The use of inhibitors СgМР-phosphodiesterase for the treatment of impotence

 

(57) Abstract:

The invention relates to the field of medicine. The proposed compounds of formula (I)

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(6R, 12aR)-2,3,6,7,12,12 a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2', 1': 6,1] pyrido[3,4-b] indole-1,4-dione; and (3S,6R,12aR)-2,3,6,7,12,12 a-hexahydro-2,3-dimethyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione and their physiologically acceptable salt and solvate for the treatment of impotence. Also we propose a method for the treatment and prevention of erectile dysfunction using the compounds and pharmaceutical compositions based on them. Method for obtaining pharmaceutical compositions. The proposed connection is more active than known in this area. 9 c. and 4 C.p. f-crystals, 1 table.

The invention relates to the use of tetracyclic derivatives, which are potent and selective inhibitors guanosin-3',5'-cyclophosphate-specific phosphodiesterase (cGMP-specific PDE), in the treatment of impotence.

Impotence can be characterized as a loss of sexual activity in men sexual intercourse and can manifest itself in the inability to achieve penile erection or ejaculation, or both. More specifically, Erik the erection, necessary for sexual intercourse. Argue that its prevalence increases with age and ranges from 2 to 7% of the male population aged 50 years and in the interval from 18 to 75% in the age between 50 and 80 years.

Reports of properly controlled clinical trials in men are rare, and efficacy of orally administered drugs is low. Although it has been shown that many different drugs cause penis erection, their effectiveness is limited by means of administration is by injection directly into the penis, namely intraurethral or intracavernosal (i. e.) injection, and they are not suitable for erectile dysfunction. Modern treatment based on i.e. injection of vasoactive substances, good results are reported with the introduction of phenoxybenzamine, phentolamine, papaverine and prostaglandin E1in mono mode, or in combination; however, the introduction of some of these agents is accompanied by pain, priapism and fibrosis of the penis. It was shown that active activators potassium channels (CSR) and vasoactive intestinal polypeptide (VIP), however, the cost and stability issues limit the application of the latter. Alternative i.e. the introduction is aloette as a partner, and from their partner.

Alternatively, pharmacological intervention to achieve erections were used a variety of penile prosthesis. Received a good short term results, but the possibility of infection and ischemia, especially in men with diabetes, don't allow this kind of treatment become paramount.

The compounds of this invention are powerful inhibitors guanosin-3', 5'-cyclophosphate-specific phosphodiesterase (cGMP PDE). In the application GB 9514464.8, which is the priority document for the present application, describes the synthesis of compounds according to this invention and their use for the treatment of impotence. In the application W095/19978, which was not published at the priority date of the present application, describes the synthesis of compounds according to this invention and their use in the treatment of other diseases associated with inhibition of cGMP PDE. Compounds may be represented by the following General formula (I):

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and their salts and solvate (e.g. hydrate) in which;

R0means a hydrogen atom, halogen or C1-6-alkyl;

R1means a hydrogen atom, a C1-6-alkyl, C2-6alkenyl,2-6-quinil, haloesters C1-6-alkyl, C3-81-3-alkyl;

R2means arbitrarily substituted monocyclic aromatic ring selected from the group consisting of benzene, thiophene, furan and pyridine or arbitrarily substituted bicyclic ring,

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attached to the rest of the molecule via one of the carbon atoms of the benzene ring, where the articulated ring a is a 5 - or 6-membered ring which may be saturated or partially or fully unsaturated and comprises carbon atoms and randomly one or two heteroatoms selected from the group consisting of oxygen atom, sulfur and nitrogen; and

R3means a hydrogen atom or a C1-3-alkyl, or R1and R3together mean 3 - or 4-membered alkyl or alkenylphenol chain.

