Pyrazolopyrimidinones for the treatment of impotence

 

(57) Abstract:

Proposed new means and method for the treatment or prevention of erectile dysfunction in an animal of the male, including humans, as well as for the treatment or prevention of sexual dysfunction in females. As the first tools used inhibitor of cGMP PDE, for example a compound of General formula I

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where the values of the radicals indicated in the formula or its pharmaceutically acceptable salt, or a pharmaceutical composition containing this compound. The tool specified first destination intended for reception by the patient orally (per os). As a means and method for the treatment or prevention of sexual dysfunction in females the proposed compound of General formula I or its pharmaceutically acceptable salts, or pharmaceutical composition containing this compound. This proposal expands the Arsenal of tools specified destination. 5 S. and 9 C.p. f-crystals.

This invention relates to the use of some pyrazole[4,3-d]pyrimidine-7-ones for the treatment of impotence.

Impotence can be defined literally as a drawback in men force for sexual intercourse and can lead to the inability to achieve penile erection or osobnosti to get or maintain an erection, adequate for sexual intercourse.

Suffer from 2 to 7% of the male population, the percentage increases with age up to 50 years old, ranging from 18 to 75% aged between 55 and 80 years. Only in the USA, for example, there are up to 10 million men impotent, in the majority of suffering rather from organic problems than psychogenic origin.

Reports of well-controlled clinical trials in humans are few, and the effectiveness of oral medication is low. Although a large number of different drugs, as shown, stimulate an erection of the penis, they are effective only after direct injection into the penis, for example intraurethral or intracavernous (I. K.), not shown for erectile dysfunction.

Currently, treatment is based on I. K. introduction vasoactive substances, and good results have been declared with phenoxybenzamine, phentolamine, papaverine and prostaglandin E1 as well as separately and in combination; however, I. K. the introduction of some of these agents are associated pain, priapism and fibrosis of the penis. Potassium channel activators (AS) and vasoactive intestinal polypeptide (BCP) is the same as shown, are active and. to., but the cost and stability of Fiesolana glyceryltrinitrate (GHP) patches, apply to the penis, which, as shown, are effective, but produce side effects as the patient and partner).

As a General alternative to pharmacological intervention used a variety of prosthetic penis to help achieve an erection. The initial results are satisfactory, but problems with infection and ischemia, especially in diabetic men, make this type of treatment is most likely the final choice than the initial therapy.

Compounds according to the invention are potent inhibitors of cyclic guanosine 3',5'-monophosphate phosphodiesterase (cGMP PDE) in contrast to their inhibited cyclic adenosine 3', 5'-monophosphate phosphodiesterase (camp PDE). This selective inhibition of enzymes leads to increased cGMP, which, in turn, provide the basis for features already described for the above-mentioned compounds in EP-A-0463756 and EP-A-0525004, namely in the treatment of stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, heart failure associated with stagnant, atherosclerosis, conditions of reduced extensibility of the blood vessels, for example, after angiol the Dov, stroke, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, and diseases characterized by disorders of gut motility, e.g., inflammatory intestinal syndrome (VCF).

Suddenly now has been discovered that the described compounds are useful in the treatment of erectile dysfunction. In addition, the compounds may be administered orally, thus eliminating the disadvantages associated with I. K. introduction, accordingly, the invention concerns the use of compounds of formula (I):

< / BR>
where R1represents H; C1-C3perfluoroalkyl; or C3-C5cycloalkyl;

R2represents H; C1-C6alkyl, optionally substituted C3-C6cycloalkyl; C1-C3perfluoroalkyl; or C3-C6cycloalkyl;

R3represents a C1-C6alkyl, optionally substituted C3-C6cycloalkyl; C1-C6perfluoroalkyl; C3-C5cycloalkyl; C3-C6alkenyl; or C3-C6quinil;

R4represents a C1-C4alkyl, optionally substituted by OH, NR5R6, CN, CONR5R6or CO2-C4alkanoyl, optionally substituted NR5R6; (hydroxy) C2-C4alkyl, optionally substituted NR5R6; (C2-C3alkoxy) C1-C3alkyl, optionally substituted by OH or NR5R6; CONR5R6; CO2R7; halogen; NR5R6; NHSO2NR5R6; NHSO2R8; SO2NR9R10; or phenyl, pyridyl, pyrimidinyl, imidazolyl,

oxazolyl, thiazolyl, thienyl or triazolyl, any of which is optionally substituted by stands;

R5and R6are each independently H or C1-C4alkyl, or together with the nitrogen atom to which they are attached, form pyrrolidinyl, piperidino, morpholino, 4-N(R11) - piperazinilnom or imidazolidinyl group, where said group is optionally substituted by stands or OH;

R7represents H or C1-C4alkyl;

R8represents a C1-C3alkyl, optionally substituted NR5R6;

R9and R10together with the nitrogen atom to which they are attached, form pyrrolidinyl, piperidino, morpholino or

4-N(R12)-piperazinilnom group, where the>or CONR13R14;

R11represents H; C1-C3alkyl, optionally substituted by phenyl; (hydroxy) C2-C3alkyl; or C1-C4alkanoyl;

R12represents H; C1-C6alkyl, (C1-C3alkoxy) C2-C6alkyl; (hydroxy) C2-C6alkyl; R13R14N) C2-C6alkyl; R13R14NOC) C1-C6alkyl; CONR13R14; CSNR13R14; or C(NH)NR13R14;

R13and R14are each independently H; C1-C4alkyl, (C1-C3alkoxy)C2-C4alkyl; or (hydroxy) C2-C4alkyl;

or their pharmaceutically acceptable salts, or pharmaceutical compositions containing any substance to obtain drugs for the treatment or prophylactic treatment of erectile dysfunction in an animal of the male, including humans.

