U.S. patent application number 14/678023 was filed with the patent office on 2015-07-30 for hetero-substituted acetanilide derivatives as analgesic agents.
The applicant listed for this patent is Janssen Pharmaceutica N.V. Invention is credited to John R. Carson, James J. McNally.
Application Number | 20150209339 14/678023 |
Document ID | / |
Family ID | 34838281 |
Filed Date | 2015-07-30 |
United States Patent
Application |
20150209339 |
Kind Code |
A1 |
Carson; John R. ; et
al. |
July 30, 2015 |
Hetero-Substituted Acetanilide Derivatives As Analgesic Agents
Abstract
Hetero-substituted acetanilide derivatives are disclosed as
analgesic agents. The compounds of the invention are useful in
methods for treating a disease or condition in a mammal
characterized by pain and/or fever.
Inventors: |
Carson; John R.;
(Norristown, PA) ; McNally; James J.; (Souderton,
PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Janssen Pharmaceutica N.V |
Beerse |
|
BE |
|
|
Family ID: |
34838281 |
Appl. No.: |
14/678023 |
Filed: |
April 3, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13716474 |
Dec 17, 2012 |
9018241 |
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14678023 |
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12751382 |
Mar 31, 2010 |
8357715 |
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13716474 |
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10778980 |
Feb 13, 2004 |
7718692 |
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12751382 |
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60439761 |
Jan 13, 2003 |
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Current U.S.
Class: |
514/354 ;
514/400; 514/406; 514/423 |
Current CPC
Class: |
A61K 31/416 20130101;
A61K 31/417 20130101; A61K 31/495 20130101; A61P 43/00 20180101;
C07D 213/81 20130101; C07D 231/14 20130101; A61K 31/4402 20130101;
A61K 31/44 20130101; A61K 31/415 20130101; C07D 207/34 20130101;
A61K 31/16 20130101; C07D 207/16 20130101; A61K 31/537 20130101;
A61K 31/54 20130101; A61K 31/40 20130101; C07D 231/56 20130101;
C07D 233/90 20130101 |
International
Class: |
A61K 31/4402 20060101
A61K031/4402; A61K 31/417 20060101 A61K031/417; A61K 31/415
20060101 A61K031/415; A61K 31/40 20060101 A61K031/40; A61K 31/416
20060101 A61K031/416 |
Claims
1. A method of controlling pain or fever in a subject in need
thereof comprising administering to the subject a compound of
Formula (I): ##STR00011## wherein: R.sup.1 and R.sup.2 taken
together with the atoms to which they are attached form a radical
selected from the group consisting of a 5 to 10 membered
cycloheteroalkanyl, 5 to 10 membered cycloheteroalkenyl and a 5 to
10 membered heteroaryl, wherein, in addition to the heteroatom N,
said radical may optionally contain 1 to 3 additional heteroatoms,
independently selected from the group consisting of O, N and S;
additionally, said radical may be further optionally substituted
with one to three substituents independently selected from the
group consisting of C.sub.1-6alkanyl and oxo; R.sup.3 is hydrogen
or C.sub.1-6alkanyl; R.sup.4 is a substituent selected from the
group consisting of hydrogen, C.sub.1-6alkanyl,
C.sub.1-6alkanyloxy, fluorinated alkanyl, fluorinated alkanyloxy,
halogen, hydroxyl, nitro, amino, C.sub.1-6alkanylamino;
C.sub.1-6dialkanylamino and cyano; n is an integer from 1 to 3; and
enantiomers, diastereomers, tautomers, solvates, or
pharmaceutically acceptable salts thereof.
2. The method of claim 1 wherein R.sup.1 and R.sup.2 taken together
with the atoms to which they are attached form a 5 to 10 membered
cycloheteroalkanyl radical, wherein, in addition to the heteroatom
N, said radical may optionally contain 1 to 3 additional
heteroatoms, independently selected from the group consisting of O,
N and S; additionally, said radical may be further optionally
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-6alkanyl and oxo;
3. The method of claim 1 wherein R.sup.1 and R.sup.2 taken together
with the atoms to which they are attached form a 5 to 10 membered
cycloheteroalkenyl radical, wherein, in addition to the heteroatom
N, said radical may optionally contain 1 to 3 additional
heteroatoms, independently selected from the group consisting of O,
N and S; additionally, said radical may be further optionally
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-6alkanyl and oxo;
4. The method of claim 1 wherein R.sup.1 and R.sup.2 taken together
with the atoms to which they are attached form a 5 to 10 membered
heteroaryl radical, wherein, in addition to the heteroatom N, said
radical may optionally contain 1 to 3 additional heteroatoms,
independently selected from the group consisting of O, N and S;
additionally, said radical may be further optionally substituted
with one to three substituents independently selected from the
group consisting of C.sub.1-6alkanyl and oxo;
5. The method of claim 1 wherein R.sup.1 and R.sup.2 taken together
with the atoms to which they are attached form a radical selected
from the group consisting of a 5 to 10 membered cycloheteroalkanyl,
5 to 10 membered cycloheteroalkenyl and a 5 to 10 membered
heteroaryl; additionally, said radical may be further optionally
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-6alkanyl and oxo;
6. The method of claim 1 wherein R.sup.3 is hydrogen.
7. The method of claim 1 wherein R.sup.4 is hydrogen.
8. The method of claim 1 wherein n is 1.
9. The method of claim 1 wherein the pain is caused by headache,
earache, dysmenorrhea, arthralgia, myalgia, musculoskeletal pain,
arthritis, immunizations, teething, tonsillectomy.
10. The method of claim 1 wherein the fever is caused by bacterial
or viral infections and as a substitute for aspirin in upper GI
disease, aspirin allergy, bleeding disorders, clients on
anticoagulant therapy, and gouty arthritis.
11-20. (canceled)
21. A method of controlling pain or fever in a subject in need
thereof comprising administering to the subject a compound of
Formula (I) wherein the compound of formula (I) is selected from
the group consisting of: Pyridine-2-carboxylic acid
(4-hydroxy-phenyl)-amide; (S)-Pyrrolidine-2-carboxylic acid
(4-hydroxy-phenyl)-amide; (R)-Pyrrolidine-2-carboxylic acid
(4-hydroxy-phenyl)-amide; 1H-Pyrrole-2-carboxylic acid
(4-hydroxy-phenyl)-amide; 1H-Indazole-3-carboxylic acid
(4-hydroxy-phenyl)-amide; 5-Methyl-1H-pyrazole-3-carboxylic acid
(4-hydroxy-phenyl)-amide; and 3H-Imidazole-4-carboxylic acid
(4-hydroxy-phenyl)-amide and enantiomers, diastereomers, tautomers,
solvates, or pharmaceutically acceptable salts thereof
22. (canceled)
23. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] Not applicable.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] The research and development of the invention described
below was not federally sponsored.
BACKGROUND OF THE INVENTION
[0003] Para-aminophenol type nonnarcotic analgesics/antipyretics
have been known for over a century. They act to decrease fever by
an effect on the hypothalamus leading to sweating and vasodilation
and inhibit the effect of pyrogens on the hypothalamic
heat-regulating centers. The mechanism of the analgesic action of
these agents is not fully understood. Although this analgesic
action was initially thought to be peripherally mediated, current
evidence supports a central mode of action (Acetaminophen-induced
hypothermia in mice: evidence for a central action of the parent
compound. Massey, Thomas E.; Walker, Robin M.; McElligott, Timothy
F.; Racz, William J. Dep. Pharmacol. Toxicol., Queen's Univ.,
Kingston, ON, Can. Toxicology (1982), 25(2-3), 187-200; Central
analgesic effect of acetaminophen but not of aspirin. Piletta,
Pierre; Porchet, Herve C.; Dayer, Pierre. Dep. Med., Univ. Hosp.,
Geneva, Switz. Clin. Pharmacol. Ther. (St. Louis) (1991), 49(4),
350-4.; Acetaminophen blocks spinal hyperalgesia induced by NMDA
and substance P. Bjoerkman, R.; Hallman, K. M.; Hedner, J.; Hedner,
T.; Henning, M. Pain (1994), 57(3), 259-64.). Suggested
biochemistries for this central mode of action include interaction
with the L-arginine-NO pathway (Piletta, ibid), modulation of brain
serotonin receptor level (Acetaminophen-induced antinociception via
central 5-HT2A receptors. Srikiatkhachorn, Anan; Tarasub, Naovarut;
Govitrapong, Piyarat. Neurochem. Int. (1999), 34(6), 491-498.) or
inhibition of COX-3 enzyme activity (N. V. Chandrasekharan, Hu Dai,
K. Lamar Turepu Roos, Nathan K. Evanson, Joshua Tomsik, Terry S.
Elton, and Daniel L. Simmons (2002) COX-3, a cyclooxygenase-1
variant inhibited by acetaminophen and other analgesic/antipyretic
drugs: Cloning, structure, and expression. Proc. Natl. Acad. Sci.
USA, 99:13926-13931, 2002). Inhibition of the COX-3 enzyme,
recently cloned from brain, points to the possible inhibition by
these agents of CNS prostaglandin synthesis. The antipyretic and
analgesic effects of these compounds are comparable to those of
aspirin.
[0004] Para-aminophenol type nonnarcotic analgesics have been used
to control pain due to headache, earache, dysmenorrhea, arthralgia,
myalgia, musculoskeletal pain, arthritis, immunizations, teething,
tonsillectomy. They are also used to reduce fever in bacterial or
viral infections and as a substitute for aspirin in upper GI
disease, aspirin allergy, bleeding disorders, clients on
anticoagulant therapy, and gouty arthritis.
[0005] Unexamined Japanese patent application 57007431 (Jan. 14,
1982) discloses various analgesic phenols. This application,
however, does not disclose or suggest the compounds of the present
invention.
[0006] U.S. Pat. No. 4,532,249 discloses derivatives of
para-acylaminophenol having analgesic activity. This patent,
however, does not disclose or suggest the compounds of the present
invention.
[0007] U.S. Pat. No. 3,689,555 discloses norbornyl
aminoacetanilides for uses in analgesics. This patent, however,
does not disclose or suggest the compounds of the present
invention.
[0008] International Patent Applications WO 96/32100 and WO
97/33860 disclose aminoalkyl-acetamides as analgesic agents. These
applications, however, do not disclose or suggest the compounds of
the present invention.
[0009] 5
[0010] U.S. Pat. No. 5,554,636 discloses
cyclicsulfonamidylalkylacetamides as analgesic agents. This patent,
however, does not disclose or suggest the compounds of the present
invention.
