U.S. patent application number 09/802086 was filed with the patent office on 2002-03-14 for 6-phenylpyridyl-2-amine derivatives useful as nos inhibitors.
Invention is credited to Lowe, John A. III.
Application Number | 20020032191 09/802086 |
Document ID | / |
Family ID | 21866837 |
Filed Date | 2002-03-14 |
United States Patent
Application |
20020032191 |
Kind Code |
A1 |
Lowe, John A. III |
March 14, 2002 |
6-phenylpyridyl-2-amine derivatives useful as NOS inhibitors
Abstract
The present invention relates to 6-phenyl-pyridin-2-ylamine
derivatives of the formula 1 wherein G, R.sup.1 and R.sup.2 are
defined as in the specification, 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 and other disorders.
Inventors: |
Lowe, John A. III;
(Stonington, CT) |
Correspondence
Address: |
PFIZER INC
150 EAST 42ND STREET
5TH FLOOR - STOP 49
NEW YORK
NY
10017-5612
US
|
Family ID: |
21866837 |
Appl. No.: |
09/802086 |
Filed: |
March 8, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09802086 |
Mar 8, 2001 |
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09325480 |
Jun 3, 1999 |
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6235750 |
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09325480 |
Jun 3, 1999 |
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PCT/IB97/01446 |
Nov 17, 1997 |
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60032793 |
Dec 6, 1996 |
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Current U.S.
Class: |
514/217.04 ;
514/304; 514/318; 514/343; 540/597; 546/125; 546/194;
546/276.4 |
Current CPC
Class: |
A61P 11/06 20180101;
A61P 3/10 20180101; A61P 11/00 20180101; A61P 27/02 20180101; A61P
25/16 20180101; A61P 25/04 20180101; A61P 27/06 20180101; C07D
213/73 20130101; C07D 413/14 20130101; A61P 25/18 20180101; A61P
25/22 20180101; C07D 417/14 20130101; A61P 25/28 20180101; A61P
25/14 20180101; A61P 1/00 20180101; A61P 7/08 20180101; A61P 25/30
20180101; A61P 25/00 20180101; A61P 1/04 20180101; C07D 401/14
20130101; A61P 25/08 20180101; A61P 35/00 20180101; C07D 405/14
20130101; A61P 25/06 20180101; C07D 401/10 20130101; A61P 9/00
20180101; A61P 13/12 20180101; A61P 19/02 20180101; A61P 43/00
20180101; A61P 29/00 20180101 |
Class at
Publication: |
514/217.04 ;
514/304; 514/318; 514/343; 546/276.4; 546/194; 546/125;
540/597 |
International
Class: |
C07D 43/02; C07D 41/02;
A61K 031/55; A61K 031/46; A61K 031/4545; A61K 031/4439 |
Claims
1. A compound of the formula 12wherein R.sup.1 and R.sup.2 are
selected, independently, from hydrogen, hydroxy, methyl and
methoxy; G is selected from [2.2.1]bicyclohept-6-ylmethyl
substituted by NR.sup.3R.sup.4; [2.2.1]bicyclohept-1-ylmethyl
substituted by NR.sup.3R.sup.4; 3-azabicyclo[3.2.1]octan-8-ol,
3N-substituted by isopropyl, benzyl, or furanylmethyl;
(5-phenyl-cyclohexylmethyl) substituted by NR.sup.3R.sup.4;
oxindolylmethyl or oxindolylmethylene, N-substituted by methyl or
2-dimethylaminoethyl; and a group of the formula 13n is zero or
one; Y is hydrogen, NR.sup.3R.sup.4, (C.sub.1-C.sub.6)alkyl or
aralkyl, wherein the aryl moiety of said aralkyl is phenyl,
naphthyl, isoxazolyl, methylenedioxybenzyl, imidazolyl, pyridyl,
furyl, thiazolyl, or isothiazolyl, and the alkyl moiety is straight
or branched and contains from 1 to 6 carbon atoms, and wherein said
(C.sub.1-C.sub.6)alkyl and the aryl moiety of said aralkyl may be
substituted with from one to three substituents, preferably from
zero to two substituents, that are selected, independently, from
phenyl, --C(O)NH.sub.2, --C(O)phenyl, halo (e.g., chloro, fluoro,
bromo or iodo), nitro, hydroxy, cyano, amino,
(C.sub.1-C.sub.4)alkoxy and (C.sub.1-C.sub.4) alkylamino; X is N
when Y is hydrogen, (C.sub.1-C.sub.6) alkyl, aralkyl, or
substituted (C.sub.1-C.sub.6)alkyl, and X is CH when Y is
NR.sup.3R.sup.4; q is zero, one or two; m is zero, one or two; and
R.sup.3 and R.sup.4 are selected, independently, from hydrogen,
(C.sub.1-C.sub.6) alkyl, --C(O)(C.sub.1-C.sub.6)alkyl, cyclohexyl,
tetrahydronaphthalene and aralkyl, wherein the aryl moiety of said
aralkyl is phenyl or naphthyl and the alkyl moiety is straight or
branched and contains from 1 to 6 carbon atoms, and wherein said
(C.sub.1-C.sub.6) alkyl or --C(O)(C.sub.1-C.sub.6)alkyl and said
tetrahydronaphthalene and the aryl moiety of said aralkyl may
optionally be substituted with from one to three substituents,
preferably from zero to two substituents, that are selected,
independently, from phenyl, halo (e.g., chloro, fluoro, bromo or
iodo), nitro, hydroxy, cyano, amino, (C.sub.1-C.sub.4) alkoxy, and
(C.sub.1-C.sub.4) alkylamino; or R.sup.3 and R.sup.4 form, together
with the nitrogen to which they are attached, a piperazine,
piperidine or pyrrolidine ring or an azabicyclic ring containing
from 6 to 14 ring members, from 1 to 3 of which are nitrogen and
the rest of which are carbon; and wherein said piperazine,
piperidine, pyrrolidine and azabicyclic rings formed by R.sup.3 and
R.sup.4 may optionally be substituted with one or more
substituents, preferably with from zero to two substituents, that
are selected, independently, from (C.sub.1-C.sub.6)alkyl, amino,
(C.sub.1-C.sub.6) alkylamino, [di-(C.sub.1-C.sub.6)alkyl]amino,
(C.sub.1-C.sub.6)alkylaceta- mido, phenyl substituted 5 to 6
membered heterocyclic rings containing from 1 to 4 rings nitrogen
atoms, benzoyl, benzoylmethyl, benzylcarbonyl, phenylaminocarbonyl,
phenylethyl and phenoxycarbonyl, and wherein the phenyl moieties of
any of the foregoing substituents may optionally be substituted
with one or more substituents, preferably with from zero to two
substituents, that are 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; or a pharmaceutically acceptable
salt of such compound.
2. A compound according to claim 1, wherein G is a group of the
formula 14wherein n is zero or one; Y is NR.sup.3R.sup.4,
(C.sub.1-C.sub.6)alkyl or aralkyl, wherein the aryl moiety of said
aralkyl is phenyl or naphthyl and the alkyl moiety is straight or
branched and contains from 1 to 6 carbon atoms, and wherein said
(C.sub.1-C.sub.6)alkyl and the aryl moiety of said aralkyl may be
substituted with from one to three substituents, preferably from
zero to two substituents, that are selected, independently, from
halo (e.g., chloro, fluoro, bromo or iodo), nitro, hydroxy, cyano,
amino, (C.sub.1-C.sub.4)alkoxy and (C.sub.1-C.sub.4) alkylamino; X
is N when Y is (C.sub.1-C.sub.6) alkyl, aralkyl, or substituted
(C.sub.1-C.sub.6)alkyl, and X is CH when Y is NR.sup.3R.sup.4; q is
zero, one or two; m is zero, one or two; and R.sup.3 and R.sup.4
are selected, independently, from (C.sub.1-C.sub.6) alkyl,
tetrahydronaphthalene and aralkyl, wherein the aryl moiety of said
aralkyl is phenyl or naphthyl and the alkyl moiety is straight or
branched and contains from 1 to 6 carbon atoms, and wherein said
(C.sub.1-C.sub.6) alkyl and said tetrahydronaphthalene and the aryl
moiety of said aralkyl may optionally be substituted with from one
to three substituents, preferably from zero to two substituents,
that are selected, independently, from halo (e, chloro, fluoro,
bromo or iodo), nitro, hydroxy, cyano, amino, (C.sub.1-C.sub.4)
alkoxy, and (C.sub.1-C.sub.4) alkylamino; or R.sup.3 and R.sup.4
form, together with the nitrogen to which they are attached, a
piperazine, piperidine or pyrrolidine ring or an azabicyclic ring
containing from 6 to 14 ring members, from 1 to 3 of which are
nitrogen and the rest of which are carbon; or a pharmaceutically
acceptable salt of such compound.
3. A compound according to claim 1, wherein q is zero or one.
4. A compound according to claim 1, wherein NR.sup.3R.sup.4 is a
piperidine, piperazine or pyrrolidine ring or a
3-aza-bicyclo[3.1.0]hex-6- -ylamine ring, and wherein said
piperazine, piperidine and pyrrolidine rings may optionally be
substituted with one or more substituents, preferably with from
zero to two substituents, that are selected, independently, from
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 rings nitrogen
atoms, benzoyl, benzoylmethyl, benzylcarbonyl, phenylaminocarbonyl,
phenylethyl and phenoxy-carbonyl, and wherein the phenyl moieties
of any of the foregoing substituents may optionally be substituted
with one or more substituents, preferably with from zero to two
substituents, that are 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; and the pharmaceutically acceptable
salts of such compounds.
5. A compound according to claim 1 wherein NR.sup.3R.sup.4 is
4-phenylethylpiperazin-1-yl, 4-methylpiperazin-1-yl,
phenethylamino, or 3-aza-bicyclo[3.1.0]hex-6-ylamine.
6. A compound according to claim 1 wherein NR.sup.3R.sup.4 is a
group of the formula 15wherein NR.sup.5R.sup.6 is NH.sub.2.
7. A compound according to claim 1 selected from the group
consisting of
6-[(N-(5-isothiazolyl)methyl)-4-(piperidin-4-yl)-phenyl]-pyridin-2-ylamin-
e;
6-[(N-(5-thiazolyl)methyl)-4-(piperidin-4-yl)-phenyl]-pyridin-2-ylamine-
;
6-[(N-(2-furyl)methyl)-4-(pyrrolidin-3-yl)-phenyl]-pyridin-2-ylamine;
and
---6-[(N-(2-methyl)propyl)-4-(pyrrolidin-3-yl)-phenyl]-pyridin-2-ylam-
ine; and pharmaceutically acceptable salts thereof.
8. A pharmaceutical composition for treating or preventing a
condition selected from the group consisting of migraine,
inflammatory diseases, stroke, acute and chronic pain, hypovolemic
shock, traumatic shock, reperfusion injury, Crohn's disease,
ulcerative colitis, septic shock, multiple sclerosis, AIDS
associated dementia, neurodegenerative diseases, neuron toxicity,
Alzheimer's disease, chemical dependencies and addictions, emesis,
epilepsy, anxiety, psychosis, head trauma, adult respiratory
distress syndrome (ARDS), morphine induced tolerance and withdrawal
symptoms, inflammatory bowel disease, osteoarthritis, rheumatoid
arthritis, ovulation, dilated cardiomyopathy, acute spinal cord
injury, Huntington's disease, Parkinson's disease, glaucoma,
macular degeneration, diabetic neuropathy, diabetic nephropathy and
cancer in a mammal, comprising an amount of a compound according to
claim 1 that is effective in treating or preventing such condition
and a pharmaceutically acceptable carrier.
9. A pharmaceutical composition for treating or preventing
depression in a mammal comprising and amount of a compound
according to claim 1 that is effective in treating or preventing
depression and a pharmaceutically acceptable carrier.
10. A method of treating or preventing a condition selected from
the group consisting of migraine, inflammatory diseases, stroke,
acute and chronic pain, hypovolemic shock, traumatic shock,
reperfusion injury, Crohn's disease, ulcerative colitis, septic
shock, multiple sclerosis, AIDS associated dementia,
neurodegenerative diseases, neuron toxicity, Alzheimer's disease,
chemical dependencies and addictions, emesis, epilepsy, anxiety,
psychosis, head trauma, adult respiratory distress syndrome (ARDS),
morphine induced tolerance and withdrawal symptoms, inflammatory
bowel disease, osteoarthritis, rheumatoid arthritis, ovulation,
dilated cardiomyopathy, acute spinal cord injury, Huntington's
disease, Parkinson's disease, glaucoma, macular degeneration,
diabetic neuropathy, diabetic nephropathy and cancer in a mammal,
comprising administering to said mammal an amount of a compound
according to claim 1, that is effective in treating or preventing
such condition.
11. A method of treating or preventing depression in a mammal
comprising administering to said mammal an amount of a compound
according to claim 1 that is effective in treating or preventing
depression.
12. A pharmaceutical composition for inhibiting nitric oxide
synthase (NOS) in a mammal, according to claim 1, comprising a NOS
inhibiting effective amount of a compound according to claim 1, and
a pharmaceutically acceptable carrier.
13. A method of inhibiting NOS in a mammal, comprising
administering to said mammal a NOS inhibiting effective amount of a
compound according to claim 1.
14. A pharmaceutical composition for treating or preventing a
condition selected from the group consisting of migraine,
inflammatory diseases, stroke, acute and chronic pain, hypovolemic
shock, traumatic shock, reperfusion injury, Crohn's disease,
ulcerative colitis, septic shock, multiple sclerosis, AIDS
associated dementia, neurodegenerative diseases, neuron toxicity,
Alzheimer's disease, chemical dependencies and addictions, emesis,
epilepsy, anxiety, psychosis, head trauma, adult respiratory
distress syndrome (ARDS), morphine induced tolerance and withdrawal
symptoms, inflammatory bowel disease, osteoarthritis, rheumatoid
arthritis, ovulation, dilated cardiomyopathy, acute spinal cord
injury, Huntington's disease, Parkinson's disease, glaucoma,
macular degeneration, diabetic neuropathy, diabetic nephropathy and
cancer in a mammal, comprising a NOS inhibiting effective amount of
a compound according to claim 1 and a pharmaceutically acceptable
carrier.
15. A pharmaceutical composition for treating or preventing
depression in a mammal, comprising a NOS inhibiting effective
amount of a compound according to claim 1 and a pharmaceutically
acceptable carrier.
16. A method of treating or preventing a condition selected from
the group consisting of migraine, inflammatory diseases, stroke,
acute and chronic pain, hypovolemic shock, traumatic shock,
reperfusion injury, Crohn's disease, ulcerative colitis, septic
shock, multiple sclerosis, AIDS associated dementia,
neurodegenerative diseases, neuron toxicity, Alzheimer's disease,
chemical dependencies and addictions, emesis, epilepsy, anxiety,
psychosis, head trauma, adult respiratory distress syndrome (ARDS),
morphine induced tolerance and withdrawal symptoms, inflammatory
bowel disease, osteoarthritis, rheumatoid arthritis, ovulation,
dilated cardiomyopathy, acute spinal cord injury, Huntington's
disease, Parkinson's disease, glaucoma, macular degeneration,
diabetic neuropathy, diabetic nephropathy and cancer in a mammal,
comprising administering to said mammal a NOS inhibiting effective
amount of a compound according to claim 1.
17. A method of treating or preventing depression in a mammal,
comprising administering to said mammal a NOS inhibiting effective
amount of a compound according to claim 1.
Description
[0001] This application is a continuation of U.S. Ser. No.
09/325,480, filed Jun. 3, 1999, which is a continuation-in-part of
PCT/IB97/01446, International Filing Date Nov. 17, 1997,
designating the United States and claiming priority of U.S.
Provisional Patent Application Ser. No. 60/032,793, filed Dec. 6,
1996.
[0002] The present invention relates to certain
6-phenylpyridyl-2-amine derivatives 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 and other disorders.
[0003] 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).
[0004] 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). 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
[0005] The present invention relates to a compound of the formula
2
[0006] wherein R.sup.1 and R.sup.2 are selected, independently,
from hydrogen, hydroxy, methyl and methoxy;
[0007] G is selected from [2.2.1]bicyclohept-6-ylmethyl substituted
by NR.sup.3R.sup.4; [2.2.1]bicyclohept-1-ylmethyl substituted by
NR.sup.3R.sup.4; 3-azabicyclo[3.2.1]octan-8-ol, 3N-substituted by
isopropyl, benzyl, or furanylmethyl; (5-phenyl-cyclohexylmethyl)
substituted by NR.sup.3R.sup.4; oxindolylmethyl or
oxindolylmethylene, N-substituted by methyl or
2-dimethylaminoethyl; and a group of the formula 3
[0008] wherein n is zero or one;
[0009] Y is hydrogen, NR.sup.3R.sup.4, (C.sub.1-C.sub.6)alkyl or
aralkyl, wherein the aryl moiety of said aralkyl is phenyl,
naphthyl, isoxazolyl, methylenedioxybenzyl, imidazolyl, pyridyl,
furyl, thiazolyl, or isothiazolyl, and the alkyl moiety is straight
or branched and contains from 1 to 6 carbon atoms, and wherein said
(C.sub.1-C.sub.6)alkyl and the aryl moiety of said aralkyl may be
substituted with from one to three substituents, preferably from
zero to two substituents, that are selected, independently, from
phenyl, --C(O)NH.sub.2, --C(O)phenyl, halo (e.g., chloro, fluoro,
bromo or iodo), nitro, hydroxy, cyano, amino,
(C.sub.1-C.sub.4)alkoxy and (C.sub.1-C.sub.4) alkylamino;
[0010] X is N when Y is hydrogen, (C.sub.1-C.sub.6) alkyl, aralkyl,
or substituted (C.sub.1-C.sub.6)alkyl, and X is CH when Y is
NR.sup.3R.sup.4;
[0011] q is zero, one or two;
[0012] m is zero, one or two; and
[0013] R.sup.3 and R.sup.4 are selected, independently, from
hydrogen, (C.sub.1-C.sub.6) alkyl, --C(O)(C.sub.1-C.sub.6)alkyl,
cyclohexyl, tetrahydronaphthalene and aralkyl, wherein the aryl
moiety of said aralkyl is phenyl or naphthyl and the alkyl moiety
is straight or branched and contains from 1 to 6 carbon atoms, and
wherein said (C.sub.1-C.sub.6) alkyl or
--C(O)(C.sub.1-C.sub.6)alkyl and said tetrahydronaphthalene and the
aryl moiety of said aralkyl may optionally be substituted with from
one to three substituents, preferably from zero to two
substituents, that are selected, independently, from phenyl, halo
(e.g., chloro, fluoro, bromo or iodo), nitro, hydroxy, cyano,
amino, (C.sub.1-C.sub.4) alkoxy, and (C.sub.1-C.sub.4)
alkylamino;
[0014] or R.sup.3 and R.sup.4 form, together with the nitrogen to
which they are attached, a piperazine, piperidine or pyrrolidine
ring or an azabicyclic ring containing from 6 to 14 ring members,
from 1 to 3 of which are nitrogen and the rest of which are
carbon;
[0015] and wherein said piperazine, piperidine, pyrrolidine and
azabicyclic rings formed by R.sup.3 and R.sup.4 may optionally be
substituted with one or more substituents, preferably with from
zero to two substituents, that are selected, independently, from
(C.sub.1-C.sub.6)alkyl, amino, (C.sub.1-C.sub.6) alkylamino,
[di-(C.sub.1-C.sub.6)alkyl]amino, (C.sub.1-C.sub.6)alkylacetamido,
phenyl substituted 5 to 6 membered heterocyclic rings containing
from 1 to 4 rings nitrogen atoms, benzoyl, benzoylmethyl,
benzylcarbonyl, phenylaminocarbonyl, phenylethyl and
phenoxycarbonyl, and wherein the phenyl moieties of any of the
foregoing substituents may optionally be substituted with one or
more substituents, preferably with from zero to two substituents,
that are 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; or a pharmaceutically acceptable
salt of such compound.
[0016] The present invention also relates to the pharmaceutically
acceptable acid addition salts of compounds of the formula 1. The
acids which are used to prepare the pharmaceutically acceptable
acid addition salts of the aforementioned base compounds of this
invention are those 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 [i.e.,
1,1-methylene-bis-(2-hydroxy-3-naphthoate)] salts.
[0017] The term "alkyl", as used herein, unless otherwise
indicated, includes saturated monovalent hydrocarbon radicals
having straight, branched or cyclic moieties or combinations
thereof.
[0018] The term "one or more substituents", as used herein, 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.
[0019] The term "halo", as used herein, unless otherwise indicated,
includes chloro, fluoro, bromo and iodo.
[0020] In one embodiment, the present invention relates to a
compound of formula I as described above, wherein G is a group of
the formula 4
[0021] wherein n is zero or one;
[0022] Y is NR.sup.3R.sup.4, (C.sub.1-C.sub.6)alkyl or aralkyl,
wherein the aryl moiety of said aralkyl is phenyl or naphthyl and
the alkyl moiety is straight or branched and contains from 1 to 6
carbon atoms, and wherein said (C.sub.1-C.sub.6)alkyl and the aryl
moiety of said aralkyl may be substituted with from one to three
substituents, preferably from zero to two substituents, that are
selected, independently, from halo (e.g., chloro, fluoro, bromo or
iodo), nitro, hydroxy, cyano, amino, (C.sub.1-C.sub.4)alkoxy and
(C.sub.1-C.sub.4) alkylamino;
[0023] X is N when Y is (C.sub.1-C.sub.6) alkyl, aralkyl, or
substituted (C.sub.1-C.sub.6)alkyl, and X is CH when Y is
NR.sup.3R.sup.4;
[0024] q is zero, one or two;
[0025] m is zero, one or two; and
[0026] R.sup.3 and R.sup.4 are selected, independently, from
(C.sub.1-C.sub.6) alkyl, tetrahydronaphthalene and aralkyl, wherein
the aryl moiety of said aralkyl is phenyl or naphthyl and the alkyl
moiety is straight or branched and contains from 1 to 6 carbon
atoms, and wherein said (C.sub.1-C.sub.6) alkyl and said
tetrahydronaphthalene and the aryl moiety of said aralkyl may
optionally be substituted with from one to three substituents,
preferably from zero to two substituents, that are selected,
independently, from halo (e.g., chloro, fluoro, bromo or iodo),
nitro, hydroxy, cyano, amino, (C.sub.1-C.sub.4) alkoxy, and
(C.sub.1-C.sub.4) alkylamino;
[0027] or R.sup.3 and R.sup.4 form, together with the nitrogen to
which they are attached, a piperazine, piperidine or pyrrolidine
ring or an azabicyclic ring containing from 6 to 14 ring members,
from 1 to 3 of which are nitrogen and the rest of which are
carbon;
[0028] or a pharmaceutically acceptable salt of such compound.
