EP1763516A2 - Tetrahydro-isoquinoleines substituees, utilisees comme inhibiteurs mmp, leur procede de fabrication et leur utilisation comme medicaments - Google Patents

Tetrahydro-isoquinoleines substituees, utilisees comme inhibiteurs mmp, leur procede de fabrication et leur utilisation comme medicaments

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Publication number
EP1763516A2
EP1763516A2 EP05757350A EP05757350A EP1763516A2 EP 1763516 A2 EP1763516 A2 EP 1763516A2 EP 05757350 A EP05757350 A EP 05757350A EP 05757350 A EP05757350 A EP 05757350A EP 1763516 A2 EP1763516 A2 EP 1763516A2
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EP
European Patent Office
Prior art keywords
alkyl
cycloalkyl
alkenyl
independently
phenyl
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Withdrawn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
EP05757350A
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German (de)
English (en)
Inventor
Armin Hofmeister
Manfred Schudok
Hans Matter
Kristin Breitschopf
Antonio Ugolini
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.)
Sanofi Aventis Deutschland GmbH
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Sanofi Aventis Deutschland GmbH
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Publication of EP1763516A2 publication Critical patent/EP1763516A2/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • 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
    • A61K31/403—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 condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • 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
    • 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
    • A61P9/10—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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • Collagenases belong to the superfamily of metalloproteinases (MP) or matrix metalloproteinases (MMPs or MMPs).
  • MP metalloproteinases
  • MMPs matrix metalloproteinases
  • the MMPs form a group of Zn-dependent enzymes involved in the biodegradation of the extracellular matrix (Yip, Y et al., Investigational New Drugs 1999, 17, 387-399 and Michaelides et al., Current Pharmaceutical Design 1999, 5 , 787-819).
  • MMPs matrix metalloproteinases
  • These MMPs are particularly capable of degrading fibrillar and non-fibrillar collagen, as well as proteoglycans, both of which are important matrix constituents.
  • MMPs are involved in wound healing, tumor invasion, metastasis migration, angiogenesis, multiple sclerosis, and heart failure (Michaelides et al., Ibid, p. 788). In particular, they play an important role in the degradation of the joint matrix in osteoarthritis and arthritis, be it osteoarthritis, osteoarthritis or rheumatoid arthritis.
  • MMP's The activity of MMP's is still essential for many of the processes involved in the atherosclerotic plaque formation play a role, such as infiltration of inflammatory cells, smooth muscle cell migration and proliferation and angiogenesis (SJ George, Exp. Opin. Invest. Drugs 2000, 9 (5), 993-1007). Furthermore, matrix degradation by MMP can cause plaque instabilities and ruptures, leading to clinical symptoms of atherosclerosis, unstable angina pectoris, myocardial infarction, or stroke (EJM Creemers et al, Circulation Res. 2001, 89, 201-210 ). Overall, the entire MMP family can degrade all components of the extracellular matrix of blood vessels; therefore, their activity is highly subject to regulatory mechanisms in normal blood vessels.
  • MMP inhibition or recovery of MMP-TIMP balance is helpful in the Treatment of atherosclerotic diseases.
  • atherosclerosis and other cardiovascular diseases by an increased MMP activity at least co-causes, such as restenosis, dilated cardiomyopathy and the already mentioned myocardial infarction. It has been shown that by applying synthetic inhibitors of MMPs in experimental animal models of these diseases significant improvements can be achieved, for.
  • MMPs cleave matrix proteins such as collagen, laminin, proteoglycans, elastin or gelatin, and further process (ie activate or deactivate) MMPs by cleaving a variety of other proteins and enzymes under physiological conditions so that they play an important role throughout the organism, with particular importance in connective tissue and bone.
  • substituent A can be C (O) NHOH or C (O) OH
  • Q may be a phenyl ring substituted zero to three times by radicals R6, R7, R8, n and m are each O, 1 or 2, and
  • X can be a covalent bond, -O-, -S-, -C (O) -,
  • R2 is a zero to trisubstituted phenyl radical
  • Z is a radical of a heterocycle or substituted heterocycle.
  • the BC ring system being characterized, inter alia, by a group in which the hydroxamic acid function A is in the 3-position.
  • Y is H, methyl, methoxy, NH 2, NO 2 or Cl, R is H or OCH 3, and
  • R 1 and / or R 2 H OH 1 O (Ci-Ci2) alkyl or O (CjC-
  • R 3 and / or R 4 H OH, O (C 1 -C 2) alkyl or O (C 1 -Ci 2) aryl, Br, Cl, NO 2, NH 2, (C-) -Ci 2) alkyl or (Ci-C ⁇
  • MMP inhibitors inhibit many MMPs simultaneously because the catalytic domain of the different MMP subtypes has a similar structure.
  • the inhibitors undesirably act on the enzymes, including those of vital function (Massova I, et al., The FASEB Journal 1998, 12, 1075-1095).
  • the compounds of the formula (I) according to the invention are potent inhibitors of the matrix metalloproteinases MMP-2 and MMP-9, and only a weak inhibition of MMP -1 point.
  • the present invention therefore relates to a compound of the formula (I)
  • Rj, R2 and R3 independently of one another H 1 F, Cl, Br, I 1 NO2, CN, OH, (C ⁇
  • OC (O) - (C 3 -C 8 ) cycloalkyl OC (O) - (C 1 -C 4 ) alkyl- (C 3 -C 8 ) cycloalkyl, OC (O) - (C 3 -C 8 ) cycloalkyl - (C 1 -C 4 ) alkyl, C (O) O- (C 1 -C 6 ) alkyl, C (O) O- (C 2 -C 6 ) alkenyl, C (O) O- (C 3 -C 8 ) cycloalkyl,
  • C (O) O- (C 1 -C 4) alkyl- (C 3 -C 8 ) cycloalkyl, C (O) O- (C 3 -C 8 ) cycloalkyl- (C 1 -C 4) alkyl, C (O) NRgRy, NRQRJ or NR 6 C (O) R 7 are where
  • R 6 and R 7 independently of one another denote H or (C 1 -C) -alkyl
  • n O, 1 or 2;
  • L is defined by -O-, -NR 14 -, a covalent bond or - (CH 2 Jq-, where R 14 is defined by H or (C 1 -C 6 ) alkyl, and
  • q 1, 2, 3 or 4
  • R 4 is phenyl or (C 5 -C 4 ) heteroaryl, where the phenyl or
  • (C 5 -C 14 ) heteroaryl radical is optionally substituted by 1, 2 or 3 substituents independently of one another selected from the group F, Cl, Br, I, CN, OH, NO 2 , (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 3 -C 8 ) cycloalkyl, (C 1 -C 4 ) alkyl- (C 3 -C 8 ) cycloalkyl, - (C 3 -C 8 ) cycloalkyl (C ⁇ iC 4) alkyl, O (C "
  • Rs and Rg are independently defined by H, (C ⁇ - C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 3 -Cs) cycloalkyl,
  • V is a covalent bond, -O- or -NH-, and wherein
  • RS and Rg together can form a 5- or 6-membered ring
