U.S. patent application number 10/606630 was filed with the patent office on 2004-04-01 for 3,3-biarylpiperidine and 2,2-biarylmorpholine derivatives.
This patent application is currently assigned to Pfizer Inc. Invention is credited to Allen, Martin P., Liras, Spiros, Segelstein, Barbara E..
Application Number | 20040063940 10/606630 |
Document ID | / |
Family ID | 22353325 |
Filed Date | 2004-04-01 |
United States Patent
Application |
20040063940 |
Kind Code |
A1 |
Liras, Spiros ; et
al. |
April 1, 2004 |
3,3-Biarylpiperidine and 2,2-biarylmorpholine derivatives
Abstract
The present invention relates to compounds of the formula I, 1
wherein Z.sup.1, Z.sup.2, X, Q, R.sup.1, R.sup.2 and R.sup.3 are
defined as in the specification, pharmaceutical compositions
containing such compounds the use of such compounds to treat
neurological and gastrointestinal disorders.
Inventors: |
Liras, Spiros; (Stonington,
CT) ; Allen, Martin P.; (North Stonington, CT)
; Segelstein, Barbara E.; (Gales Ferry, CT) |
Correspondence
Address: |
PFIZER INC
150 EAST 42ND STREET
5TH FLOOR - STOP 49
NEW YORK
NY
10017-5612
US
|
Assignee: |
Pfizer Inc
|
Family ID: |
22353325 |
Appl. No.: |
10/606630 |
Filed: |
June 26, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10606630 |
Jun 26, 2003 |
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09583714 |
May 31, 2000 |
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6586431 |
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09583714 |
May 31, 2000 |
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09369841 |
Aug 6, 1999 |
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6503905 |
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60114091 |
Dec 29, 1998 |
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Current U.S.
Class: |
544/106 ;
544/114; 544/116; 544/124; 544/127; 544/133; 544/138 |
Current CPC
Class: |
A61P 25/00 20180101;
C07D 401/10 20130101; A61P 1/00 20180101; A61P 29/00 20180101; A61P
17/06 20180101; A61P 25/30 20180101; C07D 401/04 20130101; A61P
1/04 20180101; A61P 11/06 20180101; C07D 409/10 20130101; A61P 9/10
20180101; C07D 413/04 20130101; C07D 265/30 20130101; C07D 409/04
20130101; A61P 15/00 20180101; A61P 25/04 20180101; A61P 37/00
20180101; C07D 401/06 20130101; C07D 417/06 20130101; C07D 211/34
20130101; A61P 25/32 20180101; A61P 19/02 20180101; A61P 11/00
20180101; A61P 37/06 20180101; C07D 401/14 20130101; A61P 1/12
20180101; C07D 211/20 20130101 |
Class at
Publication: |
544/106 ;
544/124; 544/116; 544/114; 544/127; 544/133; 544/138 |
International
Class: |
C07D 413/02 |
Claims
1. A compound of the formula 18R.sup.1 is hydrogen,
(C.sub.0-C.sub.8)alkoxy-(C.sub.1-C.sub.8)alkyl-, wherein the total
number of carbon atoms is eight or less, aryl,
aryl-(C.sub.1-C.sub.8)alkyl-, heteroaryl,
heteroaryl-(C.sub.1-C.sub.8)alkyl-, heterocyclic,
heterocyclic-(C.sub.1-C.sub.8)alkyl, (C.sub.3-C.sub.7)cycloalkyl-,
or (C.sub.3-C.sub.7)cycloalkyl-(C.sub.1-C.sub.8)alkyl, wherein said
aryl and the aryl moiety of said aryl-(C.sub.1-C.sub.8)alkyl- are
selected, independently, from phenyl and napthyl, and wherein said
heteroaryl and the heteroaryl moiety of said
heteroaryl-(C.sub.1-C.sub.8)alkyl- are selected, independently,
from pyrazinyl, benzofuranyl, quinolyl, isoquinolyl, benzothienyl,
isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl,
purinyl, carbazolyl, 1,2,5-thiadiazolyl, quinazolinyl, pyridazinyl,
pyrazinyl, cinnolinyl, phthalazinyl, quinoxalinyl, xanthinyl,
hypoxanthinyl, pteridinyl, 5-azacytidinyl, 5-azauracilyl,
triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl,
pyrazolopyrimidinyl, oxazolyl, oxadiazoyl, isoxazoyl, thiazolyl,
isothiazolyl, furanyl, pyrazolyl, pyrrolyl, tetrazolyl, triazolyl,
thienyl, imidazolyl, pyridinyl, and pyrimidinyl; and wherein said
heterocyclic and the heterocyclic moiety of said
heterocyclic-(C.sub.1-C.- sub.8)alkyl- are selected from saturated
or unsaturated nonaromatic monocyclic or bicyclic ring systems,
wherein said monocyclic ring systems contain from four to seven
ring carbon atoms, from one to three of which may optionally be
replaced with O, N or S, and wherein said bicyclic ring systems
contain from seven to twelve ring carbon atoms, from one to four of
which may optionally be replaced with O, N or S; and wherein any of
the aryl, heteroaryl or heterocyclic moieties of R.sup.1 may
optionally be substituted with from one to three substitutuents,
preferably with one or two substutituents, independently selected
from halo (i.e., chloro, fluoro, bromo or iodo),
(C.sub.1-C.sub.6)alkyl optionally substituted with from one to
seven (preferably with from zero to four) fluorine atoms, phenyl,
benzyl, hydroxy, acetyl, amino, cyano, nitro,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkylamino and
[(C.sub.1-C.sub.6)alkyl].sub.2amino, and wherein any of the alkyl
moieties in R.sup.1 (e.g., the alkyl moieties of alkyl, alkoxy or
alkylamino groups) may optionally be substituted with from one to
seven (preferably with from zero to four) fluorine atoms; R.sup.2
is hydrogen, aryl, heteroaryl, heterocyclic, SO.sub.2R.sup.4,
COR.sup.4, CONR.sup.5R.sup.6, COOR.sup.4, or C(OH)R.sup.5R.sup.6
wherein each of R.sup.4, R.sup.5 and R.sup.6 is defined,
independently, as R.sup.1 is defined above, or R.sup.5 and R.sup.6,
together with the carbon or nitrogen to which they are both
attached, form a three to seven membered saturated ring containing
from zero to three heterocarbons selected, independently, from O, N
and S, and wherein said aryl, heteroaryl, and heterocyclic are
defined as such terms are defined above in the definition of
R.sup.1, and wherein any of the aryl, heteroaryl and heterocyclic
moieties of R.sup.2 may optionally be substituted with from one to
three substitutuents, preferably with one or two substutituents,
independently selected from halo (i.e., chloro, fluoro, bromo or
iodo), (C.sub.1-C.sub.6)alkyl optionally substituted with from one
to seven (preferably with from zero to four) fluorine atoms,
phenyl, benzyl, hydroxy, acetyl, amino, cyano, nitro,
(C.sub.1-C.sub.6)alkoxy optionally substituted with from one to
seven (preferably with from zero to four) fluorine atoms,
(C.sub.1-C.sub.6)alkylamino and [(C.sub.1-C.sub.6)alkyl].-
sub.2amino; R.sup.3 is hydroxy, --NHSO.sub.2R.sup.7,
--C(OH)R.sup.7R.sup.8, --OC(.dbd.O)R.sup.7, fluorine or
--CONHR.sup.7, wherein R.sup.7 and R.sup.8 are the same or
different and are selected from hydrogen, (C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy and
(C.sub.1-C.sub.4)alkoxy-(C.sub.1-C.sub.4)alkyl having a total of
four or less carbon atoms, and wherein any of the alkyl moieties of
R.sup.7 and R.sup.8 may optionally be substituted with from one to
seven (preferably with from zero to four) fluorine atoms; Q is
oxygen or CH.sub.2; X is CH or N; and Z.sup.1 and Z.sup.2 are
selected, independently, from hydrogen, halo and
(C.sub.1-C.sub.5)alkyl; with the proviso that there are no two
adjacent ring oxygen atoms and no ring oxygen atom adjacent to
either a ring nitrogen atom or a ring sulfur atom in any of the
heterocyclic or heteroaryl moieties of formula I; or a
pharmaceutically acceptable salt of such compound.
2. A compound according to claim 1 wherein Q is CH.sub.2.
3. A compound according to claim 1 wherein X is CH.
4. A compound according to claim wherein X is N.
5. A compound according to claim 1 wherein Q is oxygen.
6. A compound according to claim 1 wherein R.sup.3 is OH,
CONH.sub.2, or fluoro.
7. A compound according to claim 1 wherein R.sup.2 is selected from
C(OH)(C.sub.2H.sub.6).sub.2, CONCH.sub.3(CH.sub.2CH.sub.3),
CON(C.sub.2H.sub.6).sub.2 and the following cyclic groups: 19
8. A compound according to claim 2 wherein X is CH.
9. A compound according to claim 2 wherein X is N.
10. A compound according to claim 6 wherein Q is CH.sub.2 and X is
CH.
11. A compound according to claim 7 wherein Q is CH.sub.2 and X is
CH.
12. A compound according to claim 6 wherein Q is CH.sub.2 and X is
N.
13. A compound according to claim 7 wherein Q is CH.sub.2 and X is
N.
14. A pharmaceutical composition for treating a disorder or
condition selected from inflammatory diseases such as arthritis,
psoriasis, asthma, or inflammatory bowel disease, disorders of
respiratory function such as asthma, cough and apnea, allergies,
gastrointestinal disorders such as gastritis, functional bowel
disease, irritable bowel syndrome, functional diarrhoea, functional
distension, functional pain, nonulcerogenic dyspepsia and other
disorders of motility or secretion, and emesis, stroke, shock,
brain edema, head trauma, spinal cord trauma, cerebral ischemia,
cerebral deficits subsequent to cardiac bypass surgery and
grafting, urogential tract disorders such as urinary incontinence,
chemical dependencies and addictions (e.g., addictions to or
dependencies on alcohol, opiates, benzodiazepines, nicotine, heroin
or cocaine), chronic pain, nonsomatic pain, acute pain and
neurogenic pain, systemic lupus erythematosis, Hodgkin's disease,
Sjogren's disease, epilepsy and rejection in organ transplants and
skin grafts in a mammal, comprising an amount of a compound
according to claim 1 that is effective in treating such disorder or
condition and a pharmaceutically acceptable carrier.
15. A pharmaceutical composition for treating a disorder or
condition, the treatment or prevention of which can be effected or
facilitated by modulating binding to opioid receptors in a mammal,
comprising an amount of a compound according to claim 1 that is
effective in treating such disorder or condition and a
pharmaceutically acceptable carrier.
16. A method for treating a disorder or condition selected from
inflammatory diseases such as arthritis, psoriasis, asthma, or
inflammatory bowel disease, disorders of respiratory function such
as asthma, cough and apnea, allergies, gastrointestinal disorders
such as gastritis, functional bowel disease, irritable bowel
syndrome, functional diarrhoea, functional distension, functional
pain, nonulcerogenic dyspepsia and other disorders of motility or
secretion, and emesis, stroke, shock, brain edema, head trauma,
spinal cord trauma, cerebral ischemia, cerebral deficits subsequent
to cardiac bypass surgery and grafting, urogential tract disorders
such as urinary incontinence, chemical dependencies and addictions
(e.g., addictions to or dependencies on alcohol, opiates,
benzodiazepines, nicotine, heroin or cocaine), chronic pain,
nonsomatic pain, acute pain and neurogenic pain, systemic lupus
erythematosis, Hodgkin's disease, Sjogren's disease, epilepsy and
rejection in organ transplants and skin grafts in a mammal,
comprising administering to a mammal requiring such treatment an
amount of a compound according to claim 1 that is effective in
treating such disorder or condition.
17. A method for treating a disorder or condition, the treatment of
which can be effected or facilitated by modulating binding to
opioid receptors in a mammal, comprising administering to a mammal
requiring such treatment an amount of a compound according to claim
1 that is effective in treating such disorder or condition.
18. A pharmaceutical composition for treating a disorder or
condition selected from inflammatory diseases such as arthritis,
psoriasis, asthma, or inflammatory bowel disease, disorders of
respiratory function such as asthma, cough and apnea, allergies,
gastrointestinal disorders such as gastritis, functional bowel
disease, irritable bowel syndrome, functional diarrhoea, functional
distension, functional pain, nonulcerogenic dyspepsia and other
disorders of motility or secretion, and emesis, stroke, shock,
brain edema, head trauma, spinal cord trauma, cerebral ischemia,
cerebral deficits subsequent to cardiac bypass surgery and
grafting, urogential tract disorders such as urinary incontinence,
chemical dependencies and addictions (e.g., addictions to or
dependencies on alcohol, opiates, benzodiazepines, nicotine, heroin
or cocaine), chronic pain, nonsomatic pain, acute pain and
neurogenic pain, systemic lupus erythematosis, Hodgkin's disease,
Sjogren's disease, epilepsy and rejection in organ transplants and
skin grafts in a mammal, comprising an opioid receptor binding
modulating effective amount of a compound according to claim 1 and
a pharmaceutically acceptable carrier.
19. A pharmaceutical composition for treating a disorder or
condition, the treatment or prevention of which can be effected or
facilitated by modulating binding to opioid receptors in a mammal,
comprising an opioid receptor binding modulating effective amount
of a compound according to claim I and a pharmaceutically
acceptable carrier.
20. A method for treating a disorder or condition selected from
inflammatory diseases such as arthritis, psoriasis, asthma, or
inflammatory bowel disease, disorders of respiratory function such
as asthma, cough and apnea, allergies, gastrointestinal disorders
such as gastritis, functional bowel disease, irritable bowel
syndrome, functional diarrhoea, functional distension, functional
pain, nonulcerogenic dyspepsia and other disorders of motility or
secretion, and emesis, stroke, shock, brain edema, head trauma,
spinal cord trauma, cerebral ischemia, cerebral deficits subsequent
to cardiac bypass surgery and grafting, urogential tract disorders
such as urinary incontinence, chemical dependencies and addictions
(e.g., addictions to or dependencies on alcohol, opiates,
benzodiazepines, nicotine, heroin or cocaine), chronic pain,
nonsomatic pain, acute pain and neurogenic pain, systemic lupus
erythematosis, Hodgkin's disease, Sjogren's disease, epilepsy and
rejection in organ transplants and skin grafts in a mammal,
comprising administering to a mammal requiring such treatment an
opioid receptor binding modulating effective amount of a compound
according to claim 1.
21. A method for treating a disorder or condition, the treatment or
prevention of which can be effected or facilitated by modulating
binding to opioid receptors in a mammal, comprising administering
to a mammal requiring such treatment an opioid receptor binding
modulating effective amount of a compound according to claim 1.
Description
BACKGROUND OF THE INVENTION
[0001] This invention relates to 3,3-biarylpiperidine and
2,2-biarylmorpholine derivatives which have utility as ligands for
opioid receptors.
[0002] In the study of opioid biochemistry, a variety of endogenous
opioid compounds and non-endogenous opioid compounds has been
identified. In this effort, significant research has been focused
on understanding the mechanism of opioid drug action, particlarly
as it relates to cellular and differentiated tissue opioid
receptors.
[0003] Opioid drugs are typically classified by their binding
selectivity in respect of the cellular and differentiated tissue
receptors to which a specific drug species binds as a ligand. These
receptors include mu (.mu.), delta (.delta.) and kappa (.kappa.)
receptors.
[0004] At least three subtypes of opioid receptors (mu, delta and
kappa) are described and documented in the scientific literature.
All three receptors are present in the central and peripheral
nervous systems of many species including man. Activation of delta
receptors produces antinociception in rodents and can induce
analgesia in man, in addition to influencing motility of the
gastrointestinal tract. (See Burks, T. F. (1995) in "The
Pharmacology of Opioid Peptides", edited by Tseng, L. F., Harwood
Academic Publishers).
[0005] The well known narcotic opiates such as morphine and its
analogs are selective for the opioid mu receptor. Mu receptors
mediate analgesia, respiratory depression, and inhibition of
gastrointestinal transit. Kappa receptors mediate analgesia and
sedation.
[0006] The existence of the opioid delta receptor is a relatively
recent discovery which followed the isolation and characterization
of endogenous enkephalin peptides, which are ligands for the delta
receptor. Research in the past decade has produced significant
information about the delta receptor, but a clear picture of its
function has not yet emerged. Delta receptors mediate analgesia,
but do not appear to inhibit intestinal transit in the manner
characteristic of mu receptors.
[0007] U.S. Pat. No. 4,816,586, which issued on Mar. 28, 1989 to P.
S. Portoghese, refers to various delta opioid receptor antagonists.
These compounds are described as possessing a unique opioid
receptor antagonist profile, and include compounds that are highly
selective for the delta opioid receptor.
[0008] U.S. Pat. No. 4,518,711, which issued May 21, 1985 to V. J.
Hruby et al., describes cyclic, conformationally constrained
analogs of enkephalins. These compounds include both agonists and
antagonists for the delta receptor, and are said to induce
pharmacological and therapeutic effects, such as analgesia in the
case of agonist species of such compounds. The antagonist species
of the disclosed compounds are suggested to be useful in the
treatment of schizophrenia, Alzheimer's disease, and respiratory
and cardiovascular functions.
[0009] S. Goenechea, et al, in "Investigation of the
Biotransformation of Meclozine in the Human Body," J. Clin. Chem.
Clin. Biochem., 1988, 26(2), 105-15, describe the oral
administration of a polyaryl piperazine compound in a study of
meclozine metabolization in human subjects.
[0010] In "Plasma Levels, Biotransformation and Excretion of
Oxatomide in Rats, Dogs, and Man," Xenobiotica, 1984, 15(6),
445-62, Meuldermans, W., et al., refer to a metabolic study of
plasma levels, biotransformation, and excretion of oxatomide.
[0011] T. Iwamoto, et al, in "Effects of KB-2796, A New Calcium
Antagonist, and Other Diphenylpiperazines on [.sup.3H]nitrendipine
Binding", Jpn. J Pharmacol., 1988, 48(2), 241-7, describe the
effect of a polyaryl piperazine as a calcium antagonist.
[0012] K. Natsuka, et al, in "Synthesis and Structure-Activity
Relationships of 1-Substituted 4-(1,2-Diphenylethyl)piperazine
Derivatives Having Narcotic Agonist and Antagonist Activity," J.
Med. Chem., 1987, 30 (10), 1779-1787, disclose racemates and
enantiomers of 1-substituted
4-[2-(3-hydroxyphenyl)-1-phenylethyl]piperazine derivatives.
[0013] European Patent Application No. 458,160, published on Nov.
27, 1991, refers to certain substituted diphenylmethane derivatives
as analgesic and antiinflammatory agents, including compounds
wherein the methylene bridging group (linking the two phenyl
moieties) is substituted on the methylene carbon with a piperidinyl
or piperazinyl group.
[0014] South African Patent Application No. 8604522, which was
published on Dec. 12, 1986, refers to certain N-substituted
arylalkyl and aryl-alkylene substituted amino-heterocyclic
compounds, including piperdine derivatives, as cardiovascular,
antihistamine, and anti-secretory agents.
[0015] European Patent Application No. 133,323, published on Feb.
