HU217873B - N-cycloalkyl-amine-derivatives and pharmaceutical compositions containing the same - Google Patents

Abstract

FIELD OF THE INVENTION The present invention relates to novel N-cycloalkylalkyl derivatives of the formula (I), salts thereof, and pharmaceutical compositions containing them. In formula I, R1 is furyl or thienyl; and R1 is phenenyl, with the proviso that Q is cyclopropane-1,2-diyl of formula (a); R2 is C1-6alkyl; R3 is hydrogen or C1-6alkyl; m is 1 or 2; R4 is -cycloalkyl of the formula -CH (CH2) n wherein n is 2 to 5; R5 is -phenyl or thienyl; Q is ethylene-1,2-diyl of (-CH = CH-) or cyclopropane-1,2-diyl of formula (a). The compounds of the invention have a psychotropic effect. ŕ

Description

The present invention relates to novel N-cycloalkylalkylamine derivatives of the formula (I), salts thereof and pharmaceutical compositions containing them as active ingredients.

In the general formula (I)

R _t is furyl or thienyl; and R 1 is phenyl, provided that Q is cyclopropane-1,2-diyl of formula (a);

R ₂ is C 1-6 alkyl;

R ₃ is hydrogen or C 1-6 alkyl; m is 1 or 2;

R ₄ is -CH (CH _{2) n} cycloalkyl group of formula: wherein n is 2-5;

_R5 is phenyl or thienyl;

Q is ethylene-1,2-diyl of the formula (-CH = CH-) or cyclopropane-1,2-diyl of the formula (a).

The term lower alkyl as used herein denotes straight or branched C 1 -C 5 groups.

Halogen means bromine, fluorine or preferably chlorine.

The cycloalkylalkylamine derivatives of formula (I) may have an asymmetric carbon atom; the invention also relates to optical and / or geometric isomers. The invention also relates to addition salts of the amine derivatives of formula (I). The addition salts are formed with inorganic or organic acids. The present invention also relates to solvates of the compounds of formula (I).

Suitably, the addition salts are prepared with acetic acid, benzenesulfonic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, hydrobromic acid, lactic acid, maleic acid, methanesulfonic acid, muconic acid, nitric acid, pumaric acid, tartaric acid may be used.

Animal studies have shown that the cycloalkylalkylamine derivatives of the formula I and their salts are slightly toxic and show a favorable psychotropic effect;

the use of these compounds in preventing the seizures induced by picrotoxin;

in addition, the compounds of the present invention are useful in inhibiting the gastric ulcer-inducing effect of cysteamine.

This property of the compounds is related to binding to sigma receptors.

The process of the present invention preferably provides compounds of formula (I)

R 1 is thienyl,

R ₂ is C 1-3 alkyl, preferably ethyl,

R ₃ is methyl, m is 1,

R ₄ is CH- (CH ₂ ) _n where n is 2,

_R5 is phenyl,

Q is ethylene-1,2-diyl or cyclopropane-1,2-diyl.

The amine derivatives of formula (I) is prepared by reacting a (IX) aminonitrile of formula R ₂ MGZ ₃ organomagnesium formula reagent, wherein Z ₃ is a halogen atom such as chlorine, bromine or iodine, is reacted with R ₂ and the resulting compound is optionally converted into a salt.

European Patent Application 0 298 703 discloses thiophene derivatives of general formula (A):

R 1 is thienyl,

R 1, R ₂ and R ₃ are lower alkyl,

R p _h is optionally substituted phenyl, p is 1, 2 or 3.

Among the known compounds, those compounds of the formula which are preferred

R 1 is ethyl,

R _2, R ₃ is methyl;

The _{pH of} R is phenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl or 4-chlorophenyl and p is 1 or 3.

Known compounds show low toxicity and regulate gastrointestinal motility; stimulate bowel function with reduced activity, while inhibiting hyperactive bowel function.

The chemical structure of compounds according to formula (I) is different from the known compounds, in particular carbon chain attached to _R, and R _pH marked with two different structures of the known aromatic stationary wherein; the substituents on the amino group are also different. The compounds disclosed in the European patent application also differ from the cycloalkylalkylamine derivatives of the formula I in their properties. The compounds described in European Patent Application 0 298 703 are not known to exhibit psychotropic activity, which makes them useful in the treatment of neuropsychiatric disorders. In addition, known compounds are not known to favorably influence ulcerative lesions of the gastrointestinal tract.

The intermediates used in the preparation of compounds of formula I are compounds of formula IX.

The aminonitrile derivatives of formula (IX) are prepared by first preparing an aminonitrile of formula (XII): R [-CHO] aldehyde, an HN (R ₃ ) - (CH ₂ ) _m -R _{From a} mixture of a secondary amine of formula ₄ and an alkali metal cyanide under Strecker's reaction conditions [Dyke SF et al., Tetrahedron 31, 12-19. (1975). Then, the obtained (XII) with a compound of formula (XIII) with a compound of formula wherein R ₅ is as defined in formula (I) defined above, Z ₅ represents a chlorine, bromine or iodine, or 1-alkyl-sulphonyloxy group.

The alkylation is carried out by preparing the aminonitrile of formula (XII) appropriately

EN 217 873 Β using a strong organic metal base in an inert solvent; tetrahydrofuran may be used as the solvent. Lithium N, N-diisopropylamide (LDA) is preferably used as the reagent. This compound is prepared in situ by reaction of equimolar amounts of Ν, Ν-diisopropylamine and butyllithium.

This reagent is reacted with compound (XII) for about 1-2 hours at a temperature between 20 and 100 ° C, and then reagent (XIII) is added to the anion. The reaction mixture is kept at room temperature at a temperature in the region of 20 ° C for 1-2 hours to obtain the intermediate of formula IX. The resulting compound was purified.

When the aminonitrile of formula (IX) is reacted with an organic magnesium compound of formula R ₂ MgZ _3, the compound of formula (III) is obtained. The karbonitrilcsoportot replaced by R _2, in a known manner [Leonard NJ et al. J. Am. Chem Soc 78 page 1986, (1956) page 79 and 5279th, (1957)]. The reaction is carried out in an ethereal medium such as diethyl ether, methyl tert-butyl ether, diisopropyl ether, dibutyl ether or tetrahydrofuran. Preferably, the latter solvent is used; 1 mol of compound (IX) is reacted with 1.5 to 6 mol of organic magnesium derivative for 30 minutes to 17 hours at a temperature of 5 to 50 ° C.

The process is carried out by adding 1 mol of compound (IX), preferably dissolved in tetrahydrofuran, to a solution of 4-5 mol of organic magnesium compound also in tetrahydrofuran at a temperature between 10 and 20 ° C. The reaction mixture is maintained at this temperature for 2-5 hours and the resulting complex is quenched by addition of aqueous ammonium chloride solution. The compound of formula (III) is then isolated and purified.

The following examples illustrate the present invention without limiting it.

