid solution has been completed. The mixture is stirred overnight. The precipitate that forms is collected, washed with methylene chloride and ethyl ether and dried in an oven at 45 ° C. The product (A) is obtained in 81% yield (263 g). A sample turns dark at temperatures above 200 ° C and melts with decomposition at 217 to 218 ° C.

C. trans-3,4-dichloro-N- [2- (N-methylamino) cyclopentyl] aniline and its dihydrochloride salt.

An amount of 228 g (0.7 mol) of 3,4-dichloro-N- (sulfonyloxycyclopentyl) aniline is reacted with 700 ml of 40% monomethylamine solution in water at 125 ° C. for 48 hours, where trans-3,4-dichloro-N- [2- (N-methylamino) cyclopentyljaniline is formed in solution.

The reaction product mixture (about 1500 ml) is washed with a 1/1 (v / v) water / ethyl ether mixture. The organic layer is separated from the aqueous layer, and the aqueous layer is extracted with 500 ml of ethyl ether. The combined ether layers are washed with 500 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated to a brown oil. This brown oil is chromatographed on 1500 g of silica gel by eluting with 10 liters of ethyl acetate and 10 liters of methanol and collecting 200 ml fractions. Fractions 6 to 10 contain the diamine product, trans-3,4-dichloro-N- [2- (N-methylamino) cyclopentyl] aniline. The preliminary run (fractions 1 to 5) is a mixture. The forerun is again chromatographed on 500 g of silica gel by eluting with 3000 ml of ethyl acetate and 2000 ml of methanol and collecting the eluates in 500 ml fractions. Fractions 2 to 4 of this second chromatography represent a preliminary run. Fractions 5 to 10 contain more of the amine product. After evaporation of the solvent, the diamine fraction gives 159 g of an orange oil. This oily diamine product is converted to its hydrochloride salt with excess ethyl ether / hydrochloric acid solution. The diamine hydrochloride salt is recrystallized from approximately 1000 ml of methanol and 1200 ml of ethyl ether. The subtitled diamine hydrochloride salt weighs 164.6 g, which corresponds to a yield of 71% (mp. 185 ° to 187 ° C, with foaming).

In a further synthesis, starting from the amino alcohol, and without purifying the intermediate, i.e. the 2-sul-fonyloxy compound, the procedure is as follows:

A stirred solution of 28.2 g of the amino alcohol salt, trans-3,4-dichloro-N- (2-hydroxycyclopentyl) aniline hydrochloride, in 200 ml of chloroform is mixed with 12.9 g of chlorosulfonic acid in 50 ml of chloroform within 15 minutes. The reaction mixture is then placed in a warm water bath to accelerate the escape of the hydrogen chloride formed as a by-product. The reaction mixture is then concentrated, whereupon the residue is dissolved in 100 ml of 40% aqueous monomethylamine solution. The mixture obtained is then reacted overnight in a bomb reactor at a temperature of 125 ° C. The reaction mixture obtained is cooled and extracted with 500 ml of ethyl ether. The ether extract is mixed with 200 ml of saturated sodium5

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washed chloride solution, dried over magnesium sulfate and finally concentrated to a yellow oil. The oil obtained is chromatographed on 300 g of silica gel. To remove the amino alcohol starting material, the silica gel is eluted with 3 liters of ethyl acetate. The oil is then eluted in the chromatography column with 3 liters of methanol, 6.5 g of an oily crude product being obtained after evaporation of the solvent in 25% yield. The oily diamine product obtained, trans-3,4-dichloro-N- [2- (N-methylamino) cyclopentyl] aniline, is converted into its hydrochloride salt with excess ethereal hydrochloric acid. This is recrystallized from 40 ml of methanol in about 300 ml of ethyl ether, 6.4 g of the diamine hydrochloride salt having an mp of about 175 ° C. (with softening and foaming) being obtained in a 19% yield. The nuclear magnetic resonance, IR, UV and mass spectra agree with the expected spectra of the diamine salt.

