EP1791597A2 - Arzneimittel enthaltend carbonylverbindungen sowie deren verwendung - Google Patents

Arzneimittel enthaltend carbonylverbindungen sowie deren verwendung

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Publication number
EP1791597A2
EP1791597A2 EP05774750A EP05774750A EP1791597A2 EP 1791597 A2 EP1791597 A2 EP 1791597A2 EP 05774750 A EP05774750 A EP 05774750A EP 05774750 A EP05774750 A EP 05774750A EP 1791597 A2 EP1791597 A2 EP 1791597A2
Authority
EP
European Patent Office
Prior art keywords
amide
phenyl
pyrrolidine
dicarboxylic acid
oxo
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Withdrawn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
EP05774750A
Other languages
German (de)
English (en)
French (fr)
Inventor
Bertram Cezanne
Dieter Dorsch
Werner Mederski
Christos Tsaklakidis
Johannes Gleitz
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
Application filed by Merck Patent GmbH filed Critical Merck Patent GmbH
Publication of EP1791597A2 publication Critical patent/EP1791597A2/de
Withdrawn legal-status Critical Current

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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5355—Non-condensed oxazines and containing further heterocyclic rings
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • 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
    • 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
    • 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
    • A61P9/06—Antiarrhythmics
    • 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 the use of compounds of the formula
  • R 1 and R 2 together also form a bicyclically or spirocyclically bonded 3- to 7-membered carbo- or heterocycle having from 0 to 3 N, O and / or S atoms,
  • R 3 is H, A, HC ⁇ C-CH 2 -, CH 3 -C ⁇ C-CH 2 -, -CH 2 -CH (OH) -CH 2 OH,
  • R 4 is H or A
  • E together with W represents a 3- to 7-membered saturated carbocyclic or heterocyclic ring with O to 3 N, O to
  • D is a mononuclear or binuclear unsubstituted or mono- or polysubstituted by Hal, A, OR 3 , N (R 3 ) 2 , NO 2 , CN 1 COOR 3 or CON (R 3 ) 2 substituted aromatic Carbo- or
  • Y is alkylene, cycloalkylene, het-diyl or ar-diyl,
  • T is a mono- or binuclear saturated or unsaturated
  • Carbo or heterocycle having 0 to 4 N, O and / or S atoms, which is monosubstituted or disubstituted by O,
  • NOCOR 3 is substituted and further mono-, di- or trisubstituted by R 3 , Hal, A, - [C (R 4 ) 2 ] n -Ar, - [C (R 4 ) 2 ] n -Het, - C (R 4 ) 2 ] n -cycloalkyl, OR 3 , N (R 3 ) 2 , NO 2 , CN,
  • Phenyl, naphthyl or biphenyl Phenyl, naphthyl or biphenyl
  • Ar 1 is unsubstituted or mono-, di- or trisubstituted by Hal, A, OR 4 , N (R 4 ) 2 , NO 2 , CN, COOR 4 , CON (R 4 ) 2 , NR 4 COA,
  • Phenyl, naphthyl or biphenyl Phenyl, naphthyl or biphenyl
  • SO 2 NR 4 and / or S (O) n A may be substituted
  • j go 1, 2 or 3, as well as their pharmaceutically usable derivatives, solvates, salts and
  • Stereoisomers including mixtures thereof in all ratios, for the manufacture of a medicament for the prevention and treatment of
  • thromboembolic diseases and / or thromboses as a result of surgery, genetically determined diseases with increased thrombosis, diseases of the arterial and venous vascular system, heart failure, atrial fibrillation, thrombophilia, tinnitus and / or sepsis.
  • the object of the invention was to discover new uses of the compounds of the formulas I, in particular those which can lead to O0 production of medicaments.
  • 35 can therefore be used to combat and prevent thromboembolic
  • the compounds of the formula I can furthermore inhibitors of the 5
  • Aromatic amidine derivatives having an antithrombotic effect are known, for example, from 10 of EP 0 540 051 B1, WO 98/28269, WO 00/71508, WO 00/71511, WO 00/71493, WO 00/71507, WO 00/71509, WO 00 / 71512, WO 00/71515 or WO 00/71516.
  • Cyclic guanidines for the treatment of thromboembolic disorders are described, for example, in WO 97/08165, c.
  • Aromatic heterocycles having factor Xa inhibitory activity are known, for example, from WO 96/10022. Substituted N - [(aminoiminomethyl) -phenylalkyl] -azaheterocyclylamides as factor Xa inhibitors are described in WO 96/40679.
  • the antithrombotic and anticoagulant effect of the compounds of the formula I is attributed to the inhibiting action against the activated coagulation protease, known by the name of factor Xa, or to the Q inhibition of other activated serine proteases, such as factor VIIa, factor IXa or thrombin.
  • Factor Xa is one of the proteases involved in the complex process of
  • Factor Xa catalyzes the conversion of 5
  • thrombin in thrombin. Thrombin splits fibrinogen into fibrin monomers, which contribute to thrombus formation after cross-linking. A Activation of thrombin can lead to the occurrence of thromboembolic disorders. However, inhibition of thrombin may inhibit fibrin formation involved in thrombus formation.
  • the measurement of the inhibition of thrombin can e.g. according to method 5 of G. F. Cousins et al. in Circulation 1996, 94, 1705-1712.
  • Inhibition of factor Xa can thus prevent thrombin from being formed.
  • the compounds of the formula I and their salts intervene by inhibiting the factor Xa in the blood clotting process and thus inhibit the formation of thrombi.
  • Compounds and the measurement of the anticoagulant and anti-thrombotic activity can be determined by conventional in vitro or in vivo methods. A suitable method is described e.g. from J.
  • the measurement of inhibition of factor Xa may be e.g. according to the method of T. Hara et al. in Thromb. Haemostas. 1994, 71, 314-319. 5
  • Coagulation factor VIIa after binding to tissue factor, initiates the extrinsic part of the coagulation cascade and contributes to the activation of factor X to factor Xa. Inhibition of factor VIIa thus prevents the formation of factor Xa and thus subsequent thrombin formation.
  • the inhibition of factor VIIa by the compounds of formula I and the measurement of the anticoagulant and antithrombotic activity can be determined by conventional in vitro or in vivo methods.
  • a common method for measuring the inhibition of factor VIIa is, for example by Ronning et al. in Thrombosis Research 1996, 84, 73-81.
  • the coagulation factor IXa is generated in the intrinsic coagulation cascade and is also involved in the activation of factor X to factor Xa. Inhibition of factor IXa may thus otherwise prevent factor Xa from being formed.
