EP1343506A1 - Pharmazeutische formulierung enthaltend pyrazolo 4,3-d]pyrimidine und antithrombotica, calcium-antagonisten, prostaglandine oder prostaglandinderivate - Google Patents

Pharmazeutische formulierung enthaltend pyrazolo 4,3-d]pyrimidine und antithrombotica, calcium-antagonisten, prostaglandine oder prostaglandinderivate

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Publication number
EP1343506A1
EP1343506A1 EP01990452A EP01990452A EP1343506A1 EP 1343506 A1 EP1343506 A1 EP 1343506A1 EP 01990452 A EP01990452 A EP 01990452A EP 01990452 A EP01990452 A EP 01990452A EP 1343506 A1 EP1343506 A1 EP 1343506A1
Authority
EP
European Patent Office
Prior art keywords
atoms
pharmaceutical formulation
methyl
pyrazolo
pyrimidin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01990452A
Other languages
German (de)
English (en)
French (fr)
Inventor
Hans-Michael Eggenweiler
Volker Eiermann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Patent GmbH
Original Assignee
Merck Patent GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from DE10063224A external-priority patent/DE10063224A1/de
Priority claimed from DE2000163882 external-priority patent/DE10063882A1/de
Priority claimed from DE2000164993 external-priority patent/DE10064993A1/de
Application filed by Merck Patent GmbH filed Critical Merck Patent GmbH
Publication of EP1343506A1 publication Critical patent/EP1343506A1/de
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • Antagonists are antagonists, prostaglandins or prostaglandin derivatives
  • the invention relates to pharmaceutical formulations containing at least one phosphodiesterase V inhibitor and / or its physiologically acceptable salts and / or solvates and at least one antithrombotic agent.
  • the invention particularly relates to pharmaceutical formulations containing at least one compound of the formula I.
  • R ⁇ R 2 each independently of one another H, A, OH, OA or shark,
  • R and R 2 together also alkylene with 3-5 C atoms
  • R 3 , R 4 each independently of one another H or A, X simply substituted by R 8, R 5 , R 6 or R 7 ,
  • R ° linear or branched alkylene with 1-10 C atoms, in which one or two CH 2 groups are represented by -CH CH-
  • R b cycloalkyl or cycloalkylalkylene with 5-12 C atoms
  • R 8 COOH, COOA, CONH 2 , CONHA, CON (A) 2 or CN,
  • the invention further relates to the use of the formulation for the manufacture of a medicament for the treatment of angina, high blood pressure, pulmonary high pressure, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), cor pulmonale, right heart failure, atherosclerosis, conditions of reduced patency of the cardiovascular, peripheral vascular diseases, stroke, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumors, renal failure, cirrhosis of the liver and for the treatment of female sexual disorders.
  • CHF congestive heart failure
  • COPD chronic obstructive pulmonary disease
  • cor pulmonale right heart failure
  • atherosclerosis conditions of reduced patency of the cardiovascular
  • peripheral vascular diseases stroke, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumors, renal failure, cirrhosis of the liver and for the treatment of female sexual disorders.
  • PDE V phosphodiesterase V
  • Pyrimidine derivatives are known for example from EP 201 188 or WO 93/06104.
  • PDE V inhibitors The use of other PDE V inhibitors is described e.g. in WO 94/28902.
  • Pneumology (54, Suppl. 1, S42, 2000) is described by R. Schermuly et al. the influence of PDE V inhibition on prostacyclin-induced vaso-relaxation in experimental pulmonary hypertension has been described.
  • the invention was based on the object of providing new medicaments in the form of pharmaceutical preparations which have better properties than known medicaments which can be used for the same purposes.
  • the compounds of formula I and their salts show very valuable pharmacological properties with good tolerability. In particular, they show a specific inhibition of cGMP phosphodiesterase (PDE V).
  • 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, 10, 311).
  • a modified "batch" method by WJ Thompson and MM Appleman can be used to carry out the experiments.
  • the compounds are therefore suitable for the treatment of diseases of the cardiovascular system, in particular heart failure and for the treatment and / or therapy of erectile dysfunction.
  • substituted pyrazolopyrimidinones for the treatment of impotence is e.g. described in WO 94/28902.
  • the compounds are effective as inhibitors of phenylephrine-induced contractions in corpus cavernosum preparations from rabbits.
  • This biological effect can e.g. can be detected by the method described by F. Holmquist et al. in J. Ural., 150, 1310-1315 (1993).
  • the inhibition of the contraction shows the effectiveness of the compounds according to the invention for the therapy and / or treatment of erectile dysfunction.
  • the compounds of formula I can be used as active pharmaceutical ingredients in human and veterinary medicine. They can also be used as intermediates for the production of further active pharmaceutical ingredients.
  • R ⁇ 3, R and X have the meanings given
  • L denotes CI, Br, OH, SCH 3 or a reactive esterified OH group
  • R 1 and R 2 have the meanings given
  • Convert X by, for example, hydrolyzing an ester group to a COOH group or converting a COOH group to an amide or a cyan group and / or that a compound of the formula I is converted into one of its salts.
  • the invention also relates to the use of all optically active forms (stereoisomers), the enantiomers, the racemates, the diastereomers and the hydrates and solvates of the compounds.
  • Solvates of the compounds of the formula I are understood to mean the addition of inert solvent molecules to the compounds of the formula I, which are formed on account of their mutual attraction. Solvates are e.g. Mono- or dihydrates or alcoholates.
  • radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X and L have the meanings given in the formulas I, II and III, unless 5 expressly something else is specified.
  • A means alkyl with 1-6 C atoms.
