Derivatives of benzo(g)quinoline, the method of production thereof, pharmaceutical composition and method of treatment

 

(57) Abstract:

Derivatives of benzo(g)quinoline General formula I

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where X, Y, R1-R12are specified in the claims values, and their salts. The above compound is produced by interaction of the compounds specified in the claims of the formula (II) with the compound of the formula (III). The compounds of formula (II) suitable as pharmaceuticals. 4 C. and 4 h.p. f-crystals, 6 PL.

The present invention relates to new derivatives of benzo[g] quinoline, receiving and containing pharmaceutical compositions, and method of treatment.

In particular, the present invention features a compound of formula I

< / BR>
where X represents =O or H,H,

Y represents-CH2, -O-, -NH - or-S-,

R1represents H or (C1-C4)alkyl,

R2represents H, benzyl, pyrimidyl, bis(4-forfinal)methyl or a group of the formula

< / BR>
< / BR>
where R5represents H or (C1-C4)alkyl, and R6, R7, R8and R9independently represent H, OH, NO2, CF3, (C1-C4)alkyl, acetyl, CONR10R11, COOR12[R10, R11and R12nezabitovsky a H, (C1-C4)alkyl, (C1-C4)alkylsulfonyl, trifloromethyl or a group of the formula

< / BR>
where n is the number from 1 to 5, and m is a number from 1 to 3, and

R4represents hydrogen or halogen, in free base form or salt obtained by the accession acid.

The invention includes enantiomers and their mixtures, for example, epimeria or racemic mixture, which can be represented depending on the asymmetric carbon atoms at positions 3, 4A and 10A. The preferred configuration [3R, 4aR, 10aR].

Halogen represents fluorine, chlorine, bromine or iodine, preferably chlorine or bromine.

The above-mentioned alkyl groups preferably represent methyl.

In one group of compounds of the formula I X, Y, and R1such as defined above, R2represents H, benzyl, pyrimidyl, bis (4-forfinal) methyl, naphthyl or a group of formula (a), as defined above, or (b') or (')

< / BR>
< / BR>
where R'6and R'7independently represent H, OH, NO2, CF3, acetyl, COOR12[R12the same as defined above] or CN, and R'8represents H, NO2or CN; R3is in position 6 /BR>< / BR>
where n and m are such as defined above, and R4represents hydrogen, and the configuration in positions 4A and 10A is an R-configuration.

In another group of compounds of the formula I X represents =O, Y represents-CH2-, and R1, R2, R3and R4such as defined above.

The following aspect of the present invention proposes a method of producing compounds of the formula I and their salts obtained by the accession acid, wherein the compound of formula II

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where X, Y, R1, R3and R4such as defined above, and M represents H or an alkaline metal, is subjected to the interaction with the compound of the formula III

< / BR>
where R2such as defined above, and the thus obtained compounds of formula I is isolated in free base form or salt obtained by the accession acid.

The reaction can be carried out according to known methods for the formation of amides, for example, as described in example 1. In formula II M as alkali metal may constitute, for example, sodium.

The treatment of the reaction mixtures obtained according to the above method, and purification of the compounds obtained moglice of the free bases in a known manner, and vice versa. Acceptable salts obtained by the accession acid, according to the present invention, include, for example, hydrochloride.

The initial compounds of formula II can be obtained from corresponding compounds of formula IV

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where X, Y, R1, R3and R4such as defined above, for example, as described in example 1.

Compounds of formulas III and IV are known or can be obtained analogously to known methods (European patent 77754).

The compounds of formula I and their pharmaceutically acceptable salts obtained by joining acids, referred to hereafter as the agents according to the invention exhibit useful pharmacological properties when tested in vitro using cell cultures expressing the SRIF receptor (factor inhibiting the release of growth hormone), and animals, and are therefore promising as pharmaceuticals.

In particular, the agents according to the invention associated with somatostatinoma receptors. More specifically, they are selective antagonists against somatostatinoma sst1receptors, previously referred to as as SSTR-1 receptors (Hoyer et al., TiPS, 1995, 16; 86-88), as defined in the research linking radio is the relationship to sst1receptors with a value of Rick50in the range of from about 7.5 to 9.5.