  • the inhibition of factor IXa by the compounds of formula I and the measurement of the anticoagulant and antithrombotic activity can be determined by conventional in vitro or in vivo methods. A suitable method is described e.g. Chang et al. in Journal of Biological Chemistry 1998, 273, 12089-12094.
  • the compounds of the formula I can furthermore be used for the treatment of
  • Tumors, tumors and / or tumor metastases Tumors, tumors and / or tumor metastases.
  • the compounds of the formula I can be used as active pharmaceutical ingredients in the
  • thromboembolic diseases such as Thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty, intermittent claudication, venous thrombosis, pulmonary embolism, arterial
  • Thrombosis myocardial ischemia, unstable angina, and thrombosis 5-based stroke.
  • the compounds of the formula I are also used for the treatment or prophylaxis of arteriosclerotic diseases such as coronary arterial disease, cerebral arterial disease or peripheral arterial pressure
  • the compounds of the formula I are also used in combination with other thrombolytics in myocardial infarction, and also for the prophylaxis of reocclusion after thrombolysis, percutaneous transluminal
  • the compounds of the formula I are also used for the prevention of rethrombosis in microsurgery, as anticoagulants in connection with artificial organs or in hemodialysis.
  • the compounds of the formula I are furthermore used in the 0
  • tissue plasminogen activator t-PA, modified t-PA, streptokinase or urokinase.
  • the compounds are given with the other substances mentioned either simultaneously or before or after. Particularly preferred is concomitant administration of aspirin to prevent thrombosis formation.
  • Thrombosis as a result of surgical intervention, genetic disorders with increased susceptibility to thrombosis, diseases of the arterial and venous vascular system, heart failure, atrial
  • CABG Coronaary Artery Bypass
  • the invention also relates to the use of the compounds of
  • Formula I for the manufacture of a medicament for the prevention and treatment of thromboembolic disorders and / or
  • R 1 , R 2 , E, X, Y and T are as defined in claim 1, and W is
  • D and G are as defined in claim 1 and L is Cl, Br, I or a free or reactively functionally modified OH group,
  • Formula I also includes the optically active forms (stereoisomers), the enantiomers, the racemates, the diastereomers, and the hydrates and solvates of these compounds.
  • Solvates of the compounds are understood to mean additions of inert solvent molecules to the compounds which form due to their mutual attraction. Solvates are e.g. Mono or dihydrate or alcoholates.
  • compositions of the formula I are understood, for example, as the salts of the compounds of the formula I as well as so-called prodrug compounds.
  • Formula I also includes mixtures of the compounds of the formula I 1, for example mixtures of two diastereomers, for example in a ratio of 1: 1, 1: 2, 1: 3, 1: 4, 1: 5,
  • pyrrolidine-10-carboxylic acid derivatives is preferably selected from the group
  • the invention also provides the use of the cyclopentanecarboxylic acid derivatives selected from the group
  • Stereoisomers including mixtures thereof in all ratios.
  • A is alkyl, is unbranched (linear) or branched, and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms.
  • A is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1, 1, 1, 2 or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1, 1-, 1, 2-, 1, 3-,
  • Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl,
  • Alkylene is preferably methylene, ethylene, propylene, butylene,
  • Pentylene or hexylene, further branched alkylene Pentylene or hexylene, further branched alkylene.
  • COOR 3 such as COOA, OH, OA, NH 2 , alkyl having 1, 2, 3, 4, 5 or 6 C atoms, N 3 , ethynyl, vinyl, allyloxy, - OCOR 3 , such as methylcarbonyloxy, NHCOA, such as acetamino, or NHSO 2 A, such as methylsulfonylamino
  • OCH 2 COOA such as OCH 2
  • Het 1 is a saturated 3-6 membered heterocycle having from 1 to 3 N and / or O atoms, which is unsubstituted or mono- or disubstituted by
  • Carbonyl oxygen Hal, A, OH, NH 2 , NO 2 , CN, COOA or CONH 2 , may be substituted.
  • R 2 is H, A or OH
  • CONH 2 may be substituted.
  • Het 1 is a saturated 3-6 membered heterocycle having 1 to 3 N and / or O atoms, which may be unsubstituted or monosubstituted or disubstituted by carbonyl oxygen , Het 'in this context very particularly preferably means unsubstituted or monosubstituted by carbonyl oxygen
  • R 1 and R 2 together also mean one to the Ring system spirocyclic or bicyclic bound
  • the 3- to 6-membered carbo- or heterocycle e.g. Phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, imidazolyl, piperidinyl or 1,3-dioxolanyl.
  • R 1 and R 2 together in particular denote a
  • Carbocycle preferably cyclopropyl, cyclobutyl, cyclopentyl or
  • R 3 is preferably H or A, and also phenyl, benzyl or [C (R 4 ) 2 ] n COOA, such as, for example, CH 2 COOCH 3 .
  • R 4 is preferably H or A 1 very particularly preferably H.
  • COR 2 , COR 3 or COR 4 means, for example, CHO or -COA.
  • -COA acyl
  • acyl is preferably acetyl, propionyl, but also butyryl, pentanoyl, hexanoyl or e.g. Benzoyl.
  • Hal preferably denotes F, Cl or Br, but also I.
  • Ar means e.g. Phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p- tert
  • Ar is preferably, for example, unsubstituted or monosubstituted, disubstituted or trisubstituted by Hal, A, OR 2 , OR 3 , SO 2 A, COOR 2 or CN
  • Ar particularly preferably denotes, for example, phenyl which is unsubstituted or mono- or disubstituted by halogen, A 1 OA, phenoxy, SO 2 A, SO 2 NH 2 , COOR 2 or CN, such as, for example, phenyl, 2-methylsulfonylphenyl, 2-
  • Ar is unsubstituted phenyl, 4-
  • X is more preferably -CONH- or -CON (CH 2 COOA) -.
  • Y is preferably cycloalkylene, het-diyl or ar-diyl, particularly preferably unsubstituted or mono- or disubstituted by A, OA, Cl, F, COOCH 3 , COOH, phenoxy or aminocarbonyl-substituted 1,4-phenylene, and also pyridin-diyl , preferably pyridine-2,5-diyl; Piperidinediyl or cyclohexylene.
  • Y is in particular pyridine-diyl, piperidine-diyl, cyclohexylene or phenylene unsubstituted or mono- or disubstituted by A, OA, Cl, F, COOCH 3 , COOH, phenoxy or aminocarbonyl.
