U.S. patent application number 13/146220 was filed with the patent office on 2011-11-17 for glucagon receptor antagonist compounds, compositions containing such compounds and methods of use.
Invention is credited to Sunita V. Dewnani, Songnian Lin, Emma R. Parmee, Fengqi Zhang.
Application Number | 20110281795 13/146220 |
Document ID | / |
Family ID | 42395952 |
Filed Date | 2011-11-17 |
United States Patent
Application |
20110281795 |
Kind Code |
A1 |
Lin; Songnian ; et
al. |
November 17, 2011 |
GLUCAGON RECEPTOR ANTAGONIST COMPOUNDS, COMPOSITIONS CONTAINING
SUCH COMPOUNDS AND METHODS OF USE
Abstract
Glucagon receptor antagonist compounds are disclosed. The
compounds are useful for treating type 2 diabetes and related
conditions. Pharmaceutical compositions and methods of treatment
are also included.
Inventors: |
Lin; Songnian; (Monroe,
NJ) ; Zhang; Fengqi; (Edison, NJ) ; Parmee;
Emma R.; (Scotch Plains, NJ) ; Dewnani; Sunita
V.; (Secaucus, NJ) |
Family ID: |
42395952 |
Appl. No.: |
13/146220 |
Filed: |
January 15, 2010 |
PCT Filed: |
January 15, 2010 |
PCT NO: |
PCT/US10/21098 |
371 Date: |
July 26, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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61206142 |
Jan 28, 2009 |
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Current U.S.
Class: |
514/6.5 ;
514/11.1; 514/210.02; 514/223.5; 514/249; 514/274; 514/282;
514/315; 514/326; 514/342; 514/351; 514/369; 514/378; 514/382;
514/406; 514/427; 514/443; 514/54; 548/247; 548/251; 548/253;
548/364.4; 549/58 |
Current CPC
Class: |
C07D 333/24 20130101;
C07D 413/04 20130101; C07D 333/60 20130101; C07D 409/04 20130101;
C07D 409/12 20130101; C07D 413/12 20130101; A61P 3/10 20180101 |
Class at
Publication: |
514/6.5 ; 549/58;
514/443; 548/364.4; 514/406; 548/251; 514/382; 548/253; 548/247;
514/378; 514/210.02; 514/427; 514/282; 514/223.5; 514/369; 514/342;
514/11.1; 514/315; 514/54; 514/249; 514/274; 514/326; 514/351 |
International
Class: |
A61K 31/381 20060101
A61K031/381; C07D 231/12 20060101 C07D231/12; A61K 31/4155 20060101
A61K031/4155; C07D 257/06 20060101 C07D257/06; A61K 31/41 20060101
A61K031/41; C07D 257/04 20060101 C07D257/04; C07D 261/06 20060101
C07D261/06; A61K 31/422 20060101 A61K031/422; A61K 31/397 20060101
A61K031/397; A61K 31/40 20060101 A61K031/40; A61K 31/485 20060101
A61K031/485; A61K 31/5415 20060101 A61K031/5415; A61K 31/427
20060101 A61K031/427; A61K 31/4439 20060101 A61K031/4439; A61K
38/28 20060101 A61K038/28; A61K 38/31 20060101 A61K038/31; A61K
31/445 20060101 A61K031/445; A61K 31/715 20060101 A61K031/715; A61K
31/4985 20060101 A61K031/4985; A61K 31/506 20060101 A61K031/506;
A61K 31/454 20060101 A61K031/454; A61K 31/44 20060101 A61K031/44;
A61P 3/10 20060101 A61P003/10; C07D 333/56 20060101 C07D333/56 |
Claims
1. A compound represented by formula I: ##STR00047## or a
pharmaceutically acceptable salt thereof wherein: each R.sup.1
represents H or is selected from the group consisting of halo, CN,
OH, NO.sub.2, CO.sub.2R.sup.a, NR.sup.aR.sup.b, S(O).sub.pR.sup.a,
C.sub.1-10alkyl, C.sub.2-10alkenyl or C.sub.1-10alkoxy, the alkyl
amd alkenyl portions of C.sub.1-10alkyl, C.sub.2-10alkenyl and
C.sub.1-10alkoxy being optionally substituted with 1-5 halo atoms
up to perhalo; and further optionally substituted with 1 group
selected from OH, oxo and C.sub.1-6alkoxy; p represents 0, 1 or 2;
each R.sup.a and R.sup.b independently represents H or
C.sub.1-4alkyl optionally substituted with 1-5 halo atoms up to
perhalo; and further optionally substituted with 1 group selected
from OH, oxo and C.sub.1-6alkoxy; R.sup.2 represents C.sub.1-6alkyl
or C.sub.2-6alkenyl, each optionally substituted with 1-5 halo
atoms up to perhalo, and further optionally substituted with 1
group selected from OH, oxo and C.sub.1-6alkoxy; each R.sup.3
represents H or is selected from the group consisting of halo; CN;
OH; NO.sub.2; CO.sub.2R.sup.a; NR.sup.aR.sup.b; S(O).sub.pR.sup.a;
a 5-membered heteroaryl ring containing 1-3 nitrogen atoms, 0-1
oxygen or sulfur atom, and optionally substituted with 1-2
C.sub.1-4alkyl groups; C.sub.1-10alkyl; C.sub.2-10alkenyl and
C.sub.1-10alkoxy, the alkyl and alkenyl portions of
C.sub.1-10alkyl, C.sub.2-10alkenyl and C.sub.1-10alkoxy being
optionally substituted with 1-5 halo atoms up to perhalo; and
further optionally substituted with 1 group selected from OH, oxo,
NR.sup.aR.sup.b and C.sub.1-6alkoxy; each R.sup.4 independently
represents H or is selected from the group consisting of halo, OH,
C.sub.1-4alkyl, OC.sub.1-4alkyl, haloC.sub.1-4alkyl and
haloOC.sub.1-4alkyl; m represents 0, 1 or 2; such that when m
represents 0 or 1, Z represents tetrazolyl; and when m represents
2, Z represents a member selected from the group consisting of
CO.sub.2H, SO.sub.3H and C(O)NH.sub.2.
2. A compound in accordance with claim 1 or a pharmaceutically
acceptable salt thereof wherein each R.sup.1 represents H or is
selected from the group consisting of halo, CN, C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, haloC.sub.1-6 alkyl and haloC.sub.1-6 alkoxy.
3. A compound in accordance with claim 1 or a pharmaceutically
acceptable salt thereof wherein each R.sup.1 represents H or is
selected from the group consisting of: halo selected from fluoro
and chloro; CN; CH.sub.3; OCH.sub.3; CF.sub.3 and OCF.sub.3.
4. A compound in accordance with claim 1 or a pharmaceutically
acceptable salt thereof wherein R.sup.2 represents a member
selected from the group consisting of: C.sub.1-6alkyl and
C.sub.3-4alkenyl, each optionally substituted with 1-3 halo
atoms.
5. A compound in accordance with claim 1 or a pharmaceutically
acceptable salt thereof wherein R.sup.2 represents C.sub.2-5alkyl
optionally substituted with 1-3 halo atoms.
6. A compound in accordance with claim 1 or a pharmaceutically
acceptable salt thereof wherein R.sup.2 is selected from the group
consisting of ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
sec-butyl and 3-methylbutyl, each optionally substituted with 1-3
halo atoms selected from fluoro and chloro.
7. A compound in accordance with claim 1 or a pharmaceutically
acceptable salt thereof wherein R.sup.2 is selected from the group
consisting of ethyl, n-propyl, n-butyl, CH.sub.2CH(CH.sub.3).sub.2,
CH.sub.2CH.sub.2CH(CH.sub.3).sub.2 and
CH.sub.2CH.sub.2CF.sub.3.
8. A compound in accordance with claim 1 or a pharmaceutically
acceptable salt thereof wherein each R.sup.3 represents H or is
selected from the group consisting of halo, CN, OH, SCH.sub.3 ,
SO.sub.2CH.sub.3, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, haloC.sub.1-6
alkyl, haloC.sub.1-6alkoxy and a 5-membered heteroaryl ring
containing 1-2 nitrogen atoms and 0-1 oxygen atom, said ring being
optionally substituted with 1-2 C.sub.1-4alkyl groups.
9. A compound in accordance with claim 1 or a pharmaceutically
acceptable salt thereof wherein each R.sup.3 represents H or is
selected from the group consisting of halo which is selected from
F, Cl and Br, CN, OH, SCH.sub.3, SO.sub.2CH.sub.3, C.sub.1-2alkyl,
C.sub.1-2alkoxy, haloC.sub.1-2alkyl and haloC.sub.1-2alkoxy wherein
the halo portion of haloC.sub.1-2alkyl and haloC.sub.1-2alkoxy is
selected from F and Cl, and a 5-membered heteroaryl ring containing
1-2 nitrogen atoms and 0-1 oxygen atom, said ring being optionally
substituted with 1-2 C.sub.1-4alkyl groups.
10. A compound in accordance with claim 1 or a pharmaceutically
acceptable salt thereof wherein each R.sup.3 represents H, F, Cl,
Br, CN, OH, CH.sub.3, OCH.sub.3, OCH.sub.2CH.sub.3, CHF.sub.2,
CF.sub.3, SCH.sub.3, SO.sub.2CH.sub.3, OCHF.sub.2, OCF.sub.3 and a
5-membered heteroaryl ring containing 1-2 nitrogen atoms, 0-1
oxygen atom and being optionally substituted with 1 C.sub.1-2alkyl
group.
11. A compound in accordance with claim 1 or a pharmaceutically
acceptable salt thereof wherein each R.sup.4 represents H, halo
selected from F and Cl, OH, C.sub.1-2alkyl, C.sub.1-2alkoxy,
haloC.sub.1-2alkyl and haloC.sub.1-2alkoxy wherein the halo portion
of haloC.sub.1-2alkyl and haloC.sub.1-2alkoxy is selected from F
and Cl.
12. A compound in accordance with claim 1 or a pharmaceutically
acceptable salt thereof wherein each R.sup.4 represents H, F, Cl,
OH, CH.sub.3, OCH.sub.3, CF.sub.3, and OCF.sub.3.
13. A compound in accordance with claim 1 or a pharmaceutically
acceptable salt thereof wherein each R.sup.4 represents H, F,
CH.sub.3 or OH.
14. A compound in accordance with claim 1 or a pharmaceutically
acceptable salt thereof wherein m represents 0 or 1 and Z
represents tetrazolyl.
15. A compound in accordance with claim 1 or a pharmaceutically
acceptable salt thereof wherein m is 2 and Z represents
CO.sub.2H.
16. A compound in accordance with claim 1 or a pharmaceutically
acceptable salt thereof wherein: each R.sup.1 represents H or is
selected from the group consisting of halo, CN, C.sub.1-6alkyl,
C.sub.1-6alkoxy, haloC.sub.1-6alkyl and haloC.sub.1-6alkoxy;
R.sup.2 represents a member selected from the group consisting of:
C.sub.1-6alkyl and C.sub.3-4alkenyl, each optionally substituted
with 1-3 halo atoms; each R.sup.3 represents H or is selected from
the group consisting of halo, CN, OH, SCH.sub.3, SO.sub.2CH.sub.3,
C.sub.1-6alkyl, C.sub.1-6alkoxy, haloC.sub.1-6alkyl,
haloC.sub.1-6alkoxy and a 5-membered heteroaryl ring containing 1-2
nitrogen atoms and 0-1 oxygen atom, said ring being optionally
substituted with 1-2 C.sub.1-4alkyl groups; each R.sup.4 represents
H, halo selected from F and Cl, OH, C.sub.1-2alkyl,
C.sub.1-2alkoxy, haloC.sub.1-2alkyl and haloC.sub.1-2alkoxy wherein
the halo portion of haloC.sub.1-2alkyl and haloC.sub.1-2alkoxy is
selected from F and Cl; and m is 0 or 1 and Z is tetrazolyl, or m
is 2 and Z represents CO.sub.2H.
17. A compound in accordance with claim 1 selected from the group
consisting of: ##STR00048## TABLE-US-00008 TABLE 1 ##STR00049##
EXAMPLE R.sup.1 R.sup.2 R.sup.3 5 4-Cl n-Pr H 6 4-Cl n-Pr 5-Cl,
7-Me 7 4-Cl n-Pr 5-Cl, 7-Br 8 4-Cl n-Pr 2-Me 9 4-Cl n-Pr 5-F, 7-Cl
10 4-OMe n-Pr H 11 3,4-diCl n-Pr 5-Cl 12 3,4-diCl n-Pr 5-Cl, 7-Br
13 4-Cl n-Pr 5-F, 7-CN 14 4-Cl n-Pr 5-Me, 7-CN 15 4-Cl n-Pr
5-CF.sub.3, 7-CN 16 4-Cl n-Pr 5,6-diF, 7-CN 17 4-Cl n-Pr 4,5-diF,
7-CN 18 4-Cl n-Pr 2-Me, 5-F, 7-CN 19 4-Cl n-Pr 2-Me, 5-Cl, 7-CN 20
3,5-diF n-Pr 5-CF.sub.3, 7-CN 21 3,4-diCl n-Pr 5-Cl, 7-CN 22
4-OCF.sub.3 n-Pr 5-F, 7-CN 23 4-OCF.sub.3 n-Pr 5-Me, 7-CN 24
4-OCF.sub.3 n-Pr 5-CF.sub.3, 7-CN 25 4-OCF.sub.3 n-Pr 5-Cl, 7-CN 26
4-OCF.sub.3 n-Pr 5,6-diF, 7-CN 27 4-Cl --CH.sub.2CH.sub.2CF.sub.3
5-Cl, 7-CN 28 4-Cl --CH.sub.2CH.sub.2CF.sub.3 5-Me, 7-CN 29 4-Cl
n-Bu 5-Cl, 7-CN 30 4-Cl n-Bu 5-F, 7-CN 31 4-Cl n-Bu 5-CF.sub.3,
7-CN 32 4-Cl --CH.sub.2CH(CH.sub.3).sub.2 5-Cl, 7-CN 33 4-Cl
--CH.sub.2CH(CH.sub.3).sub.2 5-F, 7-CN 34 4-Cl Et 5-Cl, 7-CN 35
4-Cl n-Pr ##STR00050## 36 4-OCF.sub.3 n-Pr ##STR00051## 37 4-Cl
n-Bu ##STR00052## 38 4-Cl n-Pr ##STR00053##
TABLE-US-00009 TABLE 2 ##STR00054## EXAMPLE Y 39 ##STR00055## 40
##STR00056## 41 ##STR00057## 42 ##STR00058## 43 ##STR00059## 44
##STR00060##
TABLE-US-00010 TABLE 3 ##STR00061## EXAMPLE R.sup.1 R.sup.2 R.sup.3
45 4-Cl n-Pr H 46 4-Cl n-Pr 5-Cl 47 4-Cl n-Pr 7-Cl 48 4-OMe n-Pr
5-Cl
or a pharmaceutically acceptable salt thereof.
18. A pharmaceutical composition comprising a compound in
accordance with claim 1 or a pharmaceutically acceptable salt
thereof in combination with a pharmaceutically acceptable
carrier.
19. A pharmaceutical composition in accordance with claim 18
further comprised of a member selected from the group consisting
of: simvastatin, mevastatin, ezetimibe, atorvastatin, metformin,
sibutramine, orlistat, Qnexa, topiramate, naltrexone, bupriopion,
phentermine, losartan, hydrochlorothiazide, buformin, phenformin,
troglitazone, pioglitazone, rosiglitazone, insulin, somatostatin,
voglibose, miglitol, acarbose, sitagliptin, vildagliptin,
saxagliptin, alogliptin, acetohexamide, carbutamide,
chlorpropamide, glibornuride, gliclazide, glimerpiride, glipizide,
gliquidine, glisoxepid, glyburide, glyhexamide, glypinamide,
phenbutamide, tolazamide, tolbutamide, tolcyclamide, nateglinide,
repaglinide, rimonabant and taranabant.
20. A method of treating type 2 diabetes mellitus in a mammalian
patient in need of such treatment comprising administering to said
patient a compound in accordance with claim 1 or a pharmaceutically
acceptable salt thereof in an amount that is effective to treat
said type 2 diabetes mellitus.
21-29. (canceled)
Description
BACKGROUND OF THE INVENTION
[0001] The present invention relates to glucagon receptor
antagonist compounds, compositions containing such compounds and
various methods of treatment relating to type 2 diabetes mellitus
and related conditions.
[0002] Diabetes refers to a disease process derived from multiple
causative factors and is characterized by elevated levels of plasma
glucose (hyperglycemia) in the fasting state or following glucose
administration during an oral glucose tolerance test. Frank
diabetes mellitus (e.g., a blood glucose level >126 mg/dL in a
fasting state) is associated with increased and premature
cardiovascular morbidity and mortality, and is related directly and
indirectly to various metabolic conditions, including alterations
of lipid, lipoprotein and apolipoprotein metabolism.
[0003] Patients with non-insulin dependent diabetes mellitus (type
2 diabetes mellitus), approximately 95% of patients with diabetes
mellitus, frequently display elevated levels of serum lipids, such
as cholesterol and triglycerides, and have poor blood-lipid
profiles, with high levels of LDLcholesterol and low levels of
HDL-cholesterol. Those suffering from Type 2 diabetes mellitus are
thus at an increased risk of developing macrovascular and
microvascular complications, including coronary heart disease,
stroke, peripheral vascular disease, hypertension (for example,
blood pressure >130/80 mmHg in a resting state), nephropathy,
neuropathy and retinopathy.
[0004] Patients having type 2 diabetes mellitus characteristically
exhibit elevated plasma insulin levels compared with nondiabetic
patients; these patients have developed a resistance to insulin
stimulation of glucose and lipid metabolism in the main
insulin-sensitive tissues (muscle, liver and adipose tissues).
Thus, Type 2 diabetes, at least early in the natural progression of
the disease is characterized primarily by insulin resistance rather
than by a decrease in insulin production, resulting in insufficient
uptake, oxidation and storage of glucose in muscle, inadequate
repression of lipolysis in adipose tissue, and excess glucose
production and secretion by the liver. The net effect of decreased
sensitivity to insulin is high levels of insulin circulating in the
blood without appropriate reduction in plasma glucose
(hyperglycemia). Hyperinsulinemia is a risk factor for developing
hypertension and may also contribute to vascular disease.
[0005] Glucagon serves as the major regulatory hormone attenuating
the effect of insulin in its inhibition of liver gluconeogenesis
and is normally secreted by alpha cells in pancreatic islets in
response to falling blood glucose levels. The hormone binds to
specific receptors in liver cells that trigger glycogenolysis and
an increase in gluconeogenesis through cAMP-mediated events. These
responses generate glucose (e.g. hepatic glucose production) to
help maintain euglyeemia by preventing blood glucose levels from
falling significantly. In addition to elevated levels of
circulating insulin, type 2 diabetics have elevated levels of
plasma glucagon and increased rates of hepatic glucose production.
Antagonists of the glucagon receptor are useful in improving
insulin responsiveness in the liver, decreasing the rate of
gluconeogenesis and glycogenolysis, and lowering the rate of
hepatic glucose output resulting in a decrease in the levels of
plasma glucose.
