U.S. patent application number 13/613090 was filed with the patent office on 2013-01-17 for glycoside derivatives and uses thereof.
This patent application is currently assigned to NOVARTIS AG. The applicant listed for this patent is Gregory Raymond BEBERNITZ. Invention is credited to Gregory Raymond BEBERNITZ.
Application Number | 20130018005 13/613090 |
Document ID | / |
Family ID | 46028035 |
Filed Date | 2013-01-17 |
United States Patent
Application |
20130018005 |
Kind Code |
A1 |
BEBERNITZ; Gregory Raymond |
January 17, 2013 |
GLYCOSIDE DERIVATIVES AND USES THEREOF
Abstract
The present invention provides a compound of formula I;
##STR00001## a method for manufacturing the compounds of the
invention, and its therapeutic uses. The present invention further
provides a combination of pharmacologically active agents and a
pharmaceutical composition.
Inventors: |
BEBERNITZ; Gregory Raymond;
(Stow, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BEBERNITZ; Gregory Raymond |
Stow |
MA |
US |
|
|
Assignee: |
NOVARTIS AG
Basel
CH
|
Family ID: |
46028035 |
Appl. No.: |
13/613090 |
Filed: |
September 13, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13439155 |
Apr 4, 2012 |
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13613090 |
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61475476 |
Apr 14, 2011 |
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Current U.S.
Class: |
514/23 ; 536/115;
536/117; 536/18.7 |
Current CPC
Class: |
A61P 3/10 20180101; A61P
3/06 20180101; A61P 13/12 20180101; C07D 405/10 20130101; A61P
19/06 20180101; A61P 9/12 20180101; A61P 7/02 20180101; A61P 7/00
20180101; C07F 9/65586 20130101; A61P 43/00 20180101; A61P 3/00
20180101; A61P 3/04 20180101 |
Class at
Publication: |
514/23 ;
536/18.7; 536/115; 536/117 |
International
Class: |
A61K 31/7048 20060101
A61K031/7048; C07H 13/12 20060101 C07H013/12; C07H 11/04 20060101
C07H011/04; A61P 3/00 20060101 A61P003/00; A61P 19/06 20060101
A61P019/06; A61P 3/04 20060101 A61P003/04; A61P 3/06 20060101
A61P003/06; A61P 9/12 20060101 A61P009/12; A61P 7/02 20060101
A61P007/02; C07H 13/04 20060101 C07H013/04; A61P 3/10 20060101
A61P003/10 |
Claims
1. A compound represented by structural formula (I): ##STR00058##
or a pharmaceutiacally acceptable salt thereof, wherein: A is
selected from the group consisting of ##STR00059## V is hydrogen,
halo or --OR.sup.1b; R.sup.1, R.sup.1a and R.sup.1b are
independently selected from the group consisting of hydrogen,
C.sub.1-6 alkyl, C.sub.6-10aryl-C.sub.1-4alkyl,
--C(O)C.sub.6-10aryl and --C(O)C.sub.1-6alkyl; R.sup.2 and
R.sup.2a, for each occurrence, are independently selected from the
group consisting of halo, hydroxy, C.sub.1-6alkyl, and
C.sub.1-6alkoxy; R.sup.3 is halo, hydroxy, C.sub.1-6alkyl,
haloC.sub.1-6alkyl, C.sub.3-10cycloalkyl, C.sub.1-6alkoxy, or
haloC.sub.1-3alkoxy; R.sup.4 is selected from the group consisting
of: ##STR00060## R.sup.5 is an amino acid sidechain; R.sup.6 is a
C.sub.1-6 alkyl, C.sub.3-10carbocyclyl,
C.sub.3-10carbocyclyl-C.sub.1-4alkyl, 3- to 10-membered
heterocyclyl, (3- to 10-membered heterocyclyl)-C.sub.1-4alkyl,
C.sub.6-10aryl, C.sub.6-10aryl-C.sub.1-4alkyl, 5- to 10-membered
heteroaryl, or (5- to 10-membered heteroaryl)-C.sub.1-4alkyl;
R.sup.7, for each occurrence, is independently hydrogen,
C.sub.1-6alkyl, C.sub.3-10carbocyclyl,
C.sub.3-10carbocyclyl-C.sub.1-4alkyl, 3- to 10-membered
heterocyclyl, (3- to 10-membered heterocyclyl)-C.sub.1-4alkyl,
C.sub.6-10aryl, C.sub.6-10aryl-C.sub.1-4alkyl, 5- to 10-membered
heteroaryl, or (5- to 10-membered heteroaryl)-C.sub.1-4alkyl; n is
0, 1, 2, or 3; and q is 0, 1, or 2.
2. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein n is 0.
3. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein q is 0.
4. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein A is ##STR00061##
5. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein V is --OR.sup.1b.
6. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.1, R.sup.1a, and R.sup.1b are hydrogen.
7. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.3 is C.sub.1-4alkyl or
C.sub.3-6cycloalkyl,
8. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.3 is ethyl or cyclopropyl.
9. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.3 is ethyl
10. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.4 is ##STR00062##
11. The compound of claim 10, or a pharmaceutically acceptable salt
thereof, wherein R.sup.5 is a naturally occurring amino acid
sidechain selected from the group consisting of the sidechain of
glycine, alanine, cysteine, asparagine, glutamine, glutamic acid,
arginine, aspartic acid, histidine, lysine, isoleucine, leucine,
methionine, phenylalanine, proline, serine, threonine, tryptophane,
tyrosine, and valine.
12. The compound of claim 11, or a pharmaceutically acceptable salt
thereof, wherein R.sup.5 is the sidechain of valine.
13. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.4 is ##STR00063##
14. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.4 is ##STR00064##
15. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein the compound is selected from the group consisting
of: (R)-2-amino-3-methyl-butyric acid
(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-p-
henyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester; carbonic
acid
(2R,3S,4R,5R,6S)-6-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmet-
hyl)-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester
methyl ester; carbonic acid
(2R,3S,4R,5R,6S)-6-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmet-
hyl)-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester
ethyl ester; carbonic acid
(2R,3S,4R,5R,6S)-6-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmet-
hyl)-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester
isobutyl ester; carbonic acid
(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-p-
henyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester ethyl
ester; carbonic acid
(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-p-
henyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester isobutyl
ester; Carbonic acid tert-butyl ester
(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-p-
henyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester; carbonic
acid bicyclo[2.2.1]hept-2-ylmethyl ester
(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-p-
henyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester; carbonic
acid (2R, 3S,4R, 5R,
6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5--
trihydroxy-tetrahydro-pyran-2-ylmethyl ester (S)-1-phenyl-ethyl
ester; phosphoric acid
(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-p-
henyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester diethyl
ester; phosphoric acid
(2R,3S,4R,5R,6S)-6-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmet-
hyl)-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester
diethyl ester; phosphoric acid
mono-{(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-e-
thyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl}
ester.
16. A pharmaceutical composition comprising a therapeutically
effective amount of a compound according to claim 1, or a
pharmaceutically acceptable salt thereof, and one or more
pharmaceutically acceptable carrier.