  • Het means e.g. 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2 -, 4- or 5-
  • B. also mean 2,3-dihydro-2-, -3-, -A- or -5-furyl, 2,5-dihydro-2-, -3-, -A- or 5-furyl, tetrahydro-2 - or -3-furyl, 1, 3-dioxolan-4-yl, tetrahydro-2- or 3-thienyl, 2,3-dihydro-1-, -2-, -3-, -A- or -5- pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -A- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2 - or 4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -A- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,
  • Het 1 is preferably, for example, 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or 5-imidazolyl, 1-, 3-, A- or 5-pyrazolyl, 2-, A- or 5-oxazolyl, 3-, A- or 5-isoxazolyl, 2-, A- or 5-thiazolyl, 3-, A- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably 1, 2,3-triazoM -, -A- or -5-yl, 1, 2,4-triazole-1 -, -3 - or 5-yl, 1- or 5-tetrazolyl, 1, 2,3-oxadiazol-4 or -5-yl, 1, 2,4-oxadiazol-3 or -5-yl, 1, 3,4 Thiadiazole-2 or -5-yl, 1, 2,4-thiadiazol-3 or -5-yl, 1, 2,3-
  • 5-, 6- or 7- benzisoxazolyl 2-, A-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, A, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, A-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, A-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-
  • heterocyclic radicals may also be partially or completely hydrogenated.
  • Het 'can so z. B. also mean 2,3-dihydro-2-, -3-, -4- or -5-furyl,
  • T preferably denotes, for example, 2-imino-piperidin-1-yl, 2-imino-pyrrolidin-1-yl, 2-imino-1H-pyridin-1-yl, 3-iminomorpholin-4-yl, 4-imino-1 / - / - pyridin-1-yl, 2,6-diimino-piperidin-1-yl, 2-iminopiperazin-1-yl, 2,6-diimino-piperazin-1-yl, 2.5 Diimino-pyrrolidin-1-yl, 2-imino-1,3-oxazolidin-3-yl, 3-imino-2 / - / - pyridazin-2-yl, 2-imino-azepan-i-yl, 2- Hydroxy-6-iminopiperazine-1-yl or 2-methoxy-6-iminopiperazine-1-yl.
  • T particularly preferably denotes piperidin-1-yl, pyrrolidin-1-yl, pyridin-1-yl, morpholin-4-yl, piperazin-1-yl, 1,3-oxazolidine which is monosubstituted or disubstituted by OO or NHNH 3-yl, pyridazin-2-yl, pyrazine-1-yl, azepan-1-yl, 2-azabicyclo [2.2.2] octan-2-yl, imidazolidinyl, thiazolyl or
  • T furthermore preferably also denotes 2-oxo-3-methoxy-1H-pyridin-1-yl.
  • D is preferably phenyl mono- or disubstituted by Hal, thienyl, pyridyl, furyl, thiazolyl, pyrrolyl or imidazolyl, particularly preferably mono- or di-substituted by Hal, phenyl, pyridyl, thienyl, furyl or imidazolyl.
  • the radical f J is preferably pyrrolidine-1, 2-diyl,
  • W is piperidine-1,2-diyl, piperidine-1,3-diyl, oxazolidine-3,4- or 3,5-diyl,
  • the compounds of the formula I can possess one or more chiral centers and therefore occur in different stereoisomeric forms.
  • Formula I encompasses all these forms.
  • the invention in particular the 0 use of those compounds of the formula I is 1 in which at least one of the said radicals has one of the preferred meanings indicated above.
  • Some preferred groups of compounds can be expressed by the following sub-formulas Ia to Iw, which correspond to the e formula I and in which the unspecified radicals have the meaning given in the formula I, wherein however
  • Carbo or heterocycle having 0 to 4 N, O and / or S
  • Ig Y is cycloalkylene, het-diyl or ar-diyl,
  • Ih Y is pyridine-diyl, piperidine-diyl, cyclohexylene or 1,4-phenylene unsubstituted or mono- or disubstituted by A, OA, Cl, F, COOCH 3 , COOH, phenoxy or aminocarbonyl;
  • Ii T is a mononuclear saturated or unsaturated
  • Il D a mono- or binuclear unsubstituted or mono- or disubstituted by HaI substituted aromatic carbocyclic or heterocycle having 0 to 4 N, O and / or S atoms,
  • R 1 and R 2 together also have a spirocyclic bond
  • R 3 is H, A, phenyl, benzyl or [C (R 4 ) 2 ] n COOA,
  • E together with W denotes a 3- to 7-membered saturated carbocyclic or heterocyclic ring having 0 to 3 N, O to 2 O and / or O to 2 S atoms, which may contain one double bond,
  • Y is cycloalkylene, het-diyl or ar-diyl
  • Ar is phenyl which is unsubstituted or mono- or disubstituted by Hal, A, OA, SO 2 A, COOR 2 , SO 2 NH 2 , CN, COOA, COOH or phenoxy,
  • T is a mononuclear saturated or unsaturated
  • Hal is F, Cl, Br or I, n is 0, 1 or 2;
  • R 4 is H or A
  • Y is pyridine-diyl, piperidine-diyl, cyclohexylene or unsubstituted or once or twice by A, OA,
  • Hal is F, Cl, Br or I, n is 0, 1 or 2;
  • R 1 is H, OO, COOR 3 , OH, OA, NH 2 , alkyl having 1, 2, 3, 4, 5 or 6 C atoms, N 3 , ethynyl, vinyl, allyloxy, -OCOR 3 ,
  • NHCOA or NHSO 2 A, R 2 H, O, OH, OA or alkyl having 1, 2, 3, 4, 5 or 6 C
  • R 1 and R 2 together also a spirocyclic bonded
  • T one or two carbonyl-substituted piperidin-1-yl, pyrrolidin-1-yl, 1 / - / - pyridine
  • Hal is F, Cl, Br or I, n is 0, 1 or 2,
  • R 1 H O, COOR 3 , OH, OA, NH 2 , alkyl with 1, 2, 3, 4, 5 or
  • R 2 H 0, OH, OA or alkyl with 1, 2, 3, 4, 5 or 6 C
  • R 1 and R 2 together also contain a spiro-cyclically bonded 3- to 6-membered carbocycle
  • R 3 is H or A
  • R 4 is H or A
  • Trifluoromethyl, ethyl, propyl, Cl or F is substituted 1,3,3 or 1,4-phenylene
  • T is morpholine-4-yl monosubstituted or disubstituted by carbonyl oxygen
  • A is unbranched or branched alkyl having 1-10 C
  • Hal is F, Cl, Br or I, n is 0, 1 or 2,
  • R 1 is H, OO, COOR 3 , OH, OA, NH 2 , alkyl having 1, 2, 3, 4, 5 or 6 C atoms, N 3 , ethynyl, vinyl, allyloxy, -OCOR 3 ,
  • R 1 and R 2 together also have a spirocyclic bond
  • R 3 is H or A
  • R 4 is H or A
  • T is mono- or di-carbonyl-substituted morpholin-4-yl
  • A is unbranched or branched alkyl of 1-10 C-
  • Hal denotes F, Cl 1 Br or I, n is 0, 1 or 2, mean
