Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-07-19
2002-12-10
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S454000, C514S455000
Reexamination Certificate
active
06492415
ABSTRACT:
This invention relates to a novel method of treatment.
EP-A-0 126 311 discloses substituted benzopyran compounds having blood pressure lowering activity, including 6-acetyl-trans-4-(4-fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol.
Also EP-A-0 376 524, EP-A-0 205 292, EP-A-0 250 077, EP-A-0 093 535, EP-A-0 150 202, EP-A-0 076 075 and WO/89/05808 (Beecham Group plc) describe certain benzopyran derivatives which possess anti-hypertensive activity.
EP-A-0 350 805 (Biersdorf), EP-A-0 277 611, EP-A-0 277 612, EP-A-0 337 179 and EP-A-0 355 565 (Hoechst Aktiengesellschaft); EP-A-0 466 131 (Nissan Chemical Industries Ltd), EP-A-0 339 562 (Yoshitomi Pharmaceuticals), EP-A-0 415 065 (E. Merck), EP-A-0 450 415 (Squibb), EP-A-0 482 934, EP-A-0 296 975, JO-2004-791 and W089/07103 also describe certain benzopyran derivatives which are believed to possess anti-hypertensive activity.
EP-A-0 430 621 and EP-A-0 385 584 (Beecham Group plc) describe the resolution of certain intermediates useful in the preparation of the compounds described in the above mentioned patent applications.
EP-A-0 139 992 (Beecham Group plc) describes certain benzopyran derivatives which have cis isomerism at position 3 and 4 which compounds are described as possessing anti-hypertensive activity.
EP-A-0 587 645, EP-A-0 673 373, EP-A-0 673 374, EP-A-0 673 248, EP-A-0 674 519, WO95/34545, WO95/34547 and WO95/34546 (SmithKline Beecham plc) describe groups of compounds possessing inter alia anti-convulsant activity, and which are also believed to have utility in the treatment or prevention of mania, depression and the effects associated with withdrawal from substances of abuse.
It has now been surprisingly found that compounds from the above groups have additional activity and are believed to have utility in the treatment and/or prophylaxis of degenerative diseases such as Huntingdon's chorea, schizophrenia, neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia and narcolepsy), tics (e.g., Giles de la Tourette's syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity) and temporomandibular joint dysfunction.
Accordingly, the present invention provides a method of treatment and/or prophylaxis of degenerative diseases such as Huntingdon's chorea, schizophrenia, neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia and narcolepsy), tics (e.g. Giles de la Tourette's syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, MS and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction,
which comprises administering to the sufferer in need thereof an effective or prophylactic amount of a compound of formula (A) or pharmaceutically acceptable salt or solvate thereof:
wherein:
P is a ring system selected from the following:
and the other variables are as defined below:
in which either a and b together represent a bond or CH
2
or a and b together represent a carbonyl group, a group C═NOR
F
, CHOR
F
or
where R
F
is hydrogen or C
1-6
alkyl; or
in which either J is nitrogen and J
a
is a lone pair of electrons, M is carbon and M
a
is R
5
; or
J is carbon and M is nitrogen and J
a
and M
a
are hydrogen; or
in which Z is oxygen or CH
2
;
wherein: 4
either Y is N and R
2
is hydrogen, or Y is C—R
1
; where:
either one of R
1
and R
2
is hydrogen and the other is selected from the class of hydrogen, C
3-8
cycloalkyl, C
1-6
alkyl optionally interrupted by oxygen or substituted by hydroxy, C
1-6
alkoxy or substituted aminocarbonyl, C
1-6
alkylcarbonyl, C
1 6
alkoxycarbonyl, C
1-6
alkylcarbonyloxy, C
1-6
alkoxy, nitro, cyano, halo, trifluoromethyl, CF
3
S, or a group CF
3
—A—, where A is —CF
2
—, —CO—, —CH
2
—, CH(OH), SO
2
, SO, CH
2
—O, or CONH, or a group CF
2
