U.S. patent application number 10/922198 was filed with the patent office on 2005-01-27 for 5-ht receptor ligands and uses thereof.
This patent application is currently assigned to Pfizer Inc. Invention is credited to Chiang, Phoebe, DaSilva-Jardine, Paul A., Garigipati, Ravi S., Guzman-Perez, Angel, Liu, Kevin K., Novomisle, William A., Welch, Willard M. JR..
Application Number | 20050020604 10/922198 |
Document ID | / |
Family ID | 23157027 |
Filed Date | 2005-01-27 |
United States Patent
Application |
20050020604 |
Kind Code |
A1 |
Chiang, Phoebe ; et
al. |
January 27, 2005 |
5-HT receptor ligands and uses thereof
Abstract
Compounds of Formula (IA) that act as 5-HT receptor ligands and
their uses in the treatment of diseases linked to the activation of
5-HT.sub.2 receptors in animals are described herein. 1
Inventors: |
Chiang, Phoebe; (East Lyme,
CT) ; Novomisle, William A.; (Stonington, CT)
; Welch, Willard M. JR.; (Mystic, CT) ;
Guzman-Perez, Angel; (Stonington, CT) ;
DaSilva-Jardine, Paul A.; (Killingworth, CT) ;
Garigipati, Ravi S.; (South Glastonbury, CT) ; Liu,
Kevin K.; (East Lyme, CT) |
Correspondence
Address: |
PFIZER INC.
PATENT DEPARTMENT, MS8260-1611
EASTERN POINT ROAD
GROTON
CT
06340
US
|
Assignee: |
Pfizer Inc
|
Family ID: |
23157027 |
Appl. No.: |
10/922198 |
Filed: |
August 19, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10922198 |
Aug 19, 2004 |
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10163881 |
Jun 5, 2002 |
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60299953 |
Jun 21, 2001 |
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Current U.S.
Class: |
514/252.11 ;
544/357 |
Current CPC
Class: |
A61P 25/22 20180101;
A61P 43/00 20180101; A61P 13/02 20180101; A61P 3/04 20180101; A61P
1/04 20180101; A61P 25/24 20180101; A61P 25/34 20180101; C07D
401/12 20130101; A61P 1/14 20180101; A61P 25/06 20180101; A61P
25/20 20180101; A61P 25/14 20180101; A61P 15/12 20180101; A61P
15/00 20180101; A61P 9/10 20180101; C07D 241/20 20130101; A61P 3/10
20180101; A61P 25/28 20180101; C07D 409/12 20130101; A61P 1/00
20180101; C07D 239/47 20130101; A61P 25/18 20180101; A61P 25/00
20180101; A61P 25/32 20180101; A61P 15/10 20180101; A61P 25/08
20180101; A61P 9/00 20180101 |
Class at
Publication: |
514/252.11 ;
544/357 |
International
Class: |
A61K 031/497 |
Claims
1-28. (cancelled).
29. A method for treating a 5-HT.sub.2 receptor-mediated disease,
condition, or disorder in an animal comprising the step of
administering to said animal a therapeutically effective amount of
a compound of Formula (IA) 13wherein Y is nitrogen; X and Z are
each independently CR, where R for each occurrence is hydrogen,
halogen, ( .sub.1-C.sub.4)alkyl, amino or
(C.sub.1-C.sub.4)alkylamino; W is amino, (C.sub.1-C.sub.4)alkyla-
mino, or acetylamino; at least one of R.sup.1a, R.sup.1b, R.sup.1d,
and R.sup.1e is independently selected from the group consisting of
halogen, nitro, amino. (C.sub.1-C.sub.4)alkylamino, cyano,
--C(O)NH.sub.2, (C.sub.1-C.sub.4)alkyl,
halo-substituted(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4) alkoxy,
and halo-substituted(C.sub.1-C.sub.4)alkoxy, or R.sup.1a and
R.sup.1b taken together form a five- or six-membered, aromatic or
partially or fully saturated fused ring, or R.sup.1a taken together
with R.sup.2a or R.sup.2b forms a five- or six-membered fully
saturated fused ring; R.sup.1c is hydrogen; R.sup.2a and R.sup.2b
are each independently hydrogen, (C.sub.1-C.sub.4)alkyl, partially
or fully saturated (C.sub.3-C.sub.6)cycloalkyl, or one of which
taken together with R.sup.1a forms a five- or six-membered, fully
saturated fused ring; n is 0, 1, or2; R.sup.3a and R.sup.3b are
each independently hydrogen, halogen, (C.sub.1-C.sub.4)alkyl, or
(C.sub.1-C.sub.4)alkyl substituted with hydroxy, fluoro, or
(C.sub.1-C.sub.4)alkoxy; R.sup.4 is hydrogen, hydroxy,
(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkyl substituted with
hydroxy or cyano, (C.sub.1-C.sub.4)alkylcarbonyl (C-C.sub.4)alkoxy,
(C.sub.1-C.sub.4)alkoxy-carbonyl, or (C.sub.3-C.sub.4)alkenyl; a
nitrogen oxide thereof, a prodrug of said compound or said nitrogen
oxide; a pharmaceutically acceptable salt of said compound, said
nitrogen oxide, or said prodrug, or a solvate or hydrate of said
compound, said nitrogen oxide, said prodrug, or said salt.
30-32. (cancelled).
33. The method of claim 29 or, 30, 31 or 32 wherein said 5-HT.sub.2
receptor-mediated disease, condition or disorder is a 5-HT.sub.2c
receptor-mediated disease, condition or disorder.
34. The method of claim 29 or 68 wherein said 5-HT.sub.2
receptor-mediated disease, condition, or disorder is selected from
the group consisting of weight loss, obesity, bulimia, premenstrual
syndrome or late luteal phase syndrome, depression, atypical
depression, bipolar disorders, psychoses, schizophrenia, migraine,
alcoholism, tobacco abuse, panic disorder, anxiety, post-traumatic
syndrome, memory loss, dementia of aging, social phobia, attention
deficit hyperactivity disorder, disruptive behavior disorders,
impulse control disorders, borderline personality disorder,
obsessive compulsive disorder, chronic fatigue syndrome, sexual
dysfunction in males, sexual dysfunction in females, anorexia
nervosa, disorders of sleep, autism, seizure disorders, epilepsy,
mutism, spinal cord injury, damage of the central nervous system,
cardiovascular disorders, gastrointestinal disorders, diabetes
insipidus, and type II diabetes.
35. A method for treating or preventing a 5-HT.sub.2
receptor-mediated disease, condition, or disorder in an animal
comprising the step of administering to said animal a
therapeutically effective amount of a pharmaceutical composition
comprising (1) a compound of Formula (IA) 14wherein Y is nitrogen;
X and Z are each independently CR, where R for each occurrence is
hydrogen, halogen, (C.sub.1-C.sub.4)alkyl, amino, or
(C.sub.1-C.sub.4)alkylamino; W is amino,
(C.sub.1-.sub.4)alkylamino, or acetylamino; at least one of
R.sup.1a, R.sup.1b, R.sup.1d, and R.sup.1e is independently
selected from the group consisting of halogen, nitro, amino.
(C.sub.1-.sub.4)alkylamino, cyano, --C(O)NH.sub.2.
(C.sub.1-C.sub.4)alkyl, halo-substituted(C.sub.1-C.sub.4)alkyl
(C.sub.1-C.sub.4) alkoxy, and
halo-substituted(C.sub.1-C.sub.4)alkoxy, or R.sup.1a and R.sup.1b
taken together form a five- or six-membered, aromatic or partially
or fully saturated fused ring, or R.sup.1a taken together with
R.sup.2a or R.sup.2b forms a five- or six-membered fully saturated
fused ring; R.sup.1c is hydrogen: R.sup.2a and R.sup.2b are each
independently hydrogen, (C.sub.1-C.sub.4)alkyl, partially or fully
saturated (C.sub.3-C.sub.6)cycloalkyl, or one of which taken
together with R.sup.1a forms a five- or six-membered, fully
saturated fused ring; n is 0, 1,or 2; R.sup.3a and R.sup.3b are
each independently hydrogen, halogen, (C.sub.1-C.sub.4)alkyl, or
(C.sub.1-.sub.4)alkyl substituted with hydroxy, fluoro, or
(C.sub.1-C.sub.4)alkoxy; R.sup.4 is hydrogen, hydroxy,
(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkyl substituted with
hydroxy or cyano, (C.sub.1-C.sub.4)alkylcarbonyl,
(C.sub.1-C.sub.4)alkoxy- , (C.sub.1-C.sub.4)alkoxy-carbonyl, or
(C.sub.3-C.sub.4)alkenyl; a nitrogen oxide thereof, a prodrug of
said compound or said nitrogen oxide; a pharmaceutically acceptable
salt of said compound, said nitrogen oxide, or said prodrug, or a
solvate or hydrate of said compound, said nitrogen oxide, said
prodrum, or said salt; and (2) a pharmaceutically acceptable
excipient, diluent, or carrier.
36. The method of claim 35 wherein said 5-HT.sub.2
receptor-mediated disease, condition or disorder is a 5-HT.sub.2c
receptor-mediated disease, condition or disorder.
37. The method of claim 35 wherein said 5-HT.sub.2
receptor-mediated disease, condition, or disorder is selected from
the group consisting of weight loss, obesity, bulimia, premenstrual
syndrome or late luteal phase syndrome, depression, atypical
depression, bipolar disorders, psychoses, schizophrenia, migraine,
alcoholism, tobacco abuse, panic disorder, anxiety, post-traumatic
syndrome, memory loss, dementia of aging, social phobia, attention
deficit hyperactivity disorder, disruptive behavior disorders,
impulse control disorders, borderline personality disorder,
obsessive compulsive disorder, chronic fatigue syndrome, sexual
dysfunction in males, sexual dysfunction in females, ariorexia
nervosa, disorders of sleep, autism, seizure disorders, epilepsy,
mutism, spinal cord injury, damage of the central nervous system,
cardiovascular disorders, gastrointestinal disorders, diabetes
insipidus, and type II diabetes.
38. A method for treating or preventing a 5-HT.sub.2
receptor-mediated disease, condition, or disorder in an animal
comprising the step of administering to said animal a
therapeutically effective amount of a pharmaceutical composition
comprising (1) a compound of Formula (IA) 15wherein Y is nitrogen:
X and Z are each independently CR, or X is CH and Z is CR,or X is
CR and Z is CH, where R for each occurrence is halogen,
(C.sub.1-C.sub.4)alkyl, amino, or (C.sub.1-C.sub.4)alkylamino: or W
is oxy or thio: at least one of R.sup.1a, R.sup.1b, R.sup.1d, and
R.sup.1e is independently selected from the group consisting of
halogen, nitro, amino, (C.sub.1-C.sub.4)alkylamino, cyano,
--C(O)NH.sub.2, (C.sub.1-C.sub.4)alkyl,
halo-substituted(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4) alkoxy,
and halo-substituted(C.sub.1-C.sub.4)alkoxy, or R.sup.1a and
R.sup.1b taken together form a five- or six-membered, aromatic or
partially or fully saturated fused ring, or R.sup.1a taken together
with R.sup.2a or R.sup.2b forms a five- or six-membered, fully
saturated fused ring; R.sup.1c is hydrogen; R.sup.2a and R.sup.2b
are each independently hydrogen, (C.sub.1-C.sub.4)alkyl, partially
or fully saturated (C.sub.3-C.sub.6)cycloalkyl, or one of which
taken together with R.sup.1a forms a five- or six-membered, fully
saturated fused ring; n is 0, 1 or2; R.sup.3a and R.sup.3b are each
independently hydrogen, halogen, (C.sub.1-C.sub.4)alkyl, or
(C.sub.1-C.sub.4)alkyl substituted with hydroxy, fluoro, or
(C.sub.1-C.sub.4)alkoxy; R.sup.4 is hydrogen, hydroxy,
(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkyl substituted with
hydroxy or cyano, (C.sub.1-C.sub.4)alkylcarbonyl,
(C.sub.1-C.sub.4)alkoxy- , (C.sub.1-C.sub.4)alkoxy-carbonyl, or
(C.sub.3-C.sub.4alkenyl; a nitrogen oxide thereof, a prodrug of
said compound or said nitrogen oxide; a pharmaceutically acceptable
salt of said compound, said nitrogen oxide, or said prodrug, or a
solvate or hydrate of said compound, said nitrogen oxide, said
prodrug, or said salt.
39-40. (cancelled).
41. The method of claim 38 wherein said 5-HT.sub.2
receptor-mediated disease, condition or disorder is a 5-HT.sub.2c
receptor-mediated disease, condition or disorder.
42. The method of claim 38 wherein said 5-HT.sub.2
receptor-mediated disease, condition, or disorder is selected from
the group consisting of weight loss, obesity, bulimia, premenstrual
syndrome or late luteal phase syndrome, depression, atypical
depression, bipolar disorders, psychoses, schizophrenia, migraine,
alcoholism, tobacco abuse, panic disorder, anxiety, post-traumatic
syndrome, memory loss, dementia of aging, social phobia, attention
deficit hyperactivity disorder, disruptive behavior disorders,
impulse control disorders, borderline personality disorder,
obsessive compulsive disorder, chronic fatigue syndrome, sexual
dysfunction in males, sexual dysfunction in females, anorexia
nervosa, disorders of sleep, autism, seizure disorders, epilepsy,
mutism, spinal cord injury, damage of the central nervous system,
cardiovascular disorders, gastrointestinal disorders, diabetes
insipidus, and type II diabetes.
43-44. (cancelled).
45. A method for treating or preventing a 5-HT.sub.2
receptor-mediated disease, condition, or disorder comprising
administering to an animal in need of such treatment a) a
therapeutically effective amount of a compound of Formula (IA)
16wherein Y is nitrogen; X and Z are each independently CR, where R
for each occurrence is hydrogen, halogen, (C.sub.1-C.sub.4alkyl,
amino. or (C.sub.1-C.sub.4)alkylamino; W is amino,
(C.sub.1-C.sub.4)alkylamino, or acetylamino; at least one of
R.sup.1a, R.sup.1b, R.sup.1d, and R.sup.1e is independently
selected from the group consisting of halogen, nitro, amino,
(C.sub.1-C.sub.4)alkylamino, cyano, --C(O)NH.sub.2,
(C.sub.1-C.sub.4)alkyl, halo-substituted(C.sub.1-C.sub.4)- alkyl,
(C.sub.1-C.sub.4) alkoxy, and
halo-substituted(C.sub.1-C.sub.4)alko- xy, or R.sup.1a and R.sup.1b
taken together form a five- or six-membered, aromatic or partially
or fully saturated fused ring, or R.sup.1a taken together with
R.sup.2a or R.sup.2b forms a five- or six-membered fully saturated
fused ring; R.sup.1c is hydrogen; R.sup.2a and R.sup.2b are each
independently hydrogen, (C.sub.1-C.sub.4)alkyl, partially or fully
saturated (C.sub.3-C.sub.6)cycloalkyl, or one of which taken
together with R.sup.1a forms a five- or six-membered, fully
saturated fused ring; n is 0, 1, or 2; R.sup.3a and R.sup.3b are
each independently hydrogen, halogen, (C.sub.1-C.sub.4)alkyl, or
(C.sub.1-C.sub.4)alkyl substituted with hydroxy, fluoro, or
(C.sub.1-C.sub.4)alkoxy; R.sup.4 is hydrogen, hydroxy,
(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkyl substituted with
hydroxy or cyano, (C.sub.1-C.sub.4)alkylcarbonyl,
(C.sub.1-C.sub.4)alkoxy- , (C.sub.1-C.sub.4.sub.1)alkoxy-carbonyl,
or (C.sub.3-C.sub.4)alkenyl; a nitrogen oxide thereof, a prodrug of
said compound or said nitrogen oxide; a pharmaceutically acceptable
salt of said compound, said nitrogen oxide, or said prodrug, or a
solvate or hydrate of said compound, said nitrogen oxide, said
prodrug, or said salt; and b) a therapeutically effective amount of
at least one additional pharmaceutical agent selected from the
group consisting of an apo-B/MTP inhibitor, an MCR-4 agonist, a
CCK-A agonist, a monoamine reuptake inhibitor, a sympathomimetic
agent, a .beta..sub.3 adrenergic receptor agonist, a dopamine
agonist, a melanocyte-stimulating hormone receptor analog, a
cannabinoid 1 receptor antagonist, a melanin concentrating hormone
antagonist, leptin, a leptin analog, a leptin receptor agonist, a
galanin antagonist, a lipase inhibitor, a bombesin agonist, a
Neuropeptide-Y antagonist, a thyromimetic agent,
dehydroepiandrosterone or an analog thereof, a glucocorticoid
receptor agonist or antagonist, an orexin receptor antagonist, a
urocortin binding protein antagonist, a glucagon-like peptide-1
receptor agonist, a ciliary neurotrophic factor, an AGRP, a ghrelin
receptor antagonist, a histamine 3 receptor antagonist or reverse
agonist, and a neuromedin U receptor agonist.
46. The method of claim 45 or 69 wherein said compound, a nitrogen
oxide thereof, a prodrug of said compound or said nitrogen oxide; a
pharmaceutically acceptable salt of said compound, said nitrogen
oxide, or said prodrug, or a solvate or hydrate of said compound,
said nitrogen oxide, said prodrug, or said salt, and said at least
one additional pharmaceutical agent is administered
simultaneously.
47. The method of claim 45 or 69 wherein said compound, a nitrogen
oxide thereof, a-prodrug of said compound or said nitrogen oxide; a
pharmaceutically acceptable salt of said compound, said nitrogen
oxide, or said prodrug, or a solvate or hydrate of said compound,
said nitrogen oxide, said prodrug, or said salt, and said at least
one additional pharmaceutical agent is administered
sequentially.
48-51. (cancelled).
52. The method of claim 45 or 69, wherein said 5-HT.sub.2
receptor-mediated disease, condition or disorder is a 5-HT.sub.2c
receptor-mediated disease, condition or disorder.
53-67. (cancelled)
68. A method for treating a 5-HT.sub.2 receptor-mediated disease,
condition, or disorder in an animal comprising the step of
administering to said animal a therapeutically effective amount of
a compound of Formula (IA) 17wherein Y is nitrogen; X and Z are
each independently CR, or X is CH and Z is CR, or X is CR and Z is
CH, where R for each occurrence is halogen, (C.sub.1-C.sub.4)alkyl,
amino, or (C.sub.1-C.sub.4)alkylamino; or W is oxy or thio; at
least one of R.sup.1aa R.sup.1b, R.sup.1d, and R.sup.1e is
independently selected from the group consisting of halogen, nitro,
amino, (C.sub.1-C.sub.4)alkylamin- o, cyano, -C(O)NH.sub.2,
(C.sub.1-C.sub.4)alkyl, halo-substituted(C.sub.1-- C.sub.4)alkyl,
(C.sub.1-C.sub.4) alkoxy, and halo-substituted(C.sub.1-C.su-
b.4)alkoxy, or R.sup.1a and R.sup.1b taken together form a five- or
six-membered, aromatic or partially or fully saturated fused ring,
or R.sup.1a taken together with R.sup.2a or R.sup.2b forms a five-
or six-membered, fully saturated fused ring; R.sup.1c is hydrogen;
R.sup.2a and R.sup.2b are each independently hydrogen,
(C.sub.1-C.sub.4)alkyl, partially or fully saturated
(C.sub.3-C.sub.6)cycloalkyl, or one of which taken together with
R.sup.1a forms a five- or six-membered, fully saturated fused ring;
n is 0, 1, or 2; R.sup.3a and R.sup.3b are each independently
hydrogen, halogen, (C.sub.1-C.sub.4)alkyl, or
(C.sub.1-C.sub.4)alkyl substituted with hydroxy, fluoro, or
(C.sub.1-C.sub.4)alkoxy; R.sup.4 is hydrogen, hydroxy,
(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkyl substituted with
hydroxy or cyano, (C, -C.sub.4)alkylcarbonyl,
(C.sub.1-C.sub.4)alkoxy, (C.sub.1-C.sub.4)alkoxy-carbonyl, or
(C.sub.3-C.sub.4)alkenyl; a nitrogen oxide thereof, a prodrug of
said compound or said nitrogen oxide; a pharmaceutically acceptable
salt of said compound, said nitrogen oxide, or said prodrug, or a
solvate or hydrate of said compound, said nitrogen oxide, said
prodrug, or said salt.
69. A method for treating or preventing a 5-HT.sub.2
receptor-mediated disease, condition, or disorder comprising
administering to an animal in need of such treatment a) a
therapeutically effective amount of a compound of Formula (IA)
18wherein Y is nitrogen; X and Z are each independently CR, or X is
CH and Z is CR, or X is CR and Z is CH, where R for each occurrence
is halogen, (C.sub.1-C.sub.4)alkyl, amino, or
(C.sub.1-C.sub.4)alkylamino; or W is oxy or thio; at least one of
R.sup.1a, R.sup.1b, R.sup.1d, and R.sup.1e is independently
selected from the group consisting of halogen, nitro, amino,
(C.sub.1-C.sub.4)alkylamin- o, cyano, -C(O)NH.sub.2,
(C.sub.1-C.sub.4)alkyl, halo-substituted(C.sub.1-- C.sub.4)alkyl,
(C.sub.1-C.sub.4) alkoxy, and halo-substituted(C.sub.1-C.su-
b.4)alkoxy, or R.sup.1a and R.sup.1b taken together form a five- or
six-membered, aromatic or partially or fully saturated fused ring,
or R.sup.1a taken together with R.sup.2a or R.sup.2b forms a five-
or six-membered, fully saturated fused ring; R.sup.1c is hydrogen;
R.sup.2a and R.sup.2b are each independently hydrogen,
(C.sub.1-C.sub.4)alkyl, partially or fully saturated
(C.sub.3-C.sub.6)cycloalkyl, or one of which taken together with
R.sup.1a forms a five- or six-membered, fully saturated fused ring;
n is 0, 1, or2; R.sup.3a and R.sup.3b are each independently
hydrogen, halogen, (C.sub.1-C.sub.4)alkyl, or
(C.sub.1-C.sub.4)alkyl substituted with hydroxy, fluoro, or
(C.sub.1-C.sub.4)alkoxy; R.sup.4 is hydrogen, hydroxy,
(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkyl substituted with
hydroxy or cyano, (C.sub.1-C.sub.4)alkylcarbonyl,
(C.sub.1-C.sub.4)alkoxy, (C.sub.1-C.sub.4)alkoxy-carbonyl, or
(C.sub.3-C.sub.4)alkenyl; a nitrogen oxide thereof, a prodrug of
said compound or said nitrogen oxide; a pharmaceutically acceptable
salt of said compound, said nitrogen oxide, or said prodrug, or a
solvate or hydrate of said compound, said nitrogen oxide, said
prodrug, or said salt; and b) a therapeutically effective amount of
at least one additional pharmaceutical agent selected from the
group consisting of an apo-B/MTP inhibitor, an MCR-4 agonist, a
CCK-A agonist, a monoamine reuptake inhibitor, a sympathomimetic
agent, a .beta..sub.3 adrenergic receptor agonist, a dopamine
agonist, a melanocyte-stimulating hormone receptor analog, a
cannabinoid 1 receptor antagonist, a melanin concentrating hormone
antagonist, leptin, a leptin analog, a leptin receptor agonist, a
galanin antagonist, a lipase inhibitor, a bombesin agonist, a
Neuropeptide-Y antagonist, a thyromimetic agent,
dehydroepiandrosterone or an analog thereof, a glucocorticoid
receptor agonist or antagonist, an orexin receptor antagonist, a
urocortin binding protein antagonist, a glucagon-like peptide-1
receptor agonist, a ciliary neurotrophic factor, an AGRP, a ghrelin
receptor antagonist, a histamine 3 receptor antagonist or reverse
agonist, and a neuromedin U receptor agonist.
Description
[0001] This application claims the benefit of U.S. Provisional Ser.
No. 60/299953 filed Jun. 21, 2001 and incorporated herein by
reference.
FIELD OF THE INVENTION
[0002] The present invention relates to pyrazine compounds that act
as 5-HT receptor ligands, in particular 5-HT.sub.2c receptor
ligands, and their uses in the prevention or treatment of diseases
linked to the activation of 5-HT.sub.2c receptors in animals.
BACKGROUND
[0003] Receptors for serotonin (5-hydroxytryptamine, 5-HT) are an
important class of G protein-coupled receptors. Serotonin is
thought to play a role in processes related to learning and memory,
sleep, thermoregulation, mood, motor activity, pain; sexual and
aggressive behaviors, appetite, neurodegenerative regulation, and
biological rhythms. As expected, serotonin is linked to
pathophysiological conditions such as anxiety, depression,
obsessive-compulsive disorders, schizophrenia, suicide, autism,
migraine, emesis, alcoholism and neurodegenerative disorders.
[0004] The serotonin receptors are currently classified into seven
subfamilies (5-HT.sub.1 through 5-HT.sub.7). See, Hoyer, D., et
al., "VII International Union of Pharmacology classification of
receptors for 5-hydroxytryptamine", Pharmacol. Rev., 56, 157-203
(1994). The subfamilies have been further divided into subtypes.
For example, the 5-HT.sub.2 receptor is currently divided into
three subtypes: 5-HT.sub.2a, 5-HT.sub.2b and 5-HT.sub.2c. The three
subtypes of 5-HT.sub.2 receptors are linked to phospholipase C with
the generation of two second messengers, diacylglycerol (which
activates protein kinase C) and inositol trisphosphate (which
releases intracellular stores of Ca.sup.2+). The 5-HT.sub.2c
receptors have a very high density in the choroid plexus, an
epithelial tissue that is the primary site of cerebrospinal fluid
production. See, Sanders-Bush, E. and S. E. Mayer,
"5-Hydroxytryptamine (Serotonin) Receptor agonists and
Antagonists", Goodman & Gilman's The Pharmacological Basis of
Therapeutics, Chapter 11, 9th Ed., McGraw-Hill, New York, N.Y.
(1996).
[0005] Julius, et al., isolated and characterized the 5-HT.sub.2c
receptor and later reported that transgenic mice lacking the 5-HT2c
receptor exhibit seizures and an eating disorder resulting in
increased consumption of food (see, U.S. Pat. Nos. 4,985,352 and
5,698,766, respectively). Consequently, compounds selective for the
5-HT.sub.2c receptor may provide useful therapies for the treatment
of seizure and eating disorders without the side effects typically
associated with nonselectivity of the ligand.
[0006] Several compounds have been proposed as 5-HT.sub.2c receptor
agonists or antagonists for use in the treatment of obesity and
other related diseases associated with decreased neurotransmission
of serotonin in mammals. See, e.g., EP 863136 (azetidine and
pyrrolidine derivatives); EP 657426 (tricyclic pyrrole
derivatives); EP 655440 (substituted 1-aminoethyl indoles); EP
572863 (pyrazinoindole derivatives); WO98/030548
(aminoalkylindazole compounds); WO 98/56768 (tricyclic pyrrole and
pyrazole derivatives); WO 99/43647 (azetidine and pyrrolidine
derivatives); WO 99/58490 (arylhydronaphthalenalkanamine
derivatives); WO 00/12475 (indoline derivatives); WO 00/12482
(indazole derivatives); WO 00/12502 (pyrroloquinoline derivatives);
WO 00/12510 (pyrroloindole, pyridoindole and azepinoindole
derivatives); WO 00/28993 (naphthylacetylpiperazine derivatives);
WO 00/44737 (aminoalkylbenzofuran derivatives); and WO 00/76984
(2,3-disubstituted pyrazines).
[0007] The non-selectivity of ligands for the various 5-HT
receptors remains a challenge. It is suspected that the
non-selectivity of some ligands contributes to various adverse side
effects such as hallucinations and cardiovascular complications.
Therefore, there remains a need for selective 5-HT.sub.2c receptor
ligands.
SUMMARY
[0008] The present invention provides compounds of Formula (IA)
which are useful as 5-HT.sub.2 receptor ligands (in particular,
5-HT2a and 5-HT.sub.2c receptor ligands). 2
[0009] wherein
[0010] Y is nitrogen;
[0011] X and Z are each independently CR, where R for each
occurrence is hydrogen, halogen, (C.sub.1-C.sub.4)alkyl, amino, or
(C.sub.1-C.sub.4)alkylamino; W is oxy, thio, amino,
(C.sub.1-C.sub.4)alkylamino, or acetylamino;
[0012] at least one of R.sup.1a, R.sup.1b, R.sup.1d, and R.sup.1e
is independently selected from the group consisting of halogen,
nitro, amino, (C.sub.1-C.sub.4)alkylamino, cyano, --C(O)NH.sub.2,
(C.sub.1-C.sub.4)alkyl, halo-substituted(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4) alkoxy, and
halo-substituted(C.sub.1-C.sub.4)alkoxy, or R.sup.1a and R.sup.1b
taken together form a five- or six-membered, aromatic or partially
or fully saturated fused ring, or R.sup.1a taken together with
R.sup.2a or R.sup.2b forms a five- or six-membered, fully saturated
fused ring;
[0013] R.sup.1c is hydrogen;
[0014] R.sup.2a and R.sup.2b are each independently hydrogen,
(C.sub.1-C.sub.4)alkyl, partially or fully saturated
(C.sub.3-C.sub.6)cycloalkyl, or one of which taken together with
R.sup.1a forms a five- or six-membered, fully saturated fused
ring;
[0015] n is 0, 1, or 2;
[0016] R.sup.3a and R.sup.3b are each independently hydrogen,
halogen, (C.sub.1-C.sub.4)alkyl, or (C.sub.1-C.sub.4)alkyl
substituted with hydroxy, fluoro, or (C.sub.1-C.sub.4)alkoxy;
[0017] R.sup.4 is hydrogen, hydroxy, (C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkyl substituted with hydroxy or cyano,
(C.sub.1-C.sub.4)alkylcarbonyl, (C.sub.1-C.sub.4)alkoxy,
(C.sub.1-C.sub.4)alkoxycarbonyl, (C.sub.3-C.sub.4)alkenyl, or an
amino-protecting group;
[0018] a nitrogen oxide thereof, a prodrug of the compound or the
nitrogen oxide; a pharmaceutically acceptable salt of the compound,
the nitrogen oxide, or the prodrug, or a solvate or hydrate of the
compound, the nitrogen oxide, the prodrug, or the salt.
[0019] Preferred compounds of Formula (IA) are those where Y is
nitrogen; X and Z are each independently CR, where R is hydrogen,
chloro, fluoro, methyl, or amino;
[0020] (i) R.sup.1a is halogen, (C.sub.1-C.sub.4)alkyl,
trifluoromethyl, methoxy, or trifluoromethoxy, and R.sup.1b,
R.sup.1d and R.sup.1e are each hydrogen,
[0021] (ii) R.sup.1b is halogen, methyl, methoxy, nitro, amino,
cyano, or --C(O)NH.sub.2 and R.sup.1a, R.sup.1d and R.sup.1e are
each hydrogen,
[0022] (iii) R.sup.1a and R.sup.1b are each independently halogen
or methyl and R.sup.1d and R.sup.1e are each hydrogen,
[0023] (iv) R.sup.1b and R.sup.1d are each independently halogen or
methyl and R.sup.1a and R.sup.1e are each hydrogen,
[0024] (v) R.sup.1b and R.sup.1d are each independently halogen or
methyl and R.sup.1b and R.sup.1e are each hydrogen,
[0025] (vi) R.sup.1a and R.sup.1e are each independently halogen or
methyl and R.sup.1b and R.sup.1d are each hydrogen, or
[0026] (vii) R.sup.1a, R.sup.1b and R.sup.1d are each independently
halogen or methyl and R.sup.1e is hydrogen;
[0027] W is oxy, thio, amino, or acetylamino; n is 1; R.sup.2a and
R.sup.2b are each independently methyl or hydrogen; R.sup.3a and
R.sup.3b are each independently hydrogen or (C.sub.1-C.sub.2)alkyl
(preferably (2R)-methyl or (2R)-ethyl); and R.sup.4 is hydrogen or
(C.sub.1-C.sub.4)alkyl; a nitrogen oxide thereof, a prodrug of the
compound or the nitrogen oxide; a pharmaceutically acceptable salt
of the compound, the nitrogen oxide, or the prodrug, or a solvate
or hydrate of the compound, the nitrogen oxide, the prodrug, or the
salt.
[0028] More preferred compounds are those where Y is N; X and Z are
each independently CR, where R is hydrogen; (i) R.sup.1a is
halogen, methyl, or trifluoromethyl and R.sup.1b, R.sup.1d and
R.sup.1e are each hydrogen, (ii) R.sup.1b is halogen, methyl,
nitro, amino, cyano or --C(O)NH.sub.2 and R.sup.1a, R.sup.1d and
R.sup.1e are each hydrogen, (iii) R.sup.1b and R.sup.1d are each
independently halogen or methyl and R.sup.1a and R.sup.1e are each
hydrogen, or (iv) R.sup.1a and R.sup.1d are each independently
halogen or methyl and R.sup.1b and R.sup.1e are each hydrogen; W is
oxy, thio, amino, or acetylamino; n is 1; R.sup.2a and R.sup.2b are
each independently methyl or hydrogen; R.sup.3a is hydrogen,
(2R)-methyl, or (2R)-ethyl; R.sup.3b is hydrogen; and R.sup.4 is
hydrogen; a nitrogen oxide thereof, a prodrug of the compound or
the nitrogen oxide; a pharmaceutically acceptable salt of the
compound, the nitrogen oxide, or the prodrug, or a solvate or
hydrate of the compound, the nitrogen oxide, the prodrug, or the
salt.
[0029] Most preferred are those compounds where Y is N, X and Z are
each independently CR, where R for each occurrence is hydrogen or
methyl; (i) R.sup.1a is halogen, or methyl and R.sup.1b, R.sup.1d
and R.sup.1e are each hydrogen, (ii) R.sup.1b is halogen, methyl,
nitro, amino, cyano, or --C(O)NH.sub.2 and R.sup.1a, R.sup.1d and
R.sup.1e are each hydrogen, (iii) R.sup.1b and R.sup.1d are each
independently halogen or methyl and R.sup.1a and R.sup.1e are each
hydrogen, or (iv) R.sup.1a and R.sup.1d are each independently
halogen or methyl and R.sup.1b and R.sup.1e are each hydrogen; W is
oxy, amino, or acetylamino; n is 1; R.sup.2a and R.sup.2b are each
independently methyl or hydrogen; R.sup.3a is hydrogen,
(2R)-methyl, or (2R)-ethyl; and R.sup.3b is hydrogen; and R.sup.4
is hydrogen; a nitrogen oxide thereof, a prodrug of the compound or
the nitrogen oxide; a pharmaceutically acceptable salt of the
compound, the nitrogen oxide, or the prodrug, or a solvate or
hydrate of the compound, the nitrogen oxide, the prodrug, or the
salt.
