U.S. patent application number 12/903458 was filed with the patent office on 2011-05-12 for indole and indazole analogs as glycogen synthase activators.
Invention is credited to David Robert Bolin, Matthew Michael Hamilton, Lee Apostle McDermott, Lin Yi.
Application Number | 20110112161 12/903458 |
Document ID | / |
Family ID | 43301914 |
Filed Date | 2011-05-12 |
United States Patent
Application |
20110112161 |
Kind Code |
A1 |
Bolin; David Robert ; et
al. |
May 12, 2011 |
INDOLE AND INDAZOLE ANALOGS AS GLYCOGEN SYNTHASE ACTIVATORS
Abstract
Provided herein are compounds of the formula (I): ##STR00001##
as well as pharmaceutically acceptable salts thereof, wherein the
substituents are as those disclosed in the specification. These
compounds, and the pharmaceutical compositions containing them, are
useful for the treatment of metabolic diseases and disorders such
as, for example, type II diabetes mellitus.
Inventors: |
Bolin; David Robert;
(Montclair, NJ) ; Hamilton; Matthew Michael;
(Hackettstown, NJ) ; McDermott; Lee Apostle;
(Aspinwall, PA) ; Yi; Lin; (Basking Ridge,
NJ) |
Family ID: |
43301914 |
Appl. No.: |
12/903458 |
Filed: |
October 13, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61260059 |
Nov 11, 2009 |
|
|
|
Current U.S.
Class: |
514/407 ;
514/406; 514/415; 548/361.1; 548/362.1; 548/509; 548/510 |
Current CPC
Class: |
C07D 231/56 20130101;
C07D 209/08 20130101; A61P 3/00 20180101 |
Class at
Publication: |
514/407 ;
514/406; 514/415; 548/361.1; 548/362.1; 548/509; 548/510 |
International
Class: |
A61K 31/416 20060101
A61K031/416; C07D 231/56 20060101 C07D231/56; A61K 31/405 20060101
A61K031/405; C07D 209/12 20060101 C07D209/12; C07D 209/08 20060101
C07D209/08; A61K 31/404 20060101 A61K031/404; A61P 3/00 20060101
A61P003/00 |
Claims
1. A compound of formula (I): ##STR00029## wherein, R1, R2, R3,
independently of each other, is hydrogen, halogen, lower alkyl or
alkoxy; R4 is hydrogen, unsubstituted lower alkyl, or lower alkyl
substituted with one to four substituents independently selected
from the group consisting of methyl, (.dbd.O) and --COOH; X is CH
or N; and Y is hydrogen or --NH.sub.2, or a pharmaceutically
acceptable salt thereof.
2. The compound according to claim 1, wherein R1, R2, R3,
independently of each other, is halogen, lower alkyl or alkoxy.
3. The compound according to claim 1, wherein R1, R2, R3,
independently of each other, is fluorine, chlorine, methyl or
methoxy.
4. The compound according to claim 1, wherein R1 and R2 are
halogen.
5. The compound according to claim 1, wherein R1 is fluorine or
chlorine.
6. The compound according to claim 1, wherein R2 is fluorine or
chlorine.
7. The compound according to claim 1, wherein R3 is halogen or
alkoxy.
8. The compound according to claim 1, wherein R3 is fluorine or
methoxy.
9. The compound according to claim 1, wherein R4 is lower alkyl
substituted with one to four substituents independently selected
from the group consisting of methyl, (.dbd.O) and --COOH.
10. The compound according to claim 1, wherein R4 is:
##STR00030##
11. The compound according to claim 1, wherein X is CH.
12. The compound according to claim 1, wherein X is N.
13. The compound according to claim 1, wherein Y is hydrogen.
14. The compound according to claim 1, wherein Y is --NH.sub.2.
15. The compound according to claim 1, wherein said compound is:
4-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-1H-indazole;
3-[4-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indazol-1-yl]-pro-
pionic acid;
6-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-1H-indazole;
[6-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indazol-1-yl]-aceti-
c acid;
3-[6-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indazol-1--
yl]-propionic acid;
6-(4',5'-difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-1H-indole;
3-[6-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-propi-
onic acid;
[6-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-y-
l]-acetic acid;
3-[6-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-butyr-
ic acid;
4-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-1H-indole;
4-[4-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-4-oxo-
-butyric acid;
4-[4-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-2,2-d-
imethyl-4-oxo-butyric acid;
[4-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-acetic
acid;
3-[4-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-
-propionic acid;
3-[4-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-butyr-
ic acid;
5-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-1H-indazol-3-
-ylamine; or
Methyl-5-(2',4',5'-trifluoro-biphenyl-4-yloxymethyl)-1H-indazol-3-ylamine-
.
16. A pharmaceutical composition, comprising a therapeutically
effective amount of a compound according to claim 1, or a
pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier and/or adjuvant.
Description
PRIORITY TO RELATED APPLICATION(S)
[0001] This application claims the benefit of U.S. Provisional
Application No. 61/260,059, filed Nov. 11, 2009, which is hereby
incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] The invention is directed to compounds, salts and
pharmaceutical compositions useful as activators of glycogen
synthase for the treatment of metabolic diseases and disorders.
[0003] All documents cited or relied upon below are expressly
incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0004] Diabetes mellitus is a common and serious disorder,
affecting 10 million people in the U.S. [Harris, M. I. Diabetes
Care 1998 21 (3S) Supplement, 11C], putting them at increased risk
of stroke, heart disease, kidney damage, blindness, and amputation.
Diabetes is characterized by decreased insulin secretion and/or an
impaired ability of peripheral tissues to respond to insulin,
resulting in increased plasma glucose levels. The incidence of
diabetes is increasing, and the increase has been associated with
increasing obesity and a sedentary life. There are two forms of
diabetes: insulin-dependent and non-insulin-dependent, with the
great majority of diabetics suffering from the
non-insulin-dependent form of the disease, known as type 2 diabetes
or non-insulin-dependent diabetes mellitus (NIDDM). Because of the
serious consequences, there is an urgent need to control
diabetes.
[0005] Treatment of NIDDM generally starts with weight loss, a
healthy diet and an exercise program. However, these factors are
often unable to control the disease, and there are a number of drug
treatments available, including insulin, metformin, sulfonylureas,
acarbose, and thiazolidinediones. Each of these treatments has
disadvantages and there is an ongoing need for new drugs to treat
diabetes.
[0006] Metformin is an effective agent that reduces fasting plasma
glucose levels and enhances the insulin sensitivity of peripheral
tissue, mainly through an increase in glycogen synthesis [De
Fronzo, R. A. Drugs 1999, 58 Suppl. 1, 29]. Metformin also leads to
reductions in the levels of LDL cholesterol and triglycerides
[Inzucchi, S. E. JAMA 2002, 287, 360]. However, it loses its
effectiveness over a period of years [Turner, R. C. et al. JAMA
1999, 281, 2005].
[0007] Thiazolidinediones are activators of the nuclear receptor
peroxisome-proliferator activated receptor-gamma. They are
effective in reducing blood glucose levels, and their efficacy has
been attributed primarily to decreasing insulin resistance in
skeletal muscle [Tadayyon, M. and Smith, S. A. Expert Opin.
Investig. Drugs 2003, 12, 307]. One disadvantage associated with
the use of thiazolidinediones is weight gain.
[0008] Sulfonylureas bind to the sulfonylurea receptor on
pancreatic beta cells, stimulate insulin secretion, and
consequently reduce blood glucose levels. Weight gain is also
associated with the use of sulfonylureas [Inzucchi, S. E. JAMA
2002, 287, 360] and, like metformin, they lose efficacy over time
[Turner, R. C. et al. JAMA 1999, 281, 2005]. A further problem
often encountered in patients treated with sulfonylureas is
hypoglycemia [Salas, M. and Caro, J. J. Adv. Drug React. Tox. Rev.