Thus, the agents according to the invention are useful for the treatment of anxiety, depression, schizophrenia, neurodegenerative diseases such as dementia, for the treatment of tumors and vascular diseases and immunological diseases, which has been confirmed in a number of standard tests, as described below:

In doses of from about 0.3 to 3 mg/kg p. O. agents according to the invention increase exploratory behavior of mice in the open half of the half-closed platform, in the model, which is indicative of anxiolytic activity (Psychopharmacology, 1986,89:31-37).

In the same model with half-closed platform agents according to the invention in the above doses also aggravate insomnia in mice. Therefore, the compounds indicated for the treatment of depression, schizophrenia and dementia, in particular Alzheimer's disease (SDAT).

In the test with the invasion in mice [Triangle, 1982, 21: 95-105; J. Clin. Psychiatry, 1994, 55: 9 (suppl.B) 4-7] agents according to the invention contribute to the study and reduce the protective ambivalence treated in the dose of from about 1 to 10 mg/kg subcutaneously mouse-invader, confirming antidepressant profile that is similar to carbamazepine is"ptx2">

In addition, these doses of the compounds according to the invention reduce aggressive behavior (attacks, stalking, biting) in case the test with matched pairs in mice [Dixon et al., J. Clin. Psychiatry 55: (9) [Sippl. In] 4-7 (1994)]. Since, as noted above, they further weaken protective behavior in the test with the invasion in mice, the compounds according to the invention show ethopharmacological profile that is very similar to the corresponding profile of carbamazepine, lithium chloride and clozapine. Therefore, they are indicated for the treatment of affective disorders, including bipolar disorders, for example, manic-depressive psychosis, extreme psychotic States, for example, mania, schizophrenia, and excessive mood swings where desirable behavioral stabilization. In addition, the compounds shown in the States of alarm, common trouble, as well as social and agoraphobia, and when those behavioral States, which are characterized by social autism, for example, negative symptoms.

The agents according to the invention is also effective in the treatment of various types of tumors, particularly tumors bearing sst1the receptor, as shown in proliferative tests with RA who Imami tumors [G. Weckbecker et al., Cancer Research 194, 54: 6334-6337]. Therefore, the compounds indicated for the treatment of, for example, breast cancer, prostate, stomach, pancreas, brain and lung (small cell lung cancer).

All of these indications, the appropriate dosage will, of course, will vary depending on, for example, used the connection of the host, the route of administration and the nature and severity of the condition to be treated. However, in General, successful results on animals obtained at a daily dosage of from about 0.1 to about 10 mg/kg animal body weight. In larger mammals, for example humans, the recommended daily dose lies in the range of from about 5 to about 200 mg, preferably from about 10 to about 100 mg of the connection, enter an accepted way in divided doses up to four times per day, or in the form of long-term release.

The agents according to the invention can be entered in free form or in the form of pharmaceutically acceptable salts. Such salts can be obtained in the traditional way and are active in the same order as the available connections.

The prior art is not known compounds with selective sst1antagonistic activity of what values Rick50> 7,0. Such compounds respectively represent an entirely new group of compounds.

In accordance with another aspect of the present invention offers selective antagonists sst1receptors for use as pharmaceuticals, and more specifically for the treatment of the aforementioned conditions, such as depression, anxiety and bipolar disorders.

In addition, the present invention features a pharmaceutical composition comprising a selective antagonist sst1receptors, for example, the agent according to the invention, in combination with at least one pharmaceutically acceptable diluent or carrier. Such compositions can be manufactured in a traditional way. Standard doses contain, for example, from about 0.25 to about 50 mg of the agent according to the invention.

Selective antagonists sst1receptors, for example, the agents according to the invention, can be introduced by any conventional means, for example, parenteral, in particular, in the form of solutions or suspensions for injection, or enterline, preferably orally, in particular in the form of tablets or capsules.

