ZA200508891B - Pyrazolidine-1,2-dicarboxyldiphenylamide derivatives as coagulation factor Xa inhibitors for the treatment of thromboses - Google Patents

Pyrazolidine-1,2-dicarboxyldiphenylamide derivatives as coagulation factor Xa inhibitors for the treatment of thromboses Download PDF

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ZA200508891B
ZA200508891B ZA200508891A ZA200508891A ZA200508891B ZA 200508891 B ZA200508891 B ZA 200508891B ZA 200508891 A ZA200508891 A ZA 200508891A ZA 200508891 A ZA200508891 A ZA 200508891A ZA 200508891 B ZA200508891 B ZA 200508891B
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phenyl
dicarboxamide
oxo
hal
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ZA200508891A
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Mederski Werner
Dorsch Dieter
Gleitz Johannes
Tsaklakidis Christos
Cezanne Bertram
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Merck Patent Gmbh
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Description

®o © 1-N- (PHENYL) -2-N- (PHENYL) PYRAZOLIDINE-1, 2-DICARBOXAMIDE DERIVATIVES AS
COAGULATION FACTOR XA INHIBITORS FOR THE TREATMENT OF THROMBOSES
The invention relates to compounds of the formula
R! uy " aaa
Ls
N © R? in which
R denotes H, A, A-CO-, Hal, -C=C-H, -C=C-A or -C=C-C(=0)-A,
R’ denotes H, =O, Hal, A, OH, OA, A-COO-, Ph-(CH;),-COO-, cycloalkyl-(CH,),-COO-, A-CONH-, A-CONA-, Ph-CONA-, Ns,
NH, NO,, CN, COOH, COOA, CONH,, CONHA, CON(A);,
O-allyl, O-propargyl, O-benzyl, =N-OH, =N-OA or =CF,
Ph denotes phenyl which is unsubstituted or mono-, di- or trisub- stituted by A, OA or Hal,
R? denotes H, Hal or A,
R® denotes a monocyclic saturated, unsaturated or aromatic het- 05 erocycle having 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di- or trisubstituted by Hal, A, OA,
CN, (CH2),OH, (CH,).Hal, NR‘R® =NH, =N-OH, =N-OA and/or carbonyl oxygen (=0), or CONRR?,
R* R® independently of one another, denote H or A,
R*and R®> together also denote an alkylene chain having 3, 4 or 5 C atoms, which may also be substituted by A, Hal, OA and/or carbonyl oxygen (=CO),
® © -2-
A denotes unbranched, branched or cyclic alkyl having 1-10 C atoms, in which 1-7 H atoms may also be replaced by F and/or chlorine,
Hal denotes F, Cl, Br or |, n denotes 0, 1, 2, 3 or 4, and pharmaceutically usable derivatives, salts, solvates and stereo- isomers thereof, including mixtures thereof in all ratios.
The invention had the object of finding novel compounds having valuable g properties, in particular those which can be used for the preparation of medicaments.
It has been found that the compounds of the formula | and salts thereof have very valuable pharmacological properties and are well tolerated. In particular, they exhibit factor Xa-inhibiting properties and can therefore be employed for combating and preventing thromboembolic diseases, such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apo- plexy, angina pectoris, restenosis after angioplasty and claudicatio inter- mittens.
The compounds of the formula | according to the invention may further- more be inhibitors of the coagulation factors factor Vila, factor IXa and thrombin in the blood coagulation cascade.
Aromatic amidine derivatives having an antithrombotic action are dis- closed, for example, in EP 0 540 051 B1, WO 98/28269, WO 00/71508,
WO 00/71511, WO 00/71493, WO 00/71507, WQ 00/71508,
WO 00/71512, WO 00/71515 or WO 00/71516. Cyclic guanidines for the treatment of thromboembolic diseases are described, for example, in
WO 97/08165. Aromatic heterocyclic compounds having a factor Xa inhi-
® © | -3- bitory activity are disclosed, for example, in WO 96/10022. Substituted
N-[(aminoiminomethyl)phenylalkyl]azaheterocyclylamides as factor Xa in- hibitors are described in WO 96/40679.
Other carboxamide derivatives are known from WO 02/48099 and
S WO 02/572386, other pyrrolidine derivatives are described in
WO 02/100830.
Further heterocyclic derivatives are known from WO 03/045912.
The antithrombotic and anticoagulant effect of the compounds according = to the invention is attributed to the inhibitory action against activated co- agulation protease, known by the name factor Xa, or to the inhibition of other activated serine proteases, such as factor Vila, factor IXa or throm- bin.
Factor Xa is one of the proteases involved in the complex process of blood coagulation. Factor Xa catalyses the conversion of prothrombin into throm- bin. Thrombin cleaves fibrinogen into fibrin monomers, which, after cross- linking, make an elementary contribution to thrombus formation. Activation of thrombin may result in the occurrence of thromboembolic diseases.
However, inhibition of thrombin may inhibit the fibrin formation involved in
E 25 thrombus formation.
The inhibition of thrombin can be measured, for example by the method of
G. F. Cousins et al. in Circulation 1996, 94, 1705-1712.
Inhibition of factor Xa can thus prevent the formation of thrombin.
The compounds of the formula | according to the invention and salts thereof engage in the blood coagulation process by inhibiting factor Xa and thus inhibit the formation of thrombuses.
oo oe
The inhibition of factor Xa by the compounds according to the invention 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, for example, by J. Hauptmann et al. in Thrombosis
S and Haemostasis 1990, 63, 220-223.
The inhibition of factor Xa can be measured, for example by the method of
T. Hara et al. in Thromb. Haemostas. 1994, 71, 314-319.
Coagulation factor Vlla initiates the extrinsic part of the coagulation cas-
EB cade after binding to tissue factor and contributes to the activation of fac- tor X to give factor Xa. Inhibition of factor Vila thus prevents the formation of factor Xa and thus subsequent thrombin formation.
The inhibition of factor Vila by the compounds according to the invention and the measurement of the anticoagulant and antithrombotic activity can be determined by conventional in-vitro or in-vivo methods. A conventional method for the measurement of the inhibition of factor Vlla is described, for example, by H. F. Ronning et al. in Thrombosis Research 1996, 84, 73-81.
Coagulation factor 1Xa is generated in the intrinsic coagulation cascade and is likewise involved in the activation of factor X to give factor Xa. Inhi- bition of factor 1Xa can therefore prevent the formation of factor Xa in a different way.
The inhibition of factor IXa by the compounds according to the invention 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, for example, by J. Chang et al. in Journal of Biologi- cal Chemistry 1998, 273, 12089-12094. :
® © -5-
The compounds according to the invention may furthermore be used for the treatment of tumours, tumour diseases and/or tumour metastases.
A correlation between tissue factor TF / factor Vila and the development of various types of cancer has been indicated by T.Taniguchi and N.R.
Lemoine in Biomed. Health Res. (2000), 41 (Molecular Pathogenesis of
Pancreatic Cancer), 57-59.