  • Is D a mono- or binuclear unsubstituted or mono- or disubstituted by Hal substituted aromatic carbocycle or heterocycle having 0 to 4 N, O and / or S atoms,
  • R 1 , R 2 are each, independently of one another, H, OO, COOR 3 , OH, OA, NH 2 , alkyl having 1, 2, 3, 4, 5 or 6 C atoms, N 3 , ethynyl, vinyl, allyloxy, OCOR 3 , NHCOA or NHSO 2 A,
  • R 1 and R 2 together also contain a spiro-cyclically bonded 3- to 6-membered carbocycle
  • R 3 is H or A, R 4 H or A 1
  • E together with W is a 3- to 7-membered saturated carbocyclic or heterocyclic ring having 0-3
  • N 0 to 2 O and / or 0 to 2 S atoms, which may contain one double bond, G (CH 2 ) n or (CH 2 ) n NH-,
  • Ar unsubstituted or mono- or disubstituted by Hal, A, OA, SO 2 A, COOR 2 , SO 2 NH 2 or CN substituted phenyl, T one or two times by carbonyl oxygen-substituted morpholin-4-yl, A is unbranched or branched alkyl 1-10 C-
  • R 1 H O, COOR 3 , OH, OA, NH 2 , alkyl with 1, 2, 3, 4, 5 or
  • R 1 and R 2 together also have a spirocyclic bond
  • R 3 is H or A
  • R 4 is H or A 1
  • Het ' is a saturated 3-6 membered heterocycle having 1 to 3 N and / or O atoms which is unsubstituted or mono- or disubstituted by carbonyl oxygen, Hal, A, OH, NH 2 , NO 2 , CN, COOA or CONH 2 , may be substituted
  • A is unbranched or branched alkyl with 1 -10 C
  • Hal is F, Cl, Br or I, n is O, 1 or 2;
  • R 1 and R 2 together also a spirocyclic bonded
  • X is CONH, COCH 2 , CO or COO, Y is unsubstituted or mono- or di-methyl,
  • N and / or O atoms which may be unsubstituted or mono- or disubstituted by carbonyl oxygen, Hal, A, OH, NH 2 , NO 2 , CN, COOA or CONH 2 , A is unbranched or branched alkyl with 1 -10 C
  • Hal is F, Cl, Br or I 1 n O 1 1 or 2; D phenyl mono- or disubstituted by Hal,
  • R 1 is ethynyl, vinyl, allyloxy, CH 3 -C ⁇ C-CH 2 -O-,
  • R 1 and R 2 together also have a spirocyclic bond
  • T is mono- or disubstituted by carbonyl oxygen or OA-substituted piperidine-1-yl, pyrrolidin-1-yl, 1 / - / - pyridine
  • Het 1 is a saturated 3-6 membered heterocycle having 1 to 3 N and / or O atoms which is unsubstituted or mono- or disubstituted by carbonyl oxygen, Hal, A, OH, NH 2 , NO 2 , CN, COOA or CONH 2 , may be substituted
  • A is unbranched or branched alkyl with 1 -10 C
  • Hal is F, Cl, Br or I, n is 0, 1 or 2;
  • R 1 H O, COOR 3 , OH, OA, NH 2 , alkyl of 1, 2, 3, 4, 5 or
  • R 2 H 0, OH, OA or alkyl with 1, 2, 3, 4, 5 or 6 C
  • R 1 and R 2 together also contain a spiro-cyclically bonded 3- to 6-membered carbocycle
  • R 3 is H or A
  • R 4 is H or A
  • Y is pyridine-diyl, piperidine-diyl, cyclohexylene or unsubstituted or once or twice by A, OA,
  • A is unbranched or branched alkyl with 1-10 C
  • Atoms and in which 1-7 H atoms may be replaced by F, Hal F, Cl, Br or I, n O, 1 or 2,
  • the starting materials may, if desired, also be formed in situ, so that they are not isolated from the reaction mixture, but immediately further reacted to the compounds of formula I.
  • the starting compounds of the formulas II, III, IV, V, VI are generally known. If they are new, they can be produced by methods known per se.
  • the reaction is usually carried out in an inert solvent, in the presence of an acid-binding agent, preferably 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, Calcium or cesium.
  • an acid-binding agent preferably 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, Calcium or cesium.
  • an organic base such as triethylamine, dimethylaniline, pyridine or quinoline or an excess of the phenol component of the formula II or of the alkylating derivative of the formula III may also be favorable.
  • the reaction time is between a few minutes and 14 days, depending on the conditions used, and the reaction temperature between about 0 ° 0 and 150 °, usually between 20 ° and 130 °.
  • 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
  • Ethylene glycol dimethyl ether diglyme
  • Ketones such as acetone or butanone
  • Amides such as acetamide, dimethylacetamide or dimethylformamide (DMF); Nitriles such as acetonitrile
  • Sulfoxides such as dimethylsulfoxide (DMSO); Sulfuric carbon
  • Carboxylic acids such as formic acid or acetic acid
  • esters such as ethyl acetate or
  • Compounds of the formula I can furthermore preferably be obtained by reacting compounds of the formula IV with compounds of the formula V.
  • the reaction is usually carried out in an inert solvent and under conditions as indicated above.
  • L is preferably Cl, Br, I or a free or reactively modified OH group, e.g. an activated ester, an imidazolide or alkylsulfonyloxy having 1-6 C atoms (preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxy having 6-10 C atoms (preferably phenyl- or p-tolylsulfonyl-o ⁇ y) -
  • an activated ester an imidazolide or alkylsulfonyloxy having 1-6 C atoms (preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxy having 6-10 C atoms (preferably phenyl- or p-tolylsulfonyl-o ⁇ y) -
  • an activated ester e.g. an imidazolide or alkylsulfony
  • Activated esters are conveniently formed in situ, e.g. B. by the addition of HOBt or N-hydroxysuccinimide.
  • the reaction is generally carried out in an inert solvent, in the presence of an acid-binding agent, preferably an organic base such as DIPEA, triethylamine, dimethylaniline, pyridine or quinoline or an excess of the carboxy component of the formula V.
  • an acid-binding agent preferably an organic base such as DIPEA, triethylamine, dimethylaniline, pyridine or quinoline or an excess of the carboxy component of the formula V.
  • an alkali or alkaline earth metal hydroxide, Carbonates or bicarbonate or another salt of a weak acid of the alkali or alkaline earth metals, preferably of potassium, sodium, calcium or cesium may be favorable.
