U.S. patent application number 11/334204 was filed with the patent office on 2006-07-20 for bicyclic heterocycles as cannabinoid receptor modulators.
Invention is credited to Bruce A. Ellsworth, William R. Ewing, Samuel Gerritz, Yanting Huang, Natesan Murugesan, Annapurna Pendri, Chongqing Sun.
Application Number | 20060160850 11/334204 |
Document ID | / |
Family ID | 36501927 |
Filed Date | 2006-07-20 |
United States Patent
Application |
20060160850 |
Kind Code |
A1 |
Sun; Chongqing ; et
al. |
July 20, 2006 |
Bicyclic heterocycles as cannabinoid receptor modulators
Abstract
The present application describes compounds according to Formula
I, pharmaceutical compositions comprising at least one compound
according to Formula I and optionally one or more additional
therapeutic agents and methods of treatment using the compounds
according to Formula I both alone and in combination with one or
more additional therapeutic agents. The compounds have the general
Formula I: ##STR1## including all prodrugs, pharmaceutically
acceptable salts and stereoisomers, R.sup.1, R.sup.2, R.sup.3, n,
and Z are described herein.
Inventors: |
Sun; Chongqing; (East
Windsor, NJ) ; Ewing; William R.; (Yardley, PA)
; Huang; Yanting; (Pennington, NJ) ; Pendri;
Annapurna; (Glastonbury, CT) ; Gerritz; Samuel;
(Guilford, CT) ; Ellsworth; Bruce A.; (Princeton,
NJ) ; Murugesan; Natesan; (Princeton Junction,
NJ) |
Correspondence
Address: |
LOUIS J. WILLE;BRISTOL-MYERS SQUIBB COMPANY
PATENT DEPARTMENT
P O BOX 4000
PRINCETON
NJ
08543-4000
US
|
Family ID: |
36501927 |
Appl. No.: |
11/334204 |
Filed: |
January 18, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60644644 |
Jan 18, 2005 |
|
|
|
Current U.S.
Class: |
514/313 ;
546/159 |
Current CPC
Class: |
C07D 401/04 20130101;
A61P 3/00 20180101; C07D 215/38 20130101; C07D 215/48 20130101;
C07D 401/12 20130101; C07D 417/06 20130101; C07D 405/12 20130101;
A61P 9/00 20180101 |
Class at
Publication: |
514/313 ;
546/159 |
International
Class: |
A61K 31/47 20060101
A61K031/47; C07D 215/38 20060101 C07D215/38; A61K 31/4709 20060101
A61K031/4709 |
Claims
1. A compound or a pharmaceutically acceptable salt or a
stereoisomer according to Formula I: ##STR124## wherein, Z is
selected from the group consisting of a direct bond, oxygen,
N(R.sup.4) and alkyl; R.sup.1 is selected from the group consisting
of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,
heteroaryl, arylalkyl, heteroarylalkyl, halo, CF.sub.3, CN; R.sup.2
is selected from the group consisting of cycloalkyl, aryl and
heteroaryl; R.sup.3 is selected from the group consisting of alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,
heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkoxy and
heteroarylalkyl; R.sup.4 is selected from the group consisting of
hydrogen, alkyl; wherein R.sub.3 and R.sub.4 may be taken together
to form a heterocyclyl; and n is an integer of 0 or 1.
2. The compound according to claim 1 wherein, n is 1.
3. The compound according to claim 2 wherein, R.sup.2 is selected
from the group consisting of aryl and heteroaryl.
4. The compound according to claim 3 wherein, R.sup.1 is selected
from the group consisting of aryl, heteroaryl, CF.sub.3 and CN.
5. The compound according to claim 4 wherein, R.sup.1 is aryl.
6. The compound according to claim 4 wherein, R.sup.1 is CN.
7. The compound according to claim 3 wherein, R.sup.3 is selected
from the group consisting of cycloalkyl, cycloalkylalkyl,
heterocyclyl and arylalkyl.
8. The compound according to claim 1 wherein the compound is
selected from the group consisting of: ##STR125## ##STR126##
##STR127##
9. A pharmaceutical composition, comprising: at least one compound
according to claim 1; and at least one pharmaceutically acceptable
diluent or carrier.
10. The pharmaceutical composition according to claim 9, further
comprising: at least one additional therapeutic agent.
11. A method for treating obesity, comprising administering to a
patient in need a therapeutically effective amount of a cannabinoid
receptor 1 (CB1) antagonist or inverse agonist according to claim
1.
12. A method for smoking cessation, comprising administering to a
patient in need a therapeutically effective amount of a cannabinoid
receptor 1 (CB1) antagonist or inverse agonist according to claim
1.
Description
RELATED APPLICATION
[0001] This application claims priority benefit under Title 35
.sctn. 119(e) of U.S. Provisional Application No. 60/644,644, filed
Jan. 18, 2005, the contents of which are herein incorporated by
reference.
BACKGROUND
[0002] Delta-9-tetrahydrocannabinol or Delta-9 THC, the principle
active component of Cannabis sativa (marijuana), is a member of a
large family of lipophilic compounds (i.e., cannabinoids) that
mediate physiological and psychotropic effects including regulation
of appetite, immunosuppression, analgesia, inflammation, emesis,
anti-nocioception, sedation, and intraocular pressure. Other
members of the cannabinoid family include the endogenous
(arachidonic acid-derived) ligands, anandamide, 2-arachidonyl
glycerol, and 2-arachidonyl glycerol ether. Cannabinoids work
through selective binding to and activation of G-protein coupled
cannabinoid receptors. Two types of cannabinoid receptors have been
cloned including CB-1 (L. A. Matsuda, et al., Nature, 346, 561-564
(1990)), and CB-2 (S. Munro, et al., Nature, 365, 61-65 (1993)).
The CB-1 receptor is highly expressed in the central and peripheral
nervous systems (M. Glass, et al., Neuroscience, 77, 299-318
(1997)), while the CB-2 receptor is highly expressed in immune
tissue, particularly in spleen and tonsils. The CB-2 receptor is
also expressed on other immune system cells, such as lymphoid cells
(S. Galiegue, et al., Eur J Biochem, 232, 54-61 (1995)). Agonist
activation of cannabinoid receptors results in inhibition of cAMP
accumulation, stimulation of MAP kinase activity, and closure of
calcium channels.
[0003] There exists substantial evidence that cannabinoids regulate
appetitive behavior. Stimulation of CB-1 activity by anandamide or
Delta-9 THC results in increased food intake and weight gain in
multiple species including humans (Williams and Kirkham,
Psychopharm., 143, 315-317 (1999)). Genetic knock-out of CB-1
result in mice that were hypophagic and lean relative to wild-type
litter mates (DiMarzo, et al., Nature, 410, 822-825 (2001)).
Published studies with CB-1 small molecule antagonists have
demonstrated decreased food intake and body weight in rats
(Trillou, et. al., Am. J. Physiol. Regul. Integr. Comp. Physiol.,
R345-R353, (2003)). Chronic administration of the CB-1 antagonist
AM-251 for two weeks resulted in substantial body weight reduction
and decreased adipose tissue mass (Hildebrandt, et. al., Eur. J.
Pharm, 462, 125-132 (2003)). There are multiple studies that have
assessed the anorexic effect of the Sanofi CB-1 antagonist,
SR-141716 (Rowland, et. al., Pyschopharm., 159, 111-116 (2001);
Colombo, et. al., Life Sci., 63, 113-117 (1998)). There are at
least two CB-1 antagonists in clinical trials for regulation of
appetite, Sanofi's SR-141716 and Solvay's SLV-319. Published Phase
IIb data reveal that SR-141716 dose-dependently reduced body weight
in human subjects over a 16 week trial period. CB-1 antagonists
have also been shown to promote cessation of smoking behavior.
Phase II clinical data on smoking cessation were presented in
September of 2002 at Sanofi-Synthelabo's Information meeting. This
data showed that 30.2% of patients treated with the highest dose of
SR-141716 stayed abstinent from cigarette smoke relative to 14.8%
for placebo.
DETAILED DESCRIPTION
[0004] The present application describes compounds according to
Formula I, pharmaceutical compositions comprising at least one
compound according to Formula I and optionally one or more
additional therapeutic agents and methods of treatment using the
compounds according to Formula I both alone and in combination with
one or more additional therapeutic agents. The compounds have the
general Formula I: ##STR2## including all prodrugs,
pharmaceutically acceptable salts and stereoisomers, R.sup.1,
R.sup.2, R.sup.3, n, and Z are described herein.
Definitions
[0005] The following definitions apply to the terms as used
throughout this specification, unless otherwise limited in specific
instances.
[0006] As used herein, the term "alkyl" denotes branched or
unbranched hydrocarbon chains containing 1 to 20 carbons,
preferably 1 to 12 carbons, and more preferably 1 to 8 carbons, in
the normal chain, such as, methyl, ethyl, propyl, isopropyl, butyl,
sec-butyl, iso-butyl, tert-butyl, pentyl, hexyl, isohexyl, heptyl,
4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl and the like.
Further, alkyl groups, as defined herein, may optionally be
substituted on any available carbon atom with one or more
functional groups commonly attached to such chains, such as, but
not limited to hydroxyl, halo, haloalkyl, mercapto or thio, cyano,
alkylthio, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl,
carbalkoyl, carboxamido, carbonyl, alkenyl, alkynyl, nitro, amino,
alkoxy, aryloxy, arylalkyloxy, heteroaryloxy, amido, --OPO.sub.3H,
--OSO.sub.3H, and the like to form alkyl groups such as
trifluoromethyl, 3-hydroxyhexyl, 2-carboxypropyl, 2-fluoroethyl,
carboxymethyl, cyanobutyl and the like.
[0007] Unless otherwise indicated, the term "alkenyl" as used
herein by itself or as part of another group refers to straight or
branched chains of 2 to 20 carbons, preferably 2 to 12 carbons, and
more preferably 2 to 8 carbons with one or more double bonds in the
normal chain, such as vinyl, 2-propenyl, 3-butenyl, 2-butenyl,
4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl,
3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl,
3-undecenyl, 4-dodecenyl, 4,8,12-tetradecatrienyl, and the like.
Further, alkenyl groups, as defined herein, may optionally be
substituted on any available carbon atom with one or more
functional groups commonly attached to such chains, such as, but
not limited to halo, haloalkyl, alkyl, alkoxy, alkynyl, aryl,
arylalkyl, cycloalkyl, amino, hydroxyl, heteroaryl,
cycloheteroalkyl, alkanoylamino, alkylamido, arylcarbonylamino,
nitro, cyano, thiol, alkylthio and/or any of the alkyl substituents
set out herein.
[0008] Unless otherwise indicated, the term "alkynyl" as used
herein by itself or as part of another group refers to straight or
branched chains of 2 to 20 carbons, preferably 2 to 12 carbons and
more preferably 2 to 8 carbons with one or more triple bonds in the
normal chain, such as 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl,
3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl,
4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl, 3-undecynyl,
4-dodecynyl and the like. Further, alkynyl groups, as defined
herein, may optionally be substituted on any available carbon atom
with one or more functional groups commonly attached to such
chains, such as, but not limited to halo, haloalkyl, alkyl, alkoxy,
alkenyl, aryl, arylalkyl, cycloalkyl, amino, hydroxyl, heteroaryl,
cycloheteroalkyl, alkanoylamino, alkylamido, arylcarbonylamino,
nitro, cyano, thiol, alkylthio and/or any of the alkyl substituents
set out herein
[0009] Unless otherwise indicated, the term "cycloalkyl" as
employed herein alone or as part of another group includes
saturated or partially unsaturated (containing one or more double
bonds) cyclic hydrocarbon groups containing 1 to 3 rings, appended
or fused, including monocyclicalkyl, bicyclicalkyl and
tricyclicalkyl, containing a total of 3 to 20 carbons forming the
rings, preferably 3 to 10 carbons, forming the ring and which may
be fused to 1 or 2 aromatic rings as described for aryl, which
include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, cyclohexenyl,
##STR3##
[0010] Further, any cycloalkyl may be optionally substituted
through any available carbon atoms with one or more groups selected
from hydrogen, halo, haloalkyl, alkyl, alkoxy, haloalkyloxy,
hydroxyl, alkenyl, alkynyl, aryl, aryloxy, heteroaryl,
heteroaryloxy, arylalkyl, heteroarylalkyl, alkylamido,
alkanoylamino, oxo, acyl, arylcarbonylamino, amino, nitro, cyano,
thiol and/or alkylthio and/or any of the alkyl substituents.
[0011] The term "cycloalkylalkyl" as used herein alone or as part
of another group refers to alkyl groups as defined above having a
cycloalkyl substituent, wherein said "cycloalkyl" and/or "alkyl"
groups may optionally be substituted as defined above.
[0012] Unless otherwise indicated, the term "aryl" as employed
herein alone or as part of another group refers to monocyclic and
bicyclic aromatic groups containing 6 to 10 carbons in the ring
portion (such as phenyl or naphthyl including 1-naphthyl and
2-naphthyl) and may optionally include one to three additional
rings fused to a carbocyclic ring or a heterocyclic ring, for
example ##STR4##
[0013] Further, "aryl", as defined herein, may optionally be
substituted with one or more functional groups, such as halo,
alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl,
cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, heteroaryl,
arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, alkoxycarbonyl,
arylcarbonyl, arylalkenyl, aminocarbonylaryl, arylthio,
arylsulfinyl, arylazo, heteroarylalkyl, heteroarylalkenyl,
heteroarylheteroaryl, heteroaryloxy, hydroxyl, nitro, cyano, amino,
substituted amino wherein the amino includes 1 or 2 substituents
(which are alkyl, aryl or any of the other aryl compounds mentioned
in the definitions), thiol, alkylthio, arylthio, heteroarylthio,
arylthioalkyl, alkoxyarylthio, alkylcarbonyl, arylcarbonyl,
alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl,
aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy,
alkylcarbonylamino, arylcarbonylamino, arylsulfinyl,
arylsulfinylalkyl, arylsulfonylamino or arylsulfonaminocarbonyl
and/or any of the alkyl substituents set out herein.
[0014] Unless otherwise indicated, the term "heteroaryl" as used
herein alone or as part of another group refers to a 5- or
6-membered aromatic ring which includes 1, 2, 3 or 4 hetero atoms
such as nitrogen, oxygen or sulfur. Such rings may be fused to an
aryl, cycloalkyl, heteroaryl or heterocyclyl and include possible
N-oxides as described in Katritzky, A. R. and Rees, C. W., eds.
Comprehensive Heterocyclic Chemistry: The Structure, Reactions,
Synthesis and Uses of Heterocyclic Compounds 1984, Pergamon Press,
New York, N.Y.; and Katritzky, A. R., Rees, C. W., Scriven, E. F.,
eds. Comprehensive Heterocyclic Chemistry II: A Review of the
Literature 1982-1995 1996, Elsevier Science, Inc., Tarrytown, N.Y.;
and references therein. Further, "heteroaryl", as defined herein,
may optionally be substituted with one or more substituents such as
the substituents included above in the definition of "substituted
alkyl" and "substituted aryl". Examples of heteroaryl groups
include the following: ##STR5## and the like.
[0015] The term "heteroarylalkyl" as used herein alone or as part
of another group refers to alkyl groups as defined above having a
heteroaryl substituent, wherein said heteroaryl and/or alkyl groups
may optionally be substituted as defined above.