In the above definition, unless otherwise indicated, alkyl groups having three or more carbon atoms, alkeline and alkyline group having four or more carbon atoms, alkoxy group having three carbon atoms, and alcoholnye groups with BH.

The compounds of formula (I) can contain one or more asymmetric centers, and thus they can exist as enantiomers or diastereoisomers. In addition, certain compounds of formula (I), which contain alkeneamine groups can exist as CIS-isomers or TRANS isomers. In each case, the invention includes both mixtures and separate individual isomers.

The compounds of formula (I) may also exist in tautomeric forms and the invention includes both mixtures and separate individual tautomers.

Pharmaceutically acceptable salts of compounds of formula (I) which contain a basic centre are, for example, non-toxic acid additive salts formed with inorganic acids type hydrochloric, Hydrobromic, sulfuric and phosphoric acids, with organogermanium acids or organosulfur acids.

The compounds of formula (I) can also provide pharmaceutically acceptable metal salts, in particular non-toxic alkali metal salts, with bases. Examples include sodium and potassium salts.

A preferred group of compounds of formula (I) is such that where R1represents H, methyl or e and allyl; R4represents a C1-C2alkyl, optionally substituted by OH, NR5R6, CN, CONR5R6or CO2R7; acetyl, optionally substituted NR5R6; hydroxyethyl, optionally substituted NR5R6; ethoxymethyl, optionally substituted by OH or NR5R6;

CH=CHCN; CH=CHCONR5R6; CH = CHCO2R7; CONR5R6; CO2H; Br; NR5R6; NHSO2NR5R6; NHSO2R8; SO2NR9R10; or pyridyl, or imidazolyl, any of which is optionally substituted by stands; R5and R6are each independently H, methyl or ethyl, or together with the nitrogen atoms to which they are attached, form piperidinyl, morpholino, 4-N(R11) - piperazinilnom or imidazolidinyl group, where said group is optionally substituted by stands or OH; R7represents H or tertbutyl; R8represents methyl or CH2CH2CH2NR5R6; R9and R10together with the nitrogen atom to which they are attached, form piperidinyl or 4-N(R12)-piperazinilnom group, where said group is optionally replaced by NR13R14or CONR13RH, C1-C3alkyl, (hydroxy) C2-C3alkyl, CSNR13R14or C(NH)NR13R14; and R13and R14are each independently H or methyl.

A more preferred group of compounds of formula (I) is such that where R1represents methyl or ethyl; R2represents a C1-C3alkyl; R3represents ethyl, H - propyl or allyl; R4represents CH2NR5R6, COCH2NR5R6CH(OH)CH2NR5R6CH2OCH2CH3CH2OCH2CH2OH,

CH2OCH2CH2NR5R6CH=CHCON(CH3)2CH=CHCO2R7, CONR5R6, CO2H, Br, NHSO2NR5R6,

NHSO2CH2CH2CH2CH2NR5R6, SO2NR9R10, 2-pyridyl, 1-imidazolyl or 1-methyl-2-imidazolyl; R5and R6together with the nitrogen atom to which they are attached, form piperidinyl, 4-hydroxypiperidine, morpholino, 4N(R11) piperazinilnom or 2-methyl-1-imidazolidinyl group; R7represents H or tertbutyl, R9and R10together with the nitrogen atom to which they are attached, form a 4-hydroxyethyl or acetyl, and R12represents H, C1-C3alkyl, 2-hydroxyethyl or CSNH2.

Especially preferred group of compounds of formula (I) is such that where R1represents methyl or ethyl; R2is an H - propyl; R3represents ethyl, H - propyl or allyl; R4is a COCH2NR5R6, CONR5R6,SO2NR9R10or 1-methyl-2-imidazolyl; R5and R6together with the nitrogen atom to which they are attached, form morpholino or 4-N(R11)-piperazinilnom group; R9and R10together with the nitrogen atom to which they are attached, form a 4-N(R12)-piperazinilnom group; R11represents methyl or acetyl; and R12represents H, methyl, 2-propyl or 2-hydroxyethyl.

The most preferred individual compounds of the invention include:

5-(2-ethoxy-5-morpholinoethyl)-1-methyl-3-H-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-7-he;

5-(5-morpholinoethyl-2-H-propoxyphenyl)- 1-methyl-3-H-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-7-he;

5-[2-ethoxy-5-(4-methyl-1-piperazinylcarbonyl)-phenyl] - 1-methyl-3-H-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-7-he;

5-[2-allyloxy-5-�-5-[4-(2-propyl)-1-piperazinylcarbonyl]-phenyl}- 1-methyl-3-H-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-7-he;

5-{ 2-ethoxy-5-[4-(2-hydroxyethyl)-1-piperazinil-sulfonyl] phenyl}-1-methyl-3-H-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-7-he;

5-{ 5-[4-(2-hydroxyethyl)-1-piperazinylcarbonyl]-2-H-propoxyphenyl} 1-methyl-3-H-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-7-he;

5-[2-ethoxy-5-(4-methyl-1-piperazinylcarbonyl)-phenyl] - 1-methyl-3-H-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-7-he;

and 5-[2-ethoxy-5-(1-methyl-2-imidazolyl)phenyl] - 1-methyl-3-H-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-7-he.

