EP1165601A2 - Promedicaments d'inhibiteurs de la thrombine - Google Patents

Promedicaments d'inhibiteurs de la thrombine

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Publication number
EP1165601A2
EP1165601A2 EP00920661A EP00920661A EP1165601A2 EP 1165601 A2 EP1165601 A2 EP 1165601A2 EP 00920661 A EP00920661 A EP 00920661A EP 00920661 A EP00920661 A EP 00920661A EP 1165601 A2 EP1165601 A2 EP 1165601A2
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EP
European Patent Office
Prior art keywords
alkyl
cycloalkyl
ooc
phenyl
radicals
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.)
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Application number
EP00920661A
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German (de)
English (en)
Inventor
Dorit Baucke
Helmut Mack
Werner Seitz
Wilfried Hornberger
Gisela Backfisch
Jürgen Delzer
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Abbott GmbH and Co KG
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BASF SE
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Publication of EP1165601A2 publication Critical patent/EP1165601A2/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B43/00—Formation or introduction of functional groups containing nitrogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/022—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2
    • C07K5/0222—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2 with the first amino acid being heterocyclic, e.g. Pro, Trp
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to prodrugs of pharmacologically active, five-membered heterocyclic amidines, from which compounds are formed in vivo, which are competitive inhibitors of trypsin-like serine proteases, especially thrombin, their preparation and their use as medicaments.
  • the invention also relates to pharmaceutical compositions containing the prodrugs of the active compounds as components, and the use of the compounds as thrombin inhibitors, anticoagulants and as anti-inflammatory agents.
  • Thrombin belongs to the group of serine proteases and plays a central role as a terminal enzyme in the blood coagulation cascade. Both the intrinsic and the extrinsic coagulation cascade lead to the formation of thrombin from prothrombin over several amplification stages. The thrombin-catalyzed cleavage of fibrinogen to fibrin then initiates blood coagulation and platelet aggregation, which in turn increases the formation of thrombin by binding platelet factor 3 and coagulation factor XIII and a whole series of highly active mediators.
  • thromboin formation and action are central events in the development of both white, arterial and red, venous thrombi and therefore potentially effective targets for pharmaceuticals.
  • thrombin inhibitors are able, independently of cofactors, to completely inhibit the effects of free thrombin as well as that bound to platelets. They can prevent thromboembolic events after percutaneous transluminal coronary angioplasty (PTCA) and lysis in the acute phase and serve as anticoagulants in the extracorporeal circulation (cardiopulmonary machine, hemodialysis). They can also be used in general for thrombosis prophylaxis, for example after surgery.
  • PTCA percutaneous transluminal coronary angioplasty
  • lysis in the acute phase and serve as anticoagulants in the extracorporeal circulation (cardiopulmonary machine, hemodialysis). They can also be used in general for thrombosis prophylaxis, for example after surgery.
  • WO 94/29336 EP 0 601 459 and WO 95/23609, WO 95/35309, WO 97/23499 and WO 98/06740 represent a further development, the agmatine being replaced by an arylamidine residue.
  • EP 0 672 658 also describes a thrombin inhibitor with an amidinothiophene (Example 65).
  • WO 98/06741 describes thrombin inhibitors with five-membered heterocyclic amidines.
  • Active substance is understood to mean the pharmacologically active substance (drug) in comparison to the substance (prodrug), which must first be metabolically converted into the active substance.
  • prodrugs over the drugs is that there are no high local concentrations of the drugs outside the destination.
  • side effects are minimized in the case of less selective drugs, since, for example, no further serine proteases are inhibited in the gastrointestinal tract if the drug essentially arises only after or during the gastrointestinal passage through metabolism of the prodrug.
  • the aim of this invention is to improve the pharmacokinetic properties of the thrombin inhibitors mentioned in particular in WO 98/06741 by means of suitable prodrugs.