[0029] Examples of preferred compounds of this invention are
compounds of the formula I, and their pharmaceutically acceptable
salts, wherein NR.sup.3R.sup.4 is:
[0030] 4-phenylethylpiperazin-1-yl;
[0031] 4-methylpiperazin-1-yl;
[0032] phenethylamino; or
[0033] 3-aza-bicyclo[3.1.0]hex-6-ylamine.
[0034] Other preferred compounds of this invention are compounds of
the formula I, and their pharmaceutically acceptable salts, wherein
NR.sup.3R.sup.4 is a group of the formula 5
[0035] wherein NR.sup.5R.sup.6 is NH.sub.2,
[0036] Other preferred compounds of this invention are compounds of
the formula I wherein G is a group of the formula A, X is nitrogen
and q is zero.
[0037] Other embodiments of this invention relate to compounds of
the formula I wherein q is zero or one.
[0038] Other embodiments of the invention relate to compounds of
the formula I wherein G is a group of the formula B and
NR.sup.3R.sup.4 does not form a cyclic moiety.
[0039] Other embodiments of this invention relate to compounds of
the formula I wherein G is a group of the formula B, m is two and
NR.sup.3R.sup.4 does not form a cyclic moiety (i.e., where N,
R.sup.3 and R.sup.4 are part of the same ring structure).
[0040] Other embodiments of this invention relate to compounds of
the formula I wherein G is a group of the formula B, m is one and
NR.sup.3R.sup.4 does not form a cyclic moiety.
[0041] Other embodiments of this invention relate to compounds of
the formula I wherein G is a group of the formula B, m is zero and
NR.sup.3R.sup.4 does not form a cyclic moiety.
[0042] Other embodiments of the invention relate to compounds of
the formula I wherein G is a group of the formula B and m is
zero.
[0043] Other embodiments of this invention relate to compounds of
the formula I wherein G is a group of the formula A and both p and
n are one.
[0044] Other embodiments of this invention relate to compounds of
the formula I wherein G is a group of the formula A, p is one, q is
zero and n is one.
[0045] Other embodiments of this invention relate to compounds of
the formula I wherein G is a group of the formula B and m is
one.
[0046] Other embodiments of this invention relate to compounds of
the formula I wherein G is a group of the formula A and p is
one.
[0047] The present invention also relates to a pharmaceutical
composition for treating or preventing a condition selected from
the group consisting of migraine, inflammatory diseases (e.g.,
asthma), stroke, acute and chronic pain, hypovolemic shock,
traumatic shock, reperfusion injury, Crohn's disease, ulcerative
colitis, septic shock, multiple sclerosis, AIDS associated
dementia, neurodegenerative diseases, neuron toxicity, Alzheimer's
disease, chemical dependencies and addiction (e.g., dependencies on
drugs, alcohol and nicotine), emesis, epilepsy, anxiety, psychosis,
head trauma, adult respiratory distress syndrome (ARDS), morphine
induced tolerance and withdrawal symptoms, inflammatory bowel
disease, osteoarthritis, rheumatoid arthritis, ovulation, dilated
cardiomyopathy, acute spinal cord injury, Huntington's disease,
Parkinson's disease, glaucoma, macular degeneration, diabetic
neuropathy, diabetic nephropathy and cancer in a mammal, including
a human, comprising an amount of a compound of the formula I, or a
pharmaceutically acceptable salt thereof that is effective in
treating or preventing such condition, and a pharmaceutically
acceptable carrier.
[0048] The present invention also relates to a pharmaceutical
composition for treating or preventing depression in a mammal,
including a human, comprising an amount of a compound of the
formula I, and a pharmaceutically acceptable carrier.
[0049] The present invention also relates to a method of treating
or preventing a condition selected from the group consisting of
migraine, inflammatory diseases (e.g., asthma), stroke, acute and
chronic pain, hypovolemic shock, traumatic shock, reperfusion
injury, Crohn's disease, ulcerative colitis, septic shock, multiple
sclerosis, AIDS associated dementia, neurodegenerative diseases,
neuron toxicity, Alzheimer's disease, chemical dependencies and
addictions (e g., dependencies on drugs, alcohol and nicotine),
emesis, epilepsy, anxiety, psychosis, head trauma, adult
respiratory distress syndrome (ARDS), morphine induced tolerance
and withdrawal symptoms, inflammatory bowel disease,
osteoarthritis, rheumatoid arthritis, ovulation, dilated
cardiomyopathy, acute spinal cord injury, Huntington's disease,
Parkinson's disease, glaucoma, macular degeneration, diabetic
neuropathy, diabetic nephropathy and cancer in a mammal, including
a human, comprising administering to said mammal an amount of a
compound of the formula I, or a pharmaceutically acceptable salt
thereof, that is effective in treating or preventing such
condition.
[0050] The present invention also relates to a method of treating
or preventing depression in a mammal, including a human, comprising
administering to said mammal an amount of a compound of the formula
I, or a pharmaceutically acceptable salt thereof, that is effective
in treating or preventing depression.
[0051] The present invention also relates to a pharmaceutical
composition for inhibiting nitric oxide synthase (NOS) in a mammal,
including a human, comprising an NOS inhibiting effective amount of
a compound of the formula I, or a pharmaceutically acceptable salt
thereof and a pharmaceutically acceptable carrier.
[0052] The present invention also relates to a method of inhibiting
NOS in a mammal, including a human, comprising administering to
said mammal a NOS inhibiting effective amount of a compound of the
formula I, or a pharmaceutically acceptable salt thereof.
[0053] The present invention also relates to a pharmaceutical
composition for treating or preventing a condition selected from
the group consisting of migraine, inflammatory diseases (e.g.,
asthma), stroke, acute and chronic pain, hypovolemic shock,
traumatic shock, reperfusion injury, Crohn's disease, ulcerative
colitis, septic shock, multiple sclerosis, AIDS associated
dementia, neurodegenerative diseases, neuron toxicity, Alzheimer's
disease, chemical dependencies and addictions (e.g., dependencies
on drugs, alcohol and nicotine), emesis, epilepsy, anxiety,
psychosis, head trauma, adult respiratory distress syndrome (ARDS),
morphine induced tolerance and withdrawal symptoms, inflammatory
bowel disease, osteoarthritis, rheumatoid arthritis, ovulation,
dilated cardiomyopathy, acute spinal cord injury, Huntington's
disease, glaucoma, macular degeneration, diabetic neuropathy,
diabetic nephropathy and cancer in a mammal, including a human,
comprising a NOS inhibiting effective amount of a compound of the
formula I, or a pharmaceutically acceptable salt thereof and a
pharmaceutically acceptable carrier.
[0054] The present invention also relates to a pharmaceutical
composition for treating or preventing depression in a mammal,
including a human, comprising a NOS inhibiting effective amount of
a compound of the formula I, or a pharmaceutically acceptable salt
thereof, and a pharmaceutically acceptable carrier.
[0055] The present invention also relates to a method of treating
or preventing a condition selected from the group consisting of
migraine, inflammatory diseases (e.g., asthma), stroke, acute and
chronic pain, hypovolemic shock, traumatic shock, reperfusion
injury, Crohn's disease, ulcerative colitis, septic shock, multiple
sclerosis, AIDS associated dementia, neurodegenerative diseases,
neuron toxicity, Alzheimer's disease, chemical dependencies and
addictions (e.g., dependencies on drugs, alcohol or nicotine),
emesis, epilepsy, anxiety, psychosis, head trauma, adult
respiratory distress syndrome (ARDS), morphine induced tolerance
and withdrawal symptoms, inflammatory bowel disease,
osteoarthritis, rheumatoid arthritis, ovulation, dilated
cardiomyopathy, acute spinal cord injury, Huntington's disease,
Parkinson's disease, glaucoma, macular degeneration, diabetic
neuropathy, diabetic nephropathy and cancer in a mammal, including
a human, comprising administering to said mammal a NOS inhibiting
effective amount of a compound of the formula I, or a
pharmaceutically acceptable salt thereof.
[0056] The present invention also relates to a method of treating
or preventing depression in a mammal, including a human, comprising
administering to said mammal a NOS inhibiting effective amount of a
compound of the formula I, or a pharmaceutically acceptable salt
thereof.
[0057] Compounds of formula I have chiral centers and therefore may
exist in different enantiomeric and diastereomeric forms. This
invention relates to all optical isomers and all stereoisomers of
compounds of the formula I and mixtures thereof, and to all
pharmaceutical compositions and methods of treatment defined above
that contain or employ them, respectively.
[0058] Formula I above includes compounds identical to those
depicted but for the fact that one or more hydrogen, carbon or
other atoms are replaced by isotopes thereof. Such compounds may be
useful as research and diagnostic tools in metabolism
pharmacokinetic studies and in binding assays.
DETAILED DESCRIPTION OF THE INVENTION
[0059] The 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,
R.sup.7, R.sup.8 and R.sup.9 and structural formula I in the
reaction schemes and discussion that follow are defined as above. 6
7 8 9 10
[0060] The starting materials used in the procedures of Schemes 1-5
are either commercially available, known in the art or readily
obtainable from known compounds using methods that will be apparent
to those skilled in the art.
[0061] Referring to Scheme 1, compound II is prepared by reaction
of 1,4-dibromobenzene with an organolithium reagent, preferably
butyl lithium, at a temperature from -100.degree. C. to about
0.degree. C., followed by addition to
2-(2,5-dimethylpyrrolyl)-pyridine at a temperature from about about
0.degree. C. to about 50.degree. C. in an ethereal solvent,
preferably diethyl ether, for about 1 to 24 hours. Compound III is
prepared by reacting II with a boronic acid derivative of the
formula
p-OHC(CH.sub.2).sub.m-2(C.sub.6H.sub.3R.sup.1R.sup.2)B(OH).su- b.2
in a solvent consisting of an alcohol, preferably ethanol,
optionally mixed with water and a halogenated hydrocarbon, at a
temperature from about 25.degree. C. to about 150.degree. C., for
about 1 to 24 hours, using a palladium-based catalyst, either
palladium-zero or palladium-two oxidation state, typically with
phosphine ligands, preferably tetrakis-triphenylphosphine
palladium.
[0062] Compound IV is prepared by reacting III with
tosylmethylisocyanide in the presence of potassium t-butoxide and
ethanol, in an ethereal solvent such as 1,2-dimethoxyethane, at a
temperature from about -100.degree. C. to about 100.degree. C., for
about 1 to 24 hours. Compound V is prepared from IV by basic
hydrolysis of the nitrile using an alkali metal hydroxide in an
aqueous alcohol-based solvent, such as aqueous ethanol, at a
temperature from about 25.degree. C. to about 125.degree. C., for
about 30 minutes to 48 hours. Compound VI is prepared from V by
dehydrative coupling with ammonia, a primary or secondary amine of
the formula R.sup.3R.sup.4NH effected by a dehydrating agent such
as a carbodiimide, for example,
N-ethyl-N-(dimethylaminopropyl)-carbodiimide, in a solvent that is
a halogenated hydrocarbon or a N,N-dialkylamide, such as
dimethylformamide, at a temperature from about 0.degree. C. to
about 100.degree. C., for about 1 to 48 hours. Compound VII is
prepared from VI by deblocking using hydroxylamine hydrochloride in
an aqueous or alcoholic solvent, preferably aqueous ethanol, at a
temperature from about 25.degree. C. to about 100.degree. C., for
about 1 to 48 hours, and may include deblocking a protecting group
such a the t-butoxycarbonyl group by reaction with trifluoroacetic
acid or a related polyhalogenated acetic acid or a gaseous hydrogen
halide such as HCl, in a halogenated hydrocarbon, ethereal solvent
or ethyl acetate, at a temperature from about -70.degree. C. to
about 100.degree. C., for about 10 minutes to 24 hours.
[0063] The final compound in Scheme 1, IB, wherein G=B, is prepared
by reduction of VII with borane, a trialkyl borane, alane, or
lithium aluminum hydride in an ethereal solvent, such as ethyl
ether or tetrahydrofuran, at a temperature from about -100.degree.
C. to about 100.degree. C., for about 30 minutes to 24 hours, and
optionally using cesium fluoride and an alkali metal or alkaline
earth carbonate in an aqueous alcoholic solvent, at a temperature
from about 25.degree. C. to about 125.degree. C. for 1 to 72
hours.
[0064] Referring to Scheme 2, compound VIII is prepared from II by
reaction with 3-pyridyl boronic acid and a palladium catalyst, in
either the palladium-zero or palladium-two oxidation state, with
ligands typically comprised of trialkyl or triaryl phosphines, such
as tetrakis-triphenylphosphine palladium, in an aqueous alcoholic
solvent at a temperature from about 25.degree. C. to about
125.degree. C. for about 1 to 48 hours. Compound IX is prepared
from VIII by alkylation with an alkyl or aralkyl halide or
sulfonate, in an ethereal, alcoholic, aqueous alcoholic, or
dialkylamine-based solvent, such as dimethylformamide, at a
temperature from about 0.degree. C. to about 125.degree. C. for
about 30 minutes to 72 hours, followed by reduction with a
borohydride- or aluminum hydride-based reagent, such as sodium
borohydride, in an ethereal, alcoholic, or aqueous-alcoholic
solvent, typically methanol, at a temperature from about 0.degree.
C. to about 125.degree. C. for about 1 to 72 hours. The final
compound in Scheme 2, compound IA-a, where G=A, n=1, and q=0, is
prepared from IX by deblocking with hydroxylamine hydrochloride in
an alcoholic or aqueous-alcoholic solvent, typically aqueous
ethanol, at a temperature from about 25.degree. C. to about
125.degree. C. for about 1 to 72 hours.
[0065] In the process of Scheme 2, the preferred value of Y in
formulas IX and IA-a is benzyl. Compounds of the formula IA-a
wherein Y is benzyl can be converted into the corresponding
compounds wherein Y is other than benzyl by debenzylation using
hydrogen or ammonium formate in the presence of a noble metal
catalyst, such as palladium, in an ethereal, halogenated
hydrocarbon, alcoholic, or aqueous alcoholic solvent, at a
temperature from 0.degree. C. to 100.degree. C. for a time from 30
minutes to 24 hours, followed by reductive amination with with an
alkyl or aralkyl aldehyde in the presence of a borohydride-based
reagent such as sodium cyanoborohydride or sodium
triacetoxyborohydride, in an ethereal, halogenated hydrocarbon,
alcoholic, or aqueous-alcoholic solvent, at a temperature from
0.degree. C. to 100.degree. C. for a time from 1 to 72 hours.
[0066] Referring to Scheme 3, compound X is prepared by reductive
amination of 2-(4-bromophenylmethyl)-piperidine with benzaldehyde
and a borohydride-based reagent such as sodium cyanoborohydride or
sodium triacetoxyborohydride, in an ethereal, halogenated
hydrocarbon, alcoholic, or aqueous-alcoholic solvent, at a
temperature from about 0.degree. C. to about 100.degree. C. for
about 1 to 72 hours. Compound XI is prepared from compound X by
reaction of compound X with an organolithium reagent, typically
butyl lithium, followed by addition of the resulting organolithium
reagent to 2-(2,5-dimethylpyrrolyl)-pyridine, in an ethereal
solvent such as ethyl ether, at a temperature from about
-70.degree. C. to about 100.degree. C. for about 30 minutes to 48
hours. The final compound in Scheme 3, IA-b, wherein G=A, n=1, q=1
and Y is benzyl, is prepared from compound XI by deblocking with
hydroxylamine hydrochloride in an alcoholic or aqueous-alcoholic
solvent, typically aqueous ethanol, at a temperature from about
25.degree. C. to about 125.degree. C. for about 1 to 72 hours.
[0067] Compounds of the formula IA-b can be converted into the
corresponding compounds wherein Y is other than benzyl using the
procedure described above for converting compounds of the formula
IA-a into the analogous compounds wherein Y is other than
benzyl.
[0068] Referring to Scheme 4, compound XII is prepared from
6-bromo-2-(2,5-dimethylpyrrolyl)-pyridine and 4-formylphenylboronic
acid in the presence of a palladium catalyst, in either the
palladium-zero or palladium-two oxidation state, with ligands
typically comprised of trialkyl or triaryl phosphines, such as
tetrakis-triphenylphosphine palladium, in an aqueous alcoholic
solvent, at a temperature from about 25.degree. C. to about
125.degree. C. for about 1 to 48 hours. Compound XIII is then
prepared from XII by reaction of XII with the enamine of a ketone
or aldehyde, typically the morpholine or pyrrolidine enamine, in a
aromatic hydrocarbon, hydrocarbon, or halogenated hydrocarbon
solvent, preferably toluene, at a temperature from about 25.degree.
C. to about 150.degree. C. for about 1 to 72 hours, followed by an
aqueous hydrolysis step, typically with aqueous hydrochloric acid,
and then reduction with hydrogen or ammonium formate in the
presence of a noble metal catalyst, such as palladium, in an
ethereal, halogenated hydrocarbon, alcoholic, or aqueous alcoholic
solvent, at a temperature from about 0.degree. C. to about
100.degree. C. for about 30 minutes to 24 hours. The final compound
in Scheme 4, IA, where G=A, q=1, X=CH, and Y=NR.sup.3R.sup.4, is
prepared by reductive amination of compound XIII with ammonia, a
primary amine, or a secondary amine in the presence of a
borohydride-based reagent such as sodium cyanoborohydride or sodium
triacetoxyborohydride, in an ethereal, halogenated hydrocarbon,
alcoholic, or aqueous-alcoholic solvent, at a temperature from
about 0.degree. C. to about 100.degree. C. for about 1 to 72 hours,
followed by deblocking with hydroxylamine hydrochloride in an
alcoholic or aqueous-alcoholic solvent, typically aqueous ethanol,
at a temperature from about 25.degree. C. to about 125.degree. C.
for about 1 to 72 hours.
[0069] Referring to Scheme 5, compound XIV is prepared from
3-(4-bromophenyl)-glutaric acid by dehydration with acetic
anhydride or a similar dehydrating reagent, followed by reaction
with benzylamine in a hydrocarbon, aromatic hydrocarbon, or
halogenated hydrocarbon solvent, at a temperature from about
25.degree. C. to about 180.degree. C. for about 1 to 48 hours,
followed by dehydration with acetic anhydride, or a similar
dehydrating reagent, at a temperature from about 25.degree. C. to
about reflux for about 1 to 48 hours. Compound XV is prepared by
reduction of XIV with borane, borane methyl sulfide, alane, or
lithium aluminum hydride in an ethereal or hydrocarbon solvent, at
a temperature from about 0.degree. C. to about 100.degree. C. for
about 30 minutes to 48 hours. Compound XVI is prepared from
compound XV by reaction of compound XV with an organolithium
reagent, typically butyl lithium, followed by addition of the
resulting organolithium reagent to
2-(2,5-dimethylpyrrolyl)-pyridine, in an ethereal solvent, such as
ethyl ether, at a temperature from about -70.degree. C. to about
100.degree. C. for about 30 minutes to 48 hours. The final compound
in Scheme 5, IA-d, where G=A, Y=H, q=0, and X=N, is prepared by
debenzylation of compound XVI using hydrogen or ammonium formate in
the presence of a noble metal catalyst, such as palladium, in an
ethereal, halogenated hydrocarbon, alcoholic, or aqueous alcoholic
solvent, at a temperature from 0.degree. C. to 100.degree. C. for a
time from 30 minutes to 24 hours, followed by deblocking with
hydroxylamine hydrochloride in an alcoholic or aqueous-alcoholic
solvent, typically aqueous ethanol, at a temperature from about
25.degree. C. to about 125.degree. C. for about 1 to 72 hours.
[0070] Compounds of the formula IA-d, which are prepared using the
procedures of Scheme 5, can be converted into the analogous
compounds wherein Y is alkyl or aralkyl, by reductive amination
with an alkyl or aralkyl aldehyde in the presence of a
borohydride-based reagent such as sodium cyanoborohydride or sodium
triacetoxyborohydride, in an ethereal, halogenated hydrocarbon,
alcoholic, or aqueous-alcoholic solvent, at a temperature from
0.degree. C. to 100.degree. C. for a time from 1 to 72 hours.
[0071] The preparation of other compounds of the 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.
[0072] 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.
[0073] The compounds of formulae 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 and then simply
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.
[0074] The active compounds of this invention and their
pharmaceutically acceptable salts are useful as NOS inhibitors
i.e., they possess the ability to inhibit the NOS enzyme in
mammals, and therefore they are able to function as therapeutic
agents in the treatment of the aforementioned disorders and
diseases in an afflicted mammal.
[0075] The active 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 (i.e., 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
species of animal 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.
[0076] The active 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.
[0077] 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.
[0078] 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.
[0079] Additionally, it is also possible to administer the active
compounds of the present invention topically when treating
inflammatory conditions of the skin and this may be done by way of
creams, jellies, gels, pastes, patches, ointments and the like, in
accordance with standard pharmaceutical practice.
[0080] The ability of compounds of the formulae I to inhibit NOS
may be determined using procedures described in the literature. The
ability of compounds of the formulae 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 the formulae 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 the compounds of the formulae 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).
[0081] Of 100 compounds of the formula I that were tested, all
exhibited an IC.sub.50<10 .mu.M for inhibition of either
inducible or neuronal NOS.
[0082] 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 C.sup.13 nuclear magnetic resonance spectra 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
[0083]
3-{2-[4'-(6-Amino-pyridin-2-yl)-biphenyl-4-yl]-ethyl}-3-aza-bicyclo-
[3.1.0]hex-6-ylamine
[0084] A. 2-(2,5-Dimethylpyrrolyl)-6-(4-bromophenyl))-pyridine
[0085] To a 100 mL 3-necked round-bottomed flask equipped with
septum and nitrogen (N.sub.2) inlet were added 3.54 gram (g) (15
mmol) 1,4-dibromobenzene and 15 mL dry ether. The solution was
cooled to -70.degree. C., and 6.25 mL (10 mmol) of a 1.6 M solution
of butyl lithium in tetrahydrofuran added dropwise over 5 minutes.
The reaction was stirred 5 minutes at -70.degree. C., then warmed
to room temperature over 15 minutes. To the resulting solution was
added a solution of 1.72 g (10 mmol)
2-(2,5-dimethylpyrrolyl)-pyridine in 5 mL ether, producing a deep
red color, and the reaction stirred 3 hours at room temperature. It
was then quenched with aqueous ammonium chloride solution, taken up
in ethyl acetate, and washed with aqueous ammonium chloride and
brine, dried over sodium sulfate, and evaporated. The residue was
chromatographed on silica gel using hexane/ethyl acetate as eluant
to afford 820 mg (25%) of an oil.
[0086] .sup.1H-NMR (.delta., CDCl.sub.3): 2.30 (s, 6H), 6.03 (s,
2H), 7.20 (dd, J=1,8, 1H), 7.64 (m, 2H), 7.73 (dd, J=1,8, 1H), 7.90
(dt, J=1,8, 1H), 8.00 (m, 2H).
