U.S. patent application number 12/518575 was filed with the patent office on 2010-02-04 for bipiperidinyl compounds, compositions containing such compounds and methods of treatment.
Invention is credited to Alan D. Adams, Stanley Freeman, Yong Huang, Conrad Santini, Jason W. Szewezyk, Harold B. Wood.
Application Number | 20100029688 12/518575 |
Document ID | / |
Family ID | 39277293 |
Filed Date | 2010-02-04 |
United States Patent
Application |
20100029688 |
Kind Code |
A1 |
Wood; Harold B. ; et
al. |
February 4, 2010 |
BIPIPERIDINYL COMPOUNDS, COMPOSITIONS CONTAINING SUCH COMPOUNDS AND
METHODS OF TREATMENT
Abstract
Bipiperidinyl compounds of the formula I, are disclosed as
useful for treating or preventing type 2 diabetes and similar
conditions. Pharmaceutically acceptable salts and solvates are
included as well. The compounds are useful as agonists of the
g-protein coupled receptor GPR-119. ##STR00001##
Inventors: |
Wood; Harold B.; (Westfield,
NJ) ; Adams; Alan D.; (Cranford, NJ) ;
Freeman; Stanley; (Avenel, NJ) ; Szewezyk; Jason
W.; (New York, NY) ; Santini; Conrad;
(Stirling, NJ) ; Huang; Yong; (Colonia,
NJ) |
Correspondence
Address: |
MERCK AND CO., INC
P O BOX 2000
RAHWAY
NJ
07065-0907
US
|
Family ID: |
39277293 |
Appl. No.: |
12/518575 |
Filed: |
December 14, 2007 |
PCT Filed: |
December 14, 2007 |
PCT NO: |
PCT/US2007/025687 |
371 Date: |
June 10, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60875980 |
Dec 20, 2006 |
|
|
|
Current U.S.
Class: |
514/255.05 ;
514/256; 514/316; 544/295; 544/328; 546/187 |
Current CPC
Class: |
A61P 9/12 20180101; A61P
3/10 20180101; C07D 413/14 20130101; A61P 1/18 20180101; C07D
417/14 20130101; A61P 3/06 20180101; A61P 9/10 20180101; A61P 27/02
20180101; A61P 3/04 20180101; A61P 5/50 20180101; C07D 401/14
20130101; A61P 7/12 20180101; A61P 25/00 20180101; A61P 13/12
20180101 |
Class at
Publication: |
514/255.05 ;
544/328; 514/256; 546/187; 514/316; 544/295 |
International
Class: |
A61K 31/497 20060101
A61K031/497; C07D 417/14 20060101 C07D417/14; A61K 31/506 20060101
A61K031/506; C07D 401/14 20060101 C07D401/14; A61K 31/4545 20060101
A61K031/4545; A61P 7/12 20060101 A61P007/12; A61P 3/04 20060101
A61P003/04 |
Claims
1. A compound represented by formula I: ##STR00386## or a
pharmaceutically acceptable salt or solvate thereof wherein: ring
##STR00387## represents phenyl or a 5-10 membered mono or bicyclic
Heteroaryl group containing at least one nitrogen atom, 0-2
additional nitrogen atoms, and 0-1 oxygen or sulfur atom; ring
##STR00388## is selected from thiadiazole, pyridyl, pyrimidine and
pyrazine; (1) CN or OH; (2) C.sub.1-6alkyl, OC.sub.1-6alkyl or
C.sub.3-6cycloalkyl, said members being optionally substituted with
1-3 halo groups and 1-2 members selected from the group consisting
of: i) S(O).sub.xC.sub.1-3alkyl, wherein x is 0, 1 or 2 and the
alkyl portion is optionally substituted with 1-3 halo atoms; ii) a
5-10 membered Heteroaryl moiety optionally substituted with 1-3
halo atoms or C.sub.1-3alkyl groups; iii) C.sub.1-3alkoxy or
haloC.sub.1-3alkoxy; iv) CN; v) NH.sub.2, NHC.sub.1-3alkyl and
N(C.sub.1-3alkyl).sub.2 the alkyl portions being optionally
substituted with 1-3 halo groups; vi) OH; vii) C(O)C.sub.1-6alkyl
the alkyl portion being optionally substituted with 1-3 halo atoms;
viii) phenyl optionally substituted with 1-2 halo atoms or
C.sub.1-3alkyl groups; ix) C(O)NR.sup.dR.sup.e, wherein R.sup.d is
selected from H and C.sub.1-3alkyl and R.sup.e is selected from H,
C.sub.1-6alkyl, C.sub.3-6cycloalkyl, a 5-6 membered Heteroaryl
group and phenyl; x) C(O).sub.2R.sup.e, wherein R.sup.e is as
defined above; xi) Heteroaryl optionally substituted with 1-2 halo
or C.sub.1-3alkyl groups; (3) S(O).sub.xC.sub.1-6alkyl, and
SO.sub.2NR.sup.dR.sup.e wherein the C.sub.1-6 alkyl group is
optionally substituted with 1-3 halo groups and x, R.sup.dand
R.sup.eare as defined above; (4) NH.sub.2, NH(C.sub.1-6alkyl) or
N(C.sub.1-6alkyl).sub.2, wherein the alkyl portions are optionally
substituted with 1-3 halo groups and 1 group selected from i)
through xi) above; (5) C(O)NR.sup.dR.sup.e, wherein R.sup.d and
R.sup.e are as defined above; (6) C(O)C.sub.1-6alkyl optionally
substituted with 1-3 halo atoms; (7) CO.sub.2R.sup.e, wherein
R.sup.e is as defined above; (8) Phenyl, a 5-10 membered Heteroaryl
or a 5-10 membered Heterocyclic moiety, each being optionally
substituted with 1-3 halo atoms and 1-2 C.sub.1-3 alkyl groups, and
the remaining R.sup.1 groups are H or halo; each R.sup.2 is H or
halo, or 1-2 are H or halo and the remainder are selected from the
group consisting of: 1) CN; 2) NR.sup.fR.sup.g, wherein R.sup.f and
R.sup.g each represent H or C.sub.1-3alkyl, 3) C.sub.1-6alkyl or
OC.sub.1-6alkyl, said alkyl and alkyl portion being optionally
substituted with 1-3 halo groups and 0-1 of NR.sup.fR.sup.g,
S(O).sub.xC.sub.1-3alkyl, SO.sub.2NR.sup.fR.sup.g and phenyl; 4)
S(O).sub.xC.sub.1-3alkyl, and 5) SO.sub.2NR.sup.fR.sup.g, and at
least one R.sup.1 and R.sup.2 group represents a moiety other than
hydrogen.
2. A compound in accordance with claim 1 wherein ring A represents
a 5-6 membered monocyclic aryl or heteroaryl group containing at
least one nitrogen atom and 0-2 additional nitrogen atoms, and 0-1
additional oxygen or sulfur atom.
3. A compound in accordance with claim 2 wherein ring A represents
a member selected from the group consisting of: phenyl, thiazole,
thiadiazole, pyridyl, pyrimidine and pyrazine.
4. A compound in accordance with claim 3 wherein ring A represents
a member selected from the group consisting of: phenyl, pyridyl,
pyrimidine and pyrazine.
5-7. (canceled)
8. A compound in accordance with claim 1 wherein: each R.sup.1 is H
or halo, or 1-2 R.sup.1 groups are selected from the group
consisting of: (1) CN; (2) C.sub.1-6alkyl, optionally substituted
with 1-3 halo groups and 1-2 members selected from the group
consisting of: i) S(O).sub.xC.sub.1-3 alkyl, wherein x is 0, 1 or
2; ii) NH.sub.2, NHCH.sub.3 and N(CH.sub.3).sub.2; iii) OH; iv)
C(O)C.sub.1-4alkyl; v) phenyl optionally substituted with 1-2 halo
atoms or C.sub.1-3alkyl groups; vi) C(O)NR.sup.dR.sup.e, wherein
R.sup.d is selected from H and CH.sub.3 and R.sup.e is selected
from H, CH.sub.3, CH.sub.2CH.sub.3, cyclopropyl, cyclopropylmethyl,
a 5-6 membered Heteroaryl group and phenyl; vii) C(O).sub.2R.sup.e,
wherein R.sup.e is as defined above; viii) Heteroaryl optionally
substituted with 1-2 halo or CH.sub.3 groups; (3)
S(O).sub.xC.sub.1-6alkyl, wherein the C.sub.1-6 alkyl group is
optionally substituted with 1-3 halo groups and x, R.sup.dand
R.sup.eare as defined above; (4) NH.sub.2, NH(C.sub.1-3alkyl) or
N(C.sub.1-3alkyl).sub.2, wherein the alkyl portions are optionally
substituted with 1-3 halo groups; (5) C(O)NR.sup.dR.sup.e, wherein
R.sup.d and R.sup.e are as defined above; (6) C(O)C.sub.1-6alkyl
optionally substituted with 1-3 halo atoms; (7) CO.sub.2R.sup.e,
wherein R.sup.e is as defined above; (8) Phenyl, a 5-6 membered
Heteroaryl or a 5-6 membered Heterocyclic moiety, each being
optionally substituted with 1-3 halo atoms and 1-2 C.sub.1-3alkyl
groups, and the remaining R.sup.1 groups are H or halo, and at
least one R.sup.1 and R.sup.2 group represents a moiety other than
hydrogen.
9. A compound in accordance with claim 8 wherein: each R.sup.1 is H
or halo selected from F and Cl, or 1-2 R.sup.1 groups are selected
from the group consisting of: (1) CN; (2) C.sub.1-6alkyl,
optionally substituted with 1-3 halo groups and 1-2 members
selected from the group consisting of: i) S(O).sub.2CH.sub.3; ii)
phenyl optionally substituted with 1-2 halo atoms or CH.sub.3
groups; iii) C(O)NR.sup.dR.sup.e, wherein R.sup.d is selected from
H and CH.sub.3 and Re is selected from H, CH.sub.3,
CH.sub.2CH.sub.3, cyclopropyl, cyclopropylmethyl, cyclopropyl
substituted with methyl, a 5-6 membered Heteroaryl group and
phenyl; (3) SO.sub.2C.sub.1-2alkyl, wherein the C.sub.1-2 alkyl
group is optionally substituted with 1-3 halo groups and x,
R.sup.dand R.sup.eare as defined above; (4) N(CH.sub.3).sub.2; (5)
C(O)NR.sup.dR.sup.e, wherein R.sup.d and R.sup.e are as defined
above; (6) CO.sub.2H or CO.sub.2CH.sub.3; and the remaining R.sup.1
groups are H or halo selected from F and Cl, and at least one
R.sup.1 and R.sup.2 group represents a moiety other than
hydrogen.
10. A compound in accordance with claim 9 wherein: 1 R.sup.1 group
is selected from the group consisting of: (1) CN; (2)
C.sub.1-4alkyl, optionally substituted with 1-3 fluoro groups and 1
member selected from the group consisting of: i) SO.sub.2CH.sub.3;
ii) phenyl optionally substituted with 1-2 fluoro, chloro or
CH.sub.3 groups; iii) C(O)NR.sup.dR.sup.e, wherein R.sup.d is H and
R.sup.e is selected from H, CH.sub.3, CH.sub.2CH.sub.3,
cyclopropyl, cyclopropyl substituted with methyl and
cyclopropylmethyl, (3) SO.sub.2CH.sub.3, (4) N(CH.sub.3).sub.2; (5)
C(O)NR.sup.dR.sup.e, wherein R.sup.d is H and R.sup.e is as defined
above; (6) CO.sub.2H or CO.sub.2CH.sub.3; and the remaining R.sup.1
groups are H or halo selected from F and Cl, and at least one
R.sup.1 and R.sup.2 group represents a moiety other than
hydrogen.
11. A compound in accordance with claim 1 wherein: each R.sup.2 is
H or halo, or 1-2 are H or halo and the remainder are selected from
the group consisting of: 1) CN; 2) NR.sup.fR.sup.g, wherein R.sup.f
and R.sup.g each represent H or CH.sub.3, 3) C.sub.1-6alkyl
optionally substituted with 1-3 fluorine atoms; and 4)
SO.sub.2C.sub.1-3alkyl, and at least one R.sup.1 and R.sup.2 group
represents a moiety other than hydrogen.
12. A compound in accordance with claim 11 wherein: each R.sup.2 is
H, Cl or F, or 1-2 are H, Cl or F and the remainder are selected
from the group consisting of: 1) CN; 2) NH.sub.2 or NHCH.sub.3; 3)
CH.sub.3 or CF.sub.3; and 4) SO.sub.2CH.sub.3, and at least one
R.sup.1 and R.sup.2 group represents a moiety other than
hydrogen.
13. A compound in accordance with claim 1 wherein: ring A
represents a 5-6 membered monocyclic aryl or heteroaryl group
containing at least one nitrogen atom and 0-2 additional nitrogen
atoms, and 0-1 additional oxygen or sulfur atom; ring B is selected
from thiadiazole, pyridyl, pyrimidine and pyrazine; each R.sup.1is
H or halo, or 1-2 R.sup.1 groups are selected from the group
consisting of: (1) CN; (2) C.sub.1-6alkyl, optionally substituted
with 1-3 halo groups and 1-2 members selected from the group
consisting of: i) S(O).sub.xC.sub.1-3alkyl, wherein x is 0, 1 or 2;
ii) NH.sub.2, NHCH.sub.3 and N(CH.sub.3).sub.2; iii) OH; iv)
C(O)C.sub.1-4alkyl; v) phenyl optionally substituted with 1-2 halo
atoms or C.sub.1-3alkyl groups; vi) C(O)NR.sup.dR.sup.e, wherein
R.sup.d is selected from H and CH.sub.3 and R.sup.e is selected
from H, CH.sub.3, CH.sub.2CH.sub.3, cyclopropyl, cyclopropylmethyl,
a 5-6 membered Heteroaryl group and phenyl; vii) C(O).sub.2R.sup.e,
wherein R.sup.e is as defined above; viii) Heteroaryl optionally
substituted with 1-2 halo or CH.sub.3 groups; (3)
S(O).sub.xC.sub.1-6alkyl, wherein the C.sub.1-6 alkyl group is
optionally substituted with 1-3 halo groups and x, R.sup.dand
R.sup.eare as defined above; (4) NH.sub.2, NH(C.sub.1-3alkyl) or
N(C.sub.1-3alkyl).sub.2, wherein the alkyl portions are optionally
substituted with 1-3 halo groups; (5) C(O)NR.sup.dR.sup.e, wherein
R.sup.d and R.sup.3 are as defined above; (6) C(O)C.sub.1-6alkyl
optionally substituted with 1-3 halo atoms; (7) CO.sub.2R.sup.e,
wherein R.sup.e is as defined above; (8) Phenyl, a 5-6 membered
Heteroaryl or a 5-6 membered Heterocyclic moiety, each being
optionally substituted with 1-3 halo atoms and 1-2 C.sub.1-3alkyl
groups, and the remaining R.sup.1 groups are H or halo, and each
R.sup.2 is H or halo, or 1-2 are H or halo and the remainder are
selected from the group consisting of: 1) CN; 2) NR.sup.fR.sup.g,
wherein R.sup.f and R.sup.g each represent H or CH.sub.3, 3)
C.sub.1-6alkyl optionally substituted with 1-3 fluorine atoms; and
4) SO.sub.2C.sub.1-3alkyl, and at least one R.sup.1 and R.sup.2
group represents a moiety other than hydrogen.
14. A compound selected from the group consisting of:
1-(5-fluoro-2-methylpyrimidin-4-yl)-1'-(5-fluoropyrimidin-2-yl)-4,4'-bipi-
peridine;
1-(5-fluoro-2-methylpyrimidin-4-yl)-1'-pyrimidin-2-yl-4,4'-bipip-
eridine;
6-[1'-(5-chloropyrimidin-2-yl)-4,4'-bipiperidin-1-yl]pyrimidine-4-
-carbonitrile;
6-(1'-pyrimidin-2-yl-4,4'-bipiperidin-1-yl)pyrimidine-4-carbonitrile;
1-(5-bromopyrimidin-2-yl)-1'-[4-(methylsulfonyl)phenyl]-4,4'-bipiperidine-
;
1-(3-methylpyrazin-2-yl)-1'-[4-(methylsulfonyl)phenyl]-4,4'-bipiperidine-
;
N,N-dimethyl-5-{1'-[4-(methylsulfonyl)phenyl]-4,4'-bipiperidin-1-yl}-1,2-
,4-thiadiazol-3-amine; methyl
4-{1'-[3-(dimethylamino)-1,2,4-thiadiazol-5-yl]-4,4'-bipiperidin-1-yl}ben-
zoate;
4-{1'-[3-(dimethylamino)-1,2,4-thiadiazol-5-yl]-4,4'-bipiperidin-1--
yl}benzoic acid;
N-cyclopropyl-4-{1'-[3-(dimethylamino)-1,2,4-thiadiazol-5-yl]-4,4'-bipipe-
ridin-1-yl}benzamide;
4-{1'-[3-(dimethylamino)-1,2,4-thiadiazol-5-yl]-4,4'-bipiperidin-1-yl}-N,-
N-dimethylbenzamide;
N,N-dimethyl-5-(1'-{4-[(methylsulfonyl)methyl]phenyl}-4,4'-bipiperidin-1--
yl)-1,2,4-thiadiazol-3-amine;
N,N-dimethyl-5-{1'-[6-(methylsulfonyl)-3-pyridinyl]-4,4'-bipiperidin-1-yl-
}-1,2,4-thiadiazol-3-amine;
5-{1'-[3-bromo-4-(methylsulfonyl)phenyl]-4,4'-bipiperidin-1-yl}-N,N-dimet-
hyl-1,2,4-thiadiazol-3-amine;
6-{1'-[3-(dimethylamino)-1,2,4-thiadiazol-5-yl]-4,4'-bipiperidin-1-yl}-N--
(1-methylcyclopropyl)nicotinamide;
4-{1'-[3-(dimethylamino)-1,2,4-thiadiazol-5-yl]-4,4'-bipiperidin-1-yl}-N--
(1-methylcyclopropyl)benzamide;
4-{1'-[3-(dimethylamino)-1,2,4-thiadiazol-5-yl]-4,4'-bipiperidin-1-yl}-2--
fluoro-N-(1-methylcyclopropyl)benzamide; TABLE-US-00019 Ex.
Structure 14.1 ##STR00389## 13.29 ##STR00390## 14.2 ##STR00391##
13.30 ##STR00392## 14.3 ##STR00393## 13.31 ##STR00394## 14.4
##STR00395## 13.32 ##STR00396## 14.5 ##STR00397## 13.33
##STR00398## 14.6 ##STR00399## 13.34 ##STR00400## 14.7 ##STR00401##
13.35 ##STR00402## 14.8 ##STR00403## 13.36 ##STR00404## 14.9
##STR00405## 15.1 ##STR00406## 14.10 ##STR00407## 15.2 ##STR00408##
14.11 ##STR00409## 15.3 ##STR00410## 14.12 ##STR00411## 15.4
##STR00412## 14.13 ##STR00413## 15.5 ##STR00414## 14.14
##STR00415## 15.6 ##STR00416## 14.14 ##STR00417## 15.7 ##STR00418##
14.15 ##STR00419## 15.8 ##STR00420## 14.15 ##STR00421## 16.1
##STR00422## 14.16 ##STR00423## 16.2 ##STR00424## 14.17
##STR00425## 16.3 ##STR00426## 14.18 ##STR00427## 16.4 ##STR00428##
14.19 ##STR00429## 16.5 ##STR00430## 14.20 ##STR00431## 16.6
##STR00432## 14.21 ##STR00433## 16.7 ##STR00434## 14.22
##STR00435## 16.8 ##STR00436## 14.23 ##STR00437## 16.9 ##STR00438##
14.24 ##STR00439## 16.10 ##STR00440## 14.25 ##STR00441## 16.11
##STR00442## 14.26 ##STR00443## 17.1 ##STR00444## 14.27
##STR00445## 17.2 ##STR00446## 14.28 ##STR00447## 17.3 ##STR00448##
14.29 ##STR00449## 17.4 ##STR00450## 14.30 ##STR00451## 17.5
##STR00452## 14.31 ##STR00453## 18.1 ##STR00454## 14.32
##STR00455## 18.2 ##STR00456## 14.33 ##STR00457## 18.3 ##STR00458##
14.34 ##STR00459## 18.4 ##STR00460## 14.35 ##STR00461## 18.5
##STR00462## 19.4 ##STR00463## 18.6 ##STR00464## 19.5 ##STR00465##
18.7 ##STR00466## 19.6 ##STR00467## 18.8 ##STR00468## 19.7
##STR00469## 18.9 ##STR00470## 19.8 ##STR00471## 18.10 ##STR00472##
19.9 ##STR00473## 18.11 ##STR00474## 19.10 ##STR00475## 18.12
##STR00476## 19.11 ##STR00477## 18.13 ##STR00478## 19.12
##STR00479## 18.14 ##STR00480## 19.13 ##STR00481## 18.15
##STR00482## 19.14 ##STR00483## 18.16 ##STR00484## 19.15
##STR00485## 18.17 ##STR00486## 19.16* ##STR00487## 19.17
##STR00488## 19.18 ##STR00489## 19.19 ##STR00490## 18.21
##STR00491## 19.20 ##STR00492## 18.22 ##STR00493## 19.21
##STR00494## 18.23 ##STR00495## 19.22 ##STR00496## 18.24
##STR00497## 19.23 ##STR00498##
18.25 ##STR00499## 19.24 ##STR00500## 18.26 ##STR00501## 19.25
##STR00502## 19.26 ##STR00503## 19.27 ##STR00504## 19.28
##STR00505## 19.29 ##STR00506## 18.31 ##STR00507## 19.30
##STR00508## 18.32 ##STR00509## 19.31 ##STR00510## 18.33
##STR00511## 19.32 ##STR00512## 18.34 ##STR00513## 19.33
##STR00514## 18.35 ##STR00515## 19.34 ##STR00516## 18.36
##STR00517## 19.35 ##STR00518## 18.37 ##STR00519## 19.36
##STR00520## 18.38 ##STR00521## 19.37 ##STR00522## 18.39
##STR00523## 19.38 ##STR00524## 18.40 ##STR00525## 19.39
##STR00526## 18.41 ##STR00527## 18.42 ##STR00528## 18.43
##STR00529## 18.44 ##STR00530## 18.45 ##STR00531## 18.46
##STR00532## 18.47 ##STR00533## 18.48 ##STR00534##
or a pharmaceutically acceptable salt or solvate thereof
15. A pharmaceutical composition comprised of a compound in
accordance with claim 1 in combination with a pharmaceutically
acceptable carrier.
16. A method of treating hyperglycemia, diabetes or insulin
resistance in a mammalian patient in need of such treatment which
comprises administering to said patient a compound in accordance
with claim 1 in an amount that is effective to treate
hyperglycemia, diabetes or insulin resistance.
17. A method treating type 2 diabetes in a mammalian patient in
need of such treatment comprising administering to the patient a
compound in accordance with claim 1 in an amount that is effective
to treat type 2 diabetes.
18. A method of treating non-insulin dependent diabetes mellitus in
a mammalian patient in need of such treatment comprising
administering to the patient a compound in accordance with claim 1
in an amount that is effective to treat non-insulin dependent
diabetes mellitus.
19. A method of treating obesity in a mammalian patient in need of
such treatment comprising administering to said patient a compound
in accordance with claim 1 in an amount that is effective to treat
obesity.
20-35. (canceled)
Description
BACKGROUND OF THE INVENTION
[0001] The present invention relates to G-protein coupled receptor
agonists. In particular, the present invention is directed to
agonists of GPR 119 that are useful for the treatment of diabetes,
especially type 2 diabetes, obesity, the metabolic syndrome and
related diseases and conditions.
[0002] Diabetes is a disease derived from multiple causative
factors. It is characterized by elevated levels of plasma glucose
(hyperglycemia) in the fasting state or after administration of
glucose during an oral glucose tolerance test. There are two
generally recognized forms of diabetes. In type 1 diabetes, or
insulin-dependent diabetes mellitus (IDDM), patients produce little
or no insulin, the hormone which regulates glucose utilization. In
type 2 diabetes, or noninsulin-dependent diabetes mellitus (T2DM),
insulin is still produced in the body, and patients demonstrate
resistance to the effects of insulin in stimulating glucose and
lipid metabolism in the main insulin-sensitive tissues, namely,
muscle, liver and adipose tissue. These patients often have normal
levels of insulin, and may have hyperinsulinemia (elevated plasma
insulin levels), as they compensate for the reduced effectiveness
of insulin by secreting increased amounts of insulin.
[0003] Insulin resistance is not primarily caused by a diminished
number of insulin receptors but rather by a post-insulin receptor
binding defect that is not yet completely understood. This lack of
responsiveness to insulin results in insufficient insulin-mediated
activation of uptake, oxidation and storage of glucose in muscle,
and inadequate insulin-mediated repression of lipolysis in adipose
tissue and of glucose production and secretion in the liver.
[0004] Persistent or uncontrolled hyperglycemia that occurs with
diabetes is associated with increased and premature morbidity and
mortality. Often abnormal glucose homeostasis is associated both
directly and indirectly with obesity, hypertension, and alterations
of the lipid, lipoprotein and apolipoprotein metabolism, as well as
other metabolic and hemodynamic disease. Patients with type 2
diabetes mellitus have a significantly increased risk of
macrovascular and microvascular complications, including
atherosclerosis, coronary heart disease, stroke, peripheral
vascular disease, hypertension, nephropathy, neuropathy, and
retinopathy. Therefore, therapeutic control of glucose homeostasis,
lipid metabolism, obesity, and hypertension are critically
important in the clinical management and treatment of diabetes
mellitus.
[0005] Patients who have insulin resistance often have several
symptoms that together are referred to as syndrome X, or the
metabolic syndrome. According to one widely used definition, a
patient having metabolic syndrome is characterized as having three
or more symptoms selected from the following group of five
symptoms: (1) abdominal obesity; (2) hypertriglyceridemia; (3) low
high-density lipoprotein cholesterol (HDL); (4) high blood
pressure; and (5) elevated fasting glucose, which may be in the
range characteristic of Type 2 diabetes if the patient is also
diabetic. Each of these symptoms is defined clinically in the Third
Report of the National Cholesterol Education Program Expert Panel
on Detection, Evaluation and Treatment of High Blood Cholesterol in
Adults (Adult Treatment Panel III, or ATP III), National Institutes
of Health, 2001, NIH Publication No. 01-3670. Patients with
metabolic syndrome, whether or not they have or develop overt
diabetes mellitus, have an increased risk of developing the
macrovascular and microvascular complications that occur with type
2 diabetes, such as atherosclerosis and coronary heart disease.
[0006] Obesity, a multifactorial pathophysiological state, is
characterized by excessive adiposity relative to body mass.
Clinically, obesity is defined by the body mass index [BMI=weight
(kg)/height (m).sup.2], corresponding to BMI values .gtoreq.30.
Obesity and being overweight increases the risk of developing
conditions such as high blood pressure, type 2 diabetes, heart
disease, stroke, osteoarthritis, sleep apnea, gallbladder disease
and cancer of the breast, prostate and colon. Higher body weights
are also associated with increases in all-cause mortality.
[0007] The mainstay of treatment for obesity is an energy-limited
diet and increased exercise. Guidelines for the management of
obesity through such regimes have been published (e.g. Snow et al.,
Ann. Intern. Med. 142:525 [2005]). Although high compliance is
difficult to achieve, such programs can produce an average weight
loss of .about.8%. A more intractable therapeutic problem appears
to be weight loss maintenance. Of dieters who manage to lose 10% or
more of their body mass in studies, 80-95% will regain that weight
within two to five years. It appears that the homeostatic
mechanisms regulating body weight are very robust, and vigorously
defend against weight loss.
[0008] There are limited pharmacological therapies for the
treatment of obesity. Orlistat (Xenical.RTM.), which reduces
intestinal fat absorption by inhibiting pancreatic lipase, and the
anorectic agent sibutramine (Reductil.RTM., Meridia.RTM.), a
central monoamine re-uptake inhibitor, are the primary agents used
to treat obesity, but are associated with gastrointestinal and
cardiovascular side effects, respectively, and have limited
efficacy and durability in reducing body weight. Other anorectics
such as phentermine, bupropion, and diethylpropion have limited use
due to side effects and, many of these drugs, like sibutramine, are
schedule IV controlled substances due to the risk of addiction.
Recently, a CB-1 antagonist, rimonabant (Accomplia) has been
launched but long term durability and efficacy remains to be
determined, and the drug has CNS side effects including
dysphoria.
[0009] In patients with BMI>40 who fail to achieve their weight
loss goals (with or without medication) and who develop
obesity-related complications, referral for bariatric surgery may
be indicated, but as with other surgical procedures, there is an
attendant risk of complications.