  • the invention relates to compounds of the formula I.
  • R 1c are independently H, CH 3 or C 2 H 5 and R 2 has the meaning given above,
  • R 2 R 3 N (0) C-C ⁇ -C, R 2 R 3 R 2 -C 2 OOC-C ⁇ -C 6 -alkyl, R 6 -alkyl NC 6 alkyl, and wherein R 2 and R 3 mean the same as above or, if R 1 R 2 R 3 is N (0) CC 1 -C 6 alkyl-, R 2 and R 3 together form a C 4 -C 6 alkylene chain,
  • R 4 H-, R 9 OOC- with R 9 C ! _ ⁇ 6 -alkyl-, C 3 _ 8 -cycloalkyl-, phenyl-,
  • R 7 is H, C 8 alkyl, phenyl, which can carry up to three identical or different radicals of the group C 4 alkyl, CF 3 , C 4 alkoxy, F or Cl, C 3 - 8 cycloalkyl, which can carry up to four identical or different C 4 alkyl radicals, R8 H-, CH 3 -,
  • Y CH, C-CH 3 , C-Cl, C-CF 3 and
  • R 18 -C ⁇ _ 8 alkyl, -C ⁇ -C 3 alkyl-C 3 -C 8 cycloalkyl, aryl or
  • -C x -C 6 alkylphenyl which can optionally carry up to three -CC 4 ⁇ alkyl, CF 3 -, F-, Cl-, NO- or -C-C 4 alkoxy radicals
  • R 19 -C ! _ 3 -alkyl, -phenyl,
  • R 20 -C ⁇ - 8 alkyl, -CH 2 CC1 3 , -C ⁇ -C 3 alkyl-C 3 -C 8 cycloalkyl,
  • -C 3 -C 8 cycloalkyl, -phenyl or -C ⁇ -C 3 alkylphenyl, which optionally up to three identical or different radicals selected from the group C ⁇ -C 4 alkyl, CF 3 -, F-, Cl- , N0 2 - or -CC 4 alkoxy radicals can carry, -CH 2 OC (O) R 10a , -CH (CH 3 ) OC (O) R 10a , wherein R 10a -C ⁇ -C ⁇ 0 alkyl, -phenyl , Benzyl-, -C 3 -C 8 -cycloalkyl or -CH-cyclohexyl, or - C (R i0b ) 2 _ C H 2 -o- (O) CR 10c , the two radicals R 10b being independent can be H, CH 3 or ethyl from one another and
  • K H, or G and K together form a -C (0) 0-, -C (0) S, -C (S) S or -C (S) 0- group,
  • Rl00C-CH 2 - R 1 OOC-CH 2 -CH 2 -, R i OOC-CH (CH 3 ) -, R x OOC-C (CH 3 ) -, Rl00C-CH (C 2 H 5 ) -, R la S (0) C-CH 2 -, R l 0 (S) C-CH 2 -, R 2 R 3 N (0) C-CH 2 -,
  • R 1 is 2-oxo-l, 3-dioxolen-4-yl-methyl, which in 5-position can be substituted by -CC 6 -alkyl or aryl,
  • Aryl- or phenyl-C -C 6 alkyl- can be, the two radicals R lc independently of one another are H, CH 3 or C 2 Hs, and R 2 has the meaning given above, R 2 OOC-C ⁇ -C 6 - Represents alkyl, RR 3 N (0) C 1 -C 6 alkyl, R 2 R 3 NC -C 6 alkyl, where R 2 and R 3 mean the same as above or if R 1 R 2 R 3 represents N (0) C 1 -C 6 -alkyl, R 2 and R 3 together form a C 4 -Cg alkylene chain,
  • R 4 H-, R 9 OOC- with R 9 C ⁇ _ ⁇ 6 -alkyl-, C 3 _ 8 -cycloalkyl-, phenyl- C ⁇ -C 4 -alkyl-, R 10 C (O) -O-CH 2 -, R 10 C (0) -0-CH (CH 3 ) -, where R 10 -C-C 4 alkyl, phenyl, benzyl, C 3 -C 8 cycloalkyl or cyclohexyl CH 2 - may, and R 5 , R 6 , R 7 and R 8 mean the same as above; (ü)
  • R i OOC-O ⁇ - R 1 OOC-CH 2 -CH 2 -, R i OOC-CH (CH 3 ) -, R i OOC-CH (C 2 H 5 ) -, HO- (CH 2 ) 2 _ 6 -,
  • R 1 H, Ci-C ⁇ -alkyl, aryl or phenyl-C 1 -C 4 -alkyl, where apart from H all of the radicals mentioned optionally have up to three identical or different radicals selected from C 1 -C 4 -alkyl, CF 3 -, F-, Cl-, N0 2 -, HO- or C ⁇ -C 4 alkoxy radicals can be,
  • R 10 C (O) -O-CH (CH 3 ) -, where R 10 can be -C-alkyl, phenyl, benzyl, C 3 -C 8 cycloalkyl or cyclohexyl CH 2 -, and R 5 , R 6 , R 7 and R 8 mean the same as above;
  • R 1 R lb -C (0) 0-C (R lc ) 2 -, R lb -C (0) NR 2 -C (R lc ) 2 -, where R lb
  • R 4 H-, R 9 OOC- with R 9 C ⁇ ⁇ 6 -Al yl-, C 3 _ 8 -cycloalkyl-, phenyl-,
  • R 1 OOC-CH 2 - R 1 OOC-CH 2 -CH 2 -, R 1 OOC-CH (CH 3 ) -, R i OOC-C (CH 3 ) 2 -,
  • N0 2 -, HO or C ⁇ -C 4 alkoxy radicals can be,
  • R 1 R lb -C (0) 0-C (R lc ) 2 -, R lb -C (0) NR -C (R lc ) 2 -, where R l
  • R 4 H-, R 9 0OC- with R 9 C ⁇ _ ⁇ 6 -alkyl-, C 3 _ 8 -cycloalkyl-, phenyl-,
  • R 1 OOC-CH 2 - R 1 OOC-CH 2 -CH 2 -, R 1 OOC-CH (CH 3 ) -, R i OOC-C (CH 3 ) 2 -, R 1 OOC-CH ( C 2 H 5 ) -, HO- (CH 2 ) 2 - 6 -,
  • R 1 H, Ci-C ⁇ -alkyl, aryl or phenyl -CC-C 4 alkyl, with all of the radicals except up to H optionally up to three C 1 -C 4 -alkyl-, CF 3 -, F -, Cl-, N0 2 -, HO- or -CC 4 alkoxy radicals can be
  • R 10 C (O) -O-CH (CH 3 ) -, where R 10 can be -C-alkyl, phenyl, benzyl, C 3 -C 8 cycloalkyl or cyclohexyl-CH 2 - and R 5 , R 6 , R 7 and R 8 mean the same as above;
  • a and B have the following meanings:
  • C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl C 1 -C 3 alkyl, C 3 C 8 cycloalkyl, C 1 -C 4 alkyloxy, C 3 -C 8 cycloalkyl C 1 C C 3 alkyloxy, C 3 -Cs cycloalkoxy, aryl or phenyl C 1 -C 6 alkyl can be, the two radicals R lc are independently H, CH 3 or C 2 Hs and R 2 has the meaning given above,
  • R 4 H-, R 9 OOC- with R 9 C ⁇ _ ⁇ 6 -alkyl-, C 3 . 8- cycloalkyl, phenyl,
  • the amino acid derivatives represented by B are preferably (D) -configured, the amino acid derivatives represented by E (L) -configured.