In the operations described in the Examples, the compounds obtained may be obtained either in sufficient purity or by purification by conventional means such as recrystallization, vacuum distillation or column chromatography. In the latter case, it is preferable to use the so-called chromatoflash technique on silica support (Merck silica gel 60, 0.04-0.06 mm particle size).

The purity, identity and physical-chemical properties of the product obtained can be determined by the following methods:

The boiling point is measured during vacuum distillation and is given in pascal;

the melting point is determined by capillary method and the values obtained are corrected without correction;

thin-layer chromatography (TLC) using silica gel plates (Merck 60F 254 ready plates); the method is briefly summarized below.

100mcg of the product to be tested is placed on the plate and then eluted with the solvent or solvent mixture listed below. The composition of the solvent mixtures is as follows:

S.A .: 100 hexanes / 10 ethyl acetate (v / v)

S.B .: 40 hexane / 10 ethyl acetate (v / v)

S. C .: 20 hexane / 10 ethyl acetate (v / v)

S.D .: 99 methylene chloride / l triethylamine (v / v)

After development, the chromatogram is examined under ultraviolet light at 254 nm and / or the plates are sprayed with Dragendorf reagent or Tholidin reagent. The examples show the RF values detected and the solvent used.

The results of elemental analysis are not routinely shown in the examples; just to mention that the test was done.

For infrared spectroscopy, a potassium bromide tablet or a film between sodium chloride windows is used, or the Nujol (R) suspension method is used, or the test is performed in carbon tetrachloride solution. The most intense absorption values are given in wavelength cm.

Nuclear Magnetic Resonance (NMR) tests are performed at 60 or 90 MHz. The test substance is solubilized in deuterochloroform. Results are expressed in ppm relative to the internal reference tetramethylsilane. If a replaceable proton is added after the addition of deuterium oxide, it is indicated in the examples.

In the examples, solvents and reagents are also denoted by the commonly used abbreviation, such as THF for tetrahydrofuran.

Examples

Experimental section - Exhibitions

Intermediate of formula XIII (Z ₅ -CH ₂ -QR ₅ )

Al) Preparation of trans-1-mesyloxymethyl-2-phenylcyclopropane (R ₅ = C ₆ H ₅ ; Z ₅ = CH ₃ SO ₂ -O; Q = cyclopropane-1,2-diyl)

A solution of trans-2-phenyl-1-cyclopropanecarboxylic acid (25.0 g, 154 mmol) in tetrahydrofuran (100 mL) was added dropwise to a solution of borane in tetrahydrofuran (230 mL, 230 mmol). The solution was refluxed for 3 hours and 130 ml of 2N sodium hydroxide solution was added dropwise. The mixture was stirred for 30 minutes and then extracted with ether; the ether phase was dried over magnesium sulfate and concentrated in vacuo. This gave a crude residue (20.8 g). The resulting trans-1-hydroxymethyl-2-phenylcyclopropane intermediate was purified by vacuum distillation. 18.2 g (80%) of boiling point 90-97 ° C / 35 Pa are obtained.

9.2 g (66 mmol) of the product obtained above and 13.8 ml (99 mmol) of triethylamine are dissolved in 100 ml of methylene chloride. To this solution, methanesulfonyl chloride (5.6 mL, 73 mmol) was added dropwise at -10 ° C under a nitrogen atmosphere. The mixture was stirred for 15 minutes at -15 ° C, followed by water, cold dilute hydrochloric acid, saturated sodium bicarbonate solution, and saturated sodium chloride solution.

HU 217 873 Β mossuk. The organic phase is then dried over magnesium sulfate at 0 ° C.

The solvent was removed by vacuum distillation at a temperature below 10 ° C and the unstable product was dissolved in anhydrous tetrahydrofuran and used as is for the next step.

A-2) trans-1-Bromomethyl-2-phenyl-cyclopropane (R ₅ = C ₆ H ₅ ; Z ₅ = Br; Q = cyclopropane-1,2-diyl)

N-bromosuccinimide (61.0 g, 0.34 mol) was added to methylene chloride (300 mL). The slurry was cooled to 0 ° C and dimethyl sulfide (29.4 mL, 0.41 mol) was added under nitrogen. After stirring for 30 minutes, the mixture was cooled to -25 ° C and then a solution of trans-1-hydroxymethyl-2-phenylcyclopropane (36.6 g, 0.23 mol) was added dropwise.

The mixture was stirred at 0 ° C for 6 hours and then at 25 ° C for 16 hours. The mixture was diluted with hexane (250 mL) and poured into ice water (250 mL). The organic layer was washed with brine and then dried over magnesium sulfate. The solvent was removed by vacuum distillation and the residue was purified by distillation. Yield: 40.8 g (85%).

Boiling point: 72 ° C / 25 Pa.

A-3) -1- (2-thienyl) -3-chloroprop-1-ene (R ₅ = 2-thienyl; Z ₅ = Cl; Q = -CH = CH-)

First Step A mixture of 104.06 g of malonic acid (1.0 mole), 56.07 g (0.50 mole) of 2-thiophenecarboxaldehyde, 250 ml of pyridine and 5 ml of piperidine was heated in a water bath for 2 hours and then heated to reflux. Boil for 5 minutes. The mixture was cooled and poured into water and treated with excess hydrochloric acid (250 mL of a 37% solution) to precipitate the product formed. This was filtered and recrystallized from ethanol / water to give pure 2-thienylacrylic acid.

Step Two: Add the above acid (37.34 g, 0.24 mol) and BF _3- ether complex (30 mL, 0.24 mol) to methanol (310 mL). The mixture was refluxed for 6 hours. The solution was cooled, poured into water and extracted with methylene chloride. The organic layers were combined, washed with saturated sodium bicarbonate solution, brine, and dried over magnesium sulfate. The solvent was removed by distillation to give a brown solid which was recrystallized from hexane; This gives pure methyl 2-thienyl acrylic acid ester.

Yield: 32.65 g (81%); Melting point 46-47 ° C.

Step Three: Lithium aluminum hydride (4.51 g, 118.9 mmol) was suspended in tetrahydrofuran (150 mL). The suspension was added slowly, with stirring, to a cooled mixture of 5.28 g (39.6 mmol) of aluminum chloride and 40 ml of diethyl ether at -10 ° C under a nitrogen atmosphere.

The methyl ester obtained above (10.0 g, 59.45 mmol) was dissolved in tetrahydrofuran (50 mL) and stirred at -10 ° C for 1.5 h. The complex is then decomposed with 3M sulfuric acid and the mixture is extracted with ether. The combined ethereal phases were washed with saturated sodium bicarbonate solution and then with saturated sodium chloride solution and dried over magnesium sulfate. The ether was evaporated in vacuo to give a brown oil (7.83 g, 94%). The crude 1- (2-thienyl) -prop-1-en-3-ol was maintained at 0 ° C (compound unstable at room temperature).