[0087] .sup.13C-NMR (.delta., CDCl.sub.3): 13.6, 107.2, 118.1,
120.2, 123.9, 127.0, 128.6, 132.0, 1337.3, 138.8, 151.8, 155.7.
[0088] MS (%): 327/329 (100/98, Br.sup.79/Br.sup.81, parent+1).
[0089] B.
2-(2,5-Dimethylpyrrolyl)-6-(4-(4-formylphenyl)phenyl))-pyridine
[0090] To a 100 mL round-bottomed flask equipped with condenser and
N.sub.2 inlet were added 630 mg (1.93 mmol)
2-(2,5-dimethylpyrrolyl)-6-(4- -bromophenyl)-pyridine, 289 mg (1.93
mmol) 4-formyl phenylboronic acid, 817 mg (7.71 mmol) sodium
carbonate, 112 mg (0.096 mmol) tetrakistriphenylphosphine
palladium, 9 mL ethanol, and 1 mL water. The mixture was heated at
reflux for 14 hours, cooled, poured into water, and extracted into
ethyl acetate. The organic layer was washed with brine, dried, and
evaporate, and the residue chromatographed on silica gel using 25%
ethyl acetate in hexane as eluant to afford 540 mg (80%) of the
product.
[0091] .sup.1H-NMR (.delta. CDCl.sub.3): 2.23 (s, 6H), 5.94 (s,
2H), 7.17 (6 J=8, 1H), 7.74 (m, 2H), 7.80 (m, 3H), 7.90 (t, J=8,
1H), 7.96 (m, 2H), 8.19 (m, 2H), 10.05 (s, 1H).
[0092] .sup.13C-NMR (.delta. CDCl.sub.3): 13.5, 107.1, 118.4,
120.2, 127.6, 127.7, 130.3, 138.7, 140.5, 146.4, 156.0, 191.9.
[0093] MS (%): 353 (100, parent+1).
[0094] C.
2-(2,5-Dimethylpyrrolyl)-6-(4-(4-(cyanomethyl)phenyl)phenyl))-py-
ridine
[0095] To a 100 mL 3N round-bottomed flask equipped with septum and
N.sub.2 inlet were added 354 mg (3.16 mmol) potassium t-butoxide
and 5 mL dry 1,2-dimethoxyethane. The mixture as cooled in a
-60.degree. C. bath (CHCl.sub.3/CO.sub.2), and a solution of 317 mg
(1.62 mmol) tosylmethylisocyanide in 5 mL dry 1,2-dimethoxyethane
added dropwise. After a few minutes, a solution of 540 mg (1.53
mmol)
2-(2,5-dimethylpyrrolyl)-6-(4-(4-formylphenyl)phenyl))-pyridine in
10 mL dry 1,2-dimethoxyethane was added dropwise, and stirring
continued at -60.degree. C. for 50 minutes. Then 5 mL methanol was
added and the reaction warmed and then refluxed for 15 minutes. The
reaction was cooled and evaporated, and the residue taken up in
water with 0.5 mL acetic acid and methylene chloride. The aqueous
layer was reextracted with methylene chloride, and the combined
organic layer washed with aqueous sodium bicarbonate solution,
dried over sodium sulfate , and evaporated. The residue was
chromatographed on silica gel using 25% ethyl acetate in hexane as
eluant to afford 220 mg (40%) of the product.
[0096] .sup.1H-NMR (.delta., CDCl.sub.3): 2.26 (s, 6H), 3.78 (s,
2H), 5.98 (s, 2H), 7.17 (.delta., J=8, 1H), 7.41 (m, 2H), 7.6-7.7
(m, 4H), 7.79 (5 J=8, 1H), 7.89 (t, J=8, 1H), 8.17 (m, 2H).
[0097] .sup.13C-NMR (.delta., CDCl.sub.3): 13.6, 23.3, 107.1,
118.3, 120.0, 127.4, 127.5, 127.8, 128.5, 128.7, 129.3, 137.6,
138.7, 140.3, 141.0, 151.8, 156.3.
[0098] MS (%): 364 (100, parent+1).
[0099] A byproduct eluting after the product was characterized as
the oxazole, 40 mg (7%): 11
[0100] D.
2-(2,5-Dimethylpyrrolyl)-6-(4-(4-(carboxymethyl)phenyl)phenyl))--
pyridine
[0101] To a 100 mL round-bottomed flask equipped with condenser and
N.sub.2 inlet were added 220 mg (0.606 mmol)
2-(2,5-dimethylpyrrolyl)-6-(-
4-(4-(cyanomethyl)phenyl)phenyl))-pyridine and 7 mL ethanol to form
a solution at reflux. A 10% solution of sodium hydroxide in water
was added slowly dropwise at reflux to maintain solution, requiring
30-60 minutes for 15 mL (and a little further ethanol). Refluxing
was maintained for a total of 2.5 hours. The reaction was cooled to
0.degree. C. and the pH adjusted with 6N hydrochloric acid to 1,
and the reaction was extracted into ethyl acetate. The organic
layer was washed with brine, dried over sodium sulfate, and
evaporated to afford the product as an oil, used directly in the
next step.
[0102] .sup.1H-NMR (.delta. CDCl.sub.3): 2.24 (s, 6H), 3.70 (s,
2H), 5.95 (s, 2H), 7.14 (3 J=8, 1H), 7.38 (m, 2H), 7.61 (m, 2H),
7.68 (m, 2H), 7.77 (8J=8, 1H), 7.87 (t, J=8, 1H), 8.13 (m, 2H).
[0103] .sup.13C-NMR (.delta.. CDCl.sub.3): 13.5, 20.8, 107.1,
118.4, 120.2, 127.3, 127.4, 128.7, 129.9, 132.9, 137.2, 138.8,
139.5, 141.6, 151.7, 156.4.
[0104] MS (%): 383 (100, parent+1).
[0105] E.
2-(2,5-Dimethylpyrrolyl)-6-(4-(4-(6-t-butylcarboxamido-3-aza-bic-
yclo[3.1.0]hex-3-ylcarboxamido)methyl)phenyl)phenyl))-pyridine
[0106] To a 100 mL round-bottomed flask equipped with N.sub.2 inlet
were added 420 mg (1.099 mmol)
2-(2,5-dimethylpyrrolyl)-6-(4-(4-(carboxymethyl-
)phenyl)phenyl))-pyridine, 218 mg (1.099 mmol)
3-aza-bicyclo[3.1.0]hex-6-y- lamine t-butylcarbamate, 211 mg (1.099
mmol) EDAC, 10 mg HOBT, 7 mL dry acetonitrile, and 337 uL (2.42
mmol) triethylamine. The reaction was stirred at room temperature
for 20 hours evaporated, and the residue chromatographed on silica
gel using 5% methanol in methylene chloride as eluant to afford the
product, 280 mg (45%).
[0107] .sup.1H-NMR (.delta., CDCl.sub.3): 1.69 (m, 2H), 2.22 (s,
6H), 3.4-3.9 (multiplets, 7H), 4.97 (bs, 1H), 5.93 (s, 2H), 7.12
(.delta., J=8, 1H), 7.29 (m, 2H), 7.57 (m, 2H), 7.67 (m, 2H), 7.75
(.delta., J=8, 1H), 7.85 (t, J=8, 1H), 8.12 (m, 2H).
[0108] .sup.13C-NMR (.delta., CDCl.sub.3): 13.5, 28.4, 42.0, 47.9,
48.8, 53.5, 79.8, 107.0 118.3, 119.9, 127.3, 127.4, 128.7, 129.5,
134.0, 137.2, 138.7, 138.9, 141.6, 151.7, 156.2, 156.4, 169.8.
[0109] MS (%): 563 (100, parent+1).
[0110] F.
2-{3-[4'-(6-amino-pyridin-2-yl)-biphenyl-4-yl]}-3-aza-bicyclo[3.-
1.0]hex-6-ylamine Acetamide
[0111] To a 100 mL round-bottomed flask equipped with condenser and
N.sub.2 inlet were added 280 mg (0.498 mmol)
2-(2,5-dimethylpyrrolyl)-6-(-
4-(4-(6-t-butylcarboxamido-3-aza-bicyclo[3.1.0]hex-3-ylcarboxamido)methyl)-
phenyl)phenyl))-pyridine, 173 mg (2.49 mmol) hydroxylamine
hydrochloride, 1 mL water and 5 mL ethanol. The reaction was
refluxed 40 hours, an additional 173 mg hydroxylamine hydrochloride
and 5 mL ethanol added, and refluxing continued 24 hours. The
reaction was cooled, poured into aqueous sodium bicarbonate
solution, and extracted with a mixture of ethyl acetate and
methanol, due to the limited solubility of the product in ethyl
acetate. The organic layer was dried over sodium sulfate and
evaporated.
[0112] The residue was taken up in 6 mL dry methylene chloride and
treated with 1.5 mL triflurooacetic acid at room temperature for
1.5 hours. The reaction was evaporated, taken up in 1 N
hydrochloric acid, washed with ethyl acetate, then the pH adjusted
to 10 with 1 N sodium hydroxide solution, and extracted with a
mixture of ethyl acetate and methanol. The organic layer was dried
over sodium sulfate and evaporated to afford 160 mg (84%) of the
product as a low-melting solid.
[0113] .sup.1H-NMR (.delta., CDCl.sub.3): 1.39 (bs, 2H), 1.78 (bs,
1H), 3.2-3.6 (multiplets, 2H), 3.41 (bs, 2H), 4.90 (bs, 1H), 6.30
(.delta., J=8, 1H), 6.83 (.delta., J=7.5, 1H), 7.06 (m, 2H), 7.29
(t, J=8, 1H), 7.38 (m, 2H), 7.44 (m, 2H), 7.69 (m, 2H).
[0114] .sup.13C-NMR (.delta., CDCl.sub.3): 25.0, 25.3, 34.9, 41.5,
107.6, 110.7, 126.8, 127.0, 127.1, 129.1, 133.2, 138.5, 129.0,
140.5, 155.3, 158.8, 170.6.
[0115] MS (%): 385 (100, parent+1).
[0116] G.
3-{2-[4'-(6-Amino-pyridin-2-yl)-biphenyl-4-yl]-ethyl}-3-aza-bicy-
clo[3.1.0]hex-6-ylamine
[0117] To a 100 mL round-bottomed flask equipped with condenser and
N.sub.2 inlet were added 160 mg (0.417 mmol)
3-{2-[4'-(6-amino-pyridin-2--
yl)-biphenyl-4-yl]}-3-aza-bicyclo[3.1.0]hex-6-ylamine acetamide, 5
mL dry tetrahydrofuran, and 0.625 mL of a 2 M solution of borane
methyl sulfide in tetrahydrofuran. The reaction was refluxed 12
hours, and additional 0.625 mL portion of borane methyl sulfide
added along with a few mL tetrahydrofuran, and refluxing continued
12 hours (due to the limited solubility of the starting material in
tetrahydrofuran). The reaction was cooled and evaporated, and 20 mL
ethanol, 1 g. sodium carbonate, and 1 g cesium fluoride added, and
the mixture refluxed 14 hours. The reaction was cooled and
evaporated, taken up in water and ethyl acetate/methanol, and the
organic layer separated, dried over sodium sulfate, and evaporated.
The resulting solid, 80 mg (52%) was taken up in methylene
chloride/methanol/ether and precipitated with 1 N HCl in ether,
then evaporated. The residue was triturated with tetrahydrofuran to
afford 48 mg (24%) of a white solid, mp 205.degree. C. (dec. above
this point).
[0118] .sup.1H-NMR (.delta., CDCl.sub.3): 1.33 (bs, 2H), 1.63 (bs,
1H), 2.60 (m, 2H), 2.71 (m, 2H), 3.05 (m, 2H), 3.59 (m, 2H), 4.56
(bs, 2H), 6.42 (.delta., J=8, 1H), 7.08 (.delta., J=7.5, 1H), 7.22
(m, 2H), 7.4-7.5 (m, 3H), 7.61 (m, 2H), 7.95 (m, 2H).
[0119] .sup.13C-NMR (.delta., CDCl.sub.3): 20.9, 32.2, 34.8, 55.0,
57.6, 107.4, 110.9, 126.9, 127.0, 128.9, 129.0, 136.3, 138.3,
138.5, 139.4, 141.0, 155.6, 158.5.
[0120] MS (%): 371 (100, parent+1).
[0121] Anal. Calc'd for C.sub.24H.sub.26N.sub.43HCl3H.sub.2O: C,
53.99; H, 6.61; N, 10.49. Found: C, 53.79; H, 6.46; N, 8.70.
EXAMPLE 2
[0122]
6-[4'-(4-Phenethyl-piperazin-1-ylmethyl)-biphenyl-4-yl]-pyridin-2-y-
lamine
[0123] A.
2-(2,5-Dimethylpyrrolyl)-6-[4'-(4-phenethyl-piperazin-1-ylmethyl-
)-biphenyl-4-yl]-pyridine
[0124] To a 100 mL round-bottomed flask equipped with N.sub.2 inlet
were added 176 mg (0.50 mmol)
2-(2,5-dimethylpyrrolyl)-6-(4-(4'-formylbiphenyl- -4-yl))-pyridine
(Example 1B), 105 mg (0.55 mmol) 2-phenylethylpiperazine, 7 mL
methanol, 30 uL (0.50 mmol) acetic acid, and 38 mg (0.60 mmol)
sodium cyanoborohydride. The reaction was stirred at room
temperature for 12 hours poured into aqueous sodium bicarbonate
solution and extracted into ethyl acetate. The organic layer was
washed with water and brine, dried over sodium sulfate, and
evaporated. The residue was chromatographed on silica gel using
methanol/methylene chloride as eluant to afford 190 mg (72%) of an
oil.
[0125] .sup.1H-NMR (.delta., CDCl.sub.3): 2.26 (s, 6H), 2.5-2.7 (m,
8H), 2.83 (m, 2H), 3.60 (s, 2H), 5.97 (s, 2H), 7.15 (.delta., J=8,
1H), 7.2-7.3 (m, 5H), 7.44 (m, 2H), 7.62 (m, 2H), 7.72 (m, 2H),
7.79 (.delta., J=8, 1H), 7.87 (t, J=8, 1H), 8.16 (m, 2H).
[0126] .sup.13C-NMR (.delta., CDCl.sub.3): 13.6, 33.7, 53.1, 53.2,
60.6, 62.8, 107.0, 118.2, 119.8, 126.1, 126.9, 127.4, 128.4, 128.7,
128.8, 129.8, 137.2, 137.7, 138.6, 139.3, 140.3, 141.9, 151.7,
156.5.
[0127] MS (%): 527 (parent+1, 100).
[0128] B.
6-[4'-(4-Phenethyl-piperazin-1-ylmethyl)-biphenyl-4-yl]-pyridin--
2-ylamine
[0129] To a 100 mL round-bottomed flask equipped with N2 inlet were
added 190 mg (0.361 mmol)
2-(2,5-dimethylpyrrolyl)-6-[4'-(4-phenethyl-piperazin-
-1-ylmethyl)-biphenyl-4-yl]-pyridine, 126 mg (1.81 mmol)
hydroxylamine hydrochloride, 1 mL water, and 5 mL ethanol. The
reaction was heated at reflux for 36 hours followed by treatment
with an additional 50 mg hydroxylamine hydrochloride and refluxing
for 24 hours. The reaction was cooled, poured into dilute aqueous
hydrochloric acid, and washed with ethyl acetate. The aqueous layer
was adjusted to pH 10 with 1 N sodium hydroxide solution and
extracted with ethyl acetate. The organic layer was washed with
brine, dried over sodium sulfate, and evaporated. The residue was
converted to the hydrochloride salt using 1 N HCl in ether to
afford 110 mg (55%) of a solid, mp 267-269.degree. C.
[0130] .sup.1H-NMR (.delta., CDCl.sub.3): 2.5-2.7 (m, 8H), 2.81 (m,
2H), 3.57 (s, 2H), 4.66 (bs, 2H), 6.42 (6, J=8, 1H), 7.10 (.delta.,
J=7.5, 1H), 7.21 (m, 3H), 7.26 (m, 2H), 7.41 (m, 2H), 7.47 (t, J=8,
1H), 7.59 (m, 2H), 7.66 (m, 2H), 8.00 (m, 2H).
[0131] .sup.13C-NMR (.delta., CDCl.sub.3): 33.7, 53.1, 53.2, 60.6,
62.8, 107.2, 110.8, 126.1, 126.9, 127.2, 127.3, 128.4, 128.7,
129.7, 137.4, 138.4, 139.5, 140.4, 141.0, 155.7, 158.4.
[0132] MS (%): 449 (parent+1, 100).
[0133] Anal. Calc'd for C.sub.30H.sub.32N.sub.43HCl{fraction
(3/2)}H.sub.2O: C, 61.59; H, 6.55; N, 9.58. Found: C, 61.64; H,
6.31; N, 9.51.
EXAMPLE 3
[0134]
3-[4'-(6-Amino-pyridin-2-yl)-biphenyl-4-ylmethyl]-3-aza-bicyclo[3.1-
.0]hex-6-ylamine
[0135] Prepared as in Example 2, using
3-aza-bicyclo[3.1.0]hex-6-ylamine t-butyl carbamate for the
reductive amination step (2A) in 67% yield as an oil:
[0136] .sup.1H-NMR (.delta., CDCl.sub.3): 1.46 (s, 9H), 1.52 (bs,
2H), 2.26 (s, 6H), 2.43 and 3.11 (multiplets, 4H), 2.94 (m, 1H),
3.61 (s, 2H), 5.97 (s, 2H), 7.14 (dd, J=1,8, 1H), 7.34 (m, 2H),
7.57 (m, 2H), 7.70 (m, 2H), 7.78 (.delta., J=7, 1H), 7.87 (t, J=8,
1H), 8.16 (m, 2H).
[0137] .sup.13C-NMR (.delta., CDCl.sub.3): 13.6, 24.6, 28.4, 30.6,
54.2, 58.6, 107.0, 118.2, 119.8, 126.8, 127.1, 127.3, 127.5, 128.7,
128.9, 132.1, 137.1, 138.6, 138.9, 142.0, 151.7, 156.5.
[0138] MS (%): 535 (parent+1, 100). followed by removal of the
protecting groups with hydroxylamine hydrochloride in aqueous
ethanol (as in Example 2B) and treatment with trifluoroacetic acid
in methylene chloride at room temperature for 3 hours to give
overall 65% yield of the trifluoroacetate salt, triturated with
tetrahydrofuran, mp 112-119.degree. C.:
[0139] .sup.1H-NMR (.delta., TFA salt in CDCl.sub.3): 2.33 (bs,
2H), 2.99 (bs, 1H), 3.29 (m, 2H), 3.70 (m, 2H), 4.41 (s, 2H), 6.98
(.delta., J=8, 1H), 7.20 (.delta., J=7.5, 1H), 7.60 (m, 2H), 7.78
(m, 2H), 7.88 (m, 2H), 7.98 (t, J=8, 1H).
[0140] .sup.13C-NMR (.delta., TFA salt in CDCl.sub.3): 23.7, 27.5,
57.1, 60.1, 6.9., 113.1, 113.9, 129.9, 130.0, 130.1, 132.7, 133.4,
133.6, 143.5, 145.1, 146.7, 149.1, 157.9.
[0141] MS (%): 357 (parent+1, 100).
[0142] Anal. Calc'd for
C.sub.23H.sub.24N.sub.43(C.sub.2F.sub.3O.sub.2H)1/- 2H.sub.2O: C,
49.23; H, 3.99; N, 7.92. Found: C, 49.14; H, 3.90; N, 7.80.
EXAMPLE 4
[0143]
3-[4'-(6-Amino-pyridin-2-yl)-biphenyl-3-ylmethyl]-3-aza-bicyclo[3.1-
.0]hex-6-ylamine
[0144] A.
2-(2,5-Dimethylpyrrolyl)-6-(4-(3-tolyl)phenyl))-pyridine
[0145] Prepared as in Example 1B using 3-tolyl boronic acid as an
oil in 39% yield.
[0146] .sup.1H-NMR (.delta., CDCl.sub.3) 2.32 (s, 6H), 2.49 (s,
3H), 6.03 (s, 2H), 7.19 (dd, J=1,8, 1H), 7.25 (m, 1H), 7.41 (t,
J=7.5, 1H), 7.53 (m, 2H), 7.77 (m, 2H), 7.81 (dd, J=1,8, 1H), 7.90
(t, J=8, 1H), 8.21 (m, 2H).
[0147] .sup.13C-NMR (.delta., CDCl.sub.3) 13.6, 21.7, 107.1, 118.3,
119.9, 124.3, 127.0, 127.4, 127.5, 127.9, 128.5, 128.7, 128.8,
137.2, 138.5, 138.7, 140.5, 142.3, 151.8, 156.5.
[0148] MS (%): 339 (parent+1, 100).
[0149] B. 2-Phthamimido-6-(4-(3-tolyl)phenyl))-pyridine
[0150] To a 100 mL round-bottomed flask equipped with condenser and
N.sub.2 inlet were added 200 mg (0.592 mmol)
2-(2,5-dimethylpyrrolyl)-6-(- 4-(3-tolyl)phenyl))-pyridine, 206 mg
(2.96 mmol) hydroxylamine hydrochloride, 4 mL ethanol and 1 mL
water. The reaction was refluxed 36 hours cooled, and poured into
dilute aqueous sodium bicarbonate solution and extracted into ethyl
acetate. The organic layer was separated, washed with brine, and
dried. The residue, as a brown oil, 138 mg (90%), was taken up in
10 mL dry toluene and treated with 116 mg (0.531 mmol)
N-carbethoxyphthalimide. The resulting solution was refluxed 20
hours cooled and evaporated. The residue was chromatographed on
silica gel using hexane/ethyl acetate as eluant to give 130 mg (56%
overall) of an oil.
[0151] .sup.1H-NMR (.delta., CDCl.sub.3): 2.40 (s, 3H), 7.15 (m,
1H), 7.34 (m, 2H), 7.42 (m, 2H), 7.65 (m, 2H), 7.79 (m, 3H), 7.92
(m, 3H), 8.07 (m, 2H).
[0152] .sup.13C-NMR (.delta., CDCl.sub.3): 21.6, 119.9, 120.1,
123.5, 123.9, 124.2, 122.2, 122.4, 127.5, 127.9, 128.3, 128.7,
131.9, 133.7, 134.2, 134.5, 135.3, 138.4, 139.0, 157.3, 166.8.
[0153] MS (%): 391 (parent+1, 100).
[0154] C.
3-[4'-(6-Phthalimido-pyridin-2-yl)-biphenyl-3-ylmethyl]-3-aza-bi-
cyclo[3.1.0]hex-6-ylamine t-butyl Carbamate
[0155] To a 100 mL round-bottomed flask equipped with condenser and
N2 inlet were added 130 mg (0.333 mmol)
2-phthamimido-6-(4-(3-tolyl)phenyl))- -pyridine, 59 mg (0.333 mmol)
N-bromosuccinimide, 10 mg diazo-bis(1-cyanocyclohexane), and 10 mL
carbon tetrachloride. The reaction was refluxed 1 hour an
additional 10 mg of diazo-bis(1-cyanocyclohexane) added, and
refluxing continued 1 hour. The reaction was then cooled, filtered
and evaporated.
