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1. WO2003020267 - UTILISATION DE COMPOSES DE PYRROLE ANNELES DANS LE TRAITEMENT DE LA DEGENERESCENCE D'UN CARTILAGE ARTICULAIRE OU D'UN OS SOUS-CHONDRAL

Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

[ EN ]

CLAIMS

1. Use of one or more than one compound of Formula (I):



wherein

X represents
CR8R9, S, O, NR12 or C(O);

A represents
CR10R11 or a bond between X and the atom carrying radicals R6 and R7;

the first of radicals R1 , R2, R3 represents
aryl, optionally substituted with one or more than one substituents independently selected among the group consisting of halogen, alkyl, halogenoalkyl, alkoxy, aryloxy, halogenoalkoxy, alkylthio, hydroxy, nitro, alkylsulfinyl, alkylsulfonyl, sulfamoyl, N-alkylsulfamoyl, N,N-di- alkylsulfamoyl, alkylsulfonamido and alkylsulfon-N-alkylamido; or
an aromatic or non-aromatic, mono- or bicyclic, optionally benzoannellated, heterocyclic group having 1, 2 or 3 heteroatoms independently selected from N, O and S and optionally being substituted with one or more than one substituents independently selected among the group consisting of halogen, alkyl, halogenoalkyl, alkoxy, aryloxy, halogenoalkoxy, alkylthio, hydroxy, nitro, alkylsulfinyl, alkylsulfonyl, sulfamoyl, N-alkylsulfamoyl, N,N-di- alkylsulfamoyl, alkylsulfonamido and alkylsulfon-N-alkylamido;

the second of radicals R1 , R2, R3 represents
alkyl, optionally substituted with one or more than one substituents independently selected among the group consisting of halogen, cycloalkyl, alkoxy, trifluormethoxy, hydroxy and trifluormethyl;
cycloalkyl, optionally substituted with one or more than one substituents independently selected among the group consisting of halogen, alkyl, halogenoalkyl, cycloalkyl, alkoxy, halogenalkoxy and hydroxy;
aryl, optionally substituted with one or more than one substituents independently selected among the group consisting of halogen, alkyl, halogenoalkyl, alkoxy, aryloxy, halogenoalkoxy, alkylthio, hydroxy, nitro, alkylsulfinyl, alkylsulfonyl, sulfamoyl, N-alkylsulfamoyl, N,N-di- alkylsulfamoyl, alkylsulfonamido and alkylsulfon-N-alkylamido; or an aromatic or non-aromatic, mono- or bicyclic, optionally benzoannellated, heterocyclic group having 1, 2 or 3, heteroatoms independently selected from N, O and S and optionally being substituted with one or more than one substituents independently selected among the group consisting of halogen, alkyl, halogenoalkyl, alkoxy, aryloxy, halogenoalkoxy, alkylthio, hydroxy, nitro, alkylsulfinyl, alkylsulfonyl, sulfamoyl, N-alkylsulfamoyl, N,N-di- alkylsulfamoyl, alkylsulfonamido and alkylsulfon-N-alkylamido;

the third of radicals R1 , R2, R3 represents
H, alkyl, halogenoalkyl, hydroxyalkyl, -CHO, -COOH, halogen, cyano, alkylsulfonyl, sulfamoyl or B-Y,
wherein
B represents alkylene or alkenylene, optionally substituted with hydroxy or alkoxy;
Y represents -COOH, SO3H, OPO(OH)2, OP(OH)2, -CHO or tetrazolyl; or

the second and the third of radicals R1, R2, R3 represent,
together with the atom they are attached to, saturated or unsaturated cycloalkyl;

R4-R11 , which may be the same or different, represent
hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, hydroxy, COOH or acyloxy, where vicinal radicals may also represent bonds or geminal radicals, together with the C atom they are attached to, may also represent carbonyl or cycloalkyl;

