U.S. patent application number 09/982362 was filed with the patent office on 2002-07-11 for substituted aryl or heteroarylamides having retinoid-like biological activity.
This patent application is currently assigned to Allergan. Invention is credited to Chandraratna, Roshantha A., Duong, Tien T., Teng, Min.
Application Number | 20020091262 09/982362 |
Document ID | / |
Family ID | 24244378 |
Filed Date | 2002-07-11 |
United States Patent
Application |
20020091262 |
Kind Code |
A1 |
Teng, Min ; et al. |
July 11, 2002 |
Substituted aryl or heteroarylamides having retinoid-like
biological activity
Abstract
Compounds of the formula 1 wherein X is CH or N; R.sub.1 is
independently H or alkyl of 1 to 6 carbons; m is an integer having
the value of 0-5; p is an integer having the value of 0-2; r is an
integer having the value 0-2; L is --(C.dbd.Z)--NH-- or
--NH--(C.dbd.Z)-- where Z is 0 or S; Y is a phenyl or naphthyl
group, or heteroaryl selected from a group consisting of pyridyl,
thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl,
oxazolyl, imidazolyl and pyrrazolyl, said phenyl, naphthyl and
heteroaryl groups being optionally substituted with one or two
R.sub.1 groups; W is a substituent selected from the group
consisting of F, Br, Cl, I, C.sub.1-6alkyl, fluoro substituted
C.sub.1-6 alkyl, NO.sub.2, N.sub.3, OH, OCH.sub.2OCH.sub.3,
OC.sub.1-10alkyl, tetrazol, CN, SO.sub.2C.sub.1-6-alkyl,
SO.sub.2C.sub.1-6-alkyl, SO.sub.2C.sub.1-6-fluor- o substituted
alkyl, SO--C.sub.1-6 alkyl, CO--C.sub.1-6alkyl, COOR.sub.8, phenyl,
phenyl itself substituted with a W group other than with phenyl or
substituted phenyl with the proviso that when X is CH and r is 0
then p is not 0 and at least one W group is not alkyl; A is
(CH.sub.2).sub.q where q is 0-5, lower branched chain alkyl having
3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6
carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1
or 2 triple bonds, and B is COOH or a pharmaceutically acceptable
salt thereof, COOR.sub.8, CONR.sub.9R.sub.10, --CH.sub.2OH,
CH.sub.2OR.sub.11, CH.sub.2OCOR.sub.11, CHO, CH(OR.sub.12).sub.2,
CHOR.sub.13O, --COR.sub.7, CR.sub.7(OR.sub.12).sub.2- ,
CR.sub.7OR.sub.13O, where R.sub.7 is an alkyl, cycloalkyl or
alkenyl group containing 1 to 5 carbons, R.sub.8 is an alkyl group
of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has
1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or
R.sub.8 is phenyl or lower alkylphenyl, R.sub.9 and R.sub.10
independently are hydrogen, an alkyl group of 1 to 10 carbons, or a
cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl,
R.sub.11 is lower alkyl, phenyl or lower alkylphenyl, R.sub.12 is
lower alkyl, and R.sub.13 is divalent alkyl radical of 2-5 carbons,
have retinoid-like biological activity.
Inventors: |
Teng, Min; (Aliso Viejo,
CA) ; Duong, Tien T.; (Irvine, CA) ;
Chandraratna, Roshantha A.; (Mission Viejo, CA) |
Correspondence
Address: |
Allergan, Inc.
2525 Dupont Drive
Irvine
CA
92612-1531
US
|
Assignee: |
Allergan
|
Family ID: |
24244378 |
Appl. No.: |
09/982362 |
Filed: |
October 16, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09982362 |
Oct 16, 2001 |
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09829310 |
Apr 9, 2001 |
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09829310 |
Apr 9, 2001 |
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09550744 |
Apr 17, 2000 |
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09550744 |
Apr 17, 2000 |
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09215509 |
Dec 17, 1998 |
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09215509 |
Dec 17, 1998 |
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08820792 |
Mar 19, 1997 |
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08820792 |
Mar 19, 1997 |
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08561999 |
Nov 22, 1995 |
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Current U.S.
Class: |
544/238 ;
544/333; 544/405; 546/269.7; 546/271.4; 546/272.7; 546/275.4;
546/280.7; 546/283.4; 546/309; 546/314 |
Current CPC
Class: |
A61P 43/00 20180101;
C07D 213/82 20130101; A61P 35/00 20180101; C07C 233/81
20130101 |
Class at
Publication: |
544/238 ;
544/333; 544/405; 546/269.7; 546/271.4; 546/272.7; 546/275.4;
546/280.7; 546/283.4; 546/314; 546/309 |
International
Class: |
C07D 417/02; C07D
413/02; C07D 43/02; C07D 41/02 |
Claims
What is claimed is:
1. A compound of the formula 10wherein X is CH or N; R.sub.1 is
independently H or alkyl of 1 to 6 carbons; m is an integer having
the value of 0-5; p is an integer having the value of 0-2; r is an
integer having the value 0-2; L is --(C.dbd.Z)--NH-- or
--NH--(C.dbd.Z)-- where Z is O or S; Y is a phenyl or naphthyl
group, or heteroaryl selected from a group consisting of pyridyl,
thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl,
oxazolyl, imidazolyl and pyrrazolyl, said phenyl, naphthyl and
heteroaryl groups being optionally substituted with one or two
R.sub.1 groups; W is a substituent selected from the group
consisting of F, Br, Cl, I, C.sub.1-6alkyl, fluoro substituted
C.sub.1-6 alkyl, NO.sub.2, N.sub.3, OH, OCH.sub.2OCH.sub.3,
OC.sub.1-10alkyl, tetrazol, CN, SO.sub.2C.sub.1-6-alkyl,
SO.sub.2C.sub.1-6-alkyl, SO.sub.2C.sub.1-6-fluoro substituted
alkyl, SO--C.sub.1-6 alkyl, CO--C.sub.1-6alkyl, COOR.sub.8, phenyl,
phenyl itself substituted with a W group other than with phenyl or
substituted phenyl with the proviso that when X is CH and r is 0
then p is not 0 and at least one W group is not alkyl; A is
(CH.sub.2).sub.q where q is 0-5, lower branched chain alkyl having
3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6
carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1
or 2 triple bonds, and B is COOH or a pharmaceutically acceptable
salt thereof, COOR.sub.8, CONR.sub.9R.sub.10, --CH.sub.2OH,
CH.sub.2OR.sub.11, CH.sub.2OCOR.sub.11, CHO, CH(OR.sub.12).sub.2,
CHOR.sub.13O, --COR.sub.7, CR.sub.7(OR.sub.12).sub.2,
CR.sub.7OR.sub.13O, where R.sub.7 is an alkyl, cycloalkyl or
alkenyl group containing 1 to 5 carbons, R.sub.8 is an alkyl group
of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has
1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or
R.sub.8 is phenyl or lower alkylphenyl, R.sub.9 and R.sub.10
independently are hydrogen, an alkyl group of 1 to 10 carbons, or a
cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl,
R.sub.11 is lower alkyl, phenyl or lower alkylphenyl, R.sub.12 is
lower alkyl, and R.sub.13 is divalent alkyl radical of 2-5
carbons.
2. A compound in accordance with claim 1 wherein L is
--(C.dbd.Z)--NH--.
3. A compound in accordance with claim 1 wherein L is
--NH--(C.dbd.Z)--.
4. A compound in accordance with claim 1 wherein X is CH.
5. A compound in accordance with claim 1 wherein X is N.
6. A compound in accordance with claim 1 wherein Y is selected from
the group consisting of phenyl, pyridyl, 2-thiazolyl, thienyl and
furyl.
7. A compound in accordance with claim 6 wherein Y is phenyl.
8. A compound in accordance with claim 1 wherein W is
branch-chained alkyl, F, NO.sub.2, Br, I, CF.sub.3, N.sub.3, or
OH.
9. A compound in accordance with claim 8 wherein (W).sub.p
represents two branch-chained alkyl groups.
10. A compound in accordance with claim 8 wherein (W).sub.r
represents one or two fluoro or one or two NO.sub.2 groups.
11. A compound of the formula 11wherein X is CH or N; R.sub.1 is
independently H or alkyl of 1 to 6 carbons; m is an integer having
the value of 0-5; p is an integer having the value of 0-2; r is an
integer having the value 0-2; Z is O or S; W is a substituent
selected from the group consisting of F, Br, Cl, I, C.sub.1-6alkyl,
fluoro substituted C.sub.1-6 alkyl, NO.sub.2, N.sub.3, OH,
OCH.sub.2OCH.sub.3, OC.sub.1-10alkyl, tetrazol, CN,
SO.sub.2C.sub.1-6-alkyl, SO.sub.2C.sub.1-6-alkyl,
SO.sub.2C.sub.1-6-fluoro substituted alkyl, SO--C.sub.1-6 alkyl,
CO--C.sub.1-6alkyl, COOR.sub.8, phenyl, phenyl itself substituted
with a W group other than with phenyl or substituted phenyl with
the proviso that when X is CH and r is 0 then p is not 0 and at
least one W group is not alkyl; A is (CH.sub.2).sub.q where q is
0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl
having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double
bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds, and B is
COOH or a pharmaceutically acceptable salt thereof, COOR.sub.8,
CONR.sub.9R.sub.10, --CH.sub.2OH, CH.sub.2OR.sub.11,
CH.sub.2OCOR.sub.11, CHO, CH(OR.sub.12).sub.2, CHOR.sub.13O,
--COR.sub.7, CR.sub.7(OR.sub.12).sub.2- , CR.sub.7OR.sub.13O, where
R.sub.7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5
carbons, R.sub.8 is an alkyl group of 1 to 10 carbons or
trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a
cycloalkyl group of 5 to 10 carbons, or R.sub.8 is phenyl or lower
alkylphenyl, R.sub.9 and R.sub.10 independently are hydrogen, an
alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10
carbons, or phenyl or lower alkylphenyl, R.sub.11 is lower alkyl,
phenyl or lower alkylphenyl, R.sub.12 is lower alkyl, and R.sub.13
is divalent alkyl radical of 2-5 carbons.
12. A compound in accordance with claim 11 wherein X is CH.
13. A compound in accordance with claim 12 wherein Z is 0.
14. A compound in accordance with claim 13 wherein A is
(CH.sub.2).sub.q, and B is COOH or a pharmaceutically acceptable
salt thereof, COOR.sub.8 or CONR.sub.9R.sub.10.