[0156] The residue was taken up in 10 mL dry acetonitrile and
treated with 66 mg (0.333 mmol) 3-aza-bicyclo[3.1.0]hex-6-ylamine
and 28 mg (0.333 mmol) sodium bicarbonate. The reaction was
refluxed 12 hours cooled, and evaporated. The residue was taken up
in ethyl acetate and water, and the organic layer separated, washed
with brine, dried over sodium sulfate and evaporated. The residue
was chromatographed on silica gel using methanol/methylene chloride
as eluant to afford 130 mg (67%) of an oil.
[0157] .sup.1H-NMR (.delta., CDCl.sub.3): 1.38 (s, 9H), 1.6-1.8 (m,
2H), 3.2-3.5 (m, 5H), 3.57 (m, 2H), 7.15 (dd, J=1,8, 1H), 7.2-7.5
(m, 4H), 7.65 (m, 3H), 7.78 (m, 3H), 7.92 (m, 2H), 8.05 (m,
2H).
[0158] .sup.13C-NMR (.delta., CDCl.sub.3): 28.3, 47.6, 50.5, 54.1,
62.1, 116.5, 118.8, 119.9, 120.1, 123.9, 126.5, 127.3, 127.4,
127.5, 128.8, 129.2, 131.8, 134.5, 136.4, 136.8, 138.9, 155.1,
157.2, 165.6, 166.7, 169.6, 169.8.
[0159] MS (%): 587 (parent+1, 100).
[0160] D.
3-[4'-(6-Amino-pyridin-2-yl)-biphenyl-3-ylmethyl]-3-aza-bicyclo[-
3.1.0]hex-6-ylamine
[0161] To a 100 mL round-bottomed flask equipped with condenser and
N.sub.2 inlet were added 130 mg (0.222 mmol)
3-[4'-(6-phthalimido-pyridin-
-2-yl)-biphenyl-3-ylmethyl]-3-aza-bicyclo[3.1.0]hex-6-ylamine
t-butyl carbamate, 20 mL methanol and 0.3 mL hydrazine. The
reaction was heated at 50.degree. C. for 2.5 hours cooled, and
evaporated. The residue was taken up in ethyl acetate and washed
with 0.2 N sodium hydroxide solution, water and brine, dried over
sodium sulfate, and evaporated.
[0162] The residue, 110 mg, was taken up in 6 mL dry methylene
chloride and treated with 1.5 mL trifluoroacetic acid at room
temperature for 2 hours. The reaction was evaporated and taken up
in ethyl acetate/0.3 N hydrochloric acid. The aqueous layer was
separated, the pH adjusted to 10 with 6 N sodium hydroxide
solution, and extracted into ethyl acetate. The organic layer was
washed with brine, dried over sodium sulfate, and evaporated. The
resulting oil was converted to the hydrochloride using 1 N HCl in
ether and triturated with tetrahydrofuran to afford 21 mg (20%) of
a solid, mp 184-196.degree. C.
[0163] .sup.1H-NMR (.delta., CDCl.sub.3): 1.37 (bs, 2H), 1.51 (bs,
1H), 2.46 and 3.02 (multiplets, 4H), 3.64 (s, 2H), 4.60 (bs, 2H),
6.46 (.delta., J=8, 1H), 7.13 (.delta., J=7.5, 1H), 7.2-7.6 (m,
5H), 8.00 (m, 2H).
[0164] .sup.13C-NMR (.delta., CDCl.sub.3): 14.0, 38.7, 54.5, 59.2,
107.1, 110.8, 115.1, 125.7, 126.8, 127.1, 127.3, 127.7, 128.6,
138.3, 138.5, 139.0, 140.6, 141.3, 155.7, 158.3.
[0165] MS (%): 357 (parent+1, 100).
EXAMPLE 5
[0166]
2-Amino-N-[4'-(6-amino-pyridin-2-yl)-biphenyl-3-yl]-propionamide
[0167] A.
2-(2,5-Dimethylpyrrolyl)-6-(4-(3-nitrophenyl)phenyl))-pyridine
[0168] Prepared as in Example 1B, using 3-nitrophenyl boronic acid
as an oil in 66% yield.
[0169] .sup.1H-NMR (.delta., CDCl.sub.3): 2.24 (s, 6H), 5.96 (s,
2H), 7.15 (.delta., J=8, 1H), 7.54 (t, J=8, 1H), 7.67 (m, 2H), 7.76
(m, 1H), 7.88 (m, 2H), 8.15 (m, 3H), 8.42 (bs, 1H).
[0170] .sup.13C-NMR (.delta., CDCl.sub.3): 13.6, 107.3, 118.4,
120.2, 121.9, 123.2, 123.4, 127.6, 128.6, 129.9, 132.9, 138.5,
138.9, 139.2, 141.9, 148.7, 151.8, 155.8.
[0171] MS (%): 370 (parent+1, 100).
[0172] B.
2-(2,5-Dimethylpyrrolyl)-6-(4-(3-aminophenyl)phenyl))-pyridine
[0173] To a 100 mL round-bottomed flask equipped with condenser and
N.sub.2 inlet were added 520 mg (1.41 mmol)
2-(2,5-dimethylpyrrolyl)-6-(4- -(3-nitrophenyl)phenyl))-pyridine,
445 mg (7.05 mmol) ammonium formate, 10 mL ethanol, and 80 mg 10%
palladium on carbon (a few mL 1,2-dichloroethane added to dissolve
the nitro compound). The reaction was refluxed 40 min, cooled, and
filtered with ethanol through Celite. The filtrate was evaporated,
taken up in ethyl acetate/dilute aqueous sodium hydroxide solution,
and the organic layer separated and washed with brine, dried over
sodium sulfate, and evaporated to an oil, 400 mg (84%).
[0174] .sup.1H-NMR (.delta., CDCl.sub.3): 2.26 (s, 6H), 3.77 (bs,
2H), 5.99 (s, 2H), 6.67 (m, 1H), 6.92 (bs, 1H), 7.04 (m, 1H), 7.14
(m, 1H), 7.23 (t, J=8, 1H), 7.67 (m, 2H), 7.75 (.delta., J=8, 1H),
7.84 (t, J=8, 1H), 8.14 (m, 2H).
[0175] .sup.13C-NMR (.delta., CDCl.sub.3): 13.5, 107.0, 113.6,
114.4, 117.3, 118.2, 119.8, 127.1, 127.3, 128.6, 129.7, 137.1,
138.6, 141.4, 142.3, 147.0, 151.6, 156.4.
[0176] MS (%): 340 (parent+1,100).
[0177] C.
2-(t-Butylcarbamoylamino)-N-[4'-(6-(2,5-dimethylpyrrolyl)-pyridi-
n-2-yl)-biphenyl-3-yl]-propionamide
[0178] To a 100 mL round-bottomed flask equipped with N.sub.2 inlet
were added 200 mg (0.590 mmol)
2-(2,5-dimethylpyrrolyl)-6-(4-(3-aminophenyl)ph- enyl))-pyridine,
117 mg (0.590 mmol) N-t-butoxycarbonylalanine, 113 mg (0.590 mmol)
EDAC, 159 mg (1.30 mmol) 4-dimethylaminopyridine, and 10 mL dry
acetonitrile. The reaction was stirred at room temperature for 12
hours evaporated, and the residue chromatographed on silica gel
using methanol/methylene chloride as eluant to afford 230 mg (76%)
of an oil.
[0179] .sup.1H-NMR (.delta., CDCl.sub.3): 1.46 (s, 9H), 1.48
(.delta., J=7, 3H), 2.24 (s, 6H), 4.55 (m, 1H), 5.62 (m, 1H), 5.96
(s, 2H), 7.11 (.delta., J=8, 1H), 7.23 (m, 2H), 7.47 (m, 1H), 7.57
(m, 2H), 7.69 (m, 1H), 7.81 (m, 2H), 8.05 (m, 2H).
[0180] .sup.13C-NMR (.delta., CDCl.sub.3): 13.5, 18.0, 28.3, 50.9,
80.4, 106.9, 118.2, 118.9, 119.7, 122.6, 127.1, 127.3, 128.6,
129.2, 137.2, 138.5, 138.6, 140.9, 141.4, 151.6, 156.3, 171.8.
[0181] MS (%): 511 (parent+1, 100).
[0182] D.
2-Amino-N-[4'-(6-amino-pyridin-2-yl)-biphenyl-3-yl]-propionamide
[0183] To a 100 mL round-bottomed flask equipped with N2 inlet were
added 230 mg (0.451 mmol)
2-(t-butylcarbamoylamino)-N-[4'-(6-(2,5-dimethylpyrro-
lyl)-pyridin-2-yl)-biphenyl-3-yl]-propionamide and 25 mL ethyl
acetate. The solution was cooled to 0.degree. C. and saturated with
HCl, then stirred at 0.degree. C. for 30 minutes and 1 hour at room
temperature. The resulting precipitate was collected and dissolved
in 20 mL methanol, treated with 1 mL water and 157 mg (2.255 mmol)
hydroxylamine hydrochloride, and refluxed 2 days. The reaction was
cooled, evaporated, and taken up in ethyl acetate/dilute
hydrochloric acid. The aqueous layer was separated, the pH adjusted
to 10 with 6 N sodium hydroxide solution, and extracted with ethyl
acetate. The organic layer was washed with brine, dried over sodium
sulfate, and evaporated. The oil was taken up in methylene
chloride, treated with decolorizing carbon, filtered through
Celite, and evaporated. The resulting oil (90 mg) was converted to
the hydrochloride salt using 1 N HCl in ether to afford a solid, 73
mg (40%), mp >215.degree. C. (dec.).
[0184] .sup.1H-NMR (.delta., CDCl.sub.3): 1.39 (.delta., J=7, 3H),
3.57 (q, J=7, 1H), 4.66 (bs, 2H), 6.40 (.delta., J=8, 1H), 7.05
(.delta., J=7.5, 1H), 7.34 (m, 2H), 7.43 (t, J=8, 1H), 7.62 (m,
4H), 7.93 (m, 2H), 9.57 (bs, 1H).
[0185] .sup.13C-NMR (.delta., CDCl.sub.3): 21.5, 51.1, 107.2,
110.7, 117.9, 118.3, 122.6, 127.1, 127.2, 129.3, 138.3, 138.6,
140.6, 141.3, 155.4, 158.3, 173.9.
[0186] MS (%): 333 (parent+1, 100).
[0187] IR (KBr, cm..sup.-1): 1657 (C.dbd.O).
EXAMPLE 6
[0188]
2-Amino-N-[4'-(6-amino-pyridin-2-yl)-biphenyl-3-yl]-3-phenyl-propio-
namide
[0189] Prepared as in Example 5, using
t-butoxycarbonylphenylalanine, with the coupling step proceeding in
58% yield, and the deblocking in 57% yield to afford the product as
the hydrochloride salt, mp 180-200.degree. C. (dec.)
[0190] .sup.1H-NMR (.delta., CDCl.sub.3): 2.81 and 3.37
(multiplets, 2H), 3.74 (dd, J=4,9, 1H), 4.62 (bs, 2H), 6.43
(.delta., J=8, 1H), 7.10 (.delta., J=7.5, 1H), 7.2-7.4 (m, 8H),
7.47 (t, J=8, 1H), 7.65 (m, 3H), 7.97 (m, 2H), 9.53 (bs, 1H).
[0191] .sup.13C-NMR (.delta., CDCl.sub.3): 40.6, 56.8, 107.2,
110.8, 118.0, 118.5, 122.8, 126.9, 127.0, 127.1, 127.2, 128.8,
129.2, 129.4, 1137.6, 138.1, 138.4, 138.6, 140.7, 141.4, 155.4,
158.2, 172.4.
[0192] MS (%): 409 (parent+1, 100).
EXAMPLE 7
[0193]
6-[4-(1-Benzyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-pyridin-2-y-
lamine
[0194] A.
2-(2,5-Dimethylpyrrolyl)-6-[4-(pyrid-3-yl)-phenyl]-pyridine
[0195] To a 100 mL round-bottomed flask equipped with condenser and
N.sub.2 inlet were added 271 mg (2.20 mmol) 3-pyridylboronic acid
(Rec. Trav. Chim., 93, 21 (1974)), 720 mg (2.20 mmol)
2-(2,5-dimethylpyrrolyl)-- 6-(4-bromophenyl)-pyridine, 933 mg (8.81
mmol) sodium carbonate, 128 mg (0.110 mmol)
tetrakistriphenylphosphine palladium, 9 mL ethanol, and 1 mL water.
The mixture was refluxed 20 hours 100 mg 3-pyridiylboronic acid
added, and refluxing continued for 2 hours. The reaction was then
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
methanol/methylene chloride as eluant to afford the product as an
oil, 350 mg (49%).
[0196] .sup.1H-NMR (.delta., CDCl.sub.3): 2.25 (s, 6H), 5.97 (s,
2H), 7.12 (.delta., J=8, 1H), 7.31 (dd, J=5,8, 1H), 7.64 (m, 2H),
7.74 (.delta., J=8, 1H), 7.83 (m, 2H), 8.16 (m, 2H), 8.59 (m, 1H),
8.90 (m, 1H).
[0197] .sup.13C-NMR (.delta., CDCl.sub.3): 13.6, 107.2, 118.3,
120.1, 123.7, 127.4, 127.6, 128.1, 128.6, 129.1, 134.2, 135.9,
138.6, 138.8, 148.2, 148.5, 128.8, 151.8, 156.0.
[0198] MS (%): 326 (parent+1, 100).
[0199] B.
2-(2,5-Dimethylpyrrolyl)-6-[4-(1-benzyl-1,2,5,6-tetrahydro-pyrid-
in-3-yl)-phenyl]-pyridine
[0200] To a 100 mL round-bottomed flask equipped with condenser and
N.sub.2 inlet were added 350 mg (1.077 mmol)
2-(2,5-dimethylpyrrolyl)-6-[- 4-(pyrid-3-yl)-phenyl]-pyridine, 10
mL dry acetonitrile, and 128 uL (1.077 mmol) benzyl bromide. The
reaction was heated at 70.degree. C. for 14 hours cooled,
evaporated, and the residue taken up in 5 mL ethanol and 4 mL
water, and treated with 149 mg (2.37 mmol) sodium cyanoborohydride
(a few mL dichloromethane was added to improve solubility). The
reaction was stirred at room temperature for 20 hours poured into
dilute aqueous sodium bicarbonate solution, and extracted with
ethyl acetate. The 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
two product fractions:
[0201]
2-(2,5-dimethylpyrrolyl)-6-[4-(1-benzyl-1,2,5,6-tetrahydro-pyridin--
3-yl)-phenyl]-pyridine as an oil, 135 mg (30%):
[0202] .sup.1H-NMR (.delta., CDCl.sub.3): 2.26 (s, 6H), 2.41 (m,
2H), 2.67 (m, 2H), 3.45 (m, 2H), 3.76 (s, 2H), 5.98 (s, 2H), 6.28
(bs, 1H), 7.13 (.delta., J=8, 1H), 7.3-7.5 (m, 7H), 7.73 (.delta.,
J=8, 1H), 7.85 (t, J=8, 1H), 8.05 (m, 2H).
[0203] .sup.13C-NMR (.delta., CDCl.sub.3): 13.6, 26.6, 49.2, 54.6,
62.9, 107.0, 118.1, 119.7, 123.5, 125.2, 126.9, 127.2, 128.4,
128.7, 129.3, 134.8, 136.9, 138.2, 138.6, 141.1, 151.7, 156.5.
[0204] MS (%): 420 (parent+1, 100), and
[0205]
2-(2,5-dimethylpyrrolyl)-6-[4-(1-benzyl-piperidin-3-yl)-phenyl]-pyr-
idine, 170 mg (37.5%):
[0206] .sup.1H-NMR (.delta., CDCl.sub.3): 1.82 (m, 4H), 2.23 (s,
6H), 2.67 (m, 1H), 2.9-3.1 (m, 4H), 3.66 (s, 2H), 5.95 (s, 2H),
7.12 (.delta., J=8, 1H), 7.2-7.5 (m, 7H), 7.73 (.delta., J=8, 1H),
7.86 (t, J=8, 1H), 8.01 (m, 2H).
[0207] .sup.13C-NMR (.delta., CDCl.sub.3): 13.6, 25.2, 31.3, 42.3,
53.5, 60.3, 63.2, 107.0, 118.2, 119.7, 127.1, 127.6, 127.7, 128.4,
128.5, 128.7, 129.5, 129.9, 133.3, 136.7, 138.7, 151.6, 156.7.
[0208] MS (%): 420 (parent+1, 100).
[0209] C.
6-[4-(1-Benzyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-pyridin--
2-ylamine
[0210] To a 100 mL round-bottomed flask equipped with condenser and
N.sub.2 inlet were added 135 mg (0.322 mmol)
2-(2,5-dimethylpyrrolyl)-6-[-
4-(1-benzyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-pyridine, 112
mg (1.61 mmol) hydroxylamine hydrochloride, 5 mL ethanol, and 1 mL
water. The reaction was refluxed 40 hours cooled, and the resulting
precipitate,
6-[4-(1-benzyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-pyridin-2-ylamine
dihydrochloride, filtered and dried, 22 mg (16.5%), mp
270-272.degree. C. Additional material was recovered from the
filtrate, 60 mg (55%) of the free base as an oil.
[0211] .sup.1H-NMR (.delta., CDCl.sub.3): 2.35 (m, 2H), 2.64 (m,
2H), 3.40 (m, 2H), 3.71 (s, 2H), 4.58 (bs, 2H), 6.21 (bs, 1H), 6.40
(.delta., J=8, 1H), 7.04 (.delta., J=7.5, 1H), 7.2-7.4 (m, 7H),
7.45 (t, J=8, 1H), 7.84 (m, 2H).
[0212] .sup.13C-NMR (.delta., CDCl.sub.3): 26.5, 49.1, 54.6, .62.8,
107.1, 110.7, 122.9, 125.0, 126.7, 126.8, 127.1, 128.3, 129.3,
134.9, 138.1, 138.2, 138.3, 138.4, 155.8.
[0213] MS (%): 342 (parent+1, 100).
[0214] Anal. Calc'd for C.sub.23H.sub.23N.sub.32HCl1/2H.sub.2O: C,
65.25; H, 6.19; N, 9.92. Found: C, 65.62; H, 6.42; N, 9.93.
EXAMPLE 8
[0215] 6-[4-(1-Benzyl-piperidin-3-yl)-phenyl]-pyridin-2-ylamine
[0216] Prepared as in Example 7C using the intermediate from
Example 7B, to afford 50 mg (30%) of a solid, mp 55-70.degree.
C.
[0217] .sup.1H-NMR (.delta., CDCl.sub.3): 1.75 (m, 2H), 2.0 (m,
2H), 2.62 (m, 1H), 2.8-3.0 (m, 4H), 3.55 (s, 2H), 4.58 (bs, 2H),
6.40 (.delta., J=8, 1H), 7.05 (.delta., J=8, 1H), 7.2-7.4 (m, 7H),
7.44 (t, J=8, 1H), 7.82 (m, 2H).
[0218] .sup.13C-NMR (.delta., CDCl.sub.3): 25.7, 31.7, 42.7, 53.7,
61.0, 63.6, 106.9, 110.7, 126.8, 127.0, 127.5, 128.2, 128.3, 129.2,
129.3, 133.8, 137.8, 138.3, 145.7, 156.1, 158.3.
[0219] MS (%): 344 (parent+1, 100).
EXAMPLE 9
[0220]
6-[4-(1-Benzyl-piperidin-2-ylmethyl)-phenyl]-pyridin-2-ylamine
[0221] A. N-Benzyl-2-(4-bromobenzyl)-piperidine
[0222] To a 100 mL round-bottomed flask equipped with N.sub.2 inlet
were added 250 mg (0.984 mmol) 2-(4-bromobenzyl)-piperidine
(prepared as described in Tetrahedron Letters, 7, 631 (1977)), 110
uL (1.08 mmol) benzaldehyde, 7 mL methanol, 74 mg (1.18 mmol)
sodium cyanoborohydride, and a few drops of acetic acid. The
reaction was stirred at room temperature, followed by additional
benzaldehyde, sodium cyanoborohydride, and acetic acid, for a total
of 16 hours then poured into dilute aqueous sodium bicarbonate
solution, 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 methanol/methylene
chloride as eluant, and the product further purified by conversion
to the hydrochloride salt in ether followed by basification using
aqueous sodium hydroxide solution to afford 175 mg (52%) of an
oil.
[0223] .sup.1H-NMR (.delta., CDCl.sub.3): 1.29 (m, 2H), 1.53 (m,
3H), 1.6 (m, 1H), 2.26 and 2.79 (multiplets, 2H), 2.60 (m, 2H),
3.15 (dd, J=3,12, 1H), 3.77 (Ab.sub.q, J=13.5, Dn=41, 2H), 7.00 (m,
1H), 7.2-7.4 (m, 8H).
[0224] .sup.13C-NMR (.delta., CDCl.sub.3): 22.4, 24.9, 28.9, 36.0,
51.0, 58.2, 61.5, 127.0, 127.2, 127.6, 128.3, 128.5, 129.2, 131.1,
131.4, 139.0, 140.9.
[0225] MS (%): 344/346 (parent+1, Br.sup.79/Br.sup.81, 100).
[0226] B.
2-(2,5-Dimethylpyrrolyl)-6-[4-(1-benzyl-piperidin-2-ylmethyl)-ph-
enyl]-pyridine
[0227] To a 100 mL 3N round-bottomed flask equipped with septum and
N.sub.2 inlet were added 175 mg (0.509 mmol)
N-benzyl-2-(4-bromobenzyl)-p- iperidine and 7 mL dry ether. The
solution was cooled to -70.degree. C., and 0.38 mL (0.610 mmol) of
a 1.6 M solution of butyl lithium in hexane added dropwise over 1
minutes. The reaction was stirred at -70.degree. C. for 5 min, then
warmed to room temperature over 20 minutes. To the stirring
reaction was then added a solution of 105 mg (0.610 mmol)
2-(2,5-dimethylpyrrolyl)-pyridine in 5 mL dry ether, and the
reaction, turning dark orange, was stirred at room temperature for
4 hours then quenched with aqueous ammonium chloride solution.
After extraction into ethyl acetate, the organic layer was washed
with brine, dried over sodium sulfate for 16 hours to effect
air-oxidation to the pyridine, and evaporated. The residue was
chromatographed on silica gel using methanol/methylene chloride as
eluant to afford 36 mg (16%) of an oil.