[0011] In view of their lack of ulcerative and anticoagulation
effects, para-aminophenol type nonnarcotic analgesics fill a need
in analgesic and antipyretic therapies in patients with problems
related to GI and cardiovascular disorders, and there is thus a
continuing need for new pharmaceutical compounds of this class.
SUMMARY OF THE INVENTION
[0012] The present invention is directed to analgesic and
anti-pyretic uses of compositions comprising a compound of Formula
(I):
##STR00001##
[0013] wherein: [0014] R.sup.1 and R.sup.2 taken together with the
atoms to which they are attached form a radical selected from the
group consisting of a 5 to 10 membered cycloheteroalkanyl, 5 to 10
membered cycloheteroalkenyl and a 5 to 10 membered heteroaryl,
wherein, in addition to the heteroatom N, said radical may
optionally contain 1 to 3 additional heteroatoms, independently
selected from the group consisting of O, N and S; additionally,
said radical may be further optionally substituted with one to
three substituents independently selected from the group consisting
of C.sub.1-6alkanyl and oxo; [0015] R.sup.3 is hydrogen or
C.sub.1-6alkanyl; [0016] R.sup.4 is a substituent selected from the
group consisting of hydrogen, C.sub.1-6alkanyl,
C.sub.1-6alkanyloxy, fluorinated alkanyl, fluorinated alkanyloxy,
halogen, hydroxyl, nitro, amino, C.sub.1-6alkanylamino;
C.sub.1-6dialkanylamino and cyano; [0017] n is an integer from 1 to
3; and enantiomers, diastereomers, tautomers, solvates, or
pharmaceutically acceptable salts thereof.
[0018] The present invention is directed to analgesic and
anti-pyretic uses of compositions comprising a compound of Formula
(II):
##STR00002##
[0019] wherein: [0020] R.sup.1 is a substituent independently
selected from the group consisting of hydrogen and
C.sub.1-6alkanyl; [0021] R.sup.2 is a substituent independently
selected from the group consisting of hydrogen, C.sub.1-6alkanyl
and dioxo; [0022] or R.sup.1 and R.sup.2 taken together with the
atoms to which they are attached form a radical selected from the
group consisting of a 5 to 10 membered cycloheteroalkanyl, 5 to 10
membered cycloheteroalkenyl and a 5 to 10 membered heteroaryl,
wherein, in addition to the heteroatom N, said radical may
optionally contain 1 to 3 additional heteroatoms, independently
selected from the group consisting of O, N and S; additionally,
said radical may be further optionally substituted with one to
three substituents independently selected from the group consisting
of C.sub.1-6alkanyl and oxo; [0023] R.sup.4 is a substituent
selected from the group consisting of hydrogen, C.sub.1-6alkanyl,
C.sub.1-6alkanyloxy, fluorinated alkanyl, fluorinated alkanyloxy,
halogen, hydroxyl, nitro, amino, C.sub.1-6alkanylamino;
C.sub.1-6dialkanylamino and cyano; [0024] n is an integer from 1 to
3; and enantiomers, diastereomers, tautomers, solvates, or
pharmaceutically acceptable salts thereof.
[0025] Finally, the present invention is directed to pharmaceutical
compositions containing compounds of Formula (I) wherein R.sup.3 is
hydrogen and R.sup.1 and R.sup.2 taken together form an optionally
substituted pyrrole.
DETAILED DESCRIPTION OF THE INVENTION
[0026] As used herein, the following underlined terms are intended
to have the following meanings:
[0027] "C.sub.a-b" (where a and b are integers) refers to a radical
containing from a to b carbon atoms inclusive. For example,
C.sub.1-3 denotes a radical containing 1, 2 or 3 carbon atoms
[0028] "Alkyl:" refers to a saturated or unsaturated, branched,
straight-chain or cyclic monovalent hydrocarbon radical derived by
the removal of one hydrogen atom from a single carbon atom of a
parent alkane, alkene or alkyne. Typical alkyl groups include, but
are not limited to, methyl; ethyls such as ethanyl, ethenyl,
ethynyl; propyls such as propan-1-yl, propan-2-yl, cyclopropan-1-yl
( ), prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl,
cycloprop-1-en-1-yl; cycloprop-2-en-1-yl, prop-1-yn-1-yl,
prop-2-yn-1-yl, etc.; butyls such as butan-1-yl, butan-2-yl,
2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl,
but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl,
but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl,
buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl,
cyclobuta-1,3-dien-1-yl, but-1-yn-1-yl, but-1-yn-3-yl,
but-3-yn-1-yl, etc.; and the like. Where specific levels of
saturation are intended, the nomenclature "alkanyl", "alkenyl"
and/or "alkynyl" is used, as defined below. In preferred
embodiments, the alkyl groups are (C.sub.1-C.sub.6) alkyl, with
(C.sub.1-C.sub.3) being particularly preferred.
[0029] "Alkanyl:" refers to a saturated branched, straight-chain or
cyclic monovalent hydrocarbon radical derived by the removal of one
hydrogen atom from a single carbon atom of a parent alkane. Typical
alkanyl groups include, but are not limited to, methanyl; ethanyl;
propanyls such as propan-1-yl, propan-2-yl, cyclopropan-1-yl, etc.;
butyanyls such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl,
2-methyl-propan-2-yl, cyclobutan-1-yl, etc.; and the like. In
preferred embodiments, the alkanyl groups are (C.sub.1-8) alkanyl,
with (C.sub.1-3) being particularly preferred.
[0030] "Alkenyl" refers to an unsaturated branched, straight-chain
or cyclic monovalent hydrocarbon radical having at least one
carbon-carbon double bond derived by the removal of one hydrogen
atom from a single carbon atom of a parent alkene. The radical may
be in either the cis or trans conformation about the double
bond(s). Typical alkenyl groups include, but are not limited to,
ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl,
prop-2-en-1-yl, prop-2-en-2-yl, cycloprop-1-en-1-yl;
cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl,
2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl,
but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,
cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl,
etc.; and the like.
[0031] "Alkynyl" refers to an unsaturated branched, straight-chain
or cyclic monovalent hydrocarbon radical having at least one carbon
carbon triple bond derived by the removal of one hydrogen atom from
a single carbon atom of a parent alkyne. Typical alkynyl groups
include, but are not limited to, ethynyl; propynyls such as
prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such as
but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the
like.
[0032] "Heteroalkyl" and Heteroalkanyl" refer to alkyl or alkanyl
radicals, respectively, in which one or more carbon atoms (and any
necessary associated hydrogen atoms) are independently replaced
with the same or different heteroatoms (including any necessary
hydrogen or other atoms). Typical heteroatoms to replace the carbon
atom(s) include, but are not limited to, N, P, O, S, Si, etc.
Preferred heteroatoms are O, N and S. Thus, heteroalkanyl radicals
can contain one or more of the same or different heteroatomic
groups, including, by way of example and not limitation, epoxy
(--O--), epidioxy (--O--O--), thioether (--S--), epidithio
(--SS--), epoxythio (--O--S--), epoxyimino (--O--NR'--), imino
(--NR'--), biimmino (--NR'--NR'--), azino (.dbd.N--N.dbd.), azo
(--N.dbd.N--), azoxy (--N--O--N--), azimino (--NR'--N.dbd.N--),
phosphano (--PH--), .lamda..sup.4-sulfano (--SH.sub.2--), sulfonyl
(--S(O).sub.2--), and the like, where each R' is independently
hydrogen or (C.sub.1-C.sub.6) alkyl.
[0033] "Parent Aromatic Ring System:" refers to an unsaturated
cyclic or polycyclic ring system having a conjugated .pi. electron
system. Specifically included within the definition of "parent
aromatic ring system" are fused ring systems in which one or more
rings are aromatic and one or more rings are saturated or
unsaturated, such as, for example, indane, indene, phenalene, etc.
Typical parent aromatic ring systems include, but are not limited
to, aceanthrylene, acenaphthylene, acephenanthrylene, anthracene,
azulene, benzene, chrysene, coronene, fluoranthene, fluorene,
hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane,
indene, naphthalene, octacene, octaphene, octalene, ovalene,
penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,
phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,
rubicene, triphenylene, trinaphthalene, and the like
[0034] "Aryl:" refers to a monovalent aromatic hydrocarbon radical
derived by the removal of one hydrogen atom from a single carbon
atom of a parent aromatic ring system. Typical aryl groups include,
but are not limited to, radicals derived from aceanthrylene,
acenaphthylene, acephenanthrylene, anthracene, azulene, benzene,
chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene,
hexalene, as-indacene, s-indacene, indane, indene, naphthalene,
octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene,
pentalene, pentaphene, perylene, phenalene, phenanthrene, picene,
pleiadene, pyrene, pyranthrene, rubicene, triphenylene,
trinaphthalene, and the like. In preferred embodiments, the aryl
group is (C.sub.5-20) aryl, with (C.sub.5-10) being particularly
preferred. Particularly preferred aryl groups are phenyl and
naphthyl groups.
[0035] "Arylalkyl:" refers to an acyclic alkyl group in which one
of the hydrogen atoms bonded to a carbon atom, typically a terminal
carbon atom, is replaced with an aryl radical. Typical arylalkyl
groups include, but are not limited to, benzyl, 2-phenylethan-1-yl,
2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl,
2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and
the like. Where specific alkyl moieties are intended, the
nomenclature arylalkanyl, arylakenyl and/or arylalkynyl is used.
[In preferred embodiments, the arylalkyl group is (C.sub.6-26)
arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the
arylalkyl group is (C.sub.1-6) and the aryl moiety is (C.sub.5-20).
In particularly preferred embodiments the arylalkyl group is
(C.sub.6-13), e.g., the alkanyl, alkenyl or alkynyl moiety of the
arylalkyl group is (C.sub.1-3) and the aryl moiety is (C.sub.5-10).
Even more preferred arylalkyl groups are phenylalkanyls.