[0016] The term "heterocyclo", "heterocycle", "heterocyclyl" or
"heterocyclic ring", as used herein, represents an unsubstituted or
substituted stable 4 to 7-membered monocyclic ring system which may
be saturated or unsaturated, and which consists of carbon atoms,
with one to four heteroatoms selected from nitrogen, oxygen or
sulfur, and wherein the nitrogen and sulfur heteroatoms may
optionally be oxidized, and the nitrogen heteroatom may optionally
be quaternized. The heterocyclic ring may be attached at any
heteroatom or carbon atom which results in the creation of a stable
structure. Examples of such heterocyclic groups include, but is not
limited to, piperidinyl, piperazinyl, oxopiperazinyl,
oxopiperidinyl, oxopyrrolidinyl, oxoazepinyl, azepinyl, pyrrolyl,
pyrrolidinyl, furanyl, thienyl, pyrazolyl, pyrazolidinyl,
imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl,
pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isooxazolyl,
isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl,
isothiazolyl, thiadiazolyl, tetrahydropyranyl, thiamorpholinyl,
thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, oxadiazolyl and
other heterocycles described in Katritzky, A. R. and Rees, C. W.,
eds. Comprehensive Heterocyclic Chemistry: The Structure,
Reactions, Synthesis and Uses of Heterocyclic Compounds 1984,
Pergamon Press, New York, N.Y.; and Katritzky, A. R., Rees, C. W.,
Scriven, E. F., eds. Comprehensive Heterocyclic Chemistry II: A
Review of the Literature 1982-1995 1996, Elsevier Science, Inc.,
Tarrytown, N.Y.; and references therein.
[0017] The term "heterocycloalkyl" as used herein alone or as part
of another group refers to alkyl groups as defined above having a
heterocyclyl substituent, wherein said heterocyclyl and/or alkyl
groups may optionally be substituted as defined above.
[0018] The terms "arylalkyl", "arylalkenyl" and "arylalkynyl" as
used alone or as part of another group refer to alkyl, alkenyl and
alkynyl groups as described above having an aryl substituent.
Representative examples of arylalkyl include, but are not limited
to, benzyl, 2-phenylethyl, 3-phenylpropyl, phenethyl, benzhydryl
and naphthylmethyl and the like.
[0019] The term "alkoxy", "aryloxy", "heteroaryloxy"
"arylalkyloxy", or "heteroarylalkyloxy" as employed herein alone or
as part of another group includes an alkyl or aryl group as defined
above linked through an oxygen atom.
[0020] The term "halogen" or "halo" as used herein alone or as part
of another group refers to chlorine, bromine, fluorine, and iodine,
with bromine, chlorine or fluorine being preferred.
[0021] The term "cyano," as used herein, refers to a --CN
group.
[0022] The term "methylene," as used herein, refers to a
--CH.sub.2-- group.
[0023] The term "nitro," as used herein, refers to a --NO.sub.2
group.
[0024] The compounds of formula I can be present as salts, which
are also within the scope of this invention. Pharmaceutically
acceptable (i.e., non-toxic, physiologically acceptable) salts are
preferred. If the compounds of formula I have, for example, at
least one basic center, they can form acid addition salts. These
are formed, for example, with strong inorganic acids, such as
mineral acids, for example sulfuric acid, phosphoric acid or a
hydrohalic acid, with organic carboxylic acids, such as
alkanecarboxylic acids of 1 to 4 carbon atoms, for example acetic
acid, which are unsubstituted or substituted, for example, by
halogen as chloroacetic acid, such as saturated or unsaturated
dicarboxylic acids, for example oxalic, malonic, succinic, maleic,
fumaric, phthalic or terephthalic acid, such as hydroxycarboxylic
acids, for example ascorbic, glycolic, lactic, malic, tartaric or
citric acid, such as amino acids, (for example aspartic or glutamic
acid or lysine or arginine), or benzoic acid, or with organic
sulfonic acids, such as (C.sub.1-C.sub.4) alkyl or arylsulfonic
acids which are unsubstituted or substituted, for example by
halogen, for example methyl- or p-toluene-sulfonic acid.
Corresponding acid addition salts can also be formed having, if
desired, an additionally present basic center. The compounds of
formula I having at least one acid group (for example COOH) can
also form salts with bases. Suitable salts with bases are, for
example, metal salts, such as alkali metal or alkaline earth metal
salts, for example sodium, potassium or magnesium salts, or salts
with ammonia or an organic amine, such as morpholine,
thiomorpholine, piperidine, pyrrolidine, a mono, di or tri-lower
alkylamine, for example ethyl, tert-butyl, diethyl, diisopropyl,
triethyl, tributyl or dimethyl-propylamine, or a mono, di or
trihydroxy lower alkylamine, for example mono, di or
triethanolamine. Corresponding internal salts may furthermore be
formed. Salts which are unsuitable for pharmaceutical uses but
which can be employed, for example, for the isolation or
purification of free compounds of formula I or their
pharmaceutically acceptable salts, are also included.
[0025] Preferred salts of the compounds of formula I which contain
a basic group include monohydrochloride, hydrogensulfate,
methanesulfonate, phosphate, nitrate or acetate.
[0026] Preferred salts of the compounds of formula I which contain
an acid group include sodium, potassium and magnesium salts and
pharmaceutically acceptable organic amines.
[0027] The term "modulator" refers to a chemical compound with
capacity to either enhance (e.g., "agonist" activity) or partially
enhance (e.g., "partial agonist" activity) or inhibit (e.g.,
"antagonist" activity or "inverse agonist" activity) a functional
property of biological activity or process (e.g., enzyme activity
or receptor binding); such enhancement or inhibition may be
contingent on the occurrence of a specific event, such as
activation of a signal transduction pathway, and/or may be manifest
only in particular cell types.
[0028] The term "bioactive metabolite" as employed herein refers to
any functional group contained in a compound of formula I with an
open valence for further substitution wherein such substitution
can, upon biotransformation, generate a compound of formula I.
Examples of such functional groups of bioactive metabolites
include, but are not limited to, --OH, --NH or functional groups
wherein the hydrogen can be replaced with a functional group such
as --PO.sub.3H.sub.2 for example, which, upon biotransformation
generates an --OH or --NH functional group of a compound of formula
I.
[0029] The term "prodrug esters" as employed herein includes esters
and carbonates formed by reacting one or more hydroxyls of
compounds of formula I with alkyl, alkoxy, or aryl substituted
acylating agents employing procedures known to those skilled in the
art to generate acetates, pivalates, methylcarbonates, benzoates
and the like. Prodrug esters may also include--but are not limited
to groups such as phosphate esters, phosphonate esters,
phosphonamidate esters, sulfate esters, sulfonate esters, and
sulfonamidate esters wherein the ester may be further substituted
with groups that confer a pharmaceutical advantage such as-but not
limited to-favorable aqueous solubility or in vivo exposure to the
bioactive component formula I.
[0030] The term "prodrug" as employed herein includes
functionalization of bioactive amine- or hydroxyl-containing
compounds of formula I to form alkyl-, acyl-, sulfonyl-,
phosphoryl-, or carbohydrate-substituted derivatives. Such
derivatives are formed by reacting compounds of formula I with
alkylating-, acylating-, sulfonylating-, or phosphorylating
reagents employing procedures known to those skilled in the art.
Alkylation of amines of formula I may result in--but are not
limited to--derivatives that include spacer units to other prodrug
moieties such as substituted alkyoxymethyl-, acyloxymethyl-,
phosphoryloxymethyl-, or sulfonyloxymethyl-groups. Alkylation of
amines of formula I may result in the generation of quarternary
amine salts that act in vivo to provide the bioactive agent (i.e.,
the compound of formula I).
[0031] Preferred prodrugs consist of a compound of formula I where
a pendant hydroxyl is phosphorylated to generate a phosphate
derivative. Such a prodrug may also include a spacer group between
the compound of formula I and the phosphate group, such as a
methyleneoxy-group. Methods to generate such a prodrug from a
compound of formula I are known to those skilled in the art, and
are listed in the references below.
[0032] Preferred prodrugs also consist of a compound of formula I
where a pendant amine, such as a pyridine group, is alkylated with
a group, such as methyl, to form a quarternary ammonium ion salt.
Methods to generate such a prodrug from a compound of formula I are
known to those skilled in the art, and are listed in the references
below.
[0033] Any compound that can be converted in vivo to provide the
bioactive agent (i.e., the compound of formula 1) is a prodrug
within the scope and spirit of the invention.
[0034] Various forms of prodrugs are well known in the art. A
comprehensive description of prodrugs and prodrug derivatives are
described in:
[0035] a) The Practice of Medicinal Chemistry, Camille G. Wermuth
et al., Ch 31, (Academic Press, 1996);
[0036] b) Design of Prodrugs, edited by H. Bundgaard, (Elsevier,
1985);
[0037] c) A Textbook of Drug Design and Development, P.
Krogsgaard-Larson and H. Bundgaard, eds. Ch 5, pgs 113-191 (Harwood
Academic Publishers, 1991);
[0038] d) Hydrolysis in Drug and Prodrug Metabolism, B. Testa and
J. M. Mayer, (Verlag Helvetica Chimica Acta AG, Zurich,
Switzerland; Wiley-VCH, Weinheim, Federal Republic of Germany,
2003);
[0039] e) Ettmayer, P.; Amidon, G. L.; Clement, B.; Testa, B.
"Lessons Learned from Marketed and Investigational Prodrugs" J.
Med. Chem. 2004, 47 (10), 2393-2404; and
[0040] f) Davidsen, S. K. et al. "N-(Acyloxyalkyl)pyridinium Salts
as Soluble Prodrugs of a Potent Platelet Activating Factor
Antagonist" J. Med. Chem. 1994, 37 (26), 4423-4429.
Said references are incorporated herein by reference.
[0041] An administration of a therapeutic agent of the invention
includes administration of a therapeutically effective amount of
the agent of the invention. The term "therapeutically effective
amount" as used herein refers to an amount of a therapeutic agent
to treat or prevent a condition treatable by administration of a
composition of the invention. That amount is the amount sufficient
to exhibit a detectable therapeutic or preventative or ameliorative
effect. The effect may include, for example, treatment or
prevention of 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, and the therapeutics or
combination of therapeutics selected for administration.
[0042] All stereoisomers of the compounds of the instant invention
are contemplated, either in mixture or in pure or substantially
pure form. The compounds of the present invention can have
asymmetric centers at any of the carbon atoms including any one of
the R substituents. Consequently, compounds of formula I can exist
in enantiomeric or diastereomeric forms or in mixtures thereof. The
processes for preparation can utilize racemates, enantiomers or
diastereomers as starting materials. When racemic or diastereomeric
products are prepared, they can be separated by conventional
methods for example, chromatographic techniques, chiral HPLC or
fractional crystallization.
[0043] The compounds of formula I of the invention can be prepared
as shown in the following reaction schemes and description thereof,
as well as relevant published literature procedures that may be
used by one skilled in the art. Exemplary reagents and procedures
for these reactions appear hereinafter and in the working
Examples.
Abbreviations
[0044] The following abbreviations are employed in the Schemes,
Examples and elsewhere herein:
AcOH=acetic acid
Boc=tert-butoxycarbonyl
Cbz=benzyloxycarbonyl
DCE=1,2-dichloroethane
DIPEA=N,N-diisopropylehtylamine
DMF=N,N-dimethylformamide
EDAC=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride
EtOAc=ethyl acetate
Et.sub.3N=triethylamine
Et.sub.2O=diethyl ether
HOBt=1-hydroxybenzotriazole hydrate
HPLC or LC=high performance liquid chromatography
LAH=lithium aluminum hydride
MeOH=methanol
MS or Mass Spec=mass spectrometry
NaCl=sodium chloride
NaHCO.sub.3=sodium bicarbonate
NaBH(OAc).sub.3=sodium triacetoxyborohydride
Na.sub.2SO.sub.4=sodium sulfate
NaOH=sodium hydroxide
NMM=4-methylmorpholine
OTf=trifluoromethanesulfonyl
PG=protecting group
PXPd=dichloro-bis(chloro-di-tert-butylphosphine)palladium
RT=room temperature
TFA=trifluoroacetic acid
THF=tetrahydrofuran
min=minute(s)
h=hour(s)
L=liter
mL=milliliter
.mu.L=microliter
g=gram(s)
mg=milligram(s)
mol=moles
mmol=millimole(s)
nM=nanomolar
[0045] Compounds of the present invention may be prepared by
procedures illustrated in the accompanying schemes.
Methods of Preparation
[0046] The compounds of the present invention may be prepared by
methods such as those illustrated in the following Scheme 1 to 6.
Solvents, temperatures, pressures, and other reaction conditions
may readily be selected by one of ordinary skill in the art.
Starting materials are commercially available or can be readily
prepared by one of ordinary skill in the art using known methods.
For all of the schemes and compounds described below, R.sup.1,
R.sup.2, R.sup.3, n, and Z are as described for a compound of
formula I. ##STR6##
[0047] As illustrated in Scheme 1, the amino group of compound II
can be suitably protected by, for example, a tert-butyloxycarbonyl,
or an acyl group as shown in III. Compound II can be obtained
commercially, or can be readily prepared by one skilled in the art.
Reduction of III via catalytic hydrogenation in the presence of a
transition metal catalyst, such as platinum oxide, or palladium
hydroxide on carbon provides intermediate IV. ##STR7##
[0048] As illustrated in Scheme 2, compound V can be reduced via
catalytic hydrogenation in the presence of a transition metal
catalyst, such as platinum oxide, or palladium hydroxide on carbon
to provide intermediate VI, which can be hydrolyzed to provide acid
VII. Conversion of the carboxylic acid of VII via Curtius
rearrangement reaction affords IV as either free or protected
amine. Compound V can be obtained commercially, or can be readily
prepared by one skilled in the art. ##STR8##
[0049] As illustrated in Scheme 3, reduction of
o-nitrophenylalanine derivative VIII via hydrogenation in the
presence of a palladium catalyst in an alcoholic solvent, e.g.
MeOH, affords lactam IX. Compound VIII in either a racemic or a
homochiral form can be obtained commercially, or can be prepared by
methods known in the literature, or can be readily prepared by one
skilled in the art. Compounds of formula X can be prepared by
reaction of IX with an alkylhalide in the presence of a base, e.g.
cesium carbonate, or an arylhalide in the presence of a transition
metal catalyst (e.g., palladium or copper). Compounds of formula XI
can be prepared by treating compound X with a reducing reagent
(e.g., borane/THF complex or LAH/THF). Treatment of XI with a
bromination reagent (e.g., benzyltrimethylammonium tribromide) or a
chlorination reagent (e.g., benzyltrimethylammonium dichloroiodate)
in the presence of a base (e.g., calcium carbonate) provides
compound XIV (Z=Br or Cl). Alternatively, treatment of intermediate
IX with an appropriate bromination reagent or a chlorination
reagent, such as the reagents mentioned above provides compound
XII. Compounds of formula XIV can be prepared from XII following
alkylation and reduction conditions analogous to those described
for preparation of X and XI. ##STR9##
[0050] As illustrated in Scheme 4, compounds of formula XV can be
prepared by reductive amination of intermediate IV with an aldehyde
in the presence of a reducing reagent (e.g., triethylsilane and
trifluoroacetic acid, or sodium triacetoxyborohydride) or with an
arylhalide in the presence of a transition metal catalyst (e.g.,
palladium or copper). Compounds of formula XVI can be prepared by
removing the N-protection group (PG) under acidic (e.g., TFA for
Boc-), basic (e.g. NaOH for amide), catalytic hydrogenation (for
Cbz-) conditions. Compounds of formula I can be prepared by
reacting amine XVI with an acylating reagent (e.g., acyl chloride,
or a carboxylic acid for formation of amide), or a chloroformate
(for formation of a carbamate), or an isocyanate (for formation of
a urea). ##STR10##
[0051] Alternatively, compounds of formula I can be prepared as
shown in Scheme 5. Compounds of formula XVII can be prepared by
removing the N-protection group (PG) in compound IV under acidic
(e.g., TFA for Boc-), basic (e.g. NaOH for amide), catalytic
hydrogenation (for Cbz-) conditions. Compounds of formula XVIII can
be prepared by reacting amine XVII with an acylating reagent (e.g.,
acyl chloride, or a carboxylic acid for formation of amide), or a
chloroformate (for formation of a carbamate), or an isocyanate (for
formation of a urea). Compounds of formula I can be prepared by
reductive amination of intermediate XVIII with an aldehyde in the
presence of a reducing reagent (e.g., triethylsilane and
trifluoroacetic acid, or sodium triacetoxyborohydride) or with an
arylhalide in the presence of a transition metal catalyst (e.g.,
palladium or copper). ##STR11##
[0052] As illustrated in Scheme 6, compounds of formula I can be
prepared via C--C bond formation by reacting intermediate XIX
(where L is a leaving group, such as Br, I or sulfonate) with an
activated R.sup.1, such as an aryl or heteroaryl boronic acid, or
an aryl or heteroaryl tin reagent in the presence of a palladium
catalyst (e.g., Pd(PPh.sub.3).sub.4). Compounds of formula I can
also be prepared via C--N bond formation by treatment of
intermediate XIX with a heterocyclic (e.g. a lactam, pyridone,
imidazole or pyrizole) in the presence of a copper catalyst.
