U.S. patent application number 13/042620 was filed with the patent office on 2011-06-30 for 5-aryl-4,5-dihydro-(1h)-pyrazolines as cannabinoid cb1 receptor agonists.
This patent application is currently assigned to Solvay Pharmaceuticals, B.V.. Invention is credited to Josephus H.M. LANGE, Bernard J. VAN VLIET, Hicham ZILAOUT.
Application Number | 20110160459 13/042620 |
Document ID | / |
Family ID | 40472358 |
Filed Date | 2011-06-30 |
United States Patent
Application |
20110160459 |
Kind Code |
A1 |
LANGE; Josephus H.M. ; et
al. |
June 30, 2011 |
5-ARYL-4,5-DIHYDRO-(1H)-PYRAZOLINES AS CANNABINOID CB1 RECEPTOR
AGONISTS
Abstract
The invention is directed to
5-(hetero)aryl-4,5-dihydro-(1H)-pyrazole (pyrazoline) derivatives
as cannabinoid CB.sub.1 receptor agonists, to pharmaceutical
compositions comprising these compounds, to methods for their
syntheses, methods for preparing novel intermediates useful for
their syntheses, and methods for preparing compositions. The
invention also relates to the uses of such compounds and
compositions, administered to patients to achieve a therapeutic
effect in disorders in which CB.sub.1 receptors are involved, or
that can be treated via manipulation of those receptors. Compounds
of the present invention include compounds of formula (I):
##STR00001## wherein the substituents have the definitions given in
the specification.
Inventors: |
LANGE; Josephus H.M.;
(Weesp, NL) ; ZILAOUT; Hicham; (Weesp, NL)
; VAN VLIET; Bernard J.; (Weesp, NL) |
Assignee: |
Solvay Pharmaceuticals,
B.V.
|
Family ID: |
40472358 |
Appl. No.: |
13/042620 |
Filed: |
March 8, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12234080 |
Sep 19, 2008 |
7928134 |
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13042620 |
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60973863 |
Sep 20, 2007 |
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Current U.S.
Class: |
546/275.4 ;
548/365.7; 548/379.4 |
Current CPC
Class: |
C07D 417/12 20130101;
C07C 235/80 20130101; C07D 405/12 20130101; C07D 403/12 20130101;
C07D 231/06 20130101; A61P 25/00 20180101; C07D 409/12 20130101;
A61P 25/28 20180101; C07C 2602/42 20170501; C07D 409/04 20130101;
C07D 401/12 20130101; C07D 401/04 20130101 |
Class at
Publication: |
546/275.4 ;
548/379.4; 548/365.7 |
International
Class: |
C07D 401/12 20060101
C07D401/12; C07D 231/06 20060101 C07D231/06; C07D 401/04 20060101
C07D401/04 |
Claims
1-10. (canceled)
11. A compound of formula (Va): ##STR00147## or a tautomer,
stereoisomer, N-oxide, isotopically-labelled analogue, or a
pharmacologically acceptable salt of any of the foregoing, wherein:
R.sub.1 is chosen from: C.sub.3-10 linear alkyl, C.sub.4-10
branched alkyl, C.sub.4-10 alkenyl, C.sub.4-10 alkynyl,
C.sub.3-10-heteroalkyl, C.sub.5-8-cycloalkyl-C.sub.1-5-alkyl, and
C.sub.5-8-heterocycloalkyl-C.sub.1-5-alkyl, each of which may be
optionally substituted with 1-5 substituents, wherein the
substituents are the same or different, and are chosen from methyl,
ethyl, hydroxy, amino, cyano and fluoro, aryl-C.sub.1-3-alkyl,
heteroaryl-C.sub.1-3-alkyl, aryl-C.sub.1-3-heteroalkyl, and
heteroaryl-C.sub.1-3-heteroalkyl, wherein the aryl or heteroaryl
groups are optionally substituted with 1-5 substituents Y, wherein
each Y is the same or different, and is chosen from
C.sub.1-3-alkyl, C.sub.1-3-alkoxy, hydroxy, halogen,
trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro,
amino, mono- or dialkyl (C.sub.1-2)-amino, mono- or dialkyl
(C.sub.1-2)-amido, (C.sub.1-3)-alkyl sulfonyl, dimethylsulfamido,
C.sub.1-3-alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano,
carbamoyl, sulfamoyl, phenyl, and acetyl, and 2-cyano-ethyl;
R.sub.2 is chosen from aryl and heteroaryl, each of which may be
optionally substituted with 1-5 substituents Y as defined above;
R.sub.5 is chosen from hydrogen and C.sub.1-2 alkyl, optionally
substituted with 1-3 fluorine atoms; and R.sub.6 is chosen from
hydrogen and C.sub.1-2 alkyl, optionally substituted with 1-3
fluorine atoms; and R.sub.8 is chosen from chloro and OR.sub.7,
where R.sub.7 is C.sub.1-3 alkyl; provided that if R.sub.2 is
phenyl and R.sub.1 is benzyl, then R.sub.7 is not ethyl.
12. A compound of formula (VI): ##STR00148## or a sodium,
potassium, lithium, or cesium salt thereof, wherein: R.sub.1 is
chosen from: C.sub.3-10 linear alkyl, C.sub.4-10 branched alkyl,
C.sub.4-10 alkenyl, C.sub.4-10 alkynyl, C.sub.3-10-heteroalkyl,
C.sub.5-8-cycloalkyl-C.sub.1-5-alkyl, and
C.sub.5-8-heterocycloalkyl-C.sub.1-5-alkyl, each of which may be
optionally substituted with 1-5 substituents, wherein the
substituents are the same or different, and are chosen from methyl,
ethyl, hydroxy, amino, cyano and fluoro, aryl-C.sub.1-3-alkyl,
heteroaryl-C.sub.1-3-alkyl, aryl-C.sub.1-3-heteroalkyl, and
heteroaryl-C.sub.1-3-heteroalkyl, wherein the aryl or heteroaryl
groups are optionally substituted with 1-5 substituents Y, wherein
each Y is the same or different, and is chosen from
C.sub.1-3-alkyl, C.sub.1-3-alkoxy, hydroxy, halogen,
trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro,
amino, mono- or dialkyl (C.sub.1-2)-amino, mono- or dialkyl
(C.sub.1-2)-amido, (C.sub.1-3)-alkyl sulfonyl, dimethylsulfamido,
C.sub.1-3-alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano,
carbamoyl, sulfamoyl, phenyl, and acetyl, and 2-cyano-ethyl;
R.sub.2 is chosen from aryl and heteroaryl, each of which may be
optionally substituted with 1-5 substituents Y as defined above;
R.sub.5 is chosen from hydrogen and C.sub.1-2 alkyl, optionally
substituted with 1-3 fluorine atoms; and R.sub.6 is chosen from
hydrogen and C.sub.1-2 alkyl, optionally substituted with 1-3
fluorine atoms; provided that if R.sub.2 is phenyl then R.sub.1 is
not benzyl.
13. (canceled)
Description
[0001] This application claims the benefit of U.S. provisional
application No. 60/973,863, filed Sep. 20, 2007, the disclosure of
which is incorporated herein by reference.
[0002] The present disclosure relates to the fields of
pharmaceutical and organic chemistry, and provides
5-(hetero)aryl-4,5-dihydro-(1H)-pyrazole (pyrazoline) derivatives,
intermediates for synthesizing these compounds, formulations
comprising these compounds, and methods of treatment using these
compounds.
[0003] The endogenous cannabinoid receptor agonist, anandamide, is
too unstable to be of practical value as a drug. The same is true
for other endocannabinoids such as 2-arachidonoyl-glycerol and
noladin ether. With the exception of
.DELTA..sup.9-tetrahydrocannabinol (.DELTA..sup.9-THC, dronabinol,
Marinol.RTM.) and Nabilone (Cesamet.RTM.) no other cannabinoid
receptor agonists have been registered as drugs. In addition,
Sativex.RTM. (an extract from the Cannabis sativa L. plant) has
been recently approved as a prescription medicine (Barnes, 2006).
Compounds like CP 55,940 and WIN 55, 212-2 are not registered
drugs, but have been, and still are, used as pharmacological
tools.
[0004] It has been postulated that cannabinoid CB.sub.1 receptors
can occur in two different states: the active `R*-state` to which
agonists bind, and the inactive `R-state` to which antagonists or
inverse agonists--such as rimonabant--bind. Both states have
considerably different three-dimensional geometries. Key
interaction in the cannabinoid-CB.sub.1 receptor model (based on
Palczewski's X-ray structure of bovine rhodopsin) is a hydrogen
bond between the carbonyl group of, e.g., the CB.sub.1 receptor
inverse agonist rimonabant, and the LYS192 residue of the CB.sub.1
receptor. This hydrogen bond has a stabilizing effect on the
Lys192-Asp366 salt bridge of the intracellular end of the
transmembrane helices 3 and 6. The existence of this specific salt
bridge is induced by a pronounced kink at Pro 358 in transmembrane
helix 6, present in the inactive R-state of the receptor, but not
in the active R*-state, which is stabilized by CB.sub.1 receptor
agonist binding (Hurst, 2002; Shim, 2002; Reggio, 2003; Pertwee,
2005 and Lange, 2005). Thus, it is not possible to apply structural
features of known CB.sub.1 receptor antagonists or inverse agonists
to design novel CB.sub.1 receptor agonists in a straightforward
manner.
[0005] Ample evidence exists that cannabinoid receptor agonists
have therapeutic possibilities as appetite stimulants,
enti-emetics, analgesics, anti-glaucoma agents (Croxford, 2003;
Drysdale, 2003), tumor growth inhibitors (Ligresti, 2003), and
agents for the treatment of neurodegenerative disorders, including
multiple sclerosis and Alzheimer's disease (Smith, 2004; Croxford,
2004).
##STR00002## ##STR00003##
[0006] Thus, there is a need to develop novel compounds with
CB.sub.1 receptor agonistic activity, structurally unrelated to
known cannabinoid receptor agonists.
DISCLOSURE
[0007] Surprisingly, the inventors found that replacing the 1-aryl
or 1-heteroaryl group in 4,5-dihydro-pyrazole CB.sub.1 receptor
antagonists described in WO 2005/074920, WO 2005/077911 or WO
2007/009689 by an optionally substituted alkyl moiety, resulted in
novel compounds with a high affinity for CB.sub.1 receptors,
wherein these compounds may act as full or partial agonists at
CB.sub.1 receptors. Moreover, most of these compounds also showed
affinity for CB.sub.2 receptors.
[0008] In one embodiment, the invention relates to compounds of
formula (I):
##STR00004##
or tautomers, stereoisomers, N-oxides, isotopically-labelled
analogues, or pharmaceutically acceptable salts of any of the
foregoing, wherein:
[0009] R.sub.1 is chosen from: [0010] C.sub.3-10 linear alkyl,
C.sub.4-10 branched alkyl, C.sub.4-10 alkenyl, C.sub.4-10 alkynyl,
C.sub.3-10-heteroalkyl, C.sub.5-8-cycloalkyl-C.sub.1-8-alky, and
C.sub.5-8-heterocycloalkyl-C.sub.1-5-alkyl, each of which may be
optionally substituted with 1-5 substituents, wherein the
substituents are the same or different, and are chosen from methyl,
ethyl, hydroxy, amino, cyano and fluoro, [0011]
aryl-C.sub.1-3-alkyl, heteroaryl-C.sub.1-3-alkyl,
aryl-C.sub.1-3-heteroalkyl, and heteroaryl-C.sub.1-3-heteroalkyl,
wherein the aryl and heteroaryl groups are optionally substituted
with 1-5 substituents Y, wherein each Y is the same or different,
and is chosen from C.sub.1-3-alkyl, C.sub.1-3-alkoxy, hydroxy,
halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy,
nitro, amino, mono- or dialkyl (C.sub.1-2)-amino, mono- or dialkyl
(C.sub.1-2)-amido, (C.sub.1-3)-alkyl sulfonyl, dimethylsulfamido,
C.sub.1-3-alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano,
carbamoyl, sulfamoyl, phenyl and acetyl, and [0012]
2-cyano-ethyl;
[0013] R.sub.2 is chosen from aryl and heteroaryl, each of which
may be optionally substituted with 1-5 substituents Y as defined
above;
[0014] R.sub.3 is chosen from: [0015] linear and branched
C.sub.3-10 alkyl, C.sub.3-8 cycloalkyl, C.sub.5-10 bicycloalkyl,
C.sub.6-10 tricycloalkyl and C.sub.8-11 tetracycloalkyl, each of
which may be optionally substituted with 1-5 substituents, wherein
the substituents are the same or different, and are chosen from
methyl, ethyl, hydroxy, amino, and fluoro, [0016] C.sub.3-8
cycloalkyl substituted with aryl and heteroaryl, wherein the aryl
and heteroaryl are optionally substituted with 1-5 substituents Y
as defined above, [0017] 2,2,2-trifluoroethyl and 2-fluoroethyl,
[0018] C.sub.5-8 heterocycloalkyl, C.sub.6-10 bicycloheteroalkyl,
and C.sub.7-10 tricycloheteroalkyl, each of which may be optionally
substituted with 1-5 substituents, wherein the substituents are the
same or different, and are chosen from methyl, ethyl, hydroxy,
amino and fluoro, [0019] C.sub.3-8
C.sub.5-10-bicycloalkyl-C.sub.1-3-alkyl, and
C.sub.6-10-tricycloalkyl-C.sub.1-3-alkyl, each of which may be
optionally substituted with 1-5 substituents, wherein the
substituents are the same or different, and are chosen from methyl,
ethyl, hydroxy, amino and fluoro, [0020] branched and linear
C.sub.3-8 heterocycloalkyl-C.sub.1-3-alkyl, C.sub.5-10
bicycloheteroalkyl-C.sub.1-3-alkyl, and C.sub.6-10
tricycloheteroalkyl-C.sub.1-3-alkyl, each of which may be
optionally substituted with 1-5 substituents, wherein the
substituents are the same or different, and are chosen from methyl,
ethyl, hydroxy, amino and fluoro, [0021] aryl and heteroaryl, each
of which may be optionally substituted with 1-5 substituents Y as
defined above, [0022] aryl-C.sub.1-5-alkyl,
heteroaryl-C.sub.1-5-alkyl, and diaryl-C.sub.1-5-alkyl, wherein the
aryl and heteroaryl groups are optionally substituted with 1-5
substituents Y as defined above, [0023] linear and branched
C.sub.4-8 alkenyl and C.sub.4-8 alkynyl, each of which may be
optionally substituted with 1-3 fluorine atoms, and [0024] branched
and linear C.sub.2-10 heteroalkyl, comprising 1-2 heteroatoms
chosen from N,
[0025] O, or S;
[0026] R.sub.4 is chosen from hydrogen and C.sub.1-4 alkyl;
[0027] R.sub.5 is chosen from hydrogen and C.sub.1-2 alkyl,
optionally substituted with 1-3 fluorine atoms; and
[0028] R.sub.6 is chosen from hydrogen and C.sub.1-2 alkyl,
optionally substituted with 1-3 fluorine atoms.
[0029] In another embodiment, the invention relates to compounds of
formula (I):
##STR00005##
or tautomers, stereoisomers, N-oxides, isotopically-labelled
analogues, or pharmaceutically acceptable salts of any of the
foregoing, wherein:
[0030] R.sub.1 is chosen from: [0031] C.sub.3-10 linear alkyl,
C.sub.4-10 branched alkyl, and
C.sub.5-8-cycloalkyl-C.sub.1-5-alkyl, each of which may be
optionally substituted with 1-3 substituents, wherein the
substituents are the same or different, and are chosen from methyl,
ethyl, cyano, and fluoro, [0032] aryl-C.sub.1-3-alkyl, wherein the
aryl group is optionally substituted with 1-3 substituents Y,
wherein each Y is the same or different, and is chosen from
C.sub.1-3-alkyl, C.sub.1-3-alkoxy, halogen, trifluoromethyl,
trifluoro-methoxy, nitro, cyano, and phenyl, and [0033]
2-cyano-ethyl;
[0034] R.sub.2 is chosen from phenyl, thienyl, benzothienyl, and
pyridyl, each of which may be optionally substituted with 1 or 2
substituents, wherein the substituents are the same or different,
and are chosen from halogen, methyl, CF.sub.3, OCH.sub.3, and
OCF.sub.3;
[0035] R.sub.3 is chosen from: [0036] linear and branched
C.sub.3-10 alkyl, C.sub.3-8 cycloalkyl, C.sub.5-10 bicycloalkyl,
and C.sub.6-10 tricycloalkyl, each of which may be optionally
substituted with 1-3 substituents, wherein the substituents are the
same or different, and are chosen from methyl, ethyl, hydroxy,
amino, fluoro and aryl, [0037] C.sub.5-8 heterocycloalkyl
optionally substituted with 1-5 substituents, wherein the
substituents are the same or different, and are chosen from methyl,
ethyl, and fluoro, [0038] C.sub.3-8 cycloalkyl-C.sub.1-3-alkyl,
C.sub.5-10-bicycloalkyl-C.sub.1-3-alkyl, and
C.sub.6-10-tricycloalkyl-C.sub.1-3-alkyl, each of which may be
optionally substituted with 1-5 substituents, wherein the
substituents are the same or different, and are chosen from methyl,
ethyl, and fluoro, [0039] aryl and heteroaryl, each of which may be
optionally substituted with 1-5 substituents Y, wherein each Y is
the same or different, and is chosen from C.sub.1-3-alkyl,
C.sub.1-3-alkoxy, halogen, trifluoromethyl, trifluoromethylthio,
trifluoromethoxy, nitro, cyano, and phenyl, [0040]
aryl-C.sub.1-5-alkyl, heteroaryl-C.sub.1-5-alkyl, and
diaryl-C.sub.1-5-alkyl, wherein the aryl and heteroaryl groups are
optionally substituted with 1-5 substituents, wherein the
substituents are the same or different, and are chosen from
C.sub.1-3-alkyl, C.sub.1-3-alkoxy, halogen, trifluoromethyl,
trifluoromethylthio, trifluoromethoxy, nitro, cyano, and phenyl,
[0041] branched and linear C.sub.2-10 heteroalkyl, comprising 1-2
heteroatoms chosen from N, O, and S; and
[0042] R.sub.4, R.sub.5, and R.sub.6 are as defined above.
[0043] In another embodiment, the invention relates to compounds of
formula (I):
##STR00006##
or tautomers, stereoisomers, N-oxides, isotopically-labelled
analogues, or pharmaceutically acceptable salts of any of the
foregoing, wherein:
[0044] R.sub.1 is chosen from: [0045] C.sub.3-8 linear alkyl,
C.sub.4-8 branched alkyl, and C.sub.5-6-cycloalkyl-C.sub.1-5-alkyl,
each of which may be optionally substituted with 1-3 substituents,
wherein the substituents are the same or different, and are chosen
from cyano and fluoro, [0046] aryl-C.sub.1-3-alkyl and
2-cyano-ethyl;
[0047] R.sub.2 is chosen from phenyl, thienyl, benzothienyl, and
pyridyl, each of which may be optionally substituted with halogen,
methyl, CF.sub.3, OCH.sub.3, and OCF.sub.3; and
[0048] R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are as defined
above.
[0049] In another embodiment, the invention relates to compounds of
formula (I):
##STR00007##
or tautomers, stereoisomers, N-oxides, isotopically-labelled
analogues, or pharmaceutically acceptable salts of any of the
foregoing, wherein:
[0050] R.sub.1 is chosen from 2-cyano-ethyl, n-propyl, n-butyl,
4,4,4-trifluorobutyl, isobutyl, n-pentyl, cyclohexylmethyl, and
phenethyl;
[0051] R.sub.2 is chosen from 2-fluorophenyl,
3-(trifluoromethyl)phenyl, 3-chlorophenyl, 3-fluorophenyl,
3-methoxyphenyl, 4-chlorophenyl, 4-fluorophenyl, benzothien-3-yl,
pyrid-2-yl, thien-3-yl, and phenyl;
[0052] R.sub.3 is chosen from 3-(trifluoromethyl)benzyl,
3-(trifluoromethyl)benzyl, 1-(4-fluorophenyl)-1-methyl-ethyl,
1-phenyl-1-methyl-ethyl, 1-phenyl-ethyl, 2-indanyl,
2-(4-fluorophenyl)-1,1-dimethyl-ethyl, 2-(trifluoromethyl)benzyl,
2,2-dimethylpropyl, 2,2-diphenylethyl, 2,2-diphenylpropyl,
2-methoxybenzyl, 2-phenyl-propyl, 2-phenyl-trans-cyclopropyl,
2-trifluoromethyl)phenyl, 3,4,5-trimethoxybenzyl,
3,4-dimethoxybenzyl, 3-fluorobenzyl, 3-methoxybenzyl,
4-chlorobenzyl, 4-methoxybenzyl, 5-methyl-thiazol-2-yl,
adamant-1-yl, adamant-2-yl, adamantylmethyl, benzyl, cycloheptyl,
cyclohexylmethyl, cyclooctyl, endo-bicyclo[2.2.1]hept-2-yl,
exo-bicyclo[2.2.1]hept-2-yl, indan-2-yl,
N,2,2,6,6-pentamethylpiperidin-4-yl, naphth-1-yl,
naphthalen-1-yl-methyl, noradamant-1-yl, pyridin-3-ylmethyl,
quinolin-3-yl, tert-butyl, (1-ethyl)propyl,
(1R,2S,5R)-rel-6,6-dimethylbicyclo[3.1.1.]heptan-2-methyl,
(3-dimethylamino)-2,2-dimethylpropyl, (furan-2-yl)methyl,
(pyridin-3-yl)-methyl, 1-(4-fluorophenyl)-1-methyl-ethyl,
1-(adamant-1-yl)-ethyl, 1-phenyl-1-methyl-ethyl,
2-(4-fluorophenyl)ethyl, 2-(7-methyl-indol-3-yl)ethyl,
2-(indol-3-yl)ethyl, 2-(thien-2-yl)ethyl,
3-(trifluoromethyl)benzyl, 3,3-diphenylpropyl, 3,4-difluorobenzyl,
4-(trifluoromethyl)benzyl,
endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl,
naphthalen-1-yl-methyl, benzyl, cyclohexylmethyl, cyclopentyl,
methyl-N-(Naphthalen-1-yl-methyl), and phenyl;
[0053] R.sub.4 is chosen from hydrogen and methyl;
[0054] R.sub.5 is chosen from hydrogen and methyl; and
[0055] R.sub.6 is hydrogen.
[0056] In another embodiment, the invention relates to compounds of
formula (I):
##STR00008##
or tautomers, stereoisomers, N-oxides, isotopically-labelled
analogues, or pharmaceutically acceptable salts of any of the
foregoing, wherein the compounds of formula (I) are optically
active enantiomers.
[0057] In a further embodiment, the invention relates to compounds
of formula (I):
##STR00009##
or tautomers, stereoisomers, N-oxides, isotopically-labelled
analogues, or pharmaceutically acceptable salts of any of the
foregoing, having cannabinoid CB.sub.1 receptor agonistic
activity.
[0058] In a further embodiment, the invention relates to compounds
of formula (I), or pharmaceutically acceptable salts thereof, for
the treatment of disorders in which cannabinoid receptors are
involved, and in addition, that can be treated via manipulation of
those receptors.