17. A method of treating a disease or condition mediated by the
sodium D-glucose co-transporter in a subject, comprising
administering to the mammal in need thereof a therapeutically
effective amount of a compound according to claim 1, or a
pharmaceutically acceptable salt thereof.
18. The method according to claim 17, wherein the disease or
condition is metabolic syndrome, Syndrome X, diabetes, insulin
resistance, decreased glucose tolerance, non-insulin-dependent
diabetes mellitus, Type II diabetes, Type I diabetes, diabetic
complications, a body weight disorder, obesity, or a leptin related
disease.
19. The method according to claim 18, wherein the disease or
condition is dyslipidemia, obesity, insulin resistance,
hypertension, microalbuminemia, hyperuricaemia, or
hypercoagulability.
20. A pharmaceutical combination comprising: i) a compound
according to claim 1, or a pharmaceutically acceptable salt
thereof, ii) at least one compound selected from a) antidiabetic
agents, b) hypolipidemic agents, c) anti-obesity agents, d)
anti-hypertensive agents, e) agonists of peroxisome
proliferator-activator receptors.
Description
BACKGROUND OF THE INVENTION
[0001] Diabetes mellitus is a metabolic disorder characterized by
recurrent or persistent hyperglycemia (high blood glucose) and
other signs, as distinct from a single disease or condition.
Glucose level abnormalities can result in serious long-term
complications, which include cardiovascular disease, chronic renal
failure, retinal damage, nerve damage (of several kinds),
microvascular damage and obesity.
[0002] Type 1 diabetes, also known as Insulin Dependent Diabetes
Mellitus (IDDM), is characterized by loss of the insulin-producing
.beta.-cells of the islets of Langerhans of the pancreas leading to
a deficiency of insulin. Type-2 diabetes previously known as
adult-onset diabetes, maturity-onset diabetes, or Non-Insulin
Dependent Diabetes Mellitus (NIDDM)--is due to a combination of
increased hepatic glucose output, defective insulin secretion, and
insulin resistance or reduced insulin sensitivity (defective
responsiveness of tissues to insulin).
[0003] Chronic hyperglycemia can also lead to onset or progression
of glucose toxicity characterized by decrease in insulin secretion
from .beta.-cell, insulin sensitivity; as a result diabetes
mellitus is self-exacerbated [Diabetes Care, 1990, 13, 610].
[0004] Chronic elevation of blood glucose level also leads to
damage of blood vessels. In diabetes, the resultant problems are
grouped under "microvascular disease" (due to damage of small blood
vessels) and "macrovascular disease" (due to damage of the
arteries). Examples of microvascular disease include diabetic
retinopathy, neuropathy and nephropathy, while examples of
macrovascular disease include coronary artery disease, stroke,
peripheral vascular disease, and diabetic myonecrosis.
[0005] Diabetic retinopathy, characterized by the growth of
weakened blood vessels in the retina as well as macular edema
(swelling of the macula), can lead to severe vision loss or
blindness. Retinal damage (from microangiopathy) makes it the most
common cause of blindness among non-elderly adults in the US.
Diabetic neuropathy is characterized by compromised nerve function
in the lower extremities. When combined with damaged blood vessels,
diabetic neuropathy can lead to diabetic foot. Other forms of
diabetic neuropathy may present as mononeuritis or autonomic
neuropathy. Diabetic nephropathy is characterized by damage to the
kidney, which can lead to chronic renal failure, eventually
requiring dialysis. Diabetes mellitus is the most common cause of
adult kidney failure worldwide. A high glycemic diet (i.e., a diet
that consists of meals that give high postprandial blood sugar) is
known to be one of the causative factors contributing to the
development of obesity.
[0006] Type 2 diabetes is characterized by insulin resistance
and/or inadequate insulin secretion in response to elevated glucose
level. Therapies for type 2 diabetes are targeted towards
increasing insulin sensitivity (such as TZDs), hepatic glucose
utilization (such as biguanides), directly modifying insulin levels
(such as insulin, insulin analogs, and insulin secretagogues),
increasing incretin hormone action (such as exenatide and
sitagliptin), or inhibiting glucose absorption from the diet (such
as alpha glucosidase inhibitors) [Nature 2001, 414, 821-827].
[0007] Glucose is unable to diffuse across the cell membrane and
requires transport proteins. The transport of glucose into
epithelial cells is mediated by a secondary active cotransport
system, the sodium-D-glucose co-transporter (SGLT), driven by a
sodium-gradient generated by the Na+/K+-ATPase. Glucose accumulated
in the epithelial cell is further transported into the blood across
the membrane by facilitated diffusion through GLUT transporters
[Kidney International 2007, 72, S27-S35].
[0008] SGLT belongs to the sodium/glucose co-transporter family
SLCA5. Two different SGLT isoforms, SGLT1 and SGLT2, have been
identified to mediate renal tubular glucose reabsorption in humans
[Curr. Opinon in Investigational Drugs (2007): 8(4), 285-292 and
references cited herein]. Both of them are characterized by their
different substrate affinity. Although both of them show 59%
homology in their amino acid sequence, they are functionally
different. SGLT1 transports glucose as well as galactose, and is
expressed both in the kidney and in the intestine, while SGLT2 is
found exclusively in the S1 and S2 segments of the renal proximal
tubule. As a consequence, glucose filtered in the glomerulus is
reabsorbed into the renal proximal tubular epithelial cells by
SGLT2, a low-affinity/high-capacity system, residing on the surface
of epithelial cell lining in S1 and S2 tubular segments. Much
smaller amounts of glucose are recovered by SGLT1, as a
high-affinity/low-capacity system, on the more distal segment of
the proximal tubule. In healthy human, more than 99% of plasma
glucose that is filtered in the kidney glomerulus is reabsorbed,
resulting in less than 1% of the total filtered glucose being
excreted in urine. It is estimated that 90% of total renal glucose
absorption is facilitated by SGLT2; remaining 10% is likely
mediated by SGLT1 [J. Parenter. Enteral Nutr. 2004, 28,
364-371].
[0009] SGLT2 was cloned as a candidate sodium glucose
co-transporter, and its tissue distribution, substrate specificity,
and affinities are reportedly very similar to those of the
low-affinity sodium glucose co-transporter in the renal proximal
tubule. A drug with a mode of action of SGLT2 inhibition will be a
novel and complementary approach to existing classes of medication
for diabetes and its associated diseases to meet the patient's
needs for both blood glucose control, while preserving insulin
secretion. In addition, SGLT2 inhibitors which lead to loss of
excess glucose (and thereby excess calories) may have additional
potential for the treatment of obesity.
[0010] Indeed small molecule SGLT2 inhibitors have been discovered
and the anti-diabetic therapeutic potential of such molecules has
been reported in literature [T-1095 (Diabetes, 1999, 48, 1794-1800,
Dapagliflozin (Diabetes, 2008, 57, 1723-1729)].
