ZA200505177B - Use of bradykinn-B2 receptor antagonists for treating osteoarthrosis - Google Patents
Use of bradykinn-B2 receptor antagonists for treating osteoarthrosis Download PDFInfo
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- ZA200505177B ZA200505177B ZA200505177A ZA200505177A ZA200505177B ZA 200505177 B ZA200505177 B ZA 200505177B ZA 200505177 A ZA200505177 A ZA 200505177A ZA 200505177 A ZA200505177 A ZA 200505177A ZA 200505177 B ZA200505177 B ZA 200505177B
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- aryl
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- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 125000004856 decahydroquinolinyl group Chemical group N1(CCCC2CCCCC12)* 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000003838 furazanyl group Chemical group 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000005438 isoindazolyl group Chemical group 0.000 description 1
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000005067 joint tissue Anatomy 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000004930 octahydroisoquinolinyl group Chemical group C1(NCCC2CCCC=C12)* 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 description 1
- 125000004625 phenanthrolinyl group Chemical group N1=C(C=CC2=CC=C3C=CC=NC3=C12)* 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000005954 phenoxathiinyl group Chemical group 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 230000002250 progressing effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 210000005065 subchondral bone plate Anatomy 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000004627 thianthrenyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3SC12)* 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/043—Kallidins; Bradykinins; Related peptides
-
- 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
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Description
Use of bradykinin-B2 receptor antagonists for treating osteoarthrosis
The invention relates to the use of peptides having bradykinin-antagonistic action for the production of pharmaceuticals for the treatment of degenerative joint diseases.
In degenerative joint diseases such as osteoarthrosis, a slowly progressing destruction of the joint takes place, which is caused in particular by the proteolytic degradation of collagen by collagenases. Collagenases belong to the superfamily of the metalloproteinases (MP) or matrix metalloprotein- ases (MMPs). MMPs are capable of degrading fibrillar and nonfibriliar collagen and proteoglycans, which are all important constituents of the cartilaginous matrix. MMP 3 is involved in the biological degradation of the extracellular matrix and is found in increased levels in patients with osteoarthrosis, which is why particular importance is ascribed to MMP 3 in the degradation of the joint matrix in osteoarthrosis (Manicourt et al. (1994)
Arthritis and Rheumatism 37:1774-83).
Bradykinin is a naturally occurring nonapeptide which has some pharmacological effects which lead to inflammation and pain. Peptides having bradykinin-antagonistic action have already been described in
European patent EP 0 370 453 B1. It is further known that peptides having bradykinin-antagonistic action can be employed in the treatment of osteoarthritis or rheumatoid arthritis (AU 638 350). Osteoarthritis and rheumatoid arthritis are joint diseases having severe inflammatory phases in the course of the disease. Lerner et al. (Arthritis and Rheumatism (1987), 30, 530-540) report that, in the context of rheumatoid arthritis, bradykinin may actually enhance bone resorption, but does not stimulate the degradation of the cartilaginous matrix itself.
In the attempt to find active compounds for the treatment of degenerative joint diseases, it has now been found that the peptide employed according to the invention inhibits the release of MMPs such as MMP-3 (and MMP-1 and MMP-13). As a result, the matrix degradation can be inhibited significantly more effectively than only by the inhibition of MMPs themselves which have already been released or formed in the tissue.