[0059] In one embodiment, the invention relates to compounds of
formula (I), or pharmaceutically acceptable salts thereof, for the
treatment of multiple sclerosis, traumatic brain injury, pain
including chronic pain, neuropathic pain, acute pain and
inflammatory pain, osteoporosis, appetite disorders, epilepsy,
Alzheimer's disease, Tourette's syndrome, cerebral ischaemia and
gastrointestinal disorders.
[0060] Other embodiments of the invention include, but are not
limited to:
[0061] pharmaceutical compositions for treating, for example, at
least one disorder or condition that may be treated by activating
at least one cannabinoid CB.sub.1 receptor, the compositions
comprising a compound of formula (I), or a pharmaceutically
acceptable salt thereof, and a pharmaceutically acceptable
carrier;
[0062] methods of treatment of at least one disorder or condition
that may be treated by activating at least one cannabinoid CB.sub.1
receptor, the methods comprising administering to a mammal in need
of such treatment a compound of formula (I) or a pharmaceutically
acceptable salt thereof;
[0063] pharmaceutical compositions for treating, for example, at
least one disorder or condition chosen multiple sclerosis,
traumatic brain injury, pain including chronic pain, neuropathic
pain, acute pain and inflammatory pain, osteoporosis, appetite
disorders, epilepsy, Alzheimer's disease, Tourette's syndrome,
cerebral ischaemia and gastrointestinal disorders;
[0064] methods of treatment of at least one disorder or condition
chosen from the disorders listed herein, the methods comprising
administering to a mammal in need of such treatment a compound of
formula (I) or a pharmaceutically acceptable salt thereof;
[0065] pharmaceutical compositions for treatment of at least one
disorder or condition chosen from the disorders listed herein, the
compositions comprising a compound of formula (I) or a
pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier;
[0066] methods of treatment of at least one disorder or condition
that may be treated by activating at least one cannabinoid CB.sub.1
receptor, the methods comprising administering to a patient in need
of such treatment a compound of formula (I) or a pharmaceutically
acceptable salt thereof; and
[0067] methods of antagonizing at least one cannabinoid CB.sub.1
receptor, which comprises administering to a subject in need
thereof, an effective amount of a compound of formula (I).
[0068] The invention also provides for the use of at least one
compound or salt according to formula (I) for the manufacture of a
medicament.
[0069] The invention further relates to combination therapies
wherein at least one compound of the invention, or a
pharmaceutically acceptable salt thereof, or a pharmaceutical
composition or formulation comprising a compound of the invention,
is administered concurrently or sequentially or as a combined
preparation with another therapeutic agent or agents, for the
treatment of one or more of the conditions listed. Such other
therapeutic agent(s) may be administered prior to, simultaneously
with, or following the administration of the compounds of the
invention.
[0070] The invention also provides compounds, pharmaceutical
compositions, kits and methods for the treatment of a disorder or
condition that may be treated by activating at least one
cannabinoid CB.sub.1 receptor, the method comprising administering
to a patient in need of such treatment a compound of formula (I) or
a pharmaceutically acceptable salt thereof.
[0071] The invention also provides methods of preparing the
compounds of the invention and the intermediates used in those
methods.
[0072] Isolation and purification of the compounds and
intermediates described herein can be affected, if desired, by any
suitable separation or purification procedure such as, for example,
filtration, extraction, crystallization, column chromatography,
thin-layer chromatography, thick-layer chromatography, preparative
low or high-pressure liquid chromatography, or a combination of
these procedures. Specific illustrations of suitable separation and
isolation procedures can be taken from the preparations and
examples. However, other equivalent separation or isolation
procedures could, of course, also be used.
[0073] The compounds of the present invention may contain one or
more asymmetric centers and can thus occur as racemates and racemic
mixtures, single enantiomers, diastereomeric mixtures and
individual diastereomers.
[0074] All compounds of the present invention do contain at least
one chiral center (at the 5-position of the 4,5-dihydropyrazole
ring). Additional asymmetric centers may be present depending upon
the nature of the various substituents on the molecule. Each such
asymmetric center will independently produce two optical isomers,
and it is intended that all of the possible optical isomers and
diastereomers in mixtures and as pure or partially purified
compounds are included within the ambit of this invention.
[0075] Cis and trans isomers of the compounds of formula (I) or of
pharmaceutically acceptable salts thereof are also within the scope
of the invention, and this also applies to tautomers of the
compounds of formula (I) or pharmaceutically acceptable salts
thereof.
[0076] Some of the crystalline forms for the compounds may exist as
polymorphs, and as such are intended to be included in the present
invention. In addition, some of the compounds may form solvates
with water (i.e., hydrates) or common organic solvents, and such
solvates are also intended to be encompassed within the scope of
this invention.
[0077] Isotopically-labeled compounds of formula (I) or
pharmaceutically acceptable salts thereof, including compounds of
formula (I) isotopically-labeled to be detectable by PET or SPECT,
are also included within the scope of the invention, and the same
applies to compounds of formula (I) labeled with [.sup.13C]--,
[.sup.14C]--, [.sup.3H]--, [.sup.18F]--, [.sup.125I]-- or other
isotopically enriched atoms, suitable for receptor binding or
metabolism studies.
[0078] The compounds of the invention may also be used as reagents
or standards in the biochemical study of neurological function,
dysfunction and disease.
DEFINITIONS
[0079] General terms used in the description of compounds herein
disclosed bear their usual meanings. The term alkyl as used herein
denotes a univalent saturated branched or straight hydrocarbon
chain. Unless otherwise stated, such chains can contain from 1 to
18 carbon atoms. Representative of such alkyl groups are methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl,
octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl,
pentadecyl, hexadecyl, heptadecyl, octadecyl, and the like. When
qualified as `lower`, the alkyl group will contain from 1 to 6
carbon atoms. The same carbon content applies to the parent term
`alkane`, and to derivative terms such as `alkoxy`. The carbon
content of various hydrocarbon containing moieties is indicated by
a prefix designating the minimum and maximum number of carbon atoms
in the moiety, i.e., the prefix C.sub.x-C.sub.y defines the number
of carbon atoms present from the integer "x" to the integer "y"
inclusive. `Alkyl(C.sub.1-3)` for example, means methyl, ethyl,
n-propyl or isopropyl, and `alkyl(C.sub.1-4)` means `methyl, ethyl,
n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl`.
The term `alkeny` denotes straight or branched hydrocarbon radicals
having one or more carbon-carbon double bonds, such as vinyl,
allyl, butenyl, etc., and for example comprises (C.sub.2-4)
alkenyl. In `alkynyl` groups the straight or branched hydrocarbon
radicals have one or more carbon-carbon triple bonds, such as
ethynyl, propargyl, 1-butynyl, 2-butynyl, etc., and e.g. includes
(C.sub.2-4) alkynyl. Unless otherwise stated, alkenyl` and `alkynyl
chains can contain from 1 to 18 carbon atoms.
[0080] The term `acyl` comprises alkyl(C.sub.1-3) carbonyl,
arylcarbonyl or aryl-alkyl(C.sub.1-3)carbonyl. `Aryl` embraces
mono- or polycyclic aromatic groups, including phenyl, naphthyl,
1,2,3,4-tetrahydro-naphtyl, indenyl, fluorenyl, anthracenyl,
phenanthrenyl, naphthacenyl and azulenyl. `Heteroaryl` embraces
mono- or polycyclic hetero-aromatic, including furyl, thienyl,
pyrrolyl, oxazolyl, thiazolyl, imidazolyl,
imidazo[2,1-b][1,3]thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl,
pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl,
indazolyl, indolyl, indolizinyl, isoindolyl, benzo[b]furanyl,
1,2,3,4-tetrahydroiso-quinolinyl, indanyl, indenyl,
benzo[b]thienyl, 2,3-dihydro-1,4-benzodioxin-5-yl, benzimidazolyl,
cinnolinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl,
phenoxazinyl, benzothiazolyl, benzo[1,2,5]thia-diazolyl, purinyl,
quinolinyl, isoquinolinyl, quinolizinyl, phtalazinyl, quinazolinyl,
quinoxalinyl, 1,8-naphthyridinyl and pteridinyl.
[0081] `Halo` or `Halogen` means chloro, fluoro, bromo or iodo;
`hetero` as in `heteroalkyl, heteroaromatic` etc. means containing
one or more N, O or S atoms. `heteroalkyl` includes alkyl groups
with heteroatoms in any position, thus including N-bound O-bound or
S-bound alkyl groups.
[0082] The term "substituted" means that the specified group or
moiety bears one or more substituents. Where any group may carry
multiple substituents, and a variety of possible substituents is
provided, the substituents are independently selected, and need not
to be the same. The term "unsubstituted" means that the specified
group bears no substituents. With reference to substituents, the
term "independently" means that when more than one of such
substituents are possible, they may be the same or different from
each other.
[0083] `C.sub.3-8-cycloalky` means cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; `C.sub.5-8
heterocycloalkyl` refers to heteroatom containing rings including
but not limited to piperidinyl, morpholinyl, azepanyl,
pyrrolidinyl, thiomorpholinyl, piperazinyl, tetrahydrofuryl,
tetrahydropyranyl; `C.sub.5-10 bicycloalkyl group` refers to
carbo-bicyclic ring systems including but not limited to
bicyclo[2.2.1]heptanyl, bicyclo[3.3.0]octanyl or the bicyclo[3.1.1]
heptanyl group; `C.sub.6-10-tricycloalkyl group` refers to
carbo-tricyclic ring systems including but not limited to the
1-adamantyl, noradamantyl or the 2-adamantyl group. The
abbreviation `C.sub.8-11 tetracycloalkyl group` refers to
carbo-tetracyclic ring systems including but not limited to the
cubyl, homocubyl or bishomocubyl group.
[0084] The terms "oxy", "thio" and "carbo" as used herein as part
of another group respectively refer to an oxygen atom, a sulphur
atom and a carbonyl (C.dbd.O) group, serving as linker between two
groups, such as for instance hydroxyl, oxyalkyl, thioalkyl,
carboxyalkyl, etc. The term "amino" as used herein alone, or as
part of another group, refers to a nitrogen atom that may be either
terminal, or a linker between two other groups, wherein the group
may be a primary, secondary or tertiary (two hydrogen atoms bonded
to the nitrogen atom, one hydrogen atom bonded to the nitrogen atom
and no hydrogen atoms bonded to the nitrogen atom, respectively)
amine. The terms "sulfinyl" and "sulfonyl" as used herein as part
of another group respectively refer to an --SO-- or an --SO.sub.2--
group.
[0085] To provide a more concise description, the terms `compound`
or `compounds` include tautomers, stereoisomers, N-oxides,
isotopically-labelled analogues, or pharmacologically acceptable
salts, also when not explicitly mentioned.
[0086] As used herein, the term "leaving group" (L) shall mean a
charged or uncharged atom or group that departs during a
substitution or displacement reaction. The term refers to groups
readily displaceable by a nucleophile, such as an amine, a thiol or
an alcohol nucleophile. Such leaving groups are well known in the
art (Smith, 2001). Examples include, but are not limited to,
N-hydroxysuccinimide, N-hydroxybenzotriazole, halides (Br, Cl, I),
triflates, mesylates, tosylates, and the like.
[0087] N-oxides of the compounds mentioned above belong to the
invention. Tertiary amines may or may not give rise to N-oxide
metabolites. The extent to what N-oxidation takes place varies from
trace amounts to a near quantitative conversion. N-oxides may be
more active than their corresponding tertiary amines, or less
active. Whilst N-oxides can easily be reduced to their
corresponding tertiary amines by chemical means, in the human body
this happens to varying degrees. Some N-oxides undergo nearly
quantitative reductive conversion to the corresponding tertiary
amines, in other cases conversion is a mere trace reaction, or even
completely absent (Bickel, 1969).
[0088] `Form` is a term encompassing all solids: polymorphs,
solvates, amorphous forms. `Crystal form` refers to various solid
forms of the same compound, for example polymorphs, solvates and
amorphous forms. `Cocrystals` are multicomponent crystals with a
unique lattice: new chemical species produced with neutral
compounds. `Amorphous forms` are non-crystalline materials with no
long range order, and generally do not give a distinctive powder
X-ray diffraction pattern. Crystal forms in general have been
described by Byrn (1995) and Martin (1995). `Polymorphs` are
crystal structures in which a compound can crystallize in different
crystal packing arrangements, all of which have the same elemental
composition. Polymorphism is a frequently occurring phenomenon,
affected by several crystallization conditions such as temperature,
level of supersaturation, the presence of impurities, polarity of
solvent, rate of cooling. Different polymorphs usually have
different X-ray diffraction patterns, solid state NMR spectra,
infrared or Raman spectra, melting points, density, hardness,
crystal shape, optical and electrical properties, stability, and
solubility. Recrystallization solvent, rate of crystallization,
storage temperature, and other factors may cause one crystal form
to dominate.
[0089] To provide a more concise description, some of the
quantitative expressions given herein are not qualified with the
term "about". It is understood that whether the term "about" is
used explicitly or not, every quantity given herein is meant to
refer to the actual given value, and it is also meant to refer to
the approximation to such given value that would reasonably be
inferred based on the ordinary skill in the art, including
approximations due to the experimental and/or measurement
conditions for such given value.
[0090] Throughout the description and the claims of this
specification the word "comprise" and variations of the word, such
as "comprising" and "comprises" is not intended to exclude other
additives, components, integers or steps.
[0091] While it may be possible for the compounds of formula (I) to
be administered as the raw chemical, in at least one embodiment,
they are presented in a `pharmaceutical composition`. According to
a further aspect, the present invention provides a pharmaceutical
composition comprising a compound of formula (I), or a
pharmaceutically acceptable salt or solvate thereof, together with
one or more pharmaceutically acceptable carriers thereof, and
optionally one or more other therapeutic ingredients. The
carrier(s) must be `acceptable` in the sense of being compatible
with the other ingredients of the formulation and not deleterious
to the recipient thereof.
[0092] The term "composition" as used herein encompasses a product
comprising specified ingredients in predetermined amounts or
proportions, as well as any product that results, directly or
indirectly, from combining specified ingredients in specified
amounts. In relation to pharmaceutical compositions, this term
encompasses a product comprising one or more active ingredients,
and an optional carrier comprising inert ingredients, as well as
any product that results, directly or indirectly, from combination,
complexation or aggregation of any two or more of the ingredients,
or from dissociation of one or more of the ingredients, or from
other types of reactions or interactions of one or more of the
ingredients. In general, pharmaceutical compositions are prepared
by uniformly and intimately bringing the active ingredient into
association with a liquid carrier or a finely divided solid carrier
or both, and then, if necessary, shaping the product into the
desired formulation. The pharmaceutical composition includes enough
of the active object compound to produce the desired effect upon
the progress or condition of diseases. Accordingly, the
pharmaceutical compositions of the present invention encompass any
composition made by admixing a compound of the present invention
and a pharmaceutically acceptable carrier. By "pharmaceutically
acceptable" it is meant the carrier, diluent or excipient must be
compatible with the other ingredients of the formulation and not
deleterious to the recipient thereof.
[0093] Within the context of this application, the term
`combination preparation` comprises both true combinations, meaning
a compound of formula (I) and other medicaments physically combined
in one preparation such as a tablet or injection fluid, as well as
`kit-of-parts`, comprising a compound of formula (I) and another
medicament in separate dosage forms, together with instructions for
use, optionally with further means for facilitating compliance with
the administration of the component compounds, e.g., label or
drawings. With true combinations, the pharmacotherapy by definition
is simultaneous. The contents of `kit-of-parts`, can be
administered either simultaneously or at different time intervals.
Therapy being either concomitant or sequential will be dependant on
the characteristics of the other medicaments used, characteristics
like onset and duration of action, plasma levels, clearance, etc.,
as well as on the disease, its stage, and characteristics of the
individual patient.
[0094] The affinity of the compounds of the invention for
cannabinoid CB.sub.1 receptors was determined as described below.
From the binding affinity measured for a given compound of formula
(I), one can estimate a theoretical lowest effective dose. At a
concentration of the compound equal to twice the measured
K.sub.i-value, nearly 100% of the cannabinoid CB.sub.1 receptors
likely will be occupied by the compound. Converting that
concentration to mg of compound per kg of patient--assuming ideal
bioavailability--results in a theoretical lowest effective dose.
Pharmacokinetic, pharmacodynamic, and other considerations may
alter the dose actually administered to a higher or lower value.
The dose of the compound to be administered will depend on the
relevant indication, the age, weight and sex of the patient and may
be determined by a physician. In general, the dosage may be in
amounts, for example from 0.01 mg/kg to 10 mg/kg. The typical daily
dose of the active ingredients varies within a wide range and will
depend on various factors such as the relevant indication, the
route of administration, the age, weight and sex of the patient and
may be determined by a physician. In general, total daily dose
administration to a patient in single or individual doses, may be
in amounts, for example, from 0.001 to 10 mg/kg body weight daily,
and more usually from 0.01 to 1,000 mg per day, of total active
ingredients. Such dosages will be administered to a patient in need
of treatment from one to three times each day, or as often as
needed for efficacy, and for periods of at least two months, more
typically for at least six months, or chronically.
[0095] The term "therapeutically effective amount" as used herein
refers to an amount of a therapeutic agent to treat a condition
treatable by administrating a composition of the invention. That
amount is the amount sufficient to exhibit a detectable therapeutic
or ameliorative response in a tissue system, animal or human. The
effect may include, for example, treating the conditions listed
herein. The precise effective amount for a subject will depend upon
the subject's size and health, the nature and extent of the
condition being treated, recommendations of the treating physician
(researcher, veterinarian, medical doctor or other clinician), and
the therapeutics, or combination of therapeutics, selected for
administration. Thus, it is not useful to specify an exact
effective amount in advance.
[0096] A "pharmaceutical salt" refers to an acid:base complex
containing an active pharmaceutical ingredient (API) along with
additional non-toxic molecular species in the same crystal
structure. The term "pharmaceutically acceptable salt" refers to
those salts that are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of humans and lower
animals without undue toxicity, irritation, allergic response,
etc., and are commensurate with a reasonable benefit/risk ratio.
Pharmaceutically acceptable salts are well-known in the art. They
can be prepared in situ when finally isolating and purifying the
compounds of the invention, or separately by reacting them with
pharmaceutically acceptable non-toxic bases or acids, including
inorganic or organic bases and inorganic or organic acids (Berge,
1977). Common anions used in pharmaceutically acceptable salts
include: chloride, bromide, sulfate, nitrate, phosphate,
bicarbonate, mesylate, esylate, isothianate, tosylate, napsylate,
besylate, acetate, propionate, maleate, benzoate, salicylate,
fumarate, citrate, lactate, maleate, tartrate, pamoate, succinate,
glycolate, hexanoate, octanoate, decanoate, stearate, oleate,
aspartate and glutamate. Common cations used as counterions in
pharmaceutically acceptable salts include: sodium, potassium,
calcium, magnesium, lithium, zinc, aluminum, arginine, lysine,
histidine, triethylamine, ethanolamine, triethanolamine,
ethilenediamine, meglumine, procaine and benzathine.
[0097] The `free base` form may be regenerated by contacting the
salt with a base or acid, and isolating the parent compound in the
conventional matter. The parent form of the compound differs from
the various salt forms in certain physical properties, such as
solubility in polar solvents, but otherwise the salts are
equivalent to the parent form of the compound for the purposes of
the present invention.
[0098] The term "treatment" as used herein refers to any treatment
of a mammalian, for example human condition or disease, and
includes: (1) inhibiting the disease or condition, i.e., arresting
its development, (2) relieving the disease or condition, i.e.,
causing the condition to regress, or (3) stopping the symptoms of
the disease. The term `inhibit` includes its generally accepted
meaning which includes restraining, alleviating, ameliorating, and
slowing, stopping or reversing progression, severity, or a
resultant symptom. As used herein, the term "medical therapy"
intends to include diagnostic and therapeutic regimens carried out
in vivo or ex vivo on humans or other mammals. `Mammals` include
animals of economic importance such as bovine, ovine, and porcine
animals, especially those that produce meat, as well as domestic
animals, sports animals, zoo animals, and in at least one
embodiment humans. The term "subject" as used herein, refers to an
animal, in at least one embodiment, a mammal, for example a human,
who has been the object of treatment, observation or
experiment.
EXAMPLES
Example 1
Materials and Methods
[0099] .sup.1H NMR spectra were recorded on a Varian UN400
instrument (400 MHz) using DMSO-d.sub.6 or CDCl.sub.3 as solvents
with tetramethylsilane as an internal standard. Chemical shifts are
given in ppm (.delta. scale) downfield from tetramethylsilane.
Coupling constants (J) are expressed in Hz. Flash chromatography
was performed using silica gel 60 (0.040-0.063 mm, Merck). Column
chromatography was performed using silica gel 60 (0.063-0.200 mm,
Merck). Sepacore chromatographic separations were carried out using
Supelco equipment, VersaFLASH.TM. columns, VersaPak.TM. silica
cartridges, Buchi UV monitor C-630, Buchi Pump module C-605, Buchi
fraction collector C-660 and Buchi pump manager C-615. Melting
points were recorded on a Buchi B-545 melting point apparatus or
determined by DSC (differential scanning calorimetry) methods.
Optical rotations ([.alpha.].sub.D) were measured on an Optical
Activity polarimeter. Specific rotations are given as deg/dm, the
concentration values are reported as g/100 mL of the specified
solvent and were recorded at 23.degree. C., unless indicated
otherwise.
Example 2
General Aspects of Syntheses
[0100] Pyrazoline derivatives can be obtained by published methods
(Bach, 1994). The synthesis of compounds having formula (I) is
outlined in Scheme 1. Additional information on activating and
coupling methods of amines to carboxylic acids can be found in the
literature (Bodanszky, 1994; Akaji, 1994; Albericio, 1997;
Montalbetti, 2005).
##STR00010##
[0101] A hydrazone derivative of general formula (II) wherein
R.sub.1 has the abovementioned meaning and R.sub.7 is a C.sub.1-3
alkyl group, such as an ethyl group, can be obtained from a
compound of general formula R.sub.1NHNH.sub.2 and ethylglyoxalate.
A hydrazone derivative of general formula (II) can be reacted with
a chlorinating agent such as tert-butyl hypochlorite or
N-chlorosuccinimide (NCS) in an inert solvent to give a compound of
general formula (III). A compound of general formula (III) wherein
R.sub.1 has the abovementioned meaning, and R.sub.7 is a C.sub.1-3
alkyl group can be reacted with a compound of general formula (IV),
wherein R.sub.2, R.sub.5 and R.sub.6 have the above-mentioned
meaning, to give a compound of general formula (V) wherein R.sub.1,
R.sub.2, R.sub.5, R.sub.6 and R.sub.7 have the abovementioned
meaning. A compound of general formula (V) can be reacted with a
base such as aqueous potassium hydroxide or lithium hydroxide to
give a carboxylic acid derivative of general formula (VI), or a
sodium, potassium, lithium or cesium salt thereof, wherein R.sub.1,
R.sub.2, R.sub.5 and R.sub.6 have the abovementioned meaning. A
compound of general formula (VI) can be reacted with an amine of
general formula R.sub.3R.sub.4NH, wherein R.sub.3 and R.sub.4 have
the abovementioned meaning, in the presence of an activating or
coupling reagent such as 2-chloro-1,3-dimethylimidazolinium
hexafluorophosphate (CIP),
O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate
(TBTU) or O-benzotriazol-1-yl-N,N,N',N'-tetramethyl-uronium
hexafluorophosphate (HBTU) in an inert organic solvent such as
dichloromethane to give a compound of general formula (I) wherein
R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 have the
abovementioned meaning. In one embodiment, a base such as
triethylamine or Hunigs base (DIPEA) may be added in such
reactions.
