BRPI0903803A2 - compound, isomer of compound, process of its preparation, intermediate compound, pharmaceutical composition; medicine, use of compounds and method of treatment - Google Patents

Abstract

SUCCESSFUL DEVICE FIXED TO SUPPORT PAPER TOWEL AND THE LIKE. It is a device comprised of a suction cup system (1) that promotes the fixation of the support on any smooth surface, such as walls, cabinets, refrigerator, windows, etc .; also comprised of a cylinder (4) for rolling paper towels, or similar products, such as toilet paper, aluminum foil, napkins, bags, plastic wrap, etc .; provided that they have a roll arrangement, that is, with a central coil through which the cylinder (4) of the support can pass; said device being comprised of two suction cups (1); a plate (2); two pins (3); and, a cylinder (4).

Description

"compound, isomer of compound, process of preparation, intermediate compound, pharmaceutical composition; medicament, use of compounds and method of treatment"

Field of the Invention

The present invention relates to a series of 2- (3-methylenedioxy) benzoyl indole derivatives, mixtures thereof in any proportions, pharmaceutically acceptable salts thereof, enantiomers, pharmaceutical compositions containing them, processes for their preparations and intermediates, as well as the same. its uses in the prophylactic and / or curative treatment for sexual dysfunction. More specifically, the present invention relates to (R) -3 - ((2- (benzo [d] [1,3] dioxol-5-carbonyl) -1H-indol-3-yl) methyl) -1-methylpiperazine derivatives -2,5-dione eS) -3 - ((2- (benzo [d] [1,3] dioxol-5-carbonyl) -1H-indol-3-yl) methyl) -1-methylpiperazine-2,5 -diona.

The present invention also contemplates a prophylactic and / or curative treatment method for erectile dysfunction using 2- (3-methylenedioxy) benzoyl indole derivatives, and more particularly (R) -3 - ({2- (benzo [d]) derivatives. [1,3] dioxol-5-carbonyl) -1H-indol-3-yl) methyl) -1-methylpiperazine-2,5-dione, and its (Sr) -3 - ((2- (benzo [d ] [1,3] dioxol-5-carbonyl) -1H-indol-3-yl) methyl) -1-methylpiperazine-2,5-dione.

The present invention encompasses such compounds and their mixtures in any proportions, their pharmaceutically acceptable salts, the pharmaceutical compositions containing them, as well as their use as stimulants of NO expression and as a selective inhibitor of phosphodiesterase enzyme, in particular of phosphodiesterase type 5 (PDE-5). 5).

Background of the Invention

Until the time of the first treatment by oral route, male sexual impotence was treated by intracavernosal injections and other means, due in particular to the numerous doubts arising from the adverse reactions that oral administration could entail in humans. Papaverine and pentoxifylline, for example, were used in the treatment of erectile dysfunction, precisely for intracavernous injections. Other effective methods of treatment were, for example, psychological therapies and surgical implants.

Oral treatment is the most acceptable to man and has emerged from clinical trials with certain decGMP PDE inhibitors, specifically PDE-5. The precursor of these compounds was 5- [2-ethoxy-5- (4-methylpiperazinylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-2-one. 7-one, or sildenafil, vasodilatory properties and potentiating effects of endothelium-derived relaxing factor (EDRF) enitrovasodilators. Sildenafil is the active ingredient in Viagra® medicine.

Subsequently, other PDE-5 inhibitor compounds have been developed and are cited in various publications of the specialized literature as well as in related publications. The most well-known are vardenafil, the drug ingredient Levitra®, and tadalafil, the active ingredient drug Cialis®.

Another class of PDE-5 specific inhibitor compounds is cited in WO 03/000691. Therein, a number of β-carboline-derived compounds are disclosed, which are prepared from the compounds of formula (A) and (B) below, disclosed, respectively, in US 6,117,881 and US 5,859,006.

The compounds of the present invention, derived from 2- (3-methylenedioxy) benzoyl indole, may be used to treat sexual dysfunction and, in one embodiment, may be used as a stimulant of NO expression and, in another embodiment, may be used. as selective inhibitors of the phosphodiesterase enzyme, in particular phosphodiesterase type 5 (PDE-5).

It is, therefore, the object of the present invention to provide new compounds of 2- (3-methylenedioxy) benzylindole derivatives, mixtures thereof, pharmaceutically acceptable salts, isomers and pharmaceutical compositions containing them, effective in the prophylactic and / or curative treatment of sexual dysfunction and / or erectile. In one embodiment, the compounds have vasodilatory and muscle relaxant properties, in another embodiment, the compounds stimulate expression of tissue NOs and in another embodiment the compounds selectively inhibit phosphodiesterase, particularly type 5 aphosphodiesterase (PDE-5). Preferably, the novel compounds of 2- (3-methylenedioxy) benzoyl indole are derivatized (R) -3 - ((2- (benzo [d] [1,3] dioxol-5-carbonyl) -1H-indole-3-one). yl) methyl) -1-methylpiperazine-2,5-dione, its (S) -3 - ((2- (benzo [d] [1,3] dioxol-5-carbonyl) -1H-indol-3) enantiomer il) methyl) -1-methylpiperazine-2,5-dione and mixtures thereof in any proportions.