SUMMARY OF THE INVENTION
[0006] The present invention relates to a compound represented by
formula I:
##STR00001##
or a pharmaceutically acceptable salt or solvate thereof
wherein:
[0007] each R.sup.1 represents H or is selected from the group
consisting of halo, CN, OH, NO.sub.2, CO.sub.2R.sup.a,
NR.sup.aR.sup.b, S(O).sub.pR.sup.a, C.sub.1-10alkyl,
C.sub.2-10alkenyl or C.sub.1-10alkoxy, the alkyl and alkenyl
portions of C.sub.1-10alkyl, C.sub.2-10alkenyl and C.sub.1-10alkoxy
being optionally substituted with 1-5 halo atoms up to perhalo; and
further optionally substituted with 1 group selected from OH, oxo
and C.sub.1-6alkox.sub.Y;
[0008] p represents 0, 1 or 2;
[0009] each R.sup.a and R.sup.b independently represents H or
C.sub.1-4alkyl optionally substituted with 1-5 halo atoms up to
perhalo; and further optionally substituted with 1 group selected
from OH, oxo and C.sub.1-6alkoxy;
[0010] R.sup.2 represents C.sub.1-6alkyl or C.sub.2-6alkenyl, each
optionally substituted with 1-5 halo atoms up to perhalo, and
further optionally substituted with 1 group selected from OH, oxo
and C.sub.1-6alkoxy; [0011] each R.sup.3 represents H or is
selected from the group consisting of halo; CN; OH; NO.sub.2;
CO.sub.2R.sup.a; NR.sup.aR.sup.b; S(O).sub.pR.sup.a; a 5-membered
heteroaryl ring containing 1-3 nitrogen atoms, 0-1 oxygen or sulfur
atom, and optionally substituted with 1-2 C.sub.1-4alkyl groups;
C.sub.1-10alkyl; C.sub.2-10 alkenyl and C.sub.1-10alkoxy, the alkyl
and alkenyl portions of C.sub.1-10alkyl, C.sub.2-10alkenyl and
C.sub.1-10alkoxy being optionally substituted with 1-5 halo atoms
up to perhalo; and further optionally substituted with 1 group
selected from OH, oxo, NR.sup.aR.sup.b and C.sub.1-6alkoxy;
[0012] each R.sup.4 independently represents H or is selected from
the group consisting of halo, OH, C.sub.1-4alkyl, OC.sub.1-4alkyl,
haloC.sub.1-4alkyl and haloOC.sub.1-4alkyl;
[0013] m represents 0, 1 or 2; such that when m represents 0 or 1,
Z represents tetrazolyl; and when m represents 2, Z represents a
member selected from the group consisting of CO.sub.2H, SO.sub.3H
and C(O)NH.sub.2.
DETAILED DESCRIPTION OF THE INVENTION
[0014] The invention is described herein in detail using the terms
defined below unless otherwise specified.
[0015] "Alkyl", as well as other groups having the prefix "alk",
such as alkoxy, alkanoyl 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, 1-10 carbon atoms are intended for linear or 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, 3-10 carbon atoms are intended,
forming 1-3 carbocyclic rings that are fused. Examples of
cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, decahydronaphthyl and the like.
[0016] "Alkenyl" means carbon chains which contain at least one
carbon-carbon double bond, and which may be linear or branched or
combinations thereof. Examples of alkenyl include vinyl, allyl,
isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl,
2-methyl-2-butenyl, and the like. Cycloalkenyl is a subset of
alkenyl. If no number is specified, 4-8 carbon atoms are included.
Examples include cyclopentenyl, cyclohexenyl and the like.
[0017] "Aryl" (Ar) means mono- and bicyclic aromatic rings
containing 6-12 carbon atoms. Examples of aryl include phenyl,
naphthyl, indenyl and the like. "Aryl" also includes monocyclic
rings fused to an aryl group. Examples include tetrahydronaphthyl,
indanyl and the like.
[0018] "Heteroaryl" (HAR) means a mono- or bicyclic aromatic ring
or ring system containing at least one heteroatom selected from 0,
S and N, with each ring containing 5 to 6 atoms. Examples include
pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl,
oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl,
tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl,
pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl,
benzofuranyl, benzothiophenyl, furo(2,3-b)pyridyl, quinolyl,
indolyl, isoquinolyl and the like. Heteroaryl also includes
aromatic heterocyclic groups fused to heterocycles that are
non-aromatic or partially aromatic, and aromatic heterocyclic
groups fused to cycloalkyl rings. Heteroaryl also includes such
groups in charged form, e.g., pyridinium.
[0019] "Halogen" (Halo) includes fluorine, chlorine, bromine and
iodine. Haloalkyl and haloalkoxy refer to halogenated alkyl and
alkoxy groups having the indicated number of carbon atoms,
substituted with one to five halo atoms, up to perhalo, and
preferably one to three halo atoms selected from fluoro and chloro.
Thus, for example, haloC.sub.1-6alkyl refers to a C.sub.1-6alkyl
group substituted with halo atoms, up to perhalo.
[0020] Numbering around the benzothiophene is conventional, as
shown below:
##STR00002##
It is also noted that while structures I, I-1 and I-2 depict the
R.sup.3 groups on the benzene ring of the benzothiophene moiety,
the R.sup.3 groups can be attached at any available point on the
thiophene portion as well.
[0021] One aspect of the invention relates to a compound
represented by formula I:
##STR00003##
or a pharmaceutically acceptable salt or solvate thereof
wherein:
[0022] each R.sup.1 represents H or is selected from the group
consisting of halo, CN, OH, NO.sub.2, CO.sub.2R.sup.a,
NR.sup.aR.sup.b, S(O).sub.pR.sup.a, C.sub.1-10alkyl,
C.sub.2-10alkenyl or C.sub.1-10alkoxy, the alkyl and alkenyl
portions of C.sub.1-10alkyl, C.sub.2-10alkenyl and C.sub.1-10alkoxy
being optionally substituted with 1-5 halo atoms up to perhalo; and
further optionally substituted with 1 group selected from OH, oxo
and C.sub.1-6aikoxY;
[0023] p represents 0, 1 or 2;
[0024] each R.sup.a and R.sup.b independently represents H or
C.sub.1-4alkyl optionally substituted with 1-5 halo atoms up to
perhalo; and further optionally substituted with 1 group selected
from OH, oxo and C.sub.1-6alkoxy ;
[0025] R.sup.2 represents C.sub.1-6alkyl or C.sub.2-6alkenyl, each
optionally substituted with 1-5 halo atoms up to perhalo, and
further optionally substituted with 1 group selected from OH, oxo
and C.sub.1-6alkoxy ;
[0026] each R.sup.3 represents H or is selected from the group
consisting of halo; CN; OH; NO.sub.2; CO.sub.2R.sup.a;
NR.sup.aR.sup.b; S(O).sub.pR.sup.a; a 5-membered heteroaryl ring
containing 1-3 nitrogen atoms, 0-1 oxygen or sulfur atom, and
optionally substituted with 1-2 C.sub.1-4alkyl groups;
C.sub.1-10alkyl; C.sub.2-10alkenyl and Cmoalkoxy, the alkyl and
alkenyl portions of C.sub.1-10alkyl, C.sub.2-10alkenyl and
C.sub.1-10 alkoxy being optionally substituted with 1-5 halo atoms
up to perhalo; and further optionally substituted with 1 group
selected from OH, oxo, NR.sup.aR.sup.b and C.sub.1-6alkoxy;
[0027] each R.sup.4 independently represents H or is selected from
the group consisting of halo, OH, C.sub.1-4alkyl, OC.sub.1-4alkyl,
haloC.sub.1-4alkyl and haloOC.sub.1-4alkyl;
[0028] m represents 0, 1 or 2; such that when m represents 0 or 1,
Z represents tetrazolyl; and when m represents 2, Z represents a
member selected from the group consisting of CO.sub.2H, SO.sub.3H
and C(O)NH.sub.2.
[0029] An aspect of the invention that is of interest relates to a
compound of formula I-1:
##STR00004##
or a pharmaceutically acceptable salt or solvate thereof . The
variables are as defined with respect to formula I.
[0030] Another aspect of the invention that is of interest relates
to a compound of formula I-2:
##STR00005##
or a pharmaceutically acceptable salt or solvate thereof. The
variables are as defined with respect to formula I.
[0031] Another aspect of the invention that is of interest relates
to compounds in accordance with formula I or a pharmaceutically
acceptable salt or solvate thereof wherein each R.sup.1 represents
H or is selected from the group consisting of halo, CN,
C.sub.1-6alkyl, C.sub.1-6alkoxy, haloC.sub.1-6alkyl and
haloC.sub.1-6alkoxy.
[0032] In particular, another aspect of the invention that is of
interest relates to compounds in accordance with formula I or a
pharmaceutically acceptable salt or solvate thereof wherein each
R.sup.1 represents H or is selected from the group consisting of:
halo selected from fluoro and chloro; CN; CH.sub.3; OCH.sub.3;
CF.sub.3 and OCF.sub.3.
[0033] Another aspect of the invention that is of interest relates
to compounds in accordance with formula I or a pharmaceutically
acceptable salt or solvate thereof wherein R.sup.2 represents a
member selected from the group consisting of: C.sub.1-6alkyl and
C.sub.3-4alkenyl, each optionally substituted with 1-3 halo
atoms.
[0034] In particular, another aspect of the invention that is of
interest relates to compounds in accordance with formula I or a
pharmaceutically acceptable salt or solvate thereof wherein R.sup.2
represents C.sub.2-5alkyl optionally substituted with 1-3 halo
atoms.
[0035] Even more particularly, another aspect of the invention that
is of interest relates to compounds in accordance with formula I or
a pharmaceutically acceptable salt or solvate thereof wherein
R.sup.2 is selected from the group consisting of ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, sec-butyl and 3-methylbutyl, each
optionally substituted with 1-3 halo atoms selected from fluoro and
chloro.
[0036] Even more particularly, another aspect of the invention that
is of interest relates to compounds in accordance with formula I or
a pharmaceutically acceptable salt or solvate thereof wherein
R.sup.2 is selected from the group consisting of ethyl, n-propyl,
n-butyl, CH.sub.2CH(CH.sub.3).sub.2,
CH.sub.2CH.sub.2CH(CH.sub.3).sub.2 and
CH.sub.2CH.sub.2CF.sub.3.
[0037] Another aspect of the invention that is of interest relates
to compounds in accordance with formula I or a pharmaceutically
acceptable salt or solvate thereof wherein each
[0038] R.sup.3 represents H or is selected from the group
consisting of halo, CN, OH, SCH.sub.3, SO.sub.2CH.sub.3,
C.sub.1-6alkyl, C.sub.1-6alkoxy, haloC.sub.1-6alkyl,
haloC.sub.1-6alkoxy and a 5-membered heteroaryl ring containing 1-2
nitrogen atoms and 0-1 oxygen atom, said ring being optionally
substituted with 1-2 C.sub.1-4alkyl groups.
[0039] More particularly, another aspect of the invention that is
of interest relates to compounds in accordance with formula I or a
pharmaceutically acceptable salt or solvate thereof wherein each
R.sup.3 represents H or is selected from the group consisting of
halo which is selected from F, Cl and Br, CN, OH, SCH.sub.3,
SO.sub.2CH.sub.3, C.sub.1-2alkyl, C.sub.1-2alkoxy,
haloC.sub.1-2alkyl and haloC.sub.1-2alkoxy wherein the halo portion
of haloC.sub.1-2alkyl and haloC.sub.1-2alkoxy is selected from F
and Cl, and a 5-membered heteroaryl ring containing 1-2 nitrogen
atoms and 0-1 oxygen atom, said ring being optionally substituted
with 1-2 C.sub.1-4alkyl groups.
[0040] Even more particularly, another aspect of the invention that
is of interest relates to compounds in accordance with formula I or
a pharmaceutically acceptable salt or solvate thereof wherein each
R.sup.3 represents H, F, Cl, Br, CN, OH, CH.sub.3, OCH.sub.3,
OCH.sub.2CH.sub.3, CHF.sub.2, CF.sub.3, SCH.sub.3,
SO.sub.2CH.sub.3, OCHF.sub.2, OCF.sub.3 and a 5-membered heteroaryl
ring containing 1-2 nitrogen atoms, 0-1 oxygen atom and being
optionally substituted with 1 C.sub.1-2alkyl group.
[0041] Another aspect of the invention that is of interest relates
to compounds in accordance with formula I or a pharmaceutically
acceptable salt or solvate thereof wherein each R.sup.4 represents
H, halo selected from F and Cl, OH, C.sub.1-2alkyl,
C.sub.1-2alkoxy, haloC.sub.1-2alkyl and haloC.sub.1-2alkoxy wherein
the halo portion of haloC.sub.1-2alkyl and haloC.sub.1-2alkoxy is
selected from F and Cl.
[0042] In particular, another aspect of the invention that is of
interest relates to compounds in accordance with formula I or a
pharmaceutically acceptable salt or solvate thereof wherein each
R.sup.4 represents H, F, Cl, OH, CH.sub.3, OCH.sub.3, CF.sub.3, and
OCF.sub.3.
[0043] More particularly, another aspect of the invention that is
of interest relates to compounds in accordance with formula I or a
pharmaceutically acceptable salt or solvate thereof wherein each
R.sup.4 represents H, F, CH.sub.3 or OH.
[0044] Another aspect of the invention that is of interest relates
to compounds in accordance with formula I or a pharmaceutically
acceptable salt or solvate thereof wherein m represents 0 or 1 and
Z represents tetrazolyl.
[0045] Another aspect of the invention that is of interest relates
to compounds in accordance with formula I or a pharmaceutically
acceptable salt or solvate thereof wherein m is 2 and Z represents
CO.sub.2H.
[0046] Another aspect of the invention that is of interest relates
to compound in accordance with formula 1 or a pharmaceutically
acceptable salt or solvate thereof wherein:
[0047] each R.sup.1 represents H or is selected from the group
consisting of halo, CN, C.sub.1-6alkyl, C.sub.1-6alkoxy,
haloC.sub.1-6alkyl and haloC.sub.1-6alkoxy;
[0048] R.sup.2 represents a member selected from the group
consisting of: C.sub.1-6alkyl and C.sub.3-4alkenyl, each optionally
substituted with 1-3 halo atoms;
[0049] each R.sup.3 represents H or is selected from the group
consisting of halo, CN, OH, SCH.sub.3, SO.sub.2CH.sub.3,
C.sub.1-6alkyl, C.sub.1-6alkoxy, haloC.sub.1-6alkyl,
haloC.sub.1-6alkoxy and a 5-membered heteroaryl ring containing 1-2
nitrogen atoms and 0-1 oxygen atom, said ring being optionally
substituted with 1-2 C.sub.1-4alkyl groups;
[0050] each R.sup.4 represents H, halo selected from F and Cl, OH,
C.sub.1-2alkyl, C.sub.1-2alkoxy, haloC.sub.1-2alkyl and
haloC.sub.1-2alkoxy wherein the halo portion of haloC.sub.1-2alkyl
and haloC.sub.1-2alkoxy is selected from F and Cl;
[0051] m is 0 or 1 and Z is tetrazolyl, or m is 2 and Z represents
CO.sub.2H.
[0052] Examples of compounds that fall within the invention
described herein are in the tables and examples contained herein.
Pharmaceutically acceptable salts and solvates of the compounds
disclosed in the tables are included as well.
[0053] Another aspect of the invention that is of interest relates
to a pharmaceutical composition comprising a compound as described
above with respect to formula I or a pharmaceutically acceptable
salt or solvate thereof in combination with a pharmaceutically
acceptable carrier.
[0054] Another aspect of the invention that is of interest relates
to a method of treating type 2 diabetes mellitus in a mammalian
patient in need of such treatment comprising administering to said
patient a compound as described above with respect to formula I or
a pharmaceutically acceptable salt or solvate thereof in an amount
that is effective to treat type 2 diabetes mellitus.
[0055] Another aspect of the invention that is of interest relates
to a method of delaying the onset of type 2 diabetes mellitus in a
mammalian patient in need thereof, comprising administering to the
patient a compound as described above in accordance with formula I
or a pharmaceutically acceptable salt or solvate thereof in an
amount that is effective to delay the onset of type 2 diabetes
mellitus.
[0056] 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 as described
above 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.
[0057] 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 an anti-diabetic effective amount of a
compound in accordance with formula I or a pharmaceutically
acceptable salt or solvate thereof as described above.
[0058] 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 comprising administering to said patient a compound
in accordance with formula I as described above or a
pharmaceutically acceptable salt or solvate thereof in an amount
that is effective to treat obesity.
[0059] 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 as described above or a
pharmaceutically acceptable salt or solvate thereof in an amount
that is effective to treat Syndrome X.
[0060] 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 as described above with respect to formula I or a
pharmaceutically acceptable salt or solvate thereof in an amount
that is effective to treat said lipid disorder.
[0061] 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 formula I as described above or a
pharmaceutically acceptable salt or solvate thereof in an amount
effective to treat atherosclerosis.
[0062] 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, 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 as described above or a pharmaceutically
acceptable salt or solvate thereof in an amount that is effective
to treat said condition.
[0063] 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, 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 as described above or a pharmaceutically
acceptable salt or solvate thereof in an amount that is effective
to delay the onset of said condition.
[0064] 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,
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 of foimula I as
described above or a pharmaceutically acceptable salt or solvate
thereof in an amount that is effective to reduce the risk of
developing said condition.
[0065] Another aspect of the invention that is of interest relates
to a method of treating a condition selected from the group
consisting of:
[0066] (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, (1.3) vascular restenosis, (14) pancreatitis, (15)
abdominal obesity, (16) neurodegenerative disease, (17)
retinopathy, (18) nephropathy, (19) neuropathy, (20) Syndrome X,
and other conditions and disorders where insulin resistance is a
component, in a mammalian patient in need of such treatment,
[0067] comprising administering to the patient effective amounts of
a compound of formula I as described above, or a pharmaceutically
acceptable salt or solvate thereof, and a another compound that is
selected from the list provided below.
