Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-04-24
2003-10-07
Ford, John M. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S197000, C544S198000, C544S208000, C544S209000
Reexamination Certificate
active
06630469
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to diamino derivatives of pyrimidines and triazines having pharmacological activity at the 5-HT
7
receptor. As such, the compounds are useful for treating various central nervous system and peripheral disorders; as well as disorders of the eye.
BACKGROUND OF THE INVENTION
The 5-HT
7
receptor is a recent member of the growing serotonin receptor family. Both human and animal 5-HT
7
receptors have recently been cloned, expressed and shown to be present in various brain areas and peripheral tissues (Eglen et al.,
Trend Pharmacol. Sci.,
1997, 18, 104-107). The 5-HT
7
receptor has been implicated in the pathophysiology of CNS disorders, such as, sleep disorders, depression, (Schwartz, et al.,
Adv. Int. Med.
1993, 38, 81-106), schizophrenia (Roth, et al.,
J. Pharmacol. Exp. Ther.,
1994, 268, 1403-1410), anxiety, obsessive compulsive disorder, migraine (Terron,
Idrugs,
1998, 1, 302-310), pain and centrally and peripherally mediated hypertension (Eglen et al., supra).
Although it is not clear which serotonergic receptor(s) activity is responsible for lowering intraocular pressure (IOP), increasing blood flow and providing neuroprotection in the eye, the 5-HT
7
receptor has been found in the retina, choroid and possibly the optic nerve head (May, et al., WO9959499, 4). The stimulation of the 5-HT
7
receptor has caused relaxation of blood vessels in mammals such as the monkey (Leung, et al.,
Br. J. Pharmacol.,
1996, 117, 926-930), dog (Cushing, et al.,
J. Pharmacol. Exp. Ther.,
1996, 277, 1560-1566) and rabbit (Martin, et al.,
Br. J. Pharmacol.,
1995, 114, 383). Stimulation of the 5-HT
7
receptor may therefore improve blood flow to the optic nerve head, macula and the retina, which is believed to be beneficial in the treatment of retinal diseases such as, glaucoma, age related macular degeneration (ARMD), and diabetic retinopathy (Chiou, et al.,
J. Ocular Pharmacol.,
1993, 9, 13-24).
The therapeutic utility of 5-HT
7
receptor ligands for the treatment of CNS and ocular disorders therefore requires the discovery of therapeutic agents with a high affinity for the 5-HT
7
receptor.
SUMMARY OF THE INVENTION
The present invention comprises 5-HT
7
receptor antagonists and partial agonists, useful for the treatment of CNS and ocular disorders. The present invention also comprises methods of treating CNS and ocular disorders in a subject in need thereof comprising the administration of 5-HT
7
antagonists and partial agonists which include compounds described in DE 2163873, DE 3717480, U.S. Pat. No. 5,491,234, WO 92/18498, U.S. Pat. No. 3,816,629, GB 1288903, WO 98/15538, DE 19704922, Mohr et al. Arch. Pharm. (Weinheim, Ger.) 1986, 319(10), 878-885, and Hadjuk et al. in J. Med. Chem. 1999, 42, 3852-3859, incorporated by reference herein.