Compounds of formula Ia can be prepared by treatment of
intermediate XIX with zinc cyanide in the presence of a palladium
catalyst, e.g. Pd(Ph.sub.3P).sub.4.
EXAMPLES
[0053] The following examples serve to better illustrate, but not
limit, some of the preferred embodiments of the invention.
Analytical HPLC and HPLC/MS Methods Employed in Characterization of
Examples.
[0054] Analytical HPLC was performed on Shimadzu LC10AS liquid
chromatographs.
[0055] Analytical HPLC/MS was performed on Shimadzu LC10AS liquid
chromatographs and Waters ZMD Mass Spectrometers using the
following methods:
Method A. Linear Gradient of 0 to 100% Solvent B Over 4 min, with 1
min Hold at 100% B
[0056] UV visualization at 220 nm
[0057] Column: Phenomenex Luna C18 4.6.times.50 mm
[0058] Flow rate: 4 ml/min
Solvent A: 0.1% trifluoroacetic acid, 90% water, 10% methanol
Solvent B: 0.1% trifluoroacetic acid, 90% methanol, 10% water
Method B. Linear Gradient of 0 to 100% Solvent B Over 8 min, with 3
min Hold at 100% B
[0059] UV visualization at 220 nm
[0060] Column: Phenomenex Luna C18 4.6.times.75 mm or Zorbax SB C18
4.6.times.75 mm
[0061] Flow rate: 2.5 ml/min
Solvent A: 0.2% phosphoric acid, 90% water, 10% methanol
Solvent B: 0.2% phosphoric acid, 90% methanol, 10% water
Method C. Linear Gradient of 10 to 100% Solvent B Over 2.50 min,
with 0.5 min Hold at 100% B
[0062] UV visualization at 220 nm
[0063] Column: Xterra MS-C18, 2.1.times.50 mm
[0064] Flow rate: 1.0 ml/min
Solvent A: 0.1% trifluoroacetic acid, 100% water
Solvent B: 0.1% trifluoroacetic acid, 100% acetonitrile
NMR Employed in Characterization of Examples.
[0065] .sup.1H NMR spectra were obtained with Bruker or JOEL
fourier transform spectrometers operating at the following
frequencies: .sup.1H NMR: 400 MHz (Bruker), or 400 MHz (JOEL);
.sup.13C NMR: 100 MHz (Bruker), or 100 MHz (JOEL). Spectra data are
reported as Chemical shift (multiplicity, number of hydrogens,
coupling constants in Hz) and are reported in ppm (.delta. units)
relative to either an internal standard (tetramethylsilane=0 ppm)
for .sup.1H NMR spectra, or are referenced to the residual solvent
peak (2.49 ppm for CD.sub.2HSOCD.sub.3, 3.30 ppm for CD.sub.2HOD,
7.24 ppm for CHCl.sub.3, 39.7 ppm for CD.sub.3SOCD.sub.3, 49.0 ppm
for CD.sub.3OD, 77.0 ppm for CDCl.sub.3). All .sup.13C NMR spectra
were proton decoupled.
Example 1
(S)-3-Amino-1,2,3,4-tetrahydroquinoline-6-carbonitrile
[0066] ##STR12##
1A. tert-Butyl 1,2,3,4-tetrahydroquinolin-3-yl-carbamate
[0067] ##STR13##
[0068] To a solution of 3-aminoquinoline (4.32 g, 30 mmol) in
anhydrous THF (100 mL) under argon at RT was added dropwise sodium
bis(trimethylsilyl)amide (1 M solution in THF, 63 mL, 63 mmol). The
resulting dark brown mixture was treated with di-tert-butyl
dicarbonate (7.2 g, 33 mmol). After stirring at RT for 2 h, the
reaction was quenched with water (30 mL), and 1N aqueous HCl (45
mL). The aqueous layer was separated and extracted with EtOAc
(2.times.70 mL). The combined organics were washed with saturated
aqueous NaCl, dried (Na.sub.2SO.sub.4) and concentrated. The
residue was chromatographed (silica gel) eluting with EtOAc (0 to
50%) in hexanes to give 3-quinolinylcarbamic acid,
1,1-dimethylethyl ester (6.5 g, 89% yield) as an off-white
solid.
[0069] To a solution of 3-quinolinylcarbamic acid,
1,1-dimethylethyl ester (6.0 g, 24.56 mmol) in MeOH (150 mL) was
added acetic acid (18 mL). The mixture was bubbled with argon for
15 min, then palladium hydroxide (20 weight % palladium on carbon)
(1.2 g) was added. The resulting suspension was subjected to
hydrogenation under 45 psi of pressure for 16 h, then filtered. The
filtrate was concentrated and the residue taken in
CH.sub.2Cl.sub.2. The resulting CH.sub.2Cl.sub.2 solution was
washed with saturated aqueous NaHCO.sub.3, saturated aqueous NaCl,
dried (Na.sub.2SO.sub.4) and concentrated. The residue was
chromatographed (silica gel) eluting with EtOAc (0 to 50%) in
hexanes to give 1A (4.6 g, 75% yield) as a white solid.
1B. (6-Bromo-1,2,3,4-tetrahydroquinolin-3-yl)-carbamic acid
tert-butyl ester
[0070] ##STR14##
[0071] To a solution of tert-butyl
1,2,3,4-tetrahydroquinolin-3-yl-carbamate (2.7 g, 10.9 mmol),
prepared as described in Example 1A, in THF (50 mL) at RT was added
dropwise a solution of pyridinium tribromide (3.83 g, 0.41 mmol) in
THF (50 mL). After addition, the reaction mixture was stirred for
15 min, then water (60 mL) and ether (60 mL) added. The aqueous
layer was separated, and extracted with EtOAc (2.times.50 mL). The
combined organics were washed with saturated aqueous NaCl, dried
(Na.sub.2SO.sub.4) and concentrated. The residue was
chromatographed (silica gel) eluting with EtOAc (0 to 50%) in
hexanes to give the title compound (2.5 g, 70% yield) as a white
solid.
1C. (6-Cyano-1,2,3,4-tetrahydroquinolin-3-yl)-carbamic acid
tert-butyl ester
[0072] ##STR15##
[0073] A solution of
(6-bromo-1,2,3,4-tetrahydroquinolin-3-yl)-carbamic acid tert-butyl
ester (250 mg, 0.76 mmol), prepared as described in Example 1B, and
zinc cyanide (88 mg, 0.75 mmol) in DMF (2.5 mL) was bubbled with
argon for 10 min, then tetrakis-(triphenylphosphine) palladium(0)
(65 mg, 0.057 mmol) was added and the solution was deoxygenated.
The reaction mixture was then heated at 90.degree. C. for 4 h,
cooled to RT, and partitioned between EtOAc and water. The aqueous
layer was separated and extracted with EtOAc (2.times.20 mL). The
combined EtOAc extracts were washed with saturated aqueous NaCl,
dried (Na.sub.2SO.sub.4) and concentrated. The residue was
chromatographed (silica gel) eluting with EtOAc (0 to 60%) in
hexanes to give the title compound (140 mg, 67% yield) as a white
solid.
1D. 3-Amino-1,2,3,4-tetrahydroquinoline-6-carbonitrile,
dihydrochloride
[0074] ##STR16##
[0075] To a solution of
(6-cyano-1,2,3,4-tetrahydroquinolin-3-yl)-carbamic acid tert-butyl
ester (546 mg, 2 mmol), prepared as described in Example 1C, in
CH.sub.2Cl.sub.2 (5 mL) at 0.degree. C. was added 4 M HCl in
dioxane (4 mL, 16 mmol). After addition, the reaction mixture was
stirred at RT for 2 h, then concentrated. The residue was stripped
with ether (3.times.), and the resulting off-white solid dried in
vacuo to afford the title compound (490 mg, 100%).
1E.
(S)-N-((S)-6-Cyano-1,2,3,4-tetrahydroquinolin-3-yl)-2-hydroxy-2-phenyl-
acetamide
[0076] ##STR17##
[0077] To a solution of
3-amino-1,2,3,4-tetrahydroquinoline-6-carbonitrile, dihydrochloride
(10.03 g, 40.7 mmol), prepared as described in Example 1D, in DMF
(100 mL) was added (S)-(+)-mandelic acid (7.45 g, 48.9 mmol),
followed by EDAC (9.37 g, 48.9 mmol), HOBt (7.49 g, 48.9 mmol) and
NMM (16.1 mL, 146.1 mmol). The reaction mixture was stirred at RT
overnight, then diluted with EtOAc (200 mL), washed with water (50
mL.times.3), 1N aqueous HCl (50 mL), water (50 mL) and saturated
aqueous NaCl, dried (Na.sub.2SO.sub.4) and concentrated. The
residue was chromatographed (silica gel) eluting with EtOAc/hexanes
(2:1 ratio), and the purified compound crystallized from acetone
three times to give the title compound as the (S, S)
diastereoisomer (2.54 g, 20% yield).
1F. (S)-3-Amino-1,2,3,4-tetrahydroquinoline-6-carbonitrile
[0078] ##STR18##
[0079] To a solution of
(S)-N-((S)-6-cyano-1,2,3,4-tetrahydroquinolin-3-yl)-2-hydroxy-2-phenylace-
tamide (2.5 g, 8.14 mmol), prepared as described in Example 1E, in
EtOH (25 mL) was added 15% aqueous sulfuric acid (25 mL). The
resulting mixture was refluxed overnight, then cooled to RT. After
removal of most of the EtOH, the mixture was diluted with water
(200 mL), extracted with CH.sub.2Cl.sub.2 (3.times.50 mL). The
aqueous layer was basified with 4N NaOH to pH=10, then extracted
with CH.sub.2Cl.sub.2 (3.times.50 mL). The combined organics were
washed with saturated aqueous NaCl, dried (Na.sub.2SO.sub.4) and
concentrated. The residue was crystallized from EtOAc/hexanes to
afford the title compound (1.026 g, 73% yield). LC/MS (method A):
retention time=0.95 min, (M+H).sup.+=174.
Example 2
(R)-3-Amino-1,2,3,4-tetrahydroquinoline-6-carbonitrile
[0080] ##STR19##
2A.
(S)-N-((R)-6-Cyano-1,2,3,4-tetrahydroquinolin-3-yl)-2-hydroxy-2-phenyl-
acetamide
[0081] ##STR20##
[0082] The title compound
(S)-N-((R)-6-cyano-1,2,3,4-tetrahydroquinolin-3-yl)-2-hydroxy-2-phenylace-
tamide was isolated as the other (S, R) diastereomer as described
in Example 1E.
2B. (R)-3-Amino-1,2,3,4-tetrahydroquinoline-6-carbonitrile
[0083] ##STR21##
[0084] The title compound was prepared from the
(S)-N-((R)-6-cyano-1,2,3,4-tetrahydroquinolin-3-yl)-2-hydroxy-2-phenylace-
tamide, prepared as described in Example 2A, by procedures
analogous to those described in Example 1F. LC/MS (method A):
retention time=0.95 min, (M+H).sup.+=174.
Example 3
(S)-N-[1-(3-Chlorobenzyl)-6-cyano-1,2,3,4-tetrahydroquinolin-3-yl]-2-cyclo-
hexyl-acetamide
[0085] ##STR22##
3A.
N-[1-(3-Chlorobenzyl)-6-cyano-1,2,3,4-tetrahydroquinolin-3-yl]-carbami-
c acid tert-butyl ester
[0086] ##STR23##
[0087] To a solution of
(6-cyano-1,2,3,4-tetrahydroquinolin-3-yl)-carbamic acid tert-butyl
ester (820 mg, 3 mmol), prepared as described in Example 1C, and
3-chloro benzaldehyde (0.34 mL, 3 mmol) in DCE (10 mL) was added
NaBH(OAc).sub.3 (1.78 g, 8.4 mmol), followed by acetic acid (0.34
mL, 6 mmol). The reaction was stirred at RT for 16 h, then quenched
with saturated aqueous NaHCO.sub.3, extracted with CH.sub.2Cl.sub.2
(30 mL.times.3). The organic extracts were washed with water,
saturated aqueous NaCl, dried (Na.sub.2SO.sub.4), and concentrated.
The resulting residue was chromatographed (silica gel) eluting with
EtOAc (10-50%) in hexanes to give the title compound (571 mg, 48%)
as a foam.
3B.
N-1-(3-Chlorobenzyl)-6-cyano-1,2,3,4-tetrahydroquinolin-3-yl)amine,
trifluoroacetic acid salt
[0088] ##STR24##
[0089] The solution of
N-[1-(3-chlorobenzyl)-6-cyano-1,2,3,4-tetrahydroquinolin-3-yl]-carbamic
acid tert-butyl ester (410 mg, 1.03 mmol), prepared as described in
Example 3A, in CH.sub.2Cl.sub.2 (2 mL)-TFA (2 mL) was stirred at RT
for 2 h, and then concentrated. The resulting residue was stripped
with toluene (5 ml.times.2) and dried in vacuum to give the title
compound (420 mg, 100%) as an oil.
3C.
N-[1-(3-Chlorobenzyl)-6-cyano-1,2,3,4-tetrahydroquinolin-3-yl]-2-cyclo-
hexyl-acetamide
[0090] ##STR25##
[0091] To a solution of
N-1-(3-chlorobenzyl)-6-cyano-1,2,3,4-tetrahydroquinolin-3-yl)amine,
trifluoroacetic acid salt (126 mg, 0.3 mmol), prepared as described
in Example 3B, cyclohexyl acetic acid (51.2 mg, 0.36 mmol), EDAC
(69 mg, 0.36 mmol) and HOBt (46 mg, 0.3 mmol) in DMF (2 mL) was
added NMM (0.13 mL, 1.2 mmol). The reaction was stirred at RT for
16 h, then diluted with H.sub.2O, extracted with EtOAc (20
mL.times.3). The organic extracts were washed with water, saturated
aqueous NaCl, dried (Na.sub.2SO.sub.4), and concentrated. The
resulting residue was chromatographed (silica gel) eluting with
EtOAc (0-25%) in hexanes to give the title compound (70 mg, 55%) as
a white solid. HPLC (method B): retention time=7.7 min, MS (ES):
m/z 422 [M+H].sup.+.
3D.
(R)-N-[1-(3-Chlorobenzyl)-6-cyano-1,2,3,4-tetrahydroquinolin-3-yl]-2-c-
yclohexyl-acetamide
[0092] ##STR26##
[0093] The title compound was separated from racemic
N-[1-(3-chlorobenzyl)-6-cyano-1,2,3,4-tetrahydroquinolin-3-yl]-2-cyclohex-
ylacetamide, prepared as described in Example 3C using chiral
preparative HPLC (Conditions: Chiralpak AD, 5 cm.times.50 cm;
eluted with 20% isopropanol in hexanes at 40 mL/min) as R-isomer.