15. A compound in accordance with claim 14 wherein (W).sub.p
represents two branch-chained alkyl groups and (W).sub.r represents
one or two fluoro or one or two NO.sub.2 groups.
16. A compound in accordance with claim 15 wherein the phenyl ring
is 1,4-substituted by the (C.dbd.Z)NH-- and --A--B-- groups.
17. A compound of the formula 12wherein X is CH or N; W.sub.1 is H
or OH; W.sub.2 is H, F or NO.sub.2; W.sub.3 is H, F or NO.sub.2;
R.sub.8 is H, CH.sub.3 or C.sub.2H.sub.5, with the proviso that
when X is CH then W.sub.1, W.sub.2 and W.sub.3 all are not H.
18. A compound in accordance with claim 17 wherein X is N.
19. A compound in accordance with claim 18 wherein W.sub.2 is F and
W.sub.3 is H.
20. A compound in accordance with claim 19 which is: ethyl
2-fluoro-4-[(2',6'-di-t-butylpyrid-4'-yl)carbamoyl]benzoate, or
2-fluoro-4-[(2',6'-di-t-butylpyrid-4'-yl)carbamoyl]benzoic
acid.
21. A compound in accordance with claim 18 where in W.sub.2 is F
and W.sub.3 is F.
22. A compound in accordance with claim 21 which is: methyl
2,6-difluoro-4-[(2',6'-di-t-butylpyrid-4'yl)carbamoyl]benzoate, or
2,6-difluoro-4-[(2',6'-di-t-butylpyrid-4'yl)carbamoyl]benzoic
acid.
23. A compound in accordance with claim 18 wherein W.sub.2 is
NO.sub.2.
24. A compound in accordance with claim 23 which is: methyl
2-nitro-4-[(2',6'-di-t-butylpyrid-4'-yl)carbamoyl]benzoate, or
2-nitro-4-[(2',6'-di-t-butylpyrid-4'-yl)carbamoyl]benzoic acid.
25. A compound in accordance with claim 18 wherein W.sub.1, W.sub.2
and W.sub.3 are all hydrogen.
26. A compound in accordance with claim 25 which is: ethyl
4-[(2',6'-di-t-butylpyrid-4'-yl)carbamoyl]benzoate, or
4-[(2',6'-di-t-butylpyrid-4'-yl)carbamoyl]benzoic acid.
27. A compound in accordance with claim 17 wherein X is CH.
28. A compound in accordance with claim 27 wherein W.sub.2 is F and
W.sub.3 is H.
29. A compound in accordance with claim 28 which is: ethyl
2-fluoro-4-[(3',5'-di-t-butylphenyl)carbamoyl]benzoate, or
2-fluoro-4-[(3',5'-di-t-butyl)phenylcarbamoyl]benzoic acid.
30. A compound in accordance with claim 27 wherein W.sub.2 is F and
W.sub.3 is F.
31. A compound in accordance with claim 30 which is: methyl
2,6-difluoro-4-[(3',5'-di-t-butylphenyl)carbamoyl]benzoate, or
2,6-difluoro-4-[(3',5'-di-t-butylphenyl)carbamoyl]benzoic acid.
32. A compound in accordance with claim 27 wherein w is OH.
33. A compound in accordance with claim 32 which is: ethyl
2-fluoro-4-[(2'-hydroxy-3',5'-di-t-butylphenyl)carbamoyl]benzoate,
or
2-lfuoro-4-[(2'-hydroxy-3',5'-di-t-butyl)phenyl-carbamoyl]benzoic
acid.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention relates to novel compounds having
retinoid-like biological activity. More specifically, the present
invention relates to amides formed between aryl or heteraryl amines
and aryl or heteroaryl carboxylic acids where one of the aromatic
or heteroaromatic moieties bears an electron withdrawing
substituent. The compounds have retinoid-like biological
activity.
[0003] 2. Background Art
[0004] Compounds which have retinoid-like activity are well known
in the art, and are described in numerous United States and other
patents and in scientific publications. It is generally known and
accepted in the art that retinoid-like activity is useful for
treating animals of the mammalian species, including humans, for
curing or alleviating the symptoms and conditions of numerous
diseases and conditions. In other words, it is generally accepted
in the art that pharmaceutical compositions having a retinoid-like
compound or compounds as the active ingredient are useful as
regulators of cell proliferation and differentiation, and
particularly as agents for treating skin-related diseases,
including, actinic keratoses, arsenic keratoses, inflammatory and
non-inflammatory acne, psoriasis, ichthyoses and other
keratinization and hyperproliferative disorders of the skin,
eczema, atopic dermatitis, Darriers disease, lichen planus,
prevention and reversal of glucocorticoid damage (steroid atrophy),
as a topical anti-microbial, as skin anti-pigmentation agents and
to treat and reverse the effects of age and photo damage to the
skin. Retinoid compounds are also useful for the prevention and
treatment of cancerous and precancerous conditions, including,
premalignant and malignant hyperproliferative diseases such as
cancers of the breast, skin, prostate, cervix, uterus, colon,
bladder, esophagus, stomach, lung, larynx, oral cavity, blood and
lymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias
and papillomas of the mucous membranes and in the treatment of
Kaposi's sarcoma. In addition, retinoid compounds can be used as
agents to treat diseases of the eye, including, without limitation,
proliferative vitreoretinopathy (PVR), retinal detachment, dry eye
and other corneopathies, as well as in the treatment and prevention
of various cardiovascular diseases, including, without limitation,
diseases associated with lipid metabolism such as dyslipidemias,
prevention of post-angioplasty restenosis and as an agent to
increase the level of circulating tissue plasminogen activator
(TPA). Other uses for retinoid compounds include the prevention and
treatment of conditions and diseases associated with human
papilloma virus (HPV), including warts and genital warts, various
inflammatory diseases such as pulmonary fibrosis, ileitis, colitis
and Krohn's disease, neurodegenerative diseases such as Alzheimer's
disease, Parkinson's disease and stroke, improper pituitary
function, including insufficient production of growth hormone,
modulation of apoptosis, including both the induction of apoptosis
and inhibition of T-Cell activated apoptosis, restoration of hair
growth, including combination therapies with the present compounds
and other agents such as Minoxidil.RTM., diseases associated with
the immune system, including use of the present compounds as
immunosuppressants and immunostimulants, modulation of organ
transplant rejection and facilitation of wound healing, including
modulation of chelosis.
[0005] U.S. Pat. No. 4,723,028 (Shudo), Published European Patent
Application Nos. 0 170 105 (Shudo), German Patent Application No.
DE 3524199 A1 (Shudo), PCT WO 91/16051 (Spada et al.), PCT WO
85/04652 (Polus) and J. Med Chem. 1988 31, 2182-2192 (Kaqechika et
al.), describe or relate to aryl and heteroary or diary substituted
olephines or amides having retinoid-like or related biological
activity.
[0006] U.S. Pat. Nos. 4,992,468, 5,013,744, 5,068,252, 5,175,185,
5,202,471, 5,264,456, 5,324,840, 5,326,898, 5,349,105, 5,391,753,
5,414,007 and 5,434,173 (assigned to the same assignee as the
present application) and patents and publications cited therein,
describe or relate to compounds which have retinoid-like biological
activity and a structure wherein a phenyl and a heteroaryl or a
phenyl and a second phenyl group is linked with an olephinic or
acetylenic linkage. Still further, several co-pending applications
and recently issued patents which are assigned to the assignee of
the present application, are directed to further compounds having
retinoid-like activity.
[0007] It is now general knowledge in the art that two main types
of retinoid receptors exist in mammals (and other organisms). The
two main types or families of receptors are respectively designated
RARs and RXRs. Within each type there are subtypes; in the RAR
family the subtypes are designated RAR.sub..alpha., RAR.sub..beta.
and RAR.sub..GAMMA., in RXR the subtypes are: RXR.sub..alpha.,
RXB.sub..beta. and RXR.sub..GAMMA.. It has also been established in
the art that the distribution of the two main retinoid receptor
types, and of the several sub-types is not uniform in the various
tissues and organs of mammalian organisms. Accordingly, among
compounds capable of binding to retinoid receptors, specificity or
selectivity for one of the main types or families, and even
specificity or selectivity for one or more subtypes within a family
of receptors, is considered a desirable pharmacological
property.
[0008] The present invention provides compounds having
retinoid-like biological activity and specifically compounds which
bind to one or more RAR retinoid receptor subtypes.
SUMMARY OF THE INVENTION
[0009] The present invention covers compounds of Formula 2
[0010] wherein X is CH or N;
[0011] R.sub.1 is independently H or alkyl of 1 to 6 carbons;
[0012] m is an integer having the value of 0-5;
[0013] p is an integer having the value of 0-2;
[0014] r is an integer having the value 0-2;
[0015] L is --(C.dbd.Z)--NH-- or --NH--(C.dbd.Z)-- where Z is 0 or
S;
[0016] Y is a phenyl or naphthyl group, or heteroaryl selected from
a group consisting of pyridyl, thienyl, furyl, pyridazinyl,
pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and
pyrrazolyl, said phenyl, naphthyl and heteroaryl groups being
optionally substituted with one or two R.sub.1 groups;
[0017] W is a substituent selected from the group consisting of F,
Br, Cl, I, C.sub.1-6alkyl, fluoro substituted C.sub.1-6 alkyl,
NO.sub.2, N.sub.3, OH, OCH.sub.2OCH.sub.3, OC.sub.1-10alkyl,
tetrazol, CN, SO.sub.2C.sub.1-6-alkyl, SO.sub.2C.sub.1-6-alkyl,
SO.sub.2C.sub.1-6-fluor- o substituted alkyl, SO--C.sub.1-6 alkyl,
CO--C.sub.1-6alkyl, COOR.sub.8, phenyl, phenyl itself substituted
with a W group other than with phenyl or substituted phenyl with
the proviso that when X is CH and r is 0 then p is not 0 and at
least one W group is not alkyl;
[0018] A is (CH.sub.2).sub.q where q is 0-5, lower branched chain
alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl
having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6
carbons and 1 or 2 triple bonds, and
[0019] B is COOH or a pharmaceutically acceptable salt thereof,
COOR.sub.8, CONR.sub.9R.sub.10, --CH.sub.2OH, CH.sub.2OR.sub.11,
CH.sub.2OCOR.sub.11, CHO, CH(OR.sub.12).sub.2, CHOR.sub.13O,
--COR.sub.7, CR.sub.7(OR.sub.12).sub.2, CR.sub.7OR.sub.13O, where
R.sub.7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5
carbons, R.sub.8 is an alkyl group of 1 to 10 carbons or
trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a
cycloalkyl group of 5 to 10 carbons, or R.sub.8 is phenyl or lower
alkylphenyl, R.sub.9 and R.sub.10 independently are hydrogen, an
alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10
carbons, or phenyl or lower alkylphenyl, R.sub.11 is lower alkyl,
phenyl or lower alkylphenyl, R.sub.12 is lower alkyl, and R.sub.13
is divalent alkyl radical of 2-5 carbons.
