Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-02-08
2001-01-09
Shah, Mukund J. (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S217030, C514S307000, C514S318000, C514S322000, C514S417000, C540S596000, C546S150000, C546S196000, C546S199000, C546S201000, C546S204000, C548S477000
Reexamination Certificate
active
06172085
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel cyclic ether compounds having very satisfactory sodium channel modulating activity, their production and use.
BACKGROUND ART
Substances which modulate the voltage-gated sodium channel are known as local anesthetics, antiarrythmic drugs, or anticonvulsants. Recent research has shown that sodium channel modulators are effective also as therapeutic drugs for central nervous system diseases and disturbances, such as ischemic central nervous disorder, brain trauma, and spinal cord injury, among others (Trends in Pharmacological Science, 16, 309-316, 1995). Ischemic or traumatic nerve injury entails retention of sodium ions in the local neurons or nerve fibers (Stroke, 20, 1377-1382, 1989) and this sodium retention leads to edematization, abnormal release of various neurotransmitters such as dopamine and glutamates (Trends in Neuroscience, 16, 415-419, 1993), and promotion of calcium ion influx by the Na
+
Ca
2+
exchanger (Neuron, 12, 295-300, 1994) to thereby cause cell injuries.
While BW619C89, lifarizine, riluzole, and certain other compounds are known as sodium channel modulators (Trends in Pharmacological Science, 16, 309-316, 1995), cyclic ethers having amino groups on fused ring systems are not known.
As cyclic ethers having amino groups on fused ring systems, the following compounds, among others, are known.
1) The aminocoumaran compounds of the following formula which has inhibitory activity of lipid peroxidation (EP-A-483772 and its counterpart, JP-A-5-140142).
wherein R
1
and R
2
each represents hydrogen, acyl, alkoxycarbonyl, or an aliphatic or aromatic group which may be substituted; R
3
, R
4
and R
5
each represents a hydroxy which may be acylated or an amino, alkoxy or aliphatic group which may be substituted, or two of R
3
, R
4
and R
5
may form a carbocycle; R
6
and R
7
each represents an aliphatic group which may be substituted and at least one of R
6
and R
7
has methylene in &agr;-position; R
8
and R
9
each represents hydrogen or an aliphatic or aromatic group which may be substituted.
2) The aminocoumaran compounds of the following formula which has inhibitory activity of lipid peroxidation (JP-A-6-41123).
wherein R
1
, R
2
, R
3
, and R
4
may be the same or different and each represents lower alkyl; ring A represents a benzene ring substituted by at least one substituent selected from among lower alkyl, lower alkoxy and halogen.
3) A crystalline salt of an enantiomer of 5-amino-2,4,6,7-tetramethyl-2-(4-phenylpiperidinomethyl)-2,3-dihydrobenzo[b]furan having inhibitory activity of lipid peroxidation (U.S. Pat. No. 5,552,552).
However, there is not report about the relationship of these compounds with sodium channel modulating activity.
Any sodium channel modulatory substance possessed of satisfactory sodium channel modulating activity coupled with favorable intracranial transfer kinetics and metabolic stability is expected to show good efficacy in central nervous system (CNS) diseases and disorders such as central nervous system ischemia, central nervous system trauma (e.g. brain trauma, spinal cord injury, whiplash injury, etc.), epilepsy, neurodegenerative diseases (e.g. amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Huntington's chorea, Parkinson's disease, diabetic neuropathy, etc.), vascular dementia (e.g. multi-infarct dementia, Binswanger's disease, etc.), manic-depressive psychosis, depression, schizophrenia, chronic pain, trigeminal neuralgia, migraine and cerebral edema. However, no fully satisfactory modulator is available today and there has been a standing need for development of a compound possessed of satisfactory sodium channel modulating activity and qualified for use as a medicine.
The inventors of the present invention explored broadly for compounds having sodium channel modulating activity and succeeded in the creation of a novel compound which is structurally characterized in that the carbon atom in 2-position of a fused cyclic ether has been concurrently substituted by a lower alkyl group and a group of the formula:
wherein each of the symbols has the same meaning as defined below, and is of the formula:
wherein
R
1
and R
2
each represents a hydrogen atom, a lower alkyl which may be substituted or an acyl;
R
3
, R
4
and R
5
each represents a lower alkyl which may be substituted or a lower alkoxy which may be substituted, or R
4
and R
5
taken together represent a 5- or 6-membered carbocyclic group;
R
6
represents a lower alkyl;
Ar represents an aromatic group which may be substituted;
ring A represents a 5- to 8-membered nitrogen-containing heterocyclic ring which may be substituted;
X represents a lower alkylene which may be substituted;
Y represents a carbon or nitrogen atom;
Za represents a group of the formula:
wherein
R
7
represents a hydrogen atom or an aromatic group which may be substituted; R
10
represents a hydrogen atom, a hydrocarbon group which may be substituted or an acyl;
Zb represents a bond or a divalent aliphatic hydrocarbon group which may be substituted and may contain oxygen, nitrogen or sulfur; and
m represents an integer of 1 to 3, or a salt thereof [hereinafter referred to briefly as compound (I)].