The invention therefore relates to the use of the compound of the formula
A-B-X-E-F-K-(D)-TIC-GM-M-F'-| {)) for the production of pharmaceuticals for the treatment of degenerative joint diseases, in which:
A a4) is a hydrogen atom, (C,-Cg)-alkyl, (C4-Cg)-alkanoyl, (C,-Cs)- alkoxycarbonyl or (C4-Cs)-alkylsulfonyl, in which in each case 1, 2 or 3 hydrogen atoms are optionally replaced by 1, 2 or three identical or different radicals from the group consisting of carboxyl, amino, (C4-C4)-alkyl, (C4-Cs)-alkylamino, hydroxyl, (C4-Cs)-alkoxy, halogen, di-(C4-C4)-alkylamino, carbamoyl, sulfamoyl, (C4-Cs)-alkoxycarbonyl, (Ce-C42)-aryl and (Cg-C12)-aryl-(C+-Cs)-alkyl, or in which in each case 1 hydrogen atom is optionally replaced by a radical from the group consisting of (C3-Cs)- cycloalkyl, (C4-Cs)-alkylsulfonyl, (C1-C4)-alkylsulfinyl, (Ce-C12)- aryl-(C4-C4)-alkylsulfonyl, (Cg-C12)-aryl-(C4-C4)-alkylsulfinyl, (Ce-C12)-aryloxy, (C3-Co)-heteroaryl and (C3-Cog)-heteroaryloxy and 1 or 2 hydrogen atoms are replaced by 1 or 2 identical or different radicals from the group consisting of carboxyl, amino, (C4-C4)-alkylamino, hydroxyl, (C1-C4)-alkoxy, halogen, di-(C4-C4)-alkylamino, carbamoyl, sulfamoyl, (Cs-C.)- alkyloxycarbonyl, (Ce-C12)-aryl and (Ce-C12)-aryl-(C1-Cs)-alkyl, az) is (C3-Cg)-cycloalkyl, carbamoyl, which can optionally be substituted on the nitrogen by (C;-
Cs)-alkyl or (Cs-C12)-aryl, (Ce-C12)-aryl, (Cs-C12)-aryloyl, (Ce-C12)-arylsulfonyl or (C3-Cg)- heteroaryl or (Cs-Co)heteroaryloyl, where in the radicals defined under a;) and ay) heteroaryl, aryloyl, arylsulfonyl and heteroaryloyl in each case is optionally substituted by 1, 2, 3 or 4 different radicals from the group consisting of carboxyl, amino, nitro, hydroxyl, cyano, (C4-C4)-alkylamino, (C4-Cs)- alkyl, (C4-Cs)-alkoxy, halogen, di-(C4-C4)-alkylamino, carbamoyl, sulfamoyl and (C;-C4)-alkoxycarbonyl, or as) is a radical of the formula Il,
R(1)—N—CH- C— li
IE
R(2) R(3) where
R(1) is defined as A under a4) or ay),
R(2) is a hydrogen atom or methyl,
R(3) is a hydrogen atom or (C4-Ce)-alkyl, where alkyl is unsubstituted or monosubstituted by amino, substituted amino, hydroxyl, carbamoyl, guanidino, substituted guanidino, ureido, mercapto, methylmercapto, phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-nitrophenyl, 4-methoxyphenyl, 4-hydroxy- phenyl, phthalimido, 4-imidazolyl, 3-indolyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl or cyclohexyl, where substituted amino is a radical -NH-A- and substituted guanidino is a radical —-NH-C(NH)-NH-A-, in which A is as : defined under a4) or ay),
B is Arg, Lys, Orn, 2,4-diaminobutyroyl or an L-homoarginine radical, where in each case the amino or the guanidino group of the side chain can be substituted by an A as described under a4) or ay);
X is a compound of the formula Illa or IlIb
G-G'-Gly (tia)
G'-NH-(CH2),-CO (Hb), in which G’ independently of one another is a radical of the formula IV
R(4) R(5) i Iv —N—CH~-C— in which R(4) and R(5) together with the atoms carrying these is a heterocyclic mono-, bi- or tricyclic ring system having 2 to 15 carbon atoms, and nis 2 to 8;
E is the radical of phenylalanine,
which is optionally substituted by halogen in the 2-, 3- or 4-ring position, or is tyrosine, O-methyltyrosine, 2-thienylalanine, 2-pyridyl- alanine or naphthylalanine;
F independently of one another is the radical of a neutral, acidic or basic aliphatic or aromatic amino acid, which can be substituted in the side chain, or is a covalent bond; (D)-Tic is the radical of the formula V
C
Ho
ANN
\Y%
A NN
G is G' or a covalent bond;
F’ is the radical of a basic amino acid Arg or Lys in the L or D form or a covalent bond, where the guanidino group or amino group of the side chain can be substituted by A as defined under a4) or az), or is a radical -NH-(CH;).- where n is 2 — 8, or a covalent bond;
I is -OH, -NH, or NHC,Hs;
K is the radical -NH-(CH3)s-CO where x is 1 to 4 or a covalent bond;
M is defined as F, and its physiologically tolerable salts.