[0068] (1) growth hormone secretagogues, growth hon none
secretagogue receptor agonists/antagonists, such as NN703,
hexarelin, MK-0677, SM-130686, CP-424,391, L-692,429, and
L-163,255, and such as those disclosed in U.S. Pat. Nos. 5,536,716,
and 6,358,951, U.S. Patent Application Nos. 2002/049196 and
2002/022637, and PCT Application Nos. WO 01/56592 and WO 02/32888;
(2) protein tyrosine phosphatase-1B (PTP-1B) inhibitors; (3)
cannabinoid receptor ligands, such as cannabinoid CB.sub.1 receptor
antagonists or inverse agonists, such as rirnonaba.nt (Sanofi
Synthelabo), AMT-251, and SR-14778 and SR 141716A (Sandi
Synthelabo), SLY-319 (Solvay), BAY 65-2520 (Bayer), and those
disclosed in U.S. Pat. Nos. 5,532,237, 4,973,587, 5,013,837,
5,081,122, 5,112,820, 5,292,736, 5,624,941, 6,028,084, PCT
Application Nos. WO 96/33159, WO 98/33765, W098/43636, W098/43635,
WO 01/09120, WO98/31227, WO98/41519, WO98/37061, WO00/10967,
WO00/10968, WO97/29079, WO99/02499, WO 01/58869, WO 01/64632, WO
01/64633, WO 01/64634, W002/076949, WO 03/007887, WO 04/048317, and
WO 05/000809; and EPO Application No. EP-658546, EP-656354,
EP-576357; (4) anti-obesity serotonergic agents, such as
fenfluramine, dexfenfluramine, phentemiine, and sibutramine;
(5)133-adrenoreceptor agonists, such as AD9677/TAK677
(Dainippon!Takeda), CL-316,243, SB 418790, BRL-37344, L-796568,
BMS-196085, BRL-35135A, CGP12177A, BTA-243, Trecadrine, Zeneca
D7114, SR 59119A, and such as those disclosed in U.S. Patent
Application Nos. 5,705,515, and U.S. Pat. No. 5,451,677 and PCT
Patent Publications WO94/18161, WO95/29159, WO97/46556, WO98/04526
and W098/32753, WO 01/74782, and WO 02/32897; (6) pancreatic lipase
inhibitors, such as orlistat (Xenical.RTM.), cetilistat, Triton
WR1339, RHC80267, lipstatin, tetrahydrolipstatin, teasaponin,
diethylumbelliferyl phosphate, and those disclosed in PCT
Application No. WO 01/77094; (7) neuropeptide Y1 antagonists, such
as B1BP3226, J-115814, BIBO 3304, LY-357897, CP-671906, GI-264879A,
and those disclosed in U.S. Pat. No. 6,001,836, and PCT Patent
Publication Nos. WO 96/14307, WO 01/23387, WO 99/51600, WO
01/85690, WO 01/85098, WO 01/85173, and WO 01/89528; (8)
neuropeptide Y5 antagonists, such as GW-569180A, GW-594884A,
GW-587081X, GW-548118X, FR226928, FR 240662, FR252384, 1229U91,
GI-264879A, CGP71683A, LY-377897, PD-160170, SR-120562A, SR-120819A
and JCF-104, and those disclosed in U.S. Pat. Nos. 6,057,335;
6,043,246; 6,140,354; 6,166,038; 6,180,653; 6,191,160; 6,313,298;
6,335,345; 6,337,332; 6,326,375; 6,329,395; 6,340,683; 6,388,077;
6,462,053; 6,649,624; and 6,723,847, hereby incorporated by
reference in their entirety; European Patent Nos. EP-01010691, and
EP-01044970; and PCT International Patent Publication Nos. WO
97/19682, WO 97/20820, WO 97/20821, WO 97/20822, WO 97/20823, WO
98/24768; WO 98/25907; WO 98/25908; WO 98/27063, WO 98/47505; WO
98/40356; WO 99/15516; WO 99127965; WO 00/64880, WO 00/68197, WO
00/69849, WO 01/09120, WO 01/14376; WO 01/85714, WO 01/85730, WO
01/07409, WO 01/02379, WO 01/02379, WO 01/23388, WO 01/23389, WO
01/44201, WO 01/62737, WO 01/62738, WO 01/09120, WO 02/22592, WO
0248152, and WO 02/49648; WO 02/094825; WO 03/014083; WO 03/10191;
WO 03/092889; WO 04/002986; and WO 04/031175; (9)
melanin-concentrating hormone (MCH) receptor antagonists, such as
those disclosed in WO 01/21577 and WO 01/21169; (10)
melanin-concentrating hormone 1 receptor (MCH1R) antagonists, such
as T-226296 (Takeda), and those disclosed in PCT Patent Application
Nos. WO 01/82925, WO 01/87834, WO 02/051809, WO 02/06245, WO
02/076929, WO 02/076947, WO 02/04433, WO 02/51809, WO 02/083134, WO
02/094799, WO 03/004027, and Japanese Patent Application Nos. JP
13226269, and JP 2004-139909; (11) melanin-concentrating hormone 2
receptor (MCH2R) agonist/antagonists; (12) orexin-1 receptor
antagonists, such as SB-334867-A, and those disclosed in PCT Patent
Application Nos. WO 01/96302, WO 01/68609, WO 02/51232, and WO
02/51838; (13) serotonin reuptake inhibitors such as fluoxetine,
paroxetine, and sertraline, and those disclosed in U.S. Patent
Application No. 6,365,633, and PCT Patent Application Nos. WO
01/27060 and WO 01/162341; (14) melanocortin agonists, such as
Melanotan II, CFI1R86036 (Chiron), ME-10142, and ME-10145
(Melacure), CH1R86036 (Chiron); PT-141, and PT-14 (Palatin); (15)
other MC4R (melanocortin 4 receptor) agonists, such as those
disclosed in: U.S. Pat. Nos. 6,410,548; 6,294,534; 6,350,760;
6,458,790; 6,472,398; 6,376,509; and 6,818,658; US Patent
Publication No. US2002/0137664; US2003/0236262; US2004/009751;
US2004/0092501; and PCT Application Nos. WO 99/64002; WO 00/74679;
WO 01/70708; WO 01/70337; WO 01/74844; WO 01/91752; WO 01/991752;
WO 02/15909; WO 02/059095; WO 02/059107; WO 02/059108; WO
02/059117; WO 02/067869; WO 02/068387; WO 02/068388; WO 02/067869;
WO 02/11715; WO 02/12166; WO 02/12178; WO 03/007949; WO 03/009847;
WO 04/024720; WO 04/078716; WO 04/078717; WO 04/087159; WO
04/089307; and WO 05/009950; (16) 5HT-2 agonists; (17) 5HT2C
(serotonin receptor 2C) agonists, such as BVT933, DPCA37215,
WAY161503, R-1065, and those disclosed in U.S. Pat. No. 3,914,250,
and PCT Application Nos, WO 02/36596, WO 02/48124, WO 02/10169, WO
01/66548, WO 02/44152, WO 02/51844, WO 02/40456, and WO 02/40457;
(18) galanin antagonists; (19) CCK agonists; (20) CCK-1 agonists
(cholecystokinin -A) agonists, such as AR-R 15849, GI 181771,
JMV-180, A-71378, A-71623 and SR146131, and those discribed in U.S.
Pat. No. 5,739,106; (21) GLP-1 agonists; (22)
corticotropin-releasing hormone agonists; (23) histamine receptor-3
(H3) modulators; (24) histamine receptor-3 (H3) antagonists/inverse
agonists, such as hioperamide, 3-(1H-imidazol-4-yl)propyl
N-(4-pentenyl)carbamate, clobenpropit, iodophenpropit, imoproxifan,
GT2394 (Gliatech), and those described and disclosed in PCT
Application No. WO 02/15905, and
O-[3-(1H-imidazol-4-yl)propanol]-carbamates (Kiec-Kononowicz, K. et
al., Pharmazie, 55:349-55 (2000)), piperidine-containing histamine
H3-receptor antagonists (Lazewska, D. et al., Pharmazie, 56:927-32
(2001), benzophenone derivatives and related compounds (Sasse, A.
et al., Arch. Pharm. (Weinheim) 334:45-52 (2001)), substituted
N-phenylcarbamates (Reidemeister, S. et al., Pharmazie, 55:83-6
(2000)), and proxifan derivatives (Sasse, A. et al., J. Med. Chem.
43:3335-43 (2000)); (25) .beta.-hydroxy steroid dehydrogenase-1
inhibitors (.beta.-HSD-1); (26) PD (phosphodiesterase) inhibitors,
such as theophylline, pentoxifylline, zaprinast, amrinone,
milrinone, cilostamide, rolipram, and cilomilast; (27)
phosphodiesterase-3B (PDE3B) inhibitors; (28) NE (norepinephrine)
transport inhibitors, such as GW 320659, despiramine, talsupram,
and nomifensine; (29) ghrelin receptor antagonists, such as those
disclosed in PCT Application Nos. WO 01/87335, and WO 02/08250;
(30) leptin, including recombinant human leptin (PEG-OB, Hoffman La
Roche) and recombinant methionyl human leptin (Amgen); (31) leptin
derivatives, such as those disclosed in U.S. Pat. Nos. 5,552,524,
5,552,523, 5,552,522, 5,521,283, and PCT International Publication
Nos. WO 96/23513, WO 96/23514, WO 96/23515, WO 96/23516, WO
96/23517, WO 96/23518, WO 96/23519, and WO 96/23520; (32) other
BRS3 (bombesin receptor subtype 3) agonists such as
[D-Phe6,beta-Ala11,Phe13,Nle14]Bn(6-14) and
[D-Phe6,Phe13]Bn(6-13)propylamide, and those compounds disclosed in
Pept. Sci. 2002 August; 8(8): 461-75); (33) CNTF (Ciliary
neurotrophic factors), such as GI-181771 (Glaxo-SmithKline),
SR146131 (Sanofi Synthelabo), butabindide, PD170,292, and PD 149164
(Pfizer); (34) CNTF derivatives, such as axokine (Regeneron), and
those disclosed in PCT Application Nos. WO 94/09134, WO 98/22128,
and WO 99/43813; (35) monoamine reuptake inhibitors, such as
sibutrarnine, and those disclosed in U.S. Pat. Nos. 4,746,680,
4,806,570, and 5,436,272, U.S. Patent Publication No. 2002/0006964
and PCT Application Nos. WO 01/27068, and WO 01/62341; (36) UCP-1
(uncoupling protein-1), 2, or 3 activators, such as phytanic acid,
4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthalenyl)-1-propeny-
l]benzoic acid (TTNPB), retinoic acid, and those disclosed in PCT
Patent Application No. WO 99/00123; (37) thyroid hormone .beta.
agonists, such as KB-2611 (KaroBioBMS), and those disclosed in PCT
Application No. WO 02/15845, and Japanese Patent Application No. JP
2000256190; (38) FAS (fatty acid synthase) inhibitors, such as
Cerulenin and C75; (39) DGAT1 (diacylglycerol acyltransferase 1)
inhibitors; (40) DGAT2 (diacylglycerol acyltransferase 2)
inhibitors; (41) ACC2 (acetyl-CoA carboxylase-2) inhibitors; (42)
glucocorticoid antagonists; (43) acyl-estrogens, such as
oleoyl-estrone, disclosed in del Mar-Grasa, M. et al., Obesity
Research, 9:202-9 (2001); (44) dipeptidyl peptidase IV (DP-IV)
inhibitors, such as isoleucine thiazolidide, valine pyrrolidide,
NVP-DPP728, LAF237, P93/01, TSL 225, TMC-2A/2B/2C, FE 999011,
P9310/K364, VIP 0177, SDZ 274-444 and sitagliptin; and the
compounds disclosed in US Patent No. U.S. Pat. No. 6,699,871, which
is incorporated herein by reference; and International Patent
Application Nos. WO 03/004498; WO 03/004496; EP 1 258 476; WO
02/083128; WO 02/062764; WO 03/000250; WO 03/002530; WO 03/002531;
WO 03/002553; WO 03/002593; WO 03/000180; and WO 03/000181; (45)
dicarboxylate transporter inhibitors; (46) glucose transporter
inhibitors; (47) phosphate transporter inhibitors; (48) Metformin
(Glucophage.RTM.); (49) Topiramate (Topimax.RTM.); (50) peptide YY,
PYY 3-36, peptide YY analogs, derivatives, and fragments such as
BTM-43073D, BTM-43004C (Olitvak, D. A. et al., Dig. Dis. Sci.
44(3):643-48 (1999)), and those disclosed in U.S. Pat. No.
5,026,685, U.S. Pat. No. 5,604,203, U.S. Pat. No. 5,574,010, U.S.
Pat. No. 5, 696,093, U.S. Pat. No. 5,936,092, U.S. Pat. No. 6,046,
162, U.S. Pat. No. 6,046,167, U.S. Pat. No. 6,093,692, U.S. Pat.
No. 6,225,445, U.S. Pat. No. 5,604,203, U.S. Pat. No. 4,002,531,
U.S. Pat. No. 4, 179,337, U.S. Pat. No. 5,122,614, U.S. Pat. NO.
5,349,052, U.S. Pat. No. 5,552,520, U.S. Pat. No. 6, 127,355, WO
95/06058, WO 98/32466, WO 03/026591, WO 03/057235, WO 03/027637,
and WO 2004/066966; (51) Neuropeptide Y2 (NPY2) receptor agonists
such NPY3-36, N acetyl [Leu(28,31)] NPY 24-36, TASP-V, and
cyclo-(28/32)-Ac-[Lys28-Glu32]-(25-36)-pNPY; (52) Neuropeptide Y4
(NPY4) agonists such as pancreatic peptide (PP) as described in
Batterham et al., J. Clin. Endocrinol. Metab. 88:3989-3992 (2003),
and other Y4 agonists such as 1229U91; (53) cyclooxygenase-2
inhibitors such as etoricoxib, celecoxib, valdecoxib, parecoxib,
lumiracoxib, BMS347070, tiracoxib or JTE522, ABT963, CS502 and
GW406381, and pharmaceutically acceptable salts thereof; (54)
Neuropeptide Y1 (NPY1) antagonists such as B1BP3226, J-I 15814,
BIBO 3304, LY-357897, CP-671906, GI-264879A and those disclosed in
U.S. Pat. No. 6,001,836; and PCT Application Nos. WO 96/14307, WO
01/23387, WO 99/51600, WO 01/85690, WO 01/85098, WO 01/85173, and
WO 01/89528; (55) Opioid antagonists such as nalmefene
(Revex.RTM.), 3-methoxynaltrexone, naloxone, naltrexone, and those
disclosed in: PCT Application No. WO 00/21509; (57) 11.beta. HSD-1
(11-beta hydroxy steroid dehydrogenase type 1) inhibitors such as
BVT 3498, BVT 2733, and those disclosed in WO 01/90091, WO
01/90090, WO 01/90092, and U.S. Pat. No. 6,730,690 and US
Publication No. US 2004-0133011, which are incorporated by
reference herein in their entirety; (56) aminorex; (57)
amphechloral; (58) amphetamine; (59) benzphetamine; (60)
chlorphentermine; (61) clobenzorex; (62) cloforex; (63) clominorex;
(64) clortermine; (65) cyclexedrine; (66) dextroamphetamine; (67)
diphemethoxidine, (68) N-ethylamphetamine; (69) fenbutrazate; (70)
fenisorex; (71) fenproporex; (72) fludorex; (73) fluminorex; (74)
furfurylmethylamphetamine; (75) levamfetamine; (76)
levophacetoperane; (77) mefenorex; (78) metamfepramone; (79)
methamphetamine; (80) norpseudoephedrine; (81) pentorex; (82)
phendimetrazine; (83) phenmetrazine; (84) picilorex; (85)
phytopharm 57; (86) zonisamide, (87) neuromedin U and analogs or
derivatives thereof, (88) oxyntomodulin and analogs or derivatives
thereof, (89) Neurokinin-1 receptor antagonists (NK-1 antagonists)
such as the compounds disclosed in: U.S. Pat. Nos. 5,162,339,
5,232,929, 5,242,930, 5,373,003, 5,387,595, 5,459,270, 5,494,926,
5,496,833, and 5,637,699; (90) Qnexa; (91) smoking cessation
agents, such as nicotine agonists, partial nicotine agonists, such
as varenicline, monoamine oxidase inhibitors (MAOIs),
antidepressants such as bupropion, doxepine, and nortriptyline; and
anxiolytic agents such as buspirone or clonidine.
[0069] Specific compounds of use in combination with a compound of
the present invention include: simvastatin, mevastatin, ezetimibe,
atorvastatin, sitagliptin, metformin, sibutramine, orlistat, Qnexa,
topiramate, naltrexone, bupriopion, phentermine, and losartan,
losartan with hydrochlorothiazide. Specific CB1 antagonists/inverse
agonists of use in combination with a compound of the present
invention include: those described in WO03/077847, including:
N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-2-(4-trifluoromethyl-
-2-pyrimidyloxy)-2-methylpropanamide,
N-[3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(5-trifluoromet-
hyl-2-pyridyloxy)-2-methylpropanamide,
N-[3-(4-chlorophenyl)-2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(5-trifluo-
romethyl-2-pyridyloxy)-2-methylpropanamide, and pharmaceutically
acceptable salts thereof; as well as those in WO05/000809, which
includes the following:
3-{1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-3-(3,5-difluorophenyl-
)-2,2-dimethylpropanenitrile,
1-{1-[1-(4-ehlorophenyl)pentyl]azetidin-3-yl}-1-(3,5-difluorophenyl)-2-me-
thylpropan-2-ol.
