U.S. patent application number 09/779318 was filed with the patent office on 2001-08-16 for 2-aminopyridines containing fused ring substituents.
Invention is credited to Lowe, John A. III.
Application Number | 20010014689 09/779318 |
Document ID | / |
Family ID | 22397690 |
Filed Date | 2001-08-16 |
United States Patent
Application |
20010014689 |
Kind Code |
A1 |
Lowe, John A. III |
August 16, 2001 |
2-aminopyridines containing fused ring substituents
Abstract
The present invention relates to 2-aminopyridine derivatives of
the formula I: 1 or pharmaceutically acceptable salts thereof,
wherein A and B are each independently H, or together, A and B form
a ring fused to the phenyl ring, said ring being saturated or
unsaturated and containing from 5 to 7 ring member atoms, where
said ring member atoms may optionally comprise from 1 to 2
heteroatoms selected independently from the group consisting of N,
O or S, provided that no two adjacent ring members are heteroatoms;
X is oxygen or a single bond; Y is (C.sub.1-C.sub.6)alkyl; R.sup.1
is hydrogen, (C.sub.1-C.sub.6)alkyl or a (C.sub.1-C.sub.6 alkyl)
group substituted with --NR.sup.2R.sup.3 wherein R.sup.2 and
R.sup.3 are either selected independently from the group consisting
of H, alkyl, aryl, aralkyl or tetrahydronaphthalene, wherein said
aryl group or said aryl moiety of said aralkyl group is phenyl or
naphthyl, said alkyl group or said alkyl moiety of said aralkyl
group contains from one to six carbon atoms and is straight-chained
or branched, and said aryl group, said tetrahydronaphthalene or
said aryl moiety of said aralkyl group is optionally substituted
with from one to three of halogen, nitro, cyano, amino,
(C.sub.1-C.sub.4)alkoxy and (C.sub.1-C.sub.4)alkylamino moieties,
or R.sup.2 and R.sup.3 form, together with the nitrogen to which
they are attached, a heterocyclic ring, or a cyclic or bicyclic
ring which is saturated or unsaturated. The compounds of the
invention have the ability to inhibit the activity of nitric oxide
synthases (NOS), and hence, are useful in the treatment of
diseases, conditions and disorders of the central nervous system,
among others.
Inventors: |
Lowe, John A. III;
(Stonington, CT) |
Correspondence
Address: |
Paul H. Ginsburg
Pfizer Inc
20th Floor
235 East 42nd Street
New York
NY
10017-5755
US
|
Family ID: |
22397690 |
Appl. No.: |
09/779318 |
Filed: |
February 8, 2001 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
09779318 |
Feb 8, 2001 |
|
|
|
09504989 |
Feb 15, 2000 |
|
|
|
6211208 |
|
|
|
|
60121597 |
Feb 25, 1999 |
|
|
|
Current U.S.
Class: |
514/337 ;
514/349; 546/276.7; 546/281.1; 546/281.7; 546/304 |
Current CPC
Class: |
A61P 3/04 20180101; A61P
31/04 20180101; A61P 11/06 20180101; A61P 27/02 20180101; A61P 1/00
20180101; A61P 25/34 20180101; A61P 29/00 20180101; A61P 43/00
20180101; C07D 213/73 20130101; A61P 9/04 20180101; A61P 19/08
20180101; A61P 1/08 20180101; A61P 25/18 20180101; A61P 25/32
20180101; A61P 9/10 20180101; A61P 25/06 20180101; A61P 25/00
20180101; A61P 1/04 20180101; A61P 25/36 20180101; A61P 35/02
20180101; A61P 7/00 20180101; A61P 11/00 20180101; A61P 13/12
20180101; A61P 17/06 20180101; A61P 25/20 20180101; A61P 17/02
20180101; A61P 25/28 20180101; A61P 25/08 20180101; A61P 35/00
20180101; A61P 19/06 20180101; A61P 25/24 20180101; A61P 3/10
20180101; A61P 9/00 20180101; A61P 25/14 20180101; A61P 19/02
20180101; A61P 27/06 20180101; A61P 25/30 20180101; A61P 17/00
20180101 |
Class at
Publication: |
514/337 ;
514/349; 546/276.7; 546/281.7; 546/281.1; 546/304 |
International
Class: |
A61K 031/4427; A61K
031/44; C07D 211/72 |
Claims
What is claimed is:
1. A compound of the formula I: 7or pharmaceutically acceptable
salts thereof, wherein A and B are each independently H, or
together, A and B form a ring fused to the phenyl ring, said ring
being saturated or unsaturated and containing from 5 to 7 ring
member atoms, where said ring member atoms may optionally comprise
from 1 to 2 heteroatoms selected independently from the group
consisting of N, O or S, provided that no two adjacent ring members
are heteroatoms; X is oxygen or a single bond; Y is
(C.sub.1-C.sub.6)alkyl; R.sup.1 is hydrogen, (C.sub.1-C.sub.6)alkyl
or a (C.sub.1-C.sub.6 alkyl) group substituted with
--NR.sup.2R.sup.3, wherein R.sup.2 and R.sup.3 are either selected
independently from the group consisting of H, alkyl, aryl, aralkyl
or tetrahydronaphthalene, wherein said aryl group or said aryl
moiety of said aralkyl group is phenyl or naphthyl, said alkyl
group or said alkyl moiety of said aralkyl group contains from one
to six carbon atoms and is straight-chained or branched, and said
aryl group, said tetrahydronaphthalene or said aryl moiety of said
aralkyl group is optionally substituted with from one to three of
halogen, nitro, cyano, amino, (C.sub.1-C.sub.4)alkoxy and
(C.sub.1-C.sub.4)alkylamino moieties, or R.sup.2 and R.sup.3 form,
together with the nitrogen to which they are attached, a
heterocyclic ring, or a cyclic or bicyclic ring which is saturated
or unsaturated.
2. The compound of claim 1, wherein the heterocyclic ring formed
from R.sup.2 and R.sup.3 is a piperidine, azetidine, piperazine or
pyrrolidine ring; wherein said piperidine, azetidine, piperazine or
pyrrolidine ring is optionally substituted with one or more
substituents selected independently from the group consisting of
(C.sub.1-C.sub.6)alkyl, amino, (C.sub.1-C.sub.6)alkylamino,
[di-(C.sub.1-C.sub.6)alkyl]amino, phenyl-substituted 5-to-6
membered heterocyclic rings containing from 1-to-4 ring nitrogen
atoms, benzoyl, benzoylmethyl, benzylcarbonyl, phenylaminocarbonyl,
phenylethyl and phenoxycarbonyl groups; and the phenyl moiety of
any of the forgoing substituents is optionally substituted with one
or more substituents which are each independently halogens,
(C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)alkoxy, nitro, amino,
cyano, CF.sub.3 or OCF.sub.3.
3. The compound of claim 1, wherein R.sup.2 and R.sup.3, together
with the nitrogen to which they are attached, form a
6-amino-3-azabicyclo[3.1.0]he- x-2-yl group of the formula:
8wherein R.sup.4 and R.sup.5 are selected independently from the
group consisting of hydrogen, (C.sub.1-C.sub.6)alkyl, phenyl,
naphthyl, (C.sub.1-C.sub.6)alkyl-C(.dbd.O- )--, HC(.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy-(C.dbd.O)--, phenyl-C(.dbd.O)--,
naphthyl-C(.dbd.O)-- and R.sup.6R.sup.7NC(.dbd.O)--, and wherein
R.sup.6 and R.sup.7 are each independently H or
(C.sub.1-C.sub.6)alkyl.
4. The compound of claim 1, wherein A and B together form a ring
fused to the phenyl ring.
5. The compound of claim 4, wherein the fused ring and the phenyl
ring comprise a naphthalene group.
6. The compound of claim 1, wherein X is oxygen.
7. The compound of claim 1, wherein Y is --CH.sub.2CH.sub.2--.
8. The compound of claim 1, wherein R.sup.1 is a
(C.sub.1-C.sub.6)alkyl group substituted with
--NR.sup.2R.sup.3.
9. The compound of claim 8, wherein R.sup.1 is a 2-substituted
ethyl group substituted with --NR.sup.2R.sup.3.
10. The compound of claim 7, wherein R.sup.2 and R.sup.3 together
with the nitrogen to which they are attached form a heterocyclic
ring selected from the group consisting of
3-azabicyclo[3.1.0]hexyl, piperidine and piperazine rings.
11. The compound of claim 10, wherein the ring is a
3-azabicyclo[3.1.0]hexyl ring.
12. The compound of claim 7, wherein each of R.sup.2 and R.sup.3 is
independently methyl, ethyl or propyl.
13. The compound of claim 1, wherein A and B together form a ring
fused to the phenyl ring, the fused ring and the phenyl ring
together comprise a naphthalene group, X is oxygen, Y is
--CH.sub.2CH.sub.2--, R.sup.1 is an
R.sup.2R.sup.3NCH.sub.2CH.sub.2-- group and R.sup.2 and R.sup.3
together form a ring selected from azabicyclohexane, piperidine and
piperazine rings, or R.sup.2 and R.sup.3 are each independently
methyl, ethyl or propyl.
14. A compound of claim 1 selected from the group consisting of
1-[4-(6-Amino-pyridin-2-yl)-napthalen-1-yloxymethyl]-cyclohexanol;
6-[4-(2-(2-Dimethylaminoethoxy)-ethoxy)-napthalen-1-yl]-pyridin-2-ylamine-
;
6-[4-(2-Hydroxy-ethoxy)-5,6,7,8-tetrahydronapthalen-1-yl]-pyridin-2-ylam-
ine; and
6-[4-(2-(2-Diethylaminoethoxy)-ethoxy)-napthalen-1-yl]-pyridin-2--
ylamine.