2002, 21, 205-217].
[0009] Acarbose is an inhibitor of the enzyme alpha-glucosidase,
which breaks down disaccharides and complex carbohydrates in the
intestine. It has lower efficacy than metformin or the
sulfonylureas, and it causes intestinal discomfort and diarrhea
which often lead to the discontinuation of its use [Inzucchi, S. E.
JAMA 2002, 287, 360].
[0010] Because none of these treatments is effective over the long
term without serious side effects, there is a need for new drugs
for the treatment of type 2 diabetes.
[0011] In skeletal muscle and liver, there are two major pathways
of glucose utilization: glycolysis, or oxidative metabolism, where
glucose is oxidized to pyruvate; and glycogenesis, or glucose
storage, where glucose is stored in the polymeric form glycogen.
The key step in the synthesis of glycogen is the addition of the
glucose derivative UDP-glucose to the growing glycogen chain, and
this step is catalyzed by the enzyme glycogen synthase [Cid, E. et
al. J. Biol. Chem. 2000, 275, 33614]. There are two isoforms of
glycogen synthase, found in liver [Bai, G. et al. J. Biol. Chem.
1990, 265, 7843] and in other peripheral tissues including muscle
[Browner, M. F. et al. Proc. Nat. Acad. Sci. U.S.A. 1989, 86,
1443]. There is clinical and genetic evidence implicating both
forms of glycogen synthase in metabolic diseases such as type 2
diabetes and cardiovascular disease. Both basal and
insulin-stimulated glycogen synthase activity in muscle cells from
diabetic subjects were significantly lower than in cells from lean
non-diabetic subjects [Henry, R. R. et al. J. Clin. Invest. 1996,
98, 1231-1236; Nikoulina, S. E. et al. J. Clin. Enocrinol. Metab.
2001, 86, 4307-4314]. Furthermore, several studies have shown that
levels of muscle [Eriksson, J. et al. N. Engl. J. Mod. 1989, 331,
337; Schulman, R. G. et al. N. Engl. J. Med. 1990, 332, 223;
Thorburn, A. W. et al. J. Clin. Invest. 1991, 87, 489] and liver
[Krssak, M. et.al. Diabetes 2004, 53, 3048] glycogen are lower in
diabetic patients than in control subjects. In addition, genetic
studies have shown associations in several populations between type
2 diabetes and/or cardiovascular disease and mutation/deletion in
the GYS1 gene encoding the muscle isoform of glycogen synthase
[Orhu-Melander, M. et al. Diabetes 1999, 48, 918; Fredriksson, J.
et.al. PLoS ONE 2007, 3, e285; Kolhberg G. et.al. N. Engl. J. Med.
2007, 357, 1507]. Patients lacking GYS2 encoding the liver isoform
of glycogen synthase, suffer from fasting ketotic hypoglycemia and
postprandial hyperglycemia, hyperlactanemia and hyperlipidemia,
supporting the essential role of liver GS in maintaining normal
nutrient metabolism. [Weinstein, D. A. et.al. Mol. Genetics. and
Metabolism, 2006, 87, 284]
[0012] Glycogen synthase is subject to complex regulation,
involving phosphorylation in at least nine sites [Lawrence, J. C.,
Jr. and Roach, P. J. Diabetes 1997, 46, 541]. The dephosphorylated
form of the enzyme is active. Glycogen synthase is phosphorylated
by a number of enzymes of which glycogen synthase kinase 3P
(GSK3.beta.) is the best understood [Tadayyon, M. and Smith, S. A.
Expert Opin. Investig. Drugs 2003, 12, 307], and glycogen synthase
is dephosphorylated by protein phosphatase type I (PP1) and protein
phosphatase type 2A (PP2A). In addition, glycogen synthase is
regulated by an endogenous ligand, glucose-6-phosphate which
allosterically stimulates the activity of glycogen synthase by
causing a change in the conformation of the enzyme that renders it
more susceptible to dephosphorylation by the protein phosphatases
to the active form of the enzyme [Gomis, R. R. et al. J. Biol.
Chem. 2002, 277, 23246].
[0013] Several mechanisms have been proposed for the effect of
insulin in reducing blood glucose levels, each resulting in an
increase in the storage of glucose as glycogen. First, glucose
uptake is increased through recruitment of the glucose transporter
GLUT4 to the plasma membrane [Holman, G. D. and Kasuga, M.
Diabetologia 1997, 40, 991]. Second, there is an increase in the
concentration of glucose-6-phosphate, the allosteric activator of
glycogen synthase [Villar-Palasi, C. and Guinovart, J. J. FASEB J.
1997, 11, 544]. Third, a kinase cascade beginning with the tyrosine
kinase activity of the insulin receptor results in the
phosphorylation and inactivation of GSK3.beta., thereby preventing
the deactivation of glycogen synthase [Cohen, P. Biochem. Soc.
Trans. 1993, 21, 555; Yeaman, S. J. Biochem. Soc. Trans. 2001, 29,
537].
[0014] Because a significant decrease in the activity of glycogen
synthase has been found in diabetic patients, and because of its
key role in glucose utilization, the activation of the enzyme
glycogen synthase holds therapeutic promise for the treatment of
metabolic diseases such as type 2 diabetes and cardiovascular
diseases. The only known allosteric activators of the enzyme are
glucose-6-phosphate [Leloir, L. F. et al. Arch. Biochem. Biophys.
1959, 81, 508] and glucosamine-6-phosphate [Virkamaki, A. and
Yki-Jarvinen, H. Diabetes 1999, 48, 1101].
[0015] The following biaryloxymethylarenecarboxylic acids are
reported to be commercially available from Otava, Toronto, Canada,
Akos Consulting & Solutions, Steinen, Germany or Princeton
BioMolecular Research, Monmouth Junction, N.J.:
4-(biphenyl-4-yloxymethyl)-benzoic acid,
3-(biphenyl-4-yloxymethyl)-benzoic acid,
[4-(biphenyl-4-yloxymethyl)-phenyl]-acetic acid,
[4-(4'-methyl-biphenyl-4-yloxymethyl)-phenyl]-acetic acid,
4-(4'-methyl-biphenyl-4-yloxymethyl)-benzoic acid,
3-(3-bromo-biphenyl-4-yloxymethyl)-benzoic acid,
[4-(3-bromo-biphenyl-4-yloxymethyl)-phenyl]-acetic acid,
2-(4'-methyl-biphenyl-4-yloxymethyl)-benzoic acid,
5-(biphenyl-4-yloxymethyl)-furan-2-carboxylic acid,
5-(4'-methyl-biphenyl-4-yloxymethyl)-furan-2-carboxylic acid,
5-(3-bromo-biphenyl-4-yloxymethyl)-furan-2-carboxylic acid,
4-(biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid,
5-methyl-4-(4'-methyl-biphenyl-4-yloxymethyl)-furan-2-carboxylic
acid,
4-(3-bromo-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic
acid, 2-(biphenyl-4-yloxymethyl)-4-methyl-thiazole-5-carboxylic
acid, [2-(biphenyl-4-yloxymethyl)-thiazol-4-yl]-acetic acid,
[2-(4'-methyl-biphenyl-4-yloxymethyl)-thiazol-4-yl]-acetic acid and
[5-(biphenyl-4-yloxymethyl)-[1,3,4]oxadiazol-2-yl]-acetic acid.
[0016] Some biaryloxymethylarenecarboxylic acids are known in the
art. However, none of these known compounds have been associated
with either the treatment of diseases mediated by the activation of
the glycogen synthase enzyme or to any pharmaceutical composition
for the treatment of diseases mediated by the activation of the
glycogen synthase enzyme. Andersen, H. S. et al. WO 9740017
discloses the structure and synthetic route to
3-(biphenyl-4-yloxymethyl)-benzoic acid as an intermediate in the
synthesis of SH2 inhibitors. Winkelmann, E. et al. DE 2842243
discloses 5-(biphenyl-4-yloxymethyl)-thiophene-2-carboxylic acid as
a hypolipemic agent. Mueller, T. et al. DE 4142514 discloses
2-(biphenyl-3-yloxymethyl)-benzoic acid as a fungicide. Ghosh, S.