  • alkyl is preferably unbranched and has 1, 2, 3, 4, 5 or 6 carbon atoms and is preferably methyl, ethyl or Q propyl, more preferably isopropyl, butyl, isobutyl, sec-butyl or tert.- Butyl, but also n-pentyl, neopentyl, isopentyl or hexyl.
  • X denotes an R 5 , R 6 or R 7 radical which is simply substituted by R 7 .
  • R 5 denotes a linear or branched alkylene radical with 1-10 C-
  • the alkylene radical preferably being, for example, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene, 1-, 2- or 3-methylbutylene, 1, 1-, 1, 2- or 2, 2-dimethylpropylene, 1-ethylpropylene, hexylene, 1-, 2-, 3- or 4-methylpentylene, 1, 1-, 1, 2-, 1, 3-, 2,2-, 2,3- o- Q.
  • R 5 also means, for example, but-2-en-ylene or hex-3-en-ylene.
  • a CH 2 group in R 5 can preferably be replaced by oxygen.
  • ⁇ Ethylene, propylene, butylene or CH 2 -0-CH 2 is very particularly preferred.
  • R 6 denotes cycloalkylalkylene with 5-12 C atoms, preferably for example cyclopentylmethylene, cyclohexylmethylene, cyclohexylethylene, cyclohexylpropylene or cyclohexylbutylene.
  • R 6 also means cycloalkyl, preferably having 5-7 carbon atoms.
  • Cycloalkyl means, for example, cyclopentyl, cyclohexyl or cycloheptyl.
  • Shark preferably means F, CI or Br, but also I.
  • the radicals R and R 2 can be the same or different and are preferably in the 3- or 4-position of the phenyl ring. They each mean, for example, in each case independently of one another H, alkyl, OH, F, CI, Br or I or together alkylene, such as, for example, propylene, butylene or pentylene, furthermore et ylenoxy, methylenedioxy or ethylenedioxy. They are also preferably each alkoxy, such as methoxy, ethoxy or propoxy.
  • the radical R 8 is preferably, for example, COOH, COOA, such as COOCH 3 or COOC2H5, CONH2, CON (CH 3 ) 2 , CONHCH3 or CN, but in particular COOH or COOA.
  • antithrombotics also includes so-called anticoagulants and antiplatelet agents (platelet aggregation inhibitors).
  • the invention relates in particular to pharmaceutical formulations containing an antithrombotic, a calcium antagonist or a prostaglandin or prostaglandin derivative and at least one compound of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above.
  • Some preferred groups of compounds can be expressed by the following sub-formulas Ia to If, which correspond to the formula I and in which the radicals which are not specified have the meaning given for the formula I, but in which in la X by COOH, COOA, CONH 2 , CONA 2 , CONHA or
  • C CN denotes substituted S 5 , phenyl or phenylmethyl
  • CN denotes R 5 , phenyl or phenylmethyl
  • R 1 , R 2 each independently of one another H, A, OH, OA or
  • R 1 and R 2 together also alkylene with 3-5 C atoms, -O-CH 2 -CH 2 -, -O-CH 2 -O- or -0-CH 2 -CH 2 -0,
  • CN is substituted R 5 , phenyl or phenylmethyl
  • R 1 , R 2 each independently of one another H, A, OH, OA or
  • R 1 and R 2 together also alkylene with 3-5 C atoms, -0-CH 2 -CH 2 -, -O-CH 2 -O- or -O-CH 2 -CH 2 -O-, X alkylene substituted by R 8 with 2-5 C-
  • R 4 alkyl with 1-6 C atoms
  • R 8 COOH or COOA, A alkyl with 1 to 6 carbon atoms,
  • R 1 , R 2 each independently of one another H, A, OH, OA or
  • R 3 alkyl with 1-6 C atoms
  • R 4 alkyl with 1-6 C atoms
  • R 1 , R 2 each independently of one another H, A, OH, OA or
  • R 1 and R 2 together also alkylene with 3-5 C atoms
  • R 3 alkyl with 1-6 C atoms
  • R 4 alkyl with 1-6 C atoms
  • the invention preferably relates to a formulation comprising [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1 H-pyrazolo [4,3-d] pyrimidin-5-ylmethoxy] acetic acid as well as its physiologically acceptable salts and / or solvates and an antithrombotic.
  • the ethanolamine salt is preferred.
  • Preferred antithrombotics are vitamin K antagonists, heparin compounds, platelet aggregation inhibitors, enzymes, factor Xa inhibitors, factor VIIa inhibitors and other antithrombotic agents.
  • Preferred vitamin K antagonists are selected from the group dicoumarol, phenindione, warfarin, phenprocoumon, acenocoumarol, ethyl biscoumacetate, clorindione, diphenadione, tioclomarol.
  • Preferred heparin compounds are selected from the group heparin, antithrombin III, dalteparin, enoxaparin, nadroparin, parnaparin, reviparin, danaparoid, tinzaparin, sulodexide.
  • Preferred platelet aggregation inhibitors are selected from the group ditazole, cloricromene, picotamide, clopidogrel, ticlopidine, acetylsalicylic acid, dipyridamole, calcium carbassalate, epoprostenol, indobufen, lloprost, abciximab, tirofiban, aloxiprin, intrif.
  • Preferred enzymes are selected from the group streptokinase, alteplase, anistreplase, urokinase, fibrinolysin, brinase, reteplase, saruplase.
  • Preferred antithrombotics are also the platelet glycoprotein receptor (IIb / IIla) antagonists which inhibit platelet aggregation.
  • IIb / IIla platelet glycoprotein receptor
  • Preferred compounds are e.g. described in EP 0 623 615 B1 on page 2 or in EP 0 741 133 A2 page 2, line 2 to page 4 line 56.