  • the first group includes prodrugs of throne-bin inhibitors (eg G equals -OH, -OR 18 , -COOR 20 ect.) Which have only a negligible antithrombotic effect as a substance, but which are converted into the corresponding active substance in the organism (G equals H). These are compounds from groups (iii) and (vi), sometimes also from groups (iv) and (v).
  • the advantage of prodrugs lies in their improved pharmacokinetic and pharmacodynamic behavior in the organism.
  • the second group includes prodrugs of thrombin inhibitors which, as prodrugs, already have a thrombin-inhibitory effect (for example A equal to RiOOC-CH (CH 3 ) - etc. in combination with G equals -H).
  • the active substance formed in the organism (drug; A equals HOOC-CH 2 -, HOOC-CH 2 -CH 2 -, HOOC-CH (CH 3) - etc., G equals -H)) also shows thrombin-inhibitory activity.
  • These are partly compounds from groups (i), (ii), (iv) and (v).
  • the advantage of these prodrugs lies in their improved pharmacological kinetic and pharmacodynamic behavior in the organism.
  • R 1 OOC-CH (CH 3 ) - etc. are double prodrugs that are converted in the organism by converting both prodrug groups into the corresponding drug (G equals -H, A equals HOOC-CH 2 - etc.).
  • the third group includes thrombin inhibitors, which per se exert their antithrombotic effect (e.g. A equals
  • R la H, -C 6 alkyl, C 7 -C 2 bicycloalkyl, C 0 tricycloalkyl, C 5 -C 8 cycloalkyl, C 5 -C 8 cycloalkyl -C 3 -Alkyl-, aryl- or
  • Phenyl-C 1 -C 3 -alkyl, where apart from H all of the radicals mentioned can optionally carry up to four identical or different radicals selected from CH 3 -, CF 3 -, F-, Cl-, HO- or methoxy radicals, or
  • R l R ib_ C ( 0 ) 0 _ c (R ⁇ C ) 2 _ # Rlb_ C (o) NR 2 -c (R 1 c) 2 -, where R l
  • R 14 H, CH 3 , Cl
  • R 15 H, CF 3 ,
  • R 17 represent H, CH 3 , CF 3 ,
  • R 18 -Ci-s-alkyl, -C ⁇ -C 3 -alkyl-C 3 -C 8 -cycloalkyl, -C ⁇ -C 3 -alkylphenyl, which optionally up to three CH 3 -, CF 3 -, F-, Can carry Cl or methoxy residues,
  • R 19 -C ⁇ _ 3 alkyl
  • R 20 -C ⁇ - 8 alkyl, -CH 2 CC1 3 , -C ⁇ -C 3 alkyl-C 5 -C 8 cycloalkyl,
  • -C 5 -C 8 cycloalkyl -phenyl or -C ⁇ ⁇ C 3 alkylphenyl, which can optionally carry up to three CH 3 -, CF 3 -, F, Cl or methoxy radicals, -CH 2 OC ( O) R 10a, -CH (CH 3) OC (O) R 10a, wherein R 10a be -C ⁇ -C 8 alkyl, -phenyl, -benzyl, -C 5 -C 8 cycloalkyl or -CH 2 -cyclohexyl can, or -C (R 10b ) 2 -CH 2 -0- (O) CR 10c , where the radicals R 10 can independently be H or CH 3 and R 10c -C ⁇ -C 3 -alkyl-C 5 -C 8 -cycloalkyl, -C 5 -C 8 cycloalkyl or -C ⁇ -C 4 alkyl means, represent or
  • K H or G and K together form a -C (0) 0- or -C (0) S group.
  • R 1 R lb -C (0) 0-C (R lc ) 2 -, where R lb -C-C 4 -alkyl-, C 5 -C 8 -cycloalkyl-, -C-C 4 -alkyloxy-, C 5 -C 8 -Cycloalkyloxy- or phenyl -CC-C 3 -alkyl-, the two radicals R lc are independently H or CH 3 , R 2 OOC -CC-C 6 -alkyl-, R 2 R 3 N ( 0) C 1 -C 6 -alkyl-, R 2 R 3 NC 2 -C 6 -alkyl-, and where R 2 and R 3 mean the same as above or if R 1 R 2 R 3 N (0) C 1 -C 6 alkyl-, R 2 and R 3 together form a butylene or pentylene chain,
  • R 6 C ⁇ _ 8 alkyl, cyclopentyl, cyclohexyl, cycloheptyl,
  • Bicyclo [2.2.2] octyl, bicylo [2.2. l] heptyl, norbornyl, adamantyl, indanyl, decalinyl, R 7 H, R 8 H, represent
  • R 14 represent H, CH 3 , Cl,
  • R 18 -C ⁇ - 8 alkyl, -C ⁇ -C 3 alkyl-C 3 -C 8 cycloalkyl, -C ⁇ -C 3 alkylphenyl, which optionally up to three CH 3 -, CF 3 -, F-, Can carry Cl or methoxy radicals
  • R 20 -Ci-g-alkyl, -C ⁇ -C 3 -alkyl-C 5 -C 8 -cycloalkyl, -C 5 -C 8 -cycloalkyl or -C ⁇ -C 3 -alkylphenyl, which optionally up to three CH 3 -,
  • Compounds of the general formula I are very particularly preferred, where A, B, D, E, G and K have the following meanings
  • R 1 H, -CC 8 alkyl, C 5 -C 8 cycloalkyl, C 5 -C 8 cycloalkyl-C 1 -C 8 -alkyl, with the exception of H all of the radicals mentioned optionally up to can carry four identical or different radicals selected from CH 3 -, CF 3 -, F, Cl or methoxy radicals, or R 1 represents 2-oxo-l, 3-dioxolen-4-yl-methyl-, which in
  • 5-position can be substituted by -CC 3 -alkyl or aryl
  • R 1 R lb -C (0) 0-CH 2 -, R ⁇ -CfO) O-CH (CH 3 ) -, where R lb C ⁇ -C -alkyl-,
  • C 5 -C 8 cycloalkyl, C 1 -C 4 alkyloxy or Cs-Cs cycloalkyloxy may be
  • R 6 cyclopentyl, cyclohexyl, cycloheptyl
  • R 14 represent H, CH 3 , Cl,
  • R 20 -C ⁇ _, -C ⁇ -C 3 alkyl-C 5 -C 8 cycloalkyl, C 5 -C 8 alkyl 8 cycloalkyl,
  • R 1 Ci-Cg-alkyl-, C 5 -C 8 -cycloalkyl-, C 5 -C 8 -cycloalkyl-CH 2 -alkyl-, where all said radicals optionally up to four identical or different radicals selected from CH 3 - or can carry methoxy is