The compounds of formula (I) and their pharmaceutically acceptable salts, methods for their preparation, methods of in vitro testing to determine the inhibitory effect on cGMP PDE and camp PDE, their pharmaceutical compositions and routes of administration for human use is described in EP-A-0463756 and EP-A-0526004.

Preliminary studies were undertaken with the purpose of isolation and characterization of cyclic nucleotide PDEs cavernous body, relaxation which leads to erection of penis. The study of substrate specificity, response to activators and sensitivity to inhibitors demonstrated that the cavernous human body contains three different enzyme PDE.

Methods

Fresh frozen human penis was obtained from Pami get about 2-4 g of tissue, and perform allocations, as follows.

Fabric coarsely grind in a cold isotonic buffer, mixed with ice (35 ml) containing 250 mm sucrose, 1 mm EDTA, 0.5 mm PMSF and 20 mm HEPES, pH of 7.2, and the mixture is subjected to a short (1 min) processing mixer/emulsifier Silversen. The homogenates prepared using tubes homogenizer with a Teflon pestle, and the soluble fraction prepared by centrifugation at 100000 g for 60 min at 4oC.

10 ml of high-speed supernatant injected into the anion exchange column, Pharmacia Mono Q (volume gaskets 1 ml), balancing buffer containing 1 mm EDTA, 0.5 mm PMSF and 20 mm HEPES, pH 7,2 (chromatographic buffer). Then the column was washed with 5 volumes of gaskets chromatographic buffer, after which Fdez elute using a continuous gradient of 0 - 500 mm NaCl (total volume of 35 ml), and collect 1 ml fractions.

Fractions from the column test on the activity of PDE using 500 nm cGMP or 500 nm camp as the substrate. The activity of camp PDE also determined in the presence of 1 μm unlabeled cGMP PDE activity of selected fractions determined in the presence of 10 mm CaCl2and 10 u/ml bovine brain of calmoduline. The appropriate fractions are combined and stored at 4oC for 500 nm. All inhibitors dissolved in DMSN (dimethylsulfoxide), and the curves of the concentration dependence of the response are built in range from 3 to 10-10to 1 10-4M as a semi-log increase. The values of the IC50calculated using an S-shaped curve fitting algorithm it includes.

Results

Soluble Fdez cavernous human body is divided into three different fractions activity. First, fraction I (marked in order of elution), represents a large section presents PDE and is highly selective with respect to cGMP as a substrate.

This fraction, as detected, is insensitive to stimulation by calcium/calmoduline and is classified as a PDEv. Fraction II hydrolyzes cGMP and camp with the activity of the latter stimulated in the presence of cGMP, and is classified as a PDEII,while the fraction III is a selective towards the camp, and this activity is inhibited in the presence of cGMP and is compatible with PDEIIIactivity.

To further characterize the PDE isoenzymes present in the fabric, perform learning using a variety of inhibitors. The study of inhibitors with fractions I and II is eriday, what faction I corresponds to the PDEV, while the fraction III clearly identified as PDEIII; fraction II (PDEII) relatively insensitive to all of the studied inhibitors.

As a summary, the above studies have identified three PDE isoenzyme in the tissue of the cavernous body. The predominant PDE is a cGMP-specific PDEValthough cGMP - stimulated cyclic amp PDEIIand cGMP - inhibiting cyclic amp PDEIIIalso present.

Compounds of the invention were investigated in vitro and, as found, are potent and selective inhibitors of cGMP - specific PDEV. For example, one of the most preferred compounds of the invention has the IC50= 6,8 v on the enzyme PDEVbut shows only weak inhibitory activity against the enzyme PDEIIand PDEIIIwith IC50equal to or more than 100 M and 34 M, respectively.

Thus, relaxation of the cavernous tissue of the body and the subsequent erection of the penis, possibly caused by increased levels of cGMP in the above-mentioned tissue, based on the inhibitory based PDE compounds of the invention.

In addition, none of the compounds of the invention tested on blagopriyatnoi acute toxicity. In mice has not occurred deaths after doses up to 100 mg/kg I. C. Certain of the most preferred compounds did not show any toxic effects in chronic receive acting in rats to 10 mg/kg and dogs up to 20 mg/kg

A person certain of the most preferred compounds was tested orally in a single dose and multiple methods of volunteers. In addition, the study patients conducted to date, confirms that one of the most preferred compounds stimulates an erection of the penis in men impotent.

Although compounds of the invention is particularly suited for the treatment of erectile dysfunction or male sexual dysfunction, they can also be used to treat female sexual dysfunction, including dysfunction of orgasm associated with clitoral disorders.

Generally, in humans, the oral intake of the compounds of the invention is the preferred method of use, which is the most convenient and eliminates the inconvenience associated with I. K. introduction. The preferred regimen medicines for the typical person is from 5 to 75 mg connections, three times daily.

In obstacles reception medication may be administered parenterally, for example under the tongue or cheek.