It is also an object of the present invention to provide processes for the preparation of 2- (3-methylenedioxy) benzoyl indole derivatives thereof mixtures, more specifically (R) -3 - ((2- (benzo [d] [1,3] dioxol) derivatives -5-carbonyl) -1H-indol-3-yl) methyl) -1-methylpiperazine-2,5-dione, its enantiomer. (S) -3 - ((2- (benzo [d] [1,3] dioxol-5-carbonyl) -1H-indol-3-yl) methyl) -1-methylpiperazine-2,5-dione and its mixtures in any proportions.

In some aspects, the present invention provides pharmaceutical compositions comprising as an active ingredient an effective amount of one or more 2- (3-methylenedioxy) benzyl indole derivatives, mixtures thereof in any proportions or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients. More specifically, the active ingredient is derived from (R) -3 - ((2- (benzo [d] [1,3] dioxol-5-carbonyl) -1H-indol-3-yl) methyl) -1-methylpiperazine-2 , 5-dione, its (S) -3 - ((2- (benzo [d] [1,3] dioxol-5-carbonyl) -1H-indol-3-yl) methyl) -1-methylpiperazine-2 enantiomer , 5-dione or mixtures thereof in any proportions.

In some aspects, the present invention provides a medicament comprising as active ingredient a therapeutically effective amount of one or more 2- (3-methylenedioxy) benzoyl indole derivatives, mixtures thereof in any proportions or pharmaceutically acceptable salts thereof. More specifically, said medicaments contain as an active ingredient (R) -3 - ((2- (benzo [d] [1,3] dioxol-5-carbonyl) -1H-indol-3-yl) methyl) -1-methylpiperazine derivatives. 2,5-dione, its (S) -3 - ((2- (benzo [d] [1,3] dioxol-5-carbonyl) -1H-indol-3-yl) methyl) -1-methylpiperazine enantiomer 2,5-dione or mixtures thereof in any proportions.

In another aspect, the present invention provides the use of 2- (3-methylenedioxy) benzoyl indole derivatives, their mixtures in any proportions or their pharmaceutically acceptable salts, for the oral and / or curative prophylactic treatment of erectile and / or sexual intercourse in men. More specifically, the 2- (3-methylenedioxy) benzoylindole derivative is the (R) -3 - ((2- (benzo [d] [1,3] dioxol-5-carbonyl) -1H-indol-3) derivative. (yl) methyl) -1-methylpiperazine-2,5-dione - and / or its (S) -3 - ((2- (benzo [d] [1,3] dioxol-5-carbonyl) -1H-indole-2-one-eneiomer) 3-yl) methyl) -1-methylpiperazine-2,5-dione.

Brief Description of the Figures

Figure 1 - Cumulative concentration-response curve of the relaxing effect of compound BL-122 (A) and vehicle (B) on the isolated rabbit cavernous body. Values represent mean ± S.E.M. of 8 preparations obtained from 6 animals. Osasterisks indicate the significance level * P <0.05, ** P <0.01, compared to the corpus cavernosum with 0% initial relaxation, after previous contraction by phenylephrine (3- 10 μΜ) corresponding to 1.7 ± 0.07g of tension.

Figure 2 - Cumulative dose-response curve for relaxing effect of compound BL-122 (A) and vehicle (B) on isolated rat aorta.

Figure 3 - Sexual behavior test of rats under the control of compound BL-122 and vehicle (saline containing 10% DMSO) administered orally at a dose of 10 mg / kg. The parameter used refers to spontaneous erections. Results are expressed as the mean ± S.E.M. (mean standard error) of 9 animals. Statistical differences were assessed by analysis of variance (ANOVA) followed by Newmann-Keuls test. P values less than 0.05 (P <0.05) were considered as indicative of significance. Detailed Description of the Invention

The present invention provides 2- (3-methylenedioxy) benzoyl indole derivatives having structures of formula (I)

<formula> formula see original document page 8 </formula>

their salts and solvates, such as hydrates, where:

R1 represents hydrogen, halogen, C1-6 alkyl or O-R 'where

R 'represents hydrogen or lower alkyls;

η represents a number ranging from 0 to 4;

R 2 represents hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, haloC 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkylC 1-3 alkyl, aryl C 1-3 alkyl or heteroaryl C 1-3 alkyl;

R3 represents hydrogen, C1-3 alkyl or R2 and R3 together represent a 3- or 4-substituent of an alkyl or alkenyl ring;

R 4 represents hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, haloC 1-6 alkyl, C 3-8 cycloalkyl, C 3-6 cycloalkylC 1-3 alkyl, aryl C 1-3 alkyl or heteroaryl C 1-3 alkyl.