They discovered surprisingly that a compound of the following formula or a salt thereof [hereinafter referred to briefly as compound (Ia)] including compound (I) has very favorable properties required of a sodium channel modulator, for example a good affinity for the sodium channel as well as high stability, and as such is fully satisfactory for use as a medicine. The present invention has been developed on the basis of the above findings:
wherein Q represents a hydrogen atom, an aromatic group which may be substituted or a group of the formula:
—Zc—Ar
wherein Zc represents a divalent aliphatic hydrocarbon group which may be substituted and may contain oxygen, nitrogen or sulfur; Ar has the same meaning as defined above; ring Aa represents a 5- to 8-membered nitrogen-containing heterocyclic ring which may be substituted or the corresponding fused benzologue system thereof; the other respective symbols have the same meanings as defined above.
DISCLOSURE OF INVENTION
The present invention is directed to
(1) compound (I),
(2) a compound of the above (1) wherein R
1
and R
2
each is
i) a hydrogen atom,
ii) a C
1-6
alkyl which may be substituted by 1 to 5 substituents selected from the group consisting of halogen, C
3-6
cycloalkyl, C
2-6
alkynyl, C
2-6
alkenyl, C
6-10
aryl, C
7-11
aralkyl, C
1-6
alkoxy, C
6-10
aryloxy, C
1-6
alkyl-carbonyl, C
6-10
aryl-carbonyl, C
1-6
alkyl-carbonyloxy, carbamoyl, amidino, imino, amino, mono-C
1-6
alkylamino, di-C
1-6
alkylamino, 3- to 6-membered cyclic amino, C
1-3
alkylenedioxy, hydroxy, nitro, cyano, mercapto, sulfo, sulfino, phosphono, sulfamoyl, mono-C
1-6
alkylsulfamoyl, di-C
1-6
alkylsulfamoyl, C
1-6
alkylthio, C
6-10
arylthio, C
1-6
alkylsulfinyl, C
6-10
arylsulfinyl, C
1-6
alkylsulfonyl and C
6-10
arylsulfonyl, or
iii) an acyl selected from the group consisting of formyl, C
1-6
alkyl-carbonyl, C
6-10
aryl-carbonyl, C
6-10
aryl-C
1-6
alkyl-carbonyl, C
1-6
alkoxy-carbonyl, C
6-10
aryl-C
1-6
alkoxy-carbonyl, C
1-6
alkylsulfonyl, C
6-10
arylsulfonyl which may be substituted by 1 to 3 C
1-6
alkyl and C
6-10
aryl-C
1-6
alkylsulfonyl;
R
3
, R
4
and R
5
each is
i) a C
1-6
alkyl which may be substituted by 1 to 5 substituents selected from the group consisting of halogen, C
3-6
cycloalkyl, C
2-6
alkynyl, C
2-6
alkenyl, C
6-10
aryl, C
7-11
aralkyl, C
1-6
alkoxy, C
6-10
aryloxy, C
1-6
alkyl-carbonyl, C
6-10
aryl-carbonyl, C
1-6
alkyl-carbonyloxy, C
6-10
aryl-carbonyloxy, carboxy, C
1-6
alkoxy-carbonyl, carbamoyl, amidino, imino, amino, mono-C
1-6
alkylamino, di-C
1-6
alkylamino, 3- to 6-membered cyclic amino, C
1-3
alkylenedioxy, hydroxy, nitro, cyano, mercapto, sulfo, sulfino, phosphono, sulfamoyl, mono-C
1-6
alkylsulfamoyl, di-C
1-6
alkylsulfamoyl, C
1-6
alkylthio, C
6-10
arylthio, C
1
Fukatsu Kohji
Hashimoto Tadatoshi
Ohkawa Shigenori
Foley & Lardner
Rao Deepak R.
Shah Mukund J.
Takeda Chemical Industries Ltd.
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