Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-11-24
2001-01-09
Qazi, Sabiha N. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S496000, C549S491000, C549S043000, C549S074000, C549S075000, C549S076000, C549S077000, C514S471000
Reexamination Certificate
active
06172103
ABSTRACT:
The invention relates to 2-cyano-3,5-dihydroxyhex-2-enecarboxamide derivatives, processes for their preparation and use thereof as pharmaceuticals.
Hyaline articular cartilage is an elastic supportive and lubricant tissue, whose biomechanical function is guaranteed by the special architecture of its matrix and its controlled renewal on the part of the cartilage cells or chondrocytes. Degenerative joint disorders such as arthroses, but also inflammatorily, immunologically or metabolically related arthritides and arthropathies are characterized by a progressive destruction of cartilage, which can lead via functional impairment and pain up to complete ankylosis. Even if different triggers have been held responsible for the various disease forms, according to the general school of thought it is common to the resulting loss of cartilage that it begins with increased proteoglycan degradation and is controlled by the chondrocytes.
For degenerative joint disorders, conventional therapeutics for these disorders are especially nonsteroidal antiinflammatories, and for autoimmunologically pronounced arthritis so-called base therapeutics such as gold compounds, penicillamine, chloroquine derivatives and methotrexate or combinations thereof, but it is common to all of them that they are not able to delay the progressive cartilage destruction.
Arthrosis is a degenerative joint disorder with inflammatory episodes and progressive cartilage destruction which can lead to functional impairment up to complete ankylosis. Until now, the accompanying inflammations and pain conditions in this disorder have been treatable, but there are no pharmaceuticals available which have been shown to be able to delay or to heal the progressive cartilage destruction. Known therapeutics for arthrosis are, for example, mixtures of sulfated glucosaminoglycans (Current Therapeutic Research, 40,6 (1986) 1034) or nonsteroidal antiinflammatories which, however, are not able to delay the cartilage loss.
Even if the pathogenesis of arthrosis is still not clarified in detail, it is regarded as certain that the chondrocytes (cartilage cells) are decisively involved in the increased matrix loss, and that of the main constituents of this matrix, especially the proteoglycans (PG) are the first to be enzymatically degraded.
It has now been found that the compounds of the formula I according to the invention either directly stimulate the proteoglycan synthesis of the cartilage cell or inhibit the increased proteoglycan degradation induced by interleukin-1.
On account of their pharmacological properties, the compounds according to the invention are outstandingly suitable for the treatment and prophylaxis of degenerative joint disorders, but also of disorders of the rheumatic type in which cartilage degradation is to be noted, such as in chronic polyarthritis, joint trauma and in chondrolysis after relatively long immobilization of the joint.
The invention relates to a compound of the formula I
and/or an optionally stereoisomeric form of the compound of the formula I and/or a physiologically tolerable salt of the compound of the formula I, where
R
1
is
a) a hydrogen atom or
b) (C
1
-C
4
)-alkyl,
R
2
is
a) (C
1
-C
12
)-alkyl,
b) (C
2
-C
12
)-alkenyl,
c) (C
2
-C
12
)-alkynyl,
d) (C
3
-C
7
)-cycloalkyl,
e) a 4- to 7-membered heterocyclic radical having 1 or 2 heteroatoms from the group consisting of oxygen, nitrogen and sulfur
f) phenyl,
g) phenyl, mono to trisubstituted by
1) (C
1
-C
4
)-alkyl,
2) halogen,
3) —CN,
4) —CF
3
,
5) —O—(C
1
-C
4
)-alkyl,
6) —O—(C
1
-C
4
)-alkyl substituted by phenyl, or
7) methylenedioxyl,
h) (C
1
-C
6
)-alkyl, monosubstituted by
1) phenyl or
2) a radical of the formula II
in which R
5
and R
6
independently of one another are a hydrogen atom or (C
1
-C
4
)-alkyl,
i) (C
2
-C
6
)-alkenyl, monosubstituted by phenyl or a radical of the formula II, or
k) (C
2
-C
6
)-alkynyl, monosubstituted by phenyl or a radical of the formula II, or
l) R
1
and R
2
together are 0,
R
3
is
a) —CF
3
,
b) —O—CF
3
,
c) —S—CF
3
,
d) —OH,
e) —NO
2
,
f) halogen,
g) benzyl,
h) phenyl,
i) —O-phenyl,
j) a hydrogen atom,
k) —CN,
l) —O-phenyl, mono- or polysubstituted by
1) (C
1
-C
4
)-alkyl,
2) halogen,
3) —O—CF
3
or
4) —O—CH
3
,
R
4
is
a) (C
1
-C
4
)-alkyl,
b) halogen, or
c) a hydrogen atom, and
n is the integer zero, 1, 2, 3 or 4.