R5 represents hydrogen or O-R 'where R' represents hydrogen or lower alkyls.In R2 and R4 the term "aryl" of the C1-3 alkyl aryl group represents the phenyl or phenyl group substituted one or more times by halogen (for example 1, 2 or 3) or C 1-6 alkyl, C 1-6 alkoxy or methylenedioxy. The term "heteroaryl" of the C1-3 alkylhetroaryl group represents the furyl or pyridyl group, optionally substituted one or more times by halogen, C1-6 alkyl or C1-6 alkoxy. The term "C 3-8 cycloalkyl" of the C 3-8 cycloalkylC 1-3 alkyl group represents a monocyclic ring containing from 3 to 8 carbon atoms. Suitable examples of the cycloalkyl ring include the C 3-6 cycloalkyl rings: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In the above definitions, the term "alkyl" represents the main alkyl chain or, where available, a branched alkyl chain of the groups that it represents. For example, the C1-4 alkyl group represents: methyl, ethyl, π-propyl, i-propyl, n-butyl, s-butyl and t-butyl. The term "alkenyl" as used above includes straight and branched chain alkenyl groups such as vinyl and allyl groups. The term "alkynyl" as used in the above definitions includes straight chain alkynyl groups such as acetylene. The term "halogen" represents fluorine, chlorine, bromine or iodine atoms. The term "C1-6alkyl halo" means an alkyl group as defined above containing from one to six carbon atoms substituted by one or more halogen atoms, for example 1, 2 or 3.

When R1 represents a halogen atom or a 0-R 'group or a C1-6 alkyl group, this substituent may be attached at any available position of the phenyl moiety of indole and in more than one position.

The compounds of formula (I) may contain one or more asymmetric centers, thus enantiomers and / or diastereoisomers may exist. In particular, in formula (I) above a chiral center is evidenced with an asterisk. This implies that the invention includes mixing the enantiomers and their separate individual forms.

The compounds of formula (I) may exist in different tautomeric forms and the invention includes a mixture of the formastautomeric and their separate individual forms.

Pharmaceutically acceptable salts of the compounds of formula (I) which have a basic center may be formed by the addition of pharmaceutically acceptable acids. Some examples include salts of: hydrochloride, hydrobromide, sulfate or bisulfate, phosphate or hydrogen phosphate, acetate, benzoate , succinate, fumarate, maleate, lactate, citrate, tartrate, gluconate, metasulfonate, benzenesulfonate and p-toluenesulfonate. The compounds of formula (I) may provide pharmaceutically acceptable metal salts, in particular alkali metal salts, with bases. For example, sodium and potassium salts.

A particular group of compounds according to the present invention are compounds of formula (I) wherein R1, R3 and R4 are hydrogen and R2 is a C1-6 alkyl group. More specifically, (R) -3 - ((2- (benzo [d] [1,3] dioxol-5-carbonyl) -1H-indol-3-yl) methyl) -1-methylpiperazine-2,5-derivatives dione and its (S) -3 - ((2- (benzo [d] [1,3] dioxol-5-carbonyl) -1H-indol-3-yl) methyl) -1-methylpiperazine-2,5-enantiomer dione, respectively compounds of formula Ib and Ic below:

<formula> formula see original document page 11 </formula>

The present invention also contemplates intermediate compounds for the preparation of the compounds of formula I above defined. Examples of such compounds are the intermediates of formula II:

<formula> formula see original document page 11 </formula>

and mixtures thereof, including racemic mixtures or solvates of these compounds, wherein R 1, R 3 and R 4 are defined in claim 1, wherein Al represents the C 1-6 alkyl group and Hal represents a halogen atom.

Other examples of intermediate compounds are formula (III):

<formula> formula see original document page 12 </formula>

and mixtures thereof, including racemic mixtures or solvates of these compounds, wherein R 1, R 2, R 3 R 4, R 5, and η are defined in claim 1, wherein Al represents the C 1-6 alkyl group Hal represents a halogen atom.

Advantageously, the (R) -3 - ((2- (benzo [d] [1,3] dioxol-5-carbonyl) -1H-indol-3-yl) methyl) -1-methylpiperazine-2,5-derivative Dione according to the present invention can be prepared from (6R, trans) -6- (1,3-benzodioxol-5-yl) -2,3,6,7,12,12a-hexahydro-2-methyl pyrazine [1 ', 2': 1,6] pyrido [3,4-b] indol-1,4-dione, as reaction below (Procedure 1): <formula> formula see original document page 13 </formula>

(Procedure 1)

An alternative route for the preparation of (R) -3 - ((2- (benzo [d] [1,3] dioxol-5-carbonyl) -1H-indol-3-yl) methyl) -1-methylpiperazine derivative 2,5-dione according to the present invention from (6R, trans) -6- (1,3-benzodioxol-5-yl) -2,3,6,7,12,12a-hexahydro-2-methyl -pyrazino [1 ', 2': 1,6] pyrido [3,4-b] indol-1,4-dione is by the reaction below (Procedure 2):

<formula> formula see original document page 13 </formula>

(Procedure 2)

In addition, the (R) -3 - ((2- (benzo [d] [1,3] dioxol-5-carbonyl) -1H-indol-3-yl) methyl) -1-methylpiperazine-2,5-derivative Dione according to the present invention can be prepared from (IR, 3R) -1- (benzo [d] [1,3] dioxol-5-yl) -2- (2-chloroacetyl) -2,3,4 9-tetrahydro-1H-pyrido [3,4-b] indole-3-carboxylate demethyl according to the reactions below (Procedure 3): <formula> formula see original document page 14 </formula>

(Procedure 3)

(S) -3 - ((2- (benzo [d] [1,3] dioxol-5-carbonyl) -1H-indol-3-yl) methyl) -1-methylpiperazine-2,5-dione enantiomer and The mixtures were prepared using the procedures described above and employing raw materials with configuration corresponding to the desired configuration for the product, and the reactions to which the raw materials are subjected did not change the configuration of the desired asymmetric center.