  • reaction time is between a few minutes and 14 days depending on the conditions used, the reaction temperature between about
  • Suitable inert solvents are the abovementioned.
  • Compounds of the formula I can furthermore preferably be obtained by reacting compounds of the formula II with compounds of the formula VI.
  • the reaction is usually carried out in an inert solvent and under conditions as indicated above.
  • L preferably denotes Cl, Br, I or a free or a reactively modified OH group, such as e.g. an activated ester, an imidazolide or alkylsulfonyloxy having 1-6 C atoms (preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxy having 6-10 C atoms (preferably phenyl- or p-tolylsulfonyl-oxy).
  • an activated ester an imidazolide or alkylsulfonyloxy having 1-6 C atoms (preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxy having 6-10 C atoms (preferably phenyl- or p-tolylsulfonyl-oxy).
  • Compounds of formula I can be further preferably obtained by reacting a compound of formula D-NH 2 , wherein D has the meaning given in claim 1, with a chloroformate derivative, for example 4-Nitrophenylchlorformiat to an intermediate carbamate, and this then with a Compound of formula II implements.
  • a chloroformate derivative for example 4-Nitrophenylchlorformiat
  • Compounds of formula I can be further obtained by liberation of compounds of formula I from one of their functional derivatives by treatment with a solvolyzing or hydrogenolysing agent.
  • Preferred starting materials for the solvolysis or hydrogenolysis are those which otherwise correspond to the formula I, but instead of one or more free amino and / or hydroxyl groups contain corresponding protected amino and / or hydroxyl groups, preferably those which, instead of an H atom, which is connected to an N-atom, carry an amino protecting group, in particular those which replace one
  • HN group carry an R'-N group, wherein R 'is an amino protecting group means, and / or those which carry a hydroxy protecting group instead of the H atom of a hydroxy group, for example those which correspond to the formula I, but instead of a group -COOH carry a group -COOR ", wherein R" represents a hydroxy protecting group.
  • amino protecting group is well known and refers to groups that are capable of protecting (blocking) an amino group from chemical reactions, but which are easily removable after the desired chemical reaction has been performed elsewhere in the molecule is. Typical of such groups are in particular unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino protecting groups are according to the desired
  • acyl group is to be understood in the broadest sense in the context of the present process. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and in particular alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups.
  • acyl groups are alkanoyl such as acetyl, propionyl, butyryl; Aralkanoyl such as phenylacetyl; Aroyl such as benzoyl or toluyl; Aryloxyalkanoyl such as POA; Alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC (tert-butyloxycarbonyl), 2-iodoethoxycarbonyl; Aralkyloxycarbonyl, such as CBZ
  • Carbobenzoxy 4-methoxybenzyloxycarbonyl, FMOC; Arylsulfonyl like
  • Preferred amino protecting groups are BOC and Mtr, furthermore CBZ,
  • hydroxy protecting group is also well known and refers to groups which are suitable for protecting a hydroxy group from chemical reactions, but which are readily removable after the desired chemical reaction has been carried out at other sites on the molecule. Typical of such groups are the abovementioned unsubstituted or substituted aryl, aralkyl or acyl groups, and also alkyl groups.
  • the nature and size of the hydroxy-protecting groups is not critical since they are removed after the desired chemical reaction or reaction sequence; preferred are groups having 1-20, in particular 1-10 C-atoms.
  • hydroxy-protecting groups include benzyl, 4-methoxybenzyl, p-nitrobenzoyl, p-toluenesulfonyl, tert-butyl and acetyl, with benzyl and tert-butyl being particularly preferred.
  • Suitable inert solvents are preferably organic, for example carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as DMF, halogenated hydrocarbons such as dichloromethane, and also alcohols such as methanol,
  • Ethanol or isopropanol as well as water.
  • mixtures of the abovementioned solvents are also suitable.
  • TFA is preferably used in excess without addition of a further solvent, perchloric acid in the form of a mixture of acetic acid and 70% perchloric acid in a ratio of 9: 1.
  • the reaction temperatures for the cleavage are suitably between about 0 and about 50 °, preferably working between 15 and 30 ° (room temperature).
  • the groups BOC, OBut and Mtr can z. B. preferably with TFA in dichloromethane or with about 3 to 5n HCl in dioxane at 15-30 ° cleaved, the FMOC group with an about 5- to 50% solution of dimethylamine, diethylamine or piperidine in DMF at 15 -30 °.
  • Hydrogenolytically removable protecting groups may be e.g. by cleavage with hydrogen in the presence of a catalyst (e.g., a noble metal catalyst such as palladium, conveniently on a support such as carbon).
  • a catalyst e.g., a noble metal catalyst such as palladium, conveniently on a support such as carbon.
  • Suitable solvents are those given above, in particular z.
  • alcohols such as methanol or ethanol or amides such as DMF.
  • the hydrogenolysis is usually carried out at temperatures between about 0 and 100 ° and pressures between about 1 and 200 bar, preferably at 20-30 ° and 1-10 bar.
  • 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, trifluoromethylbenzene, 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);
  • Hydrocarbons such as hexane, petroleum ether, benzene, toluene
  • Ketones such as acetone or butanone; Amides such as acetamide,
  • DMF dimethylsulfoxide
  • DMSO dimethylsulfoxide
  • COD carbon disulphide
  • Carboxylic acids such as formic acid or acetic acid
  • Nitro compounds such as nitromethane or nitrobenzene
  • Esters such as ethyl acetate or mixtures of said solvents.
  • Esters can e.g. with acetic acid or with NaOH or KOH in water,
  • Water THF or water dioxane be saponified at temperatures between 0 and 100 °.
  • ⁇ c or THF and / or in the presence of a base such as triethylamine or pyridine at temperatures between -60 and + 30 °.