[0228] .sup.1H-NMR (.delta., CDCl.sub.3): 1.30 (m, 2H), 1.55 (m,
3H), 1.64 (m, 1H), 2.22 (s, 6H), 2.6-2.9 (m, 4H), 3.11 and 3.25
(multiplets, 1H), 3.54 and 4.07 (multiplets, 2H), 5.93 (s, 2H),
7.01 (6, J=8, 1H), 7.2-7.4 (m, 7H), 7.72 (.delta., J=8, 1H), 7.85
(t, J=8, 1H), 7.98 (m, 2H).
[0229] .sup.13C-NMR (.delta., CDCl.sub.3): 13.5, 22.3, 25.0, 29.0,
50.8, 58.2, 61.5, 65.2, 106.9, 118.1, 119.6, 126.9, 127.0, 127.6,
128.3, 128.5, 128.7, 129.0, 129.1, 129.8, 131.1, 131.3, 138.5,
141.5, 155.5, 157.0.
[0230] MS (%): 436 (parent+1, 100).
[0231] C.
6-[4-(1-Benzyl-piperidin-2-ylmethyl)-phenyl]-pyridin-2-ylamine
[0232] To a 100 mL round-bottomed flask equipped with condenser and
N.sub.2 inlet were added 36 mg (0.0827 mmol)
2-(2,5-dimethylpyrrolyl)-6-[-
4-(1-benzyl-piperidin-2-ylmethyl)-phenyl]-pyridine, 29 mg (0.414
mmol) hydroxylamine hydrochloride, 4 mL ethanol and 1 mL water. The
reaction was refluxed 84 h (additional hydroxylamine hydrochloride
was used to complete the reaction), cooled, poured into dilute
hydrochloric acid, and washed with ethyl acetate. The aqueous layer
was adjusted to pH 10 with 6 N sodium hydroxide solution and
extracted with ethyl acetate. The organic layer was washed with
brine, dried over sodium sulfate, and evaporated. The resulting oil
was converted to the hydrochloride salt using 1 N HCl in ether to
afford a solid, 17 mg (48%), mp 70-85.degree. C.
[0233] .sup.1H-NMR (.delta., CDCl.sub.3): 1.32 (m, 2H), 1.52 (m,
3H), 1.63 (m, 1H), 2.6-2.8 (m, 2H), 3.21 (m, 1H), 3.53 (m, 2H),
4.08 (m, 2H), 4.50 (bs, 2H), 6.42 (.delta., J=8, 1H), 7.05
(.delta., J=7.5, 1H), 7.2-7.4 (m, 7H), 7.47 (t, J=8, 1H), 7.81 (m,
2H).
[0234] .sup.13C-NMR (.delta., CDCl.sub.3): 22.4, 23.8, 25.3, 36.2,
38.7, 50.9, 61.8, 106.8, 110.8, 126.7, 126.8, 128.2, 128.8, 128.9,
129.0, 129.6, 131.1, 131.3, 138.3, 141.0, 156.2, 158.6.
[0235] MS (%): 358 (parent+1, 100).
[0236] Anal. Calc'd for C.sub.24H.sub.27N.sub.32HCl3H.sub.2O: C,
59.50; H, 7.28; N, 8.67. Found: C, 59.54; H, 6.98; N, 7.32.
EXAMPLE 10
[0237] 6-{4-[1-(2,2-Diphenyl-ethyl)-piperidin-2-yl
methyl]-phenyl}-pyridin- -2-ylamine
[0238] Prepared as in Example 9, using diphenylacetaldehyde in the
step analogous to 9A, 59% yield, followed by a 33% yield in the
organolithium addition, and a 31% yield in the deblocking to afford
the product as the dihydrochloride salt, mp 168-180.degree. C.
[0239] .sup.1H-NMR (.delta., CDCl.sub.3): 1.4-1.7 (m, 6H), 2.4-3.4
(series of multiplets, 8H), 4.49 (bs, 2H), 6.43 (.delta., J=8, 1H),
7.04 (.delta., J=7.5, 1H), 7.11 (m, 2H), 7.2-7.4 (m, 10H), 7.47 (t,
J=8, 1H), 7.79 (m, 2H).
[0240] .sup.13C-NMR (.delta., CDCl.sub.3): 23.0, 23.8, 29.7, 38.7,
49.5, 50.5, 59.6, 61.6, 106.8, 110.8, 126.2, 126.7, 128.3, 129.5,
130.9, 138.4, 141.9, 144.0, 156.0, 158.2.
[0241] MS (%): 448 (parent+1, 100).
EXAMPLE 11
[0242]
6-[3-(2-Dimethylamino-cyclopentylmethyl)-phenyl]-pyridin-2-ylamine
[0243] A.
2-(4-((2-(2,5-Dimethylpyrrolyl))-pyrid-6-yl)benzylidene)cyclopen-
tanone
[0244] To a 100 mL round-bottomed flask equipped with Dean-Stark
trap topped with a condenser and N.sub.2 inlet were added 552 mg
(2.0 mmol) 2-(2,5-dimethylpyrrolyl)-6-(4-formylphenyl)-pyridine, 20
mL benzene, 0.384 mL (2.4 mmol) 4-morpholino-1-cyclohexene, and 10
mg camphorsulfonic acid. The solution was refluxed with removal of
water for 13 hours cooled, and 25 mL 3N hydrochloric acid added.
The mixture was stirred at room temperature for 1 hour then diluted
with ethyl acetate and water. The organic layer was separated,
washed with aqueous sodium bicarbonate solution and brine, dried
over sodium sulfate, and evaporated. The crude oil solidified on
standing, 460 mg (.about.100%), and was used directly in the next
step.
[0245] .sup.1H-NMR (.delta., CDCl.sub.3): 1.95 (m, 2H), 2.195 (s,
6H), 2.33 (t, J=8, 2H), 2.91 (m, 2H), 5.91 (s, 2H), 7.09 (.delta.,
J=8, 1H), 7.36 (bs, 1H), 7.55 (m, 2H), 7.71 (.delta., J=8, 1H),
7.81 (t, J=8, 1H), 8.07 (m, 2H).
[0246] .sup.13C-NMR (.delta., CDCl.sub.3): 13.5, 20.0, 29.3, 37.6,
107.1, 118.4, 120.1, 127.0, 128.2, 128.1, 130.8, 131.2, 136.4,
136.7, 138.8, 151.7, 155.6.
[0247] MS (%): 343 (parent+1, 100).
[0248] B.
2-(4-((2-(2,5-Dimethylpyrrolyl))-pyrid-6-yl)benzyl)cyclopentanon-
e
[0249] To a 100 mL round-bottomed flask equipped with condenser and
N.sub.2 inlet were added the crude material from above (2 mmol) and
4 mL 1,2-dichloroethane. After dissolution, 25 mL ethanol was
added, followed by 631 mg (10 mmol) ammonium formate and 100 mg 10%
palladium-on-carbon. The mixture was refluxed 1 hours then treated
with additional ammonium formate and palladium-on-carbon (Pd--C)
and refluxed for 1 hour. The reaction was then cooled and filtered
through Celite with ethanol and methylene chloride. The filtrate
was evaporated, taken up in ethyl acetate and aqueous sodium
bicarbonate solution, the organic layer separated, washed with
brine, dried over sodium sulfate and evaporated. The residue was
chromatographed on silica gel using ethyl acetate/hexane as eluant
to afford 410 mg (60% overall) of a foam.
[0250] .sup.1H-NMR (.delta., CDCl.sub.3): 1.56 (m, 1H), 1.70 (m,
1H), 1.93 (m, 1H), 2.06 (m, 2H), 2.24 (s, 6H), 2.29 (m, 1H), 2.36
(m, 1H), 2.61 (m, 1H), 3.19 (dd, J=4,14, 1H), 5.95 (s, 2H), 7.10
(6, J=8, 1H), 7.27 (m, 2H), 7.71 (5, J=8, 1H), 7.83 (t, J=8, 1H),
8.01 (m, 2H).
[0251] .sup.13C-NMR (.delta., CDCl.sub.3): 13.5, 20.5 29.0, 35.3,
38.1, 50.8, 107.0, 118.1, 119.6, 126.9, 128.5, 129.3, 136.3, 138.7,
141.5, 151.6, 156.6.
[0252] IR (neat, cm..sup.-1): 1735 (C=O).
[0253] MS (%): 345 (parent+1, 100).
[0254] C.
2-(2,5-Dimethylpyrrolyl)-6-[3-(2-dimethylamino-cyclopentylmethyl-
)-phenyl]-pyridine To a 100 mL round-bottomed flask equipped with
condenser and N.sub.2 inlet were added 205 mg (0.596 mmol)
2-(4-((2-(2,5-dimethylpyrrolyl))-pyrid-6-yl)benzyl)cyclopentanone,
10 mL methanol, 486 mg (5.96 mmol) dimethylamine hydrochloride, 45
mg (0.715 mmol) sodium cyanoborohydride, and 41 uL (0.715 mmol)
acetic acid. The reaction was heated at 50.degree. C. for 40 hours,
cooled, and poured into aqueous sodium bicarbonate solution. The
mixture was extracted with ethyl acetate, and the organic layer
washed with brine, dried over sodium sulfate, and evaporated. The
residue was chromatographed on silica gel using methanol/methylene
chloride (with a small amount of triethylamine) as eluant to afford
both diastereomers as an oil Less polar diastereomer, 140 mg
(63%):
[0255] .sup.1H-NMR (.delta., CDCl.sub.3): 1.51 (m, 2H), 1.63 (m,
2H), 1.86 (m, 2H),6 2.22 (s, 6H), 2.28 (m, 3H), 2.33 (s, 6H), 2.99
(m, 1H), 5.93 (s, 2H), 7.10 (.delta., J=8, 1H), 7.27 (m, 2H), 7.71
(.delta., J=8, 1H), 7.83 (t, J=8, 1H), 7.99 (m, 2H).
[0256] .sup.13C-NMR (.delta., CDCl.sub.3): 13.4, 20.3, 27.3, 28.2,
32.4, 42.8, 45.3, 71.8, 106.8, 118.0, 119.4, 126.7, 128.6, 129.4,
135.7, 138.4, 143.8, 151.5, 156.8.
[0257] MS (%): 374 (parent+1, 100).
[0258] More polar diastereomer, 10 mg (4%):
[0259] .sup.1H-NMR (.delta., CDCl.sub.3): 1.5-1.8 (m, 6H), 2.20 (s,
6H), 2.32 (s, 6H), 2.45 (dd, J=10,14, 1H), 2.60 (m, 2H), 2.95 (dd,
J=5,13.5, 1H), 5.91 (s, 2H), 7.10 (.delta., J=8, 1H), 7.27 (m, 2H),
7.71 (.delta., J=8, 1H), 7.84 (t, J=8, 1H), 7.97 (m, 2H).
[0260] .sup.13C-NMR (.delta., CDCl.sub.3): 13.4, 23.5 27.5, 30.85,
41.0, 42.3, 43.3, 72.1, 106.8, 118.0, 119.5, 126.8, 128.6, 129.4,
136.0, 138.4, 142.7, 151.5, 156.7.
[0261] MS (%): 374 (parent+1, 100).
[0262] D.
6-[3-(2-Dimethylamino-cyclopentylmethyl)-phenyl]-pyridin-2-ylami-
ne
[0263] To a 100 mL round-bottomed flask equipped with condenser and
N.sub.2 inlet were added 140 mg (0.375 mmol)
2-(2,5-dimethylpyrrolyl)-6-[-
3-(2-dimethylamino-cyclopentylmethyl)-phenyl]-pyridine, 9 mL
ethanol, 1 mL water, and 261 mg (3.75 mmol) hydroxylamine
hydrochloride. The reaction was refluxed 24 hours treated with
additional hydroxylamine hydrochloride, and refluxed a further 12
hours. It was then cooled, poured into dilute aqueous hydrochloric
acid, and washed with ethyl acetate. The aqueous layer was adjusted
to pH 10 with 6N sodium hydroxide solution, and extracted with two
portions of ethyl acetate. The combined organic layer was washed
with brine, dried over sodium sulfate, and evaporated. The
resulting oil (109 mg, 98.5%) was converted to the hydrochloride
salt using 1N HCl in ether to afford 115 mg (83%) of a white solid,
mp 60-80.degree. C.
[0264] .sup.1H-NMR (.delta., CDCl.sub.3): 1.49 (m, 2H), 1.58 (m,
2H), 1.82 (m, 2H), 2.23 (m, 2H), 2.29 (s, 6H), 2.3 (m, 1H), 2.94
(.delta., J=9.6, 1H), 4.57 (bs, 2H), 6.38 (.delta., J=8, 1H), 7.02
(.delta., J=8, 1H), 7.20 (m, 2H), 7.43 (t, J=8, 1H), 7.80 (m,
2H).
[0265] .sup.13C-NMR (.delta., CDCl.sub.3): 20.3, 27.3, 28.2, 32.3,
42.8, 45.3, 71.9, 106.7, 110.6, 126.6, 129.2, 137.1, 138.2, 142.8,
156.2, 158.2.
[0266] MS (%): 296 (parent+1, 100).
EXAMPLE 12
[0267]
6-[3-(2-(4-Methylpiperazin-1-yl)-cyclopentylmethyl)-phenyl]-pyridin-
-2-ylamine
[0268] Prepared as in Example 11, using N-methylpiperazine, to
afford a 64% yield of the product as a mixture of diastereomers as
the hydrochloride salt, mp 212-224.degree. C.
[0269] .sup.1H-NMR (.delta., CDCl.sub.3): 1.44 (m, 2H), 1.51 (m,
2H), 1.7-1.8 (m, 2H), 2.21 (m, 2H), 2.25 (s, 6H), 2.3 (m, 1H),
2.4-2.6 (m, 8H), 2.88 (m, 1H), 4.60 (bs, 2H), 6.34 (.delta., J=8,
1H), 6.99 (6, J=8, 1H), 7.16 (m, 2H), 7.40 (t, J=8, 1H), 7.77 (m,
2H).
[0270] .sup.13C-NMR (.delta., CDCl.sub.3): 20.1, 27.3, 27.4, 32.5,
42.1, 46.0, 52.7, 55.1, 70.0, 106.7, 110.5, 126.6, 129.1, 137.0,
138.2, 142.8, 156.1, 158.2.
[0271] MS (%): 351 (parent+1, 100).
EXAMPLE 13
[0272] 6-[4-(Piperidin-4-yl)-phenyl]-pyridin-2-ylamine
[0273] A. N-Benzyl-4-(4-bromophenyl)piperidine
[0274] To a 250 mL round-bottomed flask equipped with condenser and
N.sub.2 inlet were added 4.77 g (17.72 mmol)
3-(4-bromophenyl)glutaric anhydride (prepared as described in J.
Org. Chem., 21, 704 (1956)), 1.90 g (17.72 mmol) benzylamine, and
80 mL toluene. The reaction was refluxed 1.5 hours cooled, and
concentrated. The residue was taken up in 80 mL acetic anhydride,
and heated at 100.degree. C. for 16 hours then cooled and
evaporated several times with toluene to remove excess acetic
anhydride. The residue was dissolved in 80 mL dry tetrahydrofuran
and treated with 40 mL (80 mmol) of a 2 N solution of borane methyl
sulfide in tetrahydrofuran. The reaction was refluxed 18 hours
cooled, and evaporated, then dissolved in 80 mL ethanol and treated
with 3.5 g sodium carbonate and 3.5 g cesium fluoride. The reaction
was refluxed 16 hours cooled, and concentrated. The residue was
taken up in water and ethyl acetate. The organic layer was
separated, washed with brine, dried over sodium sulfate, and
evaporated. The residue was chromatographed on silica gel using
ethyl acetate/hexane as eluant to afford 2.94 g (50%) of an
oil.
[0275] .sup.1H-NMR (.delta., CDCl.sub.3): 1.78 (m, 4H), 2.08 (m,
2H), 2.47 (m, 1H), 3.02 (m, 2H), 3.56 (s, 2H), 7.10 (d, J=8, 1H),
7.2-7.4 (m, 5H), 7.41 (d, J=8, 2H).
[0276] .sup.13C-NMR (.delta., CDCl.sub.3): 33.4, 42.2, 54.1, 63.5,
119.7, 127.0, 128.2, 128.7, 129.2, 131.4, 138.4, 145.5.
[0277] MS (%): 328/330 (parent, Br.sup.79/Br.sup.81, 15/19), 91
(100).
[0278] B.
N-Benzyl-4-(4-(2-(2,5-dimethylpyrrolyl)pyrid-6-yl)phenyl)piperid-
ine
[0279] To a 125 mL three-necked round-bottomed flask equipped with
septum and N.sub.2 inlet were added 2.93 g (8.88 mmol)
N-benzyl-4-(4-bromophenyl- )piperidine and 30 mL dry ether. The
solution was cooled to -70.degree. C., and 6.66 mL (10.65 mmol) of
a 1.6 N solution of butyl lithium in hexane added dropwise over 5
minutes. After stirring a further 5 minutes at -70.degree. C., the
solution was warmed slowly to room temperature over 25 minutes. A
solution of 1.83 g (10.65 mmol) 2-(2,5-dimethylpyrrolyl)pyridine in
10 mL dry ether was then added dropwise over 5 minutes, and the
reaction, which turned slowly dark red, stirred at room temperature
for 3 hours. The reaction was quenched with aqueous ammonium
chloride solution, partitioned between ethyl acetate and water, and
the organic layer separated, washed with brine, and dried over
sodium sulfate, allowing it to stand overnight to effect
rearomatization of the pyridine ring. After evaporation of the
solvent, the residue was chromatographed on silica gel using ethyl
acetate/hexane followed by methanol/methylene chloride as eluant to
afford 1.21 g (32%) of an oil.
[0280] .sup.1H-NMR (.delta., CDCl.sub.3): 1.86 (m, 4H), 2.16 (m,
2H), 2.23 (s, 6H), 2.58 (m, 1H), 3.05 (m, 2H), 3.59 (s, 2H), 5.95
(s, 2H), 7.12 (d, J=8, 1H), 7.2-7.4 (m, 7H), 7.73 (d, J=7, 1H),
7.85 (t, J=8, 1H), 8.03 (m, 2H).
[0281] .sup.13C-NMR (.delta., CDCl.sub.3): 13.5, 33.4, 42.5, 54.2,
63.5, 106.9, 118.1, 119.6, 127.1, 127.3, 128.2, 128.7, 129.3,
131.4, 136.3, 138.3, 138.5, 148.0, 151.7, 156.8.
[0282] MS (%): 422 (parent+1, 26), 91 (100).
[0283] C.
4-(4-(2-(2,5-Dimethylpyrrolyl)pyrid-6-yl)phenyl)piperidine
[0284] To a 100 mL round-bottomed flask equipped with condenser and
N.sub.2 inlet were added 1.21 g (2.87 mmol)
N-benzyl-4-(4-(2-(2,5-dimethy-
lpyrrolyl)pyrid-6-yl)phenyl)piperidine, 30 mL ethanol, 0.90 g
(14.37 mmol) ammonium formate, and 140 mg 10% palladium-on-carbon
(Pd--C). The reaction was refluxed 1 hour treated with additional
ammonium formate and Pd-C, and refluxed 3 hours. It was then cooled
and filtered through Celite with ethanol and methylene chloride.
The filtrate was evaporated, taken up in ethyl acetate and aqueous
sodium bicarbonate solution, and the organic layer separated,
washed with brine, dried over sodium sulfate, and evaporated to
afford 734 mg (77%) of an oil.
[0285] .sup.1H-NMR (.delta., CDCl.sub.3): 1.80 (m, 4H), 2.20 (s,
6H), 2.69 (m, 1H), 2.78 (m, 2H), 3.23 (m, 2H), 3.68 (bs, 1H), 5.92
(s, 2H), 7.10 (d, J=8, 1H), 7.32 (m, 2H), 7.71 (d, J=8, 1H), 7.84
(t, J=8, 1H), 8.01 (m, 2H).
[0286] .sup.13C-NMR (.delta., CDCl.sub.3): 13.5, 33.7, 42.5, 46.7,
106.9, 118.1, 119.6, 127.2, 128.5, 128.7, 136.4, 138.5, 147.7,
151.7, 156.8.
[0287] MS (%): 332 (parent+1, 100).
[0288] D. 6-[4-(Piperidin-4-yl)-phenyl]-pyridin-2-ylamine
[0289] To a 100 mL round-bottomed flask equipped with condenser and
N.sub.2 inlet were added 100 mg (0.302 mmol)
4-(4-(2-(2,5-dimethylpyrroly- l)pyrid-6-yl)phenyl)piperidine, 10 mL
ethanol, 1 mL water, and 417 mg (6.04 mmol) hydroxylamine
hydrochloride. The reaction was refluxed 20 hours cooled, and
poured into dilute aqueous hydrochloric acid, then washed with
ethyl acetate. The aqueous layer was adjusted to pH 10 with 6 N
sodium hydroxide solution and extracted twice with ethyl acetate.
The combined organic layer was washed with brine, dried over sodium
sulfate, and evaporated. The resulting oil (77 mg, 100%) was
converted to the hydrochloride salt using HCl in, ether to afford a
tan solid, 32 mg (32%), mp dec. above 150.degree. C.
[0290] .sup.1H-NMR (.delta., CDCl.sub.3): 1.63 (m, 2H), 1.80 (m,
2H), 2.60 (m, 1H), 2.68 (m, 2H), 3.14 (m, 2H), 4.68 (bs, 2H), 6.36
(d, J=8, 1H), 6.97 (d, J=7.5, 1H), 7.22 (m, 2H), 7.41 (t, J=8, 1H),
7.79 (m, 2H).
[0291] .sup.13C-NMR (.delta., CDCl.sub.3): 34.1, 42.5, 46.8, 106.9,
110.5, 126.9, 128.3, 137.6, 138.2, 147.0, 155.9, 158.3.
[0292] MS (%): 254 (parent+1, 100).
EXAMPLE 14
[0293]
6-[3-(2-(N-Cyclohexylamino)-cyclopentylmethyl)-phenyl]-pyridin-2-yl-
amine
[0294] Prepared as in Example 11, using cyclohexylamine, to afford
a 76% yield of the less polar isomer after separation of isomers,
assigned the cis stereochemistry, as the hydrochloride salt, mp
198-205.degree. C.
[0295] .sup.1H-NMR (.delta., CDCl.sub.3): 1.0-1.9 (m, 16H), 2.21
(m, 1H), 2.34 (m, 1H), 2.45 (m, 1H), 2.82 (dd, J=5,13, 1H, assigned
cis stereochemistry), 3.21 (m, 1H), 4.52 (broad s, 2H, NH.sub.2),
6.40 (d, J=8, 1H), 7.04 (d, J=8, 1H), 7.23 (m, 2H), 7.45 (t, J=8,
1H), 7.81 (m, 2H).