[0030] Non-limiting examples of preferred compounds of Formula (IA)
include;
6'-(3-chloro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl;
6'-(3-chloro-benzyloxy)-2-ethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl;
6'-(3-fluoro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl;
6'-(3-chloro-benzyloxy)-(2R)-methyl-3,4,5,6-tetrahydro-2H-[1,2]bipyraziny-
l;
6'-(3-fluoro-benzyloxy)-(2R)-methyl-3,4,5,6-tetrahydro-2H-[1,2']bipyraz-
inyl;
6'-(3-chloro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl
4'-oxide;
6'-(2,5-dichloro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2]bipyrazi-
nyl;
6'-(2-fluoro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl;
6'-(3-nitro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl;
3-(3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl-6'-yloxymethyl)-benzonitrile;
6'-(2,5-difluoro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl;
5'-bromo-6'-(3-chloro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl;
6'-(3-bromo-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl;
3-(3,4 ,5,6-tetrahydro-2H-[1,2']bipyrazinyl-6'-yloxymethyl
)-phenylamine;
6'-(2-methyl-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl;
6'-(3-chloro-benzyloxy)-5'-fluoro-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl-
; 5'-chloro-6'-(3-chloro-benzyloxy)-3,4,5,6-tetrahydro-2H-
[1,2]bipyrazinyl;
6'-(indan-(1S)-yloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyr- azinyl;
6'-(3-methy-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl;
6'-(3-chloro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl-3'-ylamin-
e; 6'-(2-chloro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl;
6'-[2-(3-chloro-phenyl)-ethoxy]-3,4,5,6-tetrahydro-2H-
[1,2']bipyrazinyl;
6'-(2-chloro-benzyloxy)-(2R)-methyl-3,4,5,6-tetrahydro-2H-[1,2']bipyrazin-
yl;
6'-(3,4-difluoro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl;
6'-(3,5-difluoro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl;
(3-fluoro-benzyl
)-(3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl-6'-yl)-amine;
(3-chloro-benzyl)-(3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl-6'-yl)-amine;
(3,5-difluoro-benzyl)-(3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl-6'-yl)-amin-
e;
3-[(3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl-6'-ylamino)-methyl]-benzoni-
trile;
(2,5-difluoro-benzyl)-(3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl-6'-y-
l)-amine;
(3,5-dichloro-benzyl)-(3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl-6'-
-yl)-amine;
(3-chloro-benzyl)-(2-methyl-3,4,5,6-tetrahydro-2H-[1,2]bipyraz-
inyl-6'-yl)-amine;
(3-fluoro-benzyl)-(2-methyl-3,4,5,6-tetrahydro-2H-[1,2]-
bipyrazinyl-6'-yl)-amine;
(2-chloro-benzyl)-(3,4,5,6-tetrahydro-2H-[1,2']b- ipyrazinyl-6'-yl
)-amine; (2-chloro-6-fluoro-benzyl)-(3,4,5,6-tetrahydro-2-
H-[1,2]bipyrazinyl-6'-yl)-amine;
(2,3-difluoro-benzyl)-(3,4,5,6-tetrahydro-
-2H-[1,2]bipyrazinyl-6'-yl)-amine;
N-(3-chloro-benzyl)-N-(3,4,5,6-tetrahyd-
ro-2H-[1,2']bipyrazinyl-6'-yl)-acetamide;
6'-(3-chloro-benzylsulfanyl)-3,4-
,5,6-tetrahydro-2H-[1,2']bipyrazinyl; and
6'-benzylsulfanyl-3,4,5,6-tetrah- ydro-2H-[1,2]bipyrazinyl;
[0031] a nitrogen oxide thereof, a prodrug of the compound or the
nitrogen oxide; a pharmaceutically acceptable salt of the compound,
the nitrogen oxide, or the prodrug, or a solvate or hydrate of the
compound, the nitrogen oxide, the prodrug, or the salt.
[0032] Non-limiting examples of more preferred compounds of Formula
(1A) include;
6'-(3-chloro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl;
6'-(3-chloro-benzyloxy)-(2R)-methyl-3,4,5,6-tetrahydro-2H-[1,2']bipyrazin-
yl;
6'-(2-chloro-benzyloxy)-(2R)-methyl-3,4,5,6-tetrahydro-2H-[1,2']bipyra-
zinyl;
6'-(3-fluoro-benzyloxy)-(2R)-methyl-3,4,5,6-tetrahydro-2H-[1,2']bip-
yrazinyl;
6'-(2-fluoro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl;
6'-(3-fluoro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl;
6'-(3-chloro-benzyloxy)-2-ethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl;
6'-(2,5-difluoro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl;
6'-(2,5-dichloro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl;
6'-(3,5-difluoro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl;
(3-fluoro-benzyl)-(3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl-6'-yl)-amine;
(3-chloro-benzyl)-(3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl-6'-yl)-amine;
(3,5-difluoro-benzyl)-(3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl-6'-yl)-ami-
ne;
(3,5-dichloro-benzyl)-(3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl-6'-yl)--
amine;
(2-chloro-6-fluoro-benzyl)-(3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl-
-6'-yl)-amine;
6'-(3-chloro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyraz- inyl
4'-oxide;
N-(3-chloro-benzyl)-N-(3,4,5,6-tetrahydro-2H-[1,2']bipyrazi-
nyl-6'-yl)-acetamide;
6'-(3-chloro-benzylsulfanyl)-3,4,5,6-tetrahydro-2H-[-
1,2']bipyrazinyl; and
6'-(indan-(1S)-yloxy)-3,4,5,6-tetrahydro-2H-[1,2']bi-
pyrazinyl;
[0033] a nitrogen oxide thereof, a prodrug of the compound or the
nitrogen oxide; a pharmaceutically acceptable salt of the compound,
the nitrogen oxide, or the prodrug, or a solvate or hydrate of the
compound, the nitrogen oxide, the prodrug, or the salt.
[0034] Even more preferred compounds of the present invention
include:
6'-(3-chloro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl;
6'-(3-fluoro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl;
6'-(3-chloro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl
4'-oxide;
(3-fluoro-benzyl)-(3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl-6'-yl)-amine;
6'-(3-chloro-benzyloxy)-(2
R)-methyl-3,4,5,6-tetrahydro-2H-[1,2']bipyrazi- nyl;
6'-(3,5-difluoro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl;
6'-(2,5-difluoro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl;
and 6'-(indan-(1S)-yloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl;
a prodrug of the compound or the nitrogen oxide; a pharmaceutically
acceptable salt of the compound, the nitrogen oxide, or the
prodrug, or a solvate or hydrate of the compound, the nitrogen
oxide, the prodrug, or the salt.
[0035] Preferred salts of the compounds described above include
citrates, fumarates, hydrochlorides, L-malates, succinates,
D,L-tartrates and more preferred salts include citrates, L-malates
and D,L-tartrates.
[0036] In yet another embodiment of the present invention,
compounds of Formula (IC) are provided. 3
[0037] wherein
[0038] Y is N;
[0039] X and Z are each independently CR, where R for each
occurrence is hydrogen, halogen, (C.sub.1-C.sub.4)alkyl, amino, or
(C.sub.1-C.sub.4)alkylamino;
[0040] W is oxy, thio, amino, (C.sub.1-C.sub.4)alkylamino, or
acetylamino;
[0041] Q is a heteroaryl group selected from the group consisting
of pyridin-2-yl, pyridin-3-yl, furan-3-yl, furan-2-yl,
thiophen-2-yl, thiophen-3-yl, thiazol-2-yl, pyrrol-2-yl,
pyrrol-3-yl, pyrazol-3-yl, quinolin-2-yl, quinolin-3-yl,
isoquinolin-3-yl, benzofuran-2-yl, benzofuran-3-yl,
isobenzofuran-3-yl, benzothiophen-2-yl, benzothiophen-3-yl,
indol-2-yl, indol-3-yl, 2H-imidazol-2-yl, oxazol-2-yl,
isoxazol-3-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl,
1,3,4-oxadiazol-2-yl, 1,3,4-oxadiazol-5-yl, 1,2,4-triazol-3-yl,
1,2,3-thiadiazol4-yl, 1,2,3-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl,
1,3,4-thiadiazol-5-yl, and 1,2,4-oxathiazol-3-yl, where the
heteroaryl group is optionally substituted with one to three
substituents independently selected from halo,
(C.sub.1-C.sub.4)alkyl, cyano, nitro, amino,
(C.sub.1-C.sub.4)alkylamino, or (C.sub.1-C.sub.4)alkyoxy;
[0042] R.sup.2a and R.sup.2b are each independently hydrogen,
(C.sub.1-C.sub.4)alkyl, or partially or fully saturated
(C.sub.3-C.sub.6)cycloalkyl;
[0043] R.sup.3a and R.sup.3b are each independently hydrogen,
halogen, (C.sub.1-C.sub.4)alkyl, or (C.sub.1-C.sub.4)alkyl
substituted with hydroxy, fluoro, or (C.sub.1-C.sub.4)alkoxy;
[0044] R.sup.4 is hydrogen, hydroxy, (C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkyl substituted with hydroxy or cyano,
(C.sub.1-C.sub.4)alkylcarbonyl, (C.sub.1-C.sub.4)alkoxy,
(C.sub.1-C.sub.4)alkoxy-carbonyl, or (C.sub.3-C.sub.4)alkenyl;
[0045] a nitrogen oxide thereof, a prodrug of the compound or the
nitrogen oxide; a pharmaceutically acceptable salt of the compound,
the nitrogen oxide, or the prodrug, or a solvate or hydrate of the
compound, the nitrogen oxide, the prodrug, or the salt.
[0046] Non-limiting examples of preferred compounds of Formula (IC)
include:
6'-(pyridin-3-ylmethoxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl- ;
2-methyl-6'-(pyridin-3-ylmethoxy)-3,4,5,6-tetrahydro-2H-
[1,2]bipyrazinyl;
6'-(thiophen-3-ylmethoxy)-3,4,5,6-tetrahydro-2H-[1,2]bi- pyrazinyl;
6'-([1,2,3]thiadiazol-4-ylmethoxy)-3,4,5,6-tetrahydro-2H-[1,2]b-
ipyrazinyl;
6'-(6-fluoro-pyridin-2-ylmethoxy)-3,4,5,6-tetrahydro-2H-[1,2']-
bipyrazinyl;
2-methyl-6'-(6-methyl-pyridin-2-ylmethoxy)-3,4,5,6-tetrahydro-
-2H-[1,2]bipyrazinyl;
6'-(6-methyl-pyridin-2-ylmethoxy)-3,4,5,6-tetrahydro- -2H-
[1,2]bipyrazinyl; and
6'-(6-chloro-pyridin-2-ylmethoxy)-3,4,5,6-tetra-
hydro-2H-[1,2]bipyrazinyl; a nitrogen oxide thereof, a prodrug of
the compound or the nitrogen oxide; a pharmaceutically acceptable
salt of the compound, the nitrogen oxide, or the prodrug, or a
solvate or hydrate of the compound, the nitrogen oxide, the
prodrug, or the salt.
[0047] Non-limiting examples of more preferred compounds of Formula
(1C) include
6'-(6-methyl-pyridin-2-ylmethoxy)-3,4,5,6-tetrahydro-2H-[1,2']bip-
yrazinyl;
6'-(6-chloro-pyridin-2-ylmethoxy)-3,4,5,6-tetrahydro-2H-[1,2']bi-
pyrazinyl;
6'-(6-fluoro-pyridin-2-ylmethoxy)-3,4,5,6-tetrahydro-2H-[1,2']b-
ipyrazinyl;
2-(6-chloro-pyridin-2-ylmethoxy)-4-piperazin-1-yl-pyrimidine; and
2-methyl-6'-(6-methyl-pyridin-2-ylmethoxy)-3,4,5,6-tetrahydro-2H-[1,2-
']bipyrazinyl; a nitrogen oxide thereof, a prodrug of the compound
or the nitrogen oxide; a pharmaceutically acceptable salt of the
compound, the nitrogen oxide, or the prodrug, or a solvate or
hydrate of the compound, the nitrogen oxide, the prodrug, or the
salt.
[0048] Some of the compounds described herein contain at least one
chiral center; consequently, those skilled in the art will
appreciate that all stereoisomers (e.g., enantiomers and
diasteroisomers) of the compounds illustrated and discussed herein
are within the scope of the present invention. In addition,
tautomeric forms of the compounds are also within the scope of the
present invention.
[0049] In another embodiment of the present invention, a
pharmaceutical composition is provided that comprises (1) a
compound of Formula (IA) or (1C), a nitrogen oxide thereof, a
prodrug of the compound or the nitrogen oxide; a pharmaceutically
acceptable salt of the compound, the nitrogen oxide, or the
prodrug, or a solvate or hydrate of the compound, the nitrogen
oxide, the prodrug, or the salt, and (2) a pharmaceutically
acceptable excipient, diluent, or carrier.
[0050] In yet another embodiment of the present invention, a method
for treating 5-HT.sub.2 (preferably, 5-HT.sub.2c) receptor-mediated
diseases, conditions, or disorders in an animal that includes the
step of administering to the animal a therapeutically effective
amount of a compound of Formula (IB) 4
[0051] wherein
[0052] Y is N;
[0053] X and Z are each independently CR, where R for each
occurrence is hydrogen, halogen (preferably Cl or F),
(C.sub.1-C.sub.4)alkyl, amino, or (C.sub.1-C.sub.4)alkylamino;
[0054] W is oxy, thio, amino, (C.sub.1-C.sub.4)alkylamino, or
acetylamino;
[0055] R.sup.1a, R.sup.1b, R.sup.1c, R.sup.1d and R.sup.1e are each
independently hydrogen, halogen, nitro, cyano, amino,
(C.sub.1-C.sub.4)alkylamino, (C.sub.1-C.sub.4)alkyl,
halo-substituted (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy,
halo-substituted (C.sub.1-C.sub.4)alkoxy, --C(O)NH.sub.2, R a and
R.sup.1b taken together form a five- or six-membered, aromatic or
partially or fully saturated fused ring, or R.sup.1a taken together
with R.sup.2a or R.sup.2b forms a five- or six-membered, fully
saturated, fused ring;
[0056] R.sup.2a and R.sup.2b are each independently hydrogen,
(C.sub.1-C.sub.4)alkyl, partially or fully saturated
(C.sub.3-C.sub.6)cycloalkyl, or one of which taken together with
R.sup.1a forms a five- or six-membered, fully saturated fused
ring;
[0057] n is 0, 1, or 2;
[0058] R.sup.3a and R.sup.3b are each independently hydrogen,
halogen, (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkyl substituted
with hydroxy, fluoro, or (C.sub.1-C.sub.4)alkoxy;
[0059] R.sup.4 is hydrogen, hydroxy, (C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkyl substituted with hydroxy or cyano,
(C.sub.1-C.sub.4)alkylcarbonyl, (C.sub.1-C.sub.4)alkoxy,
(C.sub.1-C.sub.4)alkoxy-carbonyl, or (C.sub.3-C.sub.4)alkenyl;
[0060] a nitrogen oxide thereof, a prodrug of said compound or said
nitrogen oxide; a pharmaceutically acceptable salt of said
compound, said nitrogen oxide, or said prodrug, or a solvate or
hydrate of said compound, said nitrogen oxide, said prodrug, or
said salt.
[0061] Non-limiting examples of preferred compounds of Formula (IB)
include 6'-benzyloxy-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl;
6'-(3-chloro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl;
6'-(3-chloro-benzyloxy)-2-ethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl;
6'-(3-fluoro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl;
6'-(3-chloro-benzyloxy)-(2R)-methyl-3,4,5,6-tetrahydro-2H-[1,2]bipyraziny-
l;
6'-(3-fluoro-benzyloxy)-(2R)-methyl-3,4,5,6-tetrahydro-2H-[1,2]bipyrazi-
nyl;
6'-(3-chloro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl
4'-oxide;
6'-(2,5-dichloro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyraz-
inyl;
6'-(2-fluoro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl;
6'-(3-nitro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl;
3-(3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl-6'-yloxymethyl)-benzonitrile;
6'-(2,5-difluoro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl;
5'-bromo-6'-(3-chloro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl;
6'-(3-bromo-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl;
3-(3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl-6'-yloxymethyl)-phenylamine;
6'-(2-methyl-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl;
6'-(3-chloro-benzyloxy)-5'-fluoro-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl-
;
5'-chloro-6'-(3-chloro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyraziny-
l; 6'-(indan-(1S)-yloxy)-3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl;
6'-(3-methy-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl;
6'-(3-chloro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl-3'-ylamin-
e; 6'-(2-chloro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl;
6'-[2-(3-chloro-phenyl)-ethoxy]-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl;
6'-(2-chloro-benzyloxy)-(2R)-methyl-3,4,5,6-tetrahydro-2H-[1,2']bipyrazin-
yl;
6'-(3,4-difluoro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl;
6'-(3,5-difluoro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl;
(3-fluoro-benzyl)-(3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl-6'-yl
)-amine;
(3-chloro-benzyl)-(3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl-6'-yl)-amine;
(3,5-difluoro-benzyl)-(3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl-6'-yl)-ami-
ne; 3-[(3,4,5,6-tetrahydro-2H-[l
,2']bipyrazinyl-6'-ylamino)-methyl]-benzo- nitrile;
(2,5-difluoro-benzyl)-(3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl-6'-
-yl)-amine;
(3,5-dichloro-benzyl)-(3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl-
-6'-yl)-amine;
(3-chloro-benzyl)-(2-methyl-3,4,5,6-tetrahydro-2H-[1,2']bip-
yrazinyl-6'-yl)-amine;
(3-fluoro-benzyl)-(2-methyl-3,4,5,6-tetrahydro-2H-[-
1,2']bipyrazinyl-6'-yl)-amine;
(2-chloro-benzyl)-(3,4,5,6-tetrahydro-2H-[1-
,2']bipyrazinyl-6'-yl)-amine;
(2-chloro-6-fluoro-benzyl)-(3,4,5,6-tetrahyd-
ro-2H-[1,2']bipyrazinyl-6'-yl)-amine;
(2,3-difluoro-benzyl)-(3,4,5,6-tetra-
hydro-2H-[1,2']bipyrazinyl-6'-yl)-amine;
N-(3-chloro-benzyl)-N-(3,4,5,6-te-
trahydro-2H-[1,2']bipyrazinyl-6'-yl)-acetamide;
6'-(3-chloro-benzylsulfany- l
)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl; and
6'-benzylsulfanyl-3,4,5,6- -tetrahydro-2H-[1,2']bipyrazinyl;
[0062] a nitrogen oxide thereof, a prodrug of the compound or the
nitrogen oxide; a pharmaceutically acceptable salt of the compound,
the nitrogen oxide, or the prodrug, or a solvate or hydrate of the
compound, the nitrogen oxide, the prodrug, or the salt.
[0063] Non-limiting examples of more preferred compounds include:
6'-benzyloxy-3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl;
6'-(3-chloro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl;
6'-(3-chloro-benzyloxy)-(2R)-methyl-3,4,5,6-tetrahydro-2H-[1,2']bipyrazin-
yl;
6'-(2-chloro-benzyloxy)-(2R)-methyl-3,4,5,6-tetrahydro-2H-[1,2]bipyraz-
inyl;
6'-(3-fluoro-benzyloxy)-(2R)-methyl-3,4,5,6-tetrahydro-2H-[1,2]bipyr-
azinyl;
6'-(2-fluoro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl;
6'-(3-fluoro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl;
6'-(3-chloro-benzyloxy)-2-ethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl;
6'-(2,5-difluoro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl;
6'-(2,5-dichloro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl;
6'-(3,5-difluoro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl;
(3-fluoro-benzyl)-(3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl-6'-yl)-amine;
(3-chloro-benzyl)-(3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl-6'-yl)-amine;
(3,5-difluoro-benzyl)-(3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl-6'-yl)-amin-
e;
(3,5-dichloro-benzyl)-(3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl-6'-yl)-am-
ine;
(2-chloro-6-fluoro-benzyl)-(3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl-6'-
-yl)-amine;
6'-(3-chloro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyraziny- l
4'-oxide;
N-(3-chloro-benzyl)-N-(3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl--
6'-yl)-acetamide;
6'-(3-chloro-benzylsulfanyl)-3,4,5,6-tetrahydro-2H-[1,2]-
bipyrazinyl; and
6'-(indan-(1S)-yloxy)-3,4,5,6-tetrahydro-2H-[1,2]bipyrazi- nyl;
[0064] a nitrogen oxide thereof, a prodrug of the compound or the
nitrogen oxide; a pharmaceutically acceptable salt of the compound,
the nitrogen oxide, or the prodrug, or a solvate or hydrate of the
compound, the nitrogen oxide, the prodrug, or the salt.
[0065] Even more preferred compounds of Formula (IB) include:
6'-benzyloxy-3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl;
6'-(3-chloro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl;
6'-(3-fluoro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl;
6'-(3-chloro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl
4'-oxide;
(3-fluoro-benzyl)-(3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl-6'-yl
)-a mine;
6'-(3-chloro-benzyloxy)-(2R)-methyl-3,4,5,6-tetrahydro-2H-[1,2']bip-
yrazinyl;
6'-(3,5-difluoro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazi-
nyl;
6'-(2,5-difluoro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl;
and
6'-(indan-(1S)-yloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl;
[0066] a nitrogen oxide thereof, a prodrug of the compound or the
nitrogen oxide; a pharmaceutically acceptable salt of the compound,
the nitrogen oxide, or the prodrug, or a solvate or hydrate of the
compound, the nitrogen oxide, the prodrug, or the salt.
[0067] Compounds of the present invention may be administered in
combination with other pharmaceutical agents, such as apo-B/MTP
inhibitors, MCR-4 agonists, CCK-A agonists, monoamine reuptake
inhibitors, sympathomimetic agents, .beta..sub.3 adrenergic
receptor agonists, dopamine agonists, melanocyte-stimulating
hormone receptor analogs, cannabinoid 1 receptor antagonists,
melanin concentrating hormone antagonists, leptins, leptin analogs,
leptin receptor agonists, galanin antagonists, lipase inhibitors,
bombesin agonists, neuropeptide-Y antagonists, thyromimetic agents,
dehydroepiandrosterone or analogs thereof, glucocorticoid receptor
agonists or antagonists, orexin receptor antagonists, urocortin
binding protein antagonists, glucagon-like peptide-1 receptor
agonists, ciliary neurotrophic factors, AGRPs (human agouti-related
proteins), ghrelin receptor antagonists, histamine 3 receptor
antagonists or reverse agonists, neuromedin U receptor agonists,
and the like.
[0068] The combination therapy may be administered as (a) a single
pharmaceutical composition which comprises a compound of the
present invention, at least one additional pharmaceutical agent
described above and a pharmaceutically acceptable excipient,
diluent, or carrier; or (b) two separate pharmaceutical
compositions comprising (i) a first composition comprising a
compound of Formula (IA), (IC), or (IB) and a pharmaceutically
acceptable excipient, diluent, or carrier, and (ii) a second
composition comprising at least one additional pharmaceutical agent
described above and a pharmaceutically acceptable excipient,
diluent, or carrier. The pharmaceutical compositions may be
administered simultaneously or sequentially and in any order.
[0069] In yet another aspect of the present invention, a
pharmaceutical kit is provided for use by a consumer to treat
5-HT.sub.2 receptor-mediated diseases, conditions, or disorders in
an animal (preferably, 5-HT.sub.2c receptor-mediated diseases,
conditions or disorders). The kit comprises a) a suitable dosage
form comprising a compound of the present invention; and b)
instructions describing a method of using the dosage form to treat
or prevent a 5-HT.sub.2 receptor-mediated disease, condition, or
disorder.
[0070] In yet another embodiment of the present invention is a
pharmaceutical kit comprising: a) a first dosage form comprising
(i) a compound of the present invention and (ii) a pharmaceutically
acceptable carrier, excipient or diluent; b) a second dosage form
comprising (i) an additional pharmaceutical agent described above,
and (ii) a pharmaceutically acceptable carrier, excipient or
diluent; and c) a container.
[0071] Another aspect of the present invention is a method for
treating female sexual dysfunction (FSD) comprising the step of
administering to a female in need thereof a therapeutically
effective amount of a compound of the present invention. The method
may further include the administration of one or more additional
active agents for treating FSD. The additional active agents may be
selected from the group consisting of (1) as estrogen receptor
modulators, estrogen agonists, estrogen antagonists or combinations
thereof; (2) testosterone replacement agent, testosternone
(Tostrelle), dihydrotestosterone, dehydroepiandrosterone (DHEA), a
testosterone implant, or combinations thereof; (3) estrogen, a
combination of estrogen and medroxyprogesterone or
medroxyprogesterone acetate (MPA), or estrogen and methyl
testosterone hormone replacement therapy agent; (4) one or more
dopaminergic agents; (5) one or more of an NPY (neuropeptide Y)
inhibitor; (6) one or more of a melanocortin receptor agonist or
modulator or melanocortin enhancer; (7) one or more of an NEP
inhibitor; (8) one or more of a PDE inhibitor; and (9) one or more
of a bombesin receptor antagonist or modulator. The FSD treatments
include female sexual arousal disorder (FSAD), female orgasmic
disorder (FOD), hypoactive sexual desire disorder (HSDD), or sexual
pain disorder.
[0072] In another embodiment of the present invention, a method is
provided for treating male erectile dysfunction (MED) comprising
the step of administering to a male in need thereof a
therapeutically effective amount of a compound of the present
invention.
[0073] Another aspect of the present invention is a method of
increasing lean meat content in an edible animal comprising the
step of administering to the edible animal a lean meat increasing
amount of a compound of the present invention or a composition
comprising the compound of the present invention. The compounds of
the present invention may also be administered to the edible animal
in combination with any one of the additional pharmaceutical agents
described above.
Definitions
[0074] As used herein, the term "alkyl" refers to a hydrocarbon
radical of the general formula C.sub.nH.sub.2n+1. The alkane
radical may be straight or branched. For example, the term
"(C.sub.1-C.sub.4)alkyl" refers to a monovalent, straight, or
branched aliphatic group containing 1 to 4 carbon atoms (e.g.,
methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl,
t-butyl, and other constitutional isomers containing 1 to 4 carbon
atoms (including stereoisomers). The alkane radical may be
unsubstituted or substituted with one or more substituents. For
example, a "halo-substituted alkyl" refers to an alkyl group
substituted with one or more halogen atoms (e.g., fluoromethyl,
difluoromethyl, trifluoromethyl, perfluoroethyl, chloromethyl,
bromomethyl, and the like). Similarly, the alkyl portion of an
alkoxy, alkylamino, dialkylamino, or alkylthio group has the same
meaning as alkyl defined above and the halo-substituted alkyl
portion of a halo-substituted alkoxy, alkyl amino, dialkylamino or
alkylthio group has the same meaning as halo-substituted alkyl
defined above.
[0075] The term "partially or fully saturated cycloalkyl" refers to
nonaromatic rings that are either partially or fully hydrogenated.
For example, partially or fully saturated
(C.sub.3-C.sub.6)cycloalkyl includes groups such as cyclopropyl,
cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclpentenyl,
cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and
the like. The term "fused ring" refers to partially saturated as
well as aromatic carbocyclic and heterocyclic ring systems.
Preferably, the heterocyclic ring contains 1 or 2 heteroatoms
independently selected from nitrogen, oxygen, and sulfur
(optionally oxidized to the corresponding sulfone or sulfoxide).
Non-limiting examples of fused ring systems include naphthalene,
indane, indene, isoindene, benzofuran, isobenzofuran,
benzo[b]thiophene, benzo[c]thiophene, indole, 3H-indole,
1H-isoindole, indazole, indoxazine, benzoxazole, anthranil,
tetralin, 2H-1-benzopyran, quinoline, isoquinoline, cinnoline,
quinazoline, 2H-1,3-benzoxazine, 2H-1,4-benzoxazine,
1H-2,3-benzoxazine, 4H-2,1-benzoxazine, 2H-1,2-benzoxazine,
4H-1,4-benzoxazine, and the like.
[0076] The term "heteroaryl" refers to aromatic monocyclic or
bicyclic ring systems containing 1, 2 or 3 heteroatoms
independently selected from nitrogen, oxygen, and sulfur. The
heteroaryl group may be unsubstituted or substituted with 1 to 3
substituents. Preferred substituents include halo (Br, Cl, I, or
F), (C.sub.1-C.sub.4) alkyl, cyano, nitro, amino,
(C.sub.1-C.sub.4)alkylamino, and (C.sub.1-C.sub.4) alkoxy. Suitable
heteroaryl groups include is a heteroaryl group selected from the
group consisting of pyridin-2-yl, pyridin-3-yl, furan-3-yl,
furan-2-yl, thiophen-2-yl, thiophen-3-yl, thiazol-2-yl,
pyrrol-2-yl, pyrrol-3-yl, pyrazol-3-yl, quinolin-2-yl,
quinolin-3-yl, isoquinolin-3-yl, benzofuran-2-yl, benzofuran-3-yl,
isobenzofuran-3-yl, benzothiophen-2-yl, benzothiophen-3-yl,
indol-2-yl, indol-3-yl, 2H-imidazol-2-yl, oxazol-2-yl,
isoxazol-3-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1
,3,4-oxadiazol-2-yl, 1 ,3,4-oxadiazol-5-yl, 1,2,4-triazol-3-yl,
1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl,
1,3,4-thiadiazol-2-yl, 1,3,4-thiadiazol-5-yl,
1,2,4-oxathiazol-3-yl, and the like.
[0077] The term "substituted" means that a hydrogen atom on a
molecule has been replaced with a different atom or molecule. The
atom or molecule replacing the hydrogen atom is denoted as a
"substituent." The term substituted specifically envisions and
allows for substitutions that are common in the art. However, it is
generally understood by those skilled in the art that the
substituents should be selected so as to not adversely affect the
pharmacological characteristics of the compound or adversely
interfere with the use of the medicament.
[0078] The term "nitrogen oxide" or "N-oxide" refers to the
oxidation of at least one of the nitrogens in the pyrimidine or
pyrazine ring of the compounds of Formula (IA), (IB) or (IC)(e.g.,
mono- or di-oxide). The nitrogen mono-oxides may exist as a single
positional isomer or a mixture of positional isomers (e.g., a
mixture of 1-N-oxide and 3-N-oxide pyrimidines or a mixture of
1-N-oxide and 4-N-oxide pyrazines).
[0079] The term "protecting group" or "Pg" refers to a substituent
that is commonly employed to block or protect a particular
functionality while reacting other functional groups on the
compound. For example, an "amino-protecting group" is a substituent
attached to an amino group that blocks or protects the amino
functionality in the compound. Suitable amino-protecting groups
include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC),
benzyloxycarbonyl (CBz) and 9-fluorenylmethylenoxycarbonyl (Fmoc).
Similarly, a "hydroxy-protecting group" refers to a substituent of
a hydroxy group that blocks or protects the hydroxy functionality.
Suitable protecting groups include acetyl and silyl. A
"carboxy-protecting group" refers to a substituent of the carboxy
group that blocks or protects the carboxy functionality. Common
carboxy-protecting groups include --CH.sub.2CH.sub.2SO.sub.2Ph,
cyanoethyl, 2-(trimethylsilyl)ethyl,
2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl,
2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl,
nitroethyl and the like. For a general description of protecting
groups and their use, see T. W. Greene, Protective Groups in
Organic Synthesis, John Wiley & Sons, New York, 1991.
[0080] The term "ligand" refers to a compound that binds to a
receptor. As used herein, the ligand may possess partial or full
agonist or antagonist activity.
[0081] The phrase "therapeutically effective amount" means an
amount of a compound of the present invention that (i) treats or
prevents the particular disease, condition, or disorder, (ii)
attenuates, ameliorates, or eliminates one or more symptoms of the
particular disease, condition, or disorder, or (iii) prevents or
delays the onset of one or more symptoms of the particular disease,
condition, or disorder described herein.
[0082] The term "animal" refers to humans, companion animals (e.g.,
dogs, cats and horses), food-source animals, zoo animals, marine
animals, birds and other similar animal species. "Edible animals"
refers to food-source animals such as cows, pigs, sheep and
poultry.
[0083] The phrase "pharmaceutically acceptable" indicates that the
substance or composition must be compatible chemically and/or
toxicologically, with the other ingredients comprising a
formulation, and/or the mammal being treated therewith.
[0084] The terms "treating", "treat", or "treatment" embrace both
preventative, i.e., prophylactic, and palliative treatment.
[0085] The term "compounds of the present invention" (unless
specifically identified otherwise) refer to compounds of Formulae
(IA), (IC) and (IB), nitrogen oxides thereof, prodrugs of the
compounds or nitrogen oxides, pharmaceutically acceptable salts of
the compounds, nitrogen oxides, and/or prodrugs, and hydrates or
solvates of the compounds, nitrogen oxides, salts, and/or prodrugs,
as well as, all stereoisomers (including diastereoisomers and
enantiomers), tautomers and isotopically labeled compounds.
DETAILED DESCRIPTION
[0086] The present invention provides a method for treating or
preventing 5-HT.sub.2 receptor-mediated diseases, conditions, or
disorders by administering compounds of Formula (IB) which act as
5-HT.sub.2 receptor ligands (preferably, 5-HT.sub.2c and/or
5-HT.sub.2a receptor ligands). 5
[0087] wherein
[0088] Y is N;
[0089] X and Z are each independently CR, where R for each
occurrence is hydrogen, halogen, (C.sub.1-C.sub.4)alkyl, amino, or
(C.sub.1-C.sub.4)alkylamino;
[0090] W is oxy, thio, amino, (C.sub.1-C.sub.4)alkylamino, or
acetylamino;
[0091] R.sup.1a, R.sup.1b, R.sup.1c, R.sup.1d and R.sup.1e are each
independently hydrogen, halogen, nitro, cyano, amino,
(C.sub.1-C.sub.4)alkylamino, (C.sub.1-C.sub.4)alkyl,
halo-substituted (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy,
halo-substituted (C.sub.1-C.sub.4)alkoxy, --C(O)NH.sub.2, R.sup.1a
and R.sup.1b taken together form a five- or six-membered, aromatic
or partially or fully saturated fused ring, or R.sup.1a taken
together with R.sup.2a or R.sup.2b forms a five- or six-membered,
fully saturated, fused ring;
[0092] R.sup.2a and R.sup.2b are each independently hydrogen,
(C.sub.1-C.sub.4)alkyl, partially or fully saturated
(C.sub.3-C.sub.6)cycloalkyl, or one of which taken together with
R.sup.1a forms a five- or six-membered, fully saturated fused
ring;
[0093] n is 0, 1, or2;
[0094] R.sup.3a and R.sup.3b are each independently hydrogen,
halogen, (C.sub.1-C.sub.4)alkyl, or (C.sub.1-C.sub.4)alkyl
substituted with hydroxy, fluoro, or (C.sub.1-C.sub.4)alkoxy;
[0095] R.sup.4 is hydrogen, hydroxy, (C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkyl substituted with hydroxy or cyano,
(C.sub.1-C.sub.4)alkylcarbonyl, (C.sub.1-C.sub.4)alkoxy,
(C.sub.1-C.sub.4)alkoxy-carbonyl, or (C.sub.3-C.sub.4)alkenyl;
[0096] a nitrogen oxide thereof, a prodrug of the compound or the
nitrogen oxide; a pharmaceutically acceptable salt of the compound,
the nitrogen oxide, or the prodrug, or a solvate or hydrate of the
compound, the nitrogen oxide, the prodrug, or the salt.
[0097] Compounds of the present invention may be synthesized by
synthetic routes that include processes analogous to those known in
the chemical arts, particularly in light of the description
contained herein. The starting materials are generally available
from commercial sources such as Aldrich Chemicals (Milwaukee, Wis.)
or are readily prepared using methods well known to those skilled
in the art (e.g., prepared by methods generally described in Louis
F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19,
Wiley, N.Y. (1967-1999 ed.), or Beilsteins Handbuch der organischen
Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including supplements
(also available via the Beilstein online database)).
[0098] For illustrative purposes, the reaction schemes depicted
below provide potential routes for synthesizing the compounds of
the present invention as well as key intermediates. For a more
detailed description of the individual reaction steps, see the
Examples section. Those skilled in the art will appreciate that
other synthetic routes may be used to synthesize the inventive
compounds. Although specific starting materials and reagents are
depicted in the schemes and discussed below, other starting
materials and reagents can be easily substituted to provide a
variety of derivatives and/or reaction conditions. In addition,
many of the compounds prepared by the methods described below can
be further modified in light of this disclosure using conventional
chemistry well known to those skilled in the art. For example, a
sulfide linkage (i.e., W.dbd.S) can be easily oxidized to its
corresponding sulfinyl or sulfonyl group (i.e., W.dbd.SO or
SO.sub.2) using common oxidation procedures (e.g., oxidation with
m-chloroperbenzoic acid).