S. et al. WO 2004058679 discloses biaryloxymethylarene acids as
ligands of adenine nucleoside translocase. Van Zandt, M. C. WO
2008033455 discloses biphenyl and heteroarylphenyl derivatives as
protein phosphatase-1B inhibitors.
[0017] Glycogen synthase activators and stimulators of glycogen
production have been reported. Chu, C. A et al. US 20040266856
discloses biaryoxymethylarenecarboxylic acids as glycogen synthase
activators. Chu, C. A. WO 2005000781 discloses biaryloxymethylarene
carboxylic acids as activators of glycogen synthase. Yang, S--P.
and Huang, Y. US 20050095219 discloses hyaluronic acid compounds
that stimulate glycogen production. Gillespie, P. et al. WO
2005075468 discloses biaryoxymethylarene carboxylic acids as
glycogen synthase activators. Gillespie, P. et al. WO 2006058648
discloses biaryoxymethylarene carboxylic acids as glycogen synthase
activators. Bucala, R. et al. WO 2007044622 discloses macrophage
migration inhibitory factor agonists that stimulate glycogen
production.
SUMMARY OF THE INVENTION
[0018] The present invention is directed to compounds of the
formula I:
##STR00002##
as well as pharmaceutically acceptable salts thereof,
pharmaceutical compositions containing them and to methods of
treating diseases and disorders. The compounds and compositions
disclosed herein are glycogen synthase activators and are useful
for the treatment of metabolic diseases and disorders, preferably
diabetes mellitus, more preferably type II diabetes mellitus.
DETAILED DESCRIPTION OF THE INVENTION
[0019] In an embodiment of the present invention, provided is a
compound of formula (I):
##STR00003##
wherein, [0020] R1, R2, R3, independently of each other, is
hydrogen, halogen, lower alkyl or alkoxy; [0021] R4 is hydrogen,
unsubstituted lower alkyl, or lower alkyl substituted with one to
four substituents independently selected from the group consisting
of methyl, (.dbd.O) and --COOH; [0022] X is CH or N; and [0023] Y
is hydrogen or --NH.sub.2, or a pharmaceutically acceptable salt
thereof.
[0024] Preferably, R1, R2, R3, independently of each other, is
halogen, lower alkyl or alkoxy.
[0025] Preferably, R1, R2, R3, independently of each other, is
fluorine, chlorine, methyl or methoxy.
[0026] Preferably, R1 and R2 are halogen.
[0027] Preferably, R1 is fluorine or chlorine. Preferably, R2 is
fluorine or chlorine.
[0028] Preferably, R3 is halogen or alkoxy. Preferably, R3 is
fluorine or methoxy.
[0029] Preferably, R4 is lower alkyl substituted with one to four
substituents independently selected from the group consisting of
methyl, (.dbd.O) and --COOH.
[0030] Preferably, R4 is:
##STR00004##
[0031] Preferably, X is CH.
[0032] Preferably, X is N.
[0033] Preferably, Y is hydrogen.
[0034] Preferably, Y is --NH.sub.2.
[0035] Preferably, the compound according to formula (I) is: [0036]
4-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-1H-indazole;
[0037]
3-[4-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indazol-1-yl]-pro-
pionic acid; [0038]
6-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-1H-indazole;
[0039]
[6-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indazol-1-yl]-aceti-
c acid; [0040]
3-[6-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indazol-1-yl]-pro-
pionic acid; [0041]
6-(4',5'-difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-1H-indole;
[0042]
3-[6-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-propi-
onic acid; [0043]
[6-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-acetic
acid; [0044]
3-[6-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-butyr-
ic acid; [0045]
4-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-1H-indole;
[0046]
4-[4-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-4-oxo-
-butyric acid; [0047]
4-[4-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-2,2-d-
imethyl-4-oxo-butyric acid; [0048]
[4-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-acetic
acid; [0049]
3-[4-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-propi-
onic acid; [0050]
3-[4-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-butyr-
ic acid; [0051]
5-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-1H-indazol-3-ylamine-
; or [0052]
Methyl-5-(2',4',5'-trifluoro-biphenyl-4-yloxymethyl)-1H-indazol-3-ylamine-
.
[0053] In another embodiment, provided is a pharmaceutical
composition, comprising a therapeutically effective amount of a
compound according to formula (I), or a pharmaceutically acceptable
salt thereof, and a pharmaceutically acceptable carrier and/or
adjuvant.
[0054] It is to be understood that the terminology employed herein
is for the purpose of describing particular embodiments, and is not
intended to be limiting. Further, although any methods, devices and
materials similar or equivalent to those described herein can be
used in the practice or testing of the invention, the preferred
methods, devices and materials are now described.
[0055] As used herein, the term "alkyl", alone or in combination
with other groups, refers to a branched or straight-chain
monovalent saturated aliphatic hydrocarbon radical of one to twenty
carbon atoms, preferably one to sixteen carbon atoms, more
preferably one to ten carbon atoms.
[0056] The term "cycloalkyl" refers to a monovalent mono- or
polycarbocyclic radical of three to ten, preferably three to six
carbon atoms. This term is further exemplified by radicals such as
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
bornyl, adamantyl, indenyl and the like. In a preferred embodiment,
the "cycloalkyl" moieties can optionally be substituted with one,
two, three or four substituents with the understanding that said
substituents are not, in turn, substituted further unless indicated
otherwise in the Examples or claims below. Each substituent can
independently be, for example, alkyl, alkoxy, halogen, amino,
hydroxyl or oxygen (0=) unless otherwise specifically indicated.
Examples of cycloalkyl moieties include, but are not limited to,
optionally substituted cyclopropyl, optionally substituted
cyclobutyl, optionally substituted cyclopentyl, optionally
substituted cyclopentenyl, optionally substituted cyclohexyl,
optionally substituted cyclohexylene, optionally substituted
cycloheptyl.
[0057] The term "heterocycloalkyl" denotes a mono- or polycyclic
alkyl ring, wherein one, two or three of the carbon ring atoms is
replaced by a heteroatom such as N, O or S. Examples of
heterocycloalkyl groups include, but are not limited to,
morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl,
pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxanyl
and the like. The heterocycloalkyl groups may be unsubstituted or
substituted and attachment may be through their carbon frame or
through their heteroatom(s) where appropriate, with the
understanding that said substituents are not, in turn, substituted
further unless indicated otherwise in the Examples or claims
below.
[0058] The term "lower alkyl", alone or in combination with other
groups, refers to a branched or straight-chain alkyl radical of one
to nine carbon atoms, preferably one to six carbon atoms. This term
is further exemplified by radicals such as methyl, ethyl, n-propyl,
isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, n-pentyl,
3-methylbutyl, n-hexyl, 2-ethylbutyl and the like.
[0059] The term "aryl" refers to an aromatic mono- or
polycarbocyclic radical of 6 to 12 carbon atoms having at least one
aromatic ring. Examples of such groups include, but are not limited
to, phenyl, napthyl. 1,2,3,4-tetrahydronaphthalene,
1,2-dihydronaphthalene, indanyl, 1H-indenyl and the like.
[0060] The alkyl, lower alkyl and aryl groups may be substituted or
unsubstituted. When substituted, there will generally be, for
example, 1 to 4 substituents present, with the understanding that
said substituents are not, in turn, substituted further unless
indicated otherwise in the Examples or claims below. Substituents
may include, for example, halogen, methyl, (.dbd.O), alkoxy and
carboxylic acid.