The respective individual compounds according to this invention for the treatment of erectile dysfunction include:

CIS-2,3,6,7,12,12 and hexahydro-2-(4-pyridylmethyl)-6-(3,4-methylenedioxyphenyl) - pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione;

CIS-2,3,6,7,12,12 and hexahydro-6-(2,3-dihydrobenzo[b] furan-5-yl)-2-methylpyrazine [2',1':6,1]pyrido[3,4-b]indole-1,4-dione;

CIS-2,3,6,7,12,12 and hexahydro-6-(5-bromo-2-thienyl)-2-methylpyrazine[2',1': 6,1] pyrido[3,4-b]indole-1,4-dione;

CIS-2,3,6,7,12,12 and hexahydro-2-butyl-6-(is oxyphenyl)-pyrazino [2',1':6,1]pyrido[3,4-b]indole-1,4-dione;

(6R, 12aR)-2,3,6,7,12,12 and hexahydro-2-cyclopentyl-6-(3,4-methylenedioxyphenyl)-pyrazino [2',1':6,1]pyrido[3,4-b]indole-1,4-dione;

(6R, 12aR)-2,3,6,7,12,12 and hexahydro-2-cyclopropylmethyl-6-(4-methoxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione;

(6R, 12aR)-2,3,6,7,12,12 and hexahydro-6-(3-chloro-4-methoxyphenyl)-2-methylpyrazine [2',1':6,1]pyrido[3,4-b]indole-1,4-dione;

(6R, 12aR)-2,3,6,7,12,12 and hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione;

(6R, 12aR)-2,3,6,7,12,12 and hexahydro-6-(3,4-methylenedioxyphenyl)pyrazino [2',1':6,1]pyrido[3,4-b]indole-1,4-dione;

(5R, 12R, 14S)-1,2,3,5,6,11,12,14 and octahydro-12-(3,4-methylenedioxyphenyl)-pyrrolo[1",2":4',5']pyrazino[2',1':6,1] pyrido[3,4-b]indole-1,4-dione;

CIS-2,3,6,7,12,12 and hexahydro-2-cyclopropyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione;

(3S, 6R, 12aR)-2,3,6,7,12,12 and hexahydro-3-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione;

and their physiologically acceptable salt and solvate (e.g. hydrate).

Specific compounds of this invention are:

(6R, 12R)-2,3,6,7,12,12 and hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (compound A); and

(3S, 6R, 12R)-2,3,6,7,12,12 and hexahydro-2,3-dimethyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[ptx2">

It has been unexpectedly found that the compounds of formula (I) and, in particular, the compounds a and b suitable for the treatment of erectile dysfunction. Moreover, the compounds can be administered orally, thereby eliminating the disadvantages associated with i.e. introduction. Thus, the present invention relates to the use of compounds of formula (I) and, in particular, compounds a and b or their pharmaceutically acceptable salts or pharmaceutical composition containing each object, in the manufacture of medicaments for therapeutic or prophylactic treatment of erectile dysfunction in mammals, male sex, including humans.

Pharmaceutically acceptable salts of compounds of formula (I) and, in particular, compounds a and b, which contain a basic centre are kislotoobrazovanie salts formed during the interaction with pharmaceutically acceptable acids. Examples include cleaners containing hydrochloride, hydrobromide, sulfate or bisulfate, phosphate or acid phosphate, acetate, benzoate, succinate, fumaric, maleato, lactate, citrate, tartrate, gluconate, methanesulfonate, bansilalpet or p-toluensulfonate salt. The compounds of formula (I) and, in particular, the compounds a and b can t the s. Examples include the sodium and potassium salts.

It is shown that the compounds of the present invention are potent and selective inhibitors of cGMP-specific PDE. Currently, it has been unexpectedly discovered that the human cavernous body contains three different PDE enzyme. Then unexpectedly it was found that the predominant PDE is cGMP PDE. Due to selective inhibition of PDE V compounds according to this invention, they can increase the levels of cGMP, which, in turn, can contribute to the relaxation of the cavernous tissue of the body and the subsequent erection of the penis.

Although the compounds according to this invention was initially considered as a means to treat erectile dysfunction or sexual dysfunction in men, they can also be useful in the treatment of female sexual dysfunction, including orgasmic dysfunction associated with clitoral violations.

Males usually have the preferred route of administration of the compounds according to this invention is oral administration as the most convenient and allows you to avoid the disadvantages associated with i.e. introduction. In circumstances in which the recipient is suffering from swallowing disorders or disturbances AB is whether transbukkalno.