For veterinary use of the compounds of formula (I) or its non-toxic salt is introduced as appropriate acceptable drug in accordance with normal veterinary practice and the veterinary surgeon will determine the dosage and route of administration which will be most appropriate for a particular animal to the male.

Thus, the invention includes a pharmaceutical composition for the treatment or prevention of erectile dysfunction in an animal of the male, including humans, contain a compound of the formula (I) or its pharmaceutically acceptable salt together with a pharmaceutically acceptable diluent or carrier.

Next is provided a method for obtaining a pharmaceutical composition for the treatment or prevention of erectile dysfunction animal-male, including humans, comprising a compound of formula (I) or its pharmaceutically acceptable salt with a pharmaceutically acceptable diluent or carrier.

The invention also provides a method of treating or preventing animals-males, including humans, erectile dysfunction, which includes treatment mentioned immaculately composition, containing this substance.

The invention also includes the use of an inhibitor of cGMP PDE, or its pharmaceutically acceptable salts, or pharmaceutical compositions containing this substance, for oral treatment of erectile dysfunction in humans.

The invention also includes a method of oral treatment or prevention of erectile dysfunction in humans, which includes the oral treatment an effective amount of an inhibitor of cGMP PDE, or its pharmaceutically acceptable salts, or pharmaceutical compositions containing this substance.

In addition, the invention includes the use of an inhibitor of cGMP PDE or its pharmaceutically acceptable salts, or pharmaceutical compositions containing this substance, to obtain medications, oral for the treatment or prevention of erectile dysfunction in humans.

1. The use of the compounds of formula I:

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where R1represents H, C1- C3alkyl, C1- C3perfluoroalkyl or C3- C5cycloalkyl;

R2represents H, C1- C3alkyl, optionally substituted C3- C6cycloalkyl, C1- C3perfluoroalkyl or C3- C6cycloalkyl;

R3-C6perfluoroalkyl or C3- C5cycloalkyl, C3- C6alkenyl or C3- C6quinil;

R4represents a C1- C4alkyl, optionally substituted HE, NR5R6, CN, CONR5R6or CO2R7C2- C4alkenyl, optionally substituted by CN, CONR5R6or CO2R7C2- C4alkanoyl, optionally substituted NR5R6, (hydroxy)C2- C4alkyl, optionally substituted NR5R6, (C2- C3alkoxy)C1- C2alkyl, optionally substituted HE or NR5R6, CONR5R6, CO2R7, halogen, NR5R6, NHSO2NR5R6, NHSO2R8, SO2NR9R10or phenyl, pyridyl, pyrimidinyl, imidazolyl,

oxazolyl, thiazolyl, thienyl or triazolyl, any of which is optionally substituted by stands;

R5and R6are each independently N or C1- C4alkyl, or together with the nitrogen atom to which they are attached, form pyrrolidinyl, piperidino, morpholino, 4-(N(R11)-piperazinilnom or imidazolidinyl group, where said group is optionally substituted Mei C1- C3alkyl, optionally substituted NR5R6;

R9and R10together with the nitrogen atom to which they are attached, form pyrrolidinyl, piperidino, morpholino or 4-N(R12)-piperazinilnom group, where the specified group optionally substituted C1- C4the alkyl, C1- C3alkoxy, NR13R14or CONR13R14;

R11represents H, C1- C3alkyl, optionally substituted phenyl, (hydroxy)C2- C3alkyl or C1- C4alkanoyl;

R12represents H, C1- C6alkyl, (C1- C3alkoxy)C2- C6alkyl, (hydroxy)C2- C6alkyl, (R13R14N)C2- C6alkyl, (R13R14PIC)C1- C6alkyl, NR13R14, CSNR13R14or C(NH)NR13R14;

R13and R14are each independently H, C1- C4alkyl, (C1- C3alkoxy)C2- C4alkyl or (hydroxy)C2- C4alkyl;

or their pharmaceutically acceptable salts, or pharmaceutical compositions containing this compound for the treatment or prevention of erectile dysfunction in animal-male, R1represents H, methyl or ethyl, R2represents a C1- C3alkyl, R3represents a C2- C3alkyl or allyl, R4represents a C1- C2alkyl, optionally substituted HE, NR5R6, CN, CONR5R6or CO2R7, acetyl, optionally substituted NR5R6, hydroxyethyl, optionally substituted NR5R6ethoxymethyl, optionally substituted HE or NR5R6, CH = CHCN, CH = CHCONR5R6CH = CHCO2R7, CONR5R6, CO2H, Br, NR5R6, NHSO2NR5R6, NHSO2R8, SO2NR9R10or pyridyl or imidazolyl, any of which is optionally substituted with stands, R5and R6are each independently H, methyl or ethyl, or together with the nitrogen atom to which they are attached, form piperidinyl, morpholino, 4-N(R11)-piperazinilnom or imidazolidinyl group, where the specified group optionally substituted by stands or HE, R7represents H or tert-butyl, R8represents methyl or CH2-CH2-CH2NR5R6, R9and R10together with the nitrogen atom to which they PR is but substituted NR13R14or CONR13R14; R11represents H, methyl, benzyl, 2-hydroxyethyl or acetyl, R12represents H, C1- C3alkyl, (hydroxy)C2- C3alkyl, CSNR13R14or C(NH)NR13R14, R13and R14are each independently H or methyl.

