Pyrrolo[1,2-a]pyrazine derivatives as 5HT1A ligands

Details Pyrrolo[1,2-a]pyrazine derivatives as 5HT1A ligands Pyrrolo[1,2-a]pyrazine derivatives as 5HT1A ligands

1999-08-11

2001-09-04

Jarvis, William R. A. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06284757

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to the use of pharmacologically active 2,7-substituted octahydro-1H-pyrrolo[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 (i.e., increasing or decreasing), serotonin mediated neurotransmission.
The pharmacologically active 2,7-substituted octahydro-1 H-pyrrolo[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 disorders that can be treated by altering (i.e., increasing or decreasing) dopamine mediated neurotransmission. The dopamine receptor binding activity of such compounds is referred to in World Patent Application WO 97/23482, which designates the United States and was published on Jul. 3, 1997. This application (WO 97/23482) 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 treating a disorder that can be treated by altering (e.g., increasing or decreasing) serotonin mediated neurotransmission in a mammal, including a human, comprising administering to such mammal an amount of a compound of formula I
wherein
R
1
is phenyl, naphthyl, benzoxazolonyl, indolyl, indolonyl, benzimidazolyl, quinolyl, furyl, benzofuryl, thienyl, benzothienyl, oxazolyl, benzoxazolyl;
R
2
is H or (C
1
-C
6
)alkyl;
R
3
is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl;
R
4
is H or (C
1
-C
6
)alkyl;
R
5
is H or (C
1
-C
6
)alkyl;
wherein each group of R
1
and R
3
may be independently and optionally substituted with one to four substituents independently selected from the groups consisting of fluoro, chloro, bromo, iodo, cyano, nitro, thiocyano, —SR
4
, —SOR
4
, —SO
2
R
4
, —NHSO
2
R
4
, —(C
1
-C
6
)alkoxy, —NR
4
R
5
, —NR
4
COR
5
, —CONR
4
R
5
, phenyl, —COR
4
, —COOR
4
, —(C
1
-C
6
)alkyl substituted with one to six halogens, —(C
3
-C
6
)cycloalkyl, and trifluoromethoxy;
X is O, S, SO, SO
2
, NR
4
, C═O, CH(OH), CHR
4
,
m is 0, 1 or 2; and
n is 0, 1 or 2;
a pharmaceutically acceptable salt thereof;
that is effective in treating such disorder.
In another aspect, this invention relates to any of the foregoing methods of treatment wherein the compound of formula I or pharmaceutically acceptable salt that is employed is one wherein R
1
is phenyl, naphthyl, benzoxazolonyl, indolyl, indolonyl, benzimidazolyl, or quinolyl; and wherein R
1
and R
3
may be independently substituted with up to three substituents independently selected from the group consisting of fluoro, chloro, bromo, iodo, cyano, —NR
4
R
5
, —(C
1
-C
6
)alkoxy, —COOR
4
, —CONR
4
R
5
, —(C
1
-C
6
)alkyl, —(C
1
-C
6
)alkyl subtituted with one to six halogens, —(C
3
-C
6
)cycloalkyl, and trifluoromethoxy;
R
2
is H or CH
3
;
X is O, C═O, CHOH, —C(═O)O—, or CH
2
,
m is 0 or 1; and
n is 0 or 1.
In another aspect, this invention relates to any of the foregoing methods of treatment wherein the compound of formula I or pharmaceutically acceptable salt that is employed is one wherein
R
1
is phenyl or substituted phenyl;
R
3
is substituted or unsubstituted phenyl, pyridinyl, or pyrimidinyl; and
X is O, —C(═O)O—, or CH
2
.
In another aspect, this invention relates to any of the foregoing methods of treatment wherein the compound of formula I or pharmaceutically acceptable salt that is employed is one wherein
R
2
is H;
X is O;
m is 0; and
n is 1.
In another aspect, this invention relates to any of the foregoing methods of treatment wherein the compound of formula I or pharmaceutically acceptable salt that is employed is one wherein
R
1
is fluorophenyl, cyanophenyl or (trifluoromethyl)phenyl;
R
3
is chloropyridinyl.
In another aspect, this invention relates to any of the foregoing methods of treatment wherein the compound of formula I or pharmaceutically acceptable salt that is employed is one wherein
R
1
is fluorophenyl, cyanophenyl or (trifluoromethyl)phenyl;
R
3
is fluoropyrimidinyl.
In another aspect, this invention relates any of the foregoing methods of treatment wherein the compound of formula I or pharmaceutically acceptable salt that is employed is one wherein
R
3
is 5-chloro-2-pyridinyl.
In another aspect, this invention relates any of the foregoing methods of treatment wherein the compound of formula I or pharmaceutically acceptable salt that is employed is one wherein
R
3
is 5-fluoro-2-pyrimidinyl.
Examples of preferred methods of this invention are those that employ one of the following compounds of the formula I or a pharmaceutically acceptable salt thereof:
(7S,8aS)-7-(4-fluorophenoxy)methyl-2-(5-chloropyridin-2-yl)-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine;
(7S,8aS)-7-(3-cyanophenoxy)methyl-2-(5-chloropyidin-2-yl)-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine;
(7S,8aS)-7-(4-fluorophenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine;
(7S,8aS)-7-(3-(trifluoromethyl)phenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine;
(7S,8aS)-7-(3-cyanophenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine;
(7S,8aS)-7-(4-cyanophenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-1,2,3,4,6,7,8,8a-ctahydro-pyrrolo[1,2-a]pyrazine;
The term “treating”, as used herein, refers to retarding or reversing the progress of, or lleviating or preventing either the disorder or condition to which the term “treating” applies, or ne or more symptoms of such disorder or condition. The term “treatment”, as used herein, refers to the act of treating a disorder or condition, as the term “treating” is defined above.
The chemist of ordinary skill will recognize that certain combinations of substituents included within the scope of formula I may be chemically unstable and will avoid these combinations or alternatively protect sensitive groups with well known protecting groups.
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, unless otherwise indicated, refers to radicals having the formula —O-alkyl, wherein “alkyl” is defined as above.
The compounds of formula I contain one or more chiral centers and therefore exist in different enantiomeric and diasteriomeric forms. Formula I, as defined above, includes, and this invention relates to the use of, all optical isomers and other stereoisomers of compounds of the formula I and mixtures thereof.
This invention also relates to a method of treating a disorder or condition that can be treated by altering (i.e., increasing or decreasing) serotonin mediated neurotransmission in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula I, as defined above, or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder or condition.
This invention also relates to a method of treating migraine, headache or cluster headache in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula I, as defined above, or a pharma

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