  • phenyl or (C 5 -C 4) heteroaryl radical is optionally selected from a group
  • T is defined by a covalent bond, -O-, -S-, -O (Cj-C4) alkyl, -N (R 10 ) -, -C (O) -, -C (O) O-, - OC (Q) -, -C (O) N (R 10 ) -, -N (R 10 ) -C (O) - or -N (R 1 Q) -C (O) -N (R 1 -I ) - JSt 1 WObBi
  • R 10 and R 1 •] independently of one another are H or (C 1 -C 4) alkyl
  • Z is selected from the group phenyl, (Cs-C 1-4 heteroaryl, (C 3- Cs) heterocycloalkyl or benzocyclo (C 5 -C 7) alken-1-one, where phenyl, benzocyclo (C 5 -C 7) alkene-1-one, (Cs-C 14) heteroaryl or (C 3 -C 5) heterocycloalkyl are unsubstituted or substituted by 1, 2 or 3
  • Substituents independently selected from the group F, Cl, Br, I, CN, OH, NO 2 , (C 1 -C 6) alkyl, SO 2 (C 1 -C 6) alkyl, O (C 1 -C 4 ) alkyl O- (C 1 -C 6) alkyl, - (C 1 -C 4 ) AlK 1 -C (O) -O (C 1 -C 6 ) alkyl, O (C 1 -C 6 ) alkyl, (C 2 - C 6 ) alkenyl, (C 3 - C8) cycloalkyl, - (C 1 -C 4) alkyl- (C 3 -C 8) cycloalkyl or - (C 3 -C 8) cycloalkyl- (C 1 -C 4) alkyl, wherein one or more CH 2 groups of the alkenyl, alkyl or
  • Ri2 and R-i3 are independently defined by H,
  • (C 2 -C 6) alkynyl f C (O) -W- (C 1 -C 6) -alkyl, C (O) -W- (C 2 -C 6) -alkenyl, C (O) -W- (C 3 -C 8 ) -cycloalkyl, C (O) -W- (C 1 -C 4 ) alkyl- (C 3 -C 8) cycloalkyl, C (O) -W- (C 3 -C 8) cycloalkyl- (C 1 -C 4 ) alkyl, or C (O) - W is (C2-C6) alkynyl, wherein
  • W is a covalent bond, -O- or -NH-;
  • -C4) alkyl, (C2-C6) alkenyl, (C3-C8) cycloalkyl or (C2-C6) Alkynyl radicals may be replaced by F atoms,
  • R-j, R2 and R3 are H, A is C (O) OH, n is 1,
  • L is a covalent bond
  • R4 is 4- (4'-chloro-biphenyl); or
  • Ri and R2 are O-methyl, R3 is H, AC (O) OH, n is 1,
  • L is a covalent bond
  • R4 is 4- (4'-chloro-biphenyl); or
  • A is C (O) NHOH, n is 1,
  • L is a covalent bond
  • R4 is a phenyl radical which is unsubstituted or substituted by methyl, methoxy, NH, NO2 or
  • R-i and R2 are H, OH, or O (C-C6) alkyl, R3 is H,
  • a C (O) NHOH / n is 1,
  • L is a covalent bond
  • R4 is a phenyl radical which is unsubstituted or with H 1 OH, O (C ⁇ i-C5) alkyl or
  • the invention relates to a compound of formula (I), wherein
  • n 1
  • R4 is a pyridyl radical, wherein the pyridyl radical is optionally substituted with 1, 2 or 3 Substituents independently of one another selected from the group F 1 Cl, Br, I, CN, OH, NO 2 , (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl,
  • R 8 and Rg are independently defined by H, (C 1 -Cg) AlKyl, (C 2 -C 6) alkenyl, (C 3 -C 8 ) cycloalkyl, - (C 1 -C 4 ) alkylalkyl (C 3 -) C 8 ) CyClOalkyl, - (C 3 -
  • C 8 CyClOalkyl (C 1 -C 4 ) alkyl, (C 2 -C 6) alkynyl, C (O) -V- (C 1 -C 6) alkyl, C (O) -V- (C 2 -C 6) Alkenyl, C (O) -V- (C 3 -C 8 ) cycloalkyl,
  • V is a covalent bond, -O- or -NH-, and wherein
  • R 8 and Rg together can form a 5- or 6-membered ring
  • T is defined by a covalent bond, -O-, -S-, -O (C 1 -C 4 ) AlkYl-,
  • R 1 O and R 1 1 are independently H or (C 1 -C 4) -alkyl are,
  • Z is selected from the group phenyl, (Cs-C 14 ) heteroaryl, (C 3 -C 8 ) heterocycloalkyl or benzocyclo (C 5 -C 7 ) alkene-1-one, where phenyl, benzocyclo (C 5 -C 7 ) alkene-1 on, (Cs-C 14 ) heteroaryl or (C 3 -C 8 ) heterocycloalkyl are unsubstituted or substituted by 1, 2 or 3 Substituents independently selected from the group F, Cl, Br 1 1, CN 1 OH 1 NO 2 , (C ⁇
  • Cycloalkyl radicals may be replaced by O, or C (O), or, furthermore, O (C 2 -C 6) alkenyl, O (C3-C8) cycloalkyl, O (C 1 -C 4) alkyl- (C3-C8) cycloalkyl,
  • R 12 and R 1 3 are defined independently of one another by H,
  • W is a covalent bond, -O- or -NH-;
  • the invention relates to a compound of formula (I), wherein
  • R 1 , R 2 and R 3 independently of one another are H, F, Cl, Br, OH, NO 2 , (C 1 -C 4 -alkyl, are,
  • A is C (O) NHOH
  • L is defined by a covalent bond or - (CH 2 ) q-, where q is 1 or 2;
  • phenyl or pyridyl is unsubstituted or substituted by 1, 2 or 3
  • RgRg are a group NRgRg, where Rs and Rg independently of one another are H or (Ci-C6) alkyl, preferably by the radical N (CH3) 2,
  • T defined by a covalent bond; -O-; -S-; -O- (Ci-C4) alkyl, preferably -O-CH2-; or -0-C (O) - is defined and
  • Z is selected from the group phenyl; (C 5 -C 10) heteroaryl, preferably pyridyl, pyrazolyl or indolyl; Cs-Cy heterocycloalkyl, most preferably morpholinyl; Benzocyclo (C5-C7) alken-1-one-yl, preferably indan-1-one-yl; where phenyl, (C5-C ⁇ o) heteroaryl, Cs-Cy-heterocycloalkyl and
  • Benzocyclo (C5-C7) alken-1-one-yl are unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the
  • -CH 2 -C (O) -O (C 1 -C 6) alkyl preferably -CH 2 -C (O) -OMe or -CH2-C (0) -0Et;
  • n 1,
  • R-i and R 2 are H, OH, or O (C 1 -C 6) alkyl
  • R3 is H
  • R4 is a phenyl radical substituted with O (C-C-i2) aryl, NH2 or (CjC-j2) aryl and optionally O (C 1 -C 6) alkyl, (C 1 -C 6) alkyl, Cl;
  • the invention relates to a compound of formula (I), wherein
  • R 1, R 2 and R 3, independently of one another, are H, F, Cl, Br, OH, NO 2, (C 1 -C 4) -alkyl, O (C 1 -C 6) -alkyl,
  • A is C (O) NHOH
  • L is defined by a covalent bond or - (CH 2) q-, where
  • q 1 or 2;
  • R4 is a pyridyl radical, where the pyridyl radical is unsubstituted or substituted by 1, 2 or 3 radicals independently selected from the group F; Cl; (C 1 -C 6) alkyl, preferably methyl or ethyl; O (Ci-CQ) alkyl, preferably O-
  • pyridyl is either substituted by a group NRsRg, wherein
  • R 8 and R 9 independently of one another denote H or (C 1 -C 3) -alkyl, preferably by a radical N (CH 3) 2,
  • T defined by a covalent bond; -O-; -S-; -O- (Ci-C4) alkyl, preferably -O-CH2-; or -0-C (O) - is defined and
  • Z is selected from the group phenyl; (C5-C-jo) heteroaryl, preferably pyridyl, pyrazolyl or indolyl; Cs-Cy heterocycloalkyl, most preferably morpholinyl; Benzocyclo (C5-C7) alken-1-one-yl, preferably indan-1-one-yl; wherein phenyl, (C5-Cio) heteroaryl, Cs-Cy-heterocycloalkyl and
  • Benzocyclo (C5-C7) alken-1-one-yl are unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the
  • n 1;
  • the invention relates to a compound of formula (I), wherein
  • R-i, R2 and R3 are independently H; F; NO2; (C 1 -C 8) alkyl, preferably methyl or ethyl; 0 (C-J-Ce) AlkVl, preferably O-methyl,
  • A is C (O) NHOH
  • L is defined by a covalent bond or - (CH 2) q-, where
  • q 1 or 2;
  • R4 is phenyl or pyridyl substituted with a radical T-Z, wherein
  • T is defined by a covalent bond or -O-
  • Z is selected from the group phenyl or pyridyl, wherein the phenyl or pyridyl group is unsubstituted or substituted by 1, 2 or 3 substituents, preferably a substituent, and the substituents are independently selected from the group F, Cl or Br, preferably Cl; O (C 1 -C 6) alkyl, where one or more H atoms are represented by F
  • Atoms may be replaced, preferably O-methyl, O-ethyl, OCF3 or OCH2CF3; or NR-
  • n 1, and their pharmacologically acceptable salts.
