MXPA97010530A - Benzo (a) quinol derivatives - Google Patents

Abstract

The invention provides compounds of the formula I: wherein X, Y, R1, R2, R3 and R4 are as defined in the description, and a process for their preparation. The compounds of the formula I are useful as pharmaceuticals

Description

DERIVADOS DE BENZO fal OÜINOLINA The present invention relates to novel benzo [g] guinoline derivatives, to their preparation, to their use as pharmaceuticals, and to pharmaceutical compositions comprising them. In a more particular way, the present invention provides a compound I: where: X is = 0 or H, H; Y is -CH2-, -0-, -NH- or -S-, Ri is H or alkyl (of 1 to 4 carbon atoms), R2 is H, benzyl, pyrimidyl, bis (4-fluorophenyl) methyl or Formula group: (t) (b) (c) (d) wherein 5 is H or alkyl (from 1 to 4 carbon atoms), and R6, R7, R8 and R9 are independently H, OH, N02, CF3, alkyl (from 1 to 4 carbon atoms), acetyl, CONR | 0R11; COORi2 [wherein R <1> and R <1> are independently H or alkyl (from 1 to 4 carbon atoms)], CN, or alkyl (from 1 to 4 carbon atoms) sulfonyl. R is H, alkyl (from 1 to 4 carbon atoms), alkyl (from 1 to 4 carbon atoms) sulfonyl, trifluoromethylsulfonyl, or a group of the formula: wherein n is from 1 to 5, and m is from 1 to 3, and R 4 is hydrogen or halogen, in the form of free base or acid addition salt. The invention includes enantiomers as well as their mixtures, for example, epimeric or racemic mixtures that may be present on account of the asymmetric carbon atoms at positions 3, 4a, and 10a. The configuration [3R, 4aR, lOaR] is preferred. Halogen is fluorine, chlorine, bromine, or iodine, preferably chlorine or bromine. The alkyl groups defined above preferably represent methyl. In a group of compounds of the formula I, X, Y, and R (are as defined above, R 2 is H, benzyl, pyrimidyl, bis (4-fluorophenyl) methyl, naphthyl, or a group of the formula (a) as defined above, or (b ') or (c'): < tf) (wherein R'g and R '- are independently H, OH, NO ?, CF3, acetyl, COOR12 (where Rl2 is defined above) or CN, and R'g is H, N02, or CN; R3 is in the 6-position and is H, alkyl (1 to 4 carbon atoms), methylsulfonyl, trifluoromethylsulfonyl, or a group of the formula: wherein n and m are as defined above, and R is hydrogen, with the configuration at positions 4 a and 10 a, of R. In another group of compounds of formula I, X is = O, Y is -CH 2 -, and R ? # R., Rj, YR | they are as defined above. In a further aspect, the invention provides a process for the production of the compounds of the formula I and their acid addition salts, whereby a compound of the formula II: wherein X, Y, R, R, and R < they are as defined above, and M is H or an alkali metal, is reacted with a compound of formula III: HN N-R, m wherein R2 is as defined above, and the compounds of formula I thus obtained are recovered in the form of free base or acid addition salt. The reaction can be carried out according to the known amide formation methods, for example, as described in Example 1. In formula II, M, as an alkali metal, is, for example, sodium. The work of the reaction mixtures obtained according to the above process, and the purification of the compounds thus obtained, can be carried out according to the known procedures. Acid addition salts can be produced from the free bases in a known manner, and vice versa. Acid addition salts suitable for use in accordance with the present invention include, for example, the hydrochloride. The starting compounds of the formula II can be produced from the corresponding compounds of the formula IV: wherein X, Y, R ?, R3 and R4 are as defined above, for example, as described in Example 1. The compounds of formulas III and IV are known or can be produced in a manner analogous to the processes known. See, for example, European Patent Number 77754. The compounds of the formula I and their pharmaceutically acceptable acid addition salts, hereinafter referred to as the agents of the invention, exhibit valuable pharmacological properties when tested in vitro using cell cultures that express the SRIF receptor, and in animals, and therefore, are useful as pharmaceuticals. In particular, the agents of the invention bind to somatostatin receptors. More particularly, they are selective antagonists at the sstl receptors of Somatostatin, previously termed SSTR-1 receptors (see Hoyer et al., TiPS, 1995, 16; 86-88), determined in radioligand binding and second messenger studies [see, for example, K. Kaupmann et al., FEBS LETTERS 1993, 331: 53-59], where they exhibit a selective affinity for sstj receptors with pIC $ values or between approximately 7.5 and 9.5. The agents of the invention, therefore, are useful for the treatment of anxiety, depression, schizophrenia, neurodegenerative diseases such as dementia, for the treatment of tumors, and for vascular disorders and immunological diseases, as confirmed by a range of conventional tests. indicated below: In doses of approximately 0.3 to 3 milligrams / kilogram orally, the agents of the invention increase the exploratory behavior of mice in the open half of the half-enclosed platform, a model that is predictable for anxiolytic activity (Psychopharmacology , 1986, 89: 31-37). In the same half-enclosed platform model, the agents of the invention in the doses indicated above also increase the surveillance of the mice. Accordingly, the compounds are indicated for the treatment of depression, schizophrenia, and dementia, in particular of senile dementia of the Alzheimer's type (SDAT). In the intruder mouse test [Triangle, 1982, 21: 95-105; J. Clin. Psychiatry, 1994, 55: 9 (supplement B) 4-7], the agents of the invention increase social research and reduce defensive ambivalence in the intruder mouse treated at the indicated doses of about 1 to about 10 milligrams / kilogram subcutaneously, suggesting an antidepressant profile such as carbamazepine and lithium, a neuroleptic profile such as clozapine, and anxiolytic profile such