A first embodiment of a first aspect of the present invention is a method of treating CNS and ocular disorders comprising administration to a subject in need thereof an effective amount of a compound of Formula (I)
or a pharmaceutically acceptable salt or hydrate thereof,
wherein
V, W and X are CH or N, provided that no more than one of V, W or X can be CH;
Y is O, S(O)
m
, CH
2
, NR
9
or a covalent bond;
Z is selected from the group consisting of benzodioxolyl, cyclohexenyl, furanyl, indolyl, napthalenyl, thienyl, pyridinyl and phenyl;
optionally substituted with one to five groups, the same or different independently selected from the group consisting of halogen, C
1-4
alkyl, C
1-4
haloalkyl, O—C
1-4
alkyl, cyano, hydroxy, nitro, NHSO
2
C
1-6
alkyl, NR
7
R
8
, C(O)NH
2
and C
1-3
alkylene;
m and n are each independently 0, 1 or 2;
R
1
is hydrogen, halogen, C
1-6
alkyl, C
3-7
cycloalkyl, or NR
7
R
8
;
provided that
if V, W or X is CH, then R
1
is not halogen or NR
7
R
8
;
if V, W and X are each N, then R
1
is not hydrogen;
R
2
is C
1-4
alkyl substituted with Z′, wherein
Z′ is selected from the group consisting of benzodioxolyl, cyclohexenyl, furanyl, indolyl, napthalenyl, thienyl, pyridinyl and phenyl;
optionally substituted with one to five groups, the same or different independently selected from the group consisting of halogen, C
1-4
alkyl, C
1-4
haloalkyl, O—C
1-4
alkyl, cyano, hydroxy, nitro, NHSO
2
C
1-6
alkyl, NR
7
R
8
and C(O)NH
2
;
R
3
is hydrogen, C
1-6
alkyl or C
3-7
cycloalkyl;
R
4
and R
5
are independently hydrogen or C
1-6
alkyl or together are C
2-3
alkylene;
R
6
is hydrogen or C
1-3
alk(en)ylene
provided that
if R
6
is C
1-3
alk(en)ylene, it is attached to Z;
R
7
and R
8
are independently selected from the group consisting of hydrogen, C
1-6
alkyl, C
3-7
cycloalkyl, SO
2
C
1-6
alkyl;
or R
7
and R
8
together with the nitrogen to which they are attached can form a 5 to 8 membered heterocycle;
said heterocycle optionally containing a second heteroatom selected from the group consisting of N, O and S;
said heterocycle being optionally substituted with up to three of the same or different substituents independently selected from C
1-6
alkyl or O—C
1-6
alkyl; and
R
9
is hydrogen or (C
1-6
)alkyl.
A second embodiment of the first aspect of the present invention is a method of treating sleeping disorders, depression, schizophrenia, anxiety, obsessive compulsive disorders, circadian rhythm disorders, ocular disorders and/or centrally and peripherally mediated hypertension comprising administration to a subject in need thereof an effective amount of a compound of Formula (I) according to the first embodiment of the first aspect.
A first embodiment of a second aspect of the present invention is a method of treating sleeping disorders, depression, schizophrenia, anxiety, obsessive compulsive disorders, circadian rhythm disorders, ocular disorders and/or centrally and peripherally mediated hypertension comprising administration to a subject in need thereof an effective amount of a compound of Formula (I) according the first aspect wherein
V and W are each N;
X is CH; and
R
1
is H.
A second embodiment of the second aspect of the present invention is a method of treating sleeping disorders, depression, schizophrenia, anxiety, obsessive compulsive disorders, circadian rhythm disorders, ocular disorders and/or centrally and peripherally mediated hypertension comprising administration to a subject in need thereof an effective amount of a compound of Formula (I) according the first aspect wherein
V and W are each N;
X is CH;
Z is substituted or unsubstituted phenyl; and
R
1
is H.
A third embodiment of the second aspect of the present invention is a method of treating sleeping disorders, depression, schizophrenia, anxiety, obsessive compulsive disorders, circadian rhythm disorders, ocular disorders and/or centrally and peripherally mediated hypertension comprising administration to a subject in need thereof an effective amount of a compound of Formula (I) according to the first aspect wherein
V and W are each N;
X is CH;
Y is O or a covalent bond; and
R
1
is H.
A fourth embodiment of the second aspect of the present invention is a method of treating sleeping disorders, depression, schizophrenia, anxiety, obsessive compulsive disorders, circadian rhythm disorders, ocular disorders and/or centrally and peripherally mediated hypertension comprising administration to a subject in need thereof an effective amount of a compound of Formula (I) according to the first aspect wherein
V and W are each N;
X is CH;
Y is O or a covalent bond;
Z is substituted or unsubstituted phenyl; and
R
1
is H.
A fifth embodiment of the second aspect of the present invention is a method of treating sleeping disorders, depression, schizophrenia, anxiety, obsessive compulsive disorders, circadian rhythm disorders, ocular disorders and/or centrally and peripherally mediated hypertension comprising administration to a subject in need thereof an effective amount of a compound of Formula (I) according to the first aspect wherein
V and W are each N;
X is CH;
Y is O, S or a covalent bond;
Z is substituted or unsubstituted phenyl, indolyl, pyridinyl, thienyl or benzodioxolyl;
Z′ is su
Mattson Ronald J.
Poss Michael A.
Purandare Ashok V.
Sun Li-Qiang
Balasubramanian Venkataraman
Bristol--Myers Squibb Company
Ford John M.
Makujina Shah R.
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