[0020] In a second aspect, this invention relates to the use of the
compounds of Formula 1 for the treatment of skin-related diseases,
including, without limitation, actinic keratoses, arsenic
keratoses, inflammatory and non-inflammatory acne, psoriasis,
ichthyoses and other keratinization and hyperproliferative
disorders of the skin, eczema, atopic dermatitis, Darriers disease,
lichen planus, prevention and reversal of glucocorticoid damage
(steroid atrophy), as a topical anti-microbial, as skin
anti-pigmentation agents and to treat and reverse the effects of
age and photo damage to the skin. The compounds are also useful for
the prevention and treatment of cancerous and precancerous
conditions, including, premalignant and malignant
hyperproliferative diseases such as cancers of the breast, skin,
prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung,
larynx, oral cavity, blood and lymphatic system, metaplasias,
dysplasias, neoplasias, leukoplakias and papillomas of the mucous
membranes and in the treatment of Kaposi's sarcoma. In addition,
the present compounds can be used as agents to treat diseases of
the eye, including, without limitation, proliferative
vitreoretinopathy (PVR), retinal detachment, dry eye and other
corneopathies, as well as in the treatment and prevention of
various cardiovascular diseases, including, without limitation,
diseases associated with lipid metabolism such as dyslipidemias,
prevention of post-angioplasty restenosis and as an agent to
increase the level of circulating tissue plasminogen activator
(TPA). Other uses for the compounds of the present invention
include the prevention and treatment of conditions and diseases
associated with human papilloma virus (HPV), including warts and
genital warts, various inflammatory diseases such as pulmonary
fibrosis, ileitis, colitis and Krohn's disease, neurodegenerative
diseases such as Alzheimer's disease, Parkinson's disease and
stroke, improper pituitary function, including insufficient
production of growth hormone, modulation of apoptosis, including
both the induction of apoptosis and inhibition of T-Cell activated
apoptosis, restoration of hair growth, including combination
therapies with the present compounds and other agents such as
Minoxidil.RTM., diseases associated with the immune system,
including use of the present compounds as immunosuppressants and
immunostimulants, modulation of organ transplant rejection and
facilitation of wound healing, including modulation of
chelosis.
[0021] This invention also relates to a pharmaceutical formulation
comprising a compound of Formula 1 in admixture with a
pharmaceutically acceptable excipient.
[0022] In another aspect, this invention relates to processes for
making a compound of Formula 1 which processes comprise reacting,
in the presence of an acid acceptor or water acceptor, a compound
of Formula 2 with a compound of Formula 3 where X.sub.1 is OH,
halogen, or other group which renders the --COX.sub.1 group
reactive for amide formation, and where the remaining symbols are
defined as in connection with Formula 1. Alternatively, the process
of the invention comprises reacting a compound of Formula 2a with a
compound of Formula 3a, where the symbols are defined as above.
3
[0023] Still further, the present invention relates to such
reactions performed on the compounds of Formula 1 which cause
transformations of the B group while the reaction product still
remains within the scope of Formula 1.
General Embodiments
[0024] Definitions
[0025] The term alkyl refers to and covers any and all groups which
are known as normal alkyl, branched-chain alkyl and cycloalkyl. The
term alkenyl refers to and covers normal alkenyl, branch chain
alkenyl and cycloalkenyl groups having one or more sites of
unsaturation. Similarly, the term alkynyl refers to and covers
normal alkynyl, and branch chain alkynyl groups having one or more
triple bonds.
[0026] Lower alkyl means the above-defined broad definition of
alkyl groups having 1 to 6 carbons in case of normal lower alkyl,
and as applicable 3 to 6 carbons for lower branch chained and
cycloalkyl groups. Lower alkenyl is defined similarly having 2 to 6
carbons for normal lower alkenyl groups, and 3 to 6 carbons for
branch chained and cyclo- lower alkenyl groups. Lower alkynyl is
also defined similarly, having 2 to 6 carbons for normal lower
alkynyl groups, and 4 to 6 carbons for branch chained lower alkynyl
groups.
[0027] The term "ester" as used here refers to and covers any
compound falling within the definition of that term as classically
used in organic chemistry. It includes organic and inorganic
esters. Where B of Formula 1 is --COOH, this term covers the
products derived from treatment of this function with alcohols or
thioalcohols preferably with aliphatic alcohols having 1-6 carbons.
Where the ester is derived from compounds where B is --CH.sub.2OH,
this term covers compounds derived from organic acids capable of
forming esters including phosphorous based and sulfur based acids,
or compounds of the formula --CH.sub.2OCOR.sub.11 where R.sub.11 is
any substituted or unsubstituted aliphatic, aromatic,
heteroaromatic or aliphatic aromatic group, preferably with 1-6
carbons in the aliphatic portions.
[0028] Unless stated otherwise in this application, preferred
esters are derived from the saturated aliphatic alcohols or acids
of ten or fewer carbon atoms or the cyclic or saturated aliphatic
cyclic alcohols and acids of 5 to 10 carbon atoms. Particularly
preferred aliphatic esters are those derived from lower alkyl acids
and alcohols. Also preferred are the phenyl or lower alkyl phenyl
esters.
[0029] Amides has the meaning classically accorded that term in
organic chemistry. In this instance it includes the unsubstituted
amides and all aliphatic and aromatic mono- and di-substituted
amides. Unless stated otherwise in this application, preferred
amides are the mono- and di-substituted amides derived from the
saturated aliphatic radicals of ten or fewer carbon atoms or the
cyclic or saturated aliphatic-cyclic radicals of 5 to 10 carbon
atoms. Particularly preferred amides are those derived from
substituted and unsubstituted lower alkyl amines. Also preferred
are mono- and disubstituted amides derived from the substituted and
unsubstituted phenyl or lower alkylphenyl amines. Unsubstituted
amides are also preferred.
[0030] Acetals and ketals include the radicals of the formula-CK
where K is (--OR).sub.2. Here, R is lower alkyl. Also, K may be
--OR.sub.7O-- where R.sub.7 is lower alkyl of 2-5 carbon atoms,
straight chain or branched.
[0031] A pharmaceutically acceptable salt may be prepared for any
compounds in this invention having a functionality capable of
forming such-salt, for example an acid functionality. A
pharmaceutically acceptable salt is any salt which retains the
activity of the parent compound and does not impart any deleterious
or untoward effect on the subject to which it is administered and
in the context in which it is administered. Pharmaceutically
acceptable salts may be derived from organic or inorganic bases.
The salt may be a mono or polyvalent ion. Of particular interest
are the inorganic ions, sodium, potassium, calcium, and magnesium.
Organic salts may by be made with amines, particularly ammonium
salts such as mono-, di- and trialkyl amines or ethanol amines.
Salts may also be formed with caffeine, tromethamine and similar
molecules. Where there is a nitrogen sufficiently basic as to be
capable of forming acid addition salts, such may be formed with any
inorganic or organic acids or alkylating agent such as methyl
iodide. Preferred salts are those formed with inorganic acids such
as hydrochloric acid, sulfuric acid or phosphoric acid. Any of a
number of simple organic acids such as mono-, di- or tri- acid may
also be used.
[0032] Some of the compounds of the present invention may have
trans and cis (E and Z) isomers. In addition, the compounds of the
present invention may contain one or more chiral centers and
therefore may exist in enantiomeric and diastereomeric forms. The
scope of the present invention is intended to cover all such
isomers per se, as well as mixtures of cis and trans isomers,
mixtures of diastereomers and racemic mixtures of enantiomers
(optical isomers) as well.
[0033] With reference to the symbol X in Formula 1, compounds are
equally preferred where X is CH or N. When X is CH then the benzene
ring is preferably 1, 3, 5 substituted with the L group occupying
the 1 position and the W and/or R.sub.1 groups occupying the 3 and
5 positions. When the symbol X is N, then the pyridine ring is
preferably 2,4,6 substituted with the L group occupying the 4
position and the W and/or R.sub.1 groups occupying the 2 and 6
positions.
[0034] The L group of Formula 1 is preferably --(C.dbd.Z)--NH--,
and Z is preferably 0. In other words, those carbamoyl or amide
compounds are preferred in accordance with the present invention
where the --NH-moiety is attached to the Y group.
[0035] Referring now to the W group in Formula 1, this group is,
generally speaking, an electron withdrawing group. W is present in
the compounds of the invention either in the phenyl or pyridyl ring
(shown in Formula 1 as substituent "(W).sub.p") and/or as a
substituent of the aryl or heteroaryl group Y. Preferably, the W
group is present in the Y group, or both in the Y group and in the
phenyl or pyridyl ring discussed above. In the aryl or heteroaryl Y
moiety the W group is preferably located in the position adjacent
to the A-B group; preferably the A-B group is in para position in
the phenyl ring relative to the L (amide or carbamoyl) moiety, and
therefore the W group is preferably in meta position relative to
the L (amide or carbamoyl) moiety. Preferred W groups are F,
NO.sub.2, Br, I, CF.sub.3, N.sub.3, and OH. Alternatively, in the
phenyl or pyridyl ring (shown in Formula 1 as substituent
"(W).sub.p") W is an alkyl group, preferably branch-chained alkyl,
such as tertiary butyl, and preferably p is 2. Moreover, the
presence of one or two fluoro substituents in the Y group is
especially preferred. When the Y group is phenyl, the fluoro
substituents preferably are in the ortho and ortho' positions
relative to the A-B group.