[0102] Alternatively, an ester derivative having formula (V) can be
reacted in a so-called Weinreb amidation reaction with an amine of
general formula R.sub.3R.sub.4NH to give a compound of general
formula (I). Such Weinreb amidation reactions can be promoted by
the use of trimethylaluminum Al(CH.sub.3).sub.3 (For more
information on aluminum-mediated conversion of esters to amides,
see Levin, 1982).
[0103] Another alternative is to chlorinate a carboxylic acid
derivative having formula (VI) to the corresponding acid chloride
(Va) wherein R.sub.8 is a chloro atom using a chlorinating agent
such as thionyl chloride (SOCl.sub.2) or oxalyl chloride. The
formed acid chloride derivative can subsequently be reacted with an
amine of general formula R.sub.3R.sub.4NH to give a compound of
general formula (I), wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4,
R.sub.5 and R.sub.6 have the abovementioned meaning.
[0104] In one embodiment, the invention relates to compounds of
formula (Va):
##STR00011##
or tautomers, stereoisomers, N-oxides, isotopically-labelled
analogues, or pharmacologically acceptable salts of any of the
foregoing, wherein R.sub.1, R.sub.2, R.sub.5 and R.sub.6 have the
abovementioned meaning and R.sub.8 is chosen from chloro and
OR.sub.7, where R.sub.7 is C.sub.1-3 alkyl, provided that if
R.sub.2 is phenyl and R.sub.1 is benzyl, then R.sub.7 is not ethyl.
Such compounds are useful in the synthesis of compounds of the
general formula (I).
[0105] In another embodiment, the invention relates to compounds of
formula (VI):
##STR00012##
and to sodium, potassium, lithium and cesium salts thereof,
wherein: R.sub.1, R.sub.2, R.sub.5 and R.sub.6 have the same
meanings as given above, provided that if R.sub.2 is phenyl, then
R.sub.1 is not benzyl. Such compounds are useful in the synthesis
of compounds of the general formula (I).
##STR00013##
[0106] Alternatively, a compound of general formula (I) wherein
R.sub.5 and R.sub.6 are hydrogen atoms, and R.sub.1, R.sub.2,
R.sub.3 and R.sub.4 have the abovementioned meaning can be prepared
according to the route described in Scheme 2. A compound of general
formula (IX) wherein R.sub.2 has the abovementioned meaning can be
obtained from an aldehyde of general formula (VII) and a compound
of general formula (VIII) in the presence of a base such as aqueous
potassium hydroxide or sodium hydroxide in a solvent such as
ethanol (Annan, 1989). The formed 2-oxo-buten-3-oic acid derivative
(IX) can be reacted with a compound of general formula
R.sub.3R.sub.4NH in an inert organic solvent such as
dichloromethane in the presence of an activating or coupling
reagent such as HBTU to give an amide derivative of general formula
(X), wherein R.sub.2, R.sub.3 and R.sub.4 have the abovementioned
meaning. In one embodiment, a base such as triethylamine or Hunigs
base (DIPEA) may be added in such a reaction. A compound of general
formula (X) can be reacted with a hydrazine derivative of general
formula R.sub.1NHNH.sub.2 or its hydrate R.sub.1NHNH.sub.2.H.sub.2O
or a salt thereof, wherein R.sub.1 has the abovementioned meaning,
to give a compound of general formula (I) wherein R.sub.1, R.sub.2,
R.sub.3 and R.sub.4 have the above-mentioned meaning, and R.sub.5
and R.sub.6 are hydrogen atoms. A hydrazine of general formula
R.sub.1NHNH.sub.2 (XI) can be prepared from hydrazine or hydrazine
hydrate or a salt thereof and a compound of general formula
R.sub.1-L (XII) wherein L is a `leaving group` such as iodide,
bromide or chloride in an organic solvent such as ethanol,
analogously to the method described (Chem. Ber. 1965).
Alternatively, a hydrazine of general formula R.sub.1NHNH.sub.2
(XI) or its hydrate R.sub.1NHNH.sub.2.H.sub.2O or a salt thereof,
wherein R.sub.1 has the above-mentioned meaning, can be prepared
from a compound of general formula R.sub.1-L (XII) in an organic
solvent such as acetonitrile, in a reaction with a protected
hydrazine derivative such as tert-butylcarbazate to give a compound
of general formula (XIII) which compound of general formula (XIII)
is subsequently reacted with an acid such as hydrochloric acid in
an inert organic solvent such as 1,4-dioxane.
[0107] In one embodiment, the invention relates to compounds of the
general formula (X):
##STR00014##
wherein R.sub.2 has the same meaning as given hereinabove, R.sub.3
is a hydrogen atom, and R.sub.4 is chosen from C.sub.6-10
bicycloalkyl and C.sub.7-10 tricycloalkyl, each of which may be
optionally substituted with 1-5 substituents, wherein the
substituents are the same or different and are chosen from methyl,
ethyl, hydroxyl, amino, and fluoro or R.sub.4 is chosen from
2-phenyl-1,1-dimethyl-ethyl and 1-phenyl-1-methyl-ethyl, wherein
the phenyl groups are optionally substituted with 1-5 substituents
Y is as defined above. Such compounds being useful in the synthesis
of compounds of the general formula (I) are new.
[0108] The selection of the particular synthetic procedures depends
on factors known to those skilled in the art such as the
compatibility of functional groups with the reagents used, the
possibility to use protecting groups, catalysts, activating and
coupling reagents and the ultimate structural features present in
the final compound being prepared.
[0109] Pharmaceutically acceptable salts may be obtained using
standard procedures well known in the art, for example by mixing a
compound of the present invention with a suitable acid, for
instance an inorganic acid such as hydrochloric acid, or with an
organic acid such as fumaric acid.
[0110] According to these procedures the compounds described below
have been prepared. They are intended to further illustrate the
invention in more detail, and therefore are not deemed to restrict
the scope of the invention in any way. Other embodiments of the
invention will be apparent to those skilled in the art from
consideration of the specification and practice of the invention
disclosed herein. It is thus intended that the specification and
examples be considered as exemplary only.
Example 3
Synthesis and Spectral Data of Intermediates
Intermediate II-1
##STR00015##
[0112] To a magnetically stirred solution of oxo-acetic acid ethyl
ester (35.08 ml, 177 mmol; 50% solution in toluene) in ethanol (450
ml) was added n-pentylhydrazine (21.7 g, 212 mmol) and the
resulting solution was heated at 80.degree. C. for 16 hours. The
obtained mixture was allowed to attain room temperature and
concentrated. The resulting residue was taken up in ethylacetate
and water. The organic layer was separated and subsequently dried
over MgSO.sub.4, filtered and concentrated to give
(pentylhydrazono)acetic acid ethyl ester (Intermediate II-1) (32.2
gram, 93% yield) as a purple colored oil. .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 0.87-0.94 (m, 3H), 1.25-1.42 (m, 7H), 1.55-1.68
(m, 2H), 3.17-3.23 (m, 1H), 3.35-3.45 (m, 1H), 4.28 (q, J=7, 2H),
6.51 (br s, 1H), 6.72 (s, 1H).
Intermediate II-2
##STR00016##
[0114] Intermediate (II-2) was obtained in 94% yield analogously to
the preparation of intermediate (II-1) from oxo-acetic acid ethyl
ester and 4,4,4-trifluorobutylhydrazine.HCl.H.sub.2O (Intermediate
XI-3) in the presence of 1.2 molar equivalent of Hunig's base
(DIPEA). .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.33 (t, J=7.1
Hz, 3H), 1.84-1.97 (m, 2H), 2.11-2.27 (m, 2H), 3.33-3.40 (m, 2H),
4.28 (q, J=7.2 Hz, 2H), 6.50 (br s, 1H), 6.80 (s, 1H).
Intermediate V-1
##STR00017##
[0116] To a magnetically stirred solution of
(pentylhydrazono)acetic acid ethyl ester (Intermediate II-1) (35.16
g, 179 mmol) in ethylacetate (450 ml) was added N-chlorosuccinimide
(NCS) (26.34 g, 197 mmol) and the resulting mixture was heated at
60.degree. C. for 1 hour in a nitrogen atmosphere. To the reaction
mixture was added styrene (41.1 ml, 359 mmol) and potassium
bicarbonate (89.8 g, 897 mmol) and water (8 ml). The resulting
mixture was heated at 70.degree. C. for 16 hours. The resulting
mixture was allowed to attain room temperature, concentrated in
vacuo and the resulting residue was chromatographically separated
using Sepacore equipment (eluant: dichloromethane/methanol=98/2
v/v) to give ethyl
1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxylate
(Intermediate (V-1) (12.1 g, 22% yield) as an oil. .sup.1H-NMR (400
MHz, CDCl.sub.3) .delta. 0.83 (t, J=7, 3H), 1.13-1.28 (m, 4H), 1.35
(t, J=7, 3H), 1.53-1.67 (m, 2H), 2.89 (dd, J=16 and 13, 1H),
3.01-3.09 (m, 1H), 3.14-3.22 (m, 1H), 3.41 (dd, J=16 and 12, 1H),
4.31 (double (diastereotopic) quartet, J.about.7, 2H), 4.63 (dd,
J=13 and 12, 1H), 7.27-7.39 (m, 5H).
Intermediate V-2
##STR00018##
[0118] Intermediate (V-2) was obtained analogously to the
preparation of intermediate (V-1) from (butylhydrazono)acetic acid
ethyl ester via successive chlorination with N-chlorosuccinimide
(NCS) and treatment with trans-beta-methylstyrene. Chromatographic
purification using Sepacore equipment (eluant: petroleum eter
(40-60)/ethylacetate=9/1 v/v)) gave ethyl
1-(n-butyl)-trans-4-methyl-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-car-
boxylate (Intermediate (V-2) in 14% yield. .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 0.95 (t, J=7, 3H), 1.18-1.43 (m, 8H), 1.49-1.66
(m, 2H), 3.03-3.26 (m, 3H), 4.09 (d, J=12 Hz, 1H), 4.27-4.37 (m,
2H), 7.28-7.40 (m, 5H).
Intermediate V-3
##STR00019##
[0120] Intermediate (V-3) was obtained analogously to the
preparation of intermediate (V-1) from
(4,4,4-trifluorobutylhydrazono)acetic acid ethyl ester
(Intermediate II-2) via successive reactions with
N-chlorosuccinimide (NCS) and styrene to give crude intermediate
(V-3). This crude material was chromatographically purified by
using flash chromatography (eluant gradient: petroleum ether
(40-60)/ethylacetate=95/5=>petroleum ether
(40-60)/ethylacetate=93/7 (v/v)) to give ethyl
1-(4,4,4-trifluorobutyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxylate
(Intermediate (V-3) (34% yield). .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 1.35 (t, J=7 Hz, 3H), 1.75-2.22 (m, 4H), 2.93 (dd, J=18 and
14 Hz, 1H), 3.06-3.21 (m, 2H), 3.41 (dd, J=18 and 12 Hz, 1H), 4.33
(double (diastereotopic) quartet, J.about.7, 2H), 4.55 (dd, J=14
and 12 Hz, 1H), 7.31-7.42 (m, 5H).
Intermediate VI-1
##STR00020##
[0122] To a magnetically stirred solution of ethyl
1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxylate
(Intermediate (V-1) (11.76 g, 38.74 mmol) in tetrahydrofuran (100
ml) and water (100 ml) was added lithium hydroxide (1.86 g, 77.5
mmol) and the resulting mixture was heated at 70.degree. C. for 1
hour. The reaction mixture was allowed to attain room temperature
and diethyl ether (200 ml) and concentrated hydrochloric acid (7
ml) were added. The organic layer was separated, washed three times
with water and with brine and subsequently dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give
1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxylic acid
(Intermediate (VI-1) (7.9 g, 74% yield) as an oil. .sup.1H-NMR (400
MHz, CDCl.sub.3) .delta. 0.84 (t, J=7, 3H), 1.15-1.28 (m, 4H),
1.53-1.65 (m, 2H), 2.92 (dd, J=17 and 13, 1H), 3.02-3.11 (m, 1H),
3.18-3.27 (m, 1H), 3.44 (dd, J=17 and 13, 1 H), 4.75 t, J=13, 1H),
7.31-7.41 (m, 5H), 7.42-9.00 (br s, 1H).
Intermediate IX-1
##STR00021##
[0124] To a magnetically stirred solution of ethyl
2-fluorobenzaldehyde (11.7 ml, 110 mmol) and ethylglyoxalate (11.1
ml, 100 mmol) in ethanol (50 ml) was slowly added a solution of
sodium hydroxide (4.4 g (110 mmol) in 50 ml water) in a nitrogen
atmosphere while the temperature was kept between 0.degree. C. and
10.degree. C. After stirring for another 45 minutes the reaction
mixture was allowed to attain room temperature and stirred for 2
hours. The formed precipitate was collected by filtration and
successively washed with ethanol and a 1N HCl solution (200 ml) and
subsequently dried to give E-2-oxo-4-(2-fluorophenyl)-but-3-enoic
acid (11.1 gram, 57% yield). Melting point: 100-102.5.degree. C.
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.13-7.27 (m, 2H),
7.45-7.53 (m, 1H) 7.66-7.74 (m, 2H), 8.26 (d, J=16, 1 H), invisible
--OH proton.
Intermediate X-1
##STR00022##
[0126] To a magnetically stirred solution of the commercially
available E-2-oxo-4-phenyl-but-3-enoic acid (4.40 gram, 25 mmol) in
dichloromethane (100 ml) was successively added
1-(4-fluorophenyl)-1-methyl-ethylamine (3.83 g, 25 mmol),
N-ethyldiisopropylamine (DIPEA) (8.56 ml, 50 mmol) and
O-benzotriazol-1-yl-N,N,N',N'tetramethyluronium hexafluorophosphate
(HBTU) (9.48 gram, 25 mmol) and the resulting mixture was reacted
at room temperature for 16 hours in a nitrogen atmosphere. The
organic layer was washed twice with water and subsequently dried
over MgSO.sub.4, filtered and concentrated in vacuo to give crude
E-2-oxo-4-phenyl-but-3-enoic acid
[1-(4-fluorophenyl)-1-methyl-ethyl]amide (Intermediate X-I) as an
oil. Further chromatographic purification using Sepacore equipment
(eluant: petroleum ether/ethylacetate=95/5 (v/v)) gave intermediate
X-I as an oil which slowly solidified on standing (5.15 g, 65%
yield). .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.77 (s, 6H),
7.00-7.05 (m, 2H), 7.35-7.45 (m, 5H), 7.52 (br s, 1H), 7.61-7.65
(m, 2H), 7.73 (d, J=16, 1H), 7.92 (d, J=16, 1H).
Intermediate X-2
##STR00023##
[0128] Intermediate X-2 (E-2-oxo-4-phenyl-but-3-enoic acid
[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo-[2.2.1]hept-2-ylamide]) was
obtained from E-2-oxo-4-phenyl-but-3-enoic acid and
endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-ylamine (CAS
32511-34-5) analogously to the procedure described for intermediate
X-1. .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.84-1.00 (m, 10H),
1.21-1.29 (m, 1H), 1.38-1.48 (m, 1H), 1.53-1.62 (m, 1H), 1.70-1.86
(m, 2H), 2.33-2.44 (m, 1H), 4.22-4.30 (m, 1H), 7.20-7.26 (m, 1H),
7.39-7.46 (m, 3H), 7.65-7.70 (m, 2H), 7.78 (d, J=16, 1H), 7.95 (d,
J=16, 1H).
Intermediate X-3
##STR00024##
[0130] Intermediate X-3 (E-2-oxo-4-(2-fluorophenyl)-but-3-enoic
acid [endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-ylamide])
was obtained from E-2-oxo-4-(2-fluorophenyl)-but-3-enoic acid
(Intermediate IX-1) and
endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-ylamine
analogously to the procedure described for intermediate X-1.
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.84-1.00 (m, 10H),
1.21-1.30 (m, 1H), 1.38-1.48 (m, 1H), 1.53-1.62 (m, 1H), 1.70-1.87
(m, 2H), 2.34-2.44 (m, 1H), 4.21-4.30 (m, 1H), 7.10-7.25 (m, 3H),
7.38-7.45 (m, 1H), 7.70-7.75 (m, 1H), 7.85 (d, J=16, 1H), 8.12 (d,
J=16, 1H).
Intermediate X-4
##STR00025##
[0132] Intermediate X-4 (E-2-oxo-4-phenyl-but-3-enoic acid
[2-(4-fluorophenyl)-2,2-dimethyl-ethyl]amide was obtained from
E-2-oxo-4-phenyl-but-3-enoic acid and
2-(4-fluorophenyl)-2,2-dimethyl-ethylamine analogously to the
procedure described for intermediate X-1. .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 1.40 (s, 6H), 3.08 (s, 2H), 6.91-6.99 (m, 3H),
7.06-7.11 (m, 2H), 7.38-7.47 (m, 3H), 7.65-7.70 (m, 2H), 7.82 (d,
J=16, 1H), 7.92 (d, J=16, 1H).
Intermediate X-5
##STR00026##
[0134] Intermediate X-5 (E-2-oxo-4-(4-chlorophenyl)-but-3-enoic
acid [1-phenyl-1-methyl-ethyl]amide was obtained from
E-2-oxo-4-(4-chlorophenyl)-but-3-enoic acid and
1-phenyl-1-methyl-ethylamine analogously to the procedure described
for intermediate X-1. .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.
1.79 (s, 6H), 7.23-7.28 (m, 1H), 7.32-7.43 (m, 6H), 7.51-7.57 (m,
3H), 7.71 (d, J=16 Hz, 1H), 7.85 (d, J=16 Hz, 1H).
Intermediate X-6
##STR00027##
[0136] Intermediate X-6 (E-2-oxo-4-(3-methoxyphenyl)-but-3-enoic
acid [1-(4-fluorophenyl)-1-methyl-ethyl]amide was obtained from
E-2-oxo-4-(3-methoxyphenyl)-but-3-enoic acid and
1-(4-fluorophenyl)-1-methyl-ethylamine analogously to the procedure
described for intermediate X-1. .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 1.77 (s, 6H), 3.81 (s, 3H), 6.95-7.05 (m, 3H), 7.13-7.16
(m, 1H), 7.18-7.22 (m, 1H), 7.28-7.33 (m, 1H), 7.36-7.40 (m, 2H),
7.54 (br s, 1H), 7.71 (d, J=16 Hz, 1H), 7.88 (d, J=16 Hz, 1H).
Intermediate XI-1
##STR00028##
[0138] To a magnetically stirred solution of hydrazine hydrate (243
ml, 5 mol) was very slowly added a solution of 1-bromopentane (62
ml, 0.50 mol) in ethanol (50 ml) while keeping the temperature at
20.degree. C. The resulting mixture was reacted at room temperature
for 2 hours. The mixture was extracted with diethyl ether. The
diethyl ether extract was concentrated and BaO (5 gram) was added
to the residue. Distillation in vacuo gave n-pentylhydrazine
(Intermediate XI-1) at 30-40 mbar pressure at 72.degree.
C.-78.degree. C. (30.36 gram, 48% yield). .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 0.90 (t, J=7, 3H), 1.27-1.38 (m, 4H), 1.45-1.58
(m, 2H), 2.76 (t, J=7, 2H), 2.85 (br s, 3H).
Intermediate XI-2
##STR00029##
[0140] Step A: To a magnetically stirred solution of
tert-butylcarbazate (47.5 gram, 359 mmol) in anhydrous acetonitrile
(300 ml) was successively added DIPEA (Hunig's base) (37.6 ml, 216
mmol) and 1-bromobutane (19.3 ml, 180 mmol). The resulting mixture
was reacted at 60.degree. C. for 16 hours. The resulting mixture
was allowed to attain room temperature and subsequently
concentrated in vacuo and further purified by Sepacore
chromatography (eluant: petroleum ether 40-60/ethylacetate=4/1
(v/v)) to give N'-butylhydrazine-carboxylic acid tert-butyl ester
(intermediate XIII-1) (13.2 gram, 39%) as a pale yellow oil:
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.91 (t, J=7, 3H),
1.30-1.49 (m, 13H), 2.81-2.87 (m, 2H), 4.00 (br s, 1H), 6.20 (br s,
1H).
##STR00030##
[0141] Step B: To a magnetically stirred solution of
N'-butylhydrazine-carboxylic acid tert-butyl ester (intermediate
XIII-1) (13.17 gram, 70 mmol) in 1,4-dioxane (100 ml) was added
excess (12 mol equivalents) hydrochloric acid (12 N) and the
resulting mixture was reacted for 16 hours at room temperature. The
resulting mixture was concentrated in vacuo and triturated with
diethyl ether to give n-butylhydrazine.HCl.H.sub.2O (Intermediate
XI-2) (9.63 gram, 92% yield). .sup.1H-NMR (400 MHz,
DMSO-d.sub.6/CDCl.sub.3=4/1 (v/v)) .delta. 0.93 (t, J=7, 3H),
1.32-1.43 (m, 2H), 1.56-1.65 (m, 2H), 2.92-2.98 (m, 2H), 7.20 (br
s, 6H).
Intermediate XI-3
##STR00031##
[0143] Step A: Intermediate (XI-3) was obtained analogously to the
procedure described for intermediate (XI-2) from
tert-butylcarbazate and 1-bromo-4,4,4-trifluorobutane via
N'-(4,4,4-trifluorobutyl)hydrazine-carboxylic acid tert-butyl ester
(intermediate XIII-2): Intermediate XIII-2: .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 1.46 (s, 9H), 1.67-1.76 (m, 2H), 2.10-2.24 (m,
2H), 2.87-2.94 (m, 2H), 3.97 (br s, 1H), 6.05 (br s, 1H).
##STR00032##
[0144] Step B: N'-(4,4,4-trifluorobutyl)hydrazine-carboxylic acid
tert-butyl ester (intermediate XIII-2) was converted with excess
hydrochloric acid to intermediate (XI-3)
(4,4,4-trifluorobutylhydrazine.HCl.H.sub.2O) analogously as
described for the preparation of intermediate XI-2 (part B).
Intermediate (XI-3): .sup.1H-NMR (400 MHz, DMSO-d.sub.6 .delta.1.77
(quintet, J=7.7 Hz, 2H), 2.28-2.43 (m, 2H), 2.94 (t, J=7.4 Hz, 2H),
7.95 (br s, .about.0.3H).
Example 4
Synthesis of Specific Compounds
[0145] Compound 1
##STR00033##
N-(Adamant-2-yl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carbox-
amide
[0146] To a magnetically stirred solution of
1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxylic acid
(Intermediate (VI-1) (0.70 g, 2.55 mmol) in dichloromethane (40 ml)
was successively added 2-adamantanamine.HCl (480 mg, 2.55 mmol),
N-ethyldiisopropylamine (DIPEA) (1.78 ml, 10.22 mmol) and
2-chloro-1,3-dimethylimidazolinium hexafluorophosphate (CIP) (853
mg, 3.07 mol) and the resulting mixture was reacted at room
temperature for 16 hours in a nitrogen atmosphere. The reaction
mixture was successively washed twice with water, twice with
aqueous citric acid (0.5 M), twice with NaHCO.sub.3 (5% aqueous
solution) and brine, and subsequently dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo to give crude
N-(adamant-2-yl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carbox-
amide (1.26 g) as an orange oil. Further chromatographic
purification using Sepacore equipment (eluant: petroleum
ether/diethyl ether=85/15 (v/v)) gave compound 1 (750 mg, 67%
yield) as an oil. .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.85
(t, J=7, 3H), 1.21-1.30 (m, 4H), 1.55-1.65 (m, 2H), 1.65-1.70 (m,
2H), 1.76 (br s, 2H), 1.75-1.92 (m, 8H), 1.97-2.01 (m, 2H), 2.82
(dd, J=17 and 14, 1H), 2.92-2.97 (m, 2H), 3.42 (dd, J=17 and 11,
1H), 4.09-4.14 (m, 1H), 4.40 (dd, J=14 and 11, 1H), 6.99-7.07 (m,
1H), 7.28-7.38 (m, 5H).