[0011] Various O-aryl and O-heteroaryl glycosides have been
reported as SGLT-2 inhibitors in patent publications such as: WO
01/74834, WO 03/020737, US 04/0018998, WO 01/68660, WO 01/16147, WO
04/099230, WO 05/011592, US 06/0293252 and WO 05/021566.
[0012] Various glucopyranosyl-substituted aromatic and
heteroaromatic compounds have also been reported as SGLT-2
inhibitors in patent publications such as: WO 01/27128, WO
04/080990, US 06/0025349, WO 05/085265, WO 05/085237, WO 06/054629
and WO 06/011502.
[0013] SGLT1 is predominantly found in the intestine and plays a
major role in the absorption of D-glucose and D-galactose.
Therefore, SGLT1 inhibitors have the potential to act both in the
kidney as well as the intestine to reduce calorie intake and
hyperglycemia.
[0014] WO2004/018491 discloses pyrazole derivatives which are SGLT1
inhibitors.
[0015] Glucopyranosyl-substituted aromatic or heteroaromatic
compounds where, in general, the sugar moiety has been modified at
C4, C5, or C6 positions of pyranose have been published (US
06/0009400, US 06/0019948, US 06/0035841, US 06/0074031, US
08/0027014 and WO 08/016132).
[0016] Prodrug strategies or methodologies can be used to markedly
enhance properties of a drug or to overcome an inherent deficiency
in the pharmaceutical or pharmacokinetic properties of a drug.
Prodrugs are new chemical entities which, upon administration to
the patient, regenerates the parent molecule within the body.
Prodrugs can provide choices in modulating the conditions for
regeneration of a parent drug and for modulating the physical,
pharmaceutic, or pharmacokinetic properties of the parent drug.
However, the identification of prodrugs with desired properties is
often difficult.
SUMMARY OF THE INVENTION
[0017] The invention therefore provides a compound of the formula
(I):
##STR00002##
or a pharmaceutiacally acceptable salt thereof, wherein: [0018] A
is selected from the group consisting of
[0018] ##STR00003## [0019] V is hydrogen, halo or --OR.sup.1b;
[0020] R.sup.1, R.sup.1a and R.sup.1b are independently selected
from the group consisting of hydrogen, C.sub.1-6alkyl,
C.sub.6-10aryl-C.sub.1-4alkyl, --C(O)C.sub.6-10aryl and
--C(O)C.sub.1-6alkyl; [0021] R.sup.2 and R.sup.2a, for each
occurrence, are independently selected from the group consisting of
halo, hydroxy, C.sub.1-6alkyl, and C.sub.1-6alkoxy; [0022] R.sup.3
is halo, hydroxy, C.sub.1-6alkyl, halo C.sub.1-6alkyl,
C.sub.3-10cycloalkyl, C.sub.1-6alkoxy, or haloC.sub.1-3alkoxy;
[0023] R.sup.4 is selected from the group consisting of:
[0023] ##STR00004## [0024] R.sup.5 is an amino acid sidechain;
[0025] R.sup.6 is a C.sub.1-6alkyl, C.sub.3-10cycloalkyl,
C.sub.3-10cycloalkyl-C.sub.1-4alkyl, 3- to 10-membered
heterocycloalkyl, (3- to 10-membered
heterocycloalkyl)-C.sub.1-4alkyl, C.sub.6-10aryl,
C.sub.6-10aryl-C.sub.1-4alkyl, 5- to 10-membered heteroaryl, or (5-
to 10-membered heteroaryl)-C.sub.1-4alkyl; [0026] R.sup.7, for each
occurrance, is independently hydrogen, a C.sub.1-6alkyl,
C.sub.3-10cycloalkyl, C.sub.3-10cycloalkyl-C.sub.1-4alkyl, 3- to
10-membered heterocycloalkyl, (3- to 10-membered
heterocycloalkyl)-C.sub.1-4alkyl, C.sub.6-10aryl,
C.sub.6-10aryl-C.sub.1-4alkyl, 5- to 10-membered heteroaryl, or (5-
to 10-membered heteroaryl)-C.sub.1-4alkyl; [0027] n is 0, 1, 2, or
3; and [0028] q is 0, 1, or 2.
[0029] Compounds of the invention are useful for treating diseases
and conditions mediated by the sodium D-glucose co-transporter
(SGLT), e.g. hyperglycemia, diabetes, and the like. The invention
also provides methods of treating such diseases and conditions, and
compounds and compositions etc. for their treatment.
[0030] The compounds of the invention are prodrugs which when
metabolized in vivo possess sodium-D-glucose co-transporter (SGLT)
inhibition effects, which are beneficial for the prophylaxis,
management, treatment, control of progression, or adjunct treatment
of diseases and/or medical conditions where the inhibition of SGLT
would be beneficial, such as diabetes (including Type-I and
Type-II), hyperglycemia, obesity, dyslipidemia, insulin resistance,
and other metabolic syndrome, and/or diabetes-related complications
including retinopathy, nephropathy, neuropathy, ischemic heart
disease, arteriosclerosis, .beta.-cell dysfunction, and as
therapeutic and/or prophylactic agents for obesity.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0031] Unless specified otherwise, the term "compounds of the
present invention" refers to compounds of Formula (I) (including
the examples), and salts (preferably pharmaceutically acceptable
salts) thereof, as well as all stereoisomers (including
diastereoisomers and enantiomers), tautomers and isotopically
labeled compounds of formula (I) (e.g., deuterium substitutions),
as well as inherently formed moieties (e.g., polymorphs, solvates
and/or hydrates).
[0032] The requisite number of carbon atoms for groups such as
alkyl, alkoxy, aryl, etc., is represented as C.sub.1-6, C.sub.1-4,
etc. in the definitions below. For example, a C.sub.1-6alkoxy has
from one to six carbon atoms and a C.sub.1-10heteroaryl has from
one to 10 carbon atoms.
[0033] As used herein, the term "alkyl" refers to a fully saturated
branched or unbranched hydrocarbon moiety. Preferably the alkyl
comprises 1 to 20 carbon atoms, more preferably 1 to 16 carbon
atoms, 1 to 10 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon
atoms. Representative examples of alkyl include, but are not
limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl,
sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl,
n-hexyl, 3-methylhexyl, 2,2- dimethylpentyl, 2,3-dimethylpentyl,
n-heptyl, n-octyl, n-nonyl, or n-decyl.
[0034] As used herein, the term "haloalkyl" refers to an alkyl as
defined herein that is substituted by one or more halo groups as
defined herein. The haloalkyl can be monohaloalkyl, dihaloalkyl or
polyhaloalkyl including perhaloalkyl. A monohaloalkyl can have one
iodo, bromo, chloro or fluoro within the alkyl group. Dihaloalky
and polyhaloalkyl groups can have two or more of the same halo
atoms or a combination of different halo groups within the alkyl.
Typically the polyhaloalkyl contains up to 12, or 10, or 8, or 6,
or 4, or 3, or 2 halo groups. Non-limiting examples of haloalkyl
include fluoromethyl, difluoromethyl, trifluoromethyl,
chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl,
heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,
difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. A
perhaloalkyl refers to an alkyl having all hydrogen atoms replaced
with halo atoms.