The following examples illustrate, but are not limited to, the preparation processes for (R) -3 - ((2- (benzo [d] [1,3] dioxol-5-carbonyl) -1H-indol-3-yl) ) methyl) -1-methylpiperazine-2,5-dione, or compound BL-122 according to the procedures cited above.

Example 1

Procedure 1:

3.5g of (6R, trans) -6- (1,3-benzodioxol-5-yl) -2,3,6,7,12,12a-hexahydro-2-methylpyrazine [1 ', 2' : 1.6] pyrido [3,4-b] indol-1,4-dione were mixed at 205g DDQ at room temperature. Then, this mixture was added to 100 ml of a THFiH2O (9: 1) mixture. The reaction mixture was stirred for 8 hours at room temperature and monitored by TLC.

Additional portions of DDQ were added until all (6R, trans) -6- (1,3-benzodioxol-5-yl) -2,3,6,7,12,12ahexahydro-2-methylpyrazine [1 ', 2 ': 1,6] pyrido [3,4-b] indol-1,4-dione was consumed. After completion of the reaction, the mixture was washed with water and the product extracted into ethyl acetate. The organic phases were combined and dried over MgSO4. The solvent was partially removed, leading to precipitation of the product, which was filtered and oven dried at 609 ° C. The white solid product (compound BL-122) had the following characteristics: mp 218-221 ° C and [a] D25 = + 12 (c0.8; DMSO). 1H-NMR (500MHz - DMSO) = 11.52 (1H, s); 7.95 (1H, d, J = 3Hz); 7.61 (1H, d, J = 8Hz); 7.43 (1H, d, J = 8Hz) 7.34 (1H, dd, J = 8Hz and J = 1.5Hz); 7.25-7.28 (2H, m); 7.07-7.10 (2H, m); 6.17 (2H, s); 4.00-4.03 (1H, m); 3.33-3.48 (3H, m); 2.98 (1H, d, J = 17.5 Hz); 2.53 (3H, s). Example 2

Procedure 2:

1.4g of selenium dioxide was added in a solution containing 2.4g of (6R, trans) - 6- (1,3-benzodioxol-5-yl) -2,3,6,7,12,12a - hexahydro 2-methylpyrazino [1 ', 2': 1,6] pyrido [3,4-b] indol-1,4-dione and 60mL of dioxane. The reaction mixture was kept under stirring at reflux for 4 hours. At the end of this period the reaction mixture was filtered over celite / silica and the solvent evaporated. The solid product was recrystallized from CH 2 Cl 2 / MeOH and oven dried at a temperature of 60 ° C. The product obtained as a white solid, compound BL-122, had the following characteristics: mp 219-222 ° C and [a] d25 = + 12 ° C (c 0.8; DMSO). 1H-NMR (500MHz - DMSO) = 11.52 (1H, s); 7.95 (1H, d, J = 3Hz); 7.61 (1H, d, J = 8Hz); 7.43 (1H, d, J = 8Hz); 7.34 (1H, dd, J = 8Hz and J = 1.5Hz); 7.25-7.28 (2H, m); 7.07-7.10 (2H, m); 6.17 (2H, s); 4.00-4.03 (1H, m); 3.33-3.48 (3H, m); 2.98 (1H, d, J = 17.5 Hz); 2.53 (3H, s).

Example 3

Procedure 3:

32g of selenium dioxide was added to a solution containing 107g of 1- (benzo [d] [1,3] dioxol-5-yl) -2- (2-chloroacetyl) -2,3,4,9-tetrahydro-1H methyl pyrido [3,4-b] indole-3-carboxylate in 1,250ml of tetrathidrofuran (THF). Reaction mixture was kept under stirring and reflux for 1.5 hours. At the end of this period, the reaction mixture was filtered through celite / silica and about 30% of the solvent was removed. To the reaction mixture, 100 ml of absolute ethanol and 200 ml of a 30% solution of methylamine in ethanol were added. This mixture was refluxed for 4 hours. The solvent was partially removed, leading to precipitation of the final product, which was filtered and oven dried at 60 ° C. The product obtained as white solid, compound BL-122, had the following characteristics: mp 219-22 ° C and [Oi] D 25 = + 12 (c 0.8; DMSO). 1H NMR (500MHz - DMSO) =

II, 52 (1H, s); 7.95 (1H, d, J = 3Hz); 7.61 (1H, d, J = 8Hz) 7.43 (1H, d, J = 8Hz); 7.34 (1H, dd, J = 8Hz and J = 1.5Hz), 7.25-7.28 (2Η, m); 7.07-7.10 (2Η, m); 6.17 (2Η, s); 4.00-4.03 (1Η, m); 3.33-3.48 (3Η, m); 2.98 (1Η, d, J = 17.5 Hz); 2.53 (3H, s); 13 C NMR (125MHz - DMSO) = 186.9; 165.9; 164.8; 151.0; 147.4; 13 6.3; 132.9; 132.8; 127.5; 125.8; 124.9; 120.7; 119.8; 116.1; 112.6; 109.1; 108.0; 102.0; 55.7; 50.6; 33.0; 29.1.