[0036] With reference to the symbol Y in Formula 1, the preferred
compounds of the invention are those where Y is phenyl, pyridyl,
2-thiazolyl, thienyl, or furyl, more preferably phenyl. As far as
substitutions on the Y (phenyl) and Y (pyridyl) groups are
concerned, compounds are preferred where the phenyl group is 1,4
(para) substituted by the L and A-B groups, and where the pyridine
ring is 2,5 substituted by the L and A-B groups. (Substitution in
the 2,5 positions in the "pyridine" nomenclature corresponds to
substitution in the 6-position in the "nicotinic acid"
nomenclature.) In the preferred compounds of the invention there is
no optional R.sub.1 substituent (other than H) on the Y group.
[0037] The R.sub.1 groups, when present, preferably are H or
CH.sub.3.
[0038] The A-B group of the preferred compounds is
(CH.sub.2).sub.n--COOH or (CH.sub.2).sub.n--COOR.sub.8, where n and
R.sub.8 are defined as above. Even more preferably n is zero and
R.sub.8 is lower alkyl, or n is zero and B is COOH or a
pharmaceutically acceptable salt thereof.
[0039] The most preferred compounds of the invention are shown in
Table 1, with reference to Formula 4.
1TABLE 1 Formula 4 4 Compound # X W.sub.1 W.sub.2 W.sub.3 R.sub.8*
1 N H F H Et 2 N H F H H 3 N H H H Et 4 N H H H H 5 CH H F H Et 6
CH H F H H 7 CH OH F H Et 8 CH OH F H H 9 N H F F Me 10 N H F F H
11 CH H F F Me 12 CH H F F H 13 N H NO.sub.2 H Me 14 N H NO.sub.2 H
H 15.sup.1 CH H H H H .sup.1Compound 15 is prior art, described in
J. Med Chem. 1988, 31, 2182 (Kagechika et al.)
Modes of Administration
[0040] The compounds of this invention may be administered
systemically or topically, depending on such considerations as the
condition to be treated, need for site-specific treatment, quantity
of drug to be administered, and numerous other considerations.
[0041] In the treatment of dermatoses, it will generally be
preferred to administer the drug topically, though in certain cases
such as treatment of severe cystic acne or psoriasis, oral
administration may also be used. Any common topical formulation
such as a solution, suspension, gel, ointment, or salve and the
like may be used. Preparation of such topical formulations are well
described in the art of pharmaceutical formulations as exemplified,
for example, Remington's Pharmaceutical Science, Edition 17, Mack
Publishing Company, Easton, Pa. For topical application, these
compounds could also be administered as a powder or spray,
particularly in aerosol form. If the drug is to be administered
systemically, it may be confected as a powder, pill, tablet or the
like or as a syrup or elixir suitable for oral administration. For
intravenous or intraperitoneal administration, the compound will be
prepared as a solution or suspension capable of being administered
by injection. In certain cases, it may be useful to formulate these
compounds by injection. In certain cases, it may be useful to
formulate these compounds in suppository form or as extended
release formulation for deposit under the skin or intramuscular
injection.
[0042] Other medicaments can be added to such topical formulation
for such secondary purposes as treating skin dryness; providing
protection against light; other medications for treating
dermatoses; medicaments for preventing infection, reducing
irritation, inflammation and the like.
[0043] Treatment of dermatoses or any other indications known or
discovered to be susceptible to treatment by retinoic acid-like
compounds will be effected by administration of the therapeutically
effective dose of one or more compounds of the instant invention. A
therapeutic concentration will be that concentration which effects
reduction of the particular condition, or retards it expansion. In
certain instances, the compound potentially may be used in
prophylactic manner to prevent onset of a particular condition.
[0044] A useful therapeutic or prophylactic concentration will vary
from condition to condition and in certain instances may vary with
the severity of the condition being treated and the patient's
susceptibility to treatment. Accordingly, no single concentration
will be uniformly useful, but will require modification depending
on the particularities of the disease being treated. Such
concentrations can be arrived at through routine experimentation.
However, it is anticipated that in the treatment of, for example,
acne, or similar dermatoses, that a formulation containing between
0.01 and 1.0 milligrams per mililiter of formulation will
constitute a therapeutically effective concentration for total
application. If administered systemically, an amount between 0.01
and 5 mg per kg per day of body weight would be expected to effect
a therapeutic result in the treatment of many disease for which
these compounds are useful.
Assay of Retinoid-like Biological Activity
[0045] The retinoid-like activity of the compounds of the invention
can be confirmed in assays wherein ability of the compound to bind
to retinoid receptors is measured. As it is noted in the
introductory section of this application for patent two main types
of retinoic acid receptors (RAR and RXR) exist in mammals (and
other organisms). Within each type there are sub-types
(RAR.sub..alpha., RAR.sub..beta., RAR.sub..GAMMA., RXR.sub..alpha.,
RXR.sub..beta. and RXR.sub..GAMMA.) the distribution of which is
not uniform in the various tissues and organs of mammalian
organisms. Selective binding of only one or two retinoid receptor
subtypes within one retinoid receptor family can give rise to
beneficial pharmacological properties because of the varying
distribution of the sub-types in the several mammalian tissues or
organs. For the above-summarized reasons, binding of any or all of
the retinoid receptors, as well as specific or selective activity
in a receptor family, or selective or specific activity in any one
of the receptor subtypes, are all considered desirable
pharmacological properties.
[0046] In light of the foregoing the prior art has developed assay
procedures for testing the agonist like activity of compounds in
the RAR.sub..alpha., RAR.sub..beta., RAR.sub..GAMMA.,
RXR.sub..alpha., RXR.sub..beta. and RXR.sub..GAMMA. receptor
subtypes. For example, a chimeric receptor transactivation assay
which tests for agonist-like activity in the RAR.sub..alpha.,
RAR.sub..beta., RA.sub..GAMMA., and RXR.sub..alpha. receptor
subtypes, and which is based on work published by Feigner P. L. and
Holm M. (1989) Focus, 11 2 is described in detail in U.S. Pat. No.
5,455,265. The specification of U.S. Pat. No. 5,455,265 is
expressly incorporated herein by reference.
[0047] A holoreceptor transactivation assay and a ligand binding
assay which measure the ability of the compounds of the invention
to bind to the several retinoid receptor subtypes, respectively,
are described in published PCT Application No. WO W093/11755
(particularly on pages 30-33 and 37-41) published on Jun. 24, 1993,
the specification of which is also incorporated herein by
reference. A description of the ligand binding assay is also
provided below.
[0048] Binding Assay
[0049] All binding assays were performed in a similar fashion. All
six receptor types were derived from the expressed receptor type
(RAR .alpha., .beta., .GAMMA. and RXR .alpha., .beta., .GAMMA.)
expressed in Baculovirus. Stock solutions of all compounds were
prepared as 10 mM ethanol solutions and serial dilutions carried
out into 1:1 DMSO; ethanol. Assay buffers consisted of the
following for all six receptor assays: 8% glycerol, 120 mM KCl, 8
mM Tris, 5 mM CHAPS 4 mM DTT and 0.24 mM PMSF, pH-7.4@room
temperature.
[0050] All receptor biding assays were performed in the same
manner. The final assay volume was 250 .mu.l and contained from
10-40 .mu.g of extract protein depending on receptor being assayed
along with 5 nM of [.sup.3H] all-trans retinoic acid or 10 nM
[.sup.3H] 9-cis retinoic acid and varying concentrations of
competing ligand at concentrations that ranged from 0-10.sup.-5 M.
The assays were formatted for a 96 well minitube system.
Incubations were carried out at 4.degree. C. until equilibrium was
achieved. Non-specific binding was defined as that binding
remaining in the presence of 1000 nM of the appropriate unlabeled
retinoic acid isomer. At the end of the incubation period, 50 .mu.l
of 6.25% hydroxyapitite was added in the appropriate wash buffer.
The wash buffer consisted of 100 mM KCl, 10 mM Tris and either 5 mM
CHAPS (RXR .alpha., .beta., .GAMMA.) or 0.5% Triton X-100 (RAR
.alpha., .beta., .GAMMA.). The mixture was vortexed and incubated
for 10 minutes at 4.degree. C., centrifuged and the supernatant
removed. The hydroxyapitite was washed three more times with the
appropriate wash buffer. The receptor-ligand complex was adsorbed
by the hydroxyapitite. The amount of receptor-ligand complex was
determined by liquid scintillation counting of hydroxyapitite
pellet.
[0051] After correcting for non-specific binding, IC.sub.50 values
were determined. The IC.sub.50 value is defined as the
concentration of competing ligand needed to reduce specific binding
by 50%. The IC.sub.50 value was determined graphically from a
loglogit plot of the data. The K.sub.d values were determined by
application of the Cheng-Prussof equation to the IC.sub.50 values,
the labeled ligand concentration and the K.sub.d of the labeled
ligand.
[0052] The results of ligand binding assay are expressed in K.sub.d
numbers. (See Chena et al. Biochemical Pharmacology Vol. 22 pp
3099-3108, expressly incorporated herein by reference.)
[0053] Table 2 shows the results of the ligand binding assay for
certain exemplary compounds of the invention.
2TABLE 2 Ligand Binding Assay K.sub.d (nanomolar) Compound #
RAR.alpha. RAR.beta. RAR.GAMMA. RXR.alpha. RXR.beta. RXR.GAMMA. 2
14.00 0.00 0.00 0.00 0.00 0.00 4 19.00 0.00 0.00 0.00 0.00 0.00 6
26.0 0.00 0.00 0.00 0.00 0.00 8 77.0 0.00 0.00 0.00 0.00 0.00 10
62.0 0.00 0.00 0.00 0.00 0.00 12 87.0 0.00 0.00 0.00 0.00 0.00 14
94.0 0.00 0.00 0.00 0.00 0.00 15.sup.1 37.0 0.00 0.00 0.00 0.00
0.00 0.00 indicates value greater than 1000 nM (nanomolar)
.sup.1Compound 15 is prior art, described in J. Med Chem. 1988, 31,
2182 (Kagechika et al.)
[0054] As it can be seen from the test results summarized in Table
2, the therein indicated exemplary compounds of the invention bind
specifically or selectively to RAR.alpha. receptors.
[0055] Cancer Cell Line Assays
[0056] Materials and Methods
[0057] Hormones
[0058] All trans-Retinoic acid (t-RA) (Sigma Chemicals Co., St.