  • Adaala adamantylalanine
  • Adagly adamantylglycine
  • AIBN azobisisobutyronitrile
  • Ac acetyl Ala: alanine
  • Chg cyclohexylglycine
  • DIPEA diisopropylethylamine
  • Gly glycine for: furan urine: hydroxyamidino
  • HOSUCC hydroxysuccinimide
  • HPLC high performance liquid chromatography
  • iPr iso-propyl
  • NBS N-bromosuccinimide
  • N-Me-4-Pip-OH N-methyl-4-piperidinyl alcohol
  • TFA trifluoroacetic acid
  • TFAA trifluoroacetic anhydride thiaz: thiazole thioph: thiophene
  • N, N, N ', N'-tetramethyluronium tetrafluoroborate Z benzyloxycarbonyl n pent: n-pentyl neoPent: neo-pentyl (2, 2-dimethyl h-l-propyl) n Hex: n-hexyl c Hex: cyclohexyl n Oct: n octyl
  • MeO tetraethoxy tetraethylene glycol yl monomethyl ether
  • cycloalkyl by itself or as part of another substituent contains saturated, cyclic hydrocarbon groups which contain the stated number of carbon atoms and in which up to two CH groups can be replaced by oxygen, sulfur or nitrogen atoms.
  • C 3 _ 8 -cycloalkyl refers to saturated alicyclic rings with 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-methylcyclohexyl, cyclohexylmethylene, cycloheptyl or cyclooctyl, pyrrolidine, piperidine, morpholine. Saturated cyclic hydrocarbons without heteroatoms are preferred.
  • alkyl by itself or as part of another substituent means a linear or branched alkyl chain radical of the length given in each case, which may be saturated or unsaturated and in which up to five CH 2 groups are replaced by oxygen, sulfur or nitrogen atoms could be.
  • the heteroatoms are separated from one another by at least two carbon atoms.
  • C__ 4 -alkyl means methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-l-propyl, 1-butyl, l-but-2-enyl, 2-butyl , C !
  • C 6 -alkyl for example C 1 -alkyl, pentyl, 1-pentyl, 2-pentyl, 3-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 4-methyl-1-pentyl or 3, 3-dimethyl-butyl.
  • C 8 alkyl means in addition to the radicals specified for C 4 alkyl, for example C 6 alkyl, heptyl, 2- (2-methoxyethoxy) ethyl or octyl. Linear or branched saturated alkyl radicals without heteroatoms are preferred.
  • alkoxy by itself or as part of another substituent means a linear or branched alkyl chain radical of the length given in each case, which may be saturated or unsaturated and is bonded to the parent compound in question via an oxygen atom. So C ⁇ - 4 alkoxy eg methoxy, ethoxy, 1-propoxy, 2-propoxy, 2-methyl-2-propoxy, 2-methyl-l-propoxy, 1-butoxy, 2-butoxy.
  • aryl by itself or as part of another substituent includes mono, bi- or tricyclic aromatic hydrocarbons, such as phenyl, naphthyl, tetralinyl, indenyl, fluorenyl, indanyl, anthracenyl, phenanthrenyl.
  • the compounds of the formula I can be present as such or in the form of their salts with physiologically tolerated acids.
  • acids are: hydrochloric acid, citric acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, formic acid, maleic acid, fumaric acid, succinic acid, hydroxy succinic acid, sulfuric acid, glutaric acid, aspartic acid, pyruvic acid, benzoic acid, oxalic acid and glucuric acid, glucuronic acid, glucuronic acid, Acetylglycine.
  • thrombin Diseases based on the mitogenic effects of thrombin Diseases based on a thrombin-dependent change in contractility and permeability of epithelial cells e.g.
  • Vascular endothelial cells are based,
  • DIC disseminated intravascular coagulation
  • thrombolytics such as streptokinase, urokinase, prourokinase, t-PA, APSAC, plasminogen activators from the salivary glands of animals and the recombinant and mutated forms of all these substances, the occurrence of early reocclusion and later Restenosis according to PTCA,
  • the new compounds for the therapy and prophylaxis of thrombin-dependent thromboembolic events such as deep vein thrombosis, pulmonary embolism, myocardial or cerebral infarction and unstable angina can continue to be used for the therapy of disseminated intravascular coagulation (DIC).
  • DIC disseminated intravascular coagulation
  • thrombolytics such as streptokinase, urokinase, prourokinase, t-PA, APSAC and other plasminogen activators to shorten the reperfusion time and extend the reocclusion time.
  • Further preferred areas of application are the prevention of throbin-dependent early reocclusion and late restenosis after percutaneous transluminal coronary angioplasia, the prevention of thrombin-induced proliferation of smooth muscle cells, the prevention of active thrombin accumulation in the CNS (eg in M. Alzheimer's disease), the fight against tumors and the prevention of Mechanisms that lead to adhesion and metastasis of tumor cells.