All of these readings preferred the Olin-3-carboxylic acid, which is a combination of example 1. The specified connection has a high affinity to mouse sst1receptors (Rick50=9,1) and recombinant human sst1receptors (Rick50=7,7) and has no significant activity against a broad range of neurotransmitter receptors. At a dose of 1-10 mg/kg subcutaneously connection obviously reduces aggressive behavior in the aforementioned situational test with matched pairs and social change autism in the above test with the invasion in mice. The same effects are observed for the standard anti-manic drugs lithium and carbamazepine in doses of 3-30 mg/kg subcutaneously, confirming similar therapeutic effects in humans. However, it was found that lithium and carbamazepine are less severe means, and it is also known that they have significant side effects, such as a narrow therapeutic window and the slow start procedure.

The preferred indications are depression, anxiety and affective disorders, including bipolar disorder, for example, mania.

According to the above, the present invention also features the use of a selective behaviour for example, for the treatment of depression, anxiety and bipolar disorders.

In addition, the present invention proposes the use of a selective antagonist sst1receptors, i.e. the agent according to the invention, for manufacturing a medicinal product for the treatment of any of the above condition, namely depression, anxiety, and affective disorders.

Another object of the present invention proposes a method of treatment of any of the above condition, namely depression, anxiety and bipolar disorders, in a subject in need of such treatment, wherein the specified effect subject a therapeutically effective amount of a selective antagonist sst1receptors, namely the agent according to the invention.

The following examples illustrate the invention. Temperatures are given in degrees Celsius and miscorrection.

Example 1: 4-(4-nitrophenyl)-piperazine [3R, 4aR, 10aR] -1,2,3,44 a, 5,10,10 a - octahydro-6-methoxy-1-methylbenzo[g]quinoline-3-carboxylic acid

a)SMEs,g(mol)[3R,4aR,10aR]-1-methyl-3-methoxy-carbonyl-6-methoxy - 1,2,3,4 and 5,10,10 and octahydro-benzo[g]quinoline, 36 ml of methanol, 36 ml of tetrahydrofuran and 36 ml of 1 M aqueous sodium hydroxide solution are intensively stirred in those washed with cold 2-propanol and dried at 60oC in high vacuum. Thus obtained sodium salt of [3R,4R,10R]-1-methyl-6-methoxy - 1,2,3,4 a,5,10,10 a-octahydro-benzo[g]quinoline-3-carboxylic acid has so pl. > 230oC (decomposition); []2D0= -138,3o(0.5% in a mixture of dimethylformamide/water, 50:50).

b) Suspension 2,973 g (10 mmol) of sodium salt obtained in stage a), in 24 ml of 38% papapostolou anhydride in dimethylformamide (30 mmol) and 10 ml of absolute pyridine is stirred for 15 minutes at room temperature. After adding 2,07 g (10 mmol) of 1-(4-nitrophenyl)-piperazine stirring is continued for 16 hours at room temperature and add 100 ml of toluene and 100 ml of 2M aqueous ammonia. The precipitated crystals filtered off, washed with water and toluene, dried and recrystallized in toluene. Received specified in the header connection is so pl. 218 to 221oC. []2D0= -128,7o(0.5% in dimethylformamide).

The compounds of formula I, below, receive analogously to example 1.

In the following [3R,4aR,10aR] the compounds X is O, Y is CH2, R1represents methyl, R2and R3such as specified (OR3is in position 6), R41represents methyl, R2and R3such as specified (OR3is in position 6), R4represents H (see tab. 2).

The following [3R,4aR,10aR] the compound X is O, Y is CH2, R1represents methyl, R2and R3such as specified (OR3is in position 6), R4is a 9-Br (see tab. 3).

The following [3R,4aR,10aR] the compound X is O, Y is CH2, R1represents H, R2and R3such as specified (OR3is in position 6), R4represents H (see tab. 4).

In the following racemate X represents H,H, Y represents S, R1represents methyl, R2and R3such as specified (OR3is in position 6), R4represents H (see tab. 5).

In the following racemate X is O, Y is CH2, R1represents methyl, R2and R3such as specified (OR3is in position 7), R4represents H (see tab. 6).

