2,7-substituted octahydro-1H-pyrido[1,2-A]pyrazine...

Details 2,7-substituted octahydro-1H-pyrido[1,2-A]pyrazine... 2,7-substituted octahydro-1H-pyrido[1,2-A]pyrazine...

1999-08-05

2001-05-15

Jones, Dameron (Department: 1617)

Drug, bio-affecting and body treating compositions

In vivo diagnosis or in vivo testing

C424S001650, C544S238000, C544S295000, C544S359000, C514S279000

Reexamination Certificate

active

06231833

ABSTRACT:

Compounds of this invention have affinity for serotonin (5HT) receptors, especially the serotonin 1a receptor (5HT
1A
), and are therefore useful for treatment of diseases or conditions which are caused by disorders of the serotonin system.
BACKGROUND OF THE INVENTION
The present invention relates to the use of pharmacologically active 2,7-substituted octahydro-1H-pyrido[1,2-a]pyrazine derivatives, and their acid addition salts. The compounds of this invention are ligands for serotonin receptor subtypes, especially the 5HT
1A
receptor, and are therefore useful in the treatment of disorders that can be treated by altering (e.i., increasing or decreasing), serotonin mediated neurotransmission.
The pharmacologically active 2,7-substituted octahydro-1H-pyrido[1,2-a]pyrazine derivatives of the formula I, as defined below, are also ligands for dopamine receptor subtypes, especially the dopamine D4 receptor. They are useful in treating conditions or disorders, schizophrenia for example, that can be treated by altering (i.e., increasing or decreasing) dopamine mediated neurotransmission. The dopamine receptor binding activity of these compounds is described in more detail in U.S. Ser. No. 08/809,145, supra, now U.S. Pat. No. 5,852,031. This application Ser. No. (08/809,145) is incorporated herein by reference in its entirety.
Serotonin plays a role in several psychiatric disorders, including anxiety, Alzheimer's disease, depression, nausea and vomiting, eating disorders, and migraine. (See Rasmussen et al., “Chapter 1. Recent Progress in Serotonin (5HT)
1A
Receptor Modulators”, in
Annual Reports in Medicinal Chemistry, Section I,
30, pp. 1-9, 1995, Academic Press, Inc.; Antigas et al.,
Trends Neurosci.,
19 (9), 1996, pp. 378-383; and Wolf et al.,
Drug Development Research,
40, 1997, pp. 17-34.) Serotonin also plays a role in both the positive and negative symptoms of schizophrenia. (See Sharma et al.,
Psychiatric Annals.,
26 (2), February, 1996, pp. 88-92.)
SUMMARY OF THE INVENTION
This invention relates to a method of treatment of diseases or conditions which are caused by disorders of the serotonin system which comprises administering to a mammal in need of such treatment a compound of the formula
wherein
Ar is phenyl, naphthyl, benzoxazolonyl, indolyl, indolonyl, benzimidazolyl, quinolyl, furyl, benzofuryl, thienyl, benzothienyl, oxazolyl, benzoxazolyl;
Ar
1
is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl;
A is O, S, SO, SO
2
, C═O, CHOH, or —(CR
3
R
4
)—;
n is 0, 1 or 2;
each of Ar and Ar
1
may be independently and optionally substituted with one to four substituents independently selected from the group consisting of fluoro, chloro, bromo, iodo, cyano, nitro, thiocyano, —SR, —SOR, —SO
2
R, —NHSO
2
R, —(C
1
-C
6
)alkoxy, —NR
1
R
2
, —NRCOR
1
, —CONR
1
R
2
, Ph, —COR, COOR, —(C
1
-C
6
)alkyl, trifluoromethoxy, and —(C
1
-C
6
)alkyl substituted with one to six halogens, —(C
3
-C
6
)cycloalkyl, or trifluoromethoxy;
each and every R, R
1
and R
2
is independently selected from the group consisting of hydrogen, —(C
1
-C
6
)alkyl, —(C
1
-C
6
)alkyl substituted with one to thirteen halogens selected from fluorine, chlorine, bromine and iodine, phenyl, benzyl, —(C
2
-C
6
)alkenyl, —(C
3
-C
6
)cycloalkyl, and —(C
1
-C
6
)alkoxy;
each and every R
3
and R
4
is independently selected from a group consisting of hydrogen, methyl, ethyl, n-propyl, and i-propyl;
diastereomeric and optical isomers thereof; and
pharmaceutically acceptable salts thereof.
This invention also provides a method of treatment of a disease or condition which is caused by a disorder of the serotonin system or a disorder of the dopamine system which comprises administering to a mammal in need of such treatment a compound of the formula
wherein
