U.S. patent application number 13/224654 was filed with the patent office on 2012-03-08 for di-azetidinyl diamide as monoacylglycerol lipase inhibitors.
Invention is credited to Peter J. Connolly, Mark J. Macielag, Bin Zhu.
Application Number | 20120058986 13/224654 |
Document ID | / |
Family ID | 44645814 |
Filed Date | 2012-03-08 |
United States Patent
Application |
20120058986 |
Kind Code |
A1 |
Connolly; Peter J. ; et
al. |
March 8, 2012 |
DI-AZETIDINYL DIAMIDE AS MONOACYLGLYCEROL LIPASE INHIBITORS
Abstract
Disclosed are compounds, compositions and methods for treating
various diseases, syndromes, conditions and disorders, including
pain. Such compounds are represented by Formula (I) as follows:
##STR00001## wherein Q and Z are defined herein.
Inventors: |
Connolly; Peter J.; (Spring
House, PA) ; Macielag; Mark J.; (Spring House,
PA) ; Zhu; Bin; (Spring House, PA) |
Family ID: |
44645814 |
Appl. No.: |
13/224654 |
Filed: |
September 2, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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61379764 |
Sep 3, 2010 |
|
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Current U.S.
Class: |
514/210.18 ;
546/200; 548/153; 548/180; 548/181; 548/200; 548/224; 548/454;
548/455; 548/465; 548/953 |
Current CPC
Class: |
A61K 31/423 20130101;
A61K 31/454 20130101; C07D 417/14 20130101; A61K 31/397 20130101;
A61P 17/02 20180101; C07D 513/04 20130101; A61P 19/02 20180101;
A61P 13/02 20180101; A61P 17/00 20180101; A61P 29/00 20180101; A61K
31/427 20130101; A61P 25/04 20180101; A61P 43/00 20180101; A61P
1/02 20180101; A61P 17/04 20180101; A61P 11/02 20180101; C07D
409/14 20130101; A61P 15/00 20180101; C07D 205/04 20130101; A61P
1/04 20180101; C07D 413/14 20130101; C07D 403/14 20130101; A61K
31/428 20130101; A61P 1/06 20180101; A61P 21/00 20180101; A61K
31/429 20130101; A61P 1/00 20180101; A61P 11/00 20180101; A61P
13/10 20180101; A61K 31/4035 20130101; A61P 25/06 20180101; A61P
1/16 20180101; A61P 1/18 20180101; A61P 31/00 20180101; C07D 417/12
20130101 |
Class at
Publication: |
514/210.18 ;
548/181; 548/200; 548/180; 548/953; 548/224; 548/465; 548/455;
548/454; 546/200; 548/153 |
International
Class: |
A61K 31/427 20060101
A61K031/427; A61K 31/428 20060101 A61K031/428; C07D 403/04 20060101
C07D403/04; A61K 31/397 20060101 A61K031/397; C07D 409/14 20060101
C07D409/14; C07D 413/14 20060101 C07D413/14; A61K 31/423 20060101
A61K031/423; C07D 403/14 20060101 C07D403/14; A61K 31/4035 20060101
A61K031/4035; C07D 401/14 20060101 C07D401/14; A61K 31/454 20060101
A61K031/454; C07D 513/04 20060101 C07D513/04; A61K 31/429 20060101
A61K031/429; A61P 29/00 20060101 A61P029/00; A61P 1/00 20060101
A61P001/00; A61P 25/06 20060101 A61P025/06; A61P 19/02 20060101
A61P019/02; A61P 21/00 20060101 A61P021/00; A61P 17/00 20060101
A61P017/00; A61P 1/02 20060101 A61P001/02; A61P 17/02 20060101
A61P017/02; A61P 13/10 20060101 A61P013/10; A61P 31/00 20060101
A61P031/00; A61P 11/02 20060101 A61P011/02; A61P 17/04 20060101
A61P017/04; A61P 11/00 20060101 A61P011/00; A61P 1/18 20060101
A61P001/18; C07D 417/14 20060101 C07D417/14 |
Claims
1. A compound of Formula (I) ##STR00068## wherein Q is selected
from ##STR00069## wherein Y is C.sub.6-10aryl or a heteroaryl that
is thiazolyl, pyrrolyl, or oxazolyl; R.sup.1 is hydrogen or
C.sub.1-4 alkyl; and m is an integer from 1 to 3; Z is
C.sub.6-10aryl or a heteroaryl selected from the group consisting
of quinolinyl, benzothiophenyl, benzoxazolyl, benzothiazolyl,
benzimidazolyl, indolyl, and indazolyl; wherein Z is (i) optionally
independently substituted with one to three substituents selected
from the group consisting of C.sub.1-4 alkyl, fluoro, chloro,
bromo, trifluoromethyl, and piperidin-1-yl; provided that no more
than one substituent on Z is piperidin-1-yl or (ii) (a) substituted
with ##STR00070## and (b) optionally further substituted with one
additional methyl, chloro, fluoro, or phenyl substituent; wherein
ring A is phenyl, thienyl, or benzothiophenyl; provided that when
ring A is thienyl or benzothiophenyl, G is a bond or --CH.sub.2--
or when A is phenyl, G is selected from the group consisting of a
bond, O, --CH.sub.2--, SO.sub.2, and C(O); and R.sup.2 is
trifluoromethyl, fluoro, chloro, or methanesulfonyl; r is an
integer from 0 to 3; and enantiomers, diastereomers, and
pharmaceutically acceptable salts thereof.
2. The compound of claim 1 wherein Q is selected from ##STR00071##
wherein Y is phenyl or thiazolyl; R.sup.1 is hydrogen or methyl;
and m is 1.
3. The compound of claim 2 wherein R.sup.1 is hydrogen.
4. The compound of claim 1 wherein Z is C.sub.6-10aryl or a
heteroaryl selected from the group consisting of benzothiophenyl,
benzoxazolyl, benzothiazolyl, indolyl, and indazolyl; wherein Z is
(i) independently substituted with one to two substituents selected
from the group consisting of C.sub.1-4 alkyl, fluoro, chloro,
bromo, trifluoromethyl, and piperidin-1-yl; provided that no more
than one substituent on Z is piperidin-1-yl or ##STR00072## (ii)
(a) substituted with and (b) optionally further substituted with
one additional methyl, chloro, fluoro, or phenyl substituent;
wherein ring A is phenyl, thienyl, or benzothiophenyl; provided
that when ring A is thienyl or benzothiophenyl, G is a bond or
--CH.sub.2-- or when ring A is phenyl G is a bond, O, --CH.sub.2--,
SO.sub.2, or C(O); and R.sup.2 is trifluoromethyl, fluoro, chloro,
or methanesulfonyl; and r is an integer from 0 to 3.
5. The compound of claim 4 wherein Z is C.sub.6-10aryl or a
heteroaryl selected from the group consisting of benzothiophenyl,
benzoxazolyl, benzothiazolyl, indolyl, and indazolyl; wherein Z is
(i) optionally independently substituted with one to two
substituents selected from the group consisting of C.sub.1-4 alkyl,
fluoro, chloro, bromo, and trifluoromethyl or (ii) (a) substituted
with ##STR00073## and (b) optionally further substituted with one
additional methyl, chloro, fluoro, or phenyl substituent; wherein
ring A is phenyl or thienyl; provided that when ring A is phenyl, G
is a bond, --CH.sub.2--, or SO.sub.2 or when ring A is thienyl, G
is a bond or --CH.sub.2--; and R.sup.2 is trifluoromethyl, fluoro,
chloro, or methanesulfonyl; and r is an integer from 0 to 2.
6. A compound of Formula (I) ##STR00074## wherein: Q is selected
from ##STR00075## wherein Y is phenyl or thiazolyl; R.sup.1 is
hydrogen or methyl; and m is 1; Z is C.sub.6-10aryl or a heteroaryl
selected from the group consisting of benzothiophenyl,
benzoxazolyl, benzothiazolyl, indolyl, and indazolyl; wherein Z is
(i) independently substituted with one to two substituents selected
from the group consisting of C.sub.1-4 alkyl, fluoro, chloro,
bromo, trifluoromethyl, and piperidin-1-yl; provided that no more
than one substituent on Z is piperidin-1-yl or (ii) (a) substituted
with ##STR00076## and (b) optionally further substituted with one
additional methyl, chloro, fluoro, or phenyl substituent; wherein
ring A is phenyl, thienyl, or benzothiophenyl; provided that when
ring A is thienyl or benzothiophenyl, G is a bond or --CH.sub.2--
or when ring A is phenyl, G is a bond, O, --CH.sub.2--, SO.sub.2,
or C(O); and R.sup.2 is trifluoromethyl, fluoro, chloro, or
methanesulfonyl; and r is an integer from 0 to 3; and enantiomers,
diastereomers, and pharmaceutically acceptable salts thereof.
7. A compound of Formula (I) ##STR00077## wherein: Q is selected
from ##STR00078## wherein Y is phenyl or thiazolyl; R.sup.1 is
hydrogen; and m is 1; Z is C.sub.6-10aryl or a heteroaryl selected
from the group consisting of benzothiophenyl, benzoxazolyl,
benzothiazolyl, indolyl, and indazolyl; wherein Z is (i)
independently substituted with one to two substituents selected
from the group consisting of C.sub.1-4 alkyl, fluoro, chloro,
bromo, and trifluoromethyl or (ii) (a) substituted with
##STR00079## and (b) optionally further substituted with one
additional methyl, chloro, fluoro, or phenyl substituent; wherein
ring A is phenyl or thienyl; provided that when ring A is thienyl,
G is a bond or --CH.sub.2-- or when ring A is phenyl G is a bond,
--CH.sub.2--, or SO.sub.2; R.sup.2 is trifluoromethyl, fluoro,
chloro, or methanesulfonyl; and r is an integer from 0 to 2; and
enantiomers, diastereomers, and pharmaceutically acceptable salts
thereof.
8. A compound of Formula (Ia) ##STR00080## selected from the group
consisting of a compound wherein Y is thiazol-2-yl, R.sub.1 is H,
and Z is 1-(4-trifluoromethylphenyl)-1H-indol-5-yl; a compound
wherein Y is thiazol-4-yl, R.sub.1 is H, and Z is
4-(3-trifluoromethylphenyl)phenyl; a compound wherein Y is
thiazol-2-yl, R.sub.1 is H, and Z is
1-(phenylsulfonyl)-1H-indol-5-yl; a compound wherein Y is
thiazol-2-yl, R.sub.1 is H, and Z is 2-phenyl-benzothiazol-6-yl; a
compound wherein Y is thiazol-2-yl, R.sub.1 is H, and Z is
4-(3-trifluoromethylphenyl)phenyl; a compound wherein Y is
thiazol-2-yl, R.sub.1 is H, and Z is 6-phenyl-benzothiophen-2-yl; a
compound wherein Y is thiazol-2-yl, R.sub.1 is H, and Z is
6-trifluoromethyl-benzothiophen-2-yl; a compound wherein Y is
thiazol-2-yl, R.sub.1 is H, and Z is
4-trifluoromethyl-benzothiophen-2-yl; a compound wherein Y is
thiazol-2-yl, R.sub.1 is H, and Z is
4-(5-trifluoromethyl-thien-2-yl)-phenyl; a compound wherein Y is
thiazol-2-yl, R.sub.1 is H, and Z is 4-(phenylmethyl)-phenyl; a
compound wherein Y is thiazol-4-yl, R.sub.1 is H, and Z is
1-(4-fluorophenyl)-1H-indol-5-yl; a compound wherein Y is
thiazol-2-yl, R.sub.1 is H, and Z is
4-(4-trifluoromethylphenyl)-phenyl; a compound wherein Y is
thiazol-2-yl, R.sub.1 is H, and Z is 1-phenyl-1H-indol-5-yl; a
compound wherein Y is thiazol-4-yl, R.sub.1 is H, and Z is
4-(4-trifluoromethylphenyl)-phenyl; a compound wherein Y is
thiazol-2-yl, R.sub.1 is H, and Z is
3-methyl-5-chloro-benzothiophen-2-yl; a compound wherein Y is
thiazol-2-yl, R.sub.1 is H, and Z is
4-(4-trifluoromethylphenylmethyl)-phenyl; a compound wherein Y is
thiazol-2-yl, R.sub.1 is H, and Z is 2-phenyl-benzoxazol-6-yl; a
compound wherein Y is thiazol-2-yl, R.sub.1 is H, and Z is
4-(3-methanesulfonylphenyl)phenyl; a compound wherein Y is
thiazol-2-yl, R.sub.1 is H, and Z is 5-bromo-naphth-2-yl; a
compound wherein Y is thiazol-2-yl, R.sub.1 is H, and Z is
4-(3-trifluoromethylphenylmethyl)-phenyl; a compound wherein Y is
thiazol-2-yl, R.sub.1 is H, and Z is 6-phenyl-naphth-2-yl; a
compound wherein Y is thiazol-4-yl, R.sub.1 is H, and Z is
2-phenyl-benzothiazol-6-yl; a compound wherein Y is thiazol-2-yl,
R.sub.1 is H, and Z is 6-bromo-benzothiophen-2-yl; a compound
wherein Y is phenyl, R.sub.1 is H, and Z is 5-bromo-naphth-2-yl; a
compound wherein Y is phenyl, R.sub.1 is H, and Z is
5-phenyl-naphth-2-yl; a compound wherein Y is phenyl, R.sub.1 is H,
and Z is 4-(4-trifluoromethyl phenylmethyl)-phenyl; a compound
wherein Y is thiazol-2-yl, R.sub.1 is H, and Z is
1-phenyl-1H-indol-6-yl; a compound wherein Y is thiazol-2-yl,
R.sub.1 is H, and Z is 2-(3-trifluoromethylphenyl)-benzoxazol-6-yl;
a compound wherein Y is thiazol-2-yl, R.sub.1 is H, and Z is
4-phenyl-phenyl; a compound wherein Y is thiazol-2-yl, R.sub.1 is
H, and Z is 2-(4-trifluoromethylphenyl)-benzoxazol-6-yl; a compound
wherein Y is phenyl, R.sub.1 is H, and Z is
4-(phenylmethyl)-phenyl; a compound wherein Y is thiazol-2-yl,
R.sub.1 is H, and Z is 4-phenoxy-phenyl; a compound wherein Y is
thiazol-2-yl, R.sub.1 is H, and Z is
2-(4-chlorophenyl)-benzoxazol-6-yl; a compound wherein Y is phenyl,
R.sub.1 is H, and Z is 6-phenyl-naphth-2-yl; a compound wherein Y
is thiazol-2-yl, R.sub.1 is H, and Z is 2-phenyl-benzoxazol-5-yl; a
compound wherein Y is phenyl, R.sub.1 is H, and Z is
3-methyl-5-chloro-benzothiophen-2-yl; a compound wherein Y is
thiazol-2-yl, R.sub.1 is methyl, and Z is
6-trifluoromethyl-benzothiophen-2-yl; a compound wherein Y is
thiazol-2-yl, R.sub.1 is H, and Z is 4-(phenylcarbonyl)-phenyl; a
compound wherein Y is phenyl, R.sub.1 is H, and Z is
4-phenyl-phenyl; a compound wherein Y is thiazol-2-yl, R.sub.1 is
H, and Z is 6-bromo-naphth-2-yl; a compound wherein Y is phenyl,
R.sub.1 is H, and Z is 2-phenyl-benzoxazol-6-yl; a compound wherein
Y is phenyl, R.sub.1 is H, and Z is 6-bromo-naphth-2-yl; a compound
wherein Y is thiazol-2-yl, R.sub.1 is H, and Z is 4-bromophenyl; a
compound wherein Y is phenyl, R.sub.1 is H, and Z is
5-trifluoromethyl-benzothiophen-2-yl; a compound wherein Y is
phenyl, R.sub.1 is H, and Z is 4-phenoxy-phenyl; a compound wherein
Y is thiazol-4-yl, R.sub.1 is H, and Z is
2-bromo-benzothiazol-6-yl; a compound wherein Y is thiazol-2-yl,
R.sub.1 is H, and Z is 5-trifluoromethyl-benzothiazol-2-yl; a
compound wherein Y is thiazol-4-yl, R.sub.1 is methyl, and Z is
6-trifluoromethyl-benzothiophen-2-yl; a compound wherein Y is
thiazol-4-yl, R.sub.1 is H, and Z is
6-trifluoromethyl-benzothiophen-2-yl; a compound wherein Y is
thiazol-2-yl, R.sub.1 is H, and Z is
3-chloro-6-trifluoromethyl-benzothiophen-2-yl; a compound wherein Y
is thiazol-4-yl, R.sub.1 is H, and Z is
3-chloro-6-trifluoromethyl-benzothiophen-2-yl; a compound wherein Y
is thiazol-2-yl, R.sub.1 is H, and Z is 1-phenyl-1H-indazol-5-yl; a
compound wherein Y is thiazol-2-yl, R.sub.1 is H, and Z is
5-phenyl-naphth-2-yl; a compound wherein Y is thiazol-4-yl, R.sub.1
is H, and Z is 1-(3,4-difluorophenyl)-1H-indol-5-yl; a compound
wherein Y is thiazol-2-yl, R.sub.1 is H, and Z is
1-(2,4-difluorophenyl)-1H-indol-5-yl; a compound wherein Y is
thiazol-2-yl, R.sub.1 is H, and Z is
3-methyl-6-trifluoromethyl-benzothiophen-2-yl; a compound wherein Y
is thiazol-2-yl, R.sub.1 is H, and Z is
1-(3,4-difluorophenyl)-1H-indol-5-yl; a compound wherein Y is
thiazol-2-yl, R.sub.1 is H, and Z is
2-methyl-4-(3-trifluoromethylphenyl)-phenyl; a compound wherein Y
is thiazol-2-yl, R.sub.1 is H, and Z is
2-fluoro-4-(4-trifluoromethylphenyl)-phenyl; a compound wherein Y
is thiazol-4-yl, R.sub.1 is H, and Z is
1-(2,4-difluorophenyl)-1H-indol-5-yl; a compound wherein Y is
thiazol-2-yl, R.sub.1 is H, and Z is
1-(4-fluorophenyl)-1H-indol-5-yl; a compound wherein Y is
thiazol-2-yl, R.sub.1 is H, and Z is
1-(4-fluorophenyl)-3-methyl-1H-indol-5-yl; a compound wherein Y is
thiazol-2-yl, R.sub.1 is H, and Z is
2-methyl-4-(4-trifluoromethylphenyl)phenyl; a compound wherein Y is
thiazol-2-yl, R.sub.1 is H, and Z is
2-fluoro-4-(3-trifluoromethylphenyl)-phenyl; a compound wherein Y
is thiazol-2-yl, R.sub.1 is H, and Z is
3-methyl-6-bromo-benzothiophen-2-yl; a compound wherein Y is
thiazol-2-yl, R.sub.1 is H, and Z is
3-methyl-6-phenyl-benzothiophen-2-yl; and a compound wherein Y is
thiazol-4-yl, R.sub.1 is H, and Z is
3-methyl-6-trifluoromethyl-benzothiophen-2-yl; and pharmaceutically
acceptable salt forms thereof.
9. A compound of Formula (Ib) ##STR00081## selected from the group
consisting of a compound wherein m is 1, and Z is
3-chloro-6-phenyl-benzothiophen-2-yl; a compound wherein m is 1,
and Z is 6-phenyl-naphth-2-yl; a compound wherein m is 1, and Z is
1-(4-trifluoromethylphenyl)-1H-indol-5-yl; a compound wherein m is
1, and Z is 1-(phenylsulfonyl)-1H-indol-5-yl; a compound wherein m
is 1, and Z is 6-(3-methanesulfonylphenyl)-benzothiophen-2-yl; a
compound wherein m is 1, and Z is
3-chloro-6-bromo-benzothiophen-2-yl; a compound wherein m is 1, and
Z is 3,6-diphenyl-benzothiophen-2-yl; a compound wherein m is 1,
and Z is 1-(3-trifluoromethylphenyl)-1H-indol-5-yl; a compound
wherein m is 1, and Z is 4-(5-trifluoromethyl-thien-2-yl)-phenyl; a
compound wherein m is 1, and Z is 2-phenyl-benzoxazol-5-yl; a
compound wherein m is 1, and Z is
2-(3-trifluoromethylphenyl)-benzoxazol-6-yl; a compound wherein m
is 1, and Z is 5-phenyl-benzothiophen-2-yl; a compound wherein m is
1, and Z is 4-(3-methanesulfonylphenyl)phenyl; a compound wherein m
is 1, and Z is 6-trifluoromethyl-benzothiophen-2-yl; a compound
wherein m is 1, and Z is
5-(3-methanesulfonylphenyl)benzothiophen-2-yl; a compound wherein m
is 1, and Z is 5-bromo-naphth-2-yl; a compound wherein m is 1, and
Z is 2-phenyl-benzoxazol-6-yl; a compound wherein m is 1, and Z is
1-phenyl-1H-indol-5-yl; a compound wherein m is 1, and Z is
4-(3-trifluoromethylphenylmethyl)phenyl; a compound wherein m is 1,
and Z is 6-bromo-benzothiophen-2-yl; a compound wherein m is 1, and
Z is 2-(4-chlorophenyl)-benzoxazol-6-yl; a compound wherein m is 1,
and Z is 1-(2-trifluoromethylphenyl)-1H-indol-5-yl; a compound
wherein m is 1, and Z is 6-bromo-naphth-2-yl; a compound wherein m
is 1, and Z is 4-piperadin-1-yl-phenyl; a compound wherein m is 1,
and Z is 4-phenyl-phenyl; a compound wherein m is 1, and Z is
5-bromo-benzothiophen-2-yl; a compound wherein m is 1, and Z is
4-(phenylmethyl)phenyl; a compound wherein m is 1, and Z is
4-(benzothiophen-2-yl)phenyl a compound wherein m is 1, and Z is
4-bromophenyl; a compound wherein m is 1, and Z is
5-phenyl-naphth-2-yl; a compound wherein m is 1, and Z is
6-phenyl-benzothiophen-2-yl; a compound wherein m is 1, and Z is
3-chloro-6-trifluoromethyl-benzothiophen-2-yl; a compound wherein m
is 1, and Z is 3-chloro-6-fluoro-benzothiophen-2-yl; a compound
wherein m is 1, and Z is
3-methyl-6-trifluoromethyl-benzothiophen-2-yl; and a compound
wherein m is 1, and Z is 1-(4-fluorophenyl)-1H-indol-5-yl; and
pharmaceutically acceptable salt forms thereof.
10. A compound of Formula (Ic) ##STR00082## selected from the group
consisting of a compound wherein Z is
3-methyl-6-trifluoromethyl-benzothiophen-2-yl; a compound wherein Z
is 2-methyl-4-(3-trifluoromethylphenyl)phenyl; a compound wherein Z
is 2-methyl-4-(4-trifluoromethylphenyl)phenyl; and a compound
wherein Z is 1-(4-trifluoromethylphenyl)-1H-indol-5-yl; and
pharmaceutically acceptable salt forms thereof.
11. A pharmaceutical composition comprising a compound of claim 1
and at least one of a pharmaceutically acceptable carrier, a
pharmaceutically acceptable excipient, and a pharmaceutically
acceptable diluent.
12. A pharmaceutical composition of claim 11, wherein the
composition is a solid oral dosage form.
13. A pharmaceutical composition of claim 11, wherein the
composition is a syrup, an elixir, or a suspension.
14. A method for treating inflammatory pain in a subject in need
thereof comprising administering to the subject a therapeutically
effective amount of a compound of claim 1.
15. The method of claim 14, wherein the inflammatory pain is due to
inflammatory bowel disease, visceral pain, migraine, post operative
pain, osteoarthritis, rheumatoid arthritis, back pain, lower back
pain, joint pain, abdominal pain, chest pain, labor,
musculoskeletal diseases, skin diseases, toothache, pyresis, burn,
sunburn, snake bite, venomous snake bite, spider bite, insect
sting, neurogenic bladder, interstitial cystitis, urinary tract
infection, rhinitis, contact dermatitis/hypersensitivity, itch,
eczema, pharyngitis, mucositis, enteritis, irritable bowel
syndrome, cholecystitis, pancreatitis, postmastectomy pain
syndrome, menstrual pain, endometriosis pain, pain due to physical
trauma, headache, sinus headache, tension headache, or
arachnoiditis.
