Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-10-22
2002-02-26
Seidel, Marianne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S312000, C514S313000, C514S314000, C544S179000
Reexamination Certificate
active
06350759
ABSTRACT:
DESCRIPTION OF THE PRIOR ART
The preparation of compounds having a 1,2-dihydroquinoline structure has been described in Patent Specifications DD 227 434 and DE 4 115 535. Other compounds having the same nucleus, variously substituted, have been used in the preparation of smoked meats (GB 1537334) or as photochemical indicators (WO 89 05994). The anti-oxidant properties of tetrahydroquinoline compounds have been used in the field of lubricants (EP 072 349). Compounds of this type have also been described as inhibitors of lipid absorption (EP 028 765).
BACKGROUND OF THE INVENTION
According to Hartman's free-radical theory of ageing (J. Gerontol., 1956, 11, 298), successive oxidation attacks create “oxidation stress” conditions, which reflect an imbalance in the organism between the systems that produce free-radical species and the systems that are protective against those species (R. E. PACIFICI, K. J. A. DAVIES, Gerontology, 1991, 37, 166). Various defence mechanisms may act in synergy, allowing the action of the free radicals to be controlled. Those mechanisms may be enzymatic, as is the case for systems involving superoxide dismutase, catalase and glutathione peroxidase, or non-enzymatic in the case of vitamin E and vitamin C involvement. With age, however, those natural defences become less and less efficient, especially as a result of the oxidative inactivation of a large number of enzymes (A. CASTRES de PAULET, Ann. Biol. Clin., 1990, 48, 323).
It has been possible to link conditions of oxidation stress with disorders associated with ageing, namely atherosclerosis, cataract, non-insulin-dependent diabetes and cancer (M. HAYN et al., Life Science, 1996, 59, 537). The central nervous system is especially sensitive to oxidation stress because of its high oxygen consumption, the relatively low level of its anti-oxidation defences and the high iron content of some cerebral regions (S. A. BENKOVIC et al., J. Comp. Neurol. 1993, 338, 92; D. HARTMAN, Drugs Aging, 1993, 3, 60). Successive oxidation attacks therefore constitute one of the main etiological factors of cerebral ageing and associated disorders, namely Alzheimer's disease and chronic neurodegenerative disorders, neurodegeneracies of the basal ganglia (Parkinson's disease, Huntington's disease,.), (B. HALLIWELL, J. Neurochem., 1992, 59, 1609).
In addition to the fact that the compounds of the present invention are new, they exhibit valuable pharmacological properties. Their anti-oxidant character, being a trap for reactive oxygenated species, especially at the level of the central nervous system, means that they can be considered for use in opposing the effects of oxidation stress, especially at the cerebral level. Most of them, moreover, have the advantage of not causing a hypothermic effect at the doses used for obtaining neuroprotective action. They will therefore be useful in the treatment of disorders associated with ageing, such as atherosclerosis and cataract, in the treatment of cancer, in the treatment of cognitive disorders, and in the treatment of acute neurodegenerative disorders, such as cerebral ischaemia and epilepsy, and in the treatment of chronic neurodegenerative disorders, such as Alzheimer's disease, Pick's disease and neurodegeneracies of the basal ganglia (Parkinson's disease, Huntington's disease).