The compounds of the present invention, as well as pharmaceutically acceptable salts thereof, are potential stimulators of tissue NO expression and potential selective cGMP-specific PDE inhibitors. Thus, the compounds of formula (I) and their pharmaceutically acceptable salts are of interest in therapy, specifically in the treatment and prophylaxis, of a variety of conditions wherein stimulation of tissue NO expression or inhibition of cGMP-specific PDE are considered beneficial.

As a selective PDE-5 inhibition response presented by the compounds of the present invention, decGMP levels are high, which in turn may promote anti-platelet, anti-neutrophil, anti-vasospastic, vasodilatory, natriuretic and diuretic activities as well. such as the potentiation of the effects of endothelium-derived relaxant factor (EDRF), nitrovasodilators, atrial fatriuretic (ANF), brain natriuretic peptide (BNP), C-type natriuretic peptides (CNP), and endothelium-dependent relaxing agents, such as bradykinin, acetylcholine, and 5- The compounds of formula (I) according to the present invention have utility in the treatment and prevention of a number of disorders, including stable, unstable and variable angina, hypertension, pulmonary hypertension, congestive heart failure, renal failure, atherosclerosis, reduced disease-free states of the blood vessels, peripheral vascular disease, vascular disorders such as Raynaud's disease, erectile dysfunction, sexual dysfunction, inflammatory diseases, ataquecardiac, bronchitis, chronic asthma, allergic asthma, rhinitealergic, glaucoma and diseases characterized by disorders of intestinal demotility.

The compounds of formula (I) and their pharmaceutically acceptable salts according to the present invention may be administered by any suitable route, such as by oral, buccal, sublingual, rectal, vaginal, nasal, topical, intraperitoneal or parenteral route. Oral administration is generally preferred.

Pharmaceutical compositions comprising as an active ingredient an effective amount of one of the derivatives of formula (I) may be presented in various types of pharmaceutical formulations, such as, but not limited to: (i) optionally coated, chewable, effervescent, multilayer or soluble tablet; (ii) pills; (iii) optionally dispersible or effervescent powder; (iv) capsules of any kind, such as hard gelatin capsule, gelatinosamole capsule and amylacia; (v) tablets; (vi) granules, optionally in the form of microparticles or microcapsules, or vectorized preparations, such as liposomes, (vii) suppositories, (viii) optionally oral, nasal, ophthalmic solutions; (ix) injectable including subcutaneous, intradermal, intramuscular and intravenous; (x) suspensions; (xi) syrups;

(xii) infusion; among others.

If the pharmaceutical form is an oral administration solution or suspension, the pharmaceutically acceptable carrier may include solvents and co-solvents, buffers, preservatives, colorants, sweetening flavors, reducing agents, thickening agents, sequestering agents, surfactants, pH adjusting substances (eg hydrochloric acid, sodium hydroxide), suspending agents, antioxidants, etc. Solvents or suspending media may be: purified water and / or other hydrophilic (eg, ethanol, DMSO, propylene glycol, PEG) or hydrophobic ( eg oils). The co-solvents may be ethanol, propylene glycol, glycerol, among others. Preservatives may be phenols, parabens, benzoic acid. Reducing agents may be avitamin E, ascorbic acid, etc. Any such excipients or additives should be within the quality requirements for pharmaceutical and veterinary use established by the competent authorities.

Where the pharmaceutical form of the composition of the present invention is in tablet form, it may include one or more excipients selected from the group consisting of dediluents, disintegrants, binders, colorants and flavoring agents. The diluent may be one or more of calcium carbonate, dibasic calcium phosphate, calcium tribasic phosphate, calcium sulfate, microcrystalline cellulose, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, amidoprotein. - Gelatinized, sucrose, compressible sugar and decaffeinated sugar, and in particular can be lactose. The binder may be one or more of methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethylcellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, draganant, alginic acid propylene glycol derivatives, and alginate, and alginate. in particular it may be polyvinylpyrrolidone. The disintegrant may be one or more of low molecular weight substituted hydroxypropylcellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, sodium croscarmellose, starch, crystalline cellulose, hydroxypropyl starch, and partially pregelatinized starch.

Oral administration solutions, suspensions or syrups, for example, are in pharmaceutical presentations of the tip flasks, vials and ampoules.

Also included in the present invention are fast acting, long acting and delayed release compositions. Preferred pharmaceutical forms of the invention are single tablet, coated tablet and capsule. Pharmaceutical compositions comprising as active ingredient an effective amount of one of the derivatives of formula (I) may be presented with said single derivative or in combination with another active ingredient.

Pharmaceutical compositions as well as medicament comprising as an active ingredient an effective amount of one of the derivatives of formula (I) have uses especially for treatment and prevention in a number of disorders including stable, unstable and variable angina, hypertension, pulmonary hypertension, heart failure. congestive disease, renal failure, atherosclerosis, unhealthy conditions of reduced blood vessel clearance, peripheral vascular disease, vascular disorders such as Raynaud's disease, erectile dysfunction, sexual dysfunction, inflammatory diseases, heart attack, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma and diseases characterized by disorders of intestinal motility.