HPLC (method B): retention time=7.7 min, MS (ES): m/z 422
[M+H].sup.+. Chiral HPLC: 100% e.e.; retention time=9.4 min;
Conditions: AD (4.6.times.250 mm); Eluted with 20% isopropanol in
hexanes for 30 min at 1 mL/min.
3E.
(S)-N-[1-(3-Chlorobenzyl)-6-cyano-1,2,3,4-tetrahydroquinolin-3-yl]-2-c-
yclohexyl-acetamide
[0094] ##STR27##
[0095] The title compound was separated from racemic
N-[1-(3-chlorobenzyl)-6-cyano-1,2,3,4-tetrahydroquinolin-3-yl]-2-cyclohex-
ylacetamide, prepared as described in Example 3C using chiral
preparative HPLC (Conditions: Chiralpak AD, 5 cm.times.50 cm;
eluted with 20% isopropanol in hexanes at 40 mL/min) as S-isomer.
HPLC (method B): retention time=7.7 min, MS (ES): m/z 422
[M+H].sup.+. Chiral HPLC 100% e.e.; retention time=13.4 min;
Conditions: AD (4.6.times.250 mm); Eluted with 20% isopropanol in
hexanes for 30 min at 1 ml/min.
Examples 4 to 18
[0096] Additional compounds were prepared by procedures analogous
to those described in Example 3. The compounds of Examples 4 to 18
have the following structure, ##STR28##
[0097] where the group R.sup.1, R.sup.2, R.sup.3, the
stereochemistry, the compound name, retention time and molecular
mass are set forth in Table 1. The chromatography techniques used
to determine the compound retention times of Table 1 are as
follows: HPLC (method B). LC-MS conditions (method A) (retention
time reported using method A is specified with superscript a). The
molecular mass of the compounds listed in Table 1, where provided,
were determined by MS (ES) by the formula m/z. TABLE-US-00001 TABLE
1 Retention Time (Min.)/ Ex. Mass Specs No. R.sup.1 R.sup.2 R.sup.3
Compound Name [M+H].sup.+ 4 CN ##STR29## ##STR30##
(S)-N-(6-Cyano-1-thiazol-5- ylmethyl-1,2,3,4-tetrahydro-
quinolin-3-yl) benzamide 5.43/375 5 CN ##STR31## ##STR32##
(R)-N-(6-Cyano-1-thiazol-5- ylmethyl-1,2,3,4-tetrahydro-
quinolin-3-yl) benzamide 5.43/375 6 CN ##STR33## ##STR34##
(S)-N-(1-Benzyl-6-cyano-1,2,3,4- tetrahydroquinolin-3 yl)-2-
phenylacetamide 6.88/382 7 CN ##STR35## ##STR36##
(S)-N-(1-Benzyl-6-cyano-1,2,3,4- tetrahydroquinolin-3-yl)-2-
cyclohexylacetamide 7.52/388 8 CN ##STR37## ##STR38##
(S)-N-(1-Benzyl-6-cyano-1,2,3,4- tetrahydroquinolin-3-yl)-3-
cyclohexyl-propionamide 4.75.sup.a/405 9 CN ##STR39## ##STR40##
N-(6-Cyano-1-phenethyl-1,2,3,4- tetrahydroquinolin-3-yl)-2-
cyclohexylacetamide 7.84/402 10 CN ##STR41## ##STR42##
(S)-N-(1-Benzyl-6-cyano-1,2,3,4- tetrahydroquinolin-3-yl)-2-
morpholin-4-yl-acetamide 5.05/391 11 CN ##STR43## ##STR44##
(R)-N-(1-Benzyl-6-cyano-1,2,3,4- tetrahydroquinolin-3-yl)-2-
morpholin-4-yl-acetamide 5.04/391 12 CN ##STR45## ##STR46##
N-(6-Cyano-1-cyclohexyl-1,2,3,4- tetrahydroquinolin-3-yl)-2-
cyclohexylacetamid 6.94/380 13 Ph ##STR47## ##STR48##
N-(1-Benzyl-6-phenyl-1,2,3,4- tetrahydroquinolin-3-yl)-2-
cyclohexylacetamide 8.80/439 14 Br ##STR49## ##STR50##
(S)-N-(1-Benzyl-6-bromo-1,2,3,4- tetrahydroquinolin-3-yl)-2-
cyclohexylacetamide 8.40/442 15 Br ##STR51## ##STR52##
(R)-N-(1-Benzyl-6-bromo-1,2,3,4- tetrahydroquinolin-3-yl)-2-
cyclohexylacetamide 8.39/442 16 CN ##STR53## ##STR54##
(S)-N-[1-(3-Chloro-benzyl)-6- cyano-1,2,3,4-tetrahydroquinolin-
3-yl]-2-phenylacetamide 7.16/416 17 CN ##STR55## ##STR56##
(S)-N-(6-Cyano-1-pyridin-2- ylmethyl-1,2,3,4-tetrahydro-
quinolin-3-yl)-2-phenyl acetamide 4.67/383 18 CN ##STR57##
##STR58## N-(1-benzyl-6-cyano-1,2,3,4- tetrahydroquinolin-3-yl)-2-
methyl-2-(5- (trifluoromethyl)pyridin-2- yloxy)propanamide
3.80.sup.a/495
Example 19
1-Benzyl-6-chloro-1,2,3,4-tetrahydroquinolin-3-amine,
dihydrochloride
[0098] ##STR59##
19A. tert-Butyl
6-chloro-1,2,3,4-tetrahydroquinolin-3-ylcarbamate
[0099] ##STR60##
[0100] To a solution of tert-butyl
1,2,3,4-tetrahydroquinolin-3-yl-carbamate (28.3 g, 114 mmol),
prepared as described in Example 1A, in acetonitrile (240 mL) at RT
was added dropwise a solution of N-chlorosuccinimide (15.22 g, 114
mmol) in acetonitrile (240 mL). After addition, the reaction
mixture was stirred for 6 h, then water (500 mL) added. The mixture
was extracted with EtOAc (2.times.500 mL). The combined organics
were washed with saturated aqueous NaCl, dried (Na.sub.2SO.sub.4)
and concentrated. The residue was chromatographed (silica gel)
eluting with EtOAc/hexanes (1:5 ratio) to give the title compound
(10.6 g, 58% yield) as a white solid.
19B. tert-Butyl
1-benzyl-6-chloro-1,2,3,4-tetrahydroquinolin-3-ylcarbamate
[0101] ##STR61##
[0102] To a solution of tert-butyl
6-chloro-1,2,3,4-tetrahydroquinolin-3-ylcarbamate (310 mg, 1.096
mmol), prepared as described in Example 19A, in 1,2-dichloroethane
(7 mL) was added benzaldehyde (235 mg, 2.193 mmol), followed by
sodium triacetoxyborohydride (650 mg, 3.069 mmol) and AcOH (200 mg,
3.29 mmol). The reaction mixture was stirred at RT for 4 h, then
diluted with EtOAc, washed with saturated aqueous NaHCO.sub.3,
water, saturated aqueous NaCl, dried (Na.sub.2SO.sub.4) and
concentrated. The resulting residue was chromatographed (silica
gel) eluting with EtOAc/hexanes (1:5 ratio) to give the title
compound as light yellow foam (325 mg, 80%).
19C. 1-Benzyl-6-chloro-1,2,3,4-tetrahydroquinolin-3-amine,
dihydrochloride
[0103] ##STR62##
[0104] The title compound was prepared from tert-butyl
1-benzyl-6-chloro-1,2,3,4-tetrahydroquinolin-3-ylcarbamate,
prepared as described in Example 19B, by procedures analogous to
those described in Example 1D.
Example 20
3-(Benzo[d][1,3]dioxol-5-yl)-N-(1-benzyl-6-chloro-1,2,3,4-tetrahydroquinol-
in-3-yl)propanamide
[0105] ##STR63##
[0106] The title compound was synthesized as part of library using
the following procedure in a parallel synthesis fashion using 48
well red and blue minireactors.
[0107] Typical procedure: To a suspension of PS-DIC 110 mg/well
(Argonaut, 1.38 mmol/g loading) in DCE (0.5 mL) at room temperature
was added HOBt (5 mg in 100 .mu.L DMF), followed by
3-(benzo[d][1,3]dioxol-5-yl)propanoic acid (75 .mu.mol). To this
was added 1-benzyl-6-chloro-1,2,3,4-tetrahydroquinolin-3-amine,
dihydrochloride (14 mg, 50 .mu.mol), prepared as described in
Example 19C, in 1,2-dichloroethane (0.5 mL). The reaction mixture
was shaken at RT for 24 h, contents were filtered into a synthesis
tube rack (STR) and the solvent was dried in a speed vac. The
resulting residue was chromatographed using preparative HPLC
(conditions: Xterra MS-C18 (30.times.50 mm); eluted with 10% to
100% B, 6 min gradient. (A=100% water with 0.1% TFA and
B=acetonitrile with 0.1% TFA); flow rate at 30 mL/min; UV detection
at 220 nm) to give the title compound,
3-(benzo[d][1,3]dioxol-5-yl)-N-(1-benzyl-6-chloro-1,2,3,4-tetrahydroquino-
lin-3-yl)propanamide, (2.2 mg, 8%). HPLC (method C): retention
time=1.6 min, MS (ES): m/z 449 [M+H].sup.+.
Examples 21 to 28
[0108] Additional compounds were prepared by procedures analogous
to those described in Example 20. The compounds of Examples 21 to
28 have the following structure, ##STR64##
[0109] where the group R.sup.3, the compound name, retention time
and molecular mass are set forth in Table 2. The chromatography
techniques used to determine the compound retention times of Table
2 are as follows: LC-MS conditions (method C). The molecular mass
of the compounds listed in Table 2, where provided, were determined
by MS (ES) by the formula m/z. TABLE-US-00002 TABLE 2 Example
Retention Time (Min.)/ Number R.sup.3 Compound Name Mass Specs
[M+H].sup.+ 21 ##STR65## N-(1-benzyl-6-chloro-1,2,3,4-
tetrahydroquinolin-3-yl)-2- (benzyloxy)propanamide 1.74/435 22
##STR66## N-(1-benzyl-6-chloro-1,2,3,4-
tetrahydroquinolin-3-yl)-2-(2- methoxyphenyl)acetamide 1.67/421 23
##STR67## N-(1-benzyl-6-chloro-1,2,3,4-
tetrahydroquinolin-3-yl)-3-(3- methoxyphenyl)propanamide 1.75/435
24 ##STR68## N-(1-benzyl-6-chloro-1,2,3,4-
tetrahydroquinolin-3-yl)-2-(3,5- dimethoxyphenyl)acetamide 1.60/451
25 ##STR69## 3-(benzo[d][1,3]dioxol-5-yl)-N-(1-
benzyl-6-chloro-1,2,3,4- tetrahydroquinolin-3-yl)propanamide
1.60/449 26 ##STR70## N-(1-benzyl-6-chloro-1,2,3,4-
tetrahydroquinolin-3-yl)-2-(1,3- dioxoisoindolin-2-yl)propanamide
1.71/474 27 ##STR71## tert-butyl 2-((1-benzyl-6-chloro-
1,2,3,4-tetrahydroquinolin-3- yl)carbamoyl)benzoate 1.84/447 28
##STR72## N-(1-benzyl-6-chloro-1,2,3,4-
tetrahydroquinolin-3-yl)-2-(1H-pyrrol- 1-yl)benzamide 1.76/442
Example 29
(2R)-N-(1-Benzyl-6-(4-fluorophenyl)-1,2,3,4-tetrahydroquinolin-3-yl)-2-hyd-
roxy-3-phenylpropanamide
[0110] ##STR73##
29A. (1-Benzyl-6-bromo-1,2,3,4-tetrahydroquinolin-3-yl)-carbamic
acid tert-butyl ester
[0111] ##STR74##
[0112] To a solution of
(6-bromo-1,2,3,4-tetrahydroquinolin-3yl)-carbamic acid tert-butyl
ester (1.636 g, 5 mmol), prepared as described in Example 1B, in
DCE (16 mL) at RT was added benzaldehyde (1 mL, 10 mmol), followed
by NaBH(OAc).sub.3 (2.97 g, 14 mmol) and AcOH (0.6 mL, 10 mmol).
The reaction mixture was stirred at RT for 16 h, then quenched with
aqueous NaHCO.sub.3 (40 mL) and extracted with CH.sub.2Cl.sub.2 (50
mL.times.3). The combined extracts were washed with saturated
aqueous NaCl, dried (Na.sub.2SO.sub.4), and concentrated. The
resulting residue was chromatographed (silica gel) eluting with
0-20% of EtOAc in hexanes to give the title compound (1.70 g, 81%)
as a white foam.
29B. (tert-Butyl
1-benzyl-6-(4-fluorophenyl)-1,2,3,4-tetrahydroquinolin-3-ylcarbamate
[0113] ##STR75##
[0114] (1-Benzyl-6-bromo-1,2,3,4-tetrahydroquinolin-3-yl)-carbamic
acid tert-butyl ester (2.00 g, 4.79 mmol), prepared as described in
Example 29A, 4-fluorophenyl-boronic acid (2.01 g, 14.37 mmol) and
K.sub.2CO.sub.3 (2.65 g, 19.16 mmol) in a mixed solvent of THF (50
mL) and MeOH (25 mL) were stirred at RT for 30 min while N.sub.2
was allowed to bubble through the mixture, and then PXPd (258 mg,
0.48 mmol) was added. The reaction mixture was heated at 60.degree.
C. under N.sub.2 for 3 h. After cooling to RT, the solvent was
stripped and the residue was diluted with H.sub.2O (60 mL) and
CH.sub.2Cl.sub.2 (100 mL). The aqueous layer was extracted with
CH.sub.2Cl.sub.2 (100 mL.times.3), and the combined organic
extracts were washed with saturated aqueous NaCl (50 mL), dried
(Na.sub.2SO.sub.4), filtered and concentrated. The resulting
residue was chromatographed (silica gel) eluting with EtOAc (0-20%)
in hexanes to give the title compound (1.11 g, 54%) as a white
foam.
29C. 1-Benzyl-6-phenyl-1,2,3,4-tetrahydroquinolin-3-ylamine,
trifluoroacetic acid salt
[0115] ##STR76##
[0116] To a solution of (tert-butyl
1-benzyl-6-(4-fluorophenyl)-1,2,3,4-tetrahydroquinolin-3-ylcarbamate
(1.11 g, 2.57 mmol), prepared as described in Example 29B, in
CH.sub.2Cl.sub.2 (13 mL) at RT was added trifluoroacetic acid (13
mL). After stirring at RT for 2 h, the reaction mixture was
concentrated, and the resulting residue stripped with toluene,
dried in vacuo to give the title compound as a brown solid (1.44 g,
100%).
29D.
(2R)-N-(1-Benzyl-6-(4-fluorophenyl)-1,2,3,4-tetrahydroquinolin-3-yl)--
2-hydroxy-3-phenylpropanamide
[0117] ##STR77##
[0118] To a solution of D-(+)-3-phenyllactic acid (12 mg, 0.07
mmol), EDAC (13 mg, 0.07 mmol), HOBt (11 mg, 0.07 mmol) and DIPEA
(31 .mu.L, 0.18 mmol) in CH.sub.2Cl.sub.2 (0.6 mL) was added
1-benzyl-6-phenyl-1,2,3,4-tetrahydroquinolin-3-ylamine,
trifluoroacetic acid salt (35 mg, 0.06 mmol), prepared as described
in Example 29C. The resulting mixture was stirred at RT for
overnight. The solvent was evaporated and the residue purified by
Prep. HPLC to give the title compound (7.1 mg, 24%) as a beige
solid. HPLC (method A): retention time=4.20 min, MS (ES):
[M+1].sup.+=481.
