EP1347761A2 - Formulation pharmaceutique contenant des thienopyrimidines et des antithrombotiques, des inhibiteurs calciques, des prostaglandines ou des derives de prostaglandine (1) - Google Patents

Formulation pharmaceutique contenant des thienopyrimidines et des antithrombotiques, des inhibiteurs calciques, des prostaglandines ou des derives de prostaglandine (1)

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Publication number
EP1347761A2
EP1347761A2 EP01989533A EP01989533A EP1347761A2 EP 1347761 A2 EP1347761 A2 EP 1347761A2 EP 01989533 A EP01989533 A EP 01989533A EP 01989533 A EP01989533 A EP 01989533A EP 1347761 A2 EP1347761 A2 EP 1347761A2
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EP
European Patent Office
Prior art keywords
pyrimidin
chloro
atoms
pharmaceutical formulation
benzylamino
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Withdrawn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
EP01989533A
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German (de)
English (en)
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
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Filing date
Publication date
Priority claimed from DE2000163223 external-priority patent/DE10063223A1/de
Priority claimed from DE2000163885 external-priority patent/DE10063885A1/de
Priority claimed from DE2000164992 external-priority patent/DE10064992A1/de
Application filed by Merck Patent GmbH filed Critical Merck Patent GmbH
Publication of EP1347761A2 publication Critical patent/EP1347761A2/fr
Withdrawn legal-status Critical Current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
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • 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
    • 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
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

  • 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 or shark, wherein one of the radicals R 1 or R 2 is always ⁇ H,
  • R 1 and R 2 together also alkylene with 3-5 C atoms
  • R 3 , R 4 each independently of one another H, A, OH, OA or shark
  • R 3 and R 4 together also alkylene with 3-5 C atoms
  • X is monosubstituted by R 7 R 5 or R 6,
  • R £ linear or branched alkylene with 1 -10 C atoms, in which one or two CH 2 groups can be replaced by -CH CH groups, or R 6 cycloalkylalkylene with 6-12 C atoms,
  • R 7 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 0 cardiac vessels , 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 0 cardiac vessels
  • 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
  • PDE V phosphodiesterase V
  • PDE V inhibitors The use of other PDE V inhibitors is described e.g. in WO 94/28902.
  • PDE V phosphodiesterase V
  • Prostaglandin derivative are described in WO 00/15639 and WO 0015228.
  • 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).
  • PDE V cGMP phosphodiesterase
  • the biological activity of the compounds of the formula I can be determined by methods as described, for example, in WO 93/06104.
  • the affinity of the compounds of the invention for cGMP and cAMP phosphodiesterase is determined (to achieve concentration of the inhibitor that is required strength to cause a 50% inhibition of enzyme activity) by measuring their IC 5 o values determined.
  • 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 effectiveness of the pharmaceutical formulations according to the invention especially for the treatment of pulmonary hypertension can be detected as described by E. Braunwald in Heart Disea- se 5th edition, WB Saunders Company, 1997, chapter 6: Cardiac catheteri- zation 177-200.
  • the compounds of formula I can be used as active pharmaceutical ingredients in human and veterinary medicine. Furthermore, they can be used as intermediates for the production of further active pharmaceutical ingredients.
  • R 1 , R 2 and X have the meanings given and L is CI, Br, OH, SCH 3 or a reactive esterified OH group,
  • R 3 , R 4 and n have the meanings given
  • Convert rest X by e.g. hydrolyzing an ester group to a COOH group or converting a COOH group into an amide or a cyanide group 5 and / or converting a compound of the formula I 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 additions 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 , X, L and n have the meanings given in the formulas I, II and III, if not
  • A means alkyl with 1-6 C atoms.
  • alkyl is preferably unbranched and has 25 1, 2, 3, 4, 5 or 6 carbon atoms and is preferably methyl, ethyl or propyl, more preferably isopropyl, butyl, isobutyl, sec-butyl or tert.- Butyl, but also n-pentyl, neopentyl, isopentyl or hexyl.
  • X denotes an R 5 or R 6 radical which is simply substituted by R 7 .
  • R represents a linear or branched alkylene radical having 1-10, preferably 1-8, carbon atoms, 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-dimethyl- ",.