20, 1985, refers to certain diphenylmethyl piperazine compounds as
non-sedative antihistamines.
[0016] There is a continuing need in the art for improved opioid
compounds, particularly compounds which are free of addictive
character and other adverse side effects of conventional opiates
such as morphine and pethidine.
[0017] The present inventor has discovered a novel class of
3,3-biarylpiperidine and morpholine derivatives that are potent and
selective delta opioid ligands and are useful for treatment of
rejection in organ transplants and skin grafts, epilepsy, chronic
pain, neurogenic pain, nonsomatic pain, stroke, cerebral ischemica,
shock, head trauma, spinal cord trauma, brain edema, Hodgkin's
disease, Sjogren's disease, systemic lupus erythematosis,
gastrointestinal disorders such as gastritis, functional bowel
disease, irritable bowel syndrome, functional diarrhoea, functional
distention, nonulcerogenic dyspepsia and other disorders of
motility or secretion, and emesis, acute pain, chronic pain,
neurogenic pain, nonsomatic pain, allergies, respiratory disorders
such as asthma, cough and apnea, inflammatory disorders such as
rheumatoid arthritis, osteoarthristis, psoriasis and inflammatory
bowel disease, urogenital tract disorders such as urinary
incontinence, hypoxia (e.g., perinatal hypoxia), hypoglycemic
neuronal damage, chemical dependencies and addictions (e.g., a
dependency on, or addiction to opiates, benzodiazepines, cocaine,
nicotine or ethanol), drug or alcohol withdrawal symptoms, and
cerebral deficits subsequent to cardiac bypass surgery and
grafting.
SUMMARY OF THE INVENTION
[0018] This invention relates to compounds of the formula 2
[0019] wherein R.sup.1 is hydrogen,
(C.sub.0-C.sub.8)alkoxy-(C.sub.1-C.sub- .8)alkyl-, wherein the
total number of carbon atoms is eight or less, aryl,
aryl-(C.sub.1-C.sub.8)alkyl-, heteroaryl,
heteroaryl-(C.sub.1-C.sub- .8)alkyl-, heterocyclic,
heterocyclic-(C.sub.1-C.sub.8)alkyl, (C.sub.3-C.sub.7)cycloalkyl-,
or (C.sub.3-C.sub.7)cycloalkyl-(C.sub.1-C.s- ub.8)alkyl, wherein
said aryl and the aryl moiety of said aryl-(C.sub.1-C.sub.8)alkyl-
are selected, independently, from phenyl and napthyl, and wherein
said heteroaryl and the heteroaryl moiety of said
heteroaryl-(C.sub.1-C.sub.8)alkyl- are selected, independently,
from pyrazinyl, benzofuranyl, quinolyl, isoquinolyl, benzothienyl,
isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl,
purinyl, carbazolyl, 1,2,5-thiadiazolyl, quinazolinyl, pyridazinyl,
pyrazinyl, cinnolinyl, phthalazinyl, quinoxalinyl, xanthinyl,
hypoxanthinyl, pteridinyl, 5-azacytidinyl, 5-azauracilyl,
triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl,
pyrazolopyrimidinyl, oxazolyl, oxadiazolyl, isoxazoyl, thiazolyl,
isothiazolyl, furanyl, pyrazolyl, pyrrolyl, tetrazolyl, triazolyl,
thienyl, imidazolyl, pyridinyl, and pyrimidinyl; and wherein said
heterocyclic and the heterocyclic moiety of said
heterocyclic-(C.sub.1-C.sub.8)alkyl- are selected from saturated or
unsaturated nonaromatic monocyclic or bicyclic ring systems,
wherein said monocyclic ring systems contain from four to seven
ring carbon atoms, from one to three of which may optionally be
replaced with O, N or S, and wherein said bicyclic ring systems
contain from seven to twelve ring carbon atoms, from one to four of
which may optionally be replaced with O, N or S; and wherein any of
the aryl, heteroaryl or heterocyclic moieties of R.sup.1 may
optionally be substituted with from one to three substitutuents,
preferably with one or two substutituents, independently selected
from halo (i.e., chloro, fluoro, bromo or iodo),
(C.sub.1-C.sub.6)alkyl optionally substituted with from one to
seven (preferably with from zero to four) fluorine atoms, phenyl,
benzyl, hydroxy, acetyl, amino, cyano, nitro,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkylamino and
[(C.sub.1-C.sub.6)alkyl].sub.2amino, and wherein any of the alkyl
moieties in R.sup.1 (e.g., the alkyl moieties of alkyl, alkoxy or
alkylamino groups) may optionally be substituted with from one to
seven (preferably with from zero to four) fluorine atoms;
[0020] R.sup.2 is hydrogen, aryl, heteroaryl, heterocyclic,
SO.sub.2R.sup.4, COR.sup.4, CONR.sup.5R.sup.6, COOR.sup.4, or
C(OH)R.sup.5R.sup.6 wherein each of R.sup.4, R.sup.5 and R.sup.6 is
defined, independently, as R.sup.1 is defined above, or R.sup.5 and
R.sup.6, together with the carbon or nitrogen to which they are
both attached, form a three to seven membered saturated ring
containing from zero to three heterocarbons selected,
independently, from O, N and S, and wherein said aryl, heteroaryl,
and heterocyclic are defined as such terms are defined above in the
definition of R.sup.1, and wherein any of the aryl, heteroaryl and
heterocyclic moieties of R.sup.2 may optionally be substituted with
from one to three substitutuents, preferably with one or two
substutituents, independently selected from halo (i.e., chloro,
fluoro, bromo or iodo), (C.sub.1-C.sub.6)alkyl optionally
substituted with from one to seven (preferably with from zero to
four) fluorine atoms, phenyl, benzyl, hydroxy, acetyl, amino,
cyano, nitro, (C.sub.1-C.sub.6)alkoxy optionally substituted with
from one to seven (preferably with from zero to four) fluorine
atoms, (C.sub.1-C.sub.6)alkylamino and
[(C.sub.1-C.sub.6)alkyl].sub.2amino;
[0021] R.sup.3 is hydroxy, --NHSO.sub.2R.sup.7,
--C(OH)R.sup.7R.sup.8, --OC(.dbd.O)R.sup.7, fluorine or
--CONHR.sup.7, wherein R.sup.7 and R.sup.8 are the same or
different and are selected from hydrogen, (C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy and
(C.sub.1-C.sub.4)alkoxy-(C.sub.1-C.sub.4)alkyl having a total of
four or less carbon atoms, and wherein any of the alkyl moieties of
R.sup.7 and R.sup.8 may optionally be substituted with from one to
seven (preferably with from zero to four) fluorine atoms;
[0022] Q is oxygen or CH.sub.2;
[0023] X is CH or N; and
[0024] Z.sup.1 and Z.sup.2 are selected, independently, from
hydrogen, halo and (C.sub.1-C.sub.5)alkyl;
[0025] with the proviso that there are no two adjacent ring oxygen
atoms and no ring oxygen atom adjacent to either a ring nitrogen
atom or a ring sulfur atom in any of the heterocyclic or heteroaryl
moieties of formula I;
[0026] and the pharmaceutically acceptable salts of such
compounds.
[0027] Preferred compounds of the formula I include those wherein Q
is CH.sub.2.
[0028] Other preferred compounds of the formula I are those wherein
X is CH.
[0029] Other preferred compounds of the formula I are those wherein
R.sup.3 is OH, CONH.sub.2, or fluoro.
[0030] Other preferred compounds of the formula I are those wherein
R.sup.2 is selected from C(OH)(C.sub.2H.sub.6).sub.2,
CON(C.sub.2H.sub.6).sub.2, CONCH.sub.3(C.sub.2H.sub.6) and the
following cyclic groups: 3
[0031] Other preferred compounds of the formula I are those wherein
Z.sup.1 and Z.sup.2 are selected, independently, from hydrogen and
fluorine.
[0032] Other preferred compounds of the formula I are those wherein
R.sup.1 is selected from allyl, cyclopropylmethyl, methyl,
2,2,2-trifluoroethyl, methallyl, isopropyl, 2-pyridinyl,
2-pyrimidinyl and 4
[0033] Examples of other embodiments of the present invention are
the following:
[0034] compounds of the formula I wherein Q is oxygen and X is
CH;
[0035] compounds of the formula I wherein Q is oxygen and X is
N;
[0036] compounds of the formula I wherein Q is oxygen, X is CH and
R.sup.3 is OH, CONH.sub.2, or fluoro;
[0037] compounds of the formula I wherein Q is oxygen and X is
N;
[0038] compounds of the formula I wherein Q is CH.sub.2, X is N,
and R.sup.3is OH, CONH.sub.2, or fluoro;
[0039] compounds of the formula I wherein Q is CH.sub.2, X is N,
R.sup.3 is OH, CONH.sub.2, or fluoro, and R.sup.2 is selected from
C(OH)(C.sub.2H.sub.6).sub.2, CON(C.sub.2H.sub.6).sub.2 and one of
cyclic groups (a)-(f) depicted above; and
[0040] compounds of the formula I wherein Q is oxygen, X is CH, and
R.sup.3 is OH, CONH.sub.2, or fluoro;
[0041] compounds of the formula I wherein Q is oxygen, X is NH,
R.sup.3 is OH, CONH.sub.2, or fluoro, and R.sup.2 is selected from
C(OH)(C.sub.2H.sub.6).sub.2, CON(C.sub.2H.sub.6).sub.2 and one of
cyclic groups (a)-(f) depicted above;
[0042] compounds of the formula I wherein Q is oxygen, X is CH,
R.sup.3 is OH, CONH.sub.2 or fluoro, Z.sup.1 and Z.sup.2 or
selected, independently, from hydrogen and fluoro, and R.sup.1 is
selected from allyl, cyclopropylmethyl, methyl, methalyl,
isopropyl, 2-pyridinyl, 2-pyrimidinyl and cyclic group (g) depicted
above; and
[0043] compounds of the formula I wherein Q is oxygen, X is NH,
R.sup.3 is OH, CONH.sub.2 or fluoro, Z.sup.1 and Z.sup.2 or
selected, independently, from hydrogen and fluoro, and R.sup.1 is
selected from allyl, cyclopropylmethyl, methyl, methalyl,
isopropyl, 2-pyridinyl, 2-pyrimidinyl and cyclic group (g) depicted
above.
[0044] The compounds of formula I and their pharmaceutically
acceptable salts are opioid receptor ligands and are useful in the
treatment of a variety of neurological and gastrointestinal
disorders. Examples of disorders that can be treated with the
compounds of formula I and their pharmaceutically acceptable salts
are rejection in organ transplants and skin grafts, epilepsy,
chronic pain, neurogenic pain, nonsomatic pain, stroke, cerebral
ischemica, shock, head trauma, spinal cord trauma, brain edema,
Hodgkin's disease, Sjogren's disease, systemic lupus erythematosis,
gastrointestinal disorders such as gastritis, functional bowel
disease, irritable bowel syndrome, functional diarrhoea, functional
distention, nonulcerogenic dyspepsia and other disorders of
motility or secretion, and emesis, acute pain, chronic pain,
neurogenic pain, nonsomatic pain, allergies, respiratory disorders
such as asthma, cough and apnea, inflammatory disorders such as
rheumatoid arthritis, osteoarthritis, psoriasis and inflammatory
bowel disease, urogenital tract disorders such as urinary
incontinence, hypoxia (e.g., perinatal hypoxia), hypoglycemic
neuronal damage, chemical dependencies and addictions (e.g., a
dependency on, or addiction to opiates, benzodiazepines, cocaine,
nicotine or ethanol), drug or alcohol withdrawal symptoms, and
cerebral deficits subsequent to cardiac bypass surgery and
grafting.
[0045] The present invention also relates to the pharmaceutically
acceptable acid addition and base addition salts of compounds of
the formula I. 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. The chemical
bases that are used as reagents to prepare the pharmaceutically
acceptable base salts of this invention are those which form
non-toxic base salts with the acidic compounds of formula I. Such
non-toxic base salts include those derived from such
pharmacologically acceptable cations as sodium, potassium, calcium
and magnesium, etc.
[0046] The present invention also relates to the pharmaceutically
acceptable base addition salts of compounds of the formula I. These
salts are all prepared by conventional techniques. The chemical
bases that are used as reagents to prepare the pharmaceutically
acceptable base salts of this invention are those which form
non-toxic base salts with the acidic compounds of formula I. Such
non-toxic base salts include those derived from such
pharmacologically acceptable cations as sodium, potassium, calcium
and magnesium, etc.
[0047] For a review on pharmaceutically acceptable salts, see Berge
et al., J. Pharm. Sci., 66, 1-19 (1977).
[0048] This invention also relates to a pharmaceutical composition
for treating a disorder or condition, the treatment or prevention
of which can be effected or facilitated by modulating (i.e.,
increasing or decreasing) binding to opioid receptors in a mammal,
including a human, comprising an amount of a compound of the
formula I, or a pharmaceutically effective salt thereof, that is
effective in treating such disorder or condition and a
pharmaceutically acceptable carrier.
[0049] This invention also relates to a method of treating a
disorder or condition, the treatment of which can be effected or
facilitated by modulating binding to opioid receptors in a mammal,
comprising administering to a mammal in need of such treatment an
amount of a compound of the formula I, or a pharmaceutically
effective salt thereof, that is effective in treating such disorder
or condition.
[0050] This invention also relates to a pharmaceutical composition
for treating a disorder or condition selected from inflammatory
diseases such as arthritis (e.g., rheumatoid arthritis and
osteoarthritis), psoriasis, asthma, or inflammatory bowel disease,
disorders of respiratory function such as asthma, cough and apnea,
allergies, gastrointestinal disorders such as gastritis, functional
bowel disease, irritable bowel syndrome, functional diarrhoea,
functional distension, functional pain, nonulcerogenic dyspepsia
and other disorders of motility or secretion, and emesis, stroke,
shock, brain edema, head trauma, spinal cord trauma, cerebral
ischemia, cerebral deficits subsequent to cardiac bypass surgery
and grafting, urogential tract disorders such as urinary
incontinence, chemical dependencies and addictions (e.g.,
addictions to or dependencies on alcohol, opiates, benzodiazepines,
nicotine, heroin or cocaine), chronic pain, nonsomatic pain, acute
pain and neurogenic pain, systemic lupus erythematosis, Hodgkin's
disease, Sjogren's disease, epilepsy and rejection in organ
transplants and skin grafts in a mammal, including a human,
comprising a glutamate neurotransmission modulating effective
amount of a compound of the formula I, or a pharmaceutically salt
thereof, and a pharmaceutically acceptable carrier.
[0051] This invention also relates to a method for treating a
condition selected from inflammatory diseases such as arthritis,
psoriasis, asthma, or inflammatory bowel disease, disorders of
respiratory function such as asthma, cough and apnea, allergies,
gastrointestinal disorders such as gastritis, functional bowel
disease, irritable bowel syndrome, functional diarrhoea, functional
distension, functional pain, nonulcerogenic dyspepsia and other
disorders of motility or secretion, and emesis, stroke, shock,
brain edema, head trauma, spinal cord trauma, cerebral ischemia,
cerebral deficits subsequent to cardiac bypass surgery and
grafting, urogential tract disorders such as urinary incontinence,
chemical dependencies and addictions (es, addictions to or
dependencies on alcohol, opiates, benzodiazepines, nicotine, heroin
or cocaine), chronic pain, nonsomatic pain, acute pain and
neurogenic pain, systemic lupus erythematosis, Hodgkin's disease,
Sjogren's disease, epilepsy and rejection in organ transplants and
skin grafts, in a mammal, comprising administering to such mammal,
including a human, an opioid receptor binding modulating effective
amount of a compound of the formula I, or a pharmaceutically
acceptable salt thereof.
[0052] This invention also relates to a pharmaceutical composition
for treating a disorder or condition, the treatment of which can be
effected or facilitated by modulating binding to opioid receptors
in a mammal, including a human, comprising an opioid receptor
binding modulating effective amount of a compound of the formula I,
or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier.
[0053] This invention also relates to a method for treating a
disorder or condition, the treatment of which can be effected or
facilitated by modulating in a mammal, including a human,
comprising administering to such mammal an opioid receptor binding
modulating effective amount of a compound of the formula I or a
pharmaceutically acceptable salt thereof.
[0054] This invention also relates to a method of treating a
condition selected from inflammatory diseases such as arthritis,
psoriasis, asthma, or inflammatory bowel disease, disorders of
respiratory function such as asthma, cough and apnea, allergies,
gastrointestinal disorders such as gastritis, functional bowel
disease, irritable bowel syndrome, functional diarrhoea, functional
distension, functional pain, nonulcerogenic dyspepsia and other
disorders of motility or secretion, and emesis, stroke, shock,
brain edema, head trauma, spinal cord trauma, cerebral ischemia,
cerebral deficits subsequent to cardiac bypass surgery and
grafting, urogential tract disorders such as urinary incontinence,
chemical dependencies and addictions (e.g., addictions to or
dependencies on alcohol, opiates, benzodiazepines, nicotine, heroin
or cocaine), chronic pain, nonsomatic pain, acute pain and
neurogenic pain, systemic lupus erythematosis, Hodgkin's disease,
Sjogren's disease, epilepsy and rejection in organ transplants and
skin grafts in a mammal, comprising administering to a mammal in
need of such treatment an amount of a compound of the formula I
that is effective in treating such condition.
[0055] This invention also relates to a pharmaceutical composition
for treating a condition selected from inflammatory diseases such
as arthritis, psoriasis, asthma, or inflammatory bowel disease,
disorders of respiratory function such as asthma, cough and apnea,
allergies, gastrointestinal disorders such as gastritis, functional
bowel disease, irritable bowel syndrome, functional diarrhoea,
functional distension, functional pain, nonulcerogenic dyspepsia
and other disorders of motility or secretion, and emesis, stroke,
shock, brain edema, head trauma, spinal cord trauma, cerebral
ischemia, cerebral deficits subsequent to cardiac bypass surgery
and grafting, urogential tract disorders such as urinary
incontinence, chemical dependencies and addictions (e.g.,
addictions to or dependencies on alcohol, opiates, benzodiazepines,
nicotine, heroin or cocaine), chronic pain, nonsomatic pain, acute
pain and neurogenic pain, systemic lupus erythematosis, Hodgkin's
disease, Sjogren's disease, epilepsy and rejection in organ
transplants and skin grafts in a mammal, comprising an amount of a
compound of the formula I that is effective in treating such
condition and a pharmaceutically acceptable carrier.
[0056] Unless otherwise indicated, the alkyl groups referred to
herein, as well as the alkyl moieties of other groups referred to
herein (e.g., alkoxy), may be linear or branched, and they may also
be cyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or
cyclohexyl) or be linear or branched and contain cyclic
moieties.
[0057] The term "alkoxy", as used herein, means "-O-alkyl", wherein
"alkyl" is defined as above.
[0058] The term "alkylene", as used herein, means an alkyl group
having two available binding sites (i.e., -alkyl-, wherein alkyl is
defined as above).
[0059] The term "treating" as used herein, refers to reversing,
alleviating, inhibiting the progress of, or preventing the disorder
or condition to which such term applies, or one or more symptoms of
such disorder or condition. The term "treatment", as used herein,
refers to the act of treating, as "treating" is defined immediately
above.