The publications listed below describe an antitumoural action of TF-VII and factor Xa inhibitors in various types of tumour:
K.M. Donnelly et al. in Thromb. Haemost. 1998; 79: 1041-1047;
E.G. Fischer et al. in J. Clin. Invest. 104: 1213-1221 (1999),
B.M. Mueller et al. in J. Clin. Invest. 101: 1372-1378 (1998),
M.E. Bromberg et al. in Thromb. Haemost. 1999; 82: 88-92
The compounds of the formula | can be employed as medicament active ingredients in human and veterinary medicine, in particular for the treat- ment and prevention of thromboembolic diseases, such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty, claudicatio intermittens, venous thrombosis, pulmonary embolism, arterial thrombosis, myocardial ischae- mia, unstable angina and strokes based on thrombosis.
The compounds according to the invention are also employed for the treatment or prophylaxis of atherosclerotic diseases, such as coronary arterial disease, cerebral arterial disease or peripheral arterial disease.
The compounds are also employed in combination with other thrombolytic agents in myocardial infarction, furthermore for prophylaxis for reocclusion after thrombolysis, percutaneous transluminal angioplasty (PTCA) and coronary bypass operations.
The compounds according to the invention are furthermore used for the prevention of rethrombosis in microsurgery, furthermore as anticoagulants in connection with artificial organs or in haemodialysis.
® © 6-
The compounds are furthermore used in the cleaning of catheters and medical aids in patients in vivo, or as anticoagulants for the preservation of blood, plasma and other blood products in vitro. The compounds according to the invention are furthermore used for diseases in which blood coagula- tion makes a crucial contribution toward the course of the disease or represents a source of secondary pathology, such as, for example, in can- cer, including metastasis, inflammatory diseases, including arthritis, and diabetes.
The compounds according to the invention are furthermore used for the treatment of migraine (F. Morales-Asin et al., Headache, 40, 2000, 45-47).
In the treatment of the diseases described, the compounds according to the invention are also employed in combination with other thrombolytically active compounds, such as, for example, with the "tissue plasminogen activator" t-PA, modified t-PA, streptokinase or urokinase. The compounds according to the invention are administered either at the same time as or before or after the other substances mentioned.
Particular preference is given to simultaneous administration with aspirin in order to prevent recurrence of the clot formation.
The compounds according to the invention are also used in combination with blood platelet glycoprotein receptor (lIb/1l1a) antagonists, which inhibit blood platelet aggregation.
The invention relates to the compounds of the formula | and salts thereof and to a process for the preparation of compounds of the formula | accord- ing to Claims 1-10 and pharmaceutically usable derivatives, solvates and stereoisomers thereof, characterised in that a) a compound of the formula Il oo 7-
Hw 1 in which R has the meaning indicated in Claim 1, is reacted with a chloroformate derivative to give an intermediate car- bamate derivative, which is subsequently reacted with a compound of the formula 11-1
V R
Re ee
H § 1-1
Re in which
R' R? and R® have the meaning indicated in Claim 1, and, if R' denotes OH, the OH group is optionally in protected form, and subsequently, if desired, the OH-protecting group is removed, : 25 Of b) a compound of the formula IV
R2
HN
R3 IV, in which R? and R® have the meaning indicated in Claim 1,
® © -8- is reacted with a chloroformate derivative to give an intermediate car- bamate derivative, which is subsequently reacted with a compound of the fotnula 111-2
R
R
TL ¥ 1-2
EN
H © in which R and R' have the meaning indicated in Claim 1, and, if R' denotes OH, the OH group is optionally in protected form, and subsequently, if desired, the OH-protecting group is removed, and/or a base or acid of the formula | is converted into one of its salts.
The invention also relates to the optically active forms (stereoisomers), the enantiomers, the racemates, the diastereomers and the hydrates and sol- os vates of these compounds. The term solvates of the compounds is taken to mean adductions of inert solvent molecules onto the compounds which form owing to their mutual attractive force. Solvates are, for example, mono- or dihydrates or alcoholates.
The term pharmaceutically usable derivatives is taken to mean, for exam- ple, the salts of the compounds according to the invention and so-called prodrug compounds. :
The term prodrug derivatives is taken to mean compounds of the formula which have been modified with, for example, alkyl or acyl groups, sugars lo 2005/0850c+ ® © -9- or oligopeptides and which are rapidly cleaved in the organism to form the active compounds according to the invention.
These also include biodegradable polymer derivatives of the compounds according to the invention, as described, for example, in Int. J. Pharm. 115, 61-67 (1995).
The invention also relates to mixtures of the compounds of the formula according to the invention, for example mixtures of two diastereomers, for example in the ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000.
These are particularly preferably mixtures of stereoisomeric compounds.
For all radicals which occur more than once, such as, for example, A, their meanings are independent of one another.
Above and below, the radicals or parameters R, R? and R® have the meanings indicated under the formula |, unless expressly stated otherwise.
A denotes alkyl, is unbranched (linear) or branched, and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms. A preferably denotes 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-ethyl- propyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-,1,2-,1,3-,2,2-,23-0r 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2- methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, furthermore preferably, for example, trifluoromethyl.
A very particularly preferably denotes alkyl having 1, 2, 3,4,50r6 C atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethyl or 1,1,1-trifluoro- ethyl. A also denotes cycloalkyl.
Cycloalky! preferably denotes cyclopropyl, cyclobutyl, cyclopentyl, cyclo- hexyl or cycloheptyl.
® © -10 -
Alkylene preferably denotes methylene, ethylene, propylene, butylene, pentylene or hexylene, furthermore branched alkylene.
R preferably denotes Hal or -C=C-H.
R' preferably denotes H, =O, OH, OA, A-COO-, Ph-(CH,),-COO- or cyclo- alkyl-(CH,),-COO-, particularly preferably H, =O or OH.
R? preferably denotes H, Cl, F or alkyl having 1-6 C atoms, such as, for example, methyl, ethyl, propyl, butyl or trifluoromethyl.
R® preferably denotes a monocyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, which may be unsubsti- tuted or mono-, di- or trisubstituted by Hal, A, OA, =NH and/or carbonyl oxygen (=O), or R® also denotes CONR*R®.
R® particularly preferably denotes 2-oxopiperidin-1-yl, 2-oxopyrrolidin-1-yl, 2-ox0-1H-pyridin-1-yl, 3-oxomorpholin-4-yl, 4-oxo-1H-pyridin-1-yl, 2-oxo- 1H-pyrazin-1-yl, 2-oxoimidazolidin-1-yl, 2-iminopiperidin-1-yl, 2-imino- pyrrolidin-1-yl, 3-iminomorpholin-4-yl, 2-iminoimidazolidin-1-yl, 2-imino- 1H-pyrazin-1-yl, 2,6-dioxopiperidin1-yl, 2-oxopiperazin-1-yl, 2,6-dioxo- g 25 piperazin-1-yl, 2,5-dioxopyrrolidin-1-yl, 2-oxo-1,3-oxazolidin-3-yl, 3-oxo- 2H-pyridazin-2-yl, 2-caprolactam-1-yl (= 2-oxoazepan-1-yl), 2-azabicyclo- [2.2.2]octan-3-on-2-yl, 5,6-dihydro-1H-pyrimidin-2-oxo-1-yl, 2-oxo-1,3- oxazinan-3-yl, 4H-1,4-oxazin-4-yl, furyl, thienyl, pyrrolyl, imidazolyl, pyra- zolyl, oxazoly!, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, tri- azolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, optionally mono- or disubstituted by Hal and/or A, or CONR'R’.