[0099] In the preparation of compounds of the present invention,
protection of remote functionality (e.g., primary or secondary
amine) of intermediates may be necessary. The need for such
protection will vary depending on the nature of the remote
functionality and the conditions of the preparation methods.
Suitable amino-protecting groups (NH-Pg) include acetyl,
trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz)
and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such
protection is readily determined by one skilled in the art. For a
general description of protecting groups and their use, see T. W.
Greene, Protective Groups in Organic Synthesis, John Wiley &
Sons, New York, 1991.
[0100] Scheme I illustrates the preparation of compounds of the
present invention where W is O, S, amino or
(C.sub.1-C.sub.4)alkylamino. 6
[0101] Reaction of the di-halogen substituted heteroaryl compound
of Formula II with a compound of Formula III (R.sup.4 may
optionally be an amino-protecting group) in a suitable solvent
(e.g., ethanol, t-butanol, n-butanol, toluene, dioxane, THF, DMF,
or acetonitrile) in the presence of a suitable base (e.g., sodium
carbonate, potassium carbonate, cesium carbonate, sodium hydroxide
(NaOH), potassium hydroxide, 1,8-diazabicyclo-[5.4.0]undec-7-ene
(DBU), triethylamine (TEA) or pyridine) at about 25.degree. C. to
about 200.degree. C. for about 1 to about 168 hours gives
intermediate IV. Treatment of intermediate IV with an excess of the
appropriate amine in a solvent (e.g., EtOH, t-BuOH, dioxane, THF or
DMF) in the presence of a suitable base (e.g., sodium carbonate,
potassium carbonate, cesium carbonate, NaOH, sodium hydride, DBU,
TEA or pyridine) at about 25.degree. C. to about 200.degree. C. for
about 1 to about 7 days produces intermediate V wherein W is an
amino linking group or a (C.sub.1-C.sub.4)alkyl substituted amino
linking group. Suitable amines include benzylamine, 3-chlorobenzyl
amine, 3-fluorobenzyl amine, and the like.
[0102] Alternatively, intermediate IV may be reacted with an anion
of an appropriate alcohol or thiol in a solvent (e.g., THF,
toluene, dioxane, DMF, benzene, or a mixture of benzene and water)
with or without a catalyst such as 18-crown-6 at about 25.degree.
C. to about 200.degree. C. for about 1 to about 48 hours to yield
compounds of formula V wherein W is O or S. The anion may be
obtained by treatment of the corresponding alcohol or thiol with a
base (e.g., potassium carbonate, sodium hydride, sodium hydroxide,
potassium hydroxide, potassium t-butoxide, or sodium metal) in an
inert solvent (e.g., toluene, dioxane, DMF, THF, or benzene) at
about 25.degree. C. to about 200.degree. C. for about 1 to about 24
hours.
[0103] Suitable alcohols include benzyl alcohol, .alpha.-phenethyl
alcohol, .beta.-phenethyl alcohol, 3-fluoro-benzyl alcohol,
3-chloro-benzyl alcohol, 3-methoxybenzyl alcohol, 2-chlorobenzyl
alcohol, 3-fluoro-.alpha.-phenethyl alcohol,
2-chloro-.alpha.-phenethyl alcohol, 3-chloro-.alpha.-phenethyl
alcohol, 2,5-difluorobenzyl alcohol, 2,5-dichlorobenzyl alcohol,
3,5-difluorobenzyl alcohol, 3,5-dichlorobenzyl alcohol,
2-hydroxymethyl pyridine, 2-hydroxymethyl-6-chloro-pyridine,
2-hydroxymethyl-6-methyl-pyridine, and the like.
[0104] Suitable thiols include, .alpha.-toluenethiol,
(2-methylphenyl)methanethiol, 3-(trifluoromethyl
)-.alpha.-toluenethiol, 2-chloro-.alpha.-toluenethiol,
(3-methylphenyl)-methanethiol, 2-chloro-6-fluorobenzylmercaptan,
o-fluorobenzyl mercaptan, m-chlorobenzyl mercaptan,
2,4,6-trimethylbenzyl mercaptan, and the like.
[0105] The sulfide linkage can be oxidized to the corresponding
sulfinyl or sulfonyl using standard oxidation procedures well known
to those skilled in the art.
[0106] When R.sup.4 is an amino-protecting group, intermediate V is
deprotected to give the amine VI. For example, a BOC protected
amine may be deprotected by treatment with trifluoroacetic acid
(TFA) in CH.sub.2Cl.sub.2. The secondary amine VI may be acylated
or converted to a carbamate according to methods well known to
those skilled in the art. Alternatively, the secondary amine VI can
be alkylated to the amine VII by methods well known to those
skilled in the art. A preferred method is reductive alkylation.
Generally, reductive alkylation reactions convert intermediate VI
into a Schiff base by reaction with the desired aldehyde or ketone
in a polar solvent at a temperature from about 10.degree. C. to
about 140.degree. C. for about 2 to about 24 hours in the presence
of 3 .ANG. molecular sieves. Typically, an equivalent or a slight
excess of the aldehyde or ketone is added to the amine. Suitable
polar solvents include methylene chloride, 1,2-dichloroethane,
dimethylsulfoxide, dimethylformamide, alcohols (e.g., methanol or
ethanol), or mixtures thereof. A preferred solvent is methanol. In
the same reaction vessel, the imine is then reduced to the tertiary
amine in the presence of a reducing agent at a temperature from
about 0.degree. C. to about 10.degree. C. and then warmed to a
temperature from about 20.degree. C. to about 40.degree. C. for
about 30 minutes to about 2 hours. Suitable reducing agents include
pyridineeborane complex and metal borohydrides, such as sodium
borohydride, sodium triacetoxy borohydride and sodium
cyanoborohydride. Suitable aldehydes or ketones include
paraformaldehyde, acetaldehyde, acetone and the like.
[0107] In an alternate synthetic approach, intermediate V where W
is an amino or a (C.sub.1-C.sub.4)alkyl substituted amino linking
group may be prepared from IV with an amine or a
(C.sub.1-C.sub.4)alkyl substituted amino via metal-catalyzed
coupling reaction as described in Metal-Catalyzed Cross-Coupling
Reaction (Editors: F. Diederich, P. J. Stang; V C H, Weinheim,
1998). For example, treatment of the intermediate IV with an
appropriate amine in a suitable solvent (e.g, xylene, toluene, THF,
and dioxane) in the presence of a suitable base (e.g, sodium
t-butoxide, sodium bicarbonate, and potassium biocarbonate) and a
suitable phosphine ligand such as racemic
2,2'-bis(diphenylphosphino)-1,1- '-binaphthyl (BINAP),
triphenylphosphine, tri-t-butylphosphine or
2-dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl (AmPhos)
and a suitable palladium catalyst such as trisdibenzylideneacetone
dipalladium (Pd.sub.2(dba).sub.3) or palladium chloride at about
25.degree. C. to about 200.degree. C. for about 1 to about 24 hours
gives compound of formula V wherein W is an amine linking group.
The ratio of palladium to phosphine ligand is typically between
about 1:1 and about 1:5. Typically, about 0.01 to about 0.3
equivalent of catalyst is used relative to starting IV.
[0108] Compounds wherein X and Z are CR, where one or both of the R
groups is not hydrogen, may be obtained via the appropriate
dihalide II. For example, compounds where one R.dbd.NH.sub.2 and
the other R.dbd.H may be obtained by employing
2-amino-3,5-dibromopyrazine as starting material. Alternatively,
these types of compounds may be obtained by functionalization of a
compound of the formula V, where X.dbd.Y.dbd.CH. These
functionalization reactions are well-known to those skilled in the
art, and include electrophilic aromatic substitution reactions,
such as halogenations (e.g., chlorinations, brominations, and
fluorinations). These reactions can produce both of the two
possible monohalogenated compounds, as well as the dihalogenated
compounds, which are easily separated by common purification
methods, such as chromatography. For example, a compound of formula
V, where X.dbd.Y.dbd.CH and R.sup.4 is a nitrogen protecting group
in an inert solvent (e.g., acetonitrile, chloroform,
dichloromethane or THF) is reacted with a suitable electrophilic
halogenating agent, such as N-chlorosuccinamide,
N-bromosuccinamide, bromine, chlorine or Selecffluor.TM. at a
temperature of about -78 .degree. C. to about 100 .degree. C. for
about 1 hour to about 24 h gives mixtures of the two possible
monohalogenated compounds and the dihalogenated compound. The
relative amounts of each of these can vary depending on the
particular case.
[0109] The brominated pyrazine compounds described above can be
transformed to a variety of other derivatives by methods known to
those skilled in the art. Conveniently, they can be transformed to
alkyl derivatives via a palladium-catalyzed reaction, such as the
Suzuki reaction employing alkyl boronic acids or a derivative
thereof. For example, reaction of a brominated pyrazine with an
alkylboronic acid in the presence of a suitable palladium catalyst,
a suitable ligand, such as AmPhos or BINAP, a base, such as sodium
tert-butoxide, K.sub.3PO.sub.4, or CsCO.sub.3, in a suitable
solvent, such as toluene, THF and dioxane, at a temperature of
about 25.degree. C. to about 110.degree. C. for about 3 h to about
24 h.
[0110] Alternatively, Compound VII can be prepared according to
Scheme II below. 7
[0111] Intermediate VIII is prepared by reacting the di-halogen
substituted heteroaryl compound II with one equivalent of an
appropriate alcohol, thiol or amine using aromatic nucleophilic
substitution conditions described in Scheme 1 above. Intermediate
VIII is converted to intermediate V by reaction with piperazine III
using aromatic nucleophilic substitution conditions or
palladium-catalyzed coupling reaction conditions as described in
Scheme 1. Compound V can then be converted to compound VI and
compound VII according to the procedures described above in Scheme
1.
[0112] Compounds of the present invention where W is an amino
linking group (NH) or alkylamino linking group can also be prepared
by reductive alkylation of an amino group attached to the pyrazine
ring as illustrated in Scheme III below. The synthetic procedures
are analogous to those described above for the reductive alkylation
of intermediate VI in Scheme I. 8
[0113] The compound of Formula IX can be converted to the benzyl
amine XI by methods well known in the art. A preferred method is
reductive alkylation as described earlier in Scheme I where a
Schiff base is formed with intermediate X and then reduced with an
appropriate reducing agent. Suitable aldehydes and ketones (i.e.,
compound of Formula X) include 3-chlorobenzaldehyde,
3-fluorobenzaldehyde, m-chloroacetophenone, m-chloropropiophenone,
o-chloroacetophenone, 2-fluorobenzaldehyde, 2-chlorobenzaldehyde,
2,6-dichlorobenzaldehyde, 2,5-dichloroacetophenone,
2-chloro-5-methylacetophenone, 2,5-difluoroacetophenone,
2,5-difluoropropiophenone, 2,3-dichlorobenzaldehyde,
2,3-difluorobenzaldehyde, 2,5-difluorobenzaldehyde,
2-chloro-5-fluoroacetophenone, 5-chloro-2-methoxybenzaldehyde,
2-fluoro-5-methoxybenzaldehyde, 2,5-dichlorobenzaldehyde,
3,5-dichlorobenzaldehyde, 3,5-dichloroacetophenone,
3,5-difluorobenzaldehyde, 2,3,5-trifluorobenzaldehyde,
2,3,5-trifluoroacetophenone, 2,3,5-trifluoropropiophenone,
2,3,5-trichlorobenzaldehyde, 2,3,6-trifluorobenzaldehyde, and the
like. Treatment of the resultant compound of Formula XI with
piperazine III in a suitable solvent (e.g., ethanol, t-butanol,
n-butanol, toluene, dioxane, THF, DMF or acetonitrile) in the
presence of a suitable base (e.g., sodium carbonate, potassium
carbonate, sodium hydroxide, TEA, DBU, or pyridine) at about
25.degree. to about 200.degree. C. for about 1 day to about seven
days gives compounds of the Formula XII.
[0114] Compound XII may be oxidized to an N-oxide by reacting XII
with a suitable oxidizing agent, such as a peracid, for example,
m-chloroperbenzoic acid (mCPBA) in a suitable solvent, such as
chloroform or dichloromethane at a temperature of about -78.degree.
C. to about 65.degree. C., for about 2 h to about 24 h. Other
useful methods of carrying out this oxidation are well-known to
those skilled in the art.
[0115] Scheme IV below illustrates an alternative synthetic route
for the synthesis of Compound XVII (same as compound VI wherein W
is an amine linking group). 9
[0116] Compound II is reacted with an appropriate BOC protected
amine in the presence of a base, such as sodium hydride in DMF to
afford intermediate XV. The BOC protected amine may be obtained by
treatment of the corresponding amine with di-tert-butyl dicarbonate
in CH.sub.2Cl.sub.2 or THF. Treatment of XV with III using aromatic
nucleophilic substitution conditions or palladium-catalyzed
coupling conditions as described in Scheme 1 provides XVI.
Deprotection of compound XVI with hydrochloride or trifluoroacetic
acid in CH.sub.2Cl.sub.2 or THF (as described above) provides the
desired product XVII.
[0117] Scheme V below illustrates how to synthesize compounds of
the present invention where W is an acetylamine. 10
[0118] Acylation of XVIII with acetic anhydride in acetic acid
gives acylated product XIX. Reaction of XIX with III wherein
R.sup.4 is BOC using aromatic nucleophilic substitution conditions
or palladium-catalyzed coupling conditions as described in Scheme 1
above affords XX. Alkylation of XX with an appropriate alkylhalide
in the presence of sodium hydride in DMF provides XXI. Deprotection
of XXI with HCI or TFA in CH.sub.2Cl.sub.2 or THF as described
above yields XXII.
[0119] Conventional methods and/or techniques of separation and
purification known to one of ordinary skill in the art can be used
to isolate the compounds of the present invention, as well as the
various intermediates related thereto. Such techniques will be
well-known to one of ordinary skill in the art and may include, for
example, all types of chromatography (high pressure liquid
chromatography (HPLC), column chromatography using common
adsorbents such as silica gel, and thin-layer chromatography),
recrystallization, and differential (i.e., liquid-liquid)
extraction techniques.
[0120] The compounds of the present invention may be isolated and
used per se or in the form of its pharmaceutically acceptable salt,
solvate and/or hydrate. The term "salts" refers to inorganic and
organic salts of a compound of the present invention. These salts
can be prepared in situ during the final isolation and purification
of a compound, or by separately reacting the compound, N-oxide, or
prodrug with a suitable organic or inorganic acid and isolating the
salt thus formed. Representative salts include the hydrobromide,
hydrochloride, hydroiodide, sulfate, bisulfate, nitrate, acetate,
trifluoroacetate, oxalate, besylate, palmitiate, pamoate, malonate,
stearate, laurate, malate, borate, benzoate, lactate, phosphate,
hexafluorophosphate, benzene sulfonate, tosylate, formate, citrate,
maleate, fumarate, succinate, tartrate, naphthylate, mesylate,
glucoheptonate, lactobionate, and laurylsulphonate salts, and the
like. Preferred salts include hydrochloride, fumarate, citrate,
L-malate, and D,L-tartrate, more preferred salts include citrate,
L-malate, and D,L-tartrate. These may include cations based on the
alkali and alkaline earth metals, such as sodium, lithium,
potassium, calcium, magnesium, and the like, as well as non-toxic
ammonium, quaternary ammonium, and amine cations including, but not
limited to, ammonium, tetramethylammonium, tetraethylammonium,
methylamine, dimethylamine, trimethylamine, triethylamine,
ethylamine, and the like. See, e.g., Berge, et al., J. Pharm. Sci.,
66, 1-19 (1977).
[0121] The term "nitrogen oxide" or "N-oxide" refers to the
oxidation of at least one of the nitrogen atoms in the pyrazine
ring. Oxidation of aromatic nitrogens is well known in the art.
Typical oxidizing agents include reagents such as hydrogen
peroxide, trifluoroperacetic acid, m-chloroperbenzoic acid and the
like. In general, the oxidation is accomplished in an inert solvent
(e.g., methylene chloride or chloroform). The position of the
N-oxidation may vary depending upon the steric hinderance from
substituents on an adjacent carbon atom. The N-oxide or mixture of
N-oxides can be isolated or separated using conventional procedures
such as liquid chromatography and/or selective crystallization.
[0122] The term "prodrug" means a compound that is transformed in
vivo to yield a compound of Formula (IA, IB or IC) or a
pharmaceutically acceptable salt, hydrate or solvate of the
compound. The transformation may occur by various mechanisms, such
as through hydrolysis in blood. A discussion of the use of prodrugs
is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel
Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in
Bioreversible Carriers in Drug Design, ed. Edward B. Roche,
American Pharmaceutical Association and Pergamon Press, 1987.
[0123] For example, if a compound of the present invention contains
a carboxylic acid functional group, a prod rug can comprise an
ester formed by the replacement of the hydrogen atom of the acid
group with a group such as (C.sub.1-C.sub.8)alkyl,
(C.sub.2-C.sub.12)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having
from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having
from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to
6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7
carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to
8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9
carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10
carbon atoms, 3-phthalidyl, 4-crotonolactonyl,
gamma-butyrolacton-4-yl, di-N,
N-(C.sub.1-C.sub.2)alkylamino(C.sub.2-C.sub.3)alkyl (such as
.beta.-dimethylaminoethyl), carbamoyl-(C.sub.1-C.sub.2)alkyl,
N,N-di(C.sub.1-C.sub.2)alkylcarbamoyl-(C.sub.1-C.sub.2)alkyl and
piperidino-, pyrrolidino- or morpholino(C.sub.2-C.sub.3)alkyl.
[0124] Similarly, if a compound of the present invention contains
an alcohol functional group, a prodrug can be formed by the
replacement of the hydrogen atom of the alcohol group with a group
such as (C.sub.1-C.sub.6)alkanoyloxymethyl,
1-((C.sub.1-C.sub.6)alkanoyloxy)ethyl- ,
1-methyl-1-((C.sub.1-C.sub.6)alkanoyloxy)ethyl,
(C.sub.1-C.sub.6)alkoxyc- arbonyloxymethyl,
N-(C.sub.1-C.sub.6)alkoxycarbonylaminomethyl, succinoyl,
(C.sub.1-C.sub.6)alkanoyl, .alpha.-amino(C.sub.1-C.sub.4)alkanoyl,
arylacyl and .alpha.-aminoacyl, or
.alpha.-aminoacyl-.alpha.-aminoacyl, where each .alpha.-aminoacyl
group is independently selected from the naturally occurring
L-amino acids, P(O)(OH).sub.2,
--P(O)(O(C.sub.1-C.sub.6)alkyl).sub.2 or glycosyl (the radical
resulting from the removal of a hydroxyl group of the hemiacetal
form of a carbohydrate).
[0125] If a compound of the present invention incorporates an amine
functional group, a prodrug can be formed by the replacement of a
hydrogen s atom in the amine group with a group such as R-carbonyl,
RO-carbonyl, NRR'-carbonyl where R and R' are each independently
(C.sub.1-C.sub.10)alkyl, (C.sub.3-C.sub.7)cycloalkyl, benzyl, or
R-carbonyl is a natural .alpha.-aminoacyl or natural
.alpha.-aminoacyl-natural .alpha.-aminoacyl, --C(OH)C(O)OY' wherein
Y' is H, (C.sub.1-C.sub.6)alkyl or benzyl, --C(OY.sub.0)Y.sub.1
wherein Y.sub.0 is (C.sub.1-C.sub.4) alkyl and Y.sub.1 is
(C.sub.1-C.sub.6)alkyl, carboxy(C.sub.1-C.sub.6)alkyl,
amino(C.sub.1-C.sub.4)alkyl or mono-N- or
di-N,N-(C.sub.1-C.sub.6)alkylaminoalkyl, --C(Y.sub.2)Y.sub.3
wherein Y.sub.2 is H or methyl and Y.sub.3 is mono-N- or
di-N,N-(C.sub.1-C.sub.6)- alkylamino, morpholino, piperidin-1-yl or
pyrrolidin-1-yl.
[0126] The compounds of the present invention may contain
asymmetric or chiral centers, and, therefore, exist in different
stereoisomeric forms. It is intended that all stereoisomeric forms
of the compounds of the present invention as well as mixtures
thereof, including racemic mixtures, form part of the present
invention. In addition, the present invention embraces all
geometric and positional isomers. For example, if a compound of the
present invention incorporates a double bond or a fused ring, both
the cis- and trans- forms, as well as mixtures, are embraced within
the scope of the invention. Both the single positional isomers and
mixture of positional isomers resulting from the N-oxidation of the
pyrimidine and pyrazine rings are also within the scope of the
present invention.
[0127] Diastereomeric mixtures can be separated into their
individual diastereoisomers on the basis of their physical chemical
differences by methods well known to those skilled in the art, such
as by chromatography and/or fractional crystallization. Enantiomers
can be separated by converting the enantiomeric mixture into a
diastereomeric mixture by reaction with an appropriate optically
active compound (e.g., chiral auxiliary such as a chiral alcohol or
Mosher's acid chloride), separating the diastereoisomers and
converting (e.g., hydrolyzing) the individual diastereoisomers to
the corresponding pure enantiomers. Also, some of the compounds of
the present invention may be atropisomers (e.g., substituted
biaryls) and are considered as part of this invention. Enantiomers
can also be separated by use of a chiral HPLC column.
[0128] The compounds of the present invention may exist in
unsolvated as well as solvated forms with pharmaceutically
acceptable solvents such as water, ethanol, and the like, and it is
intended that the invention embrace both solvated and unsolvated
forms.
[0129] It is also possible that the compounds of the present
invention may exist in different tautomeric forms, and all such
forms are embraced within the scope of the invention. For example,
all of the tautomeric forms of the imidazole moiety are included in
the invention. Also, for example, all ketoenol and imine-enamine
forms of the compounds are included in the invention.
[0130] The present invention also embraces isotopically-labeled
compounds of the present invention which are identical to those
recited herein, but for the fact that one or more atoms are
replaced by an atom having an atomic mass or mass number different
from the atomic mass or mass number usually found in nature.
Examples of isotopes that can be incorporated into compounds of the
invention include isotopes of hydrogen, carbon, nitrogen, oxygen,
phosphorus, fluorine and chlorine, such as .sup.2H, .sup.3H,
.sup.13C, .sup.14C, .sup.15N, .sup.18O, .sup.17O, .sup.31P,
.sup.32P, .sup.35S, .sup.18F, and .sup.36Cl, respectively.
[0131] Certain isotopically-labeled compounds of the present
invention (e.g., those labeled with .sup.3H and .sup.14C) are
useful in compound and/or substrate tissue distribution assays.
Tritiated (i.e., .sup.3H) and carbon-14 (i.e., .sup.14C) isotopes
are particularly preferred for their ease of preparation and
detectability. Further, substitution with heavier isotopes such as
deuterium (i.e., .sup.2H) may afford certain therapeutic advantages
resulting from greater metabolic stability (e.g., increased in vivo
half-life or reduced dosage requirements) and hence may be
preferred in some circumstances. Isotopically labeled compounds of
the present invention can generally be prepared by following
procedures analogous to those disclosed in the Schemes and/or in
the Examples hereinbelow, by substituting an isotopically labeled
reagent for a non-isotopically labeled reagent.
[0132] Compounds of the present invention are useful 5-HT.sub.2
partial agonists or antagonists (preferably 5-HT.sub.2a or
5-HT.sub.2c partial agonists or antagonists); therefore, another
embodiment of the present invention is a pharmaceutical composition
comprising a therapeutically effective amount of a compound of the
present invention and a pharmaceutically acceptable excipient,
diluent or carrier.
[0133] A typical formulation is prepared by mixing a compound of
the present invention and a carrier, diluent or excipient. Suitable
carriers, diluents and excipients are well known to those skilled
in the art and include materials such as carbohydrates, waxes,
water soluble and/or swellable polymers, hydrophilic or hydrophobic
materials, gelatin, oils, solvents, water, and the like. The
particular carrier, diluent or excipient used will depend upon the
means and purpose for which the compound of the present invention
is being applied. Solvents are generally selected based on solvents
recognized by persons skilled in the art as safe (GRAS) to be
administered to a mammal. In general, safe solvents are non-toxic
aqueous solvents such as water and other non-toxic solvents that
are soluble or miscible in water. Suitable aqueous solvents include
water, ethanol, propylene glycol, polyethylene glycols (e.g.,
PEG400, PEG300), etc. and mixtures thereof. The formulations may
also include one or more buffers, stabilizing agents, surfactants,
wetting agents, lubricating agents, emulsifiers, suspending agents,
preservatives, antioxidants, opaquing agents, glidants, processing
aids, colorants, sweeteners, perfuming agents, flavoring agents and
other known additives to provide an elegant presentation of the
drug (i.e., a compound of the present invention or pharmaceutical
composition thereof) or aid in the manufacturing of the
pharmaceutical product (i.e., medicament).
[0134] The formulations may be prepared using conventional
dissolution and mixing procedures. For example, the bulk drug
substance (i.e., compound of the present invention or stabilized
form of the compound (e.g., complex with a cyclodextrin derivative
or other known complexation agent)) is dissolved in a suitable
solvent in the presence of one or more of the excipients described
above. The compound of the present invention is typically
formulated into pharmaceutical dosage forms to provide an easily
controllable dosage of the drug and to give the patient an elegant
and easily handleable product.
[0135] The pharmaceutical composition (or formulation) for
application may be packaged in a variety of ways depending upon the
method used for administering the drug. Generally, an article for
distribution includes a container having deposited therein the
pharmaceutical formulation in an appropriate form. Suitable
containers are well-known to those skilled in the art and include
materials such as bottles (plastic and glass), sachets, ampoules,
plastic bags, metal cylinders, and the like. The container may also
include a tamper-proof assemblage to prevent indiscreet access to
the contents of the package. In addition, the container has
deposited thereon a label that describes the contents of the
container. The label may also include appropriate warnings.
[0136] The present invention further provides methods of treating
5-HT.sub.2 receptor-mediated diseases, conditions, or disorders in
an animal in need of such treatment that include administering to
the animal a therapeutically effective amount of a compound of the
present invention or a pharmaceutical composition comprising an
effective amount of a compound of the present invention and a
pharmaceutically acceptable excipient, diluent, or carrier. The
method is particularly useful for treating 5-HT.sub.2c
receptor-mediated diseases, conditions, or disorders. Preferably,
the compounds of the present invention act as a partial agonist at
the 5-HT.sub.2c receptor site. More preferably, the compounds of
the present invention act as a partial agonist the 5-HT.sub.2c
receptor site and as an antagonist at the 5-HT.sub.2a receptor
site.
[0137] Preferably, the 5-HT.sub.2 receptor-mediated disease,
condition, or disorder is selected from the group consisting of
weight loss (e.g., reduction in calorie intake), obesity, bulimia,
premenstrual syndrome or late luteal phase syndrome, depression,
atypical depression, bipolar disorders, psychoses, schizophrenia,
migraine, alcoholism, tobacco abuse, panic disorder, anxiety,
post-traumatic syndrome, memory loss, dementia of aging, social
phobia, attention deficit hyperactivity disorder, disruptive
behavior disorders, impulse control disorders, borderline
personality disorder, obsessive compulsive disorder, chronic
fatigue syndrome, sexual dysfunction in males (e.g., premature
ejaculation and erectile difficulty), sexual dysfunction in
females, anorexia nervosa, disorders of sleep (e.g., sleep apnea),
autism, seizure disorders, epilepsy, mutism, spinal cord injury,
damage of the central nervous system (e.g., trauma, stroke,
neurodegenerative diseases or toxic or infective CNS diseases
(e.g., encephalitis or meningitis)), cardiovascular disorders
(e.g., thrombosis), gastrointestinal disorders (e.g., dysfunction
of gastrointestinal motility), diabetes insipidus, and type II
diabetes. Accordingly, the compounds of the present invention
described herein are useful in treating or preventing 5-HT.sub.2
receptor-mediated diseases, conditions, or disorders. Consequently,
the compounds of the present invention (including the compositions
and processes used therein) may be used in the manufacture of a
medicament for the therapeutic applications described herein
[0138] The compounds of the present invention can be administered
to a patient at dosage levels in the range of from about 0.7 mg to
about 7,000 mg per day. For a normal adult human having a body
weight of about 70 kg, a dosage in the range of from about 0.01 mg
to about 100 mg per kilogram body weight is typically sufficient.
However, some variability in the general dosage range may be
required depending upon the age and weight of the subject being
treated, the intended route of administration, the particular
compound being administered and the like. The determination of
dosage ranges and optimal dosages for a particular patient is well
within the ability of one of ordinary skill in the art having the
benefit of the instant disclosure. It is also noted that the
compounds of the present invention can be used in sustained
release, controlled release, and delayed release formulations,
which forms are also well known to one of ordinary skill in the
art.
[0139] The compounds of this invention may also be used in
conjunction with other pharmaceutical agents for the treatment of
the diseases/conditions described herein. Therefore, methods of
treatment that include administering compounds of the present
invention in combination with other pharmaceutical agents are also
provided. Suitable pharmaceutical agents that may be used in
combination with the compounds of the present invention include
anti-obesity agents such as apolipoprotein-B secretion/microsomal
triglyceride transfer protein (apo-B/MTP) inhibitors, MCR-4
agonists, cholecystokinin-A (CCK-A) agonists, monoamine reuptake
inhibitors (such as sibutramine), sympathomimetic agents,
.beta..sub.3 adrenergic receptor agonists, dopamine agonists (such
as bromocriptine), melanocyte-stimulating hormone receptor analogs,
cannabinoid 1 receptor antagonists, melanin concentrating hormone
antagonists, leptins (the OB protein), leptin analogs, leptin
receptor agonists, galanin antagonists, lipase inhibitors (such as
tetrahydrolipstatin, i.e. orlistat), anorectic agents (such as a
bombesin agonist), Neuropeptide-Y antagonists, thyromimetic agents,
dehydroepiandrosterone or an analog thereof, glucocorticoid
receptor agonists or antagonists, orexin receptor antagonists,
urocortin binding protein antagonists, glucagon-like peptide-1
receptor agonists, ciliary neurotrophic factors (such as
Axokine.TM. available from Regeneron Pharmaceuticals, Inc.,
Tarrytown, N.Y. and Procter & Gamble Company, Cincinnati,
Ohio), human agouti-related proteins (AGRP), ghrelin receptor
antagonists, histamine 3 receptor antagonists or reverse agonists,
and neuromedin U receptor agonists. Other anti-obesity agents,
including the preferred agents set forth hereinbelow, are well
known, or will be readily apparent in light of the instant
disclosure, to one of ordinary skill in the art.
[0140] Especially preferred are anti-obesity agents selected from
the group consisting of orlistat, sibutramine, bromocriptine,
ephedrine, leptin, and pseudoephedrine. Preferably, compounds of
the present invention and combination therapies are administered in
conjunction with exercise and a sensible diet.
[0141] Representative anti-obesity agents for use in the
combinations, pharmaceutical compositions, and methods of the
invention can be prepared using methods known to one of ordinary
skill in the art, for example, sibutramine can be prepared as
described in U.S. Pat. No. 4,929,629; bromocriptine can be prepared
as described in U.S. Pat. Nos. 3,752,814 and 3,752,888; and
orlistat can be prepared as described in U.S. Pat. Nos. 5,274,143;
5,420,305; 5,540,917; and 5,643,874. All of the above recited U.S.
patents are incorporated herein by reference.
[0142] The dosage of the additional pharmaceutical agent (e.g.,
anti-obesity agent) will also be generally dependent upon a number
of factors including the health of the subject being treated, the
extent of treatment desired, the nature and kind of concurrent
therapy, if any, and the frequency of treatment and the nature of
the effect desired. In general, the dosage range of an anti-obesity
agent is in the range of from about 0.001 mg to about 100 mg per
kilogram body weight of the individual per day, preferably from
about 0.1 mg to about 10 mg per kilogram body weight of the
individual per day. However, some variability in the general dosage
range may also be required depending upon the age and weight of the
subject being treated, the intended route of administration, the
particular anti-obesity agent being administered and the like. The
determination of dosage ranges and optimal dosages for a particular
patient is also well within the ability of one of ordinary skill in
the art having the benefit of the instant disclosure.
[0143] In another embodiment of the present invention, the
compounds of the present invention have been found to be useful in
the treatment of sexual dysfunction. Sexual dysfunction (SD) is a
significant clinical problem, which can affect both males and
females. The causes of SD may be both organic as well as
psychological. Organic aspects of SD are typically caused by
underlying vascular diseases, such as those associated with
hypertension or diabetes mellitus, by prescription medication
and/or by psychiatric disease such as depression. Physiological
factors include fear, performance anxiety and interpersonal
conflict. SD impairs sexual performance, diminishes self-esteem and
disrupts personal relationships thereby inducing personal distress.
In the clinic, SD disorders have been divided into female sexual
dysfunction (FSD) disorders and male sexual dysfunction (MSD)
disorders (Melman et al 1999). FSD is best defined as the
difficulty or inability of a woman to find satisfaction in sexual
expression. Male sexual dysfunction (MSD) is generally associated
with erectile dysfunction, also known as male erectile dysfunction
(MED) (Benet et al 1994--Male Erectile dysfunction assessment and
treatment options. Comp. Ther. 20: 669-673.).
[0144] The compounds of the invention are particularly beneficial
for the prophylaxis and/or treatment of sexual dysfunction in the
male (e.g. male erectile dysfunction--MED) and in the
female--female sexual dysfunction (FSD), e.g. female sexual arousal
disorder (FSAD).
[0145] It is known that some individuals can suffer from male
erectile dysfunction (MED). MED is defined as: "the inability to
achieve and/or maintain a penile erection for satisfactory sexual
performance" (NIH Consensus Development Panel on Impotence,
1993)"
[0146] It has been estimated that the prevalence of erectile
dysfunction (ED) of all degrees (minimal, moderate and complete
impotence) is 52% in men 40 to 70 years old, with higher rates in
those older than 70 (Melman,A. & Gingell, J. C. (1999). The
epidemiology and pathophysiology of erectile dysfunction. J.
Urology 161: 5-11). The condition has a significant negative impact
on the quality of life of the patient and their partner, often
resulting in increased anxiety and tension which leads to
depression and low self esteem. Whereas two decades ago, MED was
primarily considered to be a psychological disorder (Benet, A. E.
et al (1994), Male erectile dysfunction assessment and treatment
options. Comp. Ther. 20: 669-673), it is now known that for the
majority of patients there is an underlying organic cause. As a
result, much progress has been made in identifying the mechanism of
normal penile erection and the pathophysiology of MED.
[0147] Penile erection is a haemodynamic event which is dependent
upon the balance of contraction and relaxation of the corpus
cavernosal smooth muscle and vasculature of the penis (Lerner, S.
E. et al (1993). A review of erectile dysfunction: new insights and
more questions. J. Urology 149: 1246-1255). Corpus cavernosal
smooth muscle is also referred to herein as corporal smooth muscle
or in the plural sense corpus cavernosa. Relaxation of the corpus
cavernosal smooth muscle leads to an increased blood flow into the
trabecular spaces of the corpus cavernosa, causing them to expand
against the surrounding tunica and compress the draining veins.
This produces a vast elevation in blood pressure which results in
an erection (Naylor, A. M. (1998). Endogenous neurotransmitters
mediating penile erection. Br. J. Urology 81: 424-431).