[0147] Compounds 2-100 were analogously prepared.
[0148] Compound 2
##STR00034##
N-Phenyl-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide
[0149] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.87 (t, J=7 Hz,
3H), 1.17-1.34 (m, 4H), 1.55-1.73 (m, 2H), 2.85-3.08 (m, 3H), 3.49
(dd, J=17 and 11.4 Hz, 1H), 4.53 (dd, J=14 and 11.4 Hz, 1H), 7.09
(t, J=7.5 Hz, 1H), 7.28-7.42 (m, 7H), 7.62 (d, J=7.5 Hz, 2H), 8.43
(s, 1H).
[0150] Compound 3
##STR00035##
N-(4-Methoxyphenyl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-car-
boxamide
[0151] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.86 (t, J=6.9 Hz,
3H), 1.19-1.34 (m, 4H) 1.57-1.69 (m, 2H), 2.85-3.06 (m, 3H), 3.48
(dd, J=17 and 11 Hz, 1H), 3.80 (s, 3H), 4.50 (dd, J=14 and 11.4 Hz,
1H), 6.88 (d, J=9 Hz, 2H), 7.28-7.40 (m, 5H) 7.54 (d, J=9 Hz, 2H),
8.35 (br s, 1H).
[0152] Compound 4
##STR00036##
N-(Napht-1-yl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxam-
ide
[0153] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.86 (t, J=7 Hz,
3H), 1.20-1.40 (m, 4H), 1.66-1.77 (m, 2H), 2.92-3.14 (m, 3H), 3.55
(dd, J=17 and 11.4 Hz, 1H), 4.59 (dd, J=14 and 11.4 Hz, 1H),
7.30-7.44 (m, 5H), 7.46-7.61 (m, 3H), 7.67 (d, J=8.4 Hz, 1 H), 7.88
(d, J=7.5 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 8.20 (d, J=7.5 Hz, 1H),
9.05 (br s, 1H).
[0154] Compound 5
##STR00037##
N-(2-Trifluoromethyl)phenyl-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazo-
le-3-carboxamide
[0155] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.88 (t, J=7.2 Hz,
3H), 1.18-1.38 (m, 4H), 1.61-1.70 (m, 2H), 2.86-3.11 (m, 3H), 3.49
(dd, J=17 and 11.7 Hz, 1H), 4.59 (dd, J=14 and 11.4 Hz, 1H), 7.17
(t, J=7.7 Hz, 1H), 7.29-7.42 (m, 5H), 7.55 (t, J=7.8 Hz, 1 H), 7.61
(d, J=7.8 Hz, 1H), 8.45 (d, J=8.4 Hz, 1H), 9.05 (br s, 1H).
[0156] Compound 6
##STR00038##
N-(Naphthalen-1-ylmethyl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-
-3-carboxamide
[0157] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.79 (t, J=6.9 Hz,
3H), 1.07-1.25 (m, 4H), 1.44-1.58 (m, 2H), 2.78-2.92 (m, 3H), 3.46
(dd, J=17.3, and 11.3 Hz, 1H), 4.41 (dd, J=14.3 and 11.3 Hz, 1H),
5.00 (d, J=5.7 Hz, 2H), 6.90 (br t, J=5.6 Hz, 1H), 7.27-7.37 (m,
5H), 7.42-7.60 (m, 4H), 7.83 (d, J=7.8 Hz, 1H), 7.88 (d, J=1.2 Hz,
1H), 8.10 (d, J=8.1 Hz, 1H).
[0158] Compound 7
##STR00039##
N-(Pyridin-3-ylmethyl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3--
carboxamide
[0159] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.83 (t, J=6.9 Hz,
3H), 1.14-1.30 (m, 4H), 1.51-1.64 (m, 2H), 2.81-2.99 (m, 3H), 3.44
(dd, J=17.3 and 11.3 Hz, 1H), 4.45 (dd, J=14.30 and 11.29 Hz, 1H),
4.56 (d, J=6.3 Hz, 2H), 7.00 (br t, J=5.9 Hz, 1H), 7.26-7.39 (m,
6H), 7.70 (br d, J=7.8 Hz, 1H), 8.54 (dd, J=4.8 and 1.50 Hz, 1H),
8.60 (d, 1H).
[0160] Compound 8
##STR00040##
N-(Cyclohexylmethyl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-ca-
rboxamide
[0161] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.85 (t, J=6.9 Hz,
3H), 0.90-1.04 (m, 2H), 1.12-1.33 (m, 7H), 1.47-1.82 (m, 8H),
2.76-2.98 (m, 3H), 3.18 (dq, J=12.9 and 6.6 Hz, 2H), 3.41 (dd,
J=17.3 and 11 Hz, 1H), 4.39 (dd, J=14.3 and 11 Hz, 1H), 6.68 (br t,
J=5.9 Hz, 1H), 7.27-7.41 (m, 5H).
[0162] Compound 9
##STR00041##
N-(2,2-diphenylethyl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-c-
arboxamide
[0163] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.83 (t, J=7.07
Hz, 3H), 1.09-1.28 (m, 4 H), 1.43-1.58 m, 2H), 2.73-2.91 (m, 3H),
3.37 (dd, J=17.2 and 11.1 Hz, 1H), 3.98 (dd, J=7.8 and 6.2 Hz, 2H),
4.26 (t, J=7.8 Hz, 1H), 4.36 (dd, J=14.3 and 11.3 Hz, 1H), 6.62 (br
t, J=5.9 Hz, 1H), 7.18-7.37 (m, 15H).
[0164] Compound 10
##STR00042##
N-(Benzyl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide
[0165] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.83 (t, J=6.9 Hz,
3H), 1.13-1.29 (m, 4H), 1.49-1.64 (m, 2H), 2.81-2.96 (m, 3H), 3.44
(dd, J=17.3 and 11.3 Hz, 1H), 4.42 (dd, J=14.5 and 11.1 Hz, 1H),
4.54 (d, J=6 Hz, 2H), 6.94 (br t, J=5.7 Hz, 1H), 7.26-7.40 (m,
10H).
[0166] Compound 11
##STR00043##
N-[(1-Ethyl)propyl]-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-car-
boxamide
[0167] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.85 (t, J=6.9 Hz,
3H), 0.94 (t, J=7, 6 H), 1.17-1.31 (m, 4H), 1.39-1.52 (m, 2H),
1.53-1.69 (m, 4H), 2.78-2.98 (m, 3H), 3.42 (dd, J=17.3 and 11 Hz,
1H), 3.79-3.90 (m, 1H), 4.40 (dd, J=14.4 and 11.1 Hz, 1H), 6.35 (d,
J=9.3 Hz, 1H), 7.27-7.40 (m, 5H).
[0168] Compound 12
##STR00044##
N-(Exo-bicyclo[2.2.1]hept-2-yl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-py-
razole-3-carboxamide (diastereomeric mixture)
[0169] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.85 (d, J=6.9 Hz,
3H), 1.10-1.65 (m, 13 H), 1.83 (ddd, J=13.1 and 8 and 2.1 Hz, 1H),
2.25-2.34 (m, 2H), 2.76-2.97 (m, 3H), 3.40-3.41 (2.times.dd, J=18.4
and 11.1 Hz, 1H), 3.79 (br td, J=7.7 and 3.6 Hz, 1H), 4.37-4.38
(2.times.dd, J=14.4 and 11.1 and 3.3 Hz, 1H), 6.46 (br d, J=7.2 Hz,
1H), 7.27-7.40 (m, 5H).
[0170] Compound 13
##STR00045##
N-[2-(4-Fluorophenyl)ethyl]-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazo-
le-3-carboxamide
[0171] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.85 (t, J=6.9 Hz,
3H), 1.15-1.31 (m, 4H), 1.51-1.65 (m, 2H), 2.78-2.97 (m, 5H), 3.41
(dd, J=17.1 and 11.1 Hz, 1H), 3.52-3.60 (m, 2H), 4.41 (dd, J=14.3
and 11.3 Hz, 1H), 6.69 (br t, J=5.9 Hz, 1H), 7.00 (br t, J=8.7 Hz,
2H), 7.19 (dd, J=8.4 and 5.4 Hz, 2H), 7.27-7.40 (m, 5H).
[0172] Compound 14
##STR00046##
N-(1-Phenyl-ethyl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carb-
oxamide (1:1 diastereomeric mixture)
[0173] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.84 (t, J=6.5 Hz,
3H), 1.15-1.30 (m, 4H), 1.48-1.67 (m, 5H), 2.76-2.96 (m, 3H),
3.39-3.40 (2.times.dd, J=17.4 and 11.1, 1 H), 4.39-4.40
(2.times.dd, J=14.3 and 11.1 Hz, 1H), 5.14-5.25 (m, 1H), 6.86 (br
d, J=8.1 Hz, 1H), 7.26-7.41 (m, 10H).
[0174] Compound 15
##STR00047##
N-(Adamantylmethyl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-car-
boxamide
[0175] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.85 (t, J=6.9 Hz,
3H), 1.18-1.32 (m, 4H), 1.49-1.78 (m, 14H), 2.00 (br s, 3H),
2.78-3.11 (m, 5H), 3.42 (dd, J=17.1 and 11.1 Hz, 1H), 4.40 (dd,
J=14.4 and 11.1 Hz, 1H), 6.69 (br t, J=6.3 Hz, 1H), 7.26-7.40 (m,
5H).
[0176] Compound 16
##STR00048##
N-[(1-Ethyl)propyl]-1-(n-butyl)-5-(3-chlorophenyl)-4,5-dihydro-(1H)-pyraz-
ole-3-carboxamide
[0177] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.87 (t, J=7.4 Hz,
3H), 0.94 (t, J=7.4 Hz, 6 H), 1.19-1.70 (m, 8H), 2.79 (dd, J=17.3
and 14.3 Hz, 1H), 2.89-2.95 (m, 2H), 3.43 (dd, J=17.4 and 11.1 Hz,
1H), 3.79-3.90 (m, 1H), 4.36 (dd, J=14.4 and 11.1 Hz, 1H), 6.33 (br
d, J=9.3 Hz, 1H), 7.23-7.36 (m, 3H), 7.38 (br s, 1H).
[0178] Compound 17
##STR00049##
N-(Cyclooctyl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxam-
ide
[0179] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.85 (t, J=6.92
Hz, 3H), 1.16-1.31 (m, 4H), 1.48-1.75 (m, 14H), 1.82-1.94 (m, 2H),
2.76-2.97 (m, 3H), 3.40 (dd, J=17.4 and 11.1 Hz, 1H), 4.00-4.10 (m,
1H), 4.37 (dd, J=14.3 and 11 Hz, 1H), 6.58 (br d, J=8.4 Hz, 1H),
7.27-7.39 (m, 5H).
[0180] Compound 18
##STR00050##
N-(2,2-diphenylpropyl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3--
carboxamide
[0181] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.85 (t, J=7.1 Hz,
3H), 1.10-1.28 (m, 4H), 1.44-1.55 (m, 2H), 1.71 (s, 3H), 2.71-2.87
(m, 3H), 3.37 (dd, J=17.1 and 11.1 Hz, 1 H), 4.02 (d, J=6.3 Hz,
2H), 4.34 (dd, J=14.4 and 11.1 Hz, 1H), 6.41 (br t, J=5.87 Hz, 1
H), 7.19-7.37 (m, 15H).
[0182] Compound 19
##STR00051##
N-(Cycloheptyl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxa-
mide
[0183] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.85 (t, J=6.9 Hz,
3H), 1.15-1.31 (m, 4H), 1.45-1.72 (m, 12H), 1.91-2.03 (m, 2H),
2.76-2.97 (m, 3H), 3.40 (dd, J=17.1 and 11.1 Hz, 1H), 3.95-4.08 (m,
1H), 4.38 (dd, J=14.3 and 11 Hz, 1H), 6.57 (br d, J=8.4 Hz, 1H),
7.27-7.40 (m, 5H).
[0184] Compound 20
##STR00052##
N-(Quinolin-3-yl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carbo-
xamide
[0185] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.88 (t, J=6.92
Hz, 3H), 1.18-1.36 (m, 4H), 1.58-1.71 (m, 2H), 2.91-3.14 (m, 3H),
3.53 (dd, J=17.3 and 11.6 Hz, 1H), 4.62 (dd, J=13.8 and 11.7 Hz,
1H), 7.29-7.45 (m, 5H), 7.53 (br t, J=6.9 Hz, 1H), 7.62 (dt, J=7.7
and 1.50 Hz, 1H), 7.81 (d, J=7.5 Hz, 1H), 8.05 (d, J=8.4 Hz, 1H),
8.69 (s, 1H), 8.83 (d, J=2.4 Hz, 1H), 8.86 (d, J=2.7 Hz, 1H).
[0186] Compound 21
##STR00053##
N-(2-phenyl-trans-cyclopropyl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyr-
azole-3-carboxamide (diastereomeric mixture)
[0187] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.85 (t, J=6.92
Hz, 3H), 1.15-1.33 (m, 6H), 1.52-1.68 (m, 2H), 2.11-2.19 (m, 1H),
2.76-2.98 (m, 4H), 3.41 and 3.43 (2.times.dd, J=17.2 and 11.2 Hz,
1H), 4.42 (dd, J=14.1 and 11.1 Hz, 1H), 6.84 (br s, 1H), 7.15-7.39
(m, 10H).
[0188] Compound 22
##STR00054##
N-[3-(Trifluoromethyl)benzyl)]-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyr-
azole-3-carboxamide
[0189] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.83 (t, J=6.92
Hz, 3H), 1.15-1.30 (m, 4 H), 1.51-1.65 (m, 2H), 2.81-2.99 (m, 3H),
3.45 (dd, J=17.3 and 11.3 Hz, 1H), 4.46 (dd, J=14.4 and 11.4 Hz,
1H), 4.59 (s, 2H), 7.28-7.39 (m, 5H), 7.43-7.50 (m, 1H), 7.52-7.60
(m, 3H).
[0190] Compound 23
##STR00055##
N-(2,2-Dimethylpropyl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3--
carboxamide
[0191] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.85 (t, J=7.22
Hz, 3H), 0.96 (s, 9H), 1.16-1.32 (m, 4H), 1.53-1.67 (m, 2H),
2.77-2.97 (m, 3H), 3.15 (dd, J=6.6 and 1.8 Hz, 2 H), 3.42 (dd,
J=17.5 and 11.1 Hz, 1H), 4.41 (dd, J=14.4 and 11.1 Hz, 1H), 6.72
(br t, J=6.2 Hz, 1H), 7.27-7.40 (m, 5H).
[0192] Compound 24
##STR00056##
N-(2-Indanyl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxami-
de
[0193] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.82 (t, J=6.9 Hz,
3H), 1.11-1.29 (m, 4H), 1.47-1.64 (m, 2H), 2.77-2.96 (m, 4H),
3.32-3.47 (m, 3H), 4.40 (dd, J=14.3 and 11.3 Hz, 1H), 4.76-4.87 (m,
1H), 6.80 (br d, J=7.8 Hz, 1H), 7.14-7.40 (m, 10H).
[0194] Compound 25
##STR00057##
N-[(1R,2S,5R)-rel-6,6-dimethylbicyclo[3.1.1.]heptan-2-methyl]-1-(n-pentyl-
)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide (diastereomeric
mixture) (from (-)-cis-myrtanylamine (CAS 38235-68-6))
[0195] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.80-0.90 (m, 3H),
0.91 (d, J=9.6 Hz, 1H), 1.07 (s, 3H), 1.17-1.32 (m, 7H), 1.47-1.67
(m, 3H), 1.81-2.04 (m, 5H), 2.27-2.42 (m, 2H), 2.77-2.98 (m, 3H),
3.27-3.49 (m, 3H), 4.39 (dd, J=14.4 and 11.1 Hz, 1H), 6.64 (br t,
J=5.7 Hz, 1H), 7.27-7.39 (m, 5H).
[0196] Compound 26
##STR00058##
N-[(3-Dimethylamino)-2,2-dimethylpropyl]-1-(n-pentyl)-5-phenyl-4,5-dihydr-
o-(1H)-pyrazole-3-carboxamide
[0197] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.85 (t, J=6.92
Hz, 3H), 0.94 (s, 3H), 0.95 (s, 3H), 1.17-1.34 (m, 4H), 1.58-1.70
(m, 2H), 2.26 (s, 2H), 2.33 (s, 6H), 2.78-2.94 (m, 3H), 3.24 (d,
J=5.4 Hz, 2H), 3.40 (dd, J=17.1 and 10.8 Hz, 1H), 4.35 (dd, J=14.6
and 11 Hz, 1H), 7.28-7.41 (m, 5H), 8.58 (br s, 1H).
[0198] Compound 27
##STR00059##
N-(Adamantyl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxami-
de
[0199] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.84 (t, J=6.92
Hz, 3H), 1.15-1.32 (m, 4H) 1.49-1.64 (m, 2H), 1.65-1.76 (m, 7H),
2.08 (br s, 8H), 2.78 (dd, J=17.1 and 14.4 Hz, 1H), 2.89 (t, J=7.5
Hz, 2H), 3.37 (dd, J=17.3 and 11 Hz, 1H) 4.35 (dd, J=14.6 and 11
Hz, 1H), 6.40 (br s, 1H), 7.27-7.41 (m, 5H).
[0200] Compound 28
##STR00060##
N-(1-Phenyl-1-methyl-ethyl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazo-
le-3-carboxamide
[0201] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.85 (t, J=6.9 Hz,
3H), 1.16-1.33 (m, 4H), 1.51-1.69 (m, 2H), 1.75 (s, 3H), 1.77 (s,
3H), 2.78 (dd, J=17.3 and 14.6 Hz, 1H), 2.92 (br t, J=7.1 Hz, 2H),
3.35 (dd, J=17.3 and 11 Hz, 1H), 4.38 (dd, J=14.4 and 11.1 Hz, 1
H), 6.97 (br s, 1H), 7.19-7.24 (m, 1H), 7.27-7.41 (m, 7H), 7.45 (br
d, J=7.2 Hz, 2H).
[0202] Compound 29
##STR00061##
N--(N,2,2,6,6-pentamethylpiperidin-4-yl)-1-(n-pentyl)-5-phenyl-4,5-dihydr-
o-(1H)-pyrazole-3-carboxamide
[0203] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.85 (t, J=7.1 Hz,
3H), 1.10 (s, 6H). 1.16 (s, 6H). 1.19-1.30 (m, 4H). 1.37 (br t,
J=11.4 Hz, 2H), 1.50-1.68 (m, 2H), 1.86 (dd, J=12.3 and 3.3 Hz,
2H), 2.26 (s, 3H), 2.81 (dd, J=17.5 and 14.4 Hz, 1H), 2.86-2.97 (m,
2H), 3.40 (dd, J=17.1 and 11.1 Hz, 1H), 4.14-4.30 (m, 1H), 4.39
(dd, J=14.4 and 11.1 Hz, 1H), 6.39 (br d, J=8.1 Hz, 1H), 7.27-7.40
(m, 5H).
[0204] Compound 30
##STR00062##
N-Methyl-N-(Naphthalen-1-yl-methyl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H-
)-pyrazole-3-carboxamide
[0205] .sup.1H-NMR (400 MHz, CDCl.sub.3) (broad signals due to
restricted amide bond rotation) .delta. 0.56-1.78 (m, 9H),
2.48-3.08 (m, 3H), 3.10 (br s) and 3.26 (br s: Together integrates
for 3H), 3.40-3.59 (m, 1H), 4.15-4.40 (m, 1H), 5.18 (br s) and 5.50
(br d, J=16 Hz) and 5.64 (br d, J=16 Hz; Together integrates for
2H), 7.26-7.58 (m, 9H), 7.80 (br s, 1H), 7.88 (br d, J=7 Hz, 1H),
7.92-8.17 (m, 1H),
[0206] Compound 31
##STR00063##
N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-(n-pentyl)-5-
-(pyrid-2-yl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide
(diastereomeric mixture)
[0207] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 0.81-0.95 (m,
10H), 0.97 (s, 3H), 1.16-1.35 (m, 4H), 1.35-1.66 (m, 5H), 1.69 (t,
J=4.4 Hz, 1H), 1.74-1.87 (m, 1H), 2.32-2.44 (m, 1H), 2.91-3.11 (m,
3H), 3.44-3.59 (m, 1H), 4.24-4.35 (m, 1H), 4.54-4.67 (m, 1H), 6.69
(br d, J=8.4 Hz, 1H), 7.20-7.27 (m, 1H), 7.46 (dd, J=7.8 and 4.5
Hz, 1 H), 7.72 (br t, J=7.5 Hz, 1H), 8.58 (br t, J=4 Hz, 1H).
[0208] Compound 32
##STR00064##
N-(1-Phenyl-1-methyl-ethyl)-1-(n-pentyl)-5-(pyrid-2-yl)-4,5-dihydro-(1H)--
pyrazole-3-carboxamide
[0209] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 0.84 (t, J=6.9
Hz, 3H), 1.17-1.31 (m, 4 H), 1.52-1.65 (m, 2H), 1.73 (s, 3H), 1.75
(s, 3H), 2.88-3.10 (m, 3H), 3.40 (dd, J=17.3 and 11.6 Hz, 1H), 4.59
(dd, J=13.67 and 11.6 Hz, 1H), 7.02 (br s, 1H), 7.19-7.28 (m, 2H),
7.33 (br t, J=7.7 Hz, 2H), 7.40-7.48 (m, 3H), 7.74 (dt, J=7.7 and
1.8 Hz, 1H), 8.57 (br d, J=3.9 Hz, 1H).
[0210] Compound 33
##STR00065##
N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-(n-butyl)-5--
(3-chlorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide
(diastereomer 1)
[0211] Compounds 33 and 34 were separated from the corresponding
diastereomeric mixture by flash chromatography (silicagel). Eluant:
petroleum ether (40-60)/diethyl ether=4/1 v/v).
[0212] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.81-0.95 (m,
10H), 0.97 (s, 3H), 1.20-1.48 (m, 4H), 1.52-1.63 (m, 3H), 1.69 (t,
J=4.5 Hz, 1H), 1.74-1.86 (m, 1H), 2.32-2.43 (m, 1H), 2.78 (dd,
J=17.4 and 14.1 Hz, 1H), 2.95 (t, J=7.4 Hz, 2H), 3.38-3.48 (m, 1H)
4.25-4.34 (m, 1H), 4.38 (dd, J=14.1 and 11.4 Hz, 1H), 6.66 (br d,
J=9.3 Hz, 1H), 7.20-7.39 (m, 4H).
[0213] Compound 34
##STR00066##
N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-(n-butyl)-5--
(3-chlorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide
(diastereomer 2)
[0214] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.82-0.95 (m,
10H), 0.97 (s, 3H), 1.21-1.47 (m, 4H) 1.51-1.65 (m, 3H), 1.69 (t,
J=4.3 Hz, 1H), 1.75-1.86 (m, 1H), 2.33-2.43 (m, 1H), 2.79 (dd,
J=17.3 and 14.3 Hz, 1H), 2.94 (t, J=7.2 Hz, 2H), 3.42 (dd, J=17.4
and 11.1 Hz, 1H), 4.26-4.41 (m, 2H), 6.65 (d, J=9 Hz, 1H),
7.23-7.31 (m, 3 H), 7.39 (br s, 1H).