In a further embodiment, R® preferably denotes 2-oxopiperidin-1-yl, 2-oxo- pyrrolidin-1-yl, 2-oxo-1H-pyridin-1-yl, 3-oxomorpholin-4-yl, 4-oxo-1H-pyri-
® © -11 - din-1-yl, 2-oxo0-1H-pyrazin-1-yl, 2-oxoimidazolidin-1-yl, 2-iminopiperidin-1- yl, 2-iminopyrrolidin-1-yi, 3-iminomorpholin-4-yl, 2-iminoimidazolidin-1-yl, 2-imino-1H-pyrazin-1-yl, 2,6-dioxopiperidin-1-yl, 2-oxopiperazin-1-yl, 2,6- dioxopiperazin1-yl, 2,5-dioxopyrrolidin-1-yl, 2-oxo-1,3-oxazolidin-3-yl, 3-
S oxo-2H-pyridazin-2-yl, 2-caprolactam-1-yl (= 2-oxoazepan-1-yl), 2-aza- bicyclo[2.2.2]octan-3-on-2-yl, 5,6-dihydro-1H-pyrimidin-2-oxo-1-yl, 2-oxo- 1,3-0xazinan-3-yl, 4H-1,4-oxazin-4-yl, optionally mono- or disubstituted by
Hal and/or A.
R® very particularly preferably denotes 2-oxopiperidin-1-yl, 2-oxopyrrolidin- a 1-yl, 2-oxo0-1H-pyridin-1-yl, 3-oxomorpholin-4-yl, 4-oxo-1H-pyridin-1-y|, 2-ox0-1H-pyrazin-1-yl, 2-oxoimidazolidin-1-yl, 2,6-dioxopiperidin1-yl, 2-oxopiperazin-1-yl, 2,6-dioxopiperazin-1-yl, 2,5-dioxopyrrolidin-1-yl, 2-ox0-1,3-oxazolidin-3-yl, 3-oxo-2H-pyridazin-2-yl, 2-caprolactam-1-yl (= 2-oxoazepan-1-yl), 2-azabicyclo[2.2.2]-octan-3-on-2-yl, 5,6-dihydro-1H- pyrimidin-2-oxo-1-yl, 2-oxo-1,3-oxazinan-3-yl or 4H-1,4-oxazin-4-yl.
In CONR*R®, NR*R® preferably denotes methylamino, dimethylamino, ethylamino, diethylamino, pyrrolidino or piperidino.
The compounds of the formula | can have one or more centres of chirality . 25 and can therefore occur in various stereoisomeric forms. The formula encompasses all these forms.
Accordingly, the invention relates, in particular, to the compounds of the formula | 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-formulae la to Ih, which conform to the formula | and in which the radicals not designated in greater detail have the meaning indicated under the formula |, but in which

Claims (1)

  1. Patent Claims
    1. Compounds of the formula R1 (Dh R at Aa CL A, © N © R3 in which R denotes H, A, A-CO-, Hal, -C=C-H, -C=C-A or -C=C- C(=0)-A, R' denotes H, =O, Hal, A, OH, OA, A-COO-, Ph-(CHa).- COO-, cycloalkyl-(CH5),-COO-, A-CONH-, A-CONA-, Ph-CONA-, Nj, NH, NO,, CN, COOH, COOA, CONH,, CONHA, CON(A),, O-ally!, O-propargyl, O-benzyl, =N- OH, =N-OA or =CF,, Ph denotes phenyl which is unsubstituted or mono-, di- or trisubstituted by A, OA or Hal, -” R? denotes H, Hal or A, R® denotes a monocyclic saturated, unsaturated or aro- matic heterocycle having 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di- or trisubsti- tuted by Hal, A, OA, CN, (CH,).OH, (CH;).Hal, NR*R®, =NH, =N-OH, =N-OA and/or carbony! oxygen (=O), or CONR’R®, R* R® independently of one another, denote H or A, R*and R® together also denote an alkylene chain having 3, 4 or 5 C atoms, which may also be substituted by A, Hal, OA and/or carbonyl oxygen (=CO),
    ® © - 55 - A denotes unbranched, branched or cyclic alkyl having 1-10 C atoms, in which 1-7 H atoms may also be replaced by F and/or chlorine, Hal denotes F, Cl, Bror |, n denotes 0, 1, 2, 3 or 4, and pharmaceutically usable derivatives, salts, solvates and stereo- isomers thereof, including mixtures thereof in all ratios. Lo 2. Compounds according to Claim 1, in which R denotes Hal or -C=C-H, and pharmaceutically usable derivatives, salts, solvates and stereo- isomers thereof, including mixtures thereof in all ratios.
    3. Compounds according to Claim 1 or 2, in which R® denotes a monocyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di- or trisubstituted by Hal, A, OA, =NH and/or carbonyl oxygen (=O), or CONR‘R® : 25 R* R°, independently of one another, denote H or A, R* and R® together also denote an alkylene chain having 3, 4 or 5 C atoms, and pharmaceutically usable derivatives, salts, solvates and stereo- isomers thereof, including mixtures thereof in all ratios.
    4. Compounds according to one or more of Claims 1-3, in which : R® denotes 2-oxopiperidin-1-yl, 2-oxopyrrolidin-1-yl, 2-oxo- 1H-pyridin-1-yl, 3-oxomorpholin-4-yl, 4-oxo-1H-pyridin-1- yl, 2-0x0-1H-pyrazin-1-yl, 2-oxoimidazolidin-1-yl, 2-imino-
    ® Oo - 56 - piperidin-1-yl, 2-iminopyrrolidin-1-yl, 3-iminomorpholin-4- yl, 2-iminoimidazolidin-1-yl, 2-imino-1H-pyrazin-1-yl, 2,6- dioxopiperidin1-yl, 2-oxopiperazin-1-yl, 2 ,6-dioxopiperazin- 1-yl, 2,5-dioxopyrrolidin-1-yl, 2-oxo0-1,3-0xazolidin-3-yl, S 3-ox0-2H-pyridazin-2-yl, 2-caprolactam-1-yl (= 2-oxoaze- pan-1-yl), 2-azabicyclo[2.2.2]-octan-3-on-2-yl, 5,6-dihydro- 1H-pyrimidin-2-oxo-1-yl, 2-oxo0-1,3-oxazinan-3-yl, 4H-1,4- oxazin-4-yl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimi- dinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyrida- " zinyl or pyrazinyl, optionally mono- or disubstituted by Hal and/or A, or CONR'R®, R* R®, independently of one another, denote H or A, R* and R® together also denote an alkylene chain having 3, 4or 5 C atoms, and pharmaceutically usable derivatives, salts, solvates and stereo- isomers thereof, including mixtures thereof in all ratios.