A further subject of the invention is also the use according to the invention of the compound of the formula |, in which:
B is Arg, Om or Lys, where the guanidino group or the amino group of the side chain is unsubstituted or can be substituted by (C4-Cg)-alkanoyl, (C;-Ciz)-aryloyl, (C3-Cg)-heteroaryl- oyl, (C4-Cs)-alkylsulfonyl or (Cs-C12)-arylsulfonyl, where the aryl, heteroaryl, aryloyl, arylsulfonyl and hetero- aryloyl radicals can be substituted as described above under ay) by optionally 1, 2, 3 or 4 identical or different radicals;
E is phenylalanine, 2-chlorophenylalanine, 3-chlorophenyl- alanine, 2-fluorophenylalanine, 3-fluorophenylalanine, 4-fluorophenylalanine, tyrosine, = O-methyltyrosine or
B-(2-thienyl)alanine;
K is a covalent bond and
M is a covalent bond.
The invention further relates to the use according to the invention of the compound of the formula |, in which:
A is a hydrogen atom, (D)- or (L)-H-Arg, (D)- or (L)-H-Lys or (D)- or (L)-H-Orn;
B is Arg, Orn or Lys, where the guanidino group or the amino group of the side chain can be substituted by a hydrogen atom, (Cs-
Cs)-alkanoyl, (Cs-Cqz2)-aryloyl, (C3-Cg)-heteroaryloyl, (C4-Cs)-alkylsulfonyl or (Cs-C12)-arylsulfonyl, where the aryl, heteroaryl, aryloyl, aryisulfonyl and heteroaryloyl radicals can optionally be substituted by 1, 2, 3 or 4 identical or different radicals from the group consisting of methyl, methoxy and halogen;
C is Pro-Pro-Gly, Hyp-Pro-Gly or Pro-Hyp-Gly;
E is Phe or Thia;
F is Ser, Hser, Lys, Leu, Val, Nle, lle or Thr,
K is a covalent bond
M is a covalent bond
G is the radical of a heterocyclic ring system of the formula IV, selected from the radicals of the heterocycles pyrrolidine (A), piperidine (B), tetrahydroisoquinoline (C), cis- or trans- decahydroisoquinoline (D), cis-endo-octahydroindole (E), cis- exo-octahydroindole (E), trans-octahydroindole (E), cis-endo-, cis-exo-, trans-octahydrocyclopentano[b]pyrrole (F), or hydroxyproline (V);
F’ is Arg; is OH.
The invention also relates to the use according to the invention of a compound of the formula |, which is selected from the group:
H-(D)-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-Oic-Arg-OH,
H-(D)-Arg-Arg-Pro-Pro-Gly-Thia-Ser-(D)-Tic-Oic-Arg-OH,
H-(D)-Arg-Arg-Pro-Hyp-Gly-Phe-Ser-(D)-Tic-Oic-Arg-OH,
H-(D)-Arg-Arg-Hyp-Pro-Gly-Phe-Ser-(D)-Tic-Oic-Arg-OH and
H-(D)-Arg-Arg-Pro-Pro-Gly-Phe-Ser-(D)-Tic-Oic-Arg-OH.
The invention also relates to the use according to the invention of
D-arginyl-L-arginyl-L-prolyl-L-prolylglycyl-3-(2-thienyl)-L-alanyl-L-seryl-(3R)- 1,2,3,4-tetrahydro-3-isoquinolinecarbonyl-(2S,3aS,7aS)-octahydro-1H- indole-2-carbonyl-L-arginine; which is also known under the name
HOE 140.
The term “(C4-Cg)-alkyl” is understood as meaning hydrocarbon radicals whose carbon chain is straight-chain or branched and contains 1 to 8 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary-butyl, pentyl, isopentyl, neopentyl, hexyl, 2,3-dimethylbutyl, heptyl, neochexyl or octyl.
The term “halogen” is understood as meaning fluorine, chlorine, bromine or iodine.