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates especially to the compounds of the general formula (I):
wherein:
R
1
represents a hydrogen atom or a group
wherein A represents a hydrogen atom or a group —BNZ
1
Z
2
in which B represents a linear or branched (C
1
-C
6
)alkylene group and Z
1
and Z
2
independently represent a hydrogen atom or an alkyl, (C
3
-C
8
)cycloalkyl or optionally substituted aryl group or, together with the nitrogen atom carrying them, form an optionally substituted heterocycloalkyl or heteroaryl group,
R
2
and R
3
each independently represents an alkyl group, a (C
3
-C
8
)cycloalkyl group, a heterocycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, a cycloalkylalkyl group, a heterocycloalkylalkyl group, an optionally substituted arylalkyl group, an optionally substituted heteroarylalkyl group or an aminoalkyl group (optionally substituted on the nitrogen atom by one or two groups selected from alkyl, cycloalkyl, aryl and arylalkyl) or
R
2
and R
3
, together with the carbon atom carrying them, form a (C
3
-C
8
)cycloalkyl group or a monocyclic heterocycloalkyl group unsubstituted or substituted by an alkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl group,
R
40
represents a hydrogen atom or a group selected from optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl or a group Q or —V—Q wherein V represents an alkylene, alkenylene or alkynylene group and Q represents an optionally substituted (C
3
-C
8
)cycloalkyl group, an optionally substituted aryl group, an optionally substituted heterocycloalkyl group or an optionally substituted heteroaryl group,
R
41
and R
5
together form a bond or each represents a hydrogen atom,
R
6
, R
7
, R
8
and R
9
each independently represents a hydrogen atom, a halogen atom, an alkyl group, a (C
3
-C
8
)cycloalkyl group or a group —OW wherein W represents a hydrogen atom or an alkyl group, an acyl group, a (C
3
-C
8
)cycloalkyl group, a heterocycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted arylalkyl group or an optionally substituted heteroarylalkyl group (provided that R
6
, R
7
, R
8
and R
9
cannot all simultaneously represent a hydrogen atom and that at least one of them represents a group —OW as defined hereinbefore),
with the proviso that:
when R
2
and R
3
represent an alkyl group:
if each of R
6
to R
9
independently represents a hydrogen atom, an alkyl group or a group —OW wherein W represents an alkyl group, and R
41
and R
5
together form a bond, then R
40
is other than a hydrogen atom or an alkyl group,
if a single group —OW is present in the molecule and represents a hydroxy group, then R
40
is other than a hydrogen atom,
if a single group —OW is present in the molecule and represents a methoxy group, then R
40
is other than a hydroxyalkyl group,
the compound of formula (I) being other than 7-methoxy-2,2-diphenyl-1,2-dihydroquinoline,
it being understood that:
the term alkyl denotes a linear or branched chain of from 1 to 6 carbon atoms,
the term acyl denotes an alkyl-carbonyl group, alkyl being as defined hereinbefore,
the term alkenyl denotes a linear or branched chain of from 2 to 6 carbon atoms containing from 1 to 3 double bond(s),
the term alkynyl denotes a linear or branched chain of from 2 to 6 carbon atoms containing from 1 to 3 triple bond(s),
the term alkylene denotes a linear or branched bivalent group containing from 1 to 6 carbon atoms,
the term alkenylene denotes a linear or branched bivalent group containing from 2 to 6 carbon atoms and from 1 to 3 double bonds,
the term alkynylene denotes a linear or branched bivalent group containing from 2 to 6 carbon atoms and from 1 to 3 triple bonds,
the term aryl denotes a phenyl, naphthyl or biphenyl group,
the term heterocycloalkyl denotes a mono- or bi-cyclic, 4- to 11-membered group containing from 1 to 6 hetero atoms selected from nitrogen, oxygen and sulphur, it being possible for the group to contain one or more unsaturations without thereby having an aromatic character,
the term heteroaryl denotes an aromatic or partially aromatic, mono- or bi-cyclic, 4- to 11-membered group containing from 1 to 6 hetero atoms selected from nitrogen, oxygen and sulphur,
the term substituted used in respect of the expressions aryl and arylalkyl indicates that the groups concerned are substituted by one or more halogen atoms or alkyl, linear or branched (C
1
-C
6
)alkoxy, linear or branched (C
1
-C
6
)perhaloalkyl, amino (optionally substituted by 1 or 2 alkyl groups), cyano, carboxy, linear or branched (C
1
-C
6
)alkoxycarbonyl, aminocarb
Casara Patrick
Dorey Gilbert
Lestage Pierre
Lockhart Brian
Adir et Compagnie
Delacroix-Muirheld C.
Sage G. Patrick
Seidel Marianne C.
The Firm of Hueschen and Sage
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