Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-05-31
2002-09-17
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S249000, C514S253130, C514S254020, C514S254090, C514S300000, C514S373000
Reexamination Certificate
active
06451803
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to novel N-acyl and N-aroyl aralkyl amides, 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 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-piperazinyl)-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”,
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 Huntngton's disease.
World Patent Application WO 95131988, published Nov. 30, 1995, refers to the use of a 5-HT
1D
antagonist in combination with a 5HT
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
1
D 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 a compound of the formula
or the pharmaceutically acceptable salt thereof, wherein
R
1
is a group of the formula G
1
, G
2
, G
3
, G
4
, G
5
or G
6
depicted below:
wherein the broken line indicates an optional double bond;
a is zero to eight;
m is 0, 1, 2, 3 or 4;
p is 1, 2 or 3;
D is oxygen, sulfur, SO, SO
2
, or NR
7
;
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, —S(O)
t
(C
1
-C
6
)alkyl wherein t is 0, 1 or 2, —CO
2
R
10
or —CONR
11
R
12
.
R
2
is —(CH
2
)
t
B, wherein t is 0, 1, 2 or 3, and B is hydrogen, phenyl, naphthyl or a 5 or 6 membered heteroaryl group containing from one to four heteroatoms in the ring, and wherein each of the foregoing phenyl, naphthyl and heteroaryl groups may optionally be substituted with one or more substituents independently selected from chloro, fluoro, bromo, iodo, (C
1
—C
6
)alkyl, (C
1
-C
6
)alkoxy, (C
1
-C
6
)alkoxy-(C
1
C
6
)alkyl-, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, —COOH and —SO
n
(C
1
-C
6
)alkyl wherein n is 0, 1 or 2;
R
3
and R
4
are each independently hydrogen, (C
1
-C
4
)alkyl or —(CH
2
)
q
—J wherein q is 0, 1, 2 or 3, and J is phenyl or naphthyl, wherein said phenyl or naphthyl may be optionally substituted with one 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 —S(O)
k
(C
1
-C
6
)alkyl wherein k is 0, 1 or 2;
R
5
is hydrogen or (C
1
-C
3
)alkyl;
R
6
is selected from the group consisting of hydrogen, (C
1
-C
6
)alkyl optionally substituted with (C
1
-C
6
)alkoxy or one to three fluorine atoms, or [(C
1
-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
1
-C
4
)alkyl]aryl wherein the aryl moiety is phenyl, naphthyl, or heteroaryl-(CH
2
)
r
—, wherein the heteroaryl moiety is selected from the group consisting of pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl and benzisothiazolyl and r 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 heteroalkyl ring that may contain from zero to four heteroatoms selected from nitrogen, sulfur and oxygen;
each of R
10
, R
11
and R
12
is selected, independently, from the radicals set forth in the definition of R
3
; 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 from zero to four heteroatoms selected from nitrogen, sulfur and oxygen; and
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;
with the proviso that when B is hydrogen, t is not zero; and
with the proviso that when the broken line in formula G
2
is a double bond, R
8
is absent.
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&pr
Ginsburg Paul H.
Jarvis William R. A.
Pfizer INC
Richardson Peter C.
Waldron Roy F.
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