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] Cannabis sativa has been used for the treatment of pain for
many years. .DELTA..sup.9-tetrahydrocannabinol is a major active
ingredient from Cannabis sativa and an agonist of cannabinoid
receptors (Pertwee, Brit J Pharmacol, 2008, 153, 199-215). Two
cannabinoid G protein-coupled receptors have been cloned,
cannabinoid receptor type 1 (CB.sub.1 Matsuda et al., Nature, 1990,
346, 561-4) and cannabinoid receptor type 2 (CB.sub.2 Munro et al.,
Nature, 1993, 365, 61-5). CB.sub.1 is expressed centrally in brain
areas, such as the hypothalamus and nucleus accumbens as well as
peripherally in the liver, gastrointestinal tract, pancreas,
adipose tissue, and skeletal muscle (Di Marzo et al., Curr Opin
Lipidol, 2007, 18, 129-140). CB.sub.2 is predominantly expressed in
immune cells, such as monocytes (Pacher et al., Amer J Physiol,
2008, 294, H1133-H1134), and under certain conditions, also in the
brain (Benito et al., Brit J Pharmacol, 2008, 153, 277-285) and in
skeletal (Cavuoto et al., Biochem Biophys Res Commun, 2007, 364,
105-110) and cardiac (Hajrasouliha et al., Eur J Pharmacol, 2008,
579, 246-252) muscle. An abundance of pharmacological, anatomical
and electrophysiological data, using synthetic agonists, indicate
that increased cannabinoid signaling through CB.sub.1/CB.sub.2
promotes analgesia in tests of acute nociception and suppresses
hyperalgesia in models of chronic neuropathic and inflammatory pain
(Cravatt et al., J Neurobiol, 2004, 61, 149-60; Guindon et al.,
Brit J Pharmacol, 2008, 153, 319-334).
[0004] Efficacy of synthetic cannabinoid receptor agonists is well
documented. Moreover, studies using cannabinoid receptor
antagonists and knockout mice have also implicated the
endocannabinoid system as an important modulator of nociception.
Anandamide (AEA) (Devane et al., Science, 1992, 258, 1946-9) and
2-arachidinoylglycerol (2-AG) (Mechoulam et al., Biochem Pharmacol,
1995, 50, 83-90; Sugiura et al., Biochem Biophys Res Commun, 1995,
215, 89-97) are two major endocannabinoids. AEA is hydrolyzed by
fatty acid amide hydrolase (FAAH) and 2-AG is hydrolyzed by
monoacylglycerol lipase (MGL) (Piomelli, Nat Rev Neurosci, 2003, 4,
873-884). Genetic ablation of FAAH elevates endogenous AEA and
results in a CB.sub.1-dependent analgesia in models of acute and
inflammatory pain (Lichtman et al., Pain, 2004, 109, 319-27),
suggesting that the endocannabinoid system functions naturally to
inhibit pain (Cravatt et al., J Neurobiol, 2004, 61, 149-60).
Unlike the constitutive increase in endocannabinoid levels using
FAAH knockout mice, use of specific FAAH inhibitors transiently
elevates AEA levels and results in antinociception in vivo
(Kathuria et al., Nat Med, 2003, 9, 76-81). Further evidence for an
endocannabinoid-mediated antinociceptive tone is demonstrated by
the formation of AEA in the periaqueductal grey following noxious
stimulation in the periphery (Walker et al., Proc Natl Acad Sci
USA, 1999, 96, 12198-203) and, conversely, by the induction of
hyperalgesia following antisense RNA-mediated inhibition of
CB.sub.1 in the spinal cord (Dogrul et al., Pain, 2002, 100,
203-9).
[0005] With respect to 2-AG, intravenous delivery of 2-AG produces
analgesia in the tail flick (Mechoulam et al., Biochem Pharmacol,
1995, 50, 83-90) and hot plate (Lichtman et al., J Pharmacol Exp
Ther, 2002, 302, 73-9) assays. In contrast, it was demonstrated
that 2-AG given alone is not analgesic in the hot plate assay, but
when combined with other 2-monoacylglycerols (i.e., 2-linoleoyl
glycerol and 2-palmitoyl glycerol), significant analgesia is
attained, a phenomenon termed the "entourage effect" (Ben-Shabat et
al., Eur J Pharmacol, 1998, 353, 23-31). These "entourage"
2-monoacylglycerols are endogenous lipids that are co-released with
2-AG and potentiate endocannabinoid signaling, in part, by
inhibiting 2-AG breakdown, most likely by competition for the
active site on MGL. This suggests that synthetic MGL Inhibitors
will have a similar effect. Indeed, URB602, a relatively weak
synthetic MGL Inhibitor, showed an antinociceptive effect in a
murine model of acute inflammation (Comelli et al., Brit J
Pharmacol, 2007, 152, 787-794).
[0006] Although the use of synthetic cannabinoid agonists have
conclusively demonstrated that increased cannabinoid signaling
produces analgesic and anti-inflammatory effects, it has been
difficult to separate these beneficial effects from the unwanted
side effects of these compounds. An alternative approach is to
enhance the signaling of the endocannabinoid system by elevating
the level of 2-AG, the endocannabinoid of highest abundance in the
central nervous system (CNS) and gastrointestinal tract, which may
be achieved by inhibition of MGL. Therefore, MGL inhibitors are
potentially useful for the treatment of pain, inflammation, and CNS
disorders (Di Marzo et al., Curr Pharm Des, 2000, 6, 1361-80;
Jhaveri et al., Brit J Pharmacol, 2007, 152, 624-632; McCarberg
Bill et al., Amer J Ther, 2007, 14, 475-83), as well as glaucoma
and disease states arising from elevated intraocular pressure
(Njie, Ya Fatou; He, Fang; Qiao, Zhuanhong; Song, Zhao-Hui, Exp.
Eye Res., 2008, 87(2):106-14).
SUMMARY OF THE INVENTION
[0007] The present invention is directed to a compound of Formula
(I)
##STR00002##
wherein
[0008] Q is selected from
##STR00003##
[0009] wherein
[0010] Y is C.sub.6-10aryl or a heteroaryl that is thiazolyl,
pyrrolyl, or oxazolyl;
[0011] R.sup.1 is hydrogen or C.sub.1-4 alkyl; and
[0012] m is an integer from 1 to 3;
[0013] Z is C.sub.6-10aryl or a heteroaryl selected from the group
consisting of quinolinyl, benzothiophenyl, benzoxazolyl,
benzothiazolyl, benzimidazolyl, indolyl, and indazolyl;
[0014] wherein Z is
[0015] (i) optionally independently substituted with one to three
substituents selected from the group consisting of C.sub.1-4 alkyl,
fluoro, chloro, bromo, trifluoromethyl, and piperidin-1-yl;
provided that no more than one substituent on Z is piperidin-1-yl;
or
##STR00004##
[0016] (ii) [0017] (a) substituted with and [0018] (b) optionally
further substituted with one additional methyl, chloro, fluoro, or
phenyl substituent; [0019] wherein [0020] ring A is phenyl,
thienyl, or benzothiophenyl; provided that when ring A is thienyl
or benzothiophenyl, G is a bond or --CH.sub.2--; or when ring A is
phenyl, G is selected from the group consisting of a bond, O,
--CH.sub.2--, SO.sub.2, and C(O); and
[0021] R.sup.2 is trifluoromethyl, fluoro, chloro, or
methanesulfonyl;
[0022] r is an integer from 0 to 3;
and enantiomers, diastereomers, solvates and pharmaceutically
acceptable salts thereof.
[0023] The present invention also provides, inter alia, a
pharmaceutical composition comprising, consisting of and/or
consisting essentially of a pharmaceutically acceptable carrier, a
pharmaceutically acceptable excipient, and/or a pharmaceutically
acceptable diluent, and a compound of Formula (I), or a
pharmaceutically acceptable salt form thereof.
[0024] Also provided are processes for making a pharmaceutical
composition comprising, consisting of, and/or consisting
essentially of admixing a compound of Formula (I) and a
pharmaceutically acceptable carrier, a pharmaceutically acceptable
excipient, and/or a pharmaceutically acceptable diluent.
[0025] The present invention further provides, inter alia, methods
for treating or ameliorating a MGL-modulated disorder in a subject,
including a human or other mammal in which the disease, syndrome,
or condition is affected by the modulation of the MGL enzyme, such
as pain and the diseases that lead to such pain, inflammation and
CNS disorders, using a compound of Formula (I).
[0026] The present invention also provides, inter alia, methods for
producing the instant compounds and pharmaceutical compositions and
medicaments thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0027] With reference to substituents, the term "independently"
refers to the situation where when more than one substituent is
possible, the substituents may be the same or different from each
other.
[0028] The term "alkyl" whether used alone or as part of a
substituent group, refers to straight and branched carbon chains
having 1 to 8 carbon atoms. Therefore, designated numbers of carbon
atoms (e.g., C.sub.1-8) refer independently to the number of carbon
atoms in an alkyl moiety or to the alkyl portion of a larger
alkyl-containing substituent. In substituent groups with multiple
alkyl groups, such as, (C.sub.1-6alkyl).sub.2-amino-, the
C.sub.1-6alkyl groups of the dialkylamino may be the same or
different.
[0029] The term "alkoxy" refers to an --O-alkyl group, wherein the
term "alkyl" is as defined above.
[0030] The terms "alkenyl" and "alkynyl" refer to straight and
branched carbon chains having 2 or more carbon atoms, wherein an
alkenyl chain contains at least one double bond and an alkynyl
chain contains at least one triple bond.
[0031] The term "cycloalkyl" refers to saturated or partially
saturated, monocyclic or polycyclic hydrocarbon rings of 3 to 14
carbon atoms. Examples of such rings include cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and adamantyl.
[0032] The term "benzo-fused cycloalkyl" refers to a 5- to
8-membered monocyclic cycloalkyl ring fused to a benzene ring. The
carbon atom ring members that form the cycloalkyl ring may be fully
saturated or partially saturated.
[0033] The term "heterocyclyl" refers to a nonaromatic monocyclic
or bicyclic ring system having 3 to 10 ring members and which
contains carbon atoms and from 1 to 4 heteroatoms independently
selected from the group consisting of N, O, and S. Included within
the term heterocyclyl is a nonaromatic cyclic ring of 5 to 7
members in which 1 to 2 members are nitrogen, or a nonaromatic
cyclic ring of 5 to 7 members in which 0, 1 or 2 members are
nitrogen and up to 2 members are oxygen or sulfur and at least one
member must be either nitrogen, oxygen or sulfur; wherein,
optionally, the ring contains zero to one unsaturated bonds, and,
optionally, when the ring is of 6 or 7 members, it contains up to 2
unsaturated bonds. The carbon atom ring members that form a
heterocycle ring may be fully saturated or partially saturated. The
term "heterocyclyl" also includes two 5 membered monocyclic
heterocycloalkyl groups bridged to form a bicyclic ring. Such
groups are not considered to be fully aromatic and are not referred
to as heteroaryl groups. When a heterocycle is bicyclic, both rings
of the heterocycle are non-aromatic and at least one of the rings
contains a heteroatom ring member. Examples of heterocycle groups
include, and are not limited to, pyrrolinyl (including 2H-pyrrole,
2-pyrrolinyl or 3-pyrrolinyl), pyrrolidinyl, imidazolinyl,
imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl,
morpholinyl, thiomorpholinyl, and piperazinyl. Unless otherwise
noted, the heterocycle is attached to its pendant group at any
heteroatom or carbon atom that results in a stable structure.
[0034] The term "benzo-fused heterocyclyl" refers to a 5 to 7
membered monocyclic heterocycle ring fused to a benzene ring. The
heterocycle ring contains carbon atoms and from 1 to 4 heteroatoms
independently selected from the group consisting of N, O, and S.
The carbon atom ring members that form the heterocycle ring may be
fully saturated or partially saturated. Unless otherwise noted,
benzo-fused heterocycle ring is attached to its pendant group at a
carbon atom of the benzene ring.
[0035] The term "aryl" refers to an unsaturated, aromatic
monocyclic or bicyclic ring of 6 to 10 carbon members. Examples of
aryl rings include phenyl and naphthalenyl.
[0036] The term "heteroaryl" refers to an aromatic monocyclic or
bicyclic aromatic ring system having 5 to 10 ring members and which
contains carbon atoms and from 1 to 4 heteroatoms independently
selected from the group consisting of N, O, and S. Included within
the term heteroaryl are aromatic rings of 5 or 6 members wherein
the ring consists of carbon atoms and has at least one heteroatom
member. Suitable heteroatoms include nitrogen, oxygen, and sulfur.
In the case of 5 membered rings, the heteroaryl ring preferably
contains one member of nitrogen, oxygen or sulfur and, in addition,
up to 3 additional nitrogens. In the case of 6 membered rings, the
heteroaryl ring preferably contains from 1 to 3 nitrogen atoms. For
the case wherein the 6 membered ring has 3 nitrogens, at most 2
nitrogen atoms are adjacent. Examples of heteroaryl groups include
furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,
pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,
thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,
indolyl, isoindolyl, benzofuryl, benzothienyl, indazolyl,
benzimidazolyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl,
benzothiadiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl and
quinazolinyl. Unless otherwise noted, the heteroaryl is attached to
its pendant group at any heteroatom or carbon atom that results in
a stable structure.
[0037] The term "halogen" or "halo" refers to fluorine, chlorine,
bromine and iodine.
[0038] The term "formyl" refers to the group --C(.dbd.O)H.
[0039] The term "oxo" refers to the group (.dbd.O).
[0040] Whenever the term "alkyl" or "aryl" or either of their
prefix roots appear in a name of a substituent (e.g., arylalkyl,
alkylamino) the name is to be interpreted as including those
limitations given above for "alkyl" and "aryl." Designated numbers
of carbon atoms (e.g., C.sub.1-C.sub.6 and C.sub.1-6, which are
synonymous) refer independently to the number of carbon atoms in an
alkyl moiety, an aryl moiety, or in the alkyl portion of a larger
substituent in which alkyl appears as its prefix root. For alkyl
and alkoxy substituents, the designated number of carbon atoms
includes all of the independent members included within a given
range specified. For example, C.sub.1-6 alkyl would include methyl,
ethyl, propyl, butyl, pentyl and hexyl individually as well as
sub-combinations thereof (e.g., C.sub.1-2, C.sub.1-3, C.sub.1-4,
C.sub.1-5, C.sub.2-6, C.sub.3-6, C.sub.4-6, C.sub.5-6, C.sub.2-5,
etc.).
[0041] In general, under standard nomenclature rules used
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
"C.sub.1-C.sub.6 alkylcarbonyl" substituent refers to a group of
the formula:
##STR00005##
[0042] The term "R" at a stereocenter designates that the
stereocenter is purely of the R-configuration as defined in the
art; likewise, the term "S" means that the stereocenter is purely
of the S-configuration. As used herein, the terms "*R" or "*S" at a
stereocenter are used to designate that the stereocenter is of pure
but unknown configuration. As used herein, the term "RS" refers to
a stereocenter that exists as a mixture of the R- and
S-configurations. Similarly, the terms "*RS" or "*SR" refer to a
stereocenter that exists as a mixture of the R- and
S-configurations and is of unknown configuration relative to
another stereocenter within the molecule.
[0043] Compounds containing one stereocenter drawn without a stereo
bond designation are a mixture of 2 enantiomers. Compounds
containing 2 stereocenters both drawn without stereo bond
designations are a mixture of 4 diastereomers. Compounds with 2
stereocenters both labeled "RS" and drawn with stereo bond
designations are a 2-component mixture with relative
stereochemistry as drawn. Compounds with 2 stereocenters both
labeled "*RS" and drawn with stereo bond designations are a
2-component mixture with relative stereochemistry unknown.
Unlabeled stereocenters drawn without stereo bond designations are
a mixture of the R- and S-configurations. For unlabeled
stereocenters drawn with stereo bond designations, the absolute
stereochemistry is as depicted.
[0044] Unless otherwise noted, it is intended that the definition
of any substituent or variable at a particular location in a
molecule be independent of its definitions elsewhere in that
molecule. It is understood that substituents and substitution
patterns on the compounds of Formula (I), including Formulas (Ia),
(Ib), and (Ic), can be selected by one of ordinary skill in the art
to provide compounds that are chemically stable and that can be
readily synthesized by techniques known in the art as well as those
methods set forth herein.
[0045] The term "subject" refers to an animal, preferably a mammal,
most preferably a human, who has been the object of treatment,
observation or experiment.
[0046] The term "therapeutically effective amount" refers to an
amount of an active compound or pharmaceutical agent, including a
compound of the present invention, which elicits the biological or
medicinal response in a tissue system, animal or human that is
being sought by a researcher, veterinarian, medical doctor or other
clinician, which includes alleviation or partial alleviation of the
symptoms of the disease, syndrome, condition, or disorder being
treated.
[0047] The term "composition" refers to a product that includes the
specified ingredients in therapeutically effective amounts, as well
as any product that results, directly, or indirectly, from
combinations of the specified ingredients in the specified
amounts.
[0048] The term "MGL inhibitor" is intended to encompass a compound
that interacts with MGL to substantially reduce or eliminate its
catalytic activity, thereby increasing the concentrations of its
substrate(s).
[0049] The term "MGL-modulated" is used to refer to the condition
of being affected by the modulation of the MGL enzyme including the
condition of being affected by the inhibition of the MGL enzyme,
such as, for example, pain and the diseases that lead to such pain,
inflammation and CNS disorders.
[0050] As used herein, unless otherwise noted, the term "affect" or
"affected" (when referring to a disease, syndrome, condition or
disorder that is affected by the inhibition of MGL) shall include a
reduction in the frequency and/or severity of one or more symptoms
or manifestations of said disease, syndrome, condition or disorder;
and/or include the prevention of the development of one or more
symptoms or manifestations of said disease, syndrome, condition or
disorder or the development of the disease, condition, syndrome or
disorder.
[0051] The compounds of Formula (I), including Formulas (Ia), (Ib),
and (Ic), are useful in methods for treating, ameliorating and/or
preventing a disease, a syndrome, a condition or a disorder that is
affected by the inhibition of MGL. Such methods comprise, consist
of and/or consist essentially of administering to a subject,
including an animal, a mammal, and a human in need of such
treatment, amelioration and/or prevention, a therapeutically
effective amount of a compound of Formula (I), including Formulas
(Ia), (Ib), and (Ic), or an enantiomer, diastereomer, solvate or
pharmaceutically acceptable salt form thereof. In particular, the
compounds of Formula (I), including Formulas (Ia), (Ib), and (Ic),
are useful for treating, ameliorating and/or preventing pain;
diseases, syndromes, conditions, or disorders causing such pain;
inflammation and/or CNS disorders. More particularly, the compounds
of Formula (I), including Formulas (Ia), (Ib), and (Ic), are useful
for treating, ameliorating and/or preventing inflammatory pain,
inflammatory hypersensitivity conditions and/or neuropathic pain,
comprising administering to a subject in need thereof a
therapeutically effective amount of a compound of Formula (I),
including Formulas (Ia), (Ib), and (Ic), as herein defined.
[0052] Examples of inflammatory pain include pain due to a disease,
condition, syndrome, disorder, or a pain state including
inflammatory bowel disease, visceral pain, migraine, post operative
pain, osteoarthritis, rheumatoid arthritis, back pain, lower back
pain, joint pain, abdominal pain, chest pain, labor,
musculoskeletal diseases, skin diseases, toothache, pyresis, burn,
sunburn, snake bite, venomous snake bite, spider bite, insect
sting, neurogenic bladder, interstitial cystitis, urinary tract
infection, rhinitis, contact dermatitis/hypersensitivity, itch,
eczema, pharyngitis, mucositis, enteritis, irritable bowel
syndrome, cholecystitis, pancreatitis, postmastectomy pain
syndrome, menstrual pain, endometriosis, pain due to physical
trauma, headache, sinus headache, tension headache, or
arachnoiditis.
[0053] One type of inflammatory pain is inflammatory
hyperalgesia/hypersensitivity. Examples of inflammatory
hyperalgesia include a disease, syndrome, condition, disorder, or
pain state including inflammation, osteoarthritis, rheumatoid
arthritis, back pain, joint pain, abdominal pain, musculoskeletal
diseases, skin diseases, post operative pain, headaches, toothache,
burn, sunburn, insect sting, neurogenic bladder, urinary
incontinence, interstitial cystitis, urinary tract infection,
cough, asthma, chronic obstructive pulmonary disease, rhinitis,
contact dermatitis/hypersensitivity, itch, eczema, pharyngitis,
enteritis, irritable bowel syndrome, inflammatory bowel diseases
including Crohn's Disease, ulcerative colitis, urinary
incontinence, benign prostatic hypertrophy, cough, asthma,
rhinitis, nasal hypersensitivity, itch, contact dermatitis and/or
dermal allergy and chronic obstructive pulmonary disease.
[0054] In an embodiment, the present invention is directed to a
method for treating, ameliorating and/or preventing inflammatory
visceral hyperalgesia in which an enhanced visceral irritability
exists, comprising, consisting of, and/or consisting essentially of
the step of administering to a subject in need of such treatment a
therapeutically effective amount of a compound, salt or solvate of
Formula (I), including Formulas (Ia), (Ib), and (Ic). In a further
embodiment, the present invention is directed to a method for
treating inflammatory somatic hyperalgesia in which a
hypersensitivity to thermal, mechanical and/or chemical stimuli
exists, comprising administering to a mammal in need of such
treatment a therapeutically effective amount of a compound of
Formula (I), including Formulas (Ia), (Ib), and (Ic), or an
enantiomer, diastereomer, solvate or pharmaceutically acceptable
salt thereof.
[0055] A further embodiment of the present invention is directed to
a method for treating, ameliorating and/or preventing neuropathic
pain. Examples of a neuropathic pain include pain due to a disease,
syndrome, condition, disorder, or pain state including cancer,
neurological disorders, spine and peripheral nerve surgery, brain
tumor, traumatic brain injury (TBI), spinal cord trauma, chronic
pain syndrome, fibromyalgia, chronic fatigue syndrome, lupus,
sarcoidosis, peripheral neuropathy, bilateral peripheral
neuropathy, diabetic neuropathy, central pain, neuropathies
associated with spinal cord injury, stroke, amyotrophic lateral
sclerosis (ALS), Parkinson's disease, multiple sclerosis, sciatic
neuritis, mandibular joint neuralgia, peripheral neuritis,
polyneuritis, stump pain, phantom limb pain, bony fractures, oral
neuropathic pain, Charcot's pain, complex regional pain syndrome I
and II (CRPS I/II), radiculopathy, Guillain-Barre syndrome,
meralgia paresthetica, burning-mouth syndrome, optic neuritis,
postfebrile neuritis, migrating neuritis, segmental neuritis,
Gombault's neuritis, neuronitis, cervicobrachial neuralgia, cranial
neuralgia, geniculate neuralgia, glossopharyngial neuralgia,
migrainous neuralgia, idiopathic neuralgia, intercostals neuralgia,
mammary neuralgia, Morton's neuralgia, nasociliary neuralgia,
occipital neuralgia, postherpetic neuralgia, causalgia, red
neuralgia, Sluder's neuralgia, splenopalatine neuralgia,
supraorbital neuralgia, trigeminal neuralgia, vulvodynia, or vidian
neuralgia.
