Piperazinyl 5-HT1 agonists and antagonists

Details Piperazinyl 5-HT1 agonists and antagonists Piperazinyl 5-HT1 agonists and antagonists

1999-04-14

2001-08-21

Ford, John M. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S252140, C514S252190, C514S252200, C514S253090, C514S253110, C514S254010, C514S254020, C514S254040, C514S254100, C544S295000, C544S364000, C544S368000, C544S372000, C544S379000

Reexamination Certificate

active

06277852

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to novel heterocyclic carboxamides 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 94/21619, published Sept. 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,
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 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.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula
or the pharmaceutically acceptable salt thereof; wherein
Z is oxygen, S(O)
m
wherein m is 0, 1 or 2; or NQ wherein Q is hydrogen, (C
1
-C
6
)alkyl or phenyl;
X is hydrogen, chloro, fluoro, bromo, iodo, hydroxy, nitro, cyano, (C
1
-C
6
)alkyl, trifluoromethyl, (C
1
-C
6
)alkoxy, (C
1
-C
6
)alkyl S(O)
a
wherein a is 0, 1 or 2; or phenyl wherein the phenyl group is optionally substituted by hydrogen, halo, hydroxy, nitro, cyano, (C
1
-C
6
)alkyl, trifluoromethyl, (C
1
-C
6
)alkoxy, or (C
1
-C
6
)alkyl S(O)
b
wherein b is 0, 1 or 2;
Y is
wherein
M is oxygen or sulfur;
X
2
is hydrogen, fluoro, chloro, trifluoromethyl, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy or (C
1
-C
6
)alkyl S(O)
c
wherein c is 0, 1 or 2;
R
1
is a group of the formulas
wherein the broken line represents an optional double bond;
p is 1, 2 or 3;
E is oxygen or S(O)
d
wherein d is 0, 1 or 2;
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 (C
1
-C
6
)alkylS(O)
e
, wherein e is 0, 1 or 2;
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 (C
1
-C
6
)alkyl S(O)
f
, wherein f is 0, 1 or 2;
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;
R
10
is hydrogen or (C
1
-C
6
)alkyl;
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 independently selected from chloro, fluoro, bromo, iodo, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, trifluoromethyl, cyano and (C
1
-C
6
)alkyl S(O)
g
wherein g is 0, 1 or 2; and
R
3
is —(CH
2
)
t
B, wherein t 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 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 (C
1
-C
6
)alkylS(O)
h
wherein h is 0, 1 or 2.
The term “alkyl”, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.
The term “alkoxy”, as used herein, includes O-alkyl groups wherein “alkyl” is defined above.
Preferred compounds of formula I include those wherein Z is oxygen, S(O)
m
wherein m is zero; or NH.
Other preferred compounds of formula I include those wherein Y is a group of the formula
wherein R
1
is 4-methylpiperazin-1-yl and X
2
is hydrogen, fluoro or chloro.
Other preferred compounds of formula I include those wherein R
2
is hydrogen, fluoro or chloro.
Other preferred compounds of formula I include those wherein R
3
is —(CH
2
)
t
B wherein t is zero or one and B is phenyl or naphthyl wherein the phenyl and naphthyl 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 (C
1
-C
6
)alkylS(O)
h
wherein h is 0, 1 or 2.
More preferred compounds of formula I include those wherein Z is oxygen, S(O)
m
wherein m is zero; or NH; Y is a group of the formula
wherein R
1
is 4-methylpiperazin-1-yl and X
2
is hydrogen, fluoro or chloro; R
2
is hydrogen, fluoro or chloro; and R

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