3. The use of compounds on p. 2, characterized in that the compound of the formula I R1represents methyl or ethyl, R2represents a C1- C3alkyl, R3represents ethyl, N-propyl or allyl, R4represents CH2NR5R6, COCH2NR5R6CH(OH)-CH2NR5R6CH2OCH2CH3CH2-OCH2CH2OH,

CH2OCH2CH2NR5R6CH=CHCON(CH3)2CH=CHCO2R7, CONR5R6, CO2H, Br, NHSO2NR5R6, NHSO2- CH2CH2-CH2NR5R6, SO2NR9R10, 2-pyridyl, 1-imidazolyl or 1-methyl-2-imidazolin, R5and R6together with the nitrogen atom to which they are attached, form piperidinyl, 4-hydroxypiperidine, morpholino, 4-N(R11)-piperazinilnom or 2-methyl-1-imidazolidinyl g is prisoedinneny, form 4-carbamoylbiphenyl or 4-N(R12)-piperazinilnom group; R11represents H, methyl, benzyl, 2-hydroxyethyl or acetyl; and R12represents H, 2-hydroxyethyl, C1- C3alkyl or CSNH2.

4. The use of compounds on p. 3, characterized in that the compound of the formula I R1represents methyl or ethyl; R2represents n-propyl, R3represents ethyl, n-propyl or allyl, R4is a COCH2NR5R6, CONR5R6or SO2NR5R6or 1-methyl-2-imidazolyl, R5and R6together with the nitrogen atom to which they are attached, form morpholino or 4-N(R11)-piperazinilnom group, R9and R10together with the nitrogen atom to which they are attached, form a 4-N(R12)-piperazinilnom group, R11represents methyl or acetyl, R12represents H, methyl, 2-propyl or 2-hydroxyethyl.

5. The use of compounds on p. 4, characterized in that the compound of formula I is chosen from:

5-(2-ethoxy-5-morpholinoethyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-one;

5-(5-morpholinoethyl-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-is,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-one;

5-[2-allyloxy-5-(4-methyl-1-piperazinylcarbonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-one;

5-{ 2-ethoxy-5-[4-(2-propyl)-1-piperazinylcarbonyl]phenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-one;

5-{ 2-ethoxy-5-[4-(2-hydroxyethyl)-1-piperazinylmethyl] -phenyl} -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-one;

5-{ 5-[4-(2-hydroxyethyl)-1-piperazinylcarbonyl]-2-n-propoxyphenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-one;

5-[2-ethoxy-5-(4-methyl-1-piperazinylcarbonyl)-phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-one;

5-[2-ethoxy-5-(1-methyl-2-imidazolyl)phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-one.

6. A method of treating or preventing erectile dysfunction male animal, including man, comprising the introduction of a specified male 5 - 75 mg up to three times per day of the compounds of formula I according to any one of paragraphs.1 to 5, or its pharmaceutically acceptable salts, or pharmaceutical compositions containing this substance.

7. Method oral treatment or prevention of erectile dysfunction in humans, which includes oral introduction to three times a day 5 - 75 mg of inhibitor of cGMP PDE or its pharmaceutically acceptable salientia the compounds of formula I

< / BR>
where R1represents H, C1- C3alkyl, C1- C3perforances or C3- C5cycloalkyl;

R2represents H, C1- C6alkyl, optionally substituted C3- C6cycloalkyl, C1- C3perfluoroalkyl, or C3- C6cycloalkyl;

R3represents a C1- C6alkyl, optionally substituted C3- C6cycloalkyl, C1- C6perfluoroalkyl, or C3- C5cycloalkyl, C3- C6alkenyl, or C3- C6quinil;

R4represents a C1- C4alkyl, optionally substituted HE, NR5R6, CN, CONR5R6or CO2R7C2- C4alkenyl, optionally substituted by CN, CONR5R6or CO2R7C2- C4alkanoyl, optionally substituted NR5R6, (hydroxy)C2- C4alkyl, optionally substituted NR5R6, (C2- C3alkoxy)C1- C2alkyl, optionally substituted HE or NR5R6, CONR5R6, CO2R7, halogen, NR5R6, NHSO2NR5R6, NHSO2R8, SO2NR9R10or vesatile replaced by stands;

R5and R6are each independently N or C1- C4alkyl, or together with the nitrogen atom to which they are attached, form pyrrolidinyl, piperidino, morpholino, 4-(N(R11)-piperazinilnom or imidazolidinyl group, where said group is optionally substituted by stands or HE;

R7represents N or C1- C4alkyl;

R8represents a C1- C3alkyl, optionally substituted NR5R6;

R9and R10together with the nitrogen atom to which they are attached, form pyrrolidinyl, piperidino, morpholino or 4-N(R12)-piperazinilnom group, where the specified group optionally substituted C1- C4the alkyl, C1- C3alkoxy, NR13R14or CONR13R14;

R11represents H, C1- C3alkyl, optionally substituted phenyl, (hydroxy)C2- C3alkyl or C1- C4alkanoyl;

R12represents H, C1- C6alkyl, (C1- C3alkoxy), C2- C6alkyl, (hydroxy)C2- C6alkyl, (R13R14N)C2- C6alkyl, (R13R14PIC)C1- C6Alcoy, each independently H, C1- C4alkyl, (C1- C3alkoxy)C2- C4alkyl; or (hydroxy)C2- C4alkyl;

or their pharmaceutically acceptable salts, or pharmaceutical compositions containing this compound for the treatment or prevention of sexual dysfunction in females.