as diazepam. Furthermore, in these doses, the compounds of the invention reduce the aggressive behavior (attacks, aggressions, bites) in the Coupled Pair Situation Test in mice [Dixon et al., J. Clin. Psychiatry 55: (9) [Supplement B], 4-7 (1994)]. Since, as mentioned above, they additionally attenuate the defensive behavior in the intruder mouse test, the compounds of the invention exhibit an etofarmacological profile that is very similar to that of carbamazepine, lithium chloride, and clozapine. Accordingly, they are indicated for the treatment of affective disorders, including bipolar disorders, for example manic-depressive psychoses, extreme psychotic states, for example mania, schizophrenia, and excessive mood swings, when the stabilization of behavior is desired. In addition, the compounds indicated are indicated in states of anxiety, generalized anxiety, as well as social and agorophobia, as well as those states of behavior characterized by social withdrawal, for example, negative symptoms. The agents of the invention are also effective in the treatment of different kinds of tumors, particularly tumors that carry the sstj receptor, as indicated in the proliferation tests with different cancer cell lines and in tumor growth experiments in mice shaved with hormone-dependent tumors [see, for example: G. eckbecker et al., Cancer Research 1994, 5_4: 6334-6337]. Accordingly, the compounds are indicated in the treatment of, for example, cancers of the breast, prostate, colon, pancreas, brain, and lung (small cell lung cancer). For all the above-mentioned indications, the appropriate dosage, of course, will vary depending on, for example, the compound employed, the host, the mode of administration, and the nature and severity of the condition being treated. However, it is generally indicated that satisfactory results are obtained in animals at a daily dosage of about 0.1 to about 10 milligrams / kilogram of body weight of the animal. In larger mammals, for example humans, an indicated daily dosage is on the scale of about 5 to about 200 milligrams, preferably about 10 to about 100 milligrams of compound conveniently administered in divided doses up to 4 times a day, or in a sustained release form. The agents of the invention can be administered in free form or in pharmaceutically acceptable salt form. These salts can be prepared in a conventional manner, and exhibit the same order of activity as the free compounds. Previously, compounds having sst! Antagonist activity have never been described in the art. selective, that is, showing an affinity with the selective sstj receptor in the aforementioned binding test, with values of pIC50 >; 7. 0 According to the foregoing, these compounds represent an entirely novel group of compounds. In accordance with the foregoing, in a further aspect, the present invention provides selective ssti receptor antagonists for use as pharmaceuticals, more specifically for treatment in the aforementioned conditions, for example depression, anxiety, and bipolar disorders. The present invention further provides a pharmaceutical composition comprising a selective ssti receptor antagonist, for example an agent of the invention in association with at least one pharmaceutically acceptable diluent or carrier. These compositions can be formulated in a conventional manner. The unit dosage forms contain, for example, from about 0.25 to about 50 milligrams of an agent according to the invention. Antagonists of selective ssti receptors, for example the agents of the invention, can be administered by any conventional route, for example, parenterally, for example in the form of injectable solutions or suspensions, or enterally, preferably orally, for example in the form of tablets or capsules. For all the above indications, the preferred compound is piperazinamide 4- (4-nor rofenic acid) - acid [3R, 4aR, 1 OaRJ -1,2, 3, 4, a, 5, 10, 10a-octahydro- 6-methoxy-l-methyl-1-benzo [g] quinoline-3-carboxylic acid, which is the compound of example 1. This compound has a high affinity for rat sstj receptors (pICsj = 9.1), and the receptors sst, recombinant human (pICso = 7.7), without significant activity for a wide range of neurotransmitter receptors. At 1 to 10 milligrams / kilogram subcutaneously, the compound clearly minimizes aggressive behavior in the aforementioned Coupled Couple Status test, and reverses the social withdrawal in the aforementioned intruder mouse test. These effects are also observed with conventional antimalarial drugs of lithium and carbamazepine, in 3 to 30 milligrams / kilogram subcutaneously, suggesting similar therapeutic effects in man. However, it was found that lithium and carbamazepine are less potent, and are known to have considerable drawbacks, such as a narrow therapeutic window, and a slow-acting setting. The preferred indications are depression, anxiety, and affective disorders, including bipolar disorders, such as mania. In accordance with the above, the present invention also provides the use of a selective sstl receptor antagonist, for example an agent of the invention, as a pharmaceutical product, for example for the treatment of depression, anxiety, and bipolar disorders. Moreover, the present invention provides the use of a selective ssti receptor antagonist, for example an agent of the invention, for the manufacture of a medicament for the treatment of any condition mentioned above, for example depression, anxiety, and affective disorders. In still a further aspect, the present invention provides a method for the treatment of any condition mentioned above, for example depression, anxiety, and bipolar disorders, in a subject in need of such treatment, which comprises administering to this subject a therapeutically effective amount of a selective ssti receptor antagonist, for example an agent of the invention. The following examples illustrate the invention. Temperatures are given in degrees Celsius, and are not corrected.