[0056] One type of neuropathic pain is neuropathic cold allodynia,
which can be characterized by the presence of a
neuropathy-associated allodynic state in which a hypersensitivity
to cooling stimuli exists. Examples of neuropathic cold allodynia
include allodynia due to a disease, condition, syndrome, disorder
or pain state including neuropathic pain (neuralgia), pain arising
from spine and peripheral nerve surgery or trauma, traumatic brain
injury (TBI), trigeminal neuralgia, postherpetic neuralgia,
causalgia, peripheral neuropathy, diabetic neuropathy, central
pain, stroke, peripheral neuritis, polyneuritis, complex regional
pain syndrome I and II (CRPS I/II) and radiculopathy.
[0057] In a further embodiment, the present invention is directed
to a method for treating, ameliorating and/or preventing
neuropathic cold allodynia in which a hypersensitivity to a cooling
stimuli exists, comprising, consisting of, and/or consisting
essentially of the step of administering to a subject in need of
such treatment a therapeutically effective amount of a compound of
Formula (I), including Formulas (Ia), (Ib), and (Ic), or an
enantiomer, diastereomer, solvate or pharmaceutically acceptable
salt thereof.
[0058] In a further embodiment, the present invention is directed
to a method for treating, ameliorating and/or preventing CNS
disorders. Examples of CNS disorders include anxieties, such as
social anxiety, post-traumatic stress disorder, phobias, social
phobia, special phobias, panic disorder, obsessive-compulsive
disorder, acute stress disorder, separation anxiety disorder, and
generalized anxiety disorder, as well as depression, such as major
depression, bipolar disorder, seasonal affective disorder, post
natal depression, manic depression, and bipolar depression.
[0059] Embodiments of the present invention include a compound of
Formula (I)
##STR00006##
wherein [0060] a) Q is selected from
[0060] ##STR00007## [0061] wherein [0062] Y is phenyl or thiazolyl;
[0063] R.sup.1 is hydrogen or methyl; and [0064] m is 1; [0065] b)
Q is selected from
[0065] ##STR00008## [0066] wherein [0067] Y is phenyl or thiazolyl;
[0068] R.sup.1 is hydrogen; and [0069] m is 1; [0070] c) Z is
C.sub.6-10aryl or a heteroaryl selected from the group consisting
of benzothiophenyl, benzoxazolyl, benzothiazolyl, indolyl, and
indazolyl; [0071] wherein Z is [0072] (i) optionally independently
substituted with one to two substituents selected from the group
consisting of C.sub.1-4 alkyl, fluoro, chloro, bromo,
trifluoromethyl, and piperidin-1-yl; provided that no more than one
substituent on Z is piperidin-1-yl; or
[0072] ##STR00009## [0073] (ii) [0074] (a) substituted with and
[0075] (b) optionally further substituted with one additional
methyl, chloro, fluoro, or phenyl substituent; [0076] wherein
[0077] ring A is phenyl, thienyl, or benzothiophenyl; provided that
[0078] when ring A is thienyl or benzothiophenyl, G is a bond or
--CH.sub.2--; or [0079] when ring A is phenyl, G is selected from
the group consisting of a bond, O, --CH.sub.2--, SO.sub.2, or C(O);
[0080] R.sup.2 is trifluoromethyl, fluoro, chloro, or
methanesulfonyl; [0081] r is an integer from 0 to 3; [0082] d) Z is
C.sub.6-10aryl or a heteroaryl selected from the group consisting
of benzothiophenyl, benzoxazolyl, benzothiazolyl, indolyl, and
indazolyl; [0083] wherein Z is [0084] (i) optionally independently
substituted with one to two substituents selected from the group
consisting of C.sub.1-4 alkyl, fluoro, chloro, bromo, and
trifluoromethyl; or
[0084] ##STR00010## [0085] (ii) [0086] (a) substituted with and
[0087] (b) optionally further substituted with one additional
methyl, chloro, fluoro, or phenyl substituent; [0088] wherein
[0089] ring A is phenyl or thienyl; provided that when ring A is
thienyl, G is a bond or --CH.sub.2--; or [0090] when ring A is
phenyl, G is selected from the group consisting of a bond,
--CH.sub.2--, or SO.sub.2; [0091] R.sup.2 is trifluoromethyl,
fluoro, chloro, or methanesulfonyl; [0092] r is an integer from 0
to 2;
[0093] and any combination of embodiments a) through d) above,
provided that it is understood that combinations in which different
embodiments of the same substituent would be combined are
excluded;
[0094] and enantiomers, diastereomers, solvates and
pharmaceutically acceptable salts thereof.
[0095] An embodiment of the present invention is directed to a
compound of Formula (I)
##STR00011##
wherein:
[0096] Q is selected from
##STR00012##
[0097] wherein
[0098] Y is phenyl or thiazolyl;
[0099] R.sup.1 is hydrogen or methyl; and
[0100] m is 1;
[0101] Z is C.sub.6-10aryl or a heteroaryl selected from the group
consisting of benzothiophenyl, benzoxazolyl, benzothiazolyl,
indolyl, and indazolyl;
[0102] wherein Z is [0103] (i) optionally independently substituted
with one to two substituents selected from the group consisting of
C.sub.1-4 alkyl, fluoro, chloro, bromo, trifluoromethyl, and
piperidin-1-yl; provided that no more than one substituent on Z is
piperidin-1-yl; or
[0103] ##STR00013## [0104] (ii) [0105] (a) substituted with and
[0106] (b) optionally further substituted with one additional
methyl, chloro, fluoro, or phenyl substituent; [0107] wherein
[0108] ring A is phenyl, thienyl, or benzothiophenyl; provided that
[0109] when ring A is thienyl or benzothiophenyl, G is a bond or
--CH.sub.2--; or [0110] when ring A is phenyl, G is selected from
the group consisting of a bond, O, --CH.sub.2--, SO.sub.2, or
C(O);
[0111] R.sup.2 is trifluoromethyl, fluoro, chloro, or
methanesulfonyl;
[0112] r is an integer from 0 to 3;
[0113] and enantiomers, diastereomers, solvates and
pharmaceutically acceptable salts thereof.
[0114] An embodiment of the present invention is directed to a
compound of Formula (I)
##STR00014##
wherein:
[0115] Q is selected from
##STR00015##
[0116] wherein
[0117] Y is phenyl or thiazolyl;
[0118] R.sup.1 is hydrogen; and
[0119] m is 1;
[0120] Z is C.sub.6-10aryl or a heteroaryl selected from the group
consisting of benzothiophenyl, benzoxazolyl, benzothiazolyl,
indolyl, and indazolyl;
[0121] wherein Z is [0122] (i) optionally independently substituted
with one to two substituents selected from the group consisting of
C.sub.1-4 alkyl, fluoro, chloro, bromo, and trifluoromethyl; or
[0122] ##STR00016## [0123] (ii) [0124] (a) substituted with and
[0125] (b) optionally further substituted with one additional
methyl, chloro, fluoro, or phenyl substituent; [0126] wherein
[0127] ring A is phenyl or thienyl; provided that [0128] when ring
A is thienyl, G is a bond or --CH.sub.2--; or [0129] when ring A is
phenyl, G is selected from the group consisting of a bond,
--CH.sub.2--, or SO.sub.2; [0130] R.sup.2 is trifluoromethyl,
fluoro, chloro, or methanesulfonyl; [0131] r is an integer from 0
to 2;
[0132] and enantiomers, diastereomers, solvates and
pharmaceutically acceptable salts thereof.
[0133] Embodiments of the present invention are directed to
compounds of Formula (Ia), listed in Table 1, below.
TABLE-US-00001 TABLE 1 Formula (Ia) ##STR00017## Cpd No. Y R.sub.1
Z 1 thiazol-2-yl H 1-(4-trifluoromethylphenyl)-1H-indol-5-yl 2
thiazol-4-yl H 4-(3-trifluoromethylphenyl)phenyl 3 thiazol-2-yl H
1-(phenylsulfonyl)-1H-indol-5-yl 4 thiazol-2-yl H
2-phenyl-benzothiazol-6-yl 5 thiazol-2-yl H
4-(3-trifluoromethylphenyl)phenyl 6 thiazol-2-yl H
6-phenyl-benzothiophen-2-yl 7 thiazol-2-yl H
6-trifluoromethyl-benzothiophen-2-yl 8 thiazol-2-yl H
4-trifluoromethyl-benzothiophen-2-yl 9 thiazol-2-yl H
4-(5-trifluoromethyl-thien-2-yl)-phenyl 10 thiazol-2-yl H
4-(phenylmethyl)-phenyl 11 thiazol-4-yl H
1-(4-fluorophenyl)-1H-indol-5-yl 12 thiazol-2-yl H
4-(4-trifluoromethylphenyl)-phenyl 13 thiazol-2-yl H
1-phenyl-1H-indol-5-yl 14 thiazol-4-yl H
4-(4-trifluoromethylphenyl)-phenyl 15 thiazol-2-yl H
3-methyl-5-chloro-benzothiophen-2-yl 16 thiazol-2-yl H
4-(4-trifluoromethylphenylmethyl)phenyl 17 thiazol-2-yl H
2-phenyl-benzoxazol-6-yl 18 thiazol-2-yl H
4-(3-methanesulfonylphenyl)phenyl 19 thiazol-2-yl H
5-bromo-naphth-2-yl 20 thiazol-2-yl H
4-(3-trifluoromethylphenylmethyl)phenyl 21 thiazol-2-yl H
6-phenyl-naphth-2-yl 22 thiazol-4-yl H 2-phenyl-benzothiazol-6-yl
23 thiazol-2-yl H 6-bromo-benzothiophen-2-yl 24 phenyl H
5-bromo-naphth-2-yl 25 phenyl H 5-phenyl-naphth-2-yl 26 phenyl H
4-(4-trifluoromethylphenylmethyl)phenyl 27 thiazol-2-yl H
1-phenyl-1H-indol-6-yl 28 thiazol-2-yl H
2-(3-trifluoromethylphenyl)-benzoxazol-6-yl 29 thiazol-2-yl H
4-phenyl-phenyl 30 thiazol-2-yl H
2-(4-trifluoromethylphenyl)-benzoxazol-6-yl 31 phenyl H
4-(phenylmethyl)phenyl 32 thiazol-2-yl H 4-phenoxy-phenyl 33
thiazol-2-yl H 2-(4-chlorophenyl)-benzoxazol-6-yl 34 phenyl H
6-phenyl-naphth-2-yl 35 thiazol-2-yl H 2-phenyl-benzoxazol-5-yl 36
phenyl H 3-methyl-5-chloro-benzothiophen-2-yl 37 thiazol-2-yl
methyl 6-trifluoromethyl-benzothiophen-2-yl 38 thiazol-2-yl H
4-(phenylcarbonyl)-phenyl 39 phenyl H 4-phenyl-phenyl 40
thiazol-2-yl H 6-bromo-naphth-2-yl 41 phenyl H
2-phenyl-benzoxazol-6-yl 42 phenyl H 6-bromo-naphth-2-yl 43
thiazol-2-yl H 4-bromophenyl 44 phenyl H
5-trifluoromethyl-benzothiophen-2-yl 45 phenyl H 4-phenoxy-phenyl
46 thiazol-4-yl H 2-bromo-benzothiazol-6-yl 47 thiazol-2-yl H
5-trifluoromethyl-benzothiazol-2-yl 48 thiazol-4-yl methyl
6-trifluoromethyl-benzothiophen-2-yl 49 thiazol-4-yl H
6-trifluoromethyl-benzothiophen-2-yl 50 thiazol-2-yl H
3-chloro-6-trifluoromethyl-benzothiophen-2-yl 51 thiazol-4-yl H
3-chloro-6-trifluoromethyl-benzothiophen-2-yl 52 thiazol-2-yl H
1-phenyl-1H-indazol-5-yl 53 thiazol-2-yl H 5-phenyl-naphth-2-yl 54
thiazol-4-yl H 1-(3,4-difluorophenyl)-1H-indol-5-yl 55 thiazol-2-yl
H 1-(2,4-difluorophenyl)-1H-indol-5 -yl 56 thiazol-2-yl H
3-methyl-6-trifluoromethyl-benzothiophen-2-yl 57 thiazol-2-yl H
1-(3,4-difluorophenyl)-1H-indol-5-yl 58 thiazol-2-yl H
2-methyl-4-(3-trifluoromethylphenyl)-phenyl 59 thiazol-2-yl H
2-fluoro-4-(4-trifluoromethylphenyl)-phenyl 60 thiazol-4-yl H
1-(2,4-difluorophenyl)-1H-indol-5 -yl 61 thiazol-2-yl H
1-(4-fluorophenyl)-1H-indol-5-yl 62 thiazol-2-yl H
1-(4-fluorophenyl)-3-methyl-1H-indol-5-yl 63 thiazol-2-yl H
2-methyl-4-(4-trifluoromethylphenyl)phenyl 64 thiazol-2-yl H
2-fluoro-4-(3-trifluoromethylphenyl)phenyl 65 thiazol-2-yl H
3-methyl-6-bromo-benzothiophen-2-yl 66 thiazol-2-yl H
3-methyl-6-phenyl-benzothiophen-2-yl 67 thiazol-4-yl H
3-methyl-6-trifluoromethyl-benzothiophen-2-yl
and pharmaceutically acceptable salts thereof.
[0134] Embodiments of the present invention are directed to
compounds of Formula (Ib), listed in Table 2, below.
TABLE-US-00002 TABLE 2 Formula (Ib) ##STR00018## Cpd No. m Z 68 1
3-chloro-6-phenyl-benzothiophen-2-yl 69 1 6-phenyl-naphth-2-yl 70 1
1-(4-trifluoromethylphenyl)-1H-indol-5-yl 71 1
1-(phenylsulfonyl)-1H-indol-5-yl 72 1
6-(3-methanesulfonylphenyl)-benzothiophen-2-yl 73 1
3-chloro-6-bromo-benzothiophen-2-yl 74 1
3,6-diphenyl-benzothiophen-2-yl 75 1
1-(3-trifluoromethylphenyl)-1H-indol-5-yl 76 1
4-(5-trifluoromethyl-thien-2-yl)phenyl 77 1
2-phenyl-benzoxazol-5-yl 78 1
2-(3-trifluoromethylphenyl)-benzoxazol-6-yl 79 1
5-phenyl-benzothiophen-2-yl 80 1 4-(3-methanesulfonylphenyl)phenyl
81 1 6-trifluoromethyl-benzothiophen-2-yl 82 1
5-(3-methanesulfonylphenyl)benzothiophen-2-yl 83 1
5-bromo-naphth-2-yl 84 1 2-phenyl-benzoxazol-6-yl 85 1
1-phenyl-1H-indol-5-yl 86 1 4-(3-trifluoromethylphenylmethyl)phenyl
87 1 6-bromo-benzothiophen-2-yl 88 1
2-(4-chlorophenyl)-benzoxazol-6-yl 89 1
1-(2-trifluoromethylphenyl)-1H-indol-5-yl 90 1 6-bromo-naphth-2-yl
91 1 4-piperidin-1-yl-phenyl 92 1 4-phenyl-phenyl 93 1
5-bromo-benzothiophen-2-yl 94 1 4-(phenylmethyl)phenyl 95 1
4-(benzothiophen-2-yl)phenyl 96 1 4-bromophenyl 97 1
5-phenyl-naphth-2-yl 98 1 6-phenyl-benzothiophen-2-yl 99 1
3-chloro-6-trifluoromethyl-benzothiophen-2-yl 100 1
3-chloro-6-fluoro-benzothiophen-2-yl 101 1
3-methyl-6-trifluoromethyl-benzothiophen-2-yl 102 1
1-(4-fluorophenyl)-1H-indol-5-yl
and pharmaceutically acceptable salts thereof.
[0135] Embodiments of the present invention are directed to
compounds of Formula (Ic), listed in Table 3, below.
TABLE-US-00003 TABLE 3 Formula (Ic) ##STR00019## Cpd No. Z 103
3-methyl-6-trifluoromethyl-benzothiophen-2-yl 104
2-methyl-4-(3-trifluoromethylphenyl)phenyl 105
2-methyl-4-(4-trifluoromethylphenyl)phenyl 106
1-(4-trifluoromethylphenyl)-1H-indol-5-yl
and pharmaceutically acceptable salts thereof.
[0136] For use in medicine, salts of compounds of Formula (I),
including Formulas (Ia), (Ib), and (Ic), refer to non-toxic
"pharmaceutically acceptable salts." Other salts may, however, be
useful in the preparation of compounds of Formula (I), including
Formulas (Ia), (Ib), and (Ic), or of their pharmaceutically
acceptable salts thereof. Suitable pharmaceutically acceptable
salts of compounds of Formula (I), including Formulas (Ia), (Ib),
and (Ic), include acid addition salts which can, for example, be
formed by mixing a solution of the compound with a solution of a
pharmaceutically acceptable acid such as hydrochloric acid,
sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic
acid, benzoic acid, citric acid, tartaric acid, carbonic acid or
phosphoric acid. Furthermore, where the compounds of Formula (I),
including Formulas (Ia), (Ib), and (Ic), carry an acidic moiety,
suitable pharmaceutically acceptable salts thereof may include
alkali metal salts, such as sodium or potassium salts; alkaline
earth metal salts, such as, calcium or magnesium salts; and salts
formed with suitable organic ligands, such as, quaternary ammonium
salts. Thus, representative pharmaceutically acceptable salts
include acetate, benzenesulfonate, benzoate, bicarbonate,
bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate,
carbonate, chloride, clavulanate, citrate, dihydrochloride,
edetate, edisylate, estolate, esylate, fumarate, gluceptate,
gluconate, glutamate, glycollylarsanilate, hexylresorcinate,
hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate,
iodide, isothionate, lactate, lactobionate, laurate, malate,
maleate, mandelate, mesylate, methylbromide, methylnitrate,
methylsulfate, mucate, napsylate, nitrate, N-methylglucamine
ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate,
phosphate/diphosphate, polygalacturonate, salicylate, stearate,
sulfate, subacetate, succinate, tannate, tartrate, teoclate,
tosylate, triethiodide and valerate.
[0137] Representative acids and bases that may be used in the
preparation of pharmaceutically acceptable salts include acids
including acetic acid, 2,2-dichloroactic acid, acylated amino
acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid,
benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid,
(+)-camphoric acid, camphorsulfonic acid,
(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid,
caprylic acid, cinnamic acid, citric acid, cyclamic acid,
dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic
acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid,
galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic
acid, D-glucoronic acid, L-glutamic acid, .alpha.-oxo-glutaric
acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric
acid, (+)-L-lactic acid, (.+-.)-DL-lactic acid, lactobionic acid,
maleic acid, (-)-L-malic acid, malonic acid, (.+-.)-DL-mandelic
acid, methanesulfonic acid, naphthalene-2-sulfonic acid,
naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid,
nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid,
palmitic acid, pamoic acid, phosphoric acid, L-pyroglutamic acid,
salicylic acid, 4-amino-salicylic acid, sebaic acid, stearic acid,
succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid,
thiocyanic acid, p-toluenesulfonic acid and undecylenic acid; and
bases including ammonia, L-arginine, benethamine, benzathine,
calcium hydroxide, choline, deanol, diethanolamine, diethylamine,
2-(diethylamino)-ethanol, ethanolamine, ethylenediamine,
N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesium
hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium
hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide,
triethanolamine, tromethamine and zinc hydroxide.
[0138] Embodiments of the present invention include prodrugs of
compounds of Formula (I), including Formulas (Ia), (Ib), and (Ic).
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 treating or preventing
embodiments of the present invention, the term "administering"
encompasses the treatment or prevention of the various diseases,
conditions, syndromes and disorders described with the compound
specifically disclosed or with a compound that may not be
specifically disclosed, but which converts to the specified
compound in vivo after administration to a 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.
[0139] Where the compounds according to embodiments of 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. The skilled artisan will understand that the term
compound as used herein, is meant to include solvated compounds of
Formula (I), including Formulas (Ia), (Ib), and (Ic).
[0140] Where the processes for the preparation of the compounds
according to certain embodiments of 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.
[0141] One embodiment of the present invention is directed to a
composition, including a pharmaceutical composition, comprising,
consisting of, and/or consisting essentially of the (+)-enantiomer
of a compound of Formula (I) wherein said composition is
substantially free from the (-)-isomer of said compound. In the
present context, substantially free means less than about 25%,
preferably less than about 10%, more preferably less than about 5%,
even more preferably less than about 2% and even more preferably
less than about 1% of the (-)-isomer calculated as
% ( + ) - enantiomer = ( mass ( + ) - enantiomer ) ( mass ( + ) -
enantiomer ) + ( mass ( - ) - enantiomer ) .times. 100.
##EQU00001##
[0142] Another embodiment of the present invention is a
composition, including a pharmaceutical composition, comprising,
consisting of, and consisting essentially of the (-)-enantiomer of
a compound of Formula (I) wherein said composition is substantially
free from the (+)-isomer of said compound. In the present context,
substantially free from means less than about 25%, preferably less
than about 10%, more preferably less than about 5%, even more
preferably less than about 2% and even more preferably less than
about 1% of the (+)-isomer calculated as
% ( - ) - enantiomner = ( mass ( - ) - enantiomer ) ( mass ( + ) -
enantiomer ) + ( mass ( - ) - enantiomer ) .times. 100.
##EQU00002##
[0143] During any of the processes for preparation of the compounds
of the various embodiments 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, Second Edition, J. F. W.
McOmie, Plenum Press, 1973; T. W. Greene & P. G. M. Wuts,
Protective Groups in Organic Synthesis, John Wiley & Sons,
1991; and T. W. Greene & P. G. M. Wuts, Protective Groups in
Organic Synthesis, Third Edition, John Wiley & Sons, 1999. The
protecting groups may be removed at a convenient subsequent stage
using methods known from the art.
[0144] Even though the compounds of embodiments 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
pharmaceutically acceptable carrier, a pharmaceutically acceptable
excipient and/or a pharmaceutically acceptable diluent selected
with regard to the intended route of administration and standard
pharmaceutical or veterinary practice. Thus, particular embodiments
of the present invention are directed to pharmaceutical and
veterinary compositions comprising compounds of Formula (I) and at
least one pharmaceutically acceptable carrier, pharmaceutically
acceptable excipient, and/or pharmaceutically acceptable
diluent.
[0145] By way of example, in the pharmaceutical compositions of
embodiments of the present invention, the compounds of Formula (I),
including Formulas (Ia), (Ib), and (Ic), may be admixed with any
suitable binder(s), lubricant(s), suspending agent(s), coating
agent(s), solubilizing agent(s), and combinations thereof.
[0146] Solid oral dosage forms, such as tablets or capsules,
containing the compounds of the present invention may be
administered in at least one dosage form at a time, as appropriate.
It is also possible to administer the compounds in sustained
release formulations.
[0147] Additional oral forms in which the present inventive
compounds may be administered include elixirs, solutions, syrups,
and suspensions; each optionally containing flavoring agents and
coloring agents.
[0148] Alternatively, compounds of Formula (I), including Formulas
(Ia), (Ib), and (Ic), can be administered by inhalation
(intratracheal or intranasal) 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. For example, they can
be incorporated into a cream comprising, consisting of, and/or
consisting essentially of an aqueous emulsion of polyethylene
glycols or liquid paraffin. They can also be incorporated, at a
concentration of between about 1% and about 10% by weight of the
cream, into an ointment comprising, consisting of, and/or
consisting essentially of a white wax or white soft paraffin base
together with any stabilizers and preservatives as may be required.
An alternative means of administration includes transdermal
administration by using a skin or transdermal patch.
[0149] The pharmaceutical compositions of the present invention (as
well as the compounds of the present invention alone) can also be
injected parenterally, for example intracavernosally,
intravenously, intramuscularly, subcutaneously, intradermally or
intrathecally. In this case, the compositions will also include at
least one of a suitable carrier, a suitable excipient, and a
suitable diluent.
[0150] For parenteral administration, the pharmaceutical
compositions of the present invention are best used in the form of
a sterile aqueous solution that may contain other substances, for
example, enough salts and monosaccharides to make the solution
isotonic with blood.