[0010] There are several available treatments for type 2 diabetes,
each of which has its own limitations and potential risks. Physical
exercise and a reduction in dietary intake of calories often
dramatically improve the diabetic condition and are the usual
recommended first-line treatment of type 2 diabetes and of
pre-diabetic conditions associated with insulin resistance.
Compliance with this treatment is very poor because of
well-entrenched sedentary lifestyles and excess food consumption,
especially of foods containing high amounts of fat and
carbohydrates. Pharmacologic treatments have focused on three areas
of pathophysiology: (1) Hepatic glucose production (biguanides),
(2) insulin resistance (PPAR agonists), and (3) insulin
secretion.
[0011] The biguanides are a class of drugs that are widely used to
treat type 2 diabetes. The two best known biguanides, phenformin
and metformin, cause some correction of hyperglycemia. The
biguanides act primarily by inhibiting hepatic glucose production,
and they also are believed to modestly improve insulin sensitivity.
The biguanides can be used as monotherapy or in combination with
other anti-diabetic drugs, such as insulin or an insulin
secretagogues, without increasing the risk of hypoglycemia.
However, phenformin and metformin can induce lactic acidosis and
nausea/diarrhea. Metformin has a lower risk of side effects than
phenformin and is widely prescribed for the treatment of Type 2
diabetes.
[0012] The glitazones (i.e. 5-benzylthiazolidine-2,4-diones) are a
newer class of compounds that can ameliorate hyperglycemia and
other symptoms of type 2 diabetes. The glitazones that are
currently marketed (rosiglitazone and pioglitazone) are agonists of
the peroxisome proliferator activated receptor (PPAR) gamma
subtype. The PPAR-gamma agonists substantially increase insulin
sensitivity in muscle, liver and adipose tissue in several animal
models of type 2 diabetes, resulting in partial or complete
correction of elevated plasma glucose levels without the occurrence
of hypoglycemia. PPAR-gamma agonism is believed to be responsible
for the improved insulin sensititization that is observed in human
patients who are treated with the glitazones. New PPAR agonists are
currently being developed. Many of the newer PPAR compounds are
agonists of one or more of the PPAR alpha, gamma and delta
subtypes. Compounds that are agonists of both the PPAR alpha and
PPAR gamma subtypes (PPAR alpha/gamma dual agonists) are promising
because they reduce hyperglycemia and also improve lipid
metabolism. The currently marketed PPAR gamma agonists are modestly
effective in reducing plasma glucose and HemoglobinA1C. The
currently marketed compounds do not greatly improve lipid
metabolism and may actually have a negative effect on the lipid
profile. Thus, the PPAR compounds represent an important advance in
diabetic therapy, but further improvements are still needed.
[0013] Another widely used drug treatment involves the
administration of insulin secretagogues, such as the sulfonylureas
(e.g. tolbutamide and glipizide). These drugs increase the plasma
level of insulin by stimulating the pancreatic .beta.-cells to
secrete more insulin. Insulin secretion in the pancreatic
.beta.-cell is under strict regulation by glucose and an array of
metabolic, neural and hormonal signals. Glucose stimulates insulin
production and secretion through its metabolism to generate ATP and
other signaling molecules, whereas other extracellular signals act
as potentiators or inhibitors of insulin secretion through GPCR's
present on the plasma membrane. Sulfonylureas and related insulin
secretagogues act by blocking the ATP-dependent K+ channel in
.beta.-cells, which causes depolarization of the cell and the
opening of the voltage-dependent Ca2+ channels with stimulation of
insulin release. This mechanism is non-glucose dependent, and hence
insulin secretion can occur regardless of the ambient glucose
levels. This can cause insulin secretion even if the glucose level
is low, resulting in hypoglycemia, which can be fatal in severe
cases. The administration of insulin secretagogues must therefore
be carefully controlled. The insulin secretagogues are often used
as a first-line drug treatment for Type 2 diabetes.
[0014] There has been a renewed focus on pancreatic islet-based
insulin secretion that is glucose-dependent. This approach has the
potential for stabilization and restoration of .beta.-cell
function. In this regard, several orphan G-protein coupled
receptors (GPCR's) have recently been identified that are
preferentially expressed in the .beta.-cell and are implicated in
glucose dependent insulin secretion (GDIS). GPR119 is a
cell-surface Gs-coupled GPCR that is highly expressed in human (and
rodent) islets as well as in insulin-secreting cell lines. A
naturally-occurring long-chain fatty acid amide, oleoylethanolamide
(OEA) and several long chain saturated and unsaturated
lysophospholipids such as 1-palmitoyl-lysophosphatidylcholine and
2-oleoyl-lysophosphatidylcholine, as well as synthetic compounds,
have recently been identified as ligands for GPR119 (Overton, H. A.
et al., Cell Metab. 3: 167 [2006]; Soga, T. et al., Biochem.
Biophys. Res. Comm. 326: 744 [2005]). Acute administration of a
synthetic small molecule GPR119 agonist to rats reduces 24 h
cumulative food intake without significantly altering locomotor
activity and in chronic studies, reduces cumulative food intake and
body weight (Overton, H. A. et al., Cell Metab. 3: 167 [2006])
indicating that GPR119 agonists may be effective anti-obesity
agents. Synthetic GPR119 agonists also augment the release of
insulin from isolated static mouse islets only under conditions of
elevated glucose, and improve glucose tolerance in diabetic mice
and diet-induced obese (DIO) C57/B6 mice without causing
hypoglycemia. GPR119 agonists therefore have the potential to
function as anti-hyperglycemic agents that produce weight loss.
There are several potential. advantages of GPR119 as a potential
target for the treatment of type 2 diabetes and obesity. First,
since GPR119-mediated insulin secretion is glucose dependent, there
is little or no risk of hypoglycemia. Second, the weight loss
efficacy of GPR119 agonists should contribute to antihyperglycemic
efficacy in diabetic and prediabetic obese subjects, and activation
of GPR119 may allow for the simultaneous treatment of the common
co-morbidities of obesity and impaired glucose tolerance/diabetes.
Third, the limited tissue distribution of GPR119 in humans (mainly
in islets and the GI tract) suggests that there would be less
chance for side effects associated with GPR119 activity in other
tissues. Fourth, GPR119 agonists may have the potential to restore
or preserve islet function since GPR119 agonists reportedly
increase GLP-1 levels in rodents (Chu, Z. L. et al Abstract P1-19,
ENDO 2005 87.sup.th Annual Meeting, San Diego, Calif.). GLP-1 is an
incretin hormone that effects GDIS and exerts anti-apoptotic and
proliferative effects on islets. A protective effect on islets upon
GPR119 agonism would be highly advantageous, because long term
diabetes therapy often leads to the gradual diminution of islet
activity, such that after extended periods of treatment with
multiple oral antihyperglycemic agents, it is often necessary to
treat type 2 diabetic patients with daily insulin injections. By
restoring or preserving islet function, GPR119 agonists may delay
or prevent the diminution and loss of islet function in a type 2
diabetic patient.
SUMMARY OF THE INVENTION
[0015] A compound represented by formula I
##STR00002##
or a pharmaceutically acceptable salt or solvate thereof
wherein:
[0016] one of
##STR00003##
one of represents a 5-10 membered mono or bicyclic Heteroaryl group
containing at least one nitrogen atom, 0-2 additional nitrogen
atoms, and 0-1 oxygen or sulfur atom, and the other represents
phenyl or a 5-10 membered mono or bicyclic Heteroaryl group
containing at least one nitrogen atom, 0-2 additional nitrogen
atoms, and 0-1 oxygen or sulfur atom;
[0017] each R.sup.1 is H or halo, or 1-2 R.sup.1 groups are
selected from the group consisting of:
[0018] (1) CN or OH;
[0019] (2) C.sub.1-6alkyl, OC.sub.1-6alkyl or C.sub.3-6cycloalkyl,
said members being optionally substituted with 1-3 halo groups and
1-2 members selected from the group consisting of: [0020] i)
S(O).sub.xC.sub.1-3 alkyl, wherein x is 0, 1 or 2 and the alkyl
portion is optionally substituted with 1-3 halo atoms; [0021] ii) a
5-10 membered Heteroaryl moiety optionally substituted with 1-3
halo atoms or C.sub.1-3alkyl groups; [0022] iii) C.sub.1-3alkoxy or
haloC.sub.1-3alkoxy; [0023] iv) CN; [0024] v) NH.sub.2,
NHC.sub.1-3alkyl and N(C.sub.1-3alkyl).sub.2 the alkyl portions
being optionally substituted with 1-3 halo groups; [0025] vi) OH;
[0026] vii) C(O)C.sub.1-6alkyl the alkyl portion being optionally
substituted with 1-3 halo atoms; [0027] viii) phenyl optionally
substituted with 1-2 halo atoms or C.sub.1-3alkyl groups; [0028]
ix) C(O)NR.sup.dR.sup.e, wherein R.sup.d is selected from H and
C.sub.1-3alkyl and R.sup.e is selected from H, C.sub.1-6alkyl,
C.sub.3-6cycloalkyl, a 5-6 membered Heteroaryl group and phenyl;
[0029] x) C(O).sub.2R.sup.e, wherein R.sup.e is as defined above;
[0030] xi) Heteroaryl optionally substituted with 1-2 halo or
C.sub.1-3alkyl groups;
[0031] (3) S(O).sub.xC.sub.1-6alkyl, and SO.sub.2NR.sup.dR.sup.e
wherein the C.sub.1-6 alkyl group is optionally substituted with
1-3 halo groups and x, R.sup.d and R.sup.e are as defined
above;
[0032] (4) NH.sub.2, NH(C.sub.1-6alkyl) or N(C.sub.1-6alkyl).sub.2,
wherein the alkyl portions are optionally substituted with 1-3 halo
groups and 1 group selected from i) through xi) above;
[0033] (5) C(O)NR.sup.dR.sup.e, wherein R.sup.d and R.sup.e are as
defined above;
[0034] (6) C(O)C.sub.1-6alkyl optionally substituted with 1-3 halo
atoms;
[0035] (7) CO.sub.2R.sup.e, wherein R.sup.e is as defined
above;
[0036] (8) Phenyl, a 5-10 membered Heteroaryl or a 5-10 membered
Heterocyclic moiety, each being optionally substituted with 1-3
halo atoms and 1-2 C.sub.1-3 alkyl groups,
[0037] and the remaining R.sup.1 groups are H or halo;
[0038] each R.sup.2 is H or halo, or 1-2 are H or halo and the
remainder are selected from the group consisting of:
[0039] 1) CN;
[0040] 2) NR.sup.fR.sup.g, wherein R.sup.f and R.sup.g each
represent H or C.sub.1-3alkyl,
[0041] 3) C.sub.1-6alkyl or OC.sub.1-6alkyl, said alkyl and alkyl
portion being optionally substituted with 1-3 halo groups and 0-1
of NR.sup.fR.sup.g, S(O).sub.xC.sub.1-3alkyl,
SO.sub.2NR.sup.fR.sup.g and phenyl;
[0042] 4) S(O).sub.xC.sub.1-3alkyl, and
[0043] 5) SO.sub.2NR.sup.fR.sup.g,
and at least one R.sup.1 and R.sup.2 group represents a moiety
other than hydrogen.
DETAILED DESCRIPTION OF THE INVENTION
[0044] The invention is described herein in detail using the terms
defined below unless otherwise specified.
[0045] "Alkyl", as well as other groups having the prefix "alk",
such as alkoxy, and the like, means carbon chains which may be
linear, branched, or cyclic, or combinations thereof, containing
the indicated number of carbon atoms. If no number is specified,
1-6 carbon atoms are intended for linear and 3-7 carbon atoms for
branched alkyl groups. Examples of alkyl groups include methyl,
ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl,
hexyl, heptyl, octyl, nonyl and the like. Cycloalkyl is a subset of
alkyl; if no number of atoms is specified, 3-7 carbon atoms are
intended, forming 1-3 carbocyclic rings that are fused.
"Cycloalkyl" also includes monocyclic rings fused to an aryl group
in which the point of attachment is on the non-aromatic portion.
Examples of cycloalkyl include cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl,
decahydronaphthyl, indanyl and the like. Haloalkoxy and haloOalkyl
are used interchangeably and refer to halo substituted alkyl groups
linked through the oxygen atom. Haloalkyl and haloalkoxy include
mono-substituted as well as multiple substituted alkyl and alkoxy
groups, up to perhalo substituted alkyl and alkoxy. For example,
trifluoromethyl and trifluoromethoxy are included.
[0046] "Aryl" (Ar) means phenyl or naphthyl, preferably phenyl.
[0047] "Heteroaryl" (HAR) unless otherwise specified, means
monocyclic aromatic ring systems containing 5-6 atoms, at least one
of which is a heteroatom selected from O, S, S(O), SO.sub.2 and N.
Examples include, but are not limited to, pyrrolyl, isoxazolyl,
isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl,
thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl,
furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl and
the like. Heteroaryl also includes such groups in charged form,
e.g., pyridinium.
[0048] "Heterocyclyl" (Hetcy) and "heterocyclic moiety" unless
otherwise specified, means mono- and bicyclic saturated and
partially saturated rings and ring systems containing at least one
heteroatom selected from N, S and O, each of said rings having from
3 to 6 atoms in which the point of attachment may be carbon or
nitrogen. Examples of "heterocyclyl" include, but are not limited
to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,
imidazolidinyl, tetrahydrofuranyl, 1,4-dioxanyl, morpholinyl,
thiomorpholinyl, tetrahydrothienyl and the like. Heterocycles can
also exist in tautomeric forms. Heterocycles moreover includes such
moieties in charged form, e.g., piperidinium.
[0049] "Halogen" (Halo) includes fluorine, chlorine, bromine and
iodine.
[0050] One aspect of the invention that is of interest relates to a
compound represented by formula I:
##STR00004##
or a pharmaceutically acceptable salt or solvate thereof
wherein:
[0051] one of
##STR00005##
represents a 5-10 membered mono or bicyclic Heteroaryl group
containing at least one nitrogen atom, 0-2 additional nitrogen
atoms, and 0-1 oxygen or sulfur atom, and the other represents
phenyl or a 5-10 membered mono or bicyclic Heteroaryl group
containing at least one nitrogen atom, 0-2 additional nitrogen
atoms, and 0-1 oxygen or sulfur atom;
[0052] each R.sup.1 is H or halo, or 1-2 R.sup.1 groups are
selected from the group consisting of:
[0053] (1) CN or OH;
[0054] (2) C.sub.1-6alkyl, OC.sub.1-6alkyl or C.sub.3-6cycloalkyl,
said members being optionally substituted with 1-3 halo groups and
1-2 members selected from the group consisting of: [0055] i)
S(O).sub.xC.sub.1-3 alkyl, wherein x is 0, 1 or 2 and the alkyl
portion is optionally substituted with 1-3 halo atoms; [0056] ii) a
5-10 membered Heteroaryl moiety optionally substituted with 1-3
halo atoms or C.sub.1-3alkyl groups; [0057] iii) C.sub.1-3alkoxy or
haloC.sub.1-3alkoxy; [0058] iv) CN; [0059] v) NH.sub.2,
NHC.sub.1-3alkyl and N(C.sub.1-3alkyl).sub.2 the alkyl portions
being optionally substituted with 1-3 halo groups; [0060] vi) OH;
[0061] vii) C(O)C.sub.1-6alkyl the alkyl portion being optionally
substituted with 1-3 halo atoms; [0062] viii) phenyl optionally
substituted with 1-2 halo atoms or C.sub.1-3alkyl groups; [0063]
ix) C(O)NR.sup.dR.sup.e, wherein R.sup.d is selected from H and
C.sub.1-3alkyl and R.sup.e is selected from H, C.sub.1-6alkyl,
C.sub.3-6cycloalkyl, a 5-6 membered Heteroaryl group and phenyl;
[0064] x) C(O).sub.2R.sup.e, wherein R.sup.e is as defined above;
[0065] xi) Heteroaryl optionally substituted with 1-2 halo or
C.sub.1-3alkyl groups;
[0066] (3) S(O).sub.xC.sub.1-6alkyl, and SO.sub.2NR.sup.dR.sup.e
wherein the C.sub.1-6alkyl group is optionally substituted with 1-3
halo groups and x, R.sup.d and R.sup.e are as defined above;
[0067] (4) NH.sub.2, NH(C.sub.1-6alkyl) or N(C.sub.1-6alkyl).sub.2,
wherein the alkyl portions are optionally substituted with 1-3 halo
groups and 1 group selected from i) through xi) above;
[0068] (5) C(O)NR.sup.dR.sup.e, wherein R.sup.d and R.sup.e are as
defined above;
[0069] (6) C(O)C.sub.1-6alkyl optionally substituted with 1-3 halo
atoms;
[0070] (7) CO.sub.2R.sup.e, wherein R.sup.e is as defined
above;
[0071] (8) Phenyl, a 5-10 membered Heteroaryl or a 5-10 membered
Heterocyclic moiety, each being optionally substituted with 1-3
halo atoms and 1-2 C.sub.1-3 alkyl groups,
[0072] and the remaining R.sup.1 groups are H or halo;
[0073] each R.sup.2 is H or halo, or 1-2 are H or halo and the
remainder are selected from the group consisting of:
[0074] 1) CN;
[0075] 2) NR.sup.fR.sup.g, wherein R.sup.f and R.sup.g each
represent H or C.sub.1-3alkyl,
[0076] 3) C.sub.1-6alkyl or OC.sub.1-6alkyl, said alkyl and alkyl
portion being optionally substituted with 1-3 halo groups and 0-1
of NR.sup.fR.sup.g, S(O).sub.xC.sub.1-3alkyl,
SO.sub.2N.sup.fR.sup.g and phenyl;
[0077] 4) S(O).sub.xC.sub.1-3alkyl, and
[0078] 5) SO.sub.2NR.sup.fR.sup.g,
and at least one R.sup.1 and R.sup.2 group represents a moiety
other than hydrogen.
[0079] One aspect of the invention that is of interest relates to a
compound of formula I or a pharmaceutically acceptable salt or
solvate thererof wherein ring A represents a 5-6 membered
monocyclic aryl or heteroaryl group containing at least one
nitrogen atom and 0-2 additional nitrogen atoms, and 0-1 additional
oxygen or sulfur atom. Within this aspect of the invention, all
other variables are as originally defined.
[0080] More particularly, an aspect of the invention that is of
interest relates to a compound of formula I or a pharmaceutically
acceptable salt or solvate thererof wherein ring A represents a
member selected from the group consisting of: phenyl, thiazole,
thiadiazole, pyridyl, pyrimidine and pyrazine. Within this aspect
of the invention, all other variables are as originally
defined.
[0081] Even more particularly, an aspect of the invention that is
of interest relates to a compound of formula I or a
pharmaceutically acceptable salt or solvate thererof wherein ring A
represents a member selected from the group consisting of: phenyl,
pyridyl, pyrimidine and pyrazine. Within this aspect of the
invention, all other variables are as originally defined.
[0082] Another aspect of the invention that is of interest relates
to a compound of formula I or a pharmaceutically acceptable salt or
solvate thererof wherein ring B represents a 5-9 membered mono or
bicyclic heteroaryl group containing at least one nitrogen atom and
0-2 additional nitrogen atoms, and 0-1 additional oxygen or sulfur
atom. Within this aspect of the invention, all other variables are
as originally defined.
[0083] More particularly, an aspect of the invention that is of
interest relates to a compound of formula I or a pharmaceutically
acceptable salt or solvate thereof wherein ring B represents a
member selected from the group consisting of: thiazole,
thiadiazole, pyridyl, pyridazine, pyrimidine, pyrazine and
benzoxazole. Within this aspect of the invention, all other
variables are as originally defined.
[0084] Even more particularly, an aspect of the invention that is
of interest relates to a compound of formula I or a or a
pharmaceutically acceptable salt or solvate thereof wherein ring B
represents a member selected from the group consisting of:
thiadiazole, pyridyl, pyrimidine and pyrazine. Within this aspect
of the invention, all other variables are as originally
defined.
[0085] Another aspect of the invention that is of interest relates
to a compound of formula I or a pharmaceutically acceptable salt or
solvate thereof wherein:
[0086] each R.sup.1 is H or halo, or 1-2 R.sup.1 groups are
selected from the group consisting of:
[0087] (1) CN;
[0088] (2) C.sub.1-6alkyl, optionally substituted with 1-3 halo
groups and 1-2 members selected from the group consisting of:
[0089] i) S(O).sub.xC.sub.1-3alkyl, wherein x is 0, 1 or 2; [0090]
ii) NH.sub.2, NHCH.sub.3 and N(CH.sub.3).sub.2; [0091] iii) OH;
[0092] iv) C(O)C.sub.1-4alkyl; [0093] v) phenyl optionally
substituted with 1-2 halo atoms or C.sub.1-3alkyl groups; [0094]
vi) C(O)NR.sup.dR.sup.e, wherein R.sup.d is selected from H and
CH.sub.3 and R.sup.e is selected from H, CH.sub.3,
CH.sub.2CH.sub.3, cyclopropyl, cyclopropylmethyl, a 5-6 membered
Heteroaryl group and phenyl; [0095] vii) C(O).sub.2R.sup.e, wherein
R.sup.e is as defined above; [0096] viii) Heteroaryl optionally
substituted with 1-2 halo or CH.sub.3 groups;
[0097] (3) S(O).sub.xC.sub.1-6alkyl, wherein the C.sub.1-6alkyl
group is optionally substituted with 1-3 halo groups and x, R.sup.d
and R.sup.e are as defined above;
[0098] (4) NH.sub.2, NH(C.sub.1-3alkyl) or N(C.sub.1-3alkyl).sub.2,
wherein the alkyl portions are optionally substituted with 1-3 halo
groups;
[0099] (5) C(O)NR.sup.dR.sup.e, wherein R.sup.d and R.sup.e are as
defined above;
[0100] (6) C(O)C.sub.1-6alkyl optionally substituted with 1-3 halo
atoms;
[0101] (7) CO.sub.2R.sup.e, wherein R.sup.e is as defined
above;
[0102] (8) Phenyl, a 5-6 membered Heteroaryl or a 5-6 membered
Heterocyclic moiety, each being optionally substituted with 1-3
halo atoms and 1-2 C.sub.1-3alkyl groups,
[0103] and the remaining R.sup.1 groups are H or halo, and at least
one R.sup.1 and R.sup.2 group represents a moiety other than
hydrogen. Within this aspect of the invention, all other variables
are as originally defined.
[0104] More particularly, an aspect of the invention that is of
interest relates to a compound of formula I or a pharmaceutically
acceptable salt or solvate thereof wherein:
[0105] each R.sup.1 is H or halo selected from F and Cl, or 1-2
R.sup.1 groups are selected from the group consisting of:
[0106] (1) CN;
[0107] (2) C.sub.1-6alkyl, optionally substituted with 1-3 halo
groups and 1-2 members selected from the group consisting of:
[0108] i) S(O).sub.2CH.sub.3; [0109] ii) phenyl optionally
substituted with 1-2 halo atoms or CH.sub.3 groups; [0110] iii)
C(O)NR.sup.dR.sup.e, wherein R.sup.d is selected from H and
CH.sub.3 and R.sup.e is selected from H, CH.sub.3,
CH.sub.2CH.sub.3, cyclopropyl, cyclopropylmethyl, cyclopropyl
substituted with methyl, a 5-6 membered Heteroaryl group and
phenyl; [0111] (3) SO.sub.2C.sub.1-2alkyl, wherein the C.sub.1-2
alkyl group is optionally substituted with 1-3 halo groups and x,
R.sup.d and R.sup.e are as defined above;
[0112] (4) N(CH.sub.3).sub.2;
[0113] (5) C(O)NR.sup.dR.sup.e, wherein R.sup.d and R.sup.e are as
defined above;
[0114] (6) CO.sub.2H or CO.sub.2CH.sub.3;
[0115] and the remaining R.sup.1 groups are H or halo selected from
F and Cl, and at least one R.sup.1 and R.sup.2 group represents a
moiety other than hydrogen. Within this aspect of the invention,
all other variables are as originally defined.
[0116] Even more particularly, an aspect of the invention that is
of interest relates to a compound of formula I or a
pharmaceutically acceptable salt or solvate thereof wherein:
[0117] 1 R.sup.1 group is selected from the group consisting
of:
[0118] (1) CN;
[0119] (2) C.sub.1-4alkyl, optionally substituted with 1-3 fluoro
groups and 1 member selected from the group consisting of: [0120]
i) SO.sub.2CH.sub.3; [0121] ii) phenyl optionally substituted with
1-2 fluoro, chloro or CH.sub.3 groups; [0122] iii)
C(O)NR.sup.dR.sup.e, wherein R.sup.d is H and R.sup.e is selected
from H, CH.sub.3, CH.sub.2CH.sub.3, cyclopropyl, cyclopropyl
substituted with methyl and cyclopropylmethyl,
[0123] (3) SO.sub.2CH.sub.3,
[0124] (4) N(CH.sub.3).sub.2;
[0125] (5) C(O)NR.sup.dR.sup.e, wherein R.sup.d is H and R.sup.e is
as defined above;
[0126] (6) CO.sub.2H or CO.sub.2CH.sub.3;
[0127] and the remaining R.sup.1 groups are H or halo selected from
F and Cl, and at least one R.sup.1 and R.sup.2 group represents a
moiety other than hydrogen. Within this aspect of the invention,
all other variables are as originally defined.
[0128] Another aspect of the invention that is of interest relates
to a compound of formula I or a pharmaceutically acceptable salt or
solvate thereof wherein:
[0129] each R.sup.2 is H or halo, or 1-2 are H or halo and the
remainder are selected from the group consisting of:
[0130] 1) CN;
[0131] 2) NR.sup.fR.sup.g, wherein R.sup.f and R.sup.g each
represent H or CH.sub.3,
[0132] 3) C.sub.1-6alkyl optionally substituted with 1-3 fluorine
atoms; and
[0133] 4) SO.sub.2C.sub.1-3alkyl,
and at least one R.sup.1 and R.sup.2 group represents a moiety
other than hydrogen. Within this aspect of the invention, all other
variables are as originally defined.
[0134] More particularly, another aspect of the invention that is
of interest relates to a compound of formula I or a
pharmaceutically acceptable salt or solvate thereof wherein:
[0135] each R.sup.2 is H, Cl or F, or 1-2 are H, Cl or F and the
remainder are selected from the group consisting of:
[0136] 1) CN;
[0137] 2) NH.sub.2 or NHCH.sub.3;
[0138] 3) CH.sub.3 or CF.sub.3; and
[0139] 4) SO.sub.2CH.sub.3,
and at least one R.sup.1 and R.sup.2 group represents a moiety
other than hydrogen. Within this aspect of the invention, all other
variables are as originally defined.
[0140] One aspect of the invention that is of interest relates to a
compound represented by formula I:
##STR00006##
or a pharmaceutically acceptable salt or solvate thereof
wherein:
[0141] ring A represents a 5-6 membered monocyclic aryl or
heteroaryl group containing at least one nitrogen atom and 0-2
additional nitrogen atoms, and 0-1 additional oxygen or sulfur
atom;
[0142] ring B represents a 5-9 membered mono or bicyclic heteroaryl
group containing at least one nitrogen atom and 0-2 additional
nitrogen atoms, and 0-1 additional oxygen or sulfur atom;
[0143] each R.sup.1 is H or halo, or 1-2 R.sup.1 groups are
selected from the group consisting of:
[0144] (1) CN;
[0145] (2) C.sub.1-6alkyl, optionally substituted with 1-3 halo
groups and 1-2 members selected from the group consisting of:
[0146] i) S(O).sub.xC.sub.1-3alkyl, wherein x is 0, 1 or 2; [0147]
ii) NH.sub.2, NHCH.sub.3 and N(CH.sub.3).sub.2; [0148] iii) OH;
[0149] iv) C(O)C.sub.1-4alkyl; [0150] v) phenyl optionally
substituted with 1-2 halo atoms or C.sub.1-3alkyl groups; [0151]
vi) C(O)NR.sup.dR.sup.e, wherein R.sup.d is selected from H and
CH.sub.3 and R.sup.e is selected from H, CH.sub.3,
CH.sub.2CH.sub.3, cyclopropyl, cyclopropylmethyl, a 5-6 membered
Heteroaryl group and phenyl; [0152] vii) C(O).sub.2R.sup.e, wherein
R.sup.e is as defined above; [0153] viii) Heteroaryl optionally
substituted with 1-2 halo or CH.sub.3 groups;
[0154] (3) S(O).sub.xC.sub.1-6alkyl, wherein the C.sub.1-6alkyl
group is optionally substituted with 1-3 halo groups and x, R.sup.d
and R.sup.e are as defined above;
[0155] (4) NH.sub.2, NH(C.sub.1-3alkyl) or N(C.sub.1-3alkyl).sub.2,
wherein the alkyl portions are optionally substituted with 1-3 halo
groups;
[0156] (5) C(O)NR.sup.dR.sup.e, wherein R.sup.d and R.sup.e are as
defined above;
[0157] (6) C(O)C.sub.1-6alkyl optionally substituted with 1-3 halo
atoms;
[0158] (7) CO.sub.2R.sup.e, wherein R.sup.e is as defined
above;
[0159] (8) Phenyl, a 5-6 membered Heteroaryl or a 5-6 membered
Heterocyclic moiety, each being optionally substituted with 1-3
halo atoms and 1-2 C.sub.1-3alkyl groups,
[0160] and the remaining R.sup.1 groups are H or halo, and
[0161] each R.sup.2 is H or halo, or 1-2 are H or halo and the
remainder are selected from the group consisting of:
[0162] 1) CN;
[0163] 2) NR.sup.fR.sup.g, wherein R.sup.f and R.sup.g each
represent H or CH.sub.3,
[0164] 3) C.sub.1-6alkyl optionally substituted with 1-3 fluorine
atoms; and
[0165] 4) SO.sub.2C.sub.1-3alkyl,
and at least one R.sup.1 and R.sup.2 group represents a moiety
other than hydrogen. Within this aspect of the invention, all other
variables are as originally defined.