Ar is phenyl, naphthyl, benzoxazolonyl, indolyl, indolonyl, benzimidazolyl, quinolyl, furyl, benzofuryl, thienyl, benzothienyl, oxazolyl, benzoxazolyl;
Ar
1
is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl;
A is O, S, SO, SO
2
, C═O, CHOH, or —(CR
3
R
4
)—;
n is 0, 1 or 2;
each of Ar and Ar
1
may be independently and optionally substituted with one to four substituents independently selected from the group consisting of fluoro, chloro, bromo, iodo, cyano, nitro, thiocyano, —SR, —SOR, —SO
2
R, —NHSO
2
R, —(C
1
-C
6
)alkoxy, —NR
1
R
2
, —NRCOR
1
, —CONR
1
R
2
, Ph, —COR, COOR, —(C
1
-C
6
)alkyl, trifluoromethoxy, and —(C
1
-C
6
)alkyl substituted with one to six halogens, —(C
3
-C
6
)cycloalkyl, or trifluoromethoxy;
each and every R, R
1
, and R
2
is independently selected from the group consisting of hydrogen, —(C
1
-C
6
)alkyl, —(C
1
-C
6
)alkyl substituted with one to thirteen halogens selected from fluorine, chlorine, bromine and iodine, phenyl, benzyl, —(C
2
-C
6
)alkenyl, —(C
3
-C
6
)cycloalkyl, and —(C
1
-C
6
)alkoxy;
each and every R
3
and R
4
is independently selected from a group consisting of hydrogen, methyl, ethyl, n-propyl, and i-propyl; or a
diastereomeric or optical isomers thereof; or a
pharmaceutically acceptable salt thereof; in an amount effective to treat said disease or condition.
This invention also provides a method of treating a disorder or condition selected from the group consisting of migraine, headache, cluster headache, anxiety, depression, dysthymia, major depressive disorder, panic disorder, obsessive-compulsive disorder, posttraumatic stress disorder, avoidant personality disorder, borderline personality disorder, phobia, a disorder of cognition, a memory disorder, a learning disorder (including age related memory disorder) a neurodegenerative disease (including Alzheimer's disease), anxiety and/or depression associated with senile dementia or Alzheimer's disease, cancer (including prostate cancer), cerebral infarct (including that caused by stroke, ischemia or traumatic head injury), a sexual disorder, dizziness, an eating disorder, pain, chemical dependency or addiction, peptic ulcer, and attention deficit hyperactivity disorder in a mammal, comprising administering to said mammal an amount of a compound of the formula
wherein
Ar is phenyl, naphthyl, benzoxazolonyl, indolyl, indolonyl, benzimidazolyl, quinolyl, furyl, benzofuryl, thienyl, benzothienyl, oxazolyl, benzoxazolyl;
Ar
1
is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl;
A is O, S, SO, SO
2
, C═O, CHOH, or —(CR
3
R
4
)—;
n is 0, 1 or 2;
each of Ar and Ar
1
may be independently and optionally substituted with one to four substituents independently selected from the group consisting of fluoro, chloro, bromo, iodo, cyano, nitro, thiocyano, —SR, —SOR, —SO
2
R, —NHSO
2
R, —(C
1
-C
6
)alkoxy, —NR
1
R
2
, —NRCOR
1
, —CONR
1
R
2
, Ph, —COR, COOR, —(C
1
-C
6
)alkyl, trifluoromethoxy, and —(C
1
-C
6
)alkyl substituted with one to six halogens, —(C
3
-C
6
)cycloalkyl, or trifluoromethoxy;
each and every R, R
1
, and R
2
is independently selected from the group consisting of hydrogen, —(C
1
-C
6
)alkyl, —(C
1
-C
6
)alkyl substituted with one to thirteen halogens selected from fluorine, chlorine, bromine and iodine, phenyl, benzyl, —(C
2
-C
6
)alkenyl, —(C
3
-C
6
)cycloalkyl, and —(C
1
-C
6
)alkoxy;
each and every R
3
and R
4
is independently selected from a group consisting of hydrogen, methyl, ethyl, n-propyl, and i-propyl; or a
diastereomeric or optical isomers thereof; or a
pharmaceutically acceptable salt thereof; effective to treat said disorder or condition.
In one embodiment of this method, the disorder or condition being treated is migraine, headache, or cluster headache.
In another embodiment, the disorder or condition being treated is anxiety, depression, dysthymia, major depressive disorder, panic disorder, obsessive-compulsive disorder, posttraumatic stress disorder, avoidant personality disorder, borderline personality disorder, or phobia.
In another embodiment, the disorder or condition being treated is a disorder of cognition, a memory disorder, a learning disorder (including age related memory disorder), or a neurodgenerative disease (including Alzheimer's disease). In another em

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