  • propylene 1-ethylpropylene, hexylene, 1-, 2-, 3- or 4-methylpentylene, 1, 1-, 1, 2-, 1, 3-, 2,2-, 2,3- or 3,3- Dimethylbutylene, 1- or 2-ethylbutylene, 1-ethyl-1-methylpropylene, 1-ethyl-2-methylpropylene, 1, 1, 2- or 1, 2,2-trimethylpropylene, linear or branched heptylene, octylene, nonylene or decylene.
  • R 5 also means, for example, but-2-en-ylene or hex-3-en-ylene.
  • R 6 denotes cycloalkylalkylene with 6-12 C atoms, preferably for example cycclopentylmethylene, cyclohexylmethylene, cyclohexylethylene, cyclohexylpropylene or cyclohexylbutylene.
  • R 1 and R 2 are preferably H, while the other is preferably propyl or butyl, but particularly preferably ethyl or methyl. Furthermore, R 1 and R 2 together preferably also mean propylene, butylene or pentylene.
  • Shark preferably means F, CI or Br, but also I.
  • radicals R 3 and R 4 can be the same or different and are preferably in the 3- or 4-position of the phenyl ring. They each mean, for example, independently of one another H, OH, alkyl, F, CI, Br or I or together alkylene, such as propylene, butylene or pentylene, furthermore
  • Ethyleneoxy methylenedioxy or ethylenedioxy. They preferably also each represent alkoxy, such as e.g. for methoxy, ethoxy or propoxy.
  • the radical R 7 is preferably, for example, COOH, COOCH 3 , COOC 2 H 5> CONH 2 , CON (CH 3 ) 2 , CONHCH 3 or CN.
  • 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 Antagonists 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 la to le, 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 1 , R 2 each independently of one another are H, A or shark, where at least one of the radicals R 1 or R 2 is always ⁇ H, R 3 and R 4 together are alkylene with 3-5 C atoms, -0-CH 2 -CH 2 -,
  • X is R 5 or R 6 substituted by COOH or COOA;
  • R 1 , R 2 each independently of one another H, A or shark, where at least one of the radicals R 1 or R 2 is always ⁇ H, R 3 , R 4 each independently of one another H, A, OA or shark,
  • R 3 and R 4 together alkylene with 3-5 C atoms, -0-CH 2 -CH 2 -, -O-CH 2 -O- or -O-CH 2 -CH 2 -O,
  • X is R 5 or R 6 , n 1 or 2 substituted by COOH or COOA;
  • R 1 , R 2 each independently of one another H, A or shark, one of the radicals R 1 or R 2 always being ⁇ H,
  • R 1 and R 2 together also alkylene with 3-5 C atoms
  • R 3 ,, R 4 each independently of one another H, A, OA or
  • X is simply substituted by R 7, R 5 , R ü linear or branched alkylene with 1-10 C atoms, or
  • R 1 and R 2 together also alkylene with 3-5 C atoms
  • R 3 , R 4 each independently of one another H, A, OH, OA or
  • X is simply substituted by R 7, R 5 ,
  • R 5 linear or branched alkylene with 1-10 C atoms, or 0 -C 6 H 4 -CH 2 -,
  • the invention preferably relates to a formulation containing 5- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] - benzothieno [2,3-d] pyrimidine -2-yl] -valeric acid and its physiologically harmless salts and / or solvates and an antithrombotic.
  • the ethanolamine salt is preferred.
  • Preferred antithrombotics are vitamin K antagonists, Heparinverbin- applications, reindeer platelet aggregation inhibitors, enzymes, factor Xa Inhibito- 5, 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 ditazoles, cloricromes, picotamides, clopidogrel, ticlopidines,
  • Acetylsalicylic acid dipyridamole, calcium carbassalate, epoprostenol, indobufen, lloprost, abciximab, tirofiban, aloxiprin, intrifiban.