  • Preferred factor Xa and VIIa inhibitors are e.g. a) the compounds of the formula described in WO 9916751
  • R ⁇ H, A, OR 6 , N (R 6 ) 2 , N0 2> CN, shark, NHCOA, NHCOAr, NHS0 2 A, NHS0 2 Ar, COOR 6 , CON (R 6 ) 2 , CONHAr, COR 6 , COAr, S (0) n A or S (0) n Ar, R 3 A, cycloalkyl, - [C (R 6 ) 2 ] n Ar, - [C (R 6 ) 2 ] n -0-Ar, - [C (R 6 ) 2 ] n Het or -C (R 6 ) 2 C (R 6 ) 2 -Ar .
  • X is missing, -CO-, -C (R 6 ) 2 -, -C (R 6 ) 2 -C (R 6 ) 2 -, -C (R 6 ) 2 -CO-,
  • R ⁇ H, A, OR 5 , N (R 5 ) 2 , N0 2 , CN, shark, NR 5 COA, NHCOAr,
  • R 4 A cycloalkyl, - [C (R 5 ) 2 ] m Ar, - [C (R 5 ) 2 ] m Het or
  • R 5 is H, A or benzyl
  • W is a bond, -S0 2 -, -CO-, -COO- or -CONR 5 -, A alkyl with 1-20 C-atoms, in which one or two CH2-
  • N0 2 , NHCOA, NHCOAr 'and / or carbonyl oxygen substituted saturated or unsaturated heterocyclic ring system which has one, two, three or four identical or different heteroatoms such as nitrogen,
  • Ar unsubstituted or single, double or triple by A, Ar ', OR 6 , OAr', N (R 6 ) 2) N0 2 , CN, Hai, NHCOA, NHCOAr ', NHS0 2 A, NHS0 2 Ar ⁇ COOR 6 , CON (R 6 ) 2 , CONHAr ', COR 6 , COAr', S (0) n A or S (0) n Ar 'substituted phenyl or naphthyl,
  • R, R 1 are each independently H, A, - (CH) mR, - (CH 2 ) m -OA or - (CH 2 ) m-Ar,
  • R 3 ares
  • X is absent, alkylene with 1 -4 C atoms or carbonyl
  • Y is missing, NH, O or S,
  • RH unbranched or branched alkyl with 1-6 C-
  • Ar, Ar ' are each independently of one another unsubstituted or mono-, di- or triple by R, OH, Hai, CN, NO 2 , CF 3 , NH 2 , NHR, NR 2 , pyrrolidin-1-yl, piperidin-1-yl , Benzyloxy, S0 2 NH 2 , S0 2 NHR, S0 2 NR 2> -CONHR, -CONR 2 , - (CH 2 ) n -NH 2 , - (CH 2 ) n -NHR, - (CH 2 ) n-NR 2 , -0- (CH 2 ) n-NH 2) -0- (CH 2 ) n-NHR, -0- (CH 2 ) ⁇ -NR 2 , R 4 or together through -0- (CH 2 ) m -0- substituted phenyl, naphthyl or biphenyl, R 4 unsubstituted or simply substituted by -COR
  • R H or unbranched or branched alkyl with 1-6 C-
  • R 1 , R 2 each independently of one another H, A,
  • Cycloalkyl- [C (R 7 R 7 ' )] n - or Ar- [C (R 7 R 7' )] n -, R 3 , R 4 each independently of one another H, Ar, Het, R 5 , at least one of the two radicals R 5 means R 5 by -C ( NH) -NH 2 , which is also simply by -COA,
  • substituted phenyl, naphthyl or biphenyl which are optionally additionally mono- or disubstituted by A, Ar ', Het, OR 6 , NR 6 R 6' , N0 2 , CN, Hai, NR 6 COA, NR 6 COAr ', NR 6 S0 2 A, NR 6 S0 2 Ar ', COOR 6 , CO-NR 6 R 6' , COR 7 , CO-Ar ', S0 2 NR 6 R 6' , S (0) n Ar 'or S (0) n A can be substituted, R 6 , R 6 ' each independently of one another H, A, CR 7 R 7 -Ar' or
  • X, Y each independently of one another (CR 7 R 7 ) n ,
  • Hai F, CI, Br or I, n mean 0, 1 or 2, and their pharmaceutically acceptable salts and solvates,
  • R 1 unbranched, branched or cyclic alkyl having 1-20 C atoms, in which one or two CH groups can be replaced by O or S atoms, Ar, Ar 'or X,
  • A each independently of one another H, unbranched, branched or cyclic alkyl having 1-20 C atoms, Het a mono- or dinuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and / or S atoms, bound via N or C, which may be unsubstituted or substituted by A, X - (CH 2 ) n -Y,
  • R 1 unbranched, branched or cyclic alkyl having 1-20 C atoms, in which one or two CH 2 groups can be replaced by O or S atoms, Ar, Ar 'or X,
  • R ⁇ simply phenyl substituted by S (0) p A, S (0) p NHA, CF 3 , COOA, CH 2 NHA, CN or OA,
  • Ar unsubstituted or mono-, di- or trisubstituted by A, OA, NAA ', N0 2 , CF 3 , CN, Hai, NHCOA, COOA, CONAA', S (0) p A, S (0) p NAA ' Phenyl or naphthyl,
  • P is 0, 1 or 2, and their pharmaceutically acceptable salts and solvates,