[0215] Compound 35
##STR00067##
N-(1-Phenyl-1-methyl-ethyl)-1-(n-butyl)-5-(3-chlorophenyl)-4,5-dihydro-(1-
H)-pyrazole-3-carboxamide
[0216] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.87 (t, J=7.4 Hz,
3H), 1.21-1.43 (m, 2H), 1.54-1.64 (m, 2H), 1.75 (s, 3H), 1.77 (s,
3H), 2.74 (dd, J=17.4 and 14.1 Hz, 1H), 2.93 (t, J=7.3 Hz, 2H),
3.36 (dd, J=17.1 and 11.1 Hz, 1H), 4.35 (dd, J=14.3 and 11.3 Hz,
1H), 6.96 (br s, 1H), 7.21-7.30 (m, 4H), 7.31-7.38 (m, 3H), 7.45
(br d, J=8.1 Hz, 2H).
[0217] Compound 36
##STR00068##
N-[1-(4-fluorophenyl)-1-methyl-ethyl]-1-(n-butyl)-5-(3-chlorophenyl)-4,5--
dihydro-(1H)-pyrazole-3-carboxamide
[0218] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.0.87 (t, J=7.4 Hz,
3H), 1.21-1.41 (m, 2H), 1.54-1.64 (m, 2H), 1.74 (s, 3H), 1.75 (s,
3H), 2.73 (dd, J=17.4 and 14.4 Hz, 1H), 2.93 (t, J=7.4 Hz, 2H),
3.35 (dd, J=17.3 and 11.3 Hz, 1H), 4.35 (dd, J=14.1 and 11.1 Hz,
1H), 6.93 (br s, 1H), 7.01 (br t, J=8.7 Hz, 2H), 7.21-7.31 (m, 3H),
7.36-7.44 (m, 3H).
[0219] Compound 37
##STR00069##
N-(1-Phenyl-1-methyl-ethyl)-1-(n-butyl)-trans-4-methyl-5-phenyl-4,5-dihyd-
ro-(1H)-pyrazole-3-carboxamide
[0220] A Sepacore chromatographic purification was applied to
purify the crude compound 37: Eluant: Dichloromethane.
[0221] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.86 (t, J=7.4 Hz,
3H), 1.19-1.38 (m, 5H), 1.51-1.61 (m, 2H), 1.74 (s, 3H), 1.77 (s,
3H), 2.89-2.97 (m, 2H), 3.14 (dq, J=13.4 and 6.7 Hz, 1H), 3.84 (d,
J=13.2 Hz, 1H), 6.98 (br s, 1H), 7.23 (br t, J=7.4 Hz, 1H),
7.28-7.39 (m, 7H), 7.45 (br d, J=7.2 Hz, 2H).
[0222] Compound 38
##STR00070##
N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-(n-butyl)-tr-
ans-4-methyl-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide
(diastereomeric mixture)
[0223] Two successive Sepacore chromatographic purifications were
applied to isolate compound 38 from the crude reaction mixture:
Separation A: Eluant: petroleum ether (40-60)/diethyl ether=80/20.
Separation B: Eluant: petroleum ether
(40-60)/ethylacetate=90/10.
[0224] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.81-0.94 (m,
10H), 0.97 (s, 3H) 1.21-1.47 (m, 6H), 1.50-1.67 (m, 4H), 1.69 (t,
J=4.5 Hz, 1H), 1.74-1.86 (m, 1H), 2.32-2.44 (m, 1H), 2.88-3.02 (m,
2H), 3.13-3.25 (m, 1H), 3.81-3.90 (m, 1H), 4.22-4.36 (m, 1H),
6.64-6.73 (m, 1H), 7.29-7.41 (m, 5H).
[0225] Compound 39
##STR00071##
N-(Endo-bicyclo[2.2.1]hept-2-yl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-p-
yrazole-3-carboxamide (diastereomeric mixture)
[0226] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.85 (t, J=7.1 Hz,
3H), 1.16-1.38 (m, 7H), 1.40-1.68 (m, 6H), 2.06-2.17 (m, 1H), 2.24
(br s, 1H), 2.49 (br s, 1H), 2.82 (dd, J=16.5 and 14.4 Hz, 1H),
2.88-3.01 (m, 2H), 3.41 (dd, J=17.1 and 11.1 Hz, 1H), 4.13-4.24 (m,
1H), 4.35-4.47 (m, 1H), 6.60-6.73 (m, 1H), 7.28-7.43 (m, 5H).
[0227] Compounds 40-43
##STR00072##
[0228] Compound 12 was separated by preparative chiral HPLC into 4
separate stereoisomers (compounds 40, 41, 42 and 43,
respectively).
[0229]
N-(Exo-bicyclo[2.2.1]hept-2-yl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(-
1H)-pyrazole-3-carboxamide (compound 40) (stereoisomer 1; first
eluting diastereomer; retention time=10.29 minutes; Diastereomeric
excess=97%): [.alpha..sup.25.sub.D]=+147.degree., c=0.9,
methanol.
[0230] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.85 (t, J=7 Hz,
3H), 1.10-1.66 (m, 15H), 1.83 (ddd, J=13, 8 and 2.1 Hz, 1H),
2.25-2.33 (m, 2H), 2.81 (dd, J=17.3 and 14.3 Hz, 1H), 2.86-2.97 (m,
2H), 3.40 (dd, J=17.4 and 11.1 Hz, 1H), 3.79 (br td, J=7.6 and 3.4
Hz, 1H), 4.37 (dd, J=14.30 and 11 Hz, 1H), 6.45 (br d, J=7.5 Hz,
1H), 7.27-7.40 (m, 5H).
[0231]
N-(Exo-bicyclo[2.2.1]hept-2-yl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(-
1H)-pyrazole-3-carboxamide (compound 41) (stereoisomer 2; second
eluting diastereomer; retention time=12.57 minutes; Diastereomeric
excess>99%): [.alpha..sup.25.sub.D]=+158.degree., c=1.1,
methanol.
[0232] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.85 (t, J=7 Hz,
3H), 1.11-1.65 (m, 15H), 1.83 (ddd, J=13, 8 and 2.1 Hz, 1H),
2.26-2.33 (m, 2H), 2.81 (dd, J=17.3 and 14.3 Hz, 1H), 2.86-2.98 (m,
2H), 3.40 (dd, J=17.4 and 11.1 Hz, 1H), 3.79 (br td, J=7.6 and 3.4
Hz, 1H), 4.38 (dd, J=14.4 and 11.1 Hz, 1H), 6.45 (br d, J=7.2 Hz,
1H), 7.27-7.38 (m, 5H).
[0233]
N-(Exo-bicyclo[2.2.1]hept-2-yl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(-
1H)-pyrazole-3-carboxamide (compound 42) (stereoisomer 3; third
eluting diastereomer; retention time=13.71 minutes; Diastereomeric
excess>99%) [.alpha..sup.25.sub.D]=-173.degree., c=1.0,
methanol.
[0234] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.85 (t, J=7 Hz,
3H), 1.10-1.66 (m, 15H), 1.83 (ddd, J=13, 8 and 2.1 Hz, 1H),
2.24-2.34 (m, 2H), 2.81 (dd, J=17.3 and 14.3 Hz, 1H), 2.86-2.98 (m,
2H), 3.40 (dd, J=17.4 and 11.1 Hz, 1H), 3.79 (br td, J=7.6 and 3.4
Hz, 1H), 4.38 (dd, J=14.2 and 11.1 Hz, 1H), 6.45 (br d, J=7.5 Hz,
1H), 7.27-7.37 (m, 5H).
[0235]
N-(Exo-bicyclo[2.2.1]hept-2-yl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(-
1H)-pyrazole-3-carboxamide (compound 43) (stereoisomer 4; fourth
eluting diastereomer; retention time=23.01 minutes; Diastereomeric
excess>99%): [.alpha..sup.25.sub.D]=-162.degree., c=0.9,
methanol.
[0236] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.85 (t, J=7 Hz,
3H), 1.10-1.66 (m, 15H), 1.83 (ddd, J=12.9, 8.1 and 2.1 Hz, 1H),
2.25-2.34 (m, 2H), 2.81 (dd, J=17.2 and 14.4 Hz, 1H), 2.85-2.98 (m,
2H), 3.40 (dd, J=17.2 and 11.1 Hz, 1H), 3.79 (br td, J=7.6 and 3.6
Hz, 1H), 4.37 (dd, J=14.2 and 11.1 Hz, 1H), 6.45 (br d, J=7.2 Hz,
1H), 7.27-7.40 (m, 5H).
[0237] Preparative chiral HPLC method: First step: A 250.times.30
mm column was used. Stationary phase: CHIRALPAK.RTM. AD=H 5 .mu.m.
n-Heptane/isopropanol=95/05 (v/v) was used as the mobile phase.
Flow rate: 40 ml/minute. Temperature: 21.5.degree. C. Detection UV
325 nm. Second step: A 250.times.30 mm column was used. Stationary
phase: CHIRALPAK.RTM. IA 5 .mu.m. n-Heptane/ethylacetate=85/15
(v/v) was used as the mobile phase. Flow rate: 40 ml/minute.
Temperature: ambient. Detection UV 325 nm.
[0238] Analytical HPLC monitoring system: A 250.times.4.6 mm column
was used. Stationary phase: CHIRALPAK.RTM. IA-H 5 .mu.m.
n-Heptane/ethylacetate=80/20 (v/v) was used as the mobile phase.
Flow rate: 1 ml/minute. Temperature: 25.degree. C. Detection: UV
300 nm.
[0239] Compounds 44-45
##STR00073##
[0240] Racemic compound 22 (1.88 gram) was separated by preparative
chiral HPLC into 2 separate enantiomers (compounds 44 and 45,
respectively).
(+)-N-[3-(Trifluoromethyl)benzyl)]-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)--
pyrazole-3-carboxamide (compound 44)
[0241] [.alpha..sup.25.sub.D]=124.degree., c=1.0, methanol.
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.83 (t, J=6.92 Hz, 3H),
1.15-1.30 (m, 4H), 1.51-1.65 (m, 2H), 2.81-2.99 (m, 3H), 3.45 (dd,
J=17.3 and 11.3 Hz, 1H), 4.46 (dd, J=14.4 and 11.4 Hz, 1H), 4.59
(s, 2H), 7.28-7.39 (m, 5H), 7.43-7.50 (m, 1H), 7.52-7.60 (m, 3H).
Enantiomeric excess: >98%.
(-)-N-[3-(Trifluoromethyl)benzyl)]-1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)--
pyrazole-3-carboxamide (compound 45)
[0242] [.alpha..sup.25.sub.D]=-132.degree., c=0.8, methanol.
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.83 (t, J=6.92 Hz, 3H),
1.15-1.30 (m, 4H), 1.51-1.65 (m, 2H), 2.81-2.99 (m, 3H), 3.45 (dd,
J=17.3 and 11.3 Hz, 1H), 4.46 (dd, J=14.4 and 11.4 Hz, 1H), 4.59
(s, 2H), 7.28-7.39 (m, 5H), 7.43-7.50 (m, 1H), 7.52-7.60 (m, 3H).
Enantiomeric excess: >98%.
[0243] Preparative chiral HPLC method: A 250.times.76 mm column was
used. Stationary phase: CHIRALPAK.RTM. IA 20 .mu.m.
n-Heptane/dichloromethane=75/25 (v/v) was used as the mobile phase.
Flow rate: 270 ml/minute. Temperature: 25.degree. C. Detection UV
300 nm
[0244] Analytical HPLC monitoring system: A 250.times.4.6 mm column
was used. Stationary phase: CHIRALPAK.RTM. IA-H 5 .mu.m.
n-Heptane/dichloromethane=75/25 (v/v) was used as the mobile phase.
Flow rate: 1 ml/minute. Temperature: 25.degree. C. Detection: Diode
array detection (DAD) 254 and 300 nm.
Enantiomeric excess: >98%
[0245] Compound 46
##STR00074##
N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-(n-pentyl)-5-
-(4-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide
(diastereomeric mixture)
[0246] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.81-0.94 (m,
10H), 0.97 (s, 3H), 1.07-1.47 (m, 7H), 1.52-1.65 (m, 2H), 1.69 (t,
J=4.4 Hz, 1H), 1.75-1.86 (m, 1H), 2.33-2.43 (m, 1H), 2.73-2.84 (m,
1H), 2.88-2.96 (m, 2H), 3.35-3.51 (m, 1H), 4.26-4.44 (m, 2H), 6.67
(br d, J=6 Hz, 1H), 7.04 (t, J=8.4 Hz, 2H), 7.31-7.39 (m, 2H).
[0247] Compound 47
##STR00075##
N-[3-(trifluoromethyl)benzyl]-1-(n-pentyl)-5-(3-fluorophenyl)-4,5-dihydro-
-(1H)-pyrazole-3-carboxamide
[0248] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.81-0.91 (m, 3H),
1.16-1.35 (m, 4H), 1.52-1.65 (m, 2H), 2.84 (dd, J=17.4 and 14.1 Hz,
1H), 2.87-2.99 m, 2H), 3.46 (dd, J=17.4 and 11.4 Hz, 1H), 4.45 (dd,
J=14.1 and 11.4 Hz, 1H), 4.60 (d, J=6.3 Hz, 2H), 7.01 (dt, J=8.1
and 2.1 Hz, 2H), 7.07-7.16 (m, 2H), 7.33 (dt, J=7.9 and 5.8 Hz,
1H), 7.43-7.50 (m, 1H), 7.51-7.61 (m, 3H).
[0249] Compound 48
##STR00076##
N-[1-(4-fluorophenyl)-1-methyl-ethyl]-1-(n-pentyl)-5-(3-fluorophenyl)-4,5-
-dihydro-(1H)-pyrazole-3-carboxamide
[0250] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.82-0.90 (m, 3H),
1.22-1.34 (m, 4H), 1.54-1.67 (m, 2H), 1.73 (s, 3H), 1.74 (s, 3H),
2.73 (dd, J=17.4 and 14.1 Hz, 1H), 2.93 (t, J=7.4 Hz, 2H), 3.35
(dd, J=17.4 and 11.1 Hz, 1H), 4.38 (dd, J=14.3 and 11.3 Hz, 1H),
6.94 (br s, 1H), 6.96-7.05 (m, 3H), 7.07-7.14 (m, 2H), 7.28-7.35
(m, 1H), 7.37-7.44 (m, 2H).
[0251] Compound 49
##STR00077##
N-[1-(4-fluorophenyl)-1-methyl-ethyl]-1-(n-pentyl)-5-(4-fluorophenyl)-4,5-
-dihydro-(1H)-pyrazole-3-carboxamide
[0252] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.82-0.90 (m, 3H),
1.20-1.31 (m, 4H), 1.53-1.67 (m, 2H), 1.73 (s, 3H), 1.74 (s, 3H),
2.73 (dd, J=17.4 and 14.4 Hz, 1H), 2.91 (t, J=7.4 Hz, 2H), 3.33
(dd, J=17.4 and 11.1 Hz, 1H), 4.36 (dd, J=14.1 and 11.1 Hz, 1H),
6.95 (br s, 1H), 6.97-7.08 (m, 4H), 7.33 (dd, J=8.7 and 5.4 Hz,
2H), 7.41 (dd, J=8.9 and 5.3 Hz, 2H).
[0253] Compound 50
##STR00078##
N-[1-(4-fluorophenyl)-1-methyl-ethyl]-1-(n-propyl)-5-(3-fluorophenyl)-4,5-
-dihydro-(1H)-pyrazole-3-carboxamide
[0254] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.89 (t, J=7.4 Hz,
3H), 1.55-1.71 (m, 2H), 1.73 (s, 3H), 1.74 (s, 3H), 2.73 (dd,
J=17.3 and 14.3 Hz, 1H), 2.83-2.97 (m, 2H), 3.36 (dd, J=17.4 and
11.1 Hz, 1H), 4.38 (dd, J=14.3 and 11.3 Hz, 1H), 6.94 (brs, 1H),
6.96-7.05 (m, 3H), 7.07-7.15 (m, 2H), 7.28-7.35 (m, 1H), 7.40 (dd,
J=8.7 and 5.4 Hz, 2H).
[0255] Compound 51
##STR00079##
N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-(4,4,4-trifl-
uorobutyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide
(diastereomer 1)
[0256] Compounds 51 and 52 were obtained from the corresponding
diasteromeric mixture via a flash chromatographic purification
(silicagel). Eluant: petroleum ether (40-60)/ethylacetate=90/10
(v/v). Compound 52: second (slowest) eluting diastereomer: Compound
51: first (fastest) eluting diastereomer.
[0257] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.82-0.95 (m, 7H),
0.98 (s, 3H), 1.22-2.11 (m, 8H), 2.13-2.27 (m, 1H), 2.34-2.45 (m,
1H), 2.81-2.96 (m, 2H), 2.99-3.08 (m, 1H), 3.44 (dd, J=17.4 and
11.1 Hz, 1H), 4.26-4.40 (m, 2H), 6.65 (br d, J=9 Hz, 1H), 7.30-7.42
(m, 5H). [.alpha..sup.25.sub.D]=102.degree., c=1, methanol.
[0258] Compound 52
##STR00080##
N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-(4,4,4-trifl-
uorobutyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide
(diastereomer 2)
[0259] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.83-0.94 (m, 7H),
0.97 (s, 3H), 1.20-1.32 (m, 1H), 1.38-1.49 (m, 1H), 1.54-1.63 (m,
1H), 1.70 (t, J=4.4 Hz, 1H), 1.75-1.88 (m, 2H), 1.89-2.08 (m, 2H),
2.13-2.29 (m, 1H), 2.32-2.44 (m, 1H), 2.81-2.95 (m, 2H), 2.97-3.07
(m, 1H), 3.42 (dd, J=17.4 and 10.8 Hz, 1H), 4.26-4.38 (m, 2H), 6.65
(br d, J=9.3 Hz, 1H), 7.29-7.41 (m, 5H).
[.alpha..sup.25.sub.D]=-102.degree., c=1, methanol.
[0260] Compound 53
##STR00081##
N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-propyl-5-(3--
fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide (diastereomer
1)
[0261] Compounds 53 and 54 were obtained from the corresponding
diasteromeric mixture via a flash chromatographic purification
(silicagel). Eluant gradient: petroleum ether
(40-60)/ethylacetate=95/5=>petroleum ether
(40-60)/ethylacetate=90/10 (v/v). Compound 53: second (slowest)
eluting diastereomer: Compound 54: first (fastest) eluting
diastereomer.
[0262] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.83-0.94 (m,
10H), 0.97 (s, 3H), 1.21-1.30 (m, 1H), 1.36-1.47 (m, 1H), 1.54-1.73
(m, 4H), 1.74-1.86 (m, 1H), 2.31-2.43 (m, 1H), 2.80 (dd, J=17.3 and
14.3 Hz, 1H), 2.85-2.99 (m, 2H), 3.43 (dd, J=17.4 and 11.1 Hz, 1H),
4.25-4.35 (m, 1H), 4.38 (dd, J=14.1 and 11.1 Hz, 1H) 6.66 (br d,
J=9 Hz, 1H) 7.00 (br t, J=8.3 Hz, 1H), 7.09-7.18 (m, 2H), 7.28-7.37
(m, 1H). [.alpha..sup.25.sub.D]=-122.degree., c=1, methanol.
[0263] Compound 54
##STR00082##
N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-propyl-5-(3--
fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide (diastereomer
2)
[0264] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.82-0.93 (m,
10H), 0.97 (s, 3H), 1.21-1.31 (m, 1H), 1.37-1.47 (m, 1H), 1.54-1.67
(m, 3H), 1.69 (t, J=4.4 Hz, 1H), 1.74-1.86 (m, 1H), 2.31-2.43 (m,
1H), 2.79 (dd, J=17.4 and 14.1 Hz, 1H), 2.85-2.99 (m, 2 H), 3.44
(dd, J=17.1 and 11.1 Hz, 1H), 4.30 (br tt, J=9.1 and 2.4 Hz, 1H),
4.40 (dd, J=14.0 and 11.3 Hz, 1H), 6.66 (br d, J=9 Hz, 1H), 7.00
(dt, J=8.3 and 1.9 Hz, 1H), 7.08-7.15 (m, 2H), 7.31 (dd, J=7.8 and
6 Hz, 1H). [.alpha..sup.25.sub.D]=145.degree., c=1, methanol.
[0265] Compound 55
##STR00083##
N-[1-(4-fluorophenyl)-1-methyl-ethyl]-1-(4,4,4-trifluorobutyl)-5-phenyl-4-
,5-dihydro-(1H)-pyrazole-3-carboxamide
[0266] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.74 (s, 3H), 1.75
(s, 3H), 1.78-1.88 (m, 1 H), 1.89-2.06 (m, 2H), 2.14-2.26 (m, 1H),
2.80 (dd, J=17.4 and 14.4 Hz, 1H), 2.85-2.93 (m, 1H), 2.98-3.06 (m,
1H), 3.35 (dd, J=17.4 and 10.8 Hz, 1H), 4.32 (dd, J=14.6 and 11 Hz,
1H), 6.93 (br s, 1H), 7.02 (t, J=8.7 Hz, 2H), 7.29-7.38 (m, 5H),
7.38-7.44 (m, 2H).
[0267] Compound 56
##STR00084##
N-Cyclohexylmethyl-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyraz-
ole-3-carboxamide
[0268] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.86 (t, J=7, 3
H), 0.91-1.03 (m, 2H), 1.10-1.34 (m, 7H), 1.47-1.70 (m, 4H),
1.70-1.81 (m, 4H), 2.80 (dd, J=17.1 and 13.8 Hz, 1H), 2.88-3.01 (m,
2H), 3.12-3.25 (m, 2H), 3.48 (dd, J=17.1 and 11.4 Hz, 1 H), 4.73
(dd, J=13.8 and 11.4 Hz, 1H), 6.67 (br t, J .about.6.5 Hz, 1H),
7.05 (dd, J=10.1 and 8.6 Hz, 1H), 7.15 (t, J=7.5 Hz, 1H), 7.24-7.31
(m, 1H), 7.48 (dt, J=7.5 and .about.2 Hz, 1H).
[0269] Compound 57
##STR00085##
N-(Indan-2-yl)-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyrazole--
3-carboxamide
[0270] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.81-0.86 (m, 3H),
1.13-1.31 (m, 4H) 1.51-1.64 (m, 2H), 2.81 (dd, J=17.4 and 13.8 Hz,
1H), 2.86-2.97 (m, 4H), 3.32-3.41 (m, 2 H), 3.49 (dd, J=17.1 and
11.4 Hz, 1H), 4.74 (dd, J=13.7 and 11.6 Hz, 1H), 4.78-4.87 (m, 1H),
6.78 (br d, J=8.1 Hz, 1H), 7.01-7.08 (m, 1H) 7.12-7.17 (m, 1H),
7.17-7.22 (m, 2H), 7.22-7.31 (m, 3H), 7.42-7.49 (m, 1H).