  • 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
  • X is missing, -CO-, -C (R 6 ) 2 -, -C (R 6 ) 2 -C (R 6 ) 2 -, -C (R 6 ) 2 -CO-,
  • Groups and / or 1-7 H atoms can be replaced by F, Ar unsubstituted or one, two or three times by A,
  • NHSO 2 A NHSO 2 Ar ⁇ COOR 6 , CON (R 6 ) 2 , CONHAr ', COR 6 , COAr', S (0) n A or S (O) n Ar substituted phenyl or naphthyl, Ar 'unsubstituted or single, double or triple through A,
  • Hai F, CI, Br or l, n mean 0, 1 or 2, and their salts,
  • R 4 A cycloalkyl, - [C (R 5 ) 2 ] m Ar, - [C (R 5 ) 2 ] m Het or
  • W is a bond, -SO 2 -, -CO-, -COO- or -CONR 5 -,
  • NHSO ⁇ A NHSO 2 Ar ⁇ COOR 5 , CON (R 5 ) 2) CONHAr ', COR 5 , COAr', S (0) n A or S (O) n Ar substituted phenyl or naphthyl, Ar 'unsubstituted or a -, double or triple through R 1 ,
  • R 2 , R 3 , R 5 each independently of one another H, A, OR 6 , N (R 6 ) 2 ,
  • R, R 1 are each independently H, A, - (CH 2 ) m -R, - (CH 2 ) m -OA or - (CH 2 ) m -Ar,
  • R 4 CN, COOH, COOA, CONH 2 , CONHA, CONA 2 or
  • R ö H, A or NH 2 Ar unsubstituted or one, two or three times by A, cycloalkyl having 3-6 C atoms, OH, OA, shark, CN, N0 2 , CF 3 , NH 2 , NHA, NA 2) pyrrolidin-1-yl, piperidin-1-yl, Benzyloxy, S0 2 NH 2 , S0 2 NHA, S0 2 NA 2 , - (CH 2 ) n -NH 2 , - (CH 2 ) n -NHA, - (CH 2 ) n -NA 2 , -0- (CH 2 ) n-NH 2 , -0- (CH 2 ) n -NHA, -0- (CH 2 ) ⁇ -NA 2 , -0- (CH 2 ) m -0- or R 5 substituted phenyl, naphthyl or biphenyl , A alkyl with 1-6 C atoms,
  • X is absent, alkylene with 1-4 C atoms or carbonyl
  • Y is missing, NH, 0 or S,
  • R H 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, NO2, 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 ,
  • R H or 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, N0 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 ) n-NR 2 , R 4 or together with -0- (CH 2 ) m -0- substituted phenyl, naphthyl or biphenyl, or with NH 2 substituted isoquinolin
  • R ⁇ R 2 each independently ⁇
  • Cycloalkyl- [C (R 7 R 7 )] n - or Ar- [C (R 7 R 7 ' )] n -, R 3 , R 4 each independently of one another are H, Ar, Het, R 5 , where at least one of the two radicals is R 5 ,
  • 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 ,
  • OR 7 , NR 7 R 7 ' , N0 2 , CN, Hai, NR 7 COA, NR 7 S0 2 A, COOR 7 , CO-NR 7 R 7' , COR 7 , S0 2 NR 7 R 7 ' or S ( 0) n A substituted phenyl or naphthyl,
  • 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 with 1-
  • R 2 simply by S (0) p A, S (0) p NHA, CF 3 , COOA,
  • 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,
  • P is 0, 1 or 2, and their pharmaceutically acceptable salts and solvates,
  • R 2 , R 2 ' , 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 or S0 2 NHA,
  • R 3 , R 4 together (CH 2 ) P , CO (CH 2 ) p , COO (CH 2 ) n ,
  • R 5 , R 5 ' , R 5 " R 5 ' , R 5'” each independently of one another (CH 2 ) n -COOH, (CH 2 ) n-COO- (CH 2 ) n -Ar, Ar, Py or R 2 ,
  • 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, S0 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 or 4, and their pharmaceutically acceptable salts and solvates,
  • R 2 , R 2 ' , R 2 each independently of one another H, A, CF 3 , CI, F, COA,
  • R 5 , R 5 each independently of one another (CH 2 ) n -COOH, (CH 2 ) n -COOA, (CH 2 ) n -COO- (CH 2 ) m -Ar, (CH 2 ) n -COO- (CH 2 ) m - Het, Ar, Py or R 2 ,
  • R a H, A or benzyl
  • Y is missing, CH 2 , CO or S0 2 ,
  • Atoms can be replaced by F, Ar unsubstituted or single, double or triple by A,