[0035] "Alkylene" refers to a straight or branched divalent
hydrocarbon chain, having from one to twelve carbon atoms,
preferably one to 6 carbon atoms, and linking the rest of the
molecule to a radical group. Examples of alkylene groups include
methylene, ethylene, propylene, n-butylene, and the like. The
alkylene is attached to the rest of the molecule through a single
bond and to the radical group through a single bond. The points of
attachment of the alkylene to the rest of the molecule and to the
radical group can be through one carbon or any two carbons within
the chain.
[0036] "Halogen" or "halo" may be fluoro, chloro, bromo or
iodo.
[0037] As used herein, the term "alkoxy" refers to alkyl-O--,
wherein alkyl is defined herein above. Representative examples of
alkoxy include, but are not limited to, methoxy, ethoxy, propoxy,
2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy,
cyclopropyloxy-, cyclohexyloxy- and the like. Preferably, alkoxy
groups have about 1-6, more preferably about 1-4 carbons.
[0038] As used herein, the term "haloalkoxy" refers to an alkoxy as
defined herein that is substituted by one or more halo groups as
defined herein. The haloalkoxy can be monohaloalkoxy, dihaloalkoxy
or polyhaloalkoxy including perhaloalkoxy. A monohaloalkoxy can
have one iodo, bromo, chloro or fluoro within the alkoxy group.
Dihaloalkoxy and polyhaloalkoxy groups can have two or more of the
same halo atoms or a combination of different halo groups within
the alkoxy. Typically the polyhaloalkoxy contains up to 12, or 10,
or 8, or 6, or 4, or 3, or 2 halo groups. Non-limiting examples of
haloalkyl include fluoromethoxy, difluoromethoxy, trifluoromethoxy,
chloromethoxy, dichloromethoxy, trichloromethoxy,
pentafluoroethoxy, heptafluoropropoxy, difluorochloromethoxy,
dichlorofluoromethoxy, difluoroethoxy, difluoropropoxy,
dichloroethoxy and dichloropropoxy. A perhaloalkoxy refers to an
alkoxy having all hydrogen atoms replaced with halo atoms.
[0039] The term "aryl" refers to monocyclic or bicyclic aromatic
hydrocarbon groups having 6-10 carbon atoms in the ring portion.
Examples include phenyl and naphthyl.
[0040] The term "aryl" also refers to a group in which a aryl ring
is fused to one or more non-aromatic carbocyclyl provided that at
least one ring in the ring system is aromatic. Nonlimiting examples
include 2,3-dihydro-1H-inden-5-yl and
1,2,3,4-tetrahydronaphth-2-yl.
[0041] The term "arylalkyl" refers to an aryl group which is linked
to another moiety via an alkylene group which may be branched or
unbranched. Examples of arylalkyl groups include benzyl,
2-phenyl-ethyl, 2-(naphth-2-yl)-butan-1-yl, and the like.
[0042] As used herein, the term "heterocyclyl" refers to an
optionally substituted, saturated or unsaturated non-aromatic ring
or ring system, e.g., which is a 3, 4-, 5-, 6-, or 7-membered
monocyclic, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic or 10-,
11-, 12-, 13-, 14- or 15-membered tricyclic ring system and
contains at least one heteroatom selected from O, S and N, where
the N and S can also optionally be oxidized to various oxidation
states. The heterocyclic group can be attached at a heteroatom or a
carbon atom. The heterocyclyl can include fused or bridged rings as
well as spirocyclic rings. Examples of heterocycles include
dihydrofuranyl, [1,3]dioxolanyl, 1,4-dioxanyl, 1,4-dithianyl,
piperazinyl, 1,3-dioxolanyl, imidazolidinyl, imidazolinyl,
pyrrolidinyl, dihydropyranyl, oxathiolanyl, dithiolanyl,
1,3-dioxanyl, 1,3-dithianyl, oxathianyl, thiomorpholinyl, oxiranyl,
aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl,
tetrahydropyranyl, piperidinyl, morpholinyl, azepinyl, oxapinyl,
oxazepinyl and diazepinyl.
[0043] As used herein, the term "carbocyclyl" refers to saturated
or partially unsaturated (but not aromatic) monocyclic, bicyclic or
tricyclic hydrocarbon groups of 3-12 carbon atoms, preferably 3-9,
or 3-7 carbon atoms, Exemplary monocyclic hydrocarbon groups
include, but are not limited to, cyclopropyl, cyclobutyl,
cyclopentyl, cyclopentenyl, cyclohexyl or cyclohexenyl. Exemplary
bicyclic hydrocarbon groups include bornyl, decahydronaphthyl,
bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl,
6,6-dimethylbicyclo[3.1.1]heptyl,
2,6,6-trimethylbicyclo[3.1.1]heptyl, or bicyclo[2.2.2]octyl.
[0044] Exemplary tricyclic hydrocarbon groups include adamantyl, a
"cycloalkyl" is a carbocyclyl that is completely saturated.
[0045] As used herein, the term "heteroaryl" refers to a 5-14
membered monocyclic- or bicyclic- or polycyclic-aromatic ring
system having 1 to 8 heteroatoms selected from N, O or S and at
least one carbon atom, preferably from 1-10, more preferably from
1-6 carbon atoms, in the ring system. Preferably, the heteroaryl is
a 5-10 or 5-7 membered ring system. Examples of monocyclic
heteroaryl groups include pyridyl, thienyl, furanyl, pyrrolyl,
pyrazolyl, imidazoyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl and tetrazolyl.
Examples of bicyclic heteroaryl groups include indolyl,
benzofuranyl, isoquinolinyl indazolyl, indolinyl, isoindolyl,
indolizinyl, benzamidazolyl, and quinolinyl.
[0046] The term "heteroaryl" also refers to a group in which an
aromatic ring is fused to one or more non-aromatic carbocyclyl or
heterocyclyl provided that at least one ring in the ring system is
aromatic and at least one ring contains a heteroatom, for example,
3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl and
1,2,3,4-tetrahydroquinolin-7-yl.
[0047] A heteroaryl group may be mono-, bi-, tri-, or polycyclic,
preferably mono-, bi-, or tricyclic, more preferably mono- or
bicyclic.
[0048] The term "heteroarylalkyl" refers to an heteroaryl group
which is linked to another moiety via an alkylene group which may
be branched or unbranched. Examples of heteroarylalkyl groups
include 2-(pyridin-3-yl)-ethyl, 3-(quinolin-7-yl)-butan-1-yl, and
the like.
[0049] "Heteroaryl" and "heterocyclyl" is also intended to include
oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of tertiary
ring nitrogen.
[0050] Unless indicated explicitly otherwise, where combinations of
groups are referred to herein as one moiety, e.g. arylalkyl, the
last mentioned group contains the atom by which the moiety is
attached to the rest of the molecule.