The term “(C3-Cg)-cycloalkyl” is understood as meaning radicals which are derived from 3- to 8-membered monocycles such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
The term “-(Ce-Cy2)-aryl” is understood as meaning aromatic hydrocarbon radicals having 6 to 14 carbon atoms in the ring. -(Cs-C12)-aryl radicals are, for example, phenyl, naphthyl, for example 1-naphthyl, 2-naphthyl, biphenylyl, for example 2-biphenylyl, 3-biphenylyl and 4-biphenylyl, anthryl or fluorenyl. Biphenylyl radicals, naphthyl radicals and in particular phenyl radicals are preferred aryl radicals.
The term “(C3-Co)-heteroaryl” is to be understood as meaning radicals such as acridinyl, azetidinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzo- tetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydro- quinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuran{2,3-b]-tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazoly!), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,
piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyroazolidiny!, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridothiophenyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetra-hydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thia-diazinyl, 1,2,3-thiadiazolyl, 1,2,4- thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thia-diazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl.
Pyridyl; such as 2-pyridyl, 3-pyridyl or 4-pyridyl; pyrrolyl; such as 2-pyrrolyl and 3-pyrrolyl; furyl; such as 2-furyl and 3-furyl; thiophenyl, thienyl; such as 2-thienyl and 3-thienyl; imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, tetrazolyl, pyridazinyl, pyrazinyl, pyrimidinyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, 1,3-benzodioxolyl, indazolyl, benzimid- azolyl, benzoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, chromanyl, isochromanyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrido- imidazolyl, pyridopyridinyl, pyridopyrimidinyl, purinyl and pteridinyl are preferred.
The peptides employed according to the invention are prepared as described in EP 0 370 453 B1.
On account of the pharmacological properties, the compounds according to the invention are suitable for the selective prophylaxis and therapy of degenerative joint diseases such as osteoarthrosis, spondylosis or chondroporosis after joint trauma or relatively long immobilization of a joint after meniscus or patella injuries or torn ligaments. The term “osteoarthrosis” is understood as meaning a disease which chiefly develops in connection with a disparity between the strain on and the load capacity of the individual joint components and joint tissues, which is associated with increasing destruction of the cartilage and which is in the main not inflammatory. Damage to the joint cartilage, such as fraying, demedullation and hyalinization, followed by reactive changes in the subchondral bone, and also capsule changes, is prominent in the pathology. The term “spondylosis” is understood as meaning an arthrosis of the vertebral bodies, with this arthrosis being characterized by a noninflammatory loss of cartilage from the vertebral bodies and intervertebral disks.
The pharmaceuticals according to the invention can be administered by inhalative or transdermal administration or by subcutaneous, intraarticular, intraperitoneal or intravenous injection. Intraarticular administration or topical application is preferred.
Suitable solid or pharmaceutical preparation forms are, for example, suspensions, emulsions, or injectable solutions, and preparations having protracted release of active compound, in whose preparation customary excipients are used.
Preferably, the pharmaceutical preparations are prepared and administered in dose units, each unit containing as active constituent a certain dose of the compound of the formula | according to the invention. In the case of injection solutions in ampoule form, this dose can be up to approximately 300 mg, but preferably approximately 10 to 100 mg, in the case of injection solutions for intraarticular treatment up to approximately 300 micrograms, preferably 100 micrograms.
For the treatment of an adult patient, depending on the activity of the compound according to formula 1, daily doses of approximately 0.01 mg/kg to 10 mg/kg of active compound are indicated in the case of systemic administration, in the case of the administration of injection solutions daily doses of 0.001 mg/kg to 0.005 mg/kg of active compound are indicated and in the case of topical or inhalative administration, daily doses of 0.01 mg/kg to 5 mg/kg of active compound are indicated. Under certain circumstances, however, higher or lower daily doses may also be appropriate. The daily dose can be administered either by single administration in the form of an individual dose unit or else a number of smaller dose units or by multiple administration of subdivided doses at specific intervals.
The invention is illustrated below with the aid of examples.
The abbreviations used for the amino acids correspond to the three-letter code customary in peptide chemistry, as is described in Europ. J. Biochem. 138, 9 (1984). Further abbreviations used are listed below.