  • 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, COO- (CH 2 ) m -Ar ', COO- (CH 2 ) m -Het, CONH 2 , CONHA,
  • 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,
  • R 1 R 4 , Ar, Ar 'or X, R 2 simply by SA, SOA, S0 2 A, SONHA, S0 2 NHA,
  • -CH CH groups and / or also 1-7 H atoms can be replaced by F, A H or alkyl with 1-20 C atoms, A alkyl with 1-10 C atoms,
  • CONA ' 2 COA, SO 2 NH 2 , SA, SOA, S0 2 A' and / or
  • Carbonyl oxygen can be substituted, 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,
  • a H unbranched, branched or cyclic alkyl with
  • P is 0, 1 or 2, and their pharmaceutically acceptable salts and solvates,
  • substituted phenyl or naphthyl which may be replaced by -A, -OR 5 , -N (R 5 ) 2 , -N0 2) -CN, -Hai, -NR 5 COA,
  • 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 - (CH2) ⁇ -Ar '; R 8 H or A
  • W - (CR 6 R 7 ) n -, -OCR 6 R 7 -, 1, 3-phenylene, 1, 3-phenylene-C (R 6 ) 2 -, 1, 4-phenylene, 1, 4-phenylene -C (R 6 ) 2 -;
  • V - (C (R 6 ) 2 ) m -;
  • 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,
  • 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 ,
  • Het a mono-, 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 6 , -N (R 6 ) 2 , -N0 2 , -CN, -Hai, -NR 6 COA, -NR 6 S0 2 A, -COOR 6 , -CON (R 6 ) 2 , -COR 6 , -S0 2 NR6, -S (0) n A and / or carbonyl oxygen may be substituted; Shark: -F, -CI, -Br or -I;
  • 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) nA, -CF 3 , -COOR 7 , -OA;
  • 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 ',
  • R 5 , R 6 independently of one another -H, -A, - [C (R 7 R 8 )] n Ar 'or
  • R 7 , R 8 independently of one another -H or -A; WW :: - [C (R 5 R 6 )] m CONR 5 [C (R 5 R 6 )] ⁇ -, -OC (R 5 R 6 ) CONR 5 [C (R 5 R 6 )], -;
  • 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;
  • R 1 H CI, F, OH, OA, 0- (CH 2 ) n -Ar, NH 2 , NHCOA, NHCOOA,
  • R 4 H A, - (CH 2 ) n -Ar, - (CH 2 ) n -Het, - (CH 2 ) m -COOR 7 , - (CH 2 ) m -
  • R 3 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 ', X or Hai,
  • R 4 monosubstituted with S (0) k A, S (0) k NHA, CF 3 , COOA, CH 2 NHA, CN or OA, phenyl,
  • R 5 -CHal 3 , -0 (C 0) A or .
  • OA NH 2 , NHA, NA 2 , N0 2 , CF 3 , CN, Shark, NHCOA, COOA, CONH 2 , CONHA, CONA 2 , S (0) n A, S (0) n NH 2 , S (0 ) n NHA,
  • R 6 H A, [C (R 7 ) 2 ] n Ar 'or [C (R 7 ) 2 ] n Het, R 7 H or A, W CONR 6 C (R 6 ) 2 CONR 6 [C (R 6 ) 2 ] ⁇ -, -NR 6 C (R 6 ) 2 CONR 6 [C (R 6 ) 2 ], -, - [C (R 6 ) 2 ] m CONR 6 [C (R 6 ) 2 ], - or -OC (R 6 ) 2 CONR 6 [C (R 6 ) 2 ] ⁇ -,
  • Alkyl with 1 - 20 C atoms, in which one or two CH 2 groups by O or S atoms or by -CH CH groups and also 1-7 H atoms can be replaced by F,
  • 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,
  • R 1 is H, Ar, Het, cycloalkyl or A, which is replaced by OR 2 , SR 2 , N (R 2 ) 2 , Ar,
  • Het, cycloalkyl, CN, COOR 2 or CON (R 2 ) 2 can be substituted,
  • N0 2 , CN, COOR 2 or CON (R 2 ) 2 may be substituted, or piperidine-1,4-diyl,
  • a unbranched or branched alkyl having 1-10 C atoms, wherein one or two CH 2 groups by O or S atoms and / or by -CH CH groups and / or 1-7 H atoms by F can be replaced
  • 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 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, S0 3 H, or S (0) m
  • Hal F, CI, Br or I, n O or l, m is 0, 1 or 2, 5 and their pharmaceutically acceptable salts and solvates.