15. A compounds according to claim 1 of the formula I-a: 9wherein
the broken line represents an optional double bond; Y is
(C.sub.1-C.sub.6)alkyl; and R.sup.1 is hydrogen,
(C.sub.1-C.sub.6)alkyl or a (C.sub.1-C.sub.6 alkyl) group
substituted with --NR.sup.2R.sup.3, wherein R.sup.2 and R.sup.3 are
either selected independently from the group consisting of H,
alkyl, aryl, aralkyl or tetrahydronaphthalene, wherein said aryl
group or said aryl moiety of said aralkyl group is phenyl or
naphthyl, said alkyl group or said alkyl moiety of said aralkyl
group contains from one to six carbon atoms and is straight-chained
or branched, and said aryl group, said tetrahydronaphthalene or
said aryl moiety of said aralkyl group is optionally substituted
with from one to three of halogen, nitro, cyano, amino,
(C.sub.1-C.sub.4)alkoxy and (C.sub.1-C.sub.4)alkylamino moieties,
or R.sup.2 and R.sup.3 form, together with the nitrogen to which
they are attached, a heterocyclic ring, or a cyclic or bicyclic
ring which is saturated or unsaturated.
16. A compound of formula 1 selected from the group consisting of
6-[4-(2-(2-Diethylaminoethoxy)-ethoxy)-naphthalen-1-yl]-pyridin-2-ylamine-
;
6-[4-(2-(2-Dipropylaminoethoxy)-ethoxy)-naphthalen-1-yl]-pyridin-2-ylami-
ne; 6-[4-(2-(2-(N-methyl,
N-benzyl)aminoethoxy)-ethoxy)-naphthalen-1-yl]-p- yridin-2-ylamine;
6-[4-(2-(2-(1-Piperidinyl)ethoxy)-ethoxy)-naphthalen-1-y-
l]-pyridin-2-ylamine;
6-[4-(2-(2-(N-methylpiperazin-4-yl)ethoxy)-ethoxy)-n-
aphthalen-1-yl]-pyridin-2-ylamine; and
6-[4-(2-(2-(6-amino-3-azabicyclo[3.-
1.0]hex-2-yl)ethoxy)-ethoxy)-naphthalen-1-yl]-pyridin-2-ylamine.
17. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier and an amount of the compound of claim 1
effective in a mammal to treat a disease, disorder or condition
which is an: acute spinal cord injury; anxiety disorder selected
from the group consisting of panic attack, agoraphobia, panic
disorder with or without agoraphobia, agoraphobia without history
of panic disorder, specific phobia, social phobia,
obsessive-compulsive disorder, post-traumatic stress disorder and
acute stress disorder; cancer selected from the group consisting of
brain, breast, colon, lung, liver, ovarian, prostate, skin and
stomach cancers; cancer selected from the group consisting of
astrocytomas, carcinomas, glioblastomas, leukemias, lymphomas,
melanomas and sarcomas; cognitive disorder selected from the group
consisting of amnestic disorders, deliriums, dementias, and
cognitive disorders not otherwise specified; emesis; epilepsy;
gastrointestinal condition selected from the group consisting of
Crohn's disease, inflammatory bowel syndrome and ulcerative
colitis; glaucoma; headache disorder selected from the group
consisting of migraine, cluster and vascular headaches;
Huntington's disease; inflammatory disorder selected from the group
consisting of adult respiratory distress syndrome (ARDS), arthritic
disorders, asthma, dermatological lesions, gout, inflammatory bowel
disease, necrotizing vasculitides, neurogenic inflammation,
psoriasis, reperfusion injury, stroke and systemic inflammatory
response syndrome; macular degeneration; obesity; neurodegenerative
disease selected from the group consisting of Alzheimer's, ALS,
multiple sclerosis and Parkinson's; pathological condition selected
from the group consisting of cardiomyopathy, diabetic neuropathy
and diabetic nephropathy; psychotic condition selected from the
group consisting of schizophrenia, schizophreniform disorder,
schizoaffective disorder, delusional disorder, brief psychotic
disorder, shared psychotic disorder, psychotic disorder due to a
general medical condition and psychotic disorders not otherwise
specified; sleep disorder selected from the group consisting of
primary sleep disorders, sleep disorders related to another mental
disorder, sleep disorders due to a general medical condition and
sleep disorders not otherwise specified; stroke; substance-abuse
disorder selected from the group consisting of alcohol-related
disorders, amphetamine-related disorders, caffeine-related
disorders, cannabis-related disorders, cocaine-related disorders,
hallucinogen-related disorders, inhalant-related disorders,
nicotine-related disorders, opioid-related disorders,
phencyclidine-related disorders, sedative-related disorders,
hypnotic-related disorders, anxiolytic-related disorders and
polysubstance-related disorders; toxemic condition selected from
the group consisting of ARDS, hypovolemic shock, neuron toxicity,
septic shock and traumatic shock; or a traumatic condition selected
from the group consisting of chest trauma and head trauma.
18. A method of treating a mammal afflicted with a disease,
disorder or condition which is an: acute spinal cord injury;
anxiety disorder selected from the group consisting of panic
attack, agoraphobia, panic disorder with or without agoraphobia,
agoraphobia without history of panic disorder, specific phobia,
social phobia, obsessive-compulsive disorder, post-traumatic stress
disorder and acute stress disorder; cancer selected from the group
consisting of brain, breast, colon, lung, liver, ovarian, prostate,
skin and stomach cancers; cancer selected from the group consisting
of astrocytomas, carcinomas, glioblastomas, leukemias, lymphomas,
melanomas and sarcomas; cognitive disorder selected from the group
consisting of amnestic disorders, deliriums, dementias, and
cognitive disorders not otherwise specified; emesis; epilepsy;
gastrointestinal condition selected from the group consisting of
Crohn's disease, inflammatory bowel syndrome and ulcerative
colitis; glaucoma; headache disorder selected from the group
consisting of migraine, cluster and vascular headaches;
Huntington's disease; inflammatory disorder selected from the group
consisting of adult respiratory distress syndrome (ARDS), arthritic
disorders, asthma, dermatological lesions, gout, inflammatory bowel
disease, necrotizing vasculitides, neurogenic inflammation,
psoriasis, reperfusion injury, stroke and systemic inflammatory
response syndrome; macular degeneration; obesity; neurodegenerative
disease selected from the group consisting of Alzheimer's, ALS,
multiple sclerosis and Parkinson's; pathological condition selected
from the group consisting of cardiomyopathy, diabetic neuropathy
and diabetic nephropathy; psychotic condition selected from the
group consisting of schizophrenia, schizophreniform disorder,
schizoaffective disorder, delusional disorder, brief psychotic
disorder, shared psychotic disorder, psychotic disorder due to a
general medical condition and psychotic disorders not otherwise
specified; sleep disorder selected from the group consisting of
primary sleep disorders, sleep disorders related to another mental
disorder, sleep disorders due to a general medical condition and
sleep disorders not otherwise specified; stroke; substance-abuse
disorder selected from the group consisting of alcohol-related
disorders, amphetamine-related disorders, caffeine-related
disorders, cannabis-related disorders, cocaine-related disorders,
hallucinogen-related disorders, inhalant-related disorders,
nicotine-related disorders, opioid-related disorders,
phencyclidine-related disorders, sedative-related disorders,
hypnotic-related disorders, anxiolytic-related disorders and
polysubstance-related disorders; toxemic condition selected from
the group consisting of ARDS, hypovolemic shock, neuron toxicity,
septic shock and traumatic shock; or a traumatic condition selected
from the group consisting of chest trauma and head trauma, said
method comprising the administration to the mammal of an amount of
the compound of claim 1 effective to treat the disease, disorder or
condition.
19. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier and an amount of the compound of claim 1
effective to inhibit the activity of a nitric oxide synthase (NOS)
in a mammal.
20. A method of inhibiting the activity of a NOS in a mammal which
comprises the administration to the mammal of an amount of the
compound of claim 1 effective to inhibit the activity of the
NOS.
21. A pharmaceutical composition for treating a disease, disorder
or condition in a mammal, wherein said composition comprises a
pharmaceutically acceptable carrier and an amount of the compound
of claim 1 effective to inhibit the activity of the NOS in the
mammal and wherein said disease, disorder or condition is an: acute
spinal cord injury; anxiety disorder selected from the group
consisting of panic attack, agoraphobia, panic disorder with or
without agoraphobia, agoraphobia without history of panic disorder,
specific phobia, social phobia, obsessive-compulsive disorder,
post-traumatic stress disorder and acute stress disorder; cancer
selected from the group consisting of brain, breast, colon, lung,
liver, ovarian, prostate, skin and stomach cancers; cancer selected
from the group consisting of astrocytomas, carcinomas,
glioblastomas, leukemias, lymphomas, melanomas and sarcomas;
cognitive disorder selected from the group consisting of amnestic
disorders, deliriums, dementias, and cognitive disorders not
otherwise specified; emesis; epilepsy; gastrointestinal condition
selected from the group consisting of Crohn's disease, inflammatory
bowel syndrome and ulcerative colitis; glaucoma; headache disorder
selected from the group consisting of migraine, cluster and
vascular headaches; Huntington's disease; inflammatory disorder
selected from the group consisting of adult respiratory distress
syndrome (ARDS), arthritic disorders, asthma, dermatological
lesions, gout, inflammatory bowel disease, necrotizing
vasculitides, neurogenic inflammation, psoriasis, reperfusion
injury, stroke and systemic inflammatory response syndrome; macular
degeneration; obesity; neurodegenerative disease selected from the
group consisting of Alzheimer's, ALS, multiple sclerosis and
Parkinson's; pathological conditions selected from the group
consisting of cardiomyopathy, diabetic neuropathy and diabetic
nephropathy; psychotic condition selected from the group consisting
of schizophrenia, schizophreniform disorder, schizoaffective
disorder, delusional disorder, brief psychotic disorder, shared
psychotic disorder, psychotic disorder due to a general medical
condition and psychotic disorders not otherwise specified; sleep
disorder selected from the group consisting of primary sleep
disorders, sleep disorders related to another mental disorder,
sleep disorders due to a general medical condition and sleep
disorders not otherwise specified; stroke; substance-abuse disorder
selected from the group consisting of alcohol-related disorders,
amphetamine-related disorders, caffeine-related disorders,
cannabis-related disorders, cocaine-related disorders,
hallucinogen-related disorders, inhalant-related disorders,
nicotine-related disorders, opioid-related disorders,
phencyclidine-related disorders, sedative-related disorders,
hypnotic-related disorders, anxiolytic-related disorders and
polysubstance-related disorder, toxemic conditions selected from
the group consisting of ARDS, hypovolemic shock, neuron toxicity,
septic shock and traumatic shock; or traumatic conditions selected
from the group consisting of chest trauma and head trauma.
