WO1995023603A1

WO1995023603A1 - Use of 2-amino-4,5,7,8-tetrahydro-6h-thiazolo[5,4-d]azepines substituted in position 6 as medicaments having an anti-depressant effect, and preparation thereof

Info

Publication number: WO1995023603A1
Application number: PCT/EP1995/000725
Authority: WO
Inventors: Rudolf Hammer; Joachim Mierau; Franco Borsini; Erich Lehr; Raffaele Cesana; Wolfgang Grell
Original assignee: Dr. Karl Thomae Gmbh
Priority date: 1994-03-04
Filing date: 1995-02-28
Publication date: 1995-09-08
Also published as: DE4407141A1; AU3070095A; IL112846A0; CO4340739A1

Abstract

The invention concerns the use of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepines substituted in position 6 and of the general formula (I) in which A and R1 are defined as in claim 1, and their physiologically tolerated acid salts of addition for treating depression.

Description

USE OF 2-A IN0-4.5, 7.8, -TETRAHYDR0-6H-THIAZ0L0 5,4-D AZEPINES SUBSTITUTED IN 6-POSITION AS AN ANTIDEPRESSIVE

In EP A 0, 347, 766, substituted 2-amino-4, 5, 7, 8 -tetrahydro-6H-thiazolo [5, 4-d] azepines of the general formula, inter alia in the 6-position

and their physiologically tolerable acid addition salts, which have valuable pharmacological properties. These compounds are particularly suitable for the treatment of Parkinson's disease, hyperprolactinemia and schizophrenia.

Surprisingly, it has now been found that some of the above compounds of the general formula I also have antidepressant properties.

The present invention thus relates to the use of the compounds of the above general formula I in which

Rι_ a phenyl group optionally substituted by a nitro, phenyl, benzyloxy, isobutoxy, piperidino, cyano, hydroxy or amino group, a dimethoxyphenyl, naphthyl or isoquinolyl group or a pyridyl group optionally substituted by a methyl group and A is a -CH = C (R2) - or -C≡C group, where *

R2 represents an oxygen atom or a phenyl group and the carbon atom marked with * is linked to the radical R] _,

and their salts for the treatment of depression.

Preferred compounds here are those of the general formula I above, in which

A is as defined above and

R_ is a phenyl group which is optionally substituted in the 2- or 4-position by a nitro or phenyl group, a phenyl group which is substituted in the 3- or 4-position by a benzyloxy group, a 4-isobutoxy-phenyl, 2-piperidino-phenyl, 4-cyano-phenyl-, 2-hydroxy-phenyl-, 2-amino-phenyl-, 2,3-dimethoxy-phenyl-, 2,5-dimethoxy-phenyl-, naphthyl-, isoquinolino-l- yl or isoquinolin-3-yl group or a 2-pyridyl group optionally substituted in the 3- or 6-position by a methyl group,

and their physiologically acceptable acid addition salts.

For example, the following compounds may be mentioned, which fall under the general formula I mentioned above:

2-amino-6-cinnamyl-4, 5,7, 8-tetrahydro-6H-thiazolo [5,4-d] azepin,

(Z) 2-amino-6- (3-phenyl-2-propen-l-yl) -4,5,7,8-tetrahydro-6H-thiazolo [5,4-d] azepine,

2-amino-6- (3- (2-nitrophenyl) allyl) -4,5,7,8-tetrahydro-6H-thiazolo [5,4-d] azepine, 2-amino-6- (3- (4-nitrophenyl) allyl) -4,5,7,8-tetrahydro-6H-thiazolo [5, 4-d] azepine,

2-amino-6- (3- (2-biphenyl) allyl) -4,5,7,8-tetrahydro-6H-thiazo-lo [5,4-d] azepine,

2-amino-6- (3- (4-biphenyl) allyl) -4,5,7,8-tetrahydro-6H-thiazo-lo [5, 4-d] azepine,

2-amino-6- (3- (3-benzyloxyphenyl) allyl) -4,5,7,8-tetrahydro-6H-thiazolo [5,4-d] azepine,

2-amino-6- (3- (4-benzyloxy-phenyl) allyl) -4,5,7,8-tetrahydro-6H-thiazolo [5,4-d] azepine,