[0296] .sup.13C-NMR (.delta., CDCl.sub.3): 20.6, 25.2, 26.1, 28.3,
31.1, 33.9, 34.1, 43.8, 54.9, 58.3, 106.7, 110.6, 126.6, 129.1,
137.0, 138.2, 142.7, 156.2, 158.1.
[0297] MS (%): 350 (parent+1, 100).
[0298] Anal. Calc'd. for C.sub.23H.sub.31N.sub.32HCl H.sub.2O: C,
62.72; H, 8.01; N, 9.54. Found: C, 62.66; H, 8.12; N, 8.83.
EXAMPLE 15
[0299]
6-[3-(2-(N-Cyclohexylamino)-cyclopentylmethyl)-phenyl]-pyridin-2-yl-
amine
[0300] Prepared as in Example 11, using cyclohexylamine, to afford
a 85% yield of the more polar isomer after separation of isomers,
assigned the trans stereochemistry, as the hydrochloride salt, mp
175-185.degree. C.
[0301] .sup.1H-NMR (.delta., CDCl.sub.3): 0.9-1.4 (m, 6H), 1.5-2.0
(m, 11H), 2.33 (m, 1H), 2.52 (dd, J=8.5,13, 1H assigned trans
stereochemistry), 2.81 (m, 2H), 4.56 (broad s, 2H, NH.sub.2), 6.38
(d, J=8, 1H), 7.02 (d, J=8, 1H), 7.21 (m, 2H), 7.43 (t, J=8, 1H),
7.79 (m, 2H).
[0302] .sup.13C-NMR (.delta., CDCl.sub.3): 22.5, 25.1, 25.2, 26.0,
30.7, 33.3, 33.6, 34.5, 40.3, 48.0, 55.2, 61.6, 106.7, 110.6,
126.6, 129.1, 137.2, 138.2, 141.9, 156.1, 158.2.
[0303] MS (%): 350 (parent+1, 100).
[0304] Anal. Calc'd for C.sub.23H.sub.31N.sub.32HCl{fraction
(3/2)}H.sub.2O: C, 61.46; H, 8.07; N, 9.35. Found: C, 61.78; H,
8.01; N, 9.12.
EXAMPLE 16
[0305]
6-[3-(2-(N-Phenethylamino)-cyclopentylmethyl)-phenyl]-pyridin-2-yla-
mine
[0306] Prepared as in Example 11, using phenethylamine, to afford a
85% yield of the less polar isomer after separation of isomers,
assigned the cis stereochemistry, as the hydrochloride salt, mp
170-185.degree. C.
[0307] .sup.1H-NMR (.delta., CDCl.sub.3): 1.52 (m, 6H), 1.75 (m,
2H), 2.20 (m, 1H), 2.36 (dd, J=10,13, 1H), 2.7-3.0 (m, 4H), 4.53
(broad s, 2H, NH.sub.2), 6.41 (d, J=8, 1H), 7.04 (d, J=8, 1H), 7.14
(m, 2H), 7.2-7.3 (m, 5H), 7.46 (t, J=8, 1H), 7.79 (m, 2H).
[0308] .sup.13C-NMR (.delta., CDCl.sub.3): 21.2, 28.9, 30.7, 34.2,
36.7, 44.6, 49.9, 61.7, 106.9, 110.8, 126.3, 126.8, 128.6, 128.9,
139.1, 137.3, 138.4, 140.4, 142.7, 156.3, 158.3.
[0309] MS (%): 372 (parent+1, 100).
[0310] Anal. Calc'd for C.sub.25H.sub.29N.sub.3.2HCl.{fraction
(5/3)}H.sub.2O: C, 63.29; H, 7.29; N, 8.86. Found: C, 63.31; H,
7.35; N, 8.66.
EXAMPLE 17
[0311]
6-[3-(2-(N-Phenethylamino)-cyclopentylmethyl)-phenyl]-pyridin-2-yla-
mine
[0312] Prepared as in Example 11, using phenethylamine, to afford a
85% yield of the more polar isomer after separation of isomers,
assigned the trans stereochemistry, as the hydrochloride salt, mp
110-130.degree. C.
[0313] .sup.1H-NMR (.delta., CDCl.sub.3): 1.29 (m, 2H), 1.40 (m,
1H), 1.59 (m, 2H), 1.75 (m, 1H), 1.93 (m, 2H), 2.51 (dd, J=8.5,13,
1H), 2.6-2.8 (m, 5H), 4.55 (broad s, 2H, NH.sub.2), 6.40 (d, J=8,
1H), 7.05 (d, J=8, 1H), 7.2-7.4 (m, 7H), 7.46 (t, J=8, 1H), 7.81
(m, 2H).
[0314] .sup.13C-NMR (.delta., CDCl.sub.3): 22.5, 30.8, 32.6, 36.4,
40.3, 47.6, 49.70, 64.5, 106.8, 110.6, 126.0, 126.6, 128.3, 128.6,
129.0, 137.25, 138.2, 140.0, 141.8, 156.0, 158.2.
[0315] MS (%): 372 (parent+1, 100).
[0316] Anal. Calc'd for C.sub.25H.sub.29N.sub.32HCl {fraction
(3/2)}H.sub.2O: C, 63.69; H, 7.27; N, 8.91. Found: C, 63.80; H,
7.41; N, 8.53.
EXAMPLE 18
[0317]
6-[3-(2-(4-Methylpiperazin-1-yl)-cyclohexylmethyl)-phenyl]-pyridin--
2-ylamine
[0318] Prepared as in Example 11, using N-methylpiperazine, to
afford a 96% yield of the product as a mixture of diastereomers as
the hydrochloride salt, mp 195-208.degree. C.
[0319] .sup.1H-NMR (.delta., CDCl.sub.3): 1.1-1.6 (m, 8H), 1.8-1.9
(m, 3H), 2.27 (s, 3H), 2.4-2.7 (m, 8H), 2.90 (m, 1H), 4.53 (broad
s, 2H, NH.sub.2), 6.40 (d, J=8, 1H), 7.02 (d, J=8, 1H), 7.18 (m,
2H), 7.45 (t, J=8, 1H), 7.79 (m, 2H).
[0320] .sup.13C-NMR (.delta., CDCl.sub.3): 13.8, 24.5, 25.7, 26.9,
30.5, 37.2, 45.9, 50.1, 55.5, 65.8, 106.7, 110.6, 126.6, 129.1,
137.0, 138.2, 143.1, 156.2, 158.1.
[0321] MS (%): 365 (parent+1, 100).
[0322] Anal. Calc'd for C.sub.23H.sub.32N.sub.4 3HCl {fraction
(5/2)}H.sub.2O 2/3(C.sub.4H.sub.10O): C, 57.26; H, 8.11; N, 10.41.
Found: C, 57.15; H, 7.81; N, 10.11.
EXAMPLE 19
[0323]
6-[3-(2-(N-benzylamino)-cyclohexylmethyl)-phenyl]-pyridin-2-ylamine
[0324] Prepared as in Example 11, using benzylamine, to afford a
72% yield of the product as a mixture of diastereomers as the
hydrochloride salt, mp 170-185.degree. C.
[0325] .sup.1H-NMR (.delta., CDCl.sub.3): 1.3-1.4 (m, 4H), 1.6-1.8
(m, 4H), 2.57 (dd, J=9,13, 2H), 2.73 (m, 1H), 2.84 (m, 1H), 3.77
(dd, J=9,38, 2H), 4.58 (broad s, 2H, NH.sub.2), 6.40 (d, J=8, 1H),
7.05 (d, J=8, 1H), 7.2-7.4 (m, 7H), 7.46 (t, J=8, 1H), 7.82 (m,
2H).
[0326] .sup.13C-NMR (.delta., CDCl.sub.3): 25.2, 25.6, 27.0, 28.6,
39.0, 50.8, 51.3, 56.1, 60.1, 106.7, 110.6, 126.5, 126.6, 128.1,
128.3, 129.5, 137.1, 138.3, 141.2, 141.9, 142.5, 156.2, 158.2.
[0327] MS (%): 372 (parent+1, 100).
[0328] Anal. Calc'd for C.sub.25H.sub.29N.sub.32HCl{fraction
(3/2)}H.sub.2O: C, 63.69; H, 7.27; N, 8.91. Found: C, 64.03; H,
7.25; N, 8.90.
EXAMPLE 20
[0329] 6-{4-[2-(2-Ethoxy-ethylamino)-cyclohexyl
methyl]-phenyl}-pyridin-2-- ylamine
[0330] Prepared as in Example 11, using 2-ethoxyethylamine, to
afford a 100% yield of the product as a mixture of diastereomers as
the hydrochloride salt, mp 70-90.degree. C.
[0331] .sup.1H-NMR (.delta., CDCl.sub.3): 1.21 (t, J=8, 3H),
1.2-1.7 (m, 8H), 2.5-2.9 (multiplets, 3H), 3.4-3.6 (m, 7H), 4.54
(broad s, 2H, NH.sub.2), 6.39 (d, J=8, 1H), 7.03 (d, J=7.5, 1H),
7.22 (m, 2H), 7.44 (t, J=8, 1H), 7.80 (m, 2H).
[0332] .sup.13C-NMR (.delta., CDCl.sub.3): 15.2, 26.9, 28.7, 30.4,
32.2, 46.2, 46.8, 57.0, 60.5, 66.25, 70.1, 106.7, 110.6, 126.5,
129.3, 167.0, 138.2, 141.6, 142.4, 156.2, 158.2.
[0333] MS (%): 354 (parent+1, 100).
[0334] Anal. Calc'd for C.sub.22H.sub.31N.sub.3O.sub.2HCl9H.sub.2O:
C, 44.90; H, 8.73; N, 7.14. Found: C, 44.69; H, 8.82; N, 6.82.
EXAMPLE 21
[0335]
6-[4-(2-(4-Benzylpiperazin-1-yl)-cyclohexylmethyl)-phenyl]-pyridin--
2-ylamine
[0336] Prepared as in Example 11, using N-benzylpiperazine, to
afford a 67% yield of the product as a mixture of diastereomers as
the hydrochloride salt, mp 205-21 5.degree. C.
[0337] .sup.1H-NMR (.delta., CDCl.sub.3): 1.0-1.8 (m, 8H), 1.8-1.9
(m, 3H), 2.4-2.6 (m, 8H), 2.92 (m, 1H), 3.51 (singlets, 2H), 4.53
(bs, 2H, NH.sub.2), 6.40 (d, J=8, 1H), 7.03 (d, J=7, 1H), 7.1-7.3
(m, 7H), 7.45 (t, J=7.5, 1H), 7.79 (m, 2H).
[0338] .sup.13C-NMR (.delta., CDCl.sub.3): 19.8, 24.5, 25.7, 26.9,
30.5, 37.2, 50.1, 53.0, 53.5, 63.1, 65.9, 106.7, 110.6, 126.6,
126.9, 128.1, 129.1, 129.2, 137.0, 138.0, 138.2, 143.1, 156.2,
158.1.
[0339] MS (%): 441 (parent+1, 100).
[0340] Anal. Calc'd for C.sub.29H.sub.36N.sub.43HCl {fraction
(3/2)}H.sub.2O: C, 60.36; H, 7.34; N, 9.71. Found: C, 60.53; H,
7.35; N, 8.97.
EXAMPLE 22
[0341]
6-[4-(2-(4-(N-Isopropylacetamido)piperazin-1-yl)-cyclohexylmethyl)--
phenyl]-pyridin-2-ylamine
[0342] Prepared as in Example 11, using
N-(N-isopropylacetamido)piperazine- , to afford a 94% yield of the
product as a mixture of diastereomers as the hydrochloride salt, mp
180-200.degree. C. (dec.).
[0343] .sup.1H-NMR (.delta., CDCl.sub.3): 1.147 and 1.148
(doublets, J=6, 6H), 1.2-1.8 (m, 11H), 2.6 (broad m, 8H), 2.95 (s,
2H), 4.088 and 4.092 (heptets, J=6, 1H), 4.53 (broad s, 2H,
NH.sub.2), 6.40 (d, J=8, 1H), 7.02 (d, J=8, 1H), 7.17 (m, 2H), 7.45
(t, J=8, 1H), 7.79 (m, 2H).
[0344] .sup.13C-NMR (.delta., CDCl.sub.3): 22.75, 24.5, 25.7, 26.1,
30.6, 60.5, 50.2, 53.8, 61.5, 65.8, 106.7, 110.6, 126.6, 129.1,
137.0, 138.2, 143.0, 156.1, 158.2, 169.2.
[0345] MS (%): 450 (parent+1, 100).
[0346] Anal. Calc'd for C.sub.27H.sub.39N.sub.5O.sub.3HCl
1/2H.sub.2O (C.sub.4H.sub.10O): C, 57.98; H, 8.32; N, 10.91. Found:
C, 57.77; H, 7.90; N, 10.85.
EXAMPLE 23
[0347]
6-[4-((2-(Phenethyl)-[2.2.1]bicyclohept-1-yl)methyl)-phenyl]-pyridi-
n-2-ylamine
[0348] Prepared as in Example 11, using N-phenethylamine, to afford
a 73% yield of the product assigned the trans stereochemistry, mp
195-204.degree. C. (dec.).
[0349] .sup.1H-NMR (.delta., CDCl.sub.3): 1.2-1.4 (m, 4H), 1.58 (m,
2H), 1.94 (broad s, 1H), 2.27 (m, 1H), 2.33 (broad s, 1H), 2.4904
(dd, J=10,14, 2H), 2.7-2.8 (m, 4H), 3.10 (dd, J=4,11, 1H, assigned
trans stereochemistry), 4.54 (bs, 2H, NH.sub.2), 6.41 (d, J=8, 1H),
7.04 (d, J=7, 1H), 7.2-7.3 (m, 5H), 7.27 (m, 2H), 7.46 (t, J=8,
1H), 7.79 (m, 2H).
[0350] .sup.13C-NMR (.delta., CDCl.sub.3): 20.3, 22.4, 31.7, 36.6,
37.3, 39.9, 40.7, 43.3, 50.1, 59.3, 106.8, 110.7, 126.1, 126.7,
128.4, 128.7, 128.9, 137.1, 138.3, 140.4, 142.8, 156.2, 158.2.
[0351] MS (%): 398 (parent+1, 100).
[0352] Anal. Calc'd for C.sub.27H.sub.31N.sub.32HCl H.sub.2O: C,
66.39; H, 7.22; N, 8.60. Found: C, 66.00; H, 7.22; N, 8.60.
EXAMPLE 24
[0353]
6-[4-((2-(3-aza-bicyclo[3.1.0]hex-6-ylamino)-[2.2.1]bicyclohept-1-y-
l)methyl)-phenyl]-pyridin-2-ylamine
[0354] Prepared as in Example 11, using
3-aza-bicyclo[3.1.0]hex-6-ylamine, to afford a 78% yield of the
product as a mixture of diastereomers as the hydrochloride salt, mp
248-260.degree. C. (dec.).
[0355] .sup.1H-NMR (.delta., CDCl.sub.3): 1.04 (broad d, J=9, 2H),
1.29 (m, 4H), 1.53 (m, 2H), 1.59 (broad s, 1H), 1.89 (broad s, 1H),
2.12 (m, 1H), 2.21 (ddd, J=3,14, 24, 2H), 2.48 (broad s, 1H), 2.78
(dd, J=4,13, 1H assigned trans stereochemistry), 3.02 (m, 4H), 4.55
(broad s, 2H, NH.sub.2), 6.39 (d, J=8,1H), 7.02 (d, J=7.5, 1H),
7.19 (m, 2H), 7.44 (t, J=8, 1H), 7.79 (m, 2H).
[0356] .sup.13C-NMR (.delta., CDCl.sub.3): 22.4, 25.5, 25.6, 27.35,
32.5, 36.3, 36.8, 38.3, 41.3, 49.5, 52.6, 53.6, 106.8, 110.6,
126.7, 128.9, 137.1, 138.3, 142.5, 156.2, 158.3.
[0357] MS (%): 375 (parent+1, 100).
[0358] Anal. Calc'd for C.sub.24H.sub.30N.sub.43HCl 1/2H.sub.2O
{fraction (1/2)}(C.sub.4H.sub.10O): C, 58.92; H, 7.42; N, 10.57.
Found: C, 59.02; H, 7.50; N, 10.64.
EXAMPLE 25
[0359]
6-[2-(N-Phenethylamino)-5-phenyl-cyclohexylmethyl)methyl)-phenyl]-p-
yridin-2-ylamine
[0360] Prepared as in Example 11, using N-phenethylamine, to afford
a 77.5% yield of the product as a mixture of diastereomers as the
hydrochloride salt, mp 178-192.degree. C. (dec.).
[0361] .sup.1H-NMR (.delta., CDCl.sub.3): 1.2-1.5 (m, 6H), 2.2-2.5
(m, 3H), 2.84 (m, 4H), 3.03 (m, 1H), 3.13 (m, 1H), 4.49 (broad s,
2H, NH.sub.2), 6.41 (d, J=8, 1H), 7.02 (d, J=7.5 (1H), 7.2-7.4 (m,
12H), 7.46 (t, J=8, 1H), 7.74 (m, 2H).
[0362] .sup.13C-NMR (.delta., CDCl.sub.3): 32.6, 33.0, 36.7, 338.7,
38.8, 43.8, 44.7, 48.1, 60.4, 106.8, 110.8, 125.9, 126.3, 126.6,
126.8, 128.3, 128.5, 128.8, 129.6, 137.3, 138.3, 140.1, 141.0,
146.8, 156.2, 158.2.
[0363] MS (%): 462 (parent+1, 100).
[0364] Anal. Calc'd for C.sub.32H.sub.35N.sub.32HCl
1/2CH.sub.2Cl.sub.2(C.sub.4H.sub.10O): C, 66.41; H, 7.48; N, 6.37.
Found: C, 66.42; H, 7.29; N, 6.17.
EXAMPLE 26
[0365]
6-[4-((2-(Phenethylamino)-[2.2.1]bicyclohept-1-yl)methyl)-phenyl]-p-
yridin-2-ylamine
[0366] Prepared as in Example 11, using N-phenethylamine, to afford
a 96% yield of the product assigned the cis stereochemistry, mp
170-180.degree. C. (dec.).
[0367] .sup.1H-NMR (.delta., CDCl.sub.3): 1.08 (m, 1H), 1.15 (m,
1H), 1.2-1.4 (m, 4H), 1.57 (m, 2H), 1.68 (m, 1H), 2.0-2.2 (m, 2H),
2.61 (m, 1H), 2.69 (m, 4H), 2.77 (m, 1H), 4.50 (broad s, 2H,
NH.sub.2), 6.42 (d, J=8, 1H), 7.05 (d, J=8, 1H), 7.12 (m, 2H), 7.22
(m, 5H), 7.47 (t, J=8, 1H), 7.81 (m 2H).
[0368] .sup.13C-NMR (.delta., CDCl.sub.3): 22.1, 27.4, 36.4, 36.6,
37.1, 39.0, 41.7, 49.7, 52.5, 68.5, 106.8, 110.7, 126.0, 126.7,
128.4, 128.6, 128.9, 137.3, 138.3, 140.1, 142.3, 156.1, 158.2.
[0369] MS (%): 398 (parent+1, 100).
[0370] Anal. Calc'd for C.sub.27H.sub.31N.sub.32HCl H.sub.2O
{fraction (1/2)}(C.sub.4H.sub.10O): C, 66.28; H, 7.67; N, 8.00.
Found: C, 66.57; H, 7.41; N, 7.64.
EXAMPLE 27
[0371]
6-[((2-(3-aza-bicyclo[3.1.0]hex-6-ylamino)-5-phenyl-cyclohexylmethy-
l)methyl)-phenyl]-pyridin-2-ylamine
[0372] Prepared as in Example 11, using
3-aza-bicyclo[3.1.0]hex-6-ylamino, to afford a 56% yield of the
product as a mixture of diastereomers as the hydrochloride salt, mp
200-220.degree. C. (dec.).
[0373] .sup.1H-NMR (.delta., CDCl.sub.3): 1.2-3.2 (multiplets for
18H), 4.53 and 4.58 (broad singlets, 2H, NH.sub.2), 6.40 and 6.44
(doublets, J=8, 1H), 7.02 and 7.05 (doublets, J=7.5, 1H), 7.16 (m,
2H), 7.25 (m, 5H), 7.40 and 7.45 (triplets, J=8, 1H), 7.89 and 7.87
(multiplets, 2H).
[0374] .sup.13C-NMR (.delta., CDCl.sub.3): 25.3, 26.1, 30.9, 32.9,
34.6, 37.1, 39.9, 53.0, 64.9, 66.5, 106.8, 107.2, 110.8, 110.9,
125.9, 126.8, 127.0, 127.1, 128.3, 129.2, 138.4, 138.5, 156.2,
158.2.
[0375] MS (%): 439 (parent+1, 100).
EXAMPLE 28
[0376] N-Methyl-(2-aminopyrid-6-yl-benzylidene)-oxindole
[0377] Prepared as in Example 11, using N-methyloxindole, to afford
a 100% yield of the product as a mixture of diastereomers as the
hydrochloride salt, mp 170-175.degree. C. (dec.).
[0378] .sup.1H-NMR (.delta., CDCl.sub.3): 3.26 (s, 3H), 4.60 (broad
s, 2H, NH.sub.2), 6.47 (d, J=8, 1H), 6.80 (d, J=8, 1H), 6.86 (t,
J=8, 1H), 7.12 (d, J=8, 1H), 7.24 (m, 1H), 7.50 (t, J=8, 1H), 7.70
(m, 2H), 7.85 (s, 1H), 8.02 (m, 2H).
[0379] .sup.13C-NMR (.delta., CDCl.sub.3): 26.1, 107.7, 108.1,
110.9, 121.1, 121.7, 122.8 126.8, 127.1, 129.7, 132.3, 135.0,
136.7, 138.4, 140.6, 144.1, 154.9, 158.3, 168.45.
[0380] MS (%): 328 (parent+1, 100).
[0381] Anal. Calc'd for C.sub.2,H.sub.17N.sub.3O 1/4H.sub.2O: C,
76.00; H, 5.31; N, 12.66. Found: C, 75.93; H, 5.30; N, 11.87.
EXAMPLE 29
[0382] N-Methyl-(2-aminopyrid-6-yl-benzyl)-oxindole
[0383] Prepared by reduction of Example 28, to afford a 60% yield
of the product as a mixture of diastereomers as the hydrochloride
salt, mp 45-55.degree. C. (dec.).
[0384] .sup.1H-NMR (.delta., CDCl.sub.3): 2.91 (dd, J=10,14, 1H),
3.14 (s, 3H), 3.52 (dd, J=4,14, 1H), 3.73 (m, 1H), 4.53 (broad s,
2H, NH.sub.2), 6.42 (d, J=8, 1H), 6.725 (d, J=8, 1H), 6.80 (m 1H),
6.88 (t, J=7.5, 1H), 7.05 (d, J=8, 1H), 7.21 (m, 3H), 7.46 (t,
J=7.5, 1H), 7.81 (m, 2H).