R12 represents
hydrogen, alkyl or phenyl,

and optical isomers, physiologically acceptable salts and derivatives thereof,
for treating or preventing degeneration or destruction of articular cartilage and/or subchondral bone.
2. The use according to Claim 1 , wherein the first and the second of radicals R1 , R2, R3 independently represent an optionally substituted aryl or aromatic heterocyclic residue.
3. The use according to Claim 1 , wherein the third of radicals R1 , R2, R3 represents COOH or B-Y, wherein Y is COOH and B represents alkylene.
4. The use according to Claim 2, wherein the third of radicals R1 , R2, R3 represents COOH or B-Y, wherein Y is COOH and B represents alkylene.
5. The use according to Claim 1 wherein said compound of formula (I) is [6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1 H-pyrrolizine-5- yl]-acetic acid of the formula (la)



a physiologically acceptable salt or a physiologically hydrolysable ester thereof.
6. The use according to any one of Claims 1 to 5, wherein the degeneration or destruction of articular cartilage and/or subchondral bone comprises injury, damage or loss of articular cartilage and/or subchondral bone.
7. The use according to any of Claims 1 to 5, for the treatment of an early stage of said degeneration or destruction.
5 8. The use according to any of Claims 1 to 5, for treating a mammal whose status presently or prospectively is in a condition of said degeneration or destruction.
9. The use according to Claim 8, wherein said status of said mammal as presently or prospectively being in said conditon is determined by one or o more of the following:
(A) positive results from the clinical examination and evaluation of
the joints of said mammal, including measurement of hip
dysplasia progression;
(B) performance of any invasive surgical procedure on one or more 5 joints of said mammal;
(C) , positive results from an examination of one or more joints of said
mammal using noninvasive procedures including radiographic
and magnetic resonance imaging (MRI); and
(D) positive results from any biochemical test performed on body 0 fluids or joint tissue of said mammal with respect to one or more
of the following substances:
(1 ) increased interleukin-1 beta (IL-1β);
(2) increased tumor necrosis factor alpha (TNFα);
(3) increased ratio of IL-1 β to IL-1 receptor antagonist protein (IL-5 1Ra);
(4) increased expression of p55 TNF receptors (p55 TNF-R);
(5) increased interleukin-6 (IL-6); increased leukemia inhibitory
factor (LIF);
(6) unchanged or decreased insulin-like growth factor-1 (IGF-1 ); 0 (7) decreased transforming growth factor beta (TGFβ); unchanged
or decreased platelet-derived growth factor (PDGF);
(8) unchanged or decreased basic fibroblast growth factor (b-FGF);
(9) increased keratan sulfate;
(10) increased matrix metalloproteases (MMPs) including stromelysin;

(11) increased ratio of matrix metalloproteases (MMPs) including stromelysin, to tissue inhibitor of metalloproteases (TIMP);
(12) increased osteocalcin;
(13) increased alkaline phosphatase;
(14) increased cAMP responsive to hormone challenge;
(15) increased urokinase plasminogen activator (uPA);
(16) increased cartilage oligomeric matrix protein;
(17) presence of type-ll specific collagen neoepitopes and
(18) increased collagenase.
10. The use according to any of Claims 1 to 5, wherein said treatment or prevention comprises administering said compound in an amount of about 1-10 mg/kg/day.
11. The use according to any of Claims 1 to 5, wherein said treatment or prevention includes administering in addition to one or more than one compound of Formula (I) one or more members selected from the group consisting essentially of polysulfated glycosaminoglycan (PSGAG), glucosamine, chondroitin sulfate (CS), hyaluronic acid (HA), pentosan polysulfate (PPS), doxycycline, and minocycline.
12. A pharmaceutical composition, comprising:
(A) one or more than one compound of Formula (I) as defined in claim 1; and
(B) one or more members selected from the group consisting essentially of
(1) polysulfated glycosaminoglycan (PSGAG), glucosamine, chondroitin sulfate (CS), hyaluronic acid (HA), pentosan polysulfate (PPS), doxycycline, and minocycline.
13. A pharmaceutical composition according to Claim 12, wherein said compound of formula (I) is [6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl- 2,3-dihydro-1 H-pyrrolizine-5-yl]-acetic acid of the formula (la)

a physiologically acceptable salt or a physiologically hydrolysable ester thereof.
14. A method of treating or preventing degeneration or destruction of articular cartilage and/or subchondral bone in one or more joints of a mammal in need of such treatment, comprising administering to said mammal an amount therapeutically effective for treating or preventing degeneration or destruction of articular cartilage and/or subchondral bone,
of one or more than one compound of Formula (I) as defined in any one of Claims 1 to 5.