  • R 5 2, r R-> 2 ', R each independently of one another H, A, CF 3 , CI, F, COA, COOH, COOA, CONH 2 , CONHA, CONA 2 , CH 2 NH 2 , CH 2 NHCOA, CH 2 NHCOOA, OH, OA, OCF 3 , N0 2 , S0 2 A, S0 2 NH 2 or S0 2 NHA, R 3 , R 4 together (CH 2 ) P , CO (CH 2 ) p , COO (CH 2 ) n ,
  • R 5 '" , R 5 each independently of one another (CH) n -COOH,
  • Y is missing, CH 2 , CO or S0 2 ,
  • CF 3 shark, OH, OA, OCF 3 , S0 2 A, S0 2 NH 2 , S0 2 NHA, S0 2 NA 2 , NH 2 , NHA, NA 2 , NHCHO, NHCOA, NHCOOA, NACOOA, NHS0 2 A, NHS0 2 Ar, COOH, COOA,
  • P is 2, 3 or 4, and their pharmaceutically acceptable salts and solvates
  • R, R ⁇ 2 ', R r ⁇ 2 each independently of one another H, A, CF 3 , CI, F, COA, COOH, COOA, CONH 2 , CONHA, CONA 2 , CH 2 NH 2 , CH 2 NHCOA, CH 2 NHCOOA, OH, OA, OCF 3 , N0 2 , S0 2 A, S0 2 NH 2 , S0 2 NHA or S0 2 NA 2 ,
  • R 3 , R 4 together also (CH 2 ) P , (CH 2 ) n -N (R 8 ) - (CH 2 ) 2,
  • R 7 , R 7 ' , R 7 “ , R 7 " each independently of one another H, Hai, OH, OA,
  • Y is missing, CH 2 , CO or S0 2 , A unbranched, branched or cyclic alkyl with 1-
  • CF 3 shark, OH, OA, OCF 3 , S0 2 A, S0 2 NH 2 , S0 2 NHA, SO 2 NA 2 , NH 2 , NHA, NA 2 , NHCHO, NHCOA, NHCOOA, NACOOA, NHS0 2 A, NHS0 2 Ar, COOH, COOA,
  • COOA COO- (CH 2 ) m -Ar ', CONH 2 , CONHA, COA, COAr', CH 2 NH 2 , CH 2 NHA, CH 2 NHCHO, CH 2 NHCOA,
  • Hai F, CI, Br or I, n is 1 or 2
  • m is 0, 1 or 2
  • p is 2, 3, 4 or 5, and their pharmaceutically acceptable salts and solvates,
  • Ar '(CH 2 ) n -Ar Het is a mono- or dinuclear saturated, unsaturated or aromatic heterocycle with 1 to 4 N, O and / or S atoms, which is unsubstituted or mono-, di- or triple by A ', OA', NH 2 , NHA ', NA' 2 , N0 2 , CN,
  • Carbonyl oxygen can be substituted
  • Hai F, CI, Br or l, n mean 1, 2, 3, 4, 5 or 6, m 0 or 1, and their pharmaceutically acceptable salts and solvates,
  • R 1 unbranched, branched or cyclic alkyl having 1 to 20 carbon atoms, in which one or two CH 2 groups by
  • O or S atoms can be replaced, Ar, Ar 'or X, R 2 simply by S (0) p A, S (0) p NHA, CF 3 , COOA,
  • P is 0, 1 or 2, and their pharmaceutically acceptable salts and solvates,
  • substituted phenyl or naphthyl optionally substituted by -A, -OR 5 , -N (R 5 ) 2 , -N0 2 , -CN, -Hai, -NR 5 COA, -NR 5 COAr ' , -NR 5 S0 2 A , -NR 5 S0 2 Ar ', -COOR 5 , -CON (R 5 ) 2 , -CONR 5 Ar', -COR 6 , -COAr 'or S (0) n A may be substituted;
  • R 2 -N (R 5 ) 2 , -NR 5 COA, -NR 5 COAr, -NR 5 COOR 5 ;
  • R 3 , R 4 independently of one another, -H, -A, -OR 5 , -N (R 5 ) 2 , -N0 2 , -CN, -Hai, -NR 5 COA, -NR 5 COAr ', -NR 5 S0 2 A, -NR 5 S0 2 Ar ', -COOR 5 , -CON (R 5 ) 2 , -CONR 5 Ar', -COR 6 , -COAr ', -S (0) Ar ⁇ S (0) n A;
  • R 5 -H, -A, -C (R 6 R 7 ) Ar 'or -C (R 6 R 7 ) Het;
  • R 6 , R 7 independently of one another -H, -A or - (CH 2 ) ⁇ -Ar ';
  • A Alkyl having 1 to 20 carbon atoms, in which one or two
  • Ar unsubstituted or single, double or triple by -A, -Ar ', -Het, -OR 5 , -N (R 5 ) 2 , -N0 2 , -CN, -Hai, -NR 5 COA, - NR 5 COAr, -NR 5 S0 2 A, -NR 5 S0 2 Ar ', -COOR 5 , -CON (R 5 ) 2 , -CONR 5 Ar', -COR 6 , -COAr ', or -S (0) n A substituted phenyl or naphthyl; Ar ': unsubstituted or single, double or triple by -A, -OR 6 , -N (R 6 ) 2 , -N0 2 , -CN, -Hai, -NR 6 COA, -NR 6 S0 2 A, -COOR 6 , -CON (R 6 ) 2 , -
  • substituted phenyl or naphthyl optionally substituted by -A, -OR 5 , -N (R 5 ) 2 , -N0 2 , -CN, -Hai, -NR 5 COA, -NR 5 COAr ' , -NR 5 S0 2 A , -NR 5 S0 2 Ar ', -COOR 5 , -CON (R 5 ) 2 , -COR 7 , -COAr' or S (0) n A may be substituted;
  • R 2 -S (0) n A, -CF 3 , -COOR 7 , -OA;
  • R 3 , R 4 independently of one another, -H, -A, -OR 5 , -N (R 5 ) 2 , -N0 2 , -CN,
  • R 5 , R 6 independently of one another -H, -A, - [C (R 7 R 8 )] n Ar 'or - [C (R 7 R 8 )] n Het;
  • R 7 , R 8 independently of one another -H or -A;
  • A Alkyl having 1 to 20 carbon atoms, in which one or two
  • Ar unsubstituted or single, double or triple by -A, -Ar ',