2-amino-6- (3- (4-isobutoxyphenyl) allyl) -4,5,7, 8-tetrahydro-6H-thiazolo [5, 4-d] azepine,

2-Amino-6- (3- (2- (1-piperidino) phenyl) -2-propen-l-yl) -4,5,7,8-tetrahydro-6H-thiazolo [5,4-d] azepine ,

2-amino-6- (3- (4-cyano-phenyl) allyl) -4,5,7,8-tetrahydro-6H-thiazolo [5, 4-d] azepine,

2-amino-6- (3- (2-hydroxy-phenyl) allyl) -4,5,7,8-tetrahydro-6H-thiazolo [5, 4-d] azepine,

2-amino-6- (3- (2-aminophenyl) allyl) -4,5,7,8-tetrahydro-6H-thiazolo [5,4-d] azepine,

2-amino-6- (3- (2, 3-dimethoxy-phenyl) allyl) -4,5,7,8-tetrahydro-6H-thiazolo [5, 4-d] azepine,

2-amino-6- (3- (2,5-dimethoxyphenyl) allyl) -4,5,7,8-tetrahydro-6H-thiazolo [5,4-d] azepine, 2-amino-6- (2,3-diphenyl) llyl) -4,5,7,8-tetrahydro-6H-thiazolo- [5,4-d] azepine,

2-amino-6- (3-phenyl-2-propyn-1-yl) -4,5,7,8-tetrahydro-6H-thiazolo [5, 4-d] azepine,

2-amino-6- {3- (1-naphthyl) allyl) -4,5,7,8-tetrahydro-6H-thiazo-lo [5,4-d] azepine,

2-amino-6- (3- (2-naphthyl) allyl) -4,5,7,8-tetrahydro-6H-thiazo-lo [5, 4-d] azepine,

2-amino-6- (3- (1-isoquinolinyl) allyl) -4,5,7, 8-tetrahydro-6H-thiazolo [5, 4-d] azepine,

2-amino-6- (3- (3-isoquinolinyl) allyl) -4,5,7,8-tetrahydro-6H-thiazolo [5,4-d] azepine,

2-amino-6- (3- (2-pyridyl) allyl) -4,5,7, 8-tetrahydro-6H-thiazolo- [5, 4-d] azepine,

2-amino-6- (3- (3-methyl-2-pyridyl) allyl) -4,5,7,8-tetrahydro-6H-thiazolo [5, 4-d] azepine,

2-amino-6- (3- (6-methyl-2-pyridyl) allyl) -4,5,7, 8-tetrahydro-6H-thiazolo [5, 4-d] azepine and

2-Amino-6- (3- (2-pyridyl) -2-propyn-1-yl) -4,5,7,8-tetrahydro-6H-thiazolo [5,4-d] azepine

and their physiologically tolerable acid addition salts.

However, particularly preferred compounds of the above general formula I are those in which

A is a vinylene or ethynylene group and R _] _ a phenyl group optionally substituted in the 2- or 4-position by a phenyl group, a 3-benzyloxy-phenyl, 4-benzyloxy-phenyl, 2-piperidino-phenyl, 4-cyano-phenyl , 2-hydroxy-phenyl, 2-aminophenyl, 2, 3-dimethoxyphenyl, 1-naphthyl, 2-naphthyl, isoquinolin-1-yl or isoquinolin-3-yl group or one 2-pyridyl group optionally substituted in the 3- or 6-position by a methyl group,

and their physiologically acceptable acid addition salts.

The following are mentioned as particularly preferred compounds, for example:

2-amino-6- [3- (4-cyano-phenyl) allyl] -4,5,7,8-tetrahydro-6H-thiazolo [5,4-d] azepine (compound A),

2-amino-6- [3- (3-benzyloxyphenyl) allyl] -4,5,7,8-tetrahydro-6H-thiazolo [5,4-d] azepine (compound B),

2-amino-6-cinnamyl-4,5,7,8-tetrahydro-6H-thiazolo [5, 4-d] azepine (compound C),

2-amino-6- (3- (3-isoquinolinyl) allyl) -4,5,7, 8-tetrahydro-6H-thiazolo [5,4-d] azepine (compound D) and

2-amino-6- (3- (3-methyl-2-pyridyl) allyl) -4,5,7,8-tetrahydro-6H-thiazolo [5,4-d] azepine (compound E),

and their physiologically tolerable acid addition salts.