[0148] The changes that occur during the erectile process are
complex and require a high degree of co-ordinated control involving
the peripheral and central nervous systems, and the endocrine
system (Naylor, 1998). Corporal smooth muscle contraction is
modulated by sympathetic noradrenergic innervation via activation
of postsynaptic .alpha..sub.1 adrenoceptors. MED may be associated
with an increase in the endogenous smooth muscle tone of the corpus
cavernosum. However, the process of corporal smooth muscle
relaxation is mediated partly by non-adrenergic, non-cholinergic
(NANC) neurotransmission. There are a number of other NANC
neurotransmitters found in the penis, other than NO, such as
calcitonin gene related peptide (CGRP) and vasoactive intestinal
peptide (VIP). The main relaxing factor responsible for mediating
this relaxation is nitric oxide (NO), which is synthesised from
L-arginine by nitric oxide synthase (NOS) (Taub, H. C. et al
(1993). Relationship between contraction and relaxation in human
and rabbit corpus cavernosum. Urology 42: 698-704). It is thought
that reducing corporal smooth muscle tone may aid NO to induce
relaxation of the corpus cavernosum. During sexual arousal in the
male, NO is released from neurones and the endothelium and binds to
and activates soluble guanylate cyclase (sGC) located in the smooth
muscle cells and endothelium, leading to an elevation in
intracellular cyclic guanosine 3',5'-monophosphate (cGMP) levels.
This rise in CGMP leads to a relaxation of the corpus cavernosum
due to a reduction in the intracellular calcium concentration
([Ca.sup.2+].sub.i), via unknown mechanisms thought to involve
protein kinase G activation (possibly due to activation of
Ca.sup.2+ pumps and Ca.sup.2+-activated K.sup.+ channels).
[0149] The categories of female sexual dysfunction (FSD) are best
defined by contrasting them to the phases of normal female sexual
response: desire, arousal and orgasm (see S R Leiblum, (1998),
Definition and Classification of Female Sexual Disorders, Int. J.
Impotence Res., 10, S104-S106). Desire or libido is the drive for
sexual expression. Its manifestations often include sexual thoughts
either when in the company of an interested partner or when exposed
to other erotic stimuli. Arousal includes the vascular response to
sexual stimulation, an important component of which is genital
engorgement and increased vaginal lubrication, elongation of the
vagina and increased genital sensation/sensitivity and a subjective
excitement response. Orgasm is the release of sexual tension that
has culminated during arousal. Hence, FSD occurs when a woman has
an absent, inadequate or unsatisfactory response in any one or more
of these phases, usually desire, arousal or orgasm.
[0150] The American Psychiatric Association classifies female
sexual dysfunction (FSD) into four classes: FSAD, hypoactive sexual
desire disorder (HSDD), female orgasmic disorder (FOD), and sexual
pain disorders (e.g. dyspareunia and vaginismus) [see the American
Psychiatric Association's Diagnostic and Statistical Manual of
Mental Disorders, 4th Edition (DSM-IV)].
[0151] DSM-IV defines the four classes as follows:
[0152] HSDD--Persistently or recurrently deficient (or absent)
sexual fantasies and desire for sexual activity. The judgement of
deficiency or absence is made by the clinician, taking into account
factors that affect functioning, such as age and the context of the
persons life.
[0153] FSAD--Persistent or recurrent inability to attain, or to
maintain until completion of the sexual activity, an adequate
lubrication-swelling response of sexual excitement.
[0154] FOD--Persistent or recurrent delay in, or absence of, orgasm
following a normal sexual excitement phase. Women exhibit wide
variability in the type or intensity of stimulation that triggers
orgasm. The diagnosis of FOD should be based on the clinician's
judgement that the woman's orgasmic capacity is less than would be
reasonable for her age, sexual experience, and the adequacy of the
sexual stimulation she receives.
[0155] Sexual Pain Disorders such as Dyspareunia and Vaginismus.
Dysparenuia--Recurrent or persistent genital pain associated with
sexual intercourse. Vaginismus--Recurrent or persistent involuntary
spasm of the musculature of the outer third of the vagina that
interferes with sexual intercourse.
[0156] HSDD is present if a woman has no or little desire to be
sexual, and has no or few sexual thoughts or fantasies. This type
of FSD can be caused by low testosterone levels, due either to
natural menopause or to surgical menopause. Other causes in both
pre-menopausal woman (i.e. woman who are pre-menopausal and who
have not have hysterectomies) as well as post-menopausal women
include illness, medications, fatigue, depression and/or anxiety.
Factors having a potential (conscious or sub-conscious)
psychological impact such as relationship difficulties or religious
factors may be related to the presence of/development of HSDD in
females. The Diagnostic and Statistical Manual (DSM) IV of the
American Psychiatric Association defines Female Sexual Arousal
Disorder (FSAD) as being: ". . . a persistent or recurrent
inability to attain or to maintain until completion of the sexual
activity adequate lubrication-swelling response of sexual
excitement. The disturbance must cause marked distress or
interpersonal difficulty. . . .".
[0157] The arousal response consists of vasocongestion in the
pelvis, vaginal lubrication and expansion and swelling of the
external genitalia. The disturbance causes marked distress and/or
interpersonal difficulty.
[0158] FSAD is a highly prevalent sexual disorder affecting pre-,
per- and post-menopausal (.+-. hormone replacement therapy (HRT))
women. It is associated with concomitant disorders such as
depression, cardiovascular diseases, diabetes and urogenital (UG)
disorders. The primary consequences of FSAD are lack of
engorgement/swelling, lack of lubrication and lack of pleasurable
genital sensation. The secondary consequences of FSAD are reduced
sexual desire, pain during intercourse and difficulty in achieving
an orgasm. It has recently been hypothesised that there is a
vascular basis for at least a proportion of patients with symptoms
of FSAD (Goldstein etal., Int. J. Impot. Res., 10, S84-S90,1998)
with animal data supporting this view (Park et al., Int. J. Impot.
Res., 9, 27-37, 1997).
[0159] Drug candidates for treating FSAD, which are under
investigation for efficacy, are primarily erectile dysfunction
therapies that promote circulation to male genitalia. They consist
of two types of formulation, oral or sublingual medications
(Apomorphine, Phentolamine, phosphodiesterase type 5 (PDE5)
inhibitors, e.g. Sildenafil), and prostaglandin (PGE.sub.1) that
are injected or administered transurethrally in men and topically
to the genitalia in women.
[0160] The compounds of the present invention are advantageous by
providing a means for restoring a normal sexual arousal
response--namely increased genital blood flow leading to vaginal,
clitoral and labial engorgement. This will result in increased
vaginal lubrication via plasma transudation, increased vaginal
compliance and increased genital sensitivity. Hence, the present
invention provides a means to restore, or potentiate, the normal
sexual arousal response.
[0161] By female genitalia herein we mean: "The genital organs
consist of an internal and external group. The internal organs are
situated within the pelvis and consist of ovaries, the uterine
tubes, uterus and the vagina. The external organs are superficial
to the urogenital diaphragm and below the pelvic arch. They
comprise the mons pubis, the labia majora and minora pudendi, the
clitoris, the vestibule, the bulb of the vestibule, and the greater
vestibular glands" (Gray's Anatomy, C. D. Clemente, 13th American
Edition). R. J. Levin teaches us that because ". . . male and
female genitalia develop embryologically from the common tissue
anlagen, [that] male and female genital structures are argued to be
homologues of one another. Thus the clitoris is the penile
homologue and the labia homologues of the scrotal sac. . . ."
(Levin, R. J. (1991), Exp. Clin. Endocrinol., 98, 61-69).
[0162] In summary, FSAD is characterised by inadequate genital
response to sexual stimulation. The genitalia do not undergo the
engorgement that characterises normal sexual arousal. The vaginal
walls are poorly lubricated, so that intercourse is painful.
Orgasms may be impeded. Arousal disorder can be caused by reduced
oestrogen at menopause or after childbirth and during lactation, as
well as by illnesses, with vascular components such as diabetes and
atherosclerosis. Other causes result from treatment with diuretics,
antihistamines, antidepressants e.g. selective serotonin reuptake
inhibitors (SSRIs) or antihypertensive agents.
[0163] FOD is the persistent or recurrent difficulty, delay in or
absence of attaining orgasm following sufficient sexual stimulation
and arousal, which causes personal distress.
[0164] Sexual pain disorders (includes dyspareunia and vaginismus)
are characterised by pain resulting from penetration and sexual
activity and may be caused by medications which reduce lubrication,
endometriosis, pelvic inflammatory disease, inflammatory bowel
disease or urinary tract problems.
[0165] According to a further aspect, the present invention
additionally provides a method for the treatment and/or prevention
of male sexual dysfunction (MSD), in particular male erectile
dysfunction (MED) via treatment with a compound of the present
invention as detailed hereinbefore. Particularly preferred for the
treatment of MED as detailed herein is
6'-(3-Chloro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl-
.
[0166] According to a yet further aspect, the present invention
additionally provides a method for the treatment and/or prevention
of male sexual dysfunction via treatment with a combination of a
compound of the present invention as defined hereinbefore and one
or more compounds which inhibit the activity of PDE, in particular
compounds which inhibit the activity of cGMP PDE5, and/or one or
more compounds which inhibit the activity of NEP.
[0167] Men who display an insufficient response or lack of response
to treatment with Viagra.TM. may benefit either from therapy based
on treatment with compounds of the present invention alone or via
combination therapy based on compound(s) of the present invention
and a cGMP PDE5i, such as for example sildenafil. Patients with
mild to moderate MED should benefit from combined treatment based
on compound(s) of the present invention alone or in combination
with a NEPi, and patients with severe MED may also respond. Mild,
moderate and severe MED will be terms known to the man skilled in
the art, but guidance can be found in: The Journal of Urology, vol
151, 54-61 (January 1994).
[0168] MED patient groups, which are described in more detail in
Clinical Andrology vol 23,no.4, p773-782, and chapter 3 of the book
by 1. Eardley and K. Sethia "Erectile Dysfunction--Current
Investigation and Management, published by Mosby-Wolfe, are as
follows: psyhcogenic, endocrinologic, neurogenic, arteriogenic,
drug-induced sexual dysfunction (lactogenic) and sexual dysfunction
related to cavernosal factors, particularly venogenic causes.
[0169] Suitable cGMP PDE5 inhibitors for the use in combination
with a compound of the present invention for the treatment of MED
according to the present invention include: the pyrazolo
[4,3-d]pyrimidin-7-ones disclosed in EP-A-0463756; the pyrazolo
[4,3-d]pyrimidin-7-ones disclosed in published international
application WO 01/27112; the pyrazolo [4,3-d]pyrimidin-7-ones
disclosed in published international application WO 01/27113; the
indole-1,4-diones disclosed in WO95/19978 and the triazin-4-ones
disclosed in published international application WO99/24433.
[0170] More preferred are compounds such as,
5-[2-ethoxy-5-(4-methyl-1-pip-
erazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3--
d]pyrimidin-7-one (sildenafil) also known as
1-[[3-(6,7-dihydro-1-methyl-7-
-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)4-ethoxyphenyl]sulphonyl]4--
methylpiperazine (see EP-A-0463756);
[0171]
5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-
-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,
also known as 1
-{6-ethoxy-5-[3-ethyl-6,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H--
pyrazolo[4,3-d]pyrimidin-5-yl]-3-pyridylsulphonyl}4-ethylpiperazine
(see WO 01/27113, Example 8);
[0172] 5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1
-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one
(see WO 01/27112, Example 132);
[0173]
(6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyph-
enyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (IC-351,
tadalafil), i.e. the compound of examples 78 and 95 of published
international application WO95/19978, as well as the compound of
examples 1, 3, 7 and 8; and
[0174]
2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulphonyl)-phenyl]-5-methyl-
-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin4-one (vardenafil) also
known as
1-[[3-(3,4-dihydro-5-methyl-4-oxo-7-propylimidazo[5,1-f]-as-triazin-2-yl
)4-ethoxyphenyl]sulphonyl]-4-ethylpiperazine (i.e. the compound of
examples 20, 19, 337 and 336 of published international application
WO99/24433);
[0175] and pharmaceutically acceptable salts thereof.
[0176] According to a further aspect the present invention provides
a composition for the treatment of MED comprising
6'-(3-Chloro-benzyloxy)-3- ,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl
and sildenafil.
[0177] The suitability of any particular cGMP PDE5 inhibitor for
use in combination with a compound of the present invention can be
readily determined by evaluation of its potency and selectivity
using literature methods followed by evaluation of its toxicity,
absorption, metabolism, pharmacokinetics, etc in accordance with
standard pharmaceutical practice.
[0178] Preferred CGMP PDE5 inhibitors for use herein have an
IC.sub.50 at less than 100 nanomolar, more preferably, at less than
50 nanomolar, more preferably still at less than 10 nanomolar.
Preferably the CGMP PDE5 inhibitors for use in the pharmaceutical
combinations according to the present invention are selective for
the PDE5 enzyme. Preferably they have a selectivity of PDE5 over
PDE3 of greater than 100 more preferably greater than 300. More
preferably the PDE5 has a selectivity over both PDE3 and PDE4 of
greater than 100, more preferably greater than 300.
[0179] Selectivity ratios may readily be determined by the skilled
person. IC.sub.50 values for the PDE3 and PDE4 enzyme may be
determined using established literature methodology, see S A
Ballard et al, Journal of Urology, 1998, vol.159, pages
2164-2171.
[0180] Preferred herein are NEP inhibitors wherein said NEP is EC
3.4.24.11 and more preferably wherein said NEP inhibitor is a
selective inhibitor for EC 3.4.24.11, more preferably a selective
NEP inhibitor is a selective inhibitor for EC 3.4.24.11, which has
an IC.sub.50 of less than 100 nM (e.g. ompatrilat, candoxatril,
candoxatrilat, sampatrilat). Suitable NEP inhibitor compounds are
described in EP-A-1097719.
[0181] Particularly preferred NEPi compounds for as auxiliary
agents for use in the treatment of MED according to the present
invention are those described in co-pending International Patent
Application PCT/IB02/00807 filed on the 18th Mar. 2002.
[0182] Especially preferred is
(S)-2-[(1-{[3-(4-chlorophenyl)propyl]-carba- moyl}cyclo-pentyl
)methyl]-4-methoxybutanoic acid or a pharmacuetically acceptable
salt such as the sodium salt thereof as detailed at Example 22 in
PCT/IB02/00807. Details for the synthesis of this compound and the
sodium salt are provided in the Experimental Section
hereinafter.
[0183] According to a further aspect the present invention provides
a composition for the treatment of MED comprising
6'-(3-Chloro-benzyloxy)-3- ,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl
and (S)-2-[(1-{[3-(4-chlorophenyl)p-
ropyl]carbamoyl}cyclo-pentyl)methyl]4-methoxybutanoic acid.
[0184] According to yet a further aspect of the present invention,
there is provided use of a compound of the present invention for
the treatment of female sexual dysfunction (FSD).
[0185] According to another aspect of the present invention, there
is provided use of a compound of the present invention and one or
more additional active agents for the treatment of female sexual
dysfunction (FSD).
[0186] Preferably, the one or more additional active agents is/are
selected from the group consisting of:
[0187] 1) estrogen receptor modulators and/or estrogen agonists
and/or estrogen antagonists;
[0188] 2) testosterone replacement agent and/or testosternone
(Tostrelle) and/or dihydrotestosterone and/or
dehydroepiandrosterone (DHEA) and/or a testosterone implant;
[0189] 3) estrogen, estrogen and medroxyprogesterone or
medroxyprogesterone acetate (MPA) (as a combination), or estrogen
and methyl testosterone hormone replacement therapy agent;
[0190] 4) one or more dopaminergic agents;
[0191] 5) one or more of an NPY (neuropeptide Y) inhibitor;
[0192] 6) one or more of a melanocortin receptor agonist or
modulator or melanocortin enhancer;
[0193] 7) one or more of an NEP (neutral endopeptidase)
inhibitor;
[0194] 8) one or more of a PDE (phosphodiesterase) inhibitor;
and
[0195] 9) one or more of a bombesin receptor antagonist or
modulator.
[0196] Preferably, said FSD is female sexual arousal disorder
(FSAD). Alternatively, said FSD is female orgasmic disorder (FOD).
In a further alternative, said FSD is hypoactive sexual desire
disorder (HSDD). In yet a further alternative, said FSD is a sexual
pain disorder, preferably Dyspareunia or Vaginismus.
[0197] Examples of estrogen receptor modulators and/or estrogen
agonists and/or estrogen antagonists, include raloxifene or
lasofoxifene,
(-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahyd-
ronaphthalene-2-ol and pharmaceutically acceptable salts thereof
(compound (a) below), the preparation of which is detailed in WO
96/21656. 11
[0198] An example of a testosterone replacement agent is
dehydroandrostendione.
[0199] Examples of hormone replacement therapy agent include
Premarin, Cenestin, Oestrofeminal, Equin, Estrace, Estrofem,
Elleste Solo, Estring, Eastraderm TTS, Eastraderm Matrix,
Dermestril, Premphase, Preempro, Prempak, Premique, Estratest,
Estratest HS, and Tibolone.
[0200] Examples of dopaminergic agents include apomorphine or a
selective D2, D3 or D2/D.sub.3agonist such as, pramipexole and
ropirinol (as claimed in WO-0023056),L-Dopa or carbidopa, PNU95666
(as disclosed in WO-0040226).
[0201] Examples of NPY (neuropeptide Y) inhibitors include NPY1 or
NPY5 inhibitors, preferably NPY1 inhibitor. Preferably, said NPY
inhibitors (including NPY Y1 and NPY Y5) having an IC50 of less
than 100 nM, more preferably less than 50 nM. Suitable NPY, and in
particular NPY1 inhibitor compounds, are described in
EP-A-1097718.
[0202] Examples of a melanocortin receptor agonist or modulator or
melanocortin enhancer include melanotan II, PT-14, PT-141 or
compounds disclosed in WO-09964002, WO-00074679, WO-09955679,
WO-00105401, WO-00058361, WO-001 14879, WO-001 13112 or
WO-09954358.
[0203] Suitable NEP inhibitors are as described hereinabove.
[0204] According to a further aspect, the present invention
provides a composition for the treatment of FSD comprising
6'-(3-Chloro-benzyloxy)-3- ,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl
and (S)-2-[(1-{[3-(4-chlorophenyl)p-
ropyl]carbamoyl}cyclo-pentyl)methyl]4-methoxybutanoic acid.
[0205] Preferred PDE inhibitors include a PDE 2, 3, 4, 5, 7 or 8
inhibitor, preferably PDE2 or PDE5 inhibitor and more preferably a
PDE5 inhibitor (as described hereinabove), most preferably
sildenafil.
[0206] According to a further aspect, the present invention
provides a composition for the treatment of FSD comprising
6'-(3-Chloro-benzyloxy)-3- ,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl
and sildenafil.
[0207] Preferred examples of one or more of bombesin receptor
antagonists or modulators would be antagonists or modulators for
BB.sub.1, including those described in PCT/GB01/05018 (filed 14
Nov. 2001) and PCT/GB00/04380 (filed 17 Nov. 2000). Also preferred
are bombesin BB.sub.2, BB.sub.3, or BB.sub.4 receptor antagonists.
Preferred bombesin receptor antagonists are also mentioned as
"auxiliary agents" in PCT/IB01/02399 (filed 10 Dec. 2001).
[0208] It should be noted that a full list of possible "additional
active agents" can be found in PCT/IB01/02399 (filed 10 Dec.
2001)--and are described as "auxiliary agents" therein.
[0209] In accordance with yet another aspect of the present
invention, other 5-HT.sub.2c receptor agonists may be used in
addition to a compound of the present invention. Such 5-HT.sub.2c
receptor agonists include, but are not limited to, those disclosed
in Chaki and Nakazato--Expert Opin. Ther. Patents (2001),
11(11):1677-1692 (see especially Section 3.9 - 5HT.sub.2c on page
1687 and FIG. 7 on page 1686), or Isaac--Drugs of the Future
(2001), 26(4):383-393 (see especially FIG. 2 on page 385). For the
avoidance of doubt, the aforementioned publications are
incorporated herein by reference in their entireties.
[0210] Preferably, said 5-HT.sub.2c receptor agonists are selective
5-HT.sub.2c receptor agonists.
[0211] Receptor binding data or binding selectivity data may not
always correlate with or reflect functional data or functional
selectivity data. For example, a compound may be a 5-HT.sub.2c
receptor agonist when binding assays are analysed, but functionally
the compound may have the same potency at other 5-HT receptors.
Thus, the term "selective" as used herein in relation to the
present invention with respect to methods of treatment for sexual
dysfunction means "functionally selective".
[0212] Thus, according to another aspect, the present invention
additionally provides the use of 5-HT.sub.2c receptor agonists,
preferably selective 5-HT.sub.2c receptor agonists, for the
treatment of FSD, preferably FSAD, FOD, HSDD or a sexual pain
disorder (such as Dyspareunia or Vaginismus).
[0213] According to the methods of the invention, a compound of the
present invention or a combination of a compound of the present
invention and at least one additional pharmaceutical agent is
administered to a subject in need of such treatment, preferably in
the form of a pharmaceutical composition. In the combination aspect
of the invention, the compound of the present invention and at
least one other pharmaceutical agent (e.g., anti-obesity agent
described above) may be administered either separately or in the
pharmaceutical composition comprising both. It is generally
preferred that such administration be oral. However, if the subject
being treated is unable to swallow, or oral administration is
otherwise impaired or undesirable, parenteral or transdermal
administration may be appropriate.
[0214] According to the methods of the invention, when a
combination of a compound of the present invention and at least one
other pharmaceutical agent are administered together, such
administration can be sequential in time or simultaneous with the
simultaneous method being generally preferred. For sequential
administration, a compound of the present invention and the
additional pharmaceutical agent can be administered in any order.
It is generally preferred that such administration be oral. It is
especially preferred that such administration be oral and
simultaneous. When a compound of the present invention and the
additional pharmaceutical agent are administered sequentially, the
administration of each can be by the same or by different
methods.
[0215] According to the methods of the invention, a compound of the
present invention or a combination of a compound of the present
invention and at least one additional pharmaceutical agent
(referred to herein as a "combination") is preferably administered
in the form of a pharmaceutical composition. Accordingly, a
compound of the present invention or a combination can be
administered to a patient separately or together in any
conventional oral, rectal, transdermal, parenteral, (for example,
intravenous, intramuscular, or subcutaneous) intracisternal,
intravaginal, intraperitoneal, intravesical, local (for example,
powder, ointment or drop), or buccal, or nasal, dosage form.
[0216] Compositions suitable for parenteral injection generally
include pharmaceutically acceptable sterile aqueous or nonaqueous
solutions, dispersions, suspensions, or emulsions, and sterile
powders for reconstitution into sterile injectable solutions or
dispersions. Examples of suitable aqueous and nonaqueous carriers,
diluents, solvents, or vehicles include water, ethanol, polyols
(propylene glycol, polyethylene glycol, glycerol, and the like),
suitable mixtures thereof, vegetable oils (such as olive oil) and
injectable organic esters such as ethyl oleate. Proper fluidity can
be maintained, for example, by the use of a coating such as
lecithin, by the maintenance of the required particle size in the
case of dispersions, and by the use of surfactants.
[0217] These compositions may also contain adjuvants such as
preserving, wetting, emulsifying, and dispersing agents. Prevention
of microorganism contamination of the compositions can be
accomplished with various antibacterial and antifungal agents, for
example, parabens, chlorobutanol, phenol, sorbic acid, and the
like. It may also be desirable to include isotonic agents, for
example, sugars, sodium chloride, and the like. Prolonged
absorption of injectable pharmaceutical compositions can be brought
about by the use of agents capable of delaying absorption, for
example, aluminum monostearate and gelatin.
[0218] Solid dosage forms for oral administration include capsules,
tablets, powders, and granules. In such solid dosage forms, a
compound of the present invention or a combination is admixed with
at least one inert customary pharmaceutical excipient (or carrier)
such as sodium citrate or dicalcium phosphate or (a) fillers or
extenders (e.g., starches, lactose, sucrose, mannitol, silicic acid
and the like); (b) binders (e.g., carboxymethylcellulose,
alginates, gelatin, polyvinylpyrrolidone, sucrose, acacia and the
like); (c) humectants (e.g., glycerol and the like); (d)
disintegrating agents (e.g., agar-agar, calcium carbonate, potato
or tapioca starch, alginic acid, certain complex silicates, sodium
carbonate and the like); (e) solution retarders (e.g., paraffin and
the like); (f) absorption accelerators (e.g., quaternary ammonium
compounds and the like); (g) wetting agents (e.g., cetyl alcohol,
glycerol monostearate and the like); (h) adsorbents (e.g., kaolin,
bentonite and the like); and/or (i) lubricants (e.g., talc, calcium
stearate, magnesium stearate, solid polyethylene glycols, sodium
lauryl sulfate and the like). In the case of capsules and tablets,
the dosage forms may also comprise buffering agents.
[0219] Solid compositions of a similar type may also be used as
fillers in soft or hard filled gelatin capsules using such
excipients as lactose or milk sugar, as well as high molecular
weight polyethylene glycols, and the like.
[0220] Solid dosage forms such as tablets, dragees, capsules, and
granules can be prepared with coatings and shells, such as enteric
coatings and others well known in the art. They may also contain
opacifying agents, and can also be of such composition that they
release the compound of the present invention and/or the additional
pharmaceutical agent in a delayed manner. Examples of embedding
compositions that can be used are polymeric substances and waxes.
The drug can also be in micro-encapsulated form, if appropriate,
with one or more of the above-mentioned excipients.
[0221] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups, and elixirs. In addition to the compound of the present
invention or the combination, the liquid dosage form may contain
inert diluents commonly used in the art, such as water or other
solvents, solubilizing agents and emulsifiers, as for example,
ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate,
benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene
glycol, dimethylformamide, oils (e.g., cottonseed oil, groundnut
oil, corn germ oil, olive oil, castor oil, sesame seed oil and the
like), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols
and fatty acid esters of sorbitan, or mixtures of these substances,
and the like.
[0222] Besides such inert diluents, the composition can also
include adjuvants, such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring, and perfuming agents.
[0223] Suspensions, in addition to the compound of the present
invention or the combination, may further comprise suspending
agents, e.g., ethoxylated isostearyl alcohols, polyoxyethylene
sorbitol and sorbitan esters, microcrystalline cellulose, aluminum
metahydroxide, bentonite, agar-agar, and tragacanth, or mixtures of
these substances, and the like.
[0224] Compositions for rectal or vaginal administration preferably
comprise suppositories, which can be prepared by mixing a compound
of the present invention or a combination with suitable
non-irritating excipients or carriers, such as cocoa butter,
polyethylene glycol or a suppository wax which are solid at
ordinary room temperature but liquid at body temperature and
therefore melt in the rectum or vaginal cavity thereby releasing
the active component(s).
[0225] Dosage forms for topical administration of the compounds of
the present invention and combinations of the compounds of the
present invention with anti-obesity agents may comprise ointments,
powders, sprays and inhalants. The drugs are admixed under sterile
condition with a pharmaceutically acceptable carrier, and any
preservatives, buffers, or propellants that may be required.
Ophthalmic formulations, eye ointments, powders, and solutions are
also intended to be included within the scope of the present
invention.
[0226] The following paragraphs describe exemplary formulations,
dosages, etc. useful for non-human animals. The administration of
the compounds of the present invention and combinations of the
compounds of the present invention with anti-obesity agents can be
effected orally or non-orally (e.g., by injection).
[0227] An amount of a compound of the present invention or
combination of a compound of the present invention with an
anti-obesity agent is administered such that an effective dose is
received. Generally, a daily dose that is administered orally to an
animal is between about 0.01 and about 1,000 mg/kg of body weight,
preferably between about 0.01 and about 300 mg/kg of body
weight.
[0228] Conveniently, a compound of the present invention (or
combination) can be carried in the drinking water so that a
therapeutic dosage of the compound is ingested with the daily water
supply. The compound can be directly metered into drinking water,
preferably in the form of a liquid, water- soluble concentrate
(such as an aqueous solution of a water-soluble salt).
[0229] Conveniently, a compound of the present invention (or
combination) can also be added directly to the feed, as such, or in
the form of an animal feed supplement, also referred to as a premix
or concentrate. A premix or concentrate of the compound in a
carrier is more commonly employed for the inclusion of the agent in
the feed. Suitable carriers are liquid or solid, as desired, such
as water, various meals such as alfalfa meal, soybean meal,
cottonseed oil meal, linseed oil meal, corncob meal and corn meal,
molasses, urea, bone meal, and mineral mixes such as are commonly
employed in poultry feeds. A particularly effective carrier is the
respective animal feed itself; that is, a small portion of such
feed. The carrier facilitates uniform distribution of the compound
in the finished feed with which the premix is blended. Preferably,
the compound is thoroughly blended into the premix and,
subsequently, the feed. In this respect, the compound may be
dispersed or dissolved in a suitable oily vehicle such as soybean
oil, corn oil, cottonseed oil, and the like, or in a volatile
organic solvent and then blended with the carrier. It will be
appreciated that the proportions of compound in the concentrate are
capable of wide variation since the amount of the compound in the
finished feed may be adjusted by blending the appropriate
proportion of premix with the feed to obtain a desired level of
compound.
[0230] High potency concentrates may be blended by the feed
manufacturer with proteinaceous carrier such as soybean oil meal
and other meals, as described above, to produce concentrated
supplements, which are suitable for direct feeding to animals. In
such instances, the animals are permitted to consume the usual
diet. Alternatively, such concentrated supplements may be added
directly to the feed to produce a nutritionally balanced, finished
feed containing a therapeutically effective level of a compound of
the present invention. The mixtures are thoroughly blended by
standard procedures, such as in a twin shell blender, to ensure
homogeneity.
[0231] If the supplement is used as a top dressing for the feed, it
likewise helps to ensure uniformity of distribution of the compound
across the top of the dressed feed.
[0232] Drinking water and feed effective for increasing lean meat
deposition and for improving lean meat to fat ratio are generally
prepared by mixing a compound of the present invention with a
sufficient amount of animal feed to provide from about 10.sup.-3 to
about 500 ppm of the compound in the feed or water.
[0233] The preferred medicated swine, cattle, sheep and goat feed
generally contain from about 1 to about 400 grams of a compound of
the present invention (or combination) per ton of feed, the optimum
amount for these animals usually being about 50 to about 300 grams
per ton of feed.
[0234] The preferred poultry and domestic pet feeds usually contain
about 1 to about 400 grams and preferably about 10 to about 400
grams of a compound of the present invention (or combination) per
ton of feed.
[0235] For parenteral administration in animals, the compounds of
the present invention (or combination) may be prepared in the form
of a paste or a pellet and administered as an implant, usually
under the skin of the head or ear of the animal in which increase
in lean meat deposition and improvement in lean meat to fat ratio
is sought.
[0236] In general, parenteral administration involves injection of
a sufficient amount of a compound of the present invention (or
combination) to provide the animal with about 0.01 to about 20
mg/kg/day of body weight of the drug. The preferred dosage for
poultry, swine, cattle, sheep, goats and domestic pets is in the
range of from about 0.05 to about 10 mg/kg/day of body weight of
drug.
[0237] Paste formulations can be prepared by dispersing the drug in
a pharmaceutically acceptable oil such as peanut oil, sesame oil,
corn oil or the like.
[0238] Pellets containing an effective amount of a compound of the
present invention, pharmaceutical composition, or combination can
be prepared by admixing a compound of the present invention or
combination with a diluent such as carbowax, carnuba wax, and the
like, and a lubricant, such as magnesium or calcium stearate, can
be added to improve the pelleting process.
[0239] It is, of course, recognized that more than one pellet may
be administered to an animal to achieve the desired dose level
which will provide the increase in lean meat deposition and
improvement in lean meat to fat ratio desired. Moreover, implants
may also be made periodically during the animal treatment period in
order to maintain the proper drug level in the animal's body.
[0240] The present invention has several advantageous veterinary
features. For the pet owner or veterinarian who wishes to increase
leanness and/or trim unwanted fat from pet animals, the instant
invention provides the means by which this may be accomplished. For
poultry and swine breeders, utilization of the method of the
present invention yields leaner animals that command higher sale
prices from the meat industry.
[0241] Embodiments of the present invention are illustrated by the
following Examples. It is to be understood, however, that the
embodiments of the invention are not limited to the specific
details of these Examples, as other variations thereof will be
known, or apparent in light of the instant disclosure, to one of
ordinary skill in the art.
EXAMPLES
[0242] Unless specified otherwise, starting materials are generally
available from commercial sources such as Aldrich Chemicals Co.
(Milwaukee, Wis.), Lancaster Synthesis, Inc. (Windham, N.H.), Acros
Organics (Fairlawn, N.J.), Maybridge Chemical Company, Ltd.
(Cornwall, England), Tyger Scientific (Princeton, N.J.), and
AstraZeneca Pharmaceuticals (London, England).
General Experimental Procedures
[0243] NMR spectra were recorded on a Varian Unity.TM. 400
(available from Varian Inc., Palo Alto, Calif.) at room temperature
at 400 MHz for proton. Chemical shifts are expressed in parts per
million (.delta.) relative to residual solvent as an internal
reference. The peak shapes are denoted as follows: s, singlet; d,
doublet; t, triplet; q, quartet; m, multiplet; bs, broad singlet;
2s, two singlets. Atmospheric pressure chemical ionization mass
spectra (APCl) were obtained on a Fisons.TM. Plafform II
Spectrometer (carrier gas: acetonitrile: available from Micromass
Ltd, Manchester, UK). Chemical ionization mass spectra (Cl) were
obtained on a Hewlett-Packard.TM. 5989 instrument (ammonia
ionization, PBMS: available from Hewlett-Packard Company, Palo
Alto, Calif.). Electrospray ionization mass spectra (ES) were
obtained on a Waters.TM. ZMD instrument (carrier gas: acetonitrile:
available from Waters Corp., Milford, Mass.). Where the intensity
of chlorine or bromine-containing ions are described, the expected
intensity ratio was observed (approximately 3:1 for
.sup.35Cl/.sup.37Cl-containing ions and 1:1 for
.sup.79Br/.sup.31Br-containing ions) and the intensity of only the
lower mass ion is given. In some cases only representative .sup.1H
NMR peaks are given. MS peaks are reported for all examples.
Optical rotations were determined on a PerkinElmer.TM. 241
polarimeter (available from PerkinElmer Inc., Wellesley, Mass.)
using the sodium D line (.lambda.=589 nm) at the indicated
temperature and are reported as follows [.alpha.].sub.D.sup.temp,
concentration (c=g/100 mL), and solvent.
[0244] Column chromatography was performed with either Baker.TM.
silica gel (40 .mu.m; J. T. Baker, Phillipsburg, N.J.) or Silica
Gel 50 (EM Sciences.TM., Gibbstown, N.J.) in glass columns or in
Flash 40 Biotage.TM. columns (ISC, Inc., Shelton, Conn.) under low
nitrogen pressure.
Example 1
Preparation of Intermediate
6'-Chloro-2,3,5,6-tetrahydro-[1,2']bipyrazinyl- -4-carboxylic acid
tert-butyl ester (1-1a)
[0245] A mixture of 2,6-dichloropyrazine (2.98 g, 20 mmol),
piperazine-1-carboxylic acid tert-butyl ester (3.72 g, 20 mmol) and
sodium carbonate (2.12 g, 20 mmol) in t-butanol (50 mL) was heated
at reflux under nitrogen for 65 h. The solution was concentrated in
vacuo. The residue was partitioned between ethyl acetate (50 mL)
and water (50 mL). The aqueous phase was extracted with ethyl
acetate (3.times.30 mL). The combined organic extracts were washed
with brine (50 mL), dried over magnesium sulfate, filtered, and
concentrated in vacuo to give the title compound (1-1 a) as a white
solid.