3-((S)-(4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-hydroxy-2-methyl-
propyl]azetidin-1-yl}methyl)benzonitrile, 3-((S)-(4-chl
orophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidi-
n-1-yl}methyl)benzonitrile,
3-((4-chlorophenyl){3-[1-(3,5-difluorophenyl)-2,2-dimethylpropyl]azetidin-
-1-yl}methyl)benzonitrile,
3-((1S)-1-{1-[(S)-(3-cyanophenyl)(4-cyanophenypmethyl]azetidin-3-yl}-2-fl-
uoro-2-methylpropyl)-5-fluorobenzonitrile,
3-[(S)-(4-chlorophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(4H-1,2,4-triazol--
4-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile, and
5-((4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropy-
l]azetidin-1-yl}methyl)thiophene-3-carbonitrile, and
pharamecueitcally acceptable salts thereof; as well as:
3-[(S)-(4-chlorophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(5-oxo-4,5-dihydro-
-1,3,4-oxadiazol-2-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonit-
rile,
3-[(S)-(4-chlorophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(1,3,4-oxadia-
zol-2-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,
3-[(S)-(3-{(1S)-1-[3-(5-amino-1,3,4-oxadiazol-2-yl)-5-fluorophenyl]-2-flu-
oro-2-methylpropyl}azetidin-1-yl)(4-chlorophenyl)methyl]benzonitrile,
3-[(S)-(4-cyanophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(5-oxo-4,5-dihydro--
1,3,4-oxadiazol-2-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitr-
ile,
3-[(S)-(3-{(1S)-1-[3-(5-amino-1,3,4-oxadiazol-2-yl)-5-fluorophenyl]-2-
-fluoro-2-methylpropyl}azetidin-1-yl)(4-cyanophenyl)methyl]benzonitrile,
3-[(S)-(4-cyanophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(1,3,4-oxadiazol-2--
yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,
3-[(S)-(4-chlorophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(1,2,4-oxadiazol-3-
-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,
3-[(1S)-1-(1-{(S)-(4-cyanophenyl)[3-(1,2,4-oxadiazol-3-yl)phenyl]-methyl}-
azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile,
5-(3-{(1-[1-(diphenylmethyl)azetidin-3-yl]-2-fluoro-2-methylpropyl}-5-flu-
orophenyl)-1H-tetrazole,
5-(3-{1-[1-(diphenylmethyl)azetidin-3-yl]-2-fluoro-2-methylpropyl}-5-fluo-
rophenyl)-1-methyl-1H-tetrazole,
5-(3-{1-[1-(diphenylmethyl)azetidin-3-yl]-2-fluoro-2-methylpropyl}-5-fluo-
rophenyl)-2-methyl-2H-tetrazole,
3-[(4-chlorophenyl)(3-{2-fluoro-1-[3-fluoro-5-(2-methyl-2H-tetrazol-5-yl)-
phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,
3-[(4-chlorophenyl)(3-{2-fluoro-1-[3-fluoro-5-(1-methyl-1H-tetrazol-5-yl)-
phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,
3-[(4-cyanophenyl)(3-{2-fluoro-1-[3-fluoro-5-(1-methyl-1H-tetrazol-5-yl)p-
henyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,
3-[(4-cyanophenyl)(3-{2-fluoro-1-[3-fluoro-5-(2-methyl-2H-tetrazol-5-yl)p-
henyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile ,
5-{3-[(S)-{3-[(1S)-1-(3-bromo-5-fluorophenyl)-2-fluoro-2-methylpropyl]aze-
tidin-1-yl}(4-chlorophenyl)methyl]phenyl}-1,3,4-oxadiazol-2(3H)-one,
3-[(1S)-1-(1-{(S)-(4-chlorophenyl)[3-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-
-yl)phenyl]methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonit-
rile,
3-[(1S)-1-(1-{(S)-(4-cyanophenyl)[3-(5-oxo-4,5-dihydro-1,3,4-oxadiaz-
ol-2-yl)phenyl]methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenz-
onitrile,
3-[(1S)-1-(1-{(S)-(4-cyanophenyl)[3-(1,3,4-oxadiazol-2-yl)phenyl-
]methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile,
3-[(1S)-1-(1-{(S)-(4-chlorophenyl)[3-(1,3,4-oxadiazol-2-yl)phenyl]methyl}-
azetidin-3-yl)-2-fluro-2-methylpropyl]-5-fluorobenzonitrile,
3-(((1S)-1-{1-[(S)-[3-(5-amino-1,3,4-oxadidazol-2-yl)phenyl](4-chlorophen-
yl)methyl]azetidin-3-yl}-2-fluoro-2-methylpropyl)-5-fluorobenzonitrile,
3-((1S)-1-{1-[(S)-[3-(5-amino-1,3,4-oxadiazol-2-yl)phenyl](4-cyanophenyl)-
methyl]azetidin-3-yl}-2-fluoro-2-methylpropyl)-5-fluorobenzonitrile,
3-[(1S)-1-(1-{(S)-(4-cyanophenyl)[3-(1,2,3-oxadiazol-3-yl)phenyl]methyl}a-
zetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile,
3-[(1S)-1-(1-{(S)-(4-chlorophenyl)[3-(1,2,4-oxadiazol-3-yl)phenyl]methyl}-
azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile,
5-[3-((S)-(4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-meth-
ylpropyl]azetidin-1-yl}methyl)phenyl]-1,3,4-oxadiazol-2(3H)-one,
5-[3-((S)-(4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyI)-2-fluoro-2-meth-
ylpropyl]azetidin-1-yl}methyl)phenyl]-1,3,4-oxadiazol-2(3H)-one,
4-{(S)-{3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-
-yl}[3-(5-oxo-4,5-dihydro-1,3
,4-oxadiazol-2-yl)phenyl]methyl}-benzonitrile, and pharmaceutically
acceptable salts thereof.
[0070] Specific NPY5 antagonists of use in combination with a
compound of the present invention include:
3-oxo-N-(5-phenyl-2-pyrazinyl)-spiro[isobenzofiiran-1(3H),4'-piperidine]--
1'-carboxamide,
3-oxo-N-(7-trifluoromethylpyrido[3,2-b]pyridin-2-yl)spiro-[isobenzofuran--
1(3H),4'-piperidine]-1'-carboxamide,
N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro-[isobenzofuran-1(3H),4'-p-
iperidine]-1'-carboxamide,
trans-3'-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[cyclohexane-1,1'(3'H)-isoben-
zofuran]-4-carboxamide,
trans-3'-oxo-N-[1-(3-quinolyl)-4-imidazolyl]spiro[cyclohexane-1,1'(3'H)-i-
sobenzofuran]-4-carboxamide,
trans-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[4-azaiso-benzofuran-1(3H),1'-cy-
clohexane]-4'-carboxamide,
trans-N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran--
1(3H),1'-cyclohexane]-4'-carboxamide,
trans-N-[5-(2-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran--
1(3H),1'-cyclohexane]-4'-carboxamide,
trans-N-[1-(3,5-difluorophenyl)-4-imidazolyl]-3-oxospiro[7-azaisobenzofur-
an-1(3H),1'-cyclohexane]-4'-carboxamide,
trans-3-oxo-N-(1-phenyl-4-pyrazolyl)spiro[4-azaisobenzofuran-1(3H),1'-cyc-
lohexane]-4'-carboxamide,
trans-N-[1-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(-
3H),1'-cyclohexane]-4'-carboxamide,
trans-3-oxo-N-(1-phenyl-3-pyrazolyl)spiro[6-azaisobenzofuran-1(3H),1'-cyc-
lohexane]-4'-carboxamide,
trans-3-oxo-N-(2-phenyl-1,2,3-triazol-4-yl)spiro[6-azaisobenzofuran-1'(3H-
),1'-cyclohexane]-4'-carboxamide, and pharmaceutically acceptable
salts and esters thereof.
[0071] Specific ACC-1/2 inhibitors of use in combination with a
compound of the present invention include:
1'-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-6-(1H-tetrazol-5-yl)spiro[chrom-
an-2,4'-piperidin]-4-one;
(5-{1'-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-4-oxospiro[chroman-2,4'-pip-
eridin]-6-yl}-2H-tetrazol-2-yl)methyl pivalate;
5-{1'-[(8-cyclopropyl-4-methoxyquinolin-2-yl)carbonyl]-4-oxospiro[chroman-
-2,4'-piperidin]-6-yl}nicotinic acid;
1'-(8-methoxy-4-morpholin-4-yl-2-naphthoyl)-6-(1H-tetrazol-5-yl)spiro[chr-
oman-2,4'-piperidin]-4-one; and
1'-[(4-ethoxy-8-ethylquinolin-2-yl)carbonyl]-6-(1H-tetrazol-5-yl)spiro[ch-
roman-2,4'-piperidin]-4-one; and pharmaceutically acceptable salts
and esters thereof. Specific MCHIR antagonist compounds of use in
combination with a compound of the persent invention include:
1-{4-[(1-ethylazetidin-3-yl)oxy]phenyl}-4-[(4-fluorobenzyl)oxy]pyridin-2(-
1H)-one,
4-[(4-fluorobenzyl)oxy]-1-{4-[(1-isopropylazetidin-3-yl)oxy]pheny-
l}pyridin-2(1H)-one,
1-[4-(azetidin-3-yloxy)phenyl]-4-[(5-chloropyridin-2-yl)methoxy]pyridin-2-
(1H)-one,
4-[(5-chloropyridin-2-yl)methoxy]-1-{4-[(1-ethylazetidin-3-yl)ox-
y]phenyl}pyridin-2(1H)-one,
4-[(5-chloropyridin-2-yl)methoxy]-1-{4-[(1-propylazetidin-3-yl)oxy]phenyl-
}pyridin-2(1H)-one, and
4-[(5-chloropyridin-2-yl)methoxy]-1-(4-{[(2S)-1-ethylazetidin-2-yl]methox-
y}phenyl)pyridin-2(1H)-one, or a pharmaceutically acceptable salt
thereof.
[0072] Specific DP-IV inhibitors of use in combination with a
compound of the present invention are selected from
7-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(trifluoromethyl)-5,-
6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine. In particular, the
compound of formula I is favorably combined with
7-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(trifluoromethyl)-5,-
6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine, and
pharmaceutically acceptable salts thereof.
[0073] Specific 113 (histamine H3) antagonists/inverse agonists of
use in combination with a compound of the present invention
include: those described in WO05/077905,
including:3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-ethylpyrido[2,3-
-d]-pyrimidin-4(3H)-one,
3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[4,3-d]pyrimi-
din-4(3H)-one,
2-ethyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyrido[2,3-d]-
pyrimidin-4(3H)-one
2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyrido[4,3-d-
]pyrimidin-4(3H)-one,
3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2,5-dimethyl-4(3H)-quinazol-
ine,
3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methyl-5-trifluoromet-
hyl-4(3H)-quinazoline,
3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-5-methoxy-2-methyl-4(3H)-qu-
inazolinone,
3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-5-fluoro-2-methyl-4(3H)-qui-
nazolinone,
3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-7-fluoro-2-methyl-4(3H)-qui-
nazolinone,
3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-6-methoxy-2-methyl-4(3H)-qu-
inazolinone,
3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-6-fluoro-2-methyl-4(3H)-qui-
nazolinone,
3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-8-fluoro-2-methyl-4(3H)-qui-
nazolinone,
3-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[4,3-d]pyrim-
idin-4(3H)-one,
3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-6-fluoro-2-methylpyrido[3,4-
-d]pyrimidin-4(3H)-one,
3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-ethylpyrido[4,3-d]pyrimid-
in-4(3H)-one,
6-methoxy-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}pyrido[3,4-d]pyr-
imidin-4(3H)-one,
6-methoxy-2-methyl-3-{4-[3-(1-pyrrolidinyppropoxy]phenyl}pyrido[3,4-d]pyr-
imidin-4(3H)-one,
2,5-dimethyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone,
2-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-5-trifluoromethyl-4(3H)--
quinazolinone,
5-fluoro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolin-
one,
6-methoxy-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quina-
zolinone,
5-methoxy-2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}-
phenyl)-4(3H)-quinazolinone, 7-methoxy-2-methyl-3-(4-{3-[(3
S)-3-methylpiperidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,
2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyrido[2,3-d-
]pyrimidin-4(3H)-one,
5-fluoro-2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4-
(3H)-quinazolinone,
2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)pyrido[4,3--
d]pyrimidin-4(3H)-one,
6-methoxy-2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)--
4(3H)-quinazolinone,
6-methoxy-2-methyl-3-(4-{3-[(2S)-2-methylpyrrolidin-1-yl]propoxy}phenyl)--
4(3H)-quinazolinone, and pharmaceutically acceptable salts
thereof.
[0074] Specific CCK1R agonists of use in combination with a
compound of the present invention include:
3-(4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H
-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoic acid;
3-(4-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]ca-
rbonyl}-1-piperazinyl)-1-naphthoic acid;
3-(4-{[1-(3-ethoxyphenyl)-2-(4-fluorophenyl)-1H
-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoic acid;
3-(4-{[1-(3-ethoxyphenyl)-2-(2,4-difluorophenyl)-1H
-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoic acid; and
3-(4-{[1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-fluorophenyl)-1H-imidazo-
l-4-yl]carbonyl1-1-piperazinyl)-1-naphthoic acid; and
pharmaceutically acceptable salts thereof.
[0075] Specific MC4R agonists of use in combination with a compound
of the present invention include: 1)
(5S)-1'-{[(3R,4R)-1-tert-butyl-3-(2,3,4-trifluorophenyl)piperidin-4-yl]ca-
rbonyl}-3-chloro-2-methyl-5-[1-methyl-1-(1-methyl-1H-1,2,4-triazol-5-yl)et-
hyl]-5H-spiro[furo[3,4-b]pyridine-7,4'-piperidine]; 2)
(5R)-1'-{[(3R,4R)-1-tert-butyl-3-(2,3,4-trifluorophenyl)-piperidin-4-yl]c-
arbonyl}-3-chloro-2-methyl-5-[1-methyl-1-(1-methyl-1H-1,2,4-triazol-5-yl)e-
thyl]-5H-spiro[furo[3,4-b]pyridine-7,4'-piperidine];
3)2-(1'-{[3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl]carbo-
nyl}-3-chloro-2-methyl-5H-spiro[furo[3,4-b]pyridine-7,4'-piperidin]-5-yl)--
2-methylpropanenitrile; 4)
1'-{[(3,5,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl]carbonyl-
}-3-chloro-2-methyl-5-[1-methyl-1-(1-methyl-1H-1,2,4-triazol-5-yl)ethyl]-5-
H-spiro[furo[3,4-b]pyridine-7,4'-piperidine]; 5)
N-[(3R,4R)-3-({3-chloro-2-methyl-5-[1-methyl-1-(1-methyl-1H-1,2,4-triazol-
-5-yl)ethyl]-1'H,5H-spiro[furo-[3,4-b]pyridine-7,4'-piperidin]-1'-yl}carbo-
nyl)-4-(2,4-difluorophenyl)-cyclopentyl]-N-methyltetrahydro-2H-pyran-4-ami-
ne; 6)
2-[3-chloro-1'-({(1R,2R)-2-(2,4-difluorophenyl)-4-[methyl(tetrahydr-
o-2H-pyran-4-yl)amino]-cyclopentyl}-carbonyl}-2-methyl-5H-spiro[furo[3,4-b
pyridine-7,4'-piperidin]-5-yl]-2-methyl-propane-nitrile; and
pharmaceutically acceptable salts thereof. Still further,
neurokinin-1 (NK-1) receptor antagonists may be favorably employed
in combination with a compound of the present invention. NK-1
receptor antagonists of use in the present invention are fully
described in the art. Specific neurokinin-1 receptor antagonists of
use in the present invention include:
(.+-.)-(2R3R,2S3S)-N-{[2-cyclopropoxy-5-(trifluoromethoxy)-pheny-
l]methyl}-2-phenylpiperidin-3-amine ;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoropheny-
l)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine; aperpitant;
C.117493; GW597599; GW679769; R673; RO67319; R1124; R1204;
SSR146977; SSR240600; T-2328; and T2763.; or a pharmaceutically
acceptable salts thereof. Examples of other anti-obesity agents
that can be employed in combination with a compound of formula I
are disclosed in "Patent focus on new anti-obesity agents," Exp.
Opin. Ther. Patents, 10: 819-831 (2000); "Novel anti-obesity
drugs," Exp. Opin. Invest. Drugs, 9: 1317-1326 (2000); and "Recent
advances in feeding suppressing agents: potential therapeutic
strategy for the treatment of obesity, Exp. Opin. Ther. Patents,
11: 1677-1692 (2001). The role of neuropeptide Y in obesity is
discussed in Exp. Opin. Invest. Drugs, 9: 1327-1346 (2000).
Cannabinoid receptor ligands are discussed in Exp. Opin. Invest.
Drugs, 9: 1553-1571 (2000).
[0076] 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 therapeutically effective
amounts of a compound of formula I as described above and an
HMG-CoA reductase inhibitor.
[0077] 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
therapeutically effective amounts of a compound of formula I as
described above and an HMG-CoA reductase inhibitor wherein the
HMG-CoA reductase inhibitor is a statin. Even 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 therapeutically effective amounts of a
compound of formula I as described above and an HMG-CoA reductase
inhibitor, wherein the HMG CoA reductase inhibitor is a statin
selected from the group consisting of lovastatin, simvastatin,
pravastatin, fluvastatin, atorvastatin, itavastatin, rosuvastatin
and rivastatin.
[0078] 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 hypercholesterolemia, atherosclerosis,
low HDL levels, high LDL levels, hyperlipidemia,
hypertriglyceridemia and dyslipidemia, and the sequelae of such
conditions, delaying the onset or reducing the risk of developing
said condition, comprising administering to a mammalian patient in
need of such treatment therapeutically effective amounts of a
compound of formula I as described above and an HMG-CoA reductase
inhibitor.
[0079] More particularly, another aspect of the invention that is
of interest relates to a method for delaying the onset of, or
reducing the risk of developing atherosclerosis in a human patient
in need of such treatment comprising administering to said patient
effective amounts of a compound of formula I as described above and
an HMG-CoA reductase inhibitor wherein the HMG-CoA reductase
inhibitor is a statin, and even more particularly, a statin
selected from the group consisting of: lovastatin, simvastatin,
pravastatin, fluvastatin, atorvastatin, itavastatin, rosuvastatin
and rivastatin.
[0080] Yet even more particularly, another aspect of the invention
that is of interest relates to a method for delaying the onset or
reducing the risk of developing atherosclerosis in a human patient
in need of such treatment comprising administering to said patient
effective amounts of a compound of foiinula I as described above
and an HMG-CoA reductase inhibitor wherein the HMG-CoA reductase
inhibitor is simvastatin, atorvastatin or rosuvastatin.
[0081] Another aspect of the invention that is of interest relates
to a method for delaying the onset or reducing the risk of
developing atherosclerosis in a human patient in need of such
treatment comprising administering to said patient effective
amounts of a compound of formula as described above and a
cholesterol absorption inhibitor. More particularly, another aspect
of the invention that is of interest relates to a method for
delaying the onset or reducing the risk of developing
atherosclerosis in a human patient in need of such treatment
comprising administering to said patient effective amounts of a
compound of formula I as described above and a cholesterol
absorption inhibitor wherein the cholesterol absorption inhibitor
is ezetimibe.
[0082] Another aspect of the invention that is of interest relates
to a method for delaying the onset or reducing the risk of
developing the other diseases and conditions mentioned above, in a
mammalian patient in need of such treatment comprising
administering to said patient effective amounts of a compound of
formula I as described above, and a cholesterol absorption
inhibitor.
[0083] More particularly, another aspect of the invention that is
of interest relates to a method for delaying the onset or reducing
the risk of developing the other diseases and conditions mentioned
above, in a human patient in need of such treatment comprising
administering to said patient effective amounts of a compound of
formula I as described above, and a cholesterol absorption
inhibitor, wherein the cholesterol absorption inhibitor is
ezetimibe.
[0084] Another aspect of the invention that is of interest relates
to a method of treating, delaying the onset, or preventing 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 therapeutically effective amounts of a
compound of formula I or a pharmaceutically acceptable salt or
solvate thereof, and a CETP inhibiting. compound.
[0085] More particularly, an aspect of the invention that is of
interest relates to a method of treating, delaying the onset, or
preventing 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 therapeutically effective amounts of a
compound of formula I or a pharmaceutically acceptable salt or
solvate thereof, and a CETP inhibiting compound selected from
torcetrapib and anacetrapib.
[0086] Another aspect of the invention that is of interest relates
to a pharmaceutical composition comprising (1) a compound of
formula I as described above; (2) a compound selected from the list
provide above in combination with a pharmaceutically acceptable
carrier.
[0087] One pharmaceutical composition that is of interest is
comprised of a compound of formula I as described herein, or a
pharmaceutically acceptable salt or solvate thereof, in combination
with a DPP-IV inhibitor selected from the group consisting of:
##STR00006##
or a pharmaceutically acceptable salt or solvate thereof in
combination with a pharmaceutically acceptable carrier.
Optical Isomers--Diastereomers--Geometric Isomers--Tautomers
[0088] Many of the compounds of formula I contain one or more
asymmetric centers and thus occur as racemates and racemic
mixtures, single enantiomers, diastereomeric mixtures and
individual diastereomers. The present invention includes all such
isomeric forms of the compounds, in pure form as well as in
mixtures.
[0089] Some of the compounds described herein contain olefinic
double bonds, and unless specified otherwise, are meant to include
both E and Z geometric isomers.
