Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/415—1,2-Diazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/415—1,2-Diazoles
  • A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence

Definitions

• the invention relates to the use of compounds of the formula I.
• Benzyl, unsubstituted or single, double or triple by shark NO 2 , CN, COOH, CONH 2 , CONHA, CONAA ', NH 2 , NH-CO-A, NH-SO 2 A, NA-SO 2 A' , NH-CO-OA, SO 3 H, SO 2 NH-CO-A, SO 2 NR 4 R 5 , CO-NHSO 3 H, CO-NHSO 2 A, tetrazolyl or PO 3 H substituted phenyl or
• R 2 A alkoxy-CO-alkylene, HO-CO-alkylene or HO-alkylene
• R 4 , R 5 each independently of one another H or A,
• R 4 and R 5 together also represent a saturated, wholly or partly unsaturated, Q-saturated 4- to 5-membered alkylene chain in which 1 to 3 C-
• Atoms can be replaced by N and / or 1 to 2 C atoms by 1 to 2 O and / or 1 to 2 S atoms,
• DE 195 18 082 already describes the pyrazol-3-one derivatives claimed here in accordance with the second medical indication.
• the disclosure made in DE 195 18 082 is hereby incorporated into the present invention by indicating the file number with its entire content.
• the use of these compounds as selective inhibitors of cGMP-specific phosphodiesterase for the manufacture of a medicament for the treatment of diseases of the cardiovascular system is disclosed.
• substituted pyrazolopyrimidinones for the treatment of impotence is e.g. described in WO 94/28902.
• the biological activity of the compounds of the formula I can be determined by methods such as are described, for example, in WO 93/06104.
• the affinity of the compounds according to the invention for cGMP and cAMP phosphodiesterase is determined by determining their IC 50 values (concentration of the inhibitor which is required in order to achieve a 50% inhibition of the enzyme activity).
• Enzymes isolated according to known methods can be used to carry out the determinations (for example WJ Thompson et al., Biochem. 1971, 0, 311).
• a modified "batch" method by WJ Thompson and MM Appleman can be used to carry out the experiments.
• the compounds are particularly effective as inhibitors of phenylephrine-induced contractions in corpus cavernosum preparations of rabbits. This effect can be demonstrated, for example, using the method described by F. Holmquist et al. in J. Urol., 15J), 1310-1315 (1993).
• the compounds of formula I can be used as active pharmaceutical ingredients in human and veterinary medicine.
• a and A ' preferably each independently represent alkyl having 1-6 C atoms.
• alkyl is preferably unbranched and has 1, 2, 3, 4, 5 or 6 carbon atoms, preferably 1, 2, 3, 4 or 5 carbon atoms and is preferably methyl, ethyl or propyl, more preferably iso propyl, butyl, isobutyl, sec-butyl or tert-butyl, but also n-pentyl, neo-
• A also preferably denotes trifluoromethyl or pentafluoroethyl.
• Alkylene is preferably unbranched and preferably means methylene
• Ethylene, propylene, butylene or pentylene Ethylene, propylene, butylene or pentylene.
• Alkoxy preferably means methoxy, ethoxy, propoxy, butoxy, pentoxy or hexyloxy.
• the invention relates in particular to the use of those compounds of the formula I in which at least one of the said radicals has one of the preferred meanings indicated above.
• Some preferred groups of compounds can be expressed by the following sub-formulas Ia to Id, which correspond to the formula I and in which the radicals not specified have the meaning given for the formula I, but in which
• R 2 A alkoxy-CO-alkylene or HO-alkylene
• R 4 , R 5 each independently of one another H or A, R 4 and R 5 together also a saturated, completely or partially unsaturated 4- to 5-membered alkylene chain in which 1 to
• C atoms can be replaced by N and / or 1 to 2 C atoms by 1 to 2 O and / or 1 to 2 S atoms, A, A 'each independently of one another alkyl having 1 to 6 C atoms, where 1 to 7 H atoms can be substituted by F and / or Cl atoms,
• R 1 unsubstituted or simply substituted by alkoxy, unsubstituted or single, double or triple by shark, NO 2 , CN, COOH, CONH 2 , CONHA,
• CONAA ' NH 2 , NH-CO-A, NH-SO 2 A, NA-SO 2 A, NH-CO-OA, SO 3 H, SO 2 NH-CO-A, SO 2 NR 4 R 5 , CO-NHSO 3 H, CO-NHSO 2 A or tetrazolyl substituted phenyl or pyridyl, R 2 A, alkoxy-CO -alkylene or HO-alkylene, R 3 A or alkoxy,
• R 4 , R 5 each independently of one another H or A, A, A 'each independently of one another alkyl having 1 to 6 C atoms, where 1 to 7 H atoms can be substituted by F and / or Cl atoms, Hai F , Cl, Br or I mean;
• R 1 unsubstituted or monosubstituted by alkoxy, unsubstituted or mono-, di- or trisubstituted by shark, NO 2 , CN, COOH, CONH 2 , CONHA, CONAA ', NH 2 , NH-CO-A, NH -SO 2 A, NA-SO 2 A ',
• R 4 and R 5 together form a saturated, completely or partially unsaturated 4- to 5-membered alkylene chain, in which 1 to 3 carbon atoms are represented by N and / or 1 to 2 carbon atoms by 1 to 2 O and / or 1 up to 2 S atoms can be replaced, A, A 'each independently of one another alkyl having 1 to 6 carbon atoms
• Atoms where 1 to 7 H atoms can be substituted by F and / or Cl atoms, mean Shark F, Cl, Br or I;
• R 2 A alkoxy-CO-alkylene or HO-alkylene
• R 3 A alkoxy
• R 4 , R 5 each independently of one another H or A,
• R 4 and R 5 together also -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -,
• Atoms where 1 to 7 H atoms can be substituted by F and / or Cl atoms,
• the invention furthermore relates to the use of the compounds of the formula I and / or their physiologically acceptable salts for the production of pharmaceutical preparations, in particular by a non-chemical route. They can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or auxiliary and, if appropriate, in combination with one or more further active ingredients.
• the invention further relates to the use of the compounds of the formula I and / or their physiologically acceptable salts for the production of a medicament for the treatment and / or therapy of potent disorders.
• the invention further relates to pharmaceutical preparations for the treatment and / or therapy of potent disorders, comprising at least one compound of the formula I and / or one of its physiologically acceptable salts.
• the invention also relates to the use of a pharmaceutical preparation containing at least one compound of the formula I and / or at least one of its physiologically acceptable salts for the treatment and therapy of erectile dysfunction.
• Suitable carriers are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical application and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate , Gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, petroleum jelly.
• Tablets, pills, dragees, capsules, powders, granules, syrups, juices or drops are used for oral use, suppositories for rectal application, solutions, preferably oily or aqueous solutions, and also suspensions, emulsions or implants for parenteral use topical application ointments, creams or powder.
• the new compounds can also be lyophilized and the lyophilizates obtained used, for example, for the production of injectables.
• the specified preparations can be sterilized and / or contain auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, flavoring and / or several other active substances, for example one or more vitamins.
• auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, flavoring and / or several other active substances, for example one or more vitamins.
• the compounds of the formula I and their physiologically acceptable salts can be used in combating diseases in which an increase in the cGMP (cyclo-guanosine monophosphate) level leads to inhibition or prevention of inflammation and muscle relaxation.
• the compounds according to the invention can be used particularly in the treatment of diseases of the cardiovascular system and for the treatment and therapy of erectile dysfunction.
• the substances are generally preferably administered in doses between about 1 and 500 mg, in particular between 5 and 100 mg, per dosage unit.
• the daily dosage is preferably between about 0.02 and 10 mg / kg body weight.
• the specific dose for each patient depends on a wide variety of factors, for example on the effectiveness of the particular compound used, on the age, body weight, general health, sex, on the diet, on the time and route of administration, on the rate of excretion and combination of drugs and severity of the respective disease to which the therapy applies. Oral application is preferred.
• the pharmacological data demonstrate the inhibitory activity of the compounds of the formula I and their effectiveness in the therapy and / or for the treatment of erectile dysfunction.
• Example A Injection glasses
• a solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate is adjusted to pH 6.5 in 3 l of double-distilled water with 2N hydrochloric acid, sterile filtered, filled into injection glasses, lyophilized under sterile conditions and sealed sterile. Each injection glass contains 5 mg of active ingredient.
• a mixture of 20 g of an active ingredient of the formula I is melted with 100 g of soy lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.
• a solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g of NaH 2 PO 4 .2H 2 O, 28.48 g of Na 2 HPO 4 .12H 2 O and 0.1 g of benzalkonium chloride in 940 ml of double distilled water. It is adjusted to pH 6.8, made up to 1 I and sterilized by irradiation. This solution can be used in the form of eye drops.
• Example D ointment
• 500 mg of an active ingredient of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.
• Example E tablets A mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1, 2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed into tablets in a conventional manner such that each tablet contains 10 mg of active ingredient.
• Example F coated tablets
• Example E tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.
• Example G capsules
• each capsule contains 20 mg of the active ingredient.
• a solution of 1 kg of active ingredient of the formula I in 60 l of double-distilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed sterile. Each ampoule contains 10 mg of active ingredient.