For administration to man in the curative and prophylactic treatment of the above-mentioned violations of the oral dose of the compounds of formula (I) and, in particular, compounds a and b will usually be in the range of 0.5 to 800 mg per day for an average adult patient (70 kg). Thus, for a typical adult patient tablets or capsules containing 0.2-400 mg of active compound in the appropriate pharmaceutically acceptable excipient or carrier, for administration in the form of single or multiple doses of one or several times a day. Doses for transbukkalno or sublingual injection will usually be in the range of 0.1 to 400 mg as a single dose, if necessary. In practice, the physician will determine the appropriate dose schedule that is most appropriate for this patient and it will vary depending on age, weight and sensitivity of the patient. The above doses are typical for the normal case, but in special cases they may be lower or higher dose interval that is included in the scope of this invention.

For use on the person of the compounds of formula (I) and, in particular, the compounds a and b can be introduced as such, but they are usually injected in a mixture with pharmacy. For example, the compound may be administered orally, transbukkalno or sublingual in the form of tablets containing excipients such as starch or lactose, or in the shell or in capsules as such or in a mixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. Such liquid preparations can be obtained using pharmaceutically acceptable additives such as suspendresume agents (e.g. methylcellulose, semisynthetic glycerides, such as witepsol, or a mixture of glycerides, such as a mixture of stone fruits apricot oils and esters PEG-6, peg-6) or a mixture of PEG-8 and glycerides containing the remains of Caprylic/capric acids).

When used in the veterinary compound of formula (I) and, in particular, compound a or b, or their non-toxic salt is introduced in the corresponding acceptable dosage form in accordance with normal veterinary practice and the veterinary surgeon determines the dose schedule and route of administration that is most suitable for an individual animal of the male sex.

Thus, the invention includes a pharmaceutical composition for therapeutic and prophylactic treatment of erectile dysfunctie a and b or their pharmaceutically acceptable salt together with a pharmaceutically acceptable diluent or carrier.

In further provides a process of preparing a pharmaceutical composition for therapeutic and prophylactic treatment of erectile dysfunction in mammals, male sex, including humans, consists in obtaining the drug form of the compounds of formula (I) and, in particular, compounds a or b, or their pharmaceutically acceptable salts and pharmaceutically acceptable diluent or carrier.

The invention also provides a method of treatment of a male mammal, including humans, for the treatment or prevention of erectile dysfunction, which includes the processing of the above-mentioned male mammal an effective amount of the compounds of formula (I) and, in particular, compounds a or b or their pharmaceutically acceptable salts or pharmaceutical composition that includes each object.

Moreover, the invention includes the use of compounds of formula (I) and, in particular, compounds a or b, or their pharmaceutically acceptable salts or pharmaceutical composition comprising each object, in the manufacture of medicaments for therapeutic or prophylactic treatment of erectile dysfunction in the male mammal, including humans.

Soedinenii agents, which may be useful in the treatment of erectile dysfunction, mainly, as has been described here. Therefore, in another aspect, the invention provides a combination of compounds of formula (I) and, in particular, compound, or with another therapeutically active agent.

The above combination can be used in pharmaceutical dosage forms, and thus pharmaceutical formulations comprising a combination as mentioned above, with a pharmaceutically acceptable diluent or carrier, are another aspect of the invention.

Individual components of such combinations in separate pharmaceutical dosage forms may also be administered or sequentially, or simultaneously.

Specialists without difficulty will determine the dose of known therapeutic agents for use in combination with the connection according to this invention.

Compounds according to this invention can be obtained by any suitable technique known in the art, or by the following methods, which form part of the present invention. The way was mostly previously described in the priority document of the present invention GB 9514464.8 and in WO 95/19978. Tackroom Alk means C1-6-alkyl, for example methyl or ethyl, and Hal means a halogen atom, for example chlorine) primary amine R1NH2in a suitable solvent, such as alcohol (e.g. methanol or ethanol), or in a solvent mixture usually at a temperature of 20oC to the boiling point (for example, about 50oC).

The compound of formula (II) can be easily obtained by treating compounds of formula (III) compound of formula (IV)

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in a suitable solvent, such as galoidovodorodov (for example, trichloromethane or dichloromethane) or an ether (e.g. tetrahydrofuran), preferably in the presence of a base such as an organic amine (for example, trialkylamine, such as triethylamine) or a carbonate or bicarbonate of an alkali metal (for example, Panso3). The reaction easily proceeds at temperatures from -20oC to +20o(For example, when 0oC).