  • the compounds of the invention can be administered orally in a conventional manner.
  • the application can also be used with vapors or
  • Sprays are done through the nasopharynx.
  • the dosage depends on the age, condition and weight of the patient and on the type of application.
  • the daily dose of active ingredient per person is between about 10 and 2000 mg when administered orally. This dose can be given in 2 to 4 single doses or once a day as a slow-release form.
  • the new compounds can be used in the customary pharmaceutical application forms, solid or liquid, e.g. as tablets, film-coated tablets, capsules, powders, granules, dragees, solutions or sprays. These are manufactured in the usual way.
  • the active ingredients can be processed with the usual pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retardants, antioxidants and / or propellants (see H. Sucker et al .: Pharmaceuticals Technology, Thieme-Verlag, Stuttgart, 1978).
  • the application forms thus obtained normally contain the active ingredient in an amount of 0.1 to 99% by weight.
  • GIT gastrointestinal tract
  • the human colon adenocarcinoma cell lines HT-29, Caco-2 and T84 are routinely used to investigate various intestinal transport processes (Madara et al., Am. J. Phy ⁇ iol. 1988, 254: G416-G423; KL Audus et al, Pharm. Res. 1990, 7, 435-451).
  • the IEC-18 cell line also proved to be a suitable model for examining the permeability of hydrophilic substances through the intestinal membrane (Ma et al., J. Lab. Clin. Med. 1992; Duizer et al., J. Contr. Rel. 1997 ).
  • the cells are used for 17-24 days on trans well cultivated polycarbonate membranes.
  • the test chamber is arranged so that the membrane separates the apical from the basolateral compartment. Transport of the test substances from the apical
  • pH gradient 5 can be measured depending on the pH gradient, e.g. apical (pH 6.0) ⁇ basolateral (pH 8.0)
  • test substance After the cells have been incubated with the test substance, samples are taken from the apical and ba- solateral side after a defined time interval (eg 24 hours). The content of the test substance used and any metabolites in each of the two compartments is determined by HPLC (comparison of retention times) and HPLC-MS (elucidation of metabolites) analysis. The transport rate is calculated. 5
  • test substances are dissolved in isotonic saline immediately before administration to awake Sprague Dawley rats.
  • the application volumes are 1 ml / kg for intravenous bolus injection into the tail vein and 10 ml / kg for oral administration.
  • PTT activated thromboplastin time
  • Thrombin time 100 ⁇ l of citrate-treated plasma is incubated for 2 min at 37 ° C. in a coagulometer (CL 8, Kugel-Typ, Bender & Hobein, Kunststoff, FRG). After the addition of 100 ⁇ l of prewarmed (37 ° C.) thrombin reagent (Boehringer Mannheim), the time until a fibrin clot was formed was determined.
  • test substances are dissolved in isotonic saline immediately before administration to watchful mongrel dogs.
  • the application volumes are 0.1 ml / kg for intravenous bolus injection and 1 ml / kg for oral administration, which is carried out by gavage.
  • 10 20, 30, 45, 60, 90, 120, 180, 240, 300 and 360 min if necessary after 420, 480 min and 24 h) after intravenous administration of 1.0 mg / kg or
  • samples of venous blood (2 ml) are taken in citrate tubes .
  • the ecarin clotting time (ECT) in whole blood is determined.
  • the plasma thrombin time and the activated partial thromboplastin time are determined using a coagulometer.
  • the anti-F Ila activity (ATU / ml) and the concentration of the substance are determined by their anti-F Ha activity in the plasma by means of a chromogenic (S-2238) thrombin assay, calibration curves using r-hirudin and the test substance were used.
  • the plasma concentration of the test substance is the basis for the calculation of the pharmacokinetic parameters: time of the maximum plasma concentration (T max), maximum plasma concentration; Plasma half-life, to. 5 , * area under the curve (AUC); absorbed part of the test substance (F).
  • Ecarin clotting time 100 ⁇ l of citrate-treated blood are incubated for 2 min at 37 ° C. in a coagulometer (CL 8, Kugel-Typ, Bender & Hobein, Kunststoff, FRG). After the addition of 100 ⁇ l of prewarmed (37 ° C.) ecarin reagent (Pentapharm), the time until a fibrin clot is formed is determined.
  • PTT activated thromboplastin time
  • Thrombin time 100 ⁇ l of citrate-treated plasma is incubated for 2 min at 37 ° C. in a coagulometer (CL 8, Kugel-Typ, Bender & Hobein, Kunststoff, FRG). After the addition of 100 ⁇ l of prewarmed (37 ° C.) thrombin reagent (Boehringer Mannheim), the time until a fibrin clot was formed was determined.
  • the building blocks A, B, E and D are preferably constructed separately and used in a suitably protected form (see schemes I-III, use of orthogonal protective groups (P or P *) which are compatible with the synthetic method used).
  • Scheme II describes the linear structure of molecule I by coupling, alkylation, reductive amination or Michael addition
  • the corresponding amidoximes are added with the addition of bases (eg NaOH, pyridine, tertiary amines) with carbonic acid derivatives such as phosgene, di- and triphosgene, carbonyldiimidazole or chloroformic acid ester um (RE Bolton et al., Tetrahedron Lett. 1995,
  • bases eg NaOH, pyridine, tertiary amines
  • carbonic acid derivatives such as phosgene, di- and triphosgene, carbonyldiimidazole or chloroformic acid ester um
  • Scheme III describes a very efficient way of preparing the compounds I by a convergent synthesis.