[0060] Unless otherwise indicated, "halo" and "halogen", as used
herein, refer to fluorine, bromine, chlorine or iodine.
[0061] Compounds of the formula I may have chiral centers and
therefore may exist in different enantiomeric and diastereomic
forms. This invention relates to all optical isomers and all other
stereoisomers of compounds of the formula I, and to all racemic and
other mixtures thereof, and to all pharmaceutical compositions and
methods of treatment defined above that contain or employ such
isomers or mixtures.
[0062] Formula I above also includes isotopically labelled
compounds that are identical to those depicted in formula I, but
for the fact that one or more atoms are replaced by an atom having
an atomic mass or mass number different from the atomic mass or
mass number usually found in nature. Examples of isotopes that can
be incorporated into compounds of the invention include isotopes of
hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and
chlorine, such as .sup.2H, .sup.3H, .sup.13C, .sup.14C, .sup.15N,
.sup.18O, .sup.17O, .sup.31P, .sup.32P, .sup.35S, .sup.18F, and
.sup.36Cl, respectively. Certain isotopically labelled compounds of
the present invention, for example, those into which radioactive
isotopes such as .sup.3H and .sup.14C are incorporated, are useful
in drug and/or substrate tissue distribution assays. Tritiated,
i.e., .sup.3H, and carbon-14, i.e., .sup.14C, isotopes are
particularly preferred for their ease of preparation and
detectability. Further, substitution with heavier isotopes such as
deuterium, i.e., .sup.2H, can afford certain therapeutic advantages
resulting from greater metabolic stability, for example, increased
in vivo half-life or reduced dosage requirements and, hence, may be
preferred in some circumstances. Isotopically labelled compounds of
formula I of this invention can generally be prepared by carrying
out the procedures disclosed in the schemes and/or in the Examples
below, by substituting a readily available isotopically labelled
reagent for a non-isotopically labelled reagent.
DETAILED DESCRIPTION OF THE INVENTION
[0063] The compounds of formula I can be prepared according to the
methods illustrated in Schemes 1-9 and discussed below. In the
reaction schemes and discussion that follow, unless otherwise
indicated, X, Q, Y, Z.sup.1, Z.sup.2, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 and structural
formula I are defined as above.
[0064] Scheme 1 illustrates a method for the preparation of
compounds with the general formula I wherein R.sup.3 is
(C.sub.1-C.sub.6)alkoxy or fluorine, R.sup.2 is CONR.sup.5R.sup.6,
Y is carbon, Q is carbon, X is carbon and R.sup.1 is as defined
above with the proviso that it is not attached to the piperidine
nitrogen at a secondary alkyl carbon or an aryl group. Referring to
Scheme 1, a bromobenzene derivative of formula 0, wherein R.sup.3
is methoxy or fluorine, is cooled to -70.degree. C. in dry
tetrahydrofuran, and then a solution of n-butyllithium is added to
it. The resulting solution is then treated with
N-benzylpiperidin-3-one and the solution is allowed to warm to room
temperature to produce the corresponding compound of formula 1.
[0065] Alternatively, the benzene derivative of formula 0 in
tetrahydrofuran can be treated with magnesium at a temperature from
about 0.degree. C. to the reflux temperature, preferably starting
at room temperature for about three hours and then heating to
reflux and letting the reaction proceed for another hour, after
which N-benzylpiperidin-3-one is added to the mixture. The
resulting solution is then stirred at a temperature ranging from
about 0.degree. C. to the reflux temperature, preferably at about
room temperature, to produce the corresponding compound of formula
1.
[0066] The compound of formula 1, produced by either of the above
methods, in dichloroethane is then treated with phenol and aluminum
chloride or another Lewis acid (e.g., zinc chloride, boron
trifluoride etherate), and the resulting solution is stirred at a
temperature ranging from about 0.degree. C. to the reflux
temperature, preferably at about the reflux temperature, to produce
the corresponding phenol derivative of formula 2. The compound of
formula 2 is then treated with trifluoromethane sulfonic anhydride
or another suitable reagent such as N-phenyltrifluoromethanesul-
fonimide, in the presence of a base such as pyridine,
triethylamine, another trialkyl amine, an alkali metal hydride or
an alkali metal carbonate, to form the trifluoromethane sulfonate
ester of formula 3. This reaction is typically performed in
dicloromethane at a temperature ranging from about 0.degree. C. to
the reflux temperature, preferably at about room temperature.
[0067] The compound of formula 3 is placed under a carbon monoxide
atmosphere at a pressure ranging from about 14 to 100 psi, in a
solution of dimethylsulfoxide and a lower alkanol such as methanol
or ethanol, with a suitable trialkylamine base (e.g.,
triethylamine) and palladium acetate with
1,3-bis(diphenylphosphino)propane (DPPP),
1,3-bis(diphenylphosphino)-ferrocene (DPPF) or another suitable
palladium ligand. Other suitable palladium catalysts such as
bis(triphenylphosphine) palladium dichloride may also be used. This
reaction is performed at temperatures ranging from about 20.degree.
C. to 100.degree. C.
[0068] Treatment of the ester of formula 4 with an aluminum amide
of a primary or secondary amine, for example, diethyl amine, in a
solvent such as dichloroethane or toluene, at a temperature ranging
from about 20.degree. C. to about the reflux temperature,
preferably at about the reflux temperature, yields the
corresponding amide of formula 5. Variations in the nature of the
R.sup.1 group on the piperidine nitrogen can be effected in the
following manner, as illustrated by process steps
(5.fwdarw.6.fwdarw.7) in Scheme 1. The compound of formula 5 is
placed under a hydrogen atmosphere at pressures ranging from about
14 to 100 psi, in ethanol or other another solvent such as acetic
acid or methanol, to produce the corresponding compound of formula
6. This reaction is typically carried out at a temperature from
about 0.degree. C. to about the reflux temperature, preferably at
about room temperature.
[0069] Treatment of the compound of formula 6 with an aldehyde and
sodium triacetoxyborohydride or another reducing agent (e.g.,
sodium borohydride or sodium cyanoborohydride), in dicloromethane,
1,2 dichloroethane or another suitable solvent such as methanol,
ethanol or toluene, at a temperature ranging from about 0.degree.
C. to 100.degree. C., preferably at about room temperature, yields
the desired compound of formula 7. 56
[0070] Compounds of formula I wherein R.sup.1 is a group that
attaches to the piperidine nitrogen via an aryl moiety or a primary
or secondary alkyl moiety, can be prepared by treating the
corresponding compound of formula 6 with an alkylating or arylating
agent of the formula R.sup.1X, wherein X is a leaving group such as
chloro, bromo, iodo, triflate (OTf), mesylate (OMs) or tosylate
(Ots), and sodium or potassium carbonate or another alkali metal
carbonate or bicarbonate in a solvent such as dimethylformamide,
dichloromethane or 1,2 dichloroethane, at a temperature ranging
from about 20.degree. C. to 100.degree. C., as shown below in
Scheme 2. 7
[0071] Compounds of the general formula I where R.sup.3 is hydroxy
can be prepared by deprotecting the corresponding alkyl ether of
formula 7 (wherein R.sup.10 is (C.sub.1-C.sub.6)alkyl) with boron
tribromide in dicloromethane, or with aqueous hydrobromic acid and
acetic acid, or with sodium ethanethiolate in dimethylformamide, at
a temperature ranging from about 0.degree. C. to the reflux
temperature, as shown in Scheme 3. Room temperature is preferred
when boron tribromide is used, the reflux temperature is preferred
when hydrobromic acid/acetic acid is used, and about 100.degree. C.
to about 120.degree. C. is preferred when sodium ethanmethiolate is
used. 8
[0072] The carboxarnide of formula 12 can be obtained by conversion
the phenol of formula 9 in to triflate ester of formula 10 with the
additon of triflic anhydride in the presence of a base such as
pyridine, or a trialkylamine base like triethylamine, and in the
presence of dimethylamino pyridine in a solvent such as methylene
chloride, at a temperature ranging from -40.degree. C. to the
reflux temperature, preferably at 0.degree. C.. The triflate ester
of formula 10 is then converted into the nitrile of formula 11 by
treatment with zinc cyanide and a palladium catalyst such as
tetrakis triphenylphosphine palladium, in a solvent such as
dimethylformamide, or toluene, at a temperature from about
0.degree. C. to about the reflux temperature, preferably at about
the reflux temperature. The nitrile of formula 11 can be converted
into the carboxamide of formula 12 by treatment with hydrogen
peroxide and sodium carbonate in ethanol, at a temperature ranging
from about 0.degree. C. to about the reflux temperature, preferably
at about room temperature. 9
[0073] Compounds of the general formula I wherein R.sup.3 is
methoxy, hydroxy or fluorine and R.sup.2 is an aromatic or
heteroaromatic moiety (referred to in Scheme 5 as compounds of the
formula 14) can be prepared by organometalic coupling of a compound
of the formula 3 with an aryl and heteroaryl boronic acid, wherein
aryl and heteroaryl are defined as in the definitions of R.sup.1
and R.sup.2, in a solvent such as ethanol or toluene, in the
presence of a of palladium catalyst such as tetrakis
triphenylphosphine palladium and a trialkylamine base (e.g.,
triethylamine) or alkali metal carbonate base, as shown below in
Scheme 5. This reaction is generally carried out at a temperature
from about room temperature to about the reflux temperature,
preferably at about the reflux temperature. 10
[0074] Compounds of the general formula I where R.sup.3 is fluoro
or methoxy and R.sup.2 is a carbinol such as diethyl carbinol
(referred to in Scheme 6 as compounds of the formula 15) can be
prepared, as illustrated in Scheme 6 by treatment of the ester of
formula 4 with an alkyl Grignard or alkyl lithium reagent, in a
solvent such as ether or tetrahydrofuran, at a temperature ranging
from about -78.degree. C. to about the reflux temperature,
preferably starting at room temperature and heating to about the
reflux temperature. 11
[0075] Compounds of the formulas 14 (Scheme 5) and 15 (Scheme 6)
can be converted into the analogous compounds wherein
R.sup.3=CONH.sub.2 using the procedures illustrated in Schemes 3
and 4 and described above for synthesizing carboxamides of the
formula 12.
[0076] Compounds of the general formula 16 can be prepared, as
illustrated in Scheme 7, by treatment of the phenol of formula 9
with an acid chloride, in the presence of pyridine or a
trialkylamine such as triethylamine in dichloromethane,
tetrahydrofuran or another suitable solvent, at a temperature
ranging from about -78.degree. C. to about the reflux temperature,
preferably at room temperature. 12
[0077] Scheme 8 illustrates a method for preparing compounds of the
general formula I wherein Q is oxygen, R.sup.3 is methoxy, hydroxy,
R.sup.2 is CONR.sup.5R.sup.6 and R.sup.1 is as defined above.
Referring to Scheme 8, a bromobenzene derivative of formula 17,
wherein R.sup.3 is methoxy or fluorine, is cooled to -70.degree. C.
in dry tetrahydrofuran, and treated with a solution of
n-butyllithium. The resulting solution is then treated with an
appropriately substituted aryl aldehyde of the formula 18, and the
solution is allowed to warm to room temperature to produce the
corresponding compound of formula 19.
[0078] Alternatively, the benzene derivative of formula 17 in
tetrahydrofuran can be treated with magnesium at a temperature from
about 0.degree. C. to about the reflux temperature, preferably
starting at room temperature for about three hours and then heating
to reflux and letting the reaction proceed for about another hour,
after which the aryl aldehyde of formula 18 is added to the
mixture. The resulting solution is then stirred at a temperature
ranging from about 0.degree. C. to the reflux temperature,
preferably at about room temperature, to produce the corresponding
compound of formula 19.
[0079] Compounds of the formula 20 can be prepared using a Swern
oxidation. Thus, a solution of trifluroacetic anhydride in
methylene chloride is treated with DMSO at a temperature from about
-78.degree. C. to about room temperature, preferably at -78.degree.
C., and to this mixture is added a solution of the compound of
formula 19 in methylene chloride, followed by addition of a
trialkylamine base such as triethylamine. The mixture is allowed to
warm to room temperature to produce the corresponding compound of
the formula 20. Alternatively, compounds of the formula 20 can be
prepared by oxidation of the compound of formula 19 by addition of
pyridinium dichromate, in a solvent such as methylene chloride, at
a temperature from about -78.degree. C. to about the reflux
temperature, preferably at about room temperature.
[0080] Compounds of the formula 20 can be converted into compounds
of formula 21 via addition of trimethylsilyl cyanide in the
presence of zinc iodide in a solvent such as methylene chloride, at
a temperature from about -78.degree. C. to about the reflux
temperature, preferably at about room temperature, followed by
treatment of the intermediate cyanohydrine with lithium aluminum
hydride or another metal hydride source such as diisobutyl aluminum
hydride, in a solvent such as methylene chloride, at a temperature
from about -78.degree. C. to about the reflux temperature,
preferably at 0.degree. C.
[0081] Treatment of a compound of the formula 21 with a
trialkylamine base such as triethylamine and chloroacetylchloride
in a solvent such as toluene or tetrahydrofuran, at a temperature
ranging from about -40.degree. C. to about the reflux temperature,
preferably at 0.degree. C., yields the corresponding compound
having formula 22. Subsequent treatment of a dilute solution of the
resulting compound of formula 22 in a solvent such as
tetrahydrofuran or toluene with metal alkoxides, preferably
potasium t-butoxide, at a temperature ranging from about
-40.degree. C. to about the reflux temperature, preferably at about
room temperature, affords the corresponding derivative of formula
23. Reaction of the derivative of formula 23 with lithium aluminum
hydride or another metal hydride source such as dibutyl aluminum
hydride, in a solvent such as methylene chloride, at a temperature
from about -78.degree. C. to about the reflux temperature,
preferably at about 0.degree. C., affords the corresponding
compound of formula 24.
[0082] When R.sup.1 is not attached to the morpholine nitrogen at a
secondary alkyl carbon or an aryl group, the R.sup.1 group can be
added to the morpholine nitrogen of the compound of formula 24 by
reacting such compound with an aldehyde and sodium
triacetoxyborohydride or another reducing agent (e.g., sodium
borohydride or sodium cyanoborohydride) in dicloromethane, 1,2
dichloroethane or another suitable solvent such as methanol,
ethanol or toluene, at a temperature ranging from about 0.degree.
C. to 100.degree. C., preferably at about room temperature. This
reaction yields the desired compound of formula 25. When R.sup.1 is
attached to the morpholine nitrogen via an aryl moiety or a primary
or secondary alkyl moiety, it can be added to the compound of
formula 24 using the procedure illustrated in Scheme 2 and
described above. Compounds of the formula 25 can be produced by
alkylation or heteroarylation of the corresponding compound of
formula 24 using conditions identical to those described above for
the preparation of compounds of the formula 7 Scheme 2.
[0083] The compound of formula 25 is then placed under a carbon
monoxide atmosphere at a pressure ranging from about 14 to 100 psi,
in a solution of dimethylsulfoxide and a lower alkanol such as
methanol or ethanol, with a suitable trialkylamine base (e.g.,
triethylamine) and palladium acetate with
1,3-bis(diphenylphosphino)propane (DPPP) or another suitable
palladium ligand, to yield the desired compound of formula 26.
Other suitable palladium catalysts, such as bis(triphenylphosphine)
palladium dichloride, may also be used. This reaction can be
conducted at temperatures ranging from about 20.degree. C. to about
100.degree. C., preferably at about 70.degree. C. Treatment of the
ester of formula 26 with an aluminum amide of a primary or
secondary amine, for example, diethyl amine, in a solvent such as
dichloroethane or toluene, at a temperature ranging from about
20.degree. C. to about the reflux temperature, preferably at about
the reflux temperature, yields the corresponding amide of formula
27.
[0084] Compounds of the formula 28 where R.sup.3 is hydroxy can be
prepared by deprotecting the corresponding alkyl ethers of formula
27 (wherein R.sup.3 is OR.sup.10 and R.sup.10 is
(C.sub.1-C.sub.6)alkyl) with boron tribromide in dicloromethane, or
with aqueous hydrobromic acid and acetic acid, or with sodium
ethanethiolate in dimethylformamide, at a temperature ranging from
about 0.degree. C. to the about reflux temperature, as illustrated
in Scheme 3. Room temperature is preferred when boron tribromide is
used, the reflux temperature is preferred when hydrobromic
acid/acetic acid is used, and about 100.degree. C. to about
120.degree. C. is preferred when sodium ethanethiolate is used.
1314
[0085] Compounds of the formula 25 can be converted into the
corresponding compounds wherein the bromine substituent is replaced
by an aromatic or heteroaromatic substituent using the procedure
illustrated in Scheme 5 and discussed above. Compounds of the
formula 26 can be converted into the corresponding compounds
wherein R.sup.2 is --C(OH)R.sup.5R.sup.6 rather than --COOR.sup.7
using the procedure described above and illustrated in Scheme 6.
Compounds of the formula 28 can be derivatized to form the
corresponding compounds wherein R.sup.3 is --CONH.sub.2 and
--OC(.dbd.O)R.sup.7 using the procedures described above and
illustrated in Schemes 4 and 7, respectively, for preparing
compounds of the formula 12 (Scheme 4) and 16 (Scheme 7).
[0086] Scheme 9 illustrates a method for the preparation of
compounds with the general formula I wherein X is nitrogen, R.sup.3
is methoxy, hydroxy, R.sup.2 is CONR.sup.5R.sup.6 and R.sup.1 is as
defined above. Referring to Scheme 9, compounds of the formula 31
can be obtained by the treatment of phenyl acetonitrile derivatives
of the formula 29 with sodium hydride and a 2-bromopyridine or
2-halopyridine derivative of the formula 30 in dimethylformamide or
in another suitable solvent such as tetrahydrofuran, at a
temperature from about 0.degree. C. to about the reflux
temperature, preferably at about 60.degree. C.
[0087] Treatment of compounds of the formula 31 with sodium hydride
in dimethylformamide or another suitable solvent such as
tetrahydrofuran, at a temperature from about 0.degree. C. to about
the reflux temperature, preferably at 60.degree. C., followed by
the treatment with a alkylating agent such as
1-bromo-3-chloropropane, at a temperature from about 0.degree. C.
to about the reflux temperature, preferably at about 60.degree. C.,
yields the corresponding compounds of formula 32.
[0088] Reduction of the cyano group of compounds of the formula 32
with a reducing agent such as diisobutyl aluminum hydride or
another reducing metal hydride source such as lithum aluminum
hydride, in a solvent such as methylene chloride, at a temperature
from about -78.degree. C. to about the reflux temperature,
preferably at about -78.degree. C., and warming gradually to room
temperature, affords the corresponding compounds of formula 33
after vigorous stirring in a saturated aqueous Rochelle's salt
solution.
[0089] When R.sup.1 does not attach to the piperidine nitrogen at
an aryl moiety or secondary alkyl carbon, compounds of the formula
33 can be converted into the corresponding compounds of formula 34
by reacting them with an aldehyde and sodium triacetoxyborohydride
or another reducing agent (e.g., sodium borohydride or sodium
cyanoborohydride), in dicloromethane, 1,2 dichloroethane or another
suitable solvent such as methanol, ethanol or toluene, at a
temperature ranging from about 0.degree. C. to about 100.degree.