Louis, Mo.) was stored at -70.degree. C. Prior to each experiment
the compound was dissolved in 100% ethanol at 1 mM and diluted in
culture medium immediately before use. All experiments were
performed in subdued light. Controls were assayed using the same
concentration of ethanol as present in the experimental plates and
this concentration of diluent had no effect in either assay.
[0059] Cells and Cell Culture
[0060] All cell lines, RPMI 8226, ME-180 and AML-193 were obtained
from the American Type Culture Collection (ATCC, Rockville, Md.).
RPMI 8226 is a human hematopoietic cell line obtained from the
peripheral blood of a patient with multiple myeloma. The cells
resemble the lymphoblastoid cells of other human lymphocyte cell
lines and secrete .alpha.-type light chains of immunoglobulin.
RPMI-8226 cells are grown in RPMI medium (Gibco) supplemented with
10% fetal bovine serum, glutamine and antibiotics. The cells were
maintained as suspension cultures grown at 37.degree. C. in a
humidified atmosphere of 5% CO.sub.2 in air. The cells were diluted
to a concentration of 1.times.10.sup.5/ml twice a week.
[0061] ME-180 is a human epidermoid carcinoma cell line derived
from the cervix. The tumor was a highly invasive squamous cell
carcinoma with irregular cell clusters and no significant
keratinization. ME-180 cells were grown and maintained in McCoy's
5a medium (Gibco) supplemented with 10% fetal bovine serum,
glutamine and antibiotics. The cells were maintained as monolayer
cultures grown at 37.degree. C. in a humidified atmosphere of 5%
CO.sub.2 in air. The cells were diluted to a concentration of
1.times.10.sup.5/ml twice a week.
[0062] AML-193 was established from the blast cells classified as
M5 Acute Monocyte Leukemia. The growth factor, granulocyte
colony-stimulation factor (GM-CSF) as required to establish this
cell line and growth factors are necessary for its continuous
proliferation in chemically defined medium. AML-193 cells were
grown and maintained in Iscove's modified Dulbecco's medium
supplemented with 10% fetal bovine serum, glutamine and antibiotics
with 5 .mu.g/ml insulin (Sigma Chemical Co.) and 2 ng/ml rh GM-CSF
(R and D Systems). The cells were diluted to a concentration of
3.times.10.sup.5/ml twice a week.
[0063] Incorporation of .sup.3H-Thymidine
[0064] The method used for determination of the incorporation of
radiolabeled thymidine was adapted from the procedure described by
Shrivastav et al. RPMI-8226 cells were plated in a 96 well round
bottom microtiter plate (Costar) at a density of 1,000 cells/well.
To appropriate wells, retinoid test compounds were added at the
final concentrations indicated for a final volume of 150
.mu.l/well. The plates were incubated for 96 hours at 37.degree. C.
in a humidified atmosphere of 5% CO.sub.2 in air. Subsequently, 1
.mu.Ci of [5'-.sup.3H]-thymidine (Amersham, U.K. 43 Ci/mmol
specific activity) in 25 .mu.l culture medium was added to each
well and the cells were incubated for an additional 6 hours. The
cultures were further processed as described below.
[0065] ME-180 wells, harvested by trypsinization were plated in a
96 well flat bottom microtiter plate (Costar) at a density of 2,000
cells/well. The cultures were treated as described above for RPMI
8226 with the following exceptions. After incubation with thymidine
the supernatant was carefully removed, and the cells were washed
with a 0.5 mM solution of thymidine in phosphate buffered saline.
ME180 cells were briefly treated with 50 .mu.l of 2.5% trypsin to
dislodge the cells from the plate.
[0066] AML-193 cells were plated in a 96 well round bottom
microtiter plate (Costar) at a density of 1,000 cells/well. To
appropriate wells, retinoid test compounds were added at the final
concentrations indicated for a final volume of 150 .mu.l/well. The
plates were incubated for 96 hours at 37.degree. C. in a humidified
atmosphere of 5% CO.sub.2 in air. Subsequently, 1 .mu.Ci of
[5'-.sup.3H]-thymidine (Amersham, U.K., 43 Ci/mmol specific
activity) in 25 .mu.l culture medium was added to each well and the
cells were incubated for an additional 6 hours.
[0067] All cells lines were then processed as follows: the cellular
DNA was precipitated with 10% trichloroacetic acid onto glass fiber
filter mats using a SKATRON multi-well cell harvester (Skatron
Instruments, Sterling Va.). Radioactivity incorporated into DNA, as
a direct measurement of cell growth, was measured by liquid
scintillation counting. The numbers represent the mean
disintegrations per minute of incorporated thymidine from
triplicate wells .+-.SEM.
[0068] In the above noted in vitro cell lines exemplary Compound 2
of the invention caused significant decrease in the proliferation
of the tumor cell lines (as measured by incorporation of
radioactive labeled thymidine) in the 10.sup.-11 to 10.sup.-6 molar
concentration range of the test compound.
Specific Embodiments
[0069] The compounds of this invention can be made by the synthetic
chemical pathways illustrated here. The synthetic chemist will
readily appreciate that the conditions set out here are specific
embodiments which can be generalized to any and all of the
compounds represented by Formula 1.
[0070] Generally speaking the process of preparing compounds of the
invention involves the formation of an amide by the reaction of a
compound of the general Formula 2 with a compound of general
Formula 3, or by the reaction of a compound of general Formula 2a
with a compound of general Formula 3a as these formulas are defined
in the summary section of the present application for patent. Thus,
as is noted above, a compound of Formula 2 is an acid or an
"activated form" of a carboxylic acid attached to a substituted
phenyl (in Formula 1 X is CH) or to a substituted pyridyl (in
Formula 1 X is N) nucleus.
[0071] The term "activated form" of the carboxylic acid should be
understood in this regard as such derivative of the carboxylic acid
which is capable of forming an amide when reacted with a primary
amine of Formula 3. In case of the "reverse amides" the activated
form of a carboxylic acid is a derivative (Formula 3a) that is
capable of forming an amide when reacted with a primary amine of
Formula 2a. This, generally speaking, means such derivatives of a
carboxylic acid which are normally known and used in the art to
form amide linkages with an amine. Examples of suitable forms or
derivatives for this purpose are acid chlorides, acid bromides, and
esters of the carboxylic acid, particularly active esters, where
the alcohol moiety of the ester forms a good leaving group.
Presently most preferred as reagents in accordance with Formula 2
(or Formula 3a) are acid chlorides (X.sub.1 is Cl). The acid
chlorides of Formula 2 (or of Formula 3a) can be prepared by
traditional methods from the corresponding esters (X.sub.1 is for
example ethyl) by hydrolysis and treatment with thionyl chloride
(SOCl.sub.2). The acid chlorides of Formula 2 (or of Formula 3a)
can also be prepared by direct treatment of the carboxylic acids
with thionyl chloride, where the carboxylic acid, rather than an
ester thereof is available commercially or by a known synthetic
procedure. The acid chlorides of Formula 2 (or of Formula 3a) are
typically reacted with the amine of Formula 3 (or amine of Formula
2a) in an inert solvent, such as methylene chloride, in the
presence of an acid acceptor, such as pyridine.
[0072] The carboxylic acids themselves in accordance with Formula 2
(or Formula 3a) are also suitable for amide formation when reacted
with an amine, a catalyst (4-dimethylaminopyridine) in the presence
of a dehydrating agent, such as dicyclohexylcarbodiimide (DCC) or
more pereferably 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (EDC).
[0073] The carboxylic acids or the corresponding esters of Formula
2, are generally speaking, prepared as described in the chemical
scientific or patent literature and the literature procedures for
their preparation may be modified, if necessary, by such chemical
reactions or processes which per se are known in the art. Reaction
Scheme 1 provides an example for the preparation of
2,6-di-tert-butylisonicotinic acid (Compound C) which is a reagant
in accordance with Formula 2 for the preparation of several
preferred compounds of the present invention. Thus,
2,6-di-tert-butyl-4-methylpyridine (available commercially from
Aldrich Chemical Co.) is reacted with N-bromosuccinimide and
benzoyl peroxide to provide 4-bromomethyl-2,6-di-tert-butylpyridine
(Compound A). Compound A is reacted with base (sodium hydroxyde) to
yield the coresponding hydroxymethyl compound (Compound B), which
is thereafter oxidized in a Jones oxydation reaction to give
2,6-di-tert-butylisonicotinic acid (Compound C). 5
[0074] A further example of a compound which serves as a reagent
for preparing the carbamoyl (or amide) compounds of the present
invention is provided in Reaction Scheme 1, 2,4-Di-tert-butylphenol
(Aldrich) is brominated in glacial acetic acid to yield
2-bromo-4,6-di-tert-butylpheno- l (Compound D) which is thereafter
reacted with methoxymethyl chloride (MOMCl)to give
O-methoxymethyl-2-bromo-4,6-di-tert-butylphenol (Compound E).
Compound B is treated with t-butyl lithium folowed by carbon
dioxide to yield O-methoxymethyl-3,5-di-tert-butylsalicylic acid
(Compound F). Compound F is a reagent which differs from the
compounds generally encompassed by Formula 2 only in that the
hydroxyl funtion of this compound is protected by the methoxymethyl
(MOM) group. However, the methoxymethyl protecting group is removed
after formation of the carbamoyl (amide) linkage, as exemplified in
Reaction Scheme 5. Reaction of an aromatic bromo compound (such as
Compound D) with t-butyl lithium followed by carbon dioxide is a
preferred method for preparing several aromatic carboxylic acids in
accordance with Formula 2 and Formula 3a, described in the present
application. 6
[0075] Reaction Scheme 2 provides examples for the preparation of
aromatic amino carboxylic acids or esters which serve as reagents
corresponding to Formula 3 described above. Thus, in accordance
with Reaction Scheme 2, 3-nitro-6-methyl-fluorobenzene (Aldrich) is
subjected to oxidation, conversion of the resulting carboxylic acid
to an acid chloride and thereafter to an ethyl ester, followed by
reduction of the nitro group, to yield ethyl
2-fluoro-4-amino-benzoate (Compound G). As another example,
2,4,6-trifluorobenzoic acid (Aldrich) is converted to the methyl
ester through the acid chloride, and the 4-fluoro atom is displaced
by reaction with sodium azide to give the intermediate azido
compound (Compound H). Compound H is reduced by hydrogenation, to
yield methyl 2,6-difluoro-4-amino benzoate (Compound I). As still
another example, 2-nitro-4-aminobenzoic acid (Research Plus Inc.)