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• Health & Medical Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Medicinal Chemistry (AREA)
• Epidemiology (AREA)
• Reproductive Health (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Endocrinology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Gynecology & Obstetrics (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)

Applications Claiming Priority (3)

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• 1996
  • 1996-10-14 DE DE19642284A patent/DE19642284A1/de not_active Withdrawn
• 1997
  • 1997-10-08 JP JP10517987A patent/JP2001501958A/ja active Pending
  • 1997-10-08 CA CA002268823A patent/CA2268823A1/en not_active Abandoned
  • 1997-10-08 EP EP97912141A patent/EP0930881A1/de not_active Withdrawn
  • 1997-10-08 PL PL97332821A patent/PL332821A1/xx unknown
  • 1997-10-08 HU HU0000233A patent/HUP0000233A3/hu unknown
  • 1997-10-08 BR BR9712307-2A patent/BR9712307A/pt not_active Application Discontinuation
  • 1997-10-08 WO PCT/EP1997/005532 patent/WO1998016224A1/de not_active Application Discontinuation
  • 1997-10-08 AU AU49452/97A patent/AU4945297A/en not_active Abandoned
  • 1997-10-08 KR KR1019990703161A patent/KR20000049086A/ko not_active Application Discontinuation
  • 1997-10-08 CN CN97198764A patent/CN1233178A/zh active Pending
  • 1997-10-13 ZA ZA9709151A patent/ZA979151B/xx unknown
  • 1997-10-14 AR ARP970104715A patent/AR008494A1/es unknown
• 1999
  • 1999-04-13 NO NO991734A patent/NO991734L/no unknown

Non-Patent Citations (1)

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