[0151] For buccal or sublingual administration, the pharmaceutical
compositions of the present invention may be administered in the
form of tablets or lozenges, which can be formulated in a
conventional manner.
[0152] By way of further example, pharmaceutical compositions
containing at least one of the compounds of Formula (I), including
Formulas (Ia), (Ib), and (Ic), as the active ingredient can be
prepared by mixing the compound(s) with a pharmaceutically
acceptable carrier, a pharmaceutically acceptable diluent, and/or a
pharmaceutically acceptable excipient according to conventional
pharmaceutical compounding techniques. The carrier, excipient, and
diluent may take a wide variety of forms depending upon the desired
route of administration (e.g., oral, parenteral, etc.). Thus for
liquid oral preparations, such as suspensions, syrups, elixirs and
solutions, suitable carriers, excipients and diluents 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, excipients and diluents include starches, sugars,
diluents, granulating agents, lubricants, binders, disintegrating
agents and the like. Solid oral preparations also may be optionally
coated with substances, such as, sugars, or be enterically-coated
so as to modulate the major site of absorption and disintegration.
For parenteral administration, the carrier, excipient and diluent
will usually include sterile water, and other ingredients may be
added to increase solubility and preservation of the composition.
Injectable suspensions or solutions may also be prepared utilizing
aqueous carriers along with appropriate additives, such as
solubilizers and preservatives.
[0153] A therapeutically effective amount of a compound of Formula
(I), including Formulas (Ia), (Ib), and (Ic), or a pharmaceutical
composition thereof includes a dose range from about 0.1 mg to
about 3000 mg, or any particular amount or range therein, in
particular from about 1 mg to about 1000 mg, or any particular
amount or range therein; or, more particularly, from about 10 mg to
about 500 mg, or any particular amount or range therein, of active
ingredient in a regimen of about 1 to about 4 times per day for an
average (70 kg) human; although, it is apparent to one skilled in
the art that the therapeutically effective amount for a compound of
Formula (I), including Formulas (Ia), (Ib), and (Ic), will vary as
will the diseases, syndromes, conditions, and disorders being
treated.
[0154] For oral administration, a pharmaceutical composition is
preferably provided in the form of tablets containing about 0.01,
about 10, about 50, about 100, about 150, about 200, about 250, and
about 500 milligrams of a compound of Formula (I), including
Formulas (Ia), (Ib), and (Ic).
[0155] Advantageously, a compound of Formula (I), including
Formulas (Ia), (Ib), and (Ic), may be administered in a single
daily dose, or the total daily dosage may be administered in
divided doses of two, three and four times daily.
[0156] Optimal dosages of a compound of Formula (I), including
Formulas (Ia), (Ib), and (Ic), 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, syndrome, condition or disorder. In
addition, factors associated with the particular subject being
treated, including subject gender, age, weight, diet and time of
administration, will result in the need to adjust the dose to
achieve an appropriate therapeutic level and desired therapeutic
effect. The above dosages are thus exemplary of the average case.
There can be, of course, individual instances wherein higher or
lower dosage ranges are merited, and such are within the scope of
this invention.
[0157] Compounds of Formula (I), including Formulas (Ia), (Ib), and
(Ic), 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 a compound of
Formula (I), including Formulas (Ia), (Ib), and (Ic), is required
for a subject in need thereof.
[0158] As MGL inhibitors, the compounds of Formula (I), including
Formulas (Ia), (Ib), and (Ic), are useful in methods for treating
and preventing a disease, a syndrome, a condition or a disorder in
a subject, including an animal, a mammal and a human in which the
disease, the syndrome, the condition or the disorder is affected by
the modulation of the MGL enzyme. Such methods comprise, consist of
and/or consist essentially of administering to a subject, including
an animal, a mammal, and a human in need of such treatment or
prevention a therapeutically effective amount of a compound, salt
or solvate of Formula (I), including Formulas (Ia), (Ib), and (Ic).
In particular, the compounds of Formula (I), including Formulas
(Ia), (Ib), and (Ic), are useful for preventing or treating pain,
or diseases, syndromes, conditions, or disorders causing such pain,
or for treating inflammation or CNS disorders.
[0159] Examples of inflammatory pain include pain due to a disease,
condition, syndrome, disorder, or a pain state, including
inflammatory bowel disease, visceral pain, migraine, post operative
pain, osteoarthritis, rheumatoid arthritis, back pain, lower back
pain, joint pain, abdominal pain, chest pain, labor pain,
musculoskeletal diseases, skin diseases, toothache, pyresis, burn,
sunburn, snake bite, venomous snake bite, spider bite, insect
sting, neurogenic bladder, interstitial cystitis, urinary tract
infection, rhinitis, contact dermatitis/hypersensitivity, itch,
eczema, pharyngitis, mucositis, enteritis, irritable bowel
syndrome, cholecystitis, pancreatitis, postmastectomy pain
syndrome, menstrual pain, endometriosis pain, pain due to physical
trauma, headache, sinus headache, tension headache, or
arachnoiditis.
[0160] Examples of CNS disorders include anxieties, such as social
anxiety, post-traumatic stress disorder, phobias, social phobia,
special phobias, panic disorder, obsessive-compulsive disorder,
acute stress disorder, separation anxiety disorder, and generalized
anxiety disorder, as well as depression, such as major depression,
bipolar disorder, seasonal affective disorder, post natal
depression, manic depression, and bipolar depression.
General Synthetic Methods
[0161] Representative compounds of the present invention can be
synthesized in accordance with the general synthetic methods
described below and illustrated in the schemes and examples that
follow. Since the schemes are an illustration, the invention should
not be construed as being limited by the chemical reactions and
conditions described in the schemes. The various starting materials
used in the schemes and examples are commercially available or may
be prepared by methods well within the skill of persons versed in
the art. The variables are as defined herein.
[0162] Abbreviations used in the instant specification,
particularly the schemes and examples, are as follows: [0163] AcCl
acetyl chloride [0164] AcOH glacial acetic acid [0165] aq. aqueous
[0166] Bn or Bzl benzyl [0167] Boc tert-butyloxycarbonyl conc.
concentrated [0168] DCC N,N'-dicyclohcxyl-carbodiimide [0169] DCE
1,2-dichloroethane [0170] DCM dichloromethane [0171] DIPEA
diisopropyl-ethyl amine [0172] DMAP 4-dimethylaminopyridine [0173]
DMF N,N-dimethylformamide [0174] DMSO dimethylsulfoxide [0175] DPPA
diphenylphosphoryl azide [0176] EDC
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride [0177]
ESI electrospray ionization [0178] EtOAc ethyl acetate [0179] EtOH
ethanol [0180] h hour(s) [0181] HATU
O-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate [0182] HBTU
O-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate [0183] HEK human embryonic kidney [0184] HEPES
(4-(2-hydroxyethyl)-1-piperazineethane sulfonic acid [0185] HPLC
high performance liquid chromatography [0186] HOBt
N-hydroxybenzotriazole [0187] mCPBA meta-chloroperoxybenzoic acid
[0188] MeCN acetonitrile [0189] MeOH methanol [0190] MeOTf methyl
triflate [0191] MHz megahertz [0192] min minutes [0193] MS mass
spectrometry [0194] NMR nuclear magnetic resonance [0195] PIPES
piperazine-N,N'-bis(2-ethanesulfonic acid) [0196] PyBrOP
bromo-tris-pyrrolidinophosphonium hexafluorophosphate [0197] RP
reverse-phase [0198] Rt retention time [0199] TEA or Et.sub.3N
triethylamine [0200] TFA trifluoroacetic acid [0201] THF
tetrahydrofuran [0202] TLC thin layer chromatography [0203] TMS
tetramethylsilane
[0204] Scheme A illustrates a route for the synthesis of compounds
of Formula (Ia) wherein Y and Z are as defined herein and R.sub.1
is hydrogen.
##STR00020##
[0205] A compound of formula A1 (wherein P is a conventional amino
protecting group such as Boc, Fmoc, Cbz, and the like) is either
commercially available or may be prepared by known methods
described in the scientific literature. A compound of formula A1
may be treated with a carboxylic acid of formula A2 (wherein X is
hydroxy) in the presence of an appropriate coupling agent such as
HATU, DCC, EDC, HBTU, PyBrOP, and the like; and optionally in the
presence of a base such as DIPEA, to afford a compound of formula
A3. Similarly, an acid chloride of formula A2 (wherein X is chloro)
may be used to effect the acylation of a compound of formula A1. In
such case a non-nucleophilic base such as pyridine may be added to
afford a compound of Formula A3. Conventional amino deprotection of
a compound of formula A3 affords an amine of formula A4 which may
undergo a reductive alkylation with a compound of formula A5
(wherein P is a conventional amino protecting group such as Boc,
Fmoc, Cbz, and the like) in the presence of a hydride source such
as sodium triacetoxyborohydride to afford a compound of formula A6.
Removal of amino protecting group P by conventional methods affords
an amine of formula A7, which may be treated with a Z-substituted
carboxylic acid of formula A8 (wherein X is hydroxy) in the
presence of an appropriate coupling agent such as HATU, DCC, EDC,
HBTU, PyBrOP, and the like; and optionally in the presence of a
base such as DIPEA, to afford a compound of Formula (Ia).
Similarly, an acid chloride of formula A8 (wherein X is chloro) may
be used to effect the acylation of a compound of formula A7. In
such case a non-nucleophilic base such as pyridine may be added to
afford a compound of Formula (Ia).
[0206] Scheme B illustrates a route for the synthesis of compounds
of Formula (Ia) wherein Y and Z are as defined herein and R.sub.1
is C.sub.1-4alkyl.
##STR00021##
The compound of formula A5 may undergo a reductive alkylation with
a commercially available R.sub.1-substituted benzyl amine (B1) in
the presence of a hydride source, such as, sodium
triacetoxyborohydride, and in an aprotic solvent, such as,
dichloromethane, dichloroethane, and the like, to afford a compound
of formula B2. Conventional removal of amino protecting group P
followed by a reductive alkylation with a compound of formula A5,
as previously described in Scheme A, affords a compound of formula
B4. Removal of amino protecting group P affords the secondary amine
of formula B5, which may then participate in a peptide coupling
reaction with a compound of formula A8 as described in Scheme A to
afford a compound of formula B6. The benzyl protecting group may be
removed with a palladium catalyst, in the presence of formic acid
and in an alcoholic solvent, such as, methanol or ethanol, to
afford an amine of formula B7. Coupling with a compound of formula
A2 using the conditions previously described in Scheme A affords
the final compound of Formula (Ia).
[0207] Scheme C illustrates a route for the synthesis of compounds
of Formula (Ib) wherein m and Z are as defined herein.
##STR00022##
The compound of formula A1 may be treated with an aldehyde of
formula C1 in the presence of a hydride source, such as, sodium
triacetoxyborohydride, and in an aprotic solvent, such as,
dichloromethane, dichloroethane, and the like, to afford a compound
of formula C2. Removal of amino protecting group P using convention
methods affords an amine of formula C3. Reductive alkylation with a
compound of formula A5, as described in previous schemes, affords a
compound of formula C4. Amino deprotection followed by coupling
with a compound of formula A8 under peptide coupling conditions
affords a desired compound of Formula (Ib).
[0208] Scheme D illustrates a route for the synthesis of compounds
of Formula (Ic) wherein Z is as defined herein.
##STR00023##
A compound of formula D1 is either commercially available or may be
prepared by known methods described in the scientific literature.
The compound of formula D1 may be converted to a compound of
formula D2 by the action of thionyl chloride and methanol to give
the methyl ester, followed by N-bromosuccinimide in the presence of
benzoylperoxide in carbon tetrachloride to give the final methyl
bromide. Nucleophilic displacement of the bromide of formula D2
with an amine of formula A1, in the presence of an inorganic base,
such as, potassium carbonate, affords a compound of formula D3.
Conventional saponification using reagents, such as, sodium
hydroxide in ethanol affords the corresponding carboxylic acid of
formula D4. Treatment of a compound of formula D4 with EDCI, in the
presence of a coupling additive, such as, HOBt, and in the presence
of a hindered organic base, such as, DMAP, affords the cyclized
product of formula D5. Conventional amino deprotection of a
compound of formula D5 followed by reductive alkylation with a
compound of formula A5 affords a compound of formula D7. Removal of
the amino protecting group P followed by coupling with the compound
of formula A8 as previously described affords a compound of Formula
(Ic) of the present invention.
Example 1
##STR00024##
[0210] A. tert-Butyl 3-benzamidoazetidine-1-carboxylate, lc. To a
solution of 1-Boc-3-aminoazetidine 1a (1.2 g, 6.98 mmol) and
Et.sub.3N (2.4 mL, 17.3 mmol) in CH.sub.2Cl.sub.2 (70 mL) at
0.degree. C. was added benzoyl chloride 1b (0.89 mL, 7.68 mmol).
The reaction was kept at 0.degree. C. for 3 h, quenched with aq.
NaHCO.sub.3, and the resulting mixture was extracted with
CH.sub.2Cl.sub.2. The organic solution was dried over
Na.sub.2SO.sub.4 and concentrated. Purification by flash column
chromatography (silica gel, 40% EtOAc/heptane) gave compound 1c
(1.9 g).
[0211] B. tert-Butyl 3-benzamido-[1,3'-biazetidine]-1'-carboxylate,
1e. To a solution of 1c (1.45 g, 5.25 mmol) in CH.sub.2Cl.sub.2 (20
mL) at room temperature was added CF.sub.3CO.sub.2H (5 mL). The
reaction was stirred at room temperature for 1.5 h. The reaction
was concentrated and the resulting residue was dissolved in a mixed
solution of 1,2-dichloroethane (10 mL) and acetic acid (0.5 mL). To
the resulting solution at room temperature was added
1-Boc-azetidin-3-one 1d (0.99 g, 5.79 mmol), followed by
Na(OAc).sub.3BH (1.23 g, 5.80 mmol). The reaction mixture was
stirred at room temperature for 20 h. Additional
1-Boc-azetidin-3-one 1d (0.50 g, 2.92 mmol) and Na(OAc).sub.3BH
(0.62 g, 2.92 mmol) was added. The reaction was stirred for another
6 h before it was quenched by the addition of aq. NaHCO.sub.3. The
resulting mixture was extracted with CH.sub.2Cl.sub.2. The organic
solution was dried over Na.sub.2SO.sub.4 and concentrated.
Purification by flash column chromatography (silica gel, 4%
MeOH/CH.sub.2Cl.sub.2) gave compound 1e (0.93 g).
[0212] C.
N-[1'-(Biphenyl-4-ylcarbonyl)-1,3'-biazetidin-3-yl]benzamide, Cpd
39. A solution of compound 1e (65 mg, 0.20 mmol) in
CH.sub.2Cl.sub.2 (2 mL) and CF.sub.3CO.sub.2H (0.5 mL) was stirred
at room temperature for 2 h. The reaction mixture was concentrated
and the resulting residue was dissolved in CH.sub.2Cl.sub.2 (3 mL).
To this solution was added 1N HCl in ether (1 mL, 1 mmol), and the
resulting mixture was concentrated to give compound 1f. To a
mixture of compound 1f (0.20 mmol), 4-phenylbenzoic acid (59 mg,
0.30 mmol), and Et.sub.3N (0.17 mL, 1.22 mmol) in CH.sub.2Cl.sub.2
(3 mL) was added HATU (114 mg, 0.30 mmol). The reaction was stirred
at room temperature for 20 h. The mixture was diluted with
CH.sub.2Cl.sub.2, washed with aq. NaHCO.sub.3, dried over
Na.sub.2SO.sub.4 and concentrated. Purification by flash column
chromatography (silica gel, 4% MeOH/CH.sub.2Cl.sub.2) gave compound
39 (40 mg). MS 412 (M+H.sup.+).
[0213] Following the procedure described above for Example 1 and
substituting the appropriate reagents, starting materials and
purification methods known to those skilled in the art, the
following compounds of the present invention were prepared:
TABLE-US-00004 Cpd Name and data 1
N-[1'-({1-[4-(Trifluoromethyl)phenyl]-1H-indol-5-
yl}carbonyl)-1,3'-biazetidin-3-yl]-1,3-thiazole-2- carboxamide.
.sup.1H NMR (CHLOROFORM-d, 400 MHz): .delta. = 8.0 (s, 1 H),
7.50-7.90 (m, 8 H), 7.40 (s, 1H), 6.80 (s, 1H), 4.75 (m, 1 H),
4.00-4.40 (m, 4 H), 3.75 (m, 2 H), 3.55 (m, 1 H), 3.20 ppm (m, 2
H). MS 526 (M + H.sup.+). 3
N-(1'-{[1-(Phenylsulfonyl)-1H-indol-5-yl]carbonyl}-
1,3'-biazetidin-3-yl)-1,3-thiazole-2-carboxamide. MS 522 (M +
H.sup.+). 4 N-{1'-[(2-Phenyl-1,3-benzothiazol-6-yl)carbonyl]-1,3'-
biazetidin-3-yl}-1,3-thiazole-2-carboxamide MS 476 (M + H.sup.+). 9
N-[1'-({4-[5-(Trifluoromethyl)thiophen-2-
yl]phenyl}carbonyl)-1,3'-biazetidin-3-yl]-1,3-thiazole-
2-carboxamide. MS 493 (M + H.sup.+). 10
N-{1'-[(4-Benzylphenyl)carbonyl]-1,3'-biazetidin-3-
yl}-1,3-thiazole-2-carboxamide. MS 433 (M + H.sup.+). 11
N-(1'-{[1-(4-Fluorophenyl)-1H-indol-5-yl]carbonyl}-
1,3'-biazetidin-3-yl)-1,3-thiazole-4-carboxamide. MS 476 (M +
H.sup.+). 13 N-{1'-[(1-Phenyl-1H-indol-5-yl)carbonyl]-1,3'-
biazetidin-3-yl}-1,3-thiazole-2-carboxamide. MS 458 (M + H.sup.+).
15 N-{1'-[(5-Chloro-3-methyl-1-benzothiophen-2-
yl)carbonyl]-1,3'-biazetidin-3-yl}-1,3-thiazole-2- carboxamide. MS
447 (M + H.sup.+). 16 N-[1'-({4-[4-
(Trifluoromethyl)benzyl]phenyl}carbonyl)-1,3'-
biazetidin-3-yl]-1,3-thiazole-2-carboxamide. MS 501 (M + H.sup.+).
17 N-{1'-[(2-Phenyl-1,3-benzoxazol-6-yl)carbonyl]-1,3'-
biazetidin-3-yl}-1,3-thiazole-2-carboxamide .sup.1H NMR
(CHLOROFORM-d, 400 MHz): .delta. = 8.27 (m, 2 H), 7.52-7.92 (m, 8
H), 4.78 (m, 1 H), 4.20-4.40 (m, 2 H), 4.15 (m, 1 H), 4.04 (m, 1
H), 3.75 (m, 2 H), 3.55 (m, 1 H), 2.23 ppm (m, 2 H). MS 460 (M +
H.sup.+). 19 N-{1'-[(5-Bromonaphthalen-2-yl)carbonyl]-1,3'-
biazetidin-3-yl}-1,3-thiazole-2-carboxamide. MS 472 (M + H.sup.+).
20 N-[1'-({4-[3- (Trifluoromethyl)benzyl]phenyl}carbonyl)-1,3'-
biazetidin-3-yl]-1,3-thiazole-2-carboxamide. MS 501 (M + H.sup.+).
22 N-{1'-[(2-Phenyl-1,3-benzothiazol-6-yl)carbonyl]-1,3'-
biazetidin-3-yl}-1,3-thiazole-4-carboxamide. MS 476 (M + H.sup.+).
23 N-{1'-[(6-Bromo-1-benzothiophen-2-yl)carbonyl]-1,3'-
biazetidin-3-yl}-1,3-thiazole-2-carboxamide. MS 478 (M + H.sup.+).
24 N-{1'-[(5-Bromonaphthalen-2-yl)carbonyl]-1,3'-
biazetidin-3-yl}benzamide. MS 465 (M + H.sup.+). 26 N-[1'-({4-[4-
(Trifluoromethyl)benzyl]phenyl}carbonyl)-1,3'-
biazetidin-3-yl]benzamide. MS 494 (M + H.sup.+). 27
N-{1'-[(1-Phenyl-1H-indol-6-yl)carbonyl]-1,3'-
biazetidin-3-yl}-1,3-thiazole-2-carboxamide. MS 458 (M + H.sup.+).
28 N-[1'-({2-[3-(Trifluoromethyl)phenyl]-1,3-benzoxazol-
6-yl}carbonyl)-1,3'-biazetidin-3-yl]-1,3-thiazole-2- carboxamide.
MS 528 (M + H.sup.+). 29
N-[1'-(Biphenyl-4-ylcarbonyl)-1,3'-biazetidin-3-yl]-1,3-
thiazole-2-carboxamide. MS 419 (M + H.sup.+). 30
N-[1'-({2-[4-(Trifluoromethyl)phenyl]-1,3-benzoxazol-
6-yl}carbonyl)-1,3'-biazetidin-3-yl]-1,3-thiazole-2- carboxamide.
MS 528 (M + H.sup.+). 31
N-{1'-[(4-Benzylphenyl)carbonyl]-1,3'-biazetidin-3- yl}benzamide.
MS 426 (M + H.sup.+). 32
N-{1'-[(4-Phenoxyphenyl)carbonyl]-1,3'-biazetidin-3-
yl}-1,3-thiazole-2-carboxamide. MS 435 (M + H.sup.+). 33
N-(1'-{[2-(4-Chlorophenyl)-1,3-benzoxazol-6-
yl]carbonyl}-1,3'-biazetidin-3-yl)-1,3-thiazole-2- carboxamide. MS
494 (M + H.sup.+). 35
N-{1'-[(2-Phenyl-1,3-benzoxazol-5-yl)carbonyl]-1,3'-
biazetidin-3-yl}-1,3-thiazole-2-carboxamide. MS 460 (M + H.sup.+).
36 N-{1'-[(5-Chloro-3-methyl-1-benzothiophen-2-
yl)carbonyl]-1,3'-biazetidin-3-yl}benzamide MS 440 (M + H.sup.+).
38 N-(1'-{[4-(Phenylcarbonyl)phenyl]carbonyl}-1,3'-
biazetidin-3-yl)-1,3-thiazole-2-carboxamide. MS 447 (M + H.sup.+).
40 N-{1'-[(6-Bromonaphthalen-2-yl)carbonyl]-1,3'-
biazetidin-3-yl}-1,3-thiazole-2-carboxamide. MS 472 (M + H.sup.+).
41 N-{1'-[(2-Phenyl-1,3-benzoxazol-6-yl)carbonyl]-1,3'-
biazetidin-3-yl}benzamide. MS 453 (M + H.sup.+). 42
N-{1'-[(6-Bromonaphthalen-2-yl)carbonyl]-1,3'-
biazetidin-3-yl}benzamide. MS 465 (M + H.sup.+). 43
N-{1'-[(4-Bromophenyl)carbonyl]-1,3'-biazetidin-3-
yl}-1,3-thiazole-2-carboxamide. MS 421 (M + H.sup.+). 44
N-(1'-{[5-(Trifluoromethyl)-1-benzothiophen-2-
yl]carbonyl}-1,3'-biazetidin-3-yl)benzamide. MS 460 (M + H.sup.+).
45 N-{1'-[(4-Phenoxyphenyl)carbonyl]-1,3'-biazetidin-3-
yl}benzamide. MS 428 (M + H.sup.+). 46
N-{1'-[(2-Bromo-1,3-benzothiazol-6-yl)carbonyl]-1,3'-
biazetidin-3-yl}-1,3-thiazole-4-carboxamide. MS 478 (M + H.sup.+).
52 N-{1'-[(1-Phenyl-1H-indazol-5-yl)carbonyl]-1,3'-
biazetidin-3-yl}-1,3-thiazole-2-carboxamide. MS 459 (M + H.sup.+).