  • the present invention also encompasses the use of these compounds in the form of their pharmaceutically acceptable salts derived from various organic and inorganic acids and bases according to procedures known in the art
  • Such bases include, for example, alkali metal hydroxides, including potassium hydroxide, sodium hydroxide and lithium hydroxide; Alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide; Alkali metal alcoholates, e.g. Potassium ethanolate and sodium propanolate; such as
  • Hydrogen halides such as hydrogen chloride, hydrogen bromide 5 or hydrogen iodide, other mineral acids and their corresponding
  • Salts such as sulfate, nitrate or phosphate and the like, and alkyl and monoarylsulfonates such as ethanesulfonate, toluenesulfonate and benzenesulfonate, and other organic acids and their corresponding salts such as
  • pharmaceutically acceptable acid addition salts of the compounds of formula I include the following: acetate, adipate, alginate, arginate, aspartate,
  • ⁇ c benzoate benzenesulfonate (besylate), bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate, cyclopentaneproprionate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, galacterate (from mucic acid),
  • Preferred among the above salts are ammonium; the alkali metal salts sodium and
  • salts of the compounds of formula I which differ from pharmaceutically non-toxic organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, eg arginine, betaine, caffeine,
  • Alkyl halides e.g. Methyl, ethyl, isopropyl and tert-butyl chloride,
  • Di (Ci-C 4 ) alkyl sulfates for example dimethyl, diethyl and
  • compositions which are preferred include acetate, trifluoroacetate, besylate, citrate, fumarate, gluconate,
  • the free base can be prepared by contacting the salt form with a base and isolating the free base to usual
  • the free base forms differ in certain sense from their corresponding salt forms with respect to certain physical properties such as solubility in polar solvents; however, in the context of the invention, the salts otherwise correspond to their respective free base forms.
  • metals or amines such as alkali metals and alkaline earth metals or organic amines formed.
  • metals are sodium, potassium, magnesium and calcium.
  • Preferred organic amines are N, N'-dibenzylethylenediamine, chloroprocaine,
  • the base addition salts of acidic compounds of formula I are prepared by contacting the free acid form with a sufficient amount of the desired base to give the salt
  • the free acid can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner.
  • the free acid forms differ in some sense from their corresponding salt forms in terms of
  • OQ has certain physical properties such as solubility in polar
  • 35 can form pharmaceutically acceptable salts, the formula I also includes multiple salts.
  • Typical multiple salt forms include Example bitartrate, diacetate, difumarate, dimeglumine, diphosphate, disodium and trihydrochloride, but this is not intended to be limiting.
  • the term "pharmaceutically acceptable salt” in the present context means an active ingredient which contains a compound of the formula I in the form of one of its salts, especially if this salt form is the active ingredient in the Comparison to the free form of the active substance or
  • the pharmaceutically acceptable salt form of the active substance can also first give this active substance a desired pharmacokinetic property
  • the compounds of the formula I can, due to their molecular structure
  • Forms occur. They may therefore be in racemic or optically active form.
  • the pharmaceutical activity of the racemates or the stereoisomers of the compounds according to the invention may differ, it may be desirable to use the enantiomers.
  • the end product or else the intermediates may already be separated into enantiomeric compounds, chemical or physical measures known to those skilled in the art, or already be used as such in the synthesis.
  • racemic amines are formed from the mixture by reaction with an optically active release agent.
  • optically active acids such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (eg N-benzoylproline or N-benzenesulphonylproline) or the various optically active camphorsulphonic acids.
  • optically active acids such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (eg N-benzoylproline or N-benzenesulphonylproline) or the various optically active camphorsulphonic acids.
  • N-benzoylproline or N-benzenesulphonylproline
  • camphorsulphonic acids also advantageous is a chromat
  • Suitable mobile phase are aqueous or
  • the invention further provides the use of compounds according to one or more of claims 1-27, in combination with
  • the other active pharmaceutical ingredients are selected from the group of antithrombotics, antiarrhythmics, contraceptives, phosphodiesterase V inhibitors.
  • the antithrombotic is preferably selected from the group of vitamin K antagonists, heparin compounds, platelet
  • Aggregation inhibitors enzymes, factor Xa inhibitors, factor VIIa - 25
  • Inhibitors other antithrombotic agents, platelet glycoprotein receptor (IIb / IIIa) antagonists, thromboxane antagonists, platelet adhesion inhibitors.
  • the vitamin K antagonists are preferably selected from the group
  • the heparin compounds are preferably selected from the group heparin, antithrombin III, dalteparin, enoxaparin, nadroparin, pamaparin, reviparin, danaparoid, tinzaparin, sulodexide.
  • the platelet aggregation inhibitors are preferably selected from the group of ditazoles, cloricromen, picotamide, clopidogrel, ticlopidine, acetylsalicylic acid, dipyridamoles, calcium carbassalate, epoprostenol, indobufen, louprost, abciximab, tirofiban, aloxiprine, intrifiban.
  • the enzymes are preferably selected from the group streptokinase, alteplase, anistreplase, urokinase, fibrinolysin, brinase, reteplase, .g Saruplase.
  • the other antithrombotic agents are preferably selected from Defibrotide, Desirudin, Lepirudin.
  • the thromboxane antagonists are preferably selected from the
  • the antiarrhythmics are preferably selected from the group 25 a) quinidine, disopyramide, ajmaline, detmium, b) lidocaine, mexiletine, phenytoin, tocainide, c) propafenone, flecainide, d) metoprolol, esmolol, propranolol, atenolol, oxprenolol, 3Q e) Amiodarone, sotalol, f) diltiazem, verapamil, gallopamil, g) adenosine, orciprenaline, ipratropium, h) cardiac glycosides.
  • the contraceptives are preferably selected from the group desogestrel, medroxyprogesterone acetate, levonorgestrel, etonogestrel, norethisterone antagonist.
  • the PDE V - inhibitors are preferably selected from the group a) sildenafil (Viagra ®), tadalafil (Cialis ®), vardenafil (Levitra ®), b) the compounds of formula described in WO 99/55708 I
  • R 1 , R 2 are each independently H, A, OA, OH or Hal, R 1 and R 2 together also alkylene having 3-5 C atoms,
  • R s is cycloalkyl or cycloalkylalkylene having 5-12 C atoms
  • R 6 is phenyl or phenylmethyl
  • R 7 is COOH, COOA, CONH 2 , CONHA, CON (A) 2 or CN
  • A is alkyl having 1 to 6 C atoms and Hal are F, Cl, Br or I, and / or their physiologically acceptable salts and / or solvates,
  • R 1 , R 2 are each independently H, A or Hal, where one of the radicals R 1 or R 2 is always ⁇ H,
  • R 1 and R 2 together also alkylene having 3-5 C atoms
  • R 3 , R 4 are each independently H, A, OH, OA or Hal,
  • R 3 and R 4 together also alkylene having 3-5 C atoms
  • X is R 5 or R 6 which is monosubstituted by R 7 ,
  • R b is cycloalkylalkylene having 6-12 C atoms
  • R 7 is COOH, COOA, CONH 2 , CONHA, CON (A) 2 or CN,
  • A is alkyl having 1 to 6 C atoms
  • Hal is F, Cl, Br or I
  • m is 1 or 2 and n is 0, 1, 2 or 3, and / or their physiologically acceptable salts and / or solvates.
  • Preferred antithrombotics are also the platelet glycoprotein receptor (IIb / IIIa) antagonists, which inhibit platelet aggregation.