[0246] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.96 (s, 1H); 7.82
(s, 1H); 3.52-3.60 (m, 8H); 1.46 (s, 9H). MS (ES+) Calc: 298.1,
Found: 299.1 (M+1).
Preparation of Intermediate
6'-(3-Chloro-benzyloxy)-2,3,5,6-tetrahydro-[1,-
2']bipyrazinyl-4-carboxylic acid tert-butyl ester (1-1b)
[0247] A mixture of
6'-chloro-2,3,5,6-tetrahydro-[1,2]bipyrazinyl4-carboxy- lic acid
tert-butyl ester (I-1a (300 mg, 1.0 mmol), 3-chlorobenzyl alcohol
(0.142 mL, 1.2 mmol), KOH (191 mg, 3.4 mmol) and 18-crown-6 (10.6
mg, 0.04 mmol) in toluene (6 mL) was stirred at reflux for 5.5 h
and concentrated in vacuo. The residue was partitioned between
H.sub.2O (30 mL) and CH.sub.2Cl.sub.2 (30 mL). The aqueous phase
was separated and extracted with CH.sub.2Cl.sub.2 (2.times.30 mL).
The combined organic extracts were dried and concentrated in vacuo.
The crude product was purified by preparative TLC (5% MeOH in
CH.sub.2Cl.sub.2) to afford the title compound (1-1b) (380 mg).
[0248] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.63 (s, 1H); 7.59
(s, 1H); 7.40 (s, 1H); 7.27 (s, 3H); 5.26 (s, 2H); 3.51 (s, 8H);
1.46 (s, 9H). MS (ES+) Calc: 404.1, Found: 405.0 (M+1).
Preparation of
6'-(3-Chloro-benzyloxy)-3,4,5,6-tetrahvdro-2H-[1,2']bipyraz- inyl
(1-A)
[0249] To a solution of
6'-(3-chloro-benzyloxy)-2,3,5,6-tetrahydro-[1,2']b-
ipyrazinyl-4-carboxylic acid tert-butyl (1-1b) (380 mg, 0.94 mmol)
in CH.sub.2Cl.sub.2 (6 mL) was added trifluoroacetic acid (1.4 mL).
After stirring at room temperature for 2 h, the solution was
concentrated in vacuo. The residue was partitioned between 1M HCl
(20 mL) and EtOAC (30 mL). The aqueous phase was washed with EtOAc
(2.times.30 mL), basified with 3 N NaOH, and extracted with EtOAc
(3.times.30 mL). The combined organic extracts were concentrated in
vacuo to give the title compound (1-A) (252 mg) as an oil.
[0250] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.62 (s, 1H); 7.56
(s, 1H); 7.40 (s, 1H); 7.28-7.25 (m, 3H); 5.26 (s, 2H); 3.49 (t,
4H); 2.95 (t, 4H); 1.96 (s, 1H). MS (ES.sup.+) Calc: 304.1, Found:
305.1 (M+1).
Preparation of
6'-(3-Chloro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyraz- inyl,
hydrochloride (1-B)
[0251] To a solution of
6'-(3-chloro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2- ]bipyrazinyl
(1-A) in CH.sub.2Cl.sub.2 (4 mL) was added dropwise 1M HCl in ether
(1.5 mL) and then hexane (4 mL) was added. The solid was collected
and dried to give the hydrochloride salt (1-B) (300 mg).
[0252] .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.98 (br s,1H);
7.72 (s, 1H); 7.50 (s, 1H); 7.39-7.33 (m, 3H); 5.48 (br s, 2H);
4.00 (br s, 4H); 3.35 (bs, 4H). MS (ES.sup.+) Calc: 304.1, Found:
305.1 (M+1).
Preparation of 6'-(3-Chloro-benzyloxy)-3
4,5,6-tetrahydro-2H-[1,2']bipyraz- inyl, fumarate (1-C)
[0253] To a solution of
6'-(3-chloro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2- ']bipyrazinyl
1-A (252 mg, 0.83 mmol) in a mixture of isopropyl ether (8 mL) and
MeOH (1 mL) was added 0.5 M fumaric acid in MeOH (1.86 mL, 0.93
mmol) in one portion. The resulting mixture was stirred at room
temperature for 1 h. The white solid was collected by filtration
and washed with isopropyl ether followed by hexane and dried in
vacuo to give the title compound 1-C.
[0254] .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.77 (s,1H); 7.59
(s,1H); 7.44 (d,1H); 7.34-7.28 (m, 3H); 6.67 (s, 2H); 5.35 (s, 2H);
3.82-3.79 (m, 4H); 3.29-3.24. (m, 4H). MS (APCI.sup.+) Calc: 304.1,
Found: 305.4 (M+1).
Preparation of
6'-(3-Chloro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyraz- inyl,
succinate (1-D)
[0255] To a solution of
6'-(3-chloro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2- ]bipyrazinyl
1-A (183 mg, 0.60 mmol) in a mixture of isopropyl ether (3 mL) and
MeOH (1 mL) was added 0.5 M succinic acid in MeOH (1.32 mL, 0.66
mmol) in one portion. The resulting solution was concentrated. The
residue was dissolved in a mixture of MeOH (0.5 mL) and isopropyl
ether (4 mL). The clear solution was kept at room temperature for
19 h. The white solid was collected by filtration and washed with
isopropyl ether followed by hexane and dried in vacuo to give the
title compound 1-D (240 mg).
[0256] .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.75 (s, 1H); 7.57
(s, 1H); 7.44 (d, 1H); 7.34-7.29 (m, 3H); 5.35 (s, 2H); 3.79-3.76
(m, 4H); 3.30-3.28. (m, 4H); 2.50 (s, 4H). MS (APCI.sup.+) Calc:
304.1, Found: 305.3 (M+1).
[0257] Using the appropriate starting materials, the compounds
listed in Table 1 were prepared in an analogous manner to the
sequence of reactions described above for the preparation of
compound (1-A) or its corresponding hydrochloride salt (1-B),
fumarate salt (1-C), or succinate salt (1-D). Other salts were
prepared from the corresponding free bases using similar
procedures.
1 TABLE 1 MS Ex. Found No. Compound Name Calc. (M + 1) 1-E
6'-(3-Trifluoromethoxy-ben- zyloxy)-3,4,5,6- 354.1 355.1
tetrahydro-2H-[1,2']bipyrazinyl 1-F
6'-(3-Trifluoromethyl-benzyloxy)-3,4,5,6- 338.1 339.1
tetrahydro-2H-[1,2']bipyrazinyl 1-G 6'-Benzyloxy-3,4,5,6-tetrahydr-
o-2H- 270.2 271.2 [1,2']bipyrazinyl, hydrochloride 1-H
6'-(2-Fluoro-benzyloxy)-3,4,5,6-tetrahydro-2H- 288.1 289.1
[1,2']bipyrazinyl 1-I 6'-(3-Fluoro-benzyloxy)-3,4,5,6-tetrahydro-2-
H- 288.1 289.1 [1,2']bipyrazinyl, hydrochloride, 1-J
6'-(2-Chloro-benzyloxy)-3,4,5,6-tetrahydro- 304.1 305.1
2H-[1,2']bipyrazinyl 1-K 6'-(3-Chloro-benzyloxy)-(2S)-methyl-3,4,5-
,6- 318.1 319.1 tetrahydro-2H-[1,2']bipyrazinyl 1-L
6'-(3-Chloro-benzyloxy)-(2R)-methyl-3,4,5,6- 318.1 319.1
tetrahydro-2H-[1,2']bipyrazinyl 1-M 6'-(2,5-Difluoro-benzyloxy)-3,-
4,5,6-tetrahydro- 306.1 307.1 2H-[1,2']bipyrazinyl 1-N
6'-(3,5-Dichloro-benzyloxy)-3,4,5,6- 338.1 339.0
tetrahydro-2H-[1,2']bipyrazinyl 1-O 6'-(3,5-Difluoro-benzyloxy)-3,-
4,5,6-tetrahydro- 306.1 307.1 2H-[1,2']bipyrazinyl 1-P
6'-(2-Trifluoromethyl-benzyloxy)-3,4,5,6- 338.1 339.1
tetrahydro-2H-[1,2']bipyrazinyl 1-Q 6'-(2-Trifluoromethoxy-benzylo-
xy)-3,4,5,6- 354.1 355.1 tetrahydro-2H-[1,2']bipyrazinyl 1-R
6'-(4-Chloro-benzyloxy)-3,4,5,6-tetrahydro- 304.1 305.1
2H-[1,2']bipyrazinyl 1-S 6'-(4-Fluoro-benzyloxy)-3,4,5,6-tetrahydr-
o-2H- 288.1 289.1 [1,2']bipyrazinyl 1-T
6'-(2,5-Dichloro-benzyloxy)-3,4,5,6- 338.1 339.0
tetrahydro-2H-[1,2']bipyrazinyl 1-U 6'-(3-Chloro-benzyloxy)-(3R)-m-
ethyl-3,4,5,6- 318.1 319.1 tetrahydro-2H-[1,2']bipyrazinyl 1-V
6'-(3-Chloro-benzyloxy)-(3R,5S)-dimethyl- 331.1 332.1
3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl 1-W
6'-(3,5-Bis-trifluoromethyl-benzyloxy)-3,4,5,6- 406.1 407.3
tetrahydro-2H-[1,2']bipyrazinyl 1-X 6'-(3-Fluoro-5-trifluoromethyl-
-benzyloxy)- 356.1 357.3 3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl
1-Z 6'-[1-(3,5-Difluoro-phenyl)-ethoxy]-3,4,5,6- 320.1 321.3
tetrahydro-2H-[1,2']bipyrazinyl 1-AA 6'-(3,5-Dimethyl-benzyloxy)-3-
,4,5,6- 298.1 299.3 tetrahydro-2H-[1,2']bipyrazinyl 1-AB
6'-(2,5-Dimethyl-benzyloxy)-3,4,5,6- 298.1 299.3
tetrahydro-2H-[1,2']bipyrazinyl 1-AC 6'-(2,5-Difluoro-benzyloxy)-3-
,4,5,6-tetrahydro- 306.3 307.3 2H-[1,2']bipyrazinyl, fumarate 1-AD
6'-(3-Chloro-benzyloxy)-(2R)-methyl-3,4,5,6- 318.1 319.3
tetrahydro-2H-[1,2']bipyrazinyl, fumarate 1-AE
6'-[(1R)-Phenyl-ethoxy]-3,4,5,6-tetrahydro-2H- 284.4 285.3
[1,2']bipyrazinyl 1-AF 6'-[(1S)-Phenyl-ethoxy]-3,4,5,6-tetrahydro--
2H- 284.4 285.3 [1,2']bipyrazinyl 1-AG
6'-(2-Chloro-benzyloxy)-(2R)-methyl-3,4,5,6- 318.1 319.3
tetrahydro-2H-[1,2']bipyrazinyl 1-AH 6'-(2-Fluoro-benzyloxy)-(2R)--
methyl-3,4,5,6- 302.3 303.3 tetrahydro-2H-[1,2']bipyrazinyl 1-AI
6'-(3-Fluoro-benzyloxy)-(2R)-methyl-3,4,5,6- 302.3 303.3
tetrahydro-2H-[1,2']bipyrazinyl 1-AJ 6'-(2,5-Dichloro-benzyloxy)-(-
2R)-methyl- 352.1 353.3 3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl
1-AK 6'-(3-Chloro-benzyloxy)-(3S)-methyl-3,4,5,6- 318.1 319.6
tetrahydro-2H-[1,2']bipyrazinyl 1-AL 6'-(3-Fluoro-benzyloxy)-(3S)--
methyl-3,4,5,6- 302.4 303.4 tetrahydro-2H-[1,2']bipyrazinyl 1-AM
6'-(Naphthalen-1-ylmethoxy)-3,4,5,6- 320.4 321.3
tetrahydro-2H-[1,2']bipyrazinyl, hydrochloride 1-AN
6'-(2,3-Difluoro-benzyloxy)-3,4,5,6-tetrahydro- 306.3 307.3
2H-[1,2']bipyrazinyl 1-AO 6'-(2,3-Dichloro-benzyloxy)-3,4,5,6-
338.1 339.2 tetrahydro-2H-[1,2']bipyrazinyl 1-AP
6'-(2-Chloro-benzyloxy)-3,4,5,6-tetrahydro- 304.2 305.3
2H-[1,2']bipyrazinyl, fumarate 1-AQ 6'-(Indan-(1S)-yloxy)-3,4,5,6--
tetrahydro-2H- 296.4 297.3 [1,2']bipyrazinyl 1-AR
6'-(Indan-(1R)-yloxy)-3,4,5,6-tetrahydro-2H- 296.4 297.3
[1,2']bipyrazinyl 1-AS 6'-(3-Chloro-benzyloxy)-4-methyl-3,4,5,6-
318.1 319.3 tetrahydro-2H-[1,2']bipyrazinyl 1-AT
6'-(3-Fluoro-benzyloxy)-4-methyl-3,4,5,6- 302.4 303.4
tetrahydro-2H-[1,2']bipyrazinyl 1-AU 6'-(2-Fluoro-benzyloxy)-3,4,5-
,6-tetrahydro-2H- 288.1 289.1 [1,2']bipyrazinyl hydrochloride salt
1-AV 6'-(Pyridin-3-ylmethoxy)-3,4,5,6-tetrahydro- 271.1 272.3
2H-[1,2']bipyrazinyl 1-AW 6'-(Pyridin-2-ylmethoxy)-3,4,5,6-tetr-
ahydro- 271.1 272.3 2H-[1,2']bipyrazinyl hydrochloride salt 1-AX
6'-(3,4-Difluoro-benzyloxy)-3,4,5,6-tetrahydro- 306.1 307.4
2H-[1,2']bipyrazinyl 1-AY 6'-(3,4-Dichloro-benzyloxy)-3,4,5,6-
339.1 339.3 tetrahydro-2H-[1,2']bipyrazinyl 1-AZ
6'-[2-(3-Chloro-phenyl)-ethoxy]-3,4,5,6- 318.1 319.4
tetrahydro-2H-[1,2']bipyrazinyl 1-BA 6'-[2-(4-Chloro-phenyl)-ethox-
y]-3,4,5,6- 318.1 319.4 tetrahydro-2H-[1,2']bipyrazinyl 1-BB
6'-[2-(3-Fluoro-phenyl)-ethoxy]-3,4,5,6- 302.1 303.4
tetrahydro-2H-[1,2']bipyrazinyl 1-BC 6'-(3-Nitro-benzyloxy)-3,4,5,-
6-tetrahydro-2H- 315.1 316.3 [1,2']bipyrazinyl 1-BD
3-(3,4,5,6-Tetrahydro-2H-[1,2']bipyrazinyl-6'- 285.1 286.3
yloxymethyl)-phenylamine 1-BE 3-(3,4,5,6-Tetrahydro-2H-[1,2']bipyr-
azinyl-6'- 313.1 314.3 yloxymethyl)-benzamide 1-BF
6'-([1,2,3]Thiadiazol-4-ylmethoxy)-3,4,5,6- 278.1 279.2
tetrahydro-2H-[1,2']bipyrazinyl 1-BG 6'-(6-Methyl-pyridin-2-ylmeth-
oxy)-3,4,5,6- 285.2 286.4 tetrahydro-2H-[1,2']bipyrazinyl 1-BH
6'-(Furan-3-ylmethoxy)-3,4,5,6-tetrahydro-2H- 260.2 261.4
[1,2']bipyrazinyl 1-BI 6'-(3-Chloro-benzyloxy)-2-ethyl-3,4,5,6-
332.1 333.4 tetrahydro-2H-[1,2']bipyrazinyl 1-BJ
6'-(3-Chloro-thiophen-2-ylmethoxy)-3,4,5,6- 310.1 311.3
tetrahydro-2H-[1,2']bipyrazinyl hydrochloride salt 1-BK
6'-(Thiophen-2-ylmethoxy)-3,4,5,6-tetrahydro- 276.1 277.3
2H-[1,2']bipyrazinyl 1-BL 6'-(Thiophen-3-ylmethoxy)-3,4,5,6-tetrah-
ydro- 276.1 277.3 2H-[1,2']bipyrazinyl 1-BM
2-Methyl-6'-(pyridin-2-ylmethoxy)-3,4,5,6- 285.1 286.3
tetrahydro-2H-[1,2']bipyrazinyl 1-BN 2-Methyl-6'-(pyridin-3-ylmeth-
oxy)-3,4,5,6- 285.1 286.3 tetrahydro-2H-[1,2']bipyrazinyl 1-BO
2-Methyl-6'-(6-methyl-pyridin-2-ylmethoxy)- 299.2 300.4
3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl, fumarate 1-BP
6'-(6-Methoxy-pyridin-2-ylmethoxy)-3,4,5,6- 301.1 302.3
tetrahydro-2H-[1,2']bipyrazinyl 1-BQ Methyl-(6-methyl-pyridin-2-yl-
methyl)-(3,4,5,6- 298.2 299.4 tetrahydro-2H-[1,2']bipyrazinyl-6'-y-
l)-amine 1-BR (3-Fluoro-benzyl)-(2-methyl-3,4,5,6- 301.2 302.3
tetrahydro-2H-[1,2']bipyrazinyl-6'-yl)-amine 1-BS
(6-Methyl-pyridin-2-ylmethyl)-(3,4,5,6- 284.2 285.3
tetrahydro-2H-[1,2']bipyrazinyl-6'-yl)-amine formate salt 1-BT
(3-Chloro-benzyl)-(2-methyl-3,4,5,6- 317.1 318.3
tetrahydro-2H-[1,2']bipyrazinyl-6'-yl)-amine 1-BU
6'-(2-Methoxy-pyridin-3-ylmethoxy)-3,4,5,6- 301.1 302.2
tetrahydro-2H-[1,2']bipyrazinyl 1-BV 6'-(2,4-Dichloro-benzyloxy)-3-
,4,5,6- 338.1 339.1 tetrahydro-2H-[1,2']bipyrazinyl 1-BW
6'-(2-Methyl-benzyloxy)-3,4,5,6-tetrahydro- 284.2 285.2
2H-[1,2']bipyrazinyl 1-BX 6'-(3-Methoxy-benzyloxy)-3,4,5,6-tetrahy-
dro- 300.1 301.2 2H-[1,2']bipyrazinyl 1-BY
6'-(3-Chloro-benzyloxy)-2,5-dimethyl-3,4,5,6- 332.1 333.2
tetrahydro-2H-[1,2']bipyrazinyl 1-BZ 6'-(2-Chloro-benzyloxy)-2,5-d-
imethyl-3,4,5,6- 332.1 333.2 tetrahydro-2H-[1,2']bipyrazinyl 1-CA
6'-(3-Fluoro-benzyloxy)-2,5-dimethyl-3,4,5,6- 316.2 317.3
tetrahydro-2H-[1,2']bipyrazinyl 1-CB 6'-Benzylsulfanyl-3,4,5,6-tet-
rahydro-2H- 286.1 287.4 [1,2']bipyrazinyl 1-CC
6'-(3-Chloro-benzylsulfanyl)-3,4,5,6- 320.1 321.4
tetrahydro-2H-[1,2']bipyrazinyl 1-CD 6'-(4-Methyl-thiazol-2-ylmeth-
oxy)-3,4,5,6- 291.1 292.2 tetrahydro-2H-[1,2']bipyrazinyl 1-CE
6'-(3-Bromo-benzyloxy)-3,4,5,6-tetrahydro- 348.1 349.1
2H-[1,2']bipyrazinyl hydrochloride 1-CF 6'-(3-methy-benzyloxy)-3,4-
,5,6-tetrahydro-2H- 284.2 285.2 [1,2']bipyrazinyl hydrochloride
1-CG 6'-(4-Piperidin-1-ylmethyl-benzyloxy)-3,4,5,6- 367.2 368.5
tetrahydro-2H-[1,2']bipyrazinyl 1-CH 6'-[1-(2-Fluoro-pyridin-3-y-
l)-ethoxy]-3,4,5,6- 303.1 304.4 tetrahydro-2H-[1,2']bipyrazinyl
1-CI 6'-(7,8-Difluoro-quinolin-3-ylmethoxy)-3,4,5,6- 357.1
tetrahydro-2H-[1,2']bipyrazinyl 1-CJ 6'-(2-Phenyl-pyrrolidin-1-yl)-
-3,4,5,6- 309.2 310.2 tetrahydro-2H-[1,2']bipyrazinyl
Example 2
Preparation of Intermediate
(3-Chloro-benzyl)-(6-chloro-pyrazin-2-yl)-amin- e (I-2a)
[0258] To a solution of 2-amino-6-chloropyrazine (100 mg, 0.77mmol)
in 7.7 mL of anhydrous toluene was added 3-chlorobenzaldehyde (87.4
.mu.L, 0.77 mmol) followed by 50 mg of activated, powdered 4 .ANG.
molecular sieves. The reaction was refluxed under nitrogen for 3 h,
then cooled to ambient temperature and treated with sodium
borohydride (43.0 mg, 1.16 mmol). The resultant slurry was heated
to reflux under nitrogen overnight. After cooling to ambient
temperature the reaction was filtered through a pad of Celite.RTM.,
and the flitrate was concentrated in vacuo to a brown residue.
Chromatography on a silica gel preparatory TLC plate (1:1
hexane:ethyl acetate) provided 71.0 mg of the title compound
I-2a.
[0259] .sup.1H NMR (400 MHz, CDCL.sub.3) .delta. 7.78 (s, 1H); 7.71
(s, 1H); 7.35-7.25 (m, 4H); 5.53 (bs, 1H); 4.53 (d, 2H). MS
(ES.sup.+) Calc: 253, Found: 254.3 (M+1).
Preparation of Intermediate
6'-(3-Chloro-benzylamino)-2,3,5,6-tetrahydro-[-
1,2']bipyrazinyl-4-carboxylic acid tert-butyl ester (I-2b)
[0260] A mixture of (3-chloro-benzyl)-(6-chloro-pyrazin-2-yl)-amine
(I-2a) (71.0 mg, 0.28 mmol), piperazine-1-carboxylic acid
tert-butyl ester (260.2 mg, 1.40 mmol) and
1,8-diazabicyclo[5.4.0]undec-7-ene (208.9 .mu.L, 1.40 mmol) in 1.0
mL of ethanol was refluxed for 18 h under nitrogen. The reaction
was then cooled to ambient temperature and poured into 20 mL of
water. This was extracted 2.times.30 mL of ethyl acetate and the
combined organic extracts were washed with 3.times.15 mL water
followed by 15 mL of brine. The organic layer was then dried over
sodium sulfate, filtered and concentrated in vacuo to a yellow
residue that was chromatographed (prep. TLC, 1:1 hexane:ethyl
acetate) to give the title compound (I-2b) as a white solid, 13.5
mg.
[0261] .sup.1H NMR (400 MHz, CDCL.sub.3) .delta. 7.38 (s, 1H); 7.31
(s, 1H); 7.25-7.18 (m, 4H); 4.81 (bs,1H); 4.48 (d, 2H); 3.46 (bs,
8H); 1.46 (s, 9H). MS (ES.sup.+) Calc: 403, Found: 404.3 (M+1).
Preparation of (3-Chloro-benzyl)-(3,4,5,6-tetrahydro-2H-[1
2']bipyrazinyl-6'-yl)-amine (2-A)
[0262] The title compound (2-A) was prepared from
6'-(3-chloro-benzylamino-
)-2,3,5,6-tetrahydro-[1,2]bipyrazinyl-4-carboxylic acid tert-butyl
ester (I-2b). To a solution of (I-2b) in CH.sub.2Cl.sub.2 was added
trifluoroacetic acid. After stirring at room temperature for 3 h,
the mixture was poured into 1N NaOH and extracted with
CH.sub.2Cl.sub.2 (1.times.35 mL). The organic layer was washed with
brine, dried and concentrated to afford the title compound as a
free amine (2-A).
[0263] .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.33 (s, 1H);
7.27-7.15 (m, 5H); 4.46 (s, 2H); 3.41 (dd, 4H); 2.81 (dd, 4H). MS
(ES.sup.+) Calc: 303.2, Found: 304.3 (M+1).
Example 3
[0264] Example 3 illustrates alternative methods for preparing
compounds of the present invention wherein W is oxygen and further
illustrates compounds of the present invention where W is oxygen
not illustrated in Example 1.
Example 3-A
Preparation of Intermediate
3-(6-Chloro-pyrazin-2-yloxymethyl)-benzonitril- e (I-3a)
[0265] To a solution of 3-hydroxymethyl-benzonitrile (2.0 g, 15.0
mmol) and 2,6-dichloro-pyrazine (2.24 g, 15.0 mmol) in THF (150 mL)
was added 60% NaH in mineral oil (0.9 g, 22.5 mmol). After stirring
at ambient temperature for 2 h, the reaction mixture was poured
into 1N HCl (100 mL) and extracted with Ethyl Acetate (1.times.250
mL). The organic layer was washed with brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated to dryness. The
crude material was chromatographed over Silica Gel (40 g) eluting
with hexanes (1000 mL) followed by ethyl acetate (500 mL) to obtain
3.53 g of the desired pure product (1-3a) as a white solid.
[0266] MS (ES.sup.+) Calc.: 245.0, Found: 246.1 (M+1). .sup.1HNMR
(CDCl.sub.3): .delta. 8.20 (d, 2H), 7.75(d,1H), 7.69-7.62 (m, 2H),
7.5(t,1H), 5.40(s, 2H).
Preparation of Intermediate
3-(3,4,5,6-Tetrahydro-2H-[1,2']bipyrazinyl-6'--
yloxymethyl)-benzonitrile (I-3b)
[0267] A mixture of 3-(6-chloro-pyrazin-2-yloxymethyl)-benzonitrile
I-3a (3.53 g, 14.4 mmol) and piperazine (12.4 g, 143.70 mmol) in
ethanol (144 mL) was stirred under reflux for 48 h. The reaction
mixture was concentrated to dryness and the residue was dissolved
in ethyl acetate (300 mL). The ethyl acetate solution was washed
with H.sub.2O (4.times.125 mL), brine (125 mL), dried
(Na.sub.2SO.sub.4), filtered, and concentrated to dryness. The
crude material was chromatographed over Silica Gel (40 g) using 5%
methanol/ methylene chloride with 1% NH.sub.40H as the eluant to
give 3.03 g of the desired product (I-3b) as a white solid.
[0268] MS (ES.sup.+) Calc.: 295.1, Found: 296.2 (M+1). .sup.1HNMR
(CDCl.sub.3): .delta. 7.71(d, 1H), 7.68-7.58(2s+m, 4H), 7.47(m,
1H), 5.32(s, 2H), 3.54-3.50(m, 4H), 2.98-2.95(m, 4H).
Preparation of 3-(3.
4.5.6-Tetrahydro-2H-f1,2'bipyrazinyl-6'-yloxymethyl)-- benzamide
(3-A)
[0269] A solution of
3-(3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl-6'-yloxyme-
thyl)-benzonitrile I3b (3.03 g, 10.3 mM) in a mixture of methanol
(10 mL) and 1 N NaOH (51.3 mL, 51.3 mmol) was heated at 60.degree.
C. for 24 h. The reaction mixture was partitioned between H.sub.2O
(150 mL) and ethyl acetate (300 mL). The organic layer was washed
with H.sub.2O, brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated to dryness. The crude material was chromatographed
over Silica Gel (40 g) using 10% methanol/methylene chloride with
1% NH.sub.4OH as the eluant to yield 834 mg of the title compound
(3-A) as a white solid.
[0270] MS (ES.sup.+) Calc.: 313.2, Found: 314.3 (M+1). .sup.1HNMR
(CDCl.sub.3): .delta.7.96(d,1H), 7.80-7.78(dd,1H),
7.62-7.59(s+m,1H), 7.46-7.42(s+m, 2H), 5.39 (s, 2H), 3.53-3.51(m,
4H), 2.87-2.84(m, 4H).
Example 3-B
Preparation of Intermediate 2-Chloromethyl-6-fluoro-pyridine
(1-3c)
[0271] Compound I-3d was prepared according to the procedure
described in the J.Org.Chem., 2000, 65, 7718-7722.
Preparation of Intermediate (6-Fluoro-pyridin-2-yl)-methanol
(I-3d)
[0272] To a solution of 2-chloromethyl-6-fluoro-pyridine I-3c (1.43
g, 9.84 mmol) in H.sub.2O (22 mL) was added K.sub.2CO.sub.3 (1.77
g, 12.8 mmol). The reaction mixture was stirred overnight at
reflux. The cooled aqueous mixture was first extracted with heptane
(2.times.20 mL)and then ethyl acetate (2.times.50 mL). The ethyl
acetate layers were combined, washed with brine, dried
(Na.sub.2SO.sub.4), and concentrated to dryness. The crude residue
was chromatographed over silica gel (15 g) using 2%
methanol/methylene chloride with 0.5% NH.sub.4OH as the eluant to
yield 518.7 mg of the title compound (I-3d) as a yellow oil.
.sup.1HNMR (CDCl.sub.3): .delta. 7.81-7.75(q, 1H), 7.19-7.17(m,
1H), 6.84-6.81(m, 1H), 4.72 (s, 2H).
Preparation of Intermediate
2-Chloro-6-(6-fluoro-pyridin-2-ylmethoxy)-pyra- zine (I-3e)
[0273] To a solution of (6-fluoro-pyridin-2-yl)-methanol I3d (368
mg, 2.89 mmol) and 2,6-dichloro-pyrazine (431.2 mg, 2.89 mM) in THF
(14.7 mL) at room temperature was added 60% NaH in mineral oil (174
mg, 4.34 mmol). The resulting mixture was stirred at ambient
temperature for 19 h and concentrated. The residue was purified by
column chromatography (ethyl acetate/hexanes=1:4)) to afford 560 mg
of the title compound (I-3e).
[0274] MS (ES.sup.+) Calc.: 239.1, Found: 240.1 (M+1). .sup.1HNMR
(CDCl.sub.3): .delta. 8.24(s, 1H), 8.19 (s, 1H), 7.85-7.79(q, 1H),
7.34-7.32(dd, 1H), 6.91-6.88(dd, 1H), 5.42 (s, 2H).
Preparation of
6'-(6-Fluoro-pyridin-2-ylmethoxy)-3,4,5,6-tetrahydro-2H-[1,-
2']bipyrazinyl (3-B)
[0275] Following the general procedure for the preparation of I-3b
above, 2-chloro-6-(6-fluoro-pyridin-2-ylmethoxy)-pyrazine (100 mg,
0.42 mmol) and piperazine (360 mg, 4.17 mmol) were reacted to give
the title compound (3-B). The crude material was purified by
preparative TLC using 5% methanol/methylene chloride with 1%
NH.sub.4OH as the eluant to yield 23 mg of the title product
(3-B).
[0276] MS (ES.sup.+) Calc.: 289.1, Found: 290.2 (M+1). .sup.1HNMR
(CDCl.sub.3): .delta. 7.80-7.74(q,1H), 7.64-7.63 (2s, 2H),
7.32-7.30(dd, 1H), 6.84-6.82(dd,1H), 5.36 (s, 2H), 3.49-3.46 (m,
4H), 2.94-2.92 (m, 4H), 2.23 (br s,1H).
[0277] Using the appropriate starting materials, the compounds
listed in Table 2 were prepared in an analogous manner to the
sequence of reactions described above for the preparation of
compounds (3-A and 3-B).
2 TABLE 2 MS Ex. Found No. Compound Name Calc. (M + 1) 3-C
6'-(2-Pyridin-3-yl-ethoxy)- -3,4,5,6-tetrahydro-2H- 285.4 286.4
[1,2']bipyrazinyl 3-D 6'-(6-Chloro-pyridin-2-ylmethoxy)-3,4,5,6-
305.8 306.3 tetrahydro-2H-[1,2']bipyrazinyl
Example 3-E
Preparation of Intermediate
3-(6-Chloro-pyrazin-2-yloxymethyl)-benzonitril- e (I-3f)
[0278] A mixture of 2,6-dichloropyrazine (400 mg, 0.671 mmol),
3-hydroxymethyl-benzonitrile (428 mg, 0.805 mmol), KOH (181 mg,
0.805 mmol) and 18-crown-6 (28 mg, 0.027 mmol) in toluene (10 mL)
was stirred at reflux for 6 h and concentrated in vacuo. The
residue was partitioned between H.sub.2O and ethyl acetate. The
aqueous phase was separated and extracted with ethyl acetate twice.
The combined organic extracts were washed with water and brine,
dried and concentrated in vacuo. The crude product I3f (667.2 mg)
was used for next step without further purification.
Preparation
3-(3,4,5,6-Tetrahydro-2H[1,2']bipyrazinyl-6'-yloxymethyl)-benz-
onitrile (3-E)
[0279] A mixture of 3-(6-chloro-pyrazin-2-yloxymethyl)-benzonitrile
I-3f (667.2 mg, 2.716 mmol), piperazine (297 mg, 3.531 mmol),
sodium t-butoxide (287 mg, 2.987 mmol), BINAP (67.7 mg, 0.109
mmol), and Pd.sub.2(dba).sub.3 (49.7 mg, 0.054 mmol) in toluene (10
mL) was heated at 90.degree. C. overnight. The solution was cooled
to room temperature and filtered through a celite pad. The celite
pad was washed with ethyl acetate several times. The combined
filtrate was concentrated in vacuo to give the crude title
compound. The product was purified by chromatography (silica, 10%
MeOH/dichlormethane with 1% NH.sub.4OH) to give 180 mg
3-(3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl-6'-yloxymethyl)-benzonitrile
(3-E).
[0280] NMR (400 MHz, CD.sub.3OD) .delta. 7.81 (s, 1H); 7.74 (d,
1H); 7.65 (m, 2H); 7.54 (t,1H); 7.48 (s, 1H); 5.40 (s, 2H); 3.54
(t, 4H); 3.88(t, 4H). MS (ES.sup.+) Calc: 295.1, Found: 296.3
(M+1).
Example 3-F
Preparation of Intermediate
3'-Chloro-6'-(3-chloro-benzyloxy)-3,4,5,6-tetr-
ahydro-2H-[1,2']bipyrazinyl-4-carboxylic acid tert-butyl ester
(I-3h) and Intermediate
5'-Chloro-6'-(3-chloro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2-
']bipyrazinyl-4-carboxylic acid tert-butyl ester (I-3g)
[0281] A solution of
6'-(3-chloro-benzyloxy)-2,3,5,6-tetrahydro-[1,2']bipy-
razinyl-4-carboxylic acid tert-butyl ester (I-1b) (322 mg, 0.80
mmol) in CHCl.sub.3 (10 ml) at 0.degree. C. under a nitrogen
atmosphere was treated with N-chlorosuccinamide (106 mg, 0.80
mmol). The resulting mixture was allowed to warm to room
temperature and stirred for 16 h. The reaction mixture was
partitioned between CHCl.sub.2 and saturated aqueous NaHCO.sub.3
solution. The organic phase was washed with twice with saturated
aqueous NaHCO.sub.3 solution and once with brine, dried over
MgSO.sub.4 (anhydrous), filtered and concentrated in vacuo. The
residue was purified by flash chromatography (CHCl.sub.2-EtOAc 99:1
to 95:5). Three compounds were obtained in the following elution
order: dichlorinated material (45 mg, 13%), Compound I-3g (116 mg,
33%) and Compound I-3h (30 mg, 7%). The structures of the two
monochlorinated products were assigned by nOe experiments.