Example 30
(2S)-N-(1-Benzyl-6-(4-fluorophenyl)-1,2,3,4-tetrahydroquinolin-3-yl)-2-hyd-
roxy-3-phenylpropanamide
[0119] ##STR78##
[0120] To a solution of L-(-)-3-phenyllactic acid (13 mg, 0.08
mmol), EDAC (15 mg, 0.08 mmol), HOBt (12 mg, 0.08 mmol) and DIPEA
(36 .mu.L, 0.21 mmol) in CH.sub.2Cl.sub.2 (0.7 mL) was added
1-benzyl-6-phenyl-1,2,3,4-tetrahydroquinolin-3-ylamine,
trifluoroacetic acid salt (40 mg, 0.07 mmol), prepared as described
in Example 29C. The resulting mixture was stirred at RT for
overnight. The solvent was evaporated and the residue purified by
Prep. HPLC to give the title compound (22 mg, 64%) as a white
solid. HPLC (Method A): retention time=4.19 min, MS (ES):
[M+1].sup.+=481.
Examples 31 to 40
[0121] Additional compounds were prepared by procedures analogous
to those described in Example 29. The compounds of Examples 31 to
40 have the following structure, ##STR79##
[0122] where the group R.sup.3, the stereochemistry, the compound
name, retention time and molecular mass are set forth in Table 3.
The chromatography techniques used to determine the compound
retention times of Table 3 are as follows: LC-MS conditions (method
A). The molecular mass of the compounds listed in Table 3, where
provided, were determined by MS (ES) by the formula m/z.
TABLE-US-00003 TABLE 3 Example Retention Time (Min.)/ Number
R.sup.3 Compound Name Mass Specs [M+H].sup.+ 31 ##STR80##
(2S)-N-(1-benzyl-6-(4-fluorophenyl)-
1,2,3,4-tetrahydroquinolin-3-yl)-2- hydroxy-4-phenylbutanamide
3.49/495 32 ##STR81## N-(1-benzyl-6-(4-fluorophenyl)-
1,2,3,4-tetrahydroquinolin-3-yl)-2- hydroxy-3-(1H-indol-2-
yl)propanamide 4.09/520 33 ##STR82##
N-(1-benzyl-6-(4-fluorophenyl)-
1,2,3,4-tetrahydroquinolin-3-yl)-3-(2- methoxyphenyl)propanamide
4.28/495 34 ##STR83## N-(1-benzyl-6-(4-fluorophenyl)-
1,2,3,4-tetrahydroquinolin-3-yl)-3-(3- methoxyphenyl)propanamide
4.28/495 35 ##STR84## N-(1-benzyl-6-(4-fluorophenyl)-
1,2,3,4-tetrahydroquinolin-3-yl)-3-(4- methoxyphenyl)propanamide
4.24/495 36 ##STR85## N-(1-benzyl-6-(4-fluorophenyl)-
1,2,3,4-tetrahydroquinolin-3-yl)-3-(2- hydroxyphenyl)propanamide
4.13/481 37 ##STR86## N-(1-benzyl-6-(4-fluorophenyl)-
1,2,3,4-tetrahydroquinolin-3-yl)-3-(3- hydroxyphenyl)propanamide
4.06/481 38 ##STR87## N-(1-benzyl-6-(4-fluorophenyl)-
1,2,3,4-tetrahydroquinolin-3-yl)-3-(4- hydroxyphenyl)propanamide
4.01/481 39 ##STR88## N-(1-benzyl-6-(4-fluorophenyl)-
1,2,3,4-tetrahydroquinolin-3-yl)-3- phenylpropanamide 4.26/465 40
##STR89## N-(1-benzyl-6-(4-fluorophenyl)-
1,2,3,4-tetrahydroquinolin-3-yl)-2-
methyl-2-(5-(trifluoromethyl)pyridin- 2-yloxy)propanamide
4.39/564
Example 41
(S)-1-[1-(3-Chlorobenzyl)-6-cyano-1,2,3,4-tetrahydroquinolin-3-yl]-3-pheny-
lurea
[0123] ##STR90##
41A. (S)-(6-cyano-1,2,3,4-tetrahydroquinolin-3-yl)-3-phenylurea
[0124] ##STR91##
[0125] To a solution of
(S)-3-amino-1,2,3,4-tetrahydroquinoline-6-carbonitrile (52 mg, 0.3
mmol), prepared as described in Example 1F, in CH.sub.2Cl.sub.2 (2
mL) at RT was added phenyl isocyanate (33 .mu.l, 0.3 mmol)
dropwise. After addition, the reaction was stirred at RT for 1 h.
The product was collected by filtration and washed with
CH.sub.2Cl.sub.2-hexanes (1:1) to give the title compound (85 mg,
97%) as a white solid.
41B.
(S)-1-[1-(3-Chlorobenzyl)-6-cyano-1,2,3,4-tetrahydroquinolin-3-yl]-3--
phenylurea
[0126] ##STR92##
[0127] The title compound was prepared from
(S)-(6-cyano-1,2,3,4-tetrahydroquinolin-3-yl)-3-phenylurea,
prepared as described in Example 41A, and 3-chlorobenzaldehyde by
procedures analogous to those described in Example 3A. HPLC (method
B): retention time=7.2 min. MS (ES): m/z 417 [M+H].sup.+. Chiral
HPLC 100% e.e.; retention time=27.3 min; Conditions: AD
(4.6.times.250 mm); Eluted with 20% isopropanol in hexanes for 60
min at 1 mL/min.
Example 42
(S)-1-[1-(3-Chloro-benzyl)-6-cyano-1,2,3,4-tetrahydroquinolin-3-yl]-3-cycl-
ohexylurea
[0128] ##STR93##
42A.
(S)-1-[6-Cyano-1,2,3,4-tetrahydroquinolin-3-yl]-3-cyclohexyl-urea
[0129] ##STR94##
[0130] The title compound was prepared from
(S)-3-amino-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (52 mg, 0.3
mmol), prepared as described in Example 1F, and cyclohexyl
isocyanate by procedures analogous to those described in Example
41A.
42B.
(S)-1-[1-(3-Chlorobenzyl)-6-cyano-1,2,3,4-tetrahydroquinolin-3-yl]-3--
cyclohexylurea
[0131] ##STR95##
[0132] The title compound was prepared from
(S)-1-[6-cyano-1,2,3,4-tetrahydro-quinolin-3-yl]-3-cyclohexyl-urea,
prepared as described in Example 42A, and 3-chlorobenzaldehyde by
procedures analogous to those described in Example 3A. HPLC (method
B): retention time=7.50 min. MS (ES): m/z 423 [M+H].sup.+. Chiral
HPLC 100% e.e.; retention time=12.2 min; Conditions: AD
(4.6.times.250 mm); Eluted with 20% isopropanol in hexanes for 30
min at 1 mL/min.
Example 43
(S)-[1-(3-Chlorobenzyl)-6-cyano-1,2,3,4-tetrahydroquinolin-3-yl]-carbamic
acid cyclohexyl ester
[0133] ##STR96##
43A. Cyclohexyl 4-nitrophenyl carbonate
[0134] ##STR97##
[0135] To a solution of cyclohexanol (1.0 g, 10 mmol) in THF (20
mL) at 0.degree. C. was added pyridine (0.97 mL, 12 mmol). After 5
min stirring under N.sub.2, a solution of 4-nitrophenyl
chloroformate (2.2 g, 11 mmol) in THF (15 mL) was added slowly.
After addition, the reaction mixture was stirred at 0.degree. C.
for 30 min, and then at RT for 3 h. The precipitate was filtered,
the filtrate was concentrated. The resulting residue was
chromatographed (40 g silica gel) eluting with EtOAc (0-20%) in
hexanes to give the title compound (2.4 g, 91%) as a white
solid.
43B.
[1-(3-Chlorobenzyl)-6-cyano-1,2,3,4-tetrahydroquinolin-3-yl]-carbamic
acid cyclohexyl ester
[0136] ##STR98##
[0137] To a solution of
N-1-(3-chlorobenzyl)-6-cyano-1,2,3,4-tetrahydroquinolin-3-yl)amine,
trifluoroacetic acid salt (412 mg, 1.0 mmol), prepared as described
in Example 3B, in THF (4 mL) at RT was added Et.sub.3N (0.28 mL,
2.0 mmol), followed by cyclohexyl 4-nitrophenyl carbonate (292 mg,
1.1 mmol), prepared as described in Example 43A. After addition,
the mixture was stirred at RT for 16 h, and then diluted with EtOAc
(30 mL), washed with water, 1N aqueous NaOH, saturated aqueous
NaCl, dried (Na.sub.2SO.sub.4), and concentrated. The resulting
residue was chromatographed (40 g silica gel) eluting with EtOAc
(0-25%) in hexanes to give the title compound (280 mg, 66%) as a
white solid. HPLC (method B): retention time=8.00 min. MS (ES): m/z
424 [M+H].sup.+.
43C.
(S)-[1-(3-Chlorobenzyl)-6-cyano-1,2,3,4-tetrahydroquinolin-3-yl]-carb-
amic acid cyclohexyl ester
[0138] ##STR99##
[0139] The title compound was separated from racemic
[1-(3-chlorobenzyl)-6-cyano-1,2,3,4-tetrahydroquinolin-3-yl]-carbamic
acid cyclohexyl ester, prepared as described in Example 43B, using
chiral preparative HPLC (conditions: Chiralpak AD, 5.times.50 cm;
eluted with 20% isopropanol in hexanes at 40 mL/min). HPLC (method
B): retention time=8.15 min. MS (ES): m/z 424 [M+H].sup.+. Chiral
HPLC 100% e.e.; retention time=6.16 min; Conditions: OD
(4.6.times.250 mm); Eluted with 40% isopropanol in hexanes for 30
min at 1 mL/min.
Example 44
(R)-[1-(3-Chlorobenzyl)-6-cyano-1,2,3,4-tetrahydroquinolin-3-yl]-carbamic
acid cyclohexyl ester
[0140] ##STR100##
[0141] The title compound was separated from racemic
[1-(3-chlorobenzyl)-6-cyano-1,2,3,4-tetrahydroquinolin-3-yl]-carbamic
acid cyclohexyl ester, prepared as described in Example 43B, using
chiral preparative HPLC (conditions: Chiralpak AD, 5.times.50 cm;
eluted with 20% isopropanol in hexanes at 40 mL/min). HPLC (method
B): retention time=8.15 min. MS (ES): m/z 424 [M+H].sup.+. Chiral
HPLC 100% e.e.; retention time=4.87 min; Conditions: OD
(4.6.times.250 mm); Eluted with 40% isopropanol in hexanes for 30
min at 1 mL/min.
Examples 44 to 51
[0142] Additional compounds were prepared by procedures analogous
to those described in Example 43. The compounds of Examples 44 to
51 have the following structure, ##STR101##
[0143] where the group R.sup.1, R.sup.2, R.sup.3, the
stereochemistry, the compound name, retention time and molecular
mass are set forth in Table 4. The chromatography techniques used
to determine the compound retention times of Table 4 are as
follows: HPLC conditions: (method B) and LC-MS conditions: (method
A). The molecular mass of the compounds listed in Table 4, where
provided, were determined by MS (ES) by the formula m/z.
TABLE-US-00004 TABLE 4 Retention Time (Min.)/ No. Mass Specs Ex.
R.sup.1 R.sup.2 R.sup.3 Compound Name [M+H].sup.+ 44 CN ##STR102##
##STR103## (1-Benzyl-6-cyano-1,2,3,4-
tetrahydroquinolin-3-yl)-carbamic acid cyclohexyl ester 8.05/390 45
CN ##STR104## ##STR105## (S)-(1-Benzyl-6-cyano-1,2,3,4-
tetrahydroquinolin-3-yl)-carbamic acid cyclohexyl ester 8.05/390 46
CN ##STR106## ##STR107## (R)-(1-Benzyl-6-cyano-1,2,3,4-
tetrahydroquinolin-3-yl)-carbamic acid cyclohexyl ester 8.04/390 47
CN ##STR108## ##STR109## (S)-(1-Benzyl-6-cyano-1,2,3,4-
tetrahydroquinolin-3-yl)-carbamic acid benzyl ester 7.51/398 48 CN
##STR110## ##STR111## (R)-(1-Benzyl-6-cyano-1,2,3,4-
tetrahydroquinolin-3-yl)-carbamic acid benzyl ester 7.52/398 49 CN
##STR112## ##STR113## (S)-(1-Benzyl-6-cyano-1,2,3,4-
tetrahydroquinolin-3-yl)-carbamic acid tetrahydro-pyran-4-yl ester
7.22/392 50 CN ##STR114## ##STR115## (6-Cyano-1-phenethyl-1,2,3,4-
tetrahydroquinolin-3-yl)-carbamic acid cyclohexyl ester 7.24/404 51
Br ##STR116## ##STR117## (1-Benzyl-6-bromo-1,2,3,4-
tetrahydroquinolin-3-yl)-carbamic acid cyclohexyl ester
8.83/444
Example 52
(1-Benzyl-6-cyano-1,2,3,4-tetrahydroquinolin-3-yl)-carbamic acid
4-hydroxy-cyclohexyl ester
[0144] ##STR118##
52A. N-1-Benzyl-6-cyano-1,2,3,4-tetrahydroquinolin-3-yl)-amine,
hydrochloride salt
[0145] ##STR119##
[0146] The title compound was prepared from
(6-cyano-1,2,3,4-tetrahydroquinolin-3-yl)-carbamic acid tert-butyl
ester, prepared as described in Example 1C, and benzaldehyde by
procedures analogous to those described in Example 3A and 3B.
52B. (1-Benzyl-6-cyano-1,2,3,4-tetrahydroquinolin-3-yl)-carbamic
acid 4-hydroxy-cyclohexyl ester
[0147] ##STR120##
[0148] To a stirring suspension of
N-1-benzyl-6-cyano-1,2,3,4-tetrahydroquinolin-3-yl)-amine,
hydrochloride salt (277 mg, 0.92 mmol), prepared as described in
Example 52A, and NaHCO.sub.3 (773 mg, 9.2 mmol) in CH.sub.2Cl.sub.2
(10 mL) at RT was added phosgene (2.4 mL of 20% solution in
toluene). After addition, the mixture was stirred at RT for 3 h and
filtered. The filtrate was concentrated, the resultant residue
dried in vacuo, then dissolved in toluene (5 mL) and treated with
1,4-cyclohexynediol (210 mg, 1.8 mmol). The mixture was stirred at
60.degree. C. for 60 h, cooled to RT, and concentrated. The
resultant residue was chromatographed (silica gel) eluting with
EtOAc (0-25%) in hexanes to provide the title compound as a white
solid (138 mg, 37%). HPLC (method B): 99% pure, retention time=6.76
min, MS (ES): m/z 406 [M+H].sup.+.
Example 53
[1-Benzyl-6-(2H-tetrazol-5-yl)-1,2,3,4-tetrahydroquinolin-3-yl]-carbamic
acid cyclohexyl ester
[0149] ##STR121##
[0150] A solution of
(1-benzyl-6-cyano-1,2,3,4-tetrahydroquinilin-3-yl)-carbamic acid
cyclohexyl ester (195 mg, 0.5 mmol), prepared as described in
Example 44, and azidotrimethyltin (113.2 mg, 0.55 mmol) in toluene
(3 mL) was refluxed under N.sub.2 for 16 h. After cooling to RT,
the reaction was concentrated. The residue was taken in MeOH (5 mL)
and heated at 60.degree. C. for 4 h, and then concentrated. The
resulting residue was chromatographed (10 g silica gel) eluting
with MeOH (0-5%) in EtOAc to give the title compound (120 mg, 56%)
as a white solid. HPLC: (method B) 96% pure, retention time=7.8
min. MS (ES): m/z 433 [M+H].sup.+.