In this context, it is particularly important that the compounds of the general formula I above have a low α-receptor affinity and thus have a high selective activity with excellent tolerability. In addition, the good bioavailability of the above compounds is the general formula I another advantage when used as an antidepressant.

For example, the antidepressant effect of compounds A to E was demonstrated in preclinical studies in the "forced swimming test". Details of this behavioral test can be found, for example, in Willner, Psychopharmacology £ 3_, 1-16

(1984) and Borsini and Meli, Psychopharmacology 2A, 147-160

(1988).

For this purpose, the compounds were dissolved in physiological NaCl solution with the addition of 1 or 2 equivalents of 0.1 N HCl and 60 minutes before the start of the "Forced Swimming Test" intraperitoneally (Table 1) or orally (Table 2) in each case eight male Administered to rats. Physiological NaCl solution was used as the control substance. Amineptine, a known antidepressant, was tested as a comparative substance after intraperitoneal administration (Table 1). The results are shown in Tables 1 and 2.

Table 1: Investigations of the compounds A to E and of amineptine in comparison to the control (physiological NaCl solution) in the "forced swimming test" on rats (n = 8) after i.p. Gift.

Dose I mobility% change in mg / kg time (seconds) I mobility time

(i.p.) Mittel + SE versus control

NaCl solution 221 ± 8 -

Compound A 0.3 203 + 17 - 8.1

Compound A 1.0 162 + 19 * - 26.7

NaCl solution 179 ± 15 -

Compound A 1.0 100 ± 27 * - 44.1

Compound B 3.0 99 + 21 * - 44.7

NaCl solution 214 + 9 -

Compound C 1.0 156 ± 18-27.1

Compound C 3.0 115 + 23 ** - 46.3

NaCl solution 228 + 11 -

Compound D 1.0 249 ± 7 + 9.2

Compound D 3.0 153 ± 24 ** - 32.9

NaCl solution 197 + 9 -

Connection E 1.0 165 + 12 - 16.2

Connection E 3.0 60 ± 17 ** - 69.5

NaCl solution 208 ± 10 -

Amineptine 20.0 134 + 19 * - 36.6

* P <0.05; ** P <0.01 (Two-tailed Dunnett's Test) Table 2: Examination of compound A in comparison to the control (physiological NaCl solution) in the "forced swimming test" on rats (n = 8) after po administration.

Dose immobility% change in mg / kg time (sec.) Immobility time ge

(p.o.) Median 25-75% over control area

NaCl solution 241 226-249 -

Compound A 0.3 213 186-237 - 11.6

Compound A 1.0 165 * 128-204 - 31.5

Compound A 3.0 104 ** 56-116 - 56.8

Thin test: * P <0.05; ** P <0.01

The present results demonstrate the superiority of the compounds A to E over amineptins and the good bioavailability of 2-amino-6- [3- (4-cyano-phenyl) allyl] -4, 5, 7, 8-th trahydro-6H-thiazolo [5,4-d] azepine (Compound A).

On the basis of the biological data mentioned above, the compounds of the general formula I and their physiologically tolerable acid addition salts are suitable for the treatment of depression and can be added to the usual pharmaceutical preparations which essentially consist of an inert pharmaceutical carrier and an effective dose of Active ingredient exist, such as. B. tablets, dragees, capsules, wafers, powder, solutions, suspensions, emulsions, syrups, suppositories, etc., are incorporated. A therapeutically effective single dose for the indication found according to the invention is in the range between 0.1 and 100 mg, preferably between 1 and 20 mg.

The following examples are intended to explain the invention in more detail: example

2-Amino-6- [3- (4-cyano-phenyl) allyl] -4,5,7, 8-tetrahydro-6H-thiazolo [5, 4-d] azepine hydrochloride

0.70 g (2.25 mmol) 2-amino-6- [3- (4-cyano-phenyl) allyl] -

4, 5, 7, 8-tetrahydro-6H-thiazolo [5, 4-d] azepine, 10 ml ethanoi and

2.25 ml IN hydrochloric acid are heated together to reflux. The resulting clear solution is cooled in ice, slowly

Crystallization takes place. The precipitated crystals are filtered off, washed with ethanol and ether and at 100 ° C./4

Torr dried.