    5. Compounds according to one or more of Claims 1-4, in which R denotes H, =0, OH, OA, A-COO-, Ph~(CH,),-COO-, cycloalkyl-(CH,),-COO-, Ph denotes unsubstituted phenyl, and pharmaceutically usable derivatives, salts, solvates and stereo- isomers thereof, including mixtures thereof in all ratios.
    6. Compounds according to one or more of Claims 1-5, in which R denotes Hal or -C=C-H, R' denotes H, =O, OH, OA, A-COO-, Ph-(CH;),-COO-, cycloalkyl-(CH),-COO-,
    ® Oo -57 - Ph denotes unsubstituted phenyl, R? denotes H, Hal or A, R® denotes 2-oxopiperidin-1-yl, 2-oxopyrrolidin-1-yl, 2-oxo- 1H-pyridin-1-yl, 3-oxomorpholin-4-yl, 4-oxo-1H-pyridin- S 1-yl, 2-ox0-1H-pyrazin-1-yl, 2-oxoimidazolidin-1-yl, 2- iminopiperidin-1-yl, 2-iminopyrrolidin-1-yl, 3-iminomor- pholin-4-yl, 2-iminoimidazolidin-1-yl, 2-imino-1H-pyra- zin-1-yl, 2,6-dioxopiperidin1-yl, 2-oxopiperazin-1-yl, 2,6- dioxopiperazin-1-yl, 2,5-dioxopyrrolidin-1-yl, 2-oxo-1,3- oxazolidin-3-yl, 3-oxo0-2H-pyridazin-2-yl, 2-caprolactam- fo 1-yl (= 2-oxoazepan-1-yl), 2-azabicyclo[2.2.2]-octan-3- on-2-yl, 5,6-dihydro-1H-pyrimidin-2-oxo-1-yl, 2-oxo-1,3- oxazinan-3-yl, 4H-1,4-oxazin-4-yl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, iso- thiazolyl, pyridyl, pyrimidinyl, triazolyl, tetrazolyl, oxadi- azolyl, thiadiazolyl, pyridaziny! or pyrazinyl, optionally mono- or disubstituted by Hal and/or A, or CONR‘R®, R* R®, independently of one another, denote H or A, R*and R® together also denote an alkylene chain having 3, 4 or 5 : 25 C atoms, and pharmaceutically usable derivatives, salts, solvates and stereo- isomers thereof, including mixtures thereof in all ratios.
    7. Compounds according to one or more of Claims 1-6, in which rR’ denotes 2-oxopiperidin-1-yl, 2-oxopyrrolidin-1-yl, 2-oxo- 1H-pyridin-1-yl, 3-oxomorpholin-4-yl, 4-oxo-1H-pyridin-1- yl, 2-oxo-1H-pyrazin-1-yl, 2-oxoimidazolidin-1-yl, 2-imino- piperidin-1-yl, 2-iminopyrrolidin-1-yl, 3-iminomorpholin-4- yl, 2-iminoimidazolidin-1-yl, 2-imino-1H-pyrazin-1-yl, 2,6-
    © 0 -56- dioxopiperidin1-yl, 2-oxopiperazin-1-yl, 2,6-dioxopiperazin- 1-yl, 2,5-dioxopyrrolidin-1-yl, 2-oxo-1,3-oxazolidin-3-yl, 3- oxo-2H-pyridazin-2-yl, 2-caprolactam-1-yl (= 2-oxoazepan- 1-yl), 2-azabicyclo[2.2.2}-octan-3-on-2-yl, 5,6-dihydro-1H- pyrimidin-2-oxo-1-yl, 2-oxo-1,3-oxazinan-3-yl or 4H-1,4- oxazin-4-yl, optionally mono- or disubstituted by Hal and/or A, and pharmaceutically usable derivatives, salts, solvates and stereo- isomers thereof, including mixtures thereof in all ratios. vo 8. Compounds according to one or more of Claims 1-7, in which R® denotes 2-oxopiperidin-1-yl, 2-oxopyrrolidin-1-yl, 2-oxo- 1H-pyridin-1-yl, 3-oxomorpholin-4-yl, 4-oxo-1H-pyridin-1- yl, 2-ox0-1H-pyrazin-1-yl, 2-oxoimidazolidin-1-yl, 2,6-di- oxopiperidini-yl, 2-oxopiperazin-1-yl, 2,6-dioxopiperazin- 1-yl, 2,5-dioxopyrrolidin-1-yl, 2-oxo-1,3-oxazolidin-3-yl, 3- ox0-2H-pyridazin-2-yl, 2-caprolactam-1-yl (= 2-oxoazepan- 1-yl), 2-azabicyclo[2.2.2]-octan-3-on-2-yl, 5,6-dihydro-1H- pyrimidin-2-oxo-1-yl, 2-oxo-1,3-oxazinan-3-y! or 4H-1,4- oxazin-4-yl, and pharmaceutically usable derivatives, salts, solvates and stereo- isomers thereof, including mixtures thereof in all ratios.
    9. Compounds according to one or more of Claims 1-8, in which R denotes Hal or -C=C-H, R’ denotes H, =0, OH, OA, A-COO-, Ph-(CH,),-COO-, cycloalkyl-(CH2),-COO-, Ph denotes unsubstituted phenyl, R? denotes H, Hal or A. R® denotes 2-oxopiperidin-1-yl, 2-oxopyrrolidin-1-yl, 2-oxo- 1H-pyridin-1-yl, 3-oxocmorpholin-4-y|, 4-oxo-1H-pyridin-
    CI 59. 1-yl, 2-ox0-1H-pyrazin-1-yl, 2-oxoimidazolidin-1-yl, 2,6- dioxopiperidin1-yl, 2-oxopiperazin-1-yl, 2,6-dioxopipera- zin-1-yl, 2,5-dioxopyrrolidin-1-yl, 2-oxo-1,3-oxazolidin-3- yl, 3-oxo0-2H-pyridazin-2-yl, 2-caprolactam-1-yl (= 2-0x0- azepan-1-yl), 2-azabicyclo[2.2.2]-octan-3-on-2-yl, 5,6- dihydro-1H-pyrimidin-2-oxo-1-yl, 2-oxo-1,3-oxazinan-3- yl or 4H-1 4-oxazin-4-yl, A denotes unbranched, branched or cyclic alkyl having 1-10 C atoms, in which 1-7 H atoms may also be replaced by F and/or chlorine, oo Hal denotes F, Cl, Bror |, n denotes 0, 1, 2, 3 or 4, and pharmaceutically usable derivatives, salts, solvates and stereo- isomers thereof, including mixtures thereof in all ratios.