[0385] .sup.13C-NMR (.delta., CDCl.sub.3): 26.1, 36.5, 47.0, 107.0,
107.9, 110.7, 122.1, 124.6, 126.7, 127.9, 129.6, 138.0, 138.3,
138.5, 144.2, 155.7, 158.3, 177.0.
[0386] MS (%): 330 (parent+1, 100).
EXAMPLE 30
[0387]
N-(2-Dimethylaminoethyl)-(2-aminopyrid-6-yl-benzylidene)-oxindole
[0388] Prepared as in Example 28, using
N-(2-dimethylaminoethyl)oxindole, to afford a 91% yield of the
product as a mixture of diastereomers as the hydrochloride salt, mp
165-190.degree. C. (dec.).
[0389] .sup.1H-NMR (.delta., CDCl.sub.3): 2.33 (s, 6H), 2.59 (t,
J=7, 2H), 3.90 (t, J=7, 2H), 4.55 (broad s, 2H, NH.sub.2), 6.48 (d,
J=8, 1H), 6.85 (m, 2H), 7.14 (d, J=7.5, 1H), 7.24 (m, 2H), 7.51 (t,
J=8, 1H), 7.71 (m, 2H), 7.85 (s, 1H), 8.02 (m, 2H).
[0390] .sup.13C-NMR (.delta., CDCl.sub.3): 37.6, 45.1, 55.6, 107.0,
107.7, 110.4, 121.1, 122.4, 125.9, 126.2, 129.1, 131.7, 136.3,
137.8, 157.6. Not all carbons were visible in this scan due to
limited compound solubility.
[0391] MS (%): 385 (parent+1, 100).
[0392] Anal. Calc'd for C.sub.24H.sub.24N.sub.4O.sub.2HCl H.sub.2O:
C, 60.63; H, 5.94; N, 11.78. Found: C, 60.61; H, 6.13; N,
10.12.
EXAMPLE 31
[0393]
N-(2-Dimethylaminoethyl)-(2-aminopyrid-6-yl-benzyl)-oxindole
[0394] Prepared by reduction of Example 30 using
palladium-catalyzed ammonium formate, to afford a 97% yield of the
product as a mixture of diastereomers as the hydrochloride salt, mp
120-135.degree. C. (dec.).
[0395] .sup.1H-NMR (.delta., CDCl.sub.3): 2.25 (s, 6H), 2.39 9m,
2H), 2.95 (dd, J=9,14, 1H), 3.48 (dd, J=4,14, 1H), 3.7-3.9 (m, 3H),
4.47 (broad s, 2H, NH.sub.2), 6.42 (d, J=8, 1H), 7.76 (d, J=8, 1H),
6.84 (m, 1H), 6.89 (t, J=7, 1H), 7.05 (d, J=7.5, 1H), 7.18 (m, 2H),
7.25 (m, 1H), 7.46 (t, J=8, 1H), 7.79 (m, 2H).
[0396] .sup.13C-NMR (.delta., CDCl.sub.3): 36.5, 38.2, 45.6, 46.9,
55.9, 107.0, 108.1, 110.7, 122.0, 124.7, 126.6, 127.9, 128.4,
129.7, 130.9, 138.0, 138.3, 143.5, 155.8, 158.2, 176.8.
[0397] MS (%): 387 (parent+1, 100).
EXAMPLE 32
[0398]
6-[(N-5-Isoxazolylmethyl)-4-(piperidin-4-yl)-phenyl]-pyridin-2-ylam-
ine
[0399] Prepared from Example 13, using 5-bromomethylisoxazole to
alkylate 6-[4-(piperidin-4-yl)-phenyl]-pyridin-2-ylamine, in ethyl
acetate, in 90%, mp 122-127.degree. C.
[0400] .sup.1H-NMR (.delta., CDCl.sub.3): 1.81 (m, 4H), 2.18 (m,
2H), 2.485 (m, 1H), 3.00 (m, 2H), 3.735 (s, 2H), 4.57 (broad s, 2H,
NH.sub.2), 6.17 (d, J=1.5, 1H), 6.38 (d, J=8, 1H), 7.01 (d, J=8,
1H), 7.24 (m, 2H), 7.43 (t, J=8, 1H), 7.81 (m, 2H), 8.18 (d, J=1.7,
1H).
[0401] .sup.13C-NMR (.delta., CDCl.sub.3): 33.2, 41.8, 53.4, 53.9,
102.4, 106.8, 110.6, 126.8, 126.9, 137.7, 138.2, 146.4, 150.1,
155.9, 158.2, 168.9.
[0402] MS (%): 335 (parent+1, 100).
[0403] Anal. Calc'd for C.sub.20H.sub.22N.sub.4O
1/4(C.sub.4H.sub.8O.sub.2- ): C, 70.76; H, 6.79; N, 15.72. Found:
C, 70.83; H, 6.62; N, 15.73.
EXAMPLE 33
[0404]
6-[(N-Acetamido)-4-(piperidin-4-yl)-phenyl]-pyridin-2-ylamine
[0405] Prepared from Example 13, using iodoacetamide to alkylate
6-[4-(piperidin-4-yl)-phenyl]-pyridin-2-ylamine, in 55%, mp
224-227.degree. C.
[0406] .sup.1H-NMR (.delta., DMSO-d.sub.6): 1.76 (m, 2H), 2.17 (m,
1H), 2.51 (m, 2H), 2.88 (s, 2H), 2.91 (m, 4H), 5.94 (d, J=4.5, 1H),
6.39 (d, J=8, 1H), 7.01 (d, J=7, 1H), 7.19 (m, 1H), 7.30 (m, 2H),
7.44 (t, J=8, 1H), 7.90 (m, 2H).
[0407] .sup.13C-NMR (.delta., DMSO-d.sub.6): 33.0, 41.1, 54.0,
61.7, 106.7, 108.0, 126.3, 126.8, 137.3, 137.9, 146.5, 154.3,
159.4, 172.0.
[0408] MS (%): 311 (parent+1, 100).
[0409] Anal. Calc'd for C.sub.18H.sub.22N.sub.4O 1/2H.sub.2O: C,
67.69; H, 7.26; N, 17.54. Found: C, 67.96; H, 7.03; N, 17.37.
EXAMPLE 34
[0410]
6-[(N-Benzoylmethyl)-4-(piperidin-4-yl)-phenyl]-pyridin-2-ylamine
[0411] Prepared from Example 13, using phenacyl bromide to alkylate
6-[4-(piperidin-4-yl)-phenyl]-pyridin-2-ylamine, in 75%, mp
180-200.degree. C. as the hydrochloride salt.
[0412] .sup.1H-NMR (.delta., CDCl.sub.3): 1.8-2.0 (m, 4H), 2.27 (m,
2H), 2.55 (m, 1H), 3.12 (m, 2H), 3.85 (s, 2H), 4.57 (broad s, 2H,
NH.sub.2), 6.40 (d, J=8, 1H), 7.03 (d, J=7.5, 1H), 7.28 (m, 2H),
7.45 (m, 3H), 7.55 (t, J=7.5, 1H), 7.83 (m, 2H), 8.01 (m, 2H).
[0413] .sup.13C-NMR (.delta., CDCl.sub.3): 33.2, 42.0, 54.6, 64.8,
106.8, 110.6, 126.8, 127.0, 128.1, 128.5, 133.1, 136.1, 137.6,
138.3, 146.7, 155.9, 158.1, 196.7.
[0414] MS (%): 372 (parent+1, 100).
[0415] Anal. Calc'd for C.sub.24H.sub.25N.sub.3O.sub.2HCl
3/4H.sub.2O: C, 62.95; H, 6.27; N, 9.18. Found: C, 63.13; H, 6.38;
N, 9.07.
EXAMPLE 35
[0416]
6-[(N-(3,4-Dimethoxybenzyl))-4-(piperidin-4-yl)-phenyl]-pyridin-2-y-
lamine
[0417] Prepared from Example 13, using 3,4-dimethoxybenzyl bromide
to alkylate 6-[4-(piperidin-4-yl)-phenyl]-pyridin-2-ylamine, in
89%, mp 150-165.degree. C. as the hydrochloride salt.
[0418] .sup.1H-NMR (.delta., CDCl.sub.3): 1.85 (m, 4H), 2.18 (m,
2H), 2.54 (m, 1H), 3.06 (m, 2H), 3.56 (s, 2H), 3.86 (s, 3H), 3.89
(s, 3H), 4.6 (broad s, 2H), 6.40 (d, J=8, 1H), 6.82 (m, 2H), 6.95
(m, 1H), 7.02 (d, J=7.5, 1H), 7.27 (m, 2H), 7.45 (t, J=8, 1H), 7.82
(m, 2H).
[0419] .sup.13C-NMR (.delta., CDCl.sub.3): 32.9, 42.2, 53.8, 55.91,
55.935, 60.4, 62.8, 106.9, 1110.7, 110.8, 112.6, 121.7, 126.9,
127.1, 137.7, 138.3, 146.6, 148.3, 156.1, 158.3.
[0420] MS (%): 404 (parent+1, 100).
[0421] Anal. Calc'd for C.sub.25H.sub.29N.sub.3O.sub.22HCl
{fraction (7/4)}H.sub.2O: C, 59.11; H, 6.85; N, 8.27. Found: C,
59.19; H, 6.92; N, 8.21.
EXAMPLE 36
[0422]
6-[(N-(3,4-Methylenedioxybenzyl))-4-(piperidin-4-yl)-phenyl]-pyridi-
n-2-ylamine:
[0423] Prepared from Example 13, using 3,4-methylenedioxybenzyl
bromide to alkylate
6-[4-(piperidin-4-yl)-phenyl]-pyridin-2-ylamine, in 82%, mp
150-165.degree. C. as the hydrochloride salt.
[0424] .sup.1H-NMR (.delta., CDCl.sub.3): 1.87 (m, 4H), 2.11 (m,
2H), 2.53 (m, 1H), 3.05 (m, 2H), 3.51 (s, 2H), 5.94 (s, 2H), 6.41
(d, J=8, 1H), 6.76 (m, 2H), 6.89 (s, 1H), 7.02 (d, J=7.5, 1H), 7.27
(m, 2H), 7.46 (t, J=8, 1H), 7.83 (m, 2H).
[0425] .sup.13C-NMR (.delta., CDCl.sub.3):33.0, 42.2, 53.8, 62.8,
100.9, 106.9, 107.9, 109.8, 110.7, 122.6, 126.9, 127.1, 131.4,
137.7, 138.4, 146.7, 147.6, 156.1, 158.3.
[0426] MS (%): 388 (parent+1, 100).
[0427] Anal. Calc'd for C.sub.24H.sub.25N.sub.3O.sub.2{fraction
(3/2)}H.sub.2O.sub.2HCl: C, 59.14; H, 6.20; N, 8.62. Found: C,
59.22; H, 6.32; N, 8.53.
EXAMPLE 37
[0428]
6-[(N-(2-Furyl)methyl)-4-(piperidin-4-yl)-phenyl]-pyridin-2-ylamine
[0429] Prepared from Example 13, using furfuryl bromide to alkylate
6-[4-(piperidin-4-yl)-phenyl]-pyridin-2-ylamine, in 100%, mp
75-95.degree. C. as the hydrochloride salt.
[0430] .sup.1H-NMR (.delta., CDCl.sub.3): 1.8-1.9 (m, 4H), 2.11 (m,
2H), 2.49 (m, 1H), 3.02 (m, 2H), 3.56 (s, 2H), 4.6 (broad s, 2H,
NH.sub.2), 6.21 (m, 1H), 6.30 (m, 1H), 6.38 (d, J=8, 1H), 7.00 (d,
J=7.5, 1H), 7.25 (m, 2H), 7.37 (m, 1H), 7.43 (t, J=7.5, 1H), 7.80
(m, 2H).
[0431] .sup.13C-NMR (.delta., CDCl.sub.3): 33.1, 42.1, 53.8, 55.0,
136.8 128.8, 110.0, 110.6 126.8, 127.0, 137.6, 138.2, 142.1, 146.7,
151.6, 156.0, 158.2.
[0432] MS (%): 334 (parent+1, 100).
[0433] Anal. Calc'd for C.sub.21H.sub.23N.sub.3O 2HCl 3/4H.sub.2O:
C, 57.60; H, 6.56; N, 9.60. Found: C, 57.66; H, 6.69; N, 9.47.
EXAMPLE 38
[0434]
N-[4'-(6-Amino-pyridin-2-yl)-biphenyl-4-ylmethyl]-5,6-dimethoxy-1,2-
,3,4-tetrahydroisoquinoline
[0435] Prepared as in Example 2, using
5,6-dimethoxy-1,2,3,4-tetrahydroiso- quinoline for the reductive
amination step, with a 88% yield for the final deblocking, mp
205-209.degree. C.:
[0436] .sup.1H-NMR (.delta., CDCl.sub.3): 2.72 (m, 2H), 2.77 (m,
2H), 3.52 (s, 2H), 3.66 (s, 2H), 3.72 (s, 3H), 3.75 (s, 3H), 3.8
(broad s, 2H), 6.39 (d, J=8, 1H), 6.43 (s, 1H), 6.53 (s, 1H), 6.98
(d, J=7.5, 1H), 7.3-7.4 (m, 3H), 7.5-7.7 (m, 4H), 7.85 (m, 2H).
[0437] .sup.13C-NMR (.delta., CDCl.sub.3: 28.2, 50.6, 55.4, 55.8,
62.2, 107.5, 139.5, 110.9, 111.4, 125.9, 126.1, 126.9, 127.0,
127.3, 129.9, 136.7, 138.5, 138.6, 140.9, 147.2, 147.5, 155.5,
158.6.
[0438] MS (%): 452 (parent+1, 100).
[0439] Anal. Calc'd for C.sub.29H.sub.29N.sub.3O.sub.2 1/2H.sub.2O:
C, 75.63; H, 6.57; N, 9.12. Found: C, 75.75; H, 6.37; N, 9.20.
EXAMPLE 39
[0440]
6-[(N-(5-Isothiazolyl)methyl)-4-(piperidin-4-yl)-phenyl]-pyridin-2--
ylamine
[0441] Prepared from Example 13, using 5-isothiazolyl bromide to
alkylate 6-[4-(piperidin-4-yl)-phenyl]-pyridin-2-ylamine, in 95%,
mp 140-145.degree. C.
[0442] .sup.1H-NMR (.delta., CDCl.sub.3): 1.795 (m, 4H), 2.16 (m,
2H), 2.49 (m, 1H), 3.02 (m, 4H), 3.835 (s, 2H), 6.385 (d, J=8, 1H),
6.96 (d, J=7.5, 1H), 7.06 (s, 1H), 7.24 (m, 2H), 7.42 (t, J=8, 1H),
7.75 (m, 2H), 8.35 (s, 1H).
[0443] .sup.13C-NMR (.delta., CDCl.sub.3): 33.1, 41.9, 54.1, 55.4,
107.1, 110.75, 122.2, 126.9, 127.0, 1337.6, 138.4, 146.5, 155.9,
157.4, 158.3, 166.6.
[0444] MS (%): 351 (parent+1, 100).
[0445] Anal. Calc'd for C.sub.20H.sub.22N.sub.4S 1/2H.sub.2O: C,
66.82; H, 6.45; N, 15.58. Found: C, 67.08; H, 6.51; N, 15.23.
EXAMPLE 40
[0446]
6-[(N-(5-Thiazolyl)methyl)-4-(piperidin-4-yl)-phenyl]-pyridin-2-yla-
mine
[0447] Prepared from Example 13, using 5-thiazolyl bromide to
alkylate 6-[4-(piperidin-4-yl)-phenyl]-pyridin-2-ylamine, in 99%,
mp 151-154.degree. C.
[0448] .sup.1H-NMR (.delta., CDCl.sub.3): 1.81 (m, 4H), 2.145 (m,
2H), 2.50 (m, 1H), 3.00 (m, 2H), 3.77 (s, 2H), 4.57 (broad s, 2H,
NH.sub.2), 6.39 (d, J=8, 1H), 7.01 (d, J=7, 1H), 7.25 (m, 2H), 7.44
(t, J=8, 1H), 7.70 (s, 1H), 7.81 (m, 2H), 8.74 (s, 1H).
[0449] .sup.13C-NMR (.delta., CDCl.sub.3): 33.2, 42.1, 53.8, 54.3,
106.8, 110.6, 126.8, 127.0, 136.4, 137.6, 138.3, 141.7, 146.6,
153.3, 156.0, 158.2.
[0450] MS (%): 351 (parent+1, 100).
[0451] Anal. Calc'd for C.sub.20H.sub.22N.sub.4S: C, 68.54; H,
6.33; N, 15.99. Found: C, 68.21; H, 6.49; N, 15.63.
EXAMPLE 41
[0452]
6-[(N-(2-Pyridyl)methyl)-4-(piperidin-4-yl)-phenyl]-pyridin-2-ylami-
ne
[0453] Prepared from Example 13, using 2-pyridyl bromide to
alkylate 6-[4-(piperidin-4-yl)-phenyl]-pyridin-2-ylamine, in 97%,
mp 180-190.degree. C. as the hydrochloride salt.
[0454] .sup.1H-NMR (.delta., CDCl.sub.3): 1.82 (m, 4H), 2.19 (m,
2H), 2.53 (m, 1H), 3.02 (m, 2H), 3.69 (s, 2H), 4.54 (broad s, 2H,
NH.sub.2), 6.38 (d, J=8, 1H), 7.02 (d, J=7.5, 1H), 7.14 (m, 1H),
7.26 (m, 2H), 7.43 (m, 2H), 7.64 (t, J=8, 1H), 7.81 (m, 2H), 8.55
(m, 1H).
[0455] .sup.13C-NMR (.delta., CDCl.sub.3): 33.2, 42.2, 54.4, 64.9,
106.8, 110.6, 121.9, 123.2, 126.8, 127.0, 136.3, 137.6, 138.2,
146.8, 149.1, 156.0, 158.2, 158.7.
[0456] MS (%): 345 (parent+1, 100).
[0457] Anal. Calc'd for C.sub.22H.sub.24N.sub.42HCl {fraction
(7/4)}H.sub.2O: C, 58.86; H, 6.62; N, 12.48. Found: C, 58.99; H,
6.66; N, 12.24.
EXAMPLE 42
[0458]
6-[(N-(3-Pyridyl)methyl)-4-(piperidin-4-yl)-phenyl]-pyridin-2-ylami-
ne
[0459] Prepared from Example 13, using 3-pyridyl bromide to
alkylate 6-[4-(piperidin-4-yl)-phenyl]-pyridin-2-ylamine, in 86%,
mp 202-215.degree. C. as the hydrochloride salt.
[0460] .sup.1H-NMR (.delta., CDCl.sub.3): 1.81 (m, 4H), 2.10 (m,
2H), 2.51 (m, 1H), 2.96 (m, 2H), 3.53 (s, 2H), 4.625 (broad s, 2H,
NH.sub.2), 6.38 (d, J=8, 1H), 7.01 (d, J=7.5, 1H), 7.24 (m, 3H),
7.43 (t, J=8, 1H), 7.69 (m, 1H), 7.82 (m, 2H), 8.49 (m, 1H), 8.54
(m, 1H).
[0461] .sup.13C-NMR (.delta., CDCl.sub.3): 33.1, 42.1, 54.1, 60.4,
106.8, 110.6, 123.3, 126.8, 127.0, 133.7, 136.8, 137.6, 138.3,
146.6, 148.4, 150.3, 155.9, 158.2.
[0462] MS (%): 345 (parent+1, 100).
[0463] Anal. Calc'd for C.sub.22H.sub.24N.sub.43HCl {fraction
(3/2)}H.sub.2O: C, 54.95; H, 6.29; N, 11.65. Found: C, 54.93; H,
6.51; N, 11.31.
EXAMPLE 43
[0464]
6-[(N-(2-Imidazolyl)methyl)-4-(piperidin-4-yl)-phenyl]-pyridin-2-yl-
amine
[0465] Prepared from Example 13, using 2-imidazolyl aldehyde to
reductively aminate
6-[4-(piperidin-4-yl)-phenyl]-pyridin-2-ylamine, in 88%, mp
160-163.degree. C.
[0466] .sup.1H-NMR (.delta., CDCl.sub.3): 1.81 (m, 4H), 2.28 (m,
2H), 2.54 (m, 1H), 3.00 (m, 2H), 3.75 (broad s, 2H), 6.395 (d, J=8,
1H), 6.94 (m, 1H), 7.00 (d, J=7.5, 1H), 7.20 (m, 2H), 7.43 (t, J=8,
1H), 7.79 (m, 2H).
[0467] .sup.13C-NMR (.delta., CDCl.sub.3):32.6, 41.6, 54.0, 55.7,
107.0, 110.7, 127.0, 137.9, 138.4, 146.0, 155.9, 158.3.
[0468] MS (%): 334 (parent+1, 100).
[0469] Anal. Calc'd for C.sub.20H.sub.23N.sub.5 1/2H.sub.2CO.sub.3:
C, 67.56; H, 6.64; N, 19.22. Found: C, 67.48; H, 6.89; N,
18.91.
EXAMPLE 44
[0470]
6-[(N-(4-Imidazolyl)methyl)-4-(piperidin-4-yl)-phenyl]-pyridin-2-yl-
amine
[0471] Prepared from Example 13, using 4-imidazolyl aldehyde to
reductively aminate
6-[4-(piperidin-4-yl)-phenyl]-pyridin-2-ylamine, in 92%,
mp>210.degree. C. (dec.) as the hydrochloride salt.
[0472] .sup.1H-NMR (.delta., CDCl.sub.3): 1.74 (m, 4H), 2.07 (m,
2H), 2.5 (m, 1H), 2.97 (m, 2H), 3.47 (s, 2H), 5.94 (broad s, 2H,
NH.sub.2), 6.39 (d, J=8, 1H), 6.90 (broad s, 1H), 7.00 (d, J=7.4,
1H), 7.27 (m, 2H), 7.42 (t, J=8, 1H), 7.56 (m, 1H), 7.88 (m,
2H).
[0473] .sup.13C-NMR (.delta., CDCl.sub.3): 32.8, 41.4, 53.3, 54.1,
106.7, 108.0, 126.3, 126.7, 137.3, 137.9, 146.5, 154.3, 159.5.
[0474] MS (%): 334 (parent+1, 100).
[0475] Anal. Calc'd for C.sub.20H.sub.23N.sub.5.1/2H.sub.2CO.sub.3:
C, 67.56; H, 6.64; N, 19.22. Found: C, 67.99; H, 6.72; N,
19.07.
EXAMPLE 45
[0476]
6-[(N-(4-Pyridyl)methyl)-4-(piperidin-4-yl)-phenyl]-pyridin-2-ylami-
ne
[0477] Prepared from Example 13, using 4-pyridine carboxaldehyde to
reductively aminate
6-[4-(piperidin-4-yl)-phenyl]-pyridin-2-ylamine, in 74%, mp
158-163.degree. C. as the hydrochloride salt.