[0166] Examples of species that fall within the present invention
are found in the examples contained herein.
Utilities
[0167] Compounds of the present invention are potent agonists of
the GPR119 receptor. The compounds of the invention, and
pharmaceutically acceptable salts thereof are modulators of the
receptor known as GPR 119, and are therefore useful in the
treatment of diseases that are modulated by GPR119 ligands and
agonists. Many of these diseases are summarized below.
[0168] Treatment and prevention of the following diseases and
conditions are included in the present invention: Also, the
compounds of the invention may be used for the manufacture of a
medicament for treating one or more of these diseases or
conditions: [0169] (1) non-insulin dependent diabetes mellitus
(type 2 diabetes); [0170] (2) hyperglycemia; [0171] (3) the
metabolic syndrome; [0172] (4) obesity; [0173] (5) ischemia and
myocardial infarction; [0174] (6) neurological disorders such as
alzheimer's disease, schizophrenia, and impaired cognition; [0175]
(5) hypercholesterolemia; [0176] (6) hypertriglyceridemia (elevated
levels of triglyceride-rich-lipoproteins); [0177] (7) mixed or
diabetic dyslipidemia; [0178] (8) low HDL cholesterol; [0179] (9)
high LDL cholesterol; [0180] (10) hyper apo B lipoproteinemia; and
[0181] (11) atherosclerosis.
[0182] More particularly, the following diseases and conditions can
be treated using the compounds of formula I or a pharmaceutically
acceptable salt or solvate thereof. The compounds may be used for
manufacturing a medicament for the treatment or prevention of one
or more of these diseases or conditions: [0183] (1) Type 2
diabetes, and specifically hyperglycemia; [0184] (2) Metabolic
syndrome; [0185] (3) Obesity; and [0186] (4) Hypercholesterolemia
or dyslipidemias.
[0187] Because the compounds are agonists of the GPR119 receptor,
the compounds will be useful for lowering glucose, lipids, and
insulin resistance in diabetic patients and in non-diabetic
patients who have impaired glucose tolerance and/or are in a
pre-diabetic condition. The compounds are useful to ameliorate
hyperinsulinemia, which often occurs in diabetic or pre-diabetic
patients, by modulating the swings in the level of serum glucose
that often occurs in these patients. The compounds are useful for
treating or reducing insulin resistance. The compounds are useful
for treating or preventing gestational diabetes.
[0188] The compounds, compositions, and medicaments as described
herein are useful for reducing the risks of adverse sequelae
associated with metabolic syndrome, and in reducing the risk of
developing atherosclerosis, delaying the onset of atherosclerosis,
and/or reducing the risk of sequelae of atherosclerosis. Sequelae
of atherosclerosis include angina, claudication, heart attack,
stroke, and others.
[0189] By keeping hyperglycemia under control, the compounds are
useful to delay or for preventing vascular restenosis and diabetic
retinopathy.
[0190] The compounds of this invention are useful in improving or
restoring .beta.-cell function, so that they may be useful in
treating type 1 diabetes or in delaying or preventing a patient
with type 2 diabetes from needing insulin therapy.
[0191] The compounds may be useful for reducing appetite and body
weight in obese subjects and may therefore be useful in reducing
the risk of co-morbidities associated with obesity such as
hypertension, atherosclerosis, diabetes, and dyslipidemia.
[0192] By elevating levels of active GLP-1 in vivo, the compounds
are useful in treating neurological disorders such as Alzheimer's
disease, multiple sclerosis, and schizophrenia.
[0193] The compounds generally are useful for treating the
following diseases and conditions: (1) type 2 diabetes (also known
as non-insulin dependent diabetes mellitus, or T2DM), (2)
hyperglycemia, (3) low glucose tolerance, (4) insulin resistance,
(5) obesity, (6) lipid disorders, (7) dyslipidemia, (8)
hyperlipidemia, (9) hypertriglyceridemia, (10)
hypercholesterolemia, (11) low HDL levels, (12) high LDL levels,
(13) atherosclerosis and its sequelae, (14) vascular restenosis,
(15) abdominal obesity, (16) retinopathy, (17) metabolic syndrome,
(18) high blood pressure, (19) Alzheimer's disease, (20)
schizophrenia, (21) multiple sclerosis, and (22) insulin
resistance.
[0194] One aspect of the invention provides a method for the
treatment and control of mixed or diabetic dyslipidemia,
hypercholesterolemia, atherosclerosis, low HDL levels, high LDL
levels, hyperlipidemia, and/or hypertriglyceridemia, which
comprises administering to a patient in need of such treatment a
therapeutically effective amount of a compound of formula I or a
pharmaceutically acceptable salt or solvate therof. The compound
may be used alone or advantageously may be administered with a
cholesterol biosynthesis inhibitor, particularly an HMG-CoA
reductase inhibitor such as lovastatin, simvastatin, rosuvastatin,
pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, or
ZD-4522. The compound may also be used advantageously in
combination with other lipid lowering drugs such as cholesterol
absorption inhibitors (for example stanol esters, sterol glycosides
such as tiqueside, and azetidinones such as ezetimibe), ACAT
inhibitors (such as avasimibe), CETP inhibitors (for example
torcetrapib), niacin, bile acid sequestrants, microsomal
triglyceride transport inhibitors, and bile acid reuptake
inhibitors. These combination treatments are useful for the
treatment or control of conditions selected from the group
consisting of hypercholesterolemia, atherosclerosis,
hyperlipidemia, hypertriglyceridemia, dyslipidemia, high LDL, and
low HDL.
[0195] Another aspect of the invention provides a method for the
treatment and control of obesity or metabolic syndrome, which
comprises administering to a patient in need of such treatment a
therapeutically effective amount of a compound having formula I or
a pharmaceutically acceptable salt or solvate thereof. The compound
may be used alone or advantageously may be administered with an
anti-obesity agent, particularly a lipase inhibitor such as
orlistat, or a monoamine neurotransmitter uptake inhibitor such as
sibutramine, phentermine and the like. The compound may also be
used advantageously in combination with CB-1 inverse agonists or
antagonists such as rimonabant.
Administration and Dose Ranges
[0196] Any suitable route of administration may be employed for
providing a mammal, especially a human, with an effective dose of a
compound of the present invention. For example, oral, rectal,
topical, parenteral, ocular, pulmonary, nasal, and the like may be
employed. Dosage forms include tablets, troches, dispersions,
suspensions, solutions, capsules, creams, ointments, aerosols, and
the like. Preferably compounds of Formula I or a pharmaceutically
acceptable salt or solvate thereof are administered orally.
[0197] The effective dosage of active ingredient employed may vary
depending on the particular compound employed, the mode of
administration, the condition being treated and the severity of the
condition being treated. Such dosage may be ascertained readily by
a person skilled in the art.
[0198] When treating or controlling diabetes mellitus and/or
hyperglycemia or hypertriglyceridemia or other diseases for which
compounds of Formula I are indicated, generally satisfactory
results are obtained when the compounds of the present invention
are administered at a daily dosage of from about 0.1 milligram to
about 100 milligram per kilogram of animal body weight, preferably
given as a single daily dose or in divided doses two to six times a
day, or in sustained release form. For most large mammals, the
total daily dosage is from about 1.0 milligrams to about 1000
milligrams. In the case of a 70 kg adult human, the total daily
dose will generally be from about 1 milligram to about 350
milligrams. For a particularly potent compound, the dosage for an
adult human may be as low as 0.1 mg. The dosage regimen may be
adjusted within this range or even outside of this range to provide
the optimal therapeutic response.
[0199] Oral administration will usually be carried out using
tablets or capsules. Examples of doses in tablets and capsules are
0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100
mg, 200 mg, 350 mg, 500 mg, 700 mg, 750 mg, 800 mg and 1000 mg.
Other oral forms may also have the same or similar dosages.
Pharmaceutical Compositions
[0200] Another aspect of the present invention provides
pharmaceutical compositions which comprise a compound of Formula I
and a pharmaceutically acceptable carrier. The pharmaceutical
compositions of the present invention comprise a compound of
Formula I or a pharmaceutically acceptable salt or solvate as an
active ingredient, as well as a pharmaceutically acceptable carrier
and optionally other therapeutic ingredients. The term
"pharmaceutically acceptable salts" refers to salts prepared from
pharmaceutically acceptable non-toxic bases or acids including
inorganic bases or acids and organic bases or acids. A
pharmaceutical composition may also comprise a prodrug, or a
pharmaceutically acceptable salt thereof, if a prodrug is
administered.
[0201] The compositions are typically suitable for oral, rectal,
topical, parenteral (including subcutaneous, intramuscular, and
intravenous), ocular (ophthalmic), pulmonary (nasal or buccal
inhalation), or nasal administration, although the most suitable
route in any given case will depend on the nature and severity of
the condition being treated and on the particular active ingredient
selected. They may be conveniently presented in unit dosage form
and prepared by any of the methods well-known in the art of
pharmacy.
[0202] In practical use, the compound of Formula I, or the
pharmaceutically acceptable salt or solvate thereof can be combined
as the active ingredient in intimate admixture with the
pharmaceutical carrier according to conventional pharmaceutical
compounding techniques. The carrier may take a wide variety of
forms depending on the form of preparation desired for
administration, e.g., oral or parenteral (including intravenous).
In preparing the compositions for oral dosage form, any of the
usual pharmaceutical media may be employed, such as, for example,
water, glycols, oils, alcohols, flavoring agents, preservatives,
coloring agents and the like in the case of oral liquid
preparations, such as, for example, suspensions, elixirs and
solutions; or carriers such as starches, sugars, microcrystalline
cellulose, diluents, granulating agents, lubricants, binders,
disintegrating agents and the like in-the case of oral solid
preparations such as, for example, powders, hard and soft capsules
and tablets, with the solid oral preparations being preferred over
the liquid preparations.
[0203] Because of their ease of administration, tablets and
capsules represent the most advantageous oral dosage form. Solid
pharmaceutical carriers are therefore typically employed. If
desired, tablets may be coated by standard aqueous or nonaqueous
techniques. Such compositions and preparations typically comprise
at least about 0.1 percent of active compound, the remainder of the
composition being the carrier. The percentage of active compound in
these compositions may, of course, be varied and is conveniently
between about 2 percent to about 60 percent of the weight of the
dosage form. The amount of active compound in such therapeutically
useful compositions is such that an effective dosage will be
delivered.
[0204] Alternatively, the active compound can be administered
intranasally as, for example, in the form of liquid drops or a
spray.
[0205] The tablets, capsules and the like also typically contain a
binder. Examples of suitable binders include gum tragacanth,
acacia, gelatin and a synthetic or semisynthetic starch derivative,
such as hydroxypropylmethylcellulose (HPMC); excipients such as
dicalcium phosphate; a disintegrating agent such as corn starch,
potato starch, alginic acid; a lubricant such as magnesium
stearate; and in some instances, a sweetening agent such as
sucrose, lactose or saccharin. When the dosage form employed is a
capsule, it may contain, in addition to the components described
above, a liquid carrier such as a fatty oil.
[0206] Various other materials may be present as coatings or to
modify the physical form of the dosage unit. For instance, tablets
may be coated with shellac, sugar or both. Syrups and elixirs
typically contain, in addition to the active ingredient, sucrose as
a sweetening agent, methyl or propylparabens as a preservative, a
dye and a flavoring such as cherry or orange flavor.
[0207] The compound of formula I or a pharmaceutically acceptable
salt or solvate thereof may also be administered parenterally.
Solutions or suspensions of these active compounds can be prepared
in water, saline or another biocompatible vehicle, suitably mixed
with a surfactant, buffer, and the like. Dispersions can also be
prepared in glycerol, liquid polyethylene glycols and mixtures
thereof in an oil. Under ordinary conditions of storage and use,
these preparations can also contain a preservative to prevent the
growth of microorganisms.
[0208] The pharmaceutical forms suitable for injectable use include
sterile aqueous solutions and dispersions, and sterile powders for
the extemporaneous preparation of sterile injectable solutions and
dispersions. The preparation should be prepared under sterile
condituons and be fluid to the extent that easy syringability
exists. It should be sufficiently stable under the conditions of
manufacture and storage and preserved against the growth of
microorganisms such as bacteria and fungi. The carrier can be a
solvent or dispersion medium containing, for example, water,
ethanol, polyol (e.g. glycerol, propylene glycol and liquid
polyethylene glycol), suitable mixtures thereof, and suitable
oils.
Combination Therapy
[0209] Compounds of Formula I may be used in combination with other
drugs that may also be useful in the treatment or amelioration of
the diseases and conditions described herein. Such other drugs may
be administered, by a route and in an amount commonly used
therefor, contemporaneously or sequentially with a compound of
Formula I or a pharmaceutically acceptable salt or solvate thereof.
In the treatment of patients who have type 2 diabetes, insulin
resistance, obesity, metabolic syndrome, neurological disorders,
and co-morbidities that accompany these diseases, more than one
drug is commonly administered. The compounds of this invention may
generally be administered to a patient who is already taking one or
more other drugs for these conditions.
[0210] When a compound of Formula I is used contemporaneously with
one or more other drugs, a pharmaceutical composition in unit
dosage form containing such other drugs and the compound of Formula
I is preferred. However, the combination therapy also includes
therapies in which the compound of Formula I and one or more other
drugs are administered on different overlapping schedules. It is
also contemplated that when used in combination with one or more
other active ingredients, the compound of the present invention and
the other active ingredients may be used in lower doses than when
each is used singly. Accordingly, the pharmaceutical compositions
of the present invention include those that contain one or more
other active ingredients, in addition to a compound of Formula
I.
[0211] Examples of other active ingredients that may be
administered in combination with a compound of Formula I, and
either administered separately or in the same pharmaceutical
composition, include, but are not limited to:
[0212] (a) PPAR gamma agonists and partial agonists, including both
glitazones and non-glitazones (e.g. troglitazone, pioglitazone,
englitazone, MCC-555, rosiglitazone, balaglitazone, netoglitazone,
T-131, LY-3 00512, and LY-818;
[0213] (b) biguanides such as metformin and phenformin;
[0214] (c) protein tyrosine phosphatase-IB (PTP-1B) inhibitors;
[0215] (d) dipeptidyl peptidase IV (DPP-4) inhibitors, such as
sitagliptin, saxagliptin, denagliptin, SYR-322, and
vildagliptin;
[0216] (e) insulin or insulin mimetics;
[0217] (f) sulfonylureas such as tolbutamide, glimepiride,
glipizide, and related materials;
[0218] (g) .alpha.-glucosidase inhibitors (such as acarbose);
[0219] (h) agents which improve a patient's lipid profile, such as
(i) HMG-CoA reductase inhibitors (lovastatin, simvastatin,
rosuvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin,
itavastatin, ZD4522 and other statins), (ii) bile acid sequestrants
(cholestyramine, colestipol, and dialkylaminoalkyl derivatives of a
cross-linked dextran), (iii) nicotinyl alcohol, nicotinic acid or a
salt thereof, (iv) PPAR.alpha. agonists such as fenofibric acid
derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate),
(v) cholesterol absorption inhibitors, such as for example
ezetimibe, (vi) acyl CoA:cholesterol acyltransferase (ACAT)
inhibitors, such as avasimibe, (vii) CETP inhibitors, such as
torcetrapib, and (viii) phenolic anti-oxidants, such as
probucol;
[0220] (i) PPAR.alpha./.gamma. dual agonists, such as muraglitazar,
tesaglitazar, farglitazar, and JT-501;
[0221] (j) PPAR.delta. agonists such as those disclosed in
WO97/28149;
[0222] (k) antiobesity compounds such as fenfluramine,
dexfenfluramine, phentiramine, subitramine, orlistat, neuropeptide
Y5 inhibitors, Mc4r agonists, cannabinoid receptor 1 (CB-1)
antagonists/inverse agonists, and .beta..sub.3 adrenergic receptor
agonists;
[0223] (l) ileal bile acid transporter inhibitors;
[0224] (m) agents intended for use in inflammatory conditions such
as aspirin, non-steroidal anti-inflammatory drugs, glucocorticoids,
azulfidine, and cyclo-oxygenase 2 selective inhibitors;
[0225] (n) glucagon receptor antagonists;
[0226] (o) GLP-1,
[0227] (p) GIP-1,
[0228] (q) GLP-1 analogs, such as exendins, for example exenatide
(Byetta), exenatide-LAR, and liraglutide
[0229] (r) Hydroxysterol dehydrogenase-1 (HSD-1) inhibitors.
[0230] The above combinations include combinations of a compound of
the present invention not only with one other active compound, but
also with two or more other active compounds. Non-limiting examples
include combinations of compounds having Formula I or a
pharmaceutically acceptable salt or solvate thereof with two or
more active compounds selected from biguanides, sulfonylureas,
HMG-CoA reductase inhibitors, other PPAR agonists, PTP-1B
inhibitors, DPP-4 inhibitors, and anti-obesity compounds.
[0231] Another aspect of the invention that is of interest is a
pharmaceutical composition comprised of a compound of formula I or
a pharmaceutically acceptable salt or solvate thereof in
combination with a pharmaceutically acceptable carrier.
[0232] Another aspect of the invention that is of interest relates
to a method of treating hyperglycemia, diabetes or insulin
resistance in a mammalian patient in need of such treatment which
comprises administering to said patient a compound in accordance
with formula I or a pharmaceutically acceptable salt or solvate
thereof in an amount that is effective to treat hyperglycemia,
diabetes or insulin resistance.
[0233] More particularly, another aspect of the invention that is
of interest relates to a method of treating type 2 diabetes in a
mammalian patient in need of such treatment comprising
administering to the patient a compound in accordance with formula
I or a pharmaceutically acceptable salt or solvate thereof in an
amount that is effective to treat type 2 diabetes.
[0234] Yet another aspect of the invention that is of interest
relates to a method of treating non-insulin dependent diabetes
mellitus in a mammalian patient in need of such treatment
comprising administering to the patient a compound in accordance
with formula I or a pharmaceutically acceptable salt or solvate
thereof in an amount that is effective to treat non-insulin
dependent diabetes mellitus.
[0235] Yet another aspect of the invention that is of interest
relates to a method of treating obesity in a mammalian patient in
need of such treatment compriseing administering to said patient a
compound in accordance with formula I or a pharmaceutically
acceptable salt or solvate thereof in an amount that is effective
to treat obesity.
[0236] Yet another aspect of the invention that is of interest
relates to a method of treating Syndrome X in a mammalian patient
in need of such treatment, comprising administering to said patient
a compound in accordance with formula I or a pharmaceutically
acceptable salt or solvate thereof in an amount that is effective
to treat Syndrome X.
[0237] Yet another aspect of the invention that is of interest
relates to a method of treating a lipid disorder selected from the
group consisting of dyslipidemia, hyperlipidemia,
hypertriglyceridemia, hypercholesterolemia, low HDL and high LDL in
a mammalian patient in need of such treatment, comprising
administering to said patient a compound in accordance with formula
I or a pharmaceutically acceptable salt or solvate thereof in an
amount that is effective to treat said lipid disorder.
[0238] Yet another aspect of the invention that is of interest
relates to a method of treating atherosclerosis in a mammalian
patient in need of such treatment, comprising administering to said
patient a compound in accordance with a compound in accordance with
formula I or a pharmaceutically acceptable salt or solvate thereof
in an amount that is effective to treat atherosclerosis.
[0239] Yet another aspect of the invention that is of interest
relates to a method of treating a condition selected from the group
consisting of: (1) hyperglycemia, (2) low glucose tolerance, (3)
insulin resistance, (4) obesity, (5) lipid disorders, (6)
dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9)
hypercholesterolemia, (10) low HDL levels, (11) high LDL levels,
(12) atherosclerosis and its sequelae, (13) vascular restenosis,
(14) pancreatitis, (15) abdominal obesity, (16) neurodegenerative
disease, (17) retinopathy, (18) nephropathy, (19) neuropathy, (20)
Syndrome X, (21) hypertension and other conditions and disorders
where insulin resistance is a component, in a mammalian patient in
need of such treatment, comprising administering to the patient a
compound in accordance with formula I or a pharmaceutically
acceptable salt or solvate thereof in an amount that is effective
to treat said condition.
[0240] Yet another aspect of the invention that is of interest
relates to a method of delaying the onset of a condition selected
from the group consisting of (1) hyperglycemia, (2) low glucose
tolerance, (3) insulin resistance, (4) obesity, (5) lipid
disorders, (6) dyslipidemia, (7) hyperlipidemia, (8)
hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL
levels, (11) high LDL levels, (12) atherosclerosis and its
sequelae, (13) vascular restenosis, (14) pancreatitis, (15)
abdominal obesity, (16) neurodegenerative disease, (17)
retinopathy, (18) nephropathy, (19) neuropathy, (20) Syndrome X,
(21) hypertension and other conditions and disorders where insulin
resistance is a component in a mammalian patient in need thereof,
comprising administering to the patient a compound in accordance
with formula I or a pharmaceutically acceptable salt or solvate
thereof in an amount that is effective to delay the onset of said
condition.
[0241] Yet another aspect of the invention that is of interest
relates to a method of reducing the risk of developing a condition
selected from the group consisting of (1) hyperglycemia, (2) low
glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid
disorders, (6) dyslipidemia, (7) hyperlipidemia, (8)
hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL
levels, (11) high LDL levels, (12) atherosclerosis and its
sequelae, (13) vascular restenosis, (14) pancreatitis, (15)
abdominal obesity, (16) neurodegenerative disease, (17)
retinopathy, (18) nephropathy, (19) neuropathy, (20) Syndrome X,
(21) hypertension and other conditions and disorders where insulin
resistance is a component in a mammalian patient in need thereof,
comprising administering to the patient a compound in accordance
with formula I or a pharmaceutically acceptable salt or solvate
thereof in an amount that is effective to reduce the risk of
developing said condition.
[0242] Yet another aspect of the invention that is of interest
relates to a method of treating a condition selected from the group
consisting of (1) hyperglycemia, (2) low glucose tolerance, (3)
insulin resistance, (4) obesity, (5) lipid disorders, (6)
dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9)
hypercholesterolemia, (10) low HDL levels, (11) high LDL levels,
(12) atherosclerosis and its sequelae, (13) vascular restenosis,
(14) pancreatitis, (15) abdominal obesity, (16) neurodegenerative
disease, (17) retinopathy, (18) nephropathy, (19) neuropathy, (20)
Syndrome X, (21) hypertension and other conditions and disorders
where insulin resistance is a component, in a mammalian patient in
need of such treatment, comprising administering to the patient a
compound in accordance with formula I or a pharmaceutically
acceptable salt or solvate thereof in an amount that is effective
to treat said condition, and a compound selected from the group
consisting of:
[0243] (a) DP-IV inhibitors;
[0244] (b) insulin sensitizers selected from the group consisting
of (i) PPAR agonists and (ii) biguanides;
[0245] (c) insulin and insulin mimetics;
[0246] (d) sulfonylureas and other insulin secretagogues;
[0247] (e) .alpha.-glucosidase inhibitors;
[0248] (f) glucagon receptor antagonists;
[0249] (g) GLP-1, GLP-1 mimetics, and GLP-1 receptor agonists;
[0250] (h) GIP,GIP mimetics, and GIP receptor agonists;
[0251] (i) PACAP, PACAP mimetics, and PACAP receptor 3
agonists;
[0252] (j) cholesterol lowering agents selected from the group
consisting of [0253] (i) HMG-CoA reductase inhibitors, (ii)
sequestrants, (iii) nicotinyl alcohol, nicotinic acid and salts
thereof, (iv) PPAR.alpha. agonists, (v) PPAR.alpha./.gamma. dual
agonists, (vi) inhibitors of cholesterol absorption, (vii) acyl
CoA:cholesterol acyltransferase inhibitors, and (viii)
anti-oxidants;
[0254] (k) PPAR.delta. agonists;
[0255] (l) antiobesity compounds;
[0256] (m) ileal bile acid transporter inhibitors;
[0257] (n) anti-inflammatory agents excluding glucocorticoids;
[0258] (o) protein tyrosine phosphatase-1B (PTP-1B) inhibitors;
and
[0259] (p) antihypertensives including those acting on the
angiotensin or renin systems, such as angiotensin converting enzyme
inhibitors, angiotensin II receptor antagonists or renin
inhibitors, such as captopril, cilazapril, enalapril, fosinopril,
lisinopril, quinapril, ramapril, zofenopril, candesartan,
cilexetil, eprosartan, irbesartan, losartan, tasosartan,
telmisartan, and valsartan; said compounds being administered to
the patient in an amount that is effective to treat said
condition.
[0260] Yet another aspect of the invention that is of interest
relates to a method of treating a condition selected from the group
consisting of hypercholesterolemia, atherosclerosis, low HDL
levels, high LDL levels, hyperlipidemia, hypertriglyceridemia and
dyslipidemia, in a mammalian patient in need of such treatment,
comprising administering to the patient a compound in accordance
with formula I or a pharmaceutically acceptable salt or solvate
thereof and an HMG-CoA reductase inhibitor, in amounts that are
effective to treat said condition.
[0261] More particularly, another aspect of the invention that is
of interest relates to a method of treating a condition selected
from the group consisting of hypercholesterolemia, atherosclerosis,
low HDL levels, high LDL levels, hyperlipidemia,
hypertriglyceridemia and dyslipidemia, in a mammalian patient in
need of such treatment, comprising administering to the patient a
compound in accordance with formula I or a pharmaceutically
acceptable salt or solvate thereof and an HMG-CoA reductase
inhibitor in the form of a statin, said compounds being
administered in amounts that are effective for treating said
condition. Statins useful in this regard include the group
consisting of lovastatin, simvastatin, pravastatin, fluvastatin,
atorvastatin, itavastatin, ZD-4522 and rivastatin.
[0262] A method of reducing the risk of developing a condition
selected from the group consisting of hypercholesterolemia,
atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia,
hypertriglyceridemia and dyslipidemia, and the sequelae of such
conditions comprising administering to a mammalian patient in need
of such treatment a therapeutically effective amount of a compound
as defined in Claim 1 and an HMG-CoA reductase inhibitor.
[0263] More particularly, another aspect of the invention that is
of interest relates to a method of delaying the onset or reducing
the risk of developing atherosclerosis in a human patient in need
of such treatment comprising administering to the patient a
compound in accordance with formula I or a pharmaceutically
acceptable salt or solvate thereof and an HMG-CoA reductase
inhibitor in the form of a statin, said compounds being
administered in amounts that are effective for treating said
condition. Statins useful in this regard include the group
consisting of lovastatin, simvastatin, pravastatin, fluvastatin,
atorvastatin, itavastatin, ZD-4522 and rivastatin.
[0264] More particularly, another aspect of the invention that is
of interest relates to a method of treating, delaying the onset or
reducing the risk of developing atherosclerosis in a human patient
in need of such treatment comprising administering to the patient a
compound in accordance with formula I or a pharmaceutically
acceptable salt or solvate thereof and a cholesterol absorption
inhibitor, said compounds being administered in amounts that treat,
delay the onset, or reduce the risk of developing
atherosclerosis.
[0265] Even more particularly, another aspect of the invention that
is of interest relates to a method of treating, delaying the onset
or reducing the risk of developing atherosclerosis in a human
patient in need of such treatment comprising administering to the
patient a compound in accordance with formula I or a
pharmaceutically acceptable salt or solvate thereof and a
cholesterol absorption inhibitor, wherein the cholesterol
absorption inhibitor is ezetimibe, said compounds being
administered in amounts that treat, delay the onset, or reduce the
risk of developing atherosclerosis.