The compound of formula (I) can be easily obtained from the compounds of formula (III) in two stages through the stage of formation of the compounds of formula (II) isolated without purification.

The compounds of formula (I) can be obtained in the form of individual enantiomers in two stages from the corresponding enantiomer of formula (III) or in the form of mezameru formula (III).

Individual enantiomers of the compounds of this invention can be obtained from the racemate by separation using methods of separation of racemic mixtures into its constituent enantiomers, using methods known in the art, such as HPLC (IHVR, liquid chromatography high resolution) on a column with a chiral sorbent, such as hyperventilation.

The compound of formula (III) can be easily obtained from Olkiluoto ester of tryptophan formula (V)

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(where Alk such as previously described) or its salt (e.g. hydrochloride) and aldehyde R2CHO. The reaction can be easily carried out in a suitable solvent, such as galoidovodorodov (e.g. dichloromethane) or an aromatic hydrocarbon (e.g. toluene) in the presence of acid, such as triperoxonane acid. The reaction is conveniently carried out at temperatures from -20oC to the boiling point, receiving compound of formula (III) in one stage. The reaction can also be performed in a solvent such as an aromatic hydrocarbon (e.g. benzene or toluene), at boiling using nozzles Dean-stark to trap the formed water.

The reaction produces a mixture of CIS - and transnasional depending on, did as the starting material racemic or enantiomeric alkilany ester of tryptophan. Individual CIS - and TRANS-isomers can be easily separated from their mixtures by fractional crystallization or chromatography (e.g., column flash chromatography) using appropriate solvents and eluents. Similarly a pair of CIS - and TRANS-isomers can be separated by chromatography (for example, column flash chromatography) using appropriate eluents. Optically pure transisomer can be easily converted into optically pure cisisomer using appropriate ways of epimerization. One such method includes processing transisomer or mixture (e.g., a mixture in the ratio 1: 1) CIS - and TRANS-isomers methanol or aqueous solution of hydrogen chloride at a temperature of from 0oC to the boiling point of the solution. The mixture is then subjected to chromatography (e.g., column flash chromatography) to separate the formed diastereoisomer, or in the process of using water hydrogen chloride the desired cisisomer precipitates in the form of the hydrochloride, which can then be separated by filtration.

The pharmaceutical is a or b, which contain a basic centre can be obtained in the usual way. For example, a solution of the free base may be treated with an appropriate acid, either in an unmodified form or in a suitable solution, and the resulting salt allocate or by filtration or by evaporation of the solvent in vacuo. Pharmaceutically acceptable salts, formed by joining the Foundation, can be obtained in a similar manner by treating a solution of the compound, or In an appropriate basis. Both types of salts can be formed or vzaimoprevrascheny using ion-exchange resins.

Compounds according to this invention can be selected in Association with a molecule of solvent by crystallization or evaporation of the appropriate solvent.

The syntheses of compounds and intermediate compounds for use in this invention are illustrated by the following examples. The examples described earlier in the document on priority application GB 9514464.8, and corresponding intermediate compounds or number of Examples are given here in parentheses next to the number of intermediate compounds or Example of the present invention.

In the description of the examples used here Slee (1R,3R)-1,2,3,4-tetrahydro-1-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylic acid, cisisomer

To a stirred solution of the methyl ester of D-tryptophan (11 g) and piperonal (7.9 g) in anhydrous dichloromethane (400 ml), cooled to 0oC, was added dropwise triperoxonane acid (7.7 ml) and the solution was left at ambient temperature. After 4 days, the yellow solution was diluted with methylene chloride (200 ml) and washed with saturated aqueous sodium bicarbonate, then with water (I ml) and dried over sodium sulfate. The organic layer was evaporated under reduced pressure and the residue containing two geometric isomer, purified flash chromatography, elwira a mixture of dichloromethane/ethyl acetate (97/3), receiving the first product named in the title (6.5 g), So pl. 154oC.