  • Ar ' unsubstituted or single, double or triple by -A, -OR 7 , -N (R 7 ) 2 , -N0 2 , -CN, -Hai, -NR 7 COA, -NR 7 S0 2 A, -COOR 7 , -CON (R 7 ) 2, -COR 7 , -S0 2 NR 7 or -S (0) n A substituted phenyl or naphthyl;
  • Het a mono- or dinuclear saturated, unsaturated or aromatic heterocycle with 1 to 4 N, O and / or S atoms, bonded via N or C, which is unsubstituted or mono-, di- or triple by -A, - OR 7 , -N (R 7 ) 2 , -N0 2 , -CN, -Hai, -NR 7 COA, -NR 7 S0 2 A, -COOR 7 , -CON (R 7 ) 2 , -COR 7 , - S0 2 NR 7 , -S (0) n A and / or carbonyl oxygen can be substituted; Shark: -F, -CI, -Br or -I;
  • R ⁇ H one or more A, CF 3 , Br, CI, F, COA, COOH,
  • CF 3 shark, OA, OCF 3 , S0 2 A, S0 2 NH 2 , S0 2 NHA, S0 2 NA 2 , NH 2 , NHA, NA 2 , NHCHO, NHCOA, NHCOOA, NACOOA, NHS0 2 A, NHS0 2 Ar, COOH, COOA, COO- (CH 2 ) m-Ar, COO- (CH 2 ) m-Het CONH 2 , CONHA, CONA 2 , CONHAr, COA, COAr, CH 2 Ar, - (CH 2 ) m- NH 2 , - (CH 2 ) m -
  • NHA NHA, - (CH 2 ) m-NA 2 , - (CH 2 ) m-NHCHO, - (CH 2 ) m -NHCOA, - (CH 2 ) m-NHCOOA - (CH 2 ) m-NHCOO- (CH 2 ) mAr, - (CH 2 ) m -NHCOO- (CH 2 ) rn -Het, - (CH 2 ) m -Hal, - (CH 2 ) m -Het, N0 2 , CN, CSNH 2 , C [NH] SA, C [NH] OA, C [NH] NH 2 , C [NH] NHOH, C [NH] NHCOOA, C [NH] NHCOOAr substituted phenyl or naphthyl, has a mono- or dinuclear saturated, unsaturated or aromatic heterocycle with 1 to 4 N, O and / or S atoms, bonded via N
  • CF 3 shark, OH, OA, S0 2 A, S0 2 - (CH 2 ) m -Ar, S0 2 NH 2 , SO2NHA, S0 2 NA 2 , NH 2 , NHA, NA 2 , NHCHO, NHCOA, NHCOOA, NHSO 2 A, NHS0 2 Ar, COOH, COOA, COO- [CH 2 ] m-Ar, CONH 2 , CONHA, COA, COAr, CH2NH 2 , CH 2 NHA, CH 2 NHCHO, CH 2 NHCOA,
  • CH2NHCOOA N0 2 , CN, CSNH 2 , C [NH] SA, C [NH] OA, C [NH] NH 2 , C [NH] NHOH, C [NH] NHCOOA, C [NH] NHCOOAr, and / or carbonyl oxygen may be substituted,
  • R 'H, COOA, R 3 unbranched, branched or cyclic alkyl with 1-20 C-
  • Atoms can be replaced, Ar, Ar ", X or shark,
  • Ar '- (CH 2 ) n -Ar Het is a mono- or dinuclear saturated, unsaturated or aromatic heterocycle with 1 to 4 N-, O- and / or S-
  • a H unbranched, branched or cyclic alkyl with 1-20
  • R 1 , R 2 independently of one another H, A, OR 6 , N (R 6 ) 2 , N0 2 , CN, Hai, NR 6 COA, NR 6 COAr ' , NR 6 S0 2 A, NR 6 S0 2 Ar ' ,
  • R 3 S0 2 (NR 6 ) 2 , S (0) nA, CF 3 , COOR 6 , OA, CN,
  • R 4 , R 5 independently of one another H, A, OR 6 , N (R 6 ) 2 , N0 2 , CN, Hai, NR 6 COA, NR 6 COAr ', NR 6 S0 2 A, NR 6 S0 2 Ar ' ,
  • OR 7 N (R 7 ) 2 , N0 2 , CN, Hai, NR 7 COA, NR 7 S0 2 A, COOR 7 , CON (R 7 ) 2 , COR 7 , S0 2 NR 7 or S (0) n A substituted phenyl or naphthyl, Het a mono- or dinuclear saturated, unsaturated or aromatic heterocycle with 1 to 4 N, O and / or S atoms, bonded via N or C, which is unsubstituted or one, two or three times by A, OR 7 , N (R 7 ) 2 , N0 2 , CN, shark, NR 7 COA, NR 7 S0 2 A, COOR 7 , CON (R 7 ) 2 , COR 7 , S0 2 NR 7 , S (0) n A and / or Carbonyl oxygen can be substituted,
  • a unbranched or branched alkyl having 1-10 C atoms, in which one or two CH 2 groups by O or S atoms and / or by -CH CH groups and / or also 1-7 H-
  • Atoms can be replaced by F
  • Atoms that are unsubstituted or single, double or triple by shark A, OR 2 , N (R 2 ) 2 , N0 2 , CN, COOR 2 , CON (R 2 ) 2 , NR 2 COA, NR 2 S0 2 A, COR 2 , S0 2 NR 2 , SO 3 H or S (0) m A and / or carbonyl oxygen can be substituted,
  • Other preferred factor Xa inhibitors are e.g. the compounds described in the following documents: a) in WO 97/30971, page 4, line 5 to page 13, line 19; b) in EP 0 921 116 A1, page 2, line 1 to line 51; c) in EP 0 540 051 B1, page 2, line 41 to page 3, line 14; d) in EP 0 798 295 A1, page 69, line 10 to page 71, page 53;
  • Preferred other compounds are selected from the group defibrotides, desirudin or lepirudin.