The elemental analysis of the compound C12H12N2CI2. 2HC1 gives the following values:

Calculated: C 43.40 H 5.46 N 8.44 Cl 42.71

Found: C 43.74 H 5.43 N 8.41 Cl 42.63

D. trans-3,4-dichloro-N- [2- (Nmethyl-N-trichloroethoxycarbonylamino) cyclopentyl] aniIin hydrochloride.

A mixture of 3.03 g (0.03 mol) of triethylamine and 9.96 g (0.03 mol) of the free diamine, trans-3,4-dichloro-N - [2- (N-methylamino) cyclopentyl] Aniline, which was obtained with the aid of sodium hydroxide from its hydrochloride salt, in 250 ml of ethyl ether is mixed with 6.36 g (0.03 mol) of 2,2,2-trichloroethylchloroformate in 50 ml of ethyl ether, whereupon the reaction mixture for 2 hours is stirred at room temperature. Then 100 ml of saturated sodium bicarbonate solution are added. The organic layer is dried over magnesium sulfate and concentrated to a yellow oil. This is converted into its hydrochloride salt by treatment with excess ethereal hydrochloric acid. The hydrochloride salt obtained is recrystallized from a mixture of 120 ml of methanol and 400 ml of ethyl ether, 11.25 g of trans-3,4-dichloro-N- [2- (N-methyl-N-trichloroethoxy) being obtained in 80% yield. carbonylamino) cyclopentyl] aniline hydrochloride. The nuclear magnetic resonance, IR, UV and mass spectra agree with the corresponding spectra of trans-3,4-dichloro-N- [2- (N-methyl-N-trichloroethoxycarbonylamino) cyclopentyI] aniline.

E. trans-3,4-dichloro-N- [2- (N-methyl-N-trichloroethoxycarbonylamino) cyclopentyl] cyclopropanecarboxanilide.

A mixture of the 2-N-blocked diamine, prepared according to Part D above and converted to the free base, and from an equimolar amount of cyclopropanecarboxylic anhydride is heated on the steam bath overnight. Then water is heated. The mixture is diluted with ethyl ether. The organic layer is washed with 15 ° -7% sodium hydroxide solution followed by saturated sodium chloride solution, dried over magnesium sulfate and evaporated to an oil: the subtitled cyclopropane carboxanilide.

In another 2-step synthesis, in which the 2-N-. blocked diamine (part D) is not isolated, 10.6 g (0.06 mol) of 2,2,2-trichloroethyl chloroformate in 50 ml of ethyl ether are added to a mixture of 5.06 g over a period of half an hour with ice cooling ( 0.05 mol) of the triethylamine and 16.6 g (0.05 mol) of the diamine, trans-3,4-dichloro-N- [2-N-methylamino) cyclopentyl] aniline, which was released from its hydrochloride salt is in 400 ml of ethyl ether. After stirring for 2 hours at room temperature, 200 ml of saturated aqueous sodium bicarbonate solution are added. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to a yellow oil. Cyclopropanecarboxylic anhydride is then added to the oil and the solution is heated on a steam bath overnight. Then water is added and the mixture is continued during

Heating continued for 1 hour with stirring. The mixture is made basic with ISVoiger sodium hydroxide solution and extracted with ethyl ether. The ethyl ether extract is washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to give an oil, the subtitled cyclopropanecarboxanilide.

F. trans-3,4-dichloro-N- [2- (N-methylamino) cyclopentyl] cyclopropanecarboxanilide and its p-toluenesulfonate salt.

The N-blocked cyclopropanecarboxanilide from part E above and a large excess of zinc dust in 5% methanolic acetic acid are stirred at room temperature for 2 hours, refluxed for 1 hour and cooled again to room temperature. The mixture is then filtered through the filter aid (Celite®) and washed with methanol. The solvent is evaporated and the residue treated with 5N ammonium hydroxide and ethyl ether. The ether extract is washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to an oil, the subtitled cyclopropane carboxanilide. This cyclopropanecarboxanilide is converted to its p-toluenesulfonate salt by treating the oil with p-toluenesulfonic acid in a mixed solvent of methanol and ethyl ether.

25 Example 3

trans-3,4-dichloro-N- [2- (N-methylamino) cyclopentyl] -

cyclopropanecarboxanilide and its p-toluenesulfonate salt.

Procedure B.