Step Four: Dimethylsulfide (21.74 mL, 296 mmol) is added slowly at 0 ° C to a mixture of N-chlorosuccinimide (39.53 g, 296 mmol) in dry methylene chloride (180 mL). The mixture was cooled to -10 ° C and a solution of 11.86 g (84.6 mmol) of the alcohol thus obtained in 50 ml of methylene chloride was added.

The temperature of the mixture was adjusted to 0 ° C and the mixture was maintained at this temperature for 2 hours. The mixture was diluted with 100 mL of hexane and then poured into 200 mL of ice water. The organic layer was separated and the aqueous layer re-extracted with ether. The combined ethereal phases are washed and dried. The ether was removed by vacuum distillation; This gives crude 1- (2-thienyl) -3-chloropropylene as an unstable brownish red oily product. The product obtained is used as is.

Yield: 12.06 g (94%).

A-4) 1- (3-Thienyl) -3-chloroprop-1-ene.

_(R5 = 3-thienyl; Z5 = C1, Q = -CH = CH-)

The title compound can be prepared starting from 3-thiophenecarboxaldehyde as described in the previous example.

First step: 3-thienylacrylic acid.

146 ° C (ethanol / water).

Step Two: Methyl 3-Thienylacrylic Acid.

49 ° C (hexane).

Step Three: 1- (3-Thienyl) -prop-1-en-3-ol.

Unrefined oil.

Step Four: 1- (3-Thienyl) -3-chloroprop-1-ene.

A crude, amorphous, white solid.

A-5) trans-1-Chloromethyl-2- (2-thienyl) cyclopropane. (R ₅ = 2-thienyl; Z ₅ = C 1; Q = cyclopropan-1,2-diyl)

First step: Transfer 33.9 ml of anhydrous tert-butanol and 25 ml of tetrahydrofuran to anhydrous flask under nitrogen. To the mixture was added 144 ml of a 2.5 M solution of butyllithium at 0 ° C with stirring.

The mixture was allowed to warm to room temperature and stirred for 30 minutes.

A solution of the purified 2-thienylacrylic methyl esters (20.0 g) prepared in Example A3 (1) and (2) in 125 ml of tetrahydrofuran was added.

The mixture was stirred for 3 hours and then added to 600 ml of ice water. It was then extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over magnesium sulfate. The ethyl acetate was then evaporated in vacuo. 26.0 g of a redbama residue are obtained.

The resulting 2-thienylacrylic acid tert-butyl ester was purified by vacuum distillation.

Yield: 21.3 g (85%).

Boiling point: 82-90 ° C / 4 Pa.

Second step: 11.1 g of a 80% dispersion of sodium hydride in mineral oil are added with stirring to a suspension of 74.8 g of trimethylsulfoxonium iodide in 150 ml of anhydrous dimethylsulfoxide.

HU 217,873 Β

After hydrogen evolution has ceased (about 30 minutes), a solution of 54.6 g of the tert-butyl ester prepared above in 60 ml of dimethyl sulfoxide is added while maintaining the temperature below 35 ° C. The mixture was stirred for 30 minutes at room temperature and for 1.5 hours at 55-60 ° C.

The solution was cooled to 25 ° C and poured into 1000 ml of water. The mixture was extracted with ether (4 x 100 mL), and the combined ether layers were washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo to give 47.7 g of trans-2- (2-thienyl) -1-cyclopropanecarboxylic acid tert-butyl ester as a yellow oily residue which was used as is in the next step.

Step Three: A solution of 20.4 g of the tert-butyl ester obtained above in 75 ml of tetrahydrofuran is added dropwise to a suspension of 6.9 g of lithium aluminum hydride in 75 ml of anhydrous tetrahydrofuran at a temperature below 5 ° C. The mixture was allowed to warm to room temperature, stirred for 2 hours, then water (16 mL) followed by 10% aqueous sodium hydroxide solution was carefully added dropwise. Water (48 mL) was added and the resulting suspension was filtered. The precipitate was washed with ethyl acetate and the combined organic phases were dried over sodium sulfate.

The solvent was evaporated in vacuo. The residue was chromatographed on a silica gel column to give pure trans-1-hydroxymethyl-2- (2-thienyl) cyclopropane.

Yield: 16.4 g (76%).

Step Four: A solution of 15.5 g of the alcohol obtained above in 75 ml of anhydrous triethylamine is added to 40 g of dichlorotriphenylphosphorane in an anhydrous flask under nitrogen.

The suspension was stirred at 25 ° C for 24 hours. The mixture was then added to water (500 mL) and hexane (100 mL) was added. The mixture is filtered, the organic phase is separated off, and the aqueous phase is reextracted with 100 mL of hexane. The combined organic layers were dried over magnesium sulfate and the solvent was evaporated in vacuo. The residue was purified by vacuum distillation to give trans 1-chloromethyl-2- (2-thienyl) cyclopropane as a colorless oily product. Yield: 9.7 g (56%).

Boiling point: 65-70 ° C / 40 Pa.

A-6) trans-1-Chloromethyl-2- (3-thienyl) cyclopropane. _(R5 = 3-thienyl; _Z5 = C1, Q = cyclopropane-2-diyl)

The title compound can be prepared starting from 3-thienylacrylic acid methyl ester (second step of Example A-4) as described in A-5.

First step: 3-Thienylacrylic acid tert-butyl ester, boiling point 95-110 ° C / 13 Pa.

Step Two: Trans-2- (3-thienyl) -1-cyclopropanecarboxylic acid tert-butyl ester, crude oil.

Step Three: Trans-1-hydroxymethyl-2- (3-thienyl) cyclopropane, b.p. 88-120 ° C / 20 Pa.

Step Four: Trans-1-Chloromethyl-2- (3-thienyl) -cyclopropane, b.p. 60-78 ° C / 400 Pa.

Preparation of a compound of Formula IX.

General operations:

Step 1: Preparation of aminonitrile derivatives of formula XII

Sodium cyanide (5.90 g, 0.12 mol) and a water-soluble salt of the amine R ₃ -NH- (CH ₂ ) _m -R ₄ (0.12 mol) were dissolved in water (20 ml).

A solution of the aldehyde Rj-CHO (0.10 mol) in methanol (10 ml) is added over a period of 1 hour at 30 to 40 ° C. The mixture was stirred at room temperature for 4 hours and then poured into 75 ml of ice water. The mixture was then extracted with ether.

The combined ethereal phases were washed with water followed by 25% sodium bisulfide solution and again with water.

The ether is then distilled off and the crude residue is purified if desired, such as by distillation.

Step 2: Preparation of Intermediate (IX)

1.025 M N-butyllithium (10 M in hexane) was added dropwise at 20 ° C to a solution of 1.025 M diisopropylamine in 1 L anhydrous tetrahydrofuran in anhydrous flask.

