Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-09-24
2002-10-08
Bernhardt, Emily (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S254090, C514S253050, C514S253120, C514S422000, C514S424000, C544S372000, C544S373000, C544S363000, C544S365000, C548S523000, C548S550000
Reexamination Certificate
active
06462048
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to lactam derivatives to processes and 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 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 Behavoral 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, Alzheimers disease, Parkinsons disease and Huntingtons disease.
Ligands with high affinity for the 5-HT
1
receptors are well recognized as having therapeutic value for the treatment of human conditions caused by serotonin imbalance.
World Patent Application WO 95/31988, published Nov. 30, 1995, refers to the use of 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), pp 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 I, depicted below,
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
and R
7
are independently selected from hydrogen, (C
1
-C
6
) alkyl, [(C
2
-C
4
)alkyl]aryl wherein the aryl moiety is phenyl or naphthyl, and heteroaryl-(CH
2
)
g
wherein the heteroaryl moiety is selected from 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, preferably from zero to three substituents, independently selected from 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;
or R
6
and R
7
together form a 2 to 4 carbon chain;
x 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 piperizine 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;
R
8
is selected from hydrogen and (C
1
-C
3
) alkyl;
R
9
is selected from hydrogen and (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 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 (e.g., furyl, thienyl, pyridyl, pyrimidyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 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 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;
Z is CR
4
R
5
, wherein R
4
and R
5
are independently selected from hydrogen, (C
1
-C
6
)alkyl and trifluoromethyl; or Z may be one of the aryl or heteroaryl groups referred to in the definition of B above and wherein two adjacent ring members of Z are also members of ring A;
X is hydrogen, chloro, fluoro, bromo, iodo, cyano, (C
1
-C
6
)alkyl, hydroxy, trifluoromethyl, (C
1
-C
6
)alkoxy, —SO
g
(C
1
-C
6
)alkyl wherein g 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 ring that may contain from zero to four heteroatoms selected from nitrogen, sulfur and oxygen, for example, where NR
11
R
12
is pyrrolidinyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, hexamethylenediamine,diazepinyl,oxazepinyl,thiazepinyl, oxadiazepinyl, thiadiazepinyl or triazepinyl;
n is one, two, three or four; and
the broken line indicates an optional double bond;
with the proviso that n must be one when Z is an aryl or heteroaryl group;
and the pharmaceutically acceptable salts thereof.
The following are more specific embodiments of groups G
1
and G
2
.
The present invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the formula I. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)]salts.
The invention also relates to base addition salts of formula I. The chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of formula I that are acidic in nature are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or wa
Bernhardt Emily
Ginsburg P. H.
Joran A. D.
Pfizer Inc.
Richardson P. C.
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