For administration to warm-blooded animals with curative or prophylactic treatment of the above defined disorders, oral dosages of the compounds of formula (I) may be in the range 0.1-1.9 mg daily for a patient in need thereof. In practice, the physician should determine the most appropriate unitary fingerings regimen for each patient, which will vary with respect to age, weight and individual patient response.

Examples of some oral pharmaceutical formulations comprising the compounds of formula (I) according to the present invention are defined below.

Example 4

<table> table see original document page 22 </column> </row> <table> Example 6

<table> table see original document page 23 </column> </row> <table>

Example 7

<table> table see original document page 23 </column> </row> <table> Example 8

<table> table see original document page 24 </column> </row> <table>

Example 9

<table> table see original document page 24 </column> </row> <table> <table> table see original document page 25 </column> </row> <table> The preparation techniques for these formulations are known to pharmacotechnicians and known in the technical state.

The inhibitory activity of the compounds of the present invention was measured by in vitro analysis of the potency and effectiveness of the relaxing effect of compound BL-122 on muscle tissue. The inhibitory effect of muscle norelaxation compound BL-122 was tested on a rabbit and rat cavernous body, as shown in Examples 11 and 12, respectively.

Example 11

11.1. Isolation and mounting of preparations

Male rabbits weighing between 3.5 and 4.0 kg were used to carry out the experiments. The animals were anesthetized with sodium pentabarbital (40 mg / kg, i.p), abdominal cavity was opened for the removal of the animal penis. Tissues were placed in Petri dish containing Krebs-Henseleit solution pH 7.4 (118 mM NaCl; 4.8 mM KCl; 2.5 mM CaCl2; 1.2 mM MgSO4; 0.9 mM KH2PO4; 5 mM NaHCO3 11 mM glucose) heated to 37 ° C, with cartilage and adherent tissues carefully removed. In general 3 segments containing approximately 2 cm in length of the corporavernous were obtained from each animal. The preparations were mounted in glass vats containing 5 ml Krebs solution containing indomethacin (5.6 μΜ) maintained at 37 ° C, continuously mixed with a mixture of 95% O2 and 5% CO2.

The preparations were subjected to an equilibrium period of at least 90 minutes under tension of 2 g, during which time the bath solution was renewed every 15 minutes. Isometric voltage changes were recorded using a TRI-201 force transducer (Letica Scientific Instruments, Spain) coupled to a polygraph.

11.2. Analysis of the relaxant effect for the compounds studied in the corpora cavernosa Rabbit isolate

After the stabilization period, the preparations were exposed to single concentrations of 3 to 10 μΜ phenielephrine. After complete stabilization of the contractile responses to phenylephrine (about 5 minutes), the preparations were again exposed to increasing and cumulative concentrations (1 to 1000 nM). each of the compounds tested. After complete tissue re-ligation, the organs were washed several times with Krebs solution and allowed to stand for at least 60 minutes before performing the same dose-response curve again. The relaxing responses caused by the compounds were calculated as a function of the contractile response caused by phenylephrine considered as 100% contraction.

Compound BL-122 was diluted in 10 mM DMSO following serial dilution. In order to evaluate the effect of the used vehicle (DMSO) parallel control experiments were performed using the same volumes of the various dilutions of DMSO (vehicle).

Analysis of the relaxing effect on a cavernous body of rabbit showed that the addition of cumulative concentrations of 1 to 1000nM of compound BL-122 promoted relaxation in the previously contracted cavernous decorus preparations by felnilephrine (3-10μΜ), as illustrated in Figure 1. The CE50S rate of compound BL-122 was 15.9 (1.8 - 29.9) μΜ, and the maximum relaxation (efficacy) was 63.1 ± 7.8%. The control performed by treatment with the vehicle demonstrates that it does not promote relaxation in said tissues.

Example 12

12.1. Isolation and mounting of preparations

Male Wistar rats weighing between 300 - 350 g were used for the experiments. The animals were kept in an environment with humidity (60-80%) and controlled temperature (22 ± 2aC), with 12 hours light-dark cycle and free access to water and feed. Prior to the experiments, the animals were acclimatized in the laboratory for a period of 1 hour. Each animal was used only once per test.

Animals were sacrificed by deepening anesthesia with ketamine and xylazine hydrochloride, followed by exsanguination by carotid artery sectioning. After opening the thoracic cavity, the aorta was carefully removed and transferred to a Krebs-Henseleit solution Petri dish with the following composition (mM): NaCl 118; KCl 4.7; CaCl2 2.5; MgSO 4 1.2; KH2PO4 0.9; NaHC0325; glucose 11. Next, the adjacent adipose and connective tissues were carefully removed.

The vessel was sectioned into rings of approximately 3 to 4 mm in length and transferred to 5 mL total glass vats containing Krebs-Henseleit solution maintained at 37 ° C, pH 7.4 and continuously aerated with a mixture of 95% O2 and 5% CO2. Two metal rods were inserted into their light, one of which was adapted to an isometric voltage transducer coupled to a polygraph (TRI-201 - Letica ScientificInstruments). The resting tension applied to the preparations corresponded to 1.0 g and the nutrient solution was replaced every 15 minutes.