  • the invention relates to a compound of formula (I), wherein
  • R-I, R2 and R3 are independently H; F; NO2, (C 1 -C 6) alkyl, preferably methyl or ethyl; O (C 1 -C 6) alkyl, preferably O-methyl,
  • A is C (O) NHOH
  • L is defined by a covalent bond or - (CH 2) q-, where
  • q 1 or 2;
  • R 4 is pyridyl substituted with a radical T-Z, where
  • T defined by a covalent bond or -O-
  • Z is selected from the group phenyl or pyridyl, wherein the phenyl or pyridyl group is unsubstituted or substituted by 1, 2 or 3 substituents, preferably a substituent, and the substituents are independently selected from the group F, Cl or Br, preferably Cl; O (C 1 -C 6) alkyl, where one or more H atoms may be replaced by F atoms, preferably O-methyl, O-ethyl, OCF 3 or
  • R 12 and R 13 are independently defined by H, or C (O) -O- (C 1 -C 4 -alkyl,
  • n 1,
  • the invention further provides a compound of the formula (I) characterized by formula (II)
  • and R 2 independently of one another are H, F, Cl, Br, I, NO 2, CN, OH,
  • RQ and R7 independently of one another denote H or (C 1 -C 6) -alkyl, R 3 F, Cl 1 Br, I, NO 2 , CN, OH, (C 1 -C 6 ) AIKyI, (C 2 -C 6 ) alkenyl, (C 3 -C 8 ) cycloalkyl, - (C 1 -C 4 ) Alkyl- (C 3 -C 8 ) cycloalkyl, - (C 3 -C 8 ) CyClOalkyl (C 1 -C 4 ) alkyl, O (C 1 -C 6 ) alkyl, O (C 2 -C 6 ) alkenyl , O (C 3 -C 8 ) cycloalkyl, O (C 1 -C 4 ) alkyl- (C 3 -C 8 ) cycloalkyl, O (C 3 -C 8 ) cycloalkyl- (C 1 -C 4
  • n O, 1 or 2;
  • L is defined by -O-, -NR 14 -, a covalent bond or - (CH 2 ) q-, where
  • R 14 is defined by H or (C 1 -C 6 ) AIKyI, and
  • q 1, 2, 3 or 4
  • R 4 is phenyl or (Cs-C 14 ) heteroaryl, wherein the phenyl or
  • (C5-C 14 ) heteroaryl radical is optionally substituted by 1, 2 or 3 substituents independently of one another selected from the group consisting of F, Cl, Br, I, CN, OH, NO 2 ,
  • C (O) -V- (C 3 -C 8) cycloalkyl, C (O) -V- (C 1 -C 4) alkyl- (C3-C8) cycloalkyl, C (O) -V- (C3- C 8 ) are cycloalkyl- (C 1 -G 4) alkyl or C (O) -V- (C 2 -C 6 ) alkynyl, wherein
  • V is a covalent bond, -O- or -NH-, and wherein
  • R 8 and Rg together can form a 5- or 6-membered ring
  • phenyl or (Cs-C-) heteroaryl radical is optionally selected from a group
  • T is defined by a covalent bond, -O-, -S-, -O (C 1 ⁇ ) AlkYl-,
  • R 10 and R 1 1 are independently H or (C 1 -C 4) -alkyl are,
  • Z is selected from the group phenyl, (C 5 -C 4) heteroaryl, (C 3 -C 8 ) heterocycloalkyl or benzocyclo (C 5 -C 7 ) alkene-1-one, where phenyl, benzocyclo (C 5 -C 7 ) alkene 1-one, (C 5 -C 3 heteroaryl or (C 3 -C 8 ) heterocycloalkyl are unsubstituted or substituted by 1, 2 or 3
  • Substituents independently of one another selected from the group consisting of F, Cl, Br, I, CN, OH, NO 2, (C 1 -C 6 ) alkyl, 502 (C 1 -C 6 ) alkyl, 0 (C 1 -C 4 ) alkyl, O- (C 1 -C 6 ) alkyl,
  • 3 are independently defined by H,
  • W is a covalent bond, -O- or -NH-;
  • (C « -C4) alkyl, (C2-C-6) alkenyl, (C3-C8) cycloalkyl or (C-2-C6) alkynyl radicals may be replaced by F atoms,
  • the invention relates to a compound of formula (II), wherein
  • R4 is a pyridyl radical, wherein the pyridyl radical is optionally substituted with 1, 2 or 3
  • Substituents independently of one another selected from the group consisting of F, Cl, Br, I, CN, OH, NO 2 , (C 1 -C 6 ) -alkyl, (C 2 -C 6 ) -alkenyl, (C 2 -C 6 ) -alkynyl,
  • R8 and Rg are independently defined by H
  • V is a covalent bond, -O- or -NH-, and wherein
  • R 8 and Rg together can form a 5- or 6-membered ring
  • T is defined by a covalent bond, -O-, -S-, -O (C 1 -C 4) alkyl, -N (R 10 ) -, -C (O) -, -C (O) O-, - OC (O) -, -C (O) N (R 10) -, -N (R 10) -C (O) - or -N (R 1 O) -C (O) -N (R1 1) - is, where
  • R 10 and R 11 independently of one another are H or (C 1 -C 4 ) -alkyl
  • Z is selected from the group phenyl, (C 5 -C 4) heteroaryl, (C 3 -C 8) heterocycloalkyl or benzocyclo (C 5 -C 7) alkene-1-one, where phenyl, benzocyclo (C 5 -C 7) alkene-1 on, (Cs-C- ⁇ heteroaryl or (C3-C8) heterocycloalkyl are unsubstituted or substituted by 1, 2 or 3
  • Substituents independently selected from the group F, Cl, Br, I, CN, OH, NO 2 , (C " -C -C 6 ) alkyl, SO 2 (C 1 -C 6 ) alkyl, O (C 1 -C 4 ) Alkyl-O- (C 1 -C 6 ) alkyl, - (C 1 -C 4 ) alkyl-C (O) -O (C 1 -C 6 ) alkyl, O (C 1 -C 6 ) alkyl, ( C2-C6) alkenyl, (C3- C8) cycloalkyl, - (C 1 -C 4) alkyl- (C 3 -C 8) cycloalkyl or - (C 3 -C 8) cycloalkyl- (C 1 -C 4) -alkyl where one or more CH 2 groups of the alkenyl, alkyl or
  • Cycloalkyl radicals may be replaced by O, or C (O), or, furthermore, O (C 2 -C 6) alkenyl, O (C3-C8) cycloalkyl, O (C-
  • 3 are independently defined by H
  • W is a covalent bond, -O- or -NH-;
  • R 1 and R 2 independently of one another are H, F, Cl, Br, NO 2, CN, OH, (C 1 -C 6) alkyl, (C 2 -C 6) alkenyl, (C 3 -C 8) cycloalkyl, Ci-C-4) alkyl (C-3-C8) cycloalkyl, - (C3-C8) cycloalkyl- (Ci-C4) alkyl, O (Ci-C6) alkyl, O (C2-C6) alkenyl, O ( C3-C8) cycloalkyl, -O- (C-C4) alkyl- (C3-C8) cycloalkyl or