  • the appropriately protected building blocks (P *) - AB-0H and HEDL * are coupled together and the resulting intermediates (P *) - ABEDL * analogous to Scheme I and Scheme II to the end product um ⁇
  • Boc, Cbz or Fmoc are used as N-terminal protective groups
  • C-terminal protective groups are methyl, tert-butyl and benzyl ester.
  • Amidine protecting groups are preferably BOC and Cbz. 25 If the intermediate products contain olefinic double bonds, protective groups which are split off by hydrogenolysis are unsuitable.
  • Boc protective groups are removed by means of dioxane / HCl, diethyl ether / HC1, dichloromethane / HCl or TFA / DCM, Cbz protective groups hydrogenolytically or with HF, Fmoc protective groups with piperidine.
  • the saponification of ester functions takes place with LiOH in an alcoholic solvent or in dioxane / water.
  • Reversed phase HPLC separations were carried out with acetonitrile / water and HOAc buffer.
  • the starting compounds can be prepared using the following methods:
  • building blocks A for the alkylation e.g. ⁇ -bromoacetic acid tert-butyl ester, ⁇ -bromoacetic acid adamantyl ester, b-bromopropionic acid tert. -butyl ester, ⁇ -bromopropionic acid tert. -butyl ester, ⁇ -bromobutyric acid tert. -butyl ester, ⁇ -bromoacetic acid 2, 3-dimethyl-2-butyl ester, THP-protected bromoethanol, ⁇ -bromoacetic acid tert-butylamide and ⁇ -bromoacetic acid diethylamide.
  • reaction mixture 25 -45 ° C was kept.
  • the reaction mixture was allowed to come to 0 ° C., stirred at this temperature for 90 min and 150-200 ml of 38% strength aqueous hydrochloric acid were carefully added.
  • the mixture was stirred vigorously at room temperature for 15 hours.
  • the organic phase was separated off and washed with 200 ml of water each.
  • Boc- (3-Ph) -Pro-OH was analogous to a protocol by JYL Chung et al. (JYL Chung et al. J. Org. Chem. 1990, 5_, 270).
  • Boc- (D, L) -Dpa-OH (1mmol) was hydrogenated in 12 ml MeOH together with catalytic amounts of 5% Rh / Al 2 0 3 at 5 bar. After filtration and removal of the solvent in vacuo, the product 10 was obtained in quantitative yield.
  • amino acids mentioned were converted into the Boc-protected form in each case using di-tert.-butyl dicarbonate in water / dioxane and then recrystallized from ethyl acetate / He-40 xan mixtures or by column chromatography over silica gel (mobile phase: ethyl acetate / Petroleum ether mixtures) cleaned.
  • Boc-protected amino acids were used as B building blocks in accordance with Scheme I. Some of the amino acids mentioned were converted as B building blocks into the corresponding benzyl esters and linked to the appropriately protected A building blocks. In the case of compounds with still free NH function, this was then protected with a Boc group, the benzyl ester group was hydrogenated, and the AB-OH building block was purified by crystallization, salt precipitation or column chromatography. This route is exemplarily described for tBu-OOC-CH 2 - (Boc) (D) Cha-OH below.
  • N-Boc-N- (tert-butyloxycarbonylmethylene) -D-cyclohexylglycine-cyclohexylammonium salt was prepared in an analogous manner from cyclohexylglycine as a starting material.
  • the reaction mixture was concentrated on a rotary evaporator under a water jet vacuum, the residue was taken up in n-hexane and washed five times with 3 ml portions of a 5% citric acid solution, the combined organic phases were dried over sodium sulfate, the solvent was filtered off, and the mixture was concentrated and subjected the residue of a column chromatography separation (running solvent hexane / ethyl acetate 95: 5). 32.66 g (64 mmol) of the desired product were obtained.
  • N-Boc-Pyr-OH (5 g, 23.45 mmol) was dissolved in MeOH (50 ml) and HC1 in dioxane (4N, 30 ml) was added. The mixture was then heated under reflux for 12 h. The solvent was spun off and H-Pyr-OMe hydrochloride was obtained as the product. Yield: 3.84 g (100%).
  • N- (t-Bu0 2 C-CH 2 ) -N-Boc- (D) -Cha-OH 8 g, 20.75 mmol was dissolved in dichloromethane (75 ml) and at -10 ° C with Ethyldiisopropylamine (15.5 ml, 89.24 mmol) was added. After stirring at this temperature for 5 min, a solution of H-Pyr-OMe hydrochloride (3.4 g, 20.75 mmol) in dichloromethane (25 ml) was added dropwise.
  • This compound was prepared in an analogous manner from N-Boc-N- (tert-butyloxycarbonylmethylene) - (D) -cyclohexylglycm and 3,4-dehydroproline methyl ester.
  • the (L) 3, 4-dehydroproline used as an E building block is commercially available; the (D, L) -4, 5-dehydropipecolic acid can be obtained according to A. Burgstahler, CE Aiman J. Org. Chem. 25 (i960) , 489 or C. Herdeis, W. Engel Arch. Pharm 126 (1993), 297 and then convert with (Boc) 2 0 into Boc- (D, L) -Dep-OH.
  • 2-aminomethyl-oxazole-4-thiocarboxamide and 2-aminomethyl-thiazole-4-thiocarboxamide were according to G. Videnov, D. Kaier, C. Kempter and G. Jung Angew. Chemistry (1996) 108, 1604 represents, where the N-Boc-protected compounds described there were deprotected with ethereal hydrochloric acid in methylene chloride.
  • the product obtained from the previous experiment was taken up in 100 ml of methylene chloride, 30 ml of approximately 5 molar ethereal hydrochloric acid solution were added and the mixture was stirred at room temperature overnight. The reaction mixture was then evaporated to dryness in vacuo, codiluted several times with ether and then extracted from methylene chloride. 4.15 g of the desired product were obtained as a light yellow amorphous substance.