54 N-(1'-{[1-(3,4-Difluorophenyl)-1H-indol-5-
yl]carbonyl}-1,3'-biazetidin-3-yl)-1,3-thiazole-4- carboxamide. MS
494 (M + H.sup.+). 55 N-(1'-{[1-(2,4-Difluorophenyl)-1H-indol-5-
yl]carbonyl}-1,3'-biazetidin-3-yl)-1,3-thiazole-2- carboxamide. MS
494 (M + H.sup.+). 57 N-(1'-{[1-(3,4-Difluorophenyl)-1H-indol-5-
yl]carbonyl}-1,3'-biazetidin-3-yl)-1,3-thiazole-2- carboxamide. MS
494 (M + H.sup.+). 60 N-(1'-{[1-(2,4-Difluorophenyl)-1H-indol-5-
yl]carbonyl}-1,3'-biazetidin-3-yl)-1,3-thiazole-4- carboxamide. MS
494 (M + H.sup.+). 61
N-(1'-{[1-(4-Fluorophenyl)-1H-indol-5-yl]carbonyl}-
1,3'-biazetidin-3-yl)-1,3-thiazole-2-carboxamide. MS 476 (M +
H.sup.+). 62 N-(1'-{[1-(4-Fluorophenyl)-3-methyl-1H-indol-5-
yl]carbonyl}-1,3'-biazetidin-3-yl)-1,3-thiazole-2- carboxamide. MS
490 (M + H.sup.+).
Example 2
##STR00025##
[0215] A. tert-butyl
3-(1-oxoisoindolin-2-yl)azetidine-1-carboxylate, 2b. To a solution
of 1-Boc-3-aminoazetidine 1a (1.0 g, 5.8 mmol) and methyl
2-formylbenzoate 2a (0.95 g, 5.8 mmol) in 1,2-dichloroethane (30
mL) and acetic acid (1.5 mL) was added Na(OAc).sub.3BH (1.29 g,
6.08 mmol) at room temperature. The reaction was stirred for 5.5 h.
It was quenched with aq. NaHCO.sub.3, and the resulting mixture was
extracted with CH.sub.2Cl.sub.2. The organic solution was dried
over Na.sub.2SO.sub.4 and concentrated. Purification by flash
column chromatography (silica gel, 40% EtOAc/heptane) gave compound
2b (1.46 g).
[0216] B.
2-[1'-(Biphenyl-4-ylcarbonyl)-1,3'-biazetidin-3-yl]-2,3-dihydro--
1H-isoindol-1-one, Cpd 92. Compound 92 was prepared from
intermediate 2b following the procedures described in Steps B and C
of Example 1. MS 424 (M+H.sup.+).
[0217] Following the procedure described above for Example 2 and
substituting the appropriate reagents, starting materials and
purification methods known to those skilled in the art, the
following compounds of the present invention were prepared:
TABLE-US-00005 Cpd Name and data 70
2-[1'-({1-[4-(Trifluoromethyl)phenyl]-1H-indol-5-
yl}carbonyl)-1,3'-biazetidin-3-yl]-2,3-dihydro-1H- isoindol-1-one.
.sup.1H NMR (CHLOROFORM-d, 400 MHz): .delta. = 8.00 (s, 1 H), 7.80
(m, 3H), 7.40-7.70 (m, 8 H), 6.80 (m, 1H), 5.05 (m, 1 H), 4.60 (s,
2H), 4.00-4.40 (m, 4 H), 3.70 (m, 2 H), 3.60 (m, 1 H), 3.40 ppm (m,
2 H). MS 531 (M + H.sup.+). 71
2-(1'-{[1-(Phenylsulfonyl)-1H-indol-5-yl]carbonyl}-
1,3'-biazetidin-3-yl)-2,3-dihydro-1H-isoindol-1-one. MS 527 (M +
H.sup.+). 75 2-{1'-[(6-Bromo-3-chloro-1-benzothiophen-2-
yl)carbonyl]-1,3'-biazetidin-3-yl}-2,3-dihydro-1H- isoindol-1-one.
MS 531 (M + H.sup.+). 76 2-[1'-({4-[5-(Trifluoromethyl)thiophen-2-
yl]phenyl}carbonyl)-1,3'-biazetidin-3-yl]-2,3-dihydro-
1H-isoindol-1-one. .sup.1H NMR (CHLOROFORM-d, 400 MHz): .delta. =
7.30-7.80 (m, 10 H), 5.05 (m, 1 H), 4.60 (s, 2 H), 4.00-4.40 (m, 4
H), 3.70 (m, 2 H), 3.60 (m, 1 H), 3.45 ppm (m, 2 H). MS 498 (M +
H.sup.+). 77 2-{1'-[(2-Phenyl-1,3-benzoxazol-5-yl)carbonyl]-1,3'-
biazetidin-3-yl}-2,3-dihydro-1H-isoindol-1-one. .sup.1H NMR
(CHLOROFORM-d, 400 MHz): .delta. = 8.26 (dd, J = 7.4, 1.6 Hz, 2 H),
8.02 (d, J = 1.2 Hz, 2 H), 7.84 (d, J = 7.4 Hz, 2 H), 7.77 (m, 1
H), 7.46-7.64 (m, 7 H), 5.09 (m, 1 H), 4.62 (s, 2 H), 4.00-4.40 (m,
4 H), 3.69 (m, 2 H), 3.61 (m, 1 H), 3.49 ppm (br. s., 2 H). MS 465
(M + H.sup.+). 78
2-[1'-({2-[3-(Trifluoromethyl)phenyl]-1,3-benzoxazol-
6-yl}carbonyl)-1,3'-biazetidin-3-yl]-2,3-dihydro-1H-
isoindol-1-one. MS 533 (M + H.sup.+). 83
2-{1'-[(5-Bromonaphthalen-2-yl)carbonyl]-1,3'-
biazetidin-3-yl}-2,3-dihydro-1H-isoindol-1-one. MS 477 (M +
H.sup.+). 84 2-{1'-[(2-Phenyl-1,3-benzoxazol-6-yl)carbonyl]-1,3'-
biazetidin-3-yl}-2,3-dihydro-1H-isoindol-1-one. MS 465 (M +
H.sup.+). 85 2-{1'-[(1-Phenyl-1H-indol-5-yl)carbonyl]-1,3'-
biazetidin-3-yl}-2,3-dihydro-1H-isoindol-1-one. MS 463 (M +
H.sup.+). 86 2[1'-({4-[3-
(Trifluoromethyl)benzyl]phenyl}carbonyl)-1,3'-
biazetidin-3-yl]-2,3-dihydro-1H-isoindol-1-one. MS 506 (M +
H.sup.+). 88 2-(1'-{[2-(4-Chlorophenyl)-1,3-benzoxazol-6-
yl]carbonyl}-1,3'-biazetidin-3-yl)-2,3-dihydro-1H- isoindol-1-one.
MS 499 (M + H.sup.+). 89
2-[1'-({1-[2-(Trifluoromethyl)phenyl]-1H-indol-5-
yl}carbonyl)-1,3'-biazetidin-3-yl]-2,3-dihydro-1H- isoindol-1-one.
MS 531 (M + H.sup.+). 90
2-{1'-[(6-Bromonaphthalen-2-yl)carbonyl]-1,3'-
biazetidin-3-yl}-2,3-dihydro-1H-isoindol-1-one. MS 477 (M +
H.sup.+). 91 2-{1'-[(4-Piperidin-1-ylphenyl)carbonyl]-1,3'-
biazetidin-3-yl}-2,3-dihydro-1H-isoindol-1-one. MS 431 (M +
H.sup.+). 94
2-{1'-[(4-Benzylphenyl)carbonyl]-1,3'-biazetidin-3-yl}-
2,3-dihydro-1H-isoindol-1-one. MS 438 (M + H.sup.+). 96
2-{1'-[(4-Bromophenyl)carbonyl]-1,3'-biazetidin-3-yl}-
2,3-dihydro-1H-isoindol-1-one. MS 427 (M + H.sup.+). 102
2-(1'-{[1-(4-Fluorophenyl)-1H-indol-5-yl]carbonyl}-
1,3'-biazetidin-3-yl)-2,3-dihydro-1H-isoindol-1-one. MS 481 (M +
H.sup.+).
Example 3
##STR00026## ##STR00027##
[0219] A. Methyl 5-(bromomethyl)thiazole-4-carboxylate, 3b. To a
mixture of 5-methylthiazole-4-carboxylic acid 3a (0.50 g, 3.49
mmol) in MeOH (15 mL) at 0.degree. C. was added SOCl.sub.2 (0.51
mL, 6.99 mmol). The reaction was warmed up to room temperature and
then heated to reflux for 8 h. The reaction mixture was cooled to
room temperature and concentrated. The residue was dissolved in
CH.sub.2Cl.sub.2 and washed with aq. NaHCO.sub.3. The organic
solution was dried over Na.sub.2SO.sub.4 and concentrated. A
portion of the resulting mixture (250 mg, 1.59 mmol) was heated to
reflux in CCl.sub.4 (15 mL) with NBS (311 mg, 1.75 mmol) and
benzoyl peroxide (38.5 mg, 0.159 mmol) for 3 h. The reaction
mixture was concentrated and purification by flash column
chromatography (silica gel, 30% EtOAc/heptane) gave compound 3b
(250 mg).
[0220] B. Methyl
5-(((1-(tert-butoxycarbonyl)azetidin-3-yl)amino)methyl)thiazole-4-carboxy-
late, 3c. A mixture of compound 3b (250 mg, 1.06 mmol),
1-Boc-3-aminoazetidine 1a (310 mg, 1.80 mmol), and K.sub.2CO.sub.3
(248 mg, 1.80 mmol) in THF (12 mL) was heated to reflux for 6 h.
The reaction mixture was cooled to room temperature and diluted
with CH.sub.2Cl.sub.2. The resulting solution was washed with aq.
NaHCO.sub.3, dried over Na.sub.2SO.sub.4, and concentrated.
Purification by flash column chromatography (silica gel, 3%
MeOH/CH.sub.2Cl.sub.2) gave compound 3c (210 mg).
[0221] C. tert-Butyl
3-(4-oxo-4H-pyrrolo[3,4-d]thiazol-5(6H)-ylazetidine-1-carboxylate,
3e. A mixture of compound 3c (320 mg, 0.98 mmol) and LiOH.H.sub.2O
(123 mg, 2.93 mmol) in THF (8 mL) and H.sub.2O (4 mL) was stirred
at room temperature for 20 h. The pH of the reaction mixture was
adjusted to 5 with aq. 10% HCl. Concentration gave the crude
compound 3d. A mixture of compound 3d (0.98 mmol), HOBt (132 mg,
0.98 mmol), Et.sub.3N (0.41 mL, 2.93 mmol), EDCI (318 mg, 1.66
mmol), and DMAP (25 mg, 0.21 mmol) in DMF (4 mL) was heated at
65.degree. C. for 5 h. The reaction mixture was cooled to room
temperature and diluted with CH.sub.2Cl.sub.2. The solution was
washed with H.sub.2O, dried over Na.sub.2SO.sub.4 and concentrated.
Purification by flash column chromatography (silica gel, 3%
MeOH/CH.sub.2Cl.sub.2) gave compound 3e (185 mg).
[0222] D.
5-[1'-({1-[4-(Trifluoromethyl)phenyl]-1H-indol-5-yl}carbonyl)-1,-
3'-biazetidin-3-yl]-5,6-dihydro-4H-pyrrolo[3,4-d][1,3]thiazol-4-one,
Cpd 106. Compound 106 was prepared from intermediate 3e following
the procedures described in Steps B and C of Example 1, except that
1-(4-trifluoromethylphenyl)indole-5-carboxylic acid was used in
place of 4-phenylbenzoic acid. MS 538 (M+H.sup.+).
Example 4
##STR00028##
[0224] A. 6-(Trifluoromethyl)benzo[b]thiophene-2-carbonyl chloride,
4b. To a mixture of
6-(trifluoromethyl)benzo[b]thiophene-2-carboxylic acid 4a (65 mg,
0.26 mmol) in CH.sub.2Cl.sub.2 (2.5 mL) was added (COCl).sub.2
(0.026 mL, 0.30 mmol), followed by DMF (1 drop) at room
temperature. The reaction was kept at room temperature for 20 h.
The resulting solution was concentrated to give compound 4b.
[0225] B.
2-(1'-{[6-(Trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}-1,3'--
biazetidin-3-yl)-2,3-dihydro-1H-isoindol-1-one, Cpd 81. To a
solution of compound 2d (0.24 mmol) and Et.sub.3N (0.08 mL, 0.58
mmol) in CH.sub.2Cl.sub.2 (3 mL) at 0.degree. C. was added a
solution of compound 4b (0.26 mmol) in CH.sub.2Cl.sub.2 (1 mL). The
reaction was stirred at 0.degree. C. for 4 h before it was quenched
with aq. NaHCO.sub.3. The mixture was extracted with
CH.sub.2Cl.sub.2, and the organic solution was dried over
Na.sub.2SO.sub.4 and concentrated. Purification by flash column
chromatography (silica gel, 3% MeOH/CH.sub.2Cl.sub.2) gave compound
81 (57 mg). MS 472 (M+H.sup.+).
[0226] Following the procedure described above for Example 4 and
substituting the appropriate reagents, starting materials and
purification methods known to those skilled in the art, the
following compounds of the present invention were prepared:
TABLE-US-00006 Cpd Name and data 7
N-(1'-{[6-(Trifluoromethyl)-1-benzothiophen-2-
yl]carbonyl}-1,3'-biazetidin-3-yl)-1,3-thiazole-2- carboxamide. MS
467 (M + H.sup.+). 8 N-(1'-{[4-(Trifluoromethyl)-1-benzothiophen-2-
yl]carbonyl}-1,3'-biazetidin-3-yl)-1,3-thiazole-2- carboxamide. MS
467 (M + H.sup.+). 47
N-(1'-{[5-(Trifluoromethyl)-1,3-benzothiazol-2-
yl]carbonyl}-1,3'-biazetidin-3-yl)-1,3-thiazole-2- carboxamide. MS
468 (M + H.sup.+). 49
N-(1'-{[6-(Trifluoromethyl)-1-benzothiophen-2-
yl]carbonyl}-1,3'-biazetidin-3-yl)-1,3-thiazole-4- carboxamide. MS
467 (M + H.sup.+). 50
N-(1'-{[3-Chloro-6-(trifluoromethyl)-1-benzothiophen-
2-yl]carbonyl}-1,3'-biazetidin-3-yl)-1,3-thiazole-2- carboxamide.
MS 501 (M + H.sup.+). 51
N-(1'-{[3-Chloro-6-(trifluoromethyl)-1-benzothiophen-
2-yl]carbonyl}-1,3'-biazetidin-3-yl)-1,3-thiazole-4- carboxamide.
MS 501 (M + H.sup.+). 56
N-(1'-{[3-Methyl-6-(trifluoromethyl)-1-benzothiophen-
2-yl]carbonyl}-1,3'-biazetidin-3-yl)-1,3-thiazole-2- carboxamide.
.sup.1H NMR (CHLOROFORM-d, 400 MHz): .delta. = 8.10 (s, 1 H), 7.88
(m, 2 H), 7.64 (d, J = 8.2 Hz, 2 H), 7.60 (d, J = 2.8 Hz 1 H), 4.76
(m, 1 H), 4.27 (br. s., 2 H), 4.05 (m, 2 H), 3.74 (m, 2 H), 3.54
(m, 1H), 3.21 (m, 2H), 2.66 ppm (s, 3 H). MS 481 (M + H.sup.+). 65
N-{1'-[(6-Bromo-3-methyl-1-benzothiophen-2-
yl)carbonyl]-1,3'-biazetidin-3-yl}-1,3-thiazole-2- carboxamide. MS
492 (M + H.sup.+). 67
N-(1'-{[3-Methyl-6-(trifluoromethyl)-1-benzothiophen-
2-yl]carbonyl}-1,3'-biazetidin-3-yl)-1,3-thiazole-4- carboxamide.
.sup.1H NMR (CHLOROFORM-d, 400 MHz): .delta. = 8.76 (d, J = 1.6 Hz,
1 H), 8.18 (d, J = 2.4 Hz, 1 H), 8.10 (s, 1H), 7.88 (d, J = 8.0 Hz,
1 H), 7.80 (d, J = 8.0 Hz, 1 H), 7.64 (d, J = 8.0 Hz, 1 H), 4.76
(m, 1 H), 4.28 (br. s., 2 H), 4.06 (br. s., 2 H), 3.75 (m, 2 H),
3.57 (m, 1H), 3.24 (m, 2H), 2.65 ppm (s, 3 H). MS 481 (M +
H.sup.+). 73 2-{1'-[(6-Bromo-3-chloro-1-benzothiophen-2-
yl)carbonyl]-1,3'-biazetidin-3-yl}-2,3-dihydro-1H- isoindol-1-one.
MS 516 (M + H.sup.+). 87
2-{1'-[(6-Bromo-1-benzothiophen-2-yl)carbonyl]-1,3'-
biazetidin-3-yl}-2,3-dihydro-1H-isoindol-1-one. MS 483 (M +
H.sup.+). 93 2-{1'-[(5-Bromo-1-benzothiophen-2-yl)carbonyl]-1,3'-
biazetidin-3-yl}-2,3-dihydro-1H-isoindol-1-one. MS 483 (M +
H.sup.+). 99 2-(1'-{[3-Chloro-6-(trifluoromethyl)-1-benzothiophen-
2-yl]carbonyl}-1,3'-biazetidin-3-yl)-2,3-dihydro-1H-
isoindol-1-one. .sup.1H NMR (CHLOROFORM-d, 400 MHz): .delta. = 8.13
(s, 1 H), 8.00 (d, J = 8.4 Hz, 1 H), 7.83 (d, J = 7.6 Hz, 1 H),
7.72 (dd, J = 1.2, 8.4 Hz 1 H), 7.46-7.59 (m, 3 H), 5.08 (m, 1 H),
4.61 (s, 2 H), 4.31 (m, 2 H), 4.11 (m, 2 H), 3.69 (m, 3 H), 3.49
ppm (m, 2 H). MS 506 (M + H.sup.+). 100
2-{1'-[(3-Chloro-6-fluoro-1-benzothiophen-2-
yl)carbonyl]-1,3'-biazetidin-3-yl}-2,3-dihydro-1H- isoindol-1-one.
MS 456 (M + H.sup.+). 101
2-(1'-{[3-Methyl-6-(trifluoromethyl)-1-benzothiophen-
2-yl]carbonyl}-1,3'-biazetidin-3-yl)-2,3-dihydro-1H-
isoindol-1-one. .sup.1H NMR (CHLOROFORM-d, 400 MHz): .delta. = 8.10
(s, 1 H), 7.89 (d, J = 8.0 Hz, 1 H), 7.84 (d, J = 7.8 Hz, 1 H),
7.65 (d, J = 8.0 Hz, 1 H), 7.46-7.59 (m, 3H), 5.08 (m, 1 H), 4.61
(s, 2H), 4.30 (br. s., 2 H), 4.08 (m, 2 H), 3.69 (m, 2 H), 3.60 (m,
1H), 3.48 (m, 2H), 2.66 ppm (s, 3 H). MS 481 (M + H.sup.+). MS 486
(M + H.sup.+). 103
5-(1'-{[3-Methyl-6-(trifluoromethyl)-1-benzothiophen-
2-yl]carbonyl}-1,3'-biazetidin-3-yl)-5,6-dihydro-4H-
pyrrolo[3,4-d][1,3]thiazol-4-one. MS 493 (M + H.sup.+).
Example 5
##STR00029##
[0228]
2-{1'-[(6-Phenylnaphthalen-2-yl)carbonyl]-1,3'-biazetidin-3-yl}-2,3-
-dihydro-1H-isoindol-1-one, Cpd 69. A mixture of compound 90 (40
mg, 0.08 mmol), phenylboronic acid (21 mg, 0.17 mmol),
K.sub.2CO.sub.3 (23 mg, 0.17 mmol), and
Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (4 mg, 0.005 mmol) in EtOH (0.75
mL) and H.sub.2O (0.15 mL) was heated in a microwave reactor at
130.degree. C. for 30 min. The mixture was diluted with
CH.sub.2Cl.sub.2, washed with H.sub.2O, dried over Na.sub.2SO.sub.4
and concentrated. Purification by flash column chromatography
(silica gel, 3% MeOH/CH.sub.2Cl.sub.2) gave compound 69 (34 mg). MS
474 (M+H.sup.+).
[0229] Following the procedure described above for Example 5 and
substituting the appropriate reagents, starting materials and
purification methods known to those skilled in the art, the
following compounds of the present invention were prepared:
TABLE-US-00007 Cpd Name and data 2
N-(1'-{[3'-(Trifluoromethyl)biphenyl-4-yl]carbonyl}-
1,3'-biazetidin-3-yl)-1,3-thiazole-4-carboxamide. .sup.1H NMR
(CHLOROFORM-d, 400 MHz): .delta. = 8.77 (s, 1 H), 8.18 (d, J = 2.4
Hz, 1 H), 7.84 (s, 1 H), 7.57-7.79 (m, 8 H), 4.78 (m, 1 H), 4.33
(m, 1 H), 4.25 (m, 1 H), 4.12 (m, 1 H), 4.04 (m, 1 H), 3.75 (m, 2
H), 3.54 (m, 1 H), 3.20 ppm (m, 2 H). MS 487 (M + H.sup.+). 5
N-(1'-{[3'-(Trifluoromethyl)biphenyl-4-yl]carbonyl}-
1,3'-biazetidin-3-yl)-1,3-thiazole-2-carboxamide. .sup.1H NMR
(CHLOROFORM-d, 400 MHz): .delta. = 7.56-7.87 (m, 10 H), 4.76 (m, 1
H), 4.33 (s, 1 H), 4.25 (m, 1 H), 4.12 (m, 1 H), 4.03 (m, 1 H),
3.74 (m, 2 H), 3.54 (m, 1 H), 3.22 ppm (br. s., 2 H). MS 487 (M +
H.sup.+). 6 N-{1'-[(6-Phenyl-1-benzothiophen-2-yl)carbonyl]-1,3'-
biazetidin-3-yl}-1,3-thiazole-2-carboxamide. MS 475 (M + H.sup.+).
12 N-(1'-{[4'-(Trifluoromethyl)biphenyl-4-yl]carbonyl}-
1,3'-biazetidin-3-yl)-1,3-thiazole-2-carboxamide. MS 487 (M +
H.sup.+). 14 N-(1'-{[4'-(Trifluoromethyl)biphenyl-4-yl]carbonyl}-
1,3'-biazetidin-3-yl)-1,3-thiazole-4-carboxamide. MS 487 (M +
H.sup.+). 18 N-(1'-{[3'-(Methylsulfonyl)biphenyl-4-yl]carbonyl}-
1,3'-biazetidin-3-yl)-1,3-thiazole-2-carboxamide. MS 497 (M +
H.sup.+). 21 N-{1'-[(6-Phenylnaphthalen-2-yl)carbonyl]-1,3'-
biazetidin-3-yl}-1,3-thiazole-2-carboxamide. MS 469 (M + H.sup.+).
25 N-{1'-[(5-Phenylnaphthalen-2-yl)carbonyl]-1,3'-
biazetidin-3-yl}benzamide. MS 462 (M + H.sup.+). 34
N-{1'-[(6-Phenylnaphthalen-2-yl)carbonyl]-1,3'-
biazetidin-3-yl}benzamide. MS 462 (M + H.sup.+). 53
N-{1'-[(5-Phenylnaphthalen-2-yl)carbonyl]-1,3'-
biazetidin-3-yl}-1,3-thiazole-2-carboxamide. MS 469 (M + H.sup.+).