  • R 3 is F, Cl, Br 1 NO 2 , CN, OH, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 3 -C 8 ) cycloalkyl,
  • R5 is OH, NH2 or NHOH
  • L is defined by a covalent bond or - (CH 2) q-, where q is 1 or 2,
  • R 4 is phenyl or pyridyl, where phenyl and pyridyl are optionally substituted by 1,
  • T is defined by a covalent bond or -O- and
  • Z is selected from the group comprising phenyl, (Cs-C1 o) heteroaryl, preferably pyridyl, pyrazolyl or indolyl, or Cs-Cy-heterocycloalkyl, more preferably morpholinyl, or Benzocyclo (C5-C7) alken-1-on-yl, preferably indan-1-on-yl, wherein phenyl is unsubstituted, (Cs-C1 o) heteroaryl, C5-C7 heterocycloalkyl, and Benzocyclo (Cs-C7) alken-1-on-yl or 1, 2 or 3 substituents are independently selected from the group F; Cl; Br; CN; OH; or
  • (C'-C) -alkyl in which one or more H atoms may be replaced by F atoms, preferably CF 3; -SO 2 (C 1 -C 6) -alkyl, preferably -SO 2 CH 3 or O-C 1 -C 6 -alkyl, where one or more H atoms Atoms may be replaced by F atoms, preferably OMe, OEt, O (CH2) 3CH3, OCF3 or OCH2CF3; -CH2-C (O) -O (C-C6) alkyl, preferably -CH2-C (O) -OMe or -CH2-C (O) -OEt; -O- (Ci-C4) alkyl-O- (C ⁇
  • n 1,
  • R 1 and R 2 independently of one another are H or (C 1 -C 6 ) alkyl
  • R 3 is F, Cl, Br, (C 1 -C 6 ) alkyl or 0 (C 1 -C 6 ) AIkVl is,
  • AC (O) NHOH, L is defined by a covalent bond or - (CH 2) q -, wherein q is 1 or 2, R 4 is phenyl or preferably pyridyl, optionally substituted with 1, 2 or 3 radicals independently selected from Group F; Cl; NO2; (C 1 -C 6 ) AlkVl, preferably methyl or ethyl; 0 (C 1 -C 6 ) Al kVl, preferably O-methyl; wherein phenyl and pyridyl are further substituted by a group TZ, and T is defined by a covalent bond; -O-; -S-; -O- (C 1 ⁇ ) AlkVl-, preferably -O-CH 2 -; or -O-C (O) -, and Z is selected from the group consisting of phenyl or pyridyl, wherein phenyl or pyridyl is unsubstituted or substituted by 1,
  • Substituents substituted are independently selected from the group F; Cl; or O (C 1 -C 6) alkyl, where one or more H atoms may be replaced by F atoms, preferably O-methyl, O-ethyl or OCF 3; n is 1, and their pharmacologically acceptable salts.
  • R 1 and R 2 independently of one another, are H, methyl or ethyl
  • R 3 is F or O-methyl, A is C (O) NHOH,
  • R 4 is phenyl or preferably pyridyl substituted with a radical T-Z, wherein
  • T is defined by a covalent bond or -O-
  • Z is selected from the group consisting of phenyl or pyridyl, wherein the phenyl or pyridyl group is unsubstituted or substituted by 1, 2 or 3 substituents, preferably a substituent, and the substituents independently are selected from the group F, Cl, Br, or O (Ci-C6) alkyl, wherein optionally independently of one another or more H
  • -C5) alkyl radicals may be replaced by F atoms; preferably F, Cl, O-methyl, O-ethyl, OCF3, L is defined by a covalent bond, and n is 1, as well as their pharmacologically acceptable salts.
  • the compounds of the formulas (I) or (II) one or more Contain asymmetric centers, they can be configured independently of each other both S and R.
  • the compounds may exist as pure optical isomers, as diastereomers, as racemates or as mixtures in all ratios thereof.
  • heteroaryl radicals are aromatic mono-, bi- or tricyclic (C5-C14) -
  • the heteroaryl radicals can be linked over all positions, for example via 1 position, 2 position, 3 position, 4 position, 5 position, 6 position, 7 position or 8 position.
  • Heteroaryl radicals can be unsubstituted or monosubstituted or polysubstituted, for example monosubstituted, disubstituted or trisubstituted, by identical or different radicals R 1.
  • heteroaryls are 2- or 3-thienyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 1, 2,3-triazole-1, -A- or 5-yl, 1, 2,4-triazoM, -3- or -5-yl, 1- or 5-tetrazolyl, 2- , 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 1, 2,3-oxadiazol-4 or 5-yl, 1, 2,4-oxadiazol-3 or 5-yl, 1, 3,4-oxadiazol-2-yl or -5-yl, 2-, A- or 5-thiazolyl, 3-, A- or 5-isothiazolyl, 1, 3,4-thiadiazol-2 or -5-yl , 1, 2,4-thiadiazol-3 or -5-yl, 1, 2,3-thiadiazol-4 or 5-yl, 2-, 3- or 4-pyridyl, 2-,
  • Preferred heteroaryl radicals are the 5- or 6-membered heteroaryl radicals, for example imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, thiazolyl and oxazolyl, and also pyridyl and pyrimidinyl.
  • the fused ring systems benzofuranyl, benzimidazolyl and indolyl are preferred.
  • pyrazolyl, indolyl and pyridyl By the term (CH 2) q, where q is the integer zero, 1, 2, 3 or 4, for example, for n, equal to 1 is the radical methylene and n is 2, the radical ethylene.
  • the CH 2 units also include the CH 3 groups which are terminal in an alkyl chain and which are considered CH 2 -H groups in this context.
  • CH units that can be considered both as tertiary carbons, but also as part of a CH2 (-HCH-) or CH3- (H2CH-) group.