H—A′— where A′ is oxygen, sulfur, SO, SO
2
, CF
2
or CFH; trifluoromethoxy, C
1-6
alkylsulfinyl, perfluoro C
2-6
alkylsulfonyl, C
1-6
alkylsulfonyl, C
1-6
alkoxysulfinyl, C
1-6
alkoxysulfonyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, phosphono, arylcarbonyloxy, heteroarylcarbonyloxy, arylsulfinyl, heteroarylsulfinyl, arylsulfonyl, heteroarylsulfonyl in which any aromatic moiety is optionally substituted, C
1-6
alkylcarbonylamino, C
1-6
alkoxycarbonylamino, C
1-6
alkyl-thiocarbonyl, C
1-6
alkoxy-thiocarbonyl, C
1-6
alkyl-thiocarbonyloxy, 1-mercapto C
2-7
alkyl, formyl, or aminosulfinyl, aminosulfonyl or aminocarbonyl, any amino moiety being optionally substituted by one or two C
1-6
alkyl groups, or C
1-6
alkylsulfinylamino, C
1-6
alkylsulfonylamino, C
1-6
alkoxysulfinylamino or C
1-6
alkoxysulfonylamino, or ethylenyl terminally substituted by C
1-6
alkylcarbonyl, nitro or cyano, or —C(C
1-6
alkyl)NOH or —C(C
1-6
alkyl)NNH
2
,
or one of R
1
and R
2
is nitro, cyano or C
1-3
alkylcarbonyl and the other is halo, C
1-4
alkyl, methoxy or amino optionally substituted by one or two C
1-6
alkyl or by C
2-7
alkanoyl;
or R
1
and R
2
together are —(CH
2
)
4
—; (CH
2
)
x
CO(CH
2
)
y
where x is 0 to 3 and y is 0 to 3 with the proviso that x+y is at least 2x; or —CH═CH—CH═CH—; or form an optionally substituted triazole or oxadiazole ring, or together form a group CONR
c
CO where R
c
is hydrogen, C
1-6
alkyl, aralkyl or heteroarylalkyl;
Z is N only when Y is C—R
1
or Z is C—R
a
when Y is N or C—R
1
; wherein R
a
is hydrogen, halogen, nitro; C
1-4
alkylcarbonyl, C
1-4
alkyl; aryl C
1-4
alkyl, aryl C
1-4
alkenyl, heteroaryl C
1-4
alkyl or heteroaryl C
1-4
alkenyl,
R
b
is hydrogen, halogen, nitro; C
1-4
alkylcarbonyl or C
1-4
alkyl; and in which any aryl or heteroaryl or alkyl moiety associated with R
a
or R
b
are optionally substituted;
one of R
3
and R
4
is hydrogen or C
1-4
alkyl and the other is C
1-4
alkyl, CF
3
or CH
2
X
a
where X
a
is fluoro, chloro, bromo, iodo, C
1-4
alkoxy, hydroxy, C
1-4
alkylcarbonyloxy, —S—C
1-4
alkyl, nitro, amino optionally substituted by one or two C
1-4
alkyl groups; cyano or C
1-4
alkoxycarbonyl
or R
3
and R
4
together are C
2-5
polymethylene optionally substituted by C
1-4
alkyl;
R
5
is C
1-6
alkylcarbonyloxy, benzoyloxy, ONO
2
, benzyloxy, phenyloxy or C
1-6
alkoxy and R
6
and R
9
are hydrogen or R
5
is hydroxy and R
6
and R
9
are independently hydrogen or C
1-2
alkyl;
R
x
is (a)
in which:
R
11
and R
12
are independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, aralkyl, cyano, nitro, COR
13
, CONHR
13
, CONR
13
R
14
or halo where R
13
and R
14
are independently selected from hydrogen, alkyl, haloalkyl, aryl, aralkyl, cycloalkyl or (cycloalkyl)-alkyl;
R
10
is hydrogen, alkyl, haloalkyl, cycloalkyl, O—R
15
, cyano, nitro, CF
3
, halo, S-alkyl, COR
15
, COOR
15
, NR
15
CO alkyl or OCO alkyl where R
15
is hydrogen, alkyl, haloalkyl, aryl, aralkyl, cycloalkyl or (cycloalkyl)-alkyl; m is 0 or 1;
or (b) R
x
is a R
8
—N—CO—R
7
group where
R
7
is heteroaryl or phenyl; both of which are optionally substituted one or more times independently with a group or atom selected from chloro, fluoro, bromo, iodo, nitro, amino optionally substituted once or twice by C
1-4
alkyl, cyano, azido, C
1-4
alkyl, C
1-4
alkoxy, trifluoromethoxy, trifluoromethyl; optionally substituted aryloxy or heteroaryloxy; C
1-4
alkoxy substituted by one or more halogens (excluding trifluoromethoxy); amino substituted by C
1-4
alkanoyl, aroyl aryl phenylsulfonyl or C
1-4
alkylsulfonyl; C
1-4
alkyl substituted by one or more halogens (excluding trifluoromethyl) or alkoxy; phenylsulfonyl C
1-4
alkyl sulfonyl, aminosulfonyl in which the amino
Evans John Morris
Parsons Andrew
Thompson Mervyn
Upton Neil
Hall Linda E.
Kinzig Charles M.
SmithKline Beecham p.l.c.
Spivack Phyllis G.
Venetianer Stephen
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