[0266] Yet another aspect of the invention that is of interest
relates to a pharmaceutical composition that is comprised of: (1) a
compound according to formula I or a pharmaceutically acceptable
salt or solvate thereof,
(2) a compound selected from the group consisting of:
[0267] (a) DP-IV inhibitors;
[0268] (b) insulin sensitizers selected from the group consisting
of (i) PPAR agonists and (ii) biguanides;
[0269] (c) insulin and insulin mimetics;
[0270] (d) sulfonylureas and other insulin secretagogues;
[0271] (e) .alpha.-glucosidase inhibitors;
[0272] (f) glucagon receptor antagonists;
[0273] (g) GLP-1, GLP-1 mimetics, and GLP-1 receptor agonists;
[0274] (h) GIP, GIP mimetics, and GIP receptor agonists;
[0275] (i) PACAP, PACAP mimetics, and PACAP receptor 3
agonists;
[0276] (j) cholesterol lowering agents selected from the group
consisting of (i) HMG-CoA reductase inhibitors, (ii) sequestrants,
(iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv)
PPAR.alpha. agonists, (v) PPAR.alpha./.gamma. dual agonists, (vi)
inhibitors of cholesterol absorption, (vii) acyl CoA:cholesterol
acyltransferase inhibitors, and (viii) anti-oxidants;
[0277] (k) PPAR.delta. agonists;
[0278] (l) antiobesity compounds;
[0279] (m) ileal bile acid transporter inhibitors;
[0280] (n) anti-inflammatory agents other than glucocorticoids;
[0281] (o) protein tyrosine phosphatase-1B (PTP-1B) inhibitors;
and
[0282] (p) antihypertensives including those acting on the
angiotensin or renin systems, such as angiotensin converting enzyme
inhibitors, angiotensin II receptor antagonists or renin
inhibitors, such as captopril, cilazapril, enalapril, fosinopril,
lisinopril, quinapril, ramapril, zofenopril, candesartan,
cilexetil, eprosartan, irbesartan, losartan, tasosartan,
telmisartan, and valsartan; and
(3) a pharmaceutically acceptable carrier
[0283] Another aspect of the invention that is of interest relates
to the use of a compound in accordance with formula I or a
pharmaceutically acceptable salt or solvate thereof in the
manufacture of a medicament for use in treating a disease or
condition described herein.
[0284] The compounds of the invention can be prepared using the
synthetic schemes described herein. The following abbreviations are
used in the synthetic schemes:
[0285] Ac is acetyl [CH.sub.3C(O)--]; Ac.sub.2O is acetic
anhydride; AcAc is acetyl acetonate; Ar is Aryl; ArX is an aryl
halide; 9-BBN is 9-borabicyclo[3.3.1]nonane; Bn is benzyl; BOC is
tert butyloxycarbonyl; DBU is 1,8-diazabicyclo[5.4.0]undec-7-ene;
DIAD is diisopropylazodicarboxylate; DIBAL is diisobutylaluminum
hydride; DMF is N,N-dimethylformamide; DMSO is dimethyl sulfoxide;
EDAC (or EDC) is 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide
HCl; Et.sub.3N is triethylamine; Et is ethyl; EtOAc is ethyl
acetate;EtOH is ethanol; HCl is hydrochloric acid; Het-X is
heterocyclic halide; HOBt is 1-hydroxybenzotriazole; HPLC is high
pressure liquid chromatography; LG is leaving group; M is molar;
mmol is millimole; Me is methyl; MeOH is methanol; MsCl
methanesulfonyl chloride; N is normal; NaHMDS is sodium
hexamethyldisilazide; NaOAc is sodium acetate; NaOtBu is sodium
tert-butoxide; NMO is N-methylmorpholine N oxide; NMP is
N-methylpyrrolidinone; PG is a protecting group; Pd(dba).sub.2 is
tris(dibenzylideneacetone)dipalladium; PdCl.sub.2(Ph.sub.3P).sub.2
is dichlorobis-(triphenylphosphene)palladium; Ph is phenyl; PhMe is
toluene; PPh.sub.3 is triphenylphosphine; PMB is
para-methoxybenzyl; RT and r. t. indicate room temperature; TBAF is
tetrabutyl ammonium fluoride; TBS is tert-butyldimethylsilyl; tBu
is tert-butyl; Tf is triflate; TFA is trifluoroacetic acid; THF is
tetrahydrofuran; TLC is thin layer chromatography; TMEDA is
tetramethylethylenediamine; TMS is trimethylsilyl; TPAP is
tetrapropylammonium perruthenate. In the general schemes, the
designations R.sub.1-R.sub.5 serve as placeholders. The ring
containing H shown below denotes a heterocycle. In scheme 4, E is
an ester forming group, e.g., propyl, butyl, and the like.
General Schemes
[0286] The substituted bipiperidines of this invention can be
prepared by any of several methods. The specific examples detailed
below may employ some of the following general procedures.
[0287] Substituted aryl and heteroaryl coupling intermediates shown
in the schemes are commercially available or may be prepared from
readily accessible aryl, heterocycles, or other congeners via a
host of routes. Intermediates are accessible through either
modification of a preformed heteroaryl scaffold or through de novo
ring synthesis.
[0288] Many of the piperidine intermediates required for the
preparation of this invention are available commercially or through
published procedures. One of the most useful means synthese
utilizes a reduction of a suitable pyridine. Low pressure
reductions with hydrogen and 5-10% Pd on charcoal or similar
hydrogenation catalyst in acetic acid lead to the appropriate
piperidine (scheme 1).
##STR00007##
[0289] Various aryl (heteroaryl)/amine coupling methods are well
suited to production of these intermediates. A general method, SnAr
displacement, is depicted in Scheme 2.
##STR00008##
[0290] One useful synthetic method is Buchwald coupling, as
outlined in Scheme 3 and described in several literature reviews.
Scheme 3 indicates convenient methods for coupling the required
partners.
##STR00009##
[0291] Heterocyclic residues of either Arl or the Het fragment are
obtainable by de novo ring synthesis. An example of de novo ring
synthesis for thiazole and pyrimidine cases is shown in Scheme 4. A
host of methods can be used.
##STR00010## ##STR00011##
[0292] When the N-Aryl or N-heteroaryl residue is substituted with
an X group (where X.dbd.Cl, Br, I or OTf) it is possible to further
functionalize the residue utilizing palladium organometallic
mediated coupling reactions. A method with extraordinarily broad
applicability are palladium mediated couplings outlined in Scheme
5.
##STR00012##
[0293] Removal of the protecting group from the N-functionalized
derivatives described above produces compounds that can be further
functionalized. Scheme 6 describes methods of preparation.
##STR00013##
[0294] The methods described in Schemes 2-5 above can be used to
install a second aryl or heteroaryl group (Scheme 7).
##STR00014##
General Procedure 1.1 (nucleophilic aromatic substitution)
Preparative Example 1.1
tert-butyl
1'-[4-(methylsulfonyl)phenyl]-4,4'-bipiperidine-1-carboxylate
##STR00015##
[0296] A solution of tert-butyl 4,4'-bipiperidine-1-carboxylate
(100 mg; 0.373 mmol,) obtained from commercially available sources
(Arch Chemical or ABChem Inc.) and
1-fluoro-4-(methylsulfonyl)benzene (65 mg; 0.373) in DMF (5 mL) was
treated with cesium carbonate (182 mg; 0.559 mmol) and stirred at
60.degree. C. for 18 h. The reaction was diluted with ethyl acetate
(50 mL). The organic phase then washed twice with water
(2.times.150 mL). The organic phase was dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vac to a residue.
The crude product was purified by chromatography on silica gel and
eluted with ethyl acetate. The title compound was isolated.
[0297] 500 MHz NMR (CDCl3): .delta. 7.74 (d, 2H, J=9 Hz), 6.93 (d,
2H, J=8.5 Hz), 4.13 (bs, 2H), 3.91 (d, 2H, J=13 Hz), 3.00 (s, 3H),
2.84 (t, 2H, J=11.5 Hz), 2.64(t, 2H, J=12.5 Hz), 1.81 (d, 2H, J=10
Hz), 1.68 (d, 2H, J=12.5 Hz), 1.45 (s, 9H), 1.34 (m, 4H), 1.15 (m,
2H). ). LCMS calc: 422.59 obs: 423.13 (M+H).
General Procedure 1.2 (Buchwald Coupling)
Preparative Example 1.2
Preparation of tert-butyl
1'-{4-[(trifluoromethyl)sulfonyl]phenyl}-4,4'-bipiperidine-1-carboxylate
##STR00016##
[0299] The flask containing aryl bromide (35 mg, 0.12 mmol),
piperidine (HCl salt, 44.3 mg, 0.14 mmol), cesium carbonate (118
mg, 0.36 mmol), palladium acetate (1.36 mg, 0.006 mmol),
2-(diphenylphosphino)-2'-(N,N-dimethylamino)biphenyl (4.6 mg, 0.012
mmol) was applied to vacuum and refilled with argon alternatively
for 3 times. DMF (0.24 mL) was added through a syringe, and the
mixture was degassed for another 3 times. The reaction mixture was
stirred under argon at 90.degree. C. overnight, after cooling down,
ethyl acetate (4 mL) was added, and the mixture was washed with
water (0.5 mL.times.2), brine and dried over sodium sulfate.
Purification with preparative TLC (30/70 Ethyl acetate/Hexane)
yielded the title compound.
[0300] LRMS calc: 476.2; obs: 377.1 (M-99), 321.1 (M-55), 499.1
(M+23);
General Procedure 1.3
Preparative Example 1.23 (Table 1)
Preparation of tert-butyl
1'-{4-[(methylsulfonyl)methyl]phenyl}-4,4'-bipiperidine-1-carboxylate
##STR00017##
[0301] Step 1. 4-bromobenzyl methyl sulfone
##STR00018##
[0303] p-Bromobenzyl bromide (500 mg, 2 mmol) was refluxed with
MeSO.sub.2Na (306 mg, 3 mmol) in Ethanol for 1 hour. The reaction
was cooled, concentrated and purified by flash column (50%
acetone/hexanes) to give the desired product.
Step 2. tert-butyl
1'-{4-[(methylsulfonyl)methyl]phenyl}-4,4'-bipiperidine-1-carboxylate
##STR00019##
[0305] The flask containing aryl bromide (50 mg, 0.2 mmol),
piperidine (HCl salt, 73 mg, 0.24 mmol), cesium carbonate (163 mg,
0.5 mmol), palladium acetate (2.24 mg, 0.01 mmol),
bis(tri-tert-butylphosphoranyl)palladium (3.4 mg, 0.067 mmol) was
applied to vacuum and refilled with argon alternatively for 3
times. Dioxane (0.5 mL) was added through a syringe, and the
mixture was degassed for another 3 times. The reaction mixture was
stirred under argon at 80.degree. C. for 3 hours, after cooling
down, ethyl acetate (4 mL) was added, and the mixture was washed
with water (0.5 mL.times.2), brine and dried over sodium sulfate.
Purification with preparative TLC (30% acetone/hexanes) yielded the
title compound. LRMS calc: 436.2 ; obs: 437.2 (M+1).
General Procedure 1.4
Preparative Example 1.24 (Table 1)
Preparation of tert-butyl
1'-[4-(1H-1,2,4-triazol-1-yl)phenyl]-4,4'-bipiperidine-1-carboxylate
##STR00020##
[0306] Step 1 tert-butyl
1'-(4-iodophenyl)-4,4'-bipiperidine-1-carboxylate
##STR00021##
[0308] To a solution of tert-butyl
1'-phenyl-4,4'-bipiperidine-1-carboxylate (0.688 g, 2 mmol),
synthesized similarly as described for example 301, in methylene
chloride (40 mL) was added bis(collidine)iodine (I)
hexafluorophosphate (2.05 g, 4 mmol). After stirring the reaction
mixture for 10 min at room temperature, the solvent was removed
under vacuum and the residue purified by chromatography on silica
gel (hexane/ether).
Step 2 tert tert-butyl
1'-[4-(1H-1,2,4-triazol-1-yl)phenyl]-4,4'-bipiperidine-1-carboxylate
##STR00022##
[0310] tert-Butyl 1'-(4-iodophenyl)-4,4'-bipiperidine-1-carboxylate
(17 mg, 0.036 mmol) from Step 1, 1H-1,2,4-triazole (7.5 mg, 0.108
mmol), CuI (0.7 mg, 0.0036 mmol), N,N'-dimethylethane-1,2-diamine
(1 mg, 0.0072 mmol), K.sub.3PO.sub.4 (16 mg, 0.0756 mmol) were
mixed in a 1 dram vial, followed by addition of DMF (0.1 mL). The
reaction vessel was degassed and back-filled with Ar 3 times,
before it was heated at 100.degree. C. for 20 hours. The reaction
was cooled, diluted with water, extracted with EtOAc, concentrated
and purified by PTLC to give the title compound.
[0311] 500 MHz NMR (CDCl3): .delta. 8.49 (s, 1H), 8.12 (s, 1H),
7.53 (d, 2H, J=9 Hz), 7.03 (d, 2H, J=9 Hz), 4.17 (bs, 2H), 3.81 (d,
2H, J=12.5 Hz), 2.75 (dt, 2H, J=12.3 Hz, 2.3 Hz), 2.69(bs, 2H),
1.85 (d, 2H, J=11.9 Hz), 1.74 (d, 2H, J=12.1 Hz), 1.49 (s, 9H),
1.44 (m, 2H), 1.29 (m, 2H), 1.20 (m, 2H).
TABLE-US-00001 TABLE 1 Preparative Examples Procedure Chemical name
Chemical Structure (M + 1) 1.1 1 tert-butyl 1'-[4- (methylsulfonyl)
phenyl]-4,4'- bipiperidine-1- carboxylate ##STR00023## 423.1 1.9 2
tert-butyl 1'-(3- chloro-5- fluorophenyl)-4,4'- bipiperidine-1-
carboxylate ##STR00024## 341.1 (M - 55) 1.11 2 tert-butyl 1'-(3-
chloro-4- cyanophenyl)-4,4'- bipiperidine-1- carboxylate
##STR00025## 404.2 1.15 2 tert-butyl 1'-(3- chloro-5-
cyanophenyl)-4,4'- bipiperidine-1- carboxylate ##STR00026## 348.4
(M - 55) 1.17 2 tert-butyl 1'-(3- cyano-5- fluorophenyl)-4,4'-
bipiperidine-1- carboxylate ##STR00027## 332.1 (M - 55) 1.18 2
tert-butyl 1'-(4- cyano-2- fluorophenyl)-4,4'- bipiperidine-1-
carboxylate ##STR00028## 332.5 (M - 55) 1.20 2 tert-butyl 1'-[3-
chloro-4- (methylsulfonyl) phenyl]-4,4'- bipiperidine-1-
carboxylate ##STR00029## 357.0 (M - 99) 1.22 2 tert-butyl 1'-(2-
chloro-4- cyanophenyl)-4,4'- bipiperidine-1- carboxylate
##STR00030## 348.5 (M - 55) 1.23 3 tert-butyl 1'-{4-
[(methylsulfonyl) methyl]phenyl}-4,4'- bipiperidine-1- carboxylate
##STR00031## 437.2 1.25 4 tert-butyl 1'-(4- iodophenyl)-4,4'-
bipiperidine-1- carboxylate ##STR00032## 471.3 1.33 2 tert-butyl
1'-(3- chloro-4- fluorophenyl)-4,4'- bipiperidine-1- carboxylate
##STR00033## 397.6 1.35 2 tert-butyl 1'-(4- chloro-3-
fluorophenyl)-4,4'- bipiperidine-1- carboxylate ##STR00034## 397.5
1.37 2 tert-butyl 1'-(5- cyano-2- fluorophenyl)-4,4'-
bipiperidine-1- carboxylate ##STR00035## 332.1 (M - 55) 1.38 1
tert-butyl 1'-(2- chloro-4- cyanophenyl)-4,4'- bipiperidine-1-
carboxylate ##STR00036## 348.5 (M - 55)
General Procedure 2.1: (nucleophilic aromatic substitution)
Preparative Example 2.1
tert-butyl
1'-[4-(methylsulfonyl)phenyl]-4,4'-bipiperidine-1-carboxylate
##STR00037##
[0313] The tert-butyl 4,4'-bipiperidine-1-carboxylate (2.15 g, 8.0
mmol) and cesium carbonate (7.8 g, 24 mmol) were slurried in NMP
(80 ml) and the 2,6-dichloropyrazine (1.25 mg, 8.4 mmol) was added.
The mixture was stirred at 70.degree. C. for 2 h. The reactive
mixture was cooled down to r.t. and diluted with 100 mL of ethyl
acetate, washed with water 80 mL (.times.1) and brine 80 mL
(.times.1). The organic phase was dried over magnesium sulfate,
filtered, and concentrated on rotavapor. The crude material was
purified by chromatography on silica gel with 25% acetone: hexanes
to yield the titled compound. Examples reported in Table 2 can be
prepared by Procedure 2.1 described above from readily available
starting materials and tert-butyl
4,4'-bipiperidine-1-carboxylate.
TABLE-US-00002 TABLE 2 Preparative Examples Procedure Chemical name
Chemical Structure (M + 1) 2.1 2.1 tert-butyl 1'-(3,6-
dimethylpyrazin-2- yl)-4,4'-bipiperidine- 1-carboxylate
##STR00038## 375.69 2.2 2.1 tert-butyl 1'-[5- (methoxycarbonyl)
pyrazin-2-yl]-4,4'- bipiperidine-1- carboxylate ##STR00039## 405.65
2.3 2.1 tert-butyl 1'-[2- (methylthio)pyrimidin- 4-yl]-4,4'-
bipiperidine-1- carboxylate ##STR00040## 393.64 2.4 2.1 tert-butyl
1'-(6- methoxypyrazin-2- yl)-4,4'-bipiperidine- 1-carboxylate
##STR00041## 377.67 2.5 2.1 tert-butyl 1'-(6- methoxypyrimidin-4-
yl)-4,4'-bipiperidine- 1-carboxylate ##STR00042## 377.67 2.6 2.1
tert-butyl 1'-(2,6- dimethoxypyrimidin- 4-yl)-4,4'- bipiperidine-1-
carboxylate ##STR00043## 407.67 2.7 2.1 tert-butyl 1'-(3-
cyanopyrazin-2-yl)- 4,4'-bipiperidine-1- carboxylate ##STR00044##
394.57 (M + 23) 2.8 2.1 tert-butyl 1'-(2- chloropyrimidin-4-
yl)-4,4'-bipiperidine- 1-carboxylate ##STR00045## 381.56 2.9 2.1
tert-butyl 1'-(4- chloropyrimidin-2- yl)-4,4'-bipiperidine-
1-carboxylate ##STR00046## 403.53 (M + 23) 2.10 2.1 tert-butyl
1'-(2,6- dichloropyrimidin-4- yl)-4,4'-bipiperidine- 1-carboxylate
##STR00047## 415.50 2.11 2.1 tert-butyl 1'-(4,6-
dichloropyrimidin-2- yl)-4,4'-bipiperidine- 1-carboxylate
##STR00048## 437.44 (M + 23) 2.12 2.1 tert-butyl 1'-(6- amino-2-
chloropyrimidin-4- yl)-4,4'-bipiperidine- 1-carboxylate
##STR00049## 396.57 2.13 2.1 tert-butyl 1'-(2- chloro-5-
fluoropyrimidin-4- yl)-4,4'-bipiperidine- 1-carboxylate
##STR00050## 399.52 2.14 2.1 tert-butyl 1'-(5- bromopyrimidin-2-
yl)-4,4'-bipiperidine- 1-carboxylate ##STR00051## 427.52 2.15 2.1
tert-butyl 1'-(5- fluoropyrimidin-2- yl)-4,4'-bipiperidine-
1-carboxylate ##STR00052## 365.67 2.16 2.1 tert-butyl 1'-(6-
chloro-2- methylpyrimidin-4- yl)-4,4'-bipiperidine- 1-carboxylate
##STR00053## 395.53 2.17 2.1 tert-butyl 1'-(2- chloro-6-
methylpyrimidin-4- yl)-4,4'-bipiperidine- 1-carboxylate
##STR00054## 395.07 2.18 2.1 tert-butyl 1'-(6- chloro-4-
cyanopyridin-2-yl)- 4,4'-bipiperidine-1- carboxylate ##STR00055##
405.49 2.19 2.1 tert-butyl 1'-(4- cyanopyridin-2-yl)-
4,4'-bipiperidine-1- carboxylate ##STR00056## 393.12 (M + 23) 2.20
2.1 tert-butyl 1'-(3- fluoro-6- methylpyridin-2-yl)-
4,4'-bipiperidine-1- carboxylate ##STR00057## 378.13
General Procedure 3.1
Preparation of tert-butyl
1'-[2-(trifluoromethyl)pyrimidin-4-yl]-4,4'-bipiperidine-1-carboxylate
Step 1: 4-bromo-2-(trifluoromethyl)pyrimidine
##STR00058##
[0315] The 2-(trifluoromethyl)pyrimidin-4-ol (328 mg, 2.0 mmol) and
PBr.sub.3 (0.188 mL, 2.0 mmol) were mixed and heated at 150.degree.
C. for 3 h. The reaction was cooled down and quenched with ice
water, extracted with DCM (20mL.times.2) to yield the titled
compound. The organic phase was concentrated and crude material was
purified by preparative TLC with 20% Acetone: Hexane to yield
titled compound.
Step 2: tert-butyl
1'-[2-(trifluoromethyl)pyrimidin-4-yl]-4,4'-bipiperidine-1-carboxylate
##STR00059##
[0317] The tert-butyl 4,4'-bipiperidine-1-carboxylate (28.5 mg,
0.11 mmol) and cesium carbonate (106 mg, 0.32 mmol) were stirred in
NMP (0.5 ml) and the 4-bromo-2-(trifluoromethyl)pyrimidine (12 mg,
0.053 mmol) was added. The mixture was heated at 70.degree. C. for
2 h. The reaction was cooled down to r.t. and diluted with ethyl
acetate (5 mL) and was washed with water 2 mL (.times.1) and brine
2 mL (.times.1). The organic phase was dried over magnesium
sulfate, filtered, and concentrated on rotavapor. The crude
material was purified by preparative TLC with 30% acetone: hexane
to yield the titled compound. LC-MS: 415.60 (M+H).
[0318] Preparative Examples reported in Table 3 can be prepared by
Procedure 3.1 described above.
TABLE-US-00003 TABLE 3 Preparative Examples Procedure Chemical name
Chemical Structure (M + 1) 3.1 3.1 tert-butyl 1'-[2-
(trifluoromethyl) pyrimidin-4-yl]-4,4'- bipiperidine-1- carboxylate
##STR00060## 415.60 3.2 3.1 tert-butyl 1'-[6- (trifluoromethyl)
pyrimidin-4-yl]-4,4'- bipiperidine-1- carboxylate ##STR00061##
415.60 3.3 3.1 tert-butyl 1'-(2,5- dichloropyrimidin-4-
yl)-4,4'-bipiperidine- 1-carboxylate ##STR00062## 437.0 (M + 23)
3.4 3.1 tert-butyl 1'-(4,5- dichloropyrimidin-2-
yl)-4,4'-bipiperidine- 1-carboxylate ##STR00063## 315.0 (-Boc 100)
3.5 3.1 tert-butyl 1'-(4,6- dimethylpyrimidin-2-
yl)-4,4'-bipiperidine- 1-carboxylate ##STR00064## 374.2 3.8 3.1
tert-butyl 1'-(2- cyanopyrimidin-4- yl)-4,4'-bipiperidine-
1-carboxylate ##STR00065## 372 3.9 3.1 tert-butyl 1'-(2,5-
dichloropyrimidin-4- yl)-4,4'-bipiperidine- 1-carboxylate
##STR00066## 437.0 (M + 23)
General Procedure 4.1
Preparation of tert-butyl
1'-(6-methylpyrazin-2-yl)-4,4'-bipiperidine-1-carboxylate
Step 1: tert-butyl
1'-[4-(methylsulfonyl)phenyl]-4,4'-bipiperidine-1-carboxylate: same
as Procedure 2.1
##STR00067##
[0319] Step 2: tert-butyl
1'-(6-methylpyrazin-2-yl)-4,4'-bipiperidine-1-carboxylate
##STR00068##
[0321] The tert-butyl
1'-[4-(methylsulfonyl)phenyl]-4,4'-bipiperidine-1-carboxylate (100
mg, 0.26 mmol) was dissolved in THF and NMP (5 mL, 1:1) at r.t. The
catalyst iron (III) acetylacetonate (18.4 mg, 0.052 mmol) was added
under N.sub.2. Methyl magnesium bromide (3M, 0.19 mL, 0.57 mmol)
was added dropwise. The reaction was stirred for more 15 min and
was quenched with iced ammonia chloride solution (10 mL) and
extracted with ethyl acetate (10 mL). The organic phase was washed
with brine (10 mL, .times.1), dried over magnesium sulfate,
filtered, and concentrated on rotavapor. The crude material was
purified by preparative TLC with 30% acetone: hexane to yield the
title compound.
[0322] LC-MS: 361.63 (M+H).
[0323] Preparative Examples reported in Table 4 can be prepared by
Procedure 4.1 described below.
TABLE-US-00004 TABLE 4 Preparative Example Procedure Chemical name
Chemical Structure (M + 1) 4.1 4.1 tert-butyl 1'-(6-
methylpyrazin-2-yl)- 4,4'-bipiperidine-1- carboxylate ##STR00069##
361.63 4.2 4.1 tert-butyl 1'-(6- methylpyrimidin-4-
yl)-4,4'-bipiperidine- 1-carboxylate ##STR00070## 361.45 4.3 4.1
tert-butyl 1'-(6- cyclopropylpyrazin- 2-yl)-4,4'- bipiperidine-1-
carboxylate ##STR00071## 378.13 4.4 4.1 tert-butyl 1'-(5- fluoro-2-
methylpyrimidin-4- yl)-4,4'-bipiperidine- 1-carboxylate
##STR00072## 379.17 4.5 4.1 tert-butyl 1'-(2,6-
dimethylpyrimidin-4- yl)-4,4'-bipiperidine- 1-carboxylate
##STR00073## 375.17 4.6 4.1 tert-butyl 1'-(4,6-
dimethylpyrimidin-2- yl)-4,4'-bipiperidine- 1-carboxylate
##STR00074## 375.21 4.7 4.1 tert-butyl 1'-(4- cyanopyridin-2-yl)-
4,4'-bipiperidine-1- carboxylate ##STR00075## 407.64 (M + 23) 4.8
4.1 tert-butyl 1'-(5- chloro-2- methylpyrimidin-4-
yl)-4,4'-bipiperidine- 1-carboxylate ##STR00076## 395.58 4.9 4.1
tert-butyl 1'-(2,5- dimethylpyrimidin-4- yl)-4,4'-bipiperidine-
1-carboxylate ##STR00077## 375.63 4.9 4.1 tert-butyl 1'-(2-
methylpyrimidin-4- yl)-4,4'-bipiperidine- 1-carboxylate
##STR00078## 361.65 4.10 4.1 tert-butyl 1'-(6-
cyclopropylpyrimidin- 4-yl)-4,4'- bipiperidine-1- carboxylate
##STR00079## 387.20
General Procedure 5.1
Preparation of tert-butyl
1'-(6-cyanopyrazin-2-yl)-4,4'-bipiperidine-1-carboxylate
Step 1: tert-butyl
1'-[4-(methylsulfonyl)phenyl]-4,4'-bipiperidine-1-carboxylate: same
as Procedure 2.1
Step 2: tert-butyl
1'-(6-cyanopyrazin-2-yl)-4,4'-bipiperidine-1-carboxylate
##STR00080##
[0325] The tert-butyl
1'-[4-(methylsulfonyl)phenyl]-4,4'-bipiperidine-1-carboxylate (500
mg, 1.3 mmol), palladium(II) acetate (6 mg, 0.026 mmol),
N,N,N',N'-tetramethylethylenediamine (0.15 mL, 0.26 mmol),
1,5-bis(dipenylphosphino)pentane, potassium cyanide (93 mg, 1.43
mmol) were add in a seal bottle with 13 mL anhydrous toluene. The
mixture was degassed by N.sub.2 and closed and heated to
160.degree. C. overnight (16 h). The reaction was cooled down to
r.t. and diluted with ethyl acetate 50 mL, filtered through celite,
and concentrated on rotavapor. The crude material was purified by
silica gel flash chromatography with 30% acetone: hexane to yield
the title compound.
[0326] LC-MS: 394.11 (M+23).
[0327] Preparative Examples reported in Table 5 can be prepared by
Procedure 5.1.