Oic octahydro-1H-indole-2-carbonyi
Thia 2-thienylalanyl
Tic 1,2,3,4-tetrahydroisoquinolin-3-ylcarbonyi
HOE 140 was prepared as described in EP 0 370 453 B1.
Pharmacological examples
For the analysis of the disease-modifying action of HOE 140 in a cell culture model relevant to cartilage, the MMP3 expression was analyzed in the chondrosarcoma cell line SW1353 (ATCC: HTB 94). For the experiments,
SW1353 cells were cultured under standard conditions (37°C, 5% CO) in
DMEM-Glutamax with 10% of fetal calf serum (FCS) in plastic culture bottles. After detrypsinization of the cells, 50,000 cells were inoculated per well of a 96-well flat-bottom plate in medium without FCS and preincubated with the compound HOE 140 in an incubator. After one hour, the cells were stimulated by addition of human IL1-B (0.1 ng/ml, Roche) in a total volume of 300 pl. After incubation for 24 hours under standard conditions, the cell culture supernatant was taken off, centrifuged for 5 minutes and frozen at -20°C until further analysis. The MMP3 expression in the cell culture supernatants was then analyzed by means of a commercial MMP3 ELISA test system (Amersham) according to the instructions of the manufacturer.
In parallel to this, a WST cytotoxicity test was carried out with the remaining cells. For this, the commercial test system of Roche was used and the measurement was carried out according to the instructions of the manufacturer's protocol.
Table 1 below shows the results.
Bradykinin increases the MMP3 release by more than 30%. This increased release of MMP3 was inhibited by HOE 140 in a dose-dependent manner.
Table 1 MMP- 3 release from SW cells
MMP-3 release
Relative values based on
Stimulation parameter MW SD starting value
OD 450 nm unstimulated | 3 | 20
+ 0.05 uM HOE 140 + 0.1 uM HOE 140 + 0.5 uM HOE 140 + 1 uM HOE 140
Claims (7)
1. The use of the compound of the formula A-B-X-E-F-K-(D)-TIC-GM-M-F'-i (1 for the production of pharmaceuticals for the treatment of degenerative joint diseases, in which: A a;) is a hydrogen atom, (C;-Cg)-alkyl, (C1-Cs)-alkanoyl, (C+-Cs)-alkoxycarbonyl or (Ci-Cg)-alkylsulfonyl, in which in each case 1, 2 or 3 hydrogen atoms are optionally replaced by 1, 2 or three identical or different radicals from the group consisting of carboxyl, amino, (C4-Cs)-alkyl, (C4-Cs)-alkyl- amino, hydroxyl, (C:-C3)-alkoxy, halogen, di-(C1-Cs)-alkyl- amino, carbamoyl, sulfamoyl, (C;-C4)-alkoxycarbonyl, (Ce- Ci2)-aryl and (Ce-C12)-aryl-(C1-Cs)-alkyl, or in which in each case 1 hydrogen atom is optionally replaced by a radical from the group consisting of (C3-Cg)- cycloalkyl, (C4-C,)-alkylsulfonyl, (C1-Cas)-alkylsulfinyl, (Ce-C12)- aryl-(C4-Cq)-alkylsulfonyl, (Ce-Ci2)-aryl-(C4-Cs)-alkylsulfinyl, (Ce-C12)-aryloxy, (C3-Cg)-heteroaryl and (C3-Cq)-heteroaryloxy and 1 or 2 hydrogen atoms are replaced by 1 or 2 identical or different radicals from the group consisting of carboxyl, amino, (C4-C,)-alkylamino, hydroxyl, (C4-Cs)-alkoxy, halogen, di-(C4-Cq4)-alkylamino, carbamoyl, sulfamoyl, (C4-C4)- alkyloxycarbonyl, (Ce¢-C12)-aryl and (Cg-C12)-aryl-(C4-Cs)-alkyl, ay) is (C3-Cg)-cycloalkyl, carbamoyl, which can optionally be substituted on the nitrogen by (C;- Cs)-alkyl or (Cg-C12)-aryl, (Ce-C12)-aryl, (Ce-C1o)-aryloyl, (Cs-C12)-arylsulfonyl or (C3-Cs)- heteroaryl or (Cs-Cg)heteroaryloyl, where in the radicals defined under a) and a,) heteroaryl, aryloyl, arylsulfonyl and heteroaryloyl in each case is optionally substituted by 1, 2, 3 or 4 different radicals from the group consisting of carboxyl, amino, nitro, hydroxyl, cyano, (C;-C,)-alkylamino, (C1-Cs)- alkyl, (C4-Cs)-alkoxy, halogen, di-(C4-C4)-alkylamino, carbamoyl, sulfamoyl and (C4-C4)-alkoxycarbonyl, or a;) is a radical of the formula Ii,