58 N-(1'-{[3-Methyl-3'-(trifluoromethyl)biphenyl-4-
yl]carbonyl}-1,3'-biazetidin-3-yl)-1,3-thiazole-2- carboxamide. MS
501 (M + H.sup.+). 59
N-(1'-{[3-Fluoro-4'-(trifluoromethyl)biphenyl-4-
yl]carbonyl}-1,3'-biazetidin-3-yl)-1,3-thiazole-2- carboxamide. MS
505 (M + H.sup.+). 63
N-(1'-{[3-Methyl-4'-(trifluoromethyl)biphenyl-4-
yl]carbonyl}-1,3'-biazetidin-3-yl)-1,3-thiazole-2- carboxamide. MS
501 (M + H.sup.+). 64
N-(1'-{[3-Fluoro-3'-(trifluoromethyl)biphenyl-4-
yl]carbonyl}-1,3'-biazetidin-3-yl)-1,3-thiazole-2- carboxamide. MS
505 (M + H.sup.+). 66 N-{1'-[(3-Methyl-6-phenyl-1-benzothiophen-2-
yl)carbonyl]-1,3'-biazetidin-3-yl}-1,3-thiazole-2- carboxamide. MS
489 (M + H.sup.+). 68 2-{1'-[(3-Chloro-6-phenyl-1-benzothiophen-2-
yl)carbonyl]-1,3'-biazetidin-3-yl}-2,3-dihydro-1H- isoindol-1-one.
MS 515 (M + H.sup.+). 72
2-[1'-({6-[3-(Methylsulfonyl)phenyl]-1-benzothiophen-
2-yl}carbonyl)-1,3'-biazetidin-3-yl]-2,3-dihydro-1H-
isoindol-1-one. MS 558 (M + H.sup.+). 74
2-{1'-[(3,6-Diphenyl-1-benzothiophen-2-yl)carbonyl]-
1,3'-biazetidin-3-yl}-2,3-dihydro-1H-isoindol-1-one. MS 556 (M +
H.sup.+). 79 2-{1'-[(5-Phenyl-1-benzothiophen-2-yl)carbonyl]-1,3'-
biazetidin-3-yl}-2,3-dihydro-1H-isoindol-1-one. .sup.1H NMR
(CHLOROFORM-d, 400 MHz): .delta. = 8.04 (d, J = 1.6 Hz, 1 H), 7.92
(d, J = 8.4 Hz, 1 H), 7.84 (d, J = 7.6 Hz, 1 H), 7.76 (s, 1 H),
7.36-7.69 (m, 9 H), 5.09 (m, 1 H), 4.63 (s, 2 H), 4.58 (m, 1 H),
4.39 (m, 1 H), 4.29 (m, 1 H), 4.09 (m, 1 H), 3.70 (m, 2 H), 3.66
(m, 1 H), 3.51 ppm (br. s., 2 H). MS 480 (M + H.sup.+). 80
2-(1'-{[3'-(Methylsulfonyl)biphenyl-4-yl]carbonyl}-
1,3'-biazetidin-3-yl)-2,3-dihydro-1H-isoindol-1-one. MS 502 (M +
H.sup.+). 82 2-[1'-({5-[3-(Methylsulfonyl)phenyl]-1-benzothiophen-
2-yl}carbonyl)-1,3'-biazetidin-3-yl]-2,3-dihydro-1H-
isoindol-1-one. MS 558 (M + H.sup.+). 95
2-(1'-{[4-(1-Benzothiophen-2-yl)phenyl]carbonyl}-
1,3'-biazetidin-3-yl)-2,3-dihydro-1H-isoindol-1-one. MS 480 (M +
H.sup.+). 97 2-{1'-[(5-Phenylnaphthalen-2-yl)carbonyl]-1,3'-
biazetidin-3-yl}-2,3-dihydro-1H-isoindol-1-one. MS 474 (M +
H.sup.+). 98 2-{1'-[(6-Phenyl-1-benzothiophen-2-yl)carbonyl]-1,3'-
biazetidin-3-yl}-2,3-dihydro-1H-isoindol-1-one. MS 480 (M +
H.sup.+). 104 5-(1'-{[3-Methyl-3'-(trifluoromethyl)biphenyl-4-
yl]carbonyl}-1,3'-biazetidin-3-yl)-5,6-dihydro-4H-
pyrrolo[3,4-d][1,3]thiazol-4-one. MS 513 (M + H.sup.+). 105
5-(1'-{[3-Methyl-4'-(trifluoromethyl)biphenyl-4-
yl]carbonyl}-1,3'-biazetidin-3-yl)-5,6-dihydro-4H-
pyrrolo[3,4-d][1,3]thiazol-4-one. MS 513 (M + H.sup.+).
Example 6
##STR00030##
[0231] A. tert-Butyl
3-(benzyl(methyl)amino)azetidine-1-carboxylate, 6b. To a solution
of 1-Boc-azetidin-3-one 1d (1.0 g, 5.85 mmol) and
N-methyl-benzylamine 6a (1.02 g, 8.43 mmol) in 1,2-dichloroethane
(12 mL) and acetic acid (1 mL) was added Na(OAc).sub.3BH (1.30 g,
6.13 mmol). The reaction mixture was stirred at room temperature
for 20 h. The reaction was quenched by the addition of aq.
NaHCO.sub.3. The resulting mixture was extracted with
CH.sub.2Cl.sub.2. The organic solution was dried over
Na.sub.2SO.sub.4 and concentrated. Purification by flash column
chromatography (silica gel, 40% EtOAc/heptane) gave compound 6b
(1.40 g).
[0232] B. tert-Butyl
3-(benzyl(methyl)amino)-[1,3'-biazetidine]-1'-carboxylate, 6d.
Intermediate 6d was prepared following the procedure described in
Step B of Example 1.
[0233] C.
(3-(Benzylmethyl)amino)-[1,3'-biazetidin]-1'-yl)(6-(trifluoromet-
hyl)benzo[b]thiophen-2-yl)methanone, 6f. Intermediate 6f was
prepared following the procedure described in Example 4.
[0234] D.
N-Methyl-N-(1'-{[6-(trifluoromethyl)-1-benzothiophen-2-yl]carbon-
yl}-1,3'-biazetidin-3-yl)-1,3-thiazole-2-carboxamide, Cpd 37. A
mixture of compound 6f (53 mg, 0.12 mmol), HCO.sub.2H (0.2 mL), and
Pd/C (50 mg) in EtOH (4 mL) was stirred at room temperature for 24
h. Additional HCO.sub.2H (0.2 mL) and Pd/C (50 mg) was added. The
reaction was stirred for another 24 h. The mixture was filtered and
the solution was concentrated. The residue was dissolved in
CH.sub.2Cl.sub.2 and washed with 1N NaOH, dried over
Na.sub.2SO.sub.4, and concentrated to give compound 6g (34 mg). A
mixture of compound 6g (34 mg, 0.09 mmol), 2-thiazole-carboxylic
acid 6h (24 mg, 0.19 mmol), Et.sub.3N (0.05 mL, 0.36 mmol), and
HATU (70 mg, 0.18 mmol) in CH.sub.2Cl.sub.2 (3 mL) was stirred at
room temperature for 20 h. The reaction mixture was diluted with
ethyl ether and washed with aq. NaHCO.sub.3 and aq. NaCl. The
organic solution was dried over Na.sub.2SO.sub.4 and concentrated.
Purification by flash column chromatography (silica gel, 3%
MeOH/CH.sub.2Cl.sub.2) gave compound 37 (11 mg). MS 481
(M+H.sup.+).
[0235] Following the procedure described above for Example 6 and
substituting the appropriate reagents, starting materials and
purification methods known to those skilled in the art, the
following compound of the present invention was prepared:
TABLE-US-00008 Cpd Name and data 48
N-Methyl-N-(1'-{[6-(trifluoromethyl)-1-
benzothiophen-2-yl]carbonyl}-1,3'-biazetidin-3-yl)-1,3-
thiazole-4-carboxamide. MS 481 (M + H.sup.+).
[0236] Examples 7-28 provide synthetic routes to useful
intermediates for the preparation of compounds of Formula (I).
Example 7
##STR00031##
[0238] A. Methyl 1-(4-fluorophenyl)-indole-5-carboxylate, 7d. A
mixture of methyl indole-5-carboxylate 7a (0.5 g, 2.85 mmol),
1-bromo-4-fluoro-benzene 7b (2 mL, 18.21 mmol), CuI (0.544 g, 2.85
mmol), and K.sub.2CO.sub.3 (0.591 g, 4.28 mmol) was heated under
microwave at 220.degree. C. for 2.5 hours. The reaction mixture was
diluted with CH.sub.2Cl.sub.2 and filtered. The solution was
concentrated and the residue was purified by flash column
chromatography (silica gel, 15% EtOAc/heptane) to give 7c (0.58
g).
[0239] B. 1-(4-fluorophenyl)-indole-5-carboxylic acid, 7d. A
mixture of methyl 1-(4-fluorophenyl)-indole-5-carboxylate 7c (0.58
g, 2.15 mmol) and LiOH.H.sub.2O (0.36 g, 8.6 mmol) in THF (15 mL)
and H.sub.2O (10 mL) was stirred at room temperature for 5 days.
Aqueous 10% HCl solution was added to the reaction mixture to
adjust pH=3.about.4. The resulting mixture was extracted with EtOAc
(2.times.). The organic solution was washed with aq. NaCl, dried
over Na.sub.2SO.sub.4 and concentrated to give 7d (0.5 g).
[0240] Following the procedure described above for Example 7 and
substituting the appropriate reagents, starting materials, and
purification methods known to those skilled in the art, the
following intermediate was prepared:
##STR00032##
Example 8
##STR00033##
[0242] A. Ethyl
1-(3-trifluoromethyl-phenyl)-1H-indazole-5-carboxylate, 8c and
Ethyl 2-(3-trifluoromethyl-phenyl)-2H-indazole-5-carboxylate, 8d. A
mixture of ethyl 1H-indazole-5-carboxylate 8a (150 mg, 0.79 mmol),
1-bromo-3-trifluoromethylbenzene 8b (0.13 mL, 0.95 mmol), CuI (22.5
mg, 0.12 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (0.056
mL, 0.36 mmol), and K.sub.3PO.sub.4 (0.37 g, 1.74 mmol) in toluene
(1.5 mL) was heated at 110.degree. C. for 16 hours. The reaction
mixture was diluted with CH.sub.2Cl.sub.2 and filtered. The
solution was concentrated and the residue was purified by flash
column chromatography (silica gel, 10% EtOAc/heptane) to give 8c
(190 mg), followed by 8d (37 mg).
[0243] B. 1-(3-Trifluoromethyl-phenyl)-1H-indazole-5-carboxylic
acid, 8e and 2-(3-Trifluoromethyl-phenyl)-2H-indazole-5-carboxylic
acid, 8f. A mixture of 8c and 8d and LiOH in THF (120 mL) and
H.sub.2O (60 mL) was stirred at room temperature for 5 days.
Aqueous 10% HCl solution was added to the reaction mixture to
adjust pH=3.about.4. The resulting mixture was extracted with EtOAc
(2.times.). The organic solution was washed with aq. NaCl, dried
over Na.sub.2SO.sub.4 and concentrated to give 8e and 8f.
Example 9
##STR00034##
[0245] A. Methyl 2-(4-fluoro-benzoylamino)-3-hydroxy-benzoate, 9c.
A solution of 1.0 g (4.9 mmol) of methyl 2-amino-3-hydroxybenzoate
9a, 1.03 g (7.4 mmol) of 4-fluorobenzoic acid 9b, 10 mL DMF and 2.9
mL (20.6 mmol) of TEA were placed into a flask and stirred for 10
min. HATU (7.4 mmol, 2.8 g) was added and the reaction was stirred
overnight. The reaction mixture was poured into water and extracted
with EtOAc. The organics were washed with water and brine and the
solvent was evaporated to give 1.2 g of crude product, methyl
2-(4-fluoro-benzoylamino)-3-hydroxy-benzoate, 9c, which was used
without purification. MS m/z (M+H.sup.+) 290.1.
[0246] B. Methyl 2-(4-fluorophenyl)benzo[d]oxazole-4-carboxylate,
9d. Methyl 2-(4-fluoro-benzoylamino)-3-hydroxy-benzoate 9c (7.4
mmol, 1.2 g crude) and 1.3 g (7.5 mmol) of p-toluenesulfonic acid
were refluxed in 10 mL of xylene overnight. After cooling saturated
NaHCO.sub.3 was added and the resulting mixture was extracted with
EtOAc. The organic solvent was evaporated to give 1.1 g (55%) of
methyl 2-(4-fluorophenyl)benzo[d]oxazole-4-carboxylate, 9d. MS m/z
(M+H.sup.+) 272.0.
[0247] C. 2-(4-Fluorophenyl)-benzo[d]oxazole-4-carboxylic acid, 9e.
A mixture of 1.1 g (4.0 mmol) methyl
2-(4-fluorophenyl)benzo[d]oxazole-4-carboxylate 9d and 3.7 mL of 3N
aqueous NaOH in 10 mL of THF was refluxed overnight. After cooling
the reaction mixture was poured into water and acidified with conc.
HCl. The resulting solid was filtered and dried to give 830 mg
(79%) of 2-(4-fluorophenyl)-benzo[d]oxazole-4-carboxylic acid, 9e.
MS m/z (M+H.sup.+) 258.1.
[0248] Following the procedure described above for Example 9, and
substituting the appropriate reagents, starting materials, and
purification methods known to those skilled in the art, the
following intermediate compounds were prepared:
##STR00035## ##STR00036##
Example 10
##STR00037##
[0250] A. Methyl 5-phenyl-benzo[b]thiophene-2-carboxylate, 10c. A
mixture of compound 10a (542.3 mg, 2 mmol), phenyl boronic acid 10b
(268.2 mg, 2.2 mmol), Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (98 mg,
0.12 mmol), and K.sub.2CO.sub.3 (414.6 mg, 3 mmol), in a dioxane (4
mL)/water (1 mL) mixture, was placed in a capped vial and heated at
80.degree. C. overnight. The reaction mixture was then diluted with
EtOAc and water. The organic layer was concentrated under reduced
pressure and purified by flash column chromatography (silica gel,
2-10% EtOAc/heptane) to give compound 10c (510 mg). MS m/z
(M+H.sup.+) 269.1.
[0251] B. 5-Phenyl-benzo[b]thiophene-2-carboxylic acid, 10d. A
solution of compound 10c (510 mg, 1.9 mmol) and LiOH.H.sub.2O (319
mg, 7.6 mmol) in THF/H.sub.2O (10/10 mL) was stirred at room
temperature overnight. The resulting mixture was concentrated and
diluted with water. The water layer was acidified with 1N aqueous
HCl to pH.about.4 and extracted with CH.sub.2Cl.sub.2. The organic
solution was dried over Na.sub.2SO.sub.4 and concentrated to give
10d (479 mg), which was used in the next reaction without further
purification. MS m/z (M+H.sup.+) 255.0.
[0252] C. 3-Fluoro-5-phenyl-benzo[b]thiophene-2-carboxylic acid,
10e. To a solution of compound 10d (507 mg, 1.99 mmol) in THF (8
mL) at -70.degree. C. was added n-BuLi (1.6 M in hexane, 2.62 mL,
4.19 mmol). The mixture was stirred at -70.degree. C. for 1 h; then
a solution of N-fluorobenzenesulfonimide (817.3 mg, 2.59 mmol) in
THF (2 mL) was slowly added. The reaction mixture was allowed to
warm to room temperature and was stirred overnight. The resulting
mixture was partitioned between dilute aqueous HCl and EtOAc. The
organic solution was washed with water and brine, dried over
Na.sub.2SO.sub.4, and concentrated. The residue was triturated with
CH.sub.2Cl.sub.2, filtered and the solid dried to give compound 10e
(391.9 mg). MS m/z (M+H.sup.+) 273.0.
[0253] D. 3-Fluoro-5-phenyl-benzo[b]thiophene-2-carbonyl chloride,
10f. To a solution of compound 10e (136.2 mg, 0.5 mmol) in
CH.sub.2Cl.sub.2 (5 mL) at room temperature was added (COCl).sub.2
(0.064 mL, 0.75 mmol), followed by DMF (0.01 mL, 0.125 mmol). The
reaction mixture was stirred at room temperature for 18 h. The
reaction mixture was then concentrated to give compound 10f (light
pink powder).
Example 11
##STR00038##
[0255] A. 1-tert-Butyl 6-methyl
3-(4-fluorophenyl)-1H-indole-1,6-dicarboxylate, 11c. A mixture of
compound 11a (1.00 g, 2.49 mmol), 4-fluorophenyl boronic acid 11b
(523 mg, 3.74 mmol), Pd(OAc).sub.2 (44.8 mg, 0.2 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos, 204.7 mg,
0.5 mmol), and K.sub.3PO.sub.4 (1.06 g, 4.99 mmol), in toluene (5
mL) was placed in a capped vial and heated at 90.degree. C. under
N.sub.2 for 3 h. The reaction mixture was then diluted with EtOAc
and water. The organic layer was washed with brine, concentrated
under reduced pressure, and purified by flash column chromatography
(silica gel, 2-10% EtOAc/heptane) to give compound 11c as a light
yellow solid, which was further recrystallized from heptane to
obtain white solid (707 mg). MS m/z (M+H.sup.+) 370.2.
[0256] B. Methyl 3-(4-fluorophenyl)-1H-indole-6-carboxylate, 11d.
To a solution of compound 11c (705 mg, 1.91 mmol) in
CH.sub.2Cl.sub.2 (4 mL) was added trifluoroacetic acid (1.5 mL) at
room temperature. The mixture was stirred at room temperature for 2
h. The resulting mixture was concentrated to give compound 11d
(603.3 mg) as a white solid. MS m/z (M+H.sup.+) 270.1.
[0257] C. 3-(4-Fluorophenyl)-1H-indole-6-carboxylic acid, 11e. A
solution of compound 11d (303 mg, 0.79 mmol), and LiOH.H.sub.2O
(132.7 mg, 3.16 mmol) in THF/H.sub.2O (10 mL/10 mL) was stirred at
45.degree. C. for 5 h. The resulting mixture was concentrated and
diluted with water. The water layer was acidified with 1N aqueous
HCl to pH.about.4 and extracted with CH.sub.2Cl.sub.2. The organic
solution was dried over Na.sub.2SO.sub.4 and concentrated to give
11e (249 mg). MS m/z (M+H.sup.+) 256.0.
[0258] Following the procedure described above for Example 11, and
substituting the appropriate reagents, starting materials and
purification methods known to those skilled in the art, the
following intermediate compounds were prepared:
##STR00039##
Example 12
##STR00040##
[0260] A. Methyl
3-(4-fluorophenyl)-1-methyl-1H-indole-6-carboxylate, 12a. To a
solution of compound 11d (300 mg, 0.78 mmol) in DMF (3 mL) was
added NaH (60% in mineral oil, 68.9 mg, 1.72 mmol) at 0.degree. C.
The mixture was stirred at 0.degree. C. for 30 min, then CH.sub.3I
(0.053 mL, 0.86 mmol) was added and stirring continued at 0.degree.
C. for another 1 h. The resulting mixture was diluted with EtOAc
and water. The organic layer was washed with brine and
concentrated. The residue was recrystallized from heptane, filtered
and the solid dried to give compound 12a (265 mg) as a light yellow
solid. MS m/z (M+H.sup.+) 284.1.
[0261] B. 3-(4-Fluoro-phenyl)-1-methyl-1H-indole-6-carboxylic acid,
12b. A solution of compound 12a (264 mg, 0.93 mmol) and
LiOH.H.sub.2O (156.4 mg, 3.73 mmol) in THF/H.sub.2O (10 mL/10 mL)
was stirred at 45.degree. C. for 5 h. The resulting mixture was
concentrated and diluted with water. The water layer was acidified
with 1N aqueous HCl to pH.about.4 and extracted with
CH.sub.2Cl.sub.2. The organic solution was dried over
Na.sub.2SO.sub.4 and concentrated to give compound 12b (252 mg). MS
m/z (M+H.sup.+) 270.1.
[0262] Following the procedure described above for Example 12 and
substituting the appropriate reagents, starting materials and
purification methods known to those skilled in the art, the
following intermediate compound was prepared:
##STR00041##
Example 13
##STR00042##
[0264] A. Ethyl 1-Methyl-3-phenyl-1H-indazole-5-carboxylate, 13b. A
mixture of compound 13a (300 mg, 0.91 mmol), phenyl boronic acid
10b (133 mg, 1.09 mmol), Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (40 mg,
0.055 mmol), and K.sub.2CO.sub.3 (251.2 mg, 1.82 mmol), in a
toluene (2 mL)/water (0.4 mL) mixture, was placed in a capped vial
and heated at 90.degree. C. overnight. The reaction mixture was
then diluted with EtOAc and water. The organic layer was
concentrated under reduced pressure and purified by flash column
chromatography (silica gel, 2-10% EtOAc/Heptanes) to give compound
13b (231 mg). MS m/z (M+H.sup.+) 281.1.
[0265] B. 1-Methyl-3-phenyl-1H-indazole-5-carboxylic acid, 13c. A
solution compound 13b (230 mg, 0.58 mmol), and LiOH.H.sub.2O (98
mg, 2.33 mmol) in THF/H.sub.2O (10/10 mL) was stirred at 45.degree.
C. for 8 h. The resulting mixture was concentrated and diluted with
water. The water layer was acidified with 1N aqueous HCl to
pH.about.4 and extracted with CH.sub.2Cl.sub.2. The organic
solution was dried over Na.sub.2SO.sub.4 and concentrated to give
13c (206 mg). MS m/z (M+H.sup.+) 253.1.
[0266] Following the procedure described above for Example 13 and
substituting the appropriate reagents, starting materials and
purification methods known to those skilled in the art, the
following intermediate compounds were prepared:
##STR00043##
Example 14
##STR00044##
[0268] A. 3-Methyl-[1,1'-biphenyl]-4-carboxylic acid, 14b. To a
suspension of compound 14a (0.025 g, 0.115 mmol), compound 10b
(0.0139 g, 0.14 mmol), and Cs.sub.2CO.sub.3 (0.094 g, 0.288 mmol)
in dioxane (3 mL) and EtOH (1 mL) was added Pd(dppf)Cl.sub.2
(0.0084 g, 0.0115 mmol). The reaction mixture was stirred at
80.degree. C. for 3 h. After cooling, the solid was removed by
filtration and washed with CH.sub.3OH. The filtrate was
concentrated. The crude product 14b was purified by reverse phase
chromatography. MS m/z (M+H.sup.+) 213.1.
[0269] Following the procedure described above for Example 14 and
substituting the appropriate reagents, starting materials and
purification methods known to those skilled in the art, the
following intermediate compounds were prepared:
##STR00045## ##STR00046##
Example 15
##STR00047##
[0271] A. 3-Fluoro-6-trifluoromethyl-benzo[b]thiophene-2-carboxylic
acid, 15b. A solution of
6-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid 15a (2.031
mmol, 0.50 g) in THF (8 mL) at -70.degree. C. was treated with a
1.6 M solution of n-BuLi in hexanes (4.26 mmol, 2.66 mL). After 1 h
at -70.degree. C., N-fluorobenzenesulfonimide (2.64 mmol, 0.833 g)
in THF (2 mL) was slowly added and the reaction was warmed to room
temperature. After 1 h the mixture was partitioned between dilute
aqueous HCl and EtOAc. The organic layer was washed with water and
brine, and then concentrated. The residue was triturated with
CH.sub.2Cl.sub.2. The off-white precipitate was filtered and
collected to provide 15b.
[0272] B. 3-Fluoro-6-trifluoromethyl-benzo[b]thiophene-2-carbonyl
chloride, 15c. To compound 15b (0.14 g, 0.53 mmol) in
CH.sub.2Cl.sub.2 (5 mL) at room temperature was added (COCl).sub.2
(0.051 mL, 0.58 mmol), followed by 2 drops of DMF. The reaction
mixture was stirred at room temperature for 18 h. The reaction
mixture was then concentrated to give compound 15c.