Intermediate compound 2 (83)

Methyl ester of (1R,3R)-1,2,3,4-tetrahydro-2-(2-chloropropionyl)-1-(3,4-methylenedioxyphenyl)-N-pyrido[3,4-b]indole-3-carboxylic acid

To a solution of (R)-(+)-2-chloropropionic acid (191 μl, 2.2 mmol) in anhydrous dichloromethane (30 ml) was added dicyclohexylcarbodiimide (0.45 g, 2.2 mol). Then was added the intermediate compound 1 (0.7 g, 2 mmol) and the mixture was stirred at room temperature for 20 hours. The resulting precipitate of dicyclohexylamine was removed by filtration, the filtrate was evaporated the lo was led from a mixture of ether/hexane, receiving the compound named in the heading, in the form of pale yellow crystals (0.74 g). So pl. 126-128oC.

Example 1 (78) (compound A)

(6R, 12aR)-2,3,6,7,12,12 and Hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione

a) To a stirred solution of intermediate 1 (0.5 g) and sodium bicarbonate (0.14 g) in anhydrous chloroform (20 ml) was added dropwise chlorocatechol (0,27 ml) at 0oC. the resulting mixture was stirred 1 hour at the same temperature and was diluted with chloroform (20 ml). Then, with stirring, to the mixture was added dropwise water (10 ml), then was added a saturated solution of sodium bicarbonate. The organic layer was washed with water until neutral and dried over sodium sulfate. After evaporation of the solvent in vacuo was obtained methyl ester of (6R,12aR)-1,2,3,4-tetrahydro-2-chloroacetyl-1-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylic acid in the form of oil, which was led from the air, getting solid (0,38 g, so pl. 233oC) used without further purification in the next stage.

b) To a stirred suspension chloroceryle derived (0,37 g) in methanol (20 ml) was added at room temperature a solution metelli is removed under reduced pressure, the residue was dissolved in dichloromethane (50 ml). After washing with water (3h20 ml), dried over sodium sulfate and evaporated to dryness. The residue was purified flash chromatography, elwira a mixture of dichloromethane/methanol (99/1) and recrystallized from isopropanol, receiving the compound named in the heading, in the form of white crystals (0,22 g). So pl. 302-303oC.

Analysis for C22H19NaO4. Calculated, %: C 67,86; N To 4.92; N 10,79. Found, %:

WITH 67,77; N TO 4.92; N A 10.74.

[]20D= +71.00(from 1.00, chloroform).

Example 2 (117) (compound)

(3S, 6R, 12aR)-2,3,6,7,12,12 and Hexahydro-2,3-dimethyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione

To a stirred solution of intermediate compound 2 (0.3 g, of 0.68 mmol) in tetrahydrofuran (30 ml) was added at room temperature a solution of methylamine (33% in ethanol) (0.68 ml) and the resulting solution was heated at boiling in a stream of nitrogen for 6 days. The solvent was removed under reduced pressure, the residue was dissolved in dichloromethane (50 ml). After washing with water (2.25 ml) the organic phase was dried over sodium sulfate and was evaporated to dryness, the crude product was purified flash chromatography, elwira mixture diclomelan/methanol (99/1). The resulting oil was led is">

Analysis for C23H21N3O4. Calculated, %: C 68,47; N A 5.25; N 10,42. Found, %:

WITH 68,35; N 5,33; N 10,42.

[]20D= +65.20(1,15, chloroform).

Similarly, received the following connection.

Example 3

(3S, 6R, 12aR)-2,3,6,7,12,12 and Hexahydro-3-methyl-6-(3,4-methylenedioxyphenyl)pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione

Received in the form of white crystals, using ammonia as the base. So pl. point of 319-321oC.

Analysis for C22H19N3O4. Calculated, %: C 67,86; N To 4.92; N 10,79. Found, %:

WITH 67,86; N. OF 5.17; N OF 10.72.

[]20D= +1070(1, pyridine).

The compounds a and b is included in the dosage forms, details of which are given below.

Tablets for oral administration A.

Direct pressing

1. mg/tablet

Active ingredient - 50,0

Crosspovidone USNF - 8,0

Magnesium stearate Ph Eur - 1,0

Lactose anhydrous - 141,0

The active ingredient was sieved and mixed with fillers. The resulting mixture was pressed into tablets.