[0051] Amino acids have the following structural formula:
##STR00005##
wherein R'' is an amino acid sidechain. The term "amino acid
sidechain" refers to a sidechain of a naturally occurring amino
acid as well as non-standard amino acids. Naturally occurring amino
acids include glycine (sidechain is hydrogen), alanine, cysteine,
asparagine, glutamine, glutamic acid, arginine, aspartic acid,
histidine, lysine, isoleucine, leucine, methionine, phenylalanine,
proline, serine, threonine, tryptophane, tyrosine, and valine.
Non-standard amino acids include 3,5-dibromotyrosine,
3,5-diiodotyrosine, gem-dimethylglycine, hydroxylysine,
.alpha.-aminobutyric acid, hydroxyproline, lanthionine, thyroxine,
ornithine, and citrulline. A preferred amino acid sidechain is the
sidechain of valine.
[0052] A "stereoisomer" refers to a compound made up of the same
atoms bonded by the same bonds but having different
three-dimensional structures, which are not interchangeable. The
present invention contemplates various stereoisomers and mixtures
thereof and includes "enantiomers", which refers to two
stereoisomers whose molecules are non-superimposeable mirror images
of one another.
[0053] Compounds of the invention may exist in one or more
geometrical, optical, enantiomeric, diastereomeric and tautomeric
forms, including but not limited to cis- and trans-forms, E- and
Z-forms, R-, S- and meso-forms, keto-, and enol-forms. All such
isomeric forms are included within the invention. The isomeric
forms may be in isomerically pure or enriched form, as well as in
mixtures of isomers (e.g. racemic or diastereomeric mixtures).
[0054] Accordingly, the invention provides: [0055] stereoisomeric
mixtures of compounds of Formula (I); [0056] a diastereomerically
enriched or diastereomerically pure isomer of a compound of Formula
(I); or [0057] an enantiomerically enriched or enantiomerically
pure isomer of a compound of Formula (I).
[0058] Where appropriate isomers can be separated from their
mixtures by the application or adaptation of known methods (e.g.
chromatographic techniques and recrystallisation techniques). Where
appropriate isomers can be prepared by the application or
adaptation of known methods (e.g. asymmetric synthesis).
[0059] Unless otherwise indicated, the present invention is meant
to include all such possible isomers, as well as their racemic and
optically pure forms. Optically active (+) and (-), (R)- and (S)-,
or (D)- and (L)-isomers may be prepared using chiral synthons or
chiral reagents, or resolved using conventional techniques, such as
HPLC using a chiral column. When the compounds described herein
contain olefinic double bonds or other centers of geometric
asymmetry, and unless specified otherwise, it is intended that the
compounds include both E and Z geometric isomers. Likewise, all
tautomeric forms are also intended to be included.
[0060] As used herein, the terms "salt" or "salts" refers to an
acid addition or base addition salt of a compound of the invention.
"Salts" include in particular "pharmaceutical acceptable salts".
The term "pharmaceutically acceptable salts" refers to salts that
retain the biological effectiveness and properties of the compounds
of this invention and, which typically are not biologically or
otherwise undesirable. In many cases, the compounds of the present
invention are capable of forming acid and/or base salts by virtue
of the presence of amino and/or carboxyl groups or groups similar
thereto.
[0061] Pharmaceutically acceptable acid addition salts can be
formed with inorganic acids and organic acids, e.g., acetate,
aspartate, benzoate, besylate, bromide/hydrobromide,
bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate,
chloride/hydrochloride, chlortheophyllonate, citrate,
ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate,
hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate,
laurylsulfate, malate, maleate, malonate, mandelate, mesylate,
methylsulphate, naphthoate, napsylate, nicotinate, nitrate,
octadecanoate, oleate, oxalate, palmitate, pamoate,
phosphate/hydrogen phosphate/dihydrogen phosphate,
polygalacturonate, propionate, stearate, succinate,
sulfosalicylate, tartrate, tosylate and trifluoroacetate salts.
[0062] Inorganic acids from which salts can be derived include, for
example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric
acid, phosphoric acid, and the like. Organic acids from which salts
can be derived include, for example, acetic acid, propionic acid,
glycolic acid, oxalic acid, maleic acid, malonic acid, succinic
acid, fumaric acid, tartaric acid, citric acid, benzoic acid,
mandelic acid, methanesulfonic acid, ethanesulfonic acid,
toluenesulfonic acid, sulfosalicylic acid, and the like.
Pharmaceutically acceptable base addition salts can be formed with
inorganic and organic bases.
[0063] Inorganic bases from which salts can be derived include, for
example, ammonium salts and metals from columns I to XII of the
periodic table. In certain embodiments, the salts are derived from
sodium, potassium, ammonium, calcium, magnesium, iron, silver,
zinc, and copper; particularly suitable salts include ammonium,
potassium, sodium, calcium and magnesium salts.
[0064] Organic bases from which salts can be derived include, for
example, primary, secondary, and tertiary amines, substituted
amines including naturally occurring substituted amines, cyclic
amines, basic ion exchange resins, and the like. Certain organic
amines include isopropylamine, benzathine, cholinate,
diethanolamine, diethylamine, lysine, meglumine, piperazine and
tromethamine.
[0065] The pharmaceutically acceptable salts of the present
invention can be synthesized from a basic or acidic moiety, by
conventional chemical methods. Generally, such salts can be
prepared by reacting free acid forms of these compounds with a
stoichiometric amount of the appropriate base (such as Na, Ca, Mg,
or K hydroxide, carbonate, bicarbonate or the like), or by reacting
free base forms of these compounds with a stoichiometric amount of
the appropriate acid. Such reactions are typically carried out in
water or in an organic solvent, or in a mixture of the two.
Generally, use of non-aqueous media like ether, ethyl acetate,
ethanol, isopropanol, or acetonitrile is desirable, where
practicable. Lists of additional suitable salts can be found, e.g.,
in "Remington's Pharmaceutical Sciences", 20th ed., Mack Publishing
Company, Easton, Pa., (1985); and in "Handbook of Pharmaceutical
Salts: Properties, Selection, and Use" by Stahl and Wermuth
(Wiley-VCH, Weinheim, Germany, 2002).
[0066] Furthermore, the compounds of the present invention,
including their salts, can also be obtained in the form of their
hydrates or solvates, which include solvents used for their
crystallization. The compounds of the present invention may
inherently or by design form solvates with pharmaceutically
acceptable solvents (including water); therefore, it is intended
that the invention embrace both solvated and unsolvated forms. The
term "solvate" refers to a molecular complex of a compound of the
present invention (including pharmaceutically acceptable salts
thereof) with one or more solvent molecules. Such solvent molecules
are those commonly used in the pharmaceutical art, which are known
to be innocuous to the recipient, e.g., water, ethanol, and the
like. The term "hydrate" refers to the complex where the solvent
molecule is water. The compounds of the present invention,
including salts, hydrates and solvates thereof, may inherently or
by design form polymorphs.