22. A method of treating a mammal afflicted with a disease,
disorder or condition which is an: acute spinal cord injury;
anxiety disorder selected from the group consisting of panic
attack, agoraphobia, panic disorder with or without agoraphobia,
agoraphobia without history of panic disorder, specific phobia,
social phobia, obsessive-compulsive disorder, post-traumatic stress
disorder and acute stress disorder; cancer selected from the group
consisting of brain, breast, colon, lung, liver, ovarian, prostate,
skin and stomach cancers; cancer selected from the group consisting
of astrocytomas, carcinomas, glioblastomas, leukemias, lymphomas,
melanomas and sarcomas; cognitive disorder selected from the group
consisting of amnestic disorders, deliriums, dementias, and
cognitive disorders not otherwise specified; emesis; epilepsy;
gastrointestinal condition selected from the group consisting of
Crohn's disease, inflammatory bowel syndrome and ulcerative
colitis; glaucoma; headache disorder selected from the group
consisting of migraine, cluster and vascular headaches;
Huntington's disease; inflammatory disorder selected from the group
consisting of adult respiratory distress syndrome (ARDS), arthritic
disorders, asthma, dermatological lesions, gout, inflammatory bowel
disease, necrotizing vasculitides, neurogenic inflammation,
psoriasis, reperfusion injury, stroke and systemic inflammatory
response syndrome; macular degeneration; obesity; neurodegenerative
disease selected from the group consisting of Alzheimer's, ALS,
multiple sclerosis and Parkinson's; pathological conditions
selected from the group consisting of cardiomyopathy, diabetic
neuropathy and diabetic nephropathy; psychotic condition selected
from the group consisting of schizophrenia, schizophreniform
disorder, schizoaffective disorder, delusional disorder, brief
psychotic disorder, shared psychotic disorder, psychotic disorder
due to a general medical condition and psychotic disorders not
otherwise specified; sleep disorder selected from the group
consisting of primary sleep disorders, sleep disorders related to
another mental disorder, sleep disorders due to a general medical
condition and sleep disorders not otherwise specified; stroke;
substance-abuse disorder selected from the group consisting of
alcohol-related disorders, amphetamine-related disorders,
caffeine-related disorders, cannabis-related disorders,
cocaine-related disorders, hallucinogen-related disorders,
inhalant-related disorders, nicotine-related disorders,
opioid-related disorders, phencyclidine-related disorders,
sedative-related disorders, hypnotic-related disorders,
anxiolytic-related disorders and polysubstance-related disorder,
toxemic condition selected from the group consisting of ARDS,
hypovolemic shock, neuron toxicity, septic shock and traumatic
shock; or a traumatic condition selected from the group consisting
of chest trauma and head trauma, said method comprising the
administration to the mammal of an amount of the compound of claim
1 effective to inhibit the activity of a NOS in the mammal.
Description
[0001] The present invention relates to certain 2-aminopyridines
containing fused ring substituents that exhibit activity as nitric
oxide synthase (NOS) inhibitors, to pharmaceutical compositions
containing them, and to their use in the treatment and prevention
of central nervous system disorders, inflammatory disorders, septic
shock, obesity and other diseases, disorders and conditions.
[0002] There are three known isoforms of NOS: an inducible form
(I-NOS), and two constitutive forms referred to as, respectively,
neuronal NOS (N-NOS) and endothelial NOS (E-NOS). Each of these
enzymes carries out the conversion of arginine to citrulline, while
producing a molecule of nitric oxide (NO) in response to various
stimuli. It is believed that excess nitric oxide (NO) production by
NOS plays a role in the pathology of a number of disorders and
conditions in mammals. For example, NO produced by I-NOS is thought
to play a role in diseases that involve systemic hypotension, such
as toxic shock and therapy with certain cytokines. It has been
shown that cancer patients treated with cytokines such as
interleukin-1 (IL-1), interleukin-2 (IL-2) or tumor necrosis factor
(TNF) suffer cytokine-induced shock and hypotension due to NO
produced from macrophages, i.e., inducible NOS (I-NOS) (see
Chemical & Engineering News, December 20, p. 33, (1993)). I-NOS
inhibitors can reverse this. It is also believed that I-NOS plays a
role in the pathology of diseases of the central nervous system
such as ischemia. For example, inhibition of I-NOS has been shown
to ameliorate cerebral ischemic damage in rats (see Am. J.
Physiol., 268, p. R286 (1995)). Suppression of adjuvant-induced
arthritis by selective inhibition of I-NOS is reported in Eur. J.
Pharmacol., 273, p. 15-24 (1995).
[0003] NO produced by N-NOS is thought to play a role in diseases
such as cerebral ischemia, pain, and opiate tolerance. For example,
inhibition of N-NOS decreases infarct volume after proximal middle
cerebral artery occlusion in the rat (see J. Cerebr. Blood Flow
Metab., 14, p. 924-929 (1994)). N-NOS inhibition has also been
shown to be effective in antinociception, as evidenced by activity
in the late phase of the formalin-induced hindpaw licking and
acetic acid-induced abdominal constriction assays (see Br. J.
Pharmacol., 110, p. 219-224 (1993)). In addition, subcutaneous
injection of Freund's adjuvant in the rat induces an increase in
NOS-positive neurons in the spinal cord that is manifested in
increased sensitivity to pain, which can be treated with NOS
inhibitors (see Japanese Journal of Pharmacology, 75, p. 327-335
(1997)). Finally, opioid withdrawal in rodents has been reported to
be reduced by N-NOS inhibition (see Neuropsychopharmacol., 13, p.
269-293 (1995)).
SUMMARY OF THE INVENTION
[0004] This invention relates to compounds of the formula I: 2
[0005] or pharmaceutically acceptable salts thereof, wherein
[0006] A and B are each independently H, or together, A and B form
a ring fused to the phenyl ring, said ring being saturated or
unsaturated and containing from 5 to 7 ring member atoms, where
said ring member atoms may optionally comprise from 1 to 2
heteroatoms selected independently from the group consisting of N,
O or S, provided that no two adjacent ring members are
heteroatoms;
[0007] X is oxygen or a single bond;
[0008] Y is (C.sub.1-C.sub.6)alkyl;
[0009] R.sup.1 is hydrogen, (C.sub.1-C.sub.6)alkyl or a
(C.sub.1-C.sub.6 alkyl) group substituted with
--NR.sup.2R.sup.3
[0010] wherein R.sup.2 and R.sup.3 are either selected
independently from the group consisting of H, alkyl, aryl, aralkyl
or tetrahydronaphthalene, wherein said aryl group or said aryl
moiety of said aralkyl group is phenyl or naphthyl, said alkyl
group or said alkyl moiety of said aralkyl group contains from one
to six carbon atoms and is straight-chained or branched, and said
aryl group, said tetrahydronaphthalene or said aryl moiety of said
aralkyl group is optionally substituted with from one to three of
halogen, nitro, cyano, amino, (C.sub.1-C.sub.4)alkoxy and
(C.sub.1-C.sub.4)alkylamino moieties,
[0011] or R.sup.2 and R.sup.3-form, together with the nitrogen to
which they are attached, a heterocyclic ring, or a cyclic or
bicyclic ring which is saturated or unsaturated.
[0012] Preferably, the heterocyclic ring formed from R.sup.2,
R.sup.3 and the nitrogen to which they are attached is a
piperidine, azetidine, piperazine or pyrrolidine ring, optionally
substituted with one or more substituents selected independently
from the group consisting of (C.sub.1-C.sub.6)alkyl, amino,
(C.sub.1-C.sub.6) alkylamino, [di-(C.sub.1-C.sub.6)alkyl]amino,
phenyl-substituted 5- and 6-membered heterocyclic rings containing
from 1 to 4 ring nitrogen atoms, benzoyl, benzoylmethyl,
benzylcarbonyl, phenylaminocarbonyl, phenylethyl and
phenoxycarbonyl. Preferably, the piperidine, azetidine, piperazine
or pyrrolidine ring is substituted with from one to two
substituents. Moreover, the phenyl moiety of any of the foregoing
phenyl-containing substituents is itself optionally substituted
with one or more substituents selected independently from halo,
(C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)alkoxy, nitro, amino,
cyano, CF.sub.3 and OCF.sub.3; preferably with from one to two
substituents.
[0013] Preferably, the cyclic or bicyclic ring formed from
R.sup.2.sub.1 R.sup.3 and the nitrogen to which they are attached
is a 6-amino-3-azabicyclo[3.1.0]hex-3-yl ring having the formula:
3
[0014] wherein R.sup.4 and R.sup.5 are each selected independently
from the group consisting of H, (C.sub.1-C.sub.6)alkyl, phenyl,
naphthyl, (C.sub.1-C.sub.6)alkyl-C(.dbd.O)--, HC(.dbd.O)--,
(C.sub.1-C.sub.6)alkoxy- -(C.dbd.O)--, phenyl-C(.dbd.O)--,
naphthyl-C(.dbd.O)--, and R.sup.6R.sup.7NC(.dbd.O)--; R.sup.6 and
R.sup.7 are each independently hydrogen or
(C.sub.1-C.sub.6)alkyl.
[0015] The present invention also relates to preferred compounds of
the formula I-a: 4
[0016] wherein the broken line represents an optional double
bond;
[0017] Y is (C.sub.1-C.sub.6)alkyl; and
[0018] R.sup.1 is hydrogen, (C.sub.1-C.sub.6)alkyl or a
(C.sub.1-C.sub.6 alkyl) group substituted with --NR.sup.2R.sup.3,
wherein R.sup.2 and R.sup.3 are as defined above.
[0019] Some preferred compounds of formula I include:
[0020]
1-[4-(6-Amino-pyridin-2-yl)-naphthalen-1-yloxymethyl]-cyclohexanol;
[0021]
6-[4-(2-(2-Dimethylaminoethoxy)-ethoxy)-naphthalen-1-yl]-pyridin-2--
ylamine;
[0022]
6-[4-(2-Hydroxy-ethoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridin-
-2-ylamine; and
[0023]
6-[4-(2-(2-Diethylaminoethoxy)-ethoxy)-5,6,7,8-tetrahydro-naphthale-
n-1-yl]-pyridin-2-ylamine.