Example 54
[1-Benzyl-6-(2-methyl-2H-tetrazol-5-yl)-1,2,3,4-tetrahydroquinolin-3-yl]-c-
arbamic acid cyclohexyl ester
[0151] ##STR122##
[0152] To a stirred solution of
[1-benzyl-6-(2H-tetrazol-5-yl)-1,2,3,4-tetrahydroquinolin-3-yl]-carbamic
acid cyclohexyl ester (61 mg, 0.14 mmol), prepared as described in
Example 53, in CH.sub.3CN (0.5 mL)-DMF (0.5 mL)-THF (0.5 mL) at RT
was added Cs.sub.2CO.sub.3 (63.4 mg, 0.19 mmol), followed by
iodomethane (7.8 .mu.L, 0.126 mmol). The reaction mixture was
stirred at RT for 16 h and then diluted with H.sub.2O, extracted
with EtOAc (10 mL.times.3). The organic extracts were washed
saturated aqueous NaCl, dried (Na.sub.2SO.sub.4), and concentrated.
The resulting residue was purified using preparative HPLC [YMC S5
ODS (20.times.100 mm); Eluted with 50% to 90% B, 8 min gradient and
7 min hold. (A=90% H.sub.2O-10% MeOH and B=10% H.sub.2O-90% MeOH);
Flow rate at 20 mL/min. UV detection at 220 nm] to give the title
compound (regioisomer A, 35 mg, 56%) as a white solid. HPLC (method
B): 98% pure, retention time=7.9 min. MS (ES): m/z 447
[M+H].sup.+.
Example 55
[1-Benzyl-6-(1-methyl-1H-tetrazol-5-yl)-1,2,3,4-tetrahydroquinolin-3-yl]-c-
arbamic acid cyclohexyl ester
[0153] ##STR123##
[0154] The title compound (regioisomer B) was separated from the
crude mixture described in Example 54 using preparative HPLC (the
same conditions as described in Example 54). HPLC (method B): 98%
pure, retention time=7.4 min. MS (ES): m/z 447 [M+H].sup.+.
Biological Evaluation
Cannabinoid Receptor Binding Assay
[0155] Radioligand binding studies were conducted in membranes
prepared from Chinese Hamster Ovary (CHO) cells that over-express
recombinant human CB-1 (CHO-CB-1 cells). Total assay volume for the
binding studies was 100 .mu.l. 5 .mu.g of membranes were brought up
to a final volume of 95 .mu.l with Binding Buffer (25 mM HEPES, 150
mM NaCl, 2.5 mM CaCl.sub.2, 1 mM MgCl.sub.2, 0.25% BSA). The
diluted membranes were preincubated with a compound or DMSO
vehicle. The binding reaction was initiated by the addition of 2 nM
final .sup.3H-CP-55,940 (120 Ci/mmol) and proceeded for 2.5 hours
at room temperature. The binding reaction was terminated by
transferring the reaction to GF/B 96 well plates (presoaked with
0.3% polyethylenimine) using a Packard Cell Harvester. The filter
was washed with 0.25.times.PBS, 30 .mu.l MicroScint was added per
well, and the bound radiolabel was quantitated by scintillation
counting on a Packard TopCount Scintillation Counter. The CB-2
radioligand binding assay was conducted identically except that the
membranes from CHO-CB-2 cells were used.
[0156] For a compound to be considered a CB-1 antagonist, the
compound must possess a CB-1 receptor binding affinity Ki less than
13000 nM. As determined by the assay described above, the CB-1
receptor binding K.sub.i values of the working Examples fall within
the range of 0.01 nM to 10000 nM.
Cannabinoid Receptor Functional Activity Assay
[0157] Functional CB-1 inverse agonist activity of test compounds
was determined in CHO-CB-1 cells using a cAMP accumulation assay.
CHO-CB-1 cells were grown in 96 well plates to near confluence. On
the day of the functional assay, growth medium was aspirated and
100 of Assay Buffer (PBS plus 25 mM HEPES/0.1 mM
3-isobutyl-1-methylxanthine/0.1% BSA) was added. Compounds were
added to the Assay buffer diluted 1:100 from 100% DMSO and allowed
to preincubate for 10 minutes prior to addition of 5 uM forskolin.
The mixture was allowed to proceed for 15 minutes at room
temperature and was terminated by the addition of 0.1 N HCl. The
total intracellular cAMP concentration was quantitated using the
Amersham cAMP SPA kit.
Utilities and Combinations
Utilities
[0158] The compounds of the present invention are cannabinoid
receptor modulators, and include compounds which are, for example,
selective agonists, partial agonists, inverse agonists, antagonists
or partial antagonists of the cannabinoid receptor. Accordingly,
the compounds of the present invention may be useful for the
treatment or prevention of diseases and disorders associated with
G-protein coupled cannabinoid receptor activity. Preferably,
compounds of the present invention possess activity as antagonists
or inverse agonists of the CB-1 receptor, and may be used in the
treatment of diseases or disorders associated with the activity of
the CB-1 receptor.
[0159] Accordingly, the compounds of the present invention can be
administered to mammals, preferably humans, for the treatment of a
variety of conditions and disorders, including, but not limited to
metabolic and eating disorders as well as conditions associated
with metabolic disorders, (e.g., obesity, diabetes,
arteriosclerosis, hypertension, polycystic ovary disease,
cardiovascular disease, osteoarthritis, dermatological disorders,
hypertension, insulin resistance, hypercholesterolemia,
hypertriglyceridemia, cholelithiasis and sleep disorders,
hyperlipidemic conditions, bulimia nervosa and compulsive eating
disorders) or psychiatric disorders, such as substance abuse,
depression, anxiety, mania and schizophrenia. These compounds could
also be used for the improvement of cognitive function (e.g., the
treatment of dementia, including Alzheimer's disease, short term
memory loss and attention deficit disorders); neurodegenerative
disorders (e.g., Parkinson's Disease, cerebral apoplexy and
craniocerebral trauma) and hypotension (e.g., hemorrhagic and
endotoxin-inducd hypotension). These compounds could also be used
for treatment of catabolism in connection with pulmonary
dysfunction and ventilator dependency; treatment of cardiac
dysfunction (e.g., associated with valvular disease, myocardial
infarction, cardiac hypertrophy or congestive heart failure); and
improvement of the overall pulmonary function; transplant
rejection; rheumatoid arthritis; multiple sclerosis; inflammatory
bowel disease; lupus; graft vs. host disease; T-cell mediated
hypersensitivity disease; psoriasis; asthma; Hashimoto's
thyroiditis; Guillain-Barre syndrome; cancer; contact dermatitis;
allergic rhinitis; and ischemic or reperfusion injury.
[0160] Compounds useful in the treatment of appetitive or
motivational disorders regulate desires to consume sugars,
carbohydrates, alcohol or drugs and more generally to regulate the
consumption of ingredients with hedonic value. In the present
description and in the claims, appetitive disorders are understood
as meaning: disorders associated with a substance and especially
abuse of a substance and/or dependency on a substance, disorders of
eating behaviors, especially those liable to cause excess weight,
irrespective of its origin, for example: bulimia nervosa, craving
for sugars. The present invention therefore further relates to the
use of a CB-1 receptor antagonist or inverse agonist for the
treatment of bulimia and obesity, including obesity associated with
type II diabetes (non-insulin-dependent diabetes), or more
generally any disease resulting in the patient becoming overweight.
Obesity, as described herein, is defined by a body mass index
(kg/m.sup.2) of at least 26. It may be due to any cause, whether
genetic or environmental, including overeating and bulemia,
polycycstic ovary disease, craniopharyngeoma, Prader-Willi
Syndrome, Frohlich's Syndrome, Type II diabetes, growth hormone
deficiency, Turner's Syndrome and other pathological states
characterized by reduced metabolic activity or reduced energy
expenditure. As used with reference to the utilities described
herein, the term "treating" or "treatment" encompasses prevention,
partial alleviation, or cure of the disease or disorder. Further,
treatment of obesity is expected to prevent progression of medical
covariants of obesity, such as arteriosclerosis, Type II diabetes,
polycystic ovary disease, cardiovascular disease, osteoarthritis,
dermatological disorders, hypertension, insulin resistance,
hypercholesterolemia, hypertriglyceridemia, cholelithiasis and
sleep disorders.
[0161] Compounds in the present invention may also be useful in
treating substance abuse disorders, including substance dependence
or abuse without physiological dependence. Substances of abuse
include alcohol, amphetamines (or amphetamine-like substances),
caffeine, cannabis, cocaine, hallucinogens, inhalents, nicotine,
opioids, phencyclidine (or phencyclidine-like compounds),
sedative-hypnotics or benzodiazepines, and other (or unknown)
substances and combinations of the above. The terms "substance
abuse disorders" also includes drug or alcohol withdrawal syndromes
and substance-induced anxiety or mood disorder with onset during
withdrawal.
[0162] Compounds in the present invention may be useful in treating
memory impairment and cognitive disorders. The condition of memory
impairment is manifested by impairment of the ability to learn new
information and/or the inability to recall previously learned
information. Memory impairment is a primary symptom of dementia and
can also be a symptom associated with such diseases as Alzheimer's
disease, schizophrenia, Parkinson's disease, Huntington's disease,
Pick's disease, Creutzfeld-Jakob disease, HIV, cardiovascular
disease, and head trauma as well as age-related cognitive decline.
Dementias are diseases that include memory loss and additional
intellectual impairment separate from memory. Cannabinoid receptor
modulators may also be useful in treating cognitive impairments
related to attentional deficits, such as attention deficit
disorder.
[0163] Compounds in the present invention may also be useful in
treating diseases associated with dysfunction of brain dopaminergic
systems, such as Parkinson's Disease and substance abuse disorders.
Parkinsons's Disease is a neurodenerative movement disorder
characterized by bradykinesia and tremor.
[0164] As modulators of the cannabinoid receptor, the compounds of
the present invention are further useful for the treatment and
prevention of respiratory diseases and disorders. Respiratory
diseases for which cannabinoid receptor modulators are useful
include, but are not limited to, chronic pulmonary obstructive
disorder, emphysema, asthma, and bronchitis. In addition,
cannabinoid receptor modulators block the activation of lung
epithelial cells by moeties such as allergic agents, inflammatory
cytokines or smoke, thereby limiting release of mucin, cytokines,
and chemokines, or selectively inhibiting lung epithelial cell
activation.
[0165] Moreover, the compounds employed in the present invention
may stimulate inhibitory pathways in cells, particularly in
leukocytes, lung epithelial cells, or both, and are thus useful in
treating such diseases. "Leukocyte activation" is defined herein as
any or all of cell proliferation, cytokine production, adhesion
protein expression, and production of inflammatory mediators.
"Epithelial cell activation" is defined herein as the production of
any or all of mucins, cytokines, chemokines, and adhesion protein
expression.
[0166] Use of the compounds of the present invention for treating
leukocyte activation-associated disorders is exemplified by, but is
not limited to, treating a range of disorders such as: transplant
(such as organ transplant, acute transplant, xenotransplant or
heterograft or homograft (such as is employed in burn treatment))
rejection; protection from ischemic or reperfusion injury such as
ischemic or reperfusion injury incurred during organ
transplantation, myocardial infarction, stroke or other causes;
transplantation tolerance induction; arthritis (such as rheumatoid
arthritis, psoriatic arthritis or osteoarthritis); multiple
sclerosis; respiratory and pulmonary diseases including but not
limited to chronic obstructive pulmonary disease (COPD), emphysema,
bronchitis, and acute respiratory distress syndrome (ARDS);
inflammatory bowel disease, including ulcerative colitis and
Crohn's disease; lupus (systemic lupus erythematosis); graft vs.
host disease; T-cell mediated hypersensitivity diseases, including
contact hypersensitivity, delayed-type hypersensitivity, and
gluten-sensitive enteropathy (Celiac disease); psoriasis; contact
dermatitis (including that due to poison ivy); Hashimoto's
thyroiditis; Sjogren's syndrome; Autoimmune Hyperthyroidism, such
as Graves' Disease; Addison's disease (autoimmune disease of the
adrenal glands); Autoimmune polyglandular disease (also known as
autoimmune polyglandular syndrome); autoimmune alopecia; pernicious
anemia; vitiligo; autoimmune hypopituatarism; Guillain-Barre
syndrome; other autoimmune diseases; glomerulonephritis; serum
sickness; uticaria; allergic diseases such as respiratory allergies
(asthma, hayfever, allergic rhinitis) or skin allergies;
scleracierma; mycosis fungoides; acute inflammatory and respiratory
responses (such as acute respiratory distress syndrome and
ishchemia/reperfusion injury); dermatomyositis; alopecia greata;
chronic actinic dermatitis; eczema; Behcet's disease; Pustulosis
palmoplanteris; Pyoderma gangrenum; Sezary's syndrome; atopic
dermatitis; systemic schlerosis; and morphea. The term "leukocyte
activation-associated" or "leukocyte-activation mediated" disease
as used herein includes each of the above referenced diseases or
disorders. In a particular embodiment, the compounds of the present
invention are useful for treating the aforementioned exemplary
disorders irrespective of their etiology. The combined activity of
the present compounds towards monocytes, macrophages, T-cells, etc.
may be useful in treating any of the above-mentioned disorders.
[0167] Cannabinoid receptors are important in the regulation of Fc
gamma receptor responses of monocytes and macrophages. Compounds of
the present invention inhibit the Fc gamma dependent production of
TNF alpha in human monocytes/macrophages. The ability to inhibit Fc
gamma receptor dependent monocyte and macrophage responses results
in additional anti-inflammatory activity for the present compounds.
This activity is especially of value, for example, in treating
inflammatory diseases such as arthritis or inflammatory bowel
disease. In particular, the present compounds are useful for
treating autoimmune glomerulonephritis and other instances of
glomerulonephritis induced by deposition of immune complexes in the
kidney that trigger Fc gamma receptor responses leading to kidney
damage.
[0168] Cannabinoid receptors are expressed on lung epithelial
cells. These cells are responsible for the secretion of mucins and
inflammatory cytokines/chemokines in the lung and are thus
intricately involved in the generation and progression of
respiratory diseases. Cannabinoid receptor modulators regulate both
the spontaneous and the stimulated production of both mucins and
cytokines. Thus, such compounds are useful in treating respiratory
and pulmonary diseases including, COPD, ARDS, and bronchitis.
[0169] Further, cannabinoid receptors may be expressed on gut
epithelial cells and hence regulate cytokine and mucin production
and may be of clinical use in treating inflammatory diseases
related to the gut. Cannabinoid receptors are also expressed on
lymphocytes, a subset of leukocytes. Thus, cannabinoid receptor
modulators will inhibit B and T-cell activation, proliferation and
differentiation. Thus, such compounds will be useful in treating
autoimmune diseases that involve either antibody or cell mediated
responses such as multiple sclerosis and lupus.
[0170] In addition, cannabinoid receptors regulate the Fc epsilon
receptor and chemokine induced degranulation of mast cells and
basophils. These play important roles in asthma, allergic rhinitis,
and other allergic disease. Fc epsilon receptors are stimulated by
IgE-antigen complexes. Compounds of the present invention inhibit
the Fc epsilon induced degranulation responses, including the
basophil cell line, RBL. The ability to inhibit Fc epsilon receptor
dependent mast cell and basophil responses results in additional
anti-inflammatory and anti-allergic activity for the present
compounds. In particular, the present compounds are useful for
treating asthma, allergic rhinitis, and other instances of allergic
disease.