  • the invention preferably relates to a formulation comprising [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-ylmethoxy] acetic acid and its physiologically acceptable salts and / or solvates and a calcium antagonist.
  • the ethanolamine salt is preferred.
  • Calcium antagonists are preferably selected from the group of selective and non-selective calcium antagonists.
  • Selective calcium antagonists are preferably selected from the group of dihydropyridine derivatives, phenylalkylamine derivatives, benzothiazepine derivatives and other selective calcium antagonists.
  • Dihydropyridine derivatives are preferably selected from the group amlodipine, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, lacidipine, Nilvadipine, manidipine, bamidipine, lercanidipine.
  • the phenylalkylamine derivatives are preferably selected from the Verapamil, Gallopamil group.
  • the benzothiazepine derivatives are preferably diltiazem.
  • the other selective calcium antagonists preferably mean mibefradil.
  • the non-selective calcium antagonists are preferably selected from the group fendiline, bepridil, lidoflazine, perhexiline.
  • the invention preferably relates to a formulation comprising [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-ylmethoxy] acetic acid and its physiologically acceptable salts and / or solvates and a prostaglandin or prostaglandin derivative.
  • the ethanolamine salt is preferred.
  • Prostaglandins or prostaglandin derivatives are preferably selected from the group PGE 0 , PGAi, PGBi, PGF 1 ⁇ , PGA 2 , PGB 2 , 19-hydroxy-PGA ⁇ , 19-hydroxy-PGB ⁇ , 19-hydroxy-PGA 2 , 19-hydroxy-PGB 2 , PGE 3 , PGF 3 ⁇ , alprostadil (PGE-i), dinoprost (PGF 2 ), dinoprostone (PGE 2 ), epoprostenol sodium (PGI 2 ; prostacyclin sodium), gemeprost, lloprost, latanoprost,
  • prostaglandins or prostaglandin derivatives selected from the group alprostadil (PGE-i), dinoprost (PGF 2 ), dinoprostone (PGE 2 ), epoprostenol sodium (PGI 2 ; prostacyclin sodium), gemeprost, lloprost, latanoprost, misoprostol, sulprostone , Carboprost thromethamine, dinoprost thromethamine, lipoprost, metenoprost, tiaprost.
  • PGEi or prostacyclin is particularly preferred, and prostacyclin is particularly preferred.
  • R 1 , R 2 , R 3 , R 4 and X have the meanings indicated, in particular the preferred meanings indicated.
  • L is a reactive esterified OH group, this is preferably alkylsulfonyloxy with 1-6 C atoms (preferably methylsulfonyloxy) or arylsulfonyloxy with 6-10 C atoms (preferably phenyl- or p-tolylsulfonyloxy, furthermore also 2-naphthalenesulfonyloxy).
  • the compounds of the formula I can preferably be obtained by reacting compounds of the formula II with compounds of the formula III.
  • the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture, but instead are immediately reacted further to give the compounds of the formula I. On the other hand, it is possible to carry out the reaction in stages.
  • the starting compounds of the formula II and III are generally known. If they are not known, they can be produced by methods known per se.
  • the compounds of the formula II are reacted with the compounds of the formula III in the presence or absence of an inert solvent at temperatures between about -20 and about 150 °, preferably between 20 and 100 °.
  • an acid-binding agent for example an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of the alkali metal or alkaline earth metal, preferably potassium, sodium or calcium, or the addition of an organic base such as Triethylamine, dimethylamine, pyridine or quinoline or an excess of the amine component may be beneficial.
  • an acid-binding agent for example an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of the alkali metal or alkaline earth metal, preferably potassium, sodium or calcium
  • an organic base such as Triethylamine, dimethylamine, pyridine or quinoline or an excess of the amine component
  • Suitable inert solvents are, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; Glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; amides such as acetamide, dimethylacetamide, N-methylpyrrolidone
  • radical X into another radical X in a compound of formula I, e.g. by hydrolyzing an ester or a cyano group to a COOH group.
  • Ester groups can e.g. can be saponified with NaOH or KOH in water, water-THF or water-dioxane at temperatures between 0 and 100 °.
  • Carboxylic acids can e.g. with thionyl chloride in the corresponding carboxylic acid chlorides and these are converted into carboxamides. By splitting off water in a known manner, carbonitriles are obtained from these.
  • An acid of the formula I can be converted with a base into the associated acid addition salt, for example by reacting equivalent amounts of the acid and the base in an inert solvent such as ethanol and then evaporating.
  • Bases that provide physiologically acceptable salts are particularly suitable for this implementation.