2. mg/tablet

Active ingredient - 50,0

Silicon dioxide colloidal 0,5

Crosspovidone - 8,0

Dodecyl sulphate noticeable and mixed with fillers. The resulting mixture was pressed into tablets.

C. Wet granulation

1. mg/tablet

Active ingredient - 50,0

Polyvinylpyrrolidone - 150,0

The glycol - 50,0

Polysorbate 80 - 10,0

Magnesium stearate Ph Eur - 2,5

Croscarmellose-sodium - 25,0

Silicon dioxide colloidal 2,5

Microcrystalline cellulose USNF - 210,0

Polyvinylpyrrolidone, polyethylene glycol and Polysorbate 80 was dissolved in water. The resulting solution was used for granulation of the active ingredient. After drying, the granules were sieved, then extrudible (stamped) at elevated temperature and pressure. The extrudate was ground and/or sieved, and mixed with microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate. The resulting mixture was pressed into tablets.

2. mg/tablet

Active ingredient - 50,0

Polysorbate 80 - 3,0

Lactose Ph Eur - 178,0

Starch BP - 45,0

Pregelatinized corn starch BP - 22,5

Magnesium stearate and 1.5

The active ingredient was sieved and blended with lactose, starch and pregelatinized corn starch. Polysorbate 80 was dissolved in purified water. Arr is seiuli and mixed with magnesium stearate. Then the granules are extruded into pellets.

Tablets with different intensity steps can be obtained by varying the ratio of the active ingredient and excipients.

Tablets, film-coated

The tablets described above were covered with a film.

Covering suspension - % weight

Opadry white - 13,2

Purified water Ph Eur - up to 100.0*

Opadry white is a patented material received by the firm use Limited, UK, which contains hypromellose, titanium dioxide and triacetin.

* In the final product water is not defined. The maximum theoretical weight of solids applied when the coating was 20 mg/tablet. The tablets covered with a film using covering suspension and the usual equipment for coating.

Capsules

1. mg/capsule

Active ingredient - 50,0

Lactose - 148,5

Polyvinylpyrrolidone - 100,0

Magnesium stearate and 1.5

The active ingredient was sieved and mixed with fillers. Filled with a mixture of hard gelatin capsules of size 1, using the appropriate equipment.

2. mg/capsule

Active ingredient - 50,0

Microcrystallinity ingredient was sieved and mixed with fillers. Filled with a mixture of hard gelatin capsules of size 1, using the appropriate equipment.

Other doses may be obtained by varying the ratio of the active ingredient and filler, fill weight and, if necessary, change the size of the capsules.

3. mg/capsule

Active ingredient - 50,0

Labrafil M1944CS - to 1.0 ml

The active ingredient was sieved and mixed with labrafil. Filled with a mixture of soft gelatin capsules using their equipment.

Inhibitory effect on cGMP-PDE

The activity of the compounds of the present invention in respect of cGMP-PDE was measured using a single-stage analysis, adapted from Wells and others (Wells J. N. , Baird, C. E., Wu Y. J., Yardman J. G. Biophys. Acta 384, 430 (1975)). The reaction medium contained 50 mm Tris-HCI, pH 7.5, 5 mm magnesium acetate, 250 μg/ml 5'-nucleotidase, 1 mm EGTA (ethylene glycol-bis-(-(-amino-ethyl)-N,N,N', N'-tetraoxo acid) and 0.15 μm 8-[H3]-cGMP. Used the enzyme was a human recombinant PDEV (ICOS, Seattle, WA, USA).

The compounds of this invention was dissolved in DMSO (dimethyl sulfoxide), the final concentration did not exceed 2%. The incubation time was 30 minutes, a total conversion of the substrate not p is ranged on the curve of the dependence of the effect of concentration, using regular intervals of concentrations from 10 nm to 10 μm. Tests with other PDE using standard methodology has also shown that the compounds according to this invention have high selectivity with respect to cGMP-specific PDE.