[0024] Additional compounds of formula I include:
[0025]
6-[4-(2-(2-Diethylaminoethoxy)-ethoxy)-naphthalen-1-yl]-pyridin-2-y-
lamine;
[0026]
6-[4-(2-(2-Dipropylaminoethoxy)-ethoxy)-naphthalen-1-yl]-pyridin-2--
ylamine;
[0027] 6-[4-(2-(2-(N-methyl,
N-benzyl)aminoethoxy)-ethoxy)-naphthalen-1-yl-
]-pyridin-2-ylamine;
[0028]
6-[4-(2-(2-(1-Piperidinyl)ethoxy)-ethoxy)-naphthalen-1-yl]-pyridin--
2-ylamine; and
[0029]
6-[4-(2-(2-(N-methylpiperazin-4-yl)ethoxy)-ethoxy)-naphthalen-1-yl]-
-pyridin-2-ylamine.
[0030] 6-[4-(2-(2-(6-amino-3-azabicyclo[3. 1.0]
hex-2-yl)-ethoxy)-ethoxy)-- naphthalen-1-yl]-pyridin-2-ylamine.
[0031] Also provided herein is a pharmaceutical composition
comprising a pharmaceutically acceptable carrier and an amount of a
compound of this invention effective to treat various diseases,
disorders and conditions in mammals, including humans. Further
provided is a method of treating various diseases, disorders and
conditions in mammals, including humans, said method comprising
administering to the mammals an amount of a compound of this
invention effective for such treatment.
[0032] Diseases, disorders and conditions to which the compositions
and methods of this invention are directed include, without
limitation: acute spinal cord injuries; anxiety disorders selected
from the group consisting of panic attack, agoraphobia, panic
disorder with or without agoraphobia, agoraphobia without history
of panic disorder, specific phobia, social phobia,
obsessive-compulsive disorder, post-traumatic stress disorder and
acute stress disorder; cancers, whether metastatic or not, selected
from the group consisting of brain, breast, colon, lung, liver,
ovarian, prostate, skin and stomach cancers, or cancers selected
from the group consisting of astrocytomas, carcinomas,
glioblastomas, leukemias, lymphomas, melanomas and sarcomas;
cognitive disorders selected from the group consisting of amnestic
disorders (e.g., amnestic disorders due to a general medical
condition, substance-induced persisting amnestic disorder and
amnestic disorders not otherwise specified), deliriums (e.g.,
deliriums due to a general medical condition, substance-induced
delirium and delirium not otherwise specified), dementias (e.g.,
dementia of the Alzheimer's type, vascular dementia, dementia due
to a general medical condition (e.g., AIDS-, Parkinson's-, head
trauma-, and Huntington's-induced dementias), substance-induced
persisting dementia, dementia due to multiple etiologies, and
dementia not otherwise specified) and cognitive disorders not
otherwise specified; emesis; epilepsy; gastrointestinal conditions
selected from the group consisting of Crohn's disease, inflammatory
bowel syndrome and ulcerative colitis; glaucoma; headache disorders
selected from the group consisting of migraine, cluster and
vascular headaches; Huntington's diseases; inflammatory disorders,
either primarily inflammatory in presentation or which have, as a
component of their presentation, an inflammatory phase, selected
from the group consisting of adult respiratory distress syndrome
(ARDS), arthritic disorders (e.g., rheumatoid and osteoarthritis),
asthma, dermatological lesions, gout, inflammatory bowel disease,
necrotizing vasculitides (e.g., polyarteritis nodosa, serum
sickness, Wegener's granulomatosis, and Kawasaki's syndrome
(Kadison)), neurogenic inflammation, psoriasis, reperfusion injury
(e.g., following myocardial infarction, thrombolysis, septic shock,
organ transplantation and diabetes), stroke and systemic
inflammatory response syndrome; macular degeneration; obesity;
neurodegenerative diseases selected from the group consisting of
Alzheimer's, ALS, multiple sclerosis and Parkinson's diseases;
pathological conditions selected from the group consisting of
cardiomyopathy, diabetic neuropathy and diabetic nephropathy;
psychotic conditions selected from the group consisting of
schizophrenia (e.g., paranoid-type, disorganized-type,
catatonic-type, undifferentiated-type and residual-type),
schizophreniform disorder, schizoaffective disorder, delusional
disorder, brief psychotic disorder, shared psychotic disorder,
psychotic disorders due to a general medical condition and
psychotic disorders not otherwise specified; sleep disorders
selected from the group consisting of primary sleep disorders
(e.g., parasomnias and dyssomnias), sleep disorders related to
another mental disorder (including, without limitation, mood and
anxiety disorders), sleep disorders due to a general medical
condition and sleep disorders not otherwise specified; stroke;
substance-abuse disorders selected from the group consisting of
alcohol-related disorders, including alcohol-use (e.g., dependence
and abuse) and alcohol-induced (e.g., intoxication, withdrawal,
intoxication delirium, withdrawal delirium, persisting dementia,
persisting amnestic, mood, anxiety, sexual dysfunction, sleep and
not otherwise specified) disorders, amphetamine-related disorders,
including amphetamine-use (e.g., dependence and abuse) and
amphetamine-induced (e.g., intoxication, withdrawal, intoxication
delirium, psychotic, mood, anxiety, sexual dysfunction, sleep and
not otherwise-specified) disorders, caffeine-related disorders,
such as intoxication, induced-anxiety disorder, induced-sleep
disorder and disorders not otherwise specified; cannabis-related
disorders, including cannabis-use (e.g., abuse and dependence) and
cannabis-induced (e.g., intoxication, intoxication delirium,
psychotic, anxiety and not otherwise specified) disorders,
cocaine-related disorders, including cocaine-use (e.g., dependence
and abuse) and cocaine-induced (e.g., intoxication, withdrawal,
intoxication delirium, psychotic, mood, anxiety, sexual
dysfunction, sleep and not otherwise specified) disorders,
hallucinogen-related disorders, including hallucinogen-use (e.g.,
dependence and abuse) and hallucinogen-induced (e.g., intoxication,
persisting perception, intoxication delirium, psychotic, mood,
anxiety and not otherwise specified) disorders, inhalant-related
disorders, including inhalant-use (e.g., dependence and abuse) and
inhalant-induced (e.g., intoxication, intoxication delirium,
persisting dementia, psychotic, mood, anxiety and not otherwise
specified) disorders, nicotine-related disorders, such as
dependence, withdrawal and not otherwise specified disorders,
opioid related disorders, including opioid-use (e.g., dependence
and abuse) and opioid-induced (e.g., intoxication, withdrawal,
intoxication delirium, psychotic, mood, sexual dysfunction, sleep
and not otherwise-specified) disorders, phencyclidine-related
disorders, including phencyclidine-use (e.g., dependence and abuse)
and phencyclidine-induced (e.g., intoxication, intoxication
delirium, psychotic, mood, anxiety and not otherwise-specified)
disorders, sedative-, hypnotic- or anxiolytic-related disorders,
including sedative-use (e.g., dependence and abuse) and
sedative-induced disorders (e.g., intoxication, withdrawal,
intoxication delirium, withdrawal delirium, persisting dementia,
persisting amnestic, psychotic, mood, anxiety, sexual dysfunction,
sleep and not otherwise specified) disorders, polysubstance-related
disorder, other substance dependence and abuse disorders, and other
substance-induced disorders (e.g., intoxication, withdrawal,
delirium, persisting dementia, persisting amnestic, psychotic,
mood, anxiety, sexual dysfunction, sleep and not otherwise
specified) disorders; toxemic conditions selected from the group
consisting of ARDS, hypovolemic shock, neuron toxicity, septic
shock and traumatic shock; traumatic conditions, including trauma
to the head and chest; and, various additional diseases, disorders
and conditions as well.
[0033] Additionally provided herein is a pharmaceutical composition
comprising a pharmaceutically acceptable carrier and an amount of a
compound of this invention effective to inhibit the activity of a
nitric oxide synthase (NOS) in a mammal, including a human. Still
further provided herein is a method of inhibiting the activity of a
NOS in a mammal, including a human, which comprises administering
to said mammal an amount of a compound of this invention effective
to inhibit the activity of the NOS.
[0034] Additionally provided herein is a pharmaceutical composition
for treating a disease, disorder or condition, such as those set
forth above, in a mammal, including a human; said composition
comprises a pharmaceutically acceptable carrier and an amount of a
compound of this invention effective to inhibit the activity of a
NOS in the mammal. Still further provided herein is a method of
treating a mammal, including a human, afflicted with a disease,
disorder or condition, including those set forth above; said method
comprises administering to the mammal an amount of a compound of
this invention effective for such treatment.
[0035] Acids used to prepare pharmaceutically acceptable acid
addition salts of compounds of this invention from the
corresponding base compounds are those acids which form non-toxic
acid addition salts, i.e., salts containing pharmacologically
acceptable anions, such as the hydrochloride, hydrobromide,
hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid
phosphate, acetate, lactate, citrate, acid citrate, tartrate,
bitartrate, succinate, maleate, fumarate, gluconate, saccharate,
benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate,
p-toluenesulfonate and pamoate [1,1-methylene-bis-(2-hy-
droxy-3-naphthoate)] salts.
[0036] Compounds of formula I may contain chiral centers, and
therefore may exist in different enantiomeric and diastereomeric
forms; this invention is directed to all such optical and
stereoisomers of compounds of formula I, as well as mixtures
thereof, and to all pharmaceutical compositions and methods of
treatment that contain or employ them.
[0037] This invention is also directed to isotopically-labeled
compounds identical to those recited in formula I but for the fact
that one or more atoms are replaced therein 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 this invention include isotopes of
hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and
chlorine, such as .sup.2H, .sup.3H, .sup.13C, .sup.14C, .sup.15N,
.sup.18O, .sup.17O, .sup.31P, .sup.32P, 35S, .sup.18F, and
.sup.36Cl, respectively.
[0038] Compounds of formula I, prodrugs thereof, and
pharmaceutically acceptable salts of said compounds, or of said
prodrugs, which contain the aforementioned isotopes and/or other
isotopes of other atoms are within the scope of this invention.
Certain isotopically-labeled compounds of the present invention,
for example those into which radioactive isotopes such as .sup.3H
and .sup.14C are incorporated, are useful, for example, in drug
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.