[0090] Some of the compounds described herein may exist with
different points of attachment of hydrogen, referred to as
tautomers. Such an example may be a ketone and its enol form known
as keto-enol tautomers. The individual tautomers as well as
mixtures thereof are encompassed with the compounds of Formula
I.
Salts and Solvates
[0091] Salts and solvates of compounds of formula I are included in
the present invention. The term "pharmaceutically acceptable salts"
refers to salts prepared from pharmaceutically acceptable
substantially non-toxic bases or acids including inorganic or
organic bases and inorganic or organic acids, as well as salts that
can be converted into pharmaceutically acceptable salts. Salts
derived from inorganic bases include aluminum, ammonium, calcium,
copper, ferric, ferrous, lithium, magnesium, manganic salts,
manganous, potassium, sodium, zinc, and the like. Particularly
preferred are the ammonium, calcium, magnesium, potassium, and
sodium salts. Salts derived from pharmaceutically acceptable
organic non-toxic bases include salts of primary, secondary, and
tertiary amines, substituted amines including naturally occurring
substituted amines, cyclic amines, and basic ion exchange resins,
such as arginine, betaine, caffeine, choline,
NN-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,
2-dimethylaminoethanol, ethanolamine, ethylenediamine,
N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine,
histidine, hydrabamine, isopropylamine, lysine, methylglucamine,
morpholine, piperazine, piperidine, polyamine resins, procaine,
purines, theobromine, triethylamine, trimethylamine,
tripropylamine, tromethamine and the like.
[0092] When the compound of the present invention is basic, salts
may be prepared from pharmaceutically acceptable non-toxic acids,
including inorganic and organic acids. Such acids include acetic,
benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonie,
fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic,
lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric,
pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,
p-toluenesulfonic acid, and the like. Particularly preferred are
citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric,
and tartaric acids.
[0093] Solvates as used herein refers to the compound of formula I
or a salt thereof, in association with a solvent, such as water.
Representative examples include hydrates, hemihydrates, trihydrates
and the like.
[0094] References to the compounds of Formula I are intended to
include the pharmaceutically acceptable salts and solvates.
[0095] In the compounds described herein, the atoms may exhibit
their natural isotopic abundances, or one or more of the atoms may
be artificially enriched in a particular isotope having the same
atomic number, but an atomic mass or mass number different from the
atomic mass or mass number predominantly found in nature. The
present invention is meant to include all suitable isotopic
variations of the compounds of the formulas described herein. For
example, different isotopic forms of hydrogen (H) include protium
(.sup.1H) and deuterium (.sup.2H). Protium is the predominant
hydrogen isotope found in nature. Enriching for deuterium may
afford certain therapeutic advantages, such as increasing in vivo
half-life or reducing dosage requirements, or may provide a
compound useful as a standard for characterization of biological
samples. Isotopically-enriched compounds within the formulas
described herein can be prepared without undue experimentation by
conventional techniques well known to those skilled in the art or
by processes analogous to those described in the Schemes and
Examples herein using appropriate isotopically-enriched reagents
and/or intermediates.
[0096] This invention relates to a method of inhibiting the
activity of glucagon by antagonizing the glucagon receptor, thereby
reducing the rate of gluconeogenesis and glycogenolysis, and the
concentration of glucose in plasma.
[0097] The compounds of formula I can be used in the manufacture of
a medicament for the prophylactic or therapeutic treatment of
disease states in mammals associated with elevated levels of
glucose, comprised of combining the compound of formula I with the
carrier materials to provide the medicament.
Dose Ranges
[0098] The prophylactic or therapeutic dose of a compound of
formula I will, of course, vary with the nature or severity of the
condition to be treated, the particular compound selected and its
route of administration. It will also vary according to the age,
weight and response of the individual patient. In general, the
daily dose range lies within the range of from about 0.001 mg to
about 100 mg per kg body weight, preferably about 0.01 mg to about
50 mg per kg, and more preferably 0.1 to 10 mg per kg, in single or
divided doses. It may be necessary to use dosages outside of these
limits in some cases. The terms "effective amount", "anti-diabetic
effective amount" and the other terms appearing throughout the
application addressing the amount of the compound to be used refer
to the dosage ranges provided, taking into account any necessary
variation outside of these ranges, as deteimined by the skilled
physician.
[0099] Representative dosages of compounds of formula I, as well as
the pharmaceutically acceptable salts and solvates thereof, for
adults range from about 0.1 mg to about 1.0 g per day, preferably
about 1 mg to about 500 mg, in single or divided doses. Examples of
suitable dosages include 0.1mg, 1 mg, 2 mg, 5 mg, 10 mg, 20 mg, 40
mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 500 mg, 1000 mg
and similar such doses.
[0100] Representative dosages of compounds used in combination with
the compounds of formula I are known, or the determination thereof
is within the level of skill in the art, taking into account the
description provided herein.
[0101] When intravenous or oral administration is employed, a
representative dosage range is from about 0.001 mg to about 100 mg
(preferably from 0.01 mg to about 10 mg) of a compound of Formula I
per kg of body weight per day, and more preferably, about 0.1 mg to
about 10 mg of a compound of formula I per kg of body weight per
day.
Phaimaceutical Compositions
[0102] As mentioned above, the pharmaceutical composition comprises
a compound of Formula I or a pharmaceutically acceptable salt or
solvate thereof and a pharmaceutically acceptable carrier. The term
"composition" encompasses a product comprising the active and inert
ingredient(s), (pharmaceutically acceptable excipients) that make
up the carrier, as well as any product which results, directly or
indirectly, from the combination, complexation or aggregation of
any two or more of the ingredients, or from dissociation of one or
more of the ingredients, or from other types of reactions or
interactions between ingredients. Preferably the composition is
comprised of a compound of formula I in an amount that is effective
to treat, prevent or delay the onset of type 2 diabetes mellitus,
in combination with the pharmaceutically acceptable carrier.
[0103] Any suitable route of administration may be employed for
providing a mammal, especially a human, with an effective dosage of
a compound of the present invention. For example, oral, rectal,
topical, parenteral, ocular, pulmonary, nasal, and the like may be
employed. Examples of dosage forms include tablets, troches,
dispersions, suspensions, solutions, capsules, creams, ointments,
aerosols and the like, with oral tablets being preferred.
[0104] In preparing oral compositions, 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 liquids, e.g.,
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 solids, e.g., powders, capsules and tablets. Solid oral
preparations are preferred. Because of their ease of
administration, tablets and capsules represent the most
advantageous oral dosage unit forms. If desired, tablets may be
coated by standard aqueous or nonaqueous techniques.
[0105] In addition to the common dosage forms set out above, the
compounds of Formula I may also be administered by controlled
release means and/or delivery devices such as those described in
U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123;
3,630,200 and 4,008,719.
[0106] Pharmaceutical compositions of the present invention
suitable for oral administration may be presented as discrete units
such as capsules, cachets or tablets each containing a
predetermined amount of the active ingredient, as a powder or
granules or as a solution or a suspension in an aqueous liquid, a
non-aqueous liquid, an oil-in-water emulsion or a water-in-oil
liquid emulsion. Such compositions may be prepared by any
acceptable pharmaceutical process. All such methods include the
step of combining the active ingredient(s) with the carrier
components. In general, the compositions are prepared by uniformly
and intimately admixing the active ingredient(s) with a liquid or
finely divided solid carrier component, and then, if necessary,
manipulating the blend into the desired product form. For example,
a tablet may be prepared by compression or molding. Compressed
tablets may be prepared by compressing free-flowing powder or
granules, containing the active(s) optionally mixed with one or
more excipients, e.g., binders, lubricants, diluents, surfactants
and dispersants. Molded tablets may be made by molding a mixture of
the powdered compound moistened with an inert liquid. Desirably,
each tablet may contain, for example, from about 0.1 mg to about
1.0 g of the active ingredient and each cachet or capsule contains
from about 0.1 mg to about 500 mg of the active ingredient.
[0107] The following are examples of pharmaceutical dosage forms
containing a compound of Formula I:
TABLE-US-00001 Injectable Suspension (im.) mg/mL Tablet Mg/tablet
Compound of 10.0 Compound of Formula 1 25.0 Formula 1
Methylcellulose 5.0 Microcrystalline 415 Cellulose Tween 80 0.5
Povidone 14.0 Benzyl alcohol 9.0 Pregelatinized Starch 4.0
Benzalkonium 1.0 Magnesium Stearate 2.5 chloride Water for
injection t.d. 1.0 mL Total (approx.) 460 mg
TABLE-US-00002 Capsule mg/cagsule Aerosol Per Canister Compound of
25.0 Compound of Formula 1 250 mg Formula 1 Lactose 735 Lecithin,
NF Liq. Conc. 1.2 mg Mg Stearate 1.5 Trichloromethane, NF 4.025 g
Total (approx.) 761.5 mg Dichlorodifluoro- 12.15 g methane, NF
Combination Therapy
[0108] As previously described, the compounds of Formula I may be
used in combination with other drugs that are used in the
treatment/prevention/delaying the onset of type 2 diabetes
mellitus, as well as other diseases and conditions described
herein, for which compounds of Formula I are useful. Other drugs
may be administered, by a route and in an amount commonly used,
contemporaneously or sequentially with a compound of Formula I.
When a compound of Formula I is used contemporaneously with one or
more other drugs, a combination pharmaceutical composition
containing such other drugs in addition to the compound of Formula
I is preferred. Accordingly, the pharmaceutical compositions of the
present invention include those that alternatively contain one or
more other active ingredients, in addition to a compound of Formula
I. Examples of other active ingredients that may be combined with a
compound of Formula I, either administered separately or in the
same pharmaceutical compositions, include, but are not limited to:
(a) biguanides (e g., buformin, metformin, phenformin), (b) PPAR
agonists (e.g., troglitazone, pioglitazone, rosiglitazone), (c)
insulin, (d) somatostatin, (e) alpha-glucosidase inhibitors (e.g.,
voglibose, miglitol, acarbose), (f) DPP-IV inhibitors, such as
sitagliptin, vildagliptin, saxagliptin, and the like, such as those
disclosed in U.S. Pat. No. 6,699,871B1 granted on Mar. 2, 2004 (g)
LXR modulators and (h) insulin secretagogues (e.g., acetohexamide,
carbutamide, chlorpropamide, glibomuride, gliclazide, glimerpiride,
glipizide, gliquidine, glisoxepid, glyburide, glyhexamide,
glypinamide, phenbutamide, tolazamide, tolbutamide, tolcyclamide,
nateglinide and repaglinide), and CBI inhibitors, such as
rimonabant and those compounds disclosed in WO03/077847A2 published
on Sep. 25, 2003 and in WO05/000809 A1 published on Jan. 6,
2005.
[0109] An aspect of the invention that is particular interest
relates to a pharmaceutical composition that is comprised of a
compound of formula 1, or a pharmaceutically acceptable salt
thereof, and a member selected from the group consisting of:
simvastatin, mevastatin, ezetimibe, atorvastatin, metformin,
sibutramine, orlistat, Qnexa, topiramate, naltrexone, bupriopion,
phentermine, losartan, hydrochlorothiazide, buformin, phenformin,
troglitazone, pioglitazone, rosiglitazone, insulin, somatostatin,
voglibose, miglitol, acarbose, sitagliptin, vildagliptin,
saxagliptin, alogliptin, acetohexamide, carbutamide,
chlorpropamide, glibomuride, gliclazide, glimerpiride, glipizide,
gliquidine, glisoxepid, glyburide, glyhexamide, glypinamide,
phenbutamide, tolazamide, tolbutamide, tolcyclamide, nateglinide
and repaglinide, rimonabant and taranabant, in combination with a
pharmaceutically acceptable carrier.
[0110] The weight ratio of the compound of the Formula I to the
second active ingredient may be varied within wide limits and
depends upon the effective dose of each active ingredient.
Generally, an effective dose of each will be used. Thus, for
example, when a compound of the Formula I is combined with a PPAR
agonist the weight ratio of the compound of the Formula I to the
PPAR agonist will generally range from about 1000:1 to about
1:1000, preferably about 200:1 to about 1:200. Combinations of a
compound of the Formula I and other active ingredients will
generally also be within the aforementioned range, but in each
case, an effective dose of each active ingredient should be
used.
[0111] When used in combination with other agents, the dosages
noted above for the glucagon antagonist are provided along with the
usual dose for the other medication. For example, when a DPP-IV
inhibitor such as those disclosed in U.S. Pat. No. 6,699,871B1, is
included, the DPP-IV inhibitor can be used in an amount ranging
from about 1.0 mg to as high as about 1000mg, preferably about 2.5
mg to about 250 mg, and in particular, about 50 mg or about 100 mg
administered in single daily doses or in divided doses as
appropriate. Similarly, when the glucagon receptor antagonist is
used in combination with a CB1 antagonist/inverse agonist, the CB1
antagonist/inverse agonist can be used in an amount ranging from as
low as about 0.1 mg to as high as about 1000 mg, more particularly,
in an amout ranging from about 1.0 mg to about 100 mg, and even
more particularly, in an amount from about 1.0 mg to about 10 mg,
administered in single daily doses or in divided doses as
appropriate. Examples of doses of CB1 antagonist/inverse agonist
include ling, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg
and 20 mg.
Methods of Synthesis:
[0112] Compounds of the present invention can be prepared according
to the Schemes provided below as well as the procedures provided in
the Examples. The substituents are the same as in the above
Formulas except where defined otherwise or otherwise apparent to
the ordinary skilled artisan.
[0113] The novel compounds of the present invention can be readily
synthesized using techniques known to those skilled in the art,
such as those described, for example, in Advanced Organic
Chemistry, March, 5.sup.th Ed., John Wiley and Sons, New York,
N.Y., 2001; Advanced Organic Chemistry, Carey and Sundberg, Vol. A
and B, 3.sup.rd Ed., Plenum Press, Inc., New York, N.Y., 1990;
Protective groups in Organic Synthesis, Green and Wuts, 2.sup.nd
Ed., John Wiley and Sons, New York, N.Y., 1991; Comprehensive
Organic Transformations, Larock, Val Publishers, Inc., New York,
N.Y., 1988; Handbook of Heterocyclic Chemistry, Katritzky and
Pozharskii, 2.sup.nd Ed., Pergamon, New York, N.Y., 2000 and
references cited therein. The starting materials for the present
compounds may be prepared using standard synthetic transformations
of chemical precursors that are readily available from commercial
sources, including Aldrich Chemical Co. (Milwaukee, Wis.); Sigma
Chemical Co. (St. Louis, Mo.); Lancaster Synthesis (Windham, N.H.);
Ryan Scientific (Columbia, S.C.); Maybridge (Cornwall, UK); Matrix
Scientific (Columbia, S. C.); Acros, (Pittsburgh, Pa.); BioBlocks,
Inc. (San Diego, Calif.); and Trans World Chemicals (Rockville,
Md.).
[0114] The procedures described herein for synthesizing the
compounds may include one or more steps of protecting group
manipulations and of purification, such as, re-crystallization,
distillation, column chromatography, flash chromatography,
thin-layer chromatography (TLC), and high-pressure chromatography
(HPLC). The products can be characterized using various techniques
well known in the chemical arts, including proton and carbon-13
nuclear magnetic resonance (.sup.1H and .sup.13C NMR), infrared and
ultraviolet spectroscopy OR and UV), X-ray crystallography,
elemental analysis and HPLC and mass spectrometry (HPLC-MS).
Methods of protecting group manipulation, purification, structure
identification and quantification are well known to one skilled in
the art of chemical synthesis.
[0115] Appropriate solvents are those which will at least partially
dissolve one or all of the reactants and will not adversely
interact with either the reactants or the product. Suitable
solvents are aromatic hydrocarbons (e.g, toluene, xylenes),
halogenated solvents (e.g, methylene chloride, chloroform,
carbontetrachloride, chlorobenzenes), ethers (e.g, diethyl ether,
diisopropylether, tert-butyl methyl ether, diglyme,
tetrahydrofuran, dioxane, anisole), nitriles (e.g, acetonitrile,
propionitrile), ketones (e.g, 2-butanone, dithyl ketone, Cert-butyl
methyl ketone), alcohols (e.g, methanol, ethanol, n-propanol,
iso-propanol, n-butanol, t-butanol), N,N-dimethyl formamide (DMF),
dimethylsulfoxide (DMSO) and water, Mixtures of two or more
solvents can also be used. Suitable bases are, generally, alkali
metal hydroxides, alkaline earth metal hydroxides such as lithium
hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide,
and calcium hydroxide; alkali metal hydrides and alkaline earth
metal hydrides such as lithium hydride, sodium hydride, potassium
hydride and calcium hydride; alkali metal amides such as lithium
amide, sodium amide and potassium amide; alkali metal carbonates
and alkaline earth metal carbonates such as lithium carbonate,
sodium carbonate, cesium carbonate, sodium hydrogen carbonate, and
cesium hydrogen carbonate; alkali metal alkoxides and alkaline
earth metal alkoxides such as sodium methoxide, sodium ethoxide,
potassium tert-butoxide and magnesium ethoxide; alkali metal alkyls
such as methyllithium, n-butyllithium, sec-butyllithium,
t-bultyllithium, phenyllithium, alkyl magnaesium halides, organic
bases such as trimethylamine, triethylamine, triisopropylamine,
N,N-diisopropylethyl amine, piperidine, N-methyl piperidine,
morpholine, N-methyl morpholine, pyridine, collidines, lutidines,
and 4-dimethylaminopyridine; and bicyclic amines such as DBU and
DABCO.
[0116] It is understood that the functional groups present in
compounds described in the Schemes below can be further
manipulated, when appropriate, using the standard functional group
transformation techniques available to those skilled in the art, to
provide desired compounds described in this invention.
[0117] Throughout the synthesis schemes, abbreviations are used
with the following meanings unless otherwise indicated:
TABLE-US-00003 AIBN = azobisisobutyronitrile aq = aqueous BINAP =
2,2'-bis(diphenylphosphino)- Bn = benzyl 1,1'-binaphthalene BOC,
Boc = t-butyloxycarbonyl BOP = benzotriazol-1-yloxy-
tris(dimethylamino)-phosphonium hexafluorophosphate Bu = butyl,
t-Bu = t-butyl BuLi, n-BuLi = n-butyllithium CBZ, Cbz =
Benzyloxycarbonyl CDI = 1,1'-carbonyldiimidazole (S)-DAIPEN =
(S)-1,1-di(4-anisyl)-2- dba = dibenzylideneacetone = trans,trans-
isopropyl-1,2-ethylenediamine = (S)-1,1-
1,5-diphenyl-1,4-pentadien-3-one
bis(4-methoxyphenyl)-3-methylbutane- 1,2-diamine DCM =
dichloromethane 2,4-diClPh = 2,4-dichlorophenyl DIEA =
diisopropylethylamine DMAP = 4-Dimethylaminopyridine DMF =
N,N-dimethylformamide DMS = dimethyl sulfide DMSO = dimethyl
sulfoxide dppf = 1,1'-bis(diphenylphosphino)ferrocene EDC =
1-ethyl-3-(3- eq. = equivalent(s) dimethylaminopropyl)-carbodiimide
Et = ethyl EtOAc = ethyl acetate EtOH = ethanol g = gram(s) HOBT,
HOBt = 1-hydroxybenzotriazole HPLC = High pressure liquid
chromatography IPA = isopropanol = 2-propanol iPr = isopropyl =
2-propyl KHMDS = potassium KOtBu = potassium tert-butoxide
bis(trimethylsilyl)amide LC/MS = liquid chromatography - mass LDA =
lithium diisopropylamide spectrometry LHMDS = lithium M = molar
bis(trimethylsilyl)amide mCPBA = 3-chloroperoxybenzoic acid Me =
methyl MeCN, CH.sub.3CN = acetonitrile MeOH = methanol mg =
milligram(s) mL = milliliter(s) mmol = millimole(s) N = normal
NaOtBu = sodium tert-butoxide NBS = N-bromosuccinimide NCS =
N-chlorosuccinimide n-Pr = n-propyl PCC = pyridinium chlorochromate
Pd/C = palladium on activated carbon Ph = phenyl PyBOP =
Benzotriazol-1- yloxytripyrrolidinophosphonium hexafluorophosphate
RT, rt = room temperature TBAF = tetrabutylammonium fluoride Tf =
triflate = trifluoromethanesulfonate TFA = Trifluoroacetic acid THF
= tetrahydrofuran TMS = trimethylsilyl Tr = trityl =
triphenylmethyl (S)-xyl-SEGPHOS = (S)-5,5'-Bis[di(3,5-
xylyl)phosphino]-4,4'-bi-1,3-benzodioxole
[0118] Compounds of the present invention may be prepared according
to the methodology outlined in the following general synthetic
schemes.