[0061] The term "heteroaryl," refers to an aromatic mono- or
polycyclic radical of 5 to 12 atoms having at least one aromatic
ring containing one, two, or three ring heteroatoms selected from
N, O, and S, with the remaining ring atoms being C. One or two ring
carbon atoms of the heteroaryl group may be replaced with a
carbonyl group. The heteroaryl group may be substituted
independently with one, two, or three substituents, with the
understanding that said substituents are not, in turn, substituted
further unless indicated otherwise in the Examples or claims below.
Substituents may include, for example, lower alkyl and halogen.
[0062] As used herein, the term "alkoxy" means alkyl-O--; and
"alkoyl" means alkyl-CO--. Alkoxy substituent groups or
alkoxy-containing substituent groups may be substituted by, for
example, one or more alkyl groups with the understanding that said
substituents are not, in turn, substituted further unless indicated
otherwise in the Examples or claims below.
[0063] As used herein, the term "halogen" means a fluorine,
chlorine, bromine or iodine radical, preferably a fluorine,
chlorine or bromine radical, and more preferably a fluorine or
chlorine radical.
[0064] Compounds of formula (I) can have one or more asymmetric
carbon atoms and can exist in the form of optically pure
enantiomers, mixtures of enantiomers such as, for example,
racemates, optically pure diastereoisomers, mixtures of
diastereoisomers, diastereoisomeric racemates or mixtures of
diastereoisomeric racemates. The optically active forms can be
obtained for example by resolution of the racemates, by asymmetric
synthesis or asymmetric chromatography (chromatography with chiral
adsorbents or eluant). The invention embraces all of these
forms.
[0065] As used herein, the term "pharmaceutically acceptable salt"
means any pharmaceutically acceptable salt of the compound of
formula (I). Salts may be prepared from pharmaceutically acceptable
non-toxic acids and bases including inorganic and organic acids and
bases. Such acids include, for example, acetic, benzenesulfonic,
benzoic, camphorsulfonic, citric, ethenesulfonic, dichloroacetic,
formic, fumaric, gluconic, glutamic, hippuric, hydrobromic,
hydrochloric, isethionic, lactic, maleic, malic, mandelic,
methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic,
phosphoric, succinic, sulfuric, tartaric, oxalic, p-toluenesulfonic
and the like. Particularly preferred are fumaric, hydrochloric,
hydrobromic, phosphoric, succinic, sulfuric and methanesulfonic
acids. Acceptable base salts include alkali metal (e.g. sodium,
potassium), alkaline earth metal (e.g. calcium, magnesium) and
aluminium salts.
[0066] In the practice of the method of the present invention, an
effective amount of any one of the compounds of this invention or a
combination of any of the compounds of this invention or a
pharmaceutically acceptable salt thereof, is administered via any
of the usual and acceptable methods known in the art, either singly
or in combination. The compounds or compositions can thus be
administered orally (e.g., buccal cavity), sublingually,
parenterally (e.g., intramuscularly, intravenously, or
subcutaneously), rectally (e.g., by suppositories or washings),
transdermally (e.g., skin electroporation) or by inhalation (e.g.,
by aerosol), and in the form of solid, liquid or gaseous dosages,
including tablets and suspensions. The administration can be
conducted in a single unit dosage form with continuous therapy or
in a single dose therapy ad libitum. The therapeutic composition
can also be in the form of an oil emulsion or dispersion in
conjunction with a lipophilic salt such as pamoic acid, or in the
form of a biodegradable sustained-release composition for
subcutaneous or intramuscular administration.
[0067] Useful pharmaceutical carriers for the preparation of the
compositions hereof, can be solids, liquids or gases; thus, the
compositions can take the form of tablets, pills, capsules,
suppositories, powders, enterically coated or other protected
formulations (e.g. binding on ion-exchange resins or packaging in
lipid-protein vesicles), sustained release formulations, solutions,
suspensions, elixirs, aerosols, and the like. The carrier can be
selected from the various oils including those of petroleum,
animal, vegetable or synthetic origin, e.g., peanut oil, soybean
oil, mineral oil, sesame oil, and the like. Water, saline, aqueous
dextrose, and glycols are preferred liquid carriers, particularly
(when isotonic with the blood) for injectable solutions. For
example, formulations for intravenous administration comprise
sterile aqueous solutions of the active ingredient(s) which are
prepared by dissolving solid active ingredient(s) in water to
produce an aqueous solution, and rendering the solution sterile.
Suitable pharmaceutical excipients include starch, cellulose, talc,
glucose, lactose, talc, gelatin, malt, rice, flour, chalk, silica,
magnesium stearate, sodium stearate, glycerol monostearate, sodium
chloride, dried skim milk, glycerol, propylene glycol, water,
ethanol, and the like. The compositions may be subjected to
conventional pharmaceutical additives such as preservatives,
stabilizing agents, wetting or emulsifying agents, salts for
adjusting osmotic pressure, buffers and the like. Suitable
pharmaceutical carriers and their formulation are described in
Remington's Pharmaceutical Sciences by E. W. Martin. Such
compositions will, in any event, contain an effective amount of the
active compound together with a suitable carrier so as to prepare
the proper dosage form for proper administration to the
recipient.
[0068] The dose of a compound of the present invention depends on a
number of factors, such as, for example, the manner of
administration, the age and the body weight of the subject, and the
condition of the subject to be treated, and ultimately will be
decided by the attending physician or veterinarian. Such an amount
of the active compound as determined by the attending physician or
veterinarian is referred to herein, and in the claims, as a
"therapeutically effective amount". For example, the dose of a
compound of the present invention is typically in the range of
about 1 to about 1000 mg per day. Preferably, the therapeutically
effective amount is in an amount of from about 1 mg to about 500 mg
per day.
[0069] It will be appreciated, that the compounds of general
formula (I) in this invention may be derivatized at functional
groups to provide derivatives which are capable of conversion back
to the parent compound in vivo. Physiologically acceptable and
metabolically labile derivatives, which are capable of producing
the parent compounds of general formula I in vivo are also within
the scope of this invention.
[0070] Compounds of the present invention can be prepared beginning
with commercially available starting materials and utilizing
general synthetic techniques and procedures known to those skilled
in the art. Outlined below are reaction schemes suitable for
preparing such compounds. Further exemplification can be found in
the specific Examples detailed below.
[0071] Chemicals may be purchased from companies such as for
example Aldrich, Argonaut Technologies, VWR and Lancaster.
Chromatography supplies and equipment may be purchased from such
companies as for example AnaLogix, Inc, Burlington, Wis.; Biotage
AB, Charlottesville, Va.; Analytical Sales and Services, Inc.,
Pompton Plains, N.J.; Teledyne Isco, Lincoln, Nebr.; VWR
International, Bridgeport, N.J.; Varian Inc., Palo Alto, Calif.,
and Multigram II Mettler Toledo Instrument Newark, Del. Biotage,
ISCO and Analogix columns are pre-packed silica gel columns used in
standard chromatography.
[0072] Definitions as used herein include:
GS is glycogen synthase, THF is tetrahydrofuran,
DMF is N,N-dimethylformamide,
DMA is N,N-dimethylacetamide,
[0073] DMSO is dimethylsulfoxide, DCM is dichloromethane, DME is
dimethoxyethane, MeOH is methanol, EtOH is ethanol, NaOH is sodium
hydroxide, TFA is 1,1,1-trifluoroacetic acid, HOBT is
1-hydroxybenzotriazole, PyBroP is bromotripyrrolidinophosphonium
hexafluorophosphate, EDCI is
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride,
DIPEA is diisopropylethylamine, Boc is tert-butyloxycarbonyl,
NBS is N-bromosuccinimde,
[0074] Brine is saturated aqueous sodium chloride solution, TLC is
thin layer chromatography, RP HPLC is reversed phase high
performance liquid chromatography, HR-MS is high resolution mass
spectrometry, LC-MS is liquid chromatographic mass spectrometry, RT
is room or ambient temperature.