TABLE-US-00005 TABLE 5 Preparative Examples Procedure Chemical name
Chemical Structure (M + 1) 5.1 5.1 tert-butyl 1'-(6-
cyanopyrimidin-4- yl)-4,4'-bipiperidine- 1-carboxylate ##STR00081##
372.13 5.2 5.1 tert-butyl 1'-(2- cyanopyrimidin-4-
yl)-4,4'-bipiperidine- 1-carboxylate ##STR00082## 372.14 5.3 5.1
tert-butyl 1'-(2- cyano-6- methylpyrimidin-4-
yl)-4,4'-bipiperidine- 1-carboxylate ##STR00083## 408.2 (M + 23)
5.4 5.1 tert-butyl 1'-[6- (aminocarbonyl) pyrimidin-4-yl]-4,4'-
bipiperidine-1- carboxylate ##STR00084## 390.20 5.5 5.1 tert-butyl
1'-[2- (aminocarbonyl) pyrimidin-4-yl]-4,4'- bipiperidine-1-
carboxylate ##STR00085## 390.20 5.6 5.1 tert-butyl 1'-(6-
cyanopyridin-2-yl)- 4,4'-bipiperidine-1- carboxylate ##STR00086##
393.13 (M + 23) 5.7 5.1 tert-butyl 1'-(6- cyanopyrazin-2-yl)-
4,4'-bipiperidine-1- carboxylate ##STR00087## 394.11 (M + 23)
General Procedure 6.1
Preparation of tert-butyl
1'-[6-(1H-1,2,4-triazol-1-yl)pyrimidin-4-yl]-4,4'-bipiperidine-1-carboxyl-
ate
Step 1: tert-butyl
1'-(6-chloropyrimidin-4-yl)-4,4'-bipiperidine-1-carboxylate: same
as Procedure 2.1 replacing the 2,6-dichloropyrazine with
4,6-dichloropyrimidine
##STR00088##
[0328] Step 2: tert-butyl
1'-[6-(1H-1,2,4-triazol-1-yl)pyrimidin-4-yl]-4,4'-bipiperidine-1carboxyla-
te
##STR00089##
[0330] The tert-butyl
1'-(6-chloropyrimidin-4-yl)-4,4'-bipiperidine-1-carboxylate (190
mg, 0.50 mmol), 1,2,4-triazole (69 mg, 1.0 mmol), cesium carbonate
(488 mg, 1.5 mmol) were added in NMP (5 mL) and heated to 140
.degree. C. for 1.5 hours. The reaction crude were cooled down to
r.t. and diluted with ethyl acetate (10 mL), washed with water (5
mL, .times.1) and brine (5 mL, .times.1). The organic phase was
dried over magnesium sulfate, filtered and concentrated on
rotavapor. The crude mixture was purified by preparative TLC with
50% ethyl acetate: hexane to yield the title compound.
[0331] LC-MS: 414.13 (M+H).
[0332] Preparative Examples reported in Table 6 can be prepared by
Procedure 6.1 described below.
TABLE-US-00006 TABLE 6 Preparative Examples Procedure Chemical name
Chemical Structure (M + 1) 6.1 6.1 tert-butyl 1'-[6-(1H- pyrazol-1-
yl)pyrimidin-4-yl]- 4,4'-bipiperidine-1- carboxylate ##STR00090##
413.21 6.2 6.1 tert-butyl 1'-[6-(1H- 1,2,3-triazol-1-
yl)pyrimidin-4-yl]- 4,4'-bipiperidine-1- carboxylate ##STR00091##
414.11 6.3 6.1 tert-butyl 1'-[6-(2H- 1,2,3-triazol-2-
yl)pyrimidin-4-yl]- 4,4'-bipiperidine-1- carboxylate ##STR00092##
414.14 6.4 6.1 tert-butyl 1'-[6-(1H- 1,2,4-triazol-1-
yl)pyrimidin-4-yl]- 4,4'-bipiperidine-1- carboxylate ##STR00093##
414.13
General Procedure 7.1
Preparation of tert-butyl
1'-[6-(methylamino)pyrimidin-4-yl]-4,4'-bipiperidine-1-carboxylate
Step 1: tert-butyl
1'-(6-chloropyrimidin-4-yl)-4,4'-bipiperidine-1-carboxylate: same
as Procedure 6.1
Step 2: tert-butyl
1'-[6-(methylamino)pyrimidin-4-yl]-4,4'-bipiperidine-1-carboxylate
##STR00094##
[0334] The tert-butyl
1'-(6-chloropyrimidin-4-yl)-4,4'-bipiperidine-1-carboxylate (19 mg,
0.05 mmol) was added to methyl amine in MeOH (1N, 2 mL) in a sealed
bottle and heated to 50.degree. C. for 2 days. The reaction crude
were cooled down to r.t. and concentrated on rotavapor. The crude
mixture was purified by preparative TLC with 10% methanol:
dichloromethane to yield title compound.
[0335] LC-MS: 376.18 (M+H)
[0336] Preparative Examples reported in Table 7 can be prepared by
Procedure 7.1 described below.
TABLE-US-00007 TABLE 7 Preparative Examples Procedure Chemical name
Chemical Structure (M + 1) 7.1 7.1 tert-butyl 1'-[6- (methylamino)
pyrimidin-4-yl]-4,4'- bipiperidine-1- carboxylate ##STR00095##
376.18 7.2 7.1 tert-butyl 1'-[2- (methylamino)
pyrimidin-4-yl]-4,4'- bipiperidine-1- carboxylate ##STR00096##
376.18
General Procedure 8.1
Preparation of tert-butyl
1'-[6-(benzyloxy)pyrimidin-4-yl]-4,4'-bipiperidine-1-carboxylate
Step 1: tert-butyl
1'-(6-chloropyrimidin-4-yl)-4,4'-bipiperidine-1-carboxylate: same
as Procedure 6.1
Step 2: Preparation of tert-butyl
1'-[6-(benzyloxy)pyrimidin-4-yl]-4,4'-bipiperidine-1-carboxylate
##STR00097##
[0338] The tert-butyl
1'-(6-chloropyrimidin-4-yl)-4,4'-bipiperidine-1-carboxylate (100
mg, 0.26 mmol), phenylmethanol (0.031 mL, 0.29 mmol) were added to
DMF (2.6 mL), and then sodium hydride (7 mg, 0.29 mmol) was added
to the mixture. The reaction was heated to 30.degree. C. for 30
min. The reaction crude was cooled down to r.t. and quenched with
ice ammonia chloride solution (10 mL) and extracted with ethyl
acetate (10 mL). The organic phase was washed with brine (10 mL,
.times.1), dried over magnesium sulfate, filtered and concentrated
by rotavapor. The crude mixture was purified by preparative TLC
with 30% ethylacetate: hexane to yield the title compound.
[0339] LC-MS: 453.62 (M+H).
[0340] Preparative Examples reported in Table 8 can be prepared by
Procedure 8.1 described below.
TABLE-US-00008 TABLE 8 Preparative Examples Procedure Chemical name
Chemical Structure (M + 1) 8.1 8.1 tert-butyl 1'-[6-
(benzyloxy)pyrazin- 2-yl]-4,4'- bipiperidine-1- carboxylate
##STR00098## 453.62 8.2 8.1 tert-butyl 1'-[6- (benzyloxy)pyrimidin-
4-yl]-4,4'- bipiperidine-1- carboxylate ##STR00099## 453.62 8.3 8.1
tert-butyl 1'-[2- (benzyloxy)pyrimidin- 4-yl]-4,4'- bipiperidine-1-
carboxylate ##STR00100## 453.62
General Procedure 9.1
Preparation of tert-butyl
1'-(5-fluoro-2-methoxypyrimidin-4-yl)-4,4'-bipiperidine-1-carboxylate
Step 1: tert-butyl
1'-(2-chloro-5-fluoropyrimidin-4-yl)-4,4'-bipiperidine-1-carboxylate:
same as Procedure 2.1, replacing the 2,6-dichloropyrazine with
2,4-dichloro-5-fluoropyrimidine
Step 2: tert-butyl
1'-(5-fluoro-2-methoxypyrimidin-4-yl)-4,4'-bipiperidine-1-carboxylate
##STR00101##
[0342] The tert-butyl
1'-(2-chloro-5-fluoropyrimidin-4-yl)-4,4'-bipiperidine-1-carboxylate
(40 mg, 0.10 mmol) was added to NMP (1 mL), and then potassium
methoxide (8.1 mg, 0.11 mmol) was added to the mixture. The
reaction was stirred for 30 min at r.t. and was quenched with
ammonium chloride solution (5 mL), extracted with ethylacetate (10
mL). The organic phase was washed with brine (10 mL, .times.1),
dried over magnesium sulfate, filtered and concentrated by
rotavapor. The crude mixture was purified by preparative TLC with
30% acetone: hexane to yield the title compound.
[0343] LC-MS: 395.14 (M+H).
General Procedure 10.1
Preparation of tert-butyl
1'-[6-(methylsulfonyl)pyrimidin-4-yl]-4,4'-bipiperidine-1-carboxylate
Step 1: tert-butyl
1'-(6-chloropyrimidin-4-yl)-4,4'-bipiperidine-1-carboxylate: same
as Procedure 6.1
Step 2: tert-butyl
1'-[6-(methylthio)pyrimidin-4-yl]-4,4'-bipiperidine-1-carboxylate
##STR00102##
[0345] The tert-butyl
1'-(6-chloropyrimidin-4-yl)-4,4'-bipiperidine-1-carboxylate (100
mg, 0.26 mmol) was dissolved in NMP (2.6 mL), and sodium
methanethiolate (18.2 mg, 0.26 mmol) was added. The reaction was
stirred at r.t. for 30 min. The reaction crude was diluted with
ethyl acetate (10 mL) and was washed with water (10 mL, .times.1)
and brine (10 mL, .times.1), dried over magnesium sulfate, filtered
and concentrated by rotavapor. The crude mixture was purified by
preparative TLC with 30%. ethylacetate: hexane to yield the title
compound.
[0346] LC-MS: 393.64 (M+H).
Step 3: tert-butyl
1'-[6-(methylsulfonyl)pyrimidin-4-yl]-4,4'-bipiperidine-1-carboxylate
##STR00103##
[0348] The tert-butyl
1'-[6-(methylthio)pyrimidin-4-yl]-4,4'-bipiperidine-1-carboxylate
(100 mg, 0.25 mmol) was dissolved in dichloromethane (2.5 mL) and
mCPBA was added (126 mg, 0.55 mmol, max 77%). The reaction was
stirred at r.t. for 1 h and was diluted with dichloromethane (10
mL). The reaction mixture was washed with sodium thiosulfate
solution (10 mL, 1N, 1.times.) and saturated sodium bicarbonate
solution (10 mL, .times.1). The organic phase was dried over
magnesium sulfate, filtered and concentrated by rotavapor. The
crude mixture was purified by flash silica gel column
chromatography with 30% acetone: hexane to yield the title
compound.
[0349] LCMS: 447.58 (M+23).
[0350] Preparative Examples reported in Table 10 can be prepared by
Procedure 10.1 described below.
TABLE-US-00009 TABLE 10 Preparative Examples Procedure Chemical
name Chemical Structure (M + 1) 10.1 10.1 tert-butyl 1'-[6-
(methylthio) pyrimidin-4-yl]-4,4'- bipiperidine carboxylate
##STR00104## 393.64 10.2 10.1 tert-butyl 1'-[6- (methylsulfonyl)
pyrimidin-4-yl]-4,4'- bipiperidine-1- carboxylate ##STR00105##
447.58
General Procedure 11.1 (nucleophilic aromatic ubstitution)
Step 1: Preparation of 5-chloropyrazin-2-amine
##STR00106##
[0352] Pyrazin-2-amine (15.0 g, 158 mmol) was dissolved in DMF (80
ml) and the vessel cooled in a RT water bath. N-chlorosuccinimide
(21.1 g, 158 mmol) was added in three portions (0.33 equivalents)
every 30 minutes and the dark solution stirred overnight. The
mixture was diluted with DCM (1000 ml) and acetone (100 ml) and the
mixture stirred at RT for 5 minutes. The solution was filtered
through a 1 inch plug of silica (150 ml of silica) and the filter
cake washed with 15% acetone:DCM (400 ml.times.5) until the desired
material was no longer present in the wash fraction. The organics
were combined, washed with brine, dried over Na.sub.2SO.sub.4 and
concentrated in vacuo. The residue was purified by chromatography
on silica gel using a step gradient: beginning with neat DCM and
stepping up to 5% acetone:DCM.
Step 2: Preparation of 2,5-dichloropyrazine
##STR00107##
[0354] 5-Chloropyrazin-2-amine (5.0 g, 38.6 mmol) was dissolved in
acetonitrile (77 ml) under a balloon of N.sub.2. The copper(I)
chloride (5.7 g, 57.9 mmol) and copper(II) chloride (7.8 g, 57.9
mmol) were added and the slurry cooled to -10.degree. C. with an
ice:acetone bath. t-Butyl nitrite (9.15 g, 89 mmol, 90%) was added
dropwise and the solution allowed to warm to RT. The solution was
stirred for 30 minutes until rapid gas evolution ceased. The
mixture was heated to 65.degree. C. for 2.5 hours. The mixture was
cooled to RT and filtered through a 1.5 inch pad of celilte packed
into a 465 ml frit. The pad was washed with DCM (200 ml.times.4),
the wash fractions containing the desired material combined,
filtered, and concentrated in vacuo. The residue was purified by
chromatography on silica gel with 2% ether:pentane to yield the
title compound.
Step 3:
tert-butyl-1'-(5-chloropyrazin-2-yl)-4,4'-bipiperdine-1-carboxylat-
e
##STR00108##
[0356] The tert-butyl 4,4'-bipiperidine-1-carboxylate (1.27 g, 4.7
mmol) and 2,5-dichloropyrazine (670 mg, 4.5 mmol) were dissolved in
NMP (5 ml) at room temperature, and
1,8-diazabicyclo[5.4.0]-undec-7-ene (1 mL, 6.8 mmol) added
drop-wise. The mixture was heated at 110.degree. C. for 1 h,
allowed to cool to r.t. and diluted with 50 mL of ethyl acetate.
The solution was washed with water (10 mL.times.1), brine (10
mL.times.1), dried over magnesium sulfate, filtered, and
concentrated in vac. The residue was purified by chromatography on
silica gel with 10% acetone: hexanes to yield the title
compound.
[0357] LC-MS: 381.25 (M+H).
Step 4: tert-butyl
1'-(5-methylpyrazin-2-yl)-4,4'-bipiperidine-1-carboxylate
##STR00109##
[0359] The
tert-butyl-1'-(5-chloropyrazin-2-yl)-4,4'-bipiperdine-1-carboxy-
late (1.1 g, 2.9 mmol) was dissolved in 1:1 THF and NMP (30 mL) at
r.t. Iron (III) acetylacetonate (512 mg, 1.45 mmol) was added under
N.sub.2. Methyl magnesium bromide (3M, 3.9 mL, 11.6 mmol) was added
dropwise and the mixture stirred for 15 min. An ice cooled solution
of saturated ammonia chloride (30 mL, aq.) and ethyl acetate (30
mL) were added, the mixture shaken, and the phases separated. The
organic phase was washed with brine (10 mL, .times.1), dried over
magnesium sulfate, filtered, and concentrated in vac. The residue
was purified by chromatography on silica gel with 12.5% acetone:
hexanes to yield the title compound.
[0360] LC-MS: 361.32 (M+H).
General Procedure 11.2 (chlorination)
Preparative Example 11.2
tert-butyl
1'-(5-chloropyrazin-2-yl)-4,4'-bipiperidine-1-carboxylate
##STR00110##
[0362] The tert-butyl
1'-pyrazin-2-yl-4,4'-bipiperidine-1-carboxylate (64 mg, 0.19 mmol,
prepared as described for Example 8) and N-chlorosuccinimide (27
mg, 0.20 mmol) were dissolved in DMF (0.9 ml) and the solution
stirred overnight at 50.degree. C. The slurry was diluted with 15%
brine:water (40 ml) and extracted with ethyl acetate (3.times.25
ml). The combined organic fraction was washed with brine, dried
over magnesium sulfate, filtered, and the volatiles removed in vac.
The crude material was purified by chromatography on silica gel
with 10% acetone : hexanes to yield the title compound.
[0363] LRMS calc: 380.2 obs: 403.0 (M+Na).
General Procedure 11.3 (Bromination)
Preparative Example 11.15
tert-butyl
1'-(5-bromopyrazin-2-yl)-4,4'-bipiperidine-1-carboxylate
##STR00111##
[0365] The tert-butyl
1'-pyrazin-2-yl-4,4'-bipiperidine-1-carboxylate (16 mg, 0.046 mmol,
prepared as described for Example 8) and N-bromosuccinimide (8.2
mg, 0.046 mmol) were dissolved in DMF (0.2 ml) and the solution
stirred overnight at 50 C. The slurry was diluted with 15%
brine:water (40 ml) and extracted with ethyl acetate (3.times.25
ml). The combined organic fraction was washed with brine, dried
over magnesium sulfate, filtered, and the volatiles removed in vac.
The crude material was purified by chromatography on silica gel
with 20% acetone:hexanes to yield the title compound.
[0366] LRMS calc: 424.1 obs: 447.0 (M+Na).
[0367] Preparative Examples reported in Table 11 can be prepared
using general procedure 11.1 from readily available starting
materials and tert-butyl 4,4'-bipiperidine-1-carboxylate.
TABLE-US-00010 TABLE 11 Preparative Ex. # Procedure Chemical name
Chemical Structure (M + 1) 11.1 11.1 tert-butyl 1'-(1,3-
thiazol-2-yl)- 4,4'-bipiperidine- 1-carboxylate ##STR00112## 352.0
11.2 11.1 tert-butyl 1'- pyridin-2-yl-4,4'- bipiperidine-1-
carboxylate ##STR00113## 346.1 11.3 11.1 tert-butyl-1'-(5-
methylpyridin-2- yl)-4,4'- bipiperidine-1- carboxylate ##STR00114##
11.4 11.1 tert-butyl 1'- pyrazin-2-yl-4,4'- bipiperidine-1-
carboxylate ##STR00115## 369.08 (M + Na) 11.5 11.1 tert-butyl 1'-
pyrimidin-2-yl- 4,4'-bipiperidine- 1-carboxylate ##STR00116## 347.0
11.6 11.1 tert-butyl 1'-(6- cyano-2- methylpyrimidin- 4-yl)-4,4'-
bipiperidine-1- carboxylate ##STR00117## 386.4 11.7 11.1 tert-butyl
1'-(1,3- benzothiazol-2- yl)-4,4'- bipiperidine-1- carboxylate
##STR00118## 402.1 11.8 11.1 tert-butyl 1'-(5- bromo-1,3-
thiazol-2-yl)- 4,4'-bipiperidine- 1-carboxylate ##STR00119## 430.0
11.9 11.1 tert-butyl 1'-(6- chloropyrimidin- 4-yl)-4,4'-
bipiperidine-1- carboxylate ##STR00120## 381.0 11.10 11.1
tert-butyl 1'- quinoxalin-2-yl- 4,4'-bipiperidine- 1-carboxylate
##STR00121## 397.1 11.11 11.1 tert-butyl 1'-(3- methylpyrazin-2-
yl)-4,4'- bipiperidine-1- carboxylate ##STR00122## 383.1 (M + Na)
11.12 11.1 tert-butyl 1'-(5- methylpyrazin-2- yl)-4,4'-
bipiperidine-1- carboxylate ##STR00123## 383.1 (M + Na) 11.13 11.2
tert-butyl 1'-(5- chloropyrimidin- 2-yl)-4,4'- bipiperidine-1-
carboxylate ##STR00124## 380.9 11.14 11.2 tert-butyl 1'-(5-
chloro-3,6- dimethylpyrazin- 2-yl)-4,4'- bipiperidine-1-
carboxylate ##STR00125## 409.0 11.15 11.3 tert-butyl 1'-(5-
bromo-4- methylpyrimidin- 2-yl)-4,4'- bipiperidine-1- carboxylate
##STR00126## 439.0
General Procedure 11.6 (dechlorination)
Preparative Example 11.16
tert-butyl 1'-pyrimidin-4-yl-4,4'-bipiperidine-1-carboxylate
##STR00127##
[0369] The tert-butyl
1'-(6-chloropyrimidin-4-yl)-4,4'-bipiperidine-1-carboxylate (50 mg,
0.13 mmol, prepared as described for Example 13) and sodium acetate
(11 mg, 0.13 mmol) were dissolved in methanol (1.3 ml), 10%
palladium on carbon (14 mg) added and the solution stirred
overnight under a hydrogen atmosphere. The solution was diluted
with 4:1 water:saturated sodium bicarbonate (40 ml) and extracted
with ethyl acetate (3.times.25 ml). The combined organic fraction
was washed with brine, dried over magnesium sulfate, filtered, and
the volatiles removed in vac. The crude material was purified by
chromatography on silica gel with 35% acetone : hexanes to yield
the titled compound.
[0370] LRMS calc: 346.2 obs: 347.1 (M+H).
General Procedure 12.1 (nucleophilic aromatic substitution)
Preparative Example 12.1
Preparation of
tert-butyl-1'-[4-(cyano)phenyl]-4,4'-bipiperidine-1-carboxylate
##STR00128##
[0372] A solution of tert-butyl 4,4'-bipiperidine-1-carboxylate
(181 mg; 0.674 mmol) in DMF (3 mL) was treated with
4-fluorobenzonitrile (98 mg; 0.809 mmol) and cesium carbonate (264
mg; 0.809 mmol). The mixture was stirred at 70.degree. C. for 18
hr. The mixture was partitioned between isopropyl acetate (25 mL)
and pH7 phosphate buffer (10 mL). The organic was washed twice more
with pH7 phosphate buffer (2.times.10 mL). The organic was dried
over magnesium sulfate, filtered and evaporated to a solid. The
crude product was chromatographed over silica gel (PTLC; 2:1
hex/MTBE). The major band was recovered affording the title
compound. LRMS calc: 369.2 obs: 370.1 (M+H), 270.1 (M-BOC+H).
General Procedure 12.2 (Copper mediated N-arylation)
Preparative Example 12.2
Preparation of tert-butyl
1'-[4-(methylthio)phenyl]-4,4'-bipiperidine-1-carboxylate
##STR00129##
[0374] A suspension of 4-methylthiophenylboronic acid (240 mg;
1.431 mmol) in dichloromethane (6 mL) was treated with activated
powdered 4 .ANG. molecular sieves (1.5 g), Cu(OAc).sub.2 (87 mg;
0.477 mmol), tert-butyl 4,4'-bipiperidine-1-carboxylate (128 mg;
0.477 mmol) and triethylamine (134 .mu.L; 0.954 mmol). The reaction
vessel was purged with oxygen and the mixture stirred under an
oxygen atmosphere at ambient temperature for 18 hr. The now brown
mixture was filtered through Celite. The eluant was adsorbed onto
silica gel. The silica gel was exhaustively eluted without
fractionation (1:1 hex/MTBE). The eluant was evaporated to a yellow
oil and chromatographed (PTLC; 2:1 hex/MTBE). The major band was
collected affording the title compound. LRMS calc: 390.2 obs: 391.1
(M+H), 291.1 (M-BOC+H).
General Procedure 12.3 (Palladium mediated N-arylation)
Preparative Example 12.3
Preparation of
tert-Butyl-1'-[4-(methoxycarbonyl)phenyl]-4,4'-bipiperidine-1-carboxylate
##STR00130##
[0376] A 100 mL reaction flask was charged with tert-butyl
4,4'-bipiperidine-1-carboxylate (1.14 g; 4.25 mmol), methyl
4-bromobenzoate (913 mg; 4.25 mmol), cesium carbonate (4.15 g;
12.74 mmol), Pd(OAc).sub.2 (48 mg; 0.212 mmol) and
2-(diphenylphosphino)-2'-(N-N-dimethylamino)biphenyl (162 mg; 0.425
mmol). NMP (outgassed by bubbling with nitrogen for 10 min; 10 mL)
was added and the mixture stirred at 90.degree. C. for 18 hr. The
mixture was diluted with dichloromethane (100 mL) and filtered
through Celite. The filtrate was washed with water (4.times.25 mL).
The organic was dried over magnesium sulfate, filtered and
evaporated to a solid. The solid was digested at reflux (MTBE).
After cooling, the white solid was recovered by filtration. The
filtrate was evaporated and chromatographed (Horizon; 0% to 100%
EtOAc/hex; linear gradient). The fractions containing the desired
compound were recovered and combined with the solid to give the
title compound.
[0377] LRMS calc: 402.3 obs: 403.2 (M+H), 303.2 (M-BOC+H).
General Procedure 12.4 (Ester hydrolysis)
Preparative Example 12.4
Preparation of
4-[1'-(tert-butoxycarbonyl)-4,4'-bipiperidin-1-yl]benzoic acid
##STR00131##
[0379] Compound 12.3 (305 mg; 0.758 mmol) was suspended in ethanol
(5 ml) in a sealable tube. Potassium hydroxide (225 mg; 3.41 mmol)
was added. The tube was sealed and heated in a 105.degree. C. bath
for 1 hr. The solid mass was washed out with water and the pH
adjusted to 4.0 with 1N HCl. The title compound was recovered by
filtration. LRMS calc: 388.2 obs: 389.2 (M+H), 289.1 (M-BOC+H).
General Procedure 12.5 (amide formation)
Preparative Example 12.5
Preparation of
tert-Butyl-1'-{4-[(1,2,4-thiadiazol-5-ylamino)carbonyl]phenyl}-4,4'-bipip-
eridine-1-carboxylate
##STR00132##
[0381] Compound 12.4 (56 mg; 0.144 mmol) was suspended in dry DMF
(2 ml). 2-Amino-1,2,4-thiadiazole (29 mg; 0.288 mmol) was added,
followed by DMAP (35 mg; 0.288 mmol) and EDC (55 mg; 0.288 mmol).
The mixture was stirred at ambient temperature for 24 hr. The
reaction was diluted with iPrOAc (50 mL) and washed once with aq.
sodium bicarbonate (10 mL), then twice more with water (2.times.10
mL). The organic was dried over magnesium sulfate, filtered and
evaporated to a yellow solid. The solid was digested in refluxing
MTBE. The mixture was cooled and the supernatant was drawn off. The
remaining off-white solid was rinsed with cold MTBE, affording the
title compound.
[0382] LRMS calc: 471.2 obs: 472.1 (M+H), 372.1 (M-BOC+H).
[0383] Preparative Examples reported in Table 12 can be prepared by
one or more of the procedures described above (12.1-5) from readily
available starting materials and tert-butyl
4,4'-bipiperidine-1-carboxylate by one skilled in the art (*=see
below Table 1 for additional synthetic information). The LRMS of
all BOC containing compounds gave an M+1 and an M-100+1 (M-BOC+1)
ion.