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A mixture of 3,4-dichloro-N- [2- (dimethylamino) cyclopentyl] cyclopropanecarboxanilide, which has been released from its oxalate salt with sodium hydroxide, and an excess of mercury acetate in 5% aqueous acetic acid are on the steam bath during Heated for 3 days. The precipitate that forms is filtered off and washed with 10% hydrochloric acid solution. A small amount of insoluble precipitate is removed by filtration. The solution (filtrate) is made basic with concentrated ammonium hydroxide solution and extracted with ethyl ether. The ether extract is washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to an oil. This oil is converted to the p-toluenesulfonate salt with p-toluenesulfonic acid in methanol and ethyl ether. After recrystallization, the cyclopropanecarboxanilide salt mentioned in the title is obtained.

Example 4

trans-3,4-dichloro-N- (2-aminocyclopentyl) acrylanilide 50 and its $ -naphthylsulfonate salt.

A. trans-3,4-dichloro-N- (2-aminocyclopentyl) aniline and its hydrochloride.

A mixture of 16.3 g (0.05 mol) of 3,4-dichloro-N- (2-sulfo-55 nyloxycyclopentyl) aniline and (50 ml) 17N ammonium hydroxide (0.85 mol) is melted in a for 48 hours Ampoule heated to a temperature of 125 ° C. The reaction mixture is then cooled to room temperature. The contents of the ampoule are dissolved in a mixture of ethyl ether and water 60. The ethereal layer is washed with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated to a brown oil. The oil obtained is chromatographed on 300 g of silica gel. It is eluted with 2000 ml of ethyl acetate and 3000 ml of methanol. A thin layer 65 chromatographic analysis of the last 2000 ml of methanol eluate shows that it contains trans-3,4-dichloro-N- (2-aminocyclopentyl) aniline. After evaporation of most of the methanol of the amine eluate, the remainder becomes excess ethereal

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Hydrochloric acid solution treated to obtain the diamine hydrochloride salt. This is recrystallized from a mixture of about 5 ml of methanol and about 20 ml of ethyl ether, 2.4 g of trans-3,4-dichloro-N- (2-amino-cyclopentyl) aniline hydrochloride of an mp of 15% being obtained in 15% yield 103 ° C (with vigorous foaming).

The nuclear magnetic resonance, IR, UV and mass spectra correspond to the (expected) spectra of trans-3,4-dichloro-N- (2 - aminocyclopentyl) aniline hydrochloride.

B. trans-3,4-dichloro-N- [2- (N-trichloroethoxycarbonylamino) cyclopentyl] aniline and its hydrochloride salt.

A mixture of 9.54 g (0.03 mol) of the diamine from Part A, which has been liberated from a hydrochloride salt, and 3.03 g (0.03 mol) of triethylamine in 250 ml of ethyl ether, after cooling in ice 6.36 g (0.03 mol) of 2,2,2-trichloroethyl chloroformate in 25 ml of ethyl ether were added. The mixture obtained is stirred over the weekend at room temperature and then mixed with 200 ml of saturated sodium bicarbonate solution. The organic layer is washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated to a yellow oily residue, namely trans - 3,4-dichloro-N- [2- (N-trichloroethoxycarbonylamino) cyclopentyl] aniline. The hydrochloride salt is obtained by treating the yellow oily residue with excess ethereal hydrochloric acid. The salt is recrystallized from a mixture of about 300 ml of methanol and 700 ml of ethyl ether to give 8.15 g of a first batch of the aniline salt. The filtrate is evaporated, and the evaporation residue is recrystallized from a mixture of 100 ml of methanol and about 500 ml of ethyl ether. This gives a further 2.54 g of the aniline salt; the overall yield was 78%. The aniline salt has a melting point of 207 ° to 209 ° C.

The nuclear magnetic resonance, IR, UV and mass spectra correspond to the (expected) spectra of the aniline salt.

C. trans-3,4-dichloro-N- [2- (2,2,2-trichloroethoxycarbonylamino) cyclopentyl] acrylanilide.

A mixture of trans-3,4-dichloro-N- [2- (2,2,2-trichloroethoxycarbonylamino) cyclopentyl] aniline with an equimolar amount of acrylic anhydride is heated on a steam bath overnight. After adding water, the mixture is further heated for 1 hour. The mixture is diluted with ethyl ether. The developing organic layer is separated from the aqueous layer and washed with 15% sodium hydroxide and saturated sodium chloride solution, dried over magnesium sulfate and evaporated to give the subtitled n-blocked acrylanilide compound.