Yield: 0.46 g (59% of theory),

Melting point: 237 ° C (dec.)

Ber. : C 58.85 H 5.52 N 16.15 Cl 10.22

Found: 58.37 5.45 16.05 10.18

Example B

2-Amino-6- [3- (4-cyano-phenyl) allyl] -4,5,7, 8-tetrahydro-6H-thiazolo [5, 4-d] azepine dihydrochloride x 0.25 H2O

0.70 g (2.25 mmol) 2-amino-6- [3- (4-cyano-phenyl) allyl] -4,5,7,8-tetrahydro-6H-thiazolo [5,4-d] azepine , 10 ml ethanol and 4.50 ml IN hydrochloric acid are heated to reflux together. The clear solution formed is evaporated in vacuo. The foam-like residue obtained is dissolved four times in ethanol and again evaporated in vacuo. It is then dissolved hot in ethanol and cooled. The crystals obtained on cooling are filtered off and dried at 100 ° C./4 torr.

Yield: 0.70 g (81% of theory), melting point: 247 250 ° C (dec.)

Ber. x 0.25 H ₂ 0: C 52.64 H 5.30 N 14.44 Cl 18.29 Found: 52.27 5.26 14.62 18.50 Example 1

Coated tablets with 5 mg of 2-amino-6- [3- (4-cyano-phenyl) allyl] -4, 5, 7, 8-tetrahydro-6H-thiazolo [5, 4-d] azepine dihydrochloride

1 coated tablet contains:

Active substance 5.0 mg

Milk sugar 33.5 mg

Corn starch 10.0 mg

Gelatin 1.0 mg

Magnesium stearate 0.5 mg

50.0 mg

Manufacturing:

The mixture of the active substance with milk sugar and corn starch is granulated with a 10% aqueous gelatin solution through a sieve with a mesh size of 1 mm, dried at 40 ° C. and rubbed again through the sieve above. The granules thus obtained are mixed with magnesium stearate and pressed to dragee cores. The production must be carried out in darkened rooms.

Drageekern weight: 50 mg

Stamp: 5 mm, domed

The dragee cores obtained in this way are coated according to a known method with an envelope consisting essentially of sugar and talc. The finished coated tablets are polished using beeswax.

Dragee weight: 100 mg. Example 2

Coated tablets with 5 mg of 2-amino-6- [3- (4-cyano-phenyl) allyl] -4, 5, 7, 8-tetrahydro-6H-thiazolo [5,4-d] azepine

1 drag core contains:

Active substance 4, 1 mg

Milk sugar 34.4 mg

Corn starch 10.0 mg

Gelatin 1.0 mg

Magnesium stearate 0.5 mg

50.0 mg

Production analogous to example 1.

Drageekern weight: 50 mg

Stamp: 5 mm, domed

Dragee weight: 100 mg.

Example 3

Coated tablets with 10 mg of 2-amino-6- [3- (4-cyano-phenyl) allyl] -4, 5, 7, 8-tetrahydro-6H-thiazolo [5,4-d] azepine dihydrochloride

1 coated tablet contains:

Active substance 10.0 mg

Milk sugar 35.5 mg

Corn starch 12.0 mg

Gelatin 1.0 mg

Magnesium stearate 0.5 mg

59.0 mg Production analogous to example 1.

Dragee weight: 100 mg.

Example 4

Coated tablets with 10 mg of 2-amino-6- [3- (4-cyano-phenyl) allyl] -4, 5, 7, 8-tetrahydro-6H-thiazolo [5, 4-d] azepine

1 coated tablet contains:

Active substance 8.2 mg

Milk sugar 37.3 mg

Corn starch 12.0 mg

Gelatin 1.0 mg

Magnesium stearate 0.5 mg

59.0 mg

Production analogous to example 1.

Dragee weight: 100 mg.