[0119] Multiple embodiments of the present invention are summarized
in Scheme 1 which depicts the preparation of compounds Ia, Ib, and
Ic from the acid 1. It is noted that the benzothiophene can be
substituted with R.sup.3 at any available point of attachment.
Moreover, the benzothiophene can be attached to the remainder of
the molecule at position 2 or 3. The carboxylic acid intermediate I
is coupled with substituted or unsubstituted beta alanine ester
(either methyl, ethyl or t-butyl ester) using
benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium
hexafluorophosphate (BOP) and a base, generally
N,N-diisopropylethylamine (DIEA), in a solvent such as
N,N-dimethylformamide (DMF) or acetonitrile at ambient temperature
to yield compound 2. Alternatively, the conversion of 1 to 2 may be
carried out with EDC, HOBt, and a base such as DIEA in similar
solvents as those used with BOP and DIEA. Many additional peptide
coupling conditions are known and may also be used. Saponification
of ester 2 (methyl, ethyl) to give compound Ia is achieved with a
base such as aqueous lithium hydroxide (LiOH) or aqueous sodium
hydroxide in a polar solvent such as tetrahydrofuran, methanol,
ethanol or a mixture of similar solvents. In addition, compound 2,
containing a t-butyl ester, can be converted to compound Ia using
acid such as acetic acid or trifluoroacetic acid (TFA). In
additional embodiments of the invention, compounds Ib and Ic may be
prepared directly from acid 1 by coupling with the appropriately
substituted amine using the peptide coupling methods described for
the preparation of amide 2.
##STR00007##
[0120] Scheme 2 summarizes the preparation of acid intermediate 1
using procedures adapted from Organic Letters, Chung, et. al.,
2008, 10, 3037-3040. Coupling of aryl alkyl ketones 3 and aryl
bromide 4 may be achieved under transition-metal mediated
conditions such as those described in J. Am. Chem. Soc., Buchwald,
S. L., et. al., 2000, 122, 1360-1370. Ketone 5 may be prepared, for
instance, by heating 3 and 4 in the presence of a palladium source
such as Pd.sub.2(dba).sub.3, a ligand such as BINAP, a base such as
NaOtBu, and a solvent such as THF. Reduction of ketone 5 to alcohol
6 can be accomplished with various achiral reductants, for instance
NaBH.sub.4. Alternatively, dynamic kinetic resolution of ketone 5
can afford highly enantio- and diastereoenriched alcohol 6 using
catalysts such as those reviewed extensively in Angew. Chem., Int.
Ed., Noyori, R., et. al., 2001, 40, 40-73. For instance, this
reaction can be performed using a ruthenium catalyst such as
RuCl.sub.2[(S)-xyl-SEGPHOS][(S)-DAIPEN] and a base such as KOtBu in
a solvent such as 2-propanol under an atmosphere of hydrogen.
[0121] Deprotection of the t-butyl ester of alcohol 6 with an acid
such as phosphoric acid in acetonitrile solvent gives the acid
7.
[0122] Acid 1 may then be accessed by treatment of 7 with a
benzothiophene 8 in dichloromethane solvent at ambient temperature
or 60.degree. C. followed by the addition of a Bronsted acid such
as trifluoroacetic acid (TFA) or a Lewis acid such as boron
trifluoride-diethyl etherate. A wide range of substituents may be
introduced at R.sup.1, R.sup.2, and R.sup.3 on acid 1 due to the
functional group tolerance of the reactions employed in its
preparation and the wide variety of starting benzothiophenes 8 and
ketones 3 which are either commercially available or readily
prepared by methods known to those skilled in the art.
##STR00008##
[0123] While the R.sup.3 substituents are typically present in the
starting material benzothiophene 8, it is also possible to alter
the R.sup.3 substituents on advanced intermediates as shown in
Scheme 3. For instance, a bromide substituent may be further
functionalized using a variety of metal-mediated cross-coupling
reactions obvious to those skilled in the art. For instance, the
bromide substituent of intermediate 2a may be converted to nitrile
2b in the presence of a palladium catalyst such as
Pd(PPh.sub.3).sub.4 and a cyanide source such as Zn(CN).sub.2 in a
polar aprotic solvent such as DMF at a temperature of 80.degree. C.
based on the chemistry described by Kubota and Rice, Tetrahedron
Letters, 1998, 39, 2907-2910. Alternatively, intermediate 2a can be
functionalized under Suzuki coupling conditions with an aryl or
heteroaryl boronic acid 9, palladium catalyst such as
PdCl.sub.2(dppf), base such as LiOH, in a mixed solvent system such
as dioxane and water, at elevated temperatures such as 80.degree.
C. Under these conditions, the ethyl ester of intermediate 2a can
also be hydrolyzed to afford compound la directly. Numerous other
metal-mediated functionalizations of intermediates such as 2a will
be obvious to those skilled in the art.
##STR00009##
[0124] While a variety of substituted benzothiophenes 8 are
commercially available, two methods for synthesizing them are
depicted in Scheme 4. When the appropriately substituted
benzenethiol 10 is readily accessible, it may be alkylated with
bromoacetaldehyde dimethyl acetal at elevated temperatures in the
presence of a base such as potassium carbonate in a polar aprotic
solvent such as DMF. The resulting acetal intermediate 11 can then
undergo cyclocondensation to afford benzothiophene 8 upon heating
in the presence of an acid such as polyphosphoric acid in a solvent
such as chlorobenzene. An alternate preparation of benzothiophenes
proceeds from aryl fluoride 12. Aryl fluorides such as 12 may be
lithiated at the position adjacent to fluorine by a strong base
such as lithium diisopropylamide in a solvent such as THF at low
temperatures such as -70.degree. C. The resulting intermediate can
then react with a formyl electrophile such as DMF to afford the
2-fluorobenzaldehyde 13. Nucleophilic aromatic substitution of the
fluorine substituent of 13 with methyl thioglycolate and subsequent
cyclocondensation to benzothiophene 8a can be accomplished in a
single vessel by heating the reactants in the presence of a base
such as potassium carbonate in a solvent such as acetonitrile. If
desired, the 2-carbomethoxy substituent of benzothiophene 8a may be
removed to afford benzothiophene 81). Saponification of the ester
as described for the conversion of 2 to Ia (Scheme 1) yields an
acid which may be decarboxylated using a variety of procedures
known to those skilled in the art. For instance, the acid may be
treated with copper powder in quinoline at a temperature of
200.degree. C.
##STR00010##
[0125] Separation of diastereomers and regioisomers can be carried
out at various stages in the preparation of compounds I, however,
it is typically carried out on compound I using reverse-phase HPLC
or on the amide 2 using silica gel chromatography or preparative
HPLC with a chiral stationary phase.
Analytical HPLC mass spectrometry conditions: [0126] LC1: Column:
Waters Xterra MS C18 3.5.mu., 3.0.times.50 mm [0127] Temperature:
50.degree. C. [0128] Eluent: 10:90 to 100:0 v/v
acetonitrile/water+0.05% formic acid over 3.75 min. [0129] Flow
Rate: 1.2 mL/min, Injection 10 .mu.L [0130] Detection: PDA, 200-600
nm [0131] MS: mass range 150-750 amu; positive/negative ion
electrospray ionization [0132] LC2: Column: Waters Xterra IS C-18,
3.5.mu., 2.1.times.20 mm [0133] Temperature: 50.degree. C. [0134]
Eluent: 10:90 to 98:2 v/v acetonitrile/water+0.05% formic acid over
3.25 min. [0135] Flow Rate: 1.5 mL/min, Injection 5 .mu.L [0136]
Detection: PDA, 200-600 nm [0137] MS: mass range 150-750 amu;
positive/negative ion electrospray ionization [0138] LC3: Column:
Waters Xterra IS C-18, 3.5.mu., 2.1.times.20 mm [0139] Temperature:
50.degree. C. [0140] Eluent: 10:90 to 98:2 v/v
acetonitrile/water+0.05% TFA over 3.25 min. [0141] Flow Rate: 1.5
mL/min, Injection 5 .mu.L [0142] Detection: PDA, 200-600 nm [0143]
MS: mass range 150-750 amu; positive/negative ion electrospray
ionization [0144] LC4: Column: Waters Sunfire C18, 5.mu.,
4.6.times.50 mm [0145] Temperature: 50.degree. C. [0146] Eluent:
10:90 to 100:0 v/v acetonitrile/water+0.05% TFA over 3.75 min.
[0147] Flow Rate: 1.2 mL/min, Injection 10 .mu.L [0148] Detection:
PDA, 190-300 nm [0149] MS: mass range 150-700 amu; positive ion
electrospray ionization Preparative reverse-phase HPLC conditions:
[0150] Column: Kromasil 100-5-C18, 21.1.times.100 mm [0151] Flow
Rate: 20.0 mL/min [0152] Fluent: 10:90 to 100:0 v/v
acetonitrile/water+0.1% TFA over 10M min. [0153] Temperature:
ambient [0154] Detection: PDA, 254 nm
[0155] Preparative thin layer chromatography (PTLC) was performed
on 20.times.20 cm plates (500 .mu.m thick silica gel). Silica gel
chromatography was done on a Biotage Horizon flash chromatography
system.
[0156] The following examples are provided so that the invention
might be more fully understood. They should not be construed as
limiting the invention in any way.
INTERMEDIATE 1
4-{(1R)-1-[(R)-(4-CHLOROPHENYL)(HYDROXY)METHYL]BUTYL}BENZOIC
ACID
##STR00011##
[0157] Step A. tert-Butyl
4-[2-(4-chlorophenyl)-1-propylethan-2-one-1-yl]benzoate
##STR00012##
[0159] A 3-neck flask was charged with NaOtBu (2.85 g, 28.6 mmol)
and dry THF (50 mL) under nitrogen.
Tris(dibenzylideneacetone)dipalladium(0) (0.26 g, 0.28 mmol) and
(S)-Tol-Binap (0.47 g, 0.69 mmol) were then added under nitrogen.
After stirring for 15 min, 1-(4-chlorophenyl)pentan-1-one (4.21 g,
21.0 mmol) was added, followed by tert-butyl 4-bromobenzoate (5.0
g, 19.1 mmol) under nitrogen. The mixture was heated at 60.degree.
C. for 8 hours. The mixture was diluted with heptane (100 mL) and
poured into a solution of saturated NaHCO.sub.3 (aq) (60 mL) and
ice (40 g). The resulting layers were separated, and the aqueous
phase was back-extracted with methyl tert-butyl ether (50 mL). The
combined organics were washed with saturated NaHCO.sub.3 (aq) then
10% NaCl(aq). The organic solution was filtered through a bed of
silica 60 (84 g, wetted with 1:1 methyl tert-butyl ether/heptane),
and washed with 1:1 methyl tert-butyl ether/heptane (600 mL). The
combined filtrate was concentrated to afford an orange oil that was
used directly for the next step: .sup.1H NMR (500 MHz, CDCl.sub.3):
.delta. 7.91 (d, J=8.1 Hz, 2H); 7.86 (d, J=8.4 Hz, 2H); 7.35 (d,
J=8.4 Hz, 2H); 7.32 (d, J=8.2 Hz, 2H); 4.53 (t, J=7.2 Hz, 1H);
2.19-2.09 (m, 1H); 1.85-1.76 (m, 1H); 1.56 (s, 9H); 1.35-1.18 (m,
2H); 0.91 (t, J=7.3 Hz, 3H); LC1: 1.35 min. (M-tBu+H).sup.+317.
Step B. tert-Butyl
4-[(1R,2R)-2-(4-chlorophenyl)-1-propylethan-2-hydroxyl-1-yl]benzoate
##STR00013##
[0161] To degassed 2-propanol (5.0 mL) was added
RuCl.sub.2[(S)-xyl-SEGPHOS][(S)-DAIPEN] (16.2 mg, 0.0134 mmol) and
potassium t-butoxide (300 mg, 2.67 mmol). After this mixture was
stirred at room temperature for 2 hours, the material obtained in
Step A was added in 2-propanol (25 mL). This mixture was then
treated with hydrogen (100 psi) at room temperature for 18 hours.
The mixture was concentrated, then the residue was recrystallized
from IPAlwater to afford the title compound. `H NMR (400 MHz,
CDCl.sub.3) .delta. 7.96 (m, 2H), 7.32 (m, 2H), 7.26 (m, 2H), 7.22
(m, 2H), 4.76 (dd, J=7.7, 2.9 Hz, 1H), 2.89 (ddd, J=11.5, 7.7, 4.2
Hz, 1H), 1.84 (d, J=2.9 Hz, 1H), 1.62 (s, 9H), 1.61 (m, 1H), 1.41
(m, 1H), 1.05 (m, 2H), 0.76 (t, J=7.3 Hz, 3H); LC3: 2.38 min.
(M-H.sub.2O-tBu+H).sup.+301; Chiral SFC Method: Chiralpak AD-H
250.times.4.6 mm), isocratic 15% MeOH/CO.sub.2, 1.5 mL/min, 200
bar, 35.degree. C., 215 nm, 15 minutes: desired alcohol retention
time -9.8 min; enantiomeric alcohol, retention time=10.6 min;
diastereomeric alcohols retention times=5.2 and 6.3 min.
Step C.
4-{(1R)-1-[(R)-(4-Chlorophenyl)(hydroxy)methyl]butyl}benzoic
Acid
##STR00014##
[0163] Orthophosphoric acid (85 wt %, 11.4 g, 99 mmol) was added to
a slurry of tert-butyl
4-[(1R,2R)-2-(4-chlorophenyl)-1-propylethan-2-hydroxyl-1-yl]benzoate
(7.42 g, 19.8 mmol) in acetonitrile (75 mL). The mixture was purged
with nitrogen, then heated at 65.degree. C. for 3.5 hours. The
mixture was allowed to cool to 40.degree. C., then water (25 mL)
was added dropwise. Once crystallization began, additional water
(50 mL) was added and the mixture was allowed to cool to room
temperature. The precipitate was collected by vacuum filtration,
washed with 3:1 water:acetonitrile (35 mL), then dried in vacuo at
65.degree. C. overnight to afford the title compound as a light
green solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 12.71 (br
s, 1H); 7.79 (d, J=8.3 Hz, 2 H); 7.29 (d, J=8.4 Hz, 2H); 7.19-7.25
(m, 4H); 5.32 (br s, 1H); 4.76 (d, J=6.3 Hz, 1H); 2.85 (dt, J=10.7,
5.4 Hz, 1H); 1.61 (m, 1H); 1.44 (m, 1H); 1.00 (m, 2H); 0.73 (t,
J=7.3 Hz, 3H)); LC2 3.00 min. (M+H).sup.+317.
INTERMEDIATE 2
7-BROMO-5-CHLORO-1-BENZOTHIOPHENE
##STR00015##
[0164] Step A.
2-Bromo-1-[(2.2-diethoxyethyl)thio]-4-chlorobenzene
##STR00016##
[0166] Potassium carbonate (0.926 g, 9.34 mmol) then
bromoacetaldehyde dimethyl acetal (1.35 g, 6.85 mmol) were added to
a solution of 2-bromo-4-chlorobenzenethiol (1.397 g, 6.23 mmol) in
anhydrous DMF (11 mL). The mixture was heated at 70.degree. C. for
3 hours. After being allowed to cool to room temperature, the
mixture was diluted with ethyl acetate and water. The resulting
layers were separated and the aqueous phase was extracted with
ethyl acetate. The combined organics were washed with water then
saturated NaCl (aq), dried over Na.sub.2SO.sub.4, filtered, then
concentrated. The resulting light yellow oil was used directly for
the following step. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta.
7.57(d, J=2.0 Hz, 1H); 7.33 (d, J=8.5 Hz, 1H); 7.26 (dd, J=8.5, 2.0
Hz, 1H); 4.70 (t, J=5.5 Hz, 1H); 3.75-3.68 (m, 2H); 3.61-3.55 (m,
2H); 3.15 (d, J=5.5 Hz, 2H); 1.23 (t, 7.0 Hz, 6H).
Step H. 7-Bromo-5-chloro-1-benzothiophene
##STR00017##
[0168] In a round-bottomed flask fitted with a reflux condenser and
addition funnel, a mixture of chlorobenzene (11 mL) and
polyphosphoric acid (7 g) was heated to reflux. A solution of
2-bromo-1-[(2,2-diethoxyethypthio]-4-chlorobenzene in chlorobenzene
(10 mL) was added dropwise via addition funnel then the mixture was
refluxed overnight. The viscous mixture was decanted while hot.
Additional chlorobenzene (25 mL) was added to the flask, stirred at
120.degree. C. for 15 minutes, then decanted. The remaining viscous
mixture in the flask was treated with toluene (50 mL), water (25
mL), and saturated Na.sub.2CO.sub.3 (aq) (10 mL). The resulting
layers were separated, and the aqueous phase was extracted with
toluene. The toluene and chlorobenzene fractions were combined,
washed with saturated Na.sub.2CO.sub.3 (aq), then saturated NaCl
(aq), dried over Na.sub.2SO.sub.4, filtered, then concentrated. The
residue was purified by silica gel chromatography eluting with
0-10% EtOAc/hexanes to afford the title compound as a white solid.
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.78 (d, J=1.5 Hz, 1H);
7.59 (d, J=5.5 Hz, 1H); 7.53 (d, J=1.5 Hz, 1H); 7.39 (d, J=5.5 Hz,
1H).