Example 16
##STR00048##
[0274] A. 1-tert-Butyl 6-methyl
3-phenyl-1H-indole-1,6-dicarboxylate, 16a. A mixture of
1-tert-butyl 6-methyl 3-iodo-1H-indole-1,6-dicarboxylate 11a (5.02
mmol, 2.016 g), phenylboronic acid 10b (7.53 mmol, 0.92 g),
Pd(OAc).sub.2 (0.402 mmol, 90 mg), Sphos 0.904 mmol, (0.37 g), and
K.sub.3PO.sub.4 (10.1 mmol, 2.13 g) in toluene (10 mL) in sealed
reaction vial was stirred at room temperature for 2 min and then
heated at 90.degree. C. under N.sub.2 for 4 h. The reaction mixture
was quenched with EtOAc and water. The organic layer was
concentrated and purified by flash column chromatography (silica
gel, 8% EtOAc/hexanes). The desired product was collected as a
light yellow solid that was washed with small amount of hexanes to
obtain 16a as a white solid.
[0275] B. Methyl 3-phenyl-1H-indole-6-carboxylate, 16b. To a
solution of 1-tert-butyl 6-methyl
3-phenyl-1H-indole-1,6-dicarboxylate 16a (4.04 mmol, 1.42 g) in
CH.sub.2Cl.sub.2 (8 mL) was added 6 mL of TFA. The resulting
solution was stirred for 3 h. The mixture was then concentrated and
washed with hexanes to afford 16b.
[0276] C. Methyl 1-methyl-3-phenyl-1H-indole-6-carboxylate, 16c.
NaH (60% dispersion in mineral oil, 4.52 mmol, 186 mg) was added
portion-wise to a solution of methyl
3-phenyl-1H-indole-6-carboxylate (2.07 mmol, 757 mg) in DMF at
0.degree. C. and the mixture was stirred for 20 min. Methyl iodide
(2.28 mmol, 0.14 mL) was added and the reaction mixture was
maintained at 0.degree. C. for 1 h. Water was then added and the
reaction was extracted with EtOAc. The organics were concentrated
and purified by flash column chromatography (silica gel, 15%
EtOAc/hexanes) to give 16c.
[0277] D. 1-Methyl-3-phenyl-1H-indole-6-carboxylic acid, 16d. A
mixture of compound 16c (517 mg, 1.95 mmol) and LiOH (187 mg, 7.80
mmol) in THF/MeOH/H.sub.2O (4/4/4 mL) was stirred for 4 h. A 15%
citric acid solution (20 mL) was added, and the mixture was then
extracted with EtOAc (3.times.). The combined extracts were washed
with brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated
under reduced pressure. The residue, compound 16d, was dried under
reduced pressure for 18 h.
[0278] Following the procedure described above for Example 16 and
substituting the appropriate reagents, starting materials and
purification methods known to those skilled in the art, the
following intermediate compounds were prepared:
##STR00049##
Example 17
##STR00050##
[0280] A. 1-tert-Butyl 6-methyl
3-(3-(trifluromethyl)phenyl)-1H-indole-1,6-dicarboxylate, 17b. The
title compound 17b was prepared using the method described in
Example 16, substituting 17a for 10b in Step A.
[0281] B. Methyl
3-(3-(trifluoromethyl)phenyl)-1H-indole-6-carboxylate, 17c. The
title compound 17c was prepared using the method described in
Example 16, substituting 17b for 16a in Step B.
[0282] C. 3-(3-(Trifluoromethyl)phenyl)-1H-indole-6-carboxylic
acid, 17d. The title compound was prepared using the method
described in Example 16, substituting 17c for 16c in Step D.
[0283] Following the procedure described above for Example 17 and
substituting the appropriate reagents, starting materials and
purification methods known to those skilled in the art, the
following intermediate compound was prepared:
##STR00051##
Example 18
##STR00052##
[0285] A. 1-(5-Chloro-2-fluoro-phenyl)-2,2,2-trifluoro-ethanone,
18c. To a solution of LDA (2.0 M in THF/heptane/ethylbenzene, 25.3
mmol, 12.6 mL) in dry THF was slowly added
1-fluoro-4-chloro-benzene 18a (23.0 mmol, 2.45 mL) at -78.degree.
C. The mixture was stirred for 1 h at -78.degree. C. and ethyl
trifluoroacetate 18b (25.3 mmol, 3.02 mL) was added. The reaction
mixture was allowed to warm to room temperature overnight and was
quenched with saturated aqueous NH.sub.4Cl solution. The mixture
was extracted with EtOAc. The organic extracts were concentrated
and purified by flash column chromatography (silica gel, 15%
EtOAc/hexanes) to give a mixture of the compound 18c along with a
regio-isomeric by-product,
1-(5-fluoro-2-chloro-phenyl)-2,2,2-trifluoro-ethanone, in a ratio
of 5:1 (18c is the major product).
[0286] B. Methyl
5-chloro-3-(trffluoromethyl)benzo[b]thiophene-2-carboxylate, 18e. A
solution of compound 18c (6.62 mmol, 1.5 g), methyl
2-mercaptoacetate 18d (6.62 mmol, 0.6 mL), and Et.sub.3N (8.6 mmol,
1.2 mL) in acetonitrile (12 mL) was heated at 75.degree. C. for 4
h. The reaction was diluted with EtOAc and water. The organic layer
was concentrated and purified by flash column chromatography
(silica gel, 10% EtOAc/hexanes) to provide the compound 18e.
[0287] C. 5-Chloro-3-trifluoromethyl-benzo[b]thiophene-2-carboxylic
acid, 18f. A mixture of compound 18e (574 mg, 1.95 mmol) and LiOH
(187 mg, 7.80 mmol) in THF/MeOH/H.sub.2O (4/4/4 mL) was stirred for
4 h. A 15% citric acid solution (20 mL) was added, and the mixture
was then extracted with EtOAc (3.times.). The combined extracts
were washed with brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated under reduced pressure. The residue, compound 18f, was
dried under reduced pressure for 18 h and was used without
purification.
[0288] D. 5-Chloro-3-trifluoromethyl-benzo[b]thiophene-2-carbonyl
chloride, 18g. To compound 18f in CH.sub.2Cl.sub.2 (5 mL) at room
temperature was added (COCl).sub.2, followed by 2 drops of DMF. The
reaction mixture was stirred at room temperature for 18 h. The
reaction mixture was then concentrated to give compound 18g.
Example 19
##STR00053##
[0290] A. 1-(4-Chloro-2-fluoro-phenyl)-2,2,2-trifluoro-ethanone,
19b. To a solution of n-BuLi (1.6 M in hexanes, 4.68 mmol, 2.93 mL)
in dry THF was slowly added 4-chloro-2-fluoro-1-iodo-benzene 19a
(3.9 mmol, 1.0 g) at -78.degree. C. under N.sub.2. The mixture was
stirred for 1 h at -78.degree. C. and ethyl trifluoroacetate 18b
(0.51 mL, 4.29 mmol) was added. The reaction was allowed to warm to
room temperature overnight and was quenched with saturated aqueous
NH.sub.4Cl solution. The mixture was extracted with EtOAc. The
organic extracts were concentrated and purified by flash column
chromatography (silica gel, 15% EtOAc/hexanes) to give compound
19b.
[0291] B. Methyl
6-chloro-3-(trifluoromethyl)benzo[b]thiophene-2-carboxylate, 19c.
The title compound 19c was prepared using a similar method
described in Example 18, substituting 19b for 18c in Step B.
Example 20
##STR00054##
[0293] A. Methyl 3-fluoro-1H-indole-6-carboxylate, 20b. A solution
of methyl 1H-indole-6-carboxylate 20a (11.4 mmol, 2.0 g) and
N-fluoro-2,4,6-trimethylpyridinium triflate (14.8 mmol, 4.3 g) in
MeOH (100 mL) was heated at reflux for 18 h. The reaction mixture
was concentrated and purified by flash column chromatography
(silica gel, 15-20% EtOAc/hexanes) to give compound 20b as an
off-white solid.
[0294] B. Methyl
3-fluoro-1-(4-fluorophenyl)-1H-indole-6-carboxylate, 20d. Compound
20b (0.264 mmol, 51 mg), CuI (0.0264 mmol, 5 mg) and
K.sub.3PO.sub.4 (0.66 mmol, 40 mg) were combined in a sealed
reaction tube and the vial was back-flushed with N.sub.2.
4-fluoro-iodobenzene 20c (0.264 mmol, 0.0394 mL) and
N,N'-dimethylcyclohexane-1,2-diamine (0.0792 mmol, 0.0125 mL) were
added via syringe, followed by toluene. The reaction mixture was
heated at 95.degree. C. for 6 h. The reaction was diluted with
EtOAc and water. The reaction mixture was concentrated and purified
by flash column chromatography (silica gel, 20% EtOAc/hexanes) to
give compound 20d.
[0295] C. 3-Fluoro-1-(4-fluorophenyl)-1H-indole-6-carboxylic acid,
20e. The title compound 20e was prepared using the method described
in Example 18, Step C.
Example 21
##STR00055##
[0297] A. 7-Fluoro-1H-indole-5-carboxylic acid, 21b. To a solution
of 5-bromo-7-fluoroindole 21a (1.71 mmol, 365 mg) in THF at
-60.degree. C. was added n-BuLi (1.6 M solution in hexanes, 5.2
mmol, 3.2 mL). The solution was kept at -60.degree. C. for 4 h and
was then poured onto an excess of freshly crushed dry ice. Water
was added and the mixture was acidified to pH 4. The organic phase
was concentrated and the residue was purified by flash column
chromatography (silica gel, 35% EtOAc/hexanes) to give compound
21b.
Example 22
##STR00056##
[0299] A. Methyl 7-methyl-1H-indole-5-carboxylate, 22c. A mixture
of compound 22a (0.613 mmol, 156 mg), methylboronic acid 22b (0.92
mmol, 79 mg), Pd(OAc).sub.2 (0.09 mmol, 20 mg), SPhos (0.215 mmol,
88 mg), and K.sub.3PO.sub.4 (1.23 mmol, 0.26 g) in toluene (2 mL)
was heated to 100.degree. C. for 3 h in a sealed reaction vessel.
The reaction was diluted with EtOAc and water. The organic layer
was concentrated and purified by flash column chromatography
(silica gel, 10% EtOAc/hexanes) to give compound 22c.
[0300] B. Methyl
1-(4-fluorophenyl)-7-methyl-1H-indole-5-carboxylate, 22d. The title
compound was prepared using the method described in Example 20,
substituting 22c for 20b in Step B.
[0301] C. 1-(4-Fluorophenyl)-7-methyl-1H-indole-5-carboxylate, 22e.
The title compound was prepared using the method described in
Example 18, Step C.
Example 23
##STR00057##
[0303] A. Methyl 4-amino-2-chloro-benzoate, 23b. Acetyl chloride
(35.2 mmol, 2.5 mL) was added dropwise to a stirring solution of
4-amino-2-chloro-benzoic acid 23a (12.9 mmol, 2.22 g) in methanol
(50 mL). The mixture was heated at reflux for 18 h, cooled, and
concentrated under vacuum. The residue was taken up in EtOAc,
washed with saturated aqueous NaHCO.sub.3 and brine, dried, and
concentrated under vacuum. The crude product was purified by flash
column chromatography (silica gel, 30% EtOAc/hexanes) to give
compound 23b.
[0304] B. Methyl 4-amino-2-chloro-5-iodo-benzoate, 23c. To a
suspension of compound 23b (1.18 g, 6.38 mmol) and CaCO.sub.3 (12.8
mmol, 1.28 g) in MeOH (13 mL) was added a solution of iodine
monochloride (6.70 mmol, 1.09 g) in CH.sub.2Cl.sub.2 (6 mL)
dropwise at room temperature. The resulting reaction mixture was
stirred at room temperature for 1.5 h. The reaction mixture was
concentrated and then partitioned between EtOAc and water. The
organic layer was concentrated and purified by flash column
chromatography (silica gel, 20-25% EtOAc/hexanes) to provide methyl
4-amino-2-chloro-5-iodo-benzoate 23c as the major the product and
methyl 4-amino-2-chloro-3-iodo-benzoate 23d as the minor
product.
[0305] C. Methyl
4-amino-2-chloro-5-((trimethylsilyl)ethynyl)benzoate, 23e. To a
mixture of compound 23c (0.642 mmol, 200 mg), CuI (0.064 mmol, 12.2
mg) and Pd(PPh.sub.3).sub.2Cl.sub.2 (0.064 mmol, 45 mg) in THF (2
mL) was added ethynyltrimethylsilane (0.963 mmol, 95 mg) followed
by Et.sub.3N (7.19 mmol, 1 mL) under N.sub.2. The reaction mixture
was stirred at room temperature for 1.5 h and then partitioned
between EtOAc and water. The organic layer was concentrated and
purified by flash column chromatography (silica gel, 15%
EtOAc/hexanes) to give compound 23e.
[0306] D. Methyl 6-chloro-1H-indole-5-carboxylate, 23f. A mixture
of compound 23e (0.532 mmol, 150 mg) and CuI (0.32 mmol, 60 mg) in
DMF (1.5 mL) was heated at 110.degree. C. for 5 h and then cooled
to room temperature. The reaction was quenched with water and
extracted with EtOAc. The organic layer was concentrated and
purified by flash column chromatography (silica gel, 15%
EtOAc/hexanes) to give compound 23f.
Example 24
##STR00058##
[0308] A. Methyl 1-(3,4-difluorophenyl)-indole-5-carboxylate, 24c.
A mixture of methyl indole-5-carboxylate 24a (2 g, 11.4 mmol),
1-iodo-3,4-difluoro-benzene 24b (1.5 mL, 12.5 mmol), CuI (0.22 g,
1.14 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (0.54 mL,
3.43 mmol), and K.sub.3PO.sub.4 (6.06 g, 28.5 mmol) in toluene (12
mL) was heated at 110.degree. C. for 7 hours. The reaction mixture
was diluted with CH.sub.2Cl.sub.2 and filtered. The solution was
concentrated and the residue was purified by flash column
chromatography (silica gel, 20% EtOAc/heptane) to give 24c (3.0
g).
[0309] B. 1-(3,4-difluorophenyl)-indole-5-carboxylic acid, 24d. A
mixture of methyl 1-(3,4-difluorophenyl)-indole-5-carboxylate 24c
(3.0 g, 10.4 mmol) and LiOH (1.0 g, 41.8 mmol) in THF (120 mL) and
H.sub.2O (60 mL) was stirred at room temperature for 5 days.
Aqueous 10% HCl solution was added to the reaction mixture to
adjust pH=3-4. The resulting mixture was extracted with EtOAc
(2.times.). The organic solution was washed with aq. NaCl, dried
over Na.sub.2SO.sub.4 and concentrated to give 24d (2.85 g).
Example 25
##STR00059##
[0311] A. Methyl 2-phenyl-benzoxazole-6-carboxylate, 25c. A mixture
of methyl 4-amino-3-hydroxy-benzoate 25a (0.3 g, 1.8 mmol) and
benzoyl chloride 25b (0.23 mL, 2.0 mmol) in dioxane (2.5 mL) was
heated at 210.degree. C. under microwave for 15 min. The reaction
mixture was diluted with CH.sub.2Cl.sub.2 and washed with aq.
NaHCO.sub.3. The organic solution was dried over Na.sub.2SO.sub.4,
concentrated and purified by flash column chromatography (silica
gel, 20% EtOAc/heptane) to give 25c (0.39 g).
[0312] B. 2-Phenyl-benzoxazole-6-carboxylic acid, 25d. A mixture of
methyl 2-phenyl-benzoxazole-6-carboxylate 25c (0.37 g, 1.46 mmol)
and LiOH (0.10 g, 4.2 mmol) in THF (4 mL), MeOH (4 mL), and
H.sub.2O (4 mL) was stirred at room temperature for 6 h. Aqueous 1N
HCl solution was added to the mixture to adjust pH to 3-4. The
resulting mixture was extracted with EtOAc (2.times.). The organic
solution was washed with aq. NaCl, dried over Na.sub.2SO.sub.4 and
concentrated to give 25d (0.34 g).
Example 26
##STR00060##
[0314] A. Ethyl 2-phenyl-benzothiazole-6-carboxylate, 26b. A
mixture of ethyl 2-bromo-benzothiazole-6-carboxylate 26a (300 mg,
1.05 mmol), phenylboronic acid 10b (192 mg, 1.57 mmol),
K.sub.2CO.sub.3 (188 mg, 1.36 mmol) and
Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (43 mg, 0.05 mmol) in dioxane (2
mL) and H.sub.2O (0.4 ml) was heated at 120.degree. C. for 25 min
under microwave. The reaction mixture was diluted with
CH.sub.2Cl.sub.2, washed with H.sub.2O, dried over
Na.sub.2SO.sub.4, and concentrated. Purification by flash column
chromatography (silica gel, 15% EtOAc/heptane) gave 26b (220
mg).
[0315] B. 2-Phenyl-benzothiazole-6-carboxylic acid, 26c. Ethyl
2-phenyl-benzothiazole-6-carboxylate 26b (220 mg, 0.78 mmol) was
stirred with LiOH (74 mg, 3.1 mmol) in THF (4 mL) and H.sub.2O (4
mL) for 16 h. Aqueous 1N HCl solution was added to the mixture to
adjust pH to 3-4. The resulting mixture was extracted with EtOAc
(2.times.). The organic solution was washed with aq. NaCl, dried
over Na.sub.2SO.sub.4 and concentrated to give 26c (200 mg).
Example 27
##STR00061##
[0317] A. Methyl 4-((4-fluorophenyl)amino)-3-nitrobenzoate, 27c. A
mixture of methyl 4-fluoro-3-nitrobenzoate 27a (1 g, 5.02 mmol),
4-fluoroaniline 27b (4.34 mL, 5.02 mmol), and DIPEA (1.04 mL, 6.03
mmol) in DMF (10 mL) was stirred at room temperature for 2 h. Water
was added to the mixture; the resulting solid was filtered, washed
with water, and dried. The crude product 27c was used in the next
reaction without purification.
[0318] B. Methyl 3-amino-4-((4-fluorophenyl)amino)benzoate, 27d. A
mixture of 27c (1.4 g, 4.8 mmol) and SnCl.sub.2.2H.sub.2O (4.9 g,
21.7 mmol) in EtOH (50 mL) was stirred at 80.degree. C. After 4 h,
the mixture was cooled to room temperature and was slowly added to
saturated aqueous NaHCO.sub.3. The solid was filtered and washed
with H.sub.2O. The solid was triturated with EtOAc and the filtrate
was concentrated. The crude product 27d was used in the next
reaction without purification. MS m/z (M+H.sup.+) 261.1.
[0319] C. Methyl 1-(4-fluorophenyl)-1H-benzimidazole-5-carboxylate,
27e. A mixture of 27d (0.18 g, 0.693 mmol) and trimethyl
orthoformate (0.7 mL, 6.39 mmol) in DMF (2 mL) was refluxed for 5 h
and then cooled to room temperature. Water was added to the
mixture. The resulting solid was filtered, washed, with water, and
dried. The crude product 27e was used in the next reaction without
purification. MS m/z (M+H.sup.+) 271.1.
[0320] D. 1-(4-Fluorophenyl)-1H-benzo[d]imidazole-5-carboxylic
acid, 27f. To a solution of 27e (0.18 g, 0.666 mmol) in EtOH (10
mL) was added 1N aqueous NaOH (2.5 mL, 2.5 mmol). The mixture was
stirred at room temperature for 4 d. The solvent was evaporated and
1N aqueous HCl was added, followed by extraction with EtOAc. The
organic layer was dried over MgSO.sub.4 and concentrated. The crude
product 27f was purified by preparative reverse phase
chromatography. MS m/z (M+H.sup.+) 257.1.
[0321] Following the procedure described above for Example 27 and
substituting the appropriate reagents, starting materials and
purification methods known to those skilled in the art, the
following intermediate compounds were prepared.
##STR00062##
Example 28
##STR00063##
[0323] A. Methyl
2-methyl-1-(4-fluorophenyl)-1H-benzimidazole-5-carboxylate, 28a.
The title compound 28a was prepared using the method described in
Example 27, substituting trimethyl orthoacetate for trimethyl
orthoformate in Step C. The crude product 28a was used in the next
reaction without purification. MS m/z (M+H.sup.+) 285.1.
[0324] B.
2-Methyl-1-(4-fluorophenyl)-1H-benzimidazole-5-carboxylate, 28b.
The title compound 28b was prepared using the method described in
Example 28, substituting 28a for 27e in Step D. MS m/z (M+H.sup.+)
271.2.
[0325] Following the procedure described above for Example 28 and
substituting the appropriate reagents, starting materials and
purification methods known to those skilled in the art, the
following intermediate compounds were prepared.