TABLE-US-00011 TABLE 12 Preparative Exs.* Procedures Chemical name
Chemical Structure (M + 1) 12.1 12.1 tert-butyl 1'-(4-
cyanophenyl)- 4,4'-bipiperidine- 1-carboxylate ##STR00133## 370.2
270.2 (M - BOC + 1) 12.2* 12.1 tert-butyl 1'-[4- (aminocarbonyl)
phenyl]-4,4'- bipiperidine-1- carboxylate ##STR00134## 388.2 288.3
12.3 12.2 tert-butyl 1'-[4- (methylthio) phenyl]-4,4'-
bipiperidine-1- carboxylate ##STR00135## 391.2 291.3 12.4* 12.2
tert-butyl 1'-[4- (methylsulfinyl) phenyl]-4,4'- bipiperidine-1-
carboxylate ##STR00136## 407.2 307.1 12.5 12.2 tert-butyl 1'-(4-
bromophenyl)- 4,4'-bipiperidine- 1-carboxylate ##STR00137## 423.2
323.2 12.6 12.2 tert-butyl 1'-[4- (aminosulfonyl) phenyl]-4,4'-
bipiperidine-1- carboxylate ##STR00138## 423.2 323.2 12.7 12.2
tert-butyl 1'-{4- [(methylamino) sulfonyl]phenyl}-
4,4'-bipiperidine- 1-carboxylate ##STR00139## 438.2 338.3 12.8 12.2
tert-butyl 1'-{4- [(dimethylamino) sulfonyl]phenyl}-
4,4'-bipiperidine- 1-carboxylate ##STR00140## 452.2 352.3 12.9 12.2
tert-butyl 1'-(3- cyanophenyl)- 4,4'-bipiperidine- 1-carboxylate
##STR00141## 370.2 270.2 12.10 12.2 tert-butyl 1'-{3- chloro-4-
[(dimethylamino) carbonyl]phenyl}- 4,4'-bipiperidine- 1-carboxylate
##STR00142## 450.2 350.1 12.11 12.3, 4, 5 tert-butyl 1'-{4-
[(1,2,4-thiadiazol- 5-ylamino) carbonyl]phenyl}- 4,4'-bipiperidine-
1-carboxylate ##STR00143## 472.2 372.2 12.12 12.3, 4, 5 tert-butyl
1'-{4- [(1,3-thiazol-2- ylamino)carbonyl] phenyl}-4,4'-
bipiperidine-1- carboxylate ##STR00144## 471.2 371.3 12.13 12.3, 4,
5 tert-butyl 1'-{4- [(1H-imidazol-2- ylamino)carbonyl]
phenyl}-4,4'- bipiperidine-1- carboxylate ##STR00145## 454.2 354.3
12.14 12.3, 4, 5 tert-butyl 1'-{4- [(1H-1,2,4- triazol-3-
ylamino)carbonyl] phenyl}-4,4'- bipiperidine-1- carboxylate
##STR00146## 455.3 355.3 12.15 12.3, 4, 5 tert-butyl 1'-{3-
chloro-4-[(1,3- thiazol-2- ylamino)carbonyl] phenyl}-4,4'-
bipiperidine-1- carboxylate ##STR00147## 505.1 405.1 12.16 12.3, 4,
5 tert-butyl 1'-{3- fluoro-4-[(1,3- thiazol-2- ylamino)carbonyl]
phenyl}-4,4'- bipiperidine-1- carboxylate ##STR00148## 489.2 389.3
12.17 12.3, 4, 5 tert-butyl 1'-{3- fluoro-4- [(dimethylamino)
carbonyl]phenyl}- 4,4'-bipiperidine- 1-carboxylate ##STR00149##
434.2 334.3 12.18 12.2 tert-butyl 1'-{4- [(methylamino)
carbonyl]phenyl}- 4,4'-bipiperidine- 1-carboxylate ##STR00150##
402.3 302.2 12.19 12.2 tert-butyl 1'-{4- [(dimethylamino)
carbonyl]phenyl}- 4,4'-bipiperidine- 1-carboxylate ##STR00151##
416.3 316.3 12.20* 12.3, 4 tert-butyl 1'-[4-(2- amino-2-
oxoethyl)phenyl]- 4,4'-bipiperidine- 1-carboxylate ##STR00152##
402.2 302.2 12.21 12.3, 4, 5 tert-butyl 1'-(4- {[ethyl(methyl)
amino]carbonyl} phenyl]-4,4'- bipiperidine- 1-carboxylate
##STR00153## 430.3 330.2 12.22* 12.2 tert-butyl 1'-[4-
(hydroxymethyl) phenyl]-4,4'- bipiperidine- 1-carboxylate
##STR00154## 375.2 275.3 12.23 12.3, 4, 5 tert-butyl 1'-{3-
[(1,3-thiazol-2- ylamino)carbonyl] phenyl]-4,4'- bipiperidine-
1-carboxylate ##STR00155## 471.2 371.2 12.24* 12.3, 4 tert-butyl
1'-[4- (1,3-thiazol-2- yl)phenyl]-4,4'- bipiperidine-1- carboxylate
##STR00156## 428.2 328.3 12.25* 12.3, 4 tert-butyl 1'-{4-
[2-(1,3-thiazol-2- yl)ethyl]phenyl}- 4,4'-bipiperidine-
1-carboxylate ##STR00157## 456.2 356.2 12.26* 12.2 tert-butyl
1'-[4- (1,3-oxazol-2- yl)phenyl]-4,4'- bipiperidine-1- carboxylate
##STR00158## 412.2 312.2 12.27* 12.3, 4, 5 tert-butyl 1'-[4-
(4,5-dihydro-1,3- oxazol-2- yl)phenyl]-4,4'- bipiperidine-1-
carboxylate ##STR00159## 414.3 314.2 12.28 12.3 tert-butyl 1'-[6-
(methylthio)-3- pyridinyl]-4,4'- bipiperidine-1- carboxylate
##STR00160## 392.1 292.2 12.29* 12.3, 4, 5 tert-butyl 1'-{4-
[(1,3-thiazol-2- ylcarbonyl)amino] phenyl}-4,4'- bipiperidine-1-
carboxylate ##STR00161## 471.2 371.1 12.30* 12.1, 5 tert-butyl
1'-{4- [(1,3-thiazol-4- ylcarbonyl)amino] phenyl}-4,4'-
bipiperidine-1- carboxylate ##STR00162## 471.1 371.1 12.31* 12.1, 5
tert-butyl 1'-{3- chloro-4-[(1,3- thiazol-4- ylcarbonyl)amino]
phenyl}-4,4'- bipiperidine-1- carboxylate ##STR00163## 505.2 405.2
*Additional information
Preparative Example 12.2
Preparation of tert-butyl
1'-[4-(aminocarbonyl)phenyl]-4,4'-bipiperidine-1-carboxylate
##STR00164##
[0385] A solution of compound 12.1 (26 mg; 0.070 mmol) in EtOH (2
mL) was treated with an aqueous solution of NaO.sub.2H (280 .mu.L;
2M; 0.56 mmol). The mixture was refluxed for 18 hr. The reaction
was partitioned between dichloromethane and water. The organic was
dried over magnesium sulfate, filtered and evaporated to afford the
title compound as a white solid.
[0386] LRMS calc: 387.3 obs: 388.2 (M+H), 288.3 (M-BOC+H).
Preparative Example 12.4
Preparation of
tert-butyl-1'-[4-(methylsulfinyl)phenyl]-4,4'-bipiperidine-1-carboxylate
##STR00165##
[0388] A solution of compound 12.3 (76 mg; 0.195 mmol) in
dichloromethane (2 mL) was treated with mCPBA (45 mg; 75 wt %;
0.195 mmol). The mixture was stirred at ambient temperature for 30
min. The reaction was partitioned between iPrOAc (50 mL) and aq.
sodium bicarbonate (10 mL). The organic was washed three more times
with aq. sodium bicarbonate (3.times.10 mL). The organic was dried
over magnesium sulfate, filtered and evaporated to a solid. The
solid was digested in refluxing hexane. The mixture was cooled and
filtered, affording the title compound as a white solid.
[0389] LRMS calc: 406.2 obs: 407.1 (M+H), 307.2 (M-BOC+H).
Preparative Example 12.20
Preparation of
tert-butyl-1'-[4-(2-amino-2-oxoethyl)phenyl]-4,4'-bipiperidine-1-carboxyl-
ate
##STR00166##
[0391] 1-Hydroxybenzotriazole hydrate (53 mg; 0.388 mmol) was
dissolved in a solution of ammonia in methanol (5 mL; 7M). The
solution was evaporated to a white solid. A solution of
{4-[1'-(tert-butoxycarbonyl)-4,4'-bipiperidin-1-yl]phenyl}acetic
acid (52 mg; 0.129 mmol) in DMF (2 mL) was added, followed by EDC
(75 mg; 0.388 mmol). The mixture was stirred at ambient temperature
for 1 hr. The reaction was partitioned between iPrOAc (50 mL) and
aq. sodium bicarbonate (10 mL). The organic was washed twice more
with water (2.times.10 mL). The organic was dried over magnesium
sulfate, filtered and evaporated to a solid. The solid was
chromatographed (PTLC; 40:1 CH.sub.2Cl.sub.2/MeOH), affording the
title compound.
[0392] LRMS calc: 401.3 obs: 402.3 (M+H), 302.2 (M-BOC+H).
Preparative Example 12.22
Preparation of tert-Butyl
1'-[4-(hydroxymethyl)phenyl]-4,4'-bipiperidine-1-carboxylate
##STR00167##
[0394] A solution of tert-Butyl
1'-(4-formylphenyl)-4,4'-bipiperidine-1-carboxylate (72 mg; 0.193
mmol) in EtOH (1 mL) was treated with NaBH.sub.4 (8 mg; 0.213
mmol). The solution was stirred at ambient temperature for 1 hr.
The reaction was partitioned between iPrOAc and water. The organic
was dried over magnesium sulfate, filtered and evaporated to afford
the title compound.
[0395] LRMS calc: 374.3 obs: 375.3 (M+H), 275.2 (M-BOC+H).
Preparative Example 12.24
Preparation of
tert-Butyl-1'-[4-(1,3-thiazol-2-yl)phenyl]-4,4'-bipiperidine-1-carboxylat-
e
Step 1:
tert-Butyl-1'-[4-(aminocarbonothioyl)phenyl]-4,4'-bipiperidine-1-c-
arboxylate
##STR00168##
[0397] A suspension of compound 12.2 (227 mg; 0.586 mmol) in
dioxane (8 ml) was treated with Lawesson's Reagent (355 mg; 0.879
mmol). The mixture was stirred at ambient temperature for 56 hr.
The mixture was filtered and evaporated to a yellow solid. The
solid was adsorbed onto silica gel and eluted exhaustively without
fractionation (40:1 CH2Cl2/MeOH). The eluant was evaporated to a
yellow solid. The solid was chromatographed (Horizon; 0% to 7%
MeOH/CH.sub.2Cl.sub.2; linear gradient). The yellow fractions were
collected and evaporated to give the title compound.
[0398] LRMS calc: 403.2 obs: 404.2 (M+H), 304.1 (M-BOC+H).
Step 2
tert-Butyl-1'-[4-(1,3-thiazol-2-yl)phenyl]-4,4'-bipiperidine-1-carb-
oxylate
##STR00169##
[0400] A solution of the product of Example 12.24, Step 1 above
(151 mg; 0.374 mmol) in DMF (3 ml) was treated with Ac.sub.2O (1
ml) and chloroacetaldehyde (587 mg; 50% aq. solution; 3.74 mmol).
The solution was stirred at 80.degree. C. for 1 hr. The reaction
was partitioned between iPrOAc (50 mL) and aq. sodium bicarbonate
(20 mL). The organic was washed three more times with aq. sodium
bicarbonate (3.times.10 mL). The organic was dried over magnesium
sulfate, filtered and evaporated to a brown semi-solid. The solid
was digested (refluxing MTBE). The nearly homogenous solution was
allowed to stand at -10.degree. C. for 1 hr, causing the deposition
of a tan solid. The supernatant was drawn off and the solid rinsed
with MTBE. All volatiles were removed and light tan solid was
chromatographed (PTLC; 40:1 CH.sub.2Cl.sub.2/MeOH), affording the
title compound.
[0401] LRMS calc: 427.2 obs: 428.1 (M+H), 328.1 (M-BOC+H).
Preparative Example 12.25
tert-butyl-1'-{4-[2-(1,3-thiazol-2-yl)ethyl]phenyl}-4,4'-bipiperidine-1-ca-
rboxylate
Step 1:
tert-butyl-1'-[4-(3-amino-3-oxopropyl)phenyl]-4,4'-bipiperidine-1--
carboxylate
##STR00170##
[0403] This compound was prepared using the method of Example 12.20
above.
[0404] LRMS: calc. 415.3 obs. 416.2 (M+H), 316.3 (M-BOC+H).
Step 2:
tert-butyl-1'-[4-(3-amino-3-thioxopropyl)phenyl]-4,4'-bipiperidine-
-1-carboxylate
##STR00171##
[0406] This compound was prepared using the method of Example
12.24, Step 1.
[0407] LRMS: calc. 431.3 obs. 432.3 (M+H), 332.3 (M-BOC+H).
Step 3:
tert-butyl-1'-{4-[2-(1,3-thiazol-2-yl)ethyl]phenyl}-4,4'-bipiperid-
ine-1-carboxylate
##STR00172##
[0409] This compound was prepared using the method of Example
12.24, Step 2. LRMS: calc. 455.3 obs. 456.2 (M+H), 356.2
(M-BOC+H).
Preparative Example 12.26
Preparation of
tert-butyl-1'-[4-(1,3-oxazol-2-yl)phenyl]-4,4'-bipiperidine-1-carboxylate
Step 1: tert-butyl
1'-(4-iodophenyl)-4,4'-bipiperidine-1-carboxylate
##STR00173##
[0411] This compound was prepared using the method of General
Procedure 12.2. LRMS: calc. 470.1 obs. 471.2 (M+H), 371.3
(M-BOC+H).
Step 2:
tert-butyl-1'-[4-(1,3-oxazol-2-yl)phenyl]-4,4'-bipiperidine-1-carb-
oxylate
##STR00174##
[0413] A -10.degree. C. solution of MgBr.sub.2 (37 mg; 0.202 mmol)
in THF (1 mL) was treated with nBuLi (0.333 mL; 1.82M; 0.606 mmol)
The solution was stirred at -10.degree. C. for 1 hr. A solution of
oxazole (42 mg; 0.606 mmol) in THF (0.5 mL) was added and the
solution was stirred at 25.degree. C. for 2 hr. This solution was
added to a refluxing solution of tert-butyl
1'-(4-iodophenyl)-4,4'-bipiperidine-1-carboxylate (285 mg; 0.606
mmol) and PdCl.sub.2(dppf) (495 mg; 0.606 mmol) in THF (4 mL). The
mixture was refluxed 1 hr. The reaction was partitioned between
CH.sub.2Cl.sub.2 and water. The organic was dried over magnesium
sulfate, filtered and evaporated to a solid. The solid was
chromatographed (PTLC; 40:1 CH.sub.2Cl.sub.2/MeOH) to afford the
title compound.
[0414] LRMS: calc. 411.3 obs. 412.2 (M+H), 312.3 (M+H-BOC).
Preparative Example 12.27
Preparation of
tert-butyl-1'-[4-(4,5-dihydro-1,3-oxazol-2-yl)phenyl]-4,4'-bipiperidine-1-
-carboxylate
Step 1: tert-butyl
1'-(4-{[(2-hydroxyethyl)amino]carbonyl}phenyl)-4,4'-bipiperidine-1-carbox-
ylate
##STR00175##
[0416] This compound was prepared using the method of General
Procedure 12.5 and ethanolamine as starting material.
[0417] LRMS: calc. 431.3 obs. 432.2 (M+H), 332.2 (M-BOC+H).
Step 2:
tert-butyl-1'-[4-(4,5-dihydro-1,3-oxazol-2-yl)phenyl]-4,4'-bipiper-
idine-1-carboxylate
##STR00176##
[0419] A solution of tert-butyl
1'-(4-{[(2-hydroxyethyl)amino]carbonyl}phenyl)-4,4'-bipiperidine-1-carbox-
ylate (234 mg; 0.542 mmol) in dioxane (5 mL) was treated with
N,N'-diisopropylcarbodiimide (68 mg; 0.084 mmol) and Cu(OTf).sub.2
(10 mg; 0.027 mmol). The mixture was refluxed for 5 hr. The
reaction was evaporated and chromatographed (PTLC; 40:1
CH.sub.2Cl.sub.2/MeOH), giving the title compound.
[0420] LRMS: calc. 413.3 obs. 414.3 (M+H), 314.2 (M-BOC+H).
Preparative Example 12.29
Preparation of
tert-Butyl-1'-{4-[(1,3-thiazol-2-ylcarbonyl)amino]phenyl}-4,4'-bipiperidi-
ne-1-carboxylate
Step 1: tert-Butyl
1'-(4-nitrophenyl)-4,4'-bipiperidine-1-carboxylate
##STR00177##
[0422] Using General Procedure 12.1 with 4-fluoro-nitrobenzene as
starting material the title compound was obtained.
[0423] LRMS calc: 389.2 obs: 390.2 (M+H), 290.1 (M-BOC+H).
Step 2: tert-Butyl
1'-(4-aminophenyl)-4,4'-bipiperidine-1-carboxylate
##STR00178##
[0425] A suspension of the product of Example 12.29, Step 1 above
(640 mg; 1.643 mmol) in an EtOH/EtOAc mixture (15 mL; 1:2 vol.
ratio) was hydrogenated (35 psi) in the presence 10% Pd/C catalyst
(150 mg) for 1 hr. The mixture was filtered through Celite and
evaporated to afford the title compound as a gray solid.
[0426] LRMS calc: 359.3 obs: 360.2 (M+H), 260.3 (M-BOC+H).
Step 3: Thiazole-2-carboxylic acid
[0427] A solution of ethyl thiazole-2-carboxylate (1.46 g; 9.29
mmol), obtained using a literature method (Helv. Chim Acta 1945,
28, p. 924), in EtOH (10 ml) was placed in a sealable vessel and
treated with KOH (3.07 g; 46.4 mmol). The vessel was sealed and
heated at 120.degree. C. for 30 min. After cooling, the solution
was poured into water (50 mL) and the pH adjusted to 4.0 with con.
HCl. The now turbid mixture was extracted with iPrOAc (50 mL),
dried over magnesium sulfate, filtered and evaporated to a brown
oil. The oil was dissolved in CH.sub.2Cl.sub.2 and filtered, then
evaporated to afford the title compound as a brown pasty solid.
Step 4:
tert-Butyl-1'-{4-[(1,3-thiazol-2-ylcarbonyl)amino]phenyl}-4,4'-bip-
iperidine-1-carboxylate
##STR00179##
[0429] A solution of the product of Example 12.29, Step 2 above (50
mg; 0.139 mmol) and Example 12.29, Step 3 (36 mg; 0.278 mmol) in
DMF (1 ml) was treated with PyBOP (145 mg; 0.278 mmol). The
reaction was stirred at ambient temperature for 4hr. The reaction
was partitioned between iPrOAc (50 mL) and pH7 phosphate buffer (10
mL). The organic was washed twice more with pH7 buffer (2.times.10
mL). The wet organic was evaporated and repartitioned between
CH.sub.2Cl.sub.2 and water. The organic was dried over magnesium
sulfate, filtered and evaporated. The derived residue was digested
in refluxing MTBE. The red-brown supernatant was found to be
enriched in the title compound. The solution was evaporated to an
oil and chromatographed (PTLC; 20:1 CH.sub.2Cl.sub.2/MeOH). The
title compound was a rust colored solid. The material was
rechromatographed (PTLC; MTBE). The baseline band was recovered
giving the title compound as a light rust colored powdery
solid.
[0430] LRMS calc: 470.2 obs: 471.2 (M+H), 371.3 (M-BOC+H).
Preparative Example 12.30
Preparation of
tert-Butyl-1'-{4-[(1,3-thiazol-4-ylcarbonyl)amino]phenyl}-4,4'-bipiperidi-
ne-1-carboxylate
##STR00180##
[0432] This compound was prepared according to the method of
Example 12.29, Step 4.
Preparative Example 12.31
Preparation of
tert-butyl-1'-{3-chloro-4-[(1,3-thiazol-4-ylcarbonyl)amino]phenyl}-4,4'-b-
ipiperidine-1-carboxylate
Step 1: tert-Butyl
1'-(3-chloro-4-nitrophenyl)-4,4'-bipiperidine-1-carboxylate
##STR00181##
[0434] Using the method of Example 12.29, Step 1 with
2-chloro-4-fluoro-nitrobenzene as starting material the title
compound was obtained.
[0435] LRMS calc: 423.2 obs: 424.1 (M+H), 324.1 (M-BOC+H).
Step 2: tert-Butyl
1'-(3-chloro-4-aminophenyl)-4,4'-bipiperidine-1-carboxylate
##STR00182##
[0437] Using the method of Example 12.29, Step 2 the title compound
was obtained.
[0438] LRMS calc: 393.2 obs: 394.1 (M+H), 294.2 (M-BOC+H).
Step 3:
tert-Butyl-1'-{3-chloro-4-[(1,3-thiazol-4-ylcarbonyl)amino]phenyl}-
-4,4'-bipiperidine-1-carboxylate
##STR00183##
[0440] Using the method of Example 12.29, Step 4 and
thiazole-4-carboxylic acid the title compound was obtained.
[0441] LRMS calc: 504.2 obs: 505.1 (M+H), 405.1 (M-BOC+H).
General Procedure No. 13.1 (BOC Group Removal)
##STR00184##
[0443] A solution of tert-butyl
1'-[4-(methylsulfonyl)phenyl]-4,4'-bipiperidine-1-carboxylate (
4.95 g, 11.71 mmol) in CH.sub.2Cl.sub.2 (20 mL)was treated with
trifluoroacetic acid (4 mL) and stirred at room temperature for 3
hr. The reaction was diluted with CH.sub.2Cl.sub.2 (50 mL) and
washed with 1 N HCl (50 mL). The aqueous layers were combined and
washed with 5N NaOH (100 ml). The mixture was extracted with
CHCl.sub.3, dried over Na.sub.2SO.sub.4, filtered and concentrated
in vac to afford title compound.
[0444] 500 MHz NMR (CD3OD): .delta. 7.69 (d, 2H, J=9 Hz), 7.02 (d,
2H, J=9.5 Hz), 3.99 (d, 2H, J=13 Hz), 3.02 (m, 5H), 2.83 (t, 2H,
J=12 Hz), 2.52 (t, 2H, J=12 Hz), 1.83 (d, 2H, J=10 Hz), 1.72 (d,
2H, J=11 Hz), 1.24 (m, 6H). LCMS calc: 322.47 obs: 323.17(M+H).
General Procedure 13 (Nucleophilic Aromatic Substitution)
Example 13
1-(1,3-benzoxazol-2-yl)-1'-[4-(methylsulfonyl)phenyl]-4,4'-bipiperidine
##STR00185##
[0446] The 1-[4-(methylsulfonyl)phenyl]-4,4'-bipiperidine (70 mg,
0.22 mmol) and cesium carbonate (212 mg, 0.65 mmol) were slurried
in NMP (0.43 ml) and the Chlorobenzoxazole (20.3 mmol) added. The
mixture was stirred at 120 C overnight. The slurry was diluted with
15% saturated sodium bicarbonate: water (40 ml) and extracted with
DCM (3.times.25 ml). The combined organic fraction was washed with
brine, dried over magnesium sulfate, filtered, and the volatiles
removed in vac. The crude material was purified by chromatography
on silica gel with 5% acetone : DCM to yield the titled compound.
LRMS calc: 478.1 obs: 478.8, 480.8 (M+H).
[0447] The compounds of the following table are encompassed in the
present invention and are made in accordance with the procedure set
forth in Example 13 above.
TABLE-US-00012 Examples Procedure Chemical Name Structure (M + 1)
13.28 13.1 1-(1,3-benzoxazol-2-yl-1'- [4-(methylsulfonyl)
phenyl]-4,4'-bipiperidine ##STR00186## 440.17 13.29 13.1 tert
4-[1'-(5- bromopyrimidin-2-yl)- 4,4'-bipiperidin-1-yl]-2-
chlorobenzonitrile ##STR00187## 13.30 13.1
1-(5-bromopyrimidin-2-yl)- 1'-[3-chloro-4- (methylsulfonyl)phenyl]-
4,4'-bipiperidine ##STR00188## 512.9 13.31 13.1 1-[3-chloro-4-
(methylsulfonyl)phenyl]-1'- (5-fluoropyrimidin-2-yl)-
4,4'-bipiperidine ##STR00189## 453.4 13.32 13.1 1-[3-chloro-4-
(methylsulfonyl)phenyl]-1'- (6-chloropyrazin-2-yl)- 4,4'-biperidine
##STR00190## 469 13.33 13.1 2-chloro-4-(1'-pyrazin-2-yl-
4,4'-bipiperidin-1- yl)benzonitrile ##STR00191## 382.5 13.34 13.1
2-chloro-4-(1'-pyrimidin-2- yl-4,4'-bipiperidin-1- yl)benzonitrile
##STR00192## 382.5 13.35 13.1 1-(3-chloro-5-
fluorophenyl)-1'-pyrimidin- 2-yl-4,4'-bipiperidine ##STR00193##
375.1 13.36 13.1 3-fluoro-4-(1'-pyrimidin-2- yl-4,4'-bipiperidin-1-
yl)benzonitrile ##STR00194## 366.3
General Procedure 14.1
Preparation of
1-(5-fluoro-2-methylpyrimidin-4-yl)-1'-(5-fluoropyrimidin-2-yl)-4,4'-bipi-
peridine
Step 1: tert-butyl
1'-(2-chloro-5-fluoropyrimidin-4-yl)-4,4'-bipiperidine-1-carboxylate:
same as Procedure 9.1
Step 2: tert-butyl
1'-(5-fluoro-2-methylpyrimidin-4-y)-4,4'-bipiperidine-1-carboxylate:
same as Procedure 4.1, step 2
##STR00195##
[0448] Step 3:
1-(5-fluoro-2-methylpyrimidin-4-yl)-4,4'-bipiperidine
##STR00196##
[0450] The tert-butyl
1'-(5-fluoro-2-methylpyrimidin-4-yl)-4,4'-bipiperidine-1-carboxylate
(22 mg, 0.058 mmol) was mixed with 0.2 mL of TFA and stirred at
r.t. for 5 min and was concentrated on rotavapor to yield title
compound and was used directly for next step.
Step 4:
1-(5-fluoro-2-methylpyrimidin-4-yl)-1'-(5-fluoropyrimidin-2-yl)-4,-
4'-bipiperidine
##STR00197##
[0452] 1-(5-fluoro-2-methylpyrimidin-4-yl)-4,4'-bipiperidine (16
mg, 0.058 mmol) and cesium carbonate (57 mg, 0.17 mmol) were
stirred in NMP (0.6 ml) and 2-chloro-5-fluoropyrimidine (0.014 mL,
0.116 mmol) was added. The mixture was heated at 70.degree. C. for
1 h. The reaction was cooled down to r.t. and diluted with ethyl
acetate (5 mL) and was washed with water 2 mL (.times.1) and brine
2 mL (.times.1). The organic phase was dried over magnesium
sulfate, filtered, and concentrated on rotavapor. The crude
material was purified by preparative TLC with 30% acetone: hexane
to yield the titled compound. LC-MS: 375.06 (M+H). Examples
reported in Table 14 are prepared in accordance with Procedure
14.1.