[0075] The preparation of substituted biphenylphenols is described
in Scheme 1, below. Commercially available phenylboronic acid (i)
can be coupled with 4-iodophenol under palladium catalysis
conditions to form the bi-aryl-phenol (ii), where R1, R2 and R3 can
be fluoro, chloro, methyl or methoxy groups. Alternatively, the
required biphenylphenol (iv) can also be prepared through the
coupling of 4-hydroxy-arylboronic acid with the corresponding
arylbromide under palladium catalysis conditions (Scheme 1).
Non-commercially available arylbromides (v) can be prepared through
aromatic bromination.
##STR00005##
[0076] The preparation of substituted indazoles (xii) is shown in
Scheme 2. Amino-methyl benzyl alcohol (vi) can be treated with
acetic anhydride and iso-amyl-nitrite in the presence of potassium
carbonate and a phase transfer catalyst such as 18-crown-6 to give
the bis-acetyl indazole vii. Upon treatment with HBr followed by
tetrahydropyran, the bromomethyl derivative viii may be obtained.
Compound viii can be alkylated with a substituted bi-aryl-phenol
under basic conditions to form a
substituted-bi-phenyloxymethyl-indazole (ix), which may be
deprotected under acidic conditions, such as HCl or TFA in various
solvents to give substituted-bi-phenyloxymethyl-indazole (x), where
R1, R2 and R3 may be fluoro, chloro, methyl or methoxy. Xi may be
treated with a bromoacetate or bromopropionate under basic
conditions, such as lithium bis(trimethylsilyl)amide or cesium
carbonate to give ester xi, which may be hydrolyzed to acid xii,
where R1, R2 and R3 may be fluoro, chloro, methyl or methoxy and R4
may be a lower alkyl.
##STR00006##
[0077] Substituted indoles (xix) may be prepared as shown in Scheme
3. Formyl indole (xiii) may be N-protected, preferably with Boc and
then reduced to give alcohol xv, preferably with sodium
borohydride. Under Mitsunobu conditions, xv can be alkylated to
with a biphenylphenol to give ether xvi, where R1, R2 and R3 may be
fluoro, chloro, methyl or methoxy. Compound xvi may be deprotected
under mild conditions, preferably by heating in MeOH under
microwave conditions at 150.degree. C. The free indole xvii may be
alkylated under basic conditions, such as lithium
bis(trimethylsilyl)amide or cesium carbonate to give ester xviii,
which may be hydrolyzed to acid xix, where R1, R2 and R3 may be
fluoro, chloro, methyl or methoxy and R4 and R5 may be a lower
alkyl.
##STR00007##
[0078] As shown in Scheme 4, the free indole xvii may be acylated
under basic conditions, such as lithium bis(trimethylsilyl)amide or
cesium carbonate to give acid xx, where R1, R2 and R3 may be
fluoro, chloro, methyl or methoxy and R6 may be a lower alkyl.
##STR00008##
[0079] The preparation of substituted 3-amino-indazoles is shown in
Scheme 5. 5-Bromomethyl-2-fluoro-benzonitrile xx can be alkylated
with a substituted bi-aryl-phenol under basic conditions to form a
substituted-bi-phenyloxymethyl-benzonitrile (xxi), which upon
heating with hydrazine hydrate or an alkylated hydrazine, can give
amino-indazole (xxii), where R1, R2 and R3 may be fluoro, chloro,
methyl or methoxy and R7 may be a lower alkyl.
##STR00009##
[0080] The invention will now be further described in the Examples
below, which are intended as an illustration only and do not limit
the scope of the invention.
EXAMPLES
Part I
Preparation of Preferred Intermediates
4',5'-Difluoro-2'-methoxy-biphenyl-4-ol
##STR00010##
[0082] 4,5-Difluoro-2-methoxyphenyl-boronic acid (8.8 g, 46.82
mmol) and 4-iodophenol (6.86 g, 31.21 mmol) were suspended in 165
ml of DMF. H.sub.2O (40 mL) was added and the mixture was degassed
with argon. Finely ground potassium carbonate (13 g, 93.63 mmol)
and tetrakis(triphenylphosphine) palladium(0) (1.5 g, 1.29 mmol)
were added. The reaction was stirred at 80-85.degree. C. for 1 hr
under argon and cooled. The mixture was diluted with ethyl acetate
and water. The organic layer was washed with brine, dried and
solvents were evaporated. The crude product was purified by flash
chromatography, eluting with 0-8% ethyl acetate in hexanes to yield
4',5'-difluoro-2'-methoxy-biphenyl-4-ol (6.58 g, 89.3%). LR-MS (ES)
calculated for C13H10F2O2, 236.22. Found m/z 235 (M-H).
2',4',5'-Trifluoro-biphenyl-4-ol
##STR00011##
[0084] A mixture of 2,4,6-trifluorophenylboronic acid (43.8 g,
249.2 mmol), 4-iodophenol (50 g, 226.5 mmol), potassium carbonate
(78 g, 556.3 mmol), Pd (dppf)Cl.sub.2 methylene chloride complex
(5.5 g, 6.8 mmol), DMF (150 mL), and water (38 mL) was degassed,
flashed with nitrogen, and heated at 50.degree. C. overnight. The
mixture was then diluted with EtOAc and water, acidified with conc.
HCl under cooling with ice-water bath, stirred with charcoal, and
filtered through celite. The organic layer was separated, washed
with water and brine, dried over sodium sulfate, filtered, and
evaporated to afford a deep red oily product. The crude product in
EtOAc was passed through a plug of silica gel to give light brown
solid product (38 g, 75%). LC-MS (ES) calculated for C12H7F3O, 224.
Found m/z 224 [M+H].sup.+.
Part II
Preparation of Preferred Embodiments of the Invention
Example 1
4-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-1H-indazole
##STR00012##
[0086] 3-Amino-2-methyl benzyl alcohol (0.82 g, 5.98 mmol), acetic
anhydride (1.68 mL, 17.8 mmol), potassium acetate (1.75 g, 17.8
mol), isoamyl nitrite (1.82 mL, 13.7 mmol) and 18-crown-6 (79 mg,
0.3 mmol) in 25 mL CHCl3 were reacted as described in EP99/07620.
The crude product was purified by flash chromatography with a
gradient from 0-35% ethyl acetate in hexanes to yield acetic acid
1-acetyl-1H-indazol-4-ylmethyl ester.
[0087] Acetic acid 1-acetyl-1H-indazol-4-ylmethyl ester was treated
with 6 mL 48% HBr with stirring overnight and then refluxed for 5
hrs. The reaction mixture was concentrated, diluted with CH3CN and
the precipitated solid was filtered off. The residue was treated
with dihydropyran (0.53 g, 6.28 mmol) in 25 mL THF and heated to
reflux for 5 hrs. The reaction was cooled and distributed between
CH2Cl2 and saturated NaHCO3. The organic layer was separated,
washed with H.sub.2O and concentrated in vacuo. The crude product
(2.0 g) was used without further purification.
[0088] 4-Bromomethyl-1-(tetrahydro-pyran-2-yl)-1H-indazole (0.5 g,
1.69 mmol), 3-(4',5'-difluoro-2'-methoxy-biphenyl-4-ol (0.4 g, 1.69
mmol) and potassium carbonate (0.23 g, 1.69 mmol) in 15 mL THF/3 mL
DMF was heated to 70.degree. C. overnight. The reaction was cooled
and distributed between EtOAc and H.sub.2O. The organic layer was
separated and concentrated in vacuo. The crude product was purified
by flash chromatography with a gradient from 0-25% ethyl acetate in
hexanes to yield
4-(4',5'-difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-1-(tetrahydro--
pyran-2-yl)-1H-indazole as a white solid (400 mg, 52.5%). HR-MS
(ES) calculated for C26H24F2N2O3, 473.1646. Found m/z 473.1647
[M+Na].sup.+.