RO—N=CH= ’ 0
R(2) R(3)
where
R(1) is defined as A under a) or ay),
R(2) is a hydrogen atom or methyl,
R(3) is a hydrogen atom or (C;-Cg)-alkyl, where alkyl is unsubstituted or monosubstituted by amino, substituted amino, hydroxyl, carbamoyl, guanidino, substituted guanidino, ureido, mercapto, methyl- mercapto, phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-nitrophenyl, 4-methoxyphenyl, 4-hydroxyphenyi, phthalimido, 4-imidazolyl, 3-indolyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl or cyclohexyl, where substituted amino is a radical -NH-A- and substituted guanidino is a radical -NH-C(NH)-NH-A-, in which A is as defined under a4) or ay),
B is Arg, Lys, Orn, 2,4-diaminobutyroyl or an L-homo- arginine radical,
where in each case the amino or the guanidino group of the side chain can be substituted by an A as described under a4) or ay); X is a compound of the formula Illa or IIIb G'-G'-Gly (Ila) G'-NH-(CH2),-CO (Ib), in which G’ independently of one another is a radical of the formula IV R(4) R(5) 0 \Y —N—CH-C— in which R(4) and R(5) together with the atoms carrying these is a heterocyclic mono-, bi- or tricyclic ring system having 2 to 15 carbon atoms, and n is 2 to 8; E is the radical of phenylalanine, which is optionally substituted by halogen in the 2-, 3- or 4-ring position, or is tyrosine, O-methyltyrosine, 2-thienylalanine, 2-pyridylalanine or naphthylalanine; F independently of one another is the radical of a neutral, acidic or basic aliphatic or aromatic amino acid, which can be substituted in the side chain, or is a covalent bond; (D)-Tic is the radical of the formula V C Hoi PNP “0 v ANS G is G’ or a covalent bond; F’ is the radical of a basic amino acid Arg or Lys in the L or D form or a covalent bond, where the guanidino group or amino group of the side chain can be substituted by A as defined under a4) or az), or is a radical -NH-(CH3),- where nis 2 - 8, or a covalent bond, is -OH, -NH; or NHC Hs; K is the radical -NH-(CH3),-CO where x is 1 to 4 or a covalent bond; M is defined as F, and its physiologically tolerable salts.
2. The use as claimed in claim 1, wherein a compound of the formula is employed, in which: B is Arg, Orn or Lys, where the guanidino group or the amino group of the side chain is unsubstituted or can be substituted by (C4-Cg)-alkanoyl, (C7-C3)-aryloyl, (C3-Co)- heteroaryloyl, (Ci-Cg)-alkylsulfonyl or (Cg-Ci2)-
arylsulfonyl, where the aryl, heteroaryl, aryloyl, arylsulfonyl and heteroaryloyl radicals can be substituted as described above under a;) by optionally 1, 2, 3 or 4 identical or different radicals; E is phenylalanine, 2-chlorophenylalanine, 3-chloro- phenylalanine, 2-fluorophenylalanine, 3-fluorophenyl- alanine, 4-fluorophenylalanine, tyrosine, O-methyl- tyrosine or B-(2-thienyl)alanine; K is a covalent bond and M is a covalent bond.