[0067] By way of clarity, compounds of the invention included all
isotopes of the atoms present in formula (I) and any of the
examples or embodiments disclosed herein. For example, H (or
hydrogen) represents any isotopic form of hydrogen including
.sup.1H, .sup.2H(D), and .sup.3H(T); C represents any isotopic form
of carbon including .sup.12C, .sup.13C, and .sup.14C; O represents
any isotopic form of oxygen including .sup.16O, .sup.17O and
.sup.18O; N represents any isotopic form of nitrogen including
.sup.13N, .sup.14N and .sup.15N; P represents any isotopic form of
phosphorous including .sup.31P and .sup.32P; S represents any
isotopic form of sulfur including .sup.32S and .sup.35S; F
represents any isotopic form of fluorine including .sup.19F and
.sup.18F; C; represents any isotopic form of chlorine including
.sup.35Cl, .sup.37Cl and .sup.36Cl; and the like. In a preferred
embodiment, compounds represented by formula (I) comprises isomers
of the atoms therein in their naturally occurring abundance.
However, in certain instances, it is desirable to enrich one or
more atom in a particular isotope which would normally be present
in less abundance. For example, .sup.1H would normally be present
in greater than 99.98% abundance; however, a compound of the
invention can be enriched in .sup.2H or .sup.3H at one or more
positions where H is present. In particular embodiments of the
compounds of formula (I), when, for example, hydrogen is enriched
in the deuterium isotope, the symbol "D" may be used to represent
the enrichment in deuterium. In one embodiment, when a compound of
the invention is enriched in a radioactive isotope, for example
.sup.3H and .sup.14C, the compound may be useful in drug and/or
substrate tissue distribution assays. Likewise, enrichment with
positron emitting isotopes, such as .sup.11C, .sup.18F, .sup.15O
and .sup.13N, can be useful in Positron Emission Topography (PET)
studies for examining substrate receptor occupancy. It is to be
understood that the invention encompasses all such isotopic forms
which inhibit SGLT.
[0068] Isotopically-enriched compounds of Formula (I) can generally
be prepared by conventional techniques known to those skilled in
the art or by processes analogous to those described herein using
an appropriate isotopically-enriched reagent in place of the
non-enriched reagent previously employed.
[0069] Compounds of the invention, i.e. compounds of formula (I)
that contain groups capable of acting as donors and/or acceptors
for hydrogen bonds may be capable of forming co-crystals with
suitable co-crystal formers. These co-crystals may be prepared from
compounds of formula (I) by known co-crystal forming procedures.
Such procedures include grinding, heating, co-subliming,
co-melting, or contacting in solution compounds of formula (I) with
the co-crystal former under crystallization conditions and
isolating co-crystals thereby formed. Suitable co-crystal forms
include those described in WO 2004/078163. Hence the invention
further provides co-crystals comprising a compound of formula
(I).
[0070] As used herein, the term "treat", "treating" or "treatment"
of any disease or disorder refers in one embodiment, to
ameliorating the disease or disorder (i.e., slowing or arresting or
reducing the development of the disease or at least one of the
clinical symptoms thereof). In another embodiment "treat",
"treating" or "treatment" refers to alleviating or ameliorating at
least one physical parameter including those which may not be
discernible by the patient. In yet another embodiment, "treat",
"treating" or "treatment" refers to modulating the disease or
disorder, either physically, (e.g., stabilization of a discernible
symptom), physiologically, (e.g., stabilization of a physical
parameter, for example blood sugar), or both. In yet another
embodiment, "treat", "treating" or "treatment" refers to preventing
or delaying the onset or development or progression of the disease
or disorder.
[0071] As used herein, a subject is "in need of" a treatment if
such subject would benefit biologically, medically or in quality of
life from such treatment.
[0072] The amount of the compound of the invention administered
should be a therapeutically effective amount where the compound or
derivative is used for the treatment of a disease or condition or
symptom thereof, and a prophylactically effective amount where the
compound or derivative is used for the prevention of a disease or
condition or a symptom thereof.
[0073] The term "a therapeutically effective amount" of a compound
of the present invention refers to an amount of the compound of the
present invention that will elicit the biological or medical
response of a subject, for example, reduction or inhibition of an
enzyme or a protein activity, or ameliorate symptoms, alleviate
conditions, slow or delay disease progression, or prevent a
disease, etc. In one non-limiting embodiment, the term "a
therapeutically effective amount" refers to the amount of the
compound of the present invention that, when administered to a
subject, is effective to (1) at least partially alleviate, inhibit,
prevent and/or ameliorate a condition or a disease, or a symptom
thereof, wherein the condition or disease, or symptom thereof, is
(i) mediated by SGLT1 and/or SGLT2, (ii) associated with SGLT1
and/or SGLT2 activity, (iii) characterized by activity (normal or
abnormal) of SGLT1 and/or SGLT2; or (2) aleviated by reducing or
inhibiting the activity of SGLT1 and/or SGLT2. In another
non-limiting embodiment, the term "a therapeutically effective
amount" refers to the amount of the compound of the present
invention that, when administered to a cell, or a tissue, or a
non-cellular biological material, or a medium, is effective to at
least partially reducing or inhibiting the activity of SGLT1 and/or
SGLT2; or at least partially reducing or inhibiting the expression
of SGLT1 and/or SGLT2. The exact dosage will generally be dependent
on the patient's status at the time of administration. Factors that
may be taken into consideration when determining dosage include the
severity of the disease state in the patient, the general health of
the patient, the age, weight, gender, diet, time, frequency and
route of administration, drug combinations, reaction sensitivities
and the patient's tolerance or response to therapy. The precise
amount can be determined by routine experimentation, but may
ultimately lie with the judgement of the clinician. Generally, an
effective dose will be from 0.01 mg/kg/day (mass of drug compared
to mass of patient) to 1000 mg/kg/day, e.g. 1 mg/kg/day to 100
mg/kg/day or 1 mg/kg/day to 10 mg/kg/day. Compositions may be
administered individually to a patient or may be administered in
combination with other agents, drugs or hormones.
[0074] As used herein, the term "subject" refers to an animal.
Typically the animal is a mammal. A subject also refers to for
example, primates (e.g., humans, male or female), cows, sheep,
goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the
like. In certain embodiments, the subject is a primate. In yet
other embodiments, the subject is a human.
[0075] As used herein, the term "inhibit", "inhibition" or
"inhibiting" refers to the reduction or suppression of a given
condition, symptom, or disorder, or disease, or a significant
decrease in the baseline activity of a biological activity or
process.
[0076] As used herein, the terms "disease" and "condition" may be
used interchangeably or may be different in that the particular
malady or condition may not have a known causative agent (so that
etiology has not yet been worked out) and it is therefore not yet
recognized as a disease but only as an undesirable condition or
syndrome, wherein a more or less specific set of symptoms have been
identified by clinicians. As used herein, the term "disorder" is
synonymous with "condition".
[0077] The term "comprising" encompasses "including" as well as
"consisting", e.g. a composition "comprising" X may consist
exclusively of X or may include something additional, e.g. X+Y.
[0078] The word "substantially" does not exclude "completely" e.g.
a composition which is "substantially free" from Y may be
completely free from Y. Where necessary, the word "substantially"
may be omitted from the definition of the invention.
[0079] The term "about" in relation to a numerical value x means,
for example, x.+-.10%.