[0089]
4-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-1-(tetrahydro--
pyran-2-yl)-1H-indazole (0.4 g, 0.888 mmol) and 1N HCl (1.8 mL, 1.8
mmol) in 10 mL MeOH were heated to reflux for 5 hrs. The reaction
was cooled and distributed between EtOAc and H.sub.2O. The water
layer was made basic to pH 12 and the organic layer was separated
and concentrated in vacuo. The crude product was purified by flash
chromatography with a gradient from 20-100% ethyl acetate in
hexanes to yield
4-(4',5'-difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-1H-indazole as
a white solid (240 mg, 73.7%). LC-MS (ES) calculated for
C21H16F2N2O2, 366.37. Found m/z 367 [M+H].sup.+.
Example 2
3-[4-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indazol-1-yl]-prop-
ionic acid
##STR00013##
[0091]
4-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-1H-indazole
(0.09 g, 0.245 mmol), ethyl bromopropionate (0.045 g, 0.245 mmol),
cesium carbonate (81 mg, 0.294 mmol) in 6 mL DMF was stirred at RT
overnight and then heated to 90.degree. C. for 35 min. The reaction
was cooled and distributed between EtOAc and H.sub.2O. The organic
layer was separated and concentrated in vacuo. The crude product
was purified by flash chromatography with a gradient from 0-30%
ethyl acetate in hexanes to yield
3-[4-(4',5'-difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indazol-1-y-
l]-propionic acid ethyl ester as a white solid (98 mg, 85.7%).
[0092]
3-[4-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indazol-1-y-
l]-propionic acid ethyl ester (0.095 g, 0.204 mmol) and lithium
hydroxide hydrate (10 mg, 0.245 mmol) in 5 mL THF/1 mL H.sub.2O was
stirred at RT for 3 hrs. The reaction was distributed between EtOAc
and H.sub.2O. The water layer was made acidic to pH 3 with 1N HCl
and the organic layer was separated and concentrated in vacuo. The
crude product was purified by flash chromatography with a gradient
from 0-3% methanol in CH.sub.2Cl.sub.2 to yield
3-[4-(4',5'-difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indazol-1-yl]-pro-
pionic acid as a white solid (53 mg, 59%). LC-MS (ES) calculated
for C24H20F2N2O4, 438.43. Found m/z 439 [M+H].sup.+.
Example 3
6-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-1H-indazole
##STR00014##
[0094]
6-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-1H-indazole
was prepared from 3-amino-4 methyl benzyl alcohol (1 g, 0.729
mmol), as described above for
4-(4',5'-difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-1H-indazole,
to yield 510 mg of product. LC-MS (ES) calculated for C21H16F2N2O2,
366.37. Found m/z 367 [M+H].sup.+.
Example 4
[6-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indazol-1-yl]-acetic
acid
##STR00015##
[0096]
6-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-1H-indazole
(0.15 g, 0.331 mmol), ethyl bromoacetate (0.055 g, 0.331 mmol),
cesium carbonate (119 mg, 0.364 mmol) in 6 mL DMF was stirred at RT
overnight and then heated to 90.degree. C. for 35 min. The reaction
was cooled and distributed between EtOAc and H.sub.2O. The organic
layer was separated and concentrated in vacuo. The crude product
was purified by flash chromatography with a gradient from 0-30%
ethyl acetate in hexanes to yield
[6-(4',5'-difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indazol-1-yl]-
-acetic acid ethyl ester as a white solid (120 mg, 80.1%).
[0097]
[6-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indazol-1-yl]-
-acetic acid ethyl ester (0.095 g, 0.204 mmol) and lithium
hydroxide hydrate (10 mg, 0.245 mmol) in 5 mL THF/1 mL H.sub.2O was
stirred at RT for 6 hrs. The reaction was distributed between EtOAc
and H.sub.2O. The water layer was made acidic to pH 3 with 1N HCl
and the organic layer was separated and concentrated in vacuo. The
crude product was purified by trituration with Et2O to yield
[6-(4',5'-difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indazol-1-yl]-aceti-
c acid as a white solid. LC-MS (ES) calculated for C23H18F2N2O4,
424.41. Found m/z 425 [M+H].sup.+.
Example 5
[0098]
3-[6-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indazol-1-y-
l]-propionic acid
##STR00016##
[0099]
3-[6-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indazol-1-y-
l]-propionic acid was prepared from
6-(4',5'-difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-1H-indazole
(0.1 g, 0.221 mmol) and ethyl bromopropionate (40 mg, 0.221 mmol),
as described above for
[6-(4',5'-difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indazol-1-
-yl]-acetic acid, to yield 81 mg (83.6%) of product. LC-MS (ES)
calculated for C24H20F2N2O4, 438.43. Found m/z 439 [M+H].sup.+.
Example 6
6-(4',5'-difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-1H-indole
##STR00017##
[0101] To 1H-Indole-6-carbaldehyde (1 g, 1.3 mmol, 1 eq) in
acetonitrile (10 mL) was added potassium carbonate (1.5 g 11 mmol,
1.5 eq) and then di-tert-butyl-dicarbonate (2.39 g, 11 mmol, 1.5
eq). The reaction was heated, tetrahydrofuran (10 mL) was added,
and the reaction refluxed for 5 hr. The reaction cooled to RT,
diluted with ethyl acetate (150 mL) washed with NaCl solution (100
mL water, 100 mL brine), dried over sodium sulfate, concentrated,
adsorbed onto silica gel and purified by flash chromatography with
a gradient from 1-10% ethyl acetate in hexanes to yield
6-formyl-indole-1-carboxylic acid tert-butyl ester as a yellow,
viscous oil (1.2 g). LC-MS (ES) calculated for C14H15NO3, 245.1.
Found m/z 246 [M+H].sup.+.
[0102] To 6-formyl-indole-1-carboxylic acid tert-butyl ester (1.2
g) in methanol (5 mL) in an ice bath was added sodium borohydride
(0.27 mg) portion wise. The reaction was allowed to warm to room
temperature over 1.5 hr. The reaction diluted with ethyl acetate
(200 mL) washed with water (200 mL), brine (100 mL), dried over
sodium sulfate, concentrated, adsorbed onto silica gel and purified
by flash chromatography with a gradient from 5-40% ethyl acetate in
hexanes to yield 6-hydroxymethyl-indole-1-carboxylic acid
tert-butyl ester as a clear viscous oil (0.91 g, 78%) LC-MS (ES)
calculated for C14H17NO3, 247.1. Found m/z 246 [M-H].sup.+.
[0103] To 4',5'-difluoro-2'-methoxy-biphenyl-4-ol (472 mg, 2 mmol,
2 eq) was added polymer-bound triphenyl-phosphine (667 mg, 2 mmol,
2 eq) and dichloromethane (10 mL). The mixture was placed under
nitrogen, cooled in an ice bath, diisopropyl azodicarboxylate
(0.394 mL, 2 mmol, 2 eq) was added drop-wise, stirred for 1.5 hr. A
solution of 6-hydroxymethyl-indole-1-carboxylic acid tert-butyl
ester (247 mg, 1 mmol, 1 eq) and triethylamine (0.279 mL, 2 mmol, 2
eq) in dichloromethane (2 mL) was added drop to portion wise and
the reaction allowed to warm to room temperature overnight (20 hr).
The reaction was filtered over Celite, adsorbed onto silica gel,
and purified by flash chromatography with a gradient from 1-15%
ethyl acetate in hexanes to yield
6-(4',5'-difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indole-1-carboxylic
acid tert-butyl ester white/clear solid (288 mg, 62%). LC-MS (ES)
calculated for C27H25F2NO2, 465.2. Found m/z 466 [M+H].sup.+.