A compound of the formula I and/or a physiologically tolerable salt of the compound of the formula I and/or an optionally stereoisomeric form of the compound of the formula I is preferred, where
R
1
is a hydrogen atom or methyl,
R
2
is
a) (C
1
-C
4
)-alkyl,
b) (C
2
-C
7
)-alkenyl,
c) cyclopropyl,
d) phenyl,
e) a 5- to 6-membered heterocyclic radical from the group consisting of
1) pyridine,
2) furan or
3) thiophene,
f) phenyl, mono- to trisubstituted by
1) methyl,
2) —CN,
3) —CF
3
,
4) —O-methyl,
5) —O-methylphenyl or
6) methylenedioxyl,
g) (C
1
-C
4
)-alkyl substituted by the radical of the formula II, in which R
5
and R
6
independently of one another are methyl or propyl,
h) vinyl, substituted by phenyl, or
i) ethynyl, substituted by phenyl, or
k) R
1
and R
2
together are=0,
R
3
is
a) —CF
3
,
b) —Cl or
c) methyl,
R
4
is a hydrogen atom or methyl, and
n is the integer zero, 1 or 2.
A compound of the formula I and/or a physiologically tolerable salt of the compound of the formula I and/or an optionally stereoisomeric form of the compound of the formula I is particularly preferred, where
R
1
is a hydrogen atom or methyl,
R
2
is
a) methyl
b) butyl,
c) vinyl,
d) 1-methylethenyl,
e) 2-methylpropenyl,
f) 2,6-dimethylhepta-1,5-dienyl,
g) cyclopropyl,
h) phenyl,
i) phenyl, mono- or polysubstituted by
1) methylenedioxyl,
2) 4-methyl,
3) benzyloxy,
4) 4-trifluoromethyl,
5) cyano or
6) 3,4,5-trimethoxy,
k) furanyl,
l) pyridyl,
m) thiophenyl or
n) ethynylphenyl, or
o) R
1
and R
2
together are=0,
R
3
is
a) —CF
3
,
b) —Cl or
c) a hydrogen atom,
R
4
is a hydrogen atom or methyl and
n is the integer zero, 1 or 2.
The term akyl, alkenyl or alkynyl is understood as meaning radicals whose carbon chain can be straight-chain, branched or cyclic; the double or triple bonds can occur several times. Cyclic alkyl radicals are, for example, 3- to 7-membered monocycles such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. The term “4- to 7-membered heterocyclic radical having 1 or 2 heteroatoms from the group consisting of oxygen, nitrogen and sulfur” includes, for example, radicals which are derived from azetidine, pyrrole, pyran, azepine, pyrroline, pyrrolidine, pyridine, piperidine, imidazole, pyrimidine, furan, 1,2-diazepine, oxazole, pyrazine, piperazine, isoxazole, isoxazoline, morpholine, thiazole, isothiazole, isothiazolidine, thiomorpholine, thiopyran or thiophene.
Halogen is chlorine, bromine, iodine or fluorine.
Suitable physiologically tolerable salts of the compound of the formula I are, for example, alkali metal, alkaline earth metal and ammonium salts including those of organic ammonium bases.
The invention also relates to a process for the preparation of the compound of the formula I and/or a physiologically tolerable salt of the compound of the formula I and/or an optionally stereoisomeric form of the compound of the formula I, which comprises
A) treating an appropriately substituted 5-methylisoxazole-3-carboxamide or -anilide at low temperature, possibly at −80 to −40° C., with an excess (about 3 equivalents) of strong organic or preferably organometallic bases such as butyllithium, tert-butyllithium or lithium diisopropylamide in anhydrous organic solvents, such as diethyl ether, tetrahydrofuran or tert-butyl methyl ether, a deprotonation of the methyl group taking place in addition to the base-induced ring opening and this deprotonated intermediate leading with electrophilic reagents such as aldehydes, ketones or carbon dioxide, after appropriate working up by acidification and extraction, to an addition to the carbonyl group in the sense of a C—C linkage or
B) converting a carboxylic acid which can be substituted by further functional groups, o
Raiss Ruth
Schwab Wilfried
Aventis Pharma Deutschland GmbH
Finnegan, Henderson Farabow, Garrett and Dunner L.L.P.
Qazi Sabiha N.
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