Furthermore, substitution with heavier isotopes such as deuterium,
i.e., .sup.2H, can afford certain therapeutic advantages resulting
from greater metabolic stability, for example increased in vivo
half-life or reduced dosage requirements and, hence, may be
preferred in some circumstances.
[0039] Isotopically-labeled compounds of formula I of this
invention and prodrugs thereof can generally be prepared by
carrying out the procedures disclosed in the Schemes, and/or in the
Examples, set forth below, by substituting a readily available
isotopically-labeled reagent for a non-isotopically labeled
reagent.
[0040] The following terms have the stated meanings throughout this
application, unless otherwise indicated:
[0041] "Alkyl" refers to saturated monovalent hydrocarbon radicals
having straight chain moieties, branched moieties, and in the case
where the number of carbons is greater than three, cyclic moieties,
and combinations thereof;
[0042] "One or more substituents" refers to a number of
substituents that equals from one to the maximum number of
substituents possible based on the number of available bonding
sites;
[0043] "Halo" and "halogen" each refer to chloro, fluoro, bromo and
iodo;
[0044] "Treating" refers to, and includes, reversing, alleviating,
inhibiting the progress of, or preventing a disease, disorder or
condition, or one or more symptoms thereof; and "treatment" refers
to the act of treating, as defined above.
DETAILED DESCRIPTION OF THE INVENTION
[0045] Compounds of the formula I may be prepared as described in
the following reaction schemes and discussion. Unless otherwise
indicated, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and
R.sup.7 and structural formula I in the reaction schemes and
discussion that follow, are defined as above. 5
[0046] Scheme 1 illustrates a method of preparing compounds of the
formula I wherein X is oxygen and A and B form a tetramethylene
ring. Scheme 2 illustrates a method of preparing compounds of the
formula I wherein X is oxygen and A and B form a benzo ring. The
starting materials used in the procedures of Schemes 1 and 2 are
either commercially available, known in the art, or are readily
obtainable from known compounds by methods that will be apparent to
those skilled in the art.
[0047] Referring to Scheme 1, the compound of formula II is reacted
with tetrabutylammonium tribromide in 1,2-dichloroethane at about
room temperature. The product of this reaction is then treated with
benzyl bromide and potassium carbonate in a solvent such as
acetonitrile, at about the reflux temperature of the reaction
mixture, to form the compound of formula III.
[0048] The compound of formula III is then converted into
1-benzyloxy-naphthalene-4-boronic acid by the procedure described
above for preparing the boronic acid derivative of formula IV in
Scheme 1. Reaction of 1-benzyoxy-napthalene-4-boronic acid with
6-bromo-2-(2,5-dimethylpyrrolyl)pyridine in an ethanol solvent, in
the presence of sodium carbonate and tetrakistriphenyl palladium,
at about the reflux temperature of the reaction mixture, yields the
compound of formula V, which can be converted into the compound of
formula VI using the following two step process: the compound of
formula V is reacted with ammonium formate and ten percent
palladium on carbon, in an ethanol solvent, at about the reflux
temperature of the reaction mixture, to yield the analogous
compound to that having formula V, wherein the benzyloxy group of
formula V is replaced with a hydroxy group; and, the compound of
formula VI is then formed by reacting the above hydroxy derivative
with 2-bromoethylacetate and potassium carbonate in acetonitrile at
about the reflux temperature of the reaction mixture.
[0049] Basic hydrolysis of the compound of formula V, followed by
reduction with lithium aluminum hydride or borane methyl sulfide,
or other suitable metal hydrides, in tetrahydrofuran (THF) or
ether, or a suitable ethereal solvent, yields the desired compound
of the formula VI; the base hydrolysis is typically carried out
using an alkali metal or alkaline earth metal hydroxide in a
mixture of THF, methanol and water at about room temperature. The
compound of formula VI can be converted into the desired compound
of formula I as follows. The 2,5-dimethylpyrrolyl protecting group
is removed by reaction with hydroxylamine hydrochloride. This
reaction is generally carried out in an alcoholic or aqueous
alcoholic solvent, at a temperature from about room temperature to
about the reflux temperature of the reaction mixture, preferably at
about the reflux temperature, for about 8 to about 72 hours.
[0050] Compounds of the formula I that are identical to those of
formula I but for the fact that ring A is other than benzo can be
prepared in an analogous fashion, starting with the appropriate
compound that is analogous to that of formula II, wherein the
unsubstituted benzo ring of formula II is replaced by a ring other
than benzo that is within the definition of ring A.
[0051] Referring to Scheme 2, the known 1-fluoronaphthalene,
compound VII, is brominated with bromine in acetic acid at a
temperature from room temperature to reflux for 1 to 48 hours, and
the bromide cooled to about -70.degree. C. in dry tetrahydrofuran
(THF), and then a solution of n-butyl lithium is added to it. The
resulting solution is then treated with triethyl borate and allowed
to warm to room temperature to form the compound of formula VIII,
which is subsequently reacted with
6-bromo-2-(2,5-dimethylpyrrolyl)pyridine to form the compound of
formula IX. This reaction is generally carried out in an aqueous
ethanol solvent, in the presence of sodium carbonate and
tetrakistriphenylphoshine palladium, at about the reflux
temperature.
[0052] Compound IX is then treated with an alkali metal alkoxide,
prepared from, for example, sodium hydride in a polar solvent such
as dimethylformamide, at a temperature from room temperature to
140.degree. C. for 1 to 48 hours. The resulting compound, X, is
then deblocked to remove the 2,5-dimethylpyrrolyl protecting group
by reaction with hydroxylamine hydrochloride. This reaction is
generally carried out in an alcoholic or aqueous alcoholic solvent,
at a temperature from about room temperature to about the reflux
temperature of the reaction mixture, preferably at about the reflux
temperature, for about 8 to about 72 hours.
[0053] The last step in each of Schemes I and II for the
preparation of compounds of formula I comprises the removal of the
nitrogen protecting group in the form of a 2,5-dimethylpyrrolyl
ring. In general, however, compounds of formula I may be prepared
by the removal of a nitrogen protecting group from a compound of
formula I': 6
[0054] wherein Z.sup.1 is hydrogen; and Z.sup.2 is a nitrogen
protecting group; or Z.sup.1 and Z.sup.2 together comprise a
nitrogen protecting group. Commonly used nitrogen protecting groups
include an alkylcarbonyl group such as formyl, acetyl, propionyl,
etc., an alkoxycarbonyl group such as t-butoxycarbonyl, etc., an
alkoxyalkylcarbonyl group such as methoxyacetyl, methoxypropionyl,
etc., a substituted alkoxycarbonyl group such as
trichloroethoxycarbonyl, etc., a substituted alkylcarbonyl, such as
monochloromethylcarbonyl, monochloroethylcarbonyl,
dichloromethylcarbonyl, dichloroethylcarbonyl,
trichloromethylcarbonyl, trichloroethylcarbonyl,
trichloropropylcarbonyl, etc., an aralkyloxycarbonyl group such as
benzyloxycarbonyl, etc., a substituted aralkyloxycarbonyl group
such as p-nitrobenzyloxycarbonyl, etc. The removal of the nitrogen
protective group may be conducted, for example, by acid treatment
for t-butoxycarbonyl, etc., by a treatment with zinc and an acid
for trichloroethoxycarbonyl, etc. by catalytic reduction for
p-nitrobenzyloxycarbonyl, etc. The protecting group, e.g., in the
instance where Z.sup.1 and Z.sup.2 together form a nitrogen
protecting group, may comprise a ring structure, such as pyrrolyl,
etc., in addition to others known to those of skill in the art.
[0055] The preparation of other compounds of formula I not
specifically described in the foregoing experimental section can be
accomplished using combinations of the reactions described above
that will be apparent to those skilled in the art. Furthermore, in
each of the reactions discussed or illustrated above, pressure is
not critical unless otherwise indicated. Pressures from about 0.5
atmospheres to about 5 atmospheres are generally acceptable, and
ambient pressure, i.e., about 1 atmosphere, is preferred as a
matter of convenience.
[0056] The compounds of formula I ("the active compounds of this
invention") which are basic in nature are capable of forming a wide
variety of different salts with various inorganic and organic
acids. Although such salts must be pharmaceutically acceptable for
administration to animals, it is often desirable in practice to
initially isolate a compound of the formula I from the reaction
mixture as a pharmaceutically unacceptable salt, convert the latter
back to the free base compound by treatment with an alkaline
reagent, and subsequently convert the latter free base to a
pharmaceutically acceptable acid addition salt. The acid addition
salts of the active base compounds of this invention are readily
prepared by treating the base compound with a substantially
equivalent amount of the chosen mineral or organic acid in an
aqueous solvent medium or in a suitable organic solvent, such as
methanol or ethanol. Upon careful evaporation of the solvent, the
desired solid salt is readily obtained.
[0057] The compounds of this invention and their pharmaceutically
acceptable salts are useful as NOS inhibitors i.e., they possess
the ability to inhibit the activity of NOS enzymes in mammals,
including humans, and therefore, are able to function as
therapeutic agents in the treatment in the mammals of various
diseases, disorders and conditions characterized by excessive
levels of NOS activity, including, without limitation, those
diseases, disorders and conditions set forth above. The compounds'
ability to inhibit NOS activity may be determined using procedures
described in the literature. For example, the ability of compounds
of formula I to inhibit endothelial NOS may be determined by using
the procedures described by Schmidt et al. in Proc. Natl. Acad.
Sci. U.S.A., 88, pp. 365-369 (1991) and by Pollock et al., in Proc.
Natl. Acad. Sci. U.S.A., 88, pp. 10480-10484 (1991). The ability of
compounds of formula I to inhibit inducible NOS may be determined
using the procedures described by Schmidt et al., in Proc. Natl.
Acad. Sci. U.S.A. 88 pp. 365-369 (1991) and by Garvey et al. in J.
Biol. Chem., 269, pp. 26669-26676 (1994). The ability of compounds
of formula I to inhibit neuronal NOS may be determined using the
procedure described by Bredt and Snyder in Proc. Natl. Acad. Sci.
U.S.A., 87, 682-685 (1990). The contents of these documents are
incorporated herein by reference. Of four compounds of formula I
that were tested, all exhibited an IC.sub.50<10 .mu.M for
inhibition of either inducible or neuronal NOS.