[0036] "Alkanyloxy:" refers to a saturated branched, straight-chain
or cyclic monovalent hydrocarbon alcohol radical derived by the
removal of the hydrogen atom from the hydroxide oxygen of the
alcohol. Typical alkanyloxy groups include, but are not limited to,
methanyl; ethanyloxy; propanyloxy groups such as propan-1-yloxy
(CH.sub.3CH.sub.2CH.sub.2O--), propan-2-yloxy
((CH.sub.3).sub.2CHO--), cyclopropan-1-yloxy, etc.; butyanyloxy
groups such as butan-1-yloxy, butan-2-yloxy,
2-methyl-propan-1-yloxy, 2-methyl-propan-2-yloxy,
cyclobutan-1-yloxy, etc.; and the like. In preferred embodiments,
the alkanyloxy groups are (C.sub.1-8) alkanyloxy groups, with
(C.sub.1-3) being particularly preferred.
[0037] "Parent Heteroaromatic Ring System:" refers to a parent
aromatic ring system in which one carbon atom is replaced with a
heteroatom. Heteratoms to replace the carbon atoms include N, O,
and S. Specifically included within the definition of "parent
heteroaromatic ring systems" are fused ring systems in which one or
more rings are aromatic and one or more rings are saturated or
unsaturated, such as, for example, arsindole, chromane, chromene,
indole, indoline, xanthene, etc. Typical parent heteroaromatic ring
systems include, but are not limited to, carbazole, imidazole,
indazole, indole, indoline, indolizine, isoindole, isoindoline,
isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole,
oxazole, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine,
pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline,
quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole,
thiophene, triazole, xanthene, and the like.
[0038] "Heteroaryl:" refers to a monovalent heteroaromatic radical
derived by the removal of one hydrogen atom from a single atom of a
parent heteroaromatic ring system. Typical heteroaryl groups
include, but are not limited to, radicals derived from carbazole,
imidazole, indazole, indole, indoline, indolizine, isoindole,
isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine,
oxadiazole, oxazole, purine, pyran, pyrazine, pyrazole, pyridazine,
pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline,
quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole,
thiophene, triazole, xanthene, and the like. In preferred
embodiments, the heteroaryl group is a 5-20 membered heteroaryl,
with 5-10 membered heteroaryl being particularly preferred.
[0039] "Cycloheteroalkyl:" refers to a saturated or unsaturated
monocyclic or bicyclic alkyl radical in which one carbon atom is
replaced with N, O or S. In certain specified embodiments the
cycloheteroalkyl may contain up to four heteroatoms independently
selected from N, O or S. Typical cycloheteroalkyl moieties include,
but are not limited to, radicals derived from imidazolidine,
morpholine, piperazine, piperidine, pyrazolidine, pyrrolidine,
quinuclidine, and the like. In preferred embodiments, the
cycloheteroalkyl is a 3-6 membered cycloheteroalkyl.
[0040] "Cycloheteroalkanyl:" refers to a saturated monocyclic or
bicyclic alkanyl radical in which one carbon atom is replaced with
N, O or S. In certain specified embodiments the cycloheteroalkanyl
may contain up to four heteroatoms independently selected from N, O
or S. Typical cycloheteroalkanyl moieties include, but are not
limited to, radicals derived from imidazolidine, morpholine,
piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine,
and the like. In preferred embodiments, the cycloheteroalkanyl is a
3-6 membered cycloheteroalkanyl.
[0041] "Cycloheteroalkenyl:" refers to a saturated monocyclic or
bicyclic alkenyl radical in which one carbon atom is replaced with
N, O or S. In certain specified embodiments the cycloheteroalkenyl
may contain up to four heteroatoms independently selected from N, O
or S. Typical cycloheteroalkenyl moieties include, but are not
limited to, radicals derived from imidazoline, pyrazoline,
pyrroline, indoline, pyran, and the like. In preferred embodiments,
the cycloheteroalkanyl is a 3-6 membered cycloheteroalkanyl.
[0042] "Substituted:" refers to a radical in which one or more
hydrogen atoms are each independently replaced with the same or
different substituent(s). Typical substituents include, but are not
limited to, --X, --R, --O.sup.-, .dbd.O, --OR, --O--OR, --SR,
--S.sup.-, .dbd.S, --NRR, .dbd.NR, --CX.sub.3, --CN, --OCN, --SCN,
--NCO, --NCS, --NO, --NO.sub.2, .dbd.N.sub.2, --N.sub.3, --NHOH,
--S(O).sub.2O.sup.-, --S(O).sub.2OH, --S(O).sub.2R,
--P(O)(O.sup.-).sub.2, --P(O)(OH).sub.2, --C(O)R, --C(O)X, --C(S)R,
--C(S)X, --C(O)OR, --C(O)O.sup.-, --C(S)OR, --C(O)SR, --C(S)SR,
--C(O)NRR, --C(S)NRR and --C(NR)NRR, where each X is independently
a halogen (preferably --F, --Cl or --Br) and each R is
independently --H, alkyl, alkanyl, alkenyl, alkynyl, alkylidene,
alkylidyne, aryl, arylalkyl, arylheteroalkyl, heteroaryl,
heteroarylalkyl or heteroaryl-heteroalkyl, as defined herein.
Preferred substituents include hydroxy, halogen, C.sub.1-8alkyl,
C.sub.1-8alkanyloxy, fluorinated alkanyloxy, fluorinated alkyl,
C.sub.1-6alkylthio, C.sub.3-8cycloalkyl, C.sub.3-8cycloalkanyloxy,
nitro, amino, C.sub.1-8alkylamino, C.sub.1-8dialkylamino,
C.sub.3-8cycloalkylamino, cyano, carboxy,
C.sub.1-7alkanyloxycarbonyl, C.sub.1-7alkylcarbonyloxy, formyl,
carbamoyl, phenyl, aroyl, carbamoyl, amidino,
(C.sub.1-8alkylamino)carbonyl, (arylamino)carbonyl and
aryl(C.sub.1-8alkyl)carbonyl.
[0043] With reference to substituents, the term "independently"
means that when more than one of such substituent is possible, such
substituents may be the same or different from each other.
[0044] Throughout this disclosure, the terminal portion of the
designated side chain is described first, followed by the adjacent
functionality toward the point of attachment. Thus, for example, a
"phenylC.sub.1-6alkanylaminocarbonylC.sub.1-6alkyl" substituent
refers to a group of the formula
##STR00003##
[0045] The present invention is directed to analgesic and
anti-pyretic uses of compositions comprising a compound of Formula
(I):
##STR00004##
[0046] wherein: [0047] R.sup.1 and R.sup.2 taken together with the
atoms to which they are attached form a radical selected from the
group consisting of a 5 to 10 membered cycloheteroalkanyl, 5 to 10
membered cycloheteroalkenyl and a 5 to 10 membered heteroaryl,
wherein, in addition to the heteroatom N, said radical may
optionally contain 1 to 3 additional heteroatoms, independently
selected from the group consisting of O, N and S; additionally,
said radical may be further optionally substituted with one to
three substituents independently selected from the group consisting
of C.sub.1-6alkanyl and oxo; [0048] R.sup.3 is hydrogen or
C.sub.1-6alkanyl; [0049] R.sup.4 is a substituent selected from the
group consisting of hydrogen, C.sub.1-6alkanyl,
C.sub.1-6alkanyloxy, fluorinated alkanyl, fluorinated alkanyloxy,
halogen, hydroxyl, nitro, amino, C.sub.1-6alkanylamino;
C.sub.1-6dialkanylamino and cyano; [0050] n is an integer from 1 to
3; and enantiomers, diastereomers, tautomers, solvates, or
pharmaceutically acceptable salts thereof.
[0051] Embodiments of the present invention include those wherein
for compounds of formula (I): [0052] a) R.sup.1 and R.sup.2 taken
together with the atoms to which they are attached form a 5 to 10
membered cycloheteroalkanyl radical, wherein, in addition to the
heteroatom N, said radical may optionally contain 1 to 3 additional
heteroatoms, independently selected from the group consisting of O,
N and S; additionally, said radical may be further optionally
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-6alkanyl and oxo; [0053] b)
R.sup.1 and R.sup.2 taken together with the atoms to which they are
attached form a 5 to 10 membered cycloheteroalkenyl radical,
wherein, in addition to the heteroatom N, said radical may
optionally contain 1 to 3 additional heteroatoms, independently
selected from the group consisting of O, N and S; additionally,
said radical may be further optionally substituted with one to
three substituents independently selected from the group consisting
of C.sub.1-6alkanyl and oxo; [0054] c) R.sup.1 and R.sup.2 taken
together with the atoms to which they are attached form a 5 to 10
membered heteroaryl radical, wherein, in addition to the heteroatom
N, said radical may optionally contain 1 to 3 additional
heteroatoms, independently selected from the group consisting of O,
N and S; additionally, said radical may be further optionally
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-6alkanyl and oxo; [0055] d)
R.sup.1 and R.sup.2 taken together with the atoms to which they are
attached form a radical selected from the group consisting of a 5
to 10 membered cycli heteroalkyl and a 5 to 10 membered heteroaryl;
additionally, said radical may be further optionally substituted
with one to three substituents independently selected from the
group consisting of C.sub.1-6alkanyl and oxo; [0056] e) R.sup.3 is
hydrogen; [0057] f) R.sup.4 is hydrogen; [0058] g) n is 1; and
[0059] h) combinations of a) through g) above. Thus, exemplary
embodiments of the present invention are as described below.
[0060] An embodiment of the present invention is directed to
analgesic and anti-pyretic uses of compositions comprising a
compound of Formula (I) wherein: [0061] R.sup.1 and R.sup.2 taken
together with the atoms to which they are attached form a 5 to 10
membered cycloheteroalkanyl radical, wherein, in addition to the
heteroatom N, said radical may optionally contain 1 to 3 additional
heteroatoms, independently selected from the group consisting of O,
N and S; additionally, said radical may be further optionally
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-6alkanyl and oxo; [0062]
R.sup.3 is hydrogen or C.sub.1-6alkanyl; [0063] R.sup.4 is a
substituent selected from the group consisting of hydrogen,
C.sub.1-6alkanyl, C.sub.1-6alkanyloxy, fluorinated alkanyl,
fluorinated alkanyloxy, halogen, hydroxyl, nitro, amino,
C.sub.1-6alkanylamino; C.sub.1-6dialkanylamino and cyano; [0064] n
is an integer from 1 to 3; and enantiomers, diastereomers,
tautomers, solvates, or pharmaceutically acceptable salts
thereof.