INTERMEDIATE 3
7-BROMO-5-(TRIFLUOROMETHYL)-1-BENZOTHIOPHENE
##STR00018##
[0169] Step A. 3-Bromo-2-fluoro-5-(trifluoromethyl)benzaldehyde
##STR00019##
[0171] A solution of n-BuLi (2.5 M in hexanes, 1.98 mL, 4.94 mmol)
was added to a solution of diisopropylamine (0.700 mL, 4.94 mmol)
in THF (10 mL) at -30.degree. C. After 15 minutes, the mixture was
cooled to -70.degree. C., then 3-bromo-4-fluorobenzotrifluoride
(1.00 g, 4.12 mmol) was added. After 30 minutes, anhydrous DMF
(0.637 mL, 8.23 mmol) was added dropwise. After 15 minutes, acetic
acid (0.50 mL, 8.2 mmol) was added, then the mixture was diluted
with ethyl acetate and water. The resulting layers were separated,
and the aqueous phase was extracted with ethyl acetate. The
combined organics were washed with saturated NaCl (aq), dried over
Na.sub.2SO.sub.4, filtered, then concentrated. The resulting light
yellow oil was used directly for the following step. .sup.1H NMR
(500 MHz, CDCl.sub.3) .delta. 10.38 (s, 1H); 8.10-8.15 (m, 2H).
LC1: 3.44 min. Compound does not ionize.
Step B. Methyl
7-bromo-5-(trifluoromethyl)-1-benzothiophene-2-carboxylate
##STR00020##
[0173] Potassium carbonate (1.44 g, 10.42 mmol) then methyl
thioglycolate (0.487 g, 4.59 mmol) were added to a degassed
solution of 3-bromo-2-fluoro-5-(trifluoromethyl)benzaldehyde (1.13
g, 4.17 mmol) in CH.sub.3CN (11 mL). The mixture was stirred at
room temperature for 30 minutes then refluxed at 100.degree. C.
overnight. The mixture was allowed to cool to room temperature,
then water (20 mL) was added. The resulting light yellow solid was
collected by vacuum filtration, washed with water, then dried in
vacuo. The resulting ester was used directly for the following
step. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.24 (br s, 1H);
8.15 (br s, 1H); 7.86 (br s,1H); 4.02(br s,3H). LC1: 4.00 min.
Compound does not ionize.
Step C. 7-Bromo-5-(trifluoromethyl)-1-benzothiophene-2-carboxylic
Acid
##STR00021##
[0175] A solution of NaOH (4.0 M in water, 5.0 mL, 20 mmol) was
added to a solution of methyl
7-bromo-5-(trifluoromethyl)-1-benzothiophene-2-carboxylate (1.00 g,
2.95 mmol) in dioxane (11 mL). The mixture was heated at 70.degree.
C. overnight, allowed to cool to room temperature, then
concentrated. The resulting light beige solid was partitioned
between water (25 mL) and 1:1 hexanes:ethyl acetate (15 mL). The
resulting layers were separated. The aqueous layer was adjusted to
pH 2 with 2.0 M HCl (aq) then extracted four times with
CH.sub.2Cl.sub.2. The combined CH.sub.2Cl.sub.2 layers were dried
over Na.sub.2SO.sub.4, filtered, then concentrated. The resulting
acid, a light yellow solid, was used directly for the following
step. LC1: 3.58 min. Compound does not ionize.
Step D. 7-Bromo-5-(trifluoromethyl)-1-benzothiophene
##STR00022##
[0177] To a mixture of quinoline (5 mL) and copper powder (0.39 g,
6.2 mmol) in a sealed tube was added
7-bromo-5-(trifluoromethyl)-1-benzothiophene-2-carboxylic acid (1.0
g, 3.1 mmol). The mixture was heated to 200.degree. C. for 20
minutes, then allowed to cool to room temperature. The mixture was
filtered, then the collected precipitate was washed with toluene.
The filtrate was concentrated, then the resulting brown oil was
diluted with EtOAc and poured into 6.0 M HCl (aq). The layers were
separated, then the aqueous layer was extracted with ethyl acetate.
The combined organic layers were washed with 6.0 M HCl (aq), water,
then saturated NaCl (aq), dried over Na.sub.2SO4, filtered, then
concentrated. The residue was purified by silica gel chromatography
eluting with 0-1% EtOAc/hexanes to afford the title compound as a
colorless oil. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.10 (br
s, 1H); 7.77 (br s, 1H); 7.69 (d, J=5.5 Hz, 1H); 7.57 (d, J=5.5 Hz,
1H). LC1: 4.02 min. Compound does not ionize.
EXAMPLE 1
N-(4-{(1S)-1-[(5-CHLORO-7-CYANO-1-BENZOTHIEN-3-YL)(4-CHLOROPHENYL)METHYL]B-
UTYL}BENZOYL)-.beta.-ALANINE
##STR00023##
[0178] Step A. Ethyl
N-(4-{(1S)-1-[(7-bromo-5-chloro-1-benzothien-3-yl)(4-chlorophenyl)methyl]-
butyl}benzoyl)-.beta.-alaninate
##STR00024##
[0180] Boron trifluoride diethyl etherate (0.88 mL, 7.0 mmol) was
added dropwise to a solution of INTERMEDIATE 1 (0.400 g, 1.255
mmol) and INTERMEDIATE 2 (0.311 g, 1.255 mmol) in anhydrous
dichloromethane (6.5 mL) at 0.degree. C. The mixture was stirred at
0.degree. C. for 5 minutes then at room temperature overnight. The
mixture was diluted with EtOAc then washed with water. The aqueous
phase was extracted with EtOAc. The combined organics were washed
with saturated NaCl (aq), dried over Na.sub.2SO.sub.4, filtered,
then concentrated. The resulting acid, a fluffy brown solid, was
used directly for the following step. LC1: 4.34 min.
(M-H).sup.-545.
[0181] To a solution of the product from the previous step in THF
(7.3 mL) was added N,N'-carbonyldiimidazole (1.017 g, 6.27 mmol).
The mixture was stirred at room temperature for one hour, then
f3-alanine ethyl ester hydrochloride (0.964 g, 6.27 mmol) was
added, and the mixture was stirred at 60.degree. C. for 3 hours
then at room temperature overnight. The mixture was concentrated,
then the residue was purified by silica gel chromatography eluting
with 30% EtOAc/hexanes. The resulting material was further purified
by preparative HPLC (Daicel OD-H column, 2 cm.times.25 cm, 15%
IPA/Heptane, 20 mL/min) to provide the title compound as a white
solid. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.62 (d, J=8 Hz,
2H); 7.57 (d, J=1.5 Hz, 1H); 7.42 (d, J=1.5 Hz, 1H); 7.30-7.35 (m,
5H); 7.27 (d, J=8 Hz, 2H); 6.76 (t, J=6 Hz, 1H); 4.47 (d, J=11 Hz,
1H); 4.20 (q, J=7 Hz, 2H); 3.71 (q, J=6 Hz, 2H); 3.47 (td, J=11,
3.5 Hz, 1H); 2.64 (t, J=5.5 Hz, 2H); 1.31 (t, J=7 Hz, 3H);
1.44-1.56 (m, 2H); 0.99-1.08 (m, 2H); 0.77 (t, J=7 Hz, 3H). LC1:
4.34 min. (M+H).sup.+646.
Step B. Ethyl
N-(4-{(1S)-1-[(5-chloro-7-cyano-1-benzothien-3-yl)(4-chlorophenyl)methyl]-
butyl}benzoyl)-.beta.-alaninate
##STR00025##
[0183] A degassed mixture of ethyl
N-(4-{(1S)-1-[(7-bromo-5-chloro-1-benzothien-3-yl)(4-chlorophenyl)methyl]-
butyl}benzoyl)-.beta.-alaninate (0.128 g, 0.198 mmol), zinc cyanide
(0.046 g, 0.40 mmol) and tetrakis(triphenylphosphine)palladium(0)
(0.114 g, 0.099 mmol) anhydrous DMF (2.9 mL) was heated at
80.degree. C. for 2.5 hours. After cooling to room temperature, the
solution was concentrated, then the residue was purified by silica
gel chromatography eluting with 35% EtOAc/hexanes. The resulting
material was further purified by preparative HPLC (Daicel AD-H
chiral column, 2 cm.times.25 cm, 16% IPA/Heptane, 20 mL/min) to
provide the title compound as a white solid. LC1: 4.12 min.
(M+H).sup.+593.
Step C.
N-(4-{(1S)-1-[(5-Chloro-7-cyano-1-benzothien-3-yl)(4-chlorophenyl)-
methyl]butyl}benzoyl)-.beta.-alanine
##STR00026##
[0185] A solution of LiOH (2.0 M in water, 4.5 mL, 9.0 mmol) was
added to a solution of ethyl
N-(4-{(1S)-1-[(5-chloro-7-cyano-1-benzothien-3-yl)(4-chlorophenyl)methyli-
butyl]benzoyl)-.beta.-alaninate (0.100 g, 0.168 mmol) in THF (9.0
mL). The mixture was stirred at room temperature for four hours
then acidified with acetic acid and extracted with ethyl acetate.
The organics were dried over Na.sub.2SO.sub.4, filtered, then
concentrated. The resulting residue was purified by reverse-phase
HPLC eluting with 20-100% acetonitrile/water containing 0.1% TFA.
Following lyophilization, the material was further purified by
silica gel chromatography eluting with 5% MeOH in DCM containing
0.5% acetic acid to afford the title compound as a white solid.
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.77 (br s, 1H); 7.60 (d,
J=5 Hz, 2H); 7.52 (br s, 1H); 7.42 (br s,1H); 7.31-7.35 (m, 4H);
7.25 (d, J=7 Hz, 2H); 6.78 (br s,1H); 4.49 (d, J=11 Hz, 1H); 3.67
(br s, 2H); 3.44-3.47 (m, 1H); 2.66 (br, 2H); 1.45-1.53 (m, 2H);
0.98-1.05 (m, 2H); 0.73 (t, J=7 Hz, 3H). LC1: 3.97 min.
(M+H).sup.+565.
EXAMPLE 2
N-[4-((1S)-1-{(4-CHLOROPHENYL)[5-FLUORO-7-(1-METHYL-1H-PYRAZOL-5-YL)-1-BEN-
ZOTHIEN-3-YL]METHYL}PENTYL)BENZOYL]-.beta.-ALANINE
##STR00027##
[0186] Step A. Ethyl
N-(4-{(1S)-1-[(7-bromo-5-fluoro-1-benzothien-3-yl)(4-chlorophenyl)methyl]-
pentyl}benzoyl)-.beta.-alaninate
##STR00028##
[0188] Using the procedures from INTERMEDIATES 1 and 2 and EXAMPLE
1, 1-(4-chlorophenyl)hexan-1-one and 2-bromo-4-fluorobenzenethiol
were converted to the title compound. .sup.1NMR (500 MHz,
CDCl.sub.3): .delta. 7.62 (d, J=8 Hz, 2H); 7.37 (br, 1H); 7.30-7.35
(m, 6H); 7.27 (d, J=8 Hz, 2H); 6.76 (t, J=6 Hz, 1H); 4.45 (d, J=11
Hz, 1H); 4.19 (q, J=7 Hz, 2H); 3.71 (q, J=6 Hz, 2H); 3.46 (t,
J=10.5 Hz, 1H); 2.64 (t, J=5.5 Hz, 2H); 1.30 (t, J=7 Hz, 3H);
1.47-1.57 (m, 2H); 1.18-1.23 (m, 1H); 1.07-1.14 (m, 1H); 0.98-1.03
(m, 2H); 0.75 (t, J=7 Hz, 3H). LC1: 4.23 min. (M+H).sup.+644 and
646.
Step B.
N-[4-((1S)-1-{(4-Chlorophenyl)[5-fluoro-7-(1-methyl-1H-pyrazol-5-y-
l)-1-benzothien-3-yl]methyl}pentyl)benzoyl]-.beta.-alanine
##STR00029##
[0190] Dioxane (1.4 mL) and LiOH (2.0 M in water, 0.68 mL, 1.36
mmol) were added to a mixture of ethyl
N-(4-{(1S)-1-[(7-bromo-5-fiuoro-1-benzothien-3-yl)(4-chlorophenyl)methyl]-
pentyl}benzoyl)-.beta.-alaninate (23.0 mg, 0.036 mmol),
1-methyl-1H-pyrazole-5-boronic acid pinacol ester (11.0 mg, 0.053
mmol), and PdCl.sub.2(dppf) (0.029 g, 0.036 mmol) in a sealed
microwave vial under a nitrogen atmosphere. The mixture was
degassed then irradiated in a microwave reactor at 80.degree. C.
for 15 minutes. The mixture was acidified with acetic acid then
extracted with ethyl acetate. The organic layer was dried over
Na.sub.2SO.sub.4, filtered, then concentrated. The resulting
residue was purified by preparative reverse-phase HPLC eluting with
acetonitrile/water+0.1% TFA. The resulting material was further
purified by silica gel chromatography eluting with 5% MeOH/DCM+0.5%
acetic acid to afford the title compound. .sup.1H NMR (500 MHz,
CDCl.sub.3): .delta. 7.57 (br, 3H); 7.29-7.37 (m, 6H); 7.23 (d, J=6
Hz, 2H); 6.94 (d, J=7 Hz, 1H); 6.86 (br, 1H); 6.40 (br, 1H); 4.47
(d, J=11 Hz, 1H); 3.71 (br, 3H); 3.62 (br, 2H); 3.43 (t, J=9.5 Hz,
1H); 2.59 (br, 2H); 1.45-1.52 (m, 2H); 1.13-1.16 (m, 1H); 1.04-1.06
(m, 1H); 0.88-1.00 (m, 2H); 0.68 (t, J=6.5 Hz, 3H). LC1: 3.99 min.
(M+H).sup.+618.
EXAMPLE 3
4-{(1S)-1-[(7-BROMO-5-METHYL-1-BENZOTHIEN-3-YL)(4-CHLOROPHENYL)METHYL]BUTY-
L}-N-1H-TETRAZOL-5-YLBENZAMIDE
##STR00030##
[0191] Step A.
4-{(1S)-1-[(7-Bromo-5-methyl-1-benzothien-3-yl)(4-chlorophenyl)methyl]but-
yl}benzoic Acid
##STR00031##
[0193] Using the procedures from INTERMEDIATE 2 and EXAMPLE 1,
2-bromo-4-methylbenzenethiol and INTERMEDIATE 1 were converted to
the title compound. LC2: 2.82 min. Compound does not ionize.
Step B.
4-{(1S)-1-[(7-Bromo-5-methyl-1-benzothien-3-yl)(4-chlorophenyl)met-
hyl]butyl}-N-1H-tetrazol-5-ylbenzamide
##STR00032##
[0195] A mixture of
4-{(1S)-1-[(7-bromo-5-methyl-1-benzothien-3-yl)(4-chlorophenyl)methyl]but-
yl}benzoic acid (25.0 mg, 0.047 mmol) and CDI (26 mg, 0.16 mmol) in
DMF (1.0 mL) was stirred at RT for 30 minutes in a sealed tube,
then 5-amino-1H-tetrazole (23.0 mg, 0.260 mmol) was added. The
mixture was heated at 100.degree. C. for 12 hours, allowed to cool
to RT, then diluted with acetonitrile. The mixture was purified by
preparative reverse phase HPLC eluting with 47-100%
acetonitrile/water+0.1% TFA. Following lyophilization, this
afforded the title compound as a white solid. .sup.1H NMR (500 MHz,
d.sub.6-DMSO) .delta. 7.98 (br, 1H); 7.91 (d, J=8 Hz, 2H); 7.84
(br, 1H); 7.65 (d, J=8 Hz, 2H); 7.61 (d J=8 Hz, 2H); 7.39 (d, J=8.5
Hz, 2H); 7.35 (br,1H); 4.88 (d, J=12 Hz, 1H); 3.79 (t, J=11 Hz,
1H); 2.41 (s, 3H); 1.50-1.52 (m, 1H); 1.23-1.30 (m, 1H); 0.92 (q,
J=7 Hz, 2H); 0.68 (t, J=7 Hz, 3H); LC2: 2.70 min.
(M+H).sup.+594.
EXAMPLE 4
4-{(1S)-1-[(7-BROMO-5-METHYL-1-BENZOTHIEN-3-YL)(4-CHLOROPHENYL)METHYL]BUTY-
L}-N-(2H-TETRAZOL-5-YLMETHYL)BENZAMIDE
##STR00033##
[0197] A mixture of
4-{(1S)-1-[(7-bromo-5-methyl-1-benzothien-3-yl)(4-chlorophenyl)methyl]but-
yl}benzoic acid (EXAMPLE 3, Step A, 20.0 mg, 0.038 mmol),
1-(2H-tetrazol-5-yl)methanamine (10.9 mg, 0.110 mmol), EDC (22.0
mg, 0.110 mmol), HOBt (17.0 mg, 0.110 mmol) and DIEA (0.050 mL,
0.29 mmol) in DMF (1 mL) was heated at 65.degree. C. for 12 hours.
The mixture was allowed to cool to RT, diluted with acetonitrile,
then purified by preparative reverse-phase HPLC eluting with
38-100% acetonitrile/water+0.1% TFA. Following lyophilization, this
afforded the title compound as a white solid. .sup.1H NMR (500 MHz,
d.sub.6-DMSO) .delta. 9.04 (br, 1H); 7.96 (s, 1H); 7.84 (s, 1H);
7.67 (d, J=8 Hz, 2H); 7.64 (d, J=8 Hz, 2H); 7.52 (d, J=8 Hz, 2H);
7.39 (d, J=8.5 Hz, 2H); 7.35 (br, 1H); 4.84 (d, J=11.5 Hz, 1H);
4.67 (d, J=5.5 Hz, 2H); 3.74 (t, J=12 Hz, 1H); 2.40 (s, 3H);
1.44-1.52 (m, 1H); 1.24-1.32 (m, 1H); 0.91(q, J=7.5 Hz, 2H); 0.67
(t, J=7 Hz, 3H). LC2: 2.63 min. (M+H).sup.+608.
[0198] Using the chemistry described for the preparation of
INTERMEDIATES 1-3 and in EXAMPLES 1-4, the compounds in TABLES 1
and 3 were prepared as enantiopure compounds. The data listed are
for the most active stereoisomer. Most compounds in TABLE 2 were
also prepared as single stereoisomers, with the data listed being
that for the most active stereoisomer. The only exceptions are
examples 41 and 42, in which the compounds are a mixture of the two
possible diastereomers at the stereocenter on the substituent
labeled "Y" in the general structure. The R.sup.1 and R.sup.3
groups that are shown in TABLES 1-3 are specified when they
represent a value other than a hydrogen atom. The remaining R.sup.1
and R.sup.3 groups that are unspecified are hydrogen atoms.
TABLE-US-00004 TABLE 1 ##STR00034## EXAMPLE R.sup.1 R.sup.2 R.sup.3
LC-MS data 5 4-Cl n-Pr H LC1 3.87 min. (M + H).sup.+ 506.5
N-(4-{(1S)-1-[1-BENZOTHIEN-3-YL(4-CHLOROPHENYL)METHYL]
BUTYL}BENZOYL)-.beta.-ALANINE 6 4-Cl n-Pr 5-Cl, 7-Me LC1 4.08 min.