10. The use of compounds on p. 9, characterized in that the compound of the formula I R1represents H, methyl or ethyl; R2represents a C1- C3alkyl; R3represents a C2- C3alkyl or allyl; R4represents a C1- C2alkyl, optionally substituted HE, NR5R6, CN, CONR5R6or CO2R7, acetyl, optionally substituted NR5R6, hydroxyethyl, optionally substituted NR5R6ethoxymethyl, optionally substituted HE or NR5R6, CH = CHCN, CH = CHCONR5R6CH = CHCO2R7, CONR5R6, CO2H, Br, NR5R6, NHSO2NR5R6, NHSO2R8, SO2NR9R10or pyridyl or imidazolyl, any of which is optionally substituted by stands; R5and R6are each independently H, methyl or ethyl, or together with the atom imidazolidinyl group, where the specified group optionally substituted by stands or HE; R7represents H or tert-butyl; R8represents methyl or CH2CH2CH2NR5R6; R9and R10together with the nitrogen atom to which they are attached, form piperidinyl or 4-N(R12)-piperazinilnom group, where the specified group optionally substituted NR13R14or CONR13R14; R11represents H, methyl, benzyl, 2-hydroxyethyl or acetyl, R12represents H, C1- C3alkyl, (hydroxy)C2- C3alkyl, CSNR13R14or C(NH)NR13R14; R13and R14are each independently H or methyl.

11. The use of compounds on p. 10, characterized in that the compound of the formula I R1represents methyl or ethyl, R2represents a C1- C3alkyl, R3represents ethyl, N-propyl or allyl, R4represents CH2NR5R6, COCH2NR5R6CH(OH)-CH2NR5R6CH2OCH2CH3CH2-OCH2CH2OH,

CH2OCH2CH2NR5R6CH=CHCON(CH3)2CH=CHCO2R7, CONR5NR9R10, 2-pyridyl, 1-imidazolyl or 1-methyl-2-imidazolin, R5and R6together with the nitrogen atom to which they are attached, form piperidinyl, 4-hydroxypiperidine, morpholino, 4-N(R11)-piperazinilnom or 2-methyl-1-imidazolidinyl group, R7represents H or tert-butyl, R9and R10together with the nitrogen atom to which they are attached, form a 4-carbamoylbiphenyl or 4-N(R12)-piperazinilnom group; R11represents H, methyl, benzyl, 2-hydroxyethyl or acetyl; and R12represents H, 2-hydroxyethyl, C1- C3alkyl or CSNH2.

12. The use of compounds on p. 11, characterized in that the compound of the formula I R1represents methyl or ethyl; R2represents n-propyl, R3represents ethyl, n-propyl or allyl, R4is a COCH2NR5R6, CONR5R6or SO2NR5R6or 1-methyl-2-imidazolyl, R5and R6together with the nitrogen atom to which they are attached, form morpholino or 4-N(R11)-piperazinilnom group, R9and R10together with the nitrogen atom to which they are attached, form a 4-N(R12)-Pipa is silt or 2-hydroxyethyl.

13. The use of compounds on p. 12, characterized in that the compound of formula I selected from

5-(2-ethoxy-5-morpholinoethyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-one;

5-(5-morpholinoethyl-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-one;

5-[2-ethoxy-5-(4-methyl-1-piperazinylcarbonyl)phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-one;

5-[2-allyloxy-5-(4-methyl-1-piperazinylcarbonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-one;

5-{ 2-ethoxy-5-[4-(2-propyl)-1-piperazinylcarbonyl]phenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-one;

5-{ 2-ethoxy-5-[4-(2-hydroxyethyl)-1-piperazinylmethyl] -phenyl} -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-one;

5-{ 5-[4-(2-hydroxyethyl)-1-piperazinylcarbonyl]-2-n-propoxyphenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-one;

5-[2-ethoxy-5-(4-methyl-1-piperazinylcarbonyl)-phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-one;

5-[2-ethoxy-5-(1-methyl-2-imidazolyl)phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-one.

14. The method of treatment of a female for the treatment or prevention of sexual dysfunction, which includes wiki acceptable salt, or pharmaceutical compositions containing this substance.

Priority

09.06.93 - PP.1 - 5, 6, 7 - 8,

13.05.94 - PP.9 - 13, 14.

 

Same patents:

The invention relates to new pyrimidine derivative of the formula (I-1) and (I-2), where R1and R5that may be the same or different, independently represent hydrogen or C1-C3alkyl group or, taken together, form cyclopentene or tsiklogeksilnogo ring; a represents a group of formula (II) in which R1and R2represent independently from each other hydrogen or C1-C3alkyl group, and R3represents hydrogen, C1-C3alkyl group or halogen; B is 1-(substituted) -1,2,3,4-tetrahydroisoquinoline-2-yl of the formula (III-1) or 7-(substituted) -4,5,6,7-tetrahydrothieno(2,3-C)-pyridine-6-yl of the formula (III-2), where R6is hydrogen or C1-C3alkyl group, and their pharmaceutically acceptable salts, which have excellent antisecretory activity, to pharmaceutical compositions that contain the specified active ingredient, and a new intermediate compounds and processes for their preparation

The invention relates to substituted derivative asalaam, which is an effective anti-Helicobacter tools that can be used as monotherapy for eradication of Helicobacter pylori and related species