[0080] All methods described herein can be performed in any
suitable order unless otherwise indicated herein or otherwise
clearly contradicted by context. The use of any and all examples,
or exemplary language (e.g. "such as") provided herein is intended
merely to better illuminate the invention and does not pose a
limitation on the scope of the invention otherwise claimed.
[0081] As used herein, the term "a," "an," "the" and similar terms
used in the context of the present invention (especially in the
context of the claims) are to be construed to cover both the
singular and plural unless otherwise indicated herein or clearly
contradicted by the context.
[0082] Unless it is explicitly stated that a group is substituted
or may optionally be substituted, it is to be understood that the
group is unsubstituted.
Compounds of the Invention
[0083] Various embodiments of the invention are described herein.
It will be recognized that features specified in each embodiment
may be combined with other specified features to provide further
embodiments.
[0084] In one embodiment, the invention provides compounds of
formula (I):
##STR00006##
or a pharmaceutiacally acceptable salt thereof, wherein: [0085] A
is selected from the group consisting of
[0085] ##STR00007## [0086] V is hydrogen, halo or --OR.sup.1b;
[0087] R.sup.1, R.sup.1a and R.sup.1b are independently selected
from the group consisting of hydrogen, C.sub.1-6alkyl,
C.sub.6-10aryl-C.sub.1-4alkyl, --C(O)C.sub.6-10aryl and
--C(O)C.sub.1-6alkyl; [0088] R.sup.2 and R.sup.2a, for each
occurrence, are independently selected from the group consisting of
halo, hydroxy, C.sub.1-6alkyl, and C.sub.1-6alkoxy; [0089] R.sup.3
is halo, hydroxy, C.sub.1-6alkyl, haloC.sub.1-6alkyl,
C.sub.3-10cycloalkyl, C.sub.1-6alkoxy, or haloC.sub.1-3alkoxy;
[0090] R.sup.4 is selected from the group consisting of:
[0090] ##STR00008## [0091] R.sup.5 is an amino acid sidechain;
[0092] R.sup.6 is a C.sub.1-6alkyl, C.sub.3-10carbocyclyl,
C.sub.3-10carbocyclyl-C.sub.1-4alkyl, 3- to 10-membered
heterocyclyl, (3- to 10-membered heterocyclyl)-C.sub.1-4alkyl,
C.sub.6-10aryl, C.sub.6-10aryl-C.sub.1-4alkyl, 5- to 10-membered
heteroaryl, or (5- to 10-membered heteroaryl)-C.sub.1-4alkyl;
[0093] R.sup.7, for each occurrence, is independently hydrogen,
C.sub.1-6 alkyl, C.sub.3-10carbocyclyl,
C.sub.3-10carbocyclyl-C.sub.1-4alkyl, 3- to 10-membered
heterocyclyl, (3- to 10-membered heterocyclyl)-C.sub.1-4alkyl,
C.sub.6-10aryl, C.sub.6-10aryl-C.sub.1-4alkyl, 5- to 10-membered
heteroaryl, or (5- to 10-membered heteroaryl)-C.sub.1-4alkyl;
[0094] n is 0, 1, 2, or 3; and [0095] q is 0, 1, or 2.
[0096] In one embodiment the invention provides compounds of
formula (I), or a pharmaceutically acceptable salt thereof, wherein
n is 0.
[0097] In another embodiment the invention provides compounds of
formula (I), or a pharmaceutically acceptable salt thereof, wherein
q is 0.
[0098] In another embodiment the invention provides compounds of
formula (I), or a pharmaceutically acceptable salt thereof, wherein
A is
##STR00009##
[0099] In another embodiment the invention provides compounds of
formula (I), or a pharmaceutically acceptable salt thereof, wherein
V is --OOR.sup.1b.
[0100] In another embodiment the invention provides compounds of
formula (I), or a pharmaceutically acceptable salt thereof, wherein
R.sup.1, R.sup.1a, and R.sup.1b are hydrogen.
[0101] In another embodiment the invention provides compounds of
formula (I), or a pharmaceutically acceptable salt thereof, wherein
R.sup.3 is C.sub.1-4alkyl or C.sub.3-6cycloalkyl,
[0102] In another embodiment the invention provides compounds of
formula (I), or a pharmaceutically acceptable salt thereof, wherein
R.sup.3 is ethyl or cyclopropyl.
[0103] In another embodiment the invention provides compounds of
formula (I), or a pharmaceutically acceptable salt thereof, wherein
R.sup.3 is ethyl
[0104] In another embodiment the invention provides compounds of
formula (I), or a pharmaceutically acceptable salt thereof, wherein
R.sup.4 is
##STR00010##
[0105] In another embodiment the invention provides compounds of
formula (I), or a pharmaceutically acceptable salt thereof, wherein
R.sup.5 is a naturally occurring amino acid sidechain selected from
the group consisting of the sidechain of glycine, alanine,
cysteine, asparagine, glutamine, glutamic acid, arginine, aspartic
acid, histidine, lysine, isoleucine, leucine, methionine,
phenylalanine, proline, serine, threonine, tryptophane, tyrosine,
and valine.
[0106] In another embodiment the invention provides compounds of
formula (I), or a pharmaceutically acceptable salt thereof, wherein
R.sup.5 is the sidechain of valine.
[0107] In another embodiment the invention provides compounds of
formula (I), or a pharmaceutically acceptable salt thereof, wherein
R.sup.5 is a non-standard amino acid sidechain selected from the
group consisting of the sidechain of 3,5-dibromotyrosine,
3,5-diiodotyrosine, gem-dimethylglycine, hydroxylysine,
.alpha.-aminobutyric acid, hydroxyproline, lanthionine, thyroxine,
ornithine, and citrulline.
[0108] In another embodiment the invention provides compounds of
formula (I), or a pharmaceutically acceptable salt thereof, wherein
R.sup.4 is
##STR00011##
[0109] In another embodiment the invention provides compounds of
formula (I), or a pharmaceutically acceptable salt thereof, wherein
R.sup.6 is C.sub.1-6alkyl, C.sub.3-8carbocyclyl-C.sub.1-4alkyl, or
phenyl-C.sub.1-4alkyl.
[0110] In another embodiment the invention provides compounds of
formula (I), or a pharmaceutically acceptable salt thereof, wherein
R.sup.6 is methyl, ethyl, isobutyl, tert-butyl,
bicyclo[2.2.1]heptan-2-ylmethyl, or 1-phenyl-ethan-1-yl.
[0111] In another embodiment the invention provides compounds of
formula (I), or a pharmaceutically acceptable salt thereof, wherein
R.sup.4 is
##STR00012##
[0112] In another embodiment the invention provides compounds of
formula (I), or a pharmaceutically acceptable salt thereof, wherein
R.sup.7, for each occurrence, is independently hydrogen or a
C.sub.1-6alkyl.
[0113] In another embodiment the invention provides compounds of
formula (I), or a pharmaceutically acceptable salt thereof, wherein
each R.sup.7 is ethyl.
[0114] In another embodiment the invention provides compounds of
formula (I), or a pharmaceutically acceptable salt thereof, wherein
each R.sup.7 is hydrogen.
