Arylacrylamide derivatives

Details Arylacrylamide derivatives Arylacrylamide derivatives

1997-05-28

2001-07-10

Qazi, Sabiha (Department: 1616)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C544S359000

Reexamination Certificate

active

06258953

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to phenyl acrylamide derivatives, to processes and intermediates for their preparation, to pharmaceutical compositions containing them and to their medicinal use. The compounds of the present invention are selective agonists and antagonists of serotonin 1 (5-HT
1
) receptors. They are useful in treating or preventing migraine, depression and other disorders for which a 5-HT
1
agonist or antagonist is indicated.
European Patent Publication 434,561, published on Jun. 26, 1991, refers to 7-alkyl, alkoxy, and hydroxy substituted-1-(4-substituted-1-piperazinyl)-naphthalenes. The compounds are referred to as 5-HT
1
agonists and antagonists useful for the treatment of migraine, depression, anxiety, schizophrenia, stress and pain.
European Patent Publication 343,050, published on Nov. 23, 1989, refers to 7-unsubstituted, halogenated, and methoxy substituted-1-(4-substituted-1-piper-azinyl)-naphthalenes as useful 5-HT
1A
ligand therapeutics.
Glennon et al., refers to 7-methoxy-1-(1-piperazinyl)-naphthalene as a useful 5-HT
1
ligand in their article “5-HT
1D
Serotonin Receptors”,
Clinical Drug Res. Dev
., 22, 25-36 (1991).
Glennon's article “Serotonin Receptors: Clinical Implications”, Neuroscience and
Behavioral Reviews
, 14, 35-47 (1990), refers to the pharmacological effects associated with serotonin receptors including appetite suppression, thermoregulation, cardiovascular/hypotensive effects, sleep, psychosis, anxiety, depression, nausea, emesis, Alzheimer's disease, Parkinson's disease and Huntington's disease.
World Patent Application WO 95/31988, published Nov. 30, 1995, refers to the use of a 5-HT
1D
antagonist in combination with a 5-HT
1A
antagonist to treat CNS disorders such depression, generalized anxiety, panic disorder, agoraphobia, social phobias, obsessive-compulsive disorder, post-traumatic stress disorder, memory disorders, anorexia nervosa and bulimia nervosa, Parkinson's disease, tardive dyskinesias, endocrine disorders such as hyperprolactinaemia, vasospasm (particularly in the cerebral vasculature) and hypertension, disorders of the gastrointestinal tract where changes in motility and secretion are involved, as well as sexual dysfunction.
G. Maura et al.,
J. Neurochem
, 66 (1), 203-209 (1996), have stated that administration of agonists selective for 5-HT
1A
receptors or for both 5-HT
1A
and 5-HT
1D
receptors might represent a great improvement in the treatment of human cerebellar ataxias, a multifaceted syndrome for which no established therapy is available.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula
wherein R
1
is a group of the formula G
1
, G
2
, G
3
, G
4
or G
5
, depicted below,
wherein E
is oxygen, sulfur, SO or SO
2
;
R
6
is selected from the group consisting of hydrogen, (C
1
-C
6
)alkyl, [(C
2
-C
4
)alkyl]aryl wherein the aryl moiety is phenyl, naphthyl, or heteroaryl-(CH
2
)
q
—, wherein the heteroaryl moiety is selected from the group consisting of pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl and benzisothiazolyl and q is zero, one, two, three or four, and wherein said aryl and heteroaryl moieties may optionally be substituted with one or more substituents independently selected from the group consisting of chloro, fluoro, bromo, iodo, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, trifluoromethyl, cyano and —SO
g
(C
1
-C
6
)alkyl, wherein g is zero, one or two;
R
7
is selected from the group consisting of hydrogen, (C
1
-C
6
)alkyl, [(C
2
-C
4
)alkyl]aryl wherein the aryl moiety is phenyl, naphthyl, or heteroaryl-(CH
2
)
q
—, wherein the heteroaryl moiety is selected from the group consisting of pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl and benzisothiazolyl and q is zero, one, two, three or four, and wherein said aryl and heteroaryl moieties may optionally be substituted with one or more substituents independently selected from the group consisting of chloro, fluoro, bromo, iodo, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, trifluoromethyl, —C(═O)-(C
1
-C
6
)alkyl, cyano and —SO
j
(C
1
-C
6
)alkyl, wherein j is zero, one or two;
or R
6
and R
7
taken together form a 2 to 4 carbon chain;
R
8
is hydrogen or (C
1
-C
3
)alkyl;
R
9
is hydrogen or (C
1
-C
6
)alkyl;
or R
6
and R
9
, together with the nitrogen atom to which they are attached, form a 5 to 7 membered ring;
and p is one, two, or three;
R
2
is hydrogen, (C
1
-C
4
)alkyl, phenyl or naphthyl, wherein said phenyl or naphthyl may optionally be substituted with one or more substituents, preferably from zero to three substituents, independently selected from the group consisting of chloro, fluoro, bromo, iodo, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, trifluoromethyl, cyano and —SO
g
(C
1
-C
6
)alkyl, wherein g is zero, one or two;
R
3
is -(CH
2
)
m
B, wherein m is zero, one, two or three and B is hydrogen, phenyl, naphthyl or a 5 or 6 membered heteroaryl group containing from one to four hetero atoms in the ring (eq., furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzoxazinyl; etc.), and wherein each of the foregoing aryl and heteroaryl groups may optionally be substituted with one or more substituents, preferably from zero to three substituents, independently selected from the group consisting of chloro, fluoro, bromo, iodo, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, trifluoromethyl, cyano, hydroxy, —COOH and —SO
g
(C
1
-C
6
)alkyl, wherein g is zero, one or two;
R
4
is (C
1
-C
6
)alkyl or aryl or R
3
and R
4
may optionally be taken together with the nitrogen to which they are attached to form a five to seven membered heteroalkyl ring, wherein any two of the carbon atoms of said heteroalkyl ring may optionally be replaced with a heteroatom selected from the group consisting of nitrogen, oxygen or sulfur (e.g., pyrrolidine, isoxazolidine, 1,3-oxazolidin-3-yl, isothiazolidine, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, piperidine, thiomorpholine, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazine, morpholine, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, piperazine, etc.); wherein said heteroalkyl ring may optionally be substituted by aryl or heteroaryl (e.g., furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyi, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzoxazinyl; etc.);
R
5
is hydrogen, (C
1
-C
6
)alkyl or aryl, wherein aryl is selected from the group consisting of phenyl, napthyl, pyridyl or pyrimidyl, wherein any of said aryl may optionally be independently substituted on any available bonding site by any of the radicals of X;
X is hydrogen, chloro, fluoro, bromo, iodo, cyano, (C
1
-C
6
)alkyl, hydroxy, trifluoromethyl, (C
1
-C
6
)alkoxy, —SO
m
(C
1
-C
6
)alkyl wherein m is zero one or two, —CO
2
R
10
or —CONR
11
R
12
;
each of R
10
, R
11
and R
12
is selected, independently, from the radicals set forth in the definition of R
2
; or R
11
and R
12
, together with the nitrogen to which they are attached, form a 5 to 7 membered heteroalkyl ring that may contain

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