[0271] Compound 58
##STR00086##
N-(Endo-bicyclo[2.2.1]hept-2-yl)-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihy-
dro-(1H)-pyrazole-3-carboxamide (diastereomeric mixture)
[0272] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.81-0.89 (m, 4H),
1.20-1.38 (m, 6H), 1.43-1.52 (m, 2H), 1.53-1.70 (m, 4H), 2.06-2.17
(m, 1H), 2.24 (br t, J=4.5 Hz, 1H), 2.49 (br t, J=4.3 Hz, 1H), 2.79
(dd, J=17.3 and 13.7 Hz, 1H), 2.89-3.03 (m, 2H), 3.48 (dd, J=17.4
and 11.4 Hz, 1H), 4.13-4.23 (m, 1H), 4.70-4.78 (m, 1H), 6.63-6.69
(m, 1H), 7.02-7.08 (m, 1H), 7.13-7.18 (m, 1H), 7.24-7.31 (m, 1H),
7.45-7.52 (m, 1H).
[0273] Compound 59
##STR00087##
N-(Cycloheptyl)-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-
-3-carboxamide
[0274] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.86 (t, J=7 Hz,
3H), 1.20-1.32 (m, 4H), 1.46-1.71 (m, 11H), 1.92-2.03 (m, 2H),
2.74-2.84 (m, 2H), 2.90-2.98 (m, 2H), 3.47 (dd, J=17.1 and 11.4 Hz,
1H), 3.96-4.07 (m, 1H), 4.72 (dd, J=13.8 and 11.1 Hz, 1H), 6.56 (br
d, J=8.4 Hz, 1H), 7.01-7.08 (m, 1H), 7.12-7.18 (m, 1H), 7.24-7.31
(m, 1H), 7.46-7.51 (m, 1H).
[0275] Compound 60
##STR00088##
N-[3,4-difluorobenzyl]-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-p-
yrazole-3-carboxamide
[0276] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.85 (t, J=6.9 Hz,
3H), 1.17-1.33 (m, 4H), 1.54-1.70 (m, 2H), 2.84 (dd, J=17.3 and
13.7 Hz, 1H), 2.88-3.02 (m, 2H), 3.50 (dd, J=17.3 and 11.6 Hz, 1H),
4.43-4.54 (m, 2H), 4.79 (dd, J=13.8 and 11.7 Hz, 1H), 6.96 (br t,
J=6.3 Hz, 1H), 7.02-7.20 (m, 5H), 7.25-7.32 (m, 1H), 7.47 (dt,
J=7.5 and 1.8 Hz, 1H).
[0277] Compound 61
##STR00089##
N-[Naphthalen-1-ylmethyl]-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H-
)-pyrazole-3-carboxamide
[0278] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.80 (t, J=6.9 Hz,
3H), 1.21 (m, 4H), 1.49-1.61 (m, 2H), 2.79-2.97 (m, 3H), 3.53 (dd,
J=17.1 and 11.4 Hz, 1H), 4.71-4.80 (m, 1 H), 4.95-5.06 (m, 2H),
6.84-6.90 (m, 1H) m 7.02-7.08 (m, 1H), 7.15 (t, J=7.5 Hz, 1H),
7.24-7.31 (m, 1H), 7.42-7.61 (m, 5H), 7.83 (d, J=8.1 Hz, 1H), 7.90
(d, J=8.1 Hz, 1H), 8.10 (d, J=8.1 Hz, 1H).
[0279] Compound 62
##STR00090##
N-[2-(Indol-3-yl)ethyl]-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)--
pyrazole-3-carboxamide
[0280] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.86 (t, J=6.9 Hz,
3H), 1.17-1.32 (m, 4H), 1.52-1.64 (m, 2H), 2.81 (dd, J=17.3 and
13.7 Hz, 1H), 2.86-2.98 (m, 2H), 3.04 (t, J=6.9 Hz, 2H), 3.48 (dd,
J=17.1 and 11.4 Hz, 1H), 3.68 (q, J=6.6 Hz, 2H), 4.68-4.78 (m, 1H),
6.77 (br t, J=6.2 Hz, 1H), 7.01-7.10 (m, 2H), 7.14 (q, J=7.1 Hz,
2H), 7.21 (t, J=7.5 Hz, 1H), 7.24-7.31 (m, 1H), 7.38 (d, J=8.1 Hz,
1H), 7.43-7.49 (m, 1H), 7.65 (d, J=7.8 Hz, 1H), 8.06 (br s,
1H).
[0281] Compound 63
##STR00091##
N-[(Pyridin-3-yl)methyl]-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-
-pyrazole-3-carboxamide
[0282] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.81-0.89 (m, 3H),
1.15-1.33 (m, 4H), 1.53-1.69 (m, 2H), 2.84 (dd, J=17.3 and 13.7 Hz,
1H), 2.89-3.02 (m, 2H), 3.50 (dd, J=17.3 and 11.6 Hz, 1H),
4.51-4.60 (m, 2H) 4.79 (dd, J=13.8 and 11.4 Hz, 1H), 6.98 (br t,
J=6.5 Hz, 1H), 7.03-7.09 (m, 1H), 7.16 (t, J=7 Hz, 1H), 7.24-7.34
(m, 2H), 7.46 (dt, J=7.5 and 2 Hz, 1H), 7.69 (br d, J=7.8 Hz, 1H),
8.54 (br d, J=4.8 Hz, 1H), 8.58-8.62 (m, 1H).
[0283] Compound 64
##STR00092##
N-[2-(Thien-2-yl)ethyl]-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)--
pyrazole-3-carboxamide
[0284] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.84-0.90 (m, 3H),
1.18-1.34 (m, 4H), 1.56-1.67 (m, 2H), 2.80 (dd, J=17.1 and 13.8 Hz,
1H), 2.86-3.01 (m, 2H), 3.10 (t, J=6.9 Hz, 2H), 3.48 (dd, J=17.1
and 11.4 Hz, 1H), 3.62 (q, J=6.6 Hz, 2H), 4.75 (dd, J=13.8 and 11.4
Hz, 1H), 6.79 (br t, J=6.3 Hz, 1H), 6.88 (dd, J=3.2 and 1 Hz, 1H),
6.96 (dd, J=5.1 and 3.3 Hz, 1H), 7.02-7.09 (m, 1H), 7.13-7.19 (m,
2H), 7.24-7.31 (m, 1H), 7.44-7.50 (m, 1H).
[0285] Compound 65
##STR00093##
N-[3,3-diphenylpropyl]-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-p-
yrazole-3-carboxamide
[0286] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.87 (t, J=6.9 Hz,
3H), 1.20-1.34 (m, 4H), 1.55-1.69 (m, 2H), 2.31-2.39 (m, 2H), 2.77
(dd, J=17.4 and 13.8 Hz, 1H), 2.85-2.99 (m, 2H), 3.31 (q, J=8 Hz,
2H), 3.45 (dd, J=17.1 and 11.4 Hz, 1H), 4.00 (t, J=7.8 Hz, 1 H),
4.72 (dd, J=14 and 11.23 Hz, 1H), 6.59 (br t, J=6.6 Hz, 1H),
7.01-7.09 (m, 1H), 7.13-7.20 (m, 3H), 7.24-7.31 (m, 9H), 7.47 (dt,
J=7.5 and 2 Hz, 1H).
[0287] Compound 66
##STR00094##
N-[(Furan-2-yl)methyl]-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-p-
yrazole-3-carboxamide
[0288] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.82-0.90 (m, 3H),
1.17-1.35 (m, 4H), 1.54-1.69 (m, 2H), 2.82 (dd, J=17.3 and 13.7 Hz,
1H), 2.87-3.01 (m, 2H), 3.49 (dd, J=17.3 and 11.6 Hz, 1H),
4.48-4.60 (m, 2H), 4.76 (dd, J=13.7 and 11.6 Hz, 1H), 6.26-6.37 (m,
2H), 6.90 (br t, J=6 Hz, 1H), 7.02-7.09 (m, 1H), 7.12-7.18 (m, 1H),
7.24-7.32 (m, 1H), 7.36-7.40 (m, 1H), 7.46 (dt, J=8.2 and 2 Hz,
1H).
[0289] Compound 67
##STR00095##
N-Benzyl-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carb-
oxamide
[0290] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.84 (t, J=6.9 Hz,
3H), 1.17-1.32 (m, 4H), 1.54-1.66 (m, 2H), 2.84 (dd, J=17.1 and
13.8 Hz, 1H), 2.86-3.00 (m, 2H), 3.51 (dd, J=17.4 and 11.4 Hz, 1H),
4.50-4.58 (m, 2H), 4.76 (dd, J=13.8 and 11.4 Hz, 1H), 6.92 (br t,
J=6 Hz, 1H), 7.02-7.09 (m, 1H), 7.16 (dt, J=7.5 and 1.2 Hz, 1H),
7.25-7.32 (m, 3H), 7.33-7.39 (m, 3H), 7.47 (dt, J=7.1 and 1.3 Hz,
1H).
[0291] Compound 68
##STR00096##
N-Cyclopentyl-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-
-carboxamide
[0292] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.86 (t, J=6.9 Hz,
3H), 1.18-1.35 (m, 4H), 1.41-1.53 (m, 2H), 1.55-1.80 (m, 6H),
1.97-2.10 (m, 2H), 2.79 (dd, J=17.4 and 13.8 Hz, 1H), 2.87-3.01 (m,
2H), 3.48 (dd, J=17.4 and 11.4 Hz, 1H), 4.27 (sextet, J=7.1 Hz,
1H), 4.72 (dd, J=14 and 11.3 Hz, 1H), 6.54 (br d, J=7.8 Hz, 1H),
7.05 (dd, J=11 and 7.7 Hz, 1H), 7.15 (t, J=7.4 Hz, 1H), 7.24-7.32
(m, 1H), 7.48 (dt, J=7.4 and 1.6 Hz, 1H).
[0293] Compound 69
##STR00097##
N-(4-Methoxybenzyl)-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyra-
zole-3-carboxamide
[0294] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.84 (t, J=6.9 Hz,
3H), 1.17-1.32 (m, 4H), 1.54-1.67 (m, 2H), 2.82 (dd, J=17.4 and
13.8 Hz, 1H), 2.87-2.99 (m, 2H), 3.50 (dd, J=17.1 and 11.4 Hz, 1H),
3.81 (s, 3H), 4.46-4.49 (m, 2H), 4.75 (dd, J=14.1 and 11.4 Hz, 1H),
6.82-6.91 (m, 3H), 7.05 (dd, J=11 and 7.7 Hz, 1H), 7.15 (t, J=7.5
Hz, 1H), 7.24-7.31 (m, 3H), 7.47 (dt, J=7.5 and 1.8 Hz, 1H).
[0295] Compound 70
##STR00098##
N-(2-Methoxybenzyl)-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyra-
zole-3-carboxamide
[0296] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.86 (t, J=6.9 Hz,
3H), 1.18-1.33 (m, 4H), 1.56-1.67 (m, 2H), 2.80 (dd, J=17.1 and
13.8 Hz, 1H), 2.86-2.99 (m, 2H), 3.49 (dd, J=17.1 and 11.4 Hz, 1H),
3.88 (s, 3H), 4.52-4.56 (m, 2H), 4.73 (dd, J=14 and 11.3 Hz, 1H),
6.87-6.96 (m, 2H), 7.05 (dd, J=9.8 and 8.9 Hz, 1H), 7.08-7.18 (m,
2H), 7.23-7.34 (m, 3H), 7.47 (dt, J=7.6 and 2 Hz, 1H).
[0297] Compound 71
##STR00099##
N-[(1-ethyl)propyl]-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyra-
zole-3-carboxamide
[0298] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.82-0.89 (m, 3H),
0.90-0.98 (m, 6H), 1.19-1.34 (m, 4H), 1.39-1.53 (m, 2H), 1.54-1.70
(m, 4H), 2.81 (dd, J=17.1 and 13.8 Hz, 1H), 2.89-3.03 (m, 2H), 3.49
(dd, J=17.3 and 11.23 Hz, 1H), 3.79-3.91 (m, 1H), 4.75 (dd, J=13.8
and 11.4 Hz, 1H), 6.38 (br d, J=9.3 Hz, 1H), 7.01-7.09 (m, 1H),
7.16 (t, J=7.5 Hz, 1H), 7.24-7.32 (m, 1H), 7.49 (dt, J=7.5 and 1.8
Hz, 1H).
[0299] Compound 72
##STR00100##
N-(Exo-bicyclo[2.2.1]hept-2-yl)-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihyd-
ro-(1H)-pyrazole-3-carboxamide (diastereomeric mixture)
[0300] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.86 (t, J=6.9 Hz,
3H), 1.11-1.19 (m, 1H), 1.19-1.33 (m, 7H), 1.38-1.69 (m, 5H),
1.79-1.87 (m, 1H), 2.26-2.33 (m, 2H), 2.79 (dd, J=17.4 and 13.8 Hz,
1H), 2.88-3.01 (m, 2H), 3.47 (dd, J=17.4 and 11.4 Hz, 1H), 3.79
(dt, J=7.7 and 3.4 Hz, 1H), 4.68-4.77 (m, 1H), 6.48 (br d, J=7.5
Hz, 1H), 7.05 (dd, J=9.8 and 8.6 Hz, 1H), 7.12-7.18 (m, 1H),
7.24-7.31 (m, 1H), 7.44-7.51 (m, 1H).
[0301] Compound 73
##STR00101##
N-(4-chlorobenzyl)-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyraz-
ole-3-carboxamide
[0302] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.84 (t, J=6.9 Hz,
3H), 1.16-1.32 (m, 4H), 1.52-1.67 (m, 2H), 2.83 (dd, J=17.3 and
13.7 Hz, 1H), 2.88-3.01 (m, 2H), 3.50 (dd, J=17.4 and 11.4 Hz, 1H),
4.46-4.55 (m, 2H), 4.78 (dd, J=13.8 and 11.4 Hz, 1H), 6.95 (br t,
J=6.3 Hz, 1H), 7.02-7.09 (m, 1H), 7.12-7.19 (m, 1H), 7.24-7.34 (m,
5H), 7.46 (tt, J=7.5 and 2 Hz, 1H).
[0303] Compound 74
##STR00102##
N-(1-Phenyl-ethyl)-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyraz-
ole-3-carboxamide (1:1 diasteromeric mixture)
[0304] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.80-0.90 (m, 3H),
1.17-1.33 (m, 4H), 1.53-1.70 (m, 5H), 2.73-2.87 (m, 1H), 2.88-3.02
(m, 2H), 3.42-3.54 (m, 1H), 4.69-4.80 (m, 1H), 5.20 (quintet, J=7.3
Hz, 1H), 6.85 (br d, J=8.4 Hz, 1H), 7.01-7.08 (m, 1H), 7.11-7.19
(m, 1H), 7.23-7.31 (m, 2H), 7.32-7.41 (m, 4H), 7.43-7.51 (m,
1H).
[0305] Compound 75
##STR00103##
N-(Adamantylmethyl)-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyra-
zole-3-carboxamide
[0306] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.84-0.89 (m, 3H),
1.21-1.35 (m, 4H), 1.51-1.57 (m, 6H), 1.57-1.77 (m, 6H), 2.00 (br
s, 3H), 2.81 (dd, J=17.4 and 13.8 Hz, 1H), 2.90-3.10 (m, 4H), 3.49
(dd, J=17.1 and 11.4 Hz, 1H), 4.75 (dd, J=14 and 11.23 Hz, 1H),
6.69 (t, J=6.8 Hz, 1H), 7.02-7.08 (m, 1H), 7.16 (br t, J=8, 1 H),
7.24-7.31 (m, 1H), 7.49 (dt, J=7.4 and 2 Hz, 1H).
[0307] Compound 76
##STR00104##
N-(3,4-Dimethoxybenzyl)-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)--
pyrazole-3-carboxamide
[0308] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.84 (t, J=6.9 Hz,
3H), 1.15-1.32 (m, 4H), 1.54-1.66 (m, 2H), 2.83 (dd, J=17.1 and
13.8 Hz, 1H), 2.86-3.00 (m, 2H), 3.51 (dd, J=17.3 and 11.6 Hz, 1H),
3.88 (s, 3H), 3.89 (s, 3H), 4.43-4.52 (m, 2H), 4.76 (dd, J=14 and
11.6 Hz, 1H), 6.82-6.92 (m, 4H), 7.03-7.09 (m, 1H), 7.16 (t, J=7.2
Hz, 1H), 7.25-7.32 (m, 1H), 7.47 (dt, J=7.5 and 2 Hz, 1H).
[0309] Compound 77
##STR00105##
N-(3-Fluorobenzyl)-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyraz-
ole-3-carboxamide
[0310] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.0.82-0.88 (m, 3H),
1.17-1.33 (m, 4H), 1.53-1.71 (m, 2H), 2.84 (dd, J=17.3 and 13.7 Hz,
1H), 2.90-3.03 (m, 2H), 3.51 (dd, J=17.3 and 11.6 Hz, 1H),
4.48-4.58 (m, 2H), 4.79 (dd, J=13.8 and 11.4 Hz, 1H), 6.93-7.02 (m,
2H), 7.02-7.13 (m, 3H), 7.16 (t, J=7.5 Hz, 1H), 7.25-7.35 (m, 2H),
7.47 (dt, J=7.5 and 2 Hz, 1H).
[0311] Compound 78
##STR00106##
N-(2-Phenyl-propyl)-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyra-
zole-3-carboxamide (1:1 diasteromeric mixture)
[0312] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.86 (t, J=7 Hz,
3H), 1.17-1.30 (m, 4H), 1.32 (d, J=6.9 Hz, 3H), 1.52-1.63 (m, 2H),
2.72-3.06 (m, 4H), 3.34-3.51 (m, 2H), 3.58-3.67 (m, 1H), 4.65-4.76
(m, 1H), 6.57 (br t, J=6.3 Hz, 1H), 7.04 (dd, J=9.8 and 8.9 Hz,
1H), 7.11-7.17 (m, 1H), 7.21-7.30 (m, 4H), 7.30-7.36 (m, 2H),
7.42-7.49 (m, 1H).
[0313] Compound 79
##STR00107##
N-[2-(7-methyl-indol-3-yl)ethyl]-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihy-
dro-(1H)-pyrazole-3-carboxamide
[0314] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.86 (t, J=6.9 Hz,
3H), 1.18-1.31 (m, 4H), 1.53-1.65 (m, 2H), 2.49 (s, 3H), 2.80 (dd,
J=17.1 and 13.8 Hz, 1H), 2.83-2.97 (m, 2 H), 3.03 (t, J=7.1 Hz,
2H), 3.48 (dd, J=17.1 and 11.4 Hz, 1H), 3.68 (q, J=6.9 Hz, 2H),
4.72 (dd, J=13.8 and 11.4 Hz, 1H), 6.78 (t, J=6.2 Hz, 1H),
6.99-7.09 (m, 4H), 7.15 (t, J=7.5 Hz, 1H), 7.24-7.31 (m, 1H), 7.46
(dt, J=7.5 and 2 Hz, 1H), 7.50 (d, J=7.8 Hz, 1 H), 8.10 (br s,
1H).
[0315] Compound 80
##STR00108##
N-(3,4,5-Trimethoxybenzyl)-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1-
H)-pyrazole-3-carboxamide
[0316] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.84 (t, J=6.9 Hz,
3H), 1.18-1.31 (m, 4H), 1.55-1.66 (m, 2H), 2.84 (dd, J=17.3 and
13.7 Hz, 1H), 2.89-3.01 (m, 2H), 3.52 (dd, J=17.3 and 11.6 Hz, 1H),
3.84 (s, 3H), 3.87 (s, 6H), 4.42-4.52 (m, 2H), 4.78 (dd, J=13.8 and
11.4 Hz, 1H), 6.57 (s, 2H), 6.91 (br t, J=6.2 Hz, 1H), 7.06 (dd,
J=9.6 and 8.7 Hz, 1H), 7.16 (t, J=7.5 Hz, 1H), 7.25-7.32 (m, 1H),
7.44-7.50 (m, 1H).
[0317] Compound 81
##STR00109##
N-(Cyclooctyl)-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyrazole--
3-carboxamide
[0318] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.86 (t, J=6.92
Hz, 3H), 1.18-1.34 (m, 4H), 1.50-1.75 (m, 14H), 1.82-1.95 (m, 2H),
2.79 (dd, J=17.4 and 13.8 Hz, 1H), 2.87-3.02 (m, 2H), 3.47 (dd,
J=17.3 and 11.3 Hz, 1H), 4.01-4.11 (m, 1H), 4.72 (dd, J=14 and 11.3
Hz, 1H), 6.57 (br d, J=8.4 Hz, 1H), 7.01-7.09 (m, 1H), 7.12-7.18
(m, 1H), 7.24-7.31 (m, 1H), 7.45-7.51 (m, 1H).
[0319] Compound 82
##STR00110##
N-(tert-Butyl)-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyrazole--
3-carboxamide
[0320] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.86 (t, J=7.2 Hz,
3H), 1.20-1.33 (m, 4H), 1.42 (s, 9H), 1.56-1.68 (m, 2H), 2.77 (dd,
J=17.1 and 13.8 Hz, 1H), 2.92 (br t, J=7.1 Hz, 2H), 3.45 (dd,
J=17.3 and 11.3 Hz, 1H), 4.70 (dd, J=14 and 11.3 Hz, 1H), 6.50 (br
s, 1H), 7.01-7.08 (m, 1H), 7.12-7.18 (m, 1H), 7.24-7.31 (m, 1H),
7.48 (dt, J=7.5 and 1.8 Hz, 1H).
[0321] Compound 83
##STR00111##
N-(2-(Trifluoromethyl)benzyl)-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-
-(1H)-pyrazole-3-carboxamide
[0322] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.85 (t, J=6.9 Hz,
3H), 1.17-1.33 (m, 4H), 1.54-1.70 (m, 2H), 2.83 (dd, J=17.1 and
13.8 Hz, 1H), 2.88-3.02 (m, 2H), 3.50 (dd, J=17.3 and 11.6 Hz, 1H),
4.67-4.82 (m, 3H), 6.99 (br t, J=6.6 Hz, 1H), 7.02-7.09 (m, 1H),
7.15 (t, J=8.1 Hz, 1H), 7.25-7.31 (m, 1H), 7.38 (t, J=7.7 Hz, 1H),
7.46 (dt, J=7.5 and 1.8 Hz, 1H), 7.54 (t, J=7.7 Hz, 1H), 7.60-7.68
(m, 2H).
[0323] Compound 84
##STR00112##
N-(5-Methyl-thiazol-2-yl)-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H-
)-pyrazole-3-carboxamide
[0324] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.85-0.89 (m, 3H),
1.19-1.34 (m, 4H), 1.59-1.69 (m, 2H), 2.40 (s, 3H), 2.93 (dd, J=17
and 13.1 Hz, 1H), 2.97-3.14 (m, 2 H), 3.56 (dd, J=17.1 and 12.3 Hz,
1H), 4.96 (t, J=12.6 Hz, 1H), 7.05-7.12 (m, 2H), 7.18 (t, J=7.4 Hz,
1H), 7.28-7.34 (m, 1H), 7.43 (dt, J=7.5 and 1.8 Hz, 1H), 10.02 (br
s, 1H).