  • Other preferred factor Xa inhibitors are, for example, the compounds described in the following documents: 10 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;
  • Bevorzugte 5 Preferred other compounds are selected from the group defibrotides, desirudin or lepirudin.
  • the invention preferably relates to a formulation comprising 5- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] - benzothieno- 20 [2,3-d] - pyrimidin-2-yl] -valeric acid and its physiologically acceptable salts and / or solvates and at least one calcium antagonist.
  • the ethanolamine salt is preferred.
  • Preferred calcium antagonists are 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 amiodipine, felodipine, isradipine, nicardipine, nifedipine, nimodipine, ni- soldipine, nitrendipine, lacidipine, nilvadipine, manidipine, bamidipine, 3 c lercanidipine.
  • the phenylalkylamine derivatives are preferably selected from the group verapamil, gallopamil.
  • 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 containing 5- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidine -2-yl] -valeric acid and its physiologically harmless salts and / or solvates and at least one prostaglandin or prostaglandin derivative.
  • the ethanolamine salt is preferred.
  • Prostaglandins or prostaglandin derivatives are preferably selected from the group PGE 0 , PGA 1f PGBL PGF ⁇ ⁇ , PGA 2 , PGB 2 , 19-hydroxy-PGA ⁇ , 19-hydroxy-PGB !
  • prostaglandins or prostaglandin derivatives selected from the group alprostadil (PGEi), 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.
  • the compounds of the formula I and also the starting materials for their preparation are otherwise prepared by methods known per se, as described in the literature (for example in the standard works such as Houben-Weyl, methods of organic chemistry, Georg-Thieme-Verlag, Stuttgart) , are described, namely under reaction conditions which are known and suitable for the reactions mentioned. Use can also be made of variants which are known per se and are not mentioned here in detail.
  • R 1 , R 2 , R 3 , R 4 , X and n 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-NaphthaIinsulfonyloxy).
  • 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.
  • 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.
  • Compounds of the formula II can be obtained, for example, by reaction with POCI 3 from compounds which are built up from thiophene derivatives and CN-substituted alkylene carboxylic acid esters (Eur. J. Med. Chem. 23, 453 (1988).
  • 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 or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of the alkali or alkaline earth metals, 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 or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of the alkali or alkaline earth metals, 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 e.g. 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 be converted, for example with thionyl chloride, into the corresponding carboxylic acid chlorides and these into carboxylic acid amides. 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
  • the corresponding metal in particular alkali metal or alkaline earth metal, or into the corresponding ammonium salt.
  • Organic bases which provide physiologically acceptable salts, such as e.g. Ethanolamine.
  • 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 with an acid, for example by reacting equivalent amounts of the base and the acid in an inert solvent such as ethanol and subsequent evaporation.
  • acids that provide physiologically acceptable salts are suitable for this implementation.
  • inorganic acids can be used, 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, pimic acid , Fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-tol
  • 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 for oral use, suppositories for rectal use, solutions for parenteral use, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants for which 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 auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure,
  • Contain 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 excretion and 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 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 decreased patency of the cardiovascular system, peripheral vascular diseases, stroke, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumors, renal insufficiency, 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 decreased patency of the cardiovascular system
  • peripheral vascular diseases stroke, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumors, renal insufficiency, cirrhosis of
  • 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
  • cor pulmonary and / or right heart failure 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 (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 ampoules, each containing an effective amount of 5- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno- [2,3-d ] - pyrimidin-2-yl] -valeric acid, ethanolamine salt and the antithrombotic, 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 contain, for example, separate ampoules, each containing an effective amount of 5- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno- [2 , 3-d] - pyrimidin-2-yl] valeric 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 ampoules, each containing an effective amount of 5- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno- [2,3-d ] - pyrimidin-2-yl] -valeric acid, ethanolamine salt and the prostaglandin or prostaglandin derivative dissolved or in lyophilized form.