C., preferably at about room temperature. When R.sup.1 attaches to
the piperidine nitrogen via an aryl moiety or a primary or
secondary alkyl carbon, compounds of the formula 34 can be produced
by alkylation or heteroarylation of compounds of the general
formula 33 using conditions identical to those described for the
preparation of compounds of the formula 7 in Scheme 2.
[0090] The compounds of formula 34 are then placed under a carbon
monoxide atmosphere at a pressure ranging from about 14 to 100 psi,
in a solution of dimethylsulfoxide and a lower alkanol such as
methanol or ethanol, with a suitable trialkylamine base (e.g.,
triethylamine) and palladium acetate with
1,3-bis(diphenylphosphino)propane (DPPP) or another suitable
palladium ligand. Other suitable palladium catalysts such as
bis(triphenylphosphine) palladium dichloride may also be used. This
reaction, which is typically conducted at temperatures ranging from
about 20.degree. C. to about 100.degree. C., yields the desired
compound of formula 35.
[0091] Treatment of the ester of formula 35 with an aluminum amide
of a primary or secondary amine, for example, diethyl amine, in a
solvent such as dichloroethane or toluene, at a temperature ranging
from about 20.degree. C. to about the reflux temperature,
preferably at about the reflux temperature, yields the
corresponding amide of formula 36.
[0092] Compounds of the formula 37 wherein R.sup.3 is hydroxy can
be prepared by deprotecting the corresponding alkyl ethers of
formula 36 (wherein R.sup.3 is OR.sup.10 and R.sup.10 is
(C.sub.1-C.sub.6)alkyl) with boron tribromide in dicloromethane, or
with aqueous hydrobromic acid and acetic acid, or with sodium
ethanethiolate in dimethylformamide, at temperatures ranging from
about 0.degree. C. to about the reflux temperature, as shown in
Scheme 3. Room temperature is preferred when boron tribromide is
used, the reflux temperature is preferred when hydrobromic
acid/acetic acid is used, and about 100.degree. C. to about
120.degree. C. is preferred when sodium ethanmethiolate is used.
1516
[0093] Compounds of the formula 34 can be converted into the
corresponding compounds wherein the bromine substituent is replaced
by an aromatic or heteroaromatic substituent using the procedure
illustrated in Scheme 5 and discussed above. Compounds of the
formula 35 can be converted into the corresponding compounds
wherein R.sup.2 is --C(OH)R.sup.5R.sup.6 rather than --COOR.sup.7
using the procedure described above and illustrated in Scheme 6.
Compounds of the formula 37 can be derivatized to form the
corresponding compounds wherein R.sup.3 is --CONH.sub.2 and
--OC(.dbd.O)R.sup.7 using the procedures described above and
illustrated in Schemes 4 and 7, respectively, for preparing
compounds of the formula 12 (Scheme 4) and 16 (Scheme 7).
[0094] Scheme 10 illustrates a method for preparing compounds of
the general formula I wherein R.sup.3 is NHSO.sub.2R.sup.7.
Referring to Scheme 10, the phenol of formula 38 is converted into
the triflate of formula 39 by the procedures illustrated in Schemes
1 and 4 and described above, after which the triflate is
transformed into the ester of formula 40 by the procedure
illustrated in Scheme 1 and described above. The ester of formula
40 can then be converted into the carboxylic acid of formula 41 by
hydrolyzing it with lithium hydroxide in a water/THF solution at
about room temperature. Treatment of the resulting carboxlic acid
of formula 41 with diphenylphosphoryl azide and triethylamine in a
tert-butanol solvent at about the reflux temperature yields the
corresponding tert-butyl carbamate of formula 42. Acidic treatment
of the carbamate of formula 42 with trifluoroacetic acid in
methylene chloride yields the corresponding aniline of formula 43.
The aniline of forumla 43 can then be reacted with sulfonyl
chloride, in the presence of a base such as pyridine or
triethylamine, to yield the desired sulfonamide of formula I. This
reaction is preferrable carried out in a polar solvent such as
methylene chloride, dicloroethane or THF, at a temperature from
about 0.degree. C. to about the reflux temperature of the solvent.
17
[0095] The preferred method of making compounds of the formula I
wherein R.sup.3 is OH, NHSO.sub.2R.sup.7, C(OH)R.sup.7R.sup.8 or
C(.dbd.O)NHR.sup.7 is to make the analogous compounds wherein
R.sup.3 is O--(C.sub.1-C.sub.6)alkyl and then derivatize them using
standards methods well known in art and illustrated in the
foregoing schemes.
[0096] The starting materials used in the processes of Schemes 1-9
are either commercially available, known in the literature, or
readily obtainable from commercially available or known compounds
using methods that are well known in the art or described
above.
[0097] Unless indicated otherwise, the pressure of each of the
above reactions is not critical. Generally, the reactions will be
conducted at a pressure from about one to about three atmospheres,
preferably at ambient pressure (about one atmosphere).
[0098] 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.
[0099] The compounds of the formula I that are basic in nature are
capable of forming a wide variety of different salts with various
inorganic and organic acids. The acid that can be used to prepare
the pharmaceutically acceptable acid addition salts of the base
compounds of this invention are those which form non-toxic acid
addition salts, i.e., salts containing pharmacologically acceptable
anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate,
sulfate or bisulfate, phosphate or acid phosphate, acetate,
lactate, citrate or acid citrate, tartrate or bitartrate,
succinate, maleate, fumarate, gluconate, saccharate, benzoate,
methanesulfonate and pamoate [i.e.,, 1,1'-methylene-bis-(2-hydr-
oxy-3-naphthoate)] salts. 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 free base to a pharmaceutically acceptable
acid addition salt. The acid addition salts of the 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 obtained.
[0100] Compounds of the formula that are acidic in nature are
capable of forming base salts with various pharmacologically
acceptable cations. These salts are all prepared by conventional
techniques. The chemical bases that are used as reagents to prepare
the pharmaceutically acceptable base salts of this invention are
those which form non-toxic base salts with the acidic compounds of
formula I. Such non-toxic base salts include those derived from
such pharmacologically acceptable cations as sodium, potassium,
calcium and magnesium, etc. These salts can easily be prepared by
treating the corresponding acidic compounds with an aqueous
solution containing the desired pharmacologically acceptable
cations, and then evaporating the resulting solution to dryness,
preferably under reduced pressure. Alternatively, they may also be
prepared by mixing lower alkanolic solutions of the acidic
compounds and the desired alkali metal alkoxide together, and then
evaporating the resulting solution to dryness in the same manner as
before. In either case, stoichiometric quantities of reagents are
preferably employed in order to ensure completeness of reaction and
maximum yields of the desired final product.
[0101] The compounds of the formula I and the pharmaceutically
acceptable salts thereof (hereinafter, also referred to,
collectively, as "the active compounds of the invention") are
useful for the treatment of neurodegenerative, psychotropic and
drug or alcohol induced deficits and are potent opioid receptor
ligands. The active compounds of the invention may therefore be
used in the treatment of disorders and conditions, such as those
enumerated above, that can be treated by modulatiing binding to an
opioid receptor.
[0102] The ability of the compounds of formula I to bind to the
various opioid receptors and their functional activity at such
receptors can be determined as described below. Binding to the
delta opioid receptor can be determined using procedures well known
in the art, such as those referred to by Lei Fang et al., J. Pharm.
Exp. Ther., 268, 1994, 836-846 and Contreras et al., Brain
Research, 604, 1993,160-164.
[0103] In the description of binding and functional assays that
follows, the following abbreviations and terminology are used.
[0104] DAMGO is [D-Ala2,N-MePhe4,Gly5-ol]enkephalin).
[0105] U69593 is ((5a, 7a,
8b)-(+)-N-methyl-N-(7-[1-pyrrolidinyl]-1-oxasip-
ro[4,5]dec-8-yl)-benzeneacetamide).
[0106] SNC-80 is
(+)-4-[(.alpha.R)-.alpha.((2S,5R)-4-allyl-2,5-dimethyl-1--
piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide.
[0107] nor BNI is nor-binaltorphimine.
[0108] CTOP is 1,2-Dithia-5,8,11,14,17-pentaazacycloeicosane,
cyclic peptide derivative DPDPE is [D-en2,D-Pen5]enkephalin).
[0109] [3H]-DAMGO, [3H]-U69593, norBNI, and CTOP are all
commercially available from DuPont, Amersham International, RBI and
DuPont, Amersham International, RBI and DuPont respectively.
[0110] [3H]-SNC80 was prepared by Amersham International.
[0111] Opioid (mu and kappa) receptor binding assays can be
performed in guinea-pig brain membrane preparations. Binding assays
can be carried out at 25.degree. C. for 60 minutes in 50 mM Tris
(pH 7.4) buffer. [.sup.3H]-DAMGO(2 nM) and [.sup.3H]-U-69,593 (2
nM) can be used to label mu and kappa receptor binding sites,
respectively. The protein concentration can be approximately 200
.mu.g/well. Non-specific binding can be defined with 10 .mu.M
naloxone.
[0112] Delta receptor binding assays can be performed in a stable
line of CHO cells expressing the human delta receptor. The binding
assay can be carried out at 25.degree. C. for 120 minutes in 50 mM
Tris (pH 7.4) buffer. [.sup.3H]-SNC-80 can be used to label delta
receptor binding sites. The protein concentration can be
approximately 12.5 .mu.g/well. Non-specific binding can be defined
with 10 .mu.M naltrexone.
[0113] The binding reaction can be terminated by rapid filtration
through glass fibre filters, and the samples can be washed with
ice-cold 50 mM Tris buffer (pH 7.4).
[0114] Agonist activity at the delta, mu and kappa opioid receptors
can be determined as follows.
[0115] Opioid (delta, mu and kappa) activity is studied, as
described below, in two isolated tissues, the mouse deferens
(MVD)(.delta.) and the guinea-pig myentric plexus with attached
longitudinal muscle (GPMP) (.mu. and k).
[0116] MVD (DC1 strain, Charles River, 25-35 g) are suspended in 15
ml organ baths containing Mg.sup.++ free Krebs' buffer of the
following composition (mM): NaCl, 119; KCl, 4.7; NaHCO.sub.3, 25;
KH.sub.2PO.sub.4, 1.2; CaCl.sub.2, 2,5 and glucose, 11. The buffer
is gassed with 95% O.sub.2 and 5% CO.sub.2. The tissues are
suspended between platinum electrodes, attached to an isometric
transducer with 500 mg tension and stimulated with 0.03 Hz pulses
of 1-msec pulse-width at supramaximal voltage. IC.sub.50 values are
determined by the regression analysis of concentration-response
curves for inhibition of electrically-induced contractions in the
presence of 300 nM of the mu-selective antagonist CTOP. This test
is a measure of .delta. agonism.
[0117] Guinea-pig (Porcellus strain, male, 450-500 g, Dunkin
Hartley) myentric plexus with attached longitudinal muscle segments
are suspended with 1 g of tension in Krebs' buffer and stimulated
with 0.1 Hz pulses of 1-msec pulse-width at supramaximal voltage.
Mu functional activity is determined in the presence of 10 nM
nor-BNI with 1 .mu.M of the mu selective agonist, DAMGO, added to
the bath at the end of the experiment to define a maximal response.
This test is a measure of mu agonism.
[0118] Kappa functional activity is determined in the presence of
and 1 .mu.M CTOP with 1 .mu.M of the kappa selective agonist
U-69,593 added at the end of the experiment to define a maximal
response. All inhibitions of twitch height for test compounds are
expressed as a percentage of the inhibition obtained with the
standard agonist and the corresponding IC.sub.50 values
determined.
[0119] The following procedure can be used to determine the
activity of the therapeutic agents of this invention as agonists
and as antagonists of delta opioid receptors.
[0120] Cell Culture: Chinese hamster ovary cells expressing the
human delta opioid receptor are passaged twice weekly in Hamis F-12
media with L-glutamine containing 10% fetal bovine serum and 450
.mu.g/mL hygromycin. Cells are prepared for assays 3 days prior to
the experiment. 15 mL of 0.05% trypsin/EDTA is added to a confluent
triple flask, swirled and decanted to rinse. 15 mL of 0.05%
trypsin/EDTA is again added, and the flask is placed into a 37C
incubator for 2 minutes. Cells are removed from the flask by
banking, and supernatant poured off into a 50 mL tube. 30 mL of
media is then added to the flask to stop the action of the trypsin,
and then decanted into the 50 mL tube. Tube is then centrifuged for
5 minutes at 1000 rpm, media decanted, and the pellet resuspended
into 10 mL of media. Viability of the cells is assessed using
trypan blue, the cells counted and plated out into 96 well
poly-D-lysine coated plates at a density of 7,500 cells/well.
[0121] Antagonist Test Plate: Cells plated 3 days prior to assay
are rinsed twice with PBS. The plates are placed into a 37C water
bath. 50 .mu.L of assay buffer (PBS, dextrose 1 mg/mL, 5 mM MgC12,
30 mM HEPES, 66.7 .mu.g/mL of IBMX) is then added to designated
wells. Fifty microliters of appropriate drug is then added to
designated wells, and timed for 1 minute. Fifty microliters of 10
.mu.M forskolin+0.4 nM DPDPE (final assay concentration is 5 .mu.M
forskolin, 0.2 nM DPDPE) is then added to appropriate wells, and
timed for 15 minutes. The reaction is stopped by the addition of 10
.mu.L of 6N perchloric acid to all wells. To neutralize, 13 82 L of
5N KOH is added to all wells, and to stabilize 12 .mu.L of 2M Tris,
pH 7.4 is added to all wells. Mix by shaking on an orbital shaker
for 10 minutes, and centrifuge at setting 7 for 10 minutes.
Alliquot into 3H plate.
[0122] Agonist Test Plate: Cells plated 3 days prior to assay are
rinsed twice with PBS. The plates are placed into a 37.degree. C.
water bath. Fifty microliters of assay buffer (PBS, dextrose 1
mg/mL, 5 mM MgCl.sub.2, 30 mM HEPES, 66.7 .mu.g/mL of IBMX) is then
added to designated wells. Fifty microliters of appropriate drug+10
.mu.M forskolin (final assay concentration is 5 .mu.M forskolin) is
then added to all wells, and timed for 15 minutes. The reaction is
then stopped by the addition of 10 .mu.L of 6N perchloric acid to
all wells. To neutralize, 13.mu. of 5N KOH is added to all wells,
and to stablize 12 .mu.L of 2M Tris, pH 7.4 is added to all wells.
Mix by shaking on an orbital shaker for 10 minutes, and centrifuge
at setting 7 for 10 minutes. Alliquot into 3H plate.
[0123] Both test plates are placed into an Amersham 3H cAMP binding
kit overnight, and harvested onto GF/B filters previously soaked in
0.5% PEI with a Skatron using 50 mM Tris HCl pH 7.4 at 4.degree. C.
Filtermats can be air-dried overnight then place in bags with 20 ml
Betaplate scintillation cocktail and counted on a Betaplate counter
for 60 sec per sample. Data can be analyzed using Excel.
[0124] The compositions of the present invention may be formulated
in a conventional manner using one or more pharmaceutically
acceptable carriers. Thus, the active compounds of the invention
may be formulated for oral, buccal, transdermal (e.g., patch),
intranasal, parenteral (e.g., intravenous, intramuscular or
subcutaneous) or rectal administration or in a form suitable for
administration by inhalation or insufflation.
[0125] For oral administration, the pharmaceutical compositions may
take the form of, for example, tablets or capsules prepared by
conventional means with pharmaceutically acceptable excipients such
as binding agents (e.g., pregelatinised maize starch,
polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers
(e.g., lactose, microcrystalline cellulose or calcium phosphate);
lubricants (e.g., magnesium stearate, talc or silica);
disintegrants (e.g., potato starch or sodium starch glycollate); or
wetting agents (e.g., sodium lauryl sulphate). The tablets may be
coated by methods well known in the art. Liquid preparations for
oral administration may take the form of, for example, solutions,
syrups or suspensions, or they may be presented as a dry product
for constitution with water or other suitable vehicle before use.
Such liquid preparations may be prepared by conventional means with
pharmaceutically acceptable additives such as suspending agents
(e.g., sorbitol syrup, methyl cellulose or hydrogenated edible
fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous
vehicles (es, almond oil, oily esters or ethyl alcohol); and
preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic
acid).
[0126] For buccal administration the composition may take the form
of tablets or lozenges formulated in conventional manner.
[0127] The active compounds of the invention may be formulated for
parenteral administration by injection, including using
conventional catheterization techniques or infusion. Formulations
for injection may be presented in unit dosage form, e.g., in
ampules or in multi-dose containers, with an added preservative.
The compositions may take such forms as suspensions, solutions or
emulsions in oily or aqueous vehicles, and may contain formulating
agents such as suspending, stabilizing and/or dispersing agents.
Alternatively, the active ingredient may be in powder form for
reconstitution with a suitable vehicle, e.g., sterile pyrogen-free
water, before use.
[0128] The active compounds of the invention may also be formulated
in rectal compositions such as suppositories or retention enemas,
e.g., containing conventional suppository bases such as cocoa
butter or other glycerides.
[0129] For intranasal administration or administration by
inhalation, the active compounds of the invention are conveniently
delivered in the form of a solution or suspension from a pump spray
container that is squeezed or pumped by the patient or as an
aerosol spray presentation from a pressurized container or a
nebulizer, with the use of a suitable propellant, e.g.,
dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In
the case of a pressurized aerosol, the dosage unit may be
determined by providing a valve to deliver a metered amount. The
pressurized container or nebulizer may contain a solution or
suspension of the active compound. Capsules and cartridges (made,
for example, from gelatin) for use in an inhaler or insulator may
be formulated containing a powder mix of a compound of the
invention and a suitable powder base such as lactose or starch.
[0130] In general, a therapeutically effective daily oral or
intravenous dose of the compounds of formula (I) and their salts is
likely to range from 0.001 to 50 mg/kg body weight of the subject
to be treated, preferably 0.1 to 20 mg/kg. The compounds of the
formula (I) and their salts may also be administered by intravenous
infusion, at a dose which is likely to range from 0.001-10
mg/kg/hr.
[0131] Tables or capsules of the compounds may be administered
singly or two or more at a time as appropriate. It is also possible
to administer the compounds in sustained release formulations.
[0132] The physician will determine the actual dosage which will be
most suitable for an individual patient and it will vary with the
age, weight and response of the particular patient. The above
dosages are exemplary of the average case. There can, of course, be
individual instances where higher or lower dosage ranges are
merited, and such are within the scope of this invention.
[0133] Alternatively, the compounds of the formula (I) can be
administered by inhalation or in the form of a suppository or
pessary, or they may be applied topically in the form of a lotion,
solution, cream, ointment or dusting powder. An alternative means
of transdermal administration is by use of a skin patch. For
example, they can be incorporated into a cream consisting of an
aqueous emulsion of polyethylene glycols or liquid paraffin. They
can also be incorporated, at a concentration of between 1 and 10%
by weight, into an ointment consisting of a white wax or white soft
paraffin base together with such stablisers and preservatives as
may be required.