[0325] Compound 85
##STR00113##
N-(3-Methoxybenzyl)-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyra-
zole-3-carboxamide
[0326] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.84 (t, J=6.9 Hz,
3H), 1.17-1.32 (m, 4H), 1.54-1.68 (m, 2H), 2.83 (dd, J=17.1 and
13.8 Hz, 1H), 2.88-3.00 (m, 2H), 3.51 (dd, J=17.3 and 11.6 Hz, 1H),
3.81 (s, 3H), 4.48-4.57 (m, 2H), 4.76 (dd, J=13.8 and 11.4 Hz, 1H),
6.81-6.85 (m, 1H), 6.87-6.95 (m, 3H), 7.02-7.09 (m, 1H), 7.16 (t,
J=6.9 Hz, 1H), 7.24-7.31 (m, 2H), 7.47 (dt, J=7.5 and 1.8 Hz,
1H).
[0327] Compound 86
##STR00114##
N-[3-(Trifluoromethyl)benzyl]-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-
-(1H)-pyrazole-3-carboxamide
[0328] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.80-0.88 (m, 3H),
1.16-1.33 (m, 4H), 1.53-1.69 (m, 2H), 2.85 (dd, J=17.3 and 13.7 Hz,
1H), 2.90-3.03 (m, 2H), 3.51 (dd, J=17.1 and 11.7 Hz, 1H),
4.56-4.64 (m, 2H), 4.81 (dd, J=13.8 and 11.7 Hz, 1H), 7.02-7.10 (m,
2H), 7.16 (t, J=7.5 Hz, 1H), 7.25-7.33 (m, 1H), 7.43-7.50 (m, 2H),
7.52-7.57 (m, 2H), 7.58 (br s, 1H).
[0329] Compound 87
##STR00115##
N-[(1R,2S,5R)-rel-6,6-dimethylbicyclo[3.1.1.]heptan-2-methyl]-1-(n-pentyl-
)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide
(mixture of diastereoisomers) (from (-)-cis-myrtanylamine (CAS
38235-68-6))
[0330] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.84-0.93 (m, 4H),
1.06 (s, 3H), 1.21 (d, J=2.4 Hz, 3H), 1.22-1.34 (m, 4H), 1.48-1.69
(m, 3H), 1.82-2.03 (m, 5H), 2.22-2.32 (m, 1H), 2.34-2.42 (m, 1H),
2.75-2.85 (m, 1H), 2.88-3.01 (m, 2H), 3.28-3.41 (m, 2 H), 3.43-3.53
(m, 1H), 4.74 (dd, J=13.8 and 11.4 Hz, 1H), 6.64 (br t, J=6.3 Hz,
1H), 7.02-7.08 (m, 1H), 7.15 (t, J=7.5 Hz, 1H), 7.24-7.31 (m, 1H),
7.45-7.51 (m, 1H).
[0331] Compound 88
##STR00116##
N-(Adamant-1-yl)-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyrazol-
e-3-carboxamide
[0332] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.86 (t, J=7.1 Hz,
3H), 1.18-1.35 (m, 4H), 1.52-1.75 (m, 8H), 2.05-2.13 (m, 9H), 2.75
(dd, J=17.3 and 14 Hz, 1H), 2.92 (t, J=7.4 Hz, 2H), 3.44 (dd,
J=17.3 and 11.3 Hz, 1H), 4.69 (dd, J=14 and 11.3 Hz, 1H), 6.39 (br
s, 1H), 7.01-7.08 (m, 1H), 7.15 (t, J=7.4 Hz, 1H), 7.23-7.31 (m,
1H), 7.45-7.51 (m, 1H).
[0333] Compound 89
##STR00117##
N-[1-phenyl-1-methyl-ethyl]-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(-
1H)-pyrazole-3-carboxamide
[0334] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.0.86 (t, J=6.9 Hz,
3H), 1.19-1.35 (m, 4H), 1.55-1.70 (m, 2H), 1.76 (s, 3H), 1.77 (s,
3H), 2.76 (dd, J=17.5 and 13.8 Hz, 1H), 2.91-2.99 (m, 2H), 3.42
(dd, J=17.3 and 11.3 Hz, 1H), 4.72 (dd, J=14 and 11.3 Hz, 1 H),
6.96 (br s, 1H), 7.01-7.07 (m, 1H), 7.15 (t, J=7.4 Hz, 1H),
7.20-7.30 (m, 2H), 7.34 (t, J=7.7 Hz, 2H), 7.42-7.52 (m, 3H).
[0335] Compound 90
##STR00118##
N-[4-(Trifluoromethyl)benzyl]-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-
-(1H)-pyrazole-3-carboxamide
[0336] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.0.85 (t, J=6.9 Hz,
3H), 1.15-1.34 (m, 4H), 1.53-1.69 (m, 2H), 2.85 (dd, J=17.3 and
13.7 Hz, 1H), 2.90-3.03 (m, 2H), 3.51 (dd, J=17.3 and 11.6 Hz, 1H),
4.54-4.64 (m, 2H), 4.79 (dd, J=13.8 and 11.4 Hz, 1H), 6.98-7.10 (m,
2H), 7.16 (t, J=7.5 Hz, 1H), 7.24-7.33 (m, 1H), 7.43-7.50 (m, 3H),
7.60 (d, J=8.1 Hz, 2H).
[0337] Compound 91
##STR00119##
N-[1-(Adamant-1-yl)-ethyl]-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1-
H)-pyrazole-3-carboxamide (diastereomeric mixture)
[0338] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.83-0.90 (m, 3H),
1.06-1.13 (m, 3H), 1.20-1.36 (m, 4H), 1.49-1.77 (m, 14H), 1.98-2.04
(m, 3H), 2.81 (dd, J=17.3 and 14 Hz, 1H), 2.89-3.03 (m, 2H), 3.49
(dd, J=17.1 and 11.1 Hz, 1H), 3.72-3.82 (m, 1H), 4.68-4.79 (m, 1H),
6.51 (br d, J=10.2 Hz, 1H), 7.01-7.09 (m, 1H), 7.12-7.19 (m, 1 H),
7.24-7.31 (m, 1H), 7.46-7.55 (m, 1H).
[0339] Compound 92
##STR00120##
N-(Noradamant-1-yl)-1-(n-pentyl)-5-(2-fluorophenyl)-4,5-dihydro-(1H)-pyra-
zole-3-carboxamide
[0340] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.83-0.90 (m, 3H),
1.17-1.35 (m, 4H), 1.51-1.71 (m, 6H), 1.91-1.98 (m, 2H), 2.01-2.10
(m, 2H), 2.10-2.19 (m, 2H), 2.29 (br s, 2H), 2.50 (br t, J=6.8 Hz,
1H), 2.79 (dd, J=17.4 and 13.8 Hz, 1H), 2.93 (t, J=7.2 Hz, 2H),
3.46 (dd, J=17.3 and 11.3 Hz, 1H), 4.72 (dd, J=14 and 11.3 Hz, 1H),
6.79 (br s, 1H), 7.05 (ddd, J=10.2, 8.1 and 1.2 Hz, 1H), 7.15 (br
t, J=6.9 Hz, 1H), 7.24-7.32 (m, 1H), 7.48 (dt, J=7.5 and 2.1 Hz,
1H).
[0341] Compound 93
##STR00121##
N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-(n-butyl)-5--
(benzothien-3-yl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide
(diastereomer 1)
[0342] Compounds 93 and 94 were obtained from the corresponding
diasteromeric mixture via a Sepacore column (40.times.150 mm)
chromatographic purification. Eluant gradient: petroleum ether
(40-60)/diethyl ether=90/10=>petroleum ether (40-60)/diethyl
ether=80/20 (v/v)). Compound 93: first (fastest) eluting
diastereomer: Compound 94: second (slowest) eluting
diastereomer:
[0343] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.82-1.02, (m,
13H), 1.20-1.49 (m, 4H), 1.59-1.67 (m, 3H), 1.70 (t, J=4.5 Hz, 1H),
1.75-1.87 (m, 1H), 2.38 (m, 1H), 2.91-3.11 (m, 3H), 3.51 (dd,
J=17.4 and 11.4 Hz, 1H), 4.38-4.48 (m, 1H), 4.80 (dd, J=14.4 and
11.4 Hz, 1H), 6.71 (br d, J=9.3 Hz, 1H), 7.37 (dd, J=6.2 and 3.2
Hz, 2H), 7.40 (s, 1H), 7.75-7.81 (m, 1H), 7.86-7.91 (m, 1H).
[0344] Compound 94
##STR00122##
N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-(n-butyl)-5--
(benzothien-3-yl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide
(diastereomer 2)
[0345] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.82-1.03 (m,
13H), 1.20-1.51 (m, 4H). 1.62-1.68 (m, 3H), 1.70 (t, J=4.4 Hz, 1H),
1.76-1.88 (m, 1H), 2.34-2.47 (m, 1H), 2.90-3.11 (m, 3H), 3.50 (dd,
J=17.3 and 11.3 Hz, 1H), 4.27-4.37 (m, 1H), 4.78 (dd, J=14.4 and
11.4 Hz, 1H), 6.71 (br d, J=9 Hz, 1H), 7.35-7.45 (m, 3H), 7.77-7.83
(m, 1H), 7.86-7.92 (m, 1H).
[0346] Compound 95
##STR00123##
N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-(n-pentyl)-5-
-(thien-3-yl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide
(diastereomeric mixture)
[0347] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.83-0.93 (m,
10H), 0.97 (s, 3H), 1.20-1.34 (m, 5H), 1.36-1.46 (m, 1H), 1.54-1.65
(m, 3H), 1.69 (t, J=4.5 Hz, 1H), 1.73-1.86 (m, 1H), 2.32-2.42 (m,
1H), 2.80-2.90 (m, 1H), 2.90-3.04 (m, 2H), 3.31-3.41 (m, 1H),
4.26-4.34 (m, 1H), 4.46-4.56 (m, 1H), 6.66 (br d, J=9 Hz, 1H),
7.08-7.13 (m, 1H), 7.18-7.22 (m, 1H), 7.31-7.35 (m, 1H).
[0348] Compound 96
##STR00124##
N-(1-phenyl-1-methyl-ethyl)-1-(n-pentyl)-5-(thien-3-yl)-4,5-dihydro-(1H)--
pyrazole-3-carboxamide
[0349] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.83-0.90 (m, 3H),
1.20-1.33 (m, 4H), 1.53-1.68 (m, 2H), 1.76 (s, 3H), 1.77 (s, 3H),
2.80 (dd, J=17.1 and 14.1 Hz, 1H), 2.87-3.01 (m, 2H), 3.29 (dd,
J=17.1 and 10.8 Hz, 1H), 4.49 (dd, J=14.1 and 10.8 Hz, 1H), 6.96
(br s, 1H), 7.08-7.12 (m, 1H), 7.18-7.21 (m, 1H), 7.23 (br t, J=7.2
Hz, 1 H), 7.30-7.38 (m, 3H), 7.45 (br d, J=7.2 Hz, 2H).
[0350] Compound 97
##STR00125##
N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-(n-propyl)-5-
-(3-(trifluoromethyl)phenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide
(diastereomer 1)
[0351] Compounds 97 and 98 were obtained from the corresponding
diasteromeric mixture via a Sepacore column (40.times.150 mm)
chromatographic purification. Eluant gradient: petroleum ether
(40-60)/diethyl ether=90/10=>petroleum ether (40-60)/diethyl
ether=60/40 (v/v)). Compound 97: second (slowest) eluting
diastereomer: Compound 98: first (fastest) eluting
diastereomer.
[0352] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.84-0.93 (m,
10H), 0.97 (s, 3H), 1.21-1.30 (m, 1H), 1.38-1.47 (m, 1H), 1.56-1.68
(m, 3H), 1.70 (t, J=4.4 Hz, 1H), 1.76-1.86 (m, 1H), 2.33-2.43 (m,
1H), 2.80 (dd, J=17.4 and 14.4 Hz, 1H), 2.82-2.98 (m, 2 H), 3.46
(dd, J=17.4 and 11.1 Hz, 1H), 4.26-4.34 (m, 1H), 4.45 (dd, J=14.4
and 11.1 Hz, 1H), 6.67 (br d, J=9.1 Hz, 1H), 7.46-7.51 (m, 1H),
7.55-7.61 (m, 2H), 7.67 (br s, 1H).
[0353] Compound 98
##STR00126##
N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-(n-propyl)-5-
-(3-(trifluoromethyl)phenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide
(diastereomer 2)
[0354] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.82-0.94 (m,
10H), 0.97 (s, 3H), 1.20-1.35 (m, 1H), 1.38-1.48 (m, 1H), 1.54-1.67
(m, 3H), 1.69 (t, J=4.4 Hz, 1H), 1.75-1.86 (m, 1H), 2.33-2.42 (m,
1H), 2.79 (dd, J=17.3 and 14.3 Hz, 1H), 2.85-3.00 (m, 2 H), 3.48
(dd, J=17.4 and 11.4 Hz, 1H), 4.25-4.35 (m, 1H), 4.47 (dd, J=14.1
and 11.1 Hz, 1H), 6.68 (br d, J=9.1 Hz, 1H), 7.46-7.51 (m, 1H),
7.55-7.60 (m, 2H), 7.65 (br s, 1H).
[0355] Compound 99
##STR00127##
N-(1-phenyl-1-methyl-ethyl)-1-(n-propyl)-5-(3-(trifluoromethyl)phenyl)-4,-
5-dihydro-(1H)-pyrazole-3-carboxamide
[0356] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.88 (t, J=7.4 Hz,
3H), 1.55-1.71 (m, 2H), 1.76 (s, 3H), 1.77 (s, 3H), 2.75 (dd,
J=17.4 and 14.4 Hz, 1H), 2.80-2.98 (m, 2H), 3.41 (dd, J=17.4 and
11.1 Hz, 1H), 4.44 (dd, J=14.4 and 11.1 Hz, 1H), 6.97 (br s, 1H),
7.21-7.27 (m, 1H), 7.35 (br t, J=7.7 Hz, 2H), 7.43-7.52 (m, 3H),
7.55-7.60 (m, 2H), 7.65 (br s, 1H).
[0357] Compound 100
##STR00128##
N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-(n-pentyl)-5-
-(3-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide (1:1
diastereomeric mixture)
[0358] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.81-0.94 (m,
10H), 0.97 (s, 3H), 1.20-1.35 (m, 5H), 1.37-1.47 (m, 1H), 1.54-1.65
(m, 3H), 1.67-1.72 (m, 1H), 1.75-1.87 (m, 1H), 2.32-2.42 (m, 1H),
2.73-2.84 (m, 1H), 2.91-2.99 (m, 2H), 3.38-3.49 (m, 1 H), 4.26-4.45
(m, 2H), 6.66 (br d, J=6.6 Hz, 1H), 7.00 (dt, J=8.4 and 2.4 Hz,
1H), 7.08-7.17 (m, 2H), 7.28-7.35 (m, 1H).
[0359] Compound 101
##STR00129##
N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-(n-pentyl)-5-
-(2-fluorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide
(diastereomeric mixture)
[0360] To a magnetically stirred solution of
E-2-oxo-4-(2-fluorophenyl)-but-3-enoic acid
[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-ylamide]
(Intermediate X-3) (1.5 g, 4.83 mmol) in ethanol (50 ml) was
successively added acetic acid (660 ml, 11.58 mmol) and
n-pentylhydrazine (Intermediate XI-1) (1.45 ml, 9.65 mmol) and the
resulting mixture was reacted in a nitrogen atmosphere at
60.degree. C. for 8 hours in an oil bath. The reaction mixture was
allowed to attain room temperature and concentrated in vacuo. The
residue was dissolved in dichloromethane, washed with water and
subsequently dried over MgSO.sub.4, filtered and concentrated in
vacuo. Further chromatographic purification using Sepacore
equipment (eluant: petroleum ether/ethylacetate=95/5 (v/v)) gave
compound 101 (940 mg, 46% yield) as an oil. .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 0.83-0.94 (m, 10H), 1.20-1.85 (m, 14H),
2.32-2.42 (m, 1H), 2.74-2.85 (m, 1H), 2.91-3.02 (m, 2H), 3.43-3.54
(m, 1H), 4.26-4.36 (m, 1H), 4.69-4.80 (m, 1H), 6.63-6.70 (m, 1H),
7.02-7.09 (m, 1H), 7.12-7.19 (m, 1H), 7.25-7.31 (m, 1H), 7.46-7.54
(m, 1H).
[0361] Compound 102
##STR00130##
N-(1-phenyl-1-methyl-ethyl)-1-(n-butyl)-5-phenyl-4,5-dihydro-(1H)-pyrazol-
e-3-carboxamide
[0362] Compound 102 was obtained from E-2-oxo-4-phenyl-but-3-enoic
acid [1-phenyl-1-methyl-ethyl]amide and n-butylhydrazine
analogously to the procedure described for compound 101.
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.85 (t, J=7, 3H),
1.20-1.39 (m, 2H), 1.53-1.63 (m, 2H), 1.76 (s, 3H), 1.77 (s, 3H),
2.77 (dd, J=17 and 14, 1H), 2.90-2.96 (m, 2H), 3.35 (dd, J=17 and
11, 1 H), 4.37 (dd, J=14 and 11, 1 H), 6.97 (br s, 1H), 7.21-7.48
(m, 10H).
[0363] Compound 103
##STR00131##
N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-(n-butyl)-5--
phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide (diastereomeric
mixture)
[0364] Compound 103 was obtained from E-2-oxo-4-phenyl-but-3-enoic
acid [endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-ylamide]
(Intermediate X-2) and n-butylhydrazine analogously to the
procedure described for compound 101. .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 0.83-0.95 (m, 10H), 0.97 (s, 3H), 1.21-1.86 (m,
9H), 2.32-2.42 (m, 1H), 2.77-2.88 (m, 1H), 2.91-2.99 (m, 2H),
3.35-3.46 (m, 1H), 4.26-4.46 (m, 2H), 6.66 (br d, J.about.8, 1 H),
7.28-7.40 (m, 5H).
[0365] Compound 104
##STR00132##
N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-(n-pentyl)-5-
-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide (diastereomeric
mixture)
[0366] Compound 104 was obtained from E-2-oxo-4-phenyl-but-3-enoic
acid [endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-ylamide]
(Intermediate X-2) and n-pentylhydrazine (Intermediate XI-1)
analogously to the procedure described for compound 101.
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.83-0.94 (m, 10H), 0.97
(s, 3H), 1.20-1.47 (m, 5H), 1.54-1.65 (m, 3H), 1.69 (t, J .about.6,
1 H), 1.75-1.85 (m, 1H), 2.32-2.42 (m, 1H), 2.82 (dd, J=17 and 14,
1H), 2.92-2.98 (m, 2H), 3.41 (dd, J=17 and 11, 1H), 4.26-4.35 (m,
1H), 4.41 (dd, J=14 and 11, 1 H), 6.67 (br d, J.about.8, 1 H),
7.28-7.39 (m, 5H).
[0367] Compound 105
##STR00133##
N-(1-(4-fluorophenyl)-1-methyl-ethyl)-1-(n-pentyl)-5-phenyl-4,5-dihydro-(-
1H)-pyrazole-3-carboxamide
[0368] Compound 6 was obtained from E-2-oxo-4-phenyl-but-3-enoic
acid [1-(4-fluorophenyl)-1-methyl-ethyl]amide and n-pentylhydrazine
(Intermediate XI-1) analogously to the method described for
compound 101. .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.85 (t,
J=7, 3H), 1.20-1.31 (m, 4H), 1.54-1.67 (m, 2H), 1.74 (s, 3H), 1.75
(s, 3H), 2.77 (dd, J=17 and 14, 1H), 2.90-2.97 (m, 2H), 3.35 (dd,
J=17 and 11, 1H), 4.38 (dd, J=14 and 11, 1H), 6.94 (br s, 1H),
6.98-7.04 (m, 2H), 7.27-7.43 (m, 7H).
[0369] Compound 106
##STR00134##
N-(2-(4-fluorophenyl)-1,1-dimethyl-ethyl)-1-(n-pentyl)-5-phenyl-4,5-dihyd-
ro-(1H)-pyrazole-3-carboxamide
[0370] Compound 106 was obtained from E-2-oxo-4-phenyl-but-3-enoic
acid [2-(4-fluorophenyl)-2,2-dimethyl-ethyl]amide (Intermediate
X-4) and n-pentylhydrazine (Intermediate XI-1) analogously to the
procedure described for compound 101. .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 0.85 (t, J=7, 3H), 1.16-1.27 (m, 4H), 1.36 (s,
3H), 1.39 (s, 3H), 1.50-1.62 (m, 2H), 2.77-2.94 (m, 4H), 3.04 (d,
J=13, 1H), 3.10 (d, J=13, 1H), 3.41 (dd, J=18 and 12, 1 H), 4.39
(dd, J=14 and 11, 1 H), 6.38 (br s, 1H), 6.94-7.01 (m, 2H),
7.10-7.16 (m, 2H), 7.28-7.38 (m, 5H).
[0371] Furthermore, the compounds 107-118 were obtained analogously
to the method described for compound 101.
[0372] Compound 107
##STR00135##
N-[1-(4-fluorophenyl)-1-methyl-ethyl]-1-isobutyl-5-phenyl-4,5-dihydro-(1H-
)-pyrazole-3-carboxamide
[0373] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.85 (d, J=6.6 Hz,
3H), 0.88 (d, J=6.6 Hz, 3 H), 1.73 (s, 3H), 1.75 (s, 3H), 1.96-2.07
(m, 1H), 2.54 (dd, J=12.6 and 9 Hz, 1H), 2.77 (dd, J=17.4 and 14.1
Hz, 1H), 2.84 (dd, J=12.6 and 5.1 Hz, 1H), 3.34 (dd, J=17.4 and
11.1 Hz, 1H), 4.34 (dd, J=14.4 and 11.1 Hz, 1H), 6.93 (br s, 1H),
7.01 (t, J=8.9 Hz, 2H), 7.27-7.37 (m, 5H), 7.38-7.44 (m, 2H).
[0374] Compound 108
##STR00136##
N-[1-(4-fluorophenyl)-1-methyl-ethyl]-1-cyclohexylmethyl-5-phenyl-4,5-dih-
ydro-(1H)-pyrazole-3-carboxamide
[0375] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.67-0.90 (m, 2H),
1.05-1.29 (m, 4H), 1.51-1.72 (m, 4H), 1.74 (s, 3H), 1.75 (s, 3H),
1.82-1.90 (m, 1H), 2.61 (dd, J=12.8 and 8.9 Hz, 1H), 2.76 (dd,
J=17.3 and 14.3 Hz, 1H), 2.83 (dd, J=12.6 and 5.1 Hz, 1H), 3.33
(dd, J=17.3 and 11 Hz, 1H), 4.33 (dd, J=14.4 and 11.1 Hz, 1H), 6.93
(br s, 1H), 7.01 (t, J=8.7 Hz, 2H), 7.27-7.37 (m, 5H), 7.39-7.43
(m, 2H).
[0376] Compound 109
##STR00137##
N-[1-(4-fluorophenyl)-1-methyl-ethyl]-1-phenethyl-5-phenyl-4,5-dihydro-(1-
H)-pyrazole-3-carboxamide
[0377] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.74 (s, 3H), 1.75
(s, 3H), 2.77 (dd, J=17.4 and 14.4 Hz, 1H), 2.84-2.93 (m, 1H),
2.95-3.03 (m, 1H), 3.13-3.29 (m, 2H), 3.33 (dd, J=17.4 and 11.1 Hz,
1H), 4.43 (dd, J=14.4 and 11.1 Hz, 1H), 6.91 (br s, 1H), 7.02 (t,
J=8.7 Hz, 2H), 7.14 (d, J=6.9 Hz, 2H), 7.16-7.35 (m, 8H), 7.38-7.44
(m, 2H).