  • the invention further relates to the use of 5- [4- (3-chloro-4-methoxy-benzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno- [2,3-d] pyrimidine -2-yl] -valeric 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 further relates to the use of a pharmaceutical preparation comprising at least one phosphodiesterase V inhibitor and at least one prostaglandin or a prostaglandin derivative for the manufacture of a medicament for the oral treatment of pulmonary high pressure, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), Cor pulmonary and / or right heart failure.
  • a pharmaceutical preparation comprising at least one phosphodiesterase V inhibitor and at least one prostaglandin or a prostaglandin derivative for the manufacture of a medicament for the oral 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
  • 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, separated, dried organic phase over Sodium sulfate, evaporates and purifies by chromatography on silica gel and / or by crystallization.
  • Mass spectrometry (MS): El (electron impact ionization) M + FAB (Fast Atom Bombardment) (M + H) +
  • Example A Injection glasses
  • a solution of 100 g of an active ingredient of formula 1, 100 g of the antithrombotic 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 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 antithrombotic, 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
  • 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.
  • I isotonic NaCI solution fills the solution 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 formula 1, 100 g of the calcium antagonist and 5 g of disodium hydrogen phosphate is adjusted to pH 6.5 in 3 l of double-distilled water with 2 N 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.
  • 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 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 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.
  • 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.
  • 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 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 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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  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Organic Chemistry (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
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  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pulmonology (AREA)
  • Epidemiology (AREA)
  • Reproductive Health (AREA)
  • Endocrinology (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Vascular Medicine (AREA)
  • Gynecology & Obstetrics (AREA)
  • Ophthalmology & Optometry (AREA)
  • Rheumatology (AREA)
  • Urology & Nephrology (AREA)
  • Obesity (AREA)
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  • Communicable Diseases (AREA)
  • Pain & Pain Management (AREA)
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  • Otolaryngology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Hospice & Palliative Care (AREA)
  • Pregnancy & Childbirth (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

L'invention concerne une préparation pharmaceutique contenant au moins un composé de formule (I), dans laquelle R<1>, R<2>, R<3>, R<4>, n et X ont la signification indiquée dans la revendication 1, ou ses sels ou solvates physiologiquement acceptables, ainsi que a) au moins un antithrombotique ou b) au moins un inhibiteur calcique ou c) au moins une prostaglandine ou un dérivé de prostaglandine, pour la production d'un médicament destiné à traiter l'angine de poitrine, l'hypertension artérielle, l'hypertension pulmonaire, l'insuffisance cardiaque congestive, la broncho-pneumopathie chronique obstructive (BPCO), le coeur pulmonaire, l'insuffisance cardiaque droite, l'athérosclérose, les conditions de perméabilité réduite des vaisseaux cardiaques, les maladies vasculaires périphériques, l'accident vasculaire cérébral, la bronchite, l'asthme allergique, l'asthme chronique, la rhinite allergique, le glaucome, le syndrome du côlon irritable, les tumeurs, l'insuffisance rénale, la cirrhose du foie, ainsi que les troubles sexuels féminins.