The mixture was heated at 20 ° C for 15 minutes. At -72 ° C, 1.0 mol of aminonitrile (XII) was dissolved in 200 ml of tetrahydrofuran. After stirring for 1.5 hours at the above temperature, a solution of 1.025 mol of alkylation beads (XIII) in 500 ml of tetrahydrofuran was added. The mixture was stirred at -72 ° C for 20 minutes and then at room temperature for 1 hour.

Thereafter, 1.5 liters of a 10% (w / v) ammonium chloride solution and 750 ml of a 1: 1 mixture of hexane and ethyl acetate were added.

The organic phase is separated off and the aqueous phase is extracted with the above solvent mixture. The combined organic phases were washed with brine and dried over magnesium sulfate. The solvents were removed by vacuum distillation on a water bath. The purity of the resulting crude oily product is generally satisfactory, and the resulting compound is used as is in the next step. B1) 1-Cyano-1- (N-cyclopropylmethyl-N-methyl) -aminol-2-furyl) -4-phenyl-but-3-ene (in formula IX: R 1 = 2-furyl) ; R ₃ = CH ₃ ; m = l; R ₄ = (CH ₂ ) ₂ CH; R ₅ = C ₆ H ₅ ; Q = -CH = CH-] Intermediate (XII) for the preparation of 1- (N-cyclopropylmethyl-N-methyl) -amino- (2-furyl) -acetonitrile: 2-furaldehyde and N-methyl-N- cyclopropylmethylamine and sodium cyanide are used. The resulting oily product was purified by vacuum distillation. Boiling point: 82-92 ° C / 15 Pa.

Alkylation of the resulting product with cinnamyl bromide is carried out as described in the general procedures. The resulting crude oily product (yield 100) is used as is for reaction with the organo-magnesium derivative.

HU 217,873 Β

NMR: 0.10-0.15 (m, 5H); 2.10-2.45 (m, 2H); 2.55 (s,

3H); 2.90 (d, 2H); 5.70 (t, 1H); 6.35 (d, 1H);

6.85-6.95 (m, 1H); 7.10-7.45 (m, 7H)

B-2) 1-Cyano-1- [N-cyclopropylmethyl-N-methyl] -amino-4-phenyl-1- (2-thienyl) -but-3-ene (in the formula IX: R _t = 2-thienyl; R ₃ = CH ₃ ; m = l; R ₄ = (CH ₂ ) ₂ CH; R ₅ = C ₆ H ₅ ; Q = -CH = CH-] Intermediate (XII) is prepared using 2-thiophenecarboxaldehyde, N-methyl-N-cyclopropylmethylamine and sodium cyanide. The resulting alpha-amino-N-cyclopropylmethyl-N-methyl- (2-thienyl) acetonitrile was used without further purification.

Proceed as above to alkylate; cinnamyl bromide is used. An oily product is obtained in the form of a reddish-colored oil (yield 100%). The resulting compound is used as is in the reaction with the organo-magnesium compound.

NMR: 0.10-0.15 (m, 5H); 2.10-2.45 (m, 2H); 2.55 (s,

3H); 2.90 (d, 2H); 5.80 (t, 1H); 6.35 (d, 1H);

6.85-6.95 (m, 1H); 7.10-7.45 (m, 7H)

B-3) 1-Cyano-1- (N-cyclopropylmethyl-N-methyl) -amino-4-phenyl-1- (3-thienyl) -but-3-ene [R IX = thienyl; R ₃ = CH ₃ ; m = l; R ₄ = (CH ₂ ) ₂ CH; R ₅ = C ₆ H ₅ ; Q = -CH = CH-]

The title compound was prepared as described for product Β-2; starting material is 3-thiophenecarboxaldehyde.

NMR: 0.0-0.15 (m, 5H); 2.30 (m, 2H); 2.50 (s, 3H);

3.95 (q, 2H); 5.80 (m, 1H); 6.50 (d, 1H);

7.00-7.50 (m, 8H)

B-4) trans 1- (2-Cyano-2- (2-furyl) -N- (cyclopropylmethyl-N-methyl) aminoethyl] -2-phenylcyclopropane [in formula IX: R ₁ = 2-furyl, R ₃ = CH ₃ , m = 1, R 4 = (CH ₂ ) ₂ CH, R ₅ = C ₆ H ₅ , Q = cyclopropane-1,2-diyl]

The starting material is 1- (N-cyclopropylmethyl-N-methyl) -amino- (2-furyl) -acetonitrile (XII); This compound is prepared from 2-pyraldehyde and N-methyl N-cyclopropylmethylamine as described in the general procedures. Alkylation is also carried out as described in the general operations; trans-1-bromomethyl-2-phenylcyclopropane is used. The preparation is carried out according to Β-2. The red bama oil was used without further purification to react with the organic magnesium compound.

NMR: 0.10-0.90 (m, 8H); 1.30-1.80 (m, 1H);

2.20-2.30 (m, 4H); 2.40 (s, 3H); 6.30 (m, 1H);

6.50 (t, 1H); 7.10 (m, 5H); 7.40 (m, 1H)

B-5) trans 1- [2-Cyano-2- (2-thienyl) -N- (cyclopropylmethyl-N-methyl) aminoethyl] -2-phenylcyclopropem [in formula IX: R ₁ = 2-thienyl; R ₃ = CH ₃ ; m = l; R ₄ = (CH ₂ ) ₂ CH; R ₅ = C ₆ H ₅ ; Q = cyclopropane 1,2diil]

The title compound is obtained using the red oily product from B-2 and the bromo derivative from A-2 in crude form.

NMR: 0.10-1.10 (m, 10H); 2.10-2.40 (m, 3H);

2.60 (s, 3H); 6.75-6.90 (m, 1H); 7.05-7.40 (m,

7H)

B-6) trans-1- [2-Cyano-2- (3-thienyl) -N- (cyclopropylmethyl-N-methyl) aminoethyl] -2-phenylcyclopropane [in formula IX: R = 3-thienyl; R ₃ = CH ₃ ; m = l; R ₄ = (CH ₂ ) ₂ CH; R ₅ = C ₆ H ₅ ; Q = cyclopropane 1,2diil]

The title compound is obtained using the oil intermediate XII described in B-3 and the bromo derivative described in A-2 without further purification.

NMR: 0.30-1.90 (m, 9H); 2.20 (m, 4H); 2.45 (s, 3H);

6.80-7.50 (m, 8H)

B-7) 1-Cyano-1- (N-cyclopropylmethyl-N-methyl) -aminol- (2-thienyl) -4- (3-thienyl) but-3-ene (Formula IX) : R ₁ = 2-thienyl; R ₃ = CH ₃ ; m = l; R ₄ = (CH ₂ ) ₂ CH; R _s = 3-thienyl; Q = -CH = CH-j aminonitrile (XII) is prepared from 2-thiophenecarboxaldehyde according to Example B-2 and then condensed with intermediate (XIII) as described in the general procedures. The crude product obtained (100% yield) was used without further purification in the reaction with the organic magnesium compound.