D. trans-3,4-dichloro-N- (2-aminocyclopentyl) acrylanilide and its ß-naphthylsulfonate salt.

A mixture of trans-3,4-dichloro-N- [2- (2,2,2-trichloro-ethoxycarbonylamino) cyclopentyl] acrylanilide from part C above and from a large molar excess of zinc dust in 5% methanolic acetic acid. Solution is heated at room temperature overnight. The mixture is filtered through a filter aid (Celite®) and washed with methanol. The filtrate is concentrated and the residue is heated with 5N ammonium hydroxide and ethyl ether. The ether layer is washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated to an oil which is converted to the napsylate (β-naphthylsulfonic acid) salt in methanol / ethyl ether solution using an equimolar amount of β-naphthylsulfonic acid.

Either solid or liquid compositions can be prepared for oral administration. For the manufacture of solid forms of administration, e.g. of tablets, the compounds of formula I with common ingredients, such as

Talc, magnesium siearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, acacia gum, methyl cellulose and substances having a functionally similar effect as pharmaceutical diluents or carriers, mixed or blended. 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 compositions 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, together with aromatic flavors or ingredients.

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

Flowable compositions 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 filtered-sterilized before being filled into suitable vials or ampoules and sealed. Aids, e.g. Local anesthetics, preservatives and buffers, also dissolved. To improve stability, the respective mass can be frozen in a vacuum after filling into the vial and removing the water. 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 way, but with the difference 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 particular composition for better, more uniform distribution of the compound.

Rectal suppositories are solid bodies for insertion into the rectum that melt or soften at body temperature and release at least one pharmacologically or therapeutically active ingredient.

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 to increase the melting point of suppositories are, for example, spermaceti and wax. Rectal suppositories can be

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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 dosage units or in multiples thereof, for example in amounts of 2, 6 or 12.

The term “dosing unit” is to be understood as physically delimitable units which are suitable as dosing units for humans and animals, each of which contains a given amount of active material which is aimed at producing the desired therapeutic effect, diluents, carriers or excipients. The regulations for such dosing units are determined by and are directly dependent on a) the unique properties of the active material and the success sought in each case and b) the restrictions inherent in the technique of packaging an active material by administration to humans and animals.

Examples of suitable dosage units are tablets, capsules, pills, suppositories, powder 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 will depend on the mode of administration, the age, weight and condition of the patient. A dosage regulation of about. 1 to about 100 mg, preferably 10 to 90 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 relieve depression. The dose to be administered is calculated based on about 0.02 to about 1.5 mg / kg of the patient's body weight. The respective compound is brought into the form of a dosage unit with a suitable pharmaceutical carrier for convenient and effective administration. Dosage units of medicaments according to the invention preferably contain 0.5, 1, 5, 10, 20, 30, 50 or 100 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 the formula I and at least one other active ingredient-containing medicament according to the invention is determined according to the actual metering instructions for each such ingredient.

In the medicaments according to the invention, the compound of formula I can also be combined with other active substances, e.g. Analgesics such as acetylsalicylic acid, acetaminophen, PAC compound (phenacetin / acetylsalicylic acid / caffeine), anti-inflammatory or anti-inflammatory agents such as ibuprofen and the like, anxiolytics e.g. Perphenazines, amitripylene hydrochloride, chlorodiazepoxides, alprazolam, doxepin hydrochloride and the like can be combined.

Example 5

An amount of 10,000 tablets each containing 20 mg of trans-3,4-dichloro-M- [2- (N-methylamino) cyclopentyl] cyclohexanecarboxa-nilide as the active ingredient compound is made up of the following types and amounts made of ingredients:

Active ingredient combination 200 g

Dicalcium phosphate 1500 g

Methylcellulose, U.S.P. (15 cps.) 60 g

Talc 150 g

Corn starch 200 g

Magnesium stearate 12 g

The compound and the dicalcium phosphate are mixed well, granulated with 7.5% solution of methyl cellulose in water, using a screen No. 8 skillfully and carefully dried. The dried granules are passed through a "No. 12 screen, carefully mixed with the talc, starch and magnesium stearate and pressed into tablets.