  • the acid of formula I can be converted with a base (e.g. sodium or potassium hydroxide or carbonate) into the corresponding metal, in particular alkali metal or alkaline earth metal, or into the corresponding ammonium salt.
  • a base e.g. sodium or potassium hydroxide or carbonate
  • Organic bases which provide physiologically acceptable salts, such as e.g. Ethanolamine.
  • a base of the formula I can be converted into the associated acid addition salt using an acid, for example by reacting equivalent amounts of the base and the acid in an inert solvent such as ethanol and subsequent evaporation.
  • an inert solvent such as ethanol and subsequent evaporation.
  • acids which provide physiologically acceptable salts are suitable for this reaction.
  • inorganic acids those, for example sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, furthermore organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid Acetic acid, propionic acid, pivalic acid, diethyl acetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, methane or ethanesulfonic acid, hydroxyl sulfonic acid, ethoxylated sulfonic acid, ethoxylated acid - Acid, p-toluenesulfonic acid, naphthalene mono- and disulfonic acids, for
  • the invention furthermore relates to pharmaceutical formulations comprising at least one compound of the formula I and / or one of its physiologically acceptable salts and at least one antithrombotic, a calcium antagonist or at least one prostaglandin or prostaglandin derivative and also comprising one or more carriers and / or auxiliaries.
  • the pharmaceutical preparations are produced in particular by a non-chemical route.
  • the active ingredients are brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or auxiliary.
  • 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 in particular for oral use, suppositories for rectal use, solutions for parenteral use, pre- preferably oily or aqueous solutions, also suspensions, emulsions or implants, for topical application of ointments, creams or powders.
  • 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
  • Excipients 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 ingredients, e.g. one or more vitamins. They can also be administered as nasal sprays.
  • 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 elimination, combination of drugs and severity of the respective disease to which the therapy applies. Oral application is preferred.
  • the invention therefore also relates to the use of the pharmaceutical preparations described for the production of a medicament for the treatment of angina, high blood pressure, pulmonary high pressure, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), cor pulmonale, right heart failure, atherosclerosis , Conditions of reduced patency of the cardiovascular system, peripheral vascular diseases, stroke, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumors, renal insufficiency, liver cirrhosis and for the treatment of female sexual disorders.
  • CHF congestive heart failure
  • COPD chronic obstructive pulmonary disease
  • cor pulmonale right heart failure
  • atherosclerosis Conditions of reduced patency of the cardiovascular system, peripheral vascular diseases, stroke, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumors, renal insufficiency, liver cirrhos
  • the invention relates in particular to the use of the formulations according to the invention for the production of a medicament for the treatment of pulmonary high pressure, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), cor pulmonary and / or right heart failure.
  • CHF congestive heart failure
  • COPD chronic obstructive pulmonary disease
  • the components of the new pharmaceutical preparation are preferably administered in combination. However, they can also be administered individually at the same time or in succession.
  • the invention also relates to a set consisting of separate packs of (a) an effective amount of [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [ 4,3-d] pyrimidin-5-ylmethoxy] acetic acid, ethanolamine salt and (b) an effective amount of an antithrombotic.
  • the set contains suitable containers, such as boxes or boxes, individual bottles, bags or ampoules.
  • the set can e.g. contain separate ampoules, each containing an effective amount of [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-ylmethoxyj- acetic acid, ethanolamine salt and the antithrombotic are dissolved or in lyophilized form.
  • the invention further relates to the use of [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1 - pyrazolo [4,3-d] pyrimidin-5-ylmethoxyj-acetic acid, Ethanolamine salt for the manufacture of a medicament for the treatment of pulmonary high pressure, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), cor pulmonary and / or right heart failure.
  • CHF congestive heart failure
  • COPD chronic obstructive pulmonary disease
  • the invention also relates to a set (kit) consisting of separate packs of
  • the set contains suitable containers, such as boxes or boxes, individual bottles, bags or ampoules.
  • the set can contain, for example, separate ampoules, each containing an effective amount of [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidine -5- ylmethoxyj-acetic acid, ethanolamine salt and the calcium antagonist dissolved or in lyophilized form.
  • the invention also relates to a set (kit) consisting of separate packs of
  • the set contains suitable containers, such as boxes or boxes, individual bottles, bags or ampoules.
  • the set can e.g. contain separate amps, each containing an effective amount of [7- (3-chloro-4-methoxy-benzylamino) -1-methyl-3-propyl-1H-pyrazolo [4,3-d] pyrimidine-5- ylmethoxyj-acetic acid, ethanolamine salt and the prostaglandin or prostaglandin derivative dissolved or in lyophilized form.
  • customary work-up means: if necessary, water is added, if necessary, depending on the constitution of the end product, the pH is adjusted to between 2 and 10, extracted with ethyl acetate or dichloromethane, and the mixture is separated off, dries the organic phase over sodium sulfate, evaporates and purifies by chromatography on silica gel and / or by crystallization.
  • Example A Injection glasses
  • a solution of 100 g of an active ingredient of the formula I, 100 g of the antithrombotic and 5 g of disodium hydrogenphosphate is adjusted to pH 6.5 in 3 I of double-distilled water with 2N hydrochloric acid, sterile filtered, filled into injection glasses, lyophilized and sterile under sterile conditions locked. Each injection jar contains 5 mg of each active ingredient.
  • a mixture of 20 g of an active ingredient of the formula I, of 20 g of an antithrombotic with 100 g of soy lecithin and 1400 g of cocoa butter is melted, poured into molds and allowed to cool.
  • Each suppository contains 20 mg of each active ingredient.