is converted to its methyl ester (Compound K) through the
corresponding acid chloride. 7
[0076] Reaction Scheme 3 illustrates the synthesis of the primary
amine compounds of Formula 2a from the acid chlorides (X.sub.1=Cl)
or other form of activated acids of Formula 2 where the primary
amine of Formula 2a is not available by a published literature
procedure. Thus, substantially in accordance with the steps of a
Curtius rearrangement, the acid chloride of Formula 2 is reacted
with sodium azide in acetone to yield the azide compound of Formula
5. The azide of Formula 5 is heated in a polar high boiling
solvent, such as t-butanol, to provide the intermediate isocyanate
of Formula 6, which is hydrolyzed to yield a compound of Formula
2a. 8
[0077] Reaction Scheme 4 illustrates examples for preparing
compounds of Formula 3a where such compounds are not available
commercially or by a published literature procedure. Thus, by way
of example 2,5-difluoro-4-bromobenzoic acid (available by the
literature procedure of Sugawara et al. Kogyo Kaguku Zasshi 1970,
73, 972-979, incorporated herein by reference) is first esterified
by treatment with ethyl alcohol and acid to yield the corresponding
ester, and thereafter is reacted with butyl lithium followed by
carbon dioxide to give the monoester of 2,5-difluoro terephthalic
acid (Compound L). A similar sequence of reactions performed on
2,3,5,6-difluoro-4-bromobenzoic acid (available by the literature
procedure of Reuman et al. J. Med. Chem. 1995, 38, 2531-2540,
incorporated herein by reference) yields the monoester of
2,3,5,6-tetrafluoroterephthalic acid (Compound M) The just
illustrated sequence of reactions can be, generally speaking,
utilized for the synthesis of all compounds of Formula 3a with such
modification which will become readily apparent to those skilled in
the art, where such compounds are not available by a known
literature procedure.
[0078] Numerous other reactions suitable for preparing compounds of
the invention, and for converting compounds of Formula 1 within the
scope of the present invention into still further compounds of the
invention, and also for preparing the reagents of Formula 2,
Formula 3, Formula 2a and Formula 3a will become readily apparent
to those skilled in the art in light of the present disclosure. In
this regard the following general synthetic methodology, applicable
for conversion of the compounds of Formula 1 into further homologs
and/or derivatives, and also for preparing the reagents of Formula
2 and 3, (as well as 2a and 3a) is noted.
[0079] Carboxylic acids are typically esterified by refluxing the
acid in a solution of the appropriate alcohol in the presence of an
acid catalyst such as hydrogen chloride or thionyl chloride.
Alternatively, the carboxylic acid can be condensed with the
appropriate alcohol in the presence of dicyclohexylcarbodiimide and
dimethylaminopyridine. The ester is recovered and purified by
conventional means. Acetals and ketals are readily made by the
method described in March, "Advanced organic Chemistry," 2nd
Edition, McGraw-Hill Book Company, p 810). Alcohols, aldehydes and
ketones all may be protected by forming respectively, ethers and
esters, acetals or ketals by known methods such as those described
in McOmie, Plenum Publishing Press, 1973 and Protecting Groups, Ed.
Greene, John Wiley & Sons, 1981.
[0080] A means for making compounds where A is (CH.sub.2).sub.q (q
is 1-5) is to subject the compounds of Formula 1, where B is an
acid or other function, to homologation, using the well known
Arndt-Eistert method of homologation, or other known homologation
procedures. Similar homologations (and several of the other herein
mentioned synthetic transformations) can be transformed on the
reagents of Formula 3 or 3a. Compounds of the invention, where A is
an alkenyl group having one or more double bonds can be made, for
example, by having the requisite number of double bonds
incorporated into the reagent of Formula 3. Generally speaking,
such compounds where A is an unsaturated carbon chain can be
obtained by synthetic schemes well known to the practicing organic
chemist; for example by Wittig and like reactions, or by
introduction of a double bond by elimination of halogen from an
alpha-halo-carboxylic acid, ester or like carboxaldehyde. Compounds
of the invention where the A group has a triple (acetylenic) bond
can be made by using the corresponding aryl or heteroaryl aldehyde
intermediate. Such intermediate can be obtained by reactions well
known in the art, for example, by reaction of a corresponding
methyl ketone with strong base, such as lithium diisopropyl
amide.
[0081] The acids and salts derived from compounds of Formula 1 are
readily obtainable from the corresponding esters. Basic
saponification with an alkali metal base will provide the acid. For
example, an ester of Formula 1 may be dissolved in a polar solvent
such as an alkanol, preferably under an inert atmosphere at room
temperature, with about a three molar excess of base, for example,
potassium or lithium hydroxide. The solution is stirred for an
extended period of time, between 15 and 20 hours, cooled, acidified
and the hydrolysate recovered by conventional means.
[0082] The amide (in Formula 1 B is CONR.sub.9R.sub.10) may be
formed by any appropriate amidation means known in the art from the
corresponding esters or carboxylic acids. One way to prepare such
compounds is to convert an acid to an acid chloride and then treat
that compound with ammonium hydroxide or an appropriate amine.
[0083] Alcohols are made by converting the corresponding acids to
the acid chloride with thionyl chloride or other means (J. March,
"Advanced Organic Chemistry", 2nd Edition, McGraw-Hill Book
Company), then reducing the acid chloride with sodium borohydride
(March, Ibid, pg. 1124), which gives the corresponding alcohols.
Alternatively, esters may be reduced with lithium aluminum hydride
at reduced temperatures. Alkylating these alcohols with appropriate
alky halides under Williamson reaction conditions (March, Ibid, pg.
357) gives the corresponding ethers. These alcohols can be
converted to esters by reacting them with appropriate acids in the
presence of acid catalysts or dicyclohexylcarbodiimide and
dimethylaminopyridine.
[0084] Aldehydes can be prepared from the corresponding primary
alcohols using mild oxidizing agents such as pyridinium dichromate
in methylene chloride (Corey, E. J., Schmidt, G., Tet. Lett., 399,
1979), or dimethyl sulfoxide/oxalyl chloride in methylene chloride
(Omura, K., Swern, D., Tetrahedron. 1978, 34, 1651).
[0085] Ketones can be prepared from an appropriate aldehyde by
treating the aldehyde with an alkyl Grignard reagent or similar
reagent followed by oxidation.
[0086] Acetals or ketals can be prepared from the corresponding
aldehyde or ketone by the method described in March, Ibid, p
810.
[0087] Compounds of Formula 1 where B is H can be prepared from the
corresponding halogenated aromatic compounds, preferably where the
halogen is I. 9
[0088] Reaction Scheme 5 illustrates examples for the formation of
the carbamoyl (amide) compounds of the present invention by
reaction of a reagent of Formula 2 with a reagent of Formula 3.
Thus, 2,6-di-tert-butylisonicotinic acid (Compound C) is reacted
with thionyl chloride (SOCl.sub.2) to provide the intermediate acid
chloride, which is then reacted with ethyl
2-fluoro-4-amino-benzoate (Compound G) in the presence of an acid
acceptor (pyridine) to yield ethyl
2-fluoro-4-[(2'6'-di-tert-butylpyrid-4'-yl)carbamoyl]benzoate
(Compound 1). As another example, 3,5-di-tert-butylbenzoic acid
(available by the literature procedure of Kagechika et al., J. Med.
Chem. 1988, 31, 2182, incorporated herein by reference) is reacted
with thionyl chloride, followed by ethyl 2-fluoro-4-amino-benzoate
(Compound G) to yield ethyl 2-fluoro-4-[(3',
5'-di-tert-butylphenyl)carbamoyl]benzoate (Compound 5). As still
another example, O-methoxymethyl-3,5-di-tert-butylsalicylic acid
(Compound F) is reacted with ethyl 2-fluoro-4-amino-benzoate
(Compound G) in the presence of 4-dimethylaminopyridine (DMAP)
catalyst and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (EDC) to give ethyl
2-fluoro-4-[(2'-methoxymethyl-3',5'-di-tert-butylphenyl)carbamoyl]b-
enzoate (Compound N). The methoxymethyl protecting group is removed
from Compound N by treatment with borontrifluoride ethereate and
thiophenol to yield ethyl
2-fluoro-4-[(2'-hydroxy-3',5'-di-tert-butylphenyl)carbamoyl]b-
enzoate (Compound 7).
[0089] In yet another example shown in Reaction Scheme 5,
2,6-di-tert-butylisonicotinic acid (Compound C) is reacted with
thionyl chloride (SOCl.sub.2), the resulting intermediate acid
chloride is reacted with methyl 2,6-difluoro-4-amino benzoate
(Compound I), followed by saponification of the ester group, to
yield 2,6-difluoro-4-[(2',6'-di--
tert-butylpyrid-4'yl)carbamoyl]benzoic acid (Compound 10).
3,5-Di-tert-butylbenzoic acid is subjected to the same sequence of
reactions to provide
2,6-difluoro-4-[(3',5'-di-tert-butylphenyl)carbamoyl- ]benzoic acid
(Compound 12).
[0090] As yet another example, shown in Reaction Scheme 5,
2,6-di-tert-butylisonicotinic acid (Compound C) is reacted with
thionyl chloride (SOCl.sub.2), followed by methyl
2-nitro-4-aminobenzoate (Compound K) and saponification of the
ester function to give
2-nitro-4-[(2',6'-di-tert-butylpyrid-4'-yl)carbamoyl]benzoic acid
(Compound 14).
SPECIFIC EXAMPLES
[0091] 4-Bromomethyl-2,6-di-t-butylpyridine (Compound A)
[0092] To a mixture of 2,6-di-t-butyl-4-methylpyridine (Aldrich,
2.0 g, 9.73 mmol) in 25 ml of dry CCl.sub.4 was added benzoyl
peroxide (24 mg, 0.097 mmol) and NBS (1.9 g, 10.7 mmol). The
reaction mixture was refluxed for 16 hours. After it cooled to room
temperature, the solvent was removed in vacuo and the residue was
purified by column chromatography (silica gel, hexane) to give an
oil (1.957 g) which contained 82% of the desired product and 18% of
the starting material. .sup.1H NMR .delta.7.09 (s, 2H), 4.39 (s,
2H), 1.35 (s, 18H).