3. The use as claimed in claims 1 or 2, wherein a compound of the formula | is employed, in which: A is a hydrogen atom, (D)- or (L)-H-Arg, (D)- or (L)-H-Lys or (D)- or (L}-H-Omn; B is Arg, Orn or Lys, where the guanidino group or the amino group of the side chain can be substituted by a hydrogen atom, (C;- Cs)-alkanoyl, (Ce-C+2)-aryloyl, (Cs-Cg)-heteroaryloyl, (C4-Cg)-alkylsulfony! or (Cs-C12)-arylsuifonyl, where the aryl, hetero-aryl, aryloy!, arylsulfonyl and heteroaryloyl radicals can optionally be substituted by 1, 2, 3 or 4 identical or different radicals from the group consisting of methyl, methoxy and halogen; C is Pro-Pro-Gly, Hyp-Pro-Gly or Pro-Hyp-Gly; E is Phe or Thia; F is Ser, Hser, Lys, Leu, Val, Nie, lle or Thr; K is a covalent bond M is a covalent bond G is the radical of a heterocyclic ring system of the formula IV, selected from the radicals of the hetero- cycles pyrrolidine (A), piperidine (B), tetrahydro- isoquinoline (C), cis- or trans-decahydroisoquinoline (D), cis-endo-octahydroindole (E), cis-exo-octahydro- indole (E), trans-octahydroindole (E), cis-endo-, cis- exo-, trans-octahydrocyclopentano[b]pyrrole (F), or hydroxyproline (V); F is Arg; is OH.
4. The use as claimed in one or more of claims 1 to 3, wherein a compound of the formula | is selected from the group: H-(D)-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-Oic-Arg-OH, H-(D)-Arg-Arg-Pro-Pro-Gly-Thia-Ser-(D)-Tic-Oic-Arg-OH, H-(D)-Arg-Arg-Pro-Hyp-Gly-Phe-Ser-(D)-Tic-Oic-Arg-OH, H-(D)-Arg-Arg-Hyp-Pro-Gly-Phe-Ser-(D)-Tic-Oic-Arg-OH and H-(D)-Arg-Arg-Pro-Pro-Gly-Phe-Ser-(D)-Tic-Oic-Arg-OH.
5. The use as claimed in one or more of claims 1 to 4, wherein the compound D-arginyl-L-arginyl-L-prolyl-L-prolylglycyl-3-(2-thienyl)- L-alanyl-L-seryl-(3R)-1,2,3,4-tetrahydro-3-isoquinolinecarbonyl- (2S,3a8S,7aS)-octahydro-1H-indole-2-carbonyl-L-arginine is employed.
6. The use of the compound of the formula | as claimed in one or more of claims 1 to 5 for the production of a pharmaceutical for the prophylaxis and therapy of degenerative joint diseases such as osteoarthrosis, spondylosis, chondroporosis after joint trauma or relatively long immobilization of a joint after meniscus or patella injuries or torn ligaments.
7. The use of the compound of the formula | as claimed in one or more of claims 1 to 6, wherein the administration is carried out by sub- cutaneous, intraarticular, intraperitoneal or intravenous injection or transdermal administration.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10304994A DE10304994A1 (en) | 2003-02-07 | 2003-02-07 | The use of antagonists of the bradykinin B2 receptor for the treatment of osteoarthrosis |
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| Publication Number | Publication Date |
|---|---|
| ZA200505177B true ZA200505177B (en) | 2006-11-29 |
Family
ID=32797325
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|---|---|---|---|
| ZA200505177A ZA200505177B (en) | 2003-02-07 | 2005-06-27 | Use of bradykinn-B2 receptor antagonists for treating osteoarthrosis |
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| Country | Link |
|---|---|
| EP (1) | EP1594520B1 (en) |
| JP (1) | JP2006516980A (en) |
| KR (1) | KR20050105447A (en) |
| CN (1) | CN1317029C (en) |
| AR (1) | AR043036A1 (en) |
| AT (1) | ATE335500T1 (en) |
| AU (1) | AU2004210396A1 (en) |
| BR (1) | BRPI0407333A (en) |
| CA (1) | CA2514152C (en) |
| CO (1) | CO5690613A2 (en) |
| CY (1) | CY1105708T1 (en) |
| DE (2) | DE10304994A1 (en) |