[0058] The compounds of this invention and their pharmaceutically
acceptable salts can be administered via either the oral,
parenteral or topical routes. In general, these compounds are most
desirably administered in dosages ranging from about 0.01 to about
250 mg per day, in single or divided doses (e.g., from 1 to 4 doses
per day), although variations will necessarily occur depending upon
the species, weight and condition of the subject being-treated and
the particular route of administration chosen. However, a dosage
level that is in the range of about 0.07 mg to about 21 mg per kg
of body weight per day is most desirably employed. Variations may
nevertheless occur depending upon the subject being treated and its
individual response to said medicament, as well as on the type of
pharmaceutical formulation chosen and the time period and interval
at which such administration is carried out. In some instances,
dosage levels below the lower limit of the aforesaid range may be
more than adequate, while in other cases still larger doses may be
employed without causing any harmful side effect, provided that
such larger doses are first divided into several small doses for
administration throughout the day.
[0059] The compounds of the invention may be administered alone or
in combination with pharmaceutically acceptable carriers or
diluents by either of the three routes previously indicated, and
such administration may be carried out in single or multiple doses.
More particularly, the novel therapeutic agents of this invention
can be administered in a wide variety of different dosage forms,
i.e., they may be combined with various pharmaceutically acceptable
inert carriers in the form of tablets, capsules, lozenges, troches,
hard candies, powders, sprays, creams, salves, suppositories,
jellies, gels, pastes, lotions, ointments, aqueous suspensions,
injectable solutions, elixirs, syrups, and the like. Such carriers
include solid diluents or fillers, sterile aqueous media and
various non-toxic organic solvents, etc. Moreover, oral
pharmaceutical compositions can be suitably sweetened and/or
flavored. In general, the therapeutically-effective compounds of
this invention are present in such dosage forms at concentration
levels ranging from about 5.0% to about 70% by weight.
[0060] For oral administration, tablets containing various
excipients such as microcrystalline cellulose, sodium citrate,
calcium carbonate, dicalcium phosphate and glycine may be employed
along with various disintegrants such as starch (and preferably
corn, potato or tapioca starch), alginic acid and certain complex
silicates, together with granulation binders like
polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,
lubricating agents such as magnesium stearate, sodium lauryl
sulfate and talc are often very useful for tabletting purposes.
Solid compositions of a similar type may also be employed as
fillers in gelatin capsules; preferred materials in this connection
also include lactose or milk sugar as well as high molecular weight
polyethylene glycols. When aqueous suspensions and/or elixirs are
desired for oral administration, the active ingredient may be
combined with various sweetening or flavoring agents, coloring
matter or dyes, and, if so desired, emulsifying and/or suspending
agents as well, together with such diluents as water, ethanol,
propylene glycol, glycerin and various like combinations
thereof.
[0061] For parenteral administration, solutions of an active
compound of the present invention in either sesame or peanut oil or
in aqueous propylene glycol may be employed. The aqueous solutions
should be suitably buffered (preferably pH greater than 8) if
necessary and the liquid diluent first rendered isotonic. These
aqueous solutions are suitable for intravenous injection purposes.
The oily solutions are suitable for intraarticular, intramuscular
and subcutaneous injection purposes. The preparation of all these
solutions under sterile conditions is readily accomplished by
standard pharmaceutical techniques well known to those skilled in
the art.
[0062] Additionally, it is also possible to administer the active
compounds of the present invention topically for the treatment of
conditions of the skin; this may be done by way of creams, jellies,
gels, pastes, patches, ointments and the like, in accordance with
standard pharmaceutical practice.
[0063] The present invention is illustrated by the following
examples. It will be understood, however, that the invention is not
limited to the specific details of these examples. Melting points
are uncorrected. Proton nuclear magnetic resonance spectra (.sup.1H
NMR) and .sup.13C nuclear magnetic resonance spectra (.sup.13C NMR)
were measured for solutions in deuterochloroform (CDCl.sub.3) or in
CD.sub.3OD or CD.sub.3SOCD.sub.3 and peak positions are expressed
in parts per million (ppm) downfield from tetramethylsilane (TMS).
The peak shapes are denoted as follows: s, singlet; d, doublet; t,
triplet; q, quartet, m, multiplet, b, broad.
EXAMPLE 1
6-[4-(2-(2-Diethylaminoethoxy)-ethoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-
-pyridin-2-ylamine
[0064] A. 4-Bromo-5,6,7,8-tetrahydro-1-benzyloxynaphthalene
[0065] To a 250 mL round-bottomed flask equipped with addition
funnel and nitrogen (N.sub.2) inlet were added 2.96 g (20 mmol)
5,6,7,8-tetrahydro-naphthalen-1-ol and 50 mL 1,2-dichloroethane,
and with stirring a solution of 9.64 g (20 mmol) tributylammonium
tribromide in 30 mL 1,2-dichloroethane dropwise over 10 minutes.
After stirring an additional 10 minutes at room temperature, the
solution was washed with water, dilute aqueous sodium bisulfite,
and water, dried over sodium sulfate, and evaporated. The mixture
of product and tributylammonium bromide was used directly.
.sup.1H-NMR (.delta., CDCl.sub.3): 1.70 (m, 4H), 2.56 (t, J=6, 2H),
2.61 (t, J=6, 2H), 7.02 (AB, 2H), 8.0 (bs, 1H, OH); .sup.13C-NMR
(.delta., CDCl.sub.3): 22.2, 22.9, 23.8, 30.5,114.0, 114.7,126.6,
129.0, 136.7,154.1.
[0066] The above oil was dissolved in 100 mL acetonitrile, and
treated with 3.57 mL (30 mmol) benzyl bromide and 5.53 g (40 mmol)
potassium carbonate, then refluxed 14 hours. Thin layer
chromatography (TLC) showed a major spot at R.sub.f=0.3 in 10%
methylene chloride/hexane (with benzyl bromide at R.sub.f=0.4). The
reaction was cooled, poured into dilute aqueous hydrochloric
acid/ethyl acetate, and the organic layer separated, washed with
water and brine, dried over sodium sulfate, and evaporated. The
residue was chromatographed on silica gel using methylene
chloride/hexane as eluant to afford 4.0 g (63%) of an oil.
.sup.1H-NMR (.delta., CDCl.sub.3): 1.77 (m, 4H), 2.75 (m, 4H),
5.045 (s, 2H), 6.62 (d, J=9, 1H), 7.3-7.5 (m, 6H); .sup.13C-NMR
(.delta., CDCl.sub.3): 22.2, 22.9, 24.0, 30.7, 69.9, 109.8, 116.7,
127.1, 127.9, 128.6, 129.1, 129.3, 137.2,137.5, 155.6.
[0067] B. 5,6,7,8-tetrahydro-1-benzyloxynaphthalene-4-boronic
acid
[0068] Prepared from Example 1A, using butyl lithium in
tetrahydrofuran at -70.degree. C. for 1 hour, followed by treatment
with triethyl borate at -70.degree. C. for 1 hour and room
temperature for 18 hours, followed by quenching with hydrochloric
acid and extraction into ethyl acetate, followed by drying over
sodium sulfate and evaporation, as a white solid after trituration
with hexane in 72% yield. M.p. 199-205.degree. C.; .sup.1H-NMR
(.delta., CDCl.sub.3): 1.72 (m, 4H), 2.70 (m, 4H), 5.005 (s, 2H),
6.66 (m, 1H), 7.01 (d, J=8, 1H), 7.2-7.4 (m, 5H); .sup.13C-NMR
(.delta., CDCl.sub.3): 22.6, 22.9, 23.4, 30.0, 107.8, 125.9, 127.0,
127.6, 128.4,131.1, 137.5, 140.8, 156.9.
[0069] C.
2-(2,5-Dimethylpyrrolyl)-6-[4-benzyloxy-5,6,7,8-tetrahydro-napht-
halen-1-yl]-pyridine
[0070] Prepared by coupling the product of Example 1B with
6-bromo-2-(2,5-dimethylpyrrolyl)pyridine in aqueous ethanol with
tetrakistriphenylphosphine palladium as catalyst and sodium
carbonate as the base, at reflux for 18 hours, followed by cooling,
partitioning between water and ethyl acetate, drying the organic
layer over sodium sulfate, and evaporation, followed by
chromatography on silica gel using methanolmethylene chloride as
eluant, in 100% yield as an oil. .sup.1H-NMR (.delta., CDCl.sub.3):
1.81 (m, 2H), 1.91 (m, 2H), 2.29 (s, 6H), 2.93 (m, 4H), 5.19 (s,
2h), 6.02 (s, 2H), 6.91 (d, J=8, 1H), 7.21 (d, J=8, 1H), 7.32 (d,
J=8, 1H), 7.4-7.6 (m, 6H), 7.89 (t, J=8, 1H); .sup.13C-NMR
(.delta., CDCl.sub.3): 13.5, 22.5, 23.0, 24.0, 28.9, 69.8, 106.8,
108.2, 119.6, 123.1, 126.8, 127.2, 127.8, 12.9, 128.6, 128.7,
132.8, 136.8, 137.6, 138.0, 151.4, 156.8, 160.4; MS (%): 409
(parent+1, 100).
[0071] D.
2-(2,5-Dimethylpyrrolyl)-6-[4-hydroxy-5,6,7,8-tetrahydro-naphtha-
len-1-yl]-Pyridine
[0072] Prepared from the product of Example 1C using ammonium
formate and 10% palladium-on-carbon as catalyst, in ethanol at
reflux for 3 hour, followed by cooling, filtration through Celite,
evaporation, partitioning between ethyl acetate and aqueous sodium
bicarbonate solution, separation, drying over sodium sulfate, and
evaporation, in 100% yield as an low melting solid. .sup.1H-NMR
(.delta., CDCl.sub.3): 1.67 (m, 2H), 1.77 (m, 2H), 2.16 (s, 6H),
2.63 (m, 2H), 2.73 (m, 2H), 5.89 (s, 2H), 6.3 (bs, 1H, OH), 6.51
(d, J=8, 1H), 7.02 (d, J=8, 1H), 7.13 (d, J=8, 1H), 7.35 (d, J=8,
1H), 7.83 (t, J=8, 1H); .sup.13C-NMR (.delta., CDCl.sub.3): 13.3,
22.3, 22.8 23.3, 28.6, 106.6, 112.1, 119.7, 123.3, 124.2, 127.8,
128.7, 131.9, 136.6, 138.1, 151.2, 154.4, 160.5; MS (%): 319
(parent+1, 100).