    10. Compounds according to Claim 1 selected from the group 1-N-[(4-ethynylpheny!)]-2-N-{[3-chloro-4-(3-oxomorpholin-4- yl)phenyl]}pyrazolidine-1,2-dicarboxamide, 1-N-[(4-chlorophenyl)]-2-N-{[3-chloro-4-(3-oxomorpholin-4-yl)- phenyl]}pyrazolidine-1,2-dicarboxamide, - 25 1-N-[(4-chloropheny!)]-2-N-{[4-(3-oxomorpholin-4-yl)pheny!]}-4- hydroxypyrazolidine-1,2-dicarboxamide, 1-N-[(4-chloropheny!)}-2-N-{[4-(2-oxo-2H-pyridin-1-yl)phenyl]}- 4-hydroxypyrazolidine-1,2-dicarboxamide, 1-N-[(4-chlorophenyl)]-2-N-{[4-(2-oxopiperidin-1-yl)phenyl]}-4- hydroxypyrazolidine-1,2-dicarboxamide, 1-N-[(4-chloropheny!)]-2-N-{[3-methyl-4-(3-oxomorpholin-4-yl)- phenyl]}-4-hydroxypyrazolidine-1,2-dicarboxamide, 1-N-[(4-chloropheny!)]-2-N-{[3-methyl-4-(2-oxopyrrolidinyl)- phenyl]}-4-hydroxypyrazolidine-1,2-dicarboxamide,
    ® Oo - 60 - 1-N-[(4-chlorophenyt)]-2-N-{[3-fluoro-4-(3-oxomorpholin-4-yl)- phenyl]}-4-hydroxypyrazolidine-1,2-dicarboxamide, 1-N-[(4-chlorophenyt)]-2-N-{[3-chloro-4-(3-oxomorpholin-4-yl)- phenyl]}-4-hydroxypyrazolidine-1,2-dicarboxamide, 3 1-N-[(4-chlorophenyl)]-2-N{[3-fluoro-4-(2-oxopyrrolidinyl)- phenyl]}-4-hydroxypyrazolidine-1,2-dicarboxamide, 1-N-[(4-chlorophenyl)]-2-N-{[3-chloro-4-(2-oxo-2H-pyridin-1-yi)- phenyl]}-4-hydroxypyrazolidine-1,2-dicarboxamide, 1-N-[(4-chloropheny!)]-2-N-{[4-(2-azabicyclo[2.2.2]-octan-3-on- 2-yl)phenyl]}-4-hydroxypyrazolidine-1,2-dicarboxamide, co 1-N-[(4-chlorophenyl)]-2-N-{[3-trifluoromethyl-4-(2-azabicyclo-
    [2.2.2]-octan-3-on-2-yl)phenyl]}-4-hydroxypyrazolidine-1,2-dicarbox- amide, 1-N-[(4-chloropheny!)]-2-N-{[3-chloro-4-(2-azabicyclo[2.2.2]- octan-3-on-2-yl)phenyl]}-4-hydroxypyrazolidine-1,2-dicarboxamide, 1-N-[(4-chloropheny!)]-2-N-{[4-(2-ox0-2H-pyridin-1-yl)phenyl]}- pyrazolidine-1,2-dicarboxamide, 1-N-[(4-chloropheny!)]-2-N-{[3-methyl-4-(3-oxomorpholin-4-yl)- phenyl]}pyrazolidine-1,2-dicarboxamide, 1-N-[(4-chlorophenyl)]-2-N-{[3-fluoro-4-(3-oxomorpholin-4-yl)- phenyl]}pyrazolidine-1,2-dicarboxamide, 1-N-[(4-chloropheny!)]-2-N-{[3-chloro-4-(2-oxo-2H-pyridin-1-y1)- phenyl]}pyrazolidine-1,2-dicarboxamide, 1-N-[(4-chloropheny!)]-2-N-{[3-chloro-4-(2-azabicyclo[2.2 2] octan-3-on-2-yl)phenyl]}pyrazolidine-1,2-dicarboxamide, 1-N-[(4-chlorophenyl)]-2-N-{[3-methyl-4-(2-oxopyrrolidinyl)- phenyl]}pyrazolidine-1,2-dicarboxamide, 1-N-{(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-4- oxopyrazolidine-1,2-dicarboxamide, 1-N-[(4-chloropheny!)}-2-N-{[4-(2-oxopiperidinyl)pheny!]}pyra- zolidine-1,2-dicarboxamide,
    ® Oo -61 - 1-N-[(4-chloropheny!)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}- pyrazolidine-1,2-dicarboxamide, 1-N-{(4-chlorophenyl)]-2-N-{[2-fluoro-4-(3-oxomorpholin-4-yl)- phenyl]}pyrazolidine-1,2-dicarboxamide, 1-N-[(4-chloropheny!)]-2-N~{[3-trifluoromethyl|-4-(2-azabicyclo-
    [2.2.2]-octan-3-on-2-yl)phenyl]}pyrazolidine-1,2-dicarboxamide, 1-N-[(4-chloropheny!)]-2-N-{[4-(2-azabicyclo[2.2.2]-octan-3-on- 2-yl)phenyl]}pyrazolidine-1,2-dicarboxamide, 1-N-[(4-chlorophenyl)]-2-N-{[4-(2-ox0-1,3-0xazinan-3-yl)- phenyl]}pyrazolidine-1,2-dicarboxamide, 1-N-[(4-ethynylphenyl)]-2-N-{[4-(2-ox0-2H-pyridin-1-yl)phenyi]}- pyrazolidine-1,2-dicarboxamide, 1-N-[(4-ethynylpheny!)]-2-N-{[3-methyl-4-(3-oxomorpholin-4-yl)- phenyl]}pyrazolidine-1,2-dicarboxamide, 1-N-[(4-ethynylphenyl)]-2-N-{[3-chloro-4-(3-oxomorpholin-4-yl)- phenyl]}-4-hydroxypyrazolidine-1,2-dicarboxamide, 1-N-[(4-ethynylphenyl)]-2-N-{[4-(2-ox0-2H-pyridin-1-yl)phenyl]}- 4-hydroxypyrazolidine-1,2-dicarboxamide, 1-N-[(4-ethynylpheny!)]-2-N-{[3-methyl-4-(3-oxomorpholin-4-yl)- phenyl]}-4-hydroxypyrazolidine-1,2-dicarboxamide, 1-N-[(4-ethynylpheny!)]-2-N-{[3-chloro-4-(3-oxomorpholin-4-yl)- phenyl]}-(R)-4-hydroxypyrazolidine-1,2-dicarboxamide, 1-N-[(4-ethynylphenyl)]-2-N-{[4-(2-oxo-2H-pyridin-1-yl)phenyl]}- (R)-4-hydroxypyrazolidine-1,2-dicarboxamide, 1-N-[(4-ethynylphenyl)]-2-N-{[3-methyI-4-(3-oxomorpholin-4-yl)- phenyl]}-(R)-4-hydroxypyrazolidine-1,2-dicarboxamide, 1-N-[(4-ethynylphenyl)]-2-N-{[3-chloro-4-(3-oxomorpholin-4-yl)- phenyl]}-(S)-4-hydroxypyrazolidine-1,2-dicarboxamide, 1-N-[(4-ethynylpheny!)]-2-N-{[4-(2-oxo-2H-pyridin-1-yl)phenyl]}- (S)-4-hydroxypyrazolidine-1,2-dicarboxamide,
    ® Oo -62- 1-N-[(4-ethynylpheny!)]-2-N-{[3-methyl-4-(3-oxomorpholin-4-yl)- phenyl]}-(S)-4-hydroxypyrazolidine-1,2-dicarboxamide, 1-N-[(4-ethynylphenyl)]-2-N-{[3-chioro-4-(3-oxomorpholin-4-yl)- phenyl]}-4-acetoxypyrazolidine-1,2-dicarboxamide,
    S 1-N-[(4-ethynylpheny!)]-2-N-{[4-(2-oxo-2H-pyridin-1 -yh)phenyl]}-
    4-benzylcarbonyloxypyrazolidine-1,2-dicarboxamide, 1-N-[(4-ethynylpheny!)]-2-N-{[3-methyl-4-(3-oxomorpholin-4-yl)- phenyl]}-4-benzoyloxypyrazolidine-1,2-dicarboxamide,