TABLE-US-00013 Example Procedure Chemical name Chemical Structure
(M + 1) 14.1 14.1 1-(4-bromo-1,3- thiazol-2-yl)-1'-(5- fluoro-2-
methylpyrimidin-4- yl)-4,4'-bipiperidine ##STR00198## 441.98 14.2
14.1 1-(5-fluoro-2- methylpyrimidin-4- yl)-1'-(5-
fluoropyrimidin-2- yl)-4,4'-bipiperidine ##STR00199## 375.06 14.3
14.1 1-(5- bromopyrimidin-2- yl)-1'-(5-fluoro-2- methylpyrimidin-4-
yl)-4,4'-bipiperidine ##STR00200## 436.96 14.4 14.1 1-(5-chloro-2-
methylpyrimidin-4- yl)-1'-(5- fluoropyrimidin-2-
yl)-4,4'-bipiperidine ##STR00201## 391.54 14.5 14.1 1-(5-
bromopyrimidin-2- yl)-1'-(5-chloro-2- methylpyrimidin-4-
yl)-4,4'-bipiperidine ##STR00202## 453.58 14.6 14.1 1-(5-chloro-2-
methylpyrimidin-4- yl)-1'-(5- chloropyrimidin-2-
yl)-4,4'-bipiperidine ##STR00203## 407.06 14.7 14.1 6-{1'-[3-
(dimethylamino)- 1,2,4-thiadiazol-5- yl]-4,4'-bipiperidin-1-
yl}pyrimidine-4- carbonitrile ##STR00204## 399.1 14.8 14.1
1-(5-chloropyridin-2- yl)-1'-(3-chloro-1,2,4-
thiadiazol-5-yl)-4,4'- bipiperidine ##STR00205## 398.1 14.9 14.1
2-[1'-(5- chloropyridin-2-yl)- 4,4'-bipiperidin-1-yl]-
1,3-thiazole-5- carbonitrile ##STR00206## 388.2 14.10 14.1
1-(3-chloro-1,2,4- thiadiazol-5-yl)-1'-[4- (methylsulfonyl)
phenyl]-4,4'- bipiperidine ##STR00207## 441.1 14.11 14.1 1-[4-
(methylsulfonyl) phenyl]-1'-(1,2,4- thiadiazol-5-yl)-4,4'-
bipiperidine ##STR00208## 407.1 14.11 14.1 1-[4- (methylsulfonyl)
phenyl]-1'-(3-methyl- 1,2,4-thiadiazol-5- yl)-4,4'-bipiperadin
##STR00209## 421.2 14.12 14.1 2-[1'-(5- chloropyridin-2-yl)-
4,4'-bipiperidin-1- yl]isonicotinonitrile ##STR00210## 382.1 14.13
14.1 1-(5-bromo-1,3- thiazol-2-yl)-1'-(2,6- dimethylpyrimidin-4-
yl)-4,4'-bipiperidine ##STR00211## 437.1 14.14 14.1
1-(5-chloropyrazin-2- yl)-1'-(2,6- dimethylpyrimidin-4-
yl)-4,4'-bipiperidine ##STR00212## 387.2 14.15 14.1
1-(5-chloropyrimidin- 2-yl)-1'-(2,6- dimethylpyrimidin-4-
yl)-4,4'-bipiperidine ##STR00213## 387.2 14.15 14.1 2-[1'-(5-
chloropyrimidin-2- yl)-4,4'-bipiperidin-1- yl]isonicotinonitrile
##STR00214## 383.2 14.16 14.1 6-[1'-(5- chloropyrimidin-2-
2-yl)-4,4'-bipiperidin- yl]pyridine-2- carbonitrile ##STR00215##
383.2 14.17 14.1 1-(2,6- dimethylpyrimidin- 4-yl)-1'-(6-
methylpyrazin-2-yl)- 4,4'-bipiperidine ##STR00216## 367.2 14.18
14.1 1-(2,6- dimethylpyrimidin-4- yl)-1'-(5-methyl-1,3-
thiazol-2-yl)-4,4'- bipiperidine ##STR00217## 372.2 14.19 14.1
1-(5-chloropyridin-2- yl)-1'-(2,6- dimethylpyrimidin-4-
yl)-4,4'-bipiperidine0 ##STR00218## 386.2 14.20 14.1 1-(2,6-
dimethylpyrimidin-4- yl)-1'-[5- (trifluoromethyl)
pyridin-2-yl]-4,4'- bipiperidine ##STR00219## 420.2 14.21 14.1
1-(2,6- dimethylpyrimidin-4- yl)-1'-(5- methylpyrimidin-2-
yl)-4,4'-bipiperidine ##STR00220## 367.3 14.22 14.1 1-(2,6-
dimethylpyrimidin-4- yl)-1'-(5- methylpyridin-2-yl)-
4,4'-bipiperidine ##STR00221## 366.3 14.23 14.1 5-[1'-(2,6-
dimethylpyrimidin-4- yl)-4,4'-bipiperidin-1- yl]-N,N-dimethyl-
1,2,4-thiadiazol-3- amine ##STR00222## 402.2 14.24 14.1
1-(5-bromo-4- methylpyridin-2- yl)-1'-(5- chloropyrimidin-2-
yl)-4,4'-bipiperidine ##STR00223## 451.1 14.25 14.1
5-chloro-2-[1'-(5- chloropyrimidin-2- yl)-4,4'-bipiperidin-1-
yl]isonicotinonitrile ##STR00224## 417.2 14.26 14.1
3-chloro-6-[1'-(5- chloropyrimidin-2- yl)-4,4'-bipiperidin-1-
yl]pyridine-2- carbonitrile ##STR00225## 417.1 14.27 14.1
2-methyl-6-[1'-(5- methylpyrimidin-2- yl)-4,4'-bipiperidin-1-
yl]pyrimidine-4- carbonitrile ##STR00226## 378.2 14.28 14.1
4-methyl-6-[1'-(5- methylpyrimidin-2- yl)-4,4'-bipiperidin-1-
yl]pyrimidine-2- carbonitrile ##STR00227## 378.2 14.29 14.1
4-[1'-(5- chloropyrimidin-2- yl)-4,4'-bipiperidin- 1-yl]-6-
methylpyrimidine-2- carbonitrile ##STR00228## 398.2 14.30 14.1
4-[1'-(5- chloropyrazin-2-yl)- 4,4'-bipiperidin-1-yl]-
6-methylpyrimidine- 2-carbonitrile ##STR00229## 398.2 14.31 14.1
6-[1'-(5- chloropyrazin-2-yl)- 4,4'-bipiperidin-1- yl]pyrimidine-4-
carbonitrile ##STR00230## 384.2 14.32 14.1 4-[1'-(5-
chloropyrazin-2-yl)- 4,4'-bipiperidin-1- yl]pyrimidine-2-
carbonitrile ##STR00231## 384.2 14.33 14.1 6-[1'-(5-
chloropyrazin-2-yl)- 4,4'-bipiperidin-1-yl]- 2-methylpyrimidine-
4-carbonitrile ##STR00232## 398.2 14.34 14.1 6-[1'-(5-
chloropyrimidin-2- yl)-4,4'-bipiperidin- 1-methylpyrimidine-
4-carbonitrile ##STR00233## 398.2 14.35 14.1 2-methyl-6-[1'-(5-
methylpyrazin-2-yl)- 4,4'-bipiperidin-1- yl]pyrimidine-4-
carbonitrile ##STR00234## 378.3
General Procedure 15.1
Preparation of
1-(5-fluoro-2-methylpyrimidin-4-yl)-1'-pyrimidin-2-yl-4,4'-bipiperidine
Step 1: tert-butyl
1'-(2-chloro-5-fluoropyrimidin-4-yl)-4,4'-bipiperidine-1-carboxylate:
same as Procedure 6.1
##STR00235##
[0453] Step 2: tert-butyl
1'-(5-fluoro-2-methylpyrimidin-4-yl)-4,4'-bipiperidine-1-carboxylate:
same as Procedure 4.1, step 2
##STR00236##
[0454] Step 3:
1-(5-fluoro-2-methylpyrimidin-4-yl)-4,4'-bipiperidine, same as
General Procedure 12
##STR00237##
[0455] Step 4:
1-(5-fluoro-2-methylpyrimidin-4-yl)-1'-pyrimidin-2-yl-4,4'-bipiperidine
##STR00238##
[0457] 1-(5-fluoro-2-methylpyrimidin-4-yl)-4,4'-bipiperidine (10
mg, 0.036 mmol) and cesium carbonate (35 mg, 0.11 mmol) were
stirred in NMP (2 ml) and 2-chloro-5-fluoropyrimidine (8.2 mg, 0.72
mmol) was added. The mixture was heated at 110.degree. C. for 2 h.
The reaction was cooled down to r.t. and diluted with ethyl acetate
(5 mL) and was washed with water 2 mL (.times.1) and brine 2 mL
(.times.1). The organic phase was dried over magnesium sulfate,
filtered, and concentrated on rotavapor. The crude material was
purified by preparative TLC with 30% acetone: hexane to yield the
titled compound.
[0458] LC-MS: 357.60 (M+H).
[0459] Examples reported in Table 15 can be prepared by Procedure
15.1 described below.
TABLE-US-00014 TABLE 15 Example Procedure Chemical name Chemical
Structure (M + 1) 15.1 15.1 1-(5-fluoro-2- methylpyrimidin-4-yl)-
1'-pyrimidin-2-yl-4,4'- bipiperidine ##STR00239## 357.60 15.2 15.1
1-(5-fluoro-2- methylpyrimidin-4-yl)- 1'-pyrazin-2-yl-4,4'-
bipiperidine ##STR00240## 357.14 15.3 15.1 1-(5-fluoro-2-
methylpyrimidin-4-yl)- 1'-(1,3-thiazol-2-yl)- 4,4'-bipiperidine
##STR00241## 362.12 15.4 15.1 1-(5-chloropyridin-2-
yl)-1'-(5-fluoro-2- methylpyrimidin-4-yl)- 4,4'-bipiperidine
##STR00242## 390.12 15.5 15.1 1-(5-chloro-2- methylpyrimidin-4-yl)-
1'-pyrimidin-2-yl-4,4'- bipiperidine ##STR00243## 373.56 15.6 15.1
1-(5-chloro-2- methylpyrimidin-4-yl)- 1'-pyrazin-2-yl-4,4'-
bipiperidin ##STR00244## 373.56 15.7 15.1 1-(5-chloro-2-
methylpyrimidin-4-yl)- 1'-(5-fluoropyridin-2- yl)-4,4'-bipiperidine
##STR00245## 390.05 15.8 15.1 1-(5-chloro-2- methylpyrimidin-4-yl)-
1'-(5-chloropyridin-2- yl)-4,4'-bipiperidine ##STR00246##
406.05
General Procedure 16.1
Preparation of
6-[1'-(5-chloropyrimidin-2-yl)-4,4'-bipiperidin-1-yl]pyrimidine-4-carboni-
trile
Step 1: tert-butyl
1'-(6-chloropyrimidin-4-yl)-4,4'-bipiperidine-1-carboxylate: same
as Procedure 2.1
##STR00247##
[0460] Step 2: tert-butyl
1'-(6-cyanopyrimidin-4-yl)-4,4'-bipiperidine-1-carboxylate: same as
Procedure 5.1, step 2
##STR00248##
[0461] Step 3: 6-(4,4'-bipiperidin-1-yl)pyrimidine-4-carbonitrile:
same Procedure 11.1, step 3
##STR00249##
[0462] Step 4:
6-[1'-(5-chloropyrimidin-2-yl)-4,4'-bipiperidin-1-yl]pyrimidine-4-carboni-
trile: same as Procedure 11.1, step 4
##STR00250##
[0464] LC-MS: 384.05 (M+H).
[0465] Examples reported in Table 16 can be prepared in accordance
with Procedure 16.1.
TABLE-US-00015 TABLE 16 Example Procedure Chemical name Chemical
Structure (M + 1) 16.1 16.1 6-[1'-(5- chloropyrimidin-2-
yl)-4,4'-bipiperidin-1- yl]pyrimidine-4- carbonitrile ##STR00251##
384.05 16.2 16.1 6-[1'-(5- fluoropyrimidin-2-
yl)-4,4'-bipiperidin-1- yl]pyrimidine-4- carbonitrile ##STR00252##
368.09 16.3 16.1 6-[1'-(5- bromopyrimidin-2-
yl)-4,4'-bipiperidin-1- yl]pyrimidine-4- carbonitrile ##STR00253##
429.99 16.4 16.1 6-[1'-(5- chloropyrimidin-2-
yl)-4,4'-bipiperidin-1- yl]pyrimidine-2- carbonitrile ##STR00254##
384.23 16.5 16.1 6-[1'-(5- fluoropyrimidin-2-
yl)-4,4'-bipiperidin-1- yl]pyrimidine-2- carbonitrile ##STR00255##
368.26 16.6 16.1 6-[1'-(5- fluoropyrimidin-2-
yl)-4,4'-bipiperidin-1- yl]pyrazine-2- carbonitrile ##STR00256##
368.26 16.7 16.1 6-[1'-(5- chloropyrimidin-2-
yl)-4,4'-bipiperidin-1- yl]pyrazine-2- carbonitrile ##STR00257##
384.23 16.8 16.1 4-[1'-(5- methylpyrimidin-2-
yl)-4,4'-bipiperidin-1- yl]pyrimidine-2- carbonitrile ##STR00258##
364.30 16.9 16.1 4-[1'-(5-cyano-1,3- thiazol-2-yl)-4,4'-
bipiperidin-1- yl]pyrimidine-2- carbonitrile ##STR00259## 380.15
16.10 16.1 6-[1'-(5-cyano-1,3- thiazol-2-yl)-4,4'- bipiperidin-1-
yl]pyrimidine-4- carbonitrile ##STR00260## 380.15 16.11 16.1
6-[1'-(5- methylpyrimidin-2- yl)-4,4'-bipiperidin-1-
yl]pyrimidine-4- carbonitrile ##STR00261## 364.18
General Procedure 17.1
Preparation of
6-(1'-pyrimidin-2-yl-4,4'-bipiperidin-1-yl)pyrimidine-4-carbonitrile
Step 1: tert-butyl
1'-(6-chloropyrimidin-4-yl)-4,4'-bipiperidine-1-carboxylate: same
as Procedure 2.1
##STR00262##
[0466] Step 2: tert-butyl
1'-(6-cyanopyrimidin-4-yl)-4,4'-bipiperidine-1-carboxylate: same as
Procedure 5.1, step 2
##STR00263##
[0467] Step 3: 6-(4,4'-bipiperidin-1-yl)pyrimidine-4-carbonitrile:
same Procedure 11.1, step 3
##STR00264##
[0468] Step 4:
6-(1'-pyrimidin-2-yl-4,4'-bipiperidin-1-yl)pyrimidine-4-carbonitrile:
same as Procedure 12.1, step 4
##STR00265##
[0470] LC-MS: 350.13 (M+H).
[0471] Examples reported in Table 17 can be prepared in accordance
with Procedure 17.1.
TABLE-US-00016 TABLE 17 Example Procedure Chemical name Chemical
Structure (M + 1) 17.1 17.1 6-[1'-(6- methylpyrazin-2-yl)-
4,4'-bipiperidin-1- yl]pyrimidine-4- carbonitrile ##STR00266##
364.12 17.2 17.1 6-(1'-pyrimidin-2-yl- 4,4'-bipiperidin-1-
yl)pyrimidine-4- carbonitrile ##STR00267## 350.13 17.3 17.1
6-[1'-(5- chloropyridin-2-yl)- 4,4'-bipiperidin-1- yl]pyrimidine-4-
carbonitrile ##STR00268## 383.12 17.4 17.1 6-[1'-(5-
methylpyridin-2-yl)- 4,4'-bipiperidin-1- yl]pyridine-2-
carbonitrile ##STR00269## 364.12 17.5 17.1 6-[1'-(5-
methylpyridin-2-yl)- 4,4'-bipiperidin-1- yl]pyrimidine-4-
carboxamide ##STR00270## 381.37
General Procedure 18.1
Step 1: 1-(5-methylpyrazin-2-yl)-4,4'-bipiperidine
##STR00271##
[0473] The tert-butyl
1'-(5-methylpyrazin-2-yl)-4,4'-bipiperidine-1-carboxylate (1 g, 2.8
mmol) was dissolved in trifluoroacetic acid and stirred at r.t. for
5 minutes. The solution was concentrated in vac. The residue was
dissolved in toluene (10 mL) and concentrated in vac.(.times.2) to
yield the title compound.
[0474] LC-MS: 261.32 (M+H).
Step 2:
1-(2-chloro-6-methylpyrimidin-4-yl)-1'-(5-methylpyrazin-2-yl)-4,4'-
-bipiperridine
##STR00272##
[0476] The 1-(5-methylpyrazin-2-yl)-4,4'-bipiperidine (720 mg, 2.8
mmol) and 2,4-dichloro-6-methyl-pyrimidine (502 mg, 3.1 mmol) were
dissolved in NMP (30 mL), and the solution cooled to -20.degree. C.
The 1,8-diazabicyclo[5.4.0]-undec-7-ene (4.2 mL, 28 mmol) was added
drop-wise and the solution stirred for 10 minutes. The mixture was
diluted with ethyl acetate (50 mL), washed with brine (30
mL.times.2), dried over magnesium sulfate, filtered and
concentrated in vac. The residue was purified by chromatography on
silica gel with 30% acetone: hexanes to yield the title
compound.
[0477] LC-MS: 387.32 (M+H).
Step 3:
4-Methyl-6-[1'-(5-methylpyrazin-2-yl)-4,4'-bipiperidin-1-yl]pyrimi-
dine-2-carbonitrile
##STR00273##
[0479] The
1-(2-chloro-6-methylpyrimidin-4-yl)-1'-(5-methylpyrazin-2-yl)-4-
,4'-bipiperridine (700 mg, 1.8 mmol) was placed in a pressure tube
and anhydrous toluene (4 mL) added. To the stirred solution was
added: palladium(II) acetate (41 mg, 0.18 mmol),
1,5-bis(dipenylphosphino)pentane (159 mg, 0.36 mmol),
N,N,N',N'-tetramethylethylenediamine (0.11 mL, 0.724 mmol), and
potassium cyanide (235 mg, 3.62 mmol). The vessel was degassed with
N.sub.2, sealed and heated at 140.degree. C. for 16 hours. The
mixture was allowed to cool to r.t., diluted with ethyl acetate (50
mL), washed with brine (10 mL.times.1), dried over magnesium
sulfate, filtered and concentrated in vac. The residue was purified
by chromatography on silica gel with 20% acetone: hexanes to yield
the title compound.
[0480] LC-MS: 378.27 (M+H).
General Procedure 18.2 (Nucleophilic Aromatic Substitution,
150.degree. C.)
1-(3-methylpyrazin-2-yl)-1'-[4-(methylsulfonyl)phenyl]-4,4'-bipiperidine
##STR00274##
[0482] The 1-[4-(methylsulfonyl)phenyl]-4,4'-bipiperidine (80 mg,
0.25 mmol, prepared as for Example 1, Step 2) and cesium carbonate
(243 mg, 0.75 mmol) were slurried in NMP (0.5 ml) and the
2-chloro-3-methylpyrazine (38 mg, 0.30 mmol) added. The mixture was
stirred at 150 C overnight. The slurry was diluted with 15%
saturated sodium bicarbonate: water (40 ml) and extracted with DCM
(3.times.25 ml). The combined organic fraction was washed with 4:1
water: saturated sodium bicarbonate (2.times.), brine, dried over
magnesium sulfate, filtered, and the volatiles removed in vac. The
crude material was purified by chromatography on silica gel with 5%
acetone: DCM to yield the titled compound.
[0483] LRMS calc: 414.2 ohs: 415.2 (M+H).
General Procedure 18.3: (Prepartion of 2,5-dichloropyrimidine)
##STR00275##
[0485] The chloride (600 mg, 3.27 mmol) was dissolved in MeOH (6.5
ml), 10% palladium on carbon (200 mg) was added and the solution
stirred for 2 h under a hydrogen atmosphere at 50 C. The solution
was cooled to RT, filtered, diluted with 4:1 water:saturated sodium
bicarbonate (40 ml) and extracted with ethyl acetate (3.times.25
ml). The combined organic fraction was washed with brine, dried
over magnesium sulfate, filtered, and the volatiles removed in vac.
The crude material was purified by chromatography on silica gel
with ether:hexanes to yield the titled compound.
General Procedure 18.4 (Preparation of Thiazoles)
Step 1. tert-butyl
1'-(aminocarbonothioyl)-4,4'-bipiperidine-1-carboxylate
##STR00276##
[0487] The tert-butyl 4,4'-bipiperidine-1-carboxylate (2.0 g, 7.3
mmol) and 9H-fluoren-9-ylmethyl isothiocyanatidocarbonate (2.0 g,
7.3 mmol) were dissolved in DCM (14 ml) and stirred at RT for 1
hour. The solvent was removed in vac. The residue was dissolved in
DMF (15 ml), piperidine (8 ml) added and the solution stirred for 1
hour at RT. The solution was diluted with 4:1 water:saturated
sodium bicarbonate (900 ml) and extracted with ethyl acetate
(3.times.300 ml). The combined organic fraction was washed with
water (500 ml), brine, dried over magnesium sulfate, filtered, and
the volatiles removed in vac. The crude material was purified by
chromatography on silica gel starting with 10% acetone:hexanes then
changing to 10% acetone: DCM to yield the titled compound.
Step 2. tert-butyl
1'-(4-methyl-1,3-thiazol-2-yl)-4,4'-bipiperidine-1-carboxylate
##STR00277##
[0489] The 1-chloroacetone (57 mg, 0.61 mmol) and tert-butyl
1'-(aminocarbonothioyl)-4,4'-bipiperidine-1-carboxylate (prepared
as for Example 175, step 1) (200 mg, 0.61 mmol) were dissolved in
ethanol (1.2 ml) and heated at 75.degree. C. overnight. The
solution was cooled to RT, and the solvent removed in vac. The
residue was used in the subsequent procedure without further
purification.
General Procedure 18.5 (2-chloro-5-methylpyrimidine)
##STR00278##
[0491] 2,4,Dichloro-5-methylpyrimidine (3 g, 18.4 mmol) was
refluxed with Zn powder (3.61 g, 55.2 mmol) in a mixture of 28%
ammonia (6.6 mL), benzene (12 mL) and water (30 ml) overnight. The
reaction was cooled and filtered. The filtrate was extracted with
ether, washed with brine, dried over sodium sulfate and
concentrated to give the crude 2-chloro-5-methylpyrimidine.
[0492] The compounds shown in Table 18 can be prepared using of the
general procedures of General Procedure 18.
TABLE-US-00017 TABLE 18 MS Example Procedure Chemical name Chemical
Structure (M + H) 18.1 18.2 1-[4- (methylsulfonyl)
phenyl]-1'-pyrimidin- 2-yl-4,4'- bipiperidine ##STR00279## 401.1
18.2 18.2 1-[4- (methylsulfonyl) phenyl]-1'-pyrazin- 2-yl-4,4'-
bipiperidine ##STR00280## 401.1 18.3 18.2 1-(6-chloropyrazin-
2-yl)-1'[4- (methylsulfonyl) phenyl]-4,4'-bipiperidine ##STR00281##
435.02 18.4 18.2 1-(5-fluoropyrimidin- 2-yl)-1'-[4-
(methylsulfonyl) phenyl]-4,4'- bipiperidine ##STR00282## 419.0 18.5
18.2 1-(3,6- dimethylpyrazin-2- yl)-1'-[4- (methylsulfonyl)
phenyl]-4,4'- bipiperidine ##STR00283## 429.0 18.6 18.2
1-(6-methylpyrazin- 2-yl)-1'-[4- (methylsulfonyl) phenyl]-4,4'-
bipiperidine ##STR00284## 415.0 18.7 18.2 6-{1'-[4-
(methylsulfonyl) phenyl]-4,4'- bipiperidin-1- yl}nicotinonitrile
##STR00285## 425.0 18.8 18.2 1-(5-chloropyridin-2- yl)-1'-[4-
(methylsulfonyl) phenyl]-4,4'- bipiperidine ##STR00286## 433.9 18.9
18.2 1-[4- (methylsulfonyl) phenyl]-1'-pyridin 2-yl-4,4'-
bipiperidine ##STR00287## 400.0 18.10 18.2 1-(5-fluoropyridin-
2-yl)-1'-[4- (methylsulfonyl) phenyl]-4,4'- bipiperidine
##STR00288## 418.0 18.11 18.2 1-(4-methylpyridin-2- yl)-1'-[4-
(methylsulfonyl) phenyl]-4,4'- bipiperidine ##STR00289## 414.0
18.12 18.2 1-(5-bromopyridin-2- yl)-1'-[4- (methylsulfonyl)
phenyl]-4,4'- bipiperidine ##STR00290## 477.9 18.13 18.2
1-(6-chloropyridazin- 3-yl)-1'-[4- (methylsulfonyl) phenyl]-4,4'-
bipiperidine ##STR00291## 435.0 18.14 18.2 1-(5-methylpyridin-2-
yl)-1'-[4- (methylsulfonyl) phenyl]-4,4'- bipiperidine ##STR00292##
414.0 18.15 18.2 1-(6- methylpyridazin-3- yl)-1'-[4-
(methylsulfonyl) phenyl]-4,4'- bipiperidine ##STR00293## 415.1
18.16 18.2 1-[4- (methylsulfonyl) phenyl]-1'-[5- (trifluoromethyl)
pyridin-2-yl]-4,4'- bipiperidine ##STR00294## 468.0 18.17 18.2
1-(6-chloro-5- methylpyridazin- 3-yl)-1'-[4- (methylsulfonyl)
phenyl]-4,4'- bipiperidine ##STR00295## 449.0 18.18 18.2
1-(4-bromo-1,3- thiazol-2-yl)-1'-[4- (methylsulfonyl) phenyl]-4,4'-
bipiperidine ##STR00296## 483.9 18.19 18.2 1-(5-bromo-1,3-
thiazol-2-yl)-1'-[4- (methylsulfonyl) phenyl]-4,4'- bipiperidine
##STR00297## 483.9 18.20 18.2 2-{1'-[4- (methylsulfonyl)
phenyl]-4,4'- bipiperidin-1- yl}-1,3-thiazole-5- carbonitrile
##STR00298## 431.1 18.21 18.2 2-chloro-4-[1'-(5- chloropyrimidin-2-
yl)-4,4'-bipiperidin-1- yl]benzonitrile ##STR00299## 415.9 18.22
18.2 2-chloro-4-[1'-(5- chloro-3,6- dimethylpyrazin-2-
yl)-4,4'-bipiperidin-1- yl]benzonitrile ##STR00300## 444.0 18.23
18.2 1-(5-chloro-4- methylpyrimidin- 2-yl)-1'-[4- (methylsulfonyl)
phenyl]-4,4'- bipiperidine ##STR00301## 449.0 18.24 18.2
1-(5-bromo-4- methylpyrimidin- 2-yl)-1'-[4- (methylsulfonyl)
phenyl]-4,4'- bipiperidine ##STR00302## 492.9 18.25 18.2
1-(5-chloropyrimidin- 2-yl)-1'[4- (methylsulfonyl)
phenyl]-4,4'-bipiperidine ##STR00303## 435.0 18.26 18.2
2-chloro-4-[1'-(5- methylpyrimidin-2- yl)-4,4'-bipiperidin-1-
yl]benzonitrile ##STR00304## 396.0 18.27 18.3 1-[4-
(methylsulfonyl) phenyl]-1'-(4-methyl- 1,3-thiazol-2-yl)-
4,4'-bipiperidine ##STR00305## 420.0 18.28 18.3
1-(4-tert-butyl-1,3- thiazol-2-yl)-1'-[4- (methylsulfonyl)
phenyl]-4,4'- bipiperidine ##STR00306## 462.1 18.29 18.3 1-[4-
(methylsulfonyl) phenyl]-1'-[4- (trifluoromethyl)-1,3-
thiazol-2-yl]-4,4- bipiperidine ##STR00307## 474.0 18.30 18.3
1-(4,5-dimethyl-1,3- thiazol-2-yl)-1'-[4- (methylsulfonyl)
phenyl]-4,4'- bipiperidine ##STR00308## 434.0 18.31 18.2
1-(6-methylpyrazin- 2-yl)-1'-[4- (methylsulfonyl) phenyl]-4,4'-
bipiperidine ##STR00309## 415.0 18.32 18.2 1-(5- methylpyrimidin-2-
yl)-1'-[4- (methylsulfonyl) phenyl]-4,4'- bipiperidine ##STR00310##
415.1 18.33 18.2 1-(5-fluoropyrimidin- 2-yl)-1'-[5-
(methylsulfonyl) pyridin-2-yl]-4,4'- bipiperidine ##STR00311##
420.1 18.34 18.3 1-[5- (methylsulfonyl) pyridin-2-yl]-1'-(5-
methyl-1,3-thiazol-2- yl)-4,4'-bipiperidine ##STR00312## 421.1
18.35 18.2 1-[5- (methylsulfonyl) pyridin-2-yl]-1'-(5-
methyl-1,3-thiazol-2- yl)-4,4'-bipiperidine ##STR00313## 416.1
18.36 18.2 1-(5-chloropyridin- 2-yl)-1'-[5- (methylsulfonyl)
pyridin-2-yl]-4,4'- bipiperidine ##STR00314## 435.1 18.37 18.2
1-(5-bromo-1,3- thiazol-2-yl)-1'-[5- (methylsulfonyl)
pyridin-2-yl]-4,4'- bipiperidine ##STR00315## 484.9/ 486.9 18.38
18.2 1-(5-chloropyrimidin- 2-yl)-1'-[5- (methylsulfonyl)
pyridin-2-yl]-4,4'- bipiperidine ##STR00316## 436.1 18.39 18.2
1-(5-chloropyrazin- 2-yl)-1'-[5- (methylsulfonyl)
pyridin-2-yl]-4,4'- bipiperidine ##STR00317## 436.1 18.40 18.2
N,N-dimethyl-2- {1'-[5- (methylsulfonyl) pyridin-2-yl]-4,4'-
bipiperidin-1- yl}pyrimidin-5-amine ##STR00318## 445.2 18.41 18.2
N,N-dimethyl-5- {1'-[5- (methylsulfonyl) pyridin-2-yl]-4,4'-
bipiperidin-1- yl}pyrazin-2-amine ##STR00319## 445.2 18.42 18.2
1-(5- methylpyrimidin-2- yl)-1'-[5- (methylsulfonyl)
pyridin-2-yl]-4,4'- bipiperidine ##STR00320## 416.2 18.43 18.2
N-cyclopropyl-2- fluoro-4-[1'-(5- methylpyrimidin-2- yl]benzamide
##STR00321## 438.3 18.44 18.2 N-cyclopropyl-2- fluoro-4-[1'-(5-
methylpyrazin-2-yl)- 4,4'-bipiperidin-1- yl]benzamide ##STR00322##
438.2 18.45 18.2 1-(5-methylpyrazin- (methylsulfonyl)
pyridin-2-yl]-4,4'- bipiperidine ##STR00323## 416.2 18.46 18.2
4-[1'-(5- methylpyrazin-2-yl)- 4,4'-bipiperidin-1- yl]pyrimidine-2-
carbonitrile ##STR00324## 364.2 18.47 18.1 4-methyl-6-[1'-(5-
methylpyrazin-2-yl)- 4,4'-bipiperidin-1- yl]pyrimidine-2-
carbonitrile ##STR00325## 378.2 18.48 18.2 N-cyclopropyl-5-[1'-
(5-methylpyrimidin- 2-yl)-4,4'-bipiperidin- 1-yl]pyrazine-2-
carboxamide ##STR00326## 422.2
General Procedure 19.1 (Nucleophilic Aromatic Substitution)
Example 19.1
Preparation of
tert-butyl-1'-(3-chloro-1,2,4-thiadiazol-5-yl)-4,4'-bipiperidine-1-carbox-
ylate
##STR00327##
[0494] A solution of tert-butyl 4,4'-bipiperidine-1-carboxylate
(537 mg; 2.00 mmol) in dry THF (10 mL) was treated with
triethylamine (307 .mu.L; 2.20 mmol). A solution of
3,5-dichloro-1,2,4-thiadiazole (341 mg; 2.20 mmol) in THF (5 mL)
was added dropwise at ambient temperature. An immediate precipitate
was accompanied by a mild exotherm. The mixture was stirred until
it returned to ambient temperature. The mixture was filtered and
the filtrate evaporated to afford the title compound. LRMS calc:
386.2 obs: 387.2 (M+H), 287.1 (M-BOC+H).