[0282] Compound I-3g: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
1.46 (s, 9H), 3.34-3.37 (m, 4H), 3.51-3.54 (m, 4H), 5.25 (s, 2H),
7.24-7.26 (m, 3H), 7.37 (s,1H), 7.57 (s, 1H). MS (ES.sup.+) Calc:
438.1, Found: 439.2 (M+1).
[0283] Compound I-3h: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
1.48 (s, 9H), 3.48-3.57 (m, 8H), 5.35 (s, 2H), 7.29-7.33 (m, 3H),
7.41-7.42 (m, 2H). MS (ES.sup.+) Calc: 438.1, Found: 439.2
(M+1).
Preparation of
3'-Chloro-6'-(3-chloro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,-
2']bipyrazinyl hydrochloride (3-F)
[0284] A solution of
3'-Chloro-6'-(3-chloro-benzyloxy)-3,4,5,6-tetrahydro--
2H-[1,2']bipyrazinyl-4-carboxylic acid tert-butyl ester (Compound
I-3g) (40 mg, 0.091 mmol) in 1,4-dioxane (0.5 ml) at 23.degree. C.
was treated with HCl in 1,4-dioxane (4 M, 0.23 ml, 0.91 mmol). The
resulting mixture was stirred at room temperature for 5 h (during
which a precipitate appeared) and treated with ether. The solid was
collected by filtration and washed with ether to afford the title
compound 3-F (27 mg, 72%).
[0285] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 3.18 (bs, 4H),
3.55 (bs, 4H), 5.35 (s, 2H), 7.40 (m, 3H), 7.52 (s,1H), 7.77
(s,1H), 9.32-9.39 (m, 2H) MS (ES.sup.+) Calc: 338.1, Found: 339.3
(M+1).
Example 3-G
5'-Fluoro-6'-(3-chloro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl4-
-carboxylic acid tert-butyl ester (I-3i): and
3'-Fluoro-6'-(3-chloro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl4-
-carboxylic acid tert-butyl ester (I-3i')
[0286] A solution of
6'-(3-chloro-benzyloxy)-2,3,5,6-tetrahydro-[1,2']bipy-
razinyl4-carboxylic acid tert-butyl ester (1-1 b) (600 mg, 1.49
mmol) in acetonitrile (12.4 ml) at 0.degree. C. under a nitrogen
atmosphere was treated with Selectfluor.TM.
([1-(chloromethyl)4-fluoro-1,4-diazoniabicyc- lo[2.2.2]-octane
bis(tetrafluoroborate)]) (526 mg, 1.49 mmol). The resulting mixture
was allowed to warm to room temperature and stirred for 16 h. The
reaction mixture was partitioned between CH.sub.2Cl.sub.2 and
water. The organic phase was washed twice with water, twice with
saturated aqueous NaHCO.sub.3 solution and twice with brine, dried
over MgSO.sub.4 (anhydrous), filtered and concentrated in vacuo.
The residue was purified by flash chromatography (CHCl.sub.2-EtOAc
99:1 to 95:5). Three compounds were obtained in the following
elution order: difluorinated material (160 mg, 25%), Intermediate
I-3i (32 mg, 5%) and Intermediate I-3i'(141 mg, 22%). The
structures of the two monofluorinated products were assigned by
nuclear Overhauser effect (nOe) experiments.
[0287] Intermediate I-3i: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
1.48 (s, 9H), 3.41 (m, 4H), 3.54 (m, 4H), 5.36 (s, 2H), 7.05 (d,
J=3,1H), 7.30 (m, 3H), 7.43 (s,1H). MS (ES.sup.+) Calc: 422.2,
Found: 423.4 (M+1).
[0288] Intermediate I-3i': .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 1.45 (s, 9H), 3.49 (m, 8H), 5.22 (s, 2H), 7.10 (d, J=3,
1H), 7.25 (m, 3H), 7.37 (s, 1H) MS (ES.sup.+) Calc: 422.2, Found:
423.2 (M+1).
Preparation of
6'-(3-Chloro-benzyloxy)-5'-fluoro-3,4,5,6-tetrahydro-2H-[1,-
2']bipyrazinyl formate (3-G):
[0289] A solution of
6'-(3-chloro-benzyloxy)-5'-fluoro-3,4,5,6-tetrahydro--
2H-[1,2']bipyrazinyl-4-carboxylic acid tert-butyl ester (I-3i) (50
mg, 0.12 mmol) in formic acid (96%, 0.5 ml) was stirred at room
temperature for 2 h, and concentrated in vacuo. The residue was
triturated three times with ether. The title compound 3-I was
collected as a white solid (15 mg, 34%). MS (ES.sup.+) Calc: 322.1,
Found: 323.4 (M+1).
Example 3-H
Preparation of
3'-Bromo-6'-(3-chloro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2-
']bipyrazinyl-4-carboxylic acid tert-butyl ester (I-3i) and
5'-Bromo-6'-(3-chloro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl--
4-carboxylic acid tert-butyl ester (I-3i')
[0290] A solution of
6'-(3-chloro-benzyloxy)-2,3,5,6-tetrahydro-[1,2']bipy-
razinyl-4-carboxylic acid tert-butyl ester (1-1 b) (1.5 g, 3.7
mmol) in CHCl.sub.3 (44 ml) at 0.degree. C. under a nitrogen
atmosphere was treated with N-bromosuccinamide (6.49 mg, 3.53
mmol). The resulting mixture was allowed to warm to room
temperature and stirred for 16 h. The reaction mixture was
partitioned between CH.sub.2Cl.sub.2 and saturated aqueous
NaHCO.sub.3 solution. The organic phase was washed with saturated
aqueous NaHCO.sub.3 solution and with brine, dried over MgSO.sub.4
(anhydrous), filtered and concentrated in vacuo. The residue was
purified by flash chromatography (CHCl.sub.2-EtOAc 99:1 to 96:4).
Three compounds were obtained in the following elution order:
dibrominated material (68 mg, 4%), Intermediate I-3i (176 mg, 10%)
and Intermediate I-3j' (805 mg, 45%). The structures of the two
monobrominated products were assigned by nuclear Overhauser effect
(nOe) experiments.
[0291] Intermediate I-3i: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
1.49 (s, 9H), 3.32-3.37 (m, 4H), 3.55-3.58 (m, 4H), 5.28 (s, 2H),
7.27-7.31 (m, 3H), 7.41 (s, 1H), 7.65 (s, 1H). MS (ES.sup.+) Calc:
482.1, Found: 483.4 (M+1).
[0292] Intermediate I-3j': .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 1.48 (s, 9H), 3.50 (m, 8H), 5.35 (s, 2H), 7.28-7.32 (m,
3H), 7.43 (m, 2H). MS (ES.sup.+) Calc: 482.1, Found: 483.4
(M+1).
Preparation of Intermediate 6'-(3-Chloro-benzyloxy)-3'-methyl-3
4,5,6-tetrahydro-2H-[1,2']bipyrazinyl-4-carboxylic acid tert-butyl
ester (I-3k)
[0293] A mixture of
3'-bromo-6'-(3-chloro-benzyloxy)-3,4,5,6-tetrahydro-2H-
-[1,2']bipyrazinyl-4-carboxylic acid tert-butyl ester (I-3j) (82
mg, 0.17 mmol), methylboronic acid (15.3 mg, 0.25 mmol),
K.sub.3PO.sub.4 (72 mg, 0.34 mmol), dppf (4.7 mg, 0.0085 mmol) and
PdCl.sub.2dppf(CH.sub.2Cl.sub.- 2).sub.2 (6.9 mg, 0.0085 mmol) in
THF (anhydrous, 1.2 ml) under a nitrogen atmosphere was heated to
reflux for 16 h. The reaction mixture was cooled to room
temperature and filtered through a pad of silica gel, eluting with
EtOAc-hexane (6:4). The filtrate was concentrated in vacuo. The
residue was purified by preparative TLC (EtOAc-hexane 1:1) to
provide 72 mg of the title compound I-3k (>99% yield).
[0294] MS (ES.sup.+) Calc: 418.2, Found: 419.2 (M+1).
Preparation of 6
'-(3-Chloro-benzyloxy)-3'-methyl-3,4,5,6-tetrahydro-2H-[1-
,2']bipyrazinyl hydrochloride (3-H)
[0295] A solution of Intermediate I-3k (72 mg, 0.17 mmol) in HCl in
1,4-dioxane (4 M, 1.0 ml, 4 mmol) at 23.degree. C. was stirred at
room temperature for 1 h (during which a precipitate appeared) and
treated with ether. The solid was collected by filtration and
washed with ether to afford 50 mg of the title compound 3-H (75%
yield).
[0296] MS (ES.sup.+) Calc: 318.1, Found: 319.2 (M+1).
[0297] The compounds listed in Table 3 were prepared using
analogous procedures to those used for the preparation of 3-F
(hydrochloride salt) and 3-G (formate salt) using either
N-chlorosuccinamide, N-bromosuccinamide, or Selectfluor for
introducing the halogen onto the pyrazine ring.
3 TABLE 3 MS Ex. Found No. Compound Name Calc. (M + 1) 3-I
5'-Chloro-6'-(3-chloro-ben- zyloxy)-3,4,5,6- 338.1 339.3
tetrahydro-2H-[1,2']bipyrazinyl hydrochloride 3-J
3'-Fluoro-6'-(3-chloro-benzyloxy)-3,4,5,6- 322.1 323.4
tetrahydro-2H-[1,2']bipyrazinyl hydrochloride 3-K
5'-Fluoro-6'-(3-chloro-benzyloxy)-3,4,5,6- 322.1 323.4
tetrahydro-2H-[1,2']bipyrazinyl formate 3-L
3'-Bromo-6'-(3-chloro-benzyloxy)-3,4,5,6- 382.0 383.2
tetrahydro-2H-[1,2']bipyrazinyl formate 3-M
5'-Bromo-6'-(3-chloro-benzyloxy)-3,4,5,6- 382.0 383.1
tetrahydro-2H-[1,2']bipyrazinyl hydrochloride
Example 3-N
Preparation of Intermediate
3-Chloro-5-(3-chloro-benzyloxy)-pyrazine (I-3l)
[0298] A solution of 3-chlorobenyl alcohol (9.57 g, 67.1 mmol) in
toluene (134 ml) at 23.degree. C. under a nitrogen atmosphere was
treated with NaH (60% dispersion in oil, 2.5 g, 67.1 mmol). The
resulting suspension was heated to reflux for 30 min and cooled to
room temperature. The mixture was treated with 2,6-dichloropyrazine
(10.0 g, 67.1 mmol) and heated to reflux for 18 h. The reaction
mixture was cooled to room temperature and partitioned between
water and EtOAc. The organic phase was washed with brine, dried
over MgSO.sub.4 (anhydrous), filtered and concentrated in vacuo.
The residue was purified by flash chromatography
(CH.sub.2Cl.sub.2-hexanes 3:7) to afford 10.0 g of the title
compound (1-31) as a clear oil (58%).
[0299] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.36 (s, 2H), 7.33
(m, 3H), 8.18 (s, 1H), 8.19 (s, 1H) MS (ES.sup.+) Calc: 254.0,
Found: 255.2 (M+1).
Preparation of Intermediate
3-Chloro-5-(3-chloro-benzyloxy)-pyrazine 1-oxide (I-3m)
[0300] A solution of 3-chloro-5-(3-chloro-benzyloxy)-pyrazine I3I
(500 mg, 1.97 mmol) in CHCl.sub.3 (10 ml) at 0.degree. C. under a
nitrogen atmosphere, was treated with 680 mg (3.94 mmol)
m-chloroperbenzoic acid (mCPBA). The resulting mixture was allowed
to warm to room temperature, stirred at 23.degree. C. for 16 h,
heated at reflux for 2 h and cooled to room temperature. The
reaction mixture was treated with Ca(OH).sub.2 (680 mg, 3.94 mmol),
stirred at room temperature for 3 h and filtered. The solid was
washed with CH.sub.2Cl.sub.2. The filtrate and washings were
combined, dried over MgSO.sub.4 (anhydrous), filtered, and
concentrated in vacuo. The residue was purified by flash
chromatography (EtOAc-hexanes 4:6) to provide 465 mg of the title
compound (I-3m) as a white solid (87%).
[0301] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.3 (s, 2H), 7.27
(m, 3H), 7.36 (s, 1H), 7.69 (s, 1H), 7.77 (s, 1H) MS (ES.sup.+)
Calc: 270.0, Found: 271.2 (M+1).
Preparation of Intermediate
6'-(3-Chloro-benzyloxy)-3,4,5,6-tetrahydro-2H-- [1,2']bipyrazinyl
4'-oxide-4-carboxylic acid tert-butyl ester (I-3n)
[0302] A solution of 3-chloro-5-(3-chloro-benzyloxy)-pyrazine
1-oxide (I-3m) (200 mg, 0.74 mmol) in acetonitrile (2 ml) under a
nitrogen atmosphere was treated with piperazine-1-carboxylic acid
tert-butyl ester (343 mg, 1.85 mmol) and heated at reflux for 5 h.
The reaction mixture was cooled to room temperature and partitioned
between water and EtOAc. The organic phase was washed with
saturated aqueous NaHCO.sub.3 solution and was dried over
MgSO.sub.4 (anhydrous), filtered and concentrated in vacuo. The
residue was purified by preparative TLC (EtOAc-hexanes 1:1) to
provide 200 mg of the title compound I-3n (64%).
[0303] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.48 (s, 9H), 3.5
(m, 8H), 5.3 (s, 2H), 7.31 (m, 3H), 7.38 (s,1H) MS (ES.sup.+) Calc:
420.2, Found: 421.4 (M+1).
Preparation of
6'-(3-Chloro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyraz- inyl
4'-oxide hydrochloride (3-N)
[0304] A solution of
6'-(3-chloro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']b- ipyrazinyl
4'-oxide-4-carboxylic acid tert-butyl ester (I-3n) (100 mg, 0.24
mmol) in HCl in 1,4-dioxane (4 M, 2.0 ml, 8 mmol) at 23.degree. C.
was stirred at room temperature for 20 min (during which a
precipitate appeared). The solid was collected by filtration and
washed with ether to afford 85 mg of the title compound 3-N
(99%).
[0305] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 3.10 (bs, 4H),
3.73 (bs, 4H), 5.34 (s, 2H), 7.39-7.5 (m, 5H), 7.73 (s, 1H),
9.26-9.32 (m, 2H) MS (ES.sup.+) Calc: 320.1, Found: 321.3
(M+1).
Example 3-O
Preparation of Intermediate
5-Bromo-3-(3-chloro-benzyloxy)-pyrazin-2-ylami- ne (1-3o)
[0306] 3-Chlorobenzyl alcohol (2.36 mL, 20 mmol) was added slowly
with vigorous stirring to a suspension of NaH (60% dispersion in
mineral oil, 0.80 g, 20 mmol) in THF (25 mL) at room temperature
under dry nitrogen with vigorous gas evolution. The resulting
suspension was stirred for 10 min at room temperature.
2-Amino-3,5-dibromopyrazine (2.53 g, 10 mmol) was added in a single
portion to give a dark amber solution. The solution was heated to
reflux for 2 h then cooled to room temperature. The solvent was
removed in vacuo to give an oily brown solid which was dissolved in
EtOAc (50 mL). The EtOAc solution was washed with saturated aqueous
NaHCO.sub.3 (75 mL). The NaHCO.sub.3 solution was back extracted
with EtOAc (2.times.75 mL). The combined EtOAc extracts were washed
with water (100 mL) and brine (75 mL), dried over Na.sub.2SO.sub.4,
filtered, and concentrated to a viscous oily solid. The residue was
filtered through a plug of silica gel, eluting with
CH.sub.2Cl.sub.2, discarding the first two void volumes, and the
filtrate was concentrated to a pinkish solid. The solid was
dissolved in Et.sub.2O (50 mL) and treated with 4 M HCl in
1,4-dioxane (10 mL, 40 mmol). The resulting suspension was stirred
30 min at room temperature and the precipitate collected by
filtration, washing with Et.sub.2O (3.times.10 mL). The off-white
solid obtained was dried in vacuo to give 2.63 g of the
hydrochloride salt. The salt was converted to the free base by
vigorous stirring at room temperature in saturated aqueous
NaHCO.sub.3 (100 mL) and EtOAc (100 mL). After 30 min, the phases
were separated and the aqueous phase was extracted with EtOAc
(2.times.50 mL). The combined extracts were washed with brine,
dried over Na.sub.2SO.sub.4 (anhydrous), filtered, and concentrated
in vacuo to give the title compound I-3o as a pink solid (1.83 g,
58% yield).
[0307] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.67 (s, 1H); 7.44
(d, 1H); 7.35-7.31 (m, 3H); 5.36 (s, 2H); 4.87 (broad s, 2H). MS
(ES.sup.+) Calc: 313.0, Found: 314.2 (M+1).
Preparation of Intermediate
[5-Bromo-3-(3-chloro-benzyloxy)-pyrazin-2-yl]-- carbamic acid
tert-butyl ester (1-3p)
[0308] 5-Bromo-3-(3-chloro-benzyloxy)-pyrazin-2-ylamine I-3o (1.82
g, 5.8 mmol) and triethylamine (1.22 mL, 8.7 mmol) were dissolved
in 1,4-dioxane (29 mL) under dry nitrogen. 4-Dimethylaminopyridine
(71 mg, 0.58 mmol) and di-tert-butyl dicarbonate (1.9 g, 8.7 mmol)
were added in single portions and the solution was heated to
95.degree. C. The solution was stirred at 95.degree. C. for 3 h
then an additional amount of TEA (0.61 mL, 4.4 mmol) and
di-tert-butyl dicarbonate (0.95 g, 4.4 mmol) were added. The
solution was stirred an additional 30 min at 95.degree. C. then
cooled to room temperature, treated with brine, and extracted with
EtOAc (120 ml). The extract was washed with brine (120 mL), dried
over Na.sub.2SO.sub.4 (anhydrous), filtered, and concentrated in
vacuo to an amber viscous oil. Purification by silica gel column
(hexanes/EtOAc 9:1) and trituration with hexane (5 mL) gave the
title compound I-3p as a slightly yellow solid (2.26 g, 94%
yield).
[0309] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.15 (s, 1H); 7.47
(s, 1H); 7.33-7.26 (m, 3H); 5.42 (s, 2H); 1.38 (s, 9H). MS
(ES.sup.+) Calc: 413.0, Found: 358.2 ([M-56]+1, carbamic acid
fragment generated on ionization).
Prenaration of Intermediate
5'-tert-Butoxycarbonylamino-6'-(3-chloro-benzy-
loxy)-2,3,5,6-tetrahydro-[1,2']bipyrazinyl-4-carboxylic acid
tert-butyl ester (I-3q)
[0310] [5-Bromo-3-(3-chloro-benzyloxy)-pyrazin-2-yl]-carbamic acid
tert-butyl ester I-3p (2.18 g, 5.3 mmol), pperazine-1-carboxylic
acid tert-butyl ester (1.18 g, 6.3 mmol), sodium tert-butoxide
(0.71 g, 7.4 mmol), racemic BINAP (196 mg, 315 .mu.mol), and
tris(benzylideneacetone)d- ipalladium (96.5 mg, 105 .mu.mol) were
placed in a vial equipped with a septum cap. The vial was evacuated
and backfilled with dry nitrogen three times, and toluene (11 mL)
added. The mixture was heated to 80.degree. C. for 2 h then cooled
to room temperature. Resulting suspension was transferred to a
flask with CH.sub.2Cl.sub.2 and concentrated in vacuo to an amber
oily solid. Purification by silica gel column (hexanes/EtOAc 7:3)
gave the title compound I-3q as a yellow foam (560 mg, 25%
yield).
[0311] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.48 (s,1H); 7.42
(s,1H); 7.32-7.28 (m, 3H); 6.73 (broad s,1H); 5.33 (s, 2H);
3.55-3.5 (m, 4H); 3.43-3.39 (m, 4H) 1.51 (s, 9H); 1,48 (s, 9H). MS
(ES.sup.+) Calc: 519.2, Found: 520.1 (M+1).
Preparation of
6'-(3-Chloro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyraz-
inyl-5'-ylamine (3-O)
[0312]
5'-tert-Butoxycarbonylamino-6'-(3-chloro-benzyloxy)-2,3,5,6-tetrahy-
dro-[1,2]bipyrazinyl4-carboxylic acid tert-butyl ester I-3q (50 mg,
96 .mu.mol) was dissolved in CH.sub.2Cl.sub.2 (1 mL) and
trifluoroacetic acid (1 mL) was added with stirring at room
temperature. The solution was stirred at room temperature for 3 h
then diluted with CH.sub.2Cl.sub.2 (20 mL). The CH.sub.2Cl.sub.2
solution was washed with saturated aqueous NaHCO.sub.3 (3.times.50
mL) and brine (25 mL), dried over Na.sub.2SO.sub.4 (anhydrous),
filtered, and concentrated in vacuo to give the title compound 3-O
as a reddish-brown solid (29 mg, 95% yield).
[0313] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.44 (s, 1H);
7.33-7.30 (m, 3H); 7.12 (s, 1H); 5.35 (s, 2H); 4.35 (broad s, 2H);
3.29 (dd, 4H); 3.05(dd, 4H). MS (ES.sup.+) Calc: 319.1, Found:
320.4 (M+1).
Example 3-P
Preparation of the Interrnediate
3'-Amino-6'-bromo-2,3,5,6-tetrahydro-[1,2-
']bipyrazinyl-4-carboxylic acid tert-butyl ester (I-3r)
[0314] 2-Amino-3,5-dibromopyrazine (1.26 g, 5.0 mmol) and
piperazine-1-carboxylic acid tert-butyl ester (4.64 g, 25 mmol)
were placed in a dry RBF and heated with stirring to 120.degree. C.
under dry nitrogen. Molten mixture was stirred at this temperature
for 6 h and cooled to room temperature. The resulting slurry was
diluted with EtOAc (20 mL) and stirred for 20 min. Amine salts were
removed by filtration and washed with EtOAc (3.times.5 mL).
Filtrate was washed with pH 4 buffer (35 mL) and brine (35 mL),
dried over Na.sub.2SO.sub.4 (anhydrous), filtered, and concentrated
in vacuo. The residue was purified by flash chromatography
(hexanes/EtOAc 7:3) gives the title compound I-3r as an off white
solid (1.64 g, 92% yield).
[0315] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.81 (s, 1H); 4.54
(m, 2H); 3.75-3.38 (m, 4H); 3.37-2.95 (m, 4H); 1.47 (s, 9H). MS
(ES.sup.+) Calc: 357.1, Found: 358.3 (M+1).
Preparation of Intermediate
3'-Amino-6'-chloro-benzyloxy)-2,3,5,6-tetrahyd-
ro-[1,2']bipyrazinyl-4-carboxylic acid tert-butyl ester (I-3s)
[0316]
3'-Amino-6'-(3-chloro-benzyloxy)-2,3,5,6-tetrahydro-[1,2]bipyraziny-
l-4-carboxylic acid tert-butyl ester I-3s was prepared from
3'-Amino-6'-bromo-2,3,5,6-tetrahydro-[1,2']bipyrazinyl4-carboxylic
acid tert-butyl ester I3r (1.0 g, 2.8 mmol) and 3-chlorobenzyl
alcohol (0.36 mL, 3.1 mmol) in a manner analogous to compound 1-1 b
in example 1. The title compound I-3s was obtained as a red viscous
oil (394 mg, 34% yield).
[0317] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.45 (s,1H); 7.42
(s,1H); 7.32-7.22 (m, 3H); 5.22 (s, H); 4.40-4.00 (broad s,1H);
3.76-3.34 (m, 4H); 3.30-2.92 (m, 4H); 1,48 (s, 9H). MS (ES.sup.+)
Calc: 419.2, Found: 420.4 (M+1).
Preparation of
6'-(3-Chloro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyraz-
inyl-3'-ylamine (3-P)
[0318]
3'-Amino-6'-(3-chloro-benzyloxy)-2,3,5,6-tetrahydro-[1,2']bipyrazin-
yl4-carboxylic acid tert-butyl ester I-3s (150 mg, 357 .mu.mol) was
dissolved in 1,4-dioxane (6 mL) and an HCl solution (0.90 mL, 4 M
in 1,4-dioxane, 3.6 mmol) was added with stirring at 40.degree. C.
The solution was stirred at 40.degree. C. for 18 h and concentrated
in vacuo to approximately 2 mL. The mixture was diluted with
Et.sub.2O. The resulting brown solid was collected by filtration
and washed twice with Et.sub.2O. The solid was purified by
preparative HPLC to give the title compound 3-P as a tan solid (19
mg, 17% yield).
[0319] .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.44 (s, 1H); 7.45
(d, 1H); 7.39-7.27 (m, 3H); 5.28 (s, 2H); 3.46-3.34 (m, 8H). MS
(ES.sup.+) Calc: 319.1, Found: 320.6 (M+1).
Example 3-Q
Preparation of the Intermediate (2-Methyl-thiazol-4-yl)-methanol
(I-3t)
[0320] Freshly distilled 2,2,6,6-tetramethylpiperidine (1.8 mL,
10.5 mmol) was dissolved in dry THF (50 mL) in a flame-dried RBF
and cooled to -78.degree. C. under dry nitrogen. A solution of
n-butyllithium (4.8 mL, 2.1 M in hexanes, 10 mmol) was added slowly
to the cooled solution with stirring. The resulting yellow solution
was warmed to 0.degree. C., stirred for 30 min and cooled to
-78.degree. C. A solution of 4-methylthiazole (455 .mu.L, 5.0 mmol)
in dry THF (5 mL) was added by cannula. The resulting solution was
stirred for 30 min at -78.degree. C. Dry DMF (774 .mu.L, 10 mmol)
was added with stirring over 5 min. The solution was stirred at
-78.degree. C. for 1 h then warmed to room temperature. After
stirring 1 h, the solution was diluted with EtOH (20 mL) and sodium
borohydride (0.57 g, 15 mmol) was added with gas evolution. The
solution was stirred for 2 h then poured into aqueous saturated
NH.sub.4Cl (100 mL). The phases were separated and the aqueous
phase was extracted with CH.sub.2Cl.sub.2 (3.times.50 mL). The
combined organic extracts were washed with brine, dried over
MgSO.sub.4 (anhydrous), filtered, and concentrated in vacuo. The
residue was purified by flash chromatography (3% MeOH in
CH.sub.2Cl.sub.2) to give the title compound I-3t as a yellow oil
(368 mg, 57% yield).
[0321] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.26 (s, 1H); 4.86
(s, 2H); 4.37 (broad s, 1H); 2.38 (s, 3H). MS (EI) Calc: 129.0,
Found: 129 (M+).
Preparation of Intermediate
6'-(4-Methyl-thiazol-2-ylmethoxy)-2,3,5,6-tetr-
ahydro-[1,2']bipyrazinyl-4-carboxylic acid tert-butyl ester
(I-3u)
[0322] (2-Methyl-thiazol-4-yl)-methanol 1-3t (155 mg, 1.2 mmol) was
dissolved in dry toluene (5 mL) under dry nitrogen and
6'-chloro-2,3,5,6-tetrahydro-[1,2']-bipyrazinyl-4-carboxylic acid
tert-butyl ester (I-1 a) (299 mg, 1.00 mmol), powdered KOH (191 mg,
3.4 mmol), and 18-crown-6 (13.2 mg, 50 .mu.mol) were added with
stirring. The mixture was heated at reflux with vigorous stirring.
The mixture was stirred at reflux for 3 h then cooled to room
temperature. The toluene was removed in vacuo. The residue was
purified by preparative thin layer chromatography (10% methanol/90%
CH.sub.2Cl.sub.2) to give the title compound I-3u as a viscous
amber oil (375 mg, 96% yield).
[0323] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.68 (s, 1H); 7.62
(s, 1H); 6.88 (q, 1H, J=0.83 Hz); 5.58 (s, 2H); 3.65-3.35 (m, 8H);
2.45 (d, 3H, J=0.83 Hz); 1.48 (s, 9H). MS (APCI+) Calc: 391.2,
Found: 392.2 (M+1).
Preparation of
6'-(4-Methyl-thiazol-2-ylmethoxy)-3,4,5,6-tetrahydro-2H-[1,-
2']bipyrazinyl, (3-Q)
[0324]
6'-(4-Methyl-thiazol-2-ylmethoxy)-2,3,5,6-tetrahydro-[1,2]bipyrazin-
yl-4-carboxylic acid tert-butyl ester (I-3u) (376 mg, 0.96 mmol)
was dissolved in dry 1,4-dioxane (4 mL) and 4 M HCl in 1,4-dioxane
(4 mL, 16 mmol) was added with stirring. A gummy solid immediately
precipitated. Methanol (2 mL) was added to solubilize the solid.
The resulting solution was stirred at room temperature for 4 h and
concentrated to a gummy yellow solid. The residue was basified by
addition of 1 M NaOH (15 mL) and extracted with CH.sub.2Cl.sub.2
(3.times.20 mL). The combine extracts were dried over
Na.sub.2SO.sub.4 (anhydrous), filtered, and concentrated in vacuo
to an amber oil. The oil solified on drying in vacuo to give the
title compound 3-Q (274 mg, 98% yield).
[0325] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.67 (s, 1H); 7.61
(s, 1H); 6.87 (q, 1H, J=0.83 Hz); 5.58 (s, 2H); 3.57-3.53 (m, 4H);
3.00-2.95 (m, 4H); 2.45 (d, 3H, J=0.83 Hz). MS (APCI+) Calc: 291.1,
Found: 292.2 (M+1).
Example 3-R
Preparation of
5'-Bromo-6'-(3-chloro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2-
']bipyrazinyl formate (3-R)
[0326] A solution of
5'-bromo-6'-(3-chloro-benzyloxy)-3,4,5,6-tetrahydro-2-
H-[1,2']bipyrazinyl-4-carboxylic acid tert-butyl ester I-3i (25 mg,
0.052 mmol) in formic acid (96%, 0.75 ml) was stirred at room
temperature for 2 h, and concentrated in vacuo. The title compound
3-R was collected as a white solid (26 mg, >99%).
[0327] MS (ES.sup.+) Calc: 382.0, Found: 383.3 (M+1).
Example 3-S
Preparation of
5'-Bromo-6'-(3-chloro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2-
']bipyrazinyl methanesulfonate (3-S)
[0328] A solution of
5'-bromo-6'-(3-chloro-benzyloxy)-3,4,5,6-tetrahydro-2-
H-[1,2']bipyrazinyl-4-carboxylic acid tert-butyl ester I-3i (25 mg,
0.052 mmol) in 1,4-dioxane (0.5 ml) was treated with
methanesulfonic acid (6.7 .mu.l, 0.104 mmol) was stirred at room
temperature for 16 h. The mixture was treated with ether to afford
a precipitate. The supernatant was removed. The residue was treated
with ether. The supernatant was again removed to provide a solid
(26 mg, 87%).
[0329] MS (ES.sup.+) Calc: 382.0, Found: 383.3 (M+1).
Example 4
[0330] Example 4 illustrates alternative methods for preparing
compounds of the present invention wherein W is nitrogen and
further illustrates compounds of the present invention where W is
nitrogen not illustrated in Examples 1 and 2 above.
Example 4-A
Preparation of Intermediate (3-Fluoro-benzyl)-carbamic acid
tert-butyl ester (I-4a)
[0331] A mixture of 3-fluoro-benzylamine (0.25 mL, 2.19 mmol) and
Di-tert-butyl dicarbonate (0.5 mL, 2.19 mmol) in THF (5 mL) was
stirred at ambient temperature for 2 h. The reaction mixture was
poured into H.sub.2O (15 mL) and extracted with EtOAc (2.times.20
mL). The organic layers were combined, washed with brine, dried
(Na.sub.2SO.sub.4), and concentrated in vacuo to yield the title
compound I-4a (493 mg). .sup.1HNMR (CDCL.sub.3): .delta. 1.4(s,
9H), 4.3(d, 2H), 6.91-6.98 (m, 2H), 7.02-7.04 (d,1H), 7.26-7.30 (m,
1H).
Preparation of Intermediate
(6-Chloro-pyrazin-2-yl)-(3-fluoro-benzyi)-carb- amic acid
tert-butyl ester (I-4b)
[0332] A solution of (3-fluoro-benzyl)-carbamic acid tert-butyl
ester I-4a (1.21 g, 5.37 mmol) in DMF (50 mL) was treated with 60%
NaH in mineral oil (430 mg, 10.7 mmol). The resulting mixture was
stirred at ambient temperature until the gas evolution ceased. The
solution was treated with 2,6-dichloro-pyrazine (800 mg, 5.37 mmol)
and the reaction mixture was heated to 80.degree. C. under N.sub.2
and stirred for 5 h. The reaction was cooled and concentrated in
vacuo to approximately 1/3 volume. The reaction mixture was poured
into H.sub.2O (50 mL) and extracted with Ethyl Acetate (1.times.200
mL). The organic layer was washed with H.sub.2O (4.times.50 mL),
brine, dried (Na.sub.2SO.sub.4), and concentrated to dryness. The
crude product was purified by chromatography (EtOAc/Hex 5:95) to
afford the title compound I-4b (1.14 g) as a colorless oil.
[0333] MS (ES.sup.+) Calc.: 337, Found: 338.1 (M+1). .sup.1HNMR
(MeOD): .delta. 1.4(s, 9H), 5.1(s, 2H), 7.0(m, 3H), 7.3(m, 1H),
8.3(s, 1H), 9.1(s, 1H).
Preparation of Intermediate
(3-Fluoro-benzyl)-(3,4,5,6-tetrahydro-2H-[1,2'-
]bipyrazinyl-6'-yl)-carbamic acid tert-butyl ester (I-4c)
[0334] A solution of
(6-chloro-pyrazin-2-yl)-(3-fluoro-benzyl)-carbamic acid tert-butyl
ester (1.14 g, 3.39 mmol) and piperazine (1.75 g, 20 mmol) in EtOH
(34 mL) was stirred at reflux for 19 h. The reaction mixture was
cooled and concentrated in vacuo. The residue was dissolved in
Ethyl Acetate and washed with H.sub.2O (4.times.50 mL), brine,
dried (Na.sub.2SO.sub.4), and concentrated to dryness. The crude
product was chromatographed on Silica Gel (90 g) using 5% MeOH in
CH.sub.2Cl.sub.2 as the eluant to give the title compound I-4c
(1.09g) as a pale yellow oil.
[0335] MS (ES.sup.+) Calc.: 387, Found: 388.5 (M+1). .sup.1HNMR
(MeOD): .delta. 1.4(s, 9H), 2.8(m, 4H), 3.4(m, 4H), 5.1(s, 2H),
7.0(m, 3H), 7.3(m, 1H), 7.8(s, 1H), 8.3(s, 1H).
Preparation of
(3-Fluoro-benzyl)-(3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl--
6'-yl)-amine (4-A)
[0336] To a solution of
(3-fluoro-benzyl)-(3,4,5,6-tetrahydro-2H-[1,2']bip-
yrazinyl-6'-yl)-carbamic acid tert-butyl ester I-4c (30 mg, 0.08
mmol) in CH.sub.2Cl.sub.2 (1 mL) was added with trifluoroacetic
Acid (0.5 mL) and the resulting mixture was stirred at ambient
temperature for 19 h. The reaction mixture was poured into 1 N NaOH
(10 mL) and extracted with ethyl acetate (1.times.40 mL). The
organic layer was washed with brine, dried (Na.sub.2SO.sub.4), and
concentrated to give the title compound 4-A (19.3mg).