Example 1; Piperazinamide 4- (4-nitrophenyl) acid [3R.4aR. lOaR] -1.2.3.4, 4a, 5.10, lOa-octahydro-6-methoxy-1-ethyl-benzo [QS quinoline-3-carboxylic acid. a) 'A mixture of 8.681 grams (30 millimoles) of [3R, 4aR, lOaR] -1-methyl-3 | 8-methoxycarbonyl-6-methoxy-1,2, 3,4,4aa, 5, 10, 10a ] 8-Octahydro-benzo [g] quinoline, 36 milliliters of methanol, 36 milliliters of tetrahydrofuran, and 36 milliliters of a 1M aqueous sodium hydroxide solution, is stirred vigorously for 16 hours at room temperature. After cooling to 0 ° C, the reaction mixture is filtered, and the product is washed with cold 2-propanol and dried at 60 ° C in a high vacuum. The sodium salt of [3R, 4aR, lOaR] -1-methyl-6-methoxy-1, 2, 3,4,4aa, 5, 10, 10a3-octahydro-benzo [g] quinoline-33-carboxylic acid thus obtained , have a pf > 230 ° C (decomposition); [o;] D, 20 = -138.3 ° C (0.5 percent in dimethyl formamide / water, 50:50). b) A suspension of 2,973 grams (10 millimoles) of the sodium salt obtained in a), in 24 milliliters of 38% propanephosphonic anhydride in dimethyl formamide (30 millimoles), and 10 milliliters of absolute pyridine, is stirred for 15 minutes at room temperature. After the addition of 2.07 grams (10 millimoles) of piperazine 1- (4-nitrophenolic), stirring is continued for 16 hours at room temperature, and 100 milliliters of toluene and 100 milliliters of 2M aqueous ammonia are added. The precipitated crystals are filtered, washed with water and toluene, dried, and recrystallized from toluene. The resulting title compound has a m.p. from 218-221 ° C [a] D, 20 = -128.7 ° C (0.5 percent in dimethyl formamide).

The following compounds of formula I are produced in a manner analogous to Example 1. In the following compounds [3R, 4aR, lOaR], X is 0, Y is CH1, R1 is methyl, R2 and Rj are as indicated (ORj is in position 6) and R4 is H.

In the following racemates, X is 0, Y is 0, R [is methyl, RT and 3 are as indicated (OR3 is in position 6), and r4 is H.

In the following compound [3aR, 4aR, lOaR], X is 0, Y is CH2, i is methyl, R2 and R3 are as indicated (OR3 is in position 6), and R is 9-Br.

In the following compound [3aR, 4aR, lOaR], X is C, Y is CH2, i is H, R2 and 3 are as indicated (OR3 is in position 6), and R4 is H.

In the next racemate, X is H, H; Y is S, Rt is methyl, R2 and R3 are as indicated (OR3 is in position 6), and R4 is H.

The next racemate, X is O, Y is H, H; R (is methyl, R2 and R3 are as indicated (OR3 is in position 7), and R4 is H.