  • (C 1 -C 6) -alkyl denotes hydrocarbon radicals whose carbon chain is straight-chain or branched and contains 1 to 6 carbon atoms, for example methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, tert-butyl Pentyl, isopentyl, neopentyl, hexyl, 2,3-dimethylbutane or neohexyl
  • the term - (C 1 -C 4) -alkyl as a subset of (C 1 -C 6) -alkyl denotes hydrocarbon radicals whose carbon chain is straight-chain or branched and 1 to 4 carbon atoms, for example methyl, ethyl, n-propyl, iso-propyl, iso-butyl, butyl or tert-butyl, a (Ci-CßJAlkyl distr in
  • (C 2 -C 9) -alkenyl is understood to mean hydrocarbon radicals whose
  • Carbon chain is straight-chain or branched and contains 2 to 6 carbon atoms and depending on the chain length 1, 2 or 3 double bonds, for example ethenylene, propenylene, iso-propenylene, iso-butenylene or butenylene; the
  • Double bonds can, if the possibility exists in principle, be arranged E- or Z-constantly.
  • the double bonds can be both internal and terminal.
  • (C 2 -C 6) -alkynylene refers to hydrocarbon radicals whose carbon chain is straight-chain or branched and contains 2 to 6 carbon atoms and, depending on the chain length, has 1 or 2 triple bonds, for example Ethynyl, propenyl, iso-propynyl, iso-butylinyl, butynyl, pentynyl or isomers of pentynyl or hexynyl or isomers of hexynyl.
  • the triple bonds can be both internal and terminal.
  • (C3-C8) -cycloalkyl is understood to mean radicals derived from 3- to 8-membered monocycles such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
  • a - (C 1 -C 4) alkyl (C 3 -C 8) cycloalkyl group is a terminal (C 3 -C 5) -cycloalkyl group bridged by a (C 1 -C 4) alkyl radical, for example cyclopropylmethyl.
  • (C3-C8) -heterocycloalkyl is understood as meaning radicals derived from 3- to 8-membered monocycles, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, in which one or more ring atoms are oxygen atoms, sulfur atoms or nitrogen atoms , z. B. 1, 2, 3 or 4 nitrogen atoms, 1 or 2 oxygen atoms, 1 or 2 sulfur atoms or a
  • the (C3-C-8) -heterocycloalkyl radicals can be attached via all positions, for example via 1-position, 2-position, 3-position, 4-position, 5-position, 6-position, 7-position or 8 position.
  • (C 3 -C 8) -heterocycloalkyl radicals may be unsubstituted or monosubstituted or polysubstituted, for example monosubstituted, disubstituted or trisubstituted, by identical or different radicals R 1.
  • (C3-C-8) heterocycloalkyl radicals are, for example, pyrrolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, piperidinyl, pyranyl, dioxanyl, morpholinyl. Preference is given to (Cs-C ⁇ J heterocycloalkyl radicals, particularly preferred is morpholinyl.
  • Benzocyclo (C5-C-7) alkene-1-one radicals are radicals containing a (C5-C-7) ring fused to a benzyl ring and thus containing 9-11 C-atoms. Preference is given to 1,2-benzo-1,2-C5-C7-alkene-on-derivatives, with particular preference the (C5-C7) -ring being perhydrogenated.
  • Benzocyclo (C5-C7) alkene-1-ones are, for example, indan-1-one; 3,4-dihydro-2H-naphthalene-1-one or 6,7,8,9-tetrahydrobenzocyclohepten-5-one, more preferably indan-1-one.
  • Pharmacologically acceptable salts of compounds of the formula (I) are understood as meaning both their organic and inorganic salts, as described in Remington's Pharmaceutical Sciences (17th edition, page 1418 (1985)). Due to their physical and chemical stability and solubility, acidic groups are preferred to sodium, potassium, calcium and ammonium salts, among others; for basic groups include salts of maleic acid, fumaric acid,
  • Succinic acid, malic acid, tartaric acid, methylsulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid or of carboxylic acids or sulfonic acids for example as hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, acetates, lactates, maleinates, fumarates, malates, gluconates, and salts of amino acids, natural Bases or carboxylic acids are preferred.
  • the preparation of physiologically acceptable salts of compounds capable of salt formation of the formula (I) and (II), including their stereoisomeric forms, takes place in a manner known per se.
  • the compounds of the formula (I) and (II) form with basic reagents such as hydroxides, carbonates, bicarbonates, alcoholates and also ammonia or organic bases, for example trimethyl- or triethylamine, ethanolamine,
  • both inorganic and organic acids such as hydrochloric, hydrobromic, sulfuric, hemic-sulfuric, phosphoric, methanesulfonic, benzenesulfonic, p-toluenesulfonic, 4-bromobenzenesulfone, cyclohexylamidosulfone, trifluoromethylsulfone, 2 Hydroxyethanesulfonic, acetic, oxalic, tartaric, succinic, glycerol phosphoric, lactic, malic, adipic, citric, fumaric, maleic, glucuronic, glucuronic, palmitic or trifluoroacetic acids.
  • the invention further provides a process for the preparation of compounds of formulas (I) and (II) characterized as follows.
  • unsubstituted compounds of the formulas (I) can be prepared starting from the commercially available tetrahydroisoquinoline-1-carboxylic acid (IV).
  • (IV) can be synthesized by catalytic hydrogenation with hydrogen in the presence of PtO 2 of the commercially available isoquinoline-1-carboxylic acid (III) (J. Chem. Soc. 1947, 129).
  • the carboxylic acid (IV) can then be converted into the sulfonamide (V) by intermediate conversion to the corresponding trimethylsilyl ester and reaction with a sulfonyl chloride CI-S (O) 2-L-R4.
  • silylating agents for example, N, O-bistrimethylsilylacetamide (BSA) or N 1 O- Bistrimethylsilyltrifluoracetamidacetamid can be used.
  • Sulfonamide (V) can then be converted into the analogous hydroxamic acid (VI).
  • the conversion of the carboxylic acid into the carboxylic acid chloride takes place in a manner known to the person skilled in the art, for example by reaction with a chloroformate such as ethyl chloroformate CIC (O) OEt.
  • a chloroformate such as ethyl chloroformate CIC (O) OEt.
  • the analogous mixed anhydrides can be used.
  • hydroxylamine or an O-protected hydroxylamine for example trimethylsilyl-hydroxylamine, to give the desired hydroxamic acids after deprotection.
  • the example of the trimethylsilyl protected hydroxylamine is done by acidic workup.
  • Suitable Lewis acids are all customary Lewis acids known to the person skilled in the art, such as AICI3, ZnCl2, FeC-13, TiClj.,
  • protonic acid for example, trifluoromethanesulfonic acid can be used.
  • the Friedel-Crafts products (VIII) can be prepared by reductive amination with, for example, dimethoxy-ethylamine, in a manner known to those skilled in the art (see, for example, Roesky et al., Angewandte Chemie 2003, 42 (24), 2708-2710) into an acetal of Formula (IX) to be converted.
  • Triethylamine in the manner known in the art in the corresponding free base can be transferred.
  • tetrahydroisoquinoline-1-carboxylic acids or esters thereof are possible via a Pictet-Spengler cyclization, the corresponding phenylethylamines (XVI) being reacted with, for example, a glyoxylate, preferably ethylglyoxylate, in the desired tetrahydroisoquinoline-1-carboxylic acid ester of the formula (XVII) is transferred.
  • the phenylethylamines (XVI) are converted into the corresponding glyoxylamides (XVIII), for example with ethyl glyoxalate, and then treated by treatment with POCl 3 and subsequent reduction, for.
  • XVII complex hydrides or catalytic hydrogenation
  • the compounds of formula (I) show increased selectivity towards MMP-2 and MMP-9 with slight inhibition of MMP-1.