General Procedure 19.2 (Dimethylamination)
Example 19.2
Preparation of
tert-butyl-1'-[3-(dimethylamino)-1,2,4-thiadiazol-5-yl]-4,4'-bipiperidine-
-1-carboxylate
##STR00328##
[0496] In a sealable vessel, a -10.degree. C. solution of compound
19.1 (755 mg; 1.95 mmol) in DMF (10 mL) was permeated with
anhydrous dimethylamine until the initial volume had increased to
approximately 15 mL. The vessel was sealed and the solution heated
in a 100.degree. C. bath for 4 hr. After cooling the solution was
outgassed with nitrogen at ambient temperature for 30 min. The
reaction was partitioned between iPrOAc (75 mL) and water (20 mL).
The organic was washed three more times with water (3.times.20 mL),
dried over magnesium sulfate, filtered and evaporated to a solid.
The solid was digested in refluxing MTBE, cooled and allowed to
stand at ambient temperature for 72 hr. The supernatant was drawn
off and the solid rinsed with MTBE to give the title compound. LRMS
calc: 395.2 obs: 396.2 (M+H), 296.2 (M-BOC+H).
General Procedure 19.3 (Removal of BOC Protecting Group)
Example 19.3
Preparation of
5-(4,4'-bipiperidin-1-yl)-N,N-dimethyl-1,2,4-thiadiazol-3-amine
##STR00329##
[0498] A solution of compound 19.2 (410 mg; 1.036 mmol) in
CH.sub.2Cl.sub.2 (5 mL) was treated with CF.sub.3CO.sub.2H (5 mL).
The pink solution was stirred at ambient temperature for 1 hr. The
reaction was evaporated to a viscous oil. The oil was redissolved
in CH.sub.2Cl.sub.2 (50 mL) and treated with saturated aq. sodium
bicarbonate (10 mL). Solid sodium bicarbonate was added until the
pH remained >7.5. The organic was recovered, dried over
magnesium sulfate, filtered and evaporated to afford the title
compound.
General Procedure 19.4 (Nucleophilic Aromatic Substitution)
Example 19.4
Preparation of
N,N-dimethyl-5-{1'-[4-(methylsulfonyl)phenyl]-4,4'-bipiperidin-1-yl}-1,2,-
4-thiadiazol-3-amine
##STR00330##
[0500] A solution of compound 19.3 (98 mg; 0.332 mmol) in DMF (2
mL) was treated with methyl 4-fluorophenyl sulfone (115 mg; 0.664
mmol) followed by cesium carbonate (216 mg; 0.664 mmol). The
mixture was stirred at 100.degree. C. for 5 hr. The reaction was
diluted with CH.sub.2Cl.sub.2 (50 mL) and washed with water
(4.times.20 mL). The organic was dried over magnesium sulfate,
filtered and concentrated to a solid. The solid was digested
(refluxing MTBE) and cooled. The supernatant was drawn off and the
now white solid rinsed once (MTBE), affording the title compound.
LRMS calc: 449.2 obs: 450.1 (M+H).
General Procedure 19.5 (Palladium Mediated N-arylation)
Example 19.5
Preparation of methyl
4-{1'-[3-(dimethylamino)-1,2,4-thiadiazol-5-yl]-4,4'-bipiperidin-1-yl}ben-
zoate
##STR00331##
[0502] A 100 mL reaction flask was charged with compound 19.3 (1.14
g; 3.86 mmol), methyl 4-bromobenzoate (829 mg; 3.86 mmol), cesium
carbonate (3.77g; 11.47 mmol), Pd(OAc).sub.2 (44 mg; 0.192 mmol)
and 2-(diphenylphosphino)-2'-(N-N-dimethylamino)biphenyl (147 mg;
0.386 mmol). NMP (outgassed by bubbling with nitrogen for 10 min; 8
mL) was added and the mixture stirred at 90.degree. C. for 18 hr.
The mixture was diluted with dichloromethane (100 mL) and filtered
through Celite. The filtrate was washed with water (4.times.25 mL).
The organic was dried over magnesium sulfate, filtered and
evaporated to a solid. The solid was digested at reflux (MTBE).
After cooling, the white solid was recovered by filtration. The
filtrate was evaporated and chromatographed (Horizon; 0% to 100%
EtOAc/hex; linear gradient). The fractions containing the desired
compound were recovered and combined with the solid to give the
title compound. LRMS calc: 429.2 obs: 430.2 (M+H).
General Procedure 19.6 (Ester Hydrolysis)
Example 19.6
Preparation of
4-{1'-[3-(dimethylamino)-1,2,4-thiadiazol-5-yl]4,4'-bipiperidin-1-yl}benz-
oic acid
##STR00332##
[0504] Compound 19.5 (305 mg; 0.710 mmol) was suspended in ethanol
(5 ml) in a sealable tube. Potassium hydroxide (225 mg; 3.41 mmol)
was added. The tube was sealed and heated in 105.degree. C. bath
for 1 hr. The solid mass was washed out with water and the pH
adjusted to 4.0 with 1N HCl. The title compound was recovered by
filtration. LRMS calc: 415.2 obs: 416.2 (M+H).
General Procedure 19.7 (Amide Formation)
Example 19.7
Preparation of
N-cyclopropyl-4-{1'-[3-(dimethylamino)-1,2,4-thiadiazol-5-yl]-4,4'-bipipe-
ridin-1-yl}benzamide
##STR00333##
[0506] A solution of compound 19.6 (50 mg; 0.120 mmol) and
cyclopropylamine (21 mg; 0.360 mmol) in DMF (1 ml) was treated with
PyBOP (187 mg; 0.360 mmol). The reaction was stirred at ambient
temperature for 1 hr. The reaction was partitioned between iPrOAc
(30 mL) and water (10 mL). The organic was washed twice more with
water (2.times.10 mL). The wet organic (with an emulsion) was
evaporated and repartitioned between CH.sub.2Cl.sub.2 and water.
The organic was dried over magnesium sulfate, filtered and
evaporated. The solution was evaporated to an oil and
chromatographed (PTLC; 40:1 CH.sub.2Cl.sub.2/MeOH), giving the
title compound as a white solid. LRMS caic: 454.3 obs: 455.2
(M+H).
General Procedure 19.8 (Copper Mediated N-arylation)
Example 19.8
Preparation of
4-{1'-[3-(dimethylamino)-1,2,4-thiadiazol-5-yl]-4,4'-bipiperidin-1-yl}-N,-
N-dimethylbenzamide
##STR00334##
[0508] A suspension of 4-(dimethylaminocarbonyl)phenylboronic acid
(276 mg; 1.431 mmol) in dichloromethane (10 mL) was treated with
activated powdered 4 .ANG. molecular sieves (1.5 g), Cu(OAc).sub.2
(87 mg; 0.477 mmol), compound 19.3 (141 mg; 0.477 mmol) and
triethylamine (134 .mu.L; 0.954 mmol). The reaction vessel was
purged with oxygen and the mixture stirred under an oxygen
atmosphere at ambient temperature for 18 hr. The now brown mixture
was filtered through Celite. The eluant was adsorbed onto silica
gel. The silica gel was exhaustively eluted without fractionation
(40:1 CH.sub.2Cl.sub.2/MeOH). The eluant was evaporated to a yellow
oil and chromatographed (PTLC; 40:1 CH.sub.2Cl.sub.2/MeOH). The
major band was collected affording the title compound. LRMS calc:
442.3 obs: 443.2 (M+H).
[0509] The compounds of Table 19 are prepared in accordance with
General Procedure 19 using readily available starting materials and
tert-butyl 4,4'-bipiperidine-1-carboxylate. Additional information
useful in conducting the syntheses of these compounds is found
below (*=see below Table 19 for additional synthetic
information).
TABLE-US-00018 TABLE 19 Example Procedures Chemical name Chemical
Structure (M + 1) 19.4 19.1, 2, 3, 4 N,N-dimethyl-5-{1'-[4-
(methylsulfonyl)phenyl]- 4,4'-bipiperidin-1-
yl}-1,2,4-thiadiazol-3- amine ##STR00335## 450.1 19.5 19.1, 2, 3, 5
methyl 4-{1'-[3- (dimethylamino)- 1,2,4-thiadiazol-5-yl]-
4,4'-bipiperidin-1- yl}benzoate ##STR00336## 387.6 19.6 19.1, 2, 3,
5, 6, 7 N-cyclopropyl-4-{1'- [3-(dimethylamino)-
1,2,4-thiadiazol-5-yl]- 4,4'-bipiperidin-1- yl}benzamide
##STR00337## 359.1 19.7 19.1, 2, 3, 8 4-{1'-[3- (dimethylamino)-
1,2,4-thiadiazol-5-yl]- 4,4'-bipiperidin-1-yl}- N,N-dimethyl
benzamide ##STR00338## 443.2 19.8 19.1, 2, 3, 8 4-{1'-[3-
(dimethylamino)- 1,2,4-thiadiazol-5-yl]- 4,4'-bipiperidin-1-
yl}benzenesulfonamide ##STR00339## 451.3 19.9 19.1, 2, 3, 8
2-chloro-4-{1'-[3- (dimethylamino)- 1,2,4-thiadiazol-5-yl]-
4,4'-bipiperidin-1-yl}- N,N- dimethylbenzamide ##STR00340## 477.2
19.10 19.1, 2, 3, 4 5-{1'-[3-chloro-4- (methylsulfonyl)phenyl]-
4,4'-bipiperidin-1- yl}-N,N-dimethyl- 1,2,4-thiadiazol-3- amine
##STR00341## 484.1 19.11 19.1, 2, 3, 4 2-chloro-4-{1'-[3-
(dimethylamino)- 1,2,4-thiadiazol-5-yl]- 4,4'-bipiperidin-1-
yl}benzonitrile ##STR00342## 431.2 19.12 19.1, 2, 3, 4 4-{1'-[3-
(dimethylamino)- 1,2,4-thiadiazol-5-yl]- 4,4'-bipiperidin-1-
yl}benzonitrile ##STR00343## 397.1 19.13* 19.1, 2, 3, 5
N,N-dimethyl-5-(1'-{4- [(methylsulfonyl) methyl]phenyl}-4,4'-
bipiperidin-1-yl)-1,2,4- thiadiazol-3-amine ##STR00344## 464.2
19.14 1, 2, 3, 5, 6, 7 2-chloro-4-{1'-[3- (dimethylamino)-
1,2,4-thiadiazol-5-yl]- 4,4'-bipiperidin-1-yl}- N-1,3-thiazol-2-
ylbenzamide ##STR00345## 532.2 19.15 19.1, 2, 3, 4
N,N-dimethyl-5-{1'-[5- (methylsulfonyl)-2- pyridinyl]-4,4'-
bipiperidin-1-yl}- 1,2,4-thiadiazol-3- amine ##STR00346## 451.2
19.16* 19.1, 2, 3, 5* N,N-dimethyl-5-{1'-[6- (methylsulfonyl)-3-
pyridinyl]-4,4'- bipiperidin-1-yl}- 1,2,4-thiadiazol-3- amine
##STR00347## 451.1 19.17 19.1, 2, 3, 5, 6, 7 N-cyclopropyl-4-{1'-
[3-(dimethylamino)- 1,2,4-thiadiazol-5-yl]- 4,4'-bipiperidin-1-yl}-
2-fluorobenzamide ##STR00348## 473.2 19.18 19.1, 2, 3, 4, 6, 7
N-cyclopropyl-6-{1'- [3-(dimethylamino)- 1,2,4-thiadiazol-5-yl]-
4,4'-bipiperidin-1- yl}nicotinamide ##STR00349## 456.3 19.19* 19.1,
2, 3, 4 5-{1'-[3-bromo-4- (methylsulfonyl)
phenyl]-4,4'-bipiperidin-1- yl}-N, N-dimethyl- 1,2,4-thiadiazol-3-
amine ##STR00350## 528.1 19.20 19.1, 2, 3, 5, 6, 7 4-{1'-[3-
(dimethylamino)- 1,2,4-thiadiazol-5-yl]- 4,4'-bipiperidin-1-yl}-
2-fluoro-N- isopropylbenzamide ##STR00351## 475.2 19.21 19.1, 2, 3,
5, 6, 7 N-(tert-butyl)-4-{1'-[3- (dimethylamino)-
1,2,4-thiadiazol-5-yl]- 4,4'-bipiperidin-1-yl}- 2-fluorobenzamide
##STR00352## 489.3 19.22 19.1, 2, 3, 5, 6, 7 4-{1'-[3-
(dimethylamino)- 1,2,4-thiadiazol-5-yl]- 4,4'-bipiperidin-1-yl}-
2-fluoro-N,N- dimethylbenzamide ##STR00353## 461.1 19.23 19.1, 2,
3, 4, 6, 7 6-{1'-[3- (dimethylamino)- 1,2,4-thiadiazol-5-yl]-
4,4'-bipiperidin-1-yl}- N,N- dimethylnicotinamide ##STR00354##
444.3 19.24 19.1, 2, 3, 5, 6, 7 2-chloro-N- cyclopropyl-4-{1'-[3-
(dimethylamino)- 1,2,4-thiadiazol-5-yl]- 4,4'-bipiperidin-1-
yl}benzamide ##STR00355## 489.1 19.25 19.1, 2, 3, 8 5-{1'-[4-
(ethylsulfonyl)phenyl]- 4,4'-bipiperidin-1-yl}- N,N-dimethyl-1,2,4-
thiadiazol-3 -amine ##STR00356## 464.2 19.26 19.1, 2, 3, 8
5-{1'-[4- (isopropylsulfonyl) phenyl]-4,4'-bipiperidin-1-
yl}-N,N-dimethyl- 1,2,4-thiadiazol-3- amine ##STR00357## 478.2
19.27 19.1, 2, 3, 5, 6, 7 N-cyclopropyl-4-{1'- [3-(dimethylamino)-
1,2,4-thiadiazol-5-yl]- 4,4'-bipiperidin-1- yl}benzamide
##STR00358## 455.3 19.28 19.1, 2, 3, 5, 6, 7 4-{1'-[3-
(dimethylamino)- 1,2,4-thiadiazol-5-yl]- 4,4'-bipiperidin-1-yl}-
N-isopropylbenzamide ##STR00359## 457.2 19.29 19.1, 2, 3, 5, 6, 7
2-chloro-4-{1'-[3- (dimethylamino)- 1,2,4-thiadiazol-5-yl]-
4,4'-bipiperidin-1-yl}- N-isopropylbenzamide ##STR00360## 491.1
19.30 19.1, 2, 3, 5, 6, 7 N-(tert-butyl)-2- chloro-4-{1'-[3-
(dimethylamino)- 1,2,4-thiadiazol-5-yl]- 4,4'-bipiperidin-1-
yl}benzamide ##STR00361## 505.2 19.31 19.1, 2, 3, 4, 6, 7 6-{1'-[3-
(dimethylamino)- 1,2,4-thiadiazol-5-yl]- 4,4'-bipiperidin-1-yl}- N-
isopropylnicotinamide ##STR00362## 458.2 19.32 19.1, 2, 3, 4, 6, 7
N-(tert-butyl)-6-{1'-[3- (dimethylamino)- 1,2,4-thiadiazol-5-yl]-
4,4'-bipiperidin-1- yl}nicotinamide ##STR00363## 472.3 19.33 19.1,
2, 3, 5, 6, 7 N-(tert-butyl)-4-{1'-[3- (dimethylamino)-
1,2,4-thiadiazol-5-yl]- 4,4'-bipiperidin-1- yl}benzamide
##STR00364## 471.2 19.34* 19.1, 2, 3, 4, 6, 7 6-{1'-[3-
(dimethylamino)- 1,2,4-thiadiazol-5-yl]- 4,4'-bipiperidin-1-yl}-
N-(1- methylcyclopropyl) nicotinamide ##STR00365## 470.2 19.35*
19.1, 2, 3, 5, 6, 7 4-{1'-[3- (dimethylamino)-
1,2,4-thiadiazol-5-yl]- 4,4'-bipiperidin-1-yl}- N-(1-
methylcyclopropyl) benzamide ##STR00366## 469.3 19.36* 19.1, 2, 3,
5, 6, 7 4-{1'-[3- (dimethylamino)- 1,2,4-thiadiazol-5-yl]-
4,4'-bipiperidin-1-yl}- 2-fluoro-N-(1- methylcyclopropyl) benzamide
##STR00367## 486.3 19.37 19.1, 2, 3, 5, 6, 7 N-
(cyclopropylmethyl)- 4-{1'-[3- (dimethylamino)-
1,2,4-thiadiazol-5-yl]- 4,4'-bipiperidin-1- yl}benzamide
##STR00368## 469.3 19.38 19.1, 2, 3, 4, 6, 7 N-
(cyclopropylmethyl)- 6-{1'-[3- (dimethylamino)-
1,2,4-thiadiazol-5-yl]- 4,4'-bipiperidin-1- yl}nicotinamide
##STR00369## 470.2 19.39 19.1, 2, 3, 4 5-{1'-[5-chloro-2-
(methylsulfonyl) phenyl]-4,4'-bipiperidin-1- yl}-N,N-dimethyl-
1,2,4-thiadiazol-3- amine ##STR00370## 484.1 *Additional
information
Example 19.13
Preparation of
N,N-dimethyl-5-(1'-{4-[(methylsulfonyl)methyl]phenyl}-4,4'-bipiperidin-1--
yl)-1,2,4-thiadiazol-3-amine
Step 1: 4-bromobenzyl methyl sulfone
##STR00371##
[0511] p-Bromobenzyl bromide (500 mg, 2 mmol) was refluxed with
MeSO.sub.2Na (306 mg, 3 mmol) in Ethanol for 1 hour. The reaction
was cooled, concentrated and purified by flash column (50%
acetone/hexanes) to give the desired product.
Step 2: tert-butyl
1'-{4-[(methylsulfonyl)methyl]phenyl}-4,4'-bipiperidine-1-carboxylate
##STR00372##
[0513] Using the method of General Procedure 19.5 and
1-bromo-4-[(methylsulfonyl)methyl]benzene as starting materials the
title compound was obtained. LRMS calc: 463.2 obs: 464.2 (M+H).
Example 19.16
Preparation of
N,N-dimethyl-5-{1'-[6-(methylsulfonyl)-3-pyridinyl]-4,4'-bipiperidin-1-yl-
}-1,2,4-thiadiazol-3-amine
Step 1:
tert-butyl-1'-[6-(methylthio)-3-pyridinyl]-4,4'-bipiperidine-1-car-
boxylate
##STR00373##
[0515] Using the method of General Procedure 19.5 with
2-methylthio-5-bromopyridine the title compound was obtained. LRMS:
calc. 391.2 obs. 392.1 (M+H), 292.2 (M-BOC+H).
Step 2: 1-[6-(methylsulfonyl)-3-pyridinyl]-4,4'-bipiperidine
##STR00374##
[0517] A solution of
tert-butyl-1'-[6-(methylthio)-3-pyridinyl]-4,4'-bipiperidine-1-carboxylat-
e (165 mg; 0.421 mmol) in CH.sub.2Cl.sub.2 (3 mL) was treated with
TFA (3 mL). The solution was stirred at 25.degree. C. for 1 hr.
mCPBA (193 mg; 75wt %; 0.84 mmol) was added. The mixture was
stirred at 25.degree. C. for 18 hr. The mixture was filtered and
treated with aq. sodium bicarbonate. The layers were separated, and
the recovered organic was dried over magnesium sulfate. Filtration
and evaporation afforded the title compound. LRMS: calc. 323.2 obs.
324.1 (M+H).
Step 3:
1-(3-chloro-1,2,4-thiadiazol-5-yl)-1'-[6-(methylsulfonyl)-3-pyridi-
nyl]-4,4'-bipiperidine
##STR00375##
[0519] This compound was prepared using the method of General
Procedure 19.1 and the product of Example 19.16, Step2. LRMS: calc.
441.1 obs. 442.2 (M+H).
Step 4:
N,N-dimethyl-5-{1'-[6-(methylsulfonyl)-3-pyridinyl]-4,4'-bipiperid-
in-1-yl}-1,2,4-thiadiazol-3-amine
##STR00376##
[0521] This compound was prepared using the method of General
Procedure 19.2 and the product of Example 19.16, Step3. LRMS: calc.
450.2 obs. 451.3 (M+H).
Example 19.19
Preparation of
5-{1'-[3-bromo-4-(methylsulfonyl)phenyl]-4,4'-bipiperidin-1-yl}-N,N-dimet-
hyl-1,2,4-thiadiazol-3-amine
Step 1: 2-bromo-4-fluorophenyl methyl sulfide
##STR00377##
[0523] A 0.degree. C. solution of 2-bromo-4-fluoroaniline (1.50 g;
7.89 mmol) in 25% aq H.sub.2SO.sub.4 (20 mL) was treated with
sodium nitrite (583 mg; 8.45 mmol). The solution was warmed to
25.degree. C. and added to a suspension of CuSCH.sub.3 (6.11 g;
55.3 mmol) in water (50 mL). The mixture was stirred at 25.degree.
C. for 1 hr, then extracted with iPrOAc. The organic was dried over
magnesium sulfate, filtered and evaporated to a red oil.
Chromatography (Horizon; 0% to 20% MTBE/hex; linear gradient))
afforded the title compound.
Step 2: 2-bromo-4-fluorophenyl methyl sulfone
##STR00378##
[0525] A solution of 2-bromo-4-fluorophenyl methyl sulfide (614 mg;
2.78 mmol) in CH.sub.2Cl.sub.2 (10 mL) was treated with mCPBA
(1.278 g; 75wt %; 5.55 mmol). The mixture was stirred at 25.degree.
C. for 18 hr. The mixture was filtered and washed with aq. sodium
bicarbonate. The organic was dried over magnesium sulfate, filtered
and evaporated to a solid. The solid was chromatographed (PTLC; 2:1
hex/MTBE), affording the title compound.
Step 3:
5-{1'-[3-bromo-4-(methylsulfonyl)phenyl]-4,4'-bipiperidin-1-yl}-N,-
N-dimethyl-1,2,4-thiadiazol-3-amine
##STR00379##
[0527] This compound was prepared using the method of General
Procedure 19.4 with 2-bromo-4-fluorophenyl methyl sulfone as
starting material. LRMS: calc. 527.1 obs: 528.2 (M+!).
Example 19.34
Preparation of
6-{1'-[3-(dimethylamino)-1,2,4-thiadiazol-5-yl]-4,4'-bipiperidin-1-yl}N-(-
1-methylcyclopropyl)nicotinamide
Step 1: 1-methylcyclopropanecarboxamide
##STR00380##
[0529] A solution of 1-methylcyclopropane carboxylic acid (2.01 g;
20.08 mmol) in CDCl.sub.3 (40 mL) was treated with oxalyl chloride
(2.29 mL; 26.1 mmol). The solution was stirred at 25.degree. C. for
48 hr (progress followed by NMR). The reaction was permeated with
excess gaseous ammonia. The mixture was filtered and the filtrate
evaporated to give the title compound as a white solid.
Step 2: N-bromo-1-methylcyclopropanecarboxamide
##STR00381##
[0531] A solution of 1-methylcyclopropanecarboxamide (1.082 g;
10.92 mmol) in water was treated with bromine (0.57 mL; 11.06
mmol). Solid KOH (850 mg; 15.15 mmol) was added. After stirring at
25.degree. C. for 1hr, the now heterogenous mixture was extracted
with CH.sub.2Cl.sub.2. The organic was dried over magnesium
sulfate, filtered and evaporated to give the title compound as an
orange yellow-solid.
Step 3: 1-methylcyclopropyl-1-amine hydrochloride
##STR00382##
[0533] A suspension of the N-bromo-1-methylcyclopropanecarboxamide
from above in water (7 mL) was treated with NaOH (900 mg; 22.50
mmol). The mixture was stirred at 25.degree. C. for 2 hr. The now
homogenous solution was acidified to pH1 with 1N HCl and
lyophilized. The solid residue was digested in ethanol, cooled and
filtered. Evaporation afforded the title compound.
Step 4:
6-{1'-[3-(dimethylamino)-1,2,4-thiadiazol-5-yl]-4,4'-bipiperidin-1-
-yl}-(1-methylcyclopropyl)nicotinamide
##STR00383##
[0535] This compound was prepared using the method of General
Procedure 19.7 and 1-methylcyclopropyl-1-amine HCl. LRMS: calc.
469.3 obs. 470.2 (M+H).
Example 19.35
Preparation of
4-{1'-[3-(dimethylamino)-1,2,4-thiadiazol-5-yl]-4,4'-bipiperidin-1-yl}-N--
(1-methylcyclopropyl)benzamide
##STR00384##
[0537] This compound was prepared using the method of General
Procedure 19.7 and 1-methylcyclopropyl-1-amine HCl. LRMS: calc.
468.3 obs. 469.3 (M+H).
Example 19.36
4-{1'-[3-(dimethylamino)-1,2,4-thiadiazol-5-yl]-4,4'-bipiperidin-1-yl}-2-f-
luoro-N-(1-methylcyclopropyl)benzamide
##STR00385##
[0539] This compound was prepared using the method of General
Procedure 19.7 and 1-methylcyclopropyl-1-amine HCl as starting
material. LRMS: calc. 486.3 obs. 487.2 (M+H).
[0540] Measurement of GPR119 Signaling Using a Cyclic AMP (cAMP)
Homogenous Time Resolved Fluorescence (HTRF) Assay
[0541] Chinese hamster ovary (CHO) cell lines stably transfected
with the permissive guanine nucleotide binding protein alpha 15
(G.alpha.15) and a human SNP variant of GPR119 or murine GPR119
were maintained in DMEM media containing FBS,
penicillin-streptomycin, puromycin, and G418. A homogenous time
resolved fluorescence (HTRF) assay for GPR119 receptor activation
was used to measure cAMP accumulation in transfected cells upon
incubation with compounds of this invention as per the
manufacturer's instructions (CisBio, Bedford, Mass.). Cells were
incubated with compound at room temperature for 60 min, and
subsequently with XL-665 and anti-cAMP cryptate for an additional
60 min. The assay was conducted in 96 half-well plate format and
the plate was read using a Perkin Elmer Envision plate reader. For
compounds of this invention, "activation" of the GPR119 receptor in
a cAMP HTRF assay denotes induction of about a five fold increase
in intracellular cAMP concentration.
[0542] Evaluation of Glucose Dependent Insulin Secretion (GDIS) in
Static Isolated Mouse Islets.
[0543] Pancreatic islets of Langerhans were isolated from the
pancreata of 10-12 wk-old C57BL/6 mice by collagenase digestion and
discontinuous Ficoll gradient separation, a modification of the
original method of Lacy and Kostianovsky (Lacy & Kostianovsky,
1967 Diabetes 16-35-39). The islets were cultured overnight in RPMI
1640 medium (11 mM glucose, 10% FCS) before experimental treatment.
The acute effects of compounds of this invention on GDIS were
determined by 60-min static incubation with islets in
Krebs-Ringers' bicarbonate (KRB) medium. The KRB medium contained,
in mM, 143.5 Na.sup.+, 5.8 K.sup.+, 2.5 Ca.sup.2+, 1.2 Mg.sup.2+,
124.1 Cl.sup.-, 1.2 PO.sub.4.sup.3-, 1.2 SO.sub.4.sup.2+, 25
CO.sub.3.sup.2-, and 10 HEPES, pH 7.4, in addition to 2 mg/ml
bovine serum albumin, and either 2 (G2) or 16 (G16) mM glucose (pH
7.4). The static incubation was performed with round-bottomed
96-well plates (one islet/well with 200 .mu.l KRB medium). The
compounds were added to KRB medium just before the initiation of
the 60-min incubation. Insulin concentration in aliquots of the
incubation buffer was measured by the ultra-sensitive rat insulin
EIA kit from ALPCO Diagnostics (Windham, N.H.).
Example of a Pharmaceutical Formulation
[0544] As a specific embodiment of an oral composition of a
compound of the present invention, 50 mg of any of the examples is
formulated with sufficient finely divided lactose to provide a
total amount of 580 to 590 mg to fill a size O hard gelatin
capsule.
[0545] While the invention has been described and illustrated in
reference to specific embodiments thereof, various changes,
modifications, and substitutions can be made therein without
departing from the invention. For example, alternative effective
dosages may be applicable, based upon the responsiveness of the
patient being treated. Likewise, the pharmacologic response may
vary depending upon the particular active compound selected,
formulation and mode of administration. All such variations are
included within the present invention.
* * * * *