Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-03-31
2002-05-07
Gitomer, Ralph (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S316000
Reexamination Certificate
active
06384063
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel compounds having a neuron differentiation promoting activity and pharmaceutical use thereof.
BACKGROUND ART
Neurotrophic factors are proteinaceous compounds that participate in differentiation induction of neurons and in maintainance of the existence and survival of nerve cells. Nerve growth factors (hereinafter often abbreviated as NGF) are known to be representative of such compounds (Ann. Neuro., 10, 499-503 (1981)). It is manifested that NGF is deeply involved in the differentiation, existence maintenance and repair of neurons in both the central and peripheral nervous systems.
Damages of nerves caused by aging, internal and external factors often develop pathological symptoms. Such damages are found to cause, in the central nervous system, Alzheimer's disease, dementia induced by cerebro-vascular disorders, disturbance of consciousness due to cerebral contusion, tremor or muscle rigidity by Parkinson's disease, etc. It is also known that damages in the peripheral nervous system are induced by amyotrophic lateral sclerosis, spinal muscle atrophy, motor function disturbances due to neuron damages accompanied by accidents, etc., and that neuropathies are induced by diabetes mellitus, uremia, vitamin B1 or B12 deficiency , chronic liver disease, sarcoidosis, amyloidosis, hypothyrea, cancer, angiopathy, Sjögren symptoms, immunopathy accompanied by infections, hereditary disease, physical compression, drugs (carcinostatic agents, tuberculostatic agents, anti-epileptic agents, etc.) or intoxication (arsenic, thallium, carbon disulfide, etc.); in more detail, see RINSHO KENSA (Clinical Test), 40, 760-766 (1996). It was the recognition in the art that when neurons suffer irreversible damages from these disorders, it was difficult to regenerate and repair the damaged neurons. However, on the hypothesis that neuropathy could be treated if the neurotrophic factors act on neurons, development of neurotrophic factors as medicaments against neuropathy has been made. (Science, 264, 772-774 (1994)). For instance, clinical trial of NGF is in progress against Alzheimer's disease, neural damages or spinal injuries.
NGF is a series of proteins having approximately 50,000 molecular weight. For the treatment of neuropathy, it generally takes a long period of time. For these reasons, it is difficult to develop efficient administration and pharmaceutical formulation. Gene therapy namely induction of NGF gene, is also another choice for the treatment but its therapeutic effect is yet unclear.
It is known that when NGF is present, PC 12 cells—which are the established cell line cloned from rat adrenal medulla pheochromocytoma—terminate cell proliferation and differentiate into neuron-like cells with neurites. This procedure enables to screen an effective substance having a NGF-like neuron differentiation promoting activity. For example, antibiotic staurosporin was found to have the PC 12 cell differentiation promoting activity (SHINKEI KAGAKU, 26, 200-220 (1987)). A similar differentiation promoting activity was recently observed in a biological active compound NK175203 (hereinafter referred to as cystacyclin) which was produced from Streptomyces sp. NK175203 strain FERM BP-4372 (WO 95/31992).
However, the toxicity and pharmacokinetics of staurosporin m vivo make its application as a medicament difficult. It has thus been strongly desired to develop a low molecular weight compound that exhibits a neuron differentiation promoting activity, is low toxic and is readily prepared synthetically.
DISCLOSURE OF INVENTION
The present inventors have made extensive investigations on cystacycline derivatives and as a result, have found novel compounds represented by general formulas [1A], [1B], [1C], [1D], [1E] and [1F] and pharmacologically acceptable salts thereof. The present invention has thus been accomplished. The present invention relates to the following compounds and compositions comprising the same.