Me = methyl - Et = Ethyl Pr = propyl Ph = phenyl Bn = benzyl Ac = acetyl *: amorphous **: 0.5% in dimethyl formamide ***: 0.25% in dimethyl formamide. (1) = racemate [3RS, 4aRS, lOaRS] (2) = racemate [3SR, 4aRS, lOaRS] Eiemolo 45; Piperazjnamid 4- (4-nitrophenyl) acid Ü3S .4aS. lOaSl -1, 2.3.4.4a, 5, 10, lOa-octahydro-6-methoxy-l-methyl-benzo [glinoyl-3-carboxylic acid. Optical isomer of the compound of Example 1, produced in a manner analogous to Example 1. P.f. (HCl salt) = 254 ° C; [c.] 20D (free base) = + 135.3 ° C (0.5 percent in dimethyl formamide.

Claims (11)

1. A compound of the formula I where: X is = 0 or H, H; Y is -CH2-, -0-, -NH- or -S-, Ri is H or alkyl (of 1 to 4 carbon atoms), R2 is H, benzyl, pyrimidyl, bis (4-fluorophenyl) methyl or Formula group: (t) (b) (O () wherein R5 is H or alkyl (of 1 to 4 carbon atoms), and R6, R7, R8 and R9 are independently H, OH, N01, CF3, alkyl (of 1 to 4 carbon atoms), acetyl, CONR | 0R ||, C00Rj2 [where Rn and Rj2 are independently H or alkyl (from 1 to 4 carbon atoms)], CN, or alkyl (from 1 to 4 carbon atoms) sulfonyl. R3 is H, alkyl (of 1 to 4 carbon atoms), alkyl (of 1 to 4 carbon atoms) sulfonyl, trifluoromethylsulfonyl, or a group of the formula: wherein n is from 1 to 5, and m is from 1 to 3, in the form of free base or acid addition salt.

2. A compound of the formula I according to claim 1, wherein: X, Y, and R? are as defined in claim 1, R2 is H, benzyl, pyrimidyl, bis (4-fluorophenyl) methyl, naphthyl, or a group of the formula (a) as defined in claim 1, or of the formula (b1) ) or (c?): wherein R'6 and R'7 are independently H, OH, N02, CF3, acetyl, COOR) 2 (where Rt2 is defined in claim 1) or CN, and R'g is H, N02, or CN; R3 is in the 6-position and is H, alkyl (1 to 4 carbon atoms), methylsulfonyl, trifluoromethylsulfonyl, or a group of the formula: where n and m are as defined in the claim 1, and R4 is hydrogen, the configuration being at positions 4a and 10a, of R, in the form of free base or acid addition salt.

3. A compound of claim 1, which is 4- (4-nitrophenyl) piperazinamide - of [3R, 4aR, lOaR] - 1, 2, 3,4, 4a, 5, 10, 10a-octahydro-6 acid -methoxy-1-methyl-benzo [g] quinoline-3-carboxylic acid, in the form of free base or acid addition salt.

4. A selective antagonist at sst (somatostatin receptors, to be used as a pharmaceutical product.)

5. A process for the preparation of a compound of formula I, as defined in claim 1, or a salt thereof, in which includes the step of reacting a compound of formula II: wherein X, Y, R |, R3, and R are as defined in claim 1, and M is H or an alkali metal, with a compound of formula III: HN N-R, m wherein R2 is as defined in claim 1, and recovering the compound thus obtained of formula I in the form of free base or acid addition salt.

6. A compound of any of claims 1 to 3, in the form of free base or pharmaceutically acceptable acid addition salt, for use as a pharmaceutical product.

7. A compound of any of claims 1 to 4, in the form of free base or pharmaceutically acceptable acid addition salt, for use in the treatment of depression, anxiety, and bipolar disorders.

8. A pharmaceutical composition comprising a compound of any of claims 1 to 4, in free base or pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent.

9. The use of a compound of any of claims 1 to 4, in the form of free base or pharmaceutically acceptable acid addition salt, as a pharmaceutical product, for the treatment of depression, anxiety, and bipolar disorders. The use of a compound of any one of claims 1 to 4, in the form of free base or pharmaceutically acceptable acid addition salt, for the manufacture of a medicament for the treatment of depression, anxiety, and bipolar disorders. 11. A method for the treatment of depression, anxiety, and bipolar disorders, in a subject in need of such treatment, which comprises administering to this subject a therapeutically effective amount of a compound of any one of claims 1 to 4, in the form of free base or pharmaceutically acceptable acid addition salt.