[0337] MS (ES.sup.+) Calc.: 287, Found: 288.4 (M+1). .sup.1HNMR
(CDCL.sub.3): .delta. 2.9(m, 4H), 3.5(m, 4H), 4.5(m, 2H), 4.8(bm,
1H), 6.9(m, 1H), 7.0(m, 1H), 7.3(m, 3H).
[0338] The compounds listed in Table 4 were prepared using the
general procedures described in Example 4-A above with the
appropriate starting materials.
4 TABLE 4 Ex. No. Compound Name Analytical Data 4-B
(2-Fluoro-benzyl)- MS (ES.sup.+) Calc.: 287, (3,4,5,6-tetrahydro-
Found: 288.4 (M + 1). 2H-[1,2']bipyrazinyl- .sup.1HNMR (MeOD):
6'-yl)-amine .delta. 3.3(m, 4H), 3.9(m, hydrochloride salt 4H),
4.7(bs, 2H), 7.1(m, 2H), 7.3(m, 2H), 7.4(m, 2H). 4-C
(4-Chloro-benzyl)- MS (ES.sup.+) Calc.: 303, (3,4,5,6-tetrahydro-
Found: 304.4 (M + 1). 2H-[1,2']bipyrazinyl- .sup.1HNMR (MeOD):
6'-yl)-amine .delta. 3.3(m, 4H), 3.9(m, hydrochloride salt 4H),
4.6(m, 2H), 7.3(m, 5H), 7.4(m, 1H). 4-D (4-Fluoro-benzyl)- MS
(ES.sup.+) Calc.: 287, (3,4,5,6-tetrahydro- Found: 288.4 (M + 1).
2H-[1,2']bipyrazinyl- .sup.1HNMR (MeOD): 6'-yl)-amine .delta.
3.3(m, 4H), 3.9(m, hydrochloride salt 4H), 4.6(m, 2H), 7.1(m, 2H),
7.3(s, 1H), 7.4(m, 3H). 4-E (2,5-Dichloro-benzyl)- MS (ES.sup.+)
Calc.: 337, (3,4,5,6-tetrahydro- Found: 338.2 (M + 1).
2H-[1,2']bipyrazinyl- .sup.1HNMR (MeOD): 6'-yl)-amine .delta.
3.0(m, 4H), 3.6(m, 4H), 4.6(m, 2H), 7.3(m, 5H). 4-F
(3,5-Difluoro-benzyl)- MS (ES.sup.+) Calc.: 305,
(3,4,5,6-tetrahydro- Found: 306.3 (M + 1). 2H-[1,2']bipyrazinyl-
.sup.1HNMR (MeOD): 6'-yl)-amine .delta. 3.3(m, 4H), 3.9(m,
hydrochloride salt 4H), 4.6(m, 2H), 6.8(m, 1H), 7.0(m, 2H), 7.3(s,
1H), 7.5(s, 1H). 4-G (3,5-Dichloro-benzyl)- MS (ES.sup.+) Calc.:
337, (3,4,5,6-tetrahydro- Found: 338.3 (M + 1).
2H-[1,2']bipyrazinyl- .sup.1HNMR (CDCl.sub.3): 6'-yl)-amine .delta.
2.9(m, 4H), 3.4(m, 4H), 4.4(m, 2H), 4.9(m, 1H), 7.2(m, 4H), 7.4(m,
1H). 4-H (2,3-Difluoro-benzyl)- MS (ES.sup.+) Calc.: 305,
(3,4,5,6-tetrahydro- Found: 306.3 (M + 1). 2H-[1,2']bipyrazinyl-
.sup.1HNMR (CDCl.sub.3): .delta. 2.9(m, 6'-yl)-amine 4H), 3.5(m,
4H), 4.6(m, 2 4.8(m, 1H), 7.1(m, 3H), 7.2(m, 1H), 7.4(s, 1H). 4-I
(2,3-Dichloro-benzyl)- MS (ES.sup.+) Calc.: 337,
(3,4,5,6-tetrahydro- Found: 338.2 (M + 1). 2H-[1,2']bipyrazinyl-
.sup.1HNMR (CDCl.sub.3): .delta. 2.9(m, 6'-yl)-amine 4H), 3.4(m,
4H), 4.6(m, 2 4.9(m, 1H), 7.1(m, 1H), 7.2(m, 2H), 7.4(m, 2H). 4-J
(2,6-Difluoro-benzyl)- MS (ES.sup.+) Calc.: 305,
(3,4,5,6-tetrahydro- Found: 306.3 (M + 1). 2H-[1,2']bipyrazinyl-
.sup.1HNMR (CDCl.sub.3): .delta. 2.9(m, 6'-yl)-amine 4H), 3.5(m,
4H), 4.6(m, 2 4.8(m, 1H), 6.9(m, 2H), 7.2(m, 2H), 7.4(s, 1H). 4-K
(2-Chloro-6-fluoro- MS (ES.sup.+) Calc.: 321, benzyl)-(3,4,5,6-
Found: 322.3 (M + 1). tetrahydro-2H- .sup.1HNMR (CDCl.sub.3):
.delta. 2.9(m, [1,2']bipyrazinyl- 4H), 3.5(m, 4H), 4.7(m, 2
6'-yl)-amine 4.8(m, 1H), 7.0(m, 1H), 7.2(m, 2H), 7.3(s, 1H), 7.4(s,
1H)
Example 4-L
Preparation of
(3-Fluoro-benzyl)-(3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl--
6'-yl)-amine hydrochloride salt (4-L)
[0339] To a solution of
(3-fluoro-benzyl)-(3,4,5,6-tetrahydro-2H-[1,2']bip-
yrazinyl-6'-yl)-carbamic acid tert-butyl ester I-4c (1.09 g, 2.82
mmol) in Methanol (6 mL) was treated with 1.0 M HCl/ether (28.2 mL,
28.2 mmol). The reaction mixture was stirred at ambient temperature
for 19 h and concentrated in vacuo. The residue was repulped
overnight in a mixture of Methanol (5 mL) and Ether (40 mL). The
resulting tan solid was filtered and dried under high vacuum to
afford the title compound 4-L (745 mg).
[0340] MS (ES.sup.+) Calc.: 287, Found: 288.4 (M+1). .sup.1HNMR
(MeOD): .delta. 3.3(m, 4H), 3.9(m, 4H), 4.6(s, 2H), 7.0(m, 1H),
7.1(m, 11H), 7.2(m, 1H), 7.3(m, 2H), 7.5(s, 1H).
Example 4-M
Preparation of Intermediate (3-Chloro-benzyl)-carbamic acid
tert-butyl ester (I-4d)
[0341] A solution of 3-chloro-benzylamine (0.25 mL, 2.05 mmol) and
di-tert-butyl dicarbonate (0.47 mL, 2.1 mmol) in THF (10 mL) was
stirred at ambient temperature overnight. The reaction mixture was
concentrated in vacuo to a residue and chromatographed on Silica
Gel (40 g) using 10% ethyl ccetate/hexanes as the eluant to the
title compound I-4d (458 mg).
[0342] .sup.1HNMR (CDCl.sub.3): .delta. 1.4(s, 9H), 4.3(bd, 2H),
4.8(bm, 1H), 7.1(m, 1H), 7.2(bm, 3H).
Preparation of Intermediate
(3-Chloro-benzyl)-(6-chloro-pyrazin-2-yl)-carb- amic acid
tert-butyl ester (I-4e)
[0343] A solution of (3-chloro-benzyl)-carbamic acid tert-butyl
ester (458 mg, 1.9 mmol) in DMF (20mL) was treated with 60% NaH in
mineral oil (152 mg, 3.79 mmol). The resulting mixture was stirred
at room, temperature until the gas evolution ceased and
2,6-dichloro-pyrazine (282 mg, 1.89 mmol) was added. The reaction
mixture was stirred at 80.degree. C. until the LC/MS indicated the
reaction was complete. The reaction mixture was cooled and poured
into Ethyl Acetate and washed with H.sub.2O and brine. The organic
layers were combined, dried (Na.sub.2SO.sub.4), and concentrated to
yield the title compound I-4e (199 mg).
[0344] MS (ES.sup.+) Calc.: 353, Found: 354.2 (M+1). .sup.1HNMR
(CDCL.sub.3): .delta. 1.5(s, 9H), 5.1(s, 2H), 7.2(m, 3H), 7.3(m,
1H), 8.2(s, 1H), 9.1(s, 1H).
Preparation of Intermediate
(3-Chloro-benzyl)-(3,4,5,6-tetrahydro-2H-[1,2'-
]bipyrazinyl-6'-yl)-carbamic acid tert-butyl ester (I-4f)
[0345] A solution of
(3-Chloro-benzyl)-(6-chloro-pyrazin-2-yl)-carbamic acid tert-butyl
ester I-4e (68 mg, 0.19 mmol) and piperazine (99 mg, 1.15mmol) in
Ethanol (2 mL) were refluxed overnight. The reaction mixture was
cooled and poured into 0.1 M NaOH and extracted into ethyl acetate.
The organic layer was washed with H.sub.2O, brine, dried
(Na.sub.2SO.sub.4), and concentrated to give the title compound
I-4f (38 mg).
[0346] MS (ES.sup.+) Calc.: 403, Found: 404.3 (M+1). .sup.1HNMR
(CDCL.sub.3): .delta. 1.4(s, 9H), 2.9(m, 4H), 3.4(m, 4H), 5.0(s,
2H), 7.1 (m, 3H), 7.2(m, 1H), 7.8(s,1H), 8.3(s,1H).
Preparation of
(3-Chloro-benzyl)-(3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl--
6'-yl)-amine (4-M)
[0347] (3-Chloro-benzyl
)-(3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl-6'-yl )-carbamic acid
tert-butyl ester I-4f (37.5 mg, 0.09 mmol) was treated with 4.0M
HCl/Dioxane (2 mL, 8 mmol). Methanol was added until a clear
solution is formed and the mixture was stirred overnight at ambient
temperature. The reaction mixture was poured into 1N HCl and
extracted with ethyl acetate. The aqueous phase was brought to pH
14 with 5N KOH and extracted with Ethyl Acetate. The organic layers
were washed with brine, dried (Na.sub.2SO.sub.4), and concentrated
to afford the title compound 4-M (23.3 mg).
[0348] MS (ES.sup.+) Calc.: 303, Found: 304.3 (M+1). .sup.1HNMR
(MeOD): .delta. 2.9(m, 4H), 3.5(m, 4H), 4.5(bs, 2H), 7.3(bm,
6H).
Example 4-N
Preparation of
(3-Chloro-benzyl)-(3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl-6-
'-yl)-amine fumarate salt (4-N)
[0349] A solution of
(3-chloro-benzyl)-(3,4,5,6-tetrahydro-2H-[1,2']bipyra-
zinyl-6'-yl)-amine 4-M (1.14 g, 3.74 mmol) in a mixture of methanol
(15 mL) and isopropyl Ether (90 mL) was treated with a methanolic
solution of fumaric acid (434 mg in 7.5 mL Methanol, 3.74 mmol).
The resulting mixture was stirred at room temperature for 1 h.
Additional isopropyl Ether (120 mL) was then added to the reaction
mixture and stirring continued for 10 minutes. The resulting solids
were filtered from the solution and dried under high vacuum to
obtain the title compound 4-N (1.25 g).
[0350] MS (ES.sup.+) Calc.: 303, Found: 304.2 (M+1). .sup.1HNMR
(DMSO): .delta. 2.8 (m, 4H), 3.4 (m, 4H), 4.4 (m, 2H), 7.3 (bm,
6H).
Example 4-O
Preparation of
(2-Chloro-benzyl)-(3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl--
6'-yl)-amine hydrochloride salt (4-O)
[0351] The general procedure described in Example 4-A, was followed
using 2-chloro-benzylamine as the starting amine in the preparation
of the first intermediate to obtain the BOC-protected compound. The
protecting group was removed by dissolving
(2-chloro-benzyl)-(3,4,5,6-tetrahydro-2H--
[1,2]bipyrazinyl-6'-yl)-carbamic acid tert-butyl ester (102 mg,
0.25 mM) in methanol (1 mL) and treating it with 1.0M HCl/ether
(2.5 mL, 2.53 mmol). The resulting mixture was stirred and
additional Methanol was added until the solution was clear. The
reaction mixture was then stirred overnight at ambient temperature.
Ether was added to the reaction mixture until it turned cloudy and
then stirred for an additional 15 minutes. The solids were filtered
from the mixture, washed with Ether, and air-dried to afford the
title compound 4-O (41.8mg).
[0352] MS (ES.sup.+) Calc.: 303, Found: 304.4 (M+1). .sup.1HNMR
(MeOD): .delta. 3.3(m, 4H), 4.7(bs, 2H), 7.3(m, 3H), 7.4(m, 2H),
7.5(s,1H).
Example 4-P
Preparation of
(2,5-Difluoro-benzyl)-(3,4,5,6-tetrahydro-2H-[1,2']bipyrazi-
nyl-6'-yl)-amine hydrochloride salt (4-P)
[0353] The general procedure described in Example 4-A was followed
using 2,5-difluoro-benzylamine as the amine in the preparation of
the first intermediate and DMAP (1 equiv.) to give the
BOC-protected compound. The protecting group was removed by
dissolving (2,5-difluoro-benzyl)-(3,4,5,6-
-tetrahydro-2H-[1,2']bipyrazinyl-6'-yl)-carbamic acid tert-butyl
ester (99.6 mg, 0.24 mmol) in methanol (1 mL) and treating it with
1.0M HCl/Ether (3.68 mL, 3.68 mmol) and stirring the reaction
mixture overnight at ambient temperature. Additional 1.0M HCl/ether
(2mL) was added to the reaction mixture and stirring continued
overnight at room temperature. The reaction was still not complete,
therefore conc. HCl (2 drops) was added and the resulting mixture
stirred at ambient temperature overnight. Diethyl ether (20 mL) was
added to the reaction mixture and stirring continued for 1 h. The
solids were filtered from the reaction mixture, washed with Ether,
and dried under high vacuum to give the title compound 4-P (64
mg).
[0354] MS (ES.sup.+) Calc.: 305, Found: 306.3 (M+1). .sup.1HNMR
(MeOD): .delta. 3.3(m, 4H), 3.9(m, 4H), 4.6(m, 2H), 7.0(m, 1H),
7.1(m, 2H), 7.3(s, 1H), 7.5(s, 1H).
Example 4-Q
Preparation of Intermediate
6'-[Methyl-(6-methyl-pyridin-2-ylmethyl)-amino-
]-2,3,5,6-tetrahydro-[1,2']bipyrazinyl-4-carboxylic acid tert-butyl
ester (I-4g)
[0355] A mixture of
6'-chloro-2,3,5,6-tetrahydro-[1,2]bipyrazinyl-4-carbox- ylic acid
tert-butyl ester I-1a (50 mg, 0.17 mmol),
methyl-(6-methyl-pyridin-2-ylmethyl)-amine (29.6 mg, 0.22 mmol),
sodium tert-butoxide (45 mg, 0.46 mmol), BINAP (8.4 mg, 0.014
mmol), tris(dibenzylideneacetone)dipalladium(0) (6.2 mg, 0.006
mmol) in toluene (2 mL) was stirred at reflux for 2 h. The reaction
mixture was cooled, diluted with ethyl acetate, and filtered
through celite. The filtrate was concentrated in vacuo and the
residue was purified via preparative TLC (5% methanol in methylene
chloride) to yield the title compound I-4g (14.2 mg).
[0356] MS (ES.sup.+) Calc.: 398, Found: 399.4 (M+1). .sup.1HNMR
(CDCl.sub.3): .delta. 1.5(s, 9H), 2.6(m, 3H), 3.2(m, 3H), 3.5(m,
8H), 4.9(m, 2H), 6.9(m, 1H), 7.1(m, 1H), 7.4(m, 2H), 7.5(m,1H).
Preparation of
Methyl-(6-methyl-pyridin-2-ylmethyl)-(3,4,5,6-tetrahydro-2H-
-[1,2']bipyrazinyl-6'-yl)-amine (4-Q)
[0357]
6'-[Methyl-(6-methyl-pyridin-2-ylmethyl)-amino]-2,3,5,6-tetrahydro--
[1,2']-bipyrazinyl-4-carboxylic acid tert-butyl ester I-4g was
deprotected with TFA as the procedure described in Example 4-A to
afford the title compound 4-Q.
[0358] MS (ES.sup.+) Calc.: 298, Found: 299.4 (M+1). .sup.1HNMR
(CDCl.sub.3): .delta. 2.5(s, 3H), 2.9(m, 4H), 3.1(s, 3H), 3.4(m,
4H), 4.8(s, 2H), 6.9(m, 1H), 7.0(m, 1H), 7.4(m, 3H).
Example 4-R
Preparation of Intermediate 6-Methyl-pyridine-2-carbonitrile
(I-4h)
[0359] 2-Methyl-pyridine 1-oxide (10.9g, 100 mmol) was dissolved
into methylene chloride (100 mL) and dried over MgSO.sub.4. The
solution was filtered and the filtrate was added to trimethylsilyl
cyanide (16.7 mL, 125 mmol) at ambient temperature. To which was
added dropwise a solution of dimethylcarbamyl chloride (11.5 mL,
125 mmol) in methylene chloride (25 mL). The resulting mixture was
stirred at ambient temperature for 24 h. A solution of 10%
K.sub.2CO.sub.3 was added slowly to the reaction mixture and
stirring was continued for 10 minutes after the addition was
complete. The layers were separated and the aqueous layer was
extracted with methylene chloride (2.times.50 mL). The combined
organic extracts were dried (Na.sub.2SO.sub.4), and concentrated to
dryness under high vacuum to yield the title compound I-4h (6.64
g).
[0360] .sup.1HNMR (CDCl.sub.3): .delta. 2.6(s, 3H), 7.4(m,1H),
7.5(m,1H), 7.7(m,1H).
Preparation of Intermediate C-(6-Methyl-pyridin-2-yl)-methylamine
(I-4i)
[0361] To a cooled solution of 1.0 M LiAIH.sub.4 in THF (35.6 mL,
35.6 mmol) at 0.degree. C. was added dropwise a solution of
6-methyl-pyridine-2-carbonitrile I-4h (2.0 g, 16.9 mmol) in THF (34
mL). The reaction mixture was stirred at 0.degree. C. for 5 minutes
after the addition was complete and then quenched with the addition
of 1N NaOH (20 mL). The resulting reaction mixture was stirred for
1 h and filtered through celite washing well with ether. The
filtrate was diluted with 1N NaOH (20 mL) and the organic layer
separated. The organic layer was then washed with brine, dried
(Na.sub.2SO.sub.4), and concentrated in vacuo to give the desired
product I-4i (1.02 g).
[0362] .sup.1HNMR (CDCl.sub.3):.delta. 2.5(s, 3H), 3.9(s, 2H), 7.1
(m, 2H), 7.5(m,1H).
Preparation of Intermediate (6-Methyl-pyridin-2-ylmethyl)-carbamic
acid tert-butyl ester (I-4j)
[0363] The general procedure in Example 4-A was followed to obtain
the crude product. The compound was purified on Silica Gel (40 g)
using 20% ethyl acetate/hexanes as the eluant to yield the title
compound I-4i.
[0364] MS (ES.sup.+) Calc.: 222, Found: 223.3 (M+1). .sup.1HNMR
(CDCl.sub.3): .delta. 1.4(s, 9H), 2.5(s, 3H), 4.4(m, 2H), 7.0(m,
2H), 7.5(m, 1H).
Preparation of Intermediate
(6-Chloro-Pyrazin-2-yl)-(6-methyl-Pyridin-2-yl- methyl)-carbamic
acid tert-butyl ester (I-4k)
[0365] The general procedure in Example 4-A was followed to give
the crude product. The crude material was purified on Silica Gel
(40g) using 15% ethyl acetate/hexanes as the eluant to afford the
title compound I-4k.
[0366] MS (ES.sup.+) Calc.: 334, Found: 335.3 (M+1). .sup.1HNMR
(CDCl.sub.3): .delta. 1.4(s, 9H), 2.5(s, 3H), 5.2(s, 2H), 6.9(m,
1H), 7.0(m, 1H), 7.5(m, 1H), 8.2(s, 1H), 9.2(s, 1H).
Preparation of Intermediate
(6-Methyl-pyridin-2-ylmethyl)-(3,4,5,6-tetrahy-
dro-2H-[1,2']bipyrazinyl-6'-yl)-carbamic acid tert-butyl ester
(I-4l)
[0367] The general procedure in Example 4-A was followed to yield
the crude product. The crude material was purified via preparative
TLC using 10% methanol/methylene chloride with 1% NH.sub.4OH as the
eluant to give the desired compound I-4l.
[0368] MS (ES.sup.+) Calc.: 384, Found: 385.4 (M+1). .sup.1HNMR
(CDCl.sub.3): .delta. 1.4(s, 9H), 2.5(s, 3H), 2.8(m, 4H), 3.3(m,
4H), 5.1(s, 2H), 6.9(m, 2H), 7.5(m, 1H), 7.7(s, 1H), 8.5(s,
1H).
Preparation of Intermediate
(6-Methyl-pyridin-2-ylmethyl)-(3,4,5,6-tetrahy-
dro-2H-[1,2']bipyrazinyl-6'-yl)-amine (I-4m)
[0369] A solution of
(6-methyl-pyridin-2-ylmethyl)-(3,4,5,6-tetrahydro-2H--
[1,2']-bipyrazinyl-6'-yl)-carbamic acid tert-butyl ester I-4l
(196.9 mg, 0.51 mM) in methylene chloride (2 mL) was treated with
trifluoroacetic Acid (0.39 mL, 5.12 mmol). The resulting mixture
was stirred at ambient temperature overnight. The reaction mixture
was quenched with saturated NaHCO.sub.3 solution and the pH of the
aqueous layer brought to approximately 10 using 1N NaOH. The
reaction mixture was diluted with methylene chloride and separated.
The aqueous layer was extracted with methylene chloride and the
organic layers were combined, dried (Na.sub.2SO.sub.4), and
concentrated to dryness to afford the desired product 14m.
[0370] MS (ES.sup.+) Calc.: 284, Found: 285.3
Preparation of
(6-Methyl-pyridin-2-ylmethyl)-(3,4,5,6-tetrahydro-2H-[1,2']-
bipyrazinyl-6'-yl)-amine fumarate salt (4-R)
[0371] The general procedure in Example 4-N was followed using
(6-Methyl-pyridin-2-yl
methyl)-(3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl-6- '-yl)-amine
I-4m as the starting material to yield the title compound.
[0372] MS (ES.sup.+) Calc.: 284, Found: 285.3 (M+1). .sup.1HNMR
(MeOD): .delta. 2.5(s, 3H), 3.1(m, 4H), 3.6(m, 4H), 4.6(s, 2H),
6.7(m, 2H), 7.2(m, 2H), 7.3(m, 2H), 7.6(m, 1H).
Example 4-S
Preparation of Intermediate
3-[(6-Chloro-pyrazin-2-ylamino)-methyl]-benzon- itrile (I-4n)
[0373] A mixture of 2,6-dichloropyrazine (75 mg, 0.503 mmol),
3-aminomethyl-benzonitrile (73 mg, 0.553 mmol), sodium t-butoxide
(58 mg, 0.604 mmol), BINAP (12.5 mg, 0.020 mmol), and
Pd.sub.2(dba).sub.3 (9.2 mg, 0.010 mmol) in toluene (2 mL) was
heated at reflux under nitrogen for 10 h. The solution was cooled
to room temperature and filtered through a celite pad. The celite
pad was washed with ethyl acetate several times. The combined
filtrate was concentrated in vacuo to give the crude title
compound. The product was purified by chromatography (silica, 5%
MeOH/dichlormethane) to give 37.6 mg
3-[(6-chloro-pyrazin-2-ylamino)-meth- yl]-benzonitrile 1-4n.
Preparation of
3-[(3,4,5,6-Tetrahydro-2H-[1,2']bipyrazinyl-6'-ylamino)-met-
hyl]-benzonitrile (4-S)
[0374] A mixture of
3-[(6-chloro-pyrazin-2-ylamino)-methyl]-benzonitrile I-4n (37.6 mg,
0.154 mmol), piperazine (16 mg, 0.185 mmol), sodium t-butoxide (18
mg, 0.185 mmol), BINAP (3.8 mg, 0.006 mmol), and
Pd.sub.2(dba).sub.3 (2.8 mg, 0.003 mmol) in toluene (2 mL) was
heated at reflux under nitrogen for 10 h. The solution was cooled
to room temperature and filtered through a celite pad. The celite
pad was washed with ethyl acetate several times. The combined
filtrate was concentrated in vacuo to give the crude title compound
4-S. The product was purified by chromatography (silica, 10%
MeOH/dichlormethane with 1% NH.sub.4OH) to give the title compound
4-S (10 mg).
[0375] .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.67 (s,1H); 7.63
(d, 1H); 7.55 (d,1H); 7.45 (t, 1H); 7.22 (s, 1H); 7.18 (s, 1H);
4.52 (s, 2H); 3.40 (t, 4H); 2.80 (t, 4H). MS (ES.sup.+) Calc:
294.1, Found: 295.3 (M+1).
Example 4-T
Preparation of Intermediate
Indan-1-yl-(3,4,5,6-tetrahydro-2H-[1,2']bipyra- zinyl-6
'-yl)-amine-4-carboxylic acid tert-butyl ester (I-4o)
[0376] A mixture of
6'-chloro-2,3,5,6-tertrahydro-[1,2']bipyrazinyl4-carbo- xylic acid
tert-butyl ester (I-1 a) (100 mg, 0.33 mmol), (S)-1-aminoindane (49
mg, 0.37 mmol), sodium tert-butoxide (57 mg, 0.46 mmol),
Pd.sub.2(dba).sub.3 (21 mg, 0.023 mmol) and Amphos (29 mg, 0.073
mmol) in toluene (anhydrous, 2 ml) under a nitrogen atmosphere was
heated at reflux for 16 h. The reaction mixture was cooled to room
temperature and filtered through a pad of silica gel, eluting with
EtOAc-hexane (9:1). The filtrate was concentrated in vacuo. The
residue was purified by preparative TLC (EtOAc-hexane 6:4) to
provide 26 mg of the title compound I4o (20%).
[0377] MS (ES.sup.+) Calc: 395.2, Found: 396.2 (M+1).
Preparation of
Indan-1-yl-(3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl-6'-yl)-- amine
hydrochloride (4-T)
[0378] A solution of
indan-1-yl-(3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl-6-
'-yl)-amine-4-carboxylic acid tert-butyl ester I-4O (26 mg, 0.066
mmol) in HCl in 1,4-dioxane (4 M, 1.0 ml, 4 mmol) at 23.degree. C.
was stirred at room temperature for 2 h. The mixture was treated
with ether, and a precipitate appeared. The solid was collected by
filtration. The solid was dissolved in methanol and concentrated in
vacuo to afford the title compound 4-T (10 mg, 41%). MS (ES.sup.+)
Calc: 295.2, Found: 296.2 (M+1).
Example 5
[0379] Example 5 illustrates a representative compound of the
present invention where W is an acetylamino.
Preparation of Intermediate N-(6-Chloro-pyrazin-2-yl)-acetamide
(I-5a)
[0380] A solution of 6-chloro-pyrazin-2-ylamine (50 mg, 0.38 mmol)
in acetic acid (1.9 mL) was treated with acetic anhydride (0.04 mL,
0.42 mmol). The mixture was heated to reflux for 1 h, cooled to
room temperature, then poured into saturated NaHCO.sub.3 (30 mL)
and extracted with ethyl acetate (2.times.30 mL). The organic
layers were combined, washed with brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated to dryness to give the title compound
I-5a (58.6 mg).
[0381] MS (ES.sup.+) Calc.: 171.1, Found: 172.0 (M+1). .sup.1HNMR
(CDCl.sub.3): .delta. 9.42 (s,1H), 8.34 (s, 1H), 7.90 (br s, 1H)
2.24(s, 3H).
Preparation of Intermediate
6'-Acetylamino-2,3,5,6-tetrahydro-[1,2']bipyra- zinyl-4-carboxylic
acid tert-butyl ester (I-5b)
[0382] A mixture of N-(6-chloro-pyrazin-2-yl)-acetamide I-5a (58.6
mg, 0.34 mmol) and piperazine-1-carboxylic acid tert-butyl ester
(636 mg, 3.42 mmol) in ethanol (2 mL) was stirred at reflux for 24
h. The reaction mixture was diluted with ethyl acetate (40 mL) and
washed with 0.1M HCl (3.times.35 mL), brine, dried
(Na.sub.2SO.sub.4), filtered, and evaporated to dryness. The crude
residue was purified by preparative TLC using ethyl acetate as the
eluant to afford the title compound I-5b (36.9 mg).
[0383] MS (ES.sup.+) Calc.: 321.1, Found: 322.3 (M+1). .sup.1HNMR
(CDCl.sub.3): .delta. 8.75 (br s, 1H), 7.86 (s, 1H), 7.70 (br s,
1H) 2.20(s, 3H), 1.46 (s, 9H).
Preparation of Intermediate
6'-[Acetyl-(3-chloro-benzyl)-aminol-2,3,5,6-te-
trahydro-[1,2']bipyrazinyl-4-carboxylic acid tert-butyl ester
(I-5c)
[0384] To a solution of
6'-acetylamino-2,3,5,6-tetrahydro-[1,2']bipyraziny- l-4-carboxylic
acid tert-butyl ester I-5b (36.9 mg, 0.11 mmol) and
1-bromomethyl-3-chloro-benzene (15.8 .mu.L, 0.12 mmol) in DMF (1.1
mL) at room temperature was added 60% NaH in mineral oil (5 mg,
0.13 mmol). After stirring at room temperature for 4 h, the
reaction mixture was poured into H.sub.2O (10 mL) and extracted
with ethyl acetate (50 mL). The organic layer was washed with
H.sub.2O (3.times.10 mL), brine, dried (Na.sub.2SO.sub.4),
filtered, and evaporated to dryness. The crude material was
purified by preparative TLC using 50% ethyl acetate/ether with 1%
NH.sub.4OH to afford the title compound I-5c (27.1 mg).
[0385] MS (ES.sup.+) Calc.: 445.2, Found: 446.2 (M+1). .sup.1HNMR
(CD3OD): .delta. 8.07 (s, 1H), 7.85 (br s,1H), 7.33-7.16 (m, 4H)
5.01 (s, 2H), 3.57-3.42 (m, 8H),2.12(s, 3H), 1.46 (s, 9H).
Preparation of
N-(3-Chloro-benzyl)-N-(3,4,5,6-tetrahydro-2H-[1,2]bipyrazin-
yl-6'-yl)-acetamide (5-A)
[0386] To a solution of
6'-[acetyl-(3-chloro-benzyl)-amino]-2,3,5,6-tetrah-
ydro-[1,2']bipyrazinyl-4-carboxylic acid tert-butyl ester I-5c
(27.1 mg, 0.06 mmol) in methylene chloride (1 mL) was added
trifluoroacetic Acid (1 mL). The reaction mixture was stirred at
room temperature until the reaction was completed. The reaction
mixture was poured into saturated NaHCO.sub.3 (20 mL) and extracted
with methylene chloride (2.times.15 mL). The organic layers were
combined, dried (Na.sub.2SO.sub.4), filtered, and concentrated to
dryness to yield the title compound 5-A (26.2 mg).
[0387] MS (ES.sup.+) Calc.: 345.1, Found: 346.2 (M+1). .sup.1HNMR
(CDCl.sub.3): .delta. 7.95 (s,1H), 7.74 (br s, 1H), 7.32-7.11 (m,
4H), 4.97 (s, 2H), 3.57-3.52(m, 4H), 3.00-2.96 (m, 4H), 2.26 (br
s,1H), 2.13(s, 3H).
Example 6
[0388] Example 6 illustrates the synthesis of NEPi
Compound--(S)-2-[(1-{[3-
-(4-chlorophenyl)propyl]carbamoyl}cyclopentyl)methyl]-4-methoxy-butanoic
acid referred to herein below for use in combination with the
compounds of the present invention for treating female sexual
dysfunction.
Preparation of Intermediate
1-[2-(tert-Butoxycarbonyl)-4-methoxybutyl]-cyc- lopentanecarboxylic
acid (I-6a)
[0389] A solution of tert-butyl 3-(1-carboxycyclopentyl)propanoate
(12 g, 49.5mmol) (see EP274234B1, Example 35) in dry
tetrahydrofuran (100 ml) was added to a stirred solution of lithium
diisopropylamide (130 ml) in a mixture of hexane (52 ml) and
tetrahydrofuran (200 ml) at -78.degree. C. under nitrogen. After 1
hour a solution of 2-bromoethyl methyl ether in tetrahydrofuran
(100ml) was added maintaining the temperature at -78.degree. C. The
reaction mixture was allowed to warm up to room temperature
overnight. The mixture was quenched with water (100 ml) and
acidified to pH 1 with 2M hydrochloric acid, and extracted with
ethyl acetate (2.times.150 ml). The combined organic extracts were
dried over magnesium sulfate and concentrated in vacuo to give the
crude acid which was chromatographed on silica. Elution with
increasing proportions of methanol in dichloromethane (neat
dichloromethane to 1:50) gave an oil (7.7 g, 25.6 mmol, 52%); Rf
0.3 methanol, dichloromethane 1:20;
[0390] .sup.1H NMR (CDCl.sub.3 400 MHz) .delta.: 1.4 (s, 9H),
1.4-1.7 (m, 7H), 1.75-1.95 (m, 2H), 2.0-2.15 (m, 3H), 2.3-2.4 (m,
1H), 3.3 (s, 3H), 3.3-3.4 (m, 2H); LRMS: m/z 299 (M-H.sup.+).
Preparation of Intermediate
I-[(2S)-2-(tert-Butoxycarbonyl)-4-methoxybutyl-
]-cyclopentanecarboxylic acid (I-6b)
[0391] Intermediate I-6a and (+)-pseudoephedrine were
recrystallised nine times from hexane to give a white crystaline
solid. The salt was dissolved in ethyl acetate washed with 0.5M
hydrochloric acid dried over magnesium sulphate and concentrated in
vacuo the (S)-acid was obtained in 31% yield as a pale yellow oil
in >90% ee (enantiomeric excess) by NMR analysis of the .delta.
3.3 peak of the (+)-pseudoephedrine salt;
[0392] .sup.1H NMR (CDCl.sub.3 400MHz) .delta.: 1.4 (s, 9H),
1.4-1.7 (m, 7H), 1.75-1.9 (m, 2H), 2.0-2.15 (m, 3H), 2.35-2.45 (m,
1H), 3.3 (s, 3H), 3.3-3.4 (m, 2H); [.alpha.].sub.D-5.2 (EtOH, c
1.2).
Preparation of Intermediate tert-butyl
(2S)-2-{[1-({[3-(4-chlorophenyl-pro- pyl]amino}carbonyl)
cyclopentyl]methyl}-4-methoxybutanoate (I-6c)
[0393] To a solution of 1,1'-carbonyl diimidazole (73.9 g, 0.45
mol) in azeotropically dried isopropyl acetate (339 ml) was added
the isopropyl acetate solution of the Intermediate I-6b with
stirring at 60.degree. C. under an atmosphere of N.sub.2 over a
period of 1.5 hours. The transfer lines were then washed with dry
isopropyl acetate (50 ml). The resultant solution was then stirred
at 60.degree. C. for a further 4.5 hours and then the reaction
mixture was allowed to cool to room temperature and stirred for 15
hours. To the resultant solution was then added triethylamine (46.1
g, 0.46 mol), followed by 3-(4-chlorophenyl)-propylam- ine
hydrochloride (J. Med. Chem., 1996, 39, 4942-51)(94.3 g, 0.46 mol).