1) A cyclopentanone derivative represented by a formula [1A]:
wherein
X
A
is O, S, SO, SO
2
or NH;
Y
A
is a straight or branched aliphatic hydrocarbon group having 1 to 20 carbon atoms, which may be substituted or unsubstituted, or a substituted or unsubstituted aromatic hydrocarbon group or monocyclic aromatic heterocyclic ring having 3 to 6 carbon atoms;
each of Z1
A
, Z2
A
and Z3
A
, which may be the same or different and independently represents carboxy or a group derived therefrom, an unsubstituted or substituted alkyl having 1 to 4 carbon atoms, hydroxy or a group derived therefrom, amino or a group derived therefrom, sulfonate or a group derived therefrom, phosphate or a group derived therefrom, a monocyclic heteroaryl, a halogen or hydrogen; or Z2
A
and Z3
A
are combined together to form a substituted or unsubstituted aromatic hydrocarbon or aromatic heterocyclic ring; and,
Z1
A
is carboxy or a group derived therefrom, an unsubstituted or substituted alkyl having 1 to 4 carbon atoms, hydroxy or a group derived therefrom, amino or a group derived therefrom, a halogen or hydrogen, with the proviso that, when Z2
A
and Z3
A
are both hydrogen, Z1
A
is hydroxy or a group derived therefrom, amino or a group derived therefrom, sulfonate or a monocyclic aromatic heterocyclic ring, a halogen or hydrogen, and Y
A
is a substituted or unsubstituted straight or branched aliphatic hydrocarbon group having 1 to 6 carbon atoms;
with the proviso that (1) through (7) are excluded:
(1) when Z1
A
and Z2
A
are hydrogen, X
A
is S, Y
A
is methyl or benzyl and, Z3
A
is methoxycarbonyl,
(2) when Z1
A
and Z2
A
are hydrogen, X
A
is O or N, Y
A
is benzyl and, Z3
A
is carboxy, methoxycarbonyl or ethoxycarbonyl;
(3) X
A
is N or O, Z1
A
and Z3
A
are hydrogen and, Z2
A
is carboxy or methoxycarbonyl;
(4) X
A
is O, Z1
A
is hydroxy or a group derived therefrom, Z2
A
is hydrogen and, Z3
A
is amino or a group derived therefrom;
(5) X
A
is S, Y1
A
is phenyl, Z1
A
is dimethoxymethyl and, Z2
A
and Z3
A
are hydrogen;
(6) X
A
is O, Y1
A
is methyl, Z1
A
is is 1-methoxy-1-phenylthiomethyl and, Z2
A
and Z3
A
are hydrogen;
(7) Z1
A
is S, SO or SO
2
, Z2
A
is hydroxy or a group derived therefrom and, Z3
A
is hydrogen;
or a pharmacologically acceptable salt thereof;
a 2,3-di-substituted cyclopentanone derivative of formula [1B]:
wherein:
X
B
is O, S, SO, SO
2
or NH;
Y
B
is:
an unsubstituted or substituted straight or branched aliphatic hydrocarbon group having 7 to 20 carbon atoms,
a straight or branched aliphatic hydrocarbon group having 1 to 6 carbon atoms, wherein:
at least one hydrogen is substituted with COW1 (wherein W1 is an unsubstituted or substituted aromatic heterocyclic ring or saturated heterocyclic ring) and, at least one hydrogen may be further substituted with a group derived from amino; or,
at least one hydrogen is substituted with NHCOV1 (wherein V1 is an alkyl having 2 to 5 carbon atoms containing 4 to 11 halogen atoms) and at least one hydrogen may be further substituted with carboxy or a group derived therefrom; or,
at least one hydrogen is substituted with a substituted or unsubstituted monocyclic aromatic heterocyclic ring and, at least one hydrogen may be further substituted with amino or a group derived therefrom; or,
a substituted or unsubstituted aromatic hydrocarbon group or monocyclic aromatic heterocyclic ring having 3 to 6 carbon atoms;
Z
B
is carboxy or a group derived therefrom, sulfonate or a group derived therefrom, phosphate or a group derived therefrom, an unsubstituted or substituted alkyl having 1 to 4 carbon atoms, hydroxy, OR1 (wherein R1 is an unsubstituted or substituted alkyl having 1 to 4 carbon atoms or, an unsubstituted or substituted acyl having 1 to 5 carbon atoms), NHCOR2 (wherein R2 is an unsubstituted or substituted alkyl having 1 to 4 carbon atoms), NHSO
2
R2′ (wherein R2′ is an unsubstituted or substituted alkyl having 1 to 4 carbon atoms or phenyl), a monocyclic aromatic heteroc
Harada Takashi
Kuwahara Atsushi
Morino Tomio
Nagai Masashi
Nishikiori Takaaki
Gitomer Ralph
Khare Devesh
Nields & Lemack
Nippon Kayaku Kabushiki Kaisha
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