[0104] To
6-(4',5'-difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indole-1-ca-
rboxylic acid tert-butyl ester (232 mg, 0.5 mmol) was added
methanol and the mixture was microwaved at 150.degree. C. for 30
min. The reaction was concentrated and dried from dichloromethane
to yield
6-(4',5'-difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-1H-indole as a
white solid (184 mg, 99%). LC-MS (ES) calculated for C22H17F2NO2,
365.2. Found m/z 366 [M+H].sup.+.
Example 7
3-[6-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-propio-
nic Acid
##STR00018##
[0106] To
6-(4',5'-difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-1H-indole (37
mg, 0.10 mmol, 1 eq.) was added dimethylformamide (1 mL), cesium
carbonate (40 mg, 0.11 mmol, 1.1 eq.) and 3-bromo-propionic acid
ethyl ester (0.014 mL, 0.11 mmol, 1.1 eq.). The reaction was
stirred and heated at 90.degree. C. for 17 hr. The reaction was
diluted with dimethylsulfoxide, filtered, and purified by HPLC with
a 50-100% acetonitrile in water gradient to yield
3-[6-(4',5'-difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-propi-
onic acid ethyl ester as clear oil (33 mg, 73%). LC-MS (ES)
calculated for C27H25F2NO4, 465.2. Found m/z 466 [M+H].sup.+.
[0107] To
3-[6-(4',5'-difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1--
yl]-propionic acid ethyl ester (24 mg, 0.051 mmol, 1 eq.) was added
tetrahydrofuran (1 mL), water (1 mL) and lithium hydroxide
(LiOH--H.sub.2O (4.5 mg, 0.1 mmol, 2.2 eq.). The reaction was
stirred and at room temperature for 2 and then DOWEX resin
(50WX4-400, acid washed, 2 g) was added. The mixture was stirred at
room temperature, filtered, dried, and then lyophilized from
acetonitrile/water to yield
3-[6-(4',5'-difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-propi-
onic acid as an off-white solid (23 mg, 98%). LC-MS (ES) calculated
for C25H21F2NO4, 437.12. Found m/z 438 [M+H].sup.+.
Example 8
[0108]
[6-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-A-
cetic Acid
##STR00019##
[0109]
[6-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-a-
cetic acid ethyl ester was synthesized by a procedure similar to
3-[6-(4',5'-difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-propi-
onic acid ethyl ester from starting materials
6-(4',5'-difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-1H-indole and
bromo-acetic acid ethyl ester to yield the product as a white
solid/wax (25 mg, 56%). LC-MS (ES) calculated for C26H23F2NO4,
451.2. Found m/z 452 [M+H].sup.+.
[0110]
[6-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-a-
cetic acid was synthesized by a procedure similar to
3-[6-(4',5'-difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-propi-
onic acid from starting material
[6-(4',5'-difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-acetic
acid ethyl ester to yield the product as a white solid (23 mg,
82%). LC-MS (ES) calculated for C24H19F2NO4, 423.1. Found m/z 424
[M+H].sup.+.
Example 9
3-[6-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-butyri-
c Acid
##STR00020##
[0112] To
6-(4',5'-difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-1H-indole (37
mg, 0.10 mmol, 1 eq.) was added dimethylformamide (1 ml), sodium
hydride (8 mg of 60% dispersion, 0.2 mmol, 2 eq.) and
(E)-but-2-enoic acid ethyl ester (0.025 ml, 0.2 mmol, 2 eq.). The
reaction was stirred at room temperature for 18 hr and heated at
50.degree. C. for 2 hr. To the reaction was added more
(E)-but-2-enoic acid ethyl ester (0.050 ml, 0.4 mmol, 4 eq.) and
the reaction heated at 80.degree. C. for 22 hr. The reaction was
partitioned between ethyl acetate (10 mL) and aqueous citric acid
(10 mL), the organic layer separated and washed with brine
(saturated NaCl), dried over magnesium sulfate, filtered,
evaporated under reduced pressure. The crude material was dissolved
in dimethylsulfoxide and purified by HPLC with a 50-100%
acetonitrile in water gradient to yield
3-[6-(4',5'-difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-butyr-
ic acid as white solid (3 mg, 6%). LC-MS (ES) calculated for
C26H23F2NO4, 451.2. Found m/z 452 [M+H].sup.+.
Example 10
4-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-1H-indole
##STR00021##
[0114] 4-Formyl-indole-1-carboxylic acid tert-butyl ester was
synthesized by a procedure similar to 6-Formyl-indole-1-carboxylic
acid tert-butyl ester from starting materials
1H-Indole-4-carbaldehyde and di-tert-butyl-dicarbonate to yield the
product as a clear yellow oil (2 g, 80%). LC-MS (ES) calculated for
C14H15NO3, 245.1. Found m/z 244 [M-H].sup.-.
[0115] 4-Hydroxymethyl-indole-1-carboxylic acid tert-butyl ester
was synthesized by a procedure similar to
6-hydroxymethyl-indole-1-carboxylic acid tert-butyl ester from
starting material 4-formyl-indole-1-carboxylic acid tert-butyl
ester to yield the product as a clear viscous oil (0.91 g, 78%).
LC-MS (ES) calculated for C14H17NO3, 247.1. Found m/z 246
[M+H].sup.+.
[0116]
4-(4',5'-difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indole-1-carbo-
xylic acid tert-butyl ester was synthesized by a procedure similar
to
6-(4',5'-difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indole-1-carboxylic
acid tert-butyl ester from starting materials
4-hydroxymethyl-indole-1-carboxylic acid tert-butyl ester and
4',5'-difluoro-2'-methoxy-biphenyl-4-ol to yield the product as a
white solid (880 mg, 70%). LC-MS (ES) calculated for C27H25F2NO2,
465.2. Found m/z 466 [M+H].sup.+.
[0117]
4-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-1H-indole was
synthesized by a procedure similar to
6-(4',5'-difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-1H-indole from
starting material
4-(4',5'-difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indole-1-carboxylic
acid tert-butyl ester to yield the product was a white solid (156
mg, 99%). LC-MS (ES) calculated for C22H17F2NO2, 365.1. Found m/z
366 [M+H].sup.+.
Example 11
4-[4-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-4-oxo--
butyric acid
##STR00022##
[0119] To
4-(4',5'-difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-1H-indole (37
mg, 0.10 mmol, 1 eq.) was added dimethylformamide (1 mL),
triethylamine (0.154 ml, 1.1 mmol, 10 eq.) and succinic anhydride
(30 mg, 0.3 mmol, 3 eq.) the reaction was stir at 80.degree. C. for
8 hr and allowed to cool to room temperature. Lithium
bis(trimethylsilyl)amide (1 M in THF, 1.2 mL, 1.2 mmol, 12 eq) was
added and the reaction was allowed to proceed at room temperature
for 24 hr. The reaction was purified by HPLC with a 30-100%
acetonitrile in water gradient and dried from
dichloromethane/hexanes mixture to yield
4-[4-(4',5'-difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-4-oxo-
-butyric acid as a white solid (16 mg, 34%). LC-MS (ES) calculated
for C26H21F2NO5, 465.1. Found m/z 466 [M+H].sup.+.
Example 12
[0120]
4-[4-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-
-2,2-dimethyl-4-oxo-butyric acid
##STR00023##
[0121]
4-[4-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-
-2,2-dimethyl-4-oxo-butyric acid was synthesized by a procedure
similar to
4-[4-(4',5'-difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-4-oxo-
-butyric acid from starting materials
4-(4',5'-difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-1H-indole and
2,2-dimethyl-succinic anhydride to yield the product as a white
solid (13 mg, 27%). LC-MS (ES) calculated for C28H25F2NO5, 493.2.
Found m/z 494 [M+H].sup.+.