After the 60-minute equilibration period, the preparations were contracted with phenylephrine (0.3 - 1 μΜ) and after stabilization of the tonic contraction of the preparation, vascular endothelial integrity was assessed by the ability of acetylcholine (ACh, 1 μΜ) to induce relaxation of the preparations. Only preparations that presented relaxation equal to or greater than 75% were considered with intact endothelium and, therefore, were selected for the experiments. The Krebs-Henseleit solution was then renewed followed by a 30 minute equilibration period.

12.2. Analysis of the relaxant effect for compounds studied in the isolated corpus cavernosum of rats

After 30 minutes of rest, the preparations were found to be phenylephrine (0.3 - 1 μΜ) and thus the contractions were stabilized, and relaxation dose-response curves (DCR) were performed using the BL-122 compound (0.001-100 μΜ). presence of endothelium. Parallel experiments using only the DMSO solvent used to dilute the BL-122 compound were performed on tissues assembled from the same animals.

The results shown in Figure 2 show that the addition of cumulative concentrations of 1 to 1000 nM of compound BL-122 promoted relaxation in rat aortic preparations previously contracted by phenylephrine.

The activity of the compounds of the present invention on sexual behavior was measured by in vivo analysis of the effectiveness of the effect of compound BL-122 on spontaneous erections, as shown in Example 13.Example 13

13.1. Isolation and mounting of preparations

The protocol used was adapted from articles of literature (Hosseinzadeh et al., 2008; Rizzo et al., 2008).

Two days before the experiments, matched and female couples were isolated in plastic boxes. At this time, males were habituated for 1 hour per day in rectangular metal wire cages with dimensions of 40 χ 23 χ 33 cm. On the day of the test, male rats were treated with 10 mg / kg (v.o.) of compound BL-122 or only as vehicle (saline containing 10% DMSO). Immediately after, the animals were placed in the observation cages. Mice that received oral treatment remained fasting for 4 hours before the test. After 1.5 hours after oral treatment, the females were placed with their males in the cages. Spontaneous erection behavior was observed for 1 hour.

13.2. Effect of compound BL-122 on rat sexual behavior in the presence of females when administered orally.

Oral treatment with compound BL-122 at a dose of 10 mg / kg significantly increased the parameter for spontaneous erections when compared with the vehicle by about 6.4 ± 2.0 as shown in Figure 3.

Claims (22)

