Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-12-08
2002-07-23
Solola, T. A. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S235800, C544S059000, C544S060000, C544S121000, C558S426000
Reexamination Certificate
active
06423708
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to novel aralkyl and aralkylidene heterocyclic lactams and imides, to intermediates for their preparation, to pharmaceutical compositions containing them and to their medicinal use. The compounds of the present invention include selective agonists and antagonists of serotonin 1 (5-HT
1
) receptors, specifically, of one or both of the 5-HT
1A
and 5-HT
1D
receptors. They are useful in treating hypertension, all forms of depression (e.g., depression in cancer patients, depression in Parkinson's patients, postmyocardial infarction depression, subsyndromal symptomatic depression, depression in infertile women, pediatric depression, major depressive disorder, single episode depression, recurrent depression, child abuse induced depression, post partum depression, dysthymia; mild, moderate, or severe depressions with or without atypical features, melancholic features, psychotic features, catatonic features; seasonal affective disorder, geriatric depression, chronic depression; adjustment disorder with depressed mood or with anxiety and depressed mood; mixed anxiety and depression; substance induced mood disorder; and mood disorder secondary to a general medical condition), bipolar disorder (including in the depressed phase), generalized anxiety disorder, social anxiety, separation anxiety disorder, phobias (e.g., agoraphobia, social phobia and simple phobias), posttraumatic stress syndrome, avoidant personality disorder, premature ejaculation, eating disorders (e.g., binge eating disorder, anorexia nervosa and bulimia nervosa), obesity, chemical dependencies (e.g., addictions to alcohol, cocaine, heroin, phenobarbital, marijuana, nicotine and benzodiazepines), cluster headache, migraine, pain, Alzheimer's disease, obsessive-compulsive disorder; panic disorder with and without agoraphobia; memory disorders (e.g., dementia, amnestic disorders, and age-related cognitive decline (ARCD)), Parkinson's diseases (e.g., dementia in Parkinson's disease, neuroleptic-induced parkinsonism and tardive dyskinesias), endocrine disorders (e.g., hyperprolactinaemia), vasospasm (particularly in the cerebral vasculature), cerebellar ataxia, gastrointestinal tract disorders (involving changes in motility and secretion), negative symptoms of schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress incontinence, Tourette's syndrome, trichotillomania, kleptomania, male impotence, cancer (e.g. small cell lung carcinoma), chronic paroxysmal hemicrania, headache (associated with vascular disorders) autism, pervasive developmental disorder NOS, Asperger's disorder, selective mutism, chronic motor or vocal tic disorder, somatization disorder, insomnia, intermittent explosive disorder, pyromania, pathological gambling, impulse-control disorder, premenstrual dysphoric disorder , and attention-deficitlhyperactivity disorder (ADHD), 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.
PCT publication WO 94121619, published Sep. 29, 1994, refers to naphthalene derivatives as 5-HT
1
agonists and antagonists.
PCT publication WO 96/00720, published Jan. 11, 1996, refers to naphthyl ethers as useful 5-HT
1
agonists and antagonists.
European Patent Publication 701,819, published Mar. 20, 1996, refers to the use of 5-HT
1
agonists and antagonists in combination with a 5-HT re-uptake inhibitor.
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”,
Drug Dev. Res
., 22, 25-36 (1991).
Glennon's article “Serotonin Receptors: Clinical Implications”,
Neuroscience and Behavioral Reviews
, 14, 3547 (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 as 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.
European Patent Publication 666,261, published Aug. 9, 1995 refers to thiazine and thiomorpholine derivatives which are claimed to be useful for the treatment of cataracts.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula I
wherein R
1
is a group of the formula G
1
, G
2
, G
3
, G
4
, G
5
, G
6
, G
7
, G
8
or G
9
depicted below,
a is zero to eight;
each R
13
is, independently, (C
1
-C
4
)alkyl or a (C
1
-C
4
)methylene bridge from one of the ring carbons of the piperazine or piperidine ring of G
1
or G
2
, respectively, to the same or another ring carbon or a ring nitrogen of the piperazine or piperidine ring of G
1
or G
2
, respectively, having an available bonding site, or to a ring carbon of R
6
having an available bonding site;
E is oxygen, sulfur, SO or SO
2
;
X is hydrogen, chloro, fluoro, bromo, iodo, cyano, (C
1
-C
6
)alkyl, hydroxy, trifluoromethyl, (C
1
-C
6
)alkoxy, —SO
t
(C
1
-C
6
)alkyl wherein t is zero one or two, —CO
2
R
10
or —CONR
11
R
12
;
Y is an optionally substituted (C
1
-C
4
) heteroalkyl bridge that, together with the atoms to which it is attached, forms a five to seven membered heterocycle containing two to four heteroatoms selected from the group consisting of 1,3-oxazolidin-4-on-5-yl, 1,3-oxazolidin-2,4-dion-5-yl, 4,5-dihydro-1,2-oxazolidin-3-on-4-yl, 1,3-thiazolidin-4-on-5-yl, 1,3-thiazolidin-2,4-dion-5-yl, 1,3-pyrazolidin-4-on-5-yl, 1,3-imidazolidin-2,4-dion-5-yl, 1,2-pyrazolidin-3-on-4-yl, 1,2-thiazolidin-1,1,3-trion-4-yl, 1,2-thiazolidin-3-on-4-yl, tetrahydro-1,2-oxazin-3-on-4-yl, tetrahydro-1,3-oxazin-4-on-5-yl, tetrahydro-1,3-oxazin-2,4-dion-5-yl, morpholin-3-on-2-yl, morpholin-3,5-dion-2-yl, 2,3-dihydro-1,4-oxazin-3-on-2-yl, tetrahydro-1,3-thiazin-4-on-5-yl, tetrahydro-1,3-thiazin-2,4-dion-5-yl, tetrahydro-1,2-thiazin-3-on-4-yl, thiomorpholin-3-on-2-yl, thiomorpholin-3,5-dion-2-yl, 1-oxo-thiomorpholin-3-on-2-yl, 2,3-dihydro-1,4-thiazin-3-on-2-yl, hexahydro-1,2-diazin-3-on-4-yl, 4,5-dihydro-2H-pyridazin-3-on-4-yl, hexahydro-1,3-diazin-4-on-5-yl, hexahydro-1,3-diazin-2,4-dion-5-yl, piperazin-2-on-3-yl, piperazin-2,6-dion-3-yl, tetrahydro-1,3,4-thiadiazin-5-on-4-yl, 5,6-dihydro-1,3,4-thiadiazin-5-on-6-yl, 1,3,4-oxadiazin-5-on-6-yl, 5,6-dihydro-1,2,4-oxadiazin-5-on-6-yl, tetrahydro-1,2,4-oxadiazin-5-on-6-yl, 1,2,4-triazin-5-on-6-yl, tetrahydro-1,2,4-oxadiazin-5-on-6-yl, 5,6-dihydro-1,2,4-oxadiazin-5-on-6-yl, 1,2,4-oxadiazin-3,5-dion-6-yl, 1,2,4-trazin-6-on-5-yl, hexahydro-1,2-oxazepin-3-on-2-yl, hexahydro-1,3-oxazepin-4-on-5-yl, hexahydro-1,4-o
Chappell Phillip Branch
Gibbs Megan Ann
Howard Harry Ralph
Schachter Joel Barry
Sprouse Jeffrey Scott
Ginsburg Paul H.
Pfizer INC
Solola T. A.
Waldron Roy F.
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