B-8) 1-Cyano-1- (N-cyclopropylmethyl-N-methyl) -aminol- (2-furyl) -4- (2-thienyl) but-3-ene (Formula IX) R ₁ = 2-furyl; R ₃ = CH ₃ ; m = l; R ₄ = (CH ₂ ) ₂ CH; R ₅ = 2-thienyl; Q = -CH = CH-]

The title compound was prepared in the same manner as above; starting material is 2-furaldehyde and intermediate XIII. The resulting crude product (100% yield) was used without further purification in the reaction with the organic magnesium compound.

B-9) trans-1- [2-Cyano-2-phenyl- (N-cyclopropylmethyl-N-methyl) -aminoethyl] -2- (2-thienyl) -cyclopropane [in formula IX: R _t = C ₆ H ₅ ; R ₃ = CH ₃ ; m = l; R ₄ = (CH ₂ ) -, CH; R ₅ = 2-thienyl; Q = ciklopropán1,2-diyl]

The title compound was prepared in a similar manner using benzaldehyde starting material and intermediate XIII as described in Example A-5. The crude product obtained (100% yield) was used without further purification in the reaction with the organic magnesium derivative.

NMR: 0.30-2.60 (m, 6H); 2.25 (t, 2H); 2.50 (s, 3H);

6.90 (m. 3H); 7.37 (m, 3H); 7.60 (m, 2H)

B-10) trans-1- (2-Cyano-2- (3-thienyl) - (N-cyclopropylmethyl-N-methyl) aminoethyl] -2- (3-thienyl) cyclopropane [a (IX) in the general formula: R ₁ = R ₅ = 3-thienyl; R ₃ = CH ₃ ; m = 1; R ₄ = (CH ₂ ) ₂ CH; Q = cyclopropane-1,2-diyl]

The title compound was prepared as described above using thiophenecarboxaldehyde starting material and intermediate XIII as described in Example A-6. The crude product obtained (100% yield) was used in the next step without further purification.

Preparation of N-Cycloalkylalkylamine Derivatives

General operations

A 3 M solution of ethyl magnesium bromide (76.0 mL, 227 mmol) in ether was transferred to anhydrous flask under nitrogen.

HU 217,873 Β

Subsequently, 50.4 mmol of the amine nitrile of formula IX are dissolved in 65 ml of tetrahydrofuran; the solvent is previously dehydrated through a molecular sieve. The solution is maintained at 20 to 30 ° C.

The mixture was stirred for 3 hours at room temperature (about 20 ° C) and then added to 260 ml of saturated aqueous ammonium chloride solution at a temperature below 10 ° C.

The aqueous phase is separated and the organic phase is extracted three times with 2N hydrochloric acid.

The combined hydrochloric acid phases are made basic with concentrated sodium hydroxide solution and then extracted with ether. The ethereal phases were combined, washed with water and dried over sodium sulfate. The ether is distilled off and the product is purified in a known manner.

The intermediates described in Examples B-1-B-10 are reacted with ethyl magnesium bromide to give compounds of formula (I).

1-10. example

Example 1

4- (N-Cyclopropylmethyl-N-methyl) -amino-4- (2-furyl) -1-phenylhex-1-ene [R ₁ = 2-furyl; R ₂ = C ₂ H ₅ ; R ₃ = CH ₃ ; m = 1;

R ₄ = CH (CH ₂ ) ₂ ; R ₅ = C ₆ H ₅ ; Q = -CH = CH-]

The starting material is aminonitrile from Example B-1.

A yellow oily product is obtained, TLC = 055 S.B.

IR: 3080, 3030, 2980, 2880, 2800, 1600, 1560, 1500,

1465, 1380, 1230, 1160, 1020, 980, 740, 695 cmNMR: 0.10-0.60 (m, 5H); 0.90 (t, 3H); 1.90 (q, 2H)

2.30 (d, 2H); 2.40 (s, 3H); 2.80-2.90 (m, 2H);

6.20-6.60 (m, 4H); 7.30-7.40 (m, 6H)

Analysis: (C ₂₁ H ₂₇ NO) C, Η, N, O.

Example 2

4- (N-Cyclopropylmethyl-N-methyl) -amino-1-phenyl-4- (2-thienyl) -hex-1-ene [R] = 2-thienyl; R ₇ = C ₂ H ₅ ; R ₃ = CH ₃ ; m = l;

R ₄ = CH (CH ₂ ) ₂ ; R _s = C ₆ H ₅ ; Q = -CH = CH-j

Intermediate B-2 was used as starting material.

A yellow oily product is obtained; boiling point 160 ° C / 35 Pa, TLC = 0.25 S.D.

IR: 3070, 3020, 2960, 2895, 1665, 1640, 1595, 1570,

1490, 1450, 1230, 1030, 970, 825, 745, 690 cm -1 NMR: 0.05-0.55 (m, 5H); 1.90 (m, 5H); 2.30 (d, 2H);

2.50 (s, 3H); 2.90 (d, 2H) 6.10-6.60 (m, 2H);

7.00-7.10 (m, 2H); 7.20-7.30 (m, 6H)

Analysis: (C ₂₁ H ₂₇ NS) C, Η, N, S

Example 3

4- (N-Cyclopropylmethyl-N-methyl) -amino-1-phenyl-4- (3-thienyl) -hex-1-ene [R 1 = 3-thienyl; R ₂ = C ₂ H ₅ ; R ₃ = CH ₃ ; m = l;

R4 = CH _{(CH2) 2;} R ₅ = C ₆ H ₅ ; Q = -CH = CH-]

Intermediate B-3 was used as starting material.

A yellow oily product is obtained; boiling point 140 ° C / 3.5 Pa, TLC = 0.45 S.A.

IR: 3075, 3055, 3020, 2990, 2965, 2930, 2875, 2840,

2790, 1595, 1495, 1460, 1015, 980, 965, 845, 755,

740, 690, 665 cm '

NMR: 0.10-0.55 (m, 4H); 0.70 (s, 1H); 0.75 (t, 3H);

1.85 (q, 2H); 2.25 (d, 2H); 2.40 (s, 3H);

6.00-6.50 (m, 2H); 7.00-7.40 (m, 8H)

Analysis: (C ₂₁ H ₂₇ NS) C, Η, N, S

Example 4 Trans-1- [2- (N-Cyclopropylmethyl-N-methyl) -amino-2- (2-furyl) -butyl] -2-phenyl-cyclopropane [R 1 = 2-furyl; R ₂ = C ₂ H ₅ ; R ₃ = CH ₃ ; m = 1;

R ₄ = CH (CH ₂ ) ₂ ; R ₅ = C ₆ H ₅ ; Q is cyclopropane-2-diyl]

Intermediate B-4 was used as starting material.