The resultant mixture was then heated to 60.degree. C. for 7 hours
before cooling to room temperature. Deionised water (100 ml) was
then added to the reaction mixture with stirring, followed by
aqueous hydrochloric acid (190 ml of a 5 M solution) until the pH
of the aqueous layer was between pH 2 and 3. The aqueous layer was
then separated, and the organic layer was washed with aqueous
potassium carbonate (50 ml of a 0.5 M solution). The aqueous phase
was separated and organic phase was washed with saturated brine
solution (100 ml). The aqueous layer was then separated and the
organic phase was concentrated by distillation under vacuum to give
the title compound as a yellow oil (200.3 g, 443 mmol, 98%
yield);
[0394] .sup.1H NMR (CDCl.sub.3 300MHz) .delta.: 1.45 (s, 9 H),
1.45-1.56 (m, 1H), 1.56-1.74 (m, 6 H), 1.74-2.11 (m, 7 H),
2.32-2.43 (m, 1H), 2.64 (t, 2H), 3.22-3.30 (m, 2H), 3.27 (s, 3 H),
3.30-3.38 (m, 2H), 5.75-5.85 (m, br, 1H), 7.13 (d, 2 H), 7.26 (d,
2H); LRMS (ES positive): m/z 452 [M+H].sup.+ (.sup.35CI).
Preparation of
(2S)-2-{[1-({[3-(4-Chlorophenyl)pronyl]amino}carbonyl)-cycl-
opentyl]methyl}-4-methoxybutanoic acid and its sodium salt
(6-A)
[0395] To a solution of Intermediate I-6c (9.6 g, 21.2 mmol) in
dichloromethane (52 ml) was added trifluoroacetic acid (16.3 ml,
212 mmol) and the resultant solution was stirred at room
temperature for 3.75 hours under an atmosphere of N.sub.2. To the
reaction was then added aqueous sodium carbonate solution (95 ml of
a 10% w/v solution) with stirring until the pH of the aqueous layer
was between pH 2 and 3. The layers were then separated and the
organic layer was extracted with aqueous sodium carbonate solution
(2.times.20 ml of a 10% w/v solution). The aqueous layers were
combined and saturated brine (80 ml) was then added, followed by
2-butanone (40 ml). The layers were separated and the aqueous layer
was extracted again with 2-butanone (2.times.50 ml). The combined
organic layers were then dried by azeotropic distillation at
atmospheric pressure to a volume of 70 ml whereupon crystallisation
occurred and the mixture was diluted with 2-butanone (70 ml). The
product was then collected by filtration and dried at 50.degree. C.
for 65 hours under vacuum to give the crude sodium salt of the
title compound as a white solid (5.76 g) that was then purified by
recrystallisation as follows. To the crude product was added ethyl
acetate (87 ml) and ethanol (13 ml) and the remaining insoluble
material was removed by filtration. The ethanol was then removed by
azeotropic distillation at atmospheric pressure (to remove 110 ml
of solvent) and replaced with ethyl acetate (145 ml) whereupon
crystallisation occurred. The resultant crystallised product was
then collected by filtration under vacuum to give the pure sodium
salt of the title product as a white crystalline solid (4.51 g,
10.8 mmol, 51%); m.p. (ethyl acetate) 214-216.degree. C.;
[0396] .sup.1H NMR (DMSO-d.sub.6 300MHz) .delta.: 1.26-1.58 (m, 8
H), 1.62-1.74 (m, 3 H), 1.74-1.86 (m, 1H), 1.91-2.07 (m, 3 H), 2.57
(t, 2H), 3.03 (q, 2H), 3.10 (s, 3 H), 3.13-3.27 (m, 2H), 7.22 (d,
2H), 7.29 (d, 2H), 9.16 (t, br, 1 H); LRMS (ES negative); 789
[2M-H].sup.- (.sup.35CI), 394 [M-H].sup.- (.sup.35CI).
[0397] For analytical purposes the title product (i.e. the free
acid) was obtained by dissolving this sodium salt in water,
acidified with 5 M hydrochloric acid and extracted with
dichloromethane. Removal of the solvent by blowing a stream of
nitrogen over the sample gave the title product;
[0398] .sup.1H NMR (DMSO-d.sub.6 300MHz) .delta.: 1.22-1.80 (m,
11H), 1.81-1.96 (m, 2 H), 1.96-2.08 (m, 1 H), 2.93-2.27 (m, 1H),
2.53 (t, 2 H), 3.03 (q, 2 H), 3.11 (s, 3 H), 3.16-3.25 (m, 2H),
7.20 (d, 2H), 7.30 (d, 2H), 7.51 (t, 1H); LRMS (ES negative); 789
[2M-H]-(.sup.35CI), 394 [M-H].sup.- (.sup.35CI); HPLC (column:
ChiralPak AS (25.times.0.46 cm); mobile phase: hexane/lPA/acetic
acid (95/5/0.5 v/v/v); flow rate: 1.0 ml/min; temperature: ambient;
injection volume: 20 .mu.l; detection: UV@ 220 nm; Sample
concentration: 1.0 mg/ml prepared in mobile phase) Retention Time:
minor enantiomer 11.4 min (5.7%), major enantiomer 14.3 min
(94.3%).
Preparation of Mono-hydrate of the Sodium Salt of 6-A
[0399] To the sodium salt of 6-A (200 mg) was added to 1 ml of a
3.9% water in isopropanol solution. The resulting slurry was
stirred for 12 days whereupon it was isolated by filtration. The
product gave the following PXRD pattern listed in Table 5
below.
5 TABLE 5 Intensity Angle % 2-Theta .degree. % 3.552 30.8 7.154 8
9.526 3.1 10.359 15.7 10.608 14.3 11.03 5 12.369 3.7 12.939 13.2
13.233 12.3 13.835 14.2 14.345 37.9 14.887 16 15.16 16.8 16.372
24.9 16.813 6.9 17.203 22.1 17.408 32.7 17.708 13.5 17.93 29 18.313
12 18.545 23.9 18.811 14 19.7 34.2 19.978 100 20.273 90.6 20.627
51.9 20.829 29.4 20.926 28.4 21.443 52.7 21.611 41.6 21.881 21.2
22.174 24.3 22.472 47.1 22.881 35 23.141 23.2 23.478 15.1 24.088
13.9 24.313 12.6 24.588 22.7 25.013 25.8 25.514 29.9 25.987 25.5
27.107 18.2 27.395 30.6 27.869 19.2 28.716 21 28.788 19 28.989 27.2
30.232 13.4 30.672 15 30.952 17.5 31.437 15.7 31.788 13.9 32.114
24.6 32.998 13.3 33.375 18.8 33.815 14 34.266 14.4 35.705 15.7
35.989 14.1 36.514 16.7 38.151 14.6 38.925 17 39.091 19 39.961
13
[0400] Differential scanning calorimetry (DSC) was performed using
a Perkin Elmer DSC-7 instrument fitted with an automatic sample
changer. Approximately 3 mg of the sample was accurately weighed
into a 50 microlitre aluminium pan and crimp sealed with a
perforated lid. The samples were heated at 20.degree. C./minute
over the range 40.degree. C. to 300.degree. C. with a nitrogen gas
purge. Dehydration events occurred at between 50 and 150.degree. C.
and a main melt between 212 and 225.degree. C. The skilled person
will appreciate that the melting point may vary outside this range
as a result of sample impurity.
Anhydrous Salt
[0401] The sodium salt of compound 6-A gave the following PXRD
pattern listed in Table 6 below.
6 TABLE 6 Intensity Angle % 2-Theta .degree. % 5.463 12.2 6.654 100
7.546 66 9.336 31.3 10.953 9.7 11.571 55.9 12.56 10.9 13.287 22.9
15.125 33.6 15.667 60.3 16.403 17.2 17.024 62.2 17.714 95.6 18.083
31.7 18.64 28.8 18.902 82.4 19.696 40.1 20.406 33.9 20.502 31.8
20.683 45.4 20.942 31.5 21.559 92.6 21.898 66.2 22.274 36.6 22.735
30 23.36 56.5 24.126 31.9 24.388 45.2 24.72 25.8 25.298 26.7 25.579
20.4 26.718 17.6 27.151 24.2 27.46 22.7 27.737 20.2 28.56 27.1
28.926 23.8 29.802 23.5 30.454 30.7 30.885 29.2 31.48 21 32.66 16.8
34.027 23.1 34.494 17.6 36.011 19 36.997 17.4 38.704 21.2 39.961
18.7
Biological Assays
[0402] The utility of the compounds of the present invention in the
practice of the instant invention is evidenced by activity in at
least one of the protocols described hereinbelow.
5HT.sub.2c Binding Procedure
[0403] Affinity of compounds at the serotonin 5HT.sub.2c binding
site was determined by competition binding in Swiss 3T3 mouse cells
(available from the American Type Culture Collection (ATCC),
Manassas, Va.) transfected with the human 5HT.sub.2c receptor
against 3H-5HT. The method was adapted from Roth et al., J. of
Pharm. And Exp. Therap., 260(3), 1362-1365 (1992). Cells were grown
in DMEM high glucose medium, harvested, homogenized, centrifuged,
and resuspended in 50 mM Tris-HCL. They were incubated at 20
37.degree. C. for 15 minutes, centrifuged, and then resuspended
into assay buffer (50 mM Tris-HCl, 4 mM CaCl.sub.2, 0.1% ascorbic
acid, and 100 .mu.M pargyline at pH 7.7) at 100 volumes per gram.
Assay tubes contained 25 .mu.L of 10 nM .sup.3H-5HT (1 nM final
conc.), and 25 .mu.l of vehicle (assay buffer), blank (10 .mu.M
mianserin), or test compound (10.times.final volume). 200 .mu.l of
tissue homogenate was added to each tube, vortexed, and incubated
for 30 minutes at 37.degree. C. Samples were then rapidly filtered
under vacuum with a Skatron.TM.cell harvester (available from
Molecular Devices Corporation, Sunnyvale, Calif.) using GF/B
filters presoaked in 0.5% polyethyleneimine (PEI), and washed with
2.thrfore.5 mL cold 50 mM Tris-HCl. Filter mats were removed and
counted in a Wallac Betaplate counter (available from PerkinElmer
Life Sciences, Gaithersburg, Md.). Percent inhibition of specific
binding by test compounds was used to calculate the Ki, or
extrapolate concentration of test compound necessary to inhibit
one-half of the total specific binding for each compound.
[0404] The compounds from the Examples above demonstrated Ki values
for 5HT.sub.2c binding in the range from about 0.1 nM to 586.5 nM
(Example 1-AW):
5HT.sub.2A Binding Procedure
[0405] Affinity of compounds at the serotonin 5HT.sub.2A binding
site was determined by competition binding in NIH 3T3 mouse cells
transfected with the rat 5HT.sub.2A receptor using 1251-DOI. The
method was adapted from Leonhardt et al., Molecular Pharmacology,
42, 328-335 (1992). Frozen cell paste was homgenized in 50 mM
tris-HCl buffer pH 7.4 containing 2 mM MgCl.sub.2 using a Polytron
and centrifuged at 45000.times.g for ten minutes. The resulting
pellet was resuspended in fresh ice-cold 50 mM tris-HCl buffer pH
7.4 containing 2 mM MgCl.sub.2 using a Polytron.TM.and centrifuged
again at 45000.times.g for ten minutes. The final pellet was
resuspended in 50 mM tris-HCl buffer pH 7.4 containing 2 mM
MgCl.sub.2 at a concentraion of 5 mg/mL. Wells in a 96 well plate
contained 25 .mu.L of 0.7 nM 125I-DOI (70 pM final conc.), and 25
.mu.L of vehicle (assay buffer), blank (10 .mu.M cinanserin), or
test compound (10.times.final volume). 200 .mu.l of tissue
homogenate was added to each well and incubated for 15 minutes at
37.degree. C. on a shaker. Samples were then rapidly filtered under
vacuum with a cell harvester (Skatron.TM.) using GF/B filters
presoaked in 0.5% polyethyleneimine (PEI), and washed with
2.times.5 mL cold 50 mM tris-HCl. Filter mats were removed, dried
and counted in a Wallac Betaplate counter. Concentration-response
curves of the % inhibition of specific binding and log
concentration by test compounds were used to determine the
IC.sub.50 for each compound and the Ki value calculated based on
the Cheng-Prusof equation (Ki=IC50/ (1+(L/Kd)), where L is the
concentration of the radioligand used in the binding assay and the
Kd was based on previous saturation studies with the
radioligand.
[0406] The compounds from the Examples above demonstrated Ki values
for 5HT.sub.2a binding in the range from 0.5 nM to 1.0 .mu.M
(Example 4-R). No 5HT.sub.2a binding data was generated for
Examples 1-AE, 1-AF, 1-AL and 1-AH.
Functional Assay
[0407] Swiss 3T3 cells expressing r-5HT.sub.2c, r-5HT.sub.2A,
h-5HT.sub.2c or h-5HT.sub.2A receptors were seeded at a density of
12,500 cells/well in 384 well black/clear collagen-coated plates.
Forty eight (48) hrs later the cells were loaded with the calcium
sensitive dye, Fluo 4-AM (4.mu.M dissolved in DMSO containing
pluronic acid) in serum free DMEM in the presence of probenicid
(2.5 mM) for 75 minutes at 37.degree. C. in a CO.sub.2 incubator.
Unincorporated dye was removed by washing 3 times with a
HEPES-buffered saline containing probenicid (2.5 mM) using a
Skatron.TM. cell washer (final volume 30.mu.L).
[0408] Plates were added to a fluorometric imaging plate reader
(FLIPR 384 available from Molecular Devices Corporation)
individually and fluorescence measurements were taken every 2
seconds over an 85 seconds period. Test compound additions were
made simultaneously to all 384 wells after 20 seconds of baseline
recording. Concentration-response curves were generated using
Graphpad Prism.TM. (available from GraphPad Software, Inc., San
Diego, Calif.) and agonist efficacies were generated as % of the
response to 10 .mu.M 5-HT (considered as 100%). Estimation of
antagonist potencies (functional Kis) were generated by measuring
inhibition of the test compound response to 5-HT (10 nM for
5-HT.sub.2c and 50 nM for 5-HT.sub.2A) and applying the Cheng
Prusoff equation.
[0409] The functional data for the compounds listed in the Examples
above utilizing the 5-HT.sub.2c expressed NIH 3T3 cells is
summarized below.
[0410] Examples 1-A through 1-D, 1-G through 1-J, 1-L, 1-M, 1-O,
1-P, 1-AC, 1-AD, 1-AG, 1-AI, 1-AK, 1-AM through 1-AR, 1-AU through
1-CJ, 2-A, 3-A through 3-S, 4-A, 4-B, 4-E through 4-T, and 5-A
demonstrated EC.sub.50 values less than or equal to 1.0 .mu.M.
[0411] Examples 1-E, 1-F, 1-K, 1-Q, 1-S, 1-X, 1-AB, 1-AJ, and 1-AL
demonstrated EC.sub.50 values greater than 1.0 .mu.M.
[0412] Examples 1-N, 1-R, 1-U, 1-W, 1-Z, 1-AA, 1-AE, 1-AF, 1-AH,
1-AL, 1-AO, 1-AS, 1-AT, 4-C, and 4-D acted as an antagonist.
[0413] Example 1-V demonstrated no activity at 10 .mu.M.
Spontaneous Food Intake
[0414] Wistar rats was administered test compound either orally or
subcutaneously in a 30% .beta.-cyclodextrin vehicle 30 minutes
prior to the onset of the dark cycle. Food intake was monitored
using a computerized system that monitors the intake of individual
animals. Food intake was monitored for at least 16 hours after
administration of the test compound.
Sexual Dysfunction
EXAMPLE A--Treatment of MED
[0415] A representative compound of formula (I) has been
demonstrated to induce increases in penile intracavernosal pressure
(ICP) in the conscious male rat.
[0416] Test Compound:
6'-(2,5-Difluoro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1-
,2']bipyrazinyl (Example I-K)
[0417] ICP Protocol: Intra cavernosal pressure (ICP) can be
measured in the conscious rat by means of telemetric recording. A
catheter is surgically implanted into the corpus cavernosum. The
end of the catheter is linked to a device, which senses, processes,
and transmits information digitally from within the animal. A
receiver converts the radio-frequency signal from the implant to a
digital pulse stream that is readable by a data collection system.
The PC-based system collects telemetred data from the animal.
[0418] Surgery: Induce and maintain general anaesthesia using 5%
Isoflurane.RTM. in a carrier gas of 0.5 L/min oxygen and 1 L/min
nitrous oxide to induce anaesthesia, reducing to 2% Isoflurane for
maintenance anaesthesia. Administer 5mg/kg sub cutaneously (s.c.)
Carprofen (Rimadyl.RTM. Large Animal Injection, 50 mg/ml, Pfizer
Animal Health) at induction of anaesthesia, at end of day of
surgery and on the morning of first day post-surgery to minimise
pain and discomfort.
[0419] Implantation of cornus cavernosal probe: Shave the skin of
the ventral abdomen and extend to include the area around the penis
and ventral scrotum. Clean and disinfect the shaved area. Place the
rat in dorsal recumbency. Make a mid-line incision from the
external base of the penis, running caudally for approximately 2
cm. Locate and expose the internal structure of the penis and
identify the corpus cavernosum. Make a mid-line laparotomy,
approximately 4 cm in length to access the abdominal cavity. Pierce
the abdominal wall via the caudal incision with a suitable trocar
and cannula, taking care not to damage any internal organs. Place
the implant body in the abdominal cavity with the catheter
orientated caudally and pass the catheter tip through the body wall
via the preplaced cannula. Implant used is model TA11PA-C40, 8 mm
catheter, with modified 3 mm tip (Data Sciences International
Inc.). Secure the implant body to the abdominal wall using
non-absorbable sutures and partially close the abdominal incision.
Reflect the tip of the penis cranially and retract the caudal
incision to optimise the surgical field. Carefully isolate
approximately 10 mm of the internal structure of the penis from the
surrounding tissue. Carefully reflect the corpus spongiosum to one
side to give access to the corpus cavernosum. Access the corpus
cavernosum using a modified over-the-needle catheter to puncture
the tunica. Introduce the catheter tip via the preplaced catheter
and advance until fully inserted. Carefully remove the access
catheter and apply a suitable tissue adhesive to the insertion
site. Observe for leakage. Close the subcutaneous fat layer in the
caudal incision before closing with an appropriate absorbable
suture. Instil approximately 5 ml of warm saline through the
abdominal incision and complete closure of the mid-line incision.
Close the skin incision with an appropriate absorbable suture.
[0420] Postoperative care: Measure food and water intake and
monitor bodyweight daily for at least 7 days post surgery, then 2-3
times weekly. Give Lectade.RTM. (Pfizer Animal Health) in drinking
water for 3 days post surgery. House rats singly, and transfer to
reverse light/dark conditions 5 days post surgery. Named Veterinary
Surgeon (or Deputy) to issue a certificate of fitness to continue 2
days post surgery. Start using rats experimentally 7 days post
surgery.
[0421] Experimental Procedure: Perform experiment in room with
reverse light/dark conditions. On day of experiment, place rat in
home cage on receiver pad (PhysioTel.RTM. Model RPC-1, Data
Sciences International Inc.) and leave to acclimatise for
approximately one hour. Ensure that the rat has food and water ad
lib. Take baseline reading of intra cavernosal pressure (ICP) for
approximately 5 minutes. Transfer the data via a floppy disk to an
Excel spreadsheet. Inject the rat with compound subcutaneously or
via the jugular vein catheter (JVC). If using the JVC, flush
through with sterile saline after dosing and seal with a
saline/glucose lock solution. The interval between administration
of compound and ICP measurement will vary with the compound to be
tested. An interval of 30-60 min post s.c. injection is a good
guide. The test compounds were dissolved in 50% .beta.-cyclodextrin
in saline. They were administered at a dose of 5-10 mg/kg
subcutaneously (s.c.). Apomorphine hydrochloride hemihydrate (Sigma
A-4393) at 60 .mu.g/kg s.c. was used as a positive control as it
has pro-erectile properties. Record ICP over a 15 minute period,
starting at 30 minutes post injection i.e. from 30 to 35 minutes
and repeat for two further 15 minute periods commencing at 60
minutes post injection and 120 minutes post injection respectively.
Record ICP for 15 minutes. A signal from the receiver pad feeds
through to the Data Exchange Matrix.RTM. and hence to the software
(Dataquest ARTS acquisition system, Data Sciences International
Inc.). Transfer the data via a floppy disk to an Excel spreadsheet
for analysis.
[0422] Table 1 illustrates the ICP data obtained from studies using
the test compound of formula (I) as described hereinbefore. The
data in Table 7 demonstrates that
6'-(2,5-Difluoro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,-
2']bipyrazinyl induced proerectile effects in the conscious rat.
This compound significantly increased the number of erectogenic
events in a 15 minute test period when dosed at 5 mg/kg s.c.. There
was no difference in the number of erectogenic events induced at
120 minutes after dosing.
7 TABLE 7 12 Number of e- 1.5 .+-. 0.3 rectogenic e- vents @ 60 min
Number of e- 1.3 .+-. 0.5 rectogenic e- vents @ 120 min
EXAMPLE B--Compounds of Formula (I) in combination with PDE5i for
Treatment of MED
[0423] The effects of concomitant administration of compound(s) of
formula (I) in combination with a PDE5 inhibitor on the penile
intracavernosal pressure (ICP) in an anaesthetised rabbit model of
erection can be measured according to the following protocol.
Experimental Protocol
[0424] Male New Zealand rabbits (.about.2.5kg) are pre-medicated
with a combination of Medetomidine (Domitor.RTM.) 0.5 ml/kg
inramuscularly (i.m.), and Ketamine (Vetalar.RTM.) 0.25 ml/kg i.m.
whilst maintaining oxygen intake via a face mask. The rabbits are
tracheotomised using a Portex.TM. uncuffed endotracheal tube 3 ID
(internal diameter), connected to ventilator and maintained at a
ventilation rate of 30-40 breaths per minute, with an approximate
tidal volume of 18-20 ml, and a maximum airway pressure of 10 cm
H.sub.2O. Anaesthesia was then switched to Isoflurane.RTM. and
ventilation continued with O.sub.2 at 2 litres/min. The right
marginal ear vein was cannulated using a 23G or 24G catheter, and
Lactated Ringer solution perfused at 0.5 ml/min. The rabbit was
maintained at 3% Isoflurane during invasive surgery, dropping to 2%
for maintenance anaesthesia. The left jugular vein was exposed,
isolated and then cannulated with a PVC catheter (17 gauge/17G) for
the infusion of drugs and the test compounds.
[0425] The left groin area of the rabbit was shaved and a vertical
incision was made approximately 5 cm in length along the thigh. The
femoral vein and artery were exposed, isolated and then cannulated
with a PVC catheter (17G) for the infusion of drugs and compounds.
Cannulation was repeated for the femoral artery, inserting the
catheter to a depth of 10 cm to ensure that the catheter reached
the abdominal aorta. This arterial catheter was linked to a Gould
system to record blood pressure. Samples for blood gas analysis
were also taken via the arterial catheter. Systolic and diastolic
pressures were measured, and the mean arterial pressure calculated
using the formula (diastolic x2+systolic).div.3. Heart rate was
measured via the pulse oxymeter and Po-ne-mah data acquisition
software system (Ponemah Physiology Platform, Gould Instrument
Systems Inc).
[0426] A ventral midline incision was made into the abdominal
cavity. The incision was about 5 cm in length just above the pubis.
The fat and muscle was bluntly dissected away to reveal the
hypogastric nerve which runs down the body cavity. It was essential
to keep close to the side curve of the pubis wall in order to avoid
damaging the femoral vein and artery which lie above the pubis. The
sciatic and pelvic nerves lie deeper and were located after further
dissection on the dorsal side of the rabbit. Once the sciatic nerve
is identified, the pelvic nerve was easily located. The term pelvic
nerve is loosely applied; anatomy books on the subject fail to
identify the nerves in sufficient detail. However, stimulation of
the nerve causes an increase in intracavernosal pressure and
cavernosal blood flow, and innervation of the pelvic region. The
pelvic nerve was freed away from surrounding tissue and a Harvard
bipolar stimulating electrode was placed around the nerve. The
nerve was slightly lifted to give some tension, then the electrode
was secured in position. Approximately 1 ml of light paraffin oil
was placed around the nerve and electrode. This acts as a
protective lubricant to the nerve and prevents blood contamination
of the electrode. The electrode was connected to a Grass S88
Stimulator. The pelvic nerve was stimulated using the following
parameters: -5V, pulse width 0.5 ms, duration of stimulus 20
seconds with a frequency of 16 Hz. Reproducible responses were
obtained when the nerve was stimulated every 15-20 minutes. Several
stimulations using the above parameters were performed to establish
a mean control response. The compound(s) to be tested were infused,
via the jugular vein, using a Harvard 22 infusion pump allowing a
continuous 15 minute stimulation cycle. The skin and connective
tissue around the penis was removed to expose the penis. A catheter
set (Insyte-W, Becton-Dickinson 20 Gauge 1.1.times.48mm) was
inserted through the tunica albica into the left corpus cavernosal
space and the needle removed, leaving a flexible catheter. This
catheter was linked via a pressure transducer (Ohmeda 5299-04) to a
Gould system to record intracavernosal pressure (ICP). Once an
intracavernosal pressure was established, the catheter was sealed
in place using Vetbond (tissue adhesive, 3M). Heart rate was
measured via the pulse oxymeter and Po-ne-mah data acquisition
software system (Ponemah Physiology Platform, Gould Instrument
Systems Inc).
[0427] Intracavernosal blood flow was recorded either as numbers
directly from the Flowmeter using Po-ne-mah data acquisition
software (Ponemah Physiology Platform, Gould Instrument Systems
Inc), or indirectly from Gould chart recorder trace. Calibration
was set at the beginning of the experiment (0-125 ml/min/100 g
tissue).
[0428] All data are reported as mean.+-.s.e.m. (standard error of
the mean). Significant changes were identified using Student's
t-tests. The test compounds were dissolved in 50%
.beta.-cyclodextrin in saline. They were administered at a dose of
5-10mg/kg subcutaneously (s.c.).
[0429] Using the protocol described hereinbefore beneficial effects
on ICP can be demonstrated for the concomitant administration of
6'-(2,5-Difluorobenzyloxy)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl
(5 -10 mg/kg s.c.) and a selective inhibitor of PDE5
(3-ethyl-5-{5-[4-ethylpiper-
zino)sulphonyl-2-propoxyphenyl}-2-(2-pyridylmethyl)-6,7-dihydro-2H-pyrazol-
o[4,3-d]pyrimidin-7-one (as described in WO98/491066) (1 mg/kg
i.v.(intravenously)). These studies suggest that there are a number
of clinical benefits of concomitant administration of a PDE5
inhibitor and a compound of formula (I). Such benefits include
increased efficacy and opportunities to treat MED subgroups that do
not respond to other MED mono-therapies.
EXAMPLE C--Treatment of FSAD
[0430] Serotonin 5HT.sub.2C receptor agonists potentiate pelvic
nerve-stimulated increases in female genital blood flow in the
anaesthetised rabbit model of sexual arousal.
[0431] The normal sexual arousal response consists of a number of
physiological responses that are observed during sexual excitement.
These changes such as vaginal, labial and clitoral engorgement
result from increases in genital blood flow. Engorgement leads to
increased vaginal lubrication via plasma transudation, increased
vaginal compliance (relaxation of vaginal smooth muscle) and
increases in vaginal and clitoral sensitivity.
[0432] Female sexual arousal disorder (FSAD) is a highly prevalent
sexual disorder affecting up to 40% of pre-, per- and
postmenopausal (.+-.HRT) women. The primary consequence of FSAD is
reduced genital engorgement or swelling which manifests itself as a
lack of vaginal lubrication and a lack of pleasurable genital
sensation. Secondary consequences include reduced sexual desire,
pain during intercourse and difficulty in achieving orgasm. The
most common cause of FSAD is decreased genital blood flow resulting
in reduced vaginal, labial and clitoral engorgement (Berman, J.,
Goldstein, I., Werbin, T. et al. (1999a). Double blind placebo
controlled study with crossover to assess effect of sildenafil on
physiological parameters of the female sexual response. J. Urol.,
161, 805; Goldstein, I. & Berman, J. R. (1998). Vasculogenic
female sexual dysfunction: vaginal engorgement and clitoral
erectile insufficiency syndromes. Int. J. Impot. Res., 10, S84-S90;
Park, K., Goldstein, I., Andry, C., et al. (1997). Vasculogenic
female sexual dysfunction: The hemodynamic basis for vaginal
engorgement insufficiency and clitoral erectile insufficiency. Int.
J. Impotence Res., 9, 27-37; Werbin, T., Salimpour, P., Berman, L.,
et al. (1999). Effect of sexual stimulation and age on genital
blood flow in women with sexual stimulation. J. Urol., 161,
688).
[0433] As explained herein, the present invention provides a means
for restoring or potentiating the normal sexual arousal response in
women suffering from FSAD, by enhancing genital blood flow.
Method
[0434] Female New Zealand rabbits (.about.2.5kg) were pre-medicated
with a combination of Medetomidine (Domitor.RTM.) 0.5ml/kg
intramuscularly (i.m.), and Ketamine (Vetalar.RTM.) 0.25 ml/kg i.m.
whilst maintaining oxygen intake via a face mask. The rabbits were
tracheotomised using a Portex.TM. uncuffed endotracheal tube 3 ID
(internal diameter), connected to ventilator and maintained at a
ventilation rate of 30-40 breaths per minute, with an approximate
tidal volume of 18-20 ml, and a maximum airway pressure of 10 cm
H.sub.2O. Anaesthesia was then switched to Isoflurane.RTM. and
ventilation continued with O.sub.2 at 2l/min. The right marginal
ear vein was cannulated using a 23G or 24G catheter, and Lactated
Ringer solution perfused at 0.5 ml/min. The rabbit was maintained
at 3% Isoflurane.RTM. during invasive surgery, dropping to 2% for
maintenance anaesthesia.
[0435] The left groin area of the rabbit was shaved and a vertical
incision was made approximately 5 cm in length along the thigh. The
femoral vein and artery were exposed, isolated and then cannulated
with a PVC catheter (17G) for the infusion of drugs and compounds.
Cannulation was repeated for the femoral artery, inserting the
catheter to a depth of 10 cm to ensure that the catheter reached
the abdominal aorta. This arterial catheter was linked to a Gould
system to record blood pressure. Samples for blood gas analysis
were also taken via the arterial catheter. Systolic and diastolic
pressures were measured, and the mean arterial pressure calculated
using the formula (diastolic x2+systolic).div.3. Heart rate was
measured via the pulse oxymeter and Po-ne-mah data acquisition
software system (Ponemah Physiology Platform, Gould Instrument
Systems Inc).
[0436] A ventral midline incision was made into the abdominal
cavity. The incision was about 5 cm in length just above the pubis.
The fat and muscle was bluntly dissected away to reveal the
hypogastric nerve which runs down the body cavity. It was essential
to keep close to the side curve of the pubis wall in order to avoid
damaging the femoral vein and artery, which lie above the pubis.
The sciatic and pelvic nerves lie deeper and were located after
further dissection on the dorsal side of the rabbit. Once the
sciatic nerve is identified, the pelvic nerve was easily located.
The term pelvic nerve is loosely applied; anatomy books on the
subject fail to identify the nerves in sufficient detail. However,
stimulation of the nerve causes an increase in vaginal and clitoral
blood flow, and innervation of the pelvic region. The pelvic nerve
was freed away from surrounding tissue and a Harvard bipolar
stimulating electrode was placed around the nerve. The nerve was
slightly lifted to give some tension, then the electrode was
secured in position. Approximately 1 ml of light paraffin oil was
placed around the nerve and electrode. This acts as a protective
lubricant to the nerve and prevents blood contamination of the
electrode. The electrode was connected to a Grass S88 Stimulator.
The pelvic nerve was stimulated using the following parameters:
-5V, pulse width 0.5 ms, duration of stimulus 10 seconds. and a
frequency range of 2 to 16 Hz. Reproducible responses were obtained
when the nerve was stimulated every 15-20 minutes. A frequency
response curve was determined at the start of each experiment in
order to determine the optimum frequency to use as a sub-maximal
response, normally 4 Hz. A ventral midline incision was made, at
the caudal end of the pubis, to expose the pubic area. Connective
tissue was removed to expose the tunica of the clitoris, ensuring
that the wall was free from small blood vessels. The external
vaginal wall was also exposed by removing any connective tissue.
One laser Doppler flow probe was inserted 3 cm into the vagina, so
that half the probe shaft was still visible. A second probe was
positioned so that it lay just above the external clitoral wall.
The position of these probes was then adjusted until a signal was
obtained. A second probe was placed just above the surface of a
blood vessel on the external vaginal wall. Both probes were clamped
in position.
Test Compounds
[0437]
8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-
-one, which corresponds to Compound 75 of Chaki and
Nakazato--Expert Opin. Ther. Patents (2001), 11(11):1677-1692 (see
Section 3.9--5HT.sub.2c on page 1687 and FIG. 7 on page 1686), or
Compound (6) of Isaac--Drugs of the Future (2001), 26(4):383-393
(see FIG. 2 on page 385).
8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one
was dissolved in 50% .beta.-cyclodextrin in saline. It was
administered at a dose of 5 mg/kg subcutaneously (s.c.).
Data Recordal
[0438] Vaginal and clitoral blood flow was recorded either as
numbers directly from the Flowmeter using Po-ne-mah data
acquisition software (Ponemah Physiology Platform, Gould Instrument
Systems Inc), or indirectly from Gould chart recorder trace.
Calibration was set at the beginning of the experiment
(0-125ml/min/100 g tissue). All data are reported as
mean.+-.standard error of the mean (s.e.m.). Significant changes
were identified using Student's t-tests.
Results
[0439] The serotonin 5HT2C receptor agonist
(8,9-dichloro-2,3,4,4a-tetrahy-
dro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one; 5 mg/kg s.c.) acts as a
potent enhancer of pelvic-nerve stimulated (PNS) increases in
vaginal and clitoral blood flow in the anaesthetised rabbit (see
Table 8 below). The potentiation was significant 30 mins after s.c.
dosing and remained elevated for circa 1 hr. The 5HT.sub.2c agonist
had no effect on basal genital blood flow in the absence of PNS
(see Table 8 below). This reinforces our view that a 5HT2c receptor
agonist will enhance the arousal response by potentiating the
mechanism(s) that control sexual arousal/genital blood flow,
thereby treating FSAD, and will not induce arousal in the absence
of sexual stimulation. Since these agents also enhance clitoral
blood flow it is likely that they will be effective in the
treatment of orgasmic disorders.
[0440] Table 8 below illustrates that
8,9-dichloro-2,3,4,4a-tetrahydro-1H--
pyrazino[1,2-a]quinoxalin-5(6H)-one (5 mg/kg s.c.) potentiates
pelvic nerve stimulated inreases in genital blood flow circa 35%
after subcutaneous administration in the anaesthetised rabbit model
of sexual arousal.
8TABLE 8 Time after injection of Pelvic nerve Compound-induced
Compound 8,9-dichloro-2,3,4,4a- Unstimulated stimulated increases
in potentiation of tetrahydro-1H-pyrazino[1,2- - vaginal blood flow
vaginal blood flow stimulated vaginal a]quinoxalin-5(6H)-one (min)
(Laser Doppler units) (Laser Doppler units) blood flow Pre dose 148
+/- 6 241 +/- 10 -- 15 185 292 21 30 162 325 34 45 150 295 22 60
127 325 34 75 137 252 4 90 132 247 2
* * * * *