Measurement of cGMP levels

The smooth muscle cells of rat aorta (RSMC), obtained according to Chamley et al. Cell Tissue Res. 177, 503-522 (1977) was used between the tenth and twenty-fifth passage at the confluence in 24-cell culture vessels. Culture medium was removed and replaced with PBS (saline, buffered phosphate) (0.5 ml) containing the test compound at the appropriate concentration. After 30 minutes at 37oWith particles guanylate cyclase was stimulated by addition of ANF (trialname natriuretic factor) (100 nm) for 10 minutes. At the end of the incubation the medium was removed and spent two extraction by adding 65% ethanol (0.25 ml). Two ethanol extracts were combined and evaporated to dryness using a vacuum system Speed-vac. After acetylation was measured by the content of cGMP using scintillation immunoassay (AMERSHAM). It is shown that the compounds of the present invention, generally have a value IC50less than 500 nm and the value of EC50Myung is x2">

The above data demonstrate the ability of compounds of the subjects of this invention to inhibit the activity of cGMP PDE and, therefore, their applicability in the treatment of erectile dysfunction, mainly, as has been described here.

1. The compound of formula (I)

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and its salts and solvate (e.g. hydrate),

where R0means a hydrogen atom, halogen or C1-6-alkyl;

R1means a hydrogen atom, a C1-6-alkyl, C2-6alkenyl,2-6-quinil, haloesters C1-6-alkyl, C3-8-cycloalkyl,3-8-cycloalkylation1-3-alkyl, arylesterase1-3-alkyl or heteroarylboronic1-3-alkyl;

R2means arbitrarily substituted monocyclic aromatic ring selected from the group consisting of benzene, thiophene, furan and pyridine or arbitrarily substituted bicyclic ring,

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attached to the rest of the molecule via one of the carbon atoms of the benzene ring, where the articulated ring a is a 5 - or 6-membered ring which may be saturated or partially or fully unsaturated and comprises carbon atoms and randomly one or two heteroatoms, selected Il, or R1and R3together mean 3 - or 4-membered alkyl or alkenylphenol chain,

with the use in the manufacture of medicaments for the treatment and prevention of erectile dysfunction in mammals, male sex, including humans.

2. A compound selected from the group comprising (6R,12aR)-2,3,6,7,12,12 and hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1': 6,1] pyrido[3,4-b] indole-1,4-dione and (3S,6R,12aR)-2,3,6,7,12,12 and hexahydro-2,3-dimethyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2', 1': 6,1] -pyrido[3,4-b] indole-1,4-dione, and their physiologically acceptable salt and solvate having use in the manufacture of medicaments for the treatment and prevention of erectile dysfunction in mammals, male sex, including humans.

3. Method for the treatment and prevention of erectile dysfunction in mammals, male sex, including man, characterized in that it includes the introduction of the compounds of formula (I)

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and its salts and solvate (e.g. hydrate),

where R0means a hydrogen atom, halogen or C1-6-alkyl;

R1means a hydrogen atom, a C1-6-alkyl, C2-6alkenyl,2-6-quinil, haloesters C1-6-alkyl, C3-8-cycloalkyl,3-8-cycloalkylation who appoints arbitrarily substituted monocyclic aromatic ring, selected from the group consisting of benzene, thiophene, furan and pyridine or arbitrarily substituted bicyclic ring,

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attached to the rest of the molecule via one of the carbon atoms of the benzene ring, where the articulated ring a is a 5 - or 6-membered ring which may be saturated or partially or fully unsaturated and comprises carbon atoms and randomly one or two heteroatoms selected from the group consisting of oxygen atom, sulfur and nitrogen;

R3means a hydrogen atom or a C1-3-alkyl, or R1and R3together mean 3 - or 4-membered alkyl or alkenylphenol chain.

4. Method for the treatment and prevention of erectile dysfunction in mammals, male sex, including man, characterized in that it includes the introduction of a compound selected from the group comprising (6R,12aR)-2,3,6,7,12,12 and hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1': 6,1] pyrido[3,4-b] indole-1,4-dione and (3S,6R,12aR)-2,3,6,7,12,12 and hexahydro-2,3-dimethyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2', 1': 6,1] -pyrido[3,4-b] indole-1,4-dione, and their physiologically acceptable salt and solvate.