(M + H).sup.+ 552
N-(4-{(1S)-1-[(5-CHLORO-7-METHYL-1-BENZOTHIEN-3-YL)(4-
CHLOROPHENYL)METHYL]BUTYL}BENZOYL)-.beta.-ALANINE 7 4-Cl n-Pr 5-Cl,
7-Br LCl 4.26 min. (M + H).sup.+ 618.6
N-(4-{(1S)-1-[(5-CHLORO-7-BROMO-1-BENZOTHIEN-3-YL)(4-
CHLOROPHENYL)METHYL]BUTYL}BENZOYL)-.beta.-ALANINE 8 4-Cl n-Pr 2-Me
LC1 4.02 min, (M + H).sup.+ 520.6
N-(4-{(1S)-1-[(2-METHYL-1-BENZOTHIEN-3-YL)(4-
CHLOROPHENYL)METHYL]BUTYL}BENZOYL)-.beta.-ALANINE 9 4-Cl n-Pr 5-F,
7-Cl LC1 4.13 min. (M + H).sup.+ 558
N-(4-{(1S)-1-[(5-FLUORO-7-CHLORO-1-BENZOTHIEN-3-YL)(4-
CHLOROPHENYL)METHYL]BUTYL}BENZOYL)-.beta.-ALANINE 10 4-OMe n-Pr H
LCl 3.62 min. (M + H).sup.+ 502
N-(4-{(1S)-1-[1-BENZOTHIEN-3-YL(4-METHOXYPHENYL)
METHYL]BUTYL}BENZOYL)-.beta.-ALANINE 11 3,4-diCl n-Pr 5-Cl LC2 2.48
min. (M + H).sup.+ 576
N-(4-{(1S)-1-[(5-CHLORO-1-BENZOTHIEN-3-YL)(3,4-
DICHLOROPHENYL)METHYL]BUTYL}BENZOYL)-.beta.-ALANINE 12 3,4-diCl
n-Pr 5-Cl, 7-Br LC2 2.66 min. (M + H).sup.+ 654
N-(4-{(1S)-1-[(5-CHLORO-7-BROMO-1-BENZOTHIEN-3-YL)(3,4-
DICHLOROPHENYL)METHYL]BUTYL}BENZOYL)-.beta.-ALANINE 13 4-Cl n-Pr
5-F, 7-CN LC1 3.95 min, (M + H).sup.+ 549
N-(4-{(1S)-1-[(5-FLUORO-7-CYANO-1-BENZOTHIEN-3-YL)(4-
CHLOROPHENYL)METHYL]BUTYL}BENZOYL)-.beta.-ALANINE 14 4-Cl n-Pr
5-Me, 7-CN LC1 3.99 min. (M + H).sup.+ 545
N-(4-{(1S)-1-[(5-METHYL-7-CYANO-1-BENZOTHIEN-3-YL)(4-
CHLOROPHENYL)METHYL]BUTYL}BENZOYL)-.beta.-ALANINE 15 4-Cl n-Pr
5-CF.sub.3, 7-CN LC1 4.01 min. (M + H).sup.+ 599
N-(4-{(1S)-1-[(5-TRIFLUOROMETHYL-7-CYANO-1-BENZOTHIEN-3-YL)(4-
CHLOROPHENYL)METHYL]BUTYL}BENZOYL)-.beta.-ALANINE 16 4-Cl n-Pr
5,6-diF, 7-CN LC1 3.94 min. (M + H).sup.+ 567
N-(4-{(1S)-1-[(5,6-DIFLUORO-7-CYANO-1-BENZOTHIEN-3-YL)(4-
CHLOROPHENYL)METHYL]BUTYL}BENZOYL)-.beta.-ALANINE 17 4-Cl n-Pr
4,5-diF, 7-CN LC1 3.99 min. (M + H).sup.+ 567
N-(4-{(1S)-1-[(4,5-DIFLUORO-7-CYANO-1-BENZOTHIEN-3-YL)(4-
CHLOROPHENYL)METHYL]BUTYL}BENZOYL)-.beta.-ALANINE 18 4-Cl n-Pr
2-Me, 5-F, 7-CN LC1 3.99 min. (M + H).sup.+ 563
N-(4-{(1S)-1-[(2-METHYL-5-FLUORO-7-CYANO-1-BENZOTHIEN-3-YL)(4-
CHLOROPHENYL)METHYL]BUTYL}BENZOYL)-.beta.-ALANINE 19 4-Cl n-Pr
2-Me, 5-Cl, 7-CN LC1 4.06 min. (M + H).sup.+ 577
N-(4-{(1S)-1-[(2-METHYL-5-CHLORO-7-CYANO-1-BENZOTHIEN-3-YL)(4-
CHLOROPHENYL)METHYL]BUTYL}BENZOYL)-.beta.-ALANINE 20 3,5-diF n-Pr
5-CF.sub.3, 7-CN LC1 3.94 min. (M + H).sup.+ 601
N-(4-{(1S)-1-[(5-TRIFLUOROMETHYL-7-CYANO-1-BENZOTHIEN-3-YL)(3,5-
DIFLUOROPHENYL)METHYL]BUTYL}BENZOYL)-.beta.-ALANINE 21 3,4-diCl
n-Pr 5-Cl, 7-CN LC2 2.31 min. (M + H).sup.+ 601
N-(4-{(1S)-1-[(5-CHLORO-7-CYANO-1-BENZOTHIEN-3-YL)(3,4-
DICHLOROPHENYL)METHYL]BUTYL}BENZOYL)-.beta.-ALANINE 22 4-OCF.sub.3
n-Pr 5-F, 7-CN LC1 3.98 min. (M + H).sup.+ 599
N-(4-{(1S)-1-[(5-FLUOR0-7-CYANO-1-BENZOTHIEN-3-YL)(4-
TRIFLUOROMETHOXYPHENYL)METHYL]BUTYL}BENZOYL)-.beta.-ALANINE 23
4-OCF.sub.3 n-Pr 5-Me, 7-CN LC2 2.62 min. (M + H).sup.+ 595
N-(4-{(1S)-1-[(5-METHYL-7-CYANO-1-BENZOTHIEN-3-YL)(4-
TRIFLUOROMETHOXYPHENYL)METHYL]BUTYL}BENZOYL)-.beta.-ALANINE 24
4-OCF.sub.3 n-Pr 5-CF.sub.3, 7-CN LC1 4.04 min. (M + H).sup.+ 649
N-(4-{(1S)-1-[(5-TRIFLUOROMETHYL-7-CYANO-1-BENZOTHIEN-3-YL)(4-
TRIFLUOROMETHOXYPHENYL)METHYL]BUTYL}BENZOYL)-.beta.-ALANINE 25
4-OCF.sub.3 n-Pr 5-Cl, 7-CN LC2 2.67 min. (M + H).sup.+ 615
N-(4-{(1S)-1-[(5-CHLORO-7-CYANO-1-BENZOTHIEN-3-YL)(4-
TRIFLUOROMETHOXYPHENYL)METHYL]BUTYL}BENZOYL)-.beta.-ALANINE 26
4-OCF.sub.3 n-Pr 5,6-diF, 7-CN LC2 2.65 min. (M + H).sup.+ 617
N-(4-{(1S)-1-[(5,6-DIFLUORO-7-CYANO-1-BENZOTHIEN-3-YL)(4-
TRIFLUOROMETHOXYPHENYL)METHYL]BUTYL}BENZOYL)-.beta.-ALANINE 27 4-Cl
--CH.sub.2CH.sub.2CF.sub.3 5-Cl, 7-CN LC1 3.91 min. (M + H).sup.+
619 N-(4-{(1S)-1-[(5-CHLORO-7-CYANO-1-BENZOTHIEN-3-YL)(4-
CHLOROPHENYL)METHYL]-4,4,4-TRIFLUOROBUTYL}BENZOYL)-.beta.-ALANINE
28 4-Cl --CH.sub.2CH.sub.2CF.sub.3 5-Me, 7-CN LC2 2.53 min. (M +
H).sup.+ 599 N-(4-{(1S)-1-[(5-METHYL-7-CYANO-1-BENZOTHIEN-3-YL)(4-
CHLOROPHENYL)METHYL]-4,4,4-TRIFLUOROBUTYL}BENZOYL)-.beta.-ALANINE
29 4-Cl n-Bu 5-Cl, 7-CN LC1 4.13 min. (M + H).sup.+ 579
N-(4-{(1S)-1-[(5-CHLORO-7-CYANO-1-BENZOTHIEN-3-YL)(4-
CHLOROPHENYL)METHYL]PENTYL}BENZOYL)-.beta.-ALANINE 30 4-Cl n-Bu
5-F, 7-CN LC1 4.06 min. (M + H).sup.+ 561
N-(4-{(1S)-1-[(5-FLUORO-7-CYANO-1-BENZOTHIEN-3-YL)(4-
CHLOROPHENYL)METHYL]PENTYL}BENZOYL)-.beta.-ALANINE 31 4-Cl n-Bu
5-CF.sub.3, 7-CN LC1 4.20 min. (M + H).sup.+ 613
N-(4-{(1S)-1-[(5-TRIFLUOROMETHYL-7-CYANO-1-BENZOTHIEN-3-YL)(4-
CHLOROPHENYL)METHYL]PENTYL}BENZOYL)-.beta.-ALANINE 32 4-Cl
--CH.sub.2CH(CH.sub.3).sub.2 5-Cl, 7-CN LC1 4.11 min. (M + H).sup.+
579 N-(4-{(1S)-1-[(5-CHLORO-7-CYANO-1-BENZOTHIEN-3-YL)(4-
CHLOROPHENYL)METHYL]-4-METHYLBUTYL}BENZOYL)-.beta.-ALANINE 33 4-Cl
--CH.sub.2CH(CH.sub.3).sub.2 5-F, 7-CN LC1 4.03 min. (M + H).sup.+
563 N-(4-{(1S)-1-[(5-FLUORO-7-CYANO-1-BENZOTHIEN-3-YL)(4-
CHLOROPHENYL)METHYL]-4-METHYLBUTYL}BENZOYL)-.beta.-ALANINE 34 4-Cl
Et 5-Cl, 7-CN LC1 3.90 min. (M + H).sup.+ 551
N-(4-{(1S)-1-[(5-CHLORO-7-CYANO-1-BENZOTHIEN-3-YL)(4-
CHLOROPHENYL)METHYL]PROPYL}BENZOYL)-.beta.-ALANINE 35 4-Cl n-Pr
##STR00035## LC1 3.93 min. (M + H).sup.+ 620
N-[4-((1S)-1-{(4-CHLOROPHENYL)[5-CHLORO-7-(1-METHYL-1H-PYRAZOL-4-YL)-1-
BENZOTHIEN-3-YL]METHYL}BUTYL)BENZOYL]-.beta.-ALANINE 36 4-OCF.sub.3
n-Pr ##STR00036## LC1 3.86 min. (M + H).sup.+ 640
N-[4-((1S)-1-{(4-TRIFLUOROMETHOXYPHENYL)[5-FLUORO-7-(1H-PYRAZOL-3-YL)-1-
BENZOTHIEN-3-YL]METHYL}BUTYL)BENZOYL]-.beta.-ALANINE 37 4-Cl n-Bu
##STR00037## LC1 3.93 min. (M + H).sup.+ 604
N-[4-((1S)-1-{(4-CHLOROPHENYL)[5-FLUORO-7-(1H-PYRAZOL-3-YL)-1-BENZOTHIEN-3-
- YL]METHYL}PENTYL)BENZOYL]-.beta.-ALANINE 38 4-Cl n-Pr
##STR00038## LC2 2.56 min. (M + H).sup.+ 607
N-[4-((1S)-1-{(4-CHLOROPHENYL)[5-CHLORO-7-(1H-ISOXAZOL-4-YL)-1-BENZOTHIEN-
3-YL]METHYL}BUTYL)BENZOYL]-.beta.-ALANINE
TABLE-US-00005 TABLE 2 ##STR00039## EXAMPLE Y LC-MS data 39
##STR00040## LC3 2.59 min. (M + H).sup.+ 614
(2S)-3-[(4-{(1S)-1-[(5-METHYL-7-BROMO-1-BENZOTHIOPHEN-3-
YL)(4-CHLOROPHENYL)METHYL]BUTYL}BENZOYL)AMINO]-2- HYDROXYPROPANOIC
ACID 40 ##STR00041## LC3 2.63 min. (M + H).sup.+ 634
3-[(4-{(1S)-1-[(5-METHYL-7-BROMO-1-BENZOTHIOPHEN-3-YL)(4-
CHLOROPHENYL)METHYL]BUTYL}BENZOYL)AMINO]-2,2- DIFLUOROPROPANOIC
ACID 41 ##STR00042## LC3 2.70 min. (M + H).sup.+ 612
3-[(4-{(1S)-1-[(5-METHYL-7-BROMO-1-BENZOTHIOPHEN-3-YL)(4-
CHLOROPHENYL)METHYL]BUTYL}BENZOYL)AMINO]-2- METHYLPROPANOIC ACID 42
##STR00043## LC3 2.69 min. (M + H).sup.+ 612
3-[(4-{(1S)-1-[(5-METHYL-7-BROMO-1-BENZOTHIOPHEN-3-YL)(4-
CHLOROPHENYL)METHYL]BUTYL}BENZOYL)AMINO]-3- METHYLPROPANOIC ACID 43
##STR00044## LC3 2.36 min. (M + H).sup.+ 634
2-[(4-{(1S)-1-[(5-METHYL-7-BROMO-1-BENZOTHIOPHEN-3-YL)(4-
CHLOROPHENYL)METHYL]BUTYL}BENZOYL)AMINO]ETHANE SULFONIC ACID 44
##STR00045## LC3 2.57 min. (M + H).sup.+ 597
3-[(4-{(1S)-1-[(5-METHYL-7-BROMO-1-BENZOTHIOPHEN-3-YL)(4-
CHLOROPHENYL)METHYL]BUTYL}BENZOYL)AMINO]PROPANOIC AMIDE
TABLE-US-00006 TABLE 3 ##STR00046## EXAMPLE R.sup.1 R.sup.2 R.sup.3
LC-MS data 45 4-Cl n-Pr H LC1 4.07 min. (M + H).sup.+ 520.6
N-[4-((1S)-1-{(4-CHLOROPHENYL)[3-METHYL-1-
BENZOTHIEN-2-YL]METHYL}BUTYL)BENZOYL]- .beta.-ALANINE 46 4-Cl n-Pr
5-Cl LC1 4.19 min. (M + H).sup.+ 554.6
N-[4-((1S)-1-{(4-CHLOROPHENYL)[3-METHYL-5-
CHLORO-1-BENZOTHIEN-2-YL]METHYL}BUTYL) BENZOYL]-.beta.-ALANINE 47
4-Cl n-Pr 7-Cl LC1 4.22 min. (M + H).sup.+ 554.5
N-[4((1S)-1-{(4-CHLOROPHENYL)[3-METHYL-7-
CHLORO-1-BENZOTHIEN-2-YL]METHYL}BUTYL) BENZOYL]-.beta.-ALANINE 48
4-OMe n-Pr 5-Cl LC1 3.91 min. (M + H).sup.+ 550.6
N-[4((1S)-1-{(4-METHOXYPHENYL)[3-METHYL-5-
CHLORO-1-BENZOTHIEN-2-YL]METHYL}BUTYL) BENZOYL]-.beta.-ALANINE
Biological Assays
[0199] The ability of the compounds of the present invention to
inhibit the binding of glucagon and their utility in treating or
preventing type 2 diabetes mellitus and the related conditions can
be demonstrated by the following in vitro assays.
Glucagon Receptor Binding Assay
[0200] A stable CHO (Chinese hamster ovary) cell line expressing
cloned human glucagon receptor was maintained as described
(Chicchi, et. al. J Biol Chem 272, 7765-9(1997); Cascieri, et. al.
J Biol Chem 274, 8694-7(1999)). To deteiinine antagonistic binding
affinity of compounds, 0.001-0.003 mg of cell membranes from these
cells were pre-incubated with 0.100 mg WGA-coated PVT SPA beads
(Amersham) for 20 minutes at room temperature in 25 .mu.L of a
buffer containing 50 mM Tris-HCl (pH 7.5), 5 mM MgCl.sub.2, 2 mM
EDTA, 0.1% BSA and 3% glycerol in Costar 384 well plates with clear
bottoms (#3706). Next, 25 .mu.L of .sup.1251-Glucagon (New England
Nuclear, Mass.) (1.times.10.sup.44 mol per well) and either 1 .mu.L
solutions of test compounds or 0.001 mM unlabeled glucagon or DMSO
were added and mixed. After 4-12 hours incubation at room
temperature, the radioactivity bound to the cell membranes was
determined in a radioactive emission detection counter
(Wallac-Microbeta). Data were analyzed using the Data Analyzer
software program of Merck & Co., Inc. The IC.sub.50 values were
calculated using non-linear regression analysis assuming
single-site competition. IC.sub.50 values for the compounds of the
invention are generally in the range of as low as about 1 nM to as
high as about 500 nM, and thus have utility as glucagon
antagonists. The IC.sub.50 values are shown below in TABLE 4 for
the more active isomer of indicated compounds.
TABLE-US-00007 TABLE 4 Example IC.sub.50 (nM) 1 6.2 2 4.7 3 2.3 4
2.5 6 28 8 2.2 13 1.1 14 1.3 15 1.7 19 7.8 21 0.7 23 0.2 25 0.1 27
0.2 29 0.4 32 1.0 40 11.8 43 3.4 45 1.8
Inhibition of Glucagon-Stimulated Intracellular cAMP Formation
[0201] Exponentially growing CHO cells expressing human glucagon
receptor were harvested with the aid of enzyme-free dissociation
media (Specialty Media), pelleted at low speed, and re-suspended in
the Cell Stimulation Buffer included in the Flash Plate cAMP kit
(New England Nuclear, SMP0004A). The adenylate cyclase assay was
conducted as per manufacturer instructions. Briefly, compounds were
diluted from stocks in DMSO and added to cells at a final DMSO
concentration of 5%. Cells prepared as above were preincubated in
flash plates coated with anti-cAMP antibodies (NEN) in the presence
of compounds or DMSO controls for 30 minutes, then stimulated with
glucagon (250 pM) for an additional 30 minutes. The cell
stimulation was stopped by addition of equal amounts of a detection
buffer containing lysis buffer as well as .sup.125I-labeled cAMP
tracer (NEN). After 3 hours of incubation at room temperature the
bound radioactivity was determined in a liquid scintillation
counter (TopCount-Packard Instruments). Basal activity (100%
inhibition) was determined using the DMSO control while 0%
inhibition was defined at the amount of pmol cAMP produced by 250
pM glucagon. The resulting amount of cAMP generated per compound
dose was back-calculated from a cAMP standard curve based on the
percent inhibition achieved at each dose. The calculated cAMP
levels were plotted versus compound dose to obtain IC.sub.50 values
using non-linear four-parameter curve fitting with Assay Data
Analyzer software (Merck & Co., Inc.).
[0202] Certain embodiments of the invention have been described in
detail; however, numerous other embodiments are contemplated as
falling within the invention. Thus, the claims are not limited to
the specific embodiments described herein. All patents, patent
applications and publications that are cited herein are hereby
incorporated by reference in their entirety.
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