[0065] Another embodiment of the present invention is directed to
analgesic and anti-pyretic uses of compositions comprising a
compound of Formula (I) wherein: [0066] R.sup.1 and R.sup.2 taken
together with the atoms to which they are attached form a 5 to 10
membered cycloheteroalkenyl, wherein, in addition to the heteroatom
N, said radical may optionally contain 1 to 3 additional
heteroatoms, independently selected from the group consisting of O,
N and S; additionally, said radical may be further optionally
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-6alkanyl and oxo; [0067]
R.sup.3 is hydrogen or C.sub.1-6alkanyl; [0068] R.sup.4 is a
substituent selected from the group consisting of hydrogen,
C.sub.1-6alkanyl, C.sub.1-6alkanyloxy, fluorinated alkanyl,
fluorinated alkanyloxy, halogen, hydroxyl, nitro, amino,
C.sub.1-6alkanylamino; C.sub.1-6dialkanylamino and cyano; [0069] n
is an integer from 1 to 3; and enantiomers, diastereomers,
tautomers, solvates, or pharmaceutically acceptable salts
thereof.
[0070] Still another embodiment of the present invention is
directed to analgesic and anti-pyretic uses of compositions
comprising a compound of Formula (I) wherein: [0071] R.sup.1 and
R.sup.2 taken together with the atoms to which they are attached
form a 5 to 10 membered heteroaryl radical, wherein, in addition to
the heteroatom N, said radical may optionally contain 1 to 3
additional heteroatoms, independently selected from the group
consisting of O, N and S; additionally, said radical may be further
optionally substituted with one to three substituents independently
selected from the group consisting of C.sub.1-6alkanyl and oxo;
[0072] R.sup.3 is hydrogen or C.sub.1-6alkanyl; [0073] R.sup.4 is a
substituent selected from the group consisting of hydrogen,
C.sub.1-6alkanyl, C.sub.1-6alkanyloxy, fluorinated alkanyl,
fluorinated alkanyloxy, halogen, hydroxyl, nitro, amino,
C.sub.1-6alkanylamino; C.sub.1-6dialkanylamino and cyano; [0074] n
is an integer from 1 to 3; and enantiomers, diastereomers,
tautomers, solvates, or pharmaceutically acceptable salts
thereof.
[0075] Still another embodiment of the present invention is
directed to analgesic and anti-pyretic uses of compositions
comprising a compound of Formula (I) wherein: [0076] R.sup.1 and
R.sup.2 taken together with the atoms to which they are attached
form a radical selected from the group consisting of a 5 to 10
membered cycloheteroalkanyl, 5 to 10 membered cycloheteroalkenyl
and a 5 to 10 membered heteroaryl; additionally, said radical may
be further optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-6alkanyl and oxo; [0077] R.sup.3 is hydrogen or
C.sub.1-6alkanyl; [0078] R.sup.4 is a substituent selected from the
group consisting of hydrogen, C.sub.1-6alkanyl,
C.sub.1-6alkanyloxy, fluorinated alkanyl, fluorinated alkanyloxy,
halogen, hydroxyl, nitro, amino, C.sub.1-6alkanylamino;
C.sub.1-6dialkanylamino and cyano; [0079] n is an integer from 1 to
3; and enantiomers, diastereomers, tautomers, solvates, or
pharmaceutically acceptable salts thereof.
[0080] Still yet another embodiment of the present invention is
directed to analgesic and anti-pyretic uses of compositions
comprising a compound of Formula (I) wherein: [0081] R.sup.1 and
R.sup.2 taken together with the atoms to which they are attached
form a radical selected from the group consisting of a 5 to 10
membered cycloheteroalkanyl, 5 to 10 membered cycloheteroalkenyl
and a 5 to 10 membered heteroaryl, wherein, in addition to the
heteroatom N, said radical may optionally contain 1 to 3 additional
heteroatoms, independently selected from the group consisting of O,
N and S; additionally, said radical may be further optionally
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-6alkanyl and oxo; [0082]
R.sup.3 is hydrogen; [0083] R.sup.4 is a substituent selected from
the group consisting of hydrogen, C.sub.1-6alkanyl,
C.sub.1-6alkanyloxy, fluorinated alkanyl, fluorinated alkanyloxy,
halogen, hydroxyl, nitro, amino, C.sub.1-6alkanylamino;
C.sub.1-6dialkanylamino and cyano; [0084] n is an integer from 1 to
3; and enantiomers, diastereomers, tautomers, solvates, or
pharmaceutically acceptable salts thereof.
[0085] Still another embodiment of the present invention is
directed to analgesic and anti-pyretic uses of compositions
comprising a compound of Formula (I) wherein: [0086] R.sup.1 and
R.sup.2 taken together with the atoms to which they are attached
form a radical selected from the group consisting of a 5 to 10
membered cycloheteroalkanyl, 5 to 10 membered cycloheteroalkenyl
and a 5 to 10 membered heteroaryl, wherein, in addition to the
heteroatom N, said radical may optionally contain 1 to 3 additional
heteroatoms, independently selected from the group consisting of O,
N and S; additionally, said radical may be further optionally
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-6alkanyl and oxo; [0087]
R.sup.3 is hydrogen or C.sub.1-6alkanyl; [0088] R.sup.4 is
hydrogen; [0089] n is an integer from 1 to 3; and enantiomers,
diastereomers, tautomers, solvates, or pharmaceutically acceptable
salts thereof.
[0090] Still yet another embodiment of the present invention is
directed to analgesic and anti-pyretic uses of compositions
comprising a compound of Formula (I) wherein: [0091] R.sup.1 and
R.sup.2 taken together with the atoms to which they are attached
form a radical selected from the group consisting of a 5 to 10
membered cycloheteroalkanyl, 5 to 10 membered cycloheteroalkenyl
and a 5 to 10 membered heteroaryl, wherein, in addition to the
heteroatom N, said radical may optionally contain 1 to 3 additional
heteroatoms, independently selected from the group consisting of O,
N and S; additionally, said radical may be further optionally
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-6alkanyl and oxo; [0092]
R.sup.3 is hydrogen or C.sub.1-6alkanyl; [0093] R.sup.4 is a
substituent selected from the group consisting of hydrogen,
C.sub.1-6alkanyl, C.sub.1-6alkanyloxy, fluorinated alkanyl,
fluorinated alkanyloxy, halogen, hydroxyl, nitro, amino,
C.sub.1-6alkanylamino; C.sub.1-6dialkanylamino and cyano; [0094] n
is 1; and enantiomers, diastereomers, tautomers, solvates, or
pharmaceutically acceptable salts thereof.
[0095] The present invention is directed to analgesic and
anti-pyretic uses of compositions comprising a compound of Formula
(II):
##STR00005##
[0096] wherein: [0097] R.sup.1 is a substituent independently
selected from the group consisting of hydrogen and
C.sub.1-6alkanyl; [0098] R.sup.2 is a substituent independently
selected from the group consisting of hydrogen, C.sub.1-6alkanyl
and dioxo; [0099] or R.sup.1 and R.sup.2 taken together with the
atoms to which they are attached form a radical selected from the
group consisting of a 5 to 10 membered cycloheteroalkanyl, 5 to 10
membered cycloheteroalkenyl and a 5 to 10 membered heteroaryl,
wherein, in addition to the heteroatom N, said radical may
optionally contain 1 to 3 additional heteroatoms, independently
selected from the group consisting of O, N and S; additionally,
said radical may be further optionally substituted with one to
three substituents independently selected from the group consisting
of C.sub.1-6alkanyl and oxo; [0100] R.sup.4 is a substituent
selected from the group consisting of hydrogen, C.sub.1-6alkanyl,
C.sub.1-6alkanyloxy, fluorinated alkanyl, fluorinated alkanyloxy,
halogen, hydroxyl, nitro, amino, C.sub.1-6alkanylamino;
C.sub.1-6dialkanylamino and cyano; [0101] n is an integer from 1 to
3; and enantiomers, diastereomers, tautomers, solvates, or
pharmaceutically acceptable salts thereof.
[0102] Embodiments of the present invention include those wherein
for compounds of Formula (II): [0103] a) R.sup.1 and R.sup.2 taken
together with the atoms to which they are attached form a 5 to 10
membered cycloheteroalkanyl, wherein, in addition to the heteroatom
N, said radical may optionally contain 1 to 3 additional
heteroatoms, independently selected from the group consisting of O,
N and S; additionally, said radical may be further optionally
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-6alkanyl and oxo; [0104] b)
R.sup.1 and R.sup.2 taken together with the atoms to which they are
attached form a 5 to 10 membered cycloheteroalkenyl radical,
wherein, in addition to the heteroatom N, said radical may
optionally contain 1 to 3 additional heteroatoms, independently
selected from the group consisting of O, N and S; additionally,
said radical may be further optionally substituted with one to
three substituents independently selected from the group consisting
of C.sub.1-6alkanyl and oxo; [0105] c) R.sup.1 and R.sup.2 taken
together with the atoms to which they are attached form a 5 to 10
membered heteroaryl radical, wherein, in addition to the heteroatom
N, said radical may optionally contain 1 to 3 additional
heteroatoms, independently selected from the group consisting of O,
N and S; additionally, said radical may be further optionally
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-6alkanyl and oxo; [0106] d)
R.sup.1 and R.sup.2 taken together with the atoms to which they are
attached form a radical selected from the group consisting of a 5
to 10 membered cycli heteroalkyl and a 5 to 10 membered heteroaryl;
additionally, said radical may be further optionally substituted
with one to three substituents independently selected from the
group consisting of C.sub.1-6alkanyl and oxo; [0107] e) R.sup.4 is
hydrogen; [0108] f) n is 1; and [0109] g) combinations of a)
through f) above. Thus, exemplary embodiments of the present
invention are as described below.
[0110] An embodiment of the present invention is directed to
analgesic and anti-pyretic uses of compositions comprising a
compound of Formula (II) wherein: [0111] R.sup.1 and R.sup.2 taken
together with the atoms to which they are attached form a 5 to 10
membered cycloheteroalkanyl radical, wherein, in addition to the
heteroatom N, said radical may optionally contain 1 to 3 additional
heteroatoms, independently selected from the group consisting of O,
N and S; additionally, said radical may be further optionally
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-6alkanyl and oxo; [0112]
R.sup.4 is a substituent selected from the group consisting of
hydrogen, C.sub.1-6alkanyl, C.sub.1-6alkanyloxy, fluorinated
alkanyl, fluorinated alkanyloxy, halogen, hydroxyl, nitro, amino,
C.sub.1-6alkanylamino; C.sub.1-6dialkanylamino and cyano; [0113] n
is an integer from 1 to 3; and enantiomers, diastereomers,
tautomers, solvates, or pharmaceutically acceptable salts
thereof.