Me = methyl; Et = ethyl; Pr = propyl; Ph = phenyl; Bn = benzyl; AC = acetyl;

*: amorphous, * *: 0.5% in DMF, * * *: 0.25% of resinated [3S, 4aS, 10aS]-1,2,3,4,4 and, 5,10,10 and octahydro-6-methoxy-1 - methylbenzo[g]quinoline-3-carboxylic acid

Optical isomer of the compound from example 1 are obtained analogously to example 1. So pl. (HCl salt) = 254o[]2D0(free base) = +135,3o(0.5% in DMF).

Toxicological studies, including histopathology was conducted on rats and monkeys. Of rats after administration of the compounds obtained in the present examples, in the amount of 3 mg/kg/day, there has been no specific changes. Of rats after administration of 10-50 mg/kg/day in some cases was observed phospholipids. However, within a maximum of two weeks the animals were recovered. With the introduction of the apes compound obtained in example 1, in an amount up to 60 mg/kg/day have not observed any pathological changes.

1. The compound of the formula I

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where X represents = O or H, H;

Y - represents-CH2, -O - or-S-;

R1represents H or (C1-4)alkyl;

R2represents H, benzyl, pyrimidyl, bis(4-forfinal)methyl or a group of the formula

< / BR>
< / BR>
where R5represents H or (C1-4)alkyl, and R6, R7, R8and R9independently represent the 11 and R12independently are H or (C1- C4)alkyl], CN or (C1- C4)alkylsulfonyl;

R3represents H, (C1-4)alkyl, (C1-4)alkylsulfonyl, trifloromethyl or a group of the formula

< / BR>
where n is the number from 1 to 5;

R4represents H or halogen,

in free base form or salt obtained by the accession acid.

2. The compound of formula I under item 1, where X, Y and R1such, as defined in paragraph 1, R2represents H, benzyl, pyrimidyl, bis(4-forfinal)methyl, naphthyl or a group of formula (a), as defined in paragraph 1, or formula (b') or (')

< / BR>
< / BR>
where R'6and R'7independently represent H, OH, NO2, CF3, acetyl, COOR12[R12such, as defined in paragraph (1] or CN, and R'8represents H, NO2or CN,

R3is in position 6 and represents H, (C1-4)alkyl, methylsulphonyl, trifloromethyl or a group of the formula

< / BR>
where n has the following values, as defined in paragraph 1, and

R4represents hydrogen, and the configuration in positions 4A and 10A is an R-configuration,

in free base form or salt obtained connected is, , 4, 4a, 5, 10, 10a-octahydro-6-methoxy-1-methyl-benzo[g]quinoline-3-carboxylic acid, in free base form or salt obtained by the accession acid.

4. The compound according to any one of paragraphs.1 to 3 in free base form or pharmaceutically acceptable salts obtained by the accession acid, for use as pharmaceuticals.

5. The compound according to any one of paragraphs.1 to 3 in free base form or pharmaceutically acceptable salts obtained by the accession acid, for use in the treatment of depression, anxiety and bipolar disorders.

6. The method of obtaining the compounds of formula I, as defined in paragraph 1, or its salt, which includes a stage on which the compound of formula II

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where X, Y, R1, R3and R4such, as defined in paragraph 1, and M represents H or an alkaline metal,

subjected to interaction with the compound of the formula III

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where R2such, as defined in paragraph 1,

and allocate the thus obtained compound of formula I in free base form or salt obtained by the accession acid.

7. A pharmaceutical composition comprising a compound according to any one of paragraphs.1 to 4 in the form of the free bases of the carrier or diluent.

8. A method of treating depression, anxiety and bipolar disorders in a subject in need of such treatment, wherein the specified effect subject a therapeutically effective amount of a compound according to any one of paragraphs. 1 - 4 in free base form or pharmaceutically acceptable salts obtained by the accession acid.

Priority points:

05.07.1996 on PP.1, 3 and 7;

07.07.1995 on p. 2;

26.02.1996 on p. 8.

 

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