[0478] .sup.1H-NMR (.delta., CDCl.sub.3): 1.81 (m, 4H), 2.10 (m,
2H), 2.52 (m, 1H), 2.94 (m, 2H), 3.51 (s, 2H), 4.57 (broad s, 2H,
NH.sub.2), 6.39 (d, J=8, 1H), 7.02 (d, J=7, 1H), 7.28 (m, 4H), 7.43
(t, J=8, 1H), 7.83 (m, 2H), 8.52 (m, 2H).
[0479] .sup.13C-NMR (.delta., CDCl.sub.3): 33.4, 42.2, 54.4, 62.1,
106.9, 110.7, 123.9, 126.9, 127.1, 137.7, 138.3, 146.7, 148.1,
149.7, 156.0, 158.3.
[0480] MS (%): 345 (parent+1, 100).
[0481] Anal. Calc'd for C.sub.22H.sub.24N.sub.4 {fraction
(5/4)}H.sub.2O: C, 72.00; H, 7.28; N, 15.27. Found: C, 72.23; H,
6.97; N, 15.47.
EXAMPLE 46
[0482] 6-[(N
-(2-Furyl)methyl)-4-(pyrrolidin-3-yl)-phenyl]-pyridin-2-ylami-
ne
[0483] A.
Diethyl-4-[2-(2,5-dimethylpyrrolyl)-6-pyridyl]benzylidenemalonat-
e
[0484] To a 125 mL round-bottomed flask equipped with N.sub.2 inlet
were added 3.3 g (11.96 mmol)
2-(2,5-dimethylpyrrolyl)-6-(4-(4'-formylbiphenyl- -4-yl))-pyridine
(Example 1B), 1.9 g (11.96 mmol) diethyl malonate, 60 mL benzene,
51 mg (0.6 mmol) piperidine, and 10 mg benzoic acid. The reaction
was refluxed overnight, cooled, and poured into water and ethyl
acetate. The organic layer was washed with 1N hydrochloric acid,
aqueous sodium bicarbonate solution, and brine, dried over sodium
sulfate, and evaporated. The residue was chromatographed on silica
gel using methylene chloride/ethyl acetate to afford the product as
a yellow oil, 4.32 g (86.5%).
[0485] .sup.1H-NMR (.delta., CDCl.sub.3): 1.31 (t, J=7, 3H), 1.34
(t, J=7, 3H), 2.21 (s, 6H), 4.33 (q, J=7, 2H), 4.35 (q, J=7, 2H),
5.93 (s, 2H), 7.17 (d, J=8, 1H), 7.55 (m, 2H), 7.77 (m, 2H), 7.87
(t, J=8, 1H), 8.09 (m, 2H).
[0486] .sup.13C-NMR (.delta., CDCl.sub.3): 13.5, 14.0, 14.2, 61.7,
61.8, 106.1, 118.5, 120.5, 126.7, 127.2, 128.6, 129.9, 130.1,
133.7, 138.8, 140.2, 141.3, 151.8, 155.6, 164.1, 166.7.
[0487] IR (neat, cm..sup.-1): 1727 (C.dbd.O).
[0488] MS (%): 419 (parent+1, 100).
[0489] B.
Ethyl-3-[2-(2,5-dimethylpyrrolyl)-6-pyridyl]phenyl-3-cyano-propi-
onate
[0490] To a 250 mL round-bottomed flask equipped with condenser and
N.sub.2 inlet were added 4.32 g (10.33 mmol)
diethyl-4-[2-(2,5-dimethylpy- rrolyl)-6-pyridyl]benzylidenemalonate
and 100 mL ethanol. To the stirring solution was added a solution
of 672 mg (10.33 mmol) potassium cyanide in 2.6 mL water, and the
reaction heated at 60.degree. C. overnight. The reaction was cooled
and quenched with dilute hydrochloric acid, then taken up in ethyl
acetate and washed with acid and brine, dried over sodium sulfate,
and evaporated. The residue was chromatographed on silica gel using
methylene chloride/ethyl acetate as eluant to afford 3.00 9 (78%)
of an oil.
[0491] .sup.1H-NMR (.delta., CDCl.sub.3): 2.21 (s, 6H), 2.96 (m,
2H), 3.71 (s, 3H), 4.355 (t, J=7, 1H), 5.93 (s, 2H), 7.17 (d, J=8,
1H), 7.47 (m, 2H), 7.74 (d, J=8, 1H), 7.89 (t, J=8, 1H), 8.09 (m,
2H).
[0492] .sup.13C-NMR (.delta., CDCl.sub.3): 13.5, 32.9, 39.7, 52.4,
107.1, 118.4, 113.75, 120.3, 127.8, 128.6, 135.4, 138.8, 151.8,
155.8, 169.5.
[0493] IR (neat, cm..sup.-1): 2244 (CN), 1739 (C.dbd.O).
[0494] MS (%): 374 (parent+1, 100).
[0495] C.
2-(2,5-Dimethylpyrrolyl)-6-[4-(2-oxo-pyrrolidin-3-yl)-phenyl]-py-
ridine
[0496] To a 125 mL round-bottomed flask equipped with condenser and
N.sub.2 inlet were added 2.84 g (7.61 mmol)
ethyl-3-[2-(2,5-dimethylpyrro-
lyl)-6-pyridyl]phenyl-3-cyano-propionate, 50 mL ethanol, and 1 mL
concentrated hydrochloric acid. The solution was heated as 700 mg
10% palladium-on-carbon and 2.4 g (38.07 mmol) ammonium formate
were added, and the reaction heated at 80.degree. C. for 4.75
hours, with additional catalyst and ammonium formate at 1 hour
intervals. The reaction was cooled and filtered through Celite, and
the filtrate evaporated. The residue was taken up in ethyl acetate,
washed with aqueous sodium hydroxide, dried over sodium sulfate,
and evaporated. The residue was taken up in 50 mL dry toluene,
treated with 5 mL triethylamine, and heated at reflux for 1 hour.
The reaction was then cooled, washed with dilute aqueous
hydrochloric acid and brine, dried over sodium sulfate, and
evaporated. The residue was chromatographed on silica gel using
methylene chloride/methanol as eluant to afford 204.5 mg (8.1%) of
an oil.
[0497] .sup.1H-NMR (.delta., CDCl.sub.3): 2.21 (s, 6H), 2.64 (AB,
J=8.5, 17, Dn=94, 2H), 3.43 (dd, J=7,9, 1H), 3.73 (m, 1H), 3.80 (m,
1H), 5.92 (s, 2H), 7.02 (bs, 1H), 7.13 (d, J=8, 1H), 7.34 (m, 2H),
7.72 (d, J=8, 1H), 7.86 (t, J=8, 1H), 8.04 (m, 2H).
[0498] .sup.13C-NMR (.delta., CDCl.sub.3): 13.5, 38.0, 40.0, 49.5,
107.0, 118.2, 119.9, 127.2, 127.4, 128.7, 137.3, 138.7, 143.5,
151.7, 156.3, 177.8.
[0499] IR (neat, cm..sup.-1): 1708 and 1685 (C.dbd.O).
[0500] MS (%): 332 (parent+1, 100).
[0501] D.
2-(2,5-Dimethylpyrrolyl)-6-[4-(pyrrolidin-3-yl)-phenyl]-pyridine
[0502] To a 125 mL round-bottomed flask equipped with condenser and
N.sub.2 inlet were added 230 mg (1.73 mmol) aluminum chloride and 8
mL dry tetrahydrofuran. The solution was cooled to 0.degree. C.,
and 4.04 mL (4.04 mmol) of a 1.0 M solution was lithium aluminum
hydride in tetrahydrofuran was added. The reaction was stirred 20
minutes at room temperature, and cooled to -70.degree. C. The
reaction was treated with a solution of 191 mg (0.577 mmol)
2-(2,5-dimethylpyrrolyl)-6-[4-(pyrrolidin- -3-yl)-phenyl]-pyridine
in 2 mL dry tetrahydrofuran, and stirred 1 hour at -70.degree. C.
and 14 hours at room temperature. The reaction was carefully
quenched with dilute aqueous hydrochloric acid, then taken up in
methylene chloride and aqueous sodium hydroxide solution, and the
combined organic layer washed with water, dried over sodium
sulfate, and evaporated to afford 145 mg (79%) of an oil.
[0503] .sup.1H-NMR (.delta., CDCl.sub.3): 1.90 (m, 1H), 2.21 (s,
6H), 2.27 (m, 1H), 2.89 (dd, J=8,10, 1H), 3.11 (m, 1H), 3.19 (m,
1H), 3.28 (t, J=8, 1H), 3.40 (dd, J=8,10, 1H), 3.5 (bs, 1H), 5.92
(s, 2H), 7.10 (d, J=8, 1H), 7.33 (m, 2H), 7.70 (d, J=8, 1H), 7.83
(t, J=8, 1H), 8.00 (m, 2H).
[0504] .sup.13C-NMR (.delta., CDCl.sub.3): 13.5, 34.4, 45.3, 47.2,
54.8, 106.9, 118.1, 119.7, 125.5, 127.1, 127.2, 127.4, 127.6,
128.6, 136.5, 138.6, 145.3, 151.6, 156.6.
[0505] MS (%): 318 (parent+1, 100).
[0506] E.
2-(2,5-Dimethylpyrrolyl)-6-[(N-(2-furyl)methyl)-4-(pyrrolidin-3--
yl)-phenyl]-pyridine
[0507] Prepared using the procedure in Example 43 to carry out the
reductive amination with furfural, in 65% yield as an oil.
[0508] .sup.1H-NMR (.delta., CDCl.sub.3): 1.92 (m, 1H), 2.21 (s,
6H), 2.36 (m, 1H), 2.59 (t, J=9, 1H), 2.78 (m, 1H), 2.97 (m, 1H),
3.18 (t, J=9, 1H), 3.44 (m, 1H), 3.75 (Ab.sub.q, J=14, Dn=19, 2H),
5.92 (s, 2H), 6.24 (d, J=3, 1H), 6.32 (dd, J=2,3, 1H), 7.10 (d,
J=8, 1H), 7.34 (m, 2H), 7.38 (d, J=2, 1H), 7.70 (d, J=8, 1H), 7.83
(t, J=8, 1H), 7.99 (m, 2H).
[0509] .sup.13C-NMR (.delta., CDCl.sub.3): 13.4, 33.0, 43.1, 51.7,
54.1, 61.4, 106.8, 108.2, 110.1, 118.0, 119.6, 126.9, 127.1, 127.3,
128.7, 130.8, 136.3, 138.5, 142.1, 146.05, 151.5, 152.0, 156.6.
[0510] MS (%): 398 (parent+1, 100).
[0511] F.
6-[(N-(2-Furyl)methyl)-4-(pyrrolidin-3-yl)-phenyl]-pyridin-2-yla-
mine
[0512] Prepared as in Example 11D, in 77% yield, mp 60-70.degree.
C. as the hydrochloride salt.
[0513] .sup.1H-NMR (.delta., CDCl.sub.3): 1.90 (m, 1H), 2.34 (m,
1H), 2.51 (t, J=9, 1H), 2.70 (m, 1H), 2.93 (m, 1H), 3.13 (t, J=9,
1H), 3.65 (m, 1H), 3.69 (Ab.sub.q, J=14, Dn=21, 2H), 4.55 (bs, 2H,
NH.sub.2), 6.19 (d, J=3, 1H), 6.30 (dd, J=2,3, 1H), 6.40 (d, J=8,
1H), 7.02 (d, J=7, 1H), 7.29 (m, 2H), 7.36 (m, 1H), 7.45 (t, J=8,
1H), 7.81 (m, 2H).
[0514] .sup.13C-NMR (.delta., CDCl.sub.3): 33.1, 43.1, 52.0, 54.2,
61.75, 106.8, 107.7, 110.0, 110.6, 126.8, 127.1, 127.4, 167.6,
138.3, 141.9, 145.5, 152.6, 155.9, 158.2.
[0515] MS (%): 320 (parent+1, 100).
[0516] Anal. Calc'd for C.sub.20H.sub.21N.sub.3O.sub.2HCl {fraction
(5/3)}H.sub.2O: C, 56.88; H, 6.28; N, 9.95. Found: C, 56.67; H,
6.11; N, 10.15.
EXAMPLE 47
[0517]
6-[(N-(2-Methyl)propyl)-4-(pyrrolidin-3-yl)-phenyl]-pyridin-2-ylami-
ne
[0518] Prepared as in Example 46, using isobutyraldehyde, with a
73% yield in the final deblocking step to afford the product as a
solid, mp 55-70.degree. C.
[0519] .sup.1H-NMR (.delta., CDCl.sub.3): 0.93 (d, J=6.5, 6H), 1.76
(m, 1H), 1.87 (m, 1H), 2.2-2.4 (m, 3H), 2.49 (dd, J=8,9, 1H), 2.64
(m, 1H), 2.76 (m, 1H), 2.98 (t, J=9, 1H), 3.37 (h, J=7, 1H), 4.56
(bs, 2H, NH.sub.2), 6.40 (d, J=8, 1H), 7.03 (d, J=7.5, 1H), 7.32
(m, 2H), 7.45 (t, J=8, 1H), 7.81 (m, 2H).
[0520] .sup.13C-NMR (.delta., CDCl.sub.3): 21.0, 27.4, 33.2, 43.0,
54.9, 62.4, 64.9, 106.8, 110.7, 126.8, 127.5, 137.5, 138.3, 146.4,
156.0, 158.2.
[0521] MS (%): 296 (parent+1, 100).
[0522] Anal. Calc'd for C.sub.19H.sub.25N.sub.32HCl2H.sub.2O: C,
56.43; H, 7.73; N, 10.39. Found: C, 56.13; H, 7.52; N, 10.40.
EXAMPLE 48
[0523]
8-[4-(6-Amino-pyridin-2-yl)-phenyl]-3-isobutyl-3-aza-bicyclo[3.2.1]-
octan-8-ol
[0524] A.
8-[4-(6-(2,5-Dimethylpyrrolyl)-pyridin-2-yl)-phenyl]-3-benzyl-3--
aza-bicyclo[3.2.1]octan-8-ol
[0525] To a 125 mL 3-necked round-bottomed flask equipped with
septum and N.sub.2 inlet were added 1.86 g (5.70 mmol)
6-bromo-2-(2,5-dimethylpyrrol- yl)-pyridine and 40 mL dry
tetrahydrofuran. The solution was cooled to -60.degree. C., and
2.73 mL (6.84 mmol) of a 2.5M solution of butyl lithium in hexane
was added dropwise and the solution stirred 10 min at -60.degree.
C. Then a solution of 1.47 g (6.84 mmol)
3-benyl-3-aza-bicyclo[3.2.1]octan-8-one in 15 mL dry
tetrahydrofuran was added dropwise, and the reaction stirred at
-60.degree. C. for 10 minutes, and then at room temperature for 3
hours. The reaction was quenched with aqueous ammonium chloride
solution and taken up in ethyl acetate. The organic layer was
separated and washed with more aqueous ammonium chloride solution
and brine, dried over sodium sulfate, and evaporated. The residue
was chromatographed on silica gel using methanol and methylene
chloride to afford 413 mg (16%) of a yellow oil which solidified,
mp 58-68.degree. C.
[0526] .sup.1H-NMR (.delta., CDCl.sub.3): 1.45 (m, 2H), 1.84 (m,
2H), 2.22 (s, 6H), 2.46 (bs, 2H), 2.66 (m, 2H), 2.92 (m, 2H), 3.64
(s, 2H), 5.94 (s, 2H), 7.14 (d, J=8, 1H), 7.2-7.4 (m, 5H), 7.959
(m, 2H), 7.74 (d, J=8, 1H), 7.865 (t, J=8, 1H), 8.065 (m, 2H).
[0527] .sup.13C-NMR (.delta., CDCl.sub.3): 13.5, 25.5, 41.8, 54.0,
61.8, 78.9, 107.0, 118.3, 120.0, 125.9, 126.8, 127.1, 128.2, 128.7,
137.6, 138.6, 151.7, 156.4.
[0528] MS (%): 464 (parent+1, 100).
[0529] B.
8-[4-(6-(2,5-Dimethylpyrrolyl)-pyridin-2-yl)-phenyl]-3-aza-bicyc-
lo[3.2.1]octan-8-ol
[0530] Prepared as in Example 13C in 73% yield as a solid, mp
185-190.degree. C.
[0531] .sup.1H-NMR (.delta., CDCl.sub.3): 1.52 (m, 4H), 2.19 (s,
6H), 2.35 (m, 2H), 2.53 (m, 2H), 3.48 (m, 2H), 5.91 (s, 2H), 7.12
(d, J=8, 1H), 7.55 (m, 2H), 7.72 (d, J=8, 1H), 7.85 (t, J=8, 1H),
8.04 (m, 2H).
[0532] .sup.13C-NMR (.delta., CDCl.sub.3): 13.5, 24.7, 42.0, 47.1,
78.9, 107.0, 118.3, 119.9, 125.6, 127.1, 128.6, 137.5, 138.6,
147.1, 151.7, 156.4.
[0533] MS (%): 374 (parent+1, 100).
[0534] Anal. Calc'd for C.sub.24H.sub.27N.sub.3O
1/4(C.sub.4H.sub.8O.sub.3- ): C, 75.92; H, 7.39; N, 10.62. Found:
C, 76.13; H, 7.37; N, 10.33.
[0535] C.
8-[4-(6-amino-pyridin-2-yl)-phenyl]-3-aza-bicyclo[3.2.1]octan-8--
ol
[0536] Prepared as in Example 11D in 84% yield as a solid, mp
108-120.degree. C.
[0537] .sup.1H-NMR (.delta., CDCl.sub.3): 1.46 (m, 4H), 2.29 (m,
2H), 2.47 (m, 2H), 3.39 (m, 2H), 4.635 (bs, 2H, NH.sub.2), 6.365
(d, J=8, 1H), 6.94 (d, J=7.5, 1H), 7.41 (t, J=8, 1H), 7.44 (m, 2H),
7.75 (m, 2H).
[0538] .sup.13C-NMR (.delta., CDCl.sub.3): 24.4, 41.5, 46.7, 78.3,
107.3, 110.8, 125.3, 125.5, 126.9, 138.4, 138.6, 145.8, 155.6,
158.4.
[0539] MS (%): 296 (parent+1, 100).
[0540] HRMS Calc'd for C.sub.18H.sub.21N.sub.3O: 286.1763. Found:
286.1776.
[0541] D.
8-[4-(6-Amino-pyridin-2-yl)-phenyl]-3-isobutyl-3-aza-bicyclo[3.2-
.1]octan-8-ol
[0542] Prepared as in Example 47 in 27% yield, mp 167-200.degree.
C.
[0543] .sup.1H-NMR(.delta., CDCl.sub.3): 0.90 (d, J=6, 6H), 1.39
(m, 2H), 1.8 (broad m, 3H), 2.2 (broad m, 2H), 2.425 (bs, 2H), 2.64
(m, 2H), 2.83 (m, 2H), 4.51 (bs, 2H, NH.sub.2), 6.42 (d, J=8, 1H),
7.04 (d, J=7.5, 1H), 7.465 (t, J=8, 1H), 7.52 (m, 2H), 7.86 (m,
2H).
[0544] .sup.13C-NMR (.delta., CDCl.sub.3): 20.8, 25.15, 25.6, 41.5,
54.4, 65.6, 78.45, 107.4, 111.1, 125.6, 127.0, 138.6, 138.8, 155.7,
158.4.
[0545] MS (%): 352 (parent+1, 100).
[0546] Anal. Calc'd for C.sub.22H.sub.29N.sub.3O.sub.2HCl H.sub.2O:
C, 57.64; H, 7.26; N, 9.17. Found: C, 57.60; H, 7.34; N, 8.84.
EXAMPLE 49
[0547]
8-[4-(6-Amino-pyridin-2-y)-phenyl]-3-furan-2-ylmethyl-3-aza-bicyclo-
[3.2.1]octan-8-ol
[0548] Prepared as in Example 48, using furfural, with a 33% yield
in the final deblocking step to afford the product as a solid, mp
187-202.degree. C.
[0549] .sup.1H-NMR (.delta., CDCl.sub.3): 1.41 (m, 2H), 1.78 (m,
2H), 2.435 (m, 2H), 2.65 (m, 2H), 3.00 (m, 2H), 3.68 (s, 2H), 4.52
(bs, 2H, NH.sub.2), 6.24 (d, J=3, 1H), 6.32 (dd, J=2,3, 1H), 6.415
(d, J=8, 1H), 7.03 (d, J=7.5, 1H), 7.37 (d, J=2, 1H), 7.46 (t, J=8,
1H), 7.50 (m, 2H), 7.84 (m, 2H).
[0550] .sup.13C-NMR (.delta., CDCl.sub.3): 25.1, 41.5, 53.6, 53.8,
78.5, 107.3, 108.6, 110.1, 111.0, 125.6, 127.0 138.4, 139.0, 141.9,
145.1, 155.6, 158.3.
[0551] MS (%): 376 (parent+1, 100).
[0552] Anal. Calc'd for C.sub.23H.sub.25N.sub.3O.sub.2 2HCl
H.sub.2O: C, 59.23; H, 6.27; N, 9.01. Found: C, 59.17; H, 6.50; N,
8.71.
EXAMPLE 50
[0553]
8-[4-(6-Amino-pyridin-2-yl)-phenyl]-3-benzyl-3-aza-bicyclo[3.2.1]oc-
tan-8-ol
[0554] Prepared as in Example 46, deblocking after step A. to
afford the product as a solid, mp 185-200.degree. C. (dec.).
[0555] .sup.1H-NMR (.delta., CDCl.sub.3): 1.41 (m, 2H), 1.79 (m,
2H), 2.41 (bs, 2H), 2.63 (m, 2H), 2.91 (m, 2H), 3.62 (s, 2H), 4.58
(bs, 2H, NH2), 6.41 (d, J=8, 1H), 7.02 (d, J=7.5, 1H), 7.23 (m,
1H), 7.31 (m, 2H), 7.37 (m, 2H), 7.45 (t, J=8, 1H), 7.51 (m, 2H),
7.83 (m, 2H).
[0556] .sup.13C-NMR (.delta., CDCl.sub.3): 25.4, 41.7, 54.0, 61.8,
78.7, 107.3, 111.0, 125.6, 126.8, 127.0, 128.2, 128.8, 138.4,
138.9, 145.4, 155.7, 158.3.
[0557] MS (%): 386 (parent+1, 100).
[0558] Anal. Calc'd for
C.sub.25H.sub.27N.sub.3O.1/4CH.sub.2Cl.sub.2.1/2(C-
.sub.4H.sub.10O): C, 63.34; H, 6.73; N, 8.13. Found: C, 63.11; H,
6.44; N, 8.12.
* * * * *