  • IIb / IIIa platelet glycoprotein receptor
  • Preferred compounds are e.g. described in EP 0 623 615 B1 on page 10 or in EP 0 741 133 A2 page 2, line 2 to page 4 line 56.
  • the invention further relates to medicaments containing (2R.4R) - 4-hydroxy-1-pyrrolidine-1, 2-dicarboxylic acid - [(4-chloro-phenyl) -amide] -2 - ⁇ [4- (3- A ⁇ oxo-morpholin-4-yl) -phenyl] -amide ⁇ and / or its pharmaceutically usable derivatives, solvates, salts and stereoisomers, including mixtures thereof in all ratios, and a further active agent selected from the group of antithrombotics,
  • Preferred groups of other active pharmaceutical ingredients are those described above.
  • preparations can be used as medicaments in human or veterinary medicine.
  • compositions can be in the form of dosage units which comprise a predetermined amount Q 3 of active ingredient per unit dose, darge be sufficient.
  • a unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg of a compound according to the invention, depending on the treatment
  • Condition of the patient, or pharmaceutical formulations may be in
  • dosage units containing a predetermined amount of active ingredient per Dose unit included to be presented.
  • Preferred dosage unit formulations are those containing a daily or partial dose as indicated above or a corresponding fraction thereof
  • compositions may be administered by any suitable route, for example, oral
  • formulations can be prepared by any method known in the pharmaceutical art, for example, by bringing the active ingredient together with the carrier (s) or excipient (s). 20
  • compositions adapted for oral administration may be administered as separate units, e.g. Capsules or tablets; Powder or granules; Solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam foods; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
  • the active drug component with an oral, Vietnamese ⁇ toxic and pharmaceutically acceptable inert excipient, such combined, such as ethanol, glycerol, water.
  • an oral, Vietnamese ⁇ toxic and pharmaceutically acceptable inert excipient such combined, such as ethanol, glycerol, water.
  • Powders are prepared by comminuting the compound to a suitable fine size
  • Carrier such as an edible carbohydrate such as Starch or mannitol is mixed.
  • a flavor, preservative, dispersant and dye may also be present.
  • Capsules are made by preparing a powder mix as described above and filling shaped gelatin casings therewith.
  • Lubricants such as e.g. fumed silica, talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form can be added to the powder mixture before the filling process.
  • a disintegrants or solubilizers e.g. Agar-agar, calcium carbonate or sodium carbonate may also be added to improve the availability of the drug after ingestion of the capsule.
  • suitable binding, lubricating and disintegrants as well as dyes can also be incorporated into the mixture.
  • suitable binders include starch, gelatin, natural sugars, e.g. Glucose or beta-lactose, corn sweeteners, natural and synthetic gums, e.g. acacia,
  • the lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc.
  • the disintegrating agents include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum, etc.
  • the tablets are formulated by, for example, preparing a powder mixture, granulating or extruding it dry, adding a lubricant and a disintegrating agent and compressing the whole into tablets.
  • a powder mixture is prepared by treating the appropriately comminuted compound with a diluent or a base as described above, and optionally with a binder such as carboxymethyl cellulose, an alginate, gelatin or polyvinylpyrrolidone, a dissolution initiator such as paraffin Absorption accelerator, such as a quaternary salt and / or an absorbent, such as bentonite, Kaolin or dicalcium phosphate.
  • the powder mixture can be granulated by being wetted with a binder, such as, for example, syrup, starch paste, Acadia slime or solutions of cellulose or polymer materials, and pressed through a sieve.
  • the powder mixture can be run through a tabletting machine to produce non-uniformly shaped lumps which are broken up into granules.
  • the granules may be greased by adding stearic acid, a stearate salt, talc or mineral oil to prevent sticking to the tablet molds. The greased mixture is then compressed into tablets.
  • the active compounds can also be combined with a free-flowing inert carrier and then pressed directly into tablets without carrying out the granulation or dry-pressing steps 5 .
  • a transparent or impermeable protective layer consisting of a shellac seal, a layer of sugar or polymeric material and a glossy layer of wax, may be present. Dyes can be added to these coatings in order to differentiate between different dosage units.
  • Oral fluids e.g. Solution, syrups and elixirs may be prepared in unit dosage form such that a given quantity will contain a predetermined amount of the compounds.
  • Syrups can be prepared by dissolving the compounds in an appropriate taste aqueous solution while making elixirs Q using a non-toxic alcoholic vehicle.
  • Suspensions can be formulated by dispersing the compounds in a non-toxic vehicle.
  • Solubilizers and emulsifiers e.g. ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavoring additives, such as e.g.
  • Peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, among others, may also be added.
  • the unit dosage formulations for oral administration may optionally be encapsulated in microcapsules.
  • the formulation can also be prepared so that the release is prolonged or retarded, such as by coating or embedding particulate material in polymers, wax and others
  • the compounds of formula I as well as salts, solvates and physiologically functional derivatives thereof as well as the other active substances can also be administered in the form of liposome delivery systems, such as e.g. small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • liposomes can be prepared from various phospholipids, such as e.g. Cholesterol, stearylamine or phosphatidylcholines.
  • the compounds of formula I as well as the salts, solvates and physiologically functional derivatives thereof as well as the other active compounds can also be delivered using monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • Drug carriers are coupled.
  • Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol or polyethyleneoxidepolylysine substituted with palmitoyl radicals.
  • Biodegradable polymers suitable for the controlled release of a drug e.g. Polylactic acid, polyepsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxypyrans, polycyano-acrylates, and cross-linked or amphipathic block copolymers of hydrogels.
  • Formulations can be used as separate patches for longer, narrow
  • the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3 (6), 318 (1986).
  • Pharmaceutical compounds adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
  • the formulations are preferably applied as a topical ointment or cream.
  • the active ingredient can be used with either a paraffinic or water miscible cream base. Alternatively, the active ingredient can become a
  • Cream can be formulated with an oil-in-water cream base or a water-in-oil base.
  • the pharmaceutical formulations adapted for topical application to the eye include eye drops, the active ingredient being dissolved or suspended in a suitable carrier, in particular an aqueous solvent.
  • Formulations include lozenges, lozenges and mouthwashes.
  • compositions adapted for rectal administration may be presented in the form of suppositories or enemas.
  • compositions adapted for nasal administration in which the carrier substance is a solid, contain a coarse
  • Powder with a particle size for example, in the range of 20-500
  • Micrometre, recorded in the manner of snuff is administered, ie by rapid inhalation via the nasal passages from a container held close to the nose with the powder.