EP01989533A 2000-12-19 2001-11-28 Formulation pharmaceutique contenant des thienopyrimidines et des antithrombotiques, des inhibiteurs calciques, des prostaglandines ou des derives de prostaglandine (1) Withdrawn EP1347761A2 (fr)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
DE2000163223 DE10063223A1 (de) 2000-12-19 2000-12-19 Pharmazeutische Formulierung enthaltend Thienopyrimidine und Antithrombotica (1)
DE10063223 2000-12-19
DE10063885 2000-12-21
DE2000163885 DE10063885A1 (de) 2000-12-21 2000-12-21 Pharmazeutische Formulierung enthaltend Thienopyrimidine und Calcium-Antagonisten (1)
DE2000164992 DE10064992A1 (de) 2000-12-23 2000-12-23 Pharmazeutische Formulierung enthaltend Thienopyrimidine und Prostaglandine oder Prostaglandinderivate (1)
DE10064992 2000-12-23
PCT/EP2001/013915 WO2002049650A2 (fr) 2000-12-19 2001-11-28 Formulation pharmaceutique contenant des thienopyrimidines et des antithrombotiques, des inhibiteurs calciques, des prostaglandines ou des derives de prostaglandine (1)

Publications (1)

Publication Number Publication Date
EP1347761A2 true EP1347761A2 (fr) 2003-10-01

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EP01989533A Withdrawn EP1347761A2 (fr) 2000-12-19 2001-11-28 Formulation pharmaceutique contenant des thienopyrimidines et des antithrombotiques, des inhibiteurs calciques, des prostaglandines ou des derives de prostaglandine (1)

Country Status (16)

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US (1) US20040072846A1 (fr)
EP (1) EP1347761A2 (fr)
JP (1) JP2004516269A (fr)
KR (1) KR20030059351A (fr)
CN (1) CN1481242A (fr)
AR (1) AR032009A1 (fr)
AU (1) AU2002227957A1 (fr)
BR (1) BR0116255A (fr)
CA (1) CA2431074A1 (fr)
CZ (1) CZ20031754A3 (fr)
HU (1) HUP0303289A2 (fr)
MX (1) MXPA03005405A (fr)
NO (1) NO20032772D0 (fr)
PL (1) PL361805A1 (fr)
SK (1) SK8082003A3 (fr)
WO (1) WO2002049650A2 (fr)

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GB0216027D0 (en) 2002-07-10 2002-08-21 Arachnova Therapeutics Ltd New therapeutic use
CA2470210A1 (fr) * 2001-12-17 2003-06-26 Altana Pharma Ag Nouvelle utilisation d'inhibiteurs de pde5
DE602004022284D1 (de) * 2003-05-15 2009-09-10 Roskamp Res Llc Verfahren zur herstellung von medikamenten zur verringerung der amyloid-abscheidung, amyloid-neurotoxizität und mikrogliosis
JP2006348024A (ja) * 2005-05-17 2006-12-28 Santen Pharmaceut Co Ltd アミジノ誘導体を有効成分として含む神経細胞の保護剤
DE602006020434D1 (de) * 2005-05-17 2011-04-14 Santen Pharmaceutical Co Ltd Ein aminderivat als wirkstoff enthaltender angiogeneseinhibitor
DE602006018725D1 (de) * 2005-05-17 2011-01-20 Santen Pharmaceutical Co Ltd Amidin-derivate zur verwendung in der vorbeugung oder behandlung von glaukom
US20100093810A1 (en) * 2007-10-05 2010-04-15 Alzheimer's Institute Of America, Inc. Pharmaceutical Compositions for Reducing Amyloid Deposition, Amyloid Neurotoxicity, and Microgliosis
PL2214666T3 (pl) * 2007-10-05 2014-06-30 Alzheimers Inst Of America Inc Sposób ograniczania powstawania złogów amyloidu, neurotoksyczności amyloidu i mikroglejozy przez zastosowanie enancjomeru (-)-nilwadypiny
EP2384196B1 (fr) * 2008-12-30 2017-09-13 Johansson, Pär Détection de patients dans un état critique présentant un risque accru de développer une défaillance viscérale et composés pour les traiter
KR20140063605A (ko) 2011-07-19 2014-05-27 인피니티 파마슈티칼스, 인코포레이티드 헤테로사이클릭 화합물 및 그의 용도
KR101643041B1 (ko) * 2014-04-25 2016-07-28 아주대학교산학협력단 프로테아좀 저해제 및 디히드로피리딘계 화합물을 유효성분으로 함유하는 암의 예방 또는 치료용 조성물

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CZ20031754A3 (cs) 2003-09-17
HUP0303289A2 (hu) 2004-01-28
AU2002227957A1 (en) 2002-07-01
US20040072846A1 (en) 2004-04-15
CA2431074A1 (fr) 2002-06-27
MXPA03005405A (es) 2003-09-25
KR20030059351A (ko) 2003-07-07
CN1481242A (zh) 2004-03-10
PL361805A1 (en) 2004-10-04
NO20032772L (no) 2003-06-18
NO20032772D0 (no) 2003-06-18
BR0116255A (pt) 2003-12-30
WO2002049650A3 (fr) 2002-10-31
WO2002049650A2 (fr) 2002-06-27
JP2004516269A (ja) 2004-06-03
SK8082003A3 (en) 2003-10-07
AR032009A1 (es) 2003-10-22

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