[0114] Another embodiment of the present invention is directed to
analgesic and anti-pyretic uses of compositions comprising a
compound of Formula (II) wherein: [0115] R.sup.1 and R.sup.2 taken
together with the atoms to which they are attached form a 5 to 10
membered cycli heteroalkenyl, wherein, in addition to the
heteroatom N, said radical may optionally contain 1 to 3 additional
heteroatoms, independently selected from the group consisting of O,
N and S; additionally, said radical may be further optionally
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-6alkanyl and oxo; [0116]
R.sup.4 is a substituent selected from the group consisting of
hydrogen, C.sub.1-6alkanyl, C.sub.1-6alkanyloxy, fluorinated
alkanyl, fluorinated alkanyloxy, halogen, hydroxyl, nitro, amino,
C.sub.1-6alkanylamino; C.sub.1-6dialkanylamino and cyano; [0117] n
is an integer from 1 to 3; and enantiomers, diastereomers,
tautomers, solvates, or pharmaceutically acceptable salts
thereof.
[0118] Still another embodiment of the present invention is
directed to analgesic and anti-pyretic uses of compositions
comprising a compound of Formula (II) wherein: [0119] R.sup.1 and
R.sup.2 taken together with the atoms to which they are attached
form a 5 to 10 membered heteroaryl radical, wherein, in addition to
the heteroatom N, said radical may optionally contain 1 to 3
additional heteroatoms, independently selected from the group
consisting of O, N and S; additionally, said radical may be further
optionally substituted with one to three substituents independently
selected from the group consisting of C.sub.1-6alkanyl and oxo;
[0120] R.sup.4 is a substituent selected from the group consisting
of hydrogen, C.sub.1-6alkanyl, C.sub.1-6alkanyloxy, fluorinated
alkanyl, fluorinated alkanyloxy, halogen, hydroxyl, nitro, amino,
C.sub.1-6alkanylamino; C.sub.1-6dialkanylamino and cyano; [0121] n
is an integer from 1 to 3; and enantiomers, diastereomers,
tautomers, solvates, or pharmaceutically acceptable salts
thereof.
[0122] Still another embodiment of the present invention is
directed to analgesic and anti-pyretic uses of compositions
comprising a compound of Formula (II) wherein: [0123] R.sup.1 and
R.sup.2 taken together with the atoms to which they are attached
form a radical selected from the group consisting of a 5 to 10
membered cycloheteroalkanyl, 5 to 10 membered cycloheteroalkenyl
and a 5 to 10 membered heteroaryl; additionally, said radical may
be further optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-6alkanyl and oxo; [0124] R.sup.4 is a substituent selected
from the group consisting of hydrogen, C.sub.1-6alkanyl,
C.sub.1-6alkanyloxy, fluorinated alkanyl, fluorinated alkanyloxy,
halogen, hydroxyl, nitro, amino, C.sub.1-6alkanylamino;
C.sub.1-6dialkanylamino and cyano; [0125] n is an integer from 1 to
3; and enantiomers, diastereomers, tautomers, solvates, or
pharmaceutically acceptable salts thereof.
[0126] Still another embodiment of the present invention is
directed to analgesic and anti-pyretic uses of compositions
comprising a compound of Formula (II) wherein:
[0127] R.sup.1 and R.sup.2 taken together with the atoms to which
they are attached form a radical selected from the group consisting
of a 5 to 10 membered cycloheteroalkanyl, 5 to 10 membered
cycloheteroalkenyl and a 5 to 10 membered heteroaryl, wherein, in
addition to the heteroatom N, said radical may optionally contain 1
to 3 additional heteroatoms, independently selected from the group
consisting of O, N and S; additionally, said radical may be further
optionally substituted with one to three substituents independently
selected from the group consisting of C.sub.1-6alkanyl and oxo;
[0128] R.sup.4 is hydrogen; [0129] n is an integer from 1 to 3; and
enantiomers, diastereomers, tautomers, solvates, or
pharmaceutically acceptable salts thereof.
[0130] Still yet another embodiment of the present invention is
directed to analgesic and anti-pyretic uses of compositions
comprising a compound of Formula (II) wherein: [0131] R.sup.1 and
R.sup.2 taken together with the atoms to which they are attached
form a radical selected from the group consisting of a 5 to 10
membered cycloheteroalkanyl, 5 to 10 membered cycloheteroalkenyl
and a 5 to 10 membered heteroaryl, wherein, in addition to the
heteroatom N, said radical may optionally contain 1 to 3 additional
heteroatoms, independently selected from the group consisting of O,
N and S; additionally, said radical may be further optionally
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-6alkanyl and oxo; [0132]
R.sup.4 is a substituent selected from the group consisting of
hydrogen, C.sub.1-6alkanyl, C.sub.1-6alkanyloxy, fluorinated
alkanyl, fluorinated alkanyloxy, halogen, hydroxyl, nitro, amino,
C.sub.1-6alkanylamino; C.sub.1-6dialkanylamino and cyano; [0133] n
is 1; and enantiomers, diastereomers, tautomers, solvates, or
pharmaceutically acceptable salts thereof.
[0134] Another embodiment of the present invention is directed to
compositions comprising a compound of Formula (I) or Formula (II)
wherein said compound is selected from the group consisting of:
[0135] Pyridine-2-carboxylic acid (4-hydroxy-phenyl)-amide;
[0136] (S)-Pyrrolidine-2-carboxylic acid
(4-hydroxy-phenyl)-amide;
[0137] N-(4-Hydroxy-phenyl)-2-mercapto-acetamide;
[0138] N-(4-Hydroxy-phenyl)-2-methylsulfanyl-acetamide;
[0139] N-(4-Hydroxy-phenyl)-2-methanesulfonyl-acetamide;
[0140] (R)-Pyrrolidine-2-carboxylic acid
(4-hydroxy-phenyl)-amide;
[0141] 1H-Pyrrole-2-carboxylic acid (4-hydroxy-phenyl)-amide;
[0142] 1H-Indazole-3-carboxylic acid (4-hydroxy-phenyl)-amide;
[0143] 5-Methyl-1H-pyrazole-3-carboxylic acid
(4-hydroxy-phenyl)-amide; and
[0144] 3H-Imidazole-4-carboxylic acid (4-hydroxy-phenyl)-amide.
[0145] The compounds of the present invention may also be present
in the form of pharmaceutically acceptable salts. For use in
medicine, the salts of the compounds of this invention refer to
non-toxic "pharmaceutically acceptable salts" (Ref. International
J. Pharm., 1986, 33, 201-217; J. Pharm. Sci., 1997 (January), 66,
1, 1). Other salts well known to those in the art may, however, be
useful in the preparation of compounds according to this invention
or of their pharmaceutically acceptable salts. Representative
organic or inorganic acids include, but are not limited to,
hydrochloric, hydrobromic, hydriodic, perchloric, sulfuric, nitric,
phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic,
fumaric, malic, tartaric, citric, benzoic, mandelic,
methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic,
pamoic, 2-naphthalenesulfonic, p-toluenesulfonic,
cyclohexanesulfamic, salicylic, saccharinic or trifluoroacetic
acid. Representative organic or inorganic bases include, but are
not limited to, basic or cationic salts such as benzathine,
chloroprocaine, choline, diethanolamine, ethylenediamine,
meglumine, procaine, aluminum, calcium, lithium, magnesium,
potassium, sodium and zinc.
[0146] The present invention includes within its scope prodrugs of
the compounds of this invention. In general, such prodrugs will be
functional derivatives of the compounds that are readily
convertible in vivo into the required compound. Thus, in the
methods of treatment of the present invention, the term
"administering" shall encompass the treatment of the various
disorders described with the compound specifically disclosed or
with a compound which may not be specifically disclosed, but which
converts to the specified compound in vivo after administration to
the patient. Conventional procedures for the selection and
preparation of suitable prodrug derivatives are described, for
example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier,
1985.
[0147] Where the compounds according to this invention have at
least one chiral center, they may accordingly exist as enantiomers.
Where the compounds possess two or more chiral centers, they may
additionally exist as diastereomers. It is to be understood that
all such isomers and mixtures thereof are encompassed within the
scope of the present invention. Furthermore, some of the
crystalline forms for the compounds may exist as polymorphs and as
such are intended to be included in the present invention. In
addition, some of the compounds may form solvates with water (i.e.,
hydrates) or common organic solvents, and such solvates are also
intended to be encompassed within the scope of this invention.
[0148] Where the processes for the preparation of the compounds
according to the invention give rise to mixture of stereoisomers,
these isomers may be separated by conventional techniques such as
preparative chromatography. The compounds may be prepared in
racemic form, or individual enantiomers may be prepared either by
enantiospecific synthesis or by resolution. The compounds may, for
example, be resolved into their component enantiomers by standard
techniques, such as the formation of diastereomeric pairs by salt
formation with an optically active acid, such as
(-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric
acid followed by fractional crystallization and regeneration of the
free base. The compounds may also be resolved by formation of
diastereomeric esters or amides, followed by chromatographic
separation and removal of the chiral auxiliary. Alternatively, the
compounds may be resolved using a chiral HPLC column.
[0149] During any of the processes for preparation of the compounds
of the present invention, it may be necessary and/or desirable to
protect sensitive or reactive groups on any of the molecules
concerned. This may be achieved by means of conventional protecting
groups, such as those described in Protective Groups in Organic
Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.
Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis,
John Wiley & Sons, 1991. The protecting groups may be removed
at a convenient subsequent stage using methods known from the
art.
[0150] Even though the compounds of the present invention
(including their pharmaceutically, acceptable salts and
pharmaceutically acceptable solvates) can be administered alone,
they will generally be administered in admixture with a
pharmaceutical carrier, excipient or diluent selected with regard
to the intended route of administration and standard pharmaceutical
or veterinary practice. Thus, the present invention is directed to
pharmaceutical and veterinary compositions comprising compounds of
Formula (I) and one or more pharmaceutically acceptable carriers,
excipients or diluents.
[0151] By way of example, in the pharmaceutical and veterinary
compositions of the present invention, the compounds of the present
invention may be admixed with any suitable binder(s), lubricant(s),
suspending agent(s), coating agent(s), and/or solubilising
agent(s).
[0152] Tablets or capsules of the compounds may be administered
singly or two or more at a time, as appropriate. It is also
possible to administer the compounds in sustained release
formulations.