  • N-BOC-glycine nitrile (12.0 g, 76.8 mmol) and diethylamine (0.16 mL, 2.1 mmol) were dissolved in toluene (100 mL).
  • N-BOC-glycinthioamide (10.0 g, 52.6 mmol) was placed in methanol (70 mL) and 2-chloroacetoacetic acid methyl ester (7.9 g, 52.6 mmol) was added. The mixture was heated to 60 ° C. for 2 hours and then stirred at room temperature for 48 hours. The methanol was removed on a rotary evaporator and the residue was extracted with acetone / diethyl ether. The remaining precipitate was filtered off and the filtrate was concentrated. The solid obtained from the filtrate was the product (clean by TLC and HPLC). Yield: 8.7 g (30.4 mmol, 57.8%). ESI-MS: 287 (M + H + ).
  • ⁇ -BOC-glycinthioamide (5.0 g, 26.28 mmol) was dissolved in acetonitrile (60 mL) and added dropwise at 5 to 10 ° C with a solution of ethyl 2-chloro-4, 4, 4-trifluoroacetoacetate (6.38 g , 26.28 mmol) was added. The mixture was then stirred for a further 30 min at 5 ° C. and for 12 h at room temperature. The mixture was then cooled to 0 ° C. and added dropwise with triethylamine (12 mL,
  • This compound was prepared analogously to 5-aminomethyl-3-methylthiophene-2-carbonitrile, the 3-chloro-2-cyanothiophene used being prepared by dehydrating 3-chlorothiophene-2-carboxamide with trifluoroacetic anhydride.
  • the crude product obtained from e) (max. 79 mmol) was dissolved in 280 ml of pyridine and 140 ml of triethylamine and saturated at room temperature with hydrogen sulfide. The previously yellow solution turned green. The mixture was stirred at room temperature overnight. To complete the conversion, a further 15 minutes of hydrogen sulfide were introduced and the mixture was stirred at room temperature for two hours. Excess hydrogen sulfide was driven out of a washing tower using a stream of nitrogen. The reaction mixture was then concentrated on a rotary evaporator, taken up in ethyl acetate, washed several times with 20% sodium hydrogen sulfate solution, dried over magnesium sulfate and concentrated on a rotary evaporator.
  • a portion of the crude product obtained from d) (39.4 g, max. 106 mmol) was dissolved in 400 ml of pyridine and 40 ml of triethylamine and saturated with hydrogen sulfide at room temperature. The previously yellow solution turned green. The mixture was stirred at room temperature overnight. Excess hydrogen sulfide was driven out of a washing tower using a stream of nitrogen. The reaction mixture was then poured into ice-cooled 20% sodium hydrogen sulfate solution and extracted three times with ethyl acetate. The organic phase was then washed several times with 20% sodium hydrogen sulfate solution, dried over magnesium sulfate and concentrated on a rotary evaporator. 49.0 g of a solvent-containing residue were obtained, which was used in the following reaction without further purification.
  • Butyl iminodicarboxylate in 50 mL tetrahydrofuran was added dropwise, the temperature not exceeding 5 ° C.
  • the mixture was stirred at 5 to 10 ° C for three hours, allowed to warm to room temperature and stirred overnight.
  • 150 ml of a saturated ammonium chloride solution were slowly added.
  • the solvent was distilled off in a water jet vacuum, the residue was extracted four times with 60 mL ethyl acetate, the combined organic phases were washed twice with saturated sodium chloride solution, dried over magnesium sulfate and concentrated on a rotary evaporator.
  • N-Boc-5-aminomethyl-1,2,4-oxadiazole-2-carboxylic acid ethyl ester (S. Borg et al. J. Org. Chem. 1995, 60, 3112-20) was dissolved in methanol (50 mL). Ammonia was introduced into this solution at -10 ° C. to RT until the reaction was complete. The solvent was spun off. The crude product thus obtained was dissolved in dichloromethane (70 ml) and diisopropylethylamine (2.9 ml, 16.55 mmol) was added at -5 ° C.
  • Boc-3, 4-dehydroproline (5 g, 23.4 mmol) and 5-aminomethyl-2-cyanothiophene hydrochloride (4.5 g, 25.8 mmol; WO 95/23609) were dissolved in dichloromethane (25 mL) and at 0 ° C with ethyl diisopropylamine (28 mL, 163.8 mmol) with a 50% solution of propanephosphonic anhydride in ethyl acetate (24.8 mL, 117 mmol). After stirring at 0 ° C. for 1 h, the mixture was warmed to RT and stirred at RT for 12 h.
  • the reaction mixture was diluted with dichloromethane, washed with sodium hydrogen sulfate solution (4x), sodium hydrogen carbonate solution (3x) and saturated sodium chloride solution (lx). After drying over sodium sulfate and filtering off the drying agent, the solvent was distilled off in a water jet vacuum. To split off the Boc group, the residue was added to dichloromethane (95 mL), stirred at RT, evaporated to dryness, codistilled twice with dichloromethane, concentrated again and purified by column chromatography. This gave 6.6 g of the desired product, which was still slightly solvent-based.
  • Methoxyamine hydrochloride (0.7 g, 8.38 mmol were dissolved in 50 ml of methanol and converted into the corresponding acetate salt via an ion exchanger (Fluka: acetate on a polymer support, 3.0 mmol of acetate per g).
  • ion exchanger Feluka: acetate on a polymer support, 3.0 mmol of acetate per g.