A reddish-brown oily product is obtained;

TLC = 0.45 S. B

IR: 3060, 2990, 2970, 2930, 2790, 1605, 1499, 1460,

1220, 1158, 1015, 940, 885, 930, 800, 730,

700 cm * ¹

NMR: 0.40-0.95 (m, 11H); 1.20-1.70 (m, 2H);

1.95 (m, 3H); 2.15 (m, 2H); 2.35 (s, 3H); 6.05 (m,

IH); 6.35 (m, 1H); 6.85-7.35 (m, 6H)

Analysis: (C ₂₂ H ₂₉ NO) C, Η, N, O

Example 5 Trans-1- [2- (N-Cyclopropylmethyl-N-methyl) -amino-2- (2-thienyl) -butyl] -2-phenyl-cyclopropane [R 1 = 2-thienyl; R ₂ = C ₂ H ₅ ; R ₃ = CH ₃ ; m = 1;

R ₄ = CH (CH ₂ ) ₂ ; R ₅ = C ₆ H ₅ ; Q = cyclopropane-1,2-diyl] Intermediate B-5 was used as starting material.

A reddish-brown oily product is obtained;

TLC = 0.45 S.A.

IR: 3060, 2980, 2960, 2940, 2960, 2790, 1610, 1500,

1465, 1240, 1020, 830, 750, 700 cm @ ^-1 NMR: 0.10 (m, 2H); 0.40-0.50 (m, 2H);

0.80-0.95 (m, 5H); 1.30 (s, 1H); 1.50-1.90 (m,

2 H); 2.00-2.10 (m, 4H); 2.30 (d, 2H); 2.45 (s, 3H);

6.80-7.25 (m, 8H)

Analysis: (C ₂₂ H ₂₉ NS) C, Η, N, S

Example 6 trans-1- [2- (N-Cycloprogylmethyl-N-methyl) -amino-2- (3-thienyl) butyl] -2-phenylcyclopropane [R 1 = 3-thienyl; R ₂ = C ₂ H ₅ ; R ₃ = CH ₃ ; m = l;

R ₄ = CH (CH ₂ ) ₂ ; R _s = C ₆ H ₅ ; Q is cyclopropane-2-diyl]

Intermediate B-6 was used as starting material.

A reddish-brown oily product is obtained;

TLC = 0.75 S.C.

IR: 3070, 2990, 2930, 2875, 2840, 2785, 1604, 1497,

1460, 1015, 777, 693 cm * ¹

NMR: 0.05-0.15 (m, 1H); 0.25-0.55 (m, 2H);

0.60-1.10 (m, 7H); 1.40-1.75 (m, 2H); 1.75-2.10 (m, 4H); 2.15-2.35 (m, 2H); 2.40 (s, 3H);

6.85-7.40 (m, 8H)

Analysis: (C ₂₂ H ₂₉ NS) C, Η, N, S

HU 217,873 Β

Example 7

4- (N-Cyclopropylmethyl-N-methyl) -amino-4- (2-thienyl) -1- (3-thienyl) -hex-1-ene [R] = 2-thienyl; R 2 = C ₂ H ₅ ; R ₃ = CH ₃ ; m = l;

R ₄ = CH (CH ₂ ) ₂ ; R ₅ = 3-thienyl; Q = -CH = CH-]

Intermediate B-7 was used as starting material.

A yellow oily product is obtained;

Boiling point 143-151 ° C / 5 Pa, TLC = 0.50 S.A.

IR (film): 3076, 3050, 2968, 1942, 1908, 2848, 2820, 2768, 1448, 1237, 1222, 1074, 1008, 957, 852, 832, 793,757,687 cmNMR: 0.10-0.20 (m, 2 H); 0.30-0.70 (m, 2H); 0.70-1.10 (m, 1H); 0.85 (t, 1H); 1.90 (q, 2H); 2.30 (d, 2H); 2.45 (s, 3H); 2.80 (d, 2H); 6.10 (m, 1H); 6.52 (d, 1H); 6.80-7.50 (m, 6H)

Analysis: (C ₁₉ H ₂₅ NS ₂ ) C, Η, N, S

Example 8

4- (N-Cyclopropylmethyl-N-methyl) -amino-4- (2-furyl) -1- (2-thienyl) -hex-1-ene [R] = 2-furyl; R ₂ = C ₂ H ₅ ; R ₃ = CH ₃ ; m = l;

R ₄ = CH (CH ₂ ) ₂ ; R ₅ = 2-thienyl; Q = -CH = CH-]

Intermediate B-8 was used as starting material.

A yellow oily product is obtained;

Boiling point 125-145 ° C / 10 Pa, TLC = 0.40 S.A.

IR (film): 3070, 2965, 2870, 2820, 2795, 1500, 1465, 1225, 1210, 1160, 1125, 1080, 1045, 1020, 990, 960, 860, 830, 805, 737, 695 cmNMR: δ, 10-0.20 (m, 2H); 0.20-0.60 (m, 2H); 0.60-1.10 (m, 4H); 1.88 (q, 2H); 2.26 (d, 2H); 2.37 (s, 3H); Z 2.50-3.20 (m, 2H); 5.80-6.20 (m, 2H);

6.20-6.40 (m, 1H); 6.60 (d, 1H); 6.80-7.20 (m, 3H); 7.42 (s, 1H)

Analysis: (C ₁₉ H ₂₅ NOS) C, Η, N, O, S

Example 9 Trans-1- [2- (N-Cyclopropylmethyl-N-methyl) -amino-2-phenyl-butyl] -2- (2-thienyl) -cyclopropane [R 1 = C ₆ H ₅ ; R ₂ = C ₂ H ₅ ; R ₃ = CH ₃ ; m = l;

R ₄ = CH (CH ₂ ) ₂ ; R ₅ = 2-thienyl; Q is cyclopropane-2-diyl]

Intermediate B-9 was used as starting material.

A yellow oily product is obtained;

Boiling point: 135-145 ° C / 13 Pa, TLC = 0.50 S.B.

IR: 3062, 2786, 1596, 1490, 1442, 1018, 759,697 cmNMR: 0.30-0.60 (m, 2H); 0.60-1.20 (m, 8H);

1.60-2.20 (m, 6H); 2.35 (d, 2H); 2.45 (s, 3H); 6.50-6.70 (m, 1H); 6.80-6.90 (m, 1H); 6.90-7.10 (m, 1H); 7.10-7.60 (m, 5H)

Analysis: (C ₂₂ H ₂₉ NS) C, Η, N, S

Example 10 Trans-1- [2- (N-Cyclopropylmethyl-N-methyl) -amino-2- (3-thienyl) -butyl] -2- (3-thienyl) -cyclopropane [R 1 = R ₅ = 3 thienyl; R ₂ = C ₂ H ₅ ; R ₃ = CH ₃ ; m = l;

R ₄ = CH (CH ₂ ) ₂ ; Q is cyclopropane-1,2-diyl]

Intermediate B-10 was used as starting material.