    1-N-[(4-ethynylphenyl)]-2-N-{[3-chloro-4-(3-oxomorpholin-4-yl)- phenyl]}-4-tert-butylcarbonyloxypyrazolidine-1,2-dicarboxamide,
    : 1-N-[(4-ethynylphenyl)]-2-N~{[4-(2-oxo-2H-pyridin-1-yl)phenyl]}- 4-isobutylcarbonyloxypyrazolidine-1,2-dicarboxamide,
    1-N-[(4-ethynylpheny!)]-2-N-{[3-methy|-4-(3-oxomorpholin-4-yl)- phenyl]}-4-cyclohexylmethylcarbonyloxypyrazolidine-1,2-dicarbox- amide,
    1-N-[(4-ethynylphenyl)]-2-N-{[3-chloro-4-(3-oxomorpholin-4-yl)- phenyl]}-4-cyclopentylcarbonyloxypyrazolidine-1,2-dicarboxamide,
    1-N-[(4-ethynyiphenyl)]-2-N-{[4-(2-ox0-2H-pyridin-1-yl)phenyl]}- 4-cyclopropyimethylcarbonyloxypyrazolidine-1,2-dicarboxamide,
    1-N-[(4-ethynylphenyl)]-2-N-{[3-methyl-4-(3-oxomorpholin-4-yl)- phenyl]}-4-cyclobutylcarbonyloxypyrazolidine-1,2-dicarboxamide, B 25 1-N-[(4-bromopheny!)]-2-N-{[4-(2-ox0-2H-pyridin-1-yl)pheny!]}- pyrazolidine-1,2-dicarboxamide, 1-N-[(4-bromophenyl)]-2-N-{[4-(2-ox0-2H-pyridin-1-yl)phenyl]}- 4-hydroxypyrazolidine-1,2-dicarboxamide,
    1-N-[(4-bromophenyl)}-2-N-{[4-(2-ox0-2H-pyridin-1-yl)phenyl]}-
    (S)-4-hydroxypyrazolidine-1,2-dicarboxamide, 1-N-[(4-bromopheny!)]-2-N-{[4-(2-oxo-2H-pyridin-1-yl)phenyl]}- (R)-4-hydroxypyrazolidine-1,2-dicarboxamide,
    © eo -60- and pharmaceutically usable derivatives, salts, solvates and stereo- isomers thereof, including mixtures thereof in all ratios.
    11. Process for the preparation of compounds of the formula | according to Claims 1-10 and pharmacettically usable derivatives, salts, sol- vates and stereoisomers thereof, characterised in that a) acompound of the formula li R NH, J in which R has the meaning indicated in Claim 1, is reacted with a chloroformate derivative to give an intermediate carbamate derivative, which is subsequently reacted with a compound of the formula 11-1 R! N [ Re yy il-1 0 | ) Re in which R', R? and R® have the meaning indicated in Claim 1, and, if R' denotes OH, the OH group is optionally in protected form, and subsequently, if desired, the OH-protecting group is removed, or b) a compound of the formula IV
    © 0 -64- R2 H,N R3 Vv, in which R? and R® have the meaning indicated in Claim 1, is reacted with a chloroformate derivative to give an intermediate carbamate derivative, which is subsequently reacted with a compound of the formula 111-2 R R { NH TL N 11-2 “No H in which R and R' have the meaning indicated in Claim 1, and, if R' denotes OH, the OH group is optionally in protected form, and subsequently, if desired, the OH-protecting group is removed, - 25 and/or a base or acid of the formula | is converted into one of its salts.
    12. Compounds of the formula | according to one or more of Claims 1 to 10 as inhibitors of coagulation factor Xa.
    13. Compounds of the formula | according to one or more of Claims 1 to 10 as inhibitors of coagulation factor Vlla.
    ® 0 -65-
    14. Medicaments comprising at least one compound of the formula according to one or more of Claims 1 to 10 and/or pharmaceutically usable derivatives, saits, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and optionally excipients and/or adjuvants.
    15. Medicaments comprising at least one compound of the formula according to one or more of Claims 1 to 10 and/or pharmaceutically usable derivatives, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and at least one further medicament active ingredient.
    16. Use of compounds according to one or more of Claims 1 to 10 and/or physiologically acceptable salts and solvates thereof for the prepara- tion of a medicament for the treatment of thromboses, myocardial in- farction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty, claudicatio intermittens, migraine, tumours, tumour diseases and/or tumour metastases. ) 17 Set (kit) consisting of separate packs of (a) an effective amount of a compound of the formula | according to one or more of Claims 1 to 10 and/or pharmaceutically usable derivatives, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and (b) an effective amount of a further medicament active ingredi-
    ent.
    18. Use of compounds of the formula | according to one or more of Claims 1 to 10 and/or pharmaceutically usable derivatives, salts,
    ® © - 66 - solvates and stereoisomers thereof, including mixtures thereof in all ratios, for the preparation of a medicament for the treatment of thromboses, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty, claudicatio intermittens, migraine, tumours, tumour diseases and/or tumour metastases, in combination with at least one further medicament active ingredient.