Combinations
[0171] The present invention includes within its scope
pharmaceutical compositions comprising, as an active ingredient, a
therapeutically effective amount of at least one of the compounds
of formula I, alone or in combination with a pharmaceutical carrier
or diluent. Optionally, compounds of the present invention can be
used alone, in combination with other suitable therapeutic agents
useful in the treatment of the aforementioned disorders including:
anti-obesity agents; anti-diabetic agents, appetite suppressants;
cholesterol/lipid-lowering agents, HDL-raising agents, cognition
enhancing agents, agents used to treat neurodegeneration, agents
used to treat respiratory conditions, agents used to treat bowel
disorders, anti-inflammatory agents; anti-anxiety agents;
anti-depressants; anti-hypertensive agents; cardiac glycosides; and
anti-tumor agents.
[0172] Such other therapeutic agent(s) may be administered prior
to, simultaneously with, or following the administration of the
cannabinoid receptor modulators in accordance with the
invention.
[0173] Examples of suitable anti-obesity agents for use in
combination with the compounds of the present invention include
melanocortin receptor (MC4R) agonists, melanin-concentrating
hormone receptor (MCHR) antagonists, growth hormone secretagogue
receptor (GHSR) antagonists, galanin receptor modulators, orexin
antagonists, CCK agonists, GLP-1 agonists, and other
Pre-proglucagon-derived peptides; NPY1 or NPY5 antagonsist, NPY2
and NPY4 modulators, corticotropin releasing factor agonists,
histamine receptor-3 (H3) modulators, aP2 inhibitors, PPAR gamma
modulators, PPAR delta modulators, acetyl-CoA carboxylase (ACC)
inihibitors, 11-.beta.-HSD-1 inhibitors, adinopectin receptor
modulators; beta 3 adrenergic agonists, such as AJ9677
(Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer) or other
known beta 3 agonists as disclosed in U.S. Pat. Nos. 5,541,204,
5,770,615, 5,491,134, 5,776,983 and 5,488,064, a thyroid receptor
beta modulator, such as a thyroid receptor ligand as disclosed in
WO 97/21993 (U. Cal SF), WO 99/00353 (KaroBio), a lipase inhibitor,
such as orlistat or ATL-962 (Alizyme), serotonin receptor agonists,
(e.g., BVT-933 (Biovitrum)), monoamine reuptake inhibitors or
releasing agents, such as fenfluramine, dexfenfluramine,
fluvoxamine, fluoxetine, paroxetine, sertraline, chlorphentermine,
cloforex, clortermine, picilorex, sibutramine, dexamphetamine,
phentermine, phenylpropanolamine or mazindol, anorectic agents such
as topiramate (Johnson & Johnson), CNTF (ciliary neurotrophic
factor)/Axokine.RTM. (Regeneron), BDNF (brain-derived neurotrophic
factor), leptin and leptin receptor modulators, or cannabinoid-1
receptor antagonists, such as SR-141716 (Sanofi) or SLV-319
(Solvay).
[0174] Examples of suitable anti-diabetic agents for use in
combination with the compounds of the present invention include:
insulin secretagogues or insulin sensitizers, which may include
biguanides, sulfonyl ureas, glucosidase inhibitors, aldose
reductase inhibitors, PPAR .gamma. agonists such as
thiazolidinediones, PPAR .alpha. agonists (such as fibric acid
derivatives), PPAR .delta. antagonists or agonists, PPAR
.alpha./.gamma. dual agonists, 11-.beta.-HSD-1 inhibitors,
dipeptidyl peptidase IV (DP4) inhibitors, SGLT2 inhibitors,
glycogen phosphorylase inhibitors, and/or meglitinides, as well as
insulin, and/or glucagon-like peptide-1 (GLP-1), GLP-1 agonist,
and/or a PTP-1B inhibitor (protein tyrosine phosphatase-1B
inhibitor).
[0175] The antidiabetic agent may be an oral antihyperglycemic
agent preferably a biguanide such as metformin or phenformin or
salts thereof, preferably metformin HCl. Where the antidiabetic
agent is a biguanide, the compounds of the present invention will
be employed in a weight ratio to biguanide within the range from
about 0.001:1 to about 10:1, preferably from about 0.01:1 to about
5:1.
[0176] The antidiabetic agent may also preferably be a sulfonyl
urea such as glyburide (also known as glibenclamide), glimepiride
(disclosed in U.S. Pat. No. 4,379,785), glipizide, gliclazide or
chlorpropamide, other known sulfonylureas or other
antihyperglycemic agents which act on the ATP-dependent channel of
the beta-cells, with glyburide and glipizide being preferred, which
may be administered in the same or in separate oral dosage forms.
The oral antidiabetic agent may also be a glucosidase inhibitor
such as acarbose (disclosed in U.S. Pat. No. 4,904,769) or miglitol
(disclosed in U.S. Pat. No. 4,639,436), which may be administered
in the same or in a separate oral dosage forms.
[0177] The compounds of the present invention may be employed in
combination with a PPAR .gamma. agonist such as a thiazolidinedione
oral anti-diabetic agent or other insulin sensitizers (which has an
insulin sensitivity effect in NIDDM patients) such as rosiglitazone
(SKB), pioglitazone (Takeda), Mitsubishi's MCC-555 (disclosed in
U.S. Pat. No. 5,594,016), Glaxo-Welcome's GL-262570, englitazone
(CP-68722, Pfizer) or darglitazone (CP-86325, Pfizer, isaglitazone
(MIT/J&J), JTT-501 (JPNT/P&U), L-895645 (Merck), R-119702
(Sankyo/WL), NN-2344 (Dr. Reddy/NN), or YM-440 (Yamanouchi),
preferably rosiglitazone and pioglitazone.
[0178] The compounds of the present invention may be employed with
a PPAR.alpha./.gamma. dual agonist such as MK-767/KRP-297
(Merck/Kyorin; as described in, K. Yajima, et. al., Am. J. Physiol.
Endocrinol. Metab., 284: E966-E971 (2003)), AZ-242 (tesaglitazar;
Astra-Zeneca; as described in B. Ljung, et. al., J. Lipid Res., 43,
1855-1863 (2002)); muraglitazar; or the compounds described in U.S.
Pat. No. 6,414,002.
[0179] The compounds of the present invention may be employed in
combination with anti-hyperlipidemia agents, or agents used to
treat arteriosclerosis. An example of an hypolipidemic agent would
be an HMG CoA reductase inhibitor which includes, but is not
limited to, mevastatin and related compounds as disclosed in U.S.
Pat. No. 3,983,140, lovastatin (mevinolin) and related compounds as
disclosed in U.S. Pat. No. 4,231,938, pravastatin and related
compounds such as disclosed in U.S. Pat. No. 4,346,227, simvastatin
and related compounds as disclosed in U.S. Pat. Nos. 4,448,784 and
4,450,171. Other HMG CoA reductase inhibitors which may be employed
herein include, but are not limited to, fluvastatin, disclosed in
U.S. Pat. No. 5,354,772, cerivastatin disclosed in U.S. Pat. Nos.
5,006,530 and 5,177,080, atorvastatin disclosed in U.S. Pat. Nos.
4,681,893, 5,273,995, 5,385,929 and 5,686,104, pitavastatin
(Nissan/Sankyo's nisvastatin (NK-104) or itavastatin), disclosed in
U.S. Pat. No. 5,011,930, Shionogi-Astra/Zeneca rosuvastatin
(visastatin (ZD-4522)) disclosed in U.S. Pat. No. 5,260,440, and
related statin compounds disclosed in U.S. Pat. No. 5,753,675,
pyrazole analogs of mevalonolactone derivatives as disclosed in
U.S. Pat. No. 4,613,610, indene analogs of mevalonolactone
derivatives as disclosed in PCT application WO 86/03488,
6-[2-(substituted-pyrrol-1-yl)-alkyl)pyran-2-ones and derivatives
thereof as disclosed in U.S. Pat. No. 4,647,576, Searle's SC-45355
(a 3-substituted pentanedioic acid derivative) dichloroacetate,
imidazole analogs of mevalonolactone as disclosed in PCT
application WO 86/07054, 3-carboxy-2-hydroxy-propane-phosphonic
acid derivatives as disclosed in French Patent No. 2,596,393,
2,3-disubstituted pyrrole, furan and thiophene derivatives as
disclosed in European Patent Application No. 0221025, naphthyl
analogs of mevalonolactone as disclosed in U.S. Pat. No. 4,686,237,
octahydronaphthalenes such as disclosed in U.S. Pat. No. 4,499,289,
keto analogs of mevinolin (lovastatin) as disclosed in European
Patent Application No. 0,142,146 A2, and quinoline and pyridine
derivatives disclosed in U.S. Pat. Nos. 5,506,219 and 5,691,322. In
addition, phosphinic acid compounds useful in inhibiting HMG CoA
reductase suitable for use herein are disclosed in GB 2205837.
[0180] The squalene synthetase inhibitors suitable for use herein
include, but are not limited to, .alpha.-phosphono-sulfonates
disclosed in U.S. Pat. No. 5,712,396, those disclosed by Biller, et
al., J. Med. Chem., 31, 1869-1871 (1998) including isoprenoid
(phosphinyl-methyl)phosphonates as well as other known squalene
synthetase inhibitors, for example, as disclosed in U.S. Pat. Nos.
4,871,721 and 4,924,024 and in Biller, S. A., Neuenschwander, K.,
Ponpipom, M. M., and Poulter, C. D., Current Pharmaceutical Design,
2, 1-40 (1996).
[0181] In addition, other squalene synthetase inhibitors suitable
for use herein include the terpenoid pyrophosphates disclosed by P.
Ortiz de Montellano, et al., J. Med. Chem., 20, 243-249 (1977), the
farnesyl diphosphate analog A and presqualene pyrophosphate
(PSQ-PP) analogs as disclosed by Corey and Volante, J. Am. Chem.
Soc., 98, 1291-1293 (1976), phosphinylphosphonates reported by
McClard, R. W. et al., J. Am. Chem. Soc., 109, 5544 (1987) and
cyclopropanes reported by Capson, T. L., PhD dissertation, June,
1987, Dept. Med. Chem. U of Utah, Abstract, Table of Contents, pp
16, 17, 40-43, 48-51, Summary.
[0182] Other hypolipidemic agents suitable for use herein include,
but are not limited to, fibric acid derivatives, such as
fenofibrate, gemfibrozil, clofibrate, bezafibrate, ciprofibrate,
clinofibrate and the like, probucol, and related compounds as
disclosed in U.S. Pat. No. 3,674,836, probucol and gemfibrozil
being preferred, bile acid sequestrants such as cholestyramine,
colestipol and DEAE-Sephadex (SECHOLEX, POLICEXIDE) and cholestagel
(Sankyo/Geltex), as well as lipostabil (Rhone-Poulenc), Eisai
E-5050 (an N-substituted ethanolamine derivative), imanixil
(HOE-402), tetrahydrolipstatin (THL),
istigmastanylphos-phorylcholine (SPC, Roche), aminocyclodextrin
(Tanabe Seiyoku), Ajinomoto AJ-814 (azulene derivative), melinamide
(Sumitomo), Sandoz 58-035, American Cyanamid CL-277,082 and
CL-283,546 (disubstituted urea derivatives), nicotinic acid
(niacin), acipimox, acifran, neomycin, p-aminosalicylic acid,
aspirin, poly(diallylmethylamine) derivatives such as disclosed in
U.S. Pat. No. 4,759,923, quaternary amine
poly(diallyldimethylammonium chloride) and ionenes such as
disclosed in U.S. Pat. No. 4,027,009, and other known serum
cholesterol lowering agents.
[0183] The other hypolipidemic agent may be an ACAT inhibitor
(which also has anti-atherosclerosis activity) such as disclosed
in, Drugs of the Future, 24, 9-15 (1999), (Avasimibe); "The ACAT
inhibitor, Cl-1011 is effective in the prevention and regression of
aortic fatty streak area in hamsters", Nicolosi et al.,
Atherosclerosis (Shannon, Irel), 137 (1), 77-85 (1998); "The
pharmacological profile of FCE 27677: a novel ACAT inhibitor with
potent hypolipidemic activity mediated by selective suppression of
the hepatic secretion of ApoB100-containing lipoprotein", Ghiselli,
Giancarlo, Cardiovasc. Drug Rev., 16 (1), 16-30 (1998); "RP 73163:
a bioavailable alkylsulfinyl-diphenylimidazole ACAT inhibitor",
Smith, C., et al., Bioorg. Med. Chem. Lett, 6 (1), 47-50 (1996);
"ACAT inhibitors: physiologic mechanisms for hypolipidemic and
anti-atherosclerotic activities in experimental animals", Krause et
al., Editor(s): Ruffolo, Robert R., Jr.; Hollinger, Mannfred A.,
Inflammation: Mediators Pathways, 173-98 (1995), Publisher: CRC,
Boca Raton, Fla.; "ACAT inhibitors: potential anti-atherosclerotic
agents", Sliskovic et al., Curr. Med. Chem., 1 (3), 204-25 (1994);
"Inhibitors of acyl-CoA:cholesterol O-acyl transferase (ACAT) as
hypocholesterolemic agents. 6. The first water-soluble ACAT
inhibitor with lipid-regulating activity. Inhibitors of
acyl-CoA:cholesterol acyltransferase (ACAT). 7. Development of a
series of substituted
N-phenyl-N'-[(1-phenylcyclopentyl)-methyl]ureas with enhanced
hypocholesterolemic activity", Stout et al., Chemtracts: Org.
Chem., 8 (6), 359-62 (1995), or TS-962 (Taisho Pharmaceutical Co.
Ltd), as well as F-1394, CS-505, F-12511, HL-004, K-10085 and
YIC-C8-434.
[0184] The hypolipidemic agent may be an upregulator of LDL
receptor activity such as MD-700 (Taisho Pharmaceutical Co. Ltd)
and LY295427 (Eli Lilly). The hypolipidemic agent may be a
cholesterol absorption inhibitor preferably Schering-Plough's
SCH48461 (ezetimibe) as well as those disclosed in Atherosclerosis
115, 45-63 (1995) and J. Med. Chem. 41, 973 (1998).
[0185] The other lipid agent or lipid-modulating agent may be a
cholesteryl transfer protein inhibitor (CETP) such as Pfizer's
CP-529,414 as well as those disclosed in WO/0038722 and in EP
818448 (Bayer) and EP 992496, and Pharmacia's SC-744 and SC-795, as
well as CETi-1 and JTT-705.
[0186] The hypolipidemic agent may be an ileal Na.sup.+/bile acid
cotransporter inhibitor such as disclosed in Drugs of the Future,
24, 425-430 (1999). The ATP citrate lyase inhibitor which may be
employed in the combination of the invention may include, for
example, those disclosed in U.S. Pat. No. 5,447,954.
[0187] The other lipid agent also includes a phytoestrogen compound
such as disclosed in WO 00/30665 including isolated soy bean
protein, soy protein concentrate or soy flour as well as an
isoflavone such as genistein, daidzein, glycitein or equol, or
phytosterols, phytostanol or tocotrienol as disclosed in WO
2000/015201; a beta-lactam cholesterol absorption inhibitor such as
disclosed in EP 675714; an HDL upregulator such as an LXR agonist,
a PPAR .alpha.-agonist and/or an FXR agonist; an LDL catabolism
promoter such as disclosed in EP 1022272; a sodium-proton exchange
inhibitor such as disclosed in DE 19622222; an LDL-receptor inducer
or a steroidal glycoside such as disclosed in U.S. Pat. No.