Example 5

Suppositories with 10 mg 2-amino-6- [3- (4-cyano-phenyl) allyl] - 4,5,7, 8-tetrahydro-6H-thiazolo [5,4-d] azepine dihydrochloride

1 suppository contains:

Active substance 10.0 mg

Suppository mass (e.g. Witepsol W 45) 1 690.0 mg

1,700.0 mg Manufacturing;

The finely powdered substance is stirred into the molten suppository mass, which has been cooled to 40 ° C., with the aid of an immersion homogenizer. The mass is poured into slightly pre-cooled molds at 35 ° C.

Suppository weight: 1.70 g.

Example 6

Suppositories with 10 mg 2-amino-6- [3- (4-cyano-phenyl) allyl] - 4,5,7, 8-tetrahydro-6H-thiazolo [5,4-d] azepine

1 suppository contains:

Active substance 8.2 mg

Suppository mass (e.g. Witepsol W 45) 1,691.8 mg

1,700.0 mg

Production analogous to example 5.

Suppository weight: 1.70 g.

Example 7

Dropping solution with 5 mg / ml 2-amino-6- [3- (4-cyano-phenyl) allyl] - 4,5,7, 8-tetrahydro-6H-thiazolo [5,4-d] azepine dihydrochloride

100 ml drip solution contain:

p-Hydroxybenzoic acid methyl ester 0.035 g p-hydroxybenzoic acid n-propyl ester 0.015 g

Anise oil 0.050 g

Menthol 0.060 g

Pure ethanol 10,000 g

Active substance 0.500 g Citric acid 0.700 g

Sodium phosphate sec. x 2 H2O 0.300 g

Sodium cyclamate 1,000 g

Glycerin 15,000 g

Dest. Water to 100,000 ml

Manufacturing:

The esters of p-hydroxybenzoic acid, anise oil and menthol are dissolved in ethanol (solution I). The buffer substances, the active substance and sodium cyclamate are in dist. Dissolved water and added glycerin (solution II). Solution I is stirred into solution II and the mixture with dist. Make up water to the given volume. The finished drip solution is filtered through a suitable filter. The preparation and filling of the drip solution must be carried out with light protection and with protective gassing.

At game &

Ampoules with 5 mg / ml 2-amino-6- [3- (4-cyano-phenyl) allyl] - 4,5,7, 8-tetrahydro-6H-thiazolo [5,4-d] azepine dihydrochloride

1 ampoule contains:

Active substance 5.0 mg

Citric acid 7.0 mg

Sodium phosphate sec. x 2 H2O 3.0 mg

Sodium pyrosulfite 1.0 mg

Dest. Water ad 1.0 ml

Manufacturing:

The buffer substances, the active substance and sodium pyrosulfite are dissolved in succession in boiled water and cooled under CO2 fumigation. Make up to the given volume with boiled water and filter without pyrogen. Filling: in brown ampoules under protective gas. Sterilization: 20 minutes at 120 ° C.

The ampoule solution must be prepared and filled in darkened rooms.

Claims

claims

1. Use of 2-amino substituted in the 6-position

4,5,7,8-tetrahydro-6H-thiazolo [5,4-d] azepines of the general

formula

in the

R_ is a phenyl group optionally substituted by a nitro, phenyl, benzyloxy, isobutoxy, piperidino, cyano, hydroxy or amino group, a dimethoxyphenyl, naphthyl or isoquinolyl group or a pyridyl group optionally substituted by a methyl group and

A is a -CH = C (R ₂ ) - or -C≡C group, where *

R _{2 represents} a hydrogen atom or a phenyl group and the carbon atom marked with * is linked to the radical R ^,

and their physiologically acceptable acid addition salts for the treatment of depression.

2. Use of 2-amino substituted in 6 position

4,5,7,8-tetrahydro-6H-thiazolo [5,4-d] azepines of the general

formula

R ₁ - A - CH ₂ - AD

in the

R _] _ a phenyl group optionally substituted by a nitro, phenyl, benzyloxy, isobutoxy, piperidino, cyano, hydroxyl or amino group, a dimethoxyphenyl, naphthyl or isoquinolyl group or an optionally by a methyl group substituted pyridyl group and

A is a -CH = C (R2) - or -C≡C group, where *

and their physiologically tolerable acid addition salts as medicaments with an antidepressant effect.