5. Pharmaceutical composition for the treatment and prevention of erectile dysfunction in melicope the tel or the media, characterized in that it as the active ingredient contains a compound of the formula (I)

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and its salts and solvate (e.g. hydrate),

where R0means a hydrogen atom, halogen or C1-6-alkyl;

R1means a hydrogen atom, a C1-6-alkyl, C2-6alkenyl,2-6-quinil, haloesters C1-6-alkyl, C3-8-cycloalkyl,3-8-cycloalkylation1-3-alkyl, arylesterase1-3-alkyl or heteroarylboronic1-3-alkyl;

R2means arbitrarily substituted monocyclic aromatic ring selected from the group consisting of benzene, thiophene, furan and pyridine or arbitrarily substituted bicyclic ring,

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attached to the rest of the molecule via one of the carbon atoms of the benzene ring, where the articulated ring a is a 5 - or 6-membered ring which may be saturated or partially or fully unsaturated and comprises carbon atoms and randomly one or two heteroatoms selected from the group consisting of oxygen atom, sulfur and nitrogen;

R3means a hydrogen atom or a C1-3-alkyl, or R1and R3together mean 3 - or 4-membered alkyl or Alka apicauda male, including humans, containing the active ingredient and a pharmaceutically acceptable diluent or carrier, characterized in that it as the active ingredient contains a compound selected from the group comprising (6R,12aR)-2,3,6,7,12,12 and hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2', 1': 6,1]pyrido[3,4-b]indole-1,4-dione and (3S, 6R,12aR)-2,3,6,7,12,12 and hexahydro-2,3-dimethyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2', 1': 6,1] pyrido[3,4-b]indole-1,4-dione and their physiologically acceptable salt and solvate.

7. A method of obtaining a pharmaceutical composition according to p. 5 for the treatment and prevention of erectile dysfunction in mammals, male sex, including man, characterized in that compounds of the formula (I) and its physiologically acceptable salt and solvate administered in pharmaceutically acceptable diluent or carrier selected depending on the route of administration.

8. A method of obtaining a pharmaceutical composition according to p. 6 for the treatment and prevention of erectile dysfunction in mammals, male sex, including man, characterized in that a compound selected from the group comprising (6R, 12aR)-2,3,6,7,12,12 and hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1';6,1]pyrido[3,4-b]indole-1,4-dione and (3S,6R,12aR)-2,3,6,7,12,12 and hexahydro-2,3-dimethyl-6-(3,4-IU the W ill result in a pharmaceutically acceptable diluent or carrier, selected depending on the route of administration.

9. A method of treating male mammal, including humans, to prevent erectile dysfunction, characterized in that it includes the treatment of the above-mentioned male mammal an effective amount of the pharmaceutical composition under item 5 or 6.

10. The pharmaceutical composition under item 5 or 6, having use in the manufacture of medicaments for the treatment or prevention of erectile dysfunction in mammals, including humans.

11. The method according to p. 3, characterized in that the compound of formula (I) is administered through the mouth.

12. Connection on p. 1, characterized in that the compound of formula (I) is administered through the mouth.

13. Connection on p. 1, wherein the sexual dysfunction is dysfunction of orgasm.

 

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The invention relates to new alkaloids of the formula I

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present in various parts of Mappia foetida, and their pharmaceutical use and use them as the new synthons for preparing compounds with antitumor and antiviral activity, the same products are new synthons for new analogues of camptothecin and palidino

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The invention relates to bellrowan-carbolines, formula I, where R3denotes-CO-R1or group (a); R1- C1-C6alkoxy; R2- N2C1-C4alkyl, C1-C4alkoxy - C1-C2alkyl; And -- 5-6-membered unsaturated cycle, in which 1-2 carbon atoms may be replaced by N, O and/or S, which may be substituted with one R5or R6; R5and R6identical or different, denote H, C1-C6alkyl, NR7R8C1-C6alkyl which may be substituted by hydroxyl or C1-C4alkoxyl, phenyl, 5-6-membered heteroaryl residue, which contains one or two atoms of N, O or S, and phenyl and heteroaryl residue may be substituted C1-C4the alkyl, C1-C4alkoxyl, halogen, or R5and R6together,- CH2)nwhere n = 4; R7and R8- H, C1-C4alkyl, acyl, as well as their isomers, tautomers and salts

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