  • Fine particulate dusts or mists which can be produced by means of 10 different types of pressurized dosing dispensers with aerosols, nebulizers or insufflators.
  • Vaginal administration adapted pharmaceutical formulations .. c tampons, creams, gels, pastes, foams or spray formulations may be presented as pessaries.
  • Formulations include aqueous and non-aqueous sterile injection
  • the formulations may be administered in single or multiple dose containers, e.g. sealed vials and vials, and stored in the freeze-dried (lyophilized) state so that only the addition of the sterile carrier liquid, e.g. Water for
  • Injection solutions and suspensions prepared by formulation can be prepared from sterile powders, granules and tablets.
  • formulations suitable for oral administration may contain other conventional means in the art with respect to the particular type of formulation; so can For example, formulations suitable for oral administration contain flavorings.
  • a therapeutically effective amount of a compound of formula I as well as the other active ingredient will depend on a number of factors, including e.g. the age and weight of the animal, the exact condition of the disease requiring treatment, as well as its severity, the nature of the formulation and the route of administration, and is ultimately determined by the attending physician or veterinarian.
  • an effective amount of a compound is generally in the range of 0.1 to 100 mg / kg of body weight of the recipient (mammal) per day, and more typically 5 in the range of 1 to 10 mg / kg of body weight per day.
  • the actual amount per day would usually be between 70 and 700 mg, this amount as a single dose per day or more commonly in a number of divided doses (such as two, three, four, five or six) per Can be given day so that the total daily dose is the same.
  • An effective amount of a salt or solvate or a physiologically functional derivative thereof can be determined as a proportion of the effective amount of the compound per se.
  • the invention furthermore relates to compounds selected from the group a) (2R, 4S) -4- (4-aminophenoxy) -pyrrolidine-1,2-dicarboxylic acid-1 - [(4-chlorophenyl) -amide] -2 - ⁇ [4- (3-oxomorpholin-4-yl) -phenyl] -amide ⁇ , Qb) (2R, 4R) -4-methoxy-pyrrolidine-1,2-dicarboxylic acid-1 - [( 4-chlorophenyl) amide] 2 - ⁇ [4- (2-imino-5-methyl- [1,4-thiadiazol-3-yl) -phenyl] -amide ⁇ , c) (2R, 4R ) -4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid-1 - [(4-chloro-phenyl) -amide] -2 - ⁇ [4- (2-imino-5-methyl- [1,4,6] thiadia
  • the invention also relates to medicaments containing at least one compound selected from the group a) (2R, 4S) -4- (4-amino-phenoxy) -pyrrolidine-1,2-dicarboxylic acid-1 - [(4-chloro-phenyl ) -amide] -2 - ⁇ [4- (3-oxomorpholin-4-yl) -phenyl] -amide ⁇ , b) (2R, 4R) -4-Methoxy-pyrrolidine-1,2-dicarboxylic acid-1 - [(4-chlorophenyl) amide] 2 - ⁇ [4- (2-imino-5-methyl- [1,4-thiadiazol-3-yl) -phenyl] -amide ⁇ , c) ( 2R, 4R) -4-ethoxy-pyrrolidine-1,2-dicarboxylic acid-1 - [(4-chloro-phenyl) -amide] -2 - ⁇ [4- (2-imino-5-
  • the invention thus also relates to the use of
  • reaction solution is then evaporated to dryness in vacuo, the residue is taken up in 10 ml of 5% strength sodium bicarbonate solution and the sodium bicarbonate solution is extracted twice with 10 ml of ethyl acetate each time. After drying the 0 combined organic phases over sodium sulfate and stripping off the solvent, the solid residue is triturated with 20 ml of diethyl ether.
  • 2- [4- (3-oxo-morpholin-4-yl) - phenylcarbamoyl] -pyrrolidine-1-carboxylic acid Feat-butyl ester as a white powder 5; ESI 390.
  • Dioxane is mixed with 40 ml of 4N hydrochloric acid in dioxane and stirred for 12 hours at room temperature. Subsequently, the failed
  • reaction mixture is allowed within two
  • Chlorphenylisocyanat added and stirred for one hour at this temperature. It is allowed to cool and the resulting precipitate is filtered off. The filtrate is acidified with 1 N HCl and the resulting
  • Formaldehyde solution added.
  • the resulting solution is allowed to stand for 18 hours
  • reaction mixture is evaporated and the residue is chromatographed on a silica gel column with dichloromethane / methanol 95: 5 as eluent: (2R, 4R) -4-hydroxypyrrolidine-1,2-dicarboxylic acid-1 - [(5-chloropyridin-2-yl) - amide] -2 - ⁇ [4- (2-oxo-2Ay-pyridin-1-yl) -phenyl] -amide ⁇ ("A6”) as a colorless solid, ESI 454.
  • Triethylamine added. The mixture is then dripped into the mixture
  • reaction mixture is then allowed to stir for 12 hours at room temperature, evaporated to dryness in vacuo, the residue is mixed with 20 ml of methylene chloride, the methylene chloride solution is washed successively with 10 ml of saturated common salt solution and water and dried over sodium sulfate. After filtering off the drying agent and stripping off the solvent on a rotary evaporator, the residue is triturated with 30 ml of diethyl ether.
  • DMF Dimethylformamide
  • triphenylphosphine in a mixture of 0.5 ml of tetrahydrofuran and 0.5 ml of water is stirred for 12 hours at room temperature.
  • the compounds are obtained from the 4-amino compounds by a) reaction with acetyl chloride
  • Example 7 Analogously to Example 7, the compound is obtained by reacting 1-B0C-piperazine-2-carboxylic acid [4- (3-oxomorpholin-4-yl) -phenyl] -amide with 4-chlorophenyl isocyanate
  • Example 7 Analogously to Example 7 is obtained from cis-N-Boc-4-ethoxy-D-proline the
  • reaction mixture is evaporated and dried: ⁇ 4- [2- (2-chloroethoxy) -acetylamino] -phenyl ⁇ -acetic acid ethyl ester as a yellowish solid; ESI 300.
  • reaction mixture is concentrated, the residue dissolved in water and acidified to pH 3 with 1 N hydrochloric acid. It is extracted with ethyl acetate and the organic phase dried over sodium sulfate and evaporated: 4- (3-oxomorpholin-4-yl) -phenylacetic acid as a yellowish solid; ESI 236.
  • NMO N-methylmorpholine N-oxide
  • reaction mixture 25 added potassium osmate dihydrate and stirred for 48 hours. Subsequently, the reaction mixture is mixed with 6.6 g (52.6 mmol) of sodium sulfite and stirred for one more hour at room temperature. Thereafter, the reaction mixture is concentrated in vacuo, the residue in 50 ml of water

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