Example 13
[4-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-acetic
acid
##STR00024##
[0123]
[4-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-a-
cetic acid ethyl ester was synthesized by a procedure similar to
3-[6-(4',5'-difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-propi-
onic acid ethyl ester from starting materials
4-(4',5'-difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-1H-indole and
bromo-acetic acid ethyl ester to yield the product as a white
solid/wax (30 mg, 66%). LC-MS (ES) calculated for C26H23F2NO4,
451.2. Found m/z 452 [M+H].sup.+.
[0124]
[4-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-a-
cetic acid was synthesized by a procedure similar to
3-[6-(4',5'-difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-propi-
onic acid from starting material
[4-(4',5'-difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-acetic
acid ethyl ester to yield the product as a white solid (23 mg,
82%). LC-MS (ES) calculated for C24H19F2NO4, 423.1. Found m/z 424
[M+H].sup.+.
Example 14
3-[4-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-propio-
nic acid
##STR00025##
[0126]
3-[4-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-
-propionic acid ethyl ester was synthesized by a procedure similar
to
3-[6-(4',5'-difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-propi-
onic acid ethyl ester from starting materials
4-(4',5'-difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-1H-indole and
3-bromo-propionic acid ethyl ester to yield the product as a clear
to opaque oil/film (30 mg, 65%). LC-MS (ES) calculated for
C27H25F2NO4, 465.2. Found m/z 466 [M+H].sup.+.
[0127]
3-[4-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-
-propionic acid was synthesized by a procedure similar to
3-[6-(4',5'-difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-propi-
onic acid from starting material
3-[4-(4',5'-difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-propi-
onic acid ethyl ester to yield the product as a white solid (23 mg,
82%). LC-MS (ES) calculated for C25H21F2NO4, 437.1. Found m/z 438
[M+H].sup.+.
Example 15
[0128]
3-[4-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-
-butyric acid
##STR00026##
[0129]
3-[4-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-
-butyric acid was synthesized by a procedure similar to
3-[6-(4',5'-difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-butyr-
ic acid from starting materials
4-(4',5'-difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-1H-indole and
(E)-but-2-enoic acid ethyl ester to yield the product as a clear to
opaque oil/film (6 mg, 13%). LC-MS (ES) calculated for C26H23F2NO4,
451.2. Found m/z 452 [M+H].sup.+.
Example 16
5-(4',5'-Difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-1H-indazol-3-ylamine
##STR00027##
[0131] A mixture of 4',5'-difluoro-2'-methoxy-biphenyl-4-ol (2 g,
8.5 mmol), 5-bromomethyl-2-fluoro-benzonitrile (2 g, 9.3 mmol),
potassium carbonate (3.5 g, 25.4 mmol) and DMF (50 mL) was stirred
at room temperature overnight. The mixture was then diluted with
EtOAc, followed by washing with water and brine, dried over sodium
sulfate, filtered, and evaporated. The residue was purified by
flash column chromatography (0-20% EtOAc in hexane) to give title
compound. LC-MS (ES) calculated for C21H14F3NO2, 369.35. Found m/z
370 [M+H].sup.+.
[0132] A mixture of
2-fluoro-5-(4',5'-difluoro-2'-methoxy-biphenyl-4-yloxymethyl)-benzonitril-
e (150 mg, 0.41 mmol), aqueous hydrazine (excess) and n-butanol (3
mL) was heated to 150.degree. C. for 30 min via microwave reactor.
The mixture was then cooled to room temperature. The mixture was
then purified by preparative HPLC under neutral conditions to give
title compound. LC-MS (ES) calculated for C21H17F2N3O2, 381.39.
Found m/z 382 [M+H].sup.+.
Example 17
Methyl-5-(2',4',5'-trifluoro-biphenyl-4-yloxymethyl)-1H-indazol-3-ylamine
##STR00028##
[0134] A mixture of 2',4',5'-trifluoro-biphenyl-4-ol (8.4 g, 37.4
mmol), 5-bromomethyl-2-fluoro-benzonitrile (4 g, 18.7 mmol),
potassium carbonate (10.3 g, 74.8 mmol) and DMF (50 mL) was stirred
at room temperature over the weekend. The mixture was then diluted
with EtOAc, followed by washing with water and brine, dried over
sodium sulfate, filtered, and evaporated. The residue was purified
by flash column chromatography (0-15% EtOAc in hexane) to give
title compound. LC-MS (ES) calculated for C20H11F4NO, 357.31. Found
m/z 358 [M+H].sup.+.
[0135] A mixture of
2-fluoro-5-(2',4',5'-trifluoro-biphenyl-4-yloxymethyl)-benzonitrile
(500 mg, 1.4 mmol), methylhydrazine (644 mg, 14 mmol) and n-butanol
(10 mL) was heated to 150.degree. C. for 1 h via microwave reactor.
The mixture was then cooled to room temperature. The white solid
was collected by filtration, washed with cold MeOH to afford title
compound. LC-MS (ES) calculated for C21H16F3N3O, 383.38. Found m/z
384 [M+H].sup.+.
Example 18
Glycogen Synthase (GS) Assay
[0136] The following tests were carried out in order to determine
the activity of the compounds of formula (I).
[0137] Twelve .mu.L per well of substrate solution containing
glycogen (4.32 mg/ml), 2.67 mM UDP-glucose, 21.6 mM
phospho(enol)pyruvate and 2.7 mM NADH in 30 mM glycylglycine, pH
7.3 buffer was added into a polystyrene 384-well assay plate (BD
Biosciences).
[0138] Compound solutions (8 .mu.L/well) at various concentrations
(0-300 .mu.M) were added to the assay plate (columns 5-24).
Compound solution contains 30 mM glycylglycine, pH 7.3, 40 mM KCl,
20 mM MgCl.sub.2, 9.2% DMSO, with (columns 15-24) or without
(columns 5-14) 20 mM glucose 6-phosphate.
[0139] Enzyme solution (12 .mu.L/well) containing glycogen synthase
(16.88 .mu.g/ml), pyruvate kinase (0.27 mg/ml), lactate
dehydrogenase (0.27 mg/ml) in 50 mM Tris-HCl, pH 8.0, 27 mM DTT and
bovine serum albumin (BSA, 0.2 mg/ml) was added to the assay plate
(columns 3-24). As a blank control, enzyme solution without
glycogen synthase was added into the top half wells of columns 1-2.
To the bottom half wells of columns 1-2 were added a known
activator, glucose 6-phosphate (at final concentration 5 mM) in
addition to the enzyme solution. The reaction mixture was incubated
at room temperature. The assay plate was then read for absorbance
at 340 nm on an Envision reader every 3 minutes up to a total of 15
minutes.
[0140] The enzyme activity (with or without compound) was
calculated by the reaction rate and represented by the optical
density change (SOD) per minute. Percent stimulation of glycogen
synthase activity by a compound at various concentrations was
calculated by the following formula:
% stimulation=100*Rs/Rt,
[0141] wherein Rs is the reaction rate of the enzyme in the
presence of compound and Rt is the reaction rate of the enzyme in
the absence of compound.
[0142] SC.sub.200 is defined as the compound concentration that is
needed to stimulate 200% of the enzyme activity. EC.sub.50 is
defined as the compound concentration that is needed to give 50%
maximum activation.
[0143] Compounds from Example 1 through Example 17 were assayed
according to assay procedures described above and the results are
listed in Table 1 below:
TABLE-US-00001 TABLE 1 Glycogen Synthase Activation Potency Example
Number GS SC.sub.200 (.mu.M) GS EC.sub.50 (.mu.M) 1 4.57 6.56 2
5.52 26 3 3.92 6 4 2.56 7 5 0.28 1.43 6 5.3 5.37 7 0.6 3 8 2 5.16 9
0.41 2.01 10 2.86 3.88 11 0.44 2.46 12 1.19 3.04 13 0.43 3.12 14
1.46 5.49 15 2.29 6.67 16 0.6 2.79 17 3.9 18.5
[0144] It is to be understood that the invention is not limited to
the particular embodiments of the invention described above, as
variations of the particular embodiments may be made and still fall
within the scope of the appended claims.
* * * * *