| DK (1) | DK1594520T3 (en) |
| ES (1) | ES2268622T3 (en) |
| HK (1) | HK1085926A1 (en) |
| HR (1) | HRP20050701B1 (en) |
| IL (1) | IL169899A0 (en) |
| MA (1) | MA27618A1 (en) |
| ME (1) | MEP41008A (en) |
| MX (1) | MXPA05007310A (en) |
| MY (1) | MY135827A (en) |
| NO (1) | NO333903B1 (en) |
| NZ (1) | NZ541680A (en) |
| PE (1) | PE20040939A1 (en) |
| PL (1) | PL206412B1 (en) |
| PT (1) | PT1594520E (en) |
| RS (1) | RS51029B (en) |
| RU (1) | RU2329057C2 (en) |
| TW (1) | TW200505472A (en) |
| WO (1) | WO2004069266A2 (en) |
| ZA (1) | ZA200505177B (en) |
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|---|---|---|---|---|
| GB0710522D0 (en) * | 2007-06-01 | 2007-07-11 | Royal Veterinary College The | Drug delivery system comprising matrix metalloproteinase inhibitors |
| IT1391236B1 (en) * | 2008-07-11 | 2011-12-01 | St Luso Farm D'italia Spa | PHARMACEUTICAL COMPOSITIONS BASED ON ANTAGONISTS OF THE B2 KININE AND CORTICOSTEROID RECEPTOR AND THEIR USE |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IE63490B1 (en) * | 1988-11-24 | 1995-05-03 | Hoechst Ag | Peptides having bradykinin antagonist action |
| MX9100717A (en) * | 1990-08-24 | 1992-04-01 | Syntex Inc | BRADIQUININE ANTAGONISTS |
| FR2751650B1 (en) * | 1996-07-24 | 1998-10-09 | Fournier Ind & Sante | NOVEL N-BENZENESULFONYL-L-PROLINE COMPOUNDS, METHOD OF PREPARATION AND THERAPEUTIC USE |
| CA2364178C (en) * | 2000-12-05 | 2006-01-10 | Yasuhiro Katsu | N-benzenesulfonyl l-proline compounds as bradykinin antagonists |
| CA2474645C (en) * | 2002-02-01 | 2011-08-09 | Omeros Corporation | Compositions and methods for systemic inhibition of cartilage degradation |
-
2003
- 2003-02-07 DE DE10304994A patent/DE10304994A1/en not_active Withdrawn
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2004
- 2004-01-13 PE PE2004000064A patent/PE20040939A1/en not_active Application Discontinuation
- 2004-01-23 JP JP2006501585A patent/JP2006516980A/en active Pending
- 2004-01-23 KR KR1020057014116A patent/KR20050105447A/en not_active Application Discontinuation
- 2004-01-23 MX MXPA05007310A patent/MXPA05007310A/en active IP Right Grant
- 2004-01-23 WO PCT/EP2004/000550 patent/WO2004069266A2/en active IP Right Grant
- 2004-01-23 ME MEP-410/08A patent/MEP41008A/en unknown
- 2004-01-23 CA CA2514152A patent/CA2514152C/en not_active Expired - Fee Related
- 2004-01-23 DK DK04704552T patent/DK1594520T3/en active
- 2004-01-23 RU RU2005127862/15A patent/RU2329057C2/en not_active IP Right Cessation
- 2004-01-23 ES ES04704552T patent/ES2268622T3/en not_active Expired - Lifetime
- 2004-01-23 EP EP04704552A patent/EP1594520B1/en not_active Expired - Lifetime
- 2004-01-23 AT AT04704552T patent/ATE335500T1/en active
- 2004-01-23 CN CNB2004800034498A patent/CN1317029C/en not_active Expired - Fee Related
- 2004-01-23 AU AU2004210396A patent/AU2004210396A1/en not_active Abandoned
- 2004-01-23 BR BR0407333-9A patent/BRPI0407333A/en not_active IP Right Cessation
- 2004-01-23 RS YUP-2005/0565A patent/RS51029B/en unknown
- 2004-01-23 PT PT04704552T patent/PT1594520E/en unknown
- 2004-01-23 DE DE502004001159T patent/DE502004001159D1/en not_active Expired - Lifetime
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- 2005-07-26 IL IL169899A patent/IL169899A0/en unknown
- 2005-08-03 CO CO05076615A patent/CO5690613A2/en not_active Application Discontinuation
- 2005-08-04 HR HRP20050701AA patent/HRP20050701B1/en not_active IP Right Cessation
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