These tablets can be used in daily doses of 1 to 2 tablets to reduce depression in adults, the amount depending on the age and weight of the patient.

Example 6

1000 hard, two-piece gelatin capsules, each containing 10 mg of 3-bromo-N- [2- (N-methylammo) cyclopentyl] acrylanilide hydrochloride salt as the active compound, are made from the following types and amounts of ingredients:

Active connection 10 gm

Lactose 75 gm

Talc 25 gm

Magnesium stearate 1.5 gm

The ingredients are mixed well and filled into capsules of a suitable size. Capsules so made are useful in treating depression in adults at a dose of 1 to 2 capsules daily.

Example 7

1000 tablets for sublingual use are made from the following ingredients:

3-trifluoromethyl-N- [2- (methylamino) cyclopentyl] -

propionanilide, micronized 5 gm

Polyethylene glycol 4000, powdered 150 gm

Polyethylene glycol 6000, powdered 75 gm

The ingredients are mixed well and pressed into sublingual type tablets.

These tablets, each containing 5 mg of the active compound, are placed under the tongue and are useful for very quickly counteracting depression at a dose of 1 tablet per 6 hours.

Example 8

Soft gelatin capsules for oral use, each containing 10 mg of 3,4-dichloro-N- [2- (N-methylamino) cyclopentyl] ethoxycarboxanilide methanesulfonate salt, are prepared by first dispersing the micronized compound in corn oil to the material to make it encapsulable, and then encapsulate it in the known manner. These capsules can be used in daily doses of 1 to 2 capsules for the treatment of depression.

Example 9

1000 tablets, each containing 30 mg of 3,4-dichloro-N- [2- (N-methylamino) cyclopentyl] methoxyacetanilide salt, are made from the following types and amounts of ingredients:

3,4-dichloro- [2- (N-methylamino) cyclopentyl] -

methoxyacetanilide 30 gm

Lactose 355 gm

Microcrystalline cellulose NF 120 gm

Thickness 16 gm

Magnesium stearate powder 4 gm s

io

15

20th

25th

30th

35

40

45

50

55

60

65

652 595

20th

The ingredients are sieved and mixed together and pressed into tablets.

These tablets can be used to treat depression.

Example 10

A sterile preparation suitable for intramuscular injections and containing 50 mg 3-fior-N- [2- (N-methyl-N-dimethylaminoethylamino) cyclopentyl] propionanilide hydrochloride salt per milliliter is made from the following ingredients:

3-fior-N- [2- (N-methyl-N-dimethylaminoethylamino) -

cyclopentylpropionanilide hydrochloride 50 gm

5 benzyl benzoate 200 ml

Methyl paraben 1.5 gm

Propyl paraben 0.5 gm -

Cotton seed oil 1000 ml

1 ml of this sterile preparation is injected to relieve depression in adults.

Claims (5)