  • MMP inhibitors especially in the cancer indication, have reported negative side effects.
  • Several hypotheses have been made to explain the mechanisms of negative side effects.
  • the inhibition of MMP-1 for musculoskeletal side effects has been discussed (Heart Failure Reviews, 9, 63-79, 2004, Arthritis & Rheumatism, 48, 1742-1749, 2003).
  • the ratio of inhibition of MMP1 to MMP9 is 3.7.
  • the invention further relates to pharmaceutical compositions, characterized by an effective content of at least one compound of formula (I) and / or (II) and / or a physiologically acceptable salt of the compound of formula (I) and / or (II) and / or a optionally stereoisomeric form of the compound of the formula (I) and / or (II), together with a pharmaceutically suitable and physiologically tolerated carrier, additive and / or other active ingredients and excipients.
  • the compounds according to the invention are suitable for the selective prophylaxis and / or therapy of all diseases in the course of which increased activity of the metalloproteinases is involved.
  • diseases include the indications described in the introduction.
  • cardiovascular diseases such as heart remodeling after a heart attack and atherosclerosis. It also includes unstable angina pectoris, heart failure, stenosis, septic shock, and the prophylaxis of myocardial and cerebral infarctions.
  • the compounds of the formula (I) and / or (II) are furthermore suitable for the treatment of inflammations, cancers, tumor metastasis, cachexia, anorexia, ulceration, degenerative joint diseases such as osteoarthrosis, spondylosis, cartilage shrinkage after joint trauma or prolonged joint restraint after meniscal or patella injuries or torn ligaments. It also includes connective tissue disorders such as collagenosis, periodontal disease, wound healing disorders and chronic musculoskeletal disorders such as inflammatory, immunological or metabolic acute and chronic arthritides, arthropathies, myalgias and bone metabolism disorders.
  • the application of the medicaments according to the invention can be effected by oral, inhalative, rectal or transdermal administration or by subcutaneous, intra-articular, intraperitoneal or intravenous injection. The oral application is preferred.
  • the invention also relates to a process for the preparation of a medicament which comprises reacting at least one compound of the formula (I) and / or (II) with a pharmaceutically suitable and physiologically acceptable carrier and optionally further suitable active ingredients, additives or excipients brings into a suitable dosage form.
  • Suitable solid or galenic preparation forms are, for example, granules, powders, dragees, tablets, (micro) capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions and preparations with protracted release of active ingredient, in the preparation of which customary physiologically acceptable auxiliaries or carriers such as disintegrants, binders, coatings, swelling or lubricants, flavorings, sweeteners and solubilizers.
  • auxiliaries or carriers such as disintegrants, binders, coatings, swelling or lubricants, flavorings, sweeteners and solubilizers.
  • auxiliaries are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as cod liver oil, sunflower, peanut or sesame oil, polyethylene glycol and solvents such as sterile Water and mono- or polyhydric alcohols such as glycerol, called.
  • the pharmaceutical preparations are prepared and administered in dosage units, each unit containing as active ingredient a specific dose of the compound of formula I according to the invention. At fixed
  • Dosage units such as tablets, capsules, dragees or suppositories, this dose may be up to about 1000 mg, but preferably about 50 to 300 mg and for injection solutions in ampoule form up to about 300 mg, but preferably about 10 to 100 mg.
  • daily doses of about 2 mg to 1000 mg of active ingredient, preferably about 50 mg to 500 mg, are indicated for the treatment of an adult patient weighing about 70 kg. Under However, higher or lower daily doses may be appropriate.
  • the administration of the daily dose can be carried out by single administration in the form of a single unit dose or several smaller dosage units as well as by multiple subdivided doses at specific intervals.
  • the medicaments according to the invention are generally administered orally or parenterally, but also a rectal application is possible in principle.
  • Suitable solid or liquid pharmaceutical preparation forms are, for example, granules, powders, tablets, dragees, (micro) capsules, suppositories, syrups, emulsions, suspensions, aerosols, drops or injectable solutions in the form of ampoules and protracted release preparations, in the preparation of which they are customary Carriers and additives and / or aids such as disintegrants, binders, coatings, swelling, lubricants or lubricants, flavorings, sweeteners or solubilizers use.
  • Typical pharmacologically suitable carriers or excipients are, for example, magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, vitamins, cellulose and its derivatives, animal or vegetable oils, polyethylene glycols and solvents, such as sterile water. Alcohols, glycerine and polyhydric alcohols.
  • the dosage units for oral administration may be microencapsulated to delay or prolong delivery over a longer period of time, such as by coating or embedding the active ingredient in particulate form into suitable polymers, waxes or the like.
  • the pharmaceutical preparations are prepared and administered in dosage units, each unit containing as active ingredient a specific dose of one or more compounds of the spirobenzofuran lactam derivatives of the invention.
  • this dose may be up to about 500 mg, but preferably about 0.1 to 200 mg, and for injection solutions in ampoule form up to about 200 mg, but preferably about 0.5 to 100 mg, per Day.
  • the daily dose to be administered depends on body weight, age, gender and condition of the mammal. However, higher or lower daily doses may be appropriate.
  • the administration of the daily dose can be carried out either by a single dose or in several smaller dosage units as well as by a multiple administration of divided doses at specific intervals.
  • the medicaments of the invention are prepared by bringing one or more of the compounds of formula (I) and / or (II) according to the invention optionally with one or more of the usual carriers or excipients and in a suitable dosage form.
  • Example 1.3 [Acetyl- (2,2-dimethoxy-ethyl) -amino] - (2-fluoro-5-methyl-phenyl) -acetic acid, ethyl ester
  • Example 1.5 2-Acetyl-5-methyl-8-fluoro-1,2,3,4-tetrahydro-isoquinoline-1-carboxylic acid ethyl ester 3.64 g of ethyl Z-acetyl- ⁇ -methyl- ⁇ -fluoro-1H-dihydro-isoquinoline-1-carboxylate (from Example 1.4, crude product) were dissolved under standard conditions in 100 ml of ethanol with catalytic amounts of palladium on carbon (10 % ig), with full conversion of three additional catalyst was added. After filtration and removal of the solvent in vacuo, purification on silica gel (dichloromethane / methanol 98: 2) gave 2.62 g of the title compound. Yield 84% (two steps).
  • Example 2.2 2,2-Dimethoxy-ethylamino) - (5-ethyl-2-fluoro-phenyl) -acetic acid ethyl ester
  • the preparation was carried out analogously to Example 1.2. Yield: 32%.
  • Example 2.3 [acetyl- (2,2-dimethoxy-ethyl) -amino] - (5-ethyl-2-fluoro-phenyl) -acetic acid ethyl ester
  • the preparation was carried out analogously to Example 1.3. Yield: 77% after chromatography on silica gel (ethyl acetate / heptane 2: 1).
  • Example 2.4 2-Acetyl-5-ethyl-8-fluoro-1,2-dihydro-isoquinoline-1-carboxylic acid ethyl ester The preparation was carried out analogously to Example 1.4. Yield: 54% after chromatography on silica gel (ethyl acetate / heptane 1: 1).
  • Example 2.6 Scaffold B (5-ethyl-8-fluoro-tetrahydroisoquinoline-1-carboxylic acid) The preparation was carried out analogously to Example 1.6. Yield: quantitative.