1. COMPOUND characterized by having the formula (!): Wherein R1 represents hydrogen, halogen, C1-6 alkyl or 0-R # where R 'represents hydrogen or alkyls η represents a number ranging from 0 to 4. R 2 represents hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, haloC 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloC 1-3 alkyl, aryl C 1-3 alkyl or C1-3 alkyl heteroaryl; R3 represents hydrogen, C1-3 alkyl or R2 and R3 together represent a 3- or 4-substituent of an alkyl or alkenyl ring; R4 represents hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, haloC 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloC 1-3 alkyl, aryl C 1-3 alkyl or heteroaryl C 1-3 alkyl R 5 represents hydrogen or O-R 'where R' represents hydrogen or lower alkyls, or enantiomers or mixtures of enantiomers or a salt or solvate thereof. Compound according to Claim 1, characterized in that it is in hydrate form. Isomer of the compound according to claim 1, characterized in that it is selected from compounds of formula (Ib): wherein: * is a chiral carbon of R; represents hydrogen, halogen, C1-6 alkyl or O-R 'where R' represents hydrogen or lower alkyls, η represents a number ranging from 0 to 4, R2 represents hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl haloC 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloC 1-3 alkyl, aryl C 1-3 alkyl or heteroaryl C 1-3 alkyl R 3 represents hydrogen, C 1-3 alkyl or R 2 and R 3 together represent a 3- or 4-substituent of an alkyl or alkenyl ring R 4 represents hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkylC 1-3 alkyl or aryl C 1-3 alkyl or heteroaryl C 1-3 alkyl R5 represents hydrogen or O-R 'where R' represents hydrogen or lower alkyls, or an enantiomer or mixtures of enantiomers or a salt or u solvate this one. Isomer of the compound according to claim 1, characterized in that it is chosen from compounds of formula (Ic): wherein, * is a chiral carbon of configuration S; R1 represents hydrogen, halogen, C1-6 alkyl or O-R 'where R' represents hydrogen or lower alkyls; η represents a number ranging from 0 to 4. R2 represents hydrogen, C1-6 alkyl, C2-6 alkenyl, C 2-6 alkynyl, haloC 1-6 alkyl, C 3-8 cycloalkyl, C 3,8 cycloalkylC 1-3 alkyl, aryl C 1-3 alkyl or heteroaryl C 1-3 alkyl R 3 represents hydrogen, C 1-3 alkyl or R 2 and R 3 together represent a 3- or 4 - substituents on an alkyl or alkenyl ring R4 represents hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6alkyl, haloC1-6 alkyl, C3-8 cycloalkyl, C3-8 cycloalkylC1-3 alkyl or heteroaryl C1-3 alkyl; R5 represents hydrogen or O-R 'where R' represents hydrogen or lower alkyls, or an enantiomer or mixtures of enantiomers or a salt or solvate thereof. Compound according to claim 1, characterized in that R 1 represents hydrogen, R 2 represents C 1-6 alkyl and R 3 and R 4 represent hydrogen. Compound according to Claim 5, characterized in that it is 3 - ((2- (benzo [d] [1,3] dioxol-5-carbonyl) -1H-indol-3-yl) methyl) -1- methylpiperazine-2,5-dione. Compound according to Claim 6, characterized in that it is (R) -3 - ((2- (benzo [d] [1,3] dioxol-5-carbonyl) -1H-indol-3-yl) methyl) -1-methylpiperazine-2,5-dione. Compound according to Claim 6, characterized in that it is (S) -3 - ((2- (benzo [d] [1,3] dioxol-5-carbonyl) -1H-indol-3-yl) methyl) -1-methylpiperazine-2,5-dione. A process for preparing the compound according to claim 3 and represented by formula Ib, characterized in that it comprises a reaction of a compound represented by formula IV with DDQ and THF / H 2 O, according to the general formula: Preparation of the compound according to claim 3 and represented by formula Ib, characterized in that it comprises a reaction of a compound represented by formula V with SeO 2 and dioxane according to the general formula: <formula> formula see original document page 35 < / formula> A process for preparing the compound according to claim 3 and represented by formula Ib, characterized in that it comprises a reaction of a compound represented by formula VI with SeO 2 and dioxane to give an intermediate represented by formula VII; and a reaction of such an intermediate with MeNH2 and EtOH / THF according to the formula: <formula> formula see original document page 35 </formula> 12. INTERMEDIATE COMPOUND characterized by the formula (II): wherein R1 represents hydrogen, halogen, C1-6 alkyl or O-R 'where R' represents hydrogen or alkyls. R3 represents hydrogen or C1-3 alkyl or R2 and R3 together represent a 3- or 4-substituent of an alkyl or alkenyl ring, R4 represents hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkyl, halo C1-6 alkyl, C3-8 cycloalkyl C3-8 cycloalkylC1-3 alkyl, aryl C1-3 alkyl or heteroaryl C1-3 alkyl, C1-6 alkyl, Hal represents halogen, or an enantiomer or mixtures of enantiomers or a salt or solvate thereof. 13. INTERMEDIATE characterized by having the formula (III): wherein R1 represents hydrogen, halogen, C1-6 alkyl or O-R 'where R' represents hydrogen or alkyls η represents a number ranging from 0 to 4. R2 represents hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6alkyl, haloC1-6alkyl, C3-8 cycloalkyl, C3-8 cycloC1-3alkyl, C1-3 aryl C1-3 alkyl or heteroaryl R3 represents hydrogen, C1-3 alkyl or R2 and R3 together represent a 3- or 4-substituent of an alkyl or alkenyl ring, R4 represents hydrogen, C1-6 alkyl, C2-6 alkenyl, C2- alkynyl, haloC 1-6 alkyl, C 3-6 cycloalkyl, C 3-8 cycloC 1-3 alkylalkyl, C 1-3 alkyl aryl or C 1-3 alkyl heteroaryl R 5 represents hydrogen or O-R 'where R' represents hydrogen or lower alkyl; Hal represents halogen, or an enantiomer or a salt or solvate thereof. PHARMACEUTICAL COMPOSITION characterized in that it comprises one or more compounds according to any one of claims 1 to 11, or their pharmaceutically acceptable salts and pharmaceutically acceptable excipients. A medicament comprising one or more pharmaceutically effective compounds according to any one of claims 1 to 11 or pharmaceutically acceptable salts thereof. Use of the compounds according to any one of claims 1 to 11, characterized in that they are for improved sexual behavior in warm-blooded animals. Use according to claim 16, characterized in that it is for the curative or prophylactic treatment of sexual dysfunction in warm-blooded animals. Use according to claim 17, characterized in that it is for the curative and / or prophylactic treatment of erectile dysfunction in man. Use of the compounds according to any one of claims 1 to 11, characterized in that they are for curative and / or prophylactic treatment of arterial hypertension or pulmonary hypertension. A method of treating sexual dysfunction or erectile dysfunction, comprising administering the compound according to any one of claims 1 to 11. Use of the compound according to any one of claims 1 to 11, characterized in that it is for the manufacture of a drug suitable for anti-platelet, anti-neutrophil, anti-vasospastic, vasodilatory, natriuretic and diuretic treatments, as well as potentiating agents. effects of endothelium-derived relaxing factor (EDRF), nitrovasodilators, atrial natriuretic factor (ANF), brain natriuretic peptide (BNP), type C natriuretic peptides (CNP), and endothelium-dependent relaxing agents such as bradykinin, acetylcholine and 5-HT1. Use of the compound according to any one of claims 1 to 11, characterized in that it is for the manufacture of a suitable drug for treatment including stable, unstable and variable angina, hypertension, pulmonary hypertension, congestive heart failure, renal failure, atherosclerosis, conditions patients with reduced clearance of blood vessels, peripheral vascular disease, vascular disorders such as Raynaud's disease, erectile dysfunction, sexual dysfunction, inflammatory diseases, heart attack, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, and diseases characterized by intestinal motility disorders .