The invention relates to medicine, in particular to the experimental therapy, and for the prevention and treatment of atherosclerosis

The invention relates to new compounds of the formula

< / BR>
to pharmaceutically acceptable additive salts of the acid and stereoisomers of these compounds, which are used as antagonists of mediators and have a high activity against Central nervous system

The invention relates to new nucleoside analogues of 1,3-oxathiolane and their use for treating viral infections, HIV infection, hepatitis b, more specifically to the (-)-4-amino-5-fluoro-1-(2-oxymethyl-1,3-oxathiolan-5-yl)-(1H )-pyrimidine-2-ONU (I) and its pharmaceutically acceptable derivative containing pharmaceutical compositions

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an intermediate compound, i. e. tert.-butyl-(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidine-5-yl}-(4R,6S)-2,2-dimethyl[1,3]dioxane-4-yl]acetate that can be used in synthesis of compound of the formula (IV)

eliciting inhibitory effect on activity of HMG-CoA-reductase and, therefore, can be used for preparing pharmaceutical agents for treatment, for example, hypercholesterolemia, hyperproteinemia and atherosclerosis. Also, invention relates to a method for preparing indicated intermediate compound by reaction of the new parent compound - diphenyl-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine-5-ylmethyl]phosphine oxide with tert.-butyl-2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4-yl]acetate in the presence of a strong base in simple ether or aromatic solvents or their mixtures at temperature in the range from -200C to -900C. Also, invention relates to a method for preparing of compound of the formula (IV) wherein R1 means hydrogen atom or pharmaceutically acceptable cation and to a method for preparing intermediate compounds of the formula (VI):

wherein each P1 and P2 represents independently (C1-C4)-alkyl or group:

and wherein P3 represents (C1-C8)-alkyl. Applying new intermediate compounds and proposed methods provide enhancing quality and yield of compounds.

EFFECT: improved preparing methods.

9 cl, 1 tbl, 8 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 5-phenylpyrimidine or their pharmaceutically acceptable acid-additive salts that elicit properties of antagonists of neuropeptide receptor neurokinin-1 (NK-1). This allows their applying for treatment of such diseases as Alzheimer's disease, cerebrospinal sclerosis, attenuating syndrome in morphine withdrawal, cardiovascular alterations and so on. Compounds of invention correspond to the general formula (I):

wherein R1 means hydrogen or halogen; R2 means hydrogen, halogen atom, (lower)-alkyl or (lower)-alkoxy-group; R3 means halogen atom, trifluoromethyl group, (lower)-alkoxy-group or (lower)-alkyl; R4/R4' mean independently hydrogen atom or (lower)-alkyl; R5 means (lower)-alkyl, (lower)-alkoxy-group, amino-group, hydroxyl group, hydroxy-(lower)-alkyl, -(CH2)n-piperazinyl substituted optionally with lower alkyl, -(CH)n-morpholinyl, -(CH2)n+1-imidazolyl, -O-(CH2)n+1-morpholinyl, -O-(CH2)n+1-piperidinyl, (lower)-alkylsulfanyl, (lower)-alkylsulfonyl, benzylamino-group, -NH-(CH2)n+1N(R4'')2, -(CH2)n-NH-(CH2)n+1N(R4'')2, -(CH2)n+1N(R4'')2 or -O-(CH2)n+1N(R4'')2 wherein R4'' means hydrogen atom or (lower)-alkyl; R6 means hydrogen atom; R2 and R6 or R1 and R6 in common with two ring carbon atoms can represent -CH=CH-CH=CH- under condition that n for R1 is 1; n means independently 0-2; X means -C(O)N(R4'')- or -N(R4'')C(O)-. Also, invention relates to a pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds.

15 cl, 4 sch, 86 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention describes a method for preparing 1,3-oxathiolan nucleosides or a method for preparing derivatives of 1,3-oxathiolanyl-5-one that involve effective methods for formation of 1,3-oxathiolan ring followed by condensation of 1,3-oxathiolan with pyrimidine or purine base. Using indicated methods these compounds can be synthesized as separate enantiomers with high selectivity.

EFFECT: improved preparing methods.

27 cl, 3 dwg, 16 ex

FIELD: medicine.

SUBSTANCE: method involves administering typical neuroleptics according to titration scheme and tricyclic antidepressants. Neuroleptics are applied according to titration scheme in the morning and tricyclic antidepressants are introduced as intravenous drop-by-drop infusion in the evening in combination with per os application of atypic neuroleptic risperidon. After having given 12-14 intravenous infusions, strategic supporting risperidon psychopharmacotherapy in combination with tricyclic antidepressants during 4-6 months.

EFFECT: enhanced effectiveness in overcoming pharmacological resistance; accelerated schizo-affective syndrome relief.

FIELD: medicine.

SUBSTANCE: method involves applying eradicative anti-helicobacterial therapy comprising Omeprazol administration at a dose of 20 mg twice a day and Ximedone at a dose of 500 mg twice a day in 12 days long course.

EFFECT: enhanced effectiveness of eradication; reduced adverse side effects risk.

FIELD: organic chemistry, medicine, pharmacy, pharmacotherapy.