  • Example 3.1 5-Fluoro-2-methoxy-phenyl) -oxo-acetic acid ethyl ester The preparation was carried out analogously to Example 1.1. Yield: 87%.
  • Example 3.7 Scaffold C (8-methoxy-5-fluoro-tetrahydroisoquinoline-1-carboxylic acid) The preparation was carried out analogously to Example 1.6. Yield: 96%.
  • Scaffold D was prepared by catalytic hydrogenation according to literature methods
  • the enantiomerically pure scaffold D1 is prepared as described in WO9312091 (vide supra) by diastereomer separation by reaction with 3- (4-nitrophenyl) -2-amino-1,3-propanediol according to methods known per se.
  • Example 6 Scaffold D2 (L-tetrahydroisoquinoline-1-carboxylic acid)
  • the enantiomerically pure scaffold D2 is prepared as described in WO9312091 (vide supra) by diastereomer separation by reaction with 3- (4-nitrophenyl) -2-amino-1, 3-propanediol according to known methods.
  • Example 7 Scaffold E ( ⁇ -nitro-tetrahydroisoquinoline-1-carboxylic acid)
  • the synthesis of the nitrated compound scaffold E can be carried out analogously to the described synthesis of the nitrated tetrahydroisoquinoline-S-carboxylic acid derivatives described in US Pat. No. 5,962,471.
  • the tetrahydroisoquinoline-1-carboxylic acid in conc. Sulfuric acid with potassium nitrate with cooling brought to reaction to give a mixture of 6- and 7-nitro-1, 2,3,4-tetrahydroisoquinoline-1-carboxylic acid, which can be preferably separated by chromatographic methods.
  • the scaffold can be prepared by known methods, for example via a Pictet-Spengler cyclization as described in J. Org. Chem. 1975, 40, 740-43.
  • Example 9.4 4-Chlorobiphenylethanesulfonyl chloride, 4-fluorobiphenylethanesulfonyl chloride and biphenylethanesulfonyl chloride
  • Example Compounds 31 and 32 were prepared by known methods, see, for example, US 4,349,568.
  • the Sulf ⁇ nklarechlorid used for the example compound 44 was prepared according to known examples from phenoxyphenol by reaction with the triflate of trifluoroethanol analogous to US 20020103242 and subsequent chlorosulfonation with (1) chlorosulfonic acid and (2) oxalyl chloride as described in US 6,153,757.
  • Example Compounds 47, 48, 49, 57 and 58 (Table 1) were prepared by chlorosulfonation / chlorination of the corresponding precursors as described in US 6,153,757.
  • the sulphonic acid chloride used for example compound 50 (Table 1) was prepared according to known examples starting from 4-phenylphenol by reaction with the triflate of trifluoroethanol analogously to US 20020103242 and subsequent chlorosulphonation with (1) chlorosulphonic acid and (2) oxalyl chloride as described, for example, in US Pat. No. 6,153,757 produced.
  • the tetrahydroisoquinoline-i-carboxylic acid building block (1.0 eq of the respective scaffold) is initially charged in dichloromethane (5 ml / 1 mmol) and treated with 2.0 eq. Diisopropylethylamine added. After adding 1, 2 eq. BSA is stirred for two hours at room temperature and then at 0 0 C, a solution of 1.2 eq. of the sulfonyl chloride in 5 ml of dichloromethane. After standing overnight at room temperature, the reaction solution with . 1N HCl. The phases are separated and the aqueous extracted once more with dichloromethane. The combined organic phases are washed with H 2 O, dried with MgSO 4 and evaporated in vacuo
  • a carboxylic acid was dissolved in 0.5-2 molar NaOH, optionally with the addition of 10-50% of an organic co-solvent tetrahydrofuran (THF) or DMF.
  • THF organic co-solvent tetrahydrofuran
  • the acid chloride (1-1, 2 equivalents, preferably 1, 1) was dissolved in THF (concentration 0.05 to 1 M) and slowly added dropwise.
  • the autotitrator was automatically added with 2 N NaOH at room temperature to maintain the pH constant. Adjusted pH: 8-12, preferably 9-11.
  • the organic co-solvent was removed on a rotary evaporator, the aqueous solution or suspension was treated with ethyl acetate and acidified with 1 N HCl.
  • N-sulfonyl-tetrahydroisoquinoline-1-carboxylic acid was charged in dry chloroform (5 mL / 0.5 mmol) and 3 eq at room temperature. Oxalyl chloride added. It was then heated to 45 0 C for about 30 minutes. The solvent was then distilled off under reduced pressure, the residue was taken up several times in dry toluene and evaporated again. The resulting N-sulfonyl-tetrahydroisoquinoline-1-carboxylic acid chloride was taken up in chloroform (10 ml / 0.5 mmol) and washed at room temperature with 3 eq. O-trimethyl-silylhydroxylamine added.
  • reaction mixture was evaporated under reduced pressure. Chromatography of the residue on silica gel yields the desired N-sulfonyl-tetrahydroisoquinoline-1-hydroxamic acid.
  • Example 12 Chloropyridine CP-B (2- (6-chloropyridine-3-sulfonyl) -5-fluoro-8-methyl-1,2,3,4-tetrahydro-isoquinoline-1-carboxylic acid)
  • CP-B (2- (6-chloropyridine-3-sulfonyl) -5-fluoro-8-methyl-1,2,3,4-tetrahydro-isoquinoline-1-carboxylic acid
  • Dimethoxyethane was used as solvent and was stirred overnight at 80 0 C:
  • Example Compound 78 120 mg of 2- [4- (4-chloro-phenoxy) -benzenesulfonyl] -5-methyl-8-fluoro-1,2,3,4-tetrahydro-isoquinoline-1-carboxylic acid-hydroxyamide (Example Compound 78) were dissolved on a chiral phase separated. The detection of the two enantiomers was performed on an analytical chiral phase (without assignment of the absolute stereochemistry).
  • Retention time refers to the mass spectrum
  • Retention time refers to the UV spectrum
  • Example 15 Determination of the enzymatic activity of the catalytic domain of human collagenase-1 (MMP-1).
  • MMP-1 was obtained as an inactive pro-enzyme from Biocol, Potsdam (catalog no. MMP1).
  • Activation of the pro-enzyme 2 volumes of pro-enzyme are incubated with 1 volume of APMA solution at 37 0 C for 1 hour.
  • the APMA solution is prepared from a 10 mmol / L p-aminophenyl-mercuric acetate solution in 0.1 mmol / L NaOH by dilution with 3 volumes of Tris / HCl buffer pH7.5 (see below). The pH is adjusted by adding 1 mmol / L HCl between 7.0 and 7.5. After activation of the enzyme, it is diluted with the Tris / HCl buffer to a concentration of 2.5 ⁇ g / ml.
  • reaction 1 Both in reaction 1 and in reaction 2, the enzyme reaction is monitored by fluorescence spectroscopy after addition of 10 ⁇ L of a 3% (v / v) aqueous dimethylsulfoxide solution containing 0.3 mmol / L of the substrate (328 nm (extinction)). / 393 nm (emission)), and the enzyme activity is expressed as the increase in absorbance per minute.
  • the IC50 i. which required 50% inhibition of enzyme activity
  • Inhibitor concentration is determined graphically by plotting the percent inhibitions at various inhibitor concentrations.
  • the enzyme solution contains 2.5 ⁇ g / mL of the enzyme domain.