[0134] The following Examples illustrate the preparation of the
compounds of the present invention. Commercial reagents were
utilized without further purification. All NMR data were recorded
at 250, 300 or 400 MHz in deuterochloroform unless otherwise
specified and are reported in parts per million (.delta.) and are
referenced to the deuterium lock signal from the sample solvent.
All non-aqueous reactions were carried out in dry glassware with
dry solvents under an inert atmosphere for convenience and to
maximize yields. All reactions were stirred with a magnetic
stirring bar unless otherwise stated. Unless otherwise stated, all
mass spectra were obtained using chemical impact conditions.
Ambient or room temperature refers to 20-25.degree. C.
EXAMPLE 1
N,N-DIETHYL-4-[3-(3-METHOXY-PHENYL)-PIPERIDIN-3-YL]-1-BENZAMIDE
[0135] A. 1-Benzyl-3-(3-methoxy-phenyl)-piperidin-3-ol
[0136] To a suspension of magnesium (7.8 g, 325 mmol) in THF (120
mL) at room temperature under a nitrogen atmosphere was added a
solution of 3-bromoanisole (37.5 mL, 296 mmol) in THF (60 mL) over
10 min. The resulting mixture was stirred at 50.degree. C. for 4
hours and was cooled to room temperature. To the mixture was added
a solution an N-benzyl-3-piperidinone (30.0 g, 159 mmol) in THF (50
mL). The reaction was stirred at room for 10 hours. The mixture was
poured slowly over ice-water (100 mL) and the aqueous layer was
washed with EtOAc (3.times.50 mL). The combined organic extracts
were dried (MgSO.sub.4) and concentrated. The crude residue was
purified by flash chromatography with hexanes/EtOAc (3:1) to afford
38.4 g of 1-benzyl-3-(3-methoxy-phenyl- )-piperidin-3-ol .sup.1HNMR
(400 MHz, CDCl.sub.3) .delta. 7.31-7.20 (comp, 6H), 7.09 (s, 1H),
7.01 (d, 1H), 6.79 (d, 1H), 4.01-3.96 (br, 1H), 3.79 (s, 3H), 3.58
(s, 2H), 2.91 (d, 1H), 2.74 (d, 1H), 2.32 (d, 1H), 2.09-1.82 (comp,
2H), 1.81-1.61 (comp, 3H); MS (M+1) 298.2.
[0137] B.
4-[1-Benzyl-3-(3-methoxy-phenyl)-piperidin-3-yl]-phenol
[0138] To a solution of
1-benzyl-3-(3-methoxy-phenyl)-piperidin-3-ol (17.6 g, 73.1 mmol) in
(CH.sub.2).sub.2Cl.sub.2 (200 mL) was added phenol (16.7 g, 178
mmol) followed by portionwise addition (highly exothermic) of
AlCl.sub.3 (23.3 g, 178 mmol). The reaction mixture was heated to
reflux for 2 hours. The mixture was cooled to room temperature and
was slowly poured into a mixture of crushed ice (50 mL) and 30% aq.
NH.sub.4OH (120 mL). The mixture was stirred vigorously for 20
mininutes and was then filtered through celite. The celite cake was
washed with CH.sub.2Cl.sub.2 (200 mL). The organic layer was
separated and the aqueous layer was washed with CH.sub.2Cl.sub.2
(3.times.100 mL). The combined organic layers were dried
(MgSO.sub.4) and concentrated. The crude residue was purified by
flash chromatography with hexanes/EtOAc (1:1) to afford 16.3 g of
4-[1-benzyl-3-(3-methoxy-phenyl)-piperidin-3-yl]-phenol .sup.1HNMR
(400 MHz, CDCl.sub.3) 6 7.39-7.21 (comp, 5H), 7.19-7.05 (comp. 3H),
6.84 (s, 1H), 6.79 (d, 1H), 6.67-6.61 (comp, 3H), 3.73 (s, 3H),
3.50 (s, 2H), 2.86-2.79 (comp, 2H), 2.45-2.38 (comp, 2H), 2.21-2.19
(comp, 2H), 1.60-1.51 (comp, 2H); MS (M+1) 374.2.
[0139] C. Trifluoro-methanesulfonic Acid
4-[l-benzyl-3-(3-methoxy-phenyl)-- piperidin-3-yl]-phenyl ester
[0140] To a slurry of
4-[1-benzyl-3-(3-methoxy-phenyl)-piperidin-3-yl]-phe- nol (10.4 g,
27.8 mmol) in CH.sub.2Cl.sub.2 (60 mL) at 0.degree. C. was added
pyridine (3.37 mL, 41.7 mmol) followed by dropwise addition of
triflic anhydride (5.62 mL, 27.8 mmol) over 5 minutes. The reaction
mixture was stirred at 0.degree. C. for 1 hour and at room
temperature for 2 hours. The solution was then cooled to 0.degree.
C. and 40 mL of cold saturated aqueous NaHCO.sub.3 were added. The
organic layer was separated and the aqueous layer was washed with
CH.sub.2Cl.sub.2 (3.times.50 mL). The combined organic layers were
dried (MgSO.sub.4) and concentrated. The crude residue was purified
by flash chromatography with hexanes/EtOAc (4:1) to afford 9.81 g
of Trifluoro-methanesulfonic acid
4-[1-benzyl-3-(3-methoxy-phenyl)-piperidin-3-yl]-phenyl ester.
.sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.39-7.22 (comp, 7H), 7.15
(t, 1H), 7.09 (d, 2H), 6.76-6.67 (comp, 3H), 3.72 (s, 3H),
3.52-3.49 (comp, 2H), 3.08-2.91 (m, 1H), 2.2.72-2.60 (m, 1H),
2.59-2.49 (m, 1H), 2.41-2.29 (m, 1H), 2.23-2.19 (comp, 2H),
1.61-1.41 (comp, 2H); MS (M+1) 506.1.
[0141] D. 4-[1-Benzyl-3-(3-methoxy-phenyl)-piperidin-3-yl]-benzoic
acid methyl ester
[0142] To a solution of trifluoro-methanesulfonic acid
4-[1-benzyl-3-(3-methoxy-phenyl)-piperidin-3-yl]-phenyl ester (12.9
g, 25.4 mmol) in a Parr pressure bottle in MeOH (39 mL) were added
DMSO (18 mL) and triethylamine (21 mL, 151 mmol). To the reaction
mixture were added palladium acetate (3.99 g, 17.8 mmol) and
1,3-bis (diphenylphosphino) propane (5.25 g, 12.3 mmol). The
mixture was shaken under 40 psi of CO at 70.degree. C. for 4 hours.
The reaction mixture was cooled to room temperature and was diluted
with diethyl ether (600 mL). The ether layer was washed with water
(5.times.60 mL), dried (MgSO.sub.4) and concentrated. The crude
residue was purified by flash chromatography with hexanes/EtOAc
(3:1) to afford 9.82 g of 4-[1-benzyl-3-(3-methoxy-phe-
nyl)-piperidin-3-yl]-benzoic acid methyl ester. .sup.1HNMR (400
MHz, CDCl.sub.3) .delta. 7.87 (d, 2H), 7.41-7.20 (comp, 7H), 7.12
(t, 1H), 6.77 (s, 1H), 6.73 (d, 1H), 6.66 (d, 1H), 3.86 (s, 3H),
3.71 (s, 3H), 3.51 (s, 2H), 3.05 (br, 1H), 2.68 (br, 1H), 2.55 (br,
1H), 2.41-2.24 (comp, 2H), 2.22-2.18 (m, 1H) 1.61-1.42 (comp, 2H);
MS (M+1) 416.3.
[0143] E.
4-[1-Benzyl-3-(3-methoxy-phenyl)-piperidin-3-yl]-N,N-diethyl-ben-
zamide
[0144] To a solution of diethyl amine (8.21 mL, 79.6 mmol) in
CH.sub.2ClCH.sub.2Cl (20 mL) at room temperature was added a
trimethylaluminum (39.8 mL, 79.6 mmol, 2M in hexanes) dropwise. The
reaction mixture was stirred at room temperature for 1 hour. A
solution of
4-[1-benzyl-3-(3-methoxy-phenyl)-piperidin-3-yl]-benzoic acid
methyl ester (6.0 g, 14.5 mmol) in (CH.sub.2).sub.2Cl.sub.2 (6 mL)
was added and the reaction mixture was heated to reflux for 14
hours (h). The solution was then cooled 0.degree. C. and sat.
aqueous sodium bicarbonate (NaHCO.sub.3) (15 mL) was added
dropwise. The mixture was filtered through celite. The celite cake
was washed with CH.sub.2Cl.sub.2 (40 mL). The organic layer was
separated and the aqueous layer was washed with CH.sub.2Cl.sub.2
(3.times.30 mL). The combined organic layers were dried over
magnesium sulfate (MgSO.sub.4) and concentrated. The crude residue
was purified by flash chromatography with ethyl acetate (EtOAc) to
afford 6.57 g of
4-[1-benzyl-3-(3-methoxy-phenyl)-piperidin-3-yl]-N,N-diethyl-be-
nzamide. .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.41-7.20 (comp,
9H), 7.14 (t, 1H), 6.82 (s, 1H), 6.75 (d, 1H), 6.66 (d, 1H), 3.73
(s, 3H), 3.68-3.51 (comp, 2H), 3.50 (s, 2H), 3.32-3.21 (comp, 2H),
2.98-2.89 (m, 1H), 2.82-2.74 (m, 1H), 2.65-2.59 (m, 1H), 2.56-2.32
(comp, 2H), 2.29-2.19 (comp, 3H), 1.57-1.49 (comp, 1H), 1.23-1.10
(comp, 3H), 1.09-1.04 (comp, 2H); MS (M+1) 457.3.
[0145] F.
N,N-Diethyl-4-[3-(3-methoxy-phenyl)-piperidin-3-yl]-benzamide
[0146] To a solution of
4-[1-benzyl-3-(3-methoxy-phenyl)-piperidin-3-yl]-N-
,N-diethyl-benzamide in acetic acid (8 mL) in a Parr pressure
bottle was added palladium hydroxide (Pd(OH).sub.2) (10% on carbon,
0.4 g). The reaction mixture was shaken under 50 psi of H.sub.2 for
20 hours. The reaction mixture was then filterd through celite. The
celite cake was washed with
EtOAdDiethyl-4-[3-(3-methoxy-phenyl)-piperidin-3-yl]-benzamid- e as
the acetate salt. .sup.1HNMR (400 MHz, CDCl.sub.3) .delta.
7.39-7.17 (comp, 5H), 6.84-6.61 (comp, 3H), 3.74 (s, 3H), 3.73-3.60
(comp, 2H), 3.57-3.41 (comp, 2H), 3.38-3.14 (comp, 2H), 3.11-2.89
(comp, 2H), 2.48-2.26 (comp, 2H), 1.81-1.66 (comp, 2H), 1.21-1.70
(comp, 3H), 1.06-0.99 (comp, 3H); MS (M+1) 367.4.
[0147] The following compounds were made using the procedure set
forth above in Example 1, starting with a compound analogous to the
title compound of Example 1A wherein R.sup.3 is fluoro or methoxy,
and adding the appropriate amine reactant in the procedure of
Example 1E.
[0148] 4-[1-Benzyl-3-(3-methoxy-phenyl)-piperid
in-3-yl]-N-ethyl-N-methyl-- benzamide
[0149] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.31 (d, 4H), 6.82
(s, 1H), 6.76 (d, 2H), 6.67 (dd, 1H), 3.71 (s, 3H), 3.53 (br, 1H),
3.50 (s, 2H), 3.27 (br, 1H), 2.25-2.21 (comp, 2H); MS (M+1)
443.3.
[0150]
4-[1-Benzyl-3-(3-fluoro-5-methoxy-phenyl)-piperidin-3-yl]-N,N-dieth-
yl-benzamide
[0151] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.33-7.29 (comp,
4H), 7.25-7.21 (comp, 5H), 6.59 (s, 1H), 6.54 (d, 1H), 6.39 (dt,
1H), 3.69 (s, 3H), 3.54-3.45 (comp, 4H), 3.24 (br, 2H), 2.80 (br,
2H); MS (M+1) 475.3.
[0152]
4-[1-Benzyl-3-(3-methoxy-phenyl)-piperidin-3-yl]-N-(2,2,2-trifluoro-
-ethyl)-benzamide
[0153] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.64 (d, 2H),
6.76-6.66 (comp, 3H), 6.30 (br, 1H), 4.11-4.07 (comp, 2H), 3.51 (s,
2H), 2.24-2.19 (comp, 1H), MS (M+1) 483.3.
EXAMPLE 2
GENERAL PROCEDURE FOR THE REDUCTIVE ALKYLATION OF
N,N-DIETHYL-4-[3-(3-METH- OXY-PHENYL)-PIPERIDIN-3-YL]-BENZAMIDE
[0154] To a solution of
N,N-diethyl-4-[3-(3-methoxy-phenyl)-piperidin-3-yl- ]-benzamide (1
equivalent) in methylene chloride (CH.sub.2Cl.sub.2) (0.4M) was
added the aldehyde (1.2 equivalents) followed by addition of acetic
acid (1.2 equivalents) and NaBH(OAc).sub.3 (1.5 equivalents). The
reaction mixture was stirred at room temperature for 16 hours. The
mixture was then partitioned between equal volumes of
CH.sub.2Cl.sub.2 and sat. aqueous sodium bicarbonate (NaHCO.sub.3).
The organic layer was separated and the aqueous layer was washed
with CH.sub.2Cl.sub.2 (3.times.). The combined organic layers were
dried (MgSO.sub.4) and concentrated. Purification by flash
chromatography afforded the desired tertiary amines in yields
ranging from 60-95%.
[0155] The following compounds were made using a procedure similar
to that of Example 2, starting with a diarylsubstituted pyridine
wherein R.sup.3 is fluoro or methoxy and R.sup.2 is the appropriate
amide group.
[0156]
4-[1-Cyclopropylmethyl-3-(3-methoxy-phenyl)-piperidin-3-yl]-N,N-die-
thyl-benzamide
[0157] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.34 (d, 2H), 7.24
(dd, 2H), 7.13 (t, 1H), 6.91 (s, 1H), 6.84 (d, 1H), 6.66 (dd, 1H),
3.71 (s, 3H), 3.48 (br, 2H), 3.25 (br, 2H), 3.05-2.80 (comp, 2H),
2.48 (br, 2H), 2.29-2.20 (comp, 4H), 1.60-1.50 (comp, 2H), 1.23
(br, 3H), 1.08 (br, 3H), 1.00-0.92 (comp, 1H), 0.52 (d, 2H), 0.12
(d,2H); MS (M+1) 421.3.
[0158]
4-[1-Cyclopropylmethyl-3-(3-methoxy-phenyl)-piperidin-3-yl-N,N-diis-
opropyl-benzamide
[0159] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.31 (d, 2H), 6.92
(s, 1H), 6.85 (d, 1H), 6.67 (d, 1H), 2.48 (br, 2H), 2.25 (d, 4H),
1.02-0.93 (comp, 1H) 0.90-0.80 (comp, 2H), 0.53 (d, 2H), 0.12 (d,
2H); MS (M+1) 449.3.
[0160]
{4-[1-Cyclopropylmethyl-3-(3-methoxy-phenyl)-piperidin-3-yl]-phenyl-
}-(3,4-dihydro-1H-isoquinolin-2-yl)-methanone
[0161] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.37 (q, 4H), 6.91
(s, 1H), 6.84 (d, 1H), 6.69 (d, 1H), 3.74 (s, 3H), 2.94-2.80 (comp,
4H), 2.47 (br, 1H), 2.28 (br, 4H), 0.55 (d, 2H), 0.15 (br, 2H); MS
(M+1) 421.3.
[0162]
{4-[1-Cyclopropylmethyl-3-(3-methoxy-phenyl)-piperidin-3-yl]-phenyl-
}-piperidin-1-yl-methanone
[0163] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.35 (d, 2H), 7.15
(t, 1H), 6.92 (s, 1H), 6.84 (d, 1H), 6.67 (d, 1H), 3.74 (s, 3H),
3.66-3.60 (comp, 2H), 3.40-3.34 (comp, 2H), 2.25 (d, 4H), 0.53 (d,
2H), 0.12 (d, 2H); MS (M+1) 433.3.
[0164]
{4-[1-Cyclopropylimethyl-3-(3-methoxy-phenyl)-piperidin-3-yl]-pheny-
l}-morpholin-4-yl-methanone
[0165] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.39 (d, 2H), 7.27
(d, 2H), 6.90 (s, 1H), 6.83 (d, 1H), 6.68 (d, 1H), 2.25 (d, 4H),
0.53 (d, 2H), 0.12 (d, 2H); MS (M+1) 435.3.
[0166]
N,N-Diethyl4-[1-ethyl-3-(3-methoxy-phenyl)-piperidin-3-yl]-benzamid-
e
[0167] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.32 (d, 2H), 6.89
(s, 1H), 6.82 (d, 1H), 6.67 (dd, 1H), 3.74 (s, 3H), 3.50 (br, 2H),
2.42 (q, 4H) 2.25-2.22 (comp, 2H); MS (M+1) 395.2.
EXAMPLE 3
ALKYLATION OF
N,N-DIETHYL-4-[3-(3-METHOXY-PHENYL)-PIPERIDIN-3-YL]-BENZAMID- E
[0168] To a solution of
N,N-diethyl-4-[3-(3-methoxy-phenyl)-piperidin-3-yl- ]-benzamide(1
equivalent) in DMF (0.5M) was added potasium carbonate
(K.sub.2CO.sub.3) (3-10 equivalents) and the alkyl or heteroaryl
halide (1-5 equivalents). The reaction mixture was stirred at
60-120.degree. C. for 3-16 hours. The mixture was then cooled to
room temperature and filtered. The filtrate was diluted with
diethyl ether and the ether layer was washed with brine. The
organic phase was dried (MgSO.sub.4) and concentrated. Purification
by flash chromatography afforded the desired amines in yields
ranging from 30-85%.
[0169] The following compounds were made using a procedure
analogous to that of Example 3, starting with the appropriate amide
group.
[0170]
N,N-Diethyl-4-[3-(3-methoxy-phenyl)-1-pyrimidin-2-yI-piperidin-3-yl-
]-benzamide
[0171] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.35 (d, 2H), 7.33
(d, 2H), 7.23 (d, 2H), 7.14 (t, 1H), 6.91 (s, 1H), 6.86 (d, 1H),
6.68 (dd, 1H), 6.49 (t, 1H), 4.29 (q, 2H), 3.87-3.80 (comp, 1H),
3.76-3.69 (comp, 1H), 3.67 (s, 3H), 3.49 (br, 2H), 3.21 (br, 2H),
2.51-2.47 (comp, 2H), 1.62 (br, 2H), 1.18 (br, 3H), 1.06 (br, 3H);
MS (M+1) 445.4.
[0172]
N,N-Diethyl-4-[3-(3-methoxy-phenyl)-3,4,5,6-tetrahydro-2H-[1,2']bip-
yridinyl-3-yl]-benzamide
[0173] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.24-8.22 (comp,
1H), 733 (d, 2H), 6.92 (s, 1H), 6.86 (d, 1H), 6.69 (dd, 2H), 4.10
(q, 2H), 3.23 (br, 2H), 2.45 (br, 2H); MS (M+1) 444.2.