SUBSTANCE: method involves administration in mammal the effective dose of 6-hydroxy-8-[4[4-(2-pyrimidinyl)piperazinyl]butyl]-8-azaspiro[4,5]-7,9-dione or its pharmaceutically acceptable salt of acid addition or its hydrate. Method expands arsenal of medicinal agents used for suppression of fear sensation.

EFFECT: valuable properties of agent.

3 tbl, 6 dwg, 4 ex

FIELD: medicine, narcology.

SUBSTANCE: invention relates to hepatoprotective and anti-encephalopathic agent used for reducing alcoholic intoxication. Invention comprises components based on succinic, fumaric, glutamic acids and, additionally, at least one vitamin of B group. Agent can comprise additionally vegetable extracts or their mixture, L-carnitine, glycine, L-arginine, taurine and/or their mixture, methylsulfonylmethane, dihydroquercitin, dimethylsulfoxide or their mixture, nicotinamide or nicotinic acid or their mixture, energy source and sweetening agent. Also, invention proposes a method for reducing alcoholic intoxication, prophylaxis and removing withdrawal syndrome, liver protection, among them, in non-alcoholic intoxication and protection against encephalopathy. Invention provides described effects without qualifying medical control.

EFFECT: valuable medicinal properties of agent.

16 cl, 3 tbl

FIELD: organic chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention describes bicyclical nitrogen-containing heterocycles of the general formula (I): , wherein R1 means hydrogen atom, (C1-C7)-alkyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkyl, pyridyl, naphthyl, furyl-(C1-C4)-alkyl, phenyl optionally substituted with di-(C1-C7)-alkylamino-(C1-C7)-group, halogen atom, (C1-C7)-alkoxy-group or hydroxy-(C1-C7)-alkyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxy-group, amino-(C1-C7)-alkyl, amino-group or di-(C1-C7)-alkylamino-(C1-C7)-alkoxy-group; R2 means (C1-C7)-alkyl, (C3-C7)-cycloalkyl, furyl-(C1-C4)-alkyl, pyridyl or its N-oxide; phenyl optionally substituted with halogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-group, hydroxy-group or trifluoromethyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxy-group; R3 means hydrogen atom, (C1-C7)-alkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkyl, (C3-C7)-cycloalkenyl, pyridyl-(C1-C4)-alkyl, naphthyl, phenyl optionally substituted with phthalimido-(C1-C4)-alkyl, amino-(C1-C7)-alkyl, hydroxy-(C1-C7)-alkyl, (C1-C7)-alkylamino-(C1-C7)-alkyl, di-(C1-C7)-alkylamino-(C1-C7)-alkyl, morpholino-(C1-C4)-alkyl or piperazinyl-(C1-C4)-alkyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxycarbonyl or carboxy-group. Also, invention relates to pharmaceutically acceptable salts of compounds of the formula (I) as a base with acids or pharmaceutically acceptable salts of compounds of the formula (I) as acid with bases, and pharmaceutical composition based on thereof. Compounds described above show inhibitory activity with respect to tyrosine kinase and can be used in treatment or prophylaxis of inflammatory, immunological, oncological, bronchopulmonary, dermatological and cardiovascular diseases, for treatment of asthma, disorders in the central nervous system or complications associated with diabetes mellitus, or for prophylaxis against transplant rejection after surgery transplantation.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 1 tbl, 92 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention concerns a pharmaceutical composition eliciting hepatoprotective effect. The base of pharmaceutical composition comprises adducts of orotic acid with amino acids or amines as an active substance. The composition comprises effective amount of active substance and special additives in the following ratio of active substance and special additives, wt.-%: active substance, 0.05-40.0; special additives, 60.0-99.95. As special additives the composition comprises starch, mixture of vitamins, lactose, aerosil, talc, stearates, polyvinylpyrrolidone, solid confectionary fat, Tween-80, polyethylene glycol, glycerol, citric acid, benzoic acid, sodium benzoate, correcting dye-substances. Compositions are made as tablets, capsules, lozenges, suppositories, syrups. Also, invention proposes a medicinal agent comprising above said pharmaceutical composition. Invention provides high pharmaco-therapeutical effect with fitness period 2 years, not less.

EFFECT: improved and valuable pharmaceutical properties of composition.

9 cl, 6 tbl, 8 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyanoaryl (or cyanoheteroaryl)-carbonylpiperazinyl-pyrimidines of the general formula and their physiologically acceptable salts that elicit the broad spectrum of biological activity exceeding activity of structurally related known compounds. In the general formula (I) R1 represents radical OR3 wherein R3 represents saturated hydrocarbon radical with linear or branched chain and comprising from 1 to 4 carbon atoms; R2 represents phenyl radical substituted with cyano-radical (-C≡N) or radical representing 5- or 6-membered heteroaromatic ring wherein heteroatom is taken among oxygen (O), nitrogen (N) or sulfur (S) atom and substituted with cyano-radical (-C≡N). Also, invention relates to methods for preparing compounds of the general formula (I) that involve incorporation of group of the formula:

into piperazinyl-pyrimidine compound or by the condensation reaction of corresponding pyrimidine with piperazine comprising group of the formula:

. Also, invention relates to pharmaceutical composition and applying these compounds. Compounds can be used for preparing medicinal agents useful in human therapy and/or for therapeutic applying in veterinary science as agents eliciting ant-convulsive and soporific effect or for the general anesthesia.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

13 cl, 7 sch, 8 tbl, 41 ex

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