  • the substrate solution contains 0.3 mmol / L of the fluorogenic substrate (7-methoxycoumarin-4-yl) acetyl-Pro-Leu-Gly-Leu-3- (2 ', 4'-dinitrophenyl) -L-2,3-diaminopropionyl -Ala-Arg-NH2 (Bachern, Heidelberg, Germany).
  • Example 16 Preparation and determination of the enzymatic activity of the catalytic domain of human stromelysin (MMP-3) and neutrophil collagenase (MMP-8).
  • the MMP-3 enzyme solution contained 2.3 ⁇ g / ml
  • the MMP-8 enzyme solution 0.6 ⁇ g / ml one of the according to Ye et al. produced enzyme domains.
  • the substrate solution contained 1 mmol / l of the fluorogenic substrate (7-methoxycoumarin-4-yl) acetyl-Pro-Leu-Gly-Leu-3- (2 ', 4 I - dinitrophenyl) -L-2,3-diaminopropionyl-Ala -Arg-NH2 (Bachern, Heidelberg,
  • Example 17 Determination of the enzymatic activity of the catalytic domain of human collagenase-3 (MMP-13).
  • MMP-13 was obtained as an inactive pro-enzyme from INVITEK, Berlin.
  • Activation of the proenzyme 2 volumes of proenzyme were incubated with 1 volume of APMA solution at 37 0 C for 1.5 hours.
  • the APMA solution was prepared from a 10 mmol / L p-aminophenyl-mercuric acetate solution in 0.1 mmol / L NaOH by dilution with 3 volumes of Tris / HCl buffer pH 7.5 (see below). The pH was adjusted to between 7.0 and 7.5 by the addition of 1 mmol / L HCl. After activation of the enzyme, it was diluted with the Tris / HCl buffer to a concentration of 1.67 ⁇ g / ml.
  • reaction 1 To measure the enzyme activity, 10 ⁇ l of enzyme solution were incubated with 10 ⁇ l of a 3% (v / v) buffered dimethyl sulfoxide solution (reaction 1) for 15 minutes. To measure the enzyme inhibitory activity, 10 ⁇ L of enzyme solution was incubated with 10 ⁇ L of a 3% (v / v) buffered dimethyl sulfoxide solution containing the enzyme inhibitor (Reaction 2).
  • reaction 1 and reaction 2 were monitored by fluorescence spectroscopy (328 nm (absorbance) / 393 after addition of 10 ⁇ l of a 3% (v / v) aqueous dimethyl sulfoxide solution containing 0.075 mmol / L of the substrate nm (emission)).
  • the enzyme activity was expressed as the increase in absorbance / minute.
  • the inhibitory effect was calculated as percentage inhibition according to the following formula:
  • % Inhibition 100 - [(extinction increase / minute in reaction 2) / (extinction increase / minute in reaction 1) x 100].
  • the IC5Q this is the inhibitor concentration responsible for a 50% inhibition of
  • Enzyme activity was graphically determined by plotting the percent inhibitions at various inhibitor concentrations.
  • the enzyme solution contained
  • the substrate solution contained 0.075 mmol / L of the fluorogenic substrate (7-methoxycoumarin-4-yl) acetyl-Pro-Leu-Gly-Leu-3- (2 ', 4'-dinitrophenyl) -L-2,3-diaminopropionyl Ala -Arg-NH2 (Bachern, Heidelberg, Germany).
  • Example 18 Determination of the enzymatic activity of the catalytic domain of human gelatinase A (MMP-2).
  • MMPr2 was obtained as an inactive pro-enzyme from INVITEK, Berlin. Activation of the proenzyme: 2 volumes of proenzyme were incubated with 1 volume of APMA solution at 37 0 C for 0.5 hr.
  • the APMA solution was prepared from a 10 mmol / L p-aminophenyl-mercuric acetate solution in 0.1 mmol / L NaOH by dilution with 3 volumes of Tris / HCl buffer pH 7.5 (see below). The pH was adjusted to between 7.0 and 7.5 by the addition of 1 mmol / L HCl. After activation of the enzyme, it was diluted with the Tris / HCl buffer to a concentration of 0.83 ⁇ g / ml.
  • the enzyme activity was shown as the increase in absorbance / minute.
  • % Inhibition 100 - [(extinction increase / minute in reaction 2) / (extinction increase / minute in reaction 1) x 100].
  • the IC50 this is the inhibitor concentration responsible for a 50% inhibition of
  • the enzyme solution contained 0.83 ⁇ g / ml of the enzyme domain.
  • the substrate solution contained 0.3 mmol / L of the fluorogenic substrate (7-methoxycoumarin-4-yl) acetyl-Pro-Leu-Gly-Leu-3- (2 ', 4'-dinitrophenyl) -L-2,3-diaminopropionyl -Ala-Arg-NH2 (Bachern, Heidelberg, Germany).
  • Example 19 Determination of the enzymatic activity of the catalytic domain of human gelatinase B (MMP-9).
  • MMP-9 was obtained as an inactive pro-enzyme from Roche, Mannheim.
  • Activation of the proenzyme 2 volumes of proenzyme were incubated with 1 volume of APMA solution at 37 0 C for 4 hours.
  • the APMA solution was prepared from a 10 mmol / L p-aminophenyl-mercuric acetate solution in 0.1 mmol / L NaOH by dilution with 3 volumes of Tris / HCl buffer pH 7.5 (see below). The pH Value was adjusted by adding 1 mmol / L HCl between 7.0 and 7.5. After activation of the enzyme, it was diluted with the Tris / HCl buffer to a concentration of 4.2 mU / ml.
  • reaction 1 To measure the enzyme activity, 10 ⁇ l of enzyme solution were incubated with 10 ⁇ l of a 3% (v / v) buffered dimethyl sulfoxide solution (reaction 1) for 15 minutes. To measure the enzyme inhibitory activity, 10 ⁇ L of enzyme solution was incubated with 10 ⁇ L of a 3% (v / v) buffered dimethylsulfoxide solution containing the enzyme inhibitor (Reaction 2).
  • reaction 1 Both in reaction 1 and in reaction 2, the enzyme reaction was monitored by fluorescence spectroscopy after addition of 10 ⁇ L of a 3% (v / v) aqueous dimethylsulfoxide solution containing 0.15 mmol / L of the substrate (328 nm (absorbance)). / 393 nm (emission)).
  • the enzyme activity was expressed as the increase in absorbance / minute.
  • the enzyme solution contained 4.2 mU / mL of the enzyme domain.
  • the substrate solution contained 0.15 mmol / L of the fluorogenic substrate (7-methoxycoumarin-4-yl) acetyl-Pro-Leu-Gly-Leu-3- (2 ', 4'-dinitrophenyl) -L-2,3-diaminopropionyl -Ala-Arg-NH2 (Bachern, Heidelberg, Germany).
  • Table 4 shows the inhibitory profile of selected example compounds as IC-50 value in nM and the selectivity of MMP-9 against MMP-1 inhibition: Table 4:

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Abstract

L'invention concerne des composés de formule (I) dans laquelle R1, R2, R3, R4, A, n et L ont les significations indiquées dans la description. L'invention concerne en outre l'utilisation de ces composés comme médicaments pour la prophylaxie et/ou la thérapie de maladies à l'évolution desquelles participe une activité renforcée de matrice-métalloprotéinases.
EP05757350A 2004-06-30 2005-06-15 Tetrahydro-isoquinoleines substituees, utilisees comme inhibiteurs mmp, leur procede de fabrication et leur utilisation comme medicaments Withdrawn EP1763516A2 (fr)

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