    19. Intermediate compounds of the formula Iil-1 - R! (A= : GA TCA 0 Re : in which R’ denotes H, =O, Hal, A, OR? OA, A-COO-, Ph-(CH)x- COO-, cycloalkyl-(CH,),-COO-, A-CONH-, A-CONA-, Ph-CONA-, N3, NH;, NO,, CN, COOH, COOA, CONHj, CONHA, CON(A),, O-ally!l, O-propargyl, O-benzyl, =N-OH, =N-OA, or =CF,, oo 25 Ph denotes phenyl! which is unsubstituted or mono-, di- or trisubstituted by A, OA or Hal, R? denotes H, Hal or A, R® denotes a monocyclic saturated, unsaturated or aro- matic heterocycle having 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di- or trisubsti- tuted by Hal, A, OA, CN, (CH,).0OH, (CH,).Hal, NR*R® =NH, =N-OH, =N-OA and/or carbonyl oxygen (=O), CONR'R’, R* R® independently of one another, denote H or A,
    © 0 7- R*and R® together also denote an alkylene chain having 3, 4 or 5 C atoms, which may also be substituted by A, Hal, OA and/or carbonyl oxygen (=CO), R® denotes an OH-protecting group, A denotes unbranched, branched or cyclic alkyl having 1-10 C atoms, in which 1-7 H atoms may also be replaced by F and/or chlorine, Hal denotes F, Cl, Bror |, n denotes 0, 1, 2, 3 or 4, and isomers and salts thereof.
    20. Intermediate compounds according to Claim 19, in which R’ denotes H, =0, OR®, OA, A-COO-, Ph-(CH,),-COO- or cycloalkyl-(CH2),-COO-, Ph denotes unsubstituted phenyl, R? denotes H, Hal or A, rR? denotes 2-oxopiperidin-1-yl, 2-oxopyrrolidin-1-yl, 2-oxo- 1H-pyridin-1-yl, 3-oxomorpholin-4-yl, 4-oxo-1H-pyridin- 1-yl, 2-0x0-1H-pyrazin-1-yl, 2-oxoimidazolidin-1-yl, 2,6- dioxopiperidin1-yl, 2-oxopiperazin-1-yl, 2,6-dioxopipera- - 25 zin-1-yl, 2,5-dioxopyrrolidin-1-yl, 2-oxo-1,3-oxazolidin-3- yl, 3-oxo-2H-pyridazin-2-yl, 2-caprolactam-1-yl (= 2-oxo- azepan-1-yl), 2-azabicyclo[2.2.2]-octan-3-on-2-yl, 5,6- dihydro-1H-pyrimidin-2-oxo-1-yl, 2-ox0-1,3-oxazinan-3- yl or 4H-1,4-oxazin-4-y|, R® denotes an OH-protecting group, A denotes unbranched, branched or cyclic alkyl having 1-10 C atoms, in which 1-7 H atoms may also be replaced by F and/or chlorine, Hal denotes F, CI, Bror |,
    ® Oo -68 - n denotes 0, 1, 2, 3 or 4, and isomers and salts thereof.
    21. Intermediate compounds according to Claim 20, S in which R’ denotes H, =O or OR®, R? denotes H, Hal or A, R® denotes 2-oxopiperidin-1-yl, 2-oxopyrrolidin-1-yl, 2-oxo- 1H-pyridin-1-yl, 3-oxomorpholin-4-yl, 4-oxo-1H-pyridin- 1-yl, 2-ox0-1H-pyrazin-1-yl, 2-oxoimidazolidin-1-yl, 2,6- oo dioxopiperidin1-yl, 2-oxopiperazin-1-yl, 2,6-dioxopipera- zin-1-yl, 2,5-dioxopyrrolidin-1-yl, 2-oxo-1,3-oxazolidin-3- yl, 3-ox0-2H-pyridazin-2-yl, 2-caprolactam-1-yl (= 2-oxo- azepan-1-yl), 2-azabicyclo[2.2.2}-octan-3-on-2-yl, 5,6- dihydro-1H-pyrimidin-2-oxo-1-yl, 2-oxo-1,3-0xazinan-3- yl, 4H-1,4-oxazin-4-yl, R® denotes an alkylsilyl protecting group, A denotes unbranched, branched or cyclic alkyl having 1-10 C atoms, in which 1-7 H atoms may also be replaced by F and/or chlorine, Hal denotes F, Ci, Br or |, oo 25 n denotes 0, 1, 2, 3 or 4, and isomers and salts thereof.
    22. Intermediate compounds of the formula 1lI-2 Rt i Ch Hi-2 . OL H
    ® © _69- in which R denotes H, A, A-CO-, Hal, -C=C-H, -C=C-A or -C=C-C(=0)-A, rR’ denotes H, =O, Hal, A, OR®, OA, A-COO-, Ph-(CHa)x- COO-, cycloalkyl-(CH2),-COO-, A-CONH-, A-CONA-, Ph-CONA-, N3, NH, NO2, CN, COOH, COOA, CONH, CONHA, CON(A),, O-allyl, O-propargyl, O-benzyl, =N- OH, =N-OA or =CF,, Ph denotes phenyl which is unsubstituted or mono-, di- or trisubstituted by A, OA or Hal, B R® denotes an OH-protecting group, A denotes unbranched, branched or cyclic alkyl having 1-10 C atoms, in which 1-7 H atoms may also be replaced by F and/or chlorine, Hal denotes F, Cl, Br or |, n denotes 0, 1, 2, 3 or 4, where, if R' denotes H, R does not denote Cl, and isomers and salts thereof.
    23. Intermediate compounds according to Claim 22, in which R denotes Hal or -C=C-H, R' denotes H, =O, OR®, OA, A-COO-, Ph-(CH,),-COO- or cycloalkyl-(CH;),-COO-, Ph denotes phenyl which is unsubstituted or mono-, di- or trisubstituted by A, OA or Hal, R® denotes an OH-protecting group, A denotes unbranched, branched or cyclic alkyl having 1-10 C atoms, in which 1-7 H atoms may also be replaced by F and/or chlorine, Hal denotes F, Cl, Br or |,
    ® -70- PCT/EP2004/002407 n denotes 0, 1, 2, 3 or 4, where, if R' denotes H, R does not denote Cl, and isomers and salts thereof.
    24. intermediate compounds according to Claim 22, in which R denotes Hal or -C=C-H, rR denotes H, =0 or OR®, R® denotes an alkylsilyl protecting group, Hal denotes F, CI, Bror |, . where, if R' denotes H, R does not denote Cl, and isomers and salts thereof.
    25. . Intermediate compounds of the formula VI : R1 i [ _NH N Vi R7 in which R’ denotes OH or OR?, R® denotes a silyl protecting group, rR’ denotes tert-butyloxycarbonyl (BOC) or benzyloxy- carbonyl! (Z), and isomers thereof.
    26. Process for the preparation of compounds of the formula VI Rr? ! { NH VI R7 in which AMENDED SHEET
    ® -71- PCT/EP2004/002407 R! denotes OH or OR®, R® denotes a silyl protecting group, R’ denotes tert-butyloxycarbonyl (BOC) or benzyloxycarbonyl (2), - 5 and isomers thereof, obtainable by reaction of a compound of the formula VII R’-NHNH, VII, in which R” denotes BOC or Z, with silyl-protected 1,3-dibromopropan-2-ol, and optionally subsequent removal of the protecting group.