[0073] E.
2-(2,5-Dimethylpyrrolyl)-6-[4-(2-(2-diethylaminoethoxy)-ethoxy)--
5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridine
[0074] To a three-necked 125 mL round-bottomed flask equipped with
nitrogen (N.sub.2) inlet and septum were added 15 mL dry
dimethylformamide and 50 mg (1.3 mmol) sodium hydride (washed with
hexane). The reaction was cooled to 0.degree. C., and a solution of
200 mg (0.6 mmol)
2-(2,5-dimethylpyrrolyl)-6-[4-hydroxy-5,6,7,8-tetrahydro-na-
phthalen-1-yl]-pyridine in 5 mL dry dimethylformamide added
dropwise. The reaction was stirred 30 min at room temperature, then
a solution of 234 mg (1.3 mmol) diethylaminoethoxy-ethyl chloride
(J. Med. Chem., 34, 3159 (1991)) in 5 mL dry dimethylformamide
added dropwise and the reaction heated at 100.degree. C. for 20
hour, followed by more sodium hydride and chloride and heating
another 24 hour The reaction was cooled, poured into aqueous sodium
hydroxide solution, and extracted into ethyl acetate. The organic
layer was washed with water, aqueous sodium bicarbonate solution,
and brine, dried over sodium sulfate, and evaporated. The residue
was chromatographed on silica gel using methanol/methylene chloride
as eluant to afford 83 mg (30%) of an oil. .sup.1H-NMR (.delta.,
CDCl.sub.3): 1.03 (t, J=7, 6H), 1.67 (m, 2H), 1.76 (m, 2H), 2.155
(s, 6H), 2.59 (q, J=7, 4H), 2.7-2.9 (m, 6H), 3.67 (t, J=7, 2H),
3.84 (t, J=6, 2H), 4.14 (t, J=6, 2H), 5.87 (s, 2H), 6.73 (d, J=8,
1H), 7.11 (d, J=8, 1H), 7.185 (d, J=8, 1H), 7.35 (d, J=8, 1H), 7.82
(t, J=8, 1H); .sup.13C-NMR (.delta., CDCl.sub.3): 11.68, 13.33,
22.30, 22.87, 23.68, 28.66, 47.61, 52.34, 67.65, 69.67, 70.10,
106.52, 107.80, 119.48, 122.95, 126.59, 127.68, 128.62, 132.55,
136.58, 137.84, 151.21, 156.85, 160.34; MS (%): 462 (parent+1,
100).
[0075] F.
6-[4-(2-(2-Diethylaminoethoxy)-ethoxy)-5,6,7,8-tetrahydro-naphth-
alen-1-yl]-pyridin-2-ylamine
[0076] To a 100 mL round-bottomed flask equipped with condenser and
nitrogen (N.sub.2) inlet were added 83 mg (0.18 mmol)
2-(2,5-dimethylpyrrolyl)-6-[4-(2-(2-diethylaminoethoxy)-ethoxy)-5,6,7,8-t-
etrahydro-naphthalen-1-yl]-pyridine, 250 mg (3.6 mmol)
hydroxylamine hydrochloride, 10 mL ethanol, and 1 mL water. The
reaction was refluxed 40 hour, cooled, and poured into 1 N
hydrochloric acid. The aqueous layer was washed with ethyl acetate
and adjusted to pH 12 with 6 N sodium hydroxide solution, then
extracted with methylene chloride. The organic layer was dried over
sodium sulfate and evaporated to afford 76 mg (100%) of an oil,
which was converted to the hydrochloride salt with HCl in ether to
give an amorphous tan solid. .sup.1H-NMR (d, CDCl.sub.3): 1.02 (t,
J=7, 6H), 1.64 (m, 2H), 1.73 (m, 2H), 2.59 (q, J=7, 4H), 2.69 (m,
6H), 3.66 (t, J=7, 2H), 3.81 (t, J=5, 2H), 4.10 (t, J=5, 2H), 4.78
(bs, 2H), 6.37 (d, J=8, 1H), 6.62 (d, J=8, 1H), 6.67 (d, J=8, 1H),
7.08 (d, J=8, 1H), 7.41 (t, J=8, 1H); .sup.13C-NMR (.delta.,
CDCl.sub.3): 11.47, 13.66, 19.90, 22.40, 22.87, 23.68, 25.47,
28.23, 31.67, 32.57, 47.49, 52.18, 67.58, 69.68, 69.87, 106.32,
107.73, 114.33, 126.41, 126.90, 133.44, 136.32, 137.87, 156.26,
156.39, 157.82, 158.61; MS (%): 384 (parent+1, 100); HRMS
Calculated. for C.sub.23H.sub.34N.sub.3O.sub.2: 384.2651, Found:
384.2655.
EXAMPLE 2
6-[4-(2-Hydroxy-ethoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridin-2-ylam-
ine
[0077] A.
2-(2,5-Dimethylpyrrolyl)-6-[4-carboethoxymethoxy-5,6,7,8-tetrahy-
dro-naphthalen-1-yl]-pyridine
[0078] Prepared from
2-(2,5-dimethylpyrrolyl)-6-[4-hydroxy-5,6,7,8-tetrahy-
dro-naphthalen-1-yl]-pyridine (from Example 1) by alkylation with
ethyl bromoacetate, using potassium carbonate, in acetonitrile. The
mixture was refluxed 12 hours, cooled, poured into water, and
extracted into ethyl acetate. The organic layer was washed with
brine, dried over sodium sulfate, and evaporated. The residue was
chromatographed on silica gel using hexane/ethyl acetate as eluant
to an 83.5% yield of the product as an oil. .sup.1H-NMR (.delta.,
CDCl.sub.3): 1.31 (t, J=7, 3H), 1.71 (m, 2H), 1.83 (m, 2H), 2.19
(s, 6H), 4.26 (q, J=7, 2H), 4.66 (s, 2H), 5.90 (s, 2H), 6.64 (d,
J=8, 1H), 7.12 (d, J=8, 1H), 7.20 (d, J=8, 1H), 7.35 (d, J=8, 1H),
7.82 (t, J=8, 1H); .sup.13C-NMR (.delta., CDCl.sub.3): 13.4, 14.2,
22.3, 22.9, 23.7, 28.7, 61.2, 65.5, 106.7, 107.8, 119.6, 123.0,
126.9,127.7, 128.5, 133.4, 137.0, 138.1, 151.3, 156.0, 160.1,
169.0; MS (%): 405 (parent+1, 100).
[0079] B.
2-(2,5-Dimethylpyrrolyl)-6-[4-carboxymethoxy-5,6,7,8-tetrahydro--
naphthalen-1-yl]-pyridine:
[0080] Prepared from Example 2A by hydrolysis in tetrahydrofuran,
methanol and water using lithium hydroxide as the base at room
temperature for 12 hour, followed by pouring the reaction into
dilute hydrochloric acid and extraction into ethyl acetate, drying
over sodium sulfate, and evaporation, in 100% yield as a solid.
M.p. 199-206.degree. C. .sup.1H-NMR (.delta., CDCl.sub.3): 1.62 (m,
2H), 1.72 (m, 2H), 2.08 (s, 6H), 2.66 (m, 2H), 2.75 (m, 2H), 4.56
(s, 2H), 5.81 (s, 2H), 6.58 (d, J=8, 1H), 7.09 (m, 2H), 7.31 (d,
J=8, 1H), 7.80 (t, J=8, 1H); .sup.13C-NMR (.delta., CDCl.sub.3):
12.95, 22.1, 22.6, 23.4, 28.4, 65.0, 106.5, 107.7, 119.9, 123.3,
126.7, 127.4, 128.5, 132.8 136.6, 138.3, 151.1, 155.9, 160.1,
171.2; MS (%): 377 (parent+1, 100).
[0081] C.
2-(2,5-Dimethylpyrrolyl)-6-[4-(2-hydroxy-ethoxy)-5,6,7,8-tetrahy-
dro-naphthalen-1-yl]-pyridine
[0082] To a 100 mL round-bottomed flask equipped with condenser and
nitrogen (N.sub.2) inlet were added 100 mg (0.27 mmol)
2-(2,5-dimethylpyrrolyl)4-[4-carboxymethoxy-5,6,7,8-tetrahydro-naphthalen-
-1-yl]-pyridine (from Example 1), 20 mL dry tetrahydrofuran, and
0.6 mL (0.53 mmol) of a 1 M solution of lithium aluminum hydride in
tetrahydrofuran. The reaction was refluxed 16 hour, cooled, and
quenched with 1 N hydrochloric acid. The mixture was adjusted to pH
10 with 1 N aqueous sodium hydroxide solution, and extracted with
ethyl acetate. The organic layer was washed with brine, dried over
sodium sulfate, and evaporated. The residue of 118 mg (100%), an
oil, was used directly in the following step. .sup.1H-NMR (.delta.,
CDCl.sub.3): 1.69 (m, 2H), 1.78 (m, 2H), 2.16 (s, 6H), 2.7-2.9 (m,
4H), 3.95 (m, 2H), 4.08 (m, 2H), 5.885 (s, 2H), 6.73 (d, J=8, 1H),
7.13 (d, J=8, 1H), 7.20 (d, J=8, 1H), 7.35 (d, J=8, 1H), 7.83 (t,
J=8, 1H); MS (%): 363 (parent+1, 100).
[0083] D.
6-[4-(2-hydroxy-ethoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyri-
din-2-ylamine
[0084] To a 100 mL round-bottomed flask equipped with condenser and
nitrogen (N.sub.2) inlet were added 118 mg (0.27 mmol)
2-(2,5-dimethylpyrrolyl)-6-[4-(2-hydroxy-ethoxy)-5,6,7,8-tetrahydro-napht-
halen-1-yl]-pyridine, 453 mg (6.5 mmol) hydroxylamine
hydrochloride, 10 mL ethanol, and 1 mL water. The reaction was
refluxed 40 hour, cooled, and poured into 1 N hydrochloric acid.
