Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-04-20
2004-07-06
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S427000, C514S254090, C514S678000, C548S510000, C548S550000, C548S469000
Reexamination Certificate
active
06759427
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention:
The present invention is directed to tetrahydroindolone derivatives and analogues, particularly tetrahydroindolone derivatives or analogues in which the tetrahydroindolone derivative or analogue is covalently linked to another moiety to form a bifunctional conjugate.
2. General Background and State of the Art:
Diseases and degenerative conditions of the central nervous system are among the most severe, long-lasting, and chronic diseases and conditions affecting man. Although much research has been done on such diseases and conditions, effective treatment remains elusive. These diseases and conditions include Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), Parkinson's disease, multiple sclerosis, stroke, and other neurodegenerative disorders, which may be genetic, spontaneous or drug-induced.
There is therefore a need for improved compounds and methods for treating such conditions. The need for such improved compounds and methods has been increased by the discovery that such compounds are capable of increasing neuronal function, stimulating nerve growth or regeneration and can act through the induction of neurotrophic factors such as nerve growth factor, NT-3, brain-derived neurotrophic factor (BDNF), or ciliary neurotrophic factor (CNTF). Such compounds may stimulate nerve regeneration or neurogenesis in the peripheral nervous systemor central nervous system, or neuroprotection, and may therefore be of use in the treatment of the diseases and conditions referred to above.
There is therefore a particular need for the development of additional compounds that have improved activity in stimulating neuronal function, regeneration, neurogenesis, and that have neuroprotective activity. There is further a need for compounds that have activities that provide treatment for or relief from symptoms of diseases and conditions such as Alzheimer's disease, Huntington's disease, Parkinson's disease, multiple sclerosis, stroke and other neurodegenerative disorders, which may be genetic, spontaneous or drug-induced. Examples of these symptoms include reduced cognition, emotional control, and sensory or motor function. There is a particular need for the development of new compounds that have improved bioavailability. There is a further need for compounds with a greater degree of activity as measured by a dose-response curve assay and for compounds with a different spectrum of activities.
One potential basis for such compounds is the bicyclic compound tetrahydroindolone, which is isosteric with purines. However, compounds that incorporate tetrahydroindolone or its analogues and that have activities such as nootropic activity or neuroproliferative activity have not been prepared.
INVENTION SUMMARY
One aspect of the present invention is bifunctional conjugates. In general, a bifunctional conjugate according to the present invention has the schematic structure:
where:
(1) A is a 9-atom bicyclic moiety in which the five-membered ring has 1 to 3 nitrogen atoms, the bicyclic moiety having the structure:
where:
(a) N
1
is bonded to L;
(b) A
2
and A
3
are C or N:
(i) if A
2
and A
3
are both C and the bond between A
2
and A
3
is a single bond, then the bond between A
2
and R
2
is two single bonds to two hydrogen atoms or is a double bond in which R
2
is O or S and R
3
is two hydrogen atoms;
(ii) if A
2
and A
3
are both C and the bond between A
2
and A
3
is a double bond, then R
3
is hydrogen, the bond between A
2
and R
2
is a single bond and R
2
is hydrogen, halo, alkyl, alkenyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, or heteroaralkenyl;
(iii) if A
2
and A
3
are both N, then the bond between A
2
and A
3
is a double bond and R
2
and R
3
are not present;
(iv) if A
2
is N and A
3
is C, then the bond between A
2
and A
3
is a double bond, R
2
is not present, and R
3
is hydrogen;
(v) if A
2
is C, A
3
is N, and the bond between A
2
and A
3
is a double bond, then R
3
is not present, the bond between A
2
and R
2
is a single bond, and R
2
is hydrogen, halo, alkyl, alkenyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, or heteroaralkenyl;
(vi) if A
2
is C, A
3
is N, and the bond between A
2
and A
3
is a single bond, then R
3
is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, the bond between A
2
and R
2
is a double bond, and A
2
is O or S;
(c) R
5
is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkanoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, NH
2
, NHQ
1
, NQ
1
Q
2
, OH, OQ
1
, or SQ
1
, where Q
1
and Q
2
are alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, alkanoyl, aroyl, aralkanoyl, heteroaralkanoyl, heteroaroyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, or heteroaralkylsulfonyl in which the alkyl portions can be cyclic and can contain from 1 to 3 heteroatoms which can be N, O, or S, and when Q
1
and Q
2
are present together and are alkyl, they can be taken together to form a 5 or 6 member ring which may contain 1 other heteroatom which can be N, O, or S, of which the N may be further substituted with Y
2
, where Y
2
is alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkanoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkoxycarbonyl, heteroaralkoxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, aralkylaminocarbonyl, or heteroaralkylaminocarbonyl, in which the alkyl portions can be cyclic and can contain from 1 to 3 heteroatoms which can be N, O, or S;
(d) R
5′
is hydrogen unless R
5
is alkyl, in which case R
5′
is hydrogen or the same alkyl as R
5
;
(e) R
5
and R
5′
can be taken together as a double bond to C
5
and can be O, S, NQ
3
, or C which can be substituted with one or two groups R
5
, where Q
3
is alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, alkanoyl, aroyl, aralkanoyl, heteroaralkanoyl, or heteroaroyl in which the alkyl portions can be cyclic and can contain from 1 to 3 heteroatoms which can be N, O, or S;
(f) R
6
is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, NH
2
, NHQ
4
, NQ
4
Q
5
, OH, OQ
4
, or SQ
4
, where Q
4
and Q
5
are alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, alkanoyl, aroyl, aralkanoyl, heteroaralkanoyl, heteroaroyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, or heteroaralkylsulfonyl in which the alkyl portions can be cyclic and can contain from 1 to 3 heteroatoms which can be N, O, or S, and when Q
1
and Q
2
are present together and are alkyl, they can be taken together to form a 5 or 6 member ring which may contain 1 other heteroatom which can be N, O, or S, of which the N may be further substituted with Y
2
, where Y
2
is alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkanoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkoxycarbonyl, heteroaralkoxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, aralkylaminocarbonyl, or heteroaralkylaminocarbonyl, in which the alkyl portions can be cyclic and can contain from 1 to 3 heteroatoms which can be N, O, or S;
(g) R
6′
is hydrogen unless R
6
is alkyl, in which case R
6′
is hydrogen or the same alkyl as R
6
;
(h) R
6
and R
6′
can be taken together as a double bond to C
5
and can be O, S, NQ
6
, or C which can be substituted with one or two groups R
5
, and where Q6 is alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, alkanoyl, aroyl, aralkanoyl, heteroaralkanoyl, heteroaroyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, or heteroaralkylsulfonyl in which the alkyl portions can be cyclic and can contain from 1 to 3 heteroatoms which can be N, O, or S;
(i) R
7
is hydrogen unless R
5
is alky
Fick David B.
Foreman Mark M.
Glasky Alvin J.
Cullman Louis C.
Patel Sudhaker B.
Raymond Richard L.
Spectrum Pharmaceuticals Inc.
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