    27. Use of a compound of the formula | according to one or more of Claims 1 to 10 in the manufacture of a medicament for inhibiting coagulation factor Xa.
    28. Use of a compound of the formula | according to one or more of Claims 1 to 10 in the manufacture of a medicament for inhibiting coagulation factor Vila.
    20. Use of compounds of the formula | according to one or more of Claims 1 to 10 and/or pharmaceutically usable derivatives, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and at least one further medicament active ingredient for the’ preparation of a medicament for the treatment of thromboses, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty, claudicatio intermittens, migraine, tumours, tumour diseases and/or tumour metastases. } AMENDED SHEET -
    @® -72- PCT/EP2004/002407
    30. A substance or composition for use in a method of inhibiting coagulation factor Xa, said substance or composition comprising a compound of the formula | according to one or more of Claims 1 to 10, and said method comprising administering said substance or composition.
    31. A substance or composition for use in a method of inhibiting coagulation factor Vlla, said substance or composition comprising a compound of the formula | according to one or more of Claims 1 to 10, and said method comprising administering said substance or composition.
    32. A substance or composition for use in a method for the treatment of thromboses, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty, claudicatio intermittens, migraine, tumours, tumour diseases and/or tumour metastases, said substance or composition comprising a compound according to one or more of Claims 1 to 10 and/or physiologically acceptable salts and solvates thereof, and said method comprising administering said substance or composition.
    33. A substance or composition for use in a method for the treatment of thromboses, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty, claudicatio intermittens, migraine, tumours, tumour diseases and/or tumour metastases, said substance or composition comprising a compound of the formula | according to one or more of Claims 1 to 10 and/or pharmaceutically usable derivatives, salts, solvates and : stereoisomers thereof, including mixtures thereof in all ratios, and at least one further medicament active ingredient, and said method comprising administering said substance or composition. AMENDED SHEET
    ® -73- PCT/EP2004/002407
    34. A substance or composition for use with at least one further medicament active ingredient in a method for the treatment of thromboses, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty, claudicatio intermittens, migraine, tumours, tumour diseases and/or tumour metastases, said substance or composition comprising a compound of the formula | according to one or more of Claims 1 to 10 and/or pharmaceutically usable derivatives, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and said method comprising administering said substance or composition and said at least one further medicament active ingredient.
    35. A compound according to any one of claims 1 to 10, 12, 13 or 19 to 25, substantially as herein described and illustrated.
    36. A process according to claim 11 or claim 26, substantially as herein described and illustrated.
    37. A medicament according to claim 14 or claim 15, substantially as herein described and illustrated.
    38. Use according to any one of claims 16, 18 or 27 to 29, substantially as herein described and illustrated.
    39. A set (kit) according to claim 17, substantially as herein described and illustrated.
    40. A substance or composition for use in a method of treatment according to any one of claims 30 to 34, substantially as herein described and illustrated. AMENDED SHEET
    ® -74 - PCT/EP2004/002407
    41. A new compound, a new process for the preparation of a compound, a new medicament, a new use of a compound as claimed in any one of claims 1 to 10, a new use of a compound as claimed in any one of claims 1 to 10 and/or at least one further medicament active ingredient, a new set (kit), or a substance or composition for a new use in a method of treatment, substantially as herein described. AMENDED SHEET
ZA200508891A 2003-04-03 2005-11-02 Pyrazolidine-1,2-dicarboxyldiphenylamide derivatives as coagulation factor Xa inhibitors for the treatment of thromboses ZA200508891B (en)

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ZA200508891A ZA200508891B (en) 2003-04-03 2005-11-02 Pyrazolidine-1,2-dicarboxyldiphenylamide derivatives as coagulation factor Xa inhibitors for the treatment of thromboses
ZA200508889A ZA200508889B (en) 2003-04-03 2005-11-02 Pyrrolidino-1,2-dicarboxy-1-(phenylamide)-2-(4-(3-oxomorpholino-4-yl)-phenylamide) derivatives and related compounds for use as inhibitors of coagulation factor Xa in the treatment of thrombo-embolic diseases

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DE102004045796A1 (en) * 2004-09-22 2006-03-23 Merck Patent Gmbh Medicaments containing carbonyl compounds and their use
US8563573B2 (en) 2007-11-02 2013-10-22 Vertex Pharmaceuticals Incorporated Azaindole derivatives as CFTR modulators
TW201033184A (en) 2008-12-05 2010-09-16 Mochida Pharm Co Ltd Morpholinone compounds as factor IXa inhibitors
US8987242B2 (en) 2008-12-05 2015-03-24 Merck Sharp & Dohme Corp. Morpholinone compounds as factor IXA inhibitors
JP2013503163A (en) * 2009-08-31 2013-01-31 持田製薬株式会社 Morpholinone compounds as factor IXa inhibitors
US8802868B2 (en) 2010-03-25 2014-08-12 Vertex Pharmaceuticals Incorporated Solid forms of (R)-1(2,2-difluorobenzo[D][1,3]dioxo1-5-yl)-N-(1-(2,3-dihydroxypropyl-6-fluoro-2-(1-hydroxy-2-methylpropan2-yl)-1H-Indol-5-yl)-Cyclopropanecarboxamide
ES2858351T3 (en) 2010-04-22 2021-09-30 Vertex Pharma Intermediate compound for the production process of cycloalkylcaraboxamido-indole compounds
AU2013291098A1 (en) * 2012-07-19 2015-02-05 Sumitomo Dainippon Pharma Co., Ltd. 1-(cycloalkyl-carbonyl)proline derivative
EP3095786A4 (en) * 2014-01-14 2017-10-11 Sumitomo Dainippon Pharma Co., Ltd. Condensed 5-oxazolidinone derivative
CN104974148B (en) * 2014-04-14 2017-11-24 北大方正集团有限公司 The method of one kind synthesis ketone of 4 { 4 [base of 1,3 oxazolidine of (5S) 5 (amino methyl) 2 oxo 3] phenyl } morpholine 3
RU2744460C2 (en) 2014-04-15 2021-03-09 Вертекс Фармасьютикалз Инкорпорейтед Pharmaceutical compositions for treating diseases mediated by cystic fibrosis transmembrane conductance regulator
CN104098497B (en) * 2014-06-17 2016-04-13 王庚禹 A kind of new amides
MY198346A (en) * 2015-10-01 2023-08-28 Biocryst Pharm Inc Human plasma kallikrein inhibitors
CN110240591A (en) * 2018-03-08 2019-09-17 天津药物研究院有限公司 Proline derivative and its preparation method and application
CN115974856B (en) * 2022-12-28 2023-08-11 北京康立生医药技术开发有限公司 Preparation method of drug valmotustat for treating adult T-cell leukemia lymphoma

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