The aqueous layer was washed with ethyl acetate and adjusted to pH
12 with 6 N sodium hydroxide solution, then extracted with
methylene chloride. The organic layer was dried over sodium sulfate
and evaporated. The residue was chromatographed on silica gel using
methanol/methylene chloride as eluant to afford 100 mg (100%) of an
oil, which was converted to the hydrochloride salt with HCl in
ether to give a solid. M.p. 170-172.degree. C.; .sup.1H-NMR
(.delta., CDCl.sub.3): 1.65 (m, 2H), 1.75 (m, 2H), 2.67 (m, 4H),
3.88 (m, 2H), 3.90 (m, 2H), 6.38 (d, J=8, 1H), 6.62 (m, 2H), 7.08
(d, J=8, 1H), 7.42 (t, J=8, 1H); .sup.13C-NMR (.delta.,
CDCl.sub.3): 22.27, 22.39, 22.74, 23.53, 28.11, 61.15, 68.96,
106.465, 107.655, 114.20, 126.21, 126.845, 133.395, 136.32, 137.98,
156.10, 156.53, 157.745, 158.26; MS (%): 285 (parent+1, 100); HRMS
Calculated. for C.sub.17H.sub.21N.sub.2O.sub.2: 285.1603. Found:
285.1622.
EXAMPLE 3
6-[4-(2-(2-Dimethylaminoethoxy)-ethoxy)-naphthalen-1-yl]-pyridin-2-ylamine
[0085] A. 4-Bromo-1-fluoronaphthalene
[0086] To a 50 mL round-bottomed flask equipped with condenser and
N.sub.2 inlet were added 3.75 mL (5.0 g, 34.25 mmol)
1-fluoronaphthalene and 10 mL carbon tetrachloride, followed by
dropwise addition of 1.7 mL (5.5 g., 34.375 mmol) bromine over 3
min. The reaction was heated to 50-60.degree. C. as HBr was evolved
for 2 hour, then cooled and concentrated. The residue was dissolved
in methanol and kept overnight at 0.degree. C. After filtration
with cold methanol, the product, with melting point close to room
temperature, was 4.62 g (60%) of a yellow oil. .sup.1H-NMR
(.delta., CDCl.sub.3): 7.02 (t, J=8, 1H), 7.6-7.7 (m, 3H), 8.10 (d,
J=8.5, 1H), 8.20 (d, J=8.5, 1H); GCMS (%): 224/226 (parent,
Br.sup.79/Br.sup.81 100).
[0087] B. 4-Fluoronaphthalene-1-boronic acid
[0088] To a 250 mL three-necked round-bottomed flask equipped with
septum and N.sub.2 (nitrogen) inlet were added 4.62 g (20.53 mmol)
4-bromo-1-fluoronaphthalene and 100 mL dry tetrahydrofuran. The
solution was cooled to -70.degree. C., and 15.4 mL (24.64 mmol) of
a 1.6 M solution of butyl lithium in hexane was added dropwise over
5 min. The reaction was stirred at -70.degree. C. for 10 min, then
4.2 mL (3.59 g, 24.64 mmol) triethyl borate was added, and the
reaction stirred at -70.degree. C. for 20 min and warmed to room
temperature. After stirring overnight at room temperature, the
reaction was quenched with saturated aqueous ammonium chloride
solution, acidified with 1 N hydrochloric acid, and extracted into
ethyl acetate (twice). The combined organic layer was washed with
brine, dried over sodium sulfate, and evaporated. The residue was
triturated with hexane to give an off-white powder, 1.97 g (51%),
as a mixture of monoaryl and diaryl boronic acids. .sup.1H-NMR
(.delta., CDCl.sub.3): 7.2-7.4 (m, 1H), 7.5-7.7 (m, 3H), 8.0-8.5
(m, 1H), 8.5 and 9.2 (m, 1H); APCI (-) (%): 189 (parent-1, 60).
[0089] C.
2-(2,5-Dimethylpyrrolyl)-6-(4-fluoro-naphth-1-yl)pyridine
[0090] To a 50 mL round-bottomed flask equipped with condenser and
N.sub.2 inlet were added 404 mg (2.13 mmol)
4-fluoronaphthalene-1-boronic acid, 534 mg (2.13 mmol)
2-(2,5-dimethylpyrrolyl)-6-bromopyridine, 902 mg (8.51 mmol) sodium
carbonate, 150 mg tetrakistriphenylphosphine, 10 mL ethanol, and 2
mL water. The reaction was refluxed overnight, cooled, poured into
water, and extracted into ethyl acetate. After combining with
another run on a larger scale, the combined organic layer was
washed with brine, dried over sodium sulfate, and evaporated. The
residue was chromatographed on silica gel using hexane/ethyl
acetate as eluant to afford 4.72 g (85%) of an oil. .sup.1H-NMR
(.delta., CDCl.sub.3): 2.25 (s, 6H), 5.92 (s, 2H), 7.1-7.2 (m, 2H),
7.4-7.6 (m, 4H), 7.95 (t, J=8, 1H), 8.12 (d, J=8, 1H), 8.19 (d,
J=8, 1H); .sup.13C-NMR (.delta., CDCl.sub.3): 13.41, 106.97,
108.82, 109.02, 120.18, 120.78, 120.84, 123.42, 123.81, 123.96,
125.48, 126.20, 127.32, 127.68, 127.76, 128.56, 132.35, 133.90,
138.22, 151.87, 157.82, 158.30, 160.34; MS (%): 317 (parent+1,
100); HRMS Calculated. for C.sub.21H.sub.18N.sub.2F (parent+1):
317.1454, Found: 317.1462.
[0091] D.
2-(2,5-Dimethylpyrrolyl)-6-(2-(2-dimethylaminoethoxy)-ethoxy)-na-
phth-1-yl)pyridine
[0092] To a 20 mL round-bottomed flask equipped with condenser and
nitrogen (N.sub.2) inlet were added 126 mg (0.949 mml)
2-(2-dimethylaminoethoxy)ethanol and 2 mL dry dimethylformamide,
followed by 47 mg (1.187 mmol) sodium hydride (60% in oil). The
reaction was heated to 70.degree. C. to ensure complete formation
of the alkoxide, and then 150 mg (0.475 mmol)
2-(2,5-dimethylpyrrolyl)-6-(4-fluoro-naphth-1-yl- )pyridine in 2 mL
dry dimethylformamide was added, and the reaction was heated at
80.degree. C. for 30 min. The reaction was cooled, poured into
water, and extracted into ethyl acetate. After combining with
another run on a larger scale, the combined organic layer was
washed with brine, dried over sodium sulfate, and evaporated. The
residue was chromatographed on silica gel using methanol/methylene
chloride as eluant to afford 141 mg (69%) of an oil. .sup.1H-NMR
(.delta., CDCl.sub.3): 2.24 (s, 6H), 2.32 (s, 6H), 2.61 (t, J=6,
2H), 3.76 (t, J=6, 2H), 3.98 (t, J=5, 2H), 4.35 (t, J=5, 2H), 5.90
(s, 2H), 6.89 (d, J=8, 1H), 7.21 (d, J=8, 1H), 7.49 (m, 2H), 7.56
(m, 2H), 7.91 (t, J=8, 1H), 8.11 (m, 1H), 8.36 (m, 1H);
.sup.13C-NMR (.delta., CDCl.sub.3): 13.45, 45.64, 58.68, 67.87,
69.33, 69.46,104.34, 106.74,119.71, 122.40,123.48, 125.11,125.20,
125.74, 126.87, 128.22, 128.59,130.39, 131.88,138.07,151.68,
155.12, 159.02; MS (%): 430 (parent+1, 100); HRMS Calculated. for
C.sub.27H.sub.32N.sub.3O.sub.2 (parent+1): 430.2495, Found:
430.2498.
[0093] E.
6-[4-(2-(2-Dimethylaminoethoxy)-ethoxy)-naphthalen-1-yl]-pyridin-
-2-ylamine
[0094] Prepared as in Example 1F, in 91% yield. M.p.: 60-75.degree.
C. (dec.), as the hydrochloride salt. .sup.1H-NMR (.delta.,
CDCl.sub.3): 2.26 (s, 6H), 2.54 (t, J=6, 2H), 3.71 (t, J=6, 2H),
3.95 (t, J=5, 2H), 4.31 (t, J=5, 2H), 4.59 (bs, 2H), 6.41 (d, J=8,
1H), 6.83 (m, 2H), 7.435 (m, 4H), 8.09 (m, 1H), 8.31 (m, 1H);
.sup.13C-NMR (.delta., CDCl.sub.3): 45.88, 58.93, 67.96, 69.56,
69.68, 104.43, 106.54, 115.20, 122.23, 125.06, 125.68, 125.88,
126.64, 127.17, 131.60, 132.17, 137.98, 154.71, 157.77, 158.11; MS
(%): 352 (parent+1, 100); Anal. Calculated. for
C.sub.21H.sub.25N.sub.3O.sub.2.2HCl.{fraction
(9/4)}H.sub.2O.1/2(C.sub.4H- .sub.8O): C; 55.15, H; 7.14, N; 8.39.
Found: C; 55.31, H; 7.28, N; 8.64.
EXAMPLE 4
1-[4-(6-Amino-pyridin-2-yl)-naphthalen-1-yloxymethyl]-cyclohexanol
[0095] Prepared as in Example 3, using
1-hydroxy-cyclohexanemethanol, in 74% yield, as a tan powder, as
the hydrochloride salt. .sup.1H-NMR (.delta., CDCl.sub.3): 0.9-1.9
(m, 10H), 4.02 (s, 2H), 4.89 (bs, 2H), 6.54 (d, J=8, 1H), 6.87 (m,
2H), 7.5-7.6 (m, 4H), 8.10 (m, 1H), 8.31 (m, 1H); .sup.13C-NMR
(.delta., CDCl.sub.3): 18.98, 21.76, 25.86, 26.34, 29.68, 34.56,
60.40, 71.11, 75.75, 104.52, 107.08, 112.48, 115.21, 121.94,
125.30, 125.61, 125.77, 126.84, 127.48, 130.63, 132.08, 138.55,
154.83, 156.58, 157.79; MS (%): 349 (parent+1, 100); HRMS
Calculated. for C.sub.22H.sub.23N.sub.2O.sub.2: 349.1760. Found:
349.1786.
* * * * *