[0153] Alternatively, the compounds of the general Formula (I) can
be administered by inhalation or in the form of a suppository or
pessary, or they may be applied topically in the form of a lotion,
solution, cream, ointment or dusting powder. An alternative means
of transdermal administration is by use of a skin patch. For
example, they can be incorporated into a cream consisting of an
aqueous emulsion of polyethylene glycols or liquid paraffin. They
can also be incorporated, at a concentration of between 1 and 10%
by weight, into an ointment consisting of a white wax or white soft
paraffin base together with such stabilisers and preservatives as
may be required.
[0154] For some applications, preferably the compositions are
administered orally in the form of tablets containing excipients
such as starch or lactose, or in capsules or ovules either alone or
in admixture with excipients, or in the form of elixirs, solutions
or suspensions containing flavouring or coloring agents.
[0155] The compositions (as well as the compounds alone) can also
be injected parenterally, for example intracavernosally,
intravenously, intramuscularly or subcutaneously. In this case, the
compositions will comprise a suitable carrier or diluent.
[0156] For parenteral administration, the compositions are best
used in the form of a sterile aqueous solution which may contain
other substances, for example enough salts or monosaccharides to
make the solution isotonic with blood.
[0157] For buccal or sublingual administration the compositions may
be administered in the form of tablets or lozenges which can be
formulated in a conventional manner.
[0158] By way of further example, pharmaceutical and veterinary
compositions containing one or more of the compounds of the
invention described herein as the active ingredient can be prepared
by intimately mixing the compound or compounds with a
pharmaceutical carrier according to conventional pharmaceutical
compounding techniques. The carrier may take a wide variety of
forms depending upon the desired route of administration (e.g.,
oral, parenteral). Thus for liquid oral preparations such as
suspensions, elixirs and solutions, suitable carriers and additives
include water, glycols, oils, alcohols, flavoring agents,
preservatives, stabilizers, coloring agents and the like; for solid
oral preparations, such as powders, capsules and tablets, suitable
carriers and additives include starches, sugars, diluents,
granulating agents, lubricants, binders, disintegrating agents and
the like. Solid oral preparations may also be coated with
substances such as sugars or be enteric-coated so as to modulate
the major site of absorption. For parenteral administration, the
carrier will usually consist of sterile water and other ingredients
may be added to increase solubility or preservation. Injectable
suspensions or solutions may also be prepared utilizing aqueous
carriers along with appropriate additives.
[0159] Advantageously, compounds of the present invention may be
administered in a single daily dose, or the total daily dosage may
be administered in divided doses of two, three or four times daily.
Furthermore, compounds for the present invention can be
administered in intranasal form via topical use of suitable
intranasal vehicles, or via transdermal skin patches well known to
those skilled in that art. To be administered in the form of a
transdermal delivery system, the dosage administration will, of
course, be continuous rather than intermittent throughout the
dosage regimen.
[0160] A therapeutically effective amount for use of the instant
compounds or a pharmaceutical composition thereof comprises a dose
range of from about 0.01 mg to about 15,000 mg, in particular from
about 1 mg to about 5000 mg or, more particularly from about 500 mg
to about 4000 mg of active ingredient per day for an average (70
kg) human.
[0161] For oral administration, a pharmaceutical composition is
preferably provided in the form of tablets containing, 0.01, 10.0,
50.0, 100, 150, 200, 250 and 500 milligrams of the active
ingredient for the symptomatic adjustment of the dosage to the
subject to be treated.
[0162] It is also apparent to one skilled in the art that the
therapeutically effective dose for active compounds of the
invention or a pharmaceutical composition thereof will vary
according to the desired effect. Therefore, optimal dosages to be
administered may be readily determined and will vary with the
particular compound used, the mode of administration, the strength
of the preparation, and the advancement of the disease condition.
In addition, factors associated with the particular subject being
treated, including subject age, weight, diet and time of
administration, will result in the need to adjust the dose to an
appropriate therapeutic level. The above dosages are thus exemplary
of the average case. There can, of course, be individual instances
where higher or lower dosage ranges are merited, and such are
within the scope of this invention.
[0163] Compounds of this invention may be administered in any of
the foregoing compositions and dosage regimens or by means of those
compositions and dosage regimens established in the art whenever
use of the compounds of the invention as analgesics or
anti-pyretics is required for a subject in need thereof.
[0164] The invention also provides a pharmaceutical or veterinary
pack or kit comprising one or more containers filled with one or
more of the ingredients of the pharmaceutical and veterinary
compositions of the invention. Optionally associated with such
container(s) can be a notice in the form prescribed by a
governmental agency regulating the manufacture, use or sale of
pharmaceuticals or biological products, which notice reflects
approval by the agency of manufacture, use or sale for human
administration.
[0165] The compounds of Formulas (I) and (II) are useful in methods
for treating a disease or condition in a mammal characterized by
pain and/or fever. Such methods comprises administering to a mammal
in need of such treatment a therapeutically effective amount of a
compound, salt or solvate of Formulas (I) or (II). In particular,
the compounds of Formulas (I) and (II) are useful for in methods
for control of pain due to headache, earache, dysmenorrhea,
arthralgia, myalgia, musculoskeletal pain, arthritis,
immunizations, teething, tonsillectomy. They are also used to
reduce fever in bacterial or viral infections and as a substitute
for aspirin in upper GI disease, aspirin allergy, bleeding
disorders, subjects on anticoagulant therapy, and gouty
arthritis.
[0166] In another embodiment, the compounds of Formulas (I) and
(II) are useful in treatment of inflammation.
General Synthetic Methods
[0167] Representative compounds of the present invention can be
synthesized in accordance with the general synthetic methods
described below and are illustrated in the schemes that follows.
Since the schemes are an illustration, the invention should not be
construed as being limited by the chemical reactions and conditions
expressed. The preparation of the various starting materials used
in the schemes is well within the skill of persons versed in the
art.
[0168] The hetero-substituted acaetanilide analogues of formula (I)
or formula (II) that comprise this invention are synthesized using
the general chemical methods shown in Schemes A through E.
##STR00006##
[0169] Compounds of Formula (I) are prepared by coupling
commercially available anilines A1 with commercially available
carboxylic acids A2 in the presence of a coupling reagent such as
HBTU, also in the presence of a base such as DIPEA or TEA, also in
the presence of a suitable solvent such as DMF which provides
protected intermediates A3.
[0170] The benzyl protecting group is then removed under
hydrogenation conditions under pressures of about 55 psi in the
presence of a suitable palladium catalyst such as 10% palladium on
carbon which provides the target compounds of Formula (I).
##STR00007##
[0171] Compounds of Formula (II) are prepared by coupling
commercially available anilines A1 with commercially available
carboxylic acids B2 in the presence of a coupling reagent such as
HBTU, also in the presence of a base such as DIPEA or TEA, also in
the presence of a suitable solvent such as DMF which provided
protected intermediates B2.
[0172] The benzyl protecting group is then removed under
hydrogenation conditions under pressures of about 55 psi in the
presence of a suitable palladium catalyst such as 10% palladium on
carbon which provided the target compounds of Formula (II).
##STR00008##
[0173] In the case of certain imidazole compounds, the above
described schemes were modified as shown in Scheme C. The
carboxylic acid starting material is replaced with the 5-H,
10H-diimidazo[1,5-a, 1',5'-d]pyrazine-5,10-dione C1 which is
optionally substituted with R.sup.5, wherein R.sup.5 is
C.sub.1-6alkyl or oxo, which when reacted directly with anilines A1
upon heating provides the intermediates C2. The protecting group is
removed as previously described in schemes A and B to provides
compounds C3.
##STR00009##
[0174] Compounds of Formula (I) may also be prepared by directly
coupling a 4-hydroxy aniline D1 with an acid chloride D2 as shown
in Scheme D.
##STR00010##
[0175] Compounds of Formula (II) may also be prepared by directly
coupling a 4-hydroxy aniline E1 with an acid chloride E2 as shown
in Scheme E.
[0176] It is generally preferred that the respective product of
each process step be separated from other components of the
reaction mixture and subjected to purification before its use as a
starting material in a subsequent step. Separation techniques
typically include evaporation, extraction, precipitation and
filtration. Purification techniques typically include column
chromatography (Still, W. C. et. al., J. Org. Chem. 1978, 43,
2921), thin-layer chromatography, crystallization and distillation.
The structures of the final products, intermediates and starting
materials are confirmed by spectroscopic, spectrometric and
analytical methods including nuclear magnetic resonance (NMR), mass
spectrometry (MS) and liquid chromatography (HPLC). In the
descriptions for the preparation of compounds of this invention,
ethyl ether, tetrahydrofuran and dioxane are common examples of an
ethereal solvent; benzene, toluene, hexanes and cyclohexane are
typical hydrocarbon solvents and dichloromethane and dichloroethane
are representative halogenhydrocarbon solvents. In those cases
where the product is isolated as the acid addition salt the free
base may be obtained by techniques known to those skilled in the
art. In those cases in which the product is isolated as an acid
addition salt, the salt may contain one or more equivalents of the
acid.
[0177] Representative compounds of the present invention can be
synthesized in accordance with the general synthetic methods
described above and are illustrated more particularly in the
schemes that follow. Since the schemes are illustrations, the
invention should not be construed as being limited by the chemical
reactions and conditions expressed. The preparation of the various
starting materials used in the schemes is well within the skill of
persons versed in the art.
EXAMPLES
Example 1
Pyridine-2-carboxylic acid (4-hydroxy-phenyl)-amide
A. Pyridine-2-carboxylic acid (4-benzyloxyphenyl)amide
[0178] A solution of pyridine-2-carboxylic acid (2.0 g, 8.48 mmol)
in N,N-dimethylformamide (DMF) was treated with
O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HBTU) (3.5 g, 9.33 mmol) and
N,N-diisopropylethylamine (DIEA) (0.742 mL, 32.7 mmol) and stirred
at room temperature for 10 min. 4-Benzyloxyaniline hydrochloride
(2.0 g, 8.48 mmol) was added to the solution, and stirring was
continued for an additional 30 min. The solution was poured into a
saturated aqueous solution of sodium bicarbonate on ice.
Mechanically mixing the gummy residue in the bottom of the flask
caused it to solidify. The product was collected by filtration,
washed with water and dried to give a beige solid, 2.46 g (95%),
which was used without further purification in the subsequent
reaction. MS m/z 305 (MH.sup.+). .sup.1H NMR(CDCl.sub.3) .delta.