[0093] 4-Hydroxymethyl-2,6-di-t-butylpyridine (Compound B)
[0094] A heterogeneous solution of
4-bromomethyl-2,6-di-t-butylpyridine (Compound A, 1.743 g, 82%
purity) in 20 ml of 12% NaOH in water and 10 ml of 1,4-dioxane was
refluxed for 12 hours. The solution spontaneously separated into
two layers as it cooled to room temperature. The upper layer was
separated and ethyl acetate was added. This organic layer was then
washed with brine, water and dried over MgSO.sub.4. The desired
product was purified by column chromatography (ethyl acetate/hexane
1/9) to give a white solid. .sup.1H NMR .delta.7.09 (s, 2H), 4.67
(d, J=4.4 Hz, 2H), 2.3 (b, 1H), 1.36 (s, 18H).
[0095] 2,6-Di-t-butylisonicotinic Acid (Compound C)
[0096] Jone's reagent was added dropwise to a solution of
4-hydroxymethyl-2,6-di-t-butylpyridine (Compound B, 302 mg, 1.37
mmol) in 5 ml of acetone until the solution changed color from
light yellow to orange (55 drops of Jone's reagent were consumed).
After 5 minutes 2 ml of isopropanol were added to the reaction
mixture, and a green precipitate of Cr.sup.3+ salt was formed. The
precipitate was removed by filtration and the solution was diluted
with ethyl acetate, then washed with brine, water and dried over
MgSO.sub.4. After filtration, the solvent was removed to give the
desired product as a white solid (227 mg). .sup.1H NMR .delta.7.71
(s, 2H), 1.34 (s, 18H).
[0097] 2-Bromo-4,6-di-t-butylphenol (Compound D)
[0098] To a solution of 2,4-di-t-butylphenol (Aldrich, 2.0 g, 9.7
mmol) in 2 ml of HOAc was added Br.sub.2 (0.5 ml, 9.7 mmol). The
reaction mixture was stirred at room temperature for 12 hours.
Solvent was removed under reduced pressure and the residue was
purified by column chromatography (ethyl acetate/hexane 1/20) to
yield the desired product (2.54 g) as a white solid. .sup.1H NMR
.delta. 7.33 (d, J=2.3 Hz, 1H), 7.24 (d, J=2.3 Hz, 1H), 1.41 (s,
9H), 1.29 (s, 9H).
[0099] O-Methoxymethyl-2-bromo-4,6-di-t-butylphenol (Compound
E)
[0100] To a solution of 2-bromo-4,6-di-t-butylphenol (Compound D
2.54 g, 8.88 mmol) and catalytic amount of Bu.sub.4NI in 20 ml of
dry CH.sub.2Cl.sub.2 at 0.degree. C. was added
diisopropylethylamine (9.51 ml, 53 mmol), followed by methoxymethyl
chloride (2.02 ml, 26.6 mmol). The reaction mixture was heated to
45.degree. C. for 12 hours. The reaction mixture was then washed
with 10% citric acid, then NaHCO.sub.3 (sat.), brine, and dried
over MgSO.sub.4. After filtration and removal of the solvent under
reduced pressure, the residue was purified by column chromatography
(pure hexane) to yield the title compound (2.79 g) as a colorless
oil. .sup.1H NMR .delta.7.40 (d, J=2.44 Hz, 1H), 7.30 (d, J=2.4 Hz,
1H), 5.22 (s, 2H), 3.70 (s, 3H), 1.43 (s, 9H), 1.29 (s, 9H).
[0101] O-Methoxymethyl-3',5'-di-t-butylsalicylic acid (Compound
F)
[0102] To a solution of
O-methoxymethyl-2-bromo-4,6-di-t-butylphenol (Compound E, 2.79 g,
8.5 mmol) in 30 ml of dry THF at -78.degree. C. under Ar was added
11 ml of t-BuLi (1.7 M in hexane, 18.7 mmol). This mixture was
stirred at -78.degree. C. for 1 hour. Then CO.sub.2 (g) was bubbled
into the solution at -78.degree. C. for 1 hour. After removal of
the CO.sub.2 stream, the reaction mixture was stirred for an
additional hour at -78.degree. C. Then 10% of HCl was added and the
mixture was allowed to warm to room temperature and extracted with
ethyl acetate. The organic layer was washed with brine and dried
over Na.sub.2SO.sub.4. After concentration, the residue was
purified by column chromatography (ethyl acetate/hexane 1/1) to
yield the title compound as a white solid (492 mg). .sup.1H NMR
.delta. 7.75 (d, J=2.81 Hz, 1H), 7.60 (d, J=2.8 Hz, 1H), 5.07 (s,
2H), 3.62 (s, 3H), 1.33 (s, 9H), 1.26 (s, 9H).
[0103] Ethyl 4-Amino-2-fluorobenzoate (Compound G)
[0104] To a mixture of 2-fluoro-4-nitrotoluene (1.0 g, 6.4 mmol,
Aldrich) and Na.sub.2Cr.sub.2O.sub.7 (2.74 g, 8.4 mmol) in 13.7 ml
of HOAc was added slowly 6.83 ml of H.sub.2SO.sub.4. This mixture
was slowly heated to 90.degree. C. for 1 hour to give a greenish
heterogeneous solution. The mixture was cooled to room temperature
and diluted with ethyl acetate. The pH of the solution was adjusted
to 4 with aqueous NaOH. The mixture was extracted with more ethyl
acetate. The combined organic layers were washed with NaHCO.sub.3
(sat.), then brine and dried over Na.sub.2SO.sub.4. After
filtration, the solution was concentrated to dryness which then was
dissolved in 6 ml of SOCl.sub.2, and heated at 80.degree. C. for 1
hour. The excess of SOCl.sub.2was removed under reduced pressure
and the residue was dissolved in 5 ml of CH.sub.2Cl.sub.2, 2 ml of
EtOH and 2 ml of pyridine. The mixture was stirred at room
temperature for 2 hours and concentrated to dryness. Ethyl
2-fluoro-4-nitrobenzoate was obtained as a white solid after column
chromatography of the residue with ethyl acetate/hexane (1/9). This
solid was then dissolved in 10 ml of ethyl acetate, and Pd/C (50
mg) was added. Hydrogenation converted ethyl
2-fluoro-4-nitrobenzoate into the title compound.
[0105] .sup.1H NMR .delta.7.77 (t, J=8.4 Hz, 1H), 6.41 (dd,
J.sub.1=8.6, J.sub.2=2.2 Hz, 1H), 6.33 (dd, J.sub.1=13.0,
J.sub.2=2.2 Hz, 1H), 4.33 (q, J=7.1 Hz, 2H), 4.3 (b, 2H), 1.37 (t,
J=7.1 Hz, 3H).
[0106] Methyl 4-Amino-2.6-difluorobenzoate (Compound I)
[0107] A solution of trifluorobenzoic acid (150 mg, 0.85 mmol,
Aldrich) in 0.5 ml of SOCl.sub.2 was heated under reflux for 2
hours. The reaction mixture was cooled to room temperature, and
excess of SOCl.sub.2 was removed under reduced pressure. The
residue was dissolved in 1 ml of pyridine and 0.2 ml of methanol.
After stirring at room temperature for 30 min, solvent was removed
and the residue was purified by column chromatography (ethyl
acetate/hexane 1/10) to give methyl trifluorobenzoate as a
colorless oil. This oil was then dissolved in 1 ml of CH.sub.3CN,
then a solution of NaN.sub.3 (100 mg, 1.54 mmol) in 0.5 ml of water
was added. The reaction mixture was refluxed for two days. Salt was
removed by filtration and the remaining solution was concentrated
to an oil. This oil was then dissolved in 1 ml of methanol,
followed by a catalytic amount of Pd/C (10%, w/w). The reaction
mixture was hydrogenated for 12 hours. Catalyst was removed and the
solution was concentrated to an oil. After column chromatography
(ethyl acetate/hexane 1/3), the title compound was obtained as
colorless crystals.
[0108] .sup.1H NMR .delta.6.17 (d, J=10.44 Hz, 2H), 4.2 (b, 2H),
3.87 (s, 3H).
[0109] Methyl 2-Nitro-4-aminobenzoate (Compound K)
[0110] 2-Nitro-4-aminobenzoic acid (261 mg, 1.43 mmol) was
dissolved in 1 ml of SOCl.sub.2. The solution was refluxed for 1
hour. Excess SOCl.sub.2 was removed under reduced pressure and 5 ml
of CH.sub.2Cl.sub.2, 1 ml of MeOH and TEA (0.24 ml, 1.7 mmol) were
added to the residue. The reaction mixture was stirred at room
temperature for 2 hours. Excess MeOH and TEA were removed and the
residue was purified by column chromatography with ethyl
acetate/hexane (1/3) to yield the title compound as a yellow solid
(316 mg). .sup.1H NMR .delta.7.69 (d, J=8.5 Hz, 1H), 6.85 (d, J=2.2
Hz, 1H), 6.67 (dd, J=8.3; 2.1 Hz, 1H), 4.31 (b, 2H), 3.94 (s,
3H).
[0111] Ethyl
2-fluoro-4-[(2'6'-di-t-butylpyrid-4'-l)carbamoyl]benzoate (Compound
1)
[0112] A solution of 2,6-di-t-butylisonicotinic acid (Compound C,
47.3 mg, 0.20 mmol) in 2 ml of SOCl.sub.2 was heated under reflux
for 2 hours. Excess SOCl.sub.2 was removed in vacuo and the residue
was dissolved in 2 ml of dry CH.sub.2Cl.sub.2, and ethyl
2-fluoro-4-aminobenzoate (Compound G, 40.2 mg, 0.22 mmol) and
pyridine (0.0835 ml, 0.69 mmol) were added. The reaction mixture
was stirred at room temperature for 12 hours. Solvent was removed
and the residue was purified by column chromatography (ethyl
acetate/hexane 1/9) to yield the title compound (71.2 mg) as white
crystals. .sup.1H NMR .delta. 8.56 (b, 1H), 7.91 (t, J=8.36 Hz,
1H), 7.53 (dd, J=12.82, 2.0 Hz, 1H), 7.39 (dd, J=8.7, 2.0 Hz, 1H),
4.33 (q, J=7.1 Hz, 2H), 1.37 (t, J=7.1 Hz, 3H), 1.35 (s, 18H).