[0378] Compound 110
##STR00138##
N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-isobutyl-5-p-
henyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide (diastereomeric
mixture)
[0379] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 0.81-0.95 (m,
13H), 0.96 (s, 3H), 1.22-1.30 (m, 1H), 1.37-1.47 (m, 1H), 1.55-1.67
(m, 1H), 1.69 (t, J=4.5 Hz, 1H), 1.75-1.85 (m, 1H), 1.96-2.08 (m,
1H), 2.32-2.43 (m, 1H), 2.52-2.60 (m, 1H), 2.78-2.88 (m, 2H),
3.36-3.46 (m, 1H), 4.26-4.41 (m, 2H), 6.67 (br d, J=8 Hz, 1H),
7.27-7.40 (m, 5H).
[0380] Compound 111
##STR00139##
N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-cyclohexylme-
thyl-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide
(diastereomeric mixture)
[0381] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 0.70-0.95 (m,
9H), 0.98 (s, 3H), 1.04-1.32 (m, 5H), 1.37-1.48 (m, 1H), 1.55-1.90
(m, 8H), 2.32-2.43 (m, 1H), 2.60-2.70 (m, 1H), 2.77-2.89 (m, 2H),
3.35-3.46 (m, 1H), 4.26-4.42 (m, 2H), 6.65 (br d, J=9 Hz, 1H),
7.27-7.39 (m, 5H).
[0382] Compound 112
##STR00140##
N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-(2-cyano-eth-
yl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide
(diastereomeric mixture)
[0383] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 0.82-0.95 (m,
7H), 0.97 (s, 3H), 1.22-1.32 (m, 1H), 1.38-1.49 (m, 1H), 1.54-1.65
(m, 1H), 1.70 (t, J=4.7 Hz, 1H), 1.75-1.88 (m, 1H), 2.34-2.44 (m,
1H), 2.61-2.77 (m, 2H), 2.88 (dd, J=17.6 and 14.3 Hz, 1 H), 3.20
(t, J=6.8 Hz, 2H), 3.46 (dd, J=17.4 and 10.8 Hz, 1H), 4.26-4.35 (m,
1H), 4.39 (dd, J=14.4 and 10.8 Hz, 1H), 6.67 (br d, J=9 Hz, 1H),
7.31-7.44 (m, 5H).
[0384] Compound 113
##STR00141##
N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-phenethyl-5--
phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide (diastereomeric
mixture)
[0385] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 0.85-0.96 (m,
7H), 0.98 (s, 3H), 1.20-1.32 (m, 1H), 1.39-1.48 (m, 1H), 1.55-1.65
(m, 1H) 1.70 (t, J=4.5 Hz, 1H), 1.76-1.88 (m, 1H) 2.33-2.43 (m,
1H), 2.77-2.93 (m, 2H), 2.95-3.04 (m, 1H), 3.16-3.30 (m, 2H), 3.42
(dd, J=17.4 and 11.1 Hz, 1H), 4.26-4.35 (m, 1H), 4.45 (dd, J=14.4
and 11.1 Hz, 1H), 6.65 (br d, J=9.3 Hz, 1H), 7.10-7.40 (m,
10H).
[0386] Compound 114
##STR00142##
N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-(n-butyl)-5--
(4-chlorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide
(diastereomer 1)
[0387] Compounds 114 and 115 were obtained from the corresponding
diasteromeric mixture via a flash chromatographic purification.
Eluant: petroleum ether (40-60)/diethyl ether=75/25. Compound 115:
first (fastest) eluting diastereomer): Compound 114: second
(slowest) eluting diastereomer.
[0388] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.81-0.93 (m,
10H), 0.97 (s, 3H), 1.08-1.65 (m, 7H), 1.69 (t, J=4.5 Hz, 1H),
1.74-1.85 (m, 1H), 2.33-2.42 (m, 1H), 2.78 (dd, J=17.1 and 14.4 Hz,
1H), 2.92 (t, J=7.4 Hz, 2H), 3.40 (dd, J=17.4 and 11.1 Hz, 1H),
4.26-4.34 (m, 1H), 4.36 (dd, J=14.4 and 11.1 Hz, 1H), 6.65 (br d,
J=9.3 Hz, 1H), 7.33 (s, 4H).
[0389] Compound 115
##STR00143##
N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-(n-butyl)-5--
(4-chlorophenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide
(diastereomer 2)
[0390] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.82-0.93 (m,
10H), 0.97 (s, 3H), 1.18-1.63 (m, 7H), 1.69 (t, J=4.5 Hz, 1H),
1.75-1.85 (m, 1H), 2.32-2.42 (m, 1H), 2.77 (dd, J=17.3 and 14.3 Hz,
1H), 2.93 (t, J=7.4 Hz, 2H), 3.37-3.46 (m, 1H), 4.26-4.34 (m, 1H),
4.38 (dd, J=14.1 and 11.1 Hz, 1H), 6.66 (br d, J=9.3 Hz, 1H),
7.29-7.35 (m, 4H).
[0391] Compound 116
##STR00144##
N-[1-phenyl-1-methyl-ethyl]-1-n-butyl-5-(4-chlorophenyl)-4,5-dihydro-(1H)-
-pyrazole-3-carboxamide
[0392] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.86 (t, J=7.4 Hz,
3H), 1.20-1.38 (m, 2H), 1.53-1.63 (m, 2H), 1.76 (s, 3H), 1.77 (s,
3H), 2/2 (dd, J=17.3 and 14.3 Hz, 1H), 2.90 (t, J=7.4 Hz, 2H), 3.34
(dd, J=17.4 and 11.1 Hz, 1H), 4.34 (dd, J=14.4 and 11.1 Hz, 1H),
6.95 (br s, 1H), 7.20-7.26 (m, 1H), 7.28-7.37 (m, 6H), 7.45 (d,
J=7.8 Hz, 2H).
[0393] Compound 117
##STR00145##
N-(1-(4-fluorophenyl)-1-methyl-ethyl)-1-(n-butyl)-5-(3-methoxyphenyl)-4,5-
-dihydro-(1H)-pyrazole-3-carboxamide
[0394] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.85-0.89 (m, 3H),
122-1.39 (m, 2H), 1.55-1.66 (m, 2H), 1.73 (s, 3H), 1.74 (s, 3H),
2.76 (dd, J=17.3 and 14.5 Hz, 1H), 2.88-3.01 (m, 2H), 3.33 (dd,
J=17.3 and 11.1 Hz, 1H), 3.80 (s, 3H), 4.35 (dd, J=14.5 and 11.1
Hz, 1H), 6.84 (ddd, J=8.12, 2.4 and 1.1 Hz, 1H), 6.91-6.96 (m, 3H),
6.97-7.05 (m, 2H), 7.23-7.28 (m, 1H), 7.38-7.44 (m, 2H).
[0395] Compound 118
##STR00146##
N-[endo-(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1-(n-butyl)-5--
(3-methoxyphenyl)-4,5-dihydro-(1H)-pyrazole-3-carboxamide (1:1
diastereomeric mixture)
[0396] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.84-0.94 (m,
10H), 0.97 (s, 3H), 1.22-1.47 (m, 4H), 1.54-1.66 (m, 3H), 1.69 (t,
J=4.4 Hz, 1H), 1.75-1.86 (m, 1H), 2.32-2.43 (m, 1H), 2.76-2.87 (m,
1H), 2.89-3.03 (m, 2H), 3.36-3.45 (m, 1H), 3.81/3.82 (double s,
3H), 4.26-4.43 (m, 2H), 6.63-6.71 (m, 1H), 6.81-6.87 (m, 1H),
6.92-6.97 (m, 2H), 7.23-7.30 (m, 1H).
Example 5
Pharmacological Methods
In Vitro Affinity for Cannabinoid-CB.sub.1 Receptors
[0397] The affinity of the compounds of the invention for
cannabinoid CB.sub.1 receptors can be determined using membrane
preparations of Chinese hamster ovary (CHO) cells in which the
human cannabinoid CB.sub.1 receptor is stably transfected in
conjunction with [.sup.3H]CP-55,940 as radioligand. After
incubation of a freshly prepared cell membrane preparation with the
[.sup.3H]-ligand, with or without addition of one or more compounds
of the invention, separation of bound and free ligand is performed
by filtration over glassfiber filters. Radioactivity on the filter
is measured by liquid scintillation counting.
In Vitro Affinity for Cannabinoid-CB.sub.2 Receptors
[0398] The affinity of the compounds of the invention for
cannabinoid CB.sub.2 receptors can be determined using membrane
preparations of CHO cells in which the human cannabinoid CB.sub.2
receptor is stably transfected in conjunction with
[.sup.3H]CP-55,940 as radioligand. After incubation of a freshly
prepared cell membrane preparation with the [.sup.3H]-ligand, with
or without addition of one or more compounds of the invention,
separation of bound and free ligand is performed by filtration over
glassfiber filters. Radioactivity on the filter is measured by
liquid scintillation counting.
In Vitro Cannabinoid-CB.sub.1 Receptor (Ant)Agonism
[0399] In vitro CB.sub.1 receptor antagonism/agonism can be
assessed with the human CB.sub.1 receptor cloned in CHO cells. CHO
cells are grown in a Dulbecco's Modified Eagle's medium (DMEM)
culture medium, supplemented with 10% heat-inactivated fetal calf
serum. Medium is aspirated and replaced by DMEM, without fetal calf
serum, but containing [.sup.3H]-arachidonic acid and incubated
overnight in a cell culture stove (5% CO.sub.2/95% air; 37.degree.
C.; water-saturated atmosphere). During this period
[.sup.3H]-arachidonic acid is incorporated in membrane
phospholipids. On the test day, medium is aspirated and cells are
washed three times using 0.5 ml DMEM, containing 0.2% bovine serum
albumin (BSA). CB.sub.1 agonist stimulation leads to activation of
PLA.sub.2 followed by release of [.sup.3H]-arachidonic acid into
the medium. This CB.sub.1 agonist-induced release is
concentration-dependently antagonized by CB.sub.1 receptor
antagonists, such as for example rimonabant.
In Vitro Cannabinoid-CB.sub.2 Receptor (Ant)Agonism
[0400] Functional activity at the cannabinoid CB.sub.2 receptor was
assessed using a forskolin-stimulated cAMP accumulation assay. The
ability of compounds to stimulate and inhibit adenylate cyclase
activity was assessed in Chinese ovarian hamster (CHO) K.sub.1
cells expressing human CB2 (Euroscreen, Brussel) receptor. CHO
cells were grown in a CHO--S--SFM-II culture medium, supplemented
with 10% heat-inactivated foetal calf serum, 2 mM glutamine, 400
.mu.g/ml Hygromycine B and 500 .mu.g/ml G418 at 37.degree. C. in
93% air/5% CO.sub.2. For incubation with test compounds, confluent
cultures grown in 24 well plates were used. Each condition or
substance was routinely tested in quadruplicate. Cells were loaded
with 1 mCi [.sup.3H]-adenine in 0.5 ml medium per well. After 2
hours, cultures were washed with 0.5 ml PBS containing 1 mM IBMX
and incubated for 20 minutes with 0.5 ml PBS containing 1 mM IBMX
and 3.times.10.sup.-7M forskolin with or without the test compound.
Antagonistic effects of test compounds were determined as
inhibition of 0.1 .mu.M JWH-133-decreased [.sup.3H]cAMP formation.
After aspiration the reaction was stopped with 1 ml trichloroacetic
acid (5% w/v). The [.sup.3H]-ATP and [.sup.3H]-cAMP formed in the
cellular extract were assayed as follows: a volume of 0.8 ml of the
extract was passed over Dowex (50WX-4200-400 mesh) and aluminum
oxide columns, eluted with water and 0.1M imidazole (pH=7.5).
Eluates were mixed with 7 ml Ultima-Flo [AP] and the
.beta.-radioactivity was counted with a liquid scintillation
counter. The conversion of [.sup.3H]-ATP into [.sup.3H]-cAMP was
expressed as the ratio in percentage radioactivity in the cAMP
fraction as compared to the combined radioactivity in both cAMP and
ATP fractions, and basal activity was subtracted to correct for
spontaneous activity. Reference compounds used to assess
cannabinoid CB.sub.2 receptor mediated adenylate cyclase activity
were the full cannabinoid CB.sub.2 receptor agonists JWH-133
(Huffman, 1999.sup.b) and WIN 55, 212-2 (Huffman, 1999.sup.a), and
the inverse agonist or antagonist SR-144528 (Rinaldi-Carmona,
1998). Compounds were studied in a concentration range of
10.sup.-10 M to 10.sup.-6M. pEC.sub.50 and the pA.sub.2 were
calculated according to Cheng-Prusoff equation (Cheng and Prusoff,
1973). Two independent experiments were performed in
triplicate.
Example 6
Pharmacological Test Results
TABLE-US-00001 [0401] Affinity for Cb.sub.1- and CB.sub.2-
receptors, and in vitro agonistic activity on CB.sub.1- receptors
receptor binding Functional CB.sub.1 assays Human CB.sub.1 Human
CB.sub.2 Human CB.sub.1 affinity affinity agonism Cmp pK.sub.i
pK.sub.i pEC.sub.50 1 8.1 8.3 8.1 4 7.5 7.1 7.4 7 6.9 6.3 6.2 12
7.1 7.4 7.4 14 7.5 6.6 6.3 22 7.2 6.5 7.1 27 7.8 8.1 7.9 28 8.2 7.0
8.1 32 8.1 8.0 7.4 37 7.8 7.0 8.1 101 8.2 8.1 8.2 102 7.4 7.4 7.0
103 7.1 7.6 7.5 104 8.2 7.6 8.5 105 7.8 6.9 8.8 108 7.6 7.5 7.8 110
7.3 7.3 6.5
[0402] The compounds of the invention have a high affinity for
cannabinoid-CB.sub.1 and CB.sub.2 receptors, and are agonists on
CB.sub.1 receptors. Surprising, because 1,3,5-trisubstituted
pyrazoline derivatives described in e.g., WO 2005/074920, WO
2005/077911 and WO 2007/009689, as cannabinoid CB.sub.1 receptor
`modulating` agents, a definition embracing agonists, invariably
were shown to be antagonists.
Example 7
Pharmaceutical Preparations
[0403] For clinical use, compounds of formula (I) can be formulated
into pharmaceutical compositions that are important and novel
embodiments of the invention because they contain the compounds,
more particularly specific compounds disclosed herein. Types of
pharmaceutical compositions that may be used include, but are not
limited to, tablets, chewable tablets, capsules (including
microcapsules), solutions, parenteral solutions, ointments (creams
and gels), suppositories, suspensions, and other types disclosed
herein or apparent to a person skilled in the art from the
specification and general knowledge in the art. The active
ingredient, for instance, may also be in the form of an inclusion
complex in cyclodextrins, their ethers or their esters. The
compositions are used for oral, intravenous, subcutaneous,
tracheal, bronchial, intranasal, pulmonary, transdermal, buccal,
rectal, parenteral or other ways to administer. The pharmaceutical
formulation contains at least one compound of formula (I) in a
mixture with a pharmaceutically acceptable adjuvant, diluent and/or
carrier. In one embodiment, the total amount of active ingredients
may be in amounts, for example, from about 0.1% (w/w) to about 95%
(w/w) of the formulation, and from 0.5% to 50% (w/w), and further
from 1% to 25% (w/w).
[0404] The compounds of the invention can be brought into forms
suitable for administration by means of usual processes using
auxiliary substances such as liquid or solid, powdered ingredients,
such as the pharmaceutically customary liquid or solid fillers and
extenders, solvents, emulsifiers, lubricants, flavorings, colorings
and/or buffer substances. Frequently used auxiliary substances
include magnesium carbonate, titanium dioxide, lactose, saccharose,
sorbitol, mannitol and other sugars or sugar alcohols, talc,
lactoprotein, gelatin, starch, amylopectin, cellulose and its
derivatives, animal and vegetable oils such as fish liver oil,
sunflower, groundnut or sesame oil, polyethylene glycol and
solvents such as, for example, sterile water and mono- or
polyhydric alcohols such as glycerol, as well as with
disintegrating agents and lubricating agents such as magnesium
stearate, calcium stearate, sodium stearyl fumarate and
polyethylene glycol waxes. The mixture may then be processed into
granules or pressed into tablets. A tablet is prepared using the
ingredients below:
TABLE-US-00002 Ingredient Quantity (mg/tablet) COMPOUND No. 1 10
Cellulose, microcrystalline 200 Silicon dioxide, fumed 10 Stearic
acid 10 Total 230
[0405] The components are blended and compressed to form tablets
each weighing 230 mg.
[0406] The active ingredients may be separately premixed with the
other non-active ingredients, before being mixed to form a
formulation. The active ingredients may also be mixed with each
other, before being mixed with the non-active ingredients to form a
formulation.
[0407] Soft gelatin capsules may be prepared with capsules
containing a mixture of the active ingredients of the invention,
vegetable oil, fat, or other suitable vehicle for soft gelatin
capsules. Hard gelatin capsules may contain granules of the active
ingredients. Hard gelatin capsules may also contain the active
ingredients together with solid powdered ingredients such as
lactose, saccharose, sorbitol, mannitol, potato starch, corn
starch, amylopectin, cellulose derivatives or gelatin.
[0408] Dosage units for rectal administration may be prepared (i)
in the form of suppositories that contain the active substance
mixed with a neutral fat base; (ii) in the form of a gelatin rectal
capsule that contains the active substance in a mixture with a
vegetable oil, paraffin oil or other suitable vehicle for gelatin
rectal capsules; (iii) in the form of a ready-made micro enema; or
(iv) in the form of a dry micro enema formulation to be
reconstituted in a suitable solvent just prior to
administration.
[0409] Liquid preparations may be prepared in the form of syrups,
elixirs, concentrated drops or suspensions, e.g. solutions or
suspensions containing the active ingredients and the remainder
consisting, for example, of sugar or sugar alcohols and a mixture
of ethanol, water, glycerol, propylene glycol and polyethylene
glycol. If desired, such liquid preparations may contain coloring
agents, flavoring agents, preservatives, saccharine and
carboxymethyl cellulose or other thickening agents. Liquid
preparations may also be prepared in the form of a dry powder,
reconstituted with a suitable solvent prior to use. Solutions for
parenteral administration may be prepared as a solution of a
formulation of the invention in a pharmaceutically acceptable
solvent. These solutions may also contain stabilizing ingredients,
preservatives and/or buffering ingredients. Solutions for
parenteral administration may also be prepared as a dry
preparation, reconstituted with a suitable solvent before use.
[0410] Also provided according to the present invention are
formulations and `kits of parts` comprising one or more containers
filled with one or more of the ingredients of a pharmaceutical
composition of the invention, for use in medical therapy.
Associated with such container(s) can be various written materials
such as instructions for use, or a notice in the form prescribed by
a governmental agency regulating the manufacture, use or sale of
pharmaceuticals products, which notice reflects approval by the
agency of manufacture, use, or sale for human or veterinary
administration. The use of formulations of the invention in the
manufacture of medicaments for use in the treatment of a condition
in which activation of cannabinoid CB.sub.1 receptors is required
or desired, and methods of medical treatment or comprising the
administration of a therapeutically effective total amount of at
least one compound of formula (I), to a patient suffering from, or
susceptible to, a condition in which activation of cannabinoid
CB.sub.1 receptors is required or desired.
[0411] By way of example and not of limitation, several
pharmaceutical compositions are given, comprising exemplary active
compounds for systemic use or topical application. Other compounds
of the invention or combinations thereof, may be used in place of
(or in addition to) said compounds. The concentration of the active
ingredient may be varied over a wide range as discussed herein.
Amounts and types of ingredients that may be included are known in
the art.
BIBLIOGRAPHY
[0412] To the extent in which the following references are useful
to one skilled in the art, or to more fully describe this
invention, they are incorporated herein by reference. Neither
these, nor any other documents or quotes cited herein, nor
citations to any references, are admitted to be prior art documents
or citations. [0413] Akaji, K. et al., Tetrahedron Lett., 35,
3315-3318, 1994. [0414] Albericio, F., et al., Tetrahedron Lett.,
38, 4853-4856, 1997. [0415] Annan et al., J. Am. Chem. Soc. 1989,
111, 8895-8901 [0416] Bach et al., Tetrahedron, 1994, 50, 7543-7556
[0417] Barnes, M. P., Expert Opin. Pharmacother. 2006, 7, 607-615)
[0418] Berge, S. M.: "Pharmaceutical salts", J. Pharmaceutical
Science, 66, 1-19 (1977). [0419] Bickel, M. H., "The pharmacology
and Biochemistry of N-oxides", Pharmacological Reviews, 21(4),
325-355, 1969. [0420] Bodanszky, M. and A. Bodanszky: The Practice
of Peptide Synthesis, Springer-Verlag, New York, ISBN:
0-387-57505-7, 1994. [0421] Byrn et al., Pharmaceutical Research,
12(7), 945-954, 1995. [0422] Chem. Ber. 1965, 98, 1588-1597 [0423]
Cheng, Y. and Prusoff, W. H., Biochem. Pharmacol., 22, 3099-3108,
1973 [0424] Croxford, J. L., "Therapeutic potential of cannabinoids
in CNS disease", CNS Drugs, 17, 179-202, 2003. [0425] Croxford, J.
L. and Miller, S. D. "Towards cannabis and cannabinoid treatment of
multiple sclerosis", Drugs Today (Bare), 40, 663-676, 2004. [0426]
Drysdale, A. J. and Platt, B., "Cannabinoids: mechanisms and
therapeutic applications in the CNS", Curr. Med. Chem., 10,
2719-2732, 2003 [0427] Dwyer & Meilor: "Chelating agents and
Metal Chelates", Academic Press, chapter 7, 1964. [0428] Huffman et
al., Curr. Med. Chem., 6, 705-720, 1999.sup.a [0429] Huffman et
al., Bioorg. Med. Chem., 7, 2905-2914, 1999.sup.b [0430] Hurst, D.
P. et al., Mol. Pharmacol., 62, 1274-1287, 2002 [0431] Lange, J. H.
M. and Kruse, C. G. Drug Discov. Today, 10, 693-702, 2005 [0432]
Levin, J. I., Turos, E. and Weinreb, S. M., Synth Commun., 12,
989-993., 1982 [0433] Ligresti, A., et al., "Possible
endocannabinoid control of colorectal cancer growth",
Gastro-enterology, 125, 677-687, 2003. [0434] Martin, E. W.
(Editor), "Remington: The Science and Practice of Pharmacy", Mack
Publishing Company, 19.sup.th Edition, Easton, Pa, Vol 2., Chapter
83, 1447-1462, 1995. [0435] Montalbetti, C. A. G. N. & V.
Falque, Tetrahedron, 61, 10827-52. 2005. [0436] Pertwee, R. G.,
Life Sci., 76, 1307-1324, 2005 [0437] Reggio, P. H., Curr. Pharm.
Des., 9, 1607-1633, 2003 [0438] Rinaldi-Carmona et al., J.
Pharmacol. Exp. Ther., 284, 644-650, 1998 [0439] Shim, J., et al.,
J. Med. Chem., 45, 1447-1459, 2002. [0440] Smith, M. B. and March,
J., "Advanced organic chemistry, reactions, mechanisms and
structure", fifth edition, John Wiley & Sons, Inc., New York,
2001, p. 275. [0441] Smith, P. F., "Medicinal cannabis extracts for
the treatment of multiple sclerosis", Curr. Opin. Investig. Drugs,
5, 727-730, 2004 [0442] WO 2005/074920, WO 2005/077911 and WO
2007/009689
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