[0174]
4-[1-Benzooxazol-2-yl-3-(3-methoxy-phenyl)-piperidin-3-yl]-N,N-diet-
hyl-benzamide
[0175] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.41 (d, 1H), 7.04
(t, 1H), 6.90-6.86 (comp, 2H), 6.71 (dd, 1H), 4.18 (br, 2H), 3.49
(br, 2H), 2.51-2.45 (comp, 2H), 1.69 (br, 2H); MS (M+1) 484.4.
[0176]
N,N-Diethyl-4-[1-(5-fluoro-pyrimidin-2-yl)-3-(3-methoxy-phenyl)-pip-
eridin-3-yl]-benzamide
[0177] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.23 (s, 2H), 7.15
(t, 1H), 7.90-7.84 (comp, 2H), 6.69 (dd, 1H), 4.23 (q, 2H) 3.49
(br, 2H), 2.48-2.45 (comp, 2H), 1.62-1.57 (comp, 2H); MS (M+1)
463.3.
[0178]
4-[1-Allyl-3-(3-methoxy-phenyl)-piperidin-3-yl]-N,N-diethyl-benzami-
de
[0179] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.29 (d, 2H), 7.23
(d, 2H), 7.12 (t, 1H), 6.86 (s, 1H), 5.99-5.89 (comp, 1H),
5.19-5.13 (comp, 2H), 3.70 (s,3H), 3.48 (br, 2H), 2.98 (d, 2H),
2.44 (br, 2H), 2.24-2.19 (comp, 2H); MS (M+1) 407.3.
EXAMPLE 4
DEPROTECTION OF METHYL ARYL ETHERS
[0180] To a solution of methyl ether (1 equivalent) in
CH.sub.2Cl.sub.2 (0.4M) at -78.degree. C. was added a solution of
boron tribromide (1-5 equivalents) in CH.sub.2Cl.sub.2 (1.OM)
dropwise. The reaction mixture was stirred at -78.degree. C. for 1
hour was warmed to room temperature and stirred for an additional
4-6 hour. The mixture was quenched with slow addition of water and
was brought to pH 8 with a saturated water/ammonium hydroxide
(NH.sub.40H) solution. The aqueous layer was washed with
CH.sub.2Cl.sub.2. The organic phase was dried (MgSO.sub.4) and
concentrated. Purification by flash chromatography afforded the
desired phenols in yields ranging from 60-95%.
[0181] Alternatively, the methyl ethers were deprotected with
sodium hydride and ethane thiol in dimethylformamide (DMF) as
follows: To a suspension of sodium hydride (NaH) (10 equivalents)
in DMF (0.2M) at room temperature was added ethane thiol (10
equivalents) dropwise. The mixture was stirred for 5 minutes. To
the reaction mixture was added a solution of the methyl ether (1
equivalent) in DMF (0.2M). The mixture was heated to 120.degree. C.
for 10-16 hours. The reaction was cooled to room temperature and
was quenched with water. The mixture was diluted with diethyl ether
and the organic layer was washed with brine. The organic phase was
dried (MgSO.sub.4) and concentrated. Purification by flash
chromatography afforded the desired phenols in yields ranging from
60-95%.
[0182] The following compounds were made using a procedure similar
to that of Example 4.
[0183]
4-[1-Benzyl-3-(3-hydroxy-phenyl)-piperidin-3-yl]-N,N-diethyl-benzam-
ide
[0184] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.31-7.29 (comp,
4H), 7.28-7.19 (comp, 5H), 7.03 (t, 1H), 6.72 (d, 1H), 6.62 (s,
1H), 6.57 (dt 1H), 3.58-3.42 (comp, 4H), 3.47 (s, 2H), 3.25 (br,
2H), 2.88 (br, 1H), 2.72 (br, 1H), 2.49 (br, 1H), 2.38 (br, 1H),
2.25-1.95 (comp, 2H), 1.59-1.42 (comp, 2H), 1.20 (br, 3H), 1.09
(br, 3H); MS (M+1) 443.3.
[0185]
N,N-Diethyl-4-[3-(3-hydroxy-phenyl)-1-(3-phenyl-propyl)-piperidin-3-
-y]-benzamide
[0186] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.31-7.14 (comp,
9H), 7.79 (d, 1H), 6.70 (s, 1H), 6.57 (dd, 1H), 3.49 (br, 2H), 2.93
(br, 1H), 2.66-2.60 (comp, 2H), 2.23-2.17 (comp, 2H), 1.20 (br,
3H); MS (M+1) 471.2.
[0187]
4-[1-Cyclopropylmethyl-3-(3-hydroxy-phenyl)-piperidin-3-yl]-N,N-die-
thyl-benzamide
[0188] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.32 (d, 2H), 7.02
(t, 1H), 6.80 (d, 1H), 6.53 (d, 1H), 3.50 (br, 2H), 2.42 (br, 1H),
1.56-1.51 (comp; 2H), 1.00-0.90 (comp, 1H), 0.51 (d, 2H); MS (M+1)
407.1.
[0189]
N,N-Diethyl-4-[3-(3-hydroxy-phenyl)-1-thiazol-2-ylmethyl-piperidin--
3-yl]-benzamide
[0190] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.68 (d, H), 7.07
(t, 1H), 6.80-6.75 (comp, 2H), 6.61 (dd, 1H), 6.40 (br, 1H), 3.51
(br, 2H) 2.54 (comp, 2H), 2.21 (br; 2H), 1.60-1.50 (comp, 2H); MS
(M+1) 450.2.
[0191] 4-[1-Cyclohex-3-enylmethyl-3-(3-hydroxy-phenyl)-piperid
in-3-yl]-N,N-diethyl-benzamide
[0192] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.32 (d, 2H), 7.05
(t, 1H), 6.81 (d, 1H), 6.74 (d, 1H), 6.58 (dd, 1H), 3.50 (br, 2H),
1.89-1.80 (comp, 2H), 1.70-1.63 (comp; 1H), 1.54-1.42 (comp, 2H),
1.20 (br, 3H); MS (M+1) 447.2.
[0193]
4-[1-Butyl-3-(3-hydroxy-phenyl)-piperidin-3-yl]-N,N-diethyl-benzami-
de
[0194] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.30 (d, 2H), 7.05
(t, 1H), 6.80 (d, 1H), 6.70 (s, 1H), 6.56 (dd, 1H), 3.50 (br, 2H),
2.93 (br, 1H), 2.69 (br, 1H), 2.35-2.30 (comp, 3H), 1.54-1.42
(comp, 5H), 0.91 (t, 3H); MS (M+1) 409.3
[0195]
N,N-Diethyl-4-[3-(3-hydroxy-phenyl)-1-(1H-imidazol-2-ylmethyl)-pipe-
ridin-3-yl]-benzamide
[0196] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.17-7.12 (comp,
4H), 6.87 (s, 2H), 6.65 (d, 1H), 6.52 (d, 1H), 3.53 (br, 2H),
3.27-3.15 (comp, 4H), 2.60-2.50 (comp, 2H), 1.46 (br, 2H); MS (M+1)
433.3
[0197]
N,N-Diethyl-4-[3-(3-hydroxy-phenyl)-1-propyl-piperidin-3-yl]-benzam-
ide
[0198] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.31 (d, 2H), 7.04
(t, 1H), 6.80 (d, 1H), 6.71 (s, 1H), 6.56 (dd, 1H), 3.50 (br, 2H),
2.49 (br, 1H), 2.20 (br, 2H), 1.62-1.50 (comp, 4H), 0.90 (t, 3H);
MS (M+1)395.3
[0199]
N,N-Diethyl-4-[3-(3-hydroxy-phenyl)-1-(3-methyl-butyl)-piperidin-3--
yl]-benzamide
[0200] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.31 (d, 2H), 7.04
(t, 1H), 6.80 (d, 1H), 6.69 (s, 1H), 6.55 (dd, 1H), 3.50 (br, 2H),
2.51 (br, 1H), 2.39-2.24 (comp, 3H), 1.10 (br; 3H), 0.90 (d, 6H);
MS (M+1) 423.3
[0201]
{4-[1-Cyclopropylmethyl-3-(3-hydroxy-phenyl)-piperidin-3-yl]-
phenyl}-piperidin-1-yl-methanone
[0202] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.33-7.30 (comp,
2H), 7.07 (t, 1H), 6.80 (d, 1H), 6.76 (s, 1H), 6.61 (dd, 1H), 3.65
(br, 2H), 3.33 (br, 2H), 2.37 (d, 2H), 2.24 (br, 2H), 1.05-0.94
(comp, 1H), 0.55 (d, 2H), 0.15 (d, 2H); MS (M+1) 419.3.
[0203]
4-[1-Allyl-3-(3-hydroxy-phenyl)-piperidin-3-yl]-N,N-diethyl-benzami-
de
[0204] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.28 (comp, 2H),
7.04 (t, 1H), 6.78 (d, 1H), 6.68 (s, 1H), 6.56 (dd, 1H), 6.00-5.89
(comp, 1H), 5.18 (d, 1H), 5.15 (s, 1H), 3.50 (br, 2H), 2.50 (br,
1H), 2.39 (br, 1H), 1.60-1.47 (comp, 2H); MS (M+1) 393.2.
[0205] N,N-Diethyl-4-[3-(3-hyd
roxy-phenyl)-1-thiophen-3-ylmethyl-piperidi- n-3-yl]-benzamide
[0206] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.09-7.05 (comp,
2H), 7.01 (t, 1H), 6.70 (d, 1H), 6.65 (s, 1H), 6.56 (dd, 1H) 3.49
(br, 4H), 2.37 (br, 1H), 2.18 (br, 2H), 1.58-1.44 (comp, 2H); MS
(M+1) 449.3.
[0207]
4-[1-Acetyl-3-(3-hydroxy-phenyl)-piperidin-3-yl]-N,N-diethyl-benzam-
ide
[0208] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.28-7.20 (comp,
4H), 7.07 (t, 1H), 6.84 (s, 1H), 6.72 (dd, 1H), 6.66 (dd, 1H) 4.18
(d, 1H), 3.85 (d, 1H), 3.21 (br, 2H), 2.04 (s, 3H), 1.59-1.47
(comp, 2H); MS (M+1) 395.2.
[0209]
4-[1-But-2-enyl-3-(3-hydroxy-phenyl)-piperidin-3-yl]-N,N-diethylben-
zamide
[0210] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.28 (d, 2H), 7.04
(t, 1H), 6.78 (d, 1H), 6.67 (s, 1H), 6.55 (dd, 1H), 5.60-5.57(comp,
2H), 3.50 (br, 2H), 2.36 (br, 1H), 2.21 (br, 2H), 1.60-1.46 (comp,
2H); MS (M+1) 407.3.
[0211]
4-[1-Cyclopropylmethyl-3-(4-fluoro-3-hydroxy-phenyl)-piperidin-3-yl-
]-N,N-diethyl-benzamide
[0212] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.30 (d, 2H), 6.98
(d, 1H), 6.92 (dd, 1H), 6.77 (s, 1H), 3.51 (br, 2H), 2.27 (br, 2H),
1.54 (br, 2H), 0.55 (d, 2H); MS (M+1) 425.5.
[0213]
4-[1-Cyclopropymethyl-3-(3-hydroxy-phenyl)-piperidin-3-yl]-N,N-dime-
thyl-benzamide
[0214] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.33 (d, 2H), 7.04
(t, 1H), 6.81 (d, 1H), 6.70 (s, 1H), 6.54 (dd, 1H), 3.05 (s, 3H),
2.41 (br, H), 1.60-1.46 (comp, 2H), 0.51 (dd, 2H); MS (M+1)
379.1.
[0215]
N,N-Diethyl4-[3-(3-hydroxy-phenyl)-1-(3,4,4-trifluoro-but-3-enyl)-p-
iperidin-3-yl]-benzamide
[0216] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.31-7.29 (comp,
4H), 7.28-7.19 (comp, 5H), 7.03 (t, 1H), 6.72 (d, 1H), 6.62 (s,
1H), 6.57 (dt 1H), 3.50 (comp, 2H), 3.47 (s, 2H), 3.25 (br, 2H),
2.88 (br, 1H), 2.72 (br; 1H), 2.49 (br, 1H), 2.38 (br, 1H), 2.20
(comp, 2H), 1.51 (comp, 2H), 1.20 (br, 3H), 1.09 (br, 3H); MS (M+1)
443.3.
[0217] 4-[1-Cyclopropylmethyl-3-(3-hydroxy-phenyl)-piperid
in-3-yl]-N-ethyl-N-methyl-benzamide
[0218] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.33 (d, 2H), 7.05
(t, 1H), 6.82 (d, 1H), 6.72 (s, 1H), 6.56 (d, 1H), 2.42 (br, 1H),
2.32-1.17 (comp, 4H), 1.62-1.48 (comp, 2H), 0.53 (dd, 2H); MS (M+1)
393.1.
[0219]
N,N-Diethyl-4-[3-(3-hydroxy-phenyl)-1-(2-oxo-butyl)-piperidin-3-yl]-
-benzamide
[0220] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.33-7.26 (comp,
1H), 7.05 (t, 1H), 6.73 (d, 1H), 3.50 (br, 2H), 3.15-3.05 (comp,
1H), 2.24 (br, 1H), 2.11 (d, 4H); MS (M+1) 423.1.
[0221]
4-[1-Benzyl-3-(3-fluoro-5-hydroxy-phenyl)-piperidin-3-yi]-N,N-dieth-
yl-benzamide
[0222] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 6.49 (d, 1H), 6.38
(s, 1H), 6.29 (dt 1H), 3.49 (comp, 2H), 3.45 (comp, 2H), 3.25 (br,
2H); MS (M+1) 461.3.
[0223]
4-[1-Cyclopropylmethyl-3-(3-fluoro-5-hydroxy-phenyl)-piperidin-3yl]-
-N,N-diethyl-benzamide
[0224] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.29-7.27 (comp,
2H), 7.23-7.20 (comp, 2H), 6.59 (d, 1H), 6.45 (s, 1H), 6.23 (dt,
1H), 3.50 (br, 2H), 3.26 (br, 2H), 2.24 (d, 2H), 2.15 (br, 2H),
0.52 (comp, 2H), 0.10 (comp, 2H), 2.40 (br, 1H), 2.24 (comp, 2H),
1.53 (comp, 2H), 1.20 (br, 3H), 1.10 (br, 3H); MS (M+1) 425.3.
[0225]
N,N-Diethyl-4-[3-(3-fluoro-5-hydroxy-phenyl)-1-propyl-piperidin-3-y-
l]-benzamide
[0226] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 6.57 (d, 1H), 6.43
(s, 1H), 6.25 (dt, 1H), 3.50 (br, 2H), 3.25 (br, 2H), 2.41 (br,
2H), 2.27 (t, 2H) 2.13 (br, 2H); MS (M+1) 413.3.
[0227]
N,N-Diethyl-4-[1-(5-fluoro-pyrimidin-2-yl)-3-(3-hydroxy-phenyl)-pip-
eridin-3-yl]-benzamide
[0228] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.22 (s, 2H),
7.30-7.27 (comp, 2H), 7.05 (t, 1H), 6.83 (d, 1H), 6.74 (t, 1H),
4.21 (q, 2H), 3.82-3.75 (comp, 1H), 3.65-3.59 (comp, 2H), 3.49 (br,
2H), 2.41 (comp, 2H); MS (M+1) 449.3.
[0229]
N,N-Diethyl-4-[3-(3-hydroxy-phenyl)-1-pyrimidin-2-yl-piperidin-3-yl-
]-benzamide
[0230] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.34 (s, 2H), 7.05
(comp, 1H), 6.81 (d, 2H), 6.55 (d, 2H), 3.82 (comp, 1H), 3.72
(comp, 1H), 2.43 (br, 2H); MS (M+1) 431.3.
[0231]
{4-[1-Cyclopropylmethyl-3-(3-hydroxy-phenyl)-piperidin-3-ylphenyl]--
(3,4-dihydro-1H-isoquinolin-2-yl)-methanone
[0232] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.28 (d, 2H), 7.05
(t, 1H), 6.75 (d, 1H), 6.72 (s, 1H), 6.59 (dd, 1H), 6.07 (br, 1H),
3.50 (br, 2H), 3.13 (d, 1H), 2.79-2.63 (comp, 1H), 2.18 (br, 2H),
1.21 (br,3H); MS (M+1) 435.3.
[0233]
N,N-Diethyl-4-[3-(3-hydroxy-phenyl)-1-(2,2,2-trifluoro-ethyl)-piper-
idin-3-yl]-benzamide
[0234] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.38 (d, 2H),
7.27-7.19 (comp, 4H), 7.17 (t, 1H), 6.74 (s, 1H), 6.60 (dd, 1H),
2.38-2.20 (comp, 4H), 1.57 (br, 2H), 0.54 (d, 2H); MS (M+1)
435.3.
EXAMPLE 5
4-[1-BENZYL-3-(3-CARBOXYAMINO-PHENYL)-PIPERIDIN-3-YL]-N,N-DIETHYL-BENZAMID-
E
[0235] A. Trifluoro-methanesulfonic acid
3-[1-benzyl-3-(4-diethylcarbamoyl- -phenyl)-piperidin-3-yl]-phenyl
ester
[0236] To a solution of
4-[1-benzyl-3-(3-hydroxy-phenyl)-piperidin-3-yl]-N-
,N-diethyl-benzamide (0.92 g, 2.08 mmol) in CH.sub.2Cl.sub.2 (15
ml) at 0.degree. C. was added pyridine (0.25mL, 3.12 mmol) followed
by dropwise addition of triflic anhydride (0.52 mL, 3.61mmol) over
5 minutes. The reaction mixture was stirred at 0.degree. C. for 1
hour and at room temperature for 2 hours. The solution was then
cooled to 0.degree. C. and 15 mL of cold saturated aqueous
NaHCO.sub.3 were added. The organic layer was separated and the
aqueous layer was washed with CH.sub.2Cl.sub.2 (3.times.20 mL). The
combined organic layers were dried (MgSO.sub.4) and concentrated.
The crude residue was purified by flash chromatography with
hexanes/EtOAc (4:1) to afford 0.50 g of trifluoro-methanesulfonic
acid
3-[1-benzyl-3-(4-diethylcarbamoyl-phenyl)-piperidin-3-yl]-phenyl
ester. .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.39-7.18 (comp,
12H), 7.04-6.99 (m, 1H), 3.60-3.39 (comp, 4H), 3.35-3.28 (comp,
2H), 3.06-2.87 (m, 1H), 2.68-2.44 (comp, 2H), 2.38-2.25 (m, 1),
2.23-1.96 (comp, 2H), 1.64-1.39 (comp, 2H), 1.25-1.11 (comp, 3H),
1.10-0.99 (comp, 3H); MS (M+1) 575.2.
[0237] B.
4-[1-Benzyl-3-(3-cyano-phenyl)-piperldin-3-yl]-N,N-diethyl-benza-
mide
[0238] To a solution of trifluoro-methanesulfonic acid
3-[1-benzyl-3-(4-diethylcarbamoyl-phenyl)-piperidin-3-yl]-phenyl
ester (0.40 g, 0.69 mmol) in DMF (8 mL) was added zinc cyanide
(0.057 g, 0.49 mmol) and tetrakis triphenylphosphine palladium
(0.16 g, 0.14 mmol). The reaction was stirred under a nitrogen
atmosphere at 90.degree. C. for 5 hours. The mixture was cooled to
room temperatures and it was diluted with diethyl ether (30 mL).