A yellow oily product is obtained;

Boiling point: 163-166 ° C / 1 Pa, TLC = 0.25 S. A

IR: 3060, 2960, 2780, 1680, 1460, 1020, 850, 780 cmNMR: 0.30-0.60 (m, 2H); 0.60-1.10 (m, 7H);

1.50-2.40 (m, 9H); 2.37 (s, 3H); 6.70-6.90 (m,

2 H); 7.00-7.40 (m, 4H);

Analysis: (C ₂₀ H ₂₇ NS) C, Η, N, S.

1-10. The compounds prepared according to Examples 1 to 5 were subjected to pharmacological tests. Studies in mice show that the compounds have low toxicity. In addition, the inhibition of picrotoxin-induced convulsions by the test compounds was investigated.

These properties allow the compounds of the invention to be used as psychotropic agents for the treatment of neuropsychiatric disorders.

In addition, the compounds were tested for their ability to bind to mu, delta, kappa, opioid and sigma receptors in vitro.

The results show that the compounds of the invention exhibit particularly favorable binding to the sigma receptors, a property which is related to the antipsychotic activity of the compounds; detecting an effect is particularly intense in the case of compounds in which R is 2-thienyl and R ₅ is phenyl wherein.

Cycloalkylalkylamine derivatives of formula (I) were tested in rats in vivo. The compounds inhibit gastroduodenal ulcers commonly caused by cystamine administration. This effect is related to the ability to bind to local sigma receptors.

Taken together, these properties make the compounds of the present invention suitable for the treatment of asthma and neurological and / or psychiatric disorders and of the gastrointestinal tract.

The compounds of the invention are tested in the following assays.

a) Toxicity of the compounds to mice; determining LD ₅₀ -values for the compounds of: the LD ₅₀ represents the lethal dose which causes 50% mortality of the animals under the test conditions. Male mice of Swiss breed, weighing about 20 g, were used for the studies in groups 4; the animals were deprived of food on the day before the test.

Each assay is performed at four dose levels by oral administration of 100, 300, 600 and 1000 mg of test compound per kg body weight; the mass of the compounds being calculated based on the base of formula (I).

The acute toxicity of the compounds of the present invention corresponds to the value LD ₅₀ = 1000 mg, or higher. In exceptional cases, the toxicity is 600 mg / kg.

b) The psychotropic properties of the compounds of the invention were tested in mice; checking the protective effect against the anticonvulsant state caused by picrotoxin. The studies were performed by Krall et al., Epilepsy 19, 409-428. (1978)].

By administering picrotoxin, the animals are placed in a convulsive state characterized by myoclonic stretching8.

EN 217 873 fever syndrome, followed by stretching of the limbs and death of the animals. Some compounds, especially those that act on GABA / benzodiazepine / Cl ionophore complexes, provide protection against convulsive conditions in animals.

Groups of male mice of Swiss breed about 20 g were used for the studies; the test compounds are administered intraperitoneally (IP) or orally (PO) in aqueous solution.

Subsequently, the animals were given a picrotoxin solution intraperitoneally at a dose of 24 mg / kg (0.2 ml / animal); the compound is administered 30 minutes after the intraperitoneal administration or 60 minutes after the oral administration. The dose administered is sufficient to produce a seizure and then death in untreated animals. Under the experimental conditions described, the animals treated with the test compounds were found not to undergo tonic stretching.

Results can be expressed as:% of animals protected against pictrotoxin activity; animals received 50 mg / kg test compound, ip. administered or received 100 mg / kg test compound po;

or determining an ED ₅₀ for the test compounds; ED ₅₀ in this case denotes the effective dose, in mg / kg, which protects 50% of the animals during the stretching phase; the significance of the results can be represented as follows:

* result in significant p <0.05 range;

** result in significant p <0.01 range.

The test results are summarized in Table 1, which shows the effect of the compounds administered by the two routes.

Table 1

Inhibition of picotoxin-induced convulsions

Pclda number ip:% of protected animals or ED _S0 op .:% of protected animals or ED ₅₀ First N. T. 60% ** Second 50% * N. T. 4th 50% * N. T. 5th 50% * 50% * 6th 50% * 50% * 9th N. T. ED ₅₀ = 9O mg 10th 50% ED ₅₀ = 74 mg

N. T. = ncm examined

c) In vitro binding of the test compounds to sigma receptors is carried out in a manner known per se to Largent B. L. et al. Pharmacol. Exp. Ther. 238, 739-748. (1986).

The assay consisted of competing the test compounds with + [3 H] SKF 10.047, which would be a radioactive ligand for sigma receptors when used in guinea pig cerebral membranes.

The assay is performed by incubating the test compounds in various concentrations of the solution together with standard membrane samples and determining the remaining radioactivity in the solution after filtration.

From the results, the IC _{50 is} calculated, which represents the nanomolar concentration capable of inhibiting the binding of 50% of the sigma receptor-bound radioactive ligand.

The results are shown in Table 2. The results obtained with ditolylguadinine (DTG) are also shown in the table. This compound is a high affinity selective sigma receptor. [Holtzman S.G .: J. Pharm. Exp. Ther. Volume 248 3, Number 1054-1062. (1989).

Table 2

Binding of the compounds of the invention to sigma receptors

Test compound, example number IC ₅₀ (nmol) Second 95 5th 29 DTG 103

The results shown in the table demonstrate that the compounds of the invention have an affinity for sigma receptors of 1-3 times that of DTG.

The favorable affinity and low toxicity value of the cycloalkylamine derivatives of formula I render the compounds valuable.

The specific affinity of the compounds of the invention for mu, delta, kappa, sigma, opioid and phencyclidine (PCP) receptors was investigated; to our knowledge, the study of binding to these receptors can be used to evaluate psychomimetic drugs [Simon EJ, "Opiates receptor binding in Drug Research", published by Robert A. O'Brien-Marcel Dekker (1986), and Largent BL et al., Eur. J of Pharmacol. Volume 155, 345-347. (1988).

The compounds described in Examples 2 and 5 were assayed for in vitro affinity for three opioid receptors as described in Roman, F. et al., J. Pharm. Pharmacol. Volume 39, pp. 404-407. (1987); and affinity for PCP receptors were also performed as described in the literature [Vignon J. et al., "Brain Slit." Volume 280 194-197. 1983, and Volume 378, pages 133-141. (1986).

The results in Table 3 are given in IC ₅₀ . This value represents the nanomolar concentration of the test substance in solution at which the test substance is able to inhibit 50% of the binding of a specific radioactive ligand to that receptor.

HU 217,873 Β

Table 3

Investigation of affinity for sigma, mu, delta, kappa, and PCP receptors

Test compounds Mu Delta Kappa sigma PCP receptors Example number: Second 1542 7,387 1196 95 6280 5th 3024 57,043 9095 29 4226 DTG 3970 33,200 6490 103 6750

The results show that the sigma receptor affinity of the compounds of the invention can be clearly evaluated.