  • t-Bu0 2 C-CH 2 - (Boc) - (D) -Chg-Pyr-NH-CH 2 -5- (2-C NH (SCH 3 )) -thioph x HI (3.0 g, 4.0 mmol Example 1d) and the reaction mixture was heated with stirring for 15 min at 50 ° C. (TLC control (methylene chloride / acetone: 9/1)) After rotating in vacuo, the residue was purified by chromatography on silica gel, 1 , 0 g of the desired product
  • the protective groups were split off in 2N aqueous hydrochloric acid at 60 ° C. within 35 min.
  • the protective groups were cleaved using dioxane / HCl
  • H-Pyr-NH-CH 2 -5- (3-CN) -thioph-hydrochloride (Example 13a) and Boc- (D) Chg-OH were analogous to Example Ib) to Boc- (D) -Chg-Pyr-NH -CH-5- (3-CN) -thioph reacted and the Boc protective group then cleaved with hydrochloric acid in ether / ethyl acetate, where H- (D) -Chg-pyr-NH-CH-5- (3-CN ) -thioph-hydrochloride was obtained as a white solid.
  • Example 19 35 N- (methoxycarbonylmethylene) - (D) -cyclohexylglycyl-3, 4-dehydro-propyl- ⁇ 5- [3- (1,2, 4-oxadiazol-3-yl-5-one)] thienyl ⁇ methylamide hydrochloride

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Abstract

L'invention concerne des promédicaments d'amidines hétérocycliques à 5 éléments possédant une activité pharmacologique, à partir desquels sont générés in vivo des composés qui sont des inhibiteurs compétitifs des sérine-protéases de type trypsine, notamment la thrombine et des kininogénases telles que la kallikréine; ainsi que leur production et leur utilisation comme médicaments. L'invention concerne également des compositions pharmaceutiques contenant les promédicaments des composés actifs, ainsi que l'utilisation desdits composés comme inhibiteurs de la thrombine, anticoagulants et anti-inflammatoires.
EP00920661A 1999-04-09 2000-04-05 Promedicaments d'inhibiteurs de la thrombine Withdrawn EP1165601A2 (fr)

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DE10064797A1 (de) * 2000-12-22 2002-06-27 Knoll Ag Orale und parenterale pharmazeutische Formulierung, umfassend eine niedermolekulare Thrombininhibitor-Pro-Pharmakon
WO2004002985A1 (fr) * 2002-06-27 2004-01-08 Lg Life Sciences Ltd. Compose peptidique inhibiteur de la thrombine
CA2525940A1 (fr) * 2003-05-16 2004-11-25 National Institute For Biological Standards And Control (Nibsc) Melange
PT1737889E (pt) 2004-10-19 2010-12-13 Lonza Ag Método para síntese de péptidos em fase sólida
AU2006243000B2 (en) * 2005-05-05 2011-05-26 Macrophage Pharma Limited Alpha aminoacid ester-drug conjugates hydrolysable by carboxylesterase
PL1879573T3 (pl) 2005-05-10 2013-05-31 Incyte Holdings Corp Modulatory 2,3-dioksygenazy indoloaminy i sposoby ich zastosowania
US8450351B2 (en) 2005-12-20 2013-05-28 Incyte Corporation N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase
CL2007002650A1 (es) 2006-09-19 2008-02-08 Incyte Corp Compuestos derivados de heterociclo n-hidroxiamino; composicion farmaceutica, util para tratar cancer, infecciones virales y desordenes neurodegenerativos entre otras.
WO2008036642A2 (fr) * 2006-09-19 2008-03-27 Incyte Corporation N-hydroxyamidinohétérocycles en tant que modulateurs d'indoléamine 2,3-dioxygénase
JP5465720B2 (ja) 2008-07-08 2014-04-09 インサイト・コーポレイション インドールアミン２，３−ジオキシゲナーゼの阻害剤としての１，２，５−オキサジアゾール
US9206123B2 (en) 2009-12-18 2015-12-08 Activesite Pharmaceuticals, Inc. Prodrugs of inhibitors of plasma kallikrein
AU2010330743A1 (en) * 2009-12-18 2012-07-05 Activesite Pharmaceuticals, Inc. Prodrugs of inhibitors of plasma kallikrein
WO2012142308A1 (fr) 2011-04-13 2012-10-18 Activesite Pharmaceuticals, Inc. Promédicaments d'inhibiteurs de la kallicréine plasmatique
ES2799582T3 (es) 2013-11-08 2020-12-18 Incyte Holdings Corp Proceso para la síntesis de un inhibidor de indoleamina 2,3-dioxigenasa
US10081624B2 (en) * 2014-08-26 2018-09-25 Takeda Pharmaceutical Company Limited Heterocyclic compound
CN106674190B (zh) * 2016-12-13 2019-05-10 台州市创源工业技术有限公司 一种2-噻吩甲胺的合成方法

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TWI238827B (en) * 1995-12-21 2005-09-01 Astrazeneca Ab Prodrugs of thrombin inhibitors
TW523513B (en) 1996-03-01 2003-03-11 Akzo Nobel Nv Serine protease inhibitors
DE19632773A1 (de) 1996-08-14 1998-02-19 Basf Ag Neue Thrombininhibitoren
EP1049673A1 (fr) 1998-01-26 2000-11-08 Basf Aktiengesellschaft Amidines heterocycliques utilisees comme inhibiteurs de la kallicreine
JP2002501081A (ja) 1998-01-26 2002-01-15 ビーエーエスエフ アクチェンゲゼルシャフト トロンビンインヒビター
KR20000047461A (ko) * 1998-12-29 2000-07-25 성재갑 트롬빈 억제제
JP4489976B2 (ja) * 1999-04-09 2010-06-23 ビーエーエスエフ ソシエタス・ヨーロピア 補体プロテアーゼの低分子インヒビター

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