The organic layer was washed with brine (5x 10 mL), dried
(MgSO.sub.4) and concentrated. Purification with hexanes/EtOAc
(1:1) afforded 0.28 g of 4-[1-benzyl-3-(3-cyano-phenyl)-pip-
eridin-3-yl]-N,N-diethyl-benzamide. .sup.1HNMR (400 MHz,
CDCl.sub.3) .delta. 7.66 (s, 1H), 7.69-7.20 (comp, 10H), 7.15-7.13
(comp, 2H) 3.60-3.38 (comp, 4H), 3.31-3.19 (comp, 2H), 3.09-2.94
(m, 1H), 2.58-2.45 (comp, 2H), 2.22-2.17 (comp, 3H), 1.71-1.61 (m,
1H), 1.28-1.16 (comp, 3H), 1.17-1.08 (comp, 3H); MS (M+1)
452.2.
[0239] C.
4-[1-Benzyl-3-(3-carboxyamino-phenyl)-piperidin-3-yl]-N,N-diethy-
l-benzamide
[0240] To a solution of
4-[1-benzyl-cyano-phenyl)-piperidin-3-yl]-N,N-diet- hyl-benzamide
(0.50 g, 1.11 mmol) in ethanol (5 mL) was added 3N aqueous
Na.sub.2CO.sub.3 (3.25 mL) and 30% aqueous H.sub.2O.sub.2 (0.88
mL). The reaction mixture was stirred at room temperature for 8
hours. The mixture was diluted with water (2 mL) and the aqueous
layer was washed with CH.sub.2Cl.sub.2 (3.times.10 mL). The organic
layer was dried (MgSO.sub.4) and concentrated. The residue was
purified by flash chromatography with CH.sub.2Cl.sub.2/methanol
(MeOH) (10:1) to afford 0.42 mg of .sup.1HNMR (400 MHz, CDCl.sub.3)
.delta. 7.80 (s, 1H), 7.56 (d, 1H), 7.40-7.16 (comp, 11H), 5.99
(br, 1H), 5.59 (br, 1H), 3.59-3.39 (comp, 4H), 3.34-3.18 (comp,
2H), 3.06-2.88 (m, 1H), 2.81-2.62 (m, 1H), 2.41-2.27 (m, 1H),
2.25-2.17 (comp, 3H), 2.58-2.41 (comp, 2H), 1.28-1.18 (comp, 3H),
1.17-1.00 (comp, 3H) MS (M+1) 470.3.
[0241] The following examples were prepared by methods similar to
those described above in Example 5.
[0242]
4-[1-(2,2,2-trifluoroethyl)-3-(3-carboxyamino-phenyl)-piperidin-3-y-
l]-N,N-diethyl-benzamide
[0243] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.93 (s, 1H),
7.64-7.61 (m, 1H), 6.24 (br, 1H), 3.56-3.42 (comp, 2H), 2.62 (t,
1H), 1.18-1.10 (comp, 3H); MS (M+1) 462.3.
[0244]
N,N-Diethyl-4-[3-(3-carboxyamino-phenyl)-1-thiazol-2-ylmethyl-piper-
idin-3-yl]-benzamide
[0245] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.15 (s, 1H), 7.72
(d, 1H), 7.68-7.65 (m, 1H), 5.93 (br, 1H), 2.77-2.67 (comp, 2H),
1.08 (comp, 3H); MS (M+1) 477.3.
[0246]
N,N-Diethyl-4-[1-furan-2-ylmethyl-3-(3-carboxyamino-phenyl)-piperid-
in-3-yl]-benzamide
[0247] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.92 (s, 1H), 7.61
(d, 1H), 6.23 (br, 1H), 3.27-3.21 (comp, 2H), 1.18-1.01 (comp, 3H);
MS (M+1) 460.3.
EXAMPLE 6
1-CYCLOPROPYLMETHYL-3-(3-METHOXY-PHENYL)-3-(4-THIOPHEN-2-YL-PHENYL)-PIPERI-
DINE
[0248] To a solution of trifluoro-methanesulfonic acid
4-[1-cyclopropylmethyl-3-(3-methoxy-phenyl)-piperidin-3-yl]-phenyl
ester (0.1 g, 0.2 mmol) in ethanol (4.5 mL) and water (0.5 mL) was
added 2-thiophene boronic acid (0.052 g, 0.5 mmol) and sodium
carbonate (0.037 g, 0.29 mmol) and tetrakis tripheny;phosphine
palladium (0.02 g, 0.18 mmol). The reaction mixture was heated to
reflux for 2 hours. The mixture was then filtered and the filtrate
was concentrated under vacuum. The residue was purified by flash
chromatography with hexanes/EtOAc (3:1) to afford 0.08 g of
1-cyclopropylmethyl-3-(3-methoxy-phenyl)-3-(4-thiophen-2-
-yl-phenyl)-piperidine. .sup.1HNMR (400 MHz, CDCl.sub.3) .delta.
749 (d, 2H), 7.35 (d, 2H), 7.22-7.06 (comp, 3H), 7.05-7.00 (m, 1H),
6.96 (s, 1H), 6.89 (d, 1H), 6.70-6.67 (m, 1H), 3.76 (s, 3H),
3.17-2.82 (comp, 2H), 2.61-2.39 (comp, 2H), 2.27-2.18 (comp, 4H),
1.62-1.39 (comp, 3H), 0.60-0.45 (comp, 2H), 0.18-0.11 (comp, 2H);
MS (M+1) 404.2.
EXAMPLE 7
3-{4-[1-ALLYL-3-(3-METHOXY-PHENYL)-PIPERIDIN-3-YL]-PHENYL}-PENTAN-3-OL
[0249] To a solution of
4-[1-allylmethyl-3-(3-methoxy-phenyl)-piperidin-3-- yl]-benzoic
acid methyl ester (1.71 g, 4.68 mmol) in THF (30 mL) at 0.degree.
C. was added ethylmagnesium bromide (1M in tert-butylmethylether,
46.8 mL, 46.8 mmol). The ice bath was removed and the reaction was
stirred at room temperature for 1 hour. The mixture was quenched
with slow addition of water (15 mL). The aqueous layer was washed
with diethyl ether (3.times.30 mL). The combined extracts were
dried (MgSO.sub.4) and concentrated to afford 1.67 g (91%) of
3-{4-[1-allyl-3-(3-methoxy-phenyl)-piperidin-3-yl]-phenyl}-pentan-3-ol.
.sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.23-7.20 (comp, 5H), 7.15
(t, 1H), 6.85 6.84 (comp, 2H), 6.66 (dd, 1H), 6.01-5.92 (m, 1H),
5.20 (s, 1H), 5.17-5.14 (m, 1H), 3.71 (s, 3H), 3.04-2.95 (comp,
2H), 2.88-2.72 (comp, 2H), 2.50-2.40 (cornp, 2H), 2.27-2.21 (comp,
2H), 1.83-1.71 (comp, 4H), 1.57-1.49 (comp, 2H), 0.71 (dt, 6H); MS
(M+1) 394.3.
[0250] The following compounds were prepared by a procedure
analogous to that of Example 4 for the deprotection of methyl
ethers.
[0251]
3-{1-Allyl-3-[4-(1-ethyl-1-hydroxy-propyl)-phenyl]-piperidin-3-yl}--
phenol
[0252] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.21 (s, 5H), 7.09
(t, 1H), 6.84 (d, 1H), 6.73 (s, 1H), 6.55 (dd, 1H), 6.02-5.92 (m,
1H), 5.20-5.14 (comp, 2H), 3.07-2.96 (comp, 2H), 2.88-2.82 (comp,
2H), 2.50-2.40 (comp, 2H), 2.25-2.20 (comp, 2H), 1.82-1.72 (comp,
4H), 1.65 (br, 1H), 1.61-1.52 (comp, 2H), 0.71 (t, 6H); MS (M+1)
380.3.
[0253]
3-[3-[4-(1-Ethyl-1-hydroxy-propyl)-phenyl]-1-(2,2,2-trifluoro-ethyl-
)-piperidin-3-yl]-phenol
[0254] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 6.84 (dd, 1H), 6.79
(t, 1H), 4.97 (br, 1H), 2.23-2.20 (comp, 2H), 0.72 (t, 6H); MS
(M+1) 422.2.
[0255]
3-{3-[4-(1-Ethyl-1-hydroxy-propyl)-phenyl]-3,4,5,6-tetrahydro-2H-[1-
,2']bipyridinyl-3-yl}-phenol
[0256] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.17-8.16 (m, 1H),
7.07 (t, 1H), 6.71 (d, 1H), 4.25 (d, 1H), 3.96 (d, 1H), 2.47-2.35
(comp, 2H); MS (M+1) 417.3.
[0257]
3-{1-Cyclopropylmethyl-3-[4-(1-ethyl-1-hydroxy-propyl)-phenyl]-pipe-
ridin-3-yl}-phenol
[0258] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.10 (t, 1H), 6.80
(d, 1H), 6.64 (d, 1H), 2.32 (br, 1H), 2.24 (br, 1H), 0.58 (d, 2H);
MS (M+1) 394.4.
[0259] The following compounds were made using the procedure of
Example 7 followed by conversion of R.sup.3=OH to
R.sup.3=CONH.sub.2 according to the procedure of Example 5.
[0260]
3-{1-Allyl-3-[4-(1-ethyl-1-hydroxy-propyl)-phenyl]-piperidin-3-yl}--
benzamide
[0261] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.83 (s, 1H), 7.54
(d, 1H), 7.40 (d, 1H), 7.30 (t, 1H), 7.24-7.15 (comp, 4H),
6.06-5.94 (comp, 2H), 5.56 (br, 1H), 5.21-5.16 (comp, 2H), 3.00 (d,
2H), 2.69 (br, 1H), 2.56 (br, 1H), 2.42-2.28 (comp, 2H), 2.27-2.20
(m, 1H), 1.82-1.70 (comp, 4H), 1.64 (br, 1H), 1.60-1.42 (comp, 2H),
0.71 (dt, 6H); MS (M+1) 407.3.
[0262]
3-{3-[4-(1-Ethyl-1-hydroxy-propyl)-phenyl]-3,4,5,6-tetrahydro-2H-[1-
,2']bipyridinyl-3-yl}-benzamide
[0263] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.22 (d, 1H), 8.11
(s, 1H), 7.31 (t, 1H), 2.63-2.57 (comp, 2H), 2.52-2.39 (comp, 2H),
0.69 (t, 6H); MS (M+1) 444.3.
[0264]
3-[3-[4-(1-Ethyl-1-hydroxy-propyl)-phenyl]-1-(2,2,2-trifluoro-ethyl-
)-piperidin-3-yl]-benzamide
[0265] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.95 (s, 1H), 7.23
(d, 2H), 7.15 (d, 2H), 5.62 (br, 1H), 2.86 (d, 2H), 2.60-2.54 (m,
1H), 0.71 (t, 6H); MS (M+1) 431.3.
EXAMPLE 8
PROPIONIC ACID
3-(1-CYCLOPROPYLMETHYL-3-P-TOLYL-PIPERIDIN-3-YL)-PHENYL ESTER
[0266] To a solution of
3-(1-cyclopropylmethyl-3-p-tolyl-piperidin-3-yl)-p- henol (65 mg,
0.15 mmol) in CH.sub.2Cl.sub.2 (2 ml) at room temperature were
added DMAP (18 mg, 0.15 mmol), triethylamine (0.071 mL, 0.52 mmol)
and propionyl chloride (0.038 mL, 0.45 mmol). The reaction mixture
was stirred at room temperature for 12 hours. The reaction was
partitioned between 5 mL CH.sub.2Cl.sub.2 and 5 mL of aqueous
saturated NaHCO.sub.3. The aqueous layer was washed with
CH.sub.2Cl.sub.2 (3.times.5 mL), dried over Na.sub.2SO.sub.4 and
concentrated. Purification by flash chromatography with
hexanes/EtOAc (1:1) afforded 58 mg of propionic acid
3-(1-cyclopropylmethyl-3-p-tolyl-piperidin-3-yl)-phenyl ester.
.sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.33 (d, 2H), 7.26-7.19
(comp, 3H), 7.16-7.03 (comp, 2H), 6.89-6.86 (m, 1H), 3.59-3.43
(comp, 2H), 3.35-3.19 (comp, 2H), 2.59-2.53 (q, 2H), 2.52-2.41
(comp, 2H), 2.27-2.18 (comp, 4H), 1.57-1.44 (comp, 2H), 1.31-1.19
(t, 3H), 1.18-1.09 (comp, 3H), 1.08-1.01 (comp, 3H), 1.00-0.91 (m,
1H), 0.59-0.49 (comp, 2H), 0.19-0.11 (comp,1H); MS (M+1) 463.3.
[0267] The following compound was made using a procedure similar to
that of Example 8.
[0268] Isobutyric Acid
3-[1-cyclopropylmethyl-3-(4-diethylcarbamoyl-phenyl-
)-piperidin-3-yl]-phenyl ester
[0269] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.36-7.29 (comp,
2H) 7.10-7.02 (comp, 2H), 6.89-6.85 (m, 1H), 3.01-2.82 (comp, 2H),
2.81-2.75 (m, 1H), 1.28 (d, 3H); MS (M+1) 477.3.
EXAMPLE 9
4-r4-CYCLOPROPYLMETHYL-2-(3-HYDROXY-PHENYL)-MORPHOLIN-2-YL1-N,N-DIETHYLBEN-
ZAMIDE
[0270] A. (4-Bromo-phenyl)-(3-methoxy-phenyl)-methanol
[0271] To a suspension of magnesium (2.4 g, 100 mmmol), in THF (20
mL) at room temperature was added dropwise a solution of
bromoanisole (9.1 mL, 71.4 mmol) in THF (30 mL). The reaction
mixture was stirred at room temperature for 2 h and at 60.degree.
C. for 2 h. The mixture was cooled to room temperature and a
solution of 4-bromobenzaldehyde (13.2 g, 71.4 mmol) was added over
5 min. The reaction mixture was stirred at room temperature for 3 h
and was quenched by addition of aqueous saturated ammonium chloride
(NH.sub.4Cl) (30 mL). The aqueous layer was washed with ether
(3.times.40 mL), dried over Na.sub.2SO.sub.4 and concentrated.
Purification by flash chromatography with hexanes/EtOAc (10:1)
afforded 16.95 g of (4-bromo-phenyl)-(3-methoxy-phenyl)-methanol.
.sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.46-7.41 (comp, 2H),
7.27-7.18 (comp, 3H), 6.91-6.87 (comp, 2H), 6.81-6.78 (m, 1H), 5.73
(s, 1H), 3.76 (s, 3H); MS (M+1) 294.2.
[0272] B. (4-Bromo-phenyl)-(3-methoxy-phenyl)-methanone
[0273] To a solution of DMSO (8.13 mL, 114.7 mmol) in
CH.sub.2Cl.sub.2 (80 mL) at -78 was added solution of
trifluoroacetic acid (TFAA) (12.12 mL, 86.0 mmol) in
CH.sub.2Cl.sub.2 (50 mL) over 5 min. The mixture was stirred for 20
min and a solution of (4-bromo-phenyl)-(3-methoxy-phenyl)--
methanol (16.8 g, 57.4 mmol) in CH.sub.2Cl.sub.2 (50 mL) was added
dropwise over 5 min. The reaction mixture was stirred at
-78.degree. C. for 30 min and Et3N (24.0 mL, 172 mmo) was added.
The mixture was stirred at -78.degree. C. for an additional 30 min
and at room temperature for 1 h. The CH.sub.2Cl.sub.2 layer was
washed with brine (3.times.30 mL), dried over Na.sub.2SO.sub.4 and
concentrated. Purification with hexanes/EtOAc (10:1) afforded 16.0
g of (4-Bromo-phenyl)-(3-methoxy-pheny- l)-methanone. .sup.1HNMR
(400 MHz, CDCl.sub.3) .delta. 7.67-7.66 (comp, 2H), 7.64-7.60
(comp, 2H), 7.37 (m, 1H), 7.34-7.27 (comp, 2H), 7.14-7.11 (m, 1H),
3.84 (s, 3H).
[0274] C.
2-Amino-1-(4-bromo-phenyl)-1-(3-methoxy-phenyl)-ethanol
[0275] To a solution of
(4-bromo-phenyl)-(3-methoxy-phenyl)-methanone (2.06 g, 7.07 mmol),
in CH.sub.2Cl.sub.2 (3.5 mL) at room temperature was added
Znl.sub.2 (0.15 g, 0.47 mmol) followed by addition of TMSCN (4.29
mL, 32.2 mmol). The reaction mixture was stirred at room
temperature for 3 h and was quenched by addition of brine (20 mL).
The aqueous layer was washed with CH.sub.2Cl.sub.2 (3.times.30 mL)
and the combined organic extracts were dried over Na.sub.2SO.sub.4
and concentrated to afford an oil. The resulting oil was dissolved
in THF (7 mL) and the solution was added dropwise to a solution of
lithium aluminum hydride (LAH) in THF (1M, 8.13 mL) at 0.degree. C.
The mixture was stirred at 0.degree. C. for 1 h and at room
temperature for 1 h. To the solution was added H.sub.2O (1.5 mL)
followed by addition of 15% aqueous sodium hydroxide (NaOH) (1.5
mL) and H.sub.2O (4.5 mL). The mixture was filtered trough celite
and the celite was washed with EtOAc (20 mL). The filtrate was
dried over MgSO.sub.4 vand concentrated. Purification by flash
chromatography with CH.sub.2Cl.sub.2/MeOH (20:1) afforded 2.1 g of
2-amino-1-(4-bromo-phenyl)- -1-(3-methoxy-phenyl)-ethanol.
.sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.44-7.40 (comp, 2H),
7.33-7.26 (comp, 2H), 7.24-7.20 (m, 1H), 7.01-6.99 (m, 1H),
6.97-6.94 (m, 1H), 3.77 (s, 3H), 3.47-3-35 (comp, 2H), 3.29-3.24
(comp, 2H); MS (M+1) 304.1, 306.1.
[0276] D.
N-[2-(4-Bromo-phenyl)-2-hydroxy-2-(3-methoxy-phenyl)-ethyl]-2-ch-
loro-acetamide
[0277] To a solution of
2-amino-1-(4-bromo-phenyl)-1-(3-methoxy-phenyl)-et- hanol (0.94 g,
2.92 mmol) in toluene (10 mL) at 0.degree. C. was added
triethylamine (0.41 mL, 3.07 mmol). To the reaction mixture was
added a solution of chloroacetylchloride (0.23 mL, 2.92 mmol) in
toluene (1 mL) and the reaction was stirred at 0.degree. C. for 30
min. and at room temperature for 1 h. To the reaction was added
cold water (10 mL) and the mixture was stirred for 10 min. EtOAc
was added (20 mL) and the layers were separated. The aqueous layer
was washed with EtOAc (2.times.20 mL) and the combined organic
extracts were dried over MgSO.sub.4, and concentrated. Purification
by flash chromatography with hexanes/EtOAc (4:1) afforded 1.08 g of
N-[2-(4-bromo-phenyl)-2-hydroxy-2-(3-methoxy-phe-
nyl)-ethyl]-2-chloro-acetamide. .sup.1HNMR (400 MHz, CDCl.sub.3)
.delta. 7.45-7.41 (comp, 2H), 7.29-7.20 (comp, 3H), 6.97-6.96 (m,
1H), 6.93-6.90 (m, 1H), 6.86-6.85 (m, 1H), 6.85-6.79 (m, 1H),
4.14-3.98 (comp, 2H), 3.95 (s, 2H), 3.77 (s, 3H); MS (M+1) 380.0,
382.0.