  • a solution is prepared from 1 g of an active ingredient of the formula 1, 1 g of an antithrombotic, 9.38 g of NaH 2 P0 4 • 2 H 2 0, 28.48 g of Na 2 HP0 4 • 12 H 2 0 and 0.1 g 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, 500 mg of an anthrombotic agent are mixed with 99.5 g of petroleum jelly under aseptic conditions.
  • a mixture of 1 kg of active ingredient of formula 1, 1 kg of an anthrombotic, 4 kg of lactose, 1, 2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium Sium stearate is compressed into tablets in the usual way, such that each tablet contains 10 mg of each 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 each active ingredient.
  • a solution of 1 kg of active ingredient of the formula I and 1 kg of an antithrombotic 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 each active ingredient.
  • 14 g of active ingredient of the formula I and 14 g of an antithrombotic are dissolved in 10 I of isotonic NaCl solution and the solution is filled into commercially available spray vessels with a pump mechanism.
  • the solution can be sprayed into the mouth or nose.
  • One spray (approximately 0.1 ml) corresponds to a dose of approximately 0.14 mg of each active ingredient.
  • Example A ' Injection glasses
  • a solution of 100 g of an active ingredient of the formula I, 100 g of the calcium antagonist 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, ly under sterile conditions - ophilized and sealed sterile. Each injection jar contains 5 mg of each active ingredient.
  • Example B ' suppositories
  • a mixture of 20 g of an active ingredient of the formula I, 20 g of a calcium antagonist with 100 g of soy lecithin and 1400 g of cocoa butter is melted, poured into molds and allowed to cool.
  • Each suppository contains 20 mg of each active ingredient.
  • a solution is prepared from 1 g of an active ingredient of the formula 1, 1 g of a calcium antagonist, 9.38 g of NaH 2 P0 4 • 2 H 2 0, 28.48 g of Na 2 HP0 4 • 12 H 2 0 and 0, 1 g benzalkonium chloride in 940 ml double distilled
  • 500 mg of an active ingredient of the formula I, 500 mg of a calcium antagonist are mixed with 99.5 g of petroleum jelly under aseptic conditions.
  • a mixture of 1 kg of active ingredient of the formula I, 1 kg of a calcium antagonist, 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 each active ingredient.
  • 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 each active ingredient.
  • Example H ' ampoules
  • a solution of 1 kg of active ingredient of the formula I and 1 kg of a calcium antagonist 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 each active ingredient.
  • Example I inhalation spray
  • 14 g of active ingredient of the formula I and 14 g of a calcium antagonist are dissolved in 10 I of isotonic NaCI solution and the solution is filled into commercially available spray vessels with a pump mechanism.
  • the solution can be sprayed into the mouth or nose.
  • One spray (approximately 0.1 ml) corresponds to a dose of approximately 0.14 mg of each active ingredient.
  • Prostaglandins or prostaglandin derivatives and 5 g of disodium hydrogen phosphate are 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 jar contains 5 mg of each active ingredient.
  • a solution is prepared from 1 g of an active ingredient of the formula 1, 1 g of a prostaglandin or prostaglandin derivative, 9.38 g of NaH 2 PO 4 • 2 H 2 0, 28.48 g of Na 2 HP0 4 • 12 H 2 0 and 0, 1 g benzalkonium chloride in 940 ml 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.
  • Prostaglandins or prostaglandin derivatives with 99.5 g petroleum jelly under aseptic conditions Prostaglandins or prostaglandin derivatives with 99.5 g petroleum jelly under aseptic conditions.
  • a mixture of 1 kg of active ingredient of formula 1, 1 kg of a prostaglandin or prostaglandin derivative, 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 each active ingredient.
  • Example E tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.
  • a solution of 1 kg of active ingredient of the formula I and 1 kg of a prostaglandin or prostaglandin derivative in 60 l of double-distilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of each active ingredient.
  • 14 g of active ingredient of the formula I and 14 g of a prostaglandin or prostaglandin derivative are dissolved in 10 I of isotonic NaCI solution and the solution is filled into commercially available spray vessels with a pump mechanism.
  • the solution can be sprayed into the mouth or nose.
  • One spray (approximately 0.1 ml) corresponds to a dose of approximately 0.14 mg of each active ingredient.

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EP01990452A 2000-12-19 2001-11-28 Pharmazeutische formulierung enthaltend pyrazolo 4,3-d]pyrimidine und antithrombotica, calcium-antagonisten, prostaglandine oder prostaglandinderivate Withdrawn EP1343506A1 (de)

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Application Number Priority Date Filing Date Title
DE10063224 2000-12-19
DE10063224A DE10063224A1 (de) 2000-12-19 2000-12-19 Pharmazeutische Formulierung enthaltend Pyrazolo(4,3-d)pyrimidine und Antithrombotica
DE2000163882 DE10063882A1 (de) 2000-12-21 2000-12-21 Pharmazeutische Formulierung enthaltend Pyrazolo[4,3-d]pyrimidine und Calcium-Antagonisten
DE10063882 2000-12-21
DE10064993 2000-12-23
DE2000164993 DE10064993A1 (de) 2000-12-23 2000-12-23 Pharmazeutische Formulierung enthaltend Pyrazolo[4,3-d]pyrimidine und Prostaglandine oder Prostaglandinderivate
PCT/EP2001/013916 WO2002049651A1 (de) 2000-12-19 2001-11-28 Pharmazeutische formulierung enthaltend pyrazolo[4,3-d]pyrimidine und antithrombotica, calcium-antagonisten, prostaglandine oder prostaglandinderivate

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BR0115995A (pt) 2004-01-13
US20040063730A1 (en) 2004-04-01
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AR035676A1 (es) 2004-06-23
CZ20031776A3 (cs) 2003-09-17

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