[0113] Ethyl 4-[(2', 6'-di-t-butylpyrid-4'-yl)carbamoyl]benzoate
(Compound 3)
[0114] Using the same procedure as for the synthesis of ethyl
2-fluoro-4-[(2'6'-di-t-butylpyrid-4'-yl)carbamoyl]benzoate
(Compound 1) but using 2,6-di-t-butylisonicotinic acid (Compound C,
101 mg, 0.43 mmol) and ethyl 4-aminobenzoate (78 mg, 0.47 mmol),
the title compound was obtained as a white solid (135 mg). .sup.1H
NMR .delta.8.43 (b, 1H),, 8.02 (d, J=8.7 Hz, 2H), 7.75 (d, J=8.7
Hz, 2H), 7.48 (s, 2H), 4.33 (q, J=7.1 Hz, 2H), 1.38 (t, J=7.1 Hz,
3H), 1.35 (s, 18H).
[0115] Ethyl 2-Fluoro-4-[(3',5'-di-t-butylphenyl)carbamoyl]benzoate
(Compound 5)
[0116] Using the same procedure as for the synthesis of ethyl
2-fluoro-4-[(2'6'-di-t-butylpyrid-4'-yl)carbamoyl]benzoate
(Compound 1) but using 3,5-di-t-butylbenzoic acid (60 mg, 0.26
mmol, available by literature procedure, see Kagechika et al. J.
Med Chem. 1988 31, 2182-2192) and ethyl 2-fluoro-4-aminobenzoate
(Compound G, 51.5 mg, 0.28 mmol), the title compound was obtained
as a white solid (66 mg). .sup.1H NMR .delta.8.21 (b, 1H), 7.93 (t,
J=8.3 Hz, 1H), 7.79 (dd, J=12.8, 2.0 Hz, 1H), 7.67 (d, J=1.8 Hz,
2H), 7.65 (t, J=1.7 Hz, 1H), 7.35 (dd, J=8.7, 2.1 Hz, 1H), 4.36 (q,
J=7.2 Hz, 2H), 1.39 (t, J=7.2 Hz, 3H), 1.36 (s, 18H).
[0117] Ethyl
2-Fluoro-4-[(2'-methoxymethyl-3',5'-di-t-butylphenyl)carbamoy-
l]benzoate (Compound N)
[0118] To a mixture of O-methoxymethyl-3',5'-di-t-butylsalicylic
acid (Compound F, 150 mg, 0.51 mmol), 4-dimethylaminopyridine (142
mg, 0.61 mmol) and ethyl 2-fluoro-4-aminobenzoate (Compound G, 102
mg, 0.56 mmol) in 5 ml of dry CH.sub.2Cl.sub.2 was added
1-(3-di-methylaminopropyl)-3-et- hylcarbodiimide hydrochloride (117
mg, 0.61 mmol). The reaction mixture was stirred at room
temperature for 12 hours. Solvent was evaporated in vacuo and the
residue was dissolved in ethyl acetate, then washed with brine,
water and dried over MgSO.sub.4. After filtration, solvent was
removed and the residue was purified by column chromatography
(ethyl acetate/hexane 1/3) to give the title compound (58 mg).
.sup.1H NMR .delta.8.97 (b, 1H), 7.94 (t, J=8.37 Hz, 1H), 7.78 (d,
J=2.7 Hz, 1H), 7.61 (d, J=13.0 Hz, 1H), 7.56 (d, J=2.6 Hz, 1H),
7.35 (d, J=8.7 Hz, 1H), 5.00 (s, 2H), 3.53 (s, 3H), 4.38 (q, J=7.1
Hz, 2H), 1.47 (s, 9H), 1.39 (t, J=7.2 Hz, 3H), 1.33 (s, 9H).
[0119] Ethyl 2-Fluoro-4-[(2'-hydroxy-3',5'-di-t-butylphenyl
carbamoyl]benzoate (Compound 7)
[0120] To a solution of ethyl
2-fluoro-4-[(2'-methoxymethyl-3',5'-di-t-but-
ylphenyl)carbamoyl]benzoate (Compound N, 34 mg, 0.07 mmol) in 1 ml
of THF were added 10 drops of HOAc. The reaction mixture was heated
to reflux for 12 hours. Solvent was removed and ethyl acetate was
added. The solution was washed with NaCHO.sub.3 (sat.), brine,
water and dried over MgSO.sub.4. Solvent was removed in vacuo to
give an oil. The oil was allowed to be exposed to the atmosphere
for 12 hours during which time crystals formed. The crystals were
collected and washed several times with hexane to afford the title
compound as a white solid (13.5 mg). .sup.1H NMR .delta.10.73 (s,
1H), 7.98 (d, J=2.56 Hz, 1H), 7.88 (b, 1H), 7.75 (t, J=8.26 Hz,
1H), 7.60 (d, J=2.44 Hz, 1H), 7.32 (dd, J=12.3, 2.0 Hz, 1H), 7.02
(dd, J=8.6, 2.0 Hz, 1H), 4.35 (q, J=7.2 Hz, 2H), 1.39 (s, 9H), 1.37
(t, J=7.2 Hz, 3H), 1.5 (s, 9H).
[0121]
2,6-Difluoro-4-[(2',6'-di-t-butylpyrid-4'yl)carbamoyl]benzoic Acid
(Compound 10)
[0122] To 2,6-di-t-butylisonicotinic acid (Compound C, 20 mg, 0.085
mmol) was added 1 ml of SOCl.sub.2. The mixture was heated under
reflux for 2 hours. After cooling to room temperature, excess
SOCl.sub.2 was removed and the residue was dissolved in 2 ml of
CH.sub.2Cl.sub.2. To this solution was added methyl
2,6-difluoro-4-aminobenzoate (Compound I, 16 mg, 0.085 mmol) and
triethylamine (0.015 ml, 0.1 mmol). The reaction mixture was kept
at room temperature for 2 hours and then concentrated to dryness.
The residue was purified by column chromatography with ethyl
acetate/hexane (1/10) to yield the methyl ester of the title
compound. This was saponified according to the general procedure
(see below) to give the title compound as a colorless solid.
.sup.1H NMR .delta.7.44 (s, 2H), 7.40 (d, J=11.8 Hz, 2H) 1.37 (S,
18H).
[0123] 2,6-Difluoro-4-[(3',5'-di-t-butylphenyl)carbamoyl]benzoic
Acid (Compound 12)
[0124] Using the same procedure as for the preparation of
2,6-difluoro-4-[(2',6'-di-t-butylpyrid-4'yl)carbamoyl]benzoic acid
(Compound 10) but using 3,5-di-t-butylbenzoic acid (37 mg, 0.16
mmol) and methyl 2,6-difluoro-4-aminobenzoate (Compound I, 29 mg,
0.16 mmol), the title compound was obtained as colorless crystals.
.sup.1H NMR .delta.7.92 (b, 1H) 7.60 (m, 3H), 7.42 (d, J=10.0 Hz,
2H), 1.38 (s, 18H).
[0125] 2-Nitro-4-[(2',6'-di-t-butylpyrid-4'-yl)carbamoyl]benzoic
Acid (Compound 14)
[0126] Using the same procedure as for the preparation of
2,6-difluoro-4-[(2',6'-di-t-butylpyrid-4'yl)carbamoyl]benzoic acid
(Compound 10) but using 2,6-di-t-butylisonicotinic acid (40 mg,
0.17 mmol) and methyl 2-nitro-4-aminobenzoate (Compound K, 33 mg,
0.17 mmol), the title compound was obtained as a light yellow oil.
.sup.1H NMR .delta. (acetone-d.sup.6) 10.25 (b, 1H), 8.32 (s, 1H),
7.97 (d, J=8.1 Hz, 1H), 7.93 (b, 1H), 7.70 (s, 2H), 1.36 (s,
18H).
[0127] General Procedure for the Syntheses of Benzoic Acid
Derivatives by Hydrolyzing the Corresponding Methyl or Ethyl
Esters
[0128] To a solution of ester (3.0 mmol) in 20 ml of EtOH was added
5 ml of 1 N NaOH in water. The reaction mixture was stirred at room
temperature for overnight and neutralized with 10% HCl to PH=5. The
alcohol was removed by evaporation and the aqueous layer was
extracted with ethyl acetate (3.times.10 ml). The ethyl acetate
layer was further washed with NaHCO.sub.3 (sat.), brine and dried
over MgSO.sub.4. After concentration, the desired carboxylic acid
was obtained which could be recrystallized in ethyl acetate or
acetonitrile.
[0129] 2-Fluoro-4-[(2',6'-di-t-butylpyrid-4'-yl)carbamoyl]benzoic
Acid (Compound 2)
[0130] .sup.1H NMR .delta. (CD.sub.3OD) 7.92 (t, J=8.36 Hz, 1H),
7.82 (dd, J=12.82, 2.0 Hz, 1H), 7.63 (s, 2H), 7.55 (dd, J=8.7, 2.1
Hz, 1H), 1.39 (s, 18H).
[0131] 4-[(2',6'-Di-t-butylpyrid-4'-yl)carbamoyl]benzoic acid
(Compound 4)
[0132] .sup.1H NMR .delta. (CD.sub.3OD) 8.02 (d, J=8.85 Hz, 2H),
7.85 (d, J=8.85 Hz, 2H), 7.63 (s, 2H), 1.40 (s, 18H).
[0133] 2-Fluoro-4-[(3',5'-di-t-butyl)phenylcarbamoyl]benzoic Acid
(Compound 6)
[0134] .sup.1H NMR .delta. (CD.sub.3OD) 7.92 (t, J=8.3 Hz, 1H),
7.80 (dd, J=12.8, 2.0 Hz, 1H), 7.79 (d, J=1.8 Hz, 2H), 7.69 (t,
J=1.7 Hz, 1H), 7.57 (dd, J=8.7, 2.1 Hz, 1H), 1.37 (s, 18H).
[0135] 2-Fluoro-4-
[(2'-hydroxy-3',5'-di-t-butyl)phenylcarbamoyl]benzoic Acid
(Compound 8)
[0136] .sup.1H NMR .delta. (acetone-d.sub.6) 12.3 (b, 1H), 10.07
(b, 1H), 7.98 (t, J=8.48 Hz, 1H), 7.80 (m, 2H), 7.58 (d, J=2.3 Hz,
1H), 7.56 (dd, J=8.8, 2.0 Hz, 1H), 1.44 (s, 9H), 1.31 (s, 9H).
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