5,698,527 and GB 2304106; an anti-oxidant such as beta-carotene,
ascorbic acid, .alpha.-tocopherol or retinol as disclosed in WO
94/15592 as well as Vitamin C and an antihomocysteine agent such as
folic acid, a folate, Vitamin B6, Vitamin B12 and Vitamin E;
isoniazid as disclosed in WO 97/35576; a cholesterol absorption
inhibitor, an HMG-CoA synthase inhibitor, or a lanosterol
demethylase inhibitor as disclosed in WO 97/48701; a PPAR .delta.
agonist for treating dyslipidemia; or a sterol regulating element
binding protein-I (SREBP-1) as disclosed in WO 2000/050574, for
example, a sphingolipid, such as ceramide, or neutral
sphingomyelenase (N-SMase) or fragment thereof. Preferred
hypolipidemic agents are pravastatin, lovastatin, simvastatin,
atorvastatin, fluvastatin, pitavastatin and rosuvastatin, as well
as niacin and/or cholestagel.
[0188] The compounds of the present invention may be employed in
combination with anti-hypertensive agents. Examples of suitable
anti-hypertensive agents for use in combination with the compounds
of the present invention include beta adrenergic blockers, calcium
channel blockers (L-type and/or T-type; e.g. diltiazem, verapamil,
nifedipine, amlodipine and mybefradil), diuretics (e.g.,
chlorothiazide, hydrochlorothiazide, flumethiazide,
hydroflumethiazide, bendroflumethiazide, methylchlorothiazide,
trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid
tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide,
triamtrenene, amiloride, spironolactone), renin inhibitors, ACE
inhibitors (e.g., captopril, zofenopril, fosinopril, enalapril,
ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril,
lisinopril), AT-1 receptor antagonists (e.g., losartan, irbesartan,
valsartan), ET receptor antagonists (e.g., sitaxsentan, atrsentan
and compounds disclosed in U.S. Pat. Nos. 5,612,359 and 6,043,265),
Dual ET/AII antagonist (e.g., compounds disclosed in WO 00/01389),
neutral endopeptidase (NEP) inhibitors, vasopepsidase inhibitors
(dual NEP-ACE inhibitors) (e.g., omapatrilat and gemopatrilat), and
nitrates.
[0189] Cannbinoid receptor modulators could be useful in treating
other diseases associated with obesity, including sleep disorders.
Therefore, the compounds described in the present invention could
be used in combination with therapeutics for treating sleep
disorders. Examples of suitable therapies for treatment of sleeping
disorders for use in combination with the compounds of the present
invention include melatonin analogs, melatonin receptor
antagonists, ML 1 B agonists, GABA receptor modulators; NMDA
receptor modulators, histamine-3 (H3) receptor modulators, dopamine
agonists and orexin receptor modulators.
[0190] Cannabinoid receptor modulators may reduce or ameliorate
substance abuse or addictive disorders. Therefore, combination of
cannabinoid receptor modulators with agents used to treat addictive
disorders may reduce the dose requirement or improve the efficacy
of current addictive disorder therapeutics. Examples of agents used
to treat substance abuse or addictive disorders are: selective
serotonin reuptake inhibitors (SSRI), methadone, buprenorphine,
nicotine and bupropion.
[0191] Cannabinoid receptor modulators may reduce anxiety or
depression; therefore, the compounds described in this application
may be used in combination with anti-anxiety agents or
antidepressants. Examples of suitable anti-anxiety agents for use
in combination with the compounds of the present invention include
benzodiazepines (e.g., diazepam, lorazepam, oxazepam, alprazolam,
chlordiazepoxide, clonazepam, chlorazepate, halazepam and
prazepam), 5HT1A receptor agonists (e.g., buspirone, flesinoxan,
gepirone and ipsapirone), and corticotropin releasing factor (CRF)
antagonists.
[0192] Examples of suitable classes of anti-depressants for use in
combination with the compounds of the present invention include
norepinephrine reuptake inhibitors (tertiary and secondary amine
tricyclics), selective serotonin reuptake inhibitors (SSRIs)
(fluoxetine, fluvoxamine, paroxetine and sertraline), monoamine
oxidase inhibitors (MAOIs) (isocarboxazid, phenelzine,
tranylcypromine, selegiline), reversible inhibitors of monoamine
oxidase (RIMAs) (moclobemide), serotonin and norepinephrine
reuptake inhibitors (SNRIs) (venlafaxine), corticotropin releasing
factor (CRF) receptor antagonists, alpah-adrenoreceptor
antagonists, and atypical antidepressants (bupropion, lithium,
nefazodone, trazodone and viloxazine).
[0193] The combination of a conventional antipsychotic drug with a
CB-1 receptor antagonist could also enhance symptom reduction in
the treatment of psychosis or mania. Further, such a combination
could enable rapid symptom reduction, reducing the need for chronic
treatment with antipsychotic agents. Such a combination could also
reduce the effective antipsychotic dose requirement, resulting in
reduced probability of developing the motor dysfunction typical of
chronic antipsychotic treatment.
[0194] Examples of suitable antipsychotic agents for use in
combination with the compounds of the present invention include the
phenothiazine (chlorpromazine, mesoridazine, thioridazine,
acetophenazine, fluphenazine, perphenazine and trifluoperazine),
thioxanthine (chlorprothixene, thiothixene), heterocyclic
dibenzazepine (clozapine, olanzepine and aripiprazole),
butyrophenone (haloperidol), dipheyylbutylpiperidine (pimozide) and
indolone (molindolone) classes of antipsychotic agents. Other
antipsychotic agents with potential therapeutic value in
combination with the compounds in the present invention include
loxapine, sulpiride and risperidone.
[0195] Combination of the compounds in the present invention with
conventional antipsychotic drugs could also provide an enhanced
therapeutic effect for the treatment of schizophrenic disorders, as
described above for manic disorders. As used here, schizophrenic
disorders include paranoid, disorganized, catatonic,
undifferentiated and residual schizophrenia, schizophreniform
disorder, shcizoaffective disorder, delusional disorder, brief
psychotic disorder and psychotic disorder not specified. Examples
of suitable antipsychotic drugs for combination with the compounds
in the present invention include the antipsychotics mentioned
above, as well as dopamine receptor antagonists, muscarinic
receptor agonists, 5HT2A receptor antagonists and 5HT2A/dopamine
receptor antagonists or partial agonists (e.g., olanzepine,
aripiprazole, risperidone, ziprasidone).
[0196] The compounds described in the present invention could be
used to enhance the effects of cognition-enhancing agents, such as
acetylcholinesterase inhibitors (e.g., tacrine), muscarinic
receptor-1 agonists (e.g., milameline), nicotinic agonists,
glutamic acid receptor (AMPA and NMDA) modulators, and nootropic
agents (e.g., piracetam, levetiracetam). Examples of suitable
therapies for treatment of Alzheimer's disease and cognitive
disorders for use in combination with the compounds of the present
invention include donepezil, tacrine, revastigraine, 5HT6, gamma
secretase inhibitors, beta secretase inhibitors, SK channel
blockers, Maxi-K blockers, and KCNQs blockers.
[0197] The compounds described in the present invention could be
used to enhance the effects of agents used in the treatment of
Parkinson's Disease. Examples of agents used to treat Parkinson's
Disease include: levadopa with or without a COMT inhibitor,
antiglutamatergic drugs (amantadine, riluzole), alpha-2 adrenergic
antagonists such as idazoxan, opiate antagonists, such as
naltrexone, other dopamine agonists or transportor modulators, such
as ropinirole, or pramipexole or neurotrophic factors such as glial
derived neurotrophic factor (GDNF).
[0198] The compounds described in the present invention could be
used in combination with suitable anti-inflammatory agents.
Examples of suitable anti-inflammatory agents for use in
combination with the compounds of the present invention include
prednisone, dexamethasone, cyclooxygenase inhibitors (i.e., COX-1
and/or COX-2 inhibitors such as NSAIDs, aspirin, indomethacin,
ibuprofen, piroxicam, Naproxen.RTM., Celebrex.RTM., Vioxx.RTM.),
CTLA4-Ig agonists/antagonists, CD40 ligand antagonists, IMPDH
inhibitors, such as mycophenolate (CellCept.RTM.), integrin
antagonists, alpha-4 beta-7 integrin antagonists, cell adhesion
inhibitors, interferon gamma antagonists, ICAM-1, tumor necrosis
factor (TNF) antagonists (e.g., infliximab, OR1384, including
TNF-alpha inhibitors, such as tenidap, anti-TNF antibodies or
soluble TNF receptor such as etanercept (Enbrel.RTM.), rapamycin
(sirolimus or Rapamune) and leflunomide (Arava)), prostaglandin
synthesis inhibitors, budesonide, clofazimine, CNI-1493, CD4
antagonists (e.g., priliximab), p38 mitogen-activated protein
kinase inhibitors, protein tyrosine kinase (PTK) inhibitors, IKK
inhibitors, and therapies for the treatment of irritable bowel
syndrome (e.g., Zelnorm.RTM. and Maxi-K.RTM. openers such as those
disclosed in U.S. Pat. No. 6,184,231 B1).
[0199] Exemplary of such other therapeutic agents which may be used
in combination with cannabinoid receptor modulators include the
following: cyclosporins (e.g., cyclosporin A), anti-IL-2 receptor
(Anti-Tac), anti-CD45RB, anti-CD2, anti-CD3 (OKT-3), anti-CD4,
anti-CD80, anti-CD86, monoclonal antibody OKT3, agents blocking the
interaction between CD40 and gp39, such as antibodies specific for
CD40 and/or gp39 (i.e., CD154), fusion proteins constructed from
CD40 and gp39 (CD40Ig and CD8gp39), inhibitors, such as nuclear
translocation inhibitors, of NF-kappa B function, such as
deoxyspergualin (DSG), gold compounds, antiproliferative agents
such as methotrexate, FK506 (tacrolimus, Prograf), mycophenolate
mofetil, cytotoxic drugs such as azathiprine and cyclophosphamide,
anticytokines such as antiIL-4 or IL-4 receptor fusion proteins and
PDE 4 inhibitors such as Ariflo, and the PTK inhibitors disclosed
in the following U.S. patent applications, incorporated herein by
reference in their entirety: Ser. No. 09/097,338, filed Jun. 15,
1998; Ser. No. 09/094,797, filed Jun. 15, 1998; Ser. No.
09/173,413, filed Oct. 15, 1998; and Ser. No. 09/262,525, filed
Mar. 4, 1999. See also the following documents and references cited
therein and incorporated herein by reference: Hollenbaugh, D., et
al., "Cleavable CD40Ig Fusion Proteins and the Binding to Sgp39",
J. Immunol. Methods (Netherlands), 188 (1), pp. 1-7 (Dec. 15,
1995); Hollenbaugh, D., et al., "The Human T Cell Antigen Gp39, A
Member of the TNF Gene Family, Is a Ligand for the CD40 Receptor:
Expression of a Soluble Form of Gp39 with B Cell Co-Stimulatory
Activity", EMBO J. (England), 11 (12), pp. 4313-4321 (December
1992); and Moreland, L. W. et al., "Treatment of Rheumatoid
Arthritis with a Recombinant Human Tumor Necrosis Factor Receptor
(P75)-Fc Fusion Protein," New England J. of Medicine, 337 (3), pp.
141-147 (1997).
[0200] The above other therapeutic agents, when employed in
combination with the compounds of the present invention, may be
used, for example, in those amounts indicated in the Physicians'
Desk Reference (PDR) or as otherwise determined by one of ordinary
skill in the art.
[0201] The compounds of formula (I) of the invention can be
administered orally or parenterally, such as subcutaneously or
intravenously, as well as by nasal application, rectally or
sublingually to various mammalian species known to be subject to
such maladies, e.g., humans, in an effective amount up to 1 gram,
preferably up to 200 mg, more preferably up to 100 mg in a regimen
of single, two or four divided daily doses.
[0202] The compounds of the formula (I) can be administered for any
of the uses described herein by any suitable means, for example,
orally, such as in the form of tablets, capsules, granules or
powders; sublingually; bucally; parenterally, such as by
subcutaneous, intravenous, intramuscular, or intrasternal injection
or infusion techniques (e.g., as sterile injectable aqueous or
non-aqueous solutions or suspensions); nasally, including
administration to the nasal membranes, such as by inhalation spray;
topically, such as in the form of a cream or ointment; or rectally
such as in the form of suppositories; in dosage unit formulations
containing non-toxic, pharmaceutically acceptable vehicles or
diluents. The present compounds can, for example, be administered
in a form suitable for immediate release or extended release.
Immediate release or extended release can be achieved by the use of
suitable pharmaceutical compositions comprising the present
compounds, or, particularly in the case of extended release, by the
use of devices such as subcutaneous implants or osmotic pumps. The
present compounds can also be administered liposomally.
[0203] Exemplary compositions for oral administration include
suspensions which can contain, for example, microcrystalline
cellulose for imparting bulk, alginic acid or sodium alginate as a
suspending agent, methylcellulose as a viscosity enhancer, and
sweeteners or flavoring agents such as those known in the art; and
immediate release tablets which can contain, for example,
microcrystalline cellulose, dicalcium phosphate, starch, magnesium
stearate and/or lactose and/or other excipients, binders,
extenders, disintegrants, diluents and lubricants such as those
known in the art. The compounds of formula I can also be delivered
through the oral cavity by sublingual and/or buccal administration.
Molded tablets, compressed tablets or freeze-dried tablets are
exemplary forms which may be used. Exemplary compositions include
those formulating the present compound(s) with fast dissolving
diluents such as mannitol, lactose, sucrose and/or cyclodextrins.
Also included in such formulations may be high molecular weight
excipients such as celluloses (avicel) or polyethylene glycols
(PEG). Such formulations can also include an excipient to aid
mucosal adhesion such as hydroxy propyl cellulose (HPC), hydroxy
propyl methyl cellulose (HPMC), sodium carboxy methyl cellulose
(SCMC), maleic anhydride copolymer (e.g., Gantrez), and agents to
control release such as polyacrylic copolymer (e.g. Carbopol 934).
Lubricants, glidants, flavors, coloring agents and stabilizers may
also be added for ease of fabrication and use.
[0204] Exemplary compositions for nasal aerosol or inhalation
administration include solutions in saline which can contain, for
example, benzyl alcohol or other suitable preservatives, absorption
promoters to enhance bioavailability, and/or other solubilizing or
dispersing agents such as those known in the art.
[0205] Exemplary compositions for parenteral administration include
injectable solutions or suspensions which can contain, for example,
suitable non-toxic, parenterally acceptable diluents or solvents,
such as mannitol, 1,3-butanediol, water, Ringer's solution, an
isotonic sodium chloride solution, or other suitable dispersing or
wetting and suspending agents, including synthetic mono- or
diglycerides, and fatty acids, including oleic acid, or
Cremaphor.
[0206] Exemplary compositions for rectal administration include
suppositories which can contain, for example, a suitable
non-irritating excipient, such as cocoa butter, synthetic glyceride
esters or polyethylene glycols, which are solid at ordinary
temperatures, but liquify and/or dissolve in the rectal cavity to
release the drug.
[0207] Exemplary compositions for topical administration include a
topical carrier such as Plastibase (mineral oil gelled with
polyethylene).
[0208] It will be understood that the specific dose level and
frequency of dosage for any particular subject can be varied and
will depend upon a variety of factors including the activity of the
specific compound employed, the metabolic stability and length of
action of that compound, the species, age, body weight, general
health, sex and diet of the subject, the mode and time of
administration, rate of excretion, drug combination, and severity
of the particular condition.
[0209] It should be understood that while this invention has been
described herein in terms of specific embodiments set forth in
detail, such embodiments are presented by way of illustration of
the general principles of the invention, and the invention is not
necessarily limited thereto. Certain modifications and variations
in any given material, process step or chemical formula will be
readily apparent to those skilled in the art without departing from
the true spirit and scope of the present invention, and all such
modifications and variations should be considered within the scope
of the claims that follow.
* * * * *