##STR00064##
[0326] The schemes and examples described herein were used to
prepare compounds of Formula (Ia)
##STR00065##
selected from the group consisting of [0327] a compound wherein Y
is thiazol-2-yl, R.sub.1 is H, and Z is
1-(4-trifluoromethylphenyl)-1H-indol-5-yl; [0328] a compound
wherein Y is thiazol-4-yl, R.sub.1 is H, and Z is
4-(3-trifluoromethylphenyl)phenyl; [0329] a compound wherein Y is
thiazol-2-yl, R.sub.1 is H, and Z is
1-(phenylsulfonyl)-1H-indol-5-yl; [0330] a compound wherein Y is
thiazol-2-yl, R.sub.1 is H, and Z is 2-phenyl-benzothiazol-6-yl;
[0331] a compound wherein Y is thiazol-2-yl, R.sub.1 is H, and Z is
4-(3-trifluoromethylphenyl)phenyl; [0332] a compound wherein Y is
thiazol-2-yl, R.sub.1 is H, and Z is 6-phenyl-benzothiophen-2-yl;
[0333] a compound wherein Y is thiazol-2-yl, R.sub.1 is H, and Z is
6-trifluoromethyl-benzothiophen-2-yl; [0334] a compound wherein Y
is thiazol-2-yl, R.sub.1 is H, and Z is
4-trifluoromethyl-benzothiophen-2-yl; [0335] a compound wherein Y
is thiazol-2-yl, R.sub.1 is H, and Z is
4-(5-trifluoromethyl-thien-2-yl)-phenyl; [0336] a compound wherein
Y is thiazol-2-yl, R.sub.1 is H, and Z is 4-(phenylmethyl)-phenyl;
[0337] a compound wherein Y is thiazol-4-yl, R.sub.1 is H, and Z is
1-(4-fluorophenyl)-1H-indol-5-yl; [0338] a compound wherein Y is
thiazol-2-yl, R.sub.1 is H, and Z is
4-(4-trifluoromethylphenyl)-phenyl; [0339] a compound wherein Y is
thiazol-2-yl, R.sub.1 is H, and Z is 1-phenyl-1H-indol-5-yl; [0340]
a compound wherein Y is thiazol-4-yl, R.sub.1 is H, and Z is
4-(4-trifluoromethylphenyl)-phenyl; [0341] a compound wherein Y is
thiazol-2-yl, R.sub.1 is H, and Z is
3-methyl-5-chloro-benzothiophen-2-yl; [0342] a compound wherein Y
is thiazol-2-yl, R.sub.1 is H, and Z is
4-(4-trifluoromethylphenylmethyl)-phenyl; [0343] a compound wherein
Y is thiazol-2-yl, R.sub.1 is H, and Z is 2-phenyl-benzoxazol-6-yl;
[0344] a compound wherein Y is thiazol-2-yl, R.sub.1 is H, and Z is
4-(3-methanesulfonylphenyl)phenyl; [0345] a compound wherein Y is
thiazol-2-yl, R.sub.1 is H, and Z is 5-bromo-naphth-2-yl; [0346] a
compound wherein Y is thiazol-2-yl, R.sub.1 is H, and Z is
4-(3-trifluoromethylphenylmethyl)-phenyl; [0347] a compound wherein
Y is thiazol-2-yl, R.sub.1 is H, and Z is 6-phenyl-naphth-2-yl;
[0348] a compound wherein Y is thiazol-4-yl, R.sub.1 is H, and Z is
2-phenyl-benzothiazol-6-yl; [0349] a compound wherein Y is
thiazol-2-yl, R.sub.1 is H, and Z is 6-bromo-benzothiophen-2-yl;
[0350] a compound wherein Y is phenyl, R.sub.1 is H, and Z is
5-bromo-naphth-2-yl; [0351] a compound wherein Y is phenyl, R.sub.1
is H, and Z is 5-phenyl-naphth-2-yl; [0352] a compound wherein Y is
phenyl, R.sub.1 is H, and Z is 4-(4-trifluoromethyl
phenylmethyl)-phenyl; [0353] a compound wherein Y is thiazol-2-yl,
R.sub.1 is H, and Z is 1-phenyl-1H-indol-6-yl; [0354] a compound
wherein Y is thiazol-2-yl, R.sub.1 is H, and Z is
2-(3-trifluoromethylphenyl)-benzoxazol-6-yl; [0355] a compound
wherein Y is thiazol-2-yl, R.sub.1 is H, and Z is 4-phenyl-phenyl;
[0356] a compound wherein Y is thiazol-2-yl, R.sub.1 is H, and Z is
2-(4-trifluoromethylphenyl)-benzoxazol-6-yl; [0357] a compound
wherein Y is phenyl, R.sub.1 is H, and Z is
4-(phenylmethyl)-phenyl; [0358] a compound wherein Y is
thiazol-2-yl, R.sub.1 is H, and Z is 4-phenoxy-phenyl; [0359] a
compound wherein Y is thiazol-2-yl, R.sub.1 is H, and Z is
2-(4-chlorophenyl)-benzoxazol-6-yl; [0360] a compound wherein Y is
phenyl, R.sub.1 is H, and Z is 6-phenyl-naphth-2-yl; [0361] a
compound wherein Y is thiazol-2-yl, R.sub.1 is H, and Z is
2-phenyl-benzoxazol-5-yl; [0362] a compound wherein Y is phenyl,
R.sub.1 is H, and Z is 3-methyl-5-chloro-benzothiophen-2-yl; [0363]
a compound wherein Y is thiazol-2-yl, R.sub.1 is methyl, and Z is
6-trifluoromethyl-benzothiophen-2-yl; [0364] a compound wherein Y
is thiazol-2-yl, R.sub.1 is H, and Z is 4-(phenylcarbonyl)-phenyl;
[0365] a compound wherein Y is phenyl, R.sub.1 is H, and Z is
4-phenyl-phenyl; [0366] a compound wherein Y is thiazol-2-yl,
R.sub.1 is H, and Z is 6-bromo-naphth-2-yl; [0367] a compound
wherein Y is phenyl, R.sub.1 is H, and Z is
2-phenyl-benzoxazol-6-yl; [0368] a compound wherein Y is phenyl,
R.sub.1 is H, and Z is 6-bromo-naphth-2-yl; [0369] a compound
wherein Y is thiazol-2-yl, R.sub.1 is H, and Z is 4-bromophenyl;
[0370] a compound wherein Y is phenyl, R.sub.1 is H, and Z is
5-trifluoromethyl-benzothiophen-2-yl; [0371] a compound wherein Y
is phenyl, R.sub.1 is H, and Z is 4-phenoxy-phenyl; [0372] a
compound wherein Y is thiazol-4-yl, R.sub.1 is H, and Z is
2-bromo-benzothiazol-6-yl; [0373] a compound wherein Y is
thiazol-2-yl, R.sub.1 is H, and Z is
5-trifluoromethyl-benzothiazol-2-yl; [0374] a compound wherein Y is
thiazol-4-yl, R.sub.1 is methyl, and Z is
6-trifluoromethyl-benzothiophen-2-yl; [0375] a compound wherein Y
is thiazol-4-yl, R.sub.1 is H, and Z is
6-trifluoromethyl-benzothiophen-2-yl; [0376] a compound wherein Y
is thiazol-2-yl, R.sub.1 is H, and Z is
3-chloro-6-trifluoromethyl-benzothiophen-2-yl; [0377] a compound
wherein Y is thiazol-4-yl, R.sub.1 is H, and Z is
3-chloro-6-trifluoromethyl-benzothiophen-2-yl; [0378] a compound
wherein Y is thiazol-2-yl, R.sub.1 is H, and Z is
1-phenyl-1H-indazol-5-yl; [0379] a compound wherein Y is
thiazol-2-yl, R.sub.1 is H, and Z is 5-phenyl-naphth-2-yl; [0380] a
compound wherein Y is thiazol-4-yl, R.sub.1 is H, and Z is
1-(3,4-difluorophenyl)-1H-indol-5-yl; [0381] a compound wherein Y
is thiazol-2-yl, R.sub.1 is H, and Z is
1-(2,4-difluorophenyl)-1H-indol-5-yl; [0382] a compound wherein Y
is thiazol-2-yl, R.sub.1 is H, and Z is
3-methyl-6-trifluoromethyl-benzothiophen-2-yl; [0383] a compound
wherein Y is thiazol-2-yl, R.sub.1 is H, and Z is
1-(3,4-difluorophenyl)-1H-indol-5-yl; [0384] a compound wherein Y
is thiazol-2-yl, R.sub.1 is H, and Z is
2-methyl-4-(3-trifluoromethylphenyl)-phenyl; [0385] a compound
wherein Y is thiazol-2-yl, R.sub.1 is H, and Z is
2-fluoro-4-(4-trifluoromethylphenyl)-phenyl; [0386] a compound
wherein Y is thiazol-4-yl, R.sub.1 is H, and Z is
1-(2,4-difluorophenyl)-1H-indol-5-yl; [0387] a compound wherein Y
is thiazol-2-yl, R.sub.1 is H, and Z is
1-(4-fluorophenyl)-1H-indol-5-yl; [0388] a compound wherein Y is
thiazol-2-yl, R.sub.1 is H, and Z is
1-(4-fluorophenyl)-3-methyl-1H-indol-5-yl; [0389] a compound
wherein Y is thiazol-2-yl, R.sub.1 is H, and Z is
2-methyl-4-(4-trifluoromethylphenyl)phenyl; [0390] a compound
wherein Y is thiazol-2-yl, R.sub.1 is H, and Z is
2-fluoro-4-(3-trifluoromethylphenyl)-phenyl; [0391] a compound
wherein Y is thiazol-2-yl, R.sub.1 is H, and Z is
3-methyl-6-bromo-benzothiophen-2-yl; [0392] a compound wherein Y is
thiazol-2-yl, R.sub.1 is H, and Z is
3-methyl-6-phenyl-benzothiophen-2-yl; and [0393] a compound wherein
Y is thiazol-4-yl, R.sub.1 is H, and Z is
3-methyl-6-trifluoromethyl-benzothiophen-2-yl; and pharmaceutically
acceptable salt forms thereof.
[0394] The schemes and examples described herein were used to
prepare compounds of Formula (Ib)
##STR00066##
selected from the group consisting of [0395] a compound wherein m
is 1, and Z is 3-chloro-6-phenyl-benzothiophen-2-yl; [0396] a
compound wherein m is 1, and Z is 6-phenyl-naphth-2-yl; [0397] a
compound wherein m is 1, and Z is
1-(4-trifluoromethylphenyl)-1H-indol-5-yl; [0398] a compound
wherein m is 1, and Z is 1-(phenylsulfonyl)-1H-indol-5-yl; [0399] a
compound wherein m is 1, and Z is
6-(3-methanesulfonylphenyl)-benzothiophen-2-yl; [0400] a compound
wherein m is 1, and Z is 3-chloro-6-bromo-benzothiophen-2-yl;
[0401] a compound wherein m is 1, and Z is
3,6-diphenyl-benzothiophen-2-yl; [0402] a compound wherein m is 1,
and Z is 1-(3-trifluoromethylphenyl)-1H-indol-5-yl; [0403] a
compound wherein m is 1, and Z is
4-(5-trifluoromethyl-thien-2-yl)-phenyl; [0404] a compound wherein
m is 1, and Z is 2-phenyl-benzoxazol-5-yl; [0405] a compound
wherein m is 1, and Z is
2-(3-trifluoromethylphenyl)-benzoxazol-6-yl; [0406] a compound
wherein m is 1, and Z is 5-phenyl-benzothiophen-2-yl; [0407] a
compound wherein m is 1, and Z is
4-(3-methanesulfonylphenyl)phenyl; [0408] a compound wherein m is
1, and Z is 6-trifluoromethyl-benzothiophen-2-yl; [0409] a compound
wherein m is 1, and Z is
5-(3-methanesulfonylphenyl)benzothiophen-2-yl; [0410] a compound
wherein m is 1, and Z is 5-bromo-naphth-2-yl; [0411] a compound
wherein m is 1, and Z is 2-phenyl-benzoxazol-6-yl; [0412] a
compound wherein m is 1, and Z is 1-phenyl-1H-indol-5-yl; [0413] a
compound wherein m is 1, and Z is
4-(3-trifluoromethylphenylmethyl)phenyl; [0414] a compound wherein
m is 1, and Z is 6-bromo-benzothiophen-2-yl; [0415] a compound
wherein m is 1, and Z is 2-(4-chlorophenyl)-benzoxazol-6-yl; [0416]
a compound wherein m is 1, and Z is
1-(2-trifluoromethylphenyl)-1H-indol-5-yl; [0417] a compound
wherein m is 1, and Z is 6-bromo-naphth-2-yl; [0418] a compound
wherein m is 1, and Z is 4-piperadin-1-yl-phenyl; [0419] a compound
wherein m is 1, and Z is 4-phenyl-phenyl; [0420] a compound wherein
m is 1, and Z is 5-bromo-benzothiophen-2-yl; [0421] a compound
wherein m is 1, and Z is 4-(phenylmethyl)phenyl; [0422] a compound
wherein m is 1, and Z is 4-(benzothiophen-2-yl)phenyl; [0423] a
compound wherein m is 1, and Z is 4-bromophenyl; [0424] a compound
wherein m is 1, and Z is 5-phenyl-naphth-2-yl; [0425] a compound
wherein m is 1, and Z is 6-phenyl-benzothiophen-2-yl; [0426] a
compound wherein m is 1, and Z is
3-chloro-6-trifluoromethyl-benzothiophen-2-yl; [0427] a compound
wherein m is 1, and Z is 3-chloro-6-fluoro-benzothiophen-2-yl;
[0428] a compound wherein m is 1, and Z is
3-methyl-6-trifluoromethyl-benzothiophen-2-yl; and [0429] a
compound wherein m is 1, and Z is 1-(4-fluorophenyl)-1H-indol-5-yl;
and pharmaceutically acceptable salt forms thereof.
[0430] The schemes and examples described herein were used to
prepare compounds of Formula (Ic)
##STR00067##
selected from the group consisting of [0431] a compound wherein Z
is 3-methyl-6-trifluoromethyl-benzothiophen-2-yl; [0432] a compound
wherein Z is 2-methyl-4-(3-trifluoromethylphenyl)phenyl; [0433] a
compound wherein Z is 2-methyl-4-(4-trifluoromethylphenyl)phenyl;
and [0434] a compound wherein Z is
1-(4-trifluoromethylphenyl)-1H-indol-5-yl; and pharmaceutically
acceptable salt forms thereof.
BIOLOGICAL EXAMPLES
In Vitro Methods
Example 1
MGL Enzyme Activity Assay
[0435] All rate-based assays were performed in black 384-well
polypropylene PCR microplates (Abgene) in a total volume of 30
.mu.L. Substrate 4-methylumbelliferyl butyrate (4MU-B; Sigma) and
either purified mutant MGL (mut-MGLL 11-313 L179S L186S) or
purified wild type MGL (wt-MGLL 6H-11-313) were diluted separately
into 20 mM PIPES buffer (pH=7.0), containing 150 mM NaCl and 0.001%
Tween 20. Compounds of Formula (I), including Formulas I(a), I(b),
and I(c), were pre-dispensed (50 mL) into the assay plate using a
Cartesian Hummingbird prior to adding 4MU-B (25 .mu.L of 1.2.times.
solution to a final concentration of 10 .mu.M) followed by enzyme
(5 .mu.L of a 6.times. solution to a final concentration of 5 nM)
to initiate the reaction. Final compound concentrations ranged from
17 to 0.0003 .mu.M. The fluorescence change due to 4MU-B cleavage
was monitored with excitation and emission wavelengths of 335 and
440 nm, respectively, and a bandwidth of 10 nm (Safire.sup.2,
Tecan) at 37.degree. C. for 5 min.
[0436] The IC.sub.50 values for the following compounds were
determined using Microsoft Office Excel from a fit of the equation
to the concentration-response plot of the fractional activity as a
function of inhibitor concentration.
TABLE-US-00009 BIOLOGICAL DATA TABLE 1 MGL mutant MGL wild type Cpd
inh IC.sub.50 (.mu.M) inh IC.sub.50 (.mu.M) 1 0.005 <0.005 2
0.006 0.008 3 0.006 4 0.007 0.013 5 0.007 0.015 6 0.008 7 0.010
<0.005 8 0.012 9 0.013 0.506 10 0.015 0.070 11 0.015 12 0.018
<0.005 13 0.019 <0.005 14 0.027 0.009 15 0.028 16 0.032
<0.005 17 0.048 0.037 18 0.059 19 0.063 20 0.065 21 0.069 22
0.086 23 0.093 24 0.099 25 0.154 26 0.157 27 0.167 28 0.180 29
0.184 30 0.264 31 0.270 32 0.287 33 0.303 34 0.332 35 0.341 36
0.458 37 0.476 38 0.588 39 0.604 40 0.882 41 0.939 42 0.997 43
1.684 44 1.831 45 2.775 46 3.754 47 4.750 48 8.125 12.888 49
<0.005 0.014 50 <0.005 <0.005 51 <0.005 <0.005 52
<0.005 <0.005 53 <0.005 54 0.005 55 0.005 56 0.006 57
0.007 58 0.008 59 0.010 60 0.011 61 0.012 62 0.015 63 0.029 64
<0.005 65 <0.005 66 <0.005 67 <0.005 68 0.006 <0.005
69 0.008 <0.005 70 0.008 <0.005 71 0.008 72 0.009 <0.005
73 0.012 <0.005 74 0.012 <0.005 75 0.015 76 0.015 <0.005
77 0.016 0.031 78 0.017 79 0.018 0.010 80 0.019 81 0.019 82 0.022
0.016 83 0.023 84 0.031 85 0.036 86 0.050 87 0.050 88 0.096 89
0.098 90 0.154 91 0.236 92 0.242 93 0.360 94 0.412 95 0.750 96
4.674 97 <0.005 <0.005 98 <0.005 <0.005 99 <0.005
<0.005 100 <0.005 101 0.006 102 0.011 103 0.021 104 0.066 105
0.887 106 <0.005
Example 2
2-AG Accumulation Assay
[0437] To measure the accumulation of 2-AG due to inhibition of
MGL, one g rat brain was homogenized using a Polytron homogenizer
(Brinkmann, PT300) in 10 mL of 20 mM HEPES buffer (pH=7.4),
containing 125 mM NaCl, 1 mM EDTA, 5 mM KCl and 20 mM glucose.
Compounds of Formula (I) (10 .mu.M) were pre-incubated with rat
brain homogenate (50 mg). After a 15-min incubation time at
37.degree. C., CaCl.sub.2 (final concentration=10 mM) was added and
then incubated for 15 min at 37.degree. C. in a total volume of 5
mL. The reactions were stopped with 6 mL organic solvent extraction
solution of 2:1 chloroform/methanol. Accumulated 2-AG in the
organic phase was measured by a HPLC/MS method, according to the
following equation:
percent vehicle=(2-AG accumulation in the presence of compound/2-AG
accumulation in vehicle).times.100.
TABLE-US-00010 BIOLOGICAL DATA TABLE 2 Rat Brain 2AG % Rat Brain
Rat Brain 2AG Rat Brain 2AG VehCntrl Cpd 2AG % VehCntrl % VehCntrl
% VehCntrl (%) (%) No (%) @0.01 mM (%) @0.1 mM @1 mM @10 mM 1 168
370 639 2 620 3 271 4 148 5 147 347 921 7 243 8 127 9 193 160 10
659 11 220 12 215 557 13 441 14 187 15 611 16 123 17 282 355 486 18
218 19 418 20 977 21 581 23 343 24 73 49 167 50 460 51 477 52 291
53 722 54 315 55 353 56 413 57 424 58 157 59 265 60 273 61 338 62
334 63 185 64 253 65 324 66 399 67 434 68 433 69 600 70 104 165 483
736 71 400 72 781 73 295 74 323 75 1160 76 112 204 725 77 478 78
1140 79 144 253 676 80 166 81 192 409 82 490 83 416 84 152 435 85
693 86 447 87 250 88 294 89 663 97 518 98 613 99 449 100 208 101
534 102 332 103 360 106 414
Example 3
MGL ThermoFluor.RTM. Assay--Mutant
[0438] The ThermoFluor (TF) assay is a 384-well plate-based binding
assay that measures thermal stability of proteins.sup.1,2. The
experiments were carried out using instruments available from
Johnson & Johnson Pharmaceutical Research & Development,
LLC. TF dye used in all experiments was 1,8-ANS (Invitrogen: A-47).
Final TF assay conditions used for MGL studies were 0.07 mg/ml of
mutant MGL, 100 .mu.M ANS, 200 mM NaCl, 0.001% Tween-20 in 50 mM
PIPES (pH=7.0).
[0439] Screening compound plates contained 100% DMSO compound
solutions at a single concentration. For follow-up
concentration-response studies, compounds were arranged in a
pre-dispensed plate (Greiner Bio-one: 781280), wherein compounds
were serially diluted in 100% DMSO across 11 columns within a
series. Columns 12 and 24 were used as DMSO reference and contained
no compound. For both single and multiple compound
concentration-response experiments, the compound aliquots (46 mL)
were robotically predispensed directly into 384-well black assay
plates (Abgene: TF-0384/k) using the Hummingbird liquid handler.
Following compound dispension, protein and dye solutions were added
to achieve the final assay volume of 3 .mu.L. The assay solutions
were overlayed with 1 .mu.L of silicone oil (Fluka, type DC 200:
85411) to prevent evaporation.
[0440] Bar-coded assay plates were robotically loaded onto a
thermostatically controlled PCR-type thermal block and then heated
from 40 to 90.degree. C. degrees at a ramp-rate of 1.degree. C./min
for all experiments. Fluorescence was measured by continuous
illumination with UV light (Hamamatsu LC6), supplied via fiber
optics and filtered through a band-pass filter (380-400 nm; >60D
cutoff). Fluorescence emission of the entire 384-well plate was
detected by measuring light intensity using a CCD camera (Sensys,
Roper Scientific) filtered to detect 500.+-.25 nm, resulting in
simultaneous and independent readings of all 384 wells. A single
image with 20-sec exposure time was collected at each temperature,
and the sum of the pixel intensity in a given area of the assay
plate was recorded vs temperature and fit to standard equations to
yield the T.sub.m.sup.1. [0441] 1. Pantoliano, M. W., Petrella, E.
C., Kwasnoski, J. D., Lobanov, V. S., Myslik, J., Graf, E., Carver,
T., Asel, E., Springer, B. A., Lane, P., and Salemme, F. R. (2001)
J Biomol Screen 6, 429-40. [0442] 2. Matulis, D., Kranz, J. K.,
Salemme, F. R., and Todd, M. J. (2005) Biochemistry 44,
5258-66.
[0443] The K.sub.d values for certain compounds of Formula (I) were
determined from a fit of the equation to the concentration-response
plot of the fractional activity as a function of T.sub.m. For some
experiments, quantitative NMR spectroscopy (qNMR) was used to
measure concentration of the initial 100% DMSO compound solutions
and, using the same fitting method, qK.sub.d values were
determined.
TABLE-US-00011 BIOLOGICAL DATA TABLE 3 MGL mutant Cpd ThermoFluor
No. K.sub.d (.mu.M) 1 0.006 2 0.022 3 0.0333 4 0.143 5 0.0112 7
0.010 8 0.128 9 0.014 11 0.044 12 0.051 13 0.050 14 0.086 17 0.333
18 0.215 27 0.446 31 0.154 39 0.222 43 3.33 45 0.833 46 3.40 47
2.50 48 >31 49 0.0319 50 0.0007 51 0.00220 52 0.0734 56 0.00215
58 0.0666 61 0.0333 64 0.020 67 0.0107 68 0.0033 70 0.0035 71 0.050
72 0.0332 73 0.0313 74 0.0013 75 0.007 76 0.010 77 0.1 78 0.040 79
0.0333 80 0.192 81 0.016 82 0.105 84 0.060 85 0.0250 87 0.040 92
0.1 93 0.0769 94 0.091 99 0.0027 100 0.047 101 0.004 102 0.016 103
0.033 104 0.215 105 3.64
In Vivo Methods
Example 4
CFA-Induced Paw Radiant Heat Hypersensitivity
[0444] Each rat was placed in a test chamber on a warm glass
surface and allowed to acclimate for approximately 10 min. A
radiant thermal stimulus (beam of light) was focused through the
glass onto the plantar surface of each hind paw in turn. The
thermal stimulus was automatically shut off by a photoelectric
relay when the paw was moved or when the cut-off time was reached
(20 sec for radiant heat at .about.5 amps). An initial (baseline)
response latency to the thermal stimulus was recorded for each
animal prior to the injection of complete Freund's adjuvant (CFA).
Twenty-four hours following intraplantar CFA injection, the
response latency of the animal to the thermal stimulus was
re-evaluated and compared to the animal's baseline response time.
Only rats that exhibited at least a 25% reduction in response
latency (i.e., are hyperalgesic) were included in further analysis.
Immediately following the post-CFA latency assessment, the
indicated test compound or vehicle was administered orally.
Post-compound treatment withdrawal latencies were assessed at fixed
time intervals, typically 30, 60, 120, 180, and 300 min.
The percent reversal (% R) of hypersensitivity was calculated in
one of two different ways: 1) using group mean values or 2) using
individual animal values. More specifically:
[0445] Method 1. For all compounds, the % R of hypersensitivity was
calculated using the mean value for groups of animals at each time
point according to the following formula:
% reversal=[(group treatment response-group CFA response)/(group
baseline response-group CFA response)].times.100
Results were given for the maximum % reversal observed for each
compound at any time point tested.
[0446] Method 2. For some compounds, the % R of hypersensitivity
was calculated separately for each animal according to the
following formula:
% reversal=[(individual treatment response-individual CFA
response)/(individual baseline response-individual CFA
response)].times.100.
[0447] Results are given as a mean of the maximum % reversal values
calculated for each individual animal.
TABLE-US-00012 BIOLOGICAL DATA TABLE 4 dose last time Method 1:
Method 2: Cpd (mg/kg, no. of point peak % peak % No. p.o.) vehicle
animals (min) reversal reversal 1 10 HP.beta.CD 8 300 -18.6 -19.0 1
30 HP.beta.CD 8 300 10.3 7.4 2 30 HP.beta.CD 8 300 47.9 5 30
HP.beta.CD 9 300 57.4 55.8 17 30 HP.beta.CD 8 180 27 31.5 56 30
HP.beta.CD 8 300 -1.3 67 30 HP.beta.CD 8 300 35.7 70 10 HP.beta.CD
8 300 28.2 22.5 70 30 HP.beta.CD 8 300 4.7 5 76 10 HP.beta.CD 8 300
15.7 26.7 76 30 HP.beta.CD 8 300 17.1 17.7 77 30 HP.beta.CD 8 180
9.9 6.9 79 30 HP.beta.CD 8 300 33.7 99 30 HP.beta.CD 8 300 27.6 101
30 HP.beta.CD 8 300 6.1
[0448] While the foregoing specification teaches the principles of
the present invention, with examples provided for the purpose of
illustration, it will be understood that the practice of the
invention encompasses all of the usual variations, adaptations
and/or modifications as come within the scope of the following
claims and their equivalents.
* * * * *