5.07 (s, 2H), 7.0 (d, 2H), 7.30-7.50 (m, 6H), 7.70 (d, 2H), 7.92
(t, 1H), 8.32 (d, 1H) and 8.58 (d, 1H).
B. Pyridine-2-carboxylic acid (4-hydroxy-phenyl)-amide
[0179] A solution of pyridine-2-carboxylic acid
(4-benzyloxyphenyl)amide (7.7 g, 25.3 mmol) in 90% ethanol (110 mL)
was hydrogenated (60 psi) over 10% palladium on carbon (0.8 g) at
50.degree. C. for 4 hours. The catalyst was removed by filtration,
and the solvent was evaporated in vacuo. The residue was purified
by flash chromatography on silica gel, using
methanol/dichloromethane (DCM), 5/95, as the eluant, to give the
product as a beige solid, 2.54 g (47%). MS m/z 215 (MH.sup.+).
.sup.1H NMR(DMSO-d.sub.6) .delta. 6.76 (d, 2H), 7.54 to 7.76 (m,
3H), 8.05 (t, 1H), 8.14 (d, 1H), 8.72 (d, 1H), 9.30 (s, 1H) and
10.41 (s, 1H). Anal. calcd for C.sub.12H.sub.10N.sub.2O.sub.2: C,
67.28; H, 4.71; N, 13.08. Found: C, 66.99; H, 4.56; N, 12.81.
Example 2
N-(4-Hydroxy-phenyl)-2-methanesulfonyl-acetamide
A. N-(4-Benzyloxy-phenyl)-2-methanesulfonyl-acetamide
[0180] A solution of 4-benzyloxyaniline hydrochloride (4.0 g, 17.0
mmol), methanesulfonylacetic acid (2.35 g, 17.0 mmol) and HBTU
(6.89 g, 18.2 mmol) in DMF (70 mL) was stirred at ambient
temperature one minute. DIEA (6.5 mL, 37.2 mmol) was added all at
once, and the resultant solution was stirred at ambient
temperature. The solution was poured into water, and the product
crystallized. The product, 5.4 g (99%), was collected by filtration
and was used without any further purification in the subsequent
reaction. MS m/z 320 (MH.sup.+). .sup.1H NMR(DMSO-d.sub.6) .delta.
3.17 (s, 3H), 4.25 (s, 2H), 5.07 (s, 2H), 7.00 (d, 2H), 7.32-7.55
(m, 7H) and 10.32 (s, 1H).
B. N-(4-Hydroxy-phenyl)-2-methanesulfonyl-acetamide
[0181] This compound was prepared from
N-(4-benzyloxy-phenyl)-2-methanesulfonyl-acetamide, using the same
method used to prepare of pyridine-2-carboxylic acid
(4-hydroxyphenyl)amide. The product was purified by flash
chromatography, on silica gel, eluted with 5 to 10% methanol in
DCM, to give the product, 3.45 g (92%) as a colorless solid. MS m/z
230 (MH.sup.+). .sup.1H NMR(DMSO-d.sub.6) .delta. 3.18 (s, 3H),
4.22 (s, 2H), 6.72 (d, 2H), 7.36 (d, 2H), 9.35(br s, 1H) and 10.17
(s, 1H). Anal. calcd for C.sub.9H.sub.11N.sub.4OS: C, 47.15; H,
4.84; N, 6.11. Found: C, 47.04; H, 4.79; N, 6.04.
Example 3
1H-Pyrrole-2-carboxylic acid (4-hydroxy-phenyl)-amide
A. 1H-Pyrrole-2-carboxylic acid (4-benzyloxy-phenyl)-amide
[0182] This compound was prepared from 4-benzyloxyaniline (4.0 g,
17 mmol) and pyrrole-2-carboxylic acid (1.98 g, 17.8 mmol), using
the same method used to prepare pyridine-2-carboxylic acid
(4-benzyloxyphenyl)amide. The product was purified by flash
chromatography, on silica gel, using 5% methanol in DCM as the
eluant, to give the product as a colorless solid, 2.6 g (50%). MS
m/z 293 (MH.sup.+). .sup.1H NMR(DMSO-d.sub.6) .delta. 5.04 (s, 2H),
6.13 (m, 1H), 6.95-7.05 (m, 4H), 7.28-7.45 (m, 5H), 7.65 (d, 2H),
9.7 (s, 1H) and 11.65 (s, 1H).
B. 1H-Pyrrole-2-carboxylic acid (4-hydroxy-phenyl)-amide
[0183] This compound was prepared from 1H-pyrrole-2-carboxylic acid
(4-benzyloxy-phenyl)-amide (2.5 g, 8.55 mmol), using the same
method used to prepare of pyridine-2-carboxylic acid
(4-hydroxyphenyl)amide. The product was purified by flash
chromatography, on silica gel, eluted with 5 to 7.5% methanol in
DCM, to give the product as a colorless solid, 1.47 g (85%). MS m/z
203 (MH.sup.+). .sup.1H NMR(DMSO-d.sub.6) .delta. 6.14 (m, 1H),
6.72 (d, 2H), 6.92 (m, 1H), 6.99 (d, 1H), 7.47 (d, 2H), 9.19 (s,
1H). Anal. calcd for C.sub.11H.sub.10N.sub.2O.sub.2: C, 65.34; H,
4.98; N, 13.85. Found: C, 65.15; H, 4.83; N, 13.81.
Example 4
(S)-Pyrrolidine-2-carboxylic acid (4-hydroxy-phenyl)-amide
A. (S)-2-(4-Benzyloxy-phenylcarbamoyl)-pyrrolidine-1-carboxylic
acid benzyl ester
[0184] This compound was prepared from 4-benzyloxyaniline
hydrochloride (4.0 g, 17.0 mmol) and (-)-N-carbobenzyloxy-l-proline
(4.44 g, 17.8 mmol), using the same method to prepare
pyridine-2-carboxylic acid (4-benzyloxyphenyl)amide, to give the
product as a colorless solid, 7.51 g (98%), which was used without
further purification in the subsequent step. MS m/z 431 (MH.sup.+).
.sup.1H NMR(CDCl.sub.3) .delta. 1.83-2.61 (m, 4H), 3.44-3.65 (m,
2H), 4.40-4.55 (m, 1H), 5.03 (s, 2H), 5.22 (br s, 2H), 6.90 (d, 2H)
and 7.20-7.45 (m, 12H).
B. (S)-Pyrrolidine-2-carboxylic acid (4-hydroxy-phenyl)-amide
[0185] A suspension of
(S)-2-(4-benzyloxy-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid
benzyl ester (7.0 g, 16.3 mmol) in ethanol/water (70 mL/7 mL) was
hydrogenated over 10% palladium on carbon (0.41 g) at 55 psi of
hydrogen, at 50.degree. C., for 5 hours. The mixture was cooled,
and the catalyst was removed by filtration. The solvent was
evaporated in vacuo. The residue was dissolved in hot ethanol (30
mL) and treated with a saturated solution of hydrogen chloride in
ethanol (3 mL). The product crystallized as the hydrochloride salt,
1.27 g (32%), a colorless solid. MS m/z 207 (MH.sup.+). .sup.1H
NMR(DMSO-d.sub.6) .delta. 1.92 (m, 3H), 2.43 (m, 1H), 3.28 (m, 2H),
4.31 (m, 1H), 6.77 (d, 2H), 7.47 (d, 2H), 9.44 (br s, 1H) and 10.75
(s, 1H). Anal. calcd for C.sub.11H.sub.14N.sub.2O.sub.2: C, 54.44;
H, 6.23; N, 11.54. Found: C, 54.28; H, 6.06; N, 11.66.
Example 5
(R)-Pyrrolidine-2-carboxylic acid (4-hydroxy-phenyl)-amide
A. (R)-2-(4-Benzyloxy-phenylcarbamoyl)-pyrrolidine-1-carboxylic
acid benzyl ester
[0186] This compound was prepared from 4-benzyloxyaniline
hydrochloride (4.0 g, 17.0 mmol) and (+)-N-carbobenzyloxy-d-proline
(4.44 g, 17.8 mmol), using the same method to prepare
pyridine-2-carboxylic acid (4-benzyloxyphenyl)amide, to give the
product as a colorless solid, which was used without further
purification in the subsequent step. .sup.1H NMR(DMSO-d.sub.6)
.delta. 1.80-1.95 (m, 3H), 2.10-2.27 (m, 1H), 3.35-3.55 (m, 2H),
4.33 (m, 1H), 5.0 (m, 4H), 6.95 (d, 2H), 7.12-7.53 (m, 12H) and
9.95 (d, 1H).
B. (R)-Pyrrolidine-2-carboxylic acid (4-hydroxy-phenyl)-amide
[0187] This compound was prepared from
(R)-2-(4-benzyloxy-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid
benzyl ester, using the same method used to prepare
(S)-pyrrolidine-2-carboxylic acid (4-hydroxy-phenyl)-amide. The
free base was dissolved in hot isopropanol (20 mL) and treated with
a saturated solution of hydrogen chloride in isopropanol (3 mL).
The product crystallized as the hydrochloride salt, 2.43 g (59% for
2 steps). MS m/z 207 (MH.sup.+). .sup.1H NMR(DMSO-d.sub.6) .delta.
1.93 (m, 3H), 2.39 (m, 1H), 3.26 (m, 2H), 4.35 (t, 1H), 6.76 (d,
2H), 7.43 (d, 2H), 9.43 (br s, 1H) and 10.70 (s, 1H). Anal. calcd
for C.sub.11H.sub.14N.sub.2O.sub.2: C, 54.44; H, 6.23; N, 11.54.
Found: C, 54.33; H, 6.26; N, 11.57.
Example 6
1H-Indazole-3-carboxylic acid (4-hydroxy-phenyl)-amide
A. 1H-Indazole-3-carboxylic acid (4-benzyloxy-phenyl)-amide
[0188] DIEA (9.3 mL, 53.4 mmol) was added to a solution of
4-benzyloxyaniline hydrochloride (4.0 g, 17.0 mmol),
indazole-3-carboxylic acid (2.89 g, 17.8 mmol) and HBTU (7.1 g,
18.7 mmol) in DMF (60 mL), and the resulting solution was stirred
at ambient temperature for 24 hours. The solution was heated to
70.degree. C. for 4 hours, and then poured into a mixture of
saturated aqueous sodium bicarbonate on ice. The product, an off
white solid, 6.0 g, was collected by filtration, washed with water
and used without further purification in the subsequent reaction.