3. Use of 2-amino substituted in the 6-position

4,5,7,8-tetrahydro-6H-thiazolo [5,4-d] azepines of the general

formula

in the

A is a -CH = C (R ₂ ) - or -C≡C group, where *

R2 represents a hydrogen atom or a phenyl group and the carbon atom marked with * is linked to the radical R ^, and their physiologically tolerable acid addition salts for the manufacture of a medicament with an antidepressant effect.

4. Use according to claims 1 to 3, characterized gekenn¬ characterized in that a compound of general formula I is set in which

A is as defined in claim 1 and

R _] _ a phenyl group which is optionally substituted in the 2- or 4-position by a nitro or phenyl group, a phenyl group which is substituted in the 3- or 4-position by a benzyloxy group, a 4-isobutoxy-phenyl, 2-piperidino-phenyl -, 4-cyano-phenyl-, 2-hydroxy-phenyl-, 2-amino-phenyl-, 2,3-dimethoxy-phenyl-, 2,5-dimethoxy-phenyl-, naphthyl-, isoquinoline- l-yl or isoquinolin-3-yl group or a 2-pyridyl group optionally substituted in the 3- or 6-position by a methyl group,

and their physiologically acceptable acid addition salts.

5. Use according to claims 1 to 3, characterized gekenn¬ characterized in that a compound of general formula I is set in which

A is a vinylene or ethynylene group and

R _] _ a phenyl group optionally substituted in the 2- or 4-position by a phenyl group, a 3-benzyloxy-phenyl, 4-benzyloxy-phenyl, 2-piperidino-phenyl, 4-cyano-phenyl nyl-, 2-hydroxy-phenyl-, 2-amino-phenyl-, 2,3-dimethoxy-phenyl-, l-naphthyl-, 2-naphthyl-, isoquinolin-1-yl- or isoquinolin-3 -yl group or a 2-pyridyl group optionally substituted in the 3- or 6-position by a methyl group, and their physiologically acceptable acid addition salts.

6. Use according to claims 1 to 3, characterized gekenn¬ characterized in that a compound of general formula I is set in which

A is a vinylene group and

R_ is a phenyl group optionally substituted by a 4-cyano or 3-benzyloxy group, a 2-pyridyl group optionally substituted by a methyl group in the 3- or 6-position, an isoquinolin-1-yl or isoquinolin-3-yl Group means

and their physiologically acceptable acid addition salts.

7. Use according to claims 1 to 3, characterized gekenn¬ characterized in that one of the following compounds of general formula I is used:

2-amino-6- [3- (4-cyano-phenyl) allyl] -4,5,7,8-tetrahydro-6H-thiazolo [5,4-d] azepine,

2-amino-6- [3- (3-benzyloxyphenyl) allyl] -4,5,7,8-tetrahydro-6H-thiazolo [5,4-d] azepine,

2-amino-6-cinnamyl-4, 5,7, 8-tetrahydro-6H-thiazolo [5,4-d] azepin,

2-Amino-6- (3- (3-isoquinolinyl) allyl) -4,5,7, 8-tetrahydro-6H-thiazolo [5,4-d] azepine or

2-amino-6- (3- (3-methyl-2-pyridyl) allyl) -4,5,7, 8-tetrahydro-6H-thiazolo [5,4-d] azepine

and their physiologically tolerable acid addition salts. 8. Use according to claims 1 to 3, characterized gekenn¬ characterized in that the following compound of general formula I is used:

2-amino-6- [3- (4-cyano-phenyl) allyl] -4,5,7,

8-tetrahydro-6H-thiazolo [5,4-d] azepine and

their physiologically tolerated acid addition salts.

9. Use according to claims 1 to 3, characterized gekenn¬ characterized in that the following compound of general formula I is used:

2-amino-6-cinnamyl-4, 5,7, 8-tetrahydro-6H-thiazolo [5,4-d] azepine and

their physiologically tolerated acid addition salts.

10. Use according to claims 1 to 3, characterized gekenn¬ characterized in that the following compound of general formula I is used:

2-amino-6- (3- (3-methyl-2-pyridyl) allyl) -4,5,7, 8-tetrahydro-6H-thiazolo [5, 4-d] azepine and

their physiologically tolerated acid addition salts.