[0278] E.
6-(4-Bromo-phenyl)-6-(3-methoxy-phenyl)-morpholin-3-one
[0279] To a solution of
N-[2-(4-bromo-phenyl)-2-hydroxy-2-(3-methoxy-pheny-
l)-ethyl]-2-chloro-acetamide (3.67 g, 9.2 mmol), in benzene (205
mL) at room temperature was added t-BuOK (4.54 g, 40.5 mmol). The
reaction mixture was stirred at room temperature for 2 h. To the
mixture was added water (40 mL) and the aqueous layer was washed
with CH.sub.2Cl.sub.2 (2.times.50 mL). The combined organic
extracts were dried over MgSO.sub.4 and concentrated. Purification
by flash chromatography with hexanes/EtOAc (3:1) afforded 3.34 g of
6-(4-bromo-phenyl)-6-(3-methoxy-phenyl)-morpholi- n-3-one.
.sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.46-7.41 (comp, 2H),
7.27-7.17 (comp, 2H), 6.89-6.70 (comp, 3H), 6.69 (br, 1H), 4.10 (s,
2H), 3.93-3.80 (comp, 2H), 3.76 (s, 3H); MS (M+1) 362.1, 364.1.
[0280] F. 2-(4-Bromo-phenyl)-2-(3-methoxy-phenyl)-morpholine
[0281] To a solution of LAH in THF (1M, 13.9 mL) at 0.degree. C.
was added a solution of
6-(4-bromo-phenyl)-6-(3-methoxy-phenyl)-morpholin-3-one (3.34 g,
9.23 mmol) in THF (15 mL). The reaction mixture was stirred at
0.degree. C. for 1 h and at room temperature for 16 h. To the
mixture was added H.sub.2O (6.2 mL) followed by addition of 15%
aqueous NaOH (6.2 mL) and H.sub.2O (7 mL). The mixture was filtered
through celite and the celite was washed with EtOAc (50 mL). The
filtrate was dried over MgSO.sub.4 and concentrated to afford 2.82
g of 2-(4-bromo-phenyl)-2-(3-m- ethoxy-phenyl)-morpholine.
.sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.43-7.36 (comp, 2H),
7.33-7.20 (comp, 3H), 6.98-6.82 (comp, 2H), 6.79-6.75 (m, 1H), 3.76
(s, 3H), 3.68-3.69 (comp, 2H), 3.45-3.29 (comp, 2H), 2.93-2.88
(comp, 2H); MS (M+1) 348.01, 350.0.
[0282] G.
2-(4-Bromo-phenyl)4-cyclopropylmethyl-2-(3-methoxy-phenyl)-morph-
oline
[0283] Prepared by methods similar to those described in Examples 2
and 3. .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.42-7.38 (comp,
2H), 7.30-7.18 (comp, 3H), 7.08-6.97 (m, 1H), 6.96-6.84 (m, 1H),
6.79-6.71 (m, 1H), 3.76 (s, 3H), 3.75-3.61 (comp, 2H), 3.15-2.88
(comp, 2H), 2,59-2.51 (comp, 2H), 2.29-2.19 (comp, 2H), 1.01-0.84
(m, 1H), 0.50-0.49 (comp, 2H), 0.18-0.11 (comp, 2H); MS (M+1)
402.0, 404.0.
[0284] H.
4-[4-Cyclopropylmethyl-2-(3-methoxy-phenyl)-morpholin-2-yl]-benz-
oic acid methyl ester
[0285] Prepared by a procedure similar to that described in example
1D. .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.94 (d, 2H), 7.48 (d,
2H), 7.21-7.18 (m, 1H), 6.98 (s, 1H), 6.91 (d, 1H), 6.74 (dd, 1H),
3.87 (s, 3H), 3.75 (s, 3H), 3.74-3.63 (comp, 2H), 3.09-2.92 (comp,
2H), 2.56-2.48 (comp, 2H), 2.31-2.18 (comp, 2H), 0.98-0.88 (m, IH),
0.59-0.51 (comp, 2H), 0.14-0.10 (comp, 1H); MS (M+1) 382.1.
[0286] I.
4-[4-Cyclopropylmethyl-2-(3-methoxy-phenyl)-morpholin-2-yl]-N,N--
diethyl-benzamide
[0287] Prepared by a method similar to that described in Example
1E. .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.40 (d, 1H), 7.28 (d,
2H), 7.23-7.18 (m, 1H), 7.06-6.98 (m, 1H), 6.93 (d, 1H) 6.75 (dd,
1H), 3.76 (s, 3H), 3.75-3.76 (comp, 2H), 3.55-3.49 (comp, 2H),
3.32-3.19 (comp, 2H), 3.16-3.02 (m, 1H), 2.99-2.84 (m, 1H),
2.58-2.43 (comp, 2H), 2.34-2.26 (m, 1H), 2.25-2.18 (m, 1H),
1.26-1.17 (comp, 3H), 1.16-1.04 (comp, 3H), 0.99-0.90 (m, 1H),
0.59-0.51 (comp, 2H), 0.14-0.10 (comp, 2H); MS (M+1) 423.3.
[0288] J.
4-[4-Cyclopropylmethyl-2-(3-hydroxy-phenyl)-morpholin-2-yl]-N,N--
diethyl-benzamide
[0289] Prepared by a method similar to that described- in Example
4. .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.38 (d, 1H), 7.26 (d,
2H), 7.12-7.06 (m, 1H), 6.91 (d, 1H), 6.82 (s, 1H), 6.61 (dd, 1H),
3.79-3.63 (comp, 2H), 3.59-3.42 (comp, 2H), 3.35-3.19 (comp, 2H),
3.08-2.83 (comp, 2H), 2.61-2.44 (comp, 2H), 2.32-2.18 (comp, 2H),
1.29-1.19 (comp, 3H), 1.18-1.01 (comp, 3H), 0.99-0.89 (m, 1H),
0.59-0.49 (comp, 2H), 0.15-0.10 (comp, 2H); MS (M+1) 409.1.
[0290] The following examples were prepared by procedures described
above in Example 9.
[0291]
4-[4-Allyl-2-(3-hydroxy-phenyl)-morpholin-2-yl]-N,N-diethyl-benzami-
de
[0292] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 6.81 (s, 1H),
6.02-5.83 (m, 1H), 5.29-5.16 (comp, 2H), 3.04-2.98 (comp, 2H),
2.58-2.43 (comp, 2H); MS (M+1) 395.3.
[0293]
4-[4-Benzyl-2-(3-hydroxy-phenyl)-morpholin-2-yl]-N,N-diethyl-benzam-
ide
[0294] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.13-7.06 (m, 1H),
6.81-6.75 (comp, 2H), 6.67 (d, 1H), 3.79-3.61 (comp, 2H), 3.32-3.18
(comp, 2H); MS (M+1) 445.3.
[0295] The following compound was prepared by the procedure of
Example 9 and subsequent conversion of R.sup.3=OH to
R.sup.3=CONH.sub.2 according to the procedure of Example 5.
[0296]
4-14-Cyclopropylmethyl-2-(3-carboxyamino-phenyl)-morpholin-2-yl]-N,-
N-diethyl-benzamide
[0297] .sup.1HNMR.(400 MHz, CDCl.sub.3) .delta. 7.91 (s, 1H),
7.70-7.61 (comp, 1H), 3.81-3.63 (comp, 2H), 0.61-0.44 (comp, 2H),
0.21-0.15 (comp, 2H); MS (M+1) 436.3.
EXAMPLE 10
[0298] A.
(5-Bromo-pyridin-2-yl)-(3-methoxy-phenyl)-acetonitrile
[0299] To a suspension of hexane washed 60% sodium hydride (2.65,
66.0 mmol) in DMF (30 mL) at 0.degree. C. was added 3-methoxyphenyl
acetonitrile (8.0 g, 54.3 mmol). The reaction mixture was stirred
at 0.degree. C. for 30 min. A solution of 2,5-dibromopyridine
(15.45 g, 65.2 mmol) in DMF (20 mL) was added and the reaction was
stirred at room temperature for 20 min and at 50.degree. C. for 30
min. To the reaction mixture was added H.sub.2O (20 mL) and
Et.sub.2O (200 mL). The organic layer was washed with brine
(5.times.50 mL), dried over Na.sub.2SO.sub.4 and concentrated.
Purification by flash chromatography with hexanes/EtOAc (10:1)
afforded 10.6 g of (5-Bromo-pyridin-2-yl)-(3-methoxy-phenyl)-aceto-
nitrile. .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.63 (s,1H), 7.80
(dd, 1H), 7.27 (comp, 2H), 6.98 (d, 1H), 6.87 (s,1H), 6.84 (m, 1H),
5.28 (s, 1H), 5.23 (s, 3H); MS (M+1) 303.0, 305.0.
[0300] B.
2-(5-Bromo-pyridin-2-yl)-5-chloro-2-(3-methoxy-phenyl)-pentaneni-
trile
[0301] To a suspension of hexane washed 60% sodium hydride (0.35 g,
8.6 mmol) in DMF (2 mL) at 0.degree. C. was added a solution of
(5-bromo-pyridin-2-yl)-(3-methoxy-phenyl)-acetonitrile (1.75 g,
5.76 mmol) in DMF (5 mL). The reaction mixture was stirred at
0.degree. C. for 30 min and at room temperature for 1 h.
1-bromo-3-chloropropane (0.69 mL, 6.91 mmol) was added and the
mixture was stirred at room temperature for 4 h. To the reaction
mixture was added H.sub.2O (5 mL) and Et.sub.2O and the organic
layer was washed with brine (5.times.5 mL), dried over
Na.sub.2SO.sub.4 and concentrated. Purification by flash
chromatography with hexanes/EtOAc (10:1) yielded 1.81 g of
2-(5-bromo-pyridin-2-yl)-5-ch-
loro-2-(3-methoxy-phenyl)-pentanenitrile. .sup.1HNMR (400 MHz,
CDCl.sub.3) .delta. 8.65 (s, 1H), 7.76 (dd, 1H), 7.36 (d, 1h),
7.27-7.21 (m, 1H), 7.03 (d, 1H), 6.98 (s, 1H), 6.82 (dd,1H), 4.77
(s, 3H), 3.55 (t, 2H), 2.79-2.70 (comp, 1H), 2.62-2.52 (comp, 1H)
1.89-1.79 (comp, 2H); MS (M+1)378.8, 380.8.
[0302] C.
5-Bromo-3'-(3-methoxy-phenyl)-1',2',3',4',5',6'-hexahydro-[2,3']-
bipyridinyl
[0303] To a solution of
2-(5-bromo-pyridin-2-yl)-5-chloro-2-(3-methoxy-phe-
nyl)-pentanenitrile (0.54 g, 1.43 mmol) in CH.sub.2Cl.sub.2 (3 mL)
at -78.degree. C. was added DIBAL in CH.sub.2Cl.sub.2 (1M, 3.2 mL).
The reaction mixture was stirred at -78 for 1 h and at room
temperature for 4 h. The solution was poured to a saturated aqueous
solution of Rochelle's salt (10 mL) and the resulting mixture was
stirred vigorously for 16 h. The aqueous layer was washed with
CH.sub.2Cl.sub.2 (3.times.10 mL), and the combined extracts were
dried over Na.sub.2SO.sub.4 and concentrated. Purification by flash
chromatography with CH.sub.2Cl.sub.2/MeOH (10:1) yielded 0.36 g of
5-bromo-3'-(3-methoxy-phenyl)-1',2',3',4',5',6'-hexahyd-
ro-[2,3']bipyridinyl. .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.62
(s, 1H), 7.63 (dd, 1H), 7.24-7.18(m, 1H), 6.91 (d, 1H) 6.81-6.67
(comp, 3H), 3.96-3.90 (m, 1H), 3.75 (s, 3H), 3.09-3.00 (comp, 2H),
2.82-2.74 (m, 1H), 2.54-2.48 (m, IH), 2.41-2.34 (m, 1H) 1.64-1.60
(m, 1H) 1.38-1.31 (m, 1H); MS(M+1) 347.1, 349.1.
[0304] D.
5-Bromo-1'-benzyl-3'-(3-methoxy-phenyl)-1',2',3',4',5',6'-hexahy-
dro-[2,3']bipyridinyl
[0305] Prepared by methods similar to those described in Examples 2
and 3.
[0306] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.55 (s, 1H), 7.62
(dd, 1H), 7.42-7.21 (comp, 6H), 7.20-7.12 (m, 1H), 7.01 (d, 1H),
6.81-6.74 (m, 1H), 6.67 (dd, 1H) 3.78 (s, 3H), 3.59-3.41 (comp,
2H), 3.20-3.12 (m, 1H), 2.81-2.25 (comp, 4H), 2.18-2.04 (m, 1H),
1.62-1.41 (comp, 2H); MS(M+1) 437.2, 439.3.
[0307] E.
1'-Benzyl-3'-(3-methoxy-phenyl)-1',2',3',4',5',6'-hexahydro-[2,3-
']bipyridinyl-5-carboxylic acid methyl ester
[0308] Prepared by a method similar to that of Example 1D.
[0309] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 9.10 (s, 1H), 8.10
(dd, IH) 7.41-7.01 (comp, 7H), 6.81-6.77 (comp, 2H), 6.67 (dd, 1H),
3.90 (s, 3H), 3.70 (s, 3H), 3.61-3.42 (comp, 2H), 3.25-3.15 (m,
1H), 2.85-2.75 (comp, 2H), 2.61-2.53 (m, 1H), 2.41-2.38 (m, 1H),
2.20-2.12 (m, 1H), 1.62-1.55 (comp, 2H); MS(M+1) 417.2.
[0310] F.
1'-Benzyl-3'-(3-methoxy-phenyl)-1',2',3',4',5',6'-hexahydro-[2,3-
']bipyridinyl-5-carboxylic acid diethylamide
[0311] Prepared by a method similar to that of Example 1E.
[0312] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.53 (s, 1H), 7.55
(dd, 1H), 7.38-7.21 (comp, 5H), 7.18-7.09 (comp, 2H), 6.83-6.78
(comp, 2H), 6.68-6.62 (m, 1H), 3.71 (s, 3H), 3.60-3.42 (comp, 4H),
3.38-3.22 (comp 2H), 3.18-3.07 (m, 1H), 2.92-2.82 (m, 1H),
2.65-2.61 (m, 1H), 2.58-2.40 (comp, 2H), 2.18-2.03 (m, 1H),
1.64-1.43 (comp, 2H), 1.34-1.10 (comp, 6H); MS (M+1) 449.3
[0313] G.
1'-Benzyl-3'-(3-hydroxy-phenyl)-1',2',3',4',5',6'-hexahydro-[2,3-
']bipyridinyl-5-carboxylic acid diethylamide
[0314] Prepared by a method similar to that of Example 4.
.sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.53 (s, 1H), 7.55 (d,
1H), 7.40-7.21 (comp, 5H), 7.19-7.08 (m, 1H), 7.03-6.89 (m, 1H),
6.77-6.62 (comp, 2H), 6.58-6.52 (m, 1H), 3.60-3.42 (comp, 4H),
3.36-3.22 (comp, 2H), 3.18-3.04 (m, 1H), 2.82-2.78 (m 1H),
2.71-2.26 (comp, 3H), 2.18-2.03 (m, 1H), 1.62-1.44 (comp, 2H),
1.35-1.10 (comp, 6H); MS(M+1) 444.2.
[0315] The following compounds were prepared by methods similar to
those described in Example 10.
[0316]
1'-(5-Fluoro-pyrimidin-2-yl)-3'-(3-hydroxy-phenyl)-1',2',3',4',5',6-
'-hexahydro-[2,3']bipyridinyl-5-carboxylic acid diethylamide
[0317] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.20 (s, 2H), 4.57
(d, 1H), 4.17 (d, 1H); MS (M+1) 450.3.
[0318]
3'-(3-Hydroxy-phenyl)-1'-pyrimidin-2-yl-1',2',3',4',5',6'-hexahydro-
-[2,3']bipyridinyl-5-carboxylic acid diethylamide
[0319] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.33(s, 2H) 6.49
(d, 2H) 4.57 (d, 1H), 4.17 (d, 1H); MS(M+1) 432.3.
[0320]
1'-Cyclopropylmethyl-3'-(3-hydroxy-phenyl)-1',2',3',4',5',6'-hexahy-
dro-[2,3']bipyridinyl-5-carboxylic acid diethylamide
[0321] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.58 (dd, 1H),
1.01-0.84 (m, 1H), 0.57-0.49 (comp, 2H), 0.17-0.11 (comp, 2H);
MS(M+1) 408.4.
[0322]
3'-(3-Hydroxy-phenyl)-1'-propyl-1',2',3',4',5',6'-hexahydro-[2,3']b-
ipyridinyl-5-carboxylic acid diethylamide
[0323] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 6.78 (s, 1H), 6.62
(d, 1H), 2.20-2.12 (m, 1H), 1.160.99 (comp, 3H); MS(M+1) 396.4.
[0324]
3'-(3-Hydroxy-phenyl)-1'-pentyl-1',2',3',4',5',6'-hexahydro-[2,3']b-
ipyridinyl-5-carboxylic acid diethylamide
[0325] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 2.60-2.40 (comp,
4H), 1.41-1.10 (comp, 8H), 0.87 (t, 3H); MS(M+1) 424.3.
[0326]
3'-(3-Hydroxy-phenyl)-1'-isobutyl-1',2',3',4',5',6'-hexahydro-[2,3'-
]bipyridinyl-5-carboxylic acid diethylamide
[0327] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.58 (dd, 1H), 6.82
(s, 1H), 3.31-3.23 (comp, 2H), 1.00-0.70 (comp, 6H); MS (M+1)
410.3.
[0328]
3'-(3-Hydroxy-phenyl)-3',4',5',6'-tetrahydro-2'H-[2,1';3',2"]terpyr-
idine-5"-carboxylic acid diethylamide
[0329] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 9.02 (s, 1H), 8.29
(d, 1H), 7.39-7.34 (m, 1H), 6.87 (br, 1H); MS (M+1) 431.3.
[0330]
3'-(3-Hydroxy-phenyl)-1'-(2-methyl-butyl)-1',2',3',4',5',6'-hexahyd-
ro-[2,3']bipyridinyl-5-carboxylic acid diethylamide
[0331] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.53-8.50 (m, 1H),
6.83 (s, 1H), 2.92-2.64 (comp, 2H), 1.17-1.09 (comp, 3H); MS (M+1)
424.4.
* * * * *