MS m/z 344 (MH.sup.+). .sup.1H NMR(DMSO-d.sub.6) .delta. 5.11 (s,
2H), 7.02 (d, 2H), 7.26-7.48 (m, 7H), 7.67 (d, 1H), 7.75 (d, 2H),
7.81 (d, 1H), 8.24 (d, 1H) and 10.24 (s, 1H).
B. 1H-Indazole-3-carboxylic acid (4-hydroxy-phenyl)-amide
[0189] This compound was prepared from 1H-Indazole-3-carboxylic
acid (4-benzyloxy-phenyl)-amide, using the same method used to
prepare (S)-pyrrolidine-2-carboxylic acid (4-hydroxy-phenyl)-amide.
The product was purified by flash chromatography, on silica gel,
eluted with 5 to 10% methanol in DCM, to give the product as an off
white solid, 2.6 g (60% for 2 steps). MS m/z 254 (MH.sup.+).
.sup.1H NMR(DMSO-d.sub.6) .delta. 6.74 (d, 2H), 7.26-7.34 (m, 1H),
7.43-7.51 (m, 1H), 7.67-7.73 (m, 3H), 8.24 (d, 1H), 9.25 (s, 1H),
10.10 (s, 1H) and 13.72 (s, 1H). Anal. calcd for
C.sub.14H.sub.11N.sub.3O.sub.2: C, 66.40; H, 4.38; N, 16.59. Found:
C, 66.15; H, 4.20; N, 16.82.
Example 7
5-Methyl-1H-pyrazole-3-carboxylic acid (4-hydroxy-phenyl)-amide
A. 5-Methyl-1H-pyrazole-3-carboxylic acid
(4-benzyloxy-phenyl)-amide
[0190] This compound was prepared from 4-benzyloxyaniline
hydrochloride (4.0 g, 17.0 mmol) and 5-methylpyrazole-2-carboxylic
acid (2.25 g, 17.8 mmol), using the same method used to prepare
pyridine-2-carboxylic acid (4-benzyloxyphenyl)amide, to give the
product as a solid. The product was used without further
purification in the subsequent reaction. MS m/z 308 (MH.sup.+).
.sup.1H NMR(CDCl.sub.3+MeOD-d.sub.4) .delta. 2.34 (s, 3H), 5.06 (s,
2H), 6.62 (s, 1H), 6.96 (d, 2H), 7.31 (m, 7H) and 7.58 (d, 1H).
B. 5-Methyl-1H-pyrazole-3-carboxylic acid
(4-hydroxy-phenyl)-amide
[0191] This compound was prepared from
5-methyl-1H-pyrazole-3-carboxylic acid (4-benzyloxy-phenyl)-amide,
using the same method used to prepare pyridine-2-carboxylic acid
(4-hydroxyphenyl)amide. The product was purified by flash
chromatography, on silica gel, eluted with 5 to 10% methanol in DCM
as the eluant, to give the product as an off white solid, 2.75 g
(68%). MS m/z 218 (MH.sup.+). .sup.1H NMR(DMSO-d.sub.6) .delta.
2.28 (s, 3H), 6.47 (s, 1H), 6.71 (d, 2H), 7.55 (d, 2H), 9.19 (s,
1H), 9.67 (s, 1H) and 13.00 (s, 1H). Anal. calcd for
C.sub.11H.sub.11N.sub.3O.sub.2: C, 60.08; H, 5.17; N, 19.10. Found:
C, 60.00; H, 4.99; N, 19.25.
Example 8
3H-Imidazole-4-carboxylic acid (4-hydroxy-phenyl)-amide
A. 3-H-Imidazole-4-carboxylic acid (4-benzyloxyphenyl)amide.
[0192] An intimate mixture of 4.25 g (22 mmol) of 5-H,
10H-diimidazo[1,5-a, 1',5'-d]pyrazine-5,10-dione and 9.04 g (45
mmol) of 4-benzyloxyaniline was heated on a steam bath for 30 min.
The residue was flash chromatographed with 5% MeOH in
CH.sub.2Cl.sub.2 to give 4.8 g of the title compound (66% yield).
MS m/z 294 (MH.sup.+). .sup.1H NMR(CDCl.sub.3) .delta. 5.07 (s,
2H), 7.0 (d, 2H), 7.30-7.50 (m, 3H), 7.7-7.8 (m, 4H), 9.8 (s 1H),
12.6 (s, 1H).
B. 3-H-Imidazole-4-carboxylic acid (4-hydroxy-phenyl)-amide
[0193] A solution of 3-H-imidazole-4-carboxylic acid
(4-benzyloxyphenyl)amide. (3.3 g, 11.2 mmol) in glacial acetic acid
(70 mL) was hydrogenated (60 psi) over g of 10% palladium on carbon
(0.3 g) at 25.degree. C. for 18 hours. The catalyst was removed by
filtration, and the solvent was evaporated in vacuo. The residue
was stirred with NaHCO.sub.3 solution and the solid collected.
There was obtained 2.4 g (100% yield) of the title compound as a
yellow solid. MS m/z 204 (MH.sup.+). .sup.1H NMR(DMSO-d.sub.6)
.delta. 6.7 (dd, 2H), 7.5 (dd, 2H), 7.7 (s, 1H), 7.8 (s, 1H), 9.1
(s, 1H), 9.6 (s, 1H) and 12.5 (s, 1H).
Example 9
N-(4-Hydroxy-phenyl)-2-mercapto-acetamide
[0194] A mixture of 4-aminophenol (4.0 g, 36.7 mmol) and
mercaptoacetic acid (2.93 g, 38.5 mmol) under an atmosphere of
carbon dioxide was heated to reflux (oil bath temperature
.about.120.degree. C.) for 4 hours. The mixture was cooled and
diluted with 2 N hydrochloric acid (.about.100 mL). A purple solid,
1.3 g, was collected by filtration and washed with water. The
product was purified by flash chromatography, on silica gel, eluted
with 5 to 10% methanol in DCM, to give a colorless solid, 1.03 g
(15%). MS m/z 184 (MH.sup.+). .sup.1H NMR(DMSO-d.sub.6) .delta.
2.08 (t, 1H), 3.24 (s, 2H), 6.70 (d, 2H), 7.35 (d, 2H), 9.21 (br s,
1H) and 9.83 (s, 1H). Anal. calcd for C.sub.8H.sub.9NO.sub.2S: C,
52.44; H, 4.95; N, 7.64. Found: C, 52.57; H, 4.95; N, 7.40.
BIOLOGICAL EXAMPLES
Example 1
Mouse Abdominal Irritant Test (MAIT)
[0195] Male CD1 mice (weighing from 18-24 g) are used to determine
the antinociceptive effects associated with the compositions of the
invention. The mice are all dosed orally with the compounds
specified, dissolved in distilled water or suspended in 0.5%
Methocel.TM. (hydroxypropyl methylcellulose) in water. The dosing
volume is 10 mL/kg.
[0196] The procedure used in detecting and comparing the analgesic
activity of different classes of analgesic drugs for which there is
a good correlation with human efficacy is the prevention of
acetylcholine-induced abdominal constriction in mice (H. Collier et
al., Br. J. Pharmacol., 32, 295 (1968)).
[0197] Mice, intubated with various doses of the compound or
vehicle such as distilled water, or distilled water 0.5%
Methocel.TM. (hydroxypropyl methylcellulose) in water, are injected
intraperitoneally with a challenge dose of acetylcholine bromide.
The acetylcholine is completely dissolved in distilled water at a
concentration of 5.5 mg/kg and injected at the rate of 0.20 mL/20
g. For scoring purposes, an "abdominal constriction" is defined as
a contraction of the abdominal musculature accompanied by arching
of the back and extension of the limbs. The mice are observed for
10 minutes for the presence or absence of the abdominal
constriction response beginning immediately after receiving the
acetylcholine dose, administered at a certain time after the oral
administration of the test drug or vehicle. Each mouse is used only
once.
[0198] The percent of inhibition of this response is calculated as
follows:
% Inhibition=100.times.(Number of Nonresponders)/(Number of Animals
in Group)
TABLE-US-00001 TABLE 2 Antinociceptive Effect in Mouse Abdominal
Irritant Test Effect @ 300 Compound mg/kg Pyridine-2-carboxylic
acid (4- 60.0 hydroxy-phenyl)-amide (S)-Pyrrolidine-2-carboxylic
acid (4- 40.0 hydroxy-phenyl)-amide N-(4-Hydroxy-phenyl)-2- 45.0
methylsulfanyl-acetamide N-(4-Hydroxy-phenyl)-2- 40.0
methanesulfonyl-acetamide (R)-Pyrrolidine-2-carboxylic acid 20.0
(4-hydroxy-phenyl)-amide 1H-Pyrrole-2-carboxylic acid (4- 86.7
hydroxy-phenyl)-amide 1H-Indazole-3-carboxylic acid (4- 20.0
hydroxy-phenyl)-amide 5-Methyl-1H-pyrazole-3-carboxylic 73.3 acid
(4-hydroxy-phenyl)-amide N-(4-Hydroxy-phenyl)-2-mercapto- 40.0
acetamide
Example 2
Antipyretic Evaluation of Compounds
[0199] Groups of 10 male rats are weighed, color-coded, rectal
temperatures taken (24 hours.+-.15 minutes prior to dose
administration) and recorded. Food is removed but water remains
available ad libitum. Each rat is injected subcutaneously into the
central dorsal region with 5 ml of a 15% yeast suspension.
Twenty-three hours (.+-.15 minutes) after yeast injection, body
weights and rectal temperatures are taken and recorded. Twenty-four
hours (.+-.15 minutes) after yeast injection, the vehicle and test
articles are administered orally. Temperatures are taken and
recorded one hour (.+-.5 minutes) following test article or vehicle
administration.
[0200] The mean rectal temperatures for the test article and
vehicle control groups are calculated at 23 and 25 hours (.+-.15
minutes) and subjected to an ANOVA followed by a Tukey HSD Multiple
Comparison Test (p.ltoreq.0.05)--Systat, version 9.0.
[0201] As represented in Table 3, the oral administration of
compound 1, at 600 mg/kg produces a statistically significant
(p.ltoreq.1.05) decrease in body temperature in rats relative to
the vehicle-treated group.
TABLE-US-00002 TABLE 3 Antipyretic Effect in Rats Antipyresis
Compound deg C. @ 600 mpk Pyridine-2-carboxylic acid (4- -2.17
hydroxy-phenyl)-amide
* * * * *