652 595 2nd PATENT CLAIMS 1. Medicament with an antidepressant effect, characterized in that it is an antidepressant, non-toxic amount of a compound of the formula R R C = Q C = Q (i) (I ') Q R Ri or its pharmacologically acceptable salts in addition to a pharmaceutical diluent, wherein in formula I the wavy line in the 1-position of the cyclopentyl ring indicates the cis or trans configuration of the substituents in the 1- and 2-positions and the symbols have the following meanings: p zero or 1, Oxygen or sulfur, Ci to C3 alkyl, vinyl, C3 to C6 cycloalkyl, ethoxy or methoxymethyl, Hydrogen or Cr to c3-alkyl, R2 is hydrogen, Ci to C3 alkyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, benzyl, phenethyl or C3 to C6alkenyl with an allyl double bond, where Ri and R2 are not both C1-C3 alkyl, and Y and Z are each hydrogen, halogen with an atomic number of 9 to 35, trifluoromethyl, methyl, ethyl, methoxy or Ethoxy, with the following requirements: Z = hydrogen when Y = trifluoromethyl; if Z = hydrogen and Y = methoxy or ethoxy, Y is in the 3-position of the benzene nucleus; and when Y and Z are both halogen or methoxy or ethoxy, they are in the 3,4 or 3,5 positions of the benzene. around. 2. Composition according to claim 2, characterized in that it contains one of the following compounds of formula I: 3,4-dichloro-N- {2- [N-methyl-N- (N ', N'-dimethylaminoethyl) amino] cyclopentyl} propionanilide, 3,4-dichloro-N- [2- (N ', N'-dimethylaminoethylamino) cyclopentyl] propionanilide, 3,4-dichloro-N- [2- (N ', N'-dimethylaminopropylamino) cyclopentyl] propionanilide, 3,4-dichloro-N- {2- [N-methyl-N- (N ', N'-dimethylaminopropyl) amino] cyclopentyl} propionanilide, 3,4-dichloro-N- [2- (N ', N'-dimethylaminoethylamino) cyclopentyljcyclopropanecarboxanilide, 3,4-dichloro-N- {2 - [(N ', N'-dimethylaminopropyl) amino] cyclopentyl} acrylanilide, 3,4-dichloro-N- {2- [N-methyl-N- (N ', N'-dimethylamino-ethyl) amino] cyclopentyl} methoxyacetanilide, 3,4-dichloro-N- {2- [N-methyl-N- (N ', N'-dimethylaminopropyl) amino] cyclopentyl} carbethoxyanilide, 3,4-dichloro-N- [2- (N-methylamino) cyclopentyl] cyclopropane-carboxanilide, 3,4-dichloro-N- (2-aminocyclopentyl) acrylanilide, or a pharmacologically acceptable salt of the above compounds. 3. Compound of the formula and the pharmacologically acceptable salts, wherein in formula l P the wavy line in the 1-position of the cyclopentane ring indicates the cis or trans configuration of the substituents in the 1- and 2-position and the symbols have the following meanings: p zero or 1, Q oxygen or sulfur, 20 R vinyl, c3- to Cö-cycloalkyl, ethoxy or methoxymethyl, Ri hydrogen or Ci-to c3-alkyl, R? Hydrogen, Cr to C3-alkyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, benzyl, phenethyl or C3 to Cö-alkenyl with allyl double bond, where not both Ri and R2 are Gi to C3 alkyl, and Y and Z are each hydrogen, a halogen with atomic numbers 9 to 35, trifluoromethyl, methyl, ethyl, methoxy or ethoxy, with the following requirements: Z is hydrogen when Y is trifluoromethyl; when Y is meth-30 oxy or ethoxy and Z is hydrogen, Y is in the 3-position of the benzene ring; and when Y and Z are both halogen, methoxy or ethoxy, these residues take the 3,4 or 3,5 position of the benzene ring. 4. A compound according to claim 3, characterized in that in formula F R for c3- to Cö-cycloalkyl, Ri for hydrogen, Rz for Cr to C3-alkyl and at least one of the symbols Y and Z for halogen with a 40 atom number from 9 to 35 in the 3- or 4-position, trifluoromethyl in the 3-position or methyl in the 3- or 4-position together with one of the halogens mentioned are in the adjacent 3- or 4-position, and their pharmacologically acceptable salts. 45 5. irans-2,4-dichloro-N- [2- (N-methylamino) cyclopentyl] cyclohexane carboxanilide according to claim 4. 6. Connection according to claim 3, characterized in that p = zero; 50 Q is an oxygen atom; R is a c3 to Cg cycloalkyl radical or a vinyl, methoxymethyl or ethoxy radical; Ri and R2 are both hydrogen atoms, or one of the radicals Ri and R2 is a hydrogen atom and the other is a Cr to 55 C3-alkyl radical and at least one of the radicals Y and Z is a halogen atom having an atomic number from 9 to 35 in the 3- or 4-position, one Trifluoromethyl radical in the 3-position, or a methyl radical in the 3- or 4-position in combination with one of the halogen 60 atoms mentioned in the adjacent 3- or 4-position, or their pharmacologically acceptable salts. 7. 3,4-dichloro-N- [2- (N ', N'-dimethylaminoethylamino) cyclopentyl cyclopropanecarboxanilide, 3,4-dichloro-N- [2- (N ', N'-dimethylaminopropylamino) cyclo-65 pentyl] acrylanilide, 3,4-dichloro-N- [2- (N-methylamino) cyclopentyl] cyclopropane-carboxanilide, 3,4-dichloro-N- (2-aminocyclopentyl) acrylicilanide, 3rd 652 595 or a pharmacologically acceptable salt of the above compounds, as a connection according to claim 3.