The measured IC sigma receptor affinitásnál ₅₀ -values arbitrary one's account, this value is compared to the measured IC for MU, delta and kappa receptors ₅₀ -ér15 low polydispersity values; calculations are made for the compound of Example 5, which has the highest intensity of sigma receptor affinity.

Comparing these values with those obtained with DTG gives the following results:

Test compounds Mu Delta Kappa sigma PCP receptors Example number 5th 104 1967 314 1 145 DTG 38 322 63 1 65

The results show that the affinity for the sigma receptors of the compounds of the present invention is at least one hundred times higher than the affinity for the other kappa receptors and 2000 times higher than that obtained for the delta receptor.

Comparing the results with the values obtained with DTG, the compound of Example 5 is at least twice as selective for the sigma receptor affinity as the DTG compound used for comparison.

d) The effect of the compounds of the present invention on the gastrointestinal tract was investigated in rats. Test the ability of test compounds to inhibit gastroduodenal ulceration in the presence of cis-teaminin-induced ulcers.

Studies in rats are described by Robert et al., Digestion, Vol. 11, pp. 199-211. (1974)].

Groups of female rats of Wistar breed, average weight 200 g, were used for the studies. The animals were administered 400 mg / kg cysteamine hydrochloride by subcutaneous injection. Test compounds are administered orally or subcutaneously 1 hour or 30 minutes prior to administration of the ulcer agent.

After 18 hours, the animals are sacrificed by moving the cervical spine; the stomach and duodenum were separated, rinsed with saline and fixed on a board. In the anthropilor-duodenal zone, the formation of ulcers is monitored and expressed in mm ² . The area is calculated by multiplying the two opposing diagonals by 60 in the lesion. Statistical evaluation of the results is performed using the Student method, which is used for the examination of ulcerated surfaces; groups of animals receiving vehicle alone are used as controls.

The results, expressed in ED ₅₀ , are shown in Table 4.

ED _S0 represents the effective dose value, in mg / kg, which reduces cysteamine-induced ulcer formation by 50%.

Table 4

Inhibition of cysteamine-induced gastroduodenal ulcer

Test compound ED ₅₀ , mg / kg Example number: Second 48.2 5th 45.7

These pharmacological properties of the compounds of the present invention, while having low toxicity, allow the compounds to be used as active ingredients in pharmaceutical compositions, and the composition has neurological and / or psychiatric disorders such as depressive states, memory disorders, behavioral disorders, schizophrenia, Alzheimer's disease, Parkinson's disease. and

EN 217 873 Β used to treat and prevent senile dementia.

In addition, the cycloalkylalkylamine derivatives of formula (I) are useful in the treatment of gastrointestinal disorders; these include gastrointestinal motility disorders, gastro-oesophageal, gastro-duodenal reflux, and gastric and / or duodenal ulcers.

The compounds of the invention will generally be administered in a unit dose of 1 to 500 mg, preferably 5 to 200 mg, depending upon the condition of the subject being treated and the severity of the disease. The daily therapeutic dose may be divided into several doses; the daily dose is usually between 0.5 and 1500 mg. Generally, a daily dose of 5 to 500 mg, divided into 2 to 4 times, provides a beneficial effect. 15

The compounds of the present invention may be administered to patients in a variety of pharmaceutical formulations such as tablets, dragees, capsules, powders, solutions, suspensions, gels or suppositories. A base or a salt thereof may be used to prepare these pharmaceutical compositions.

In pharmaceutical compositions, the active ingredient is present in an amount of 5 to 90% by weight. Auxiliaries and vehicles commonly used in medicine have a weight of 95 to 10% by weight. In the case of liquid preparations, the active ingredient content is between 0.1 and 10% by weight, in this case the concentration of excipients and carriers is 99.9-90% by weight.

The preparation of the formulations is as follows

lot illustrates: Composition of the preparation: 30 Active ingredient (Compound of Example 5) 10.0-50.0 mg Poly (vinylpyrrolidone) 20.0 mg Carboxymethyl starch 8.0 mg Magnesium stearate 2.0 mg Colloidal silica 0.4 mg 35 Lactose, ad 200.0 mg

The active ingredient is mixed with lactose in an aqueous alcoholic solution and granulated with polyvinylpyrrolidone solution. The resulting material was dried and passed through a 1 mm mesh screen. The carboxymethyl starch is mixed with the colloidal silica and added to the former granulate; magnesium stearate is then added to the resulting mixture, and after intense mixing, tablets (200 mg) are compressed.

Claims (4)

PATENT CLAIMS 1. N-cycloalkylalkylamine derivatives of the formula (I) and salts thereof, wherein R _t is furyl or thienyl; or phenyl, provided that Q is cyclopropane-1,2-diyl of formula (a); R ₂ is C 1 -C 6 alkyl; R ₃ is hydrogen or C 1-6 alkyl; m is 1 or 2; R ₄ is cycloalkyl of the formula -CH (CH ₂ ) _n wherein n is 2-5; _R5 is phenyl or thienyl; Q is ethylene-1,2-diyl of the formula (-CH = CH-) or cyclopropane-1,2-diyl of the formula (a). 2. A pharmaceutical composition comprising an N-cycloalkylalkylamine derivative of the Formula I, or a salt thereof, wherein: R 1 is furyl or thienyl; or phenyl, provided that Q is cyclopropane-1,2-diyl of formula (a); R ₂ is C 1-6 alkyl; R ₃ is hydrogen or C 1-6 alkyl; m is 1 or 2; R ₄ is cycloalkyl of formula -CH (CH ₂ ) wherein n is 2-5; _R5 is phenyl or thienyl; Q is ethylene-1,2-diyl of the formula (-CH = CH-) or cyclopropane-1,2-diyl of the formula (a); and pharmaceutically acceptable excipients and carriers. 3. N-cycloalkylalkylamine derivatives of the formula (I) and salts thereof, wherein R 1 is furyl or thienyl; R ₂ is C 1-6 alkyl; R ₃ is hydrogen or C 1-6 alkyl; m is 1 or 2; R ₄ is cycloalkyl of the formula -CH (CH ₂ ) _n wherein n is 2-5; _R5 is phenyl or thienyl; Q is ethylene-1,2-diyl of the formula (-CH = CH-) or cyclopropane-1,2-diyl of the formula (a). 4. A pharmaceutical composition comprising a N-cycloalkylalkylamine derivative of the Formula I, or a salt thereof, wherein: Rj is furyl or thienyl; R ₂ is C 1-6 alkyl; R ₃ is hydrogen or C 1-6 alkyl; m is 1 or 2; R ₄ is cycloalkyl of the formula -CH (CH ₂ ) _n wherein n is 2-5; _R5 is phenyl or thienyl; Q is ethylene-1,2-diyl of the formula (-CH = CH-) or cyclopropane-1,2-diyl of the formula (a); and pharmaceutically acceptable excipients and carriers.