[0115] In another embodiment the invention provides compounds of
formula (I), or a pharmaceutiacally acceptable salt thereof,
wherein: [0116] A is selected from the group consisting of
[0116] ##STR00013## [0117] V is --OR.sup.1b; [0118] R.sup.1,
R.sup.1a and R.sup.1b are hydrogen; [0119] R.sup.3 is
C.sub.1-6alkyl or C.sub.3-10cycloalkyl; [0120] R.sup.4 is:
[0120] ##STR00014## [0121] R.sup.5 is an amino acid sidechain; and
[0122] n and q are 0.
[0123] In another embodiment the invention provides compounds of
formula (I), or a pharmaceutiacally acceptable salt thereof,
wherein: [0124] A is selected from the group consisting of
[0124] ##STR00015## [0125] V is --OR.sup.1b; [0126] R.sup.1,
R.sup.1a and R.sup.1b are hydrogen; [0127] R.sup.3 is
C.sub.1-6alkyl or C.sub.3-10cycloalkyl; [0128] R.sup.4 is:
[0128] ##STR00016## [0129] R.sup.5 is valine sidechain; and [0130]
n and q are 0.
[0131] In another embodiment the invention provides compounds of
formula (I), or a pharmaceutiacally acceptable salt thereof,
wherein: [0132] A is selected from the group consisting of
[0132] ##STR00017## [0133] V is hydrogen, halo or --OR.sup.1b;
[0134] R.sup.1, R.sup.1a and R.sup.1b are hydrogen; [0135] R.sup.3
is C.sub.1-6alkyl or C.sub.3-10cycloalkyl; [0136] R.sup.4 is:
[0136] ##STR00018## [0137] R.sup.6 is a C.sub.1-6alkyl,
C.sub.3-10carbocyclyl-C.sub.1-4alkyl, or
C.sub.6-10aryl-C.sub.1-4alkyl; and [0138] n and q are 0.
[0139] In another embodiment the invention provides compounds of
formula (I), or a pharmaceutiacally acceptable salt thereof,
wherein: [0140] A is selected from the group consisting of
[0140] ##STR00019## [0141] V is hydrogen, halo or --OR.sup.1b;
[0142] R.sup.1, R.sup.1a and R.sup.1b are hydrogen; [0143] R.sup.3
is C.sub.1-6alkyl or C.sub.3-10cycloalkyl; [0144] R.sup.4 is:
[0144] ##STR00020## [0145] R.sup.6 is methyl, ethyl, isobutyl,
tert-butyl, bicyclo[2.2.1]heptan-2-ylmethyl, or
1-phenyl-ethan-1-yl; and [0146] n and q are 0.
[0147] In another embodiment the invention provides compounds of
formula (I), or a pharmaceutiacally acceptable salt thereof,
wherein: [0148] A is selected from the group consisting of
[0148] ##STR00021## [0149] V is hydrogen, halo or --OR.sup.1b;
[0150] R.sup.1, R.sup.1a and R.sup.1b are hydrogen; [0151] R.sup.3
is C.sub.1-6alkyl or C.sub.3-10cycloalkyl; [0152] R.sup.4 is:
[0152] ##STR00022## [0153] R.sup.7, for each occurrence, is
independently hydrogen or C.sub.1-6alkyl; and [0154] n and q are
0.
[0155] In another embodiment the invention provides compounds of
formula (I), or a pharmaceutiacally acceptable salt thereof,
wherein: [0156] A is selected from the group consisting of
[0156] ##STR00023## [0157] V is hydrogen, halo or --OR.sup.1b;
[0158] R.sup.1, R.sup.1a and R.sup.1b are hydrogen; [0159] R.sup.3
is C.sub.1-6alkyl or C.sub.3-10cycloalkyl; [0160] R.sup.4 is:
[0160] ##STR00024## [0161] each R.sup.7 is hydrogen or each R.sup.7
is ethyl; and [0162] n and q are 0.
[0163] In another embodiment the invention provides compounds of
formula (I), or a pharmaceutically acceptable salt thereof, wherein
the compound is selected from the group consisting of: [0164]
(R)-2-amino-3-methyl-butyric acid
(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-p-
henyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester; [0165]
carbonic acid
(2R,3S,4R,5R,6S)-6-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6--
ylmethyl)-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl
ester methyl ester; [0166] carbonic acid
(2R,3S,4R,5R,6S)-6-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmet-
hyl)-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester
ethyl ester; [0167] carbonic acid
(2R,3S,4R,5R,6S)-6-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmet-
hyl)-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester
isobutyl ester; [0168] carbonic acid
(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-p-
henyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester ethyl
ester; [0169] carbonic acid
(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-p-
henyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester isobutyl
ester; [0170] Carbonic acid tert-butyl ester
(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-p-
henyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester; [0171]
carbonic acid bicyclo[2.2.1]hept-2-ylmethyl ester
(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-p-
henyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester; [0172]
carbonic acid
(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-et-
hyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester
(S)-1-phenyl-ethyl ester; [0173] phosphoric acid
(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-p-
henyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester diethyl
ester; [0174] phosphoric acid
(2R,3S,4R,5R,6S)-6-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmet-
hyl)-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester
diethyl ester;
[0175] phosphoric acid
mono-{(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-e-
thyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl}
ester.
[0176] In another embodiment, the variables in formula (I) are
those defined by the groups in the Examples section below.
[0177] In another embodiment individual compounds according to the
invention are those listed in the Examples section below.
Treatment of Diseases and Conditions
[0178] Compounds of Formula (I) have been found to be inhibitors of
SGLT. As used herein, inhibition of SGLT means inhibition
exclusively of SGLT2, inhibition exclusively of SGLT1 or inhibition
of both SGLT1 and SGLT2.
[0179] The invention provides a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, for use in therapy. The
invention further provides a pharmaceutical composition comprising
a compound of Formula (I), or a pharmaceutically acceptable salt
thereof, in combination with a pharmaceutically acceptable
excipient.
[0180] The invention further provides a method for the treatment of
a disease or condition mediated by the sodium D-glucose
co-transporter, comprising the step of administering a
therapeutically effective amount of a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, to a subject. The
invention also provides the use of a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, in the manufacture of a
medicament for the treatment of a disease or condition mediated by
the sodium D-glucose co-transporter. The invention also provides a
compound of Formula (I), or a pharmaceutically acceptable salt
thereof, for use in treating a disease or condition mediated by the
sodium D-glucose co-transporter.
[0181] The SGLT inhibitory activity of the compounds of the
invention may be demonstrated by the SGLT2 and SGLT1 assays
disclosed hereinbelow. Preferred compounds of the invention have an
IC.sub.50 in the SGLT2 assay of <100 nM, in one embodiment
<30 nM, in one embodiment <20 nM, in one embodiment <10
nM, in another embodiment <5 nM, and in another embodiment <1
nM, and in another embodiment <0.5 nM. In another embodiment,
preferred compounds of the invention have an IC.sub.50 in the SGLT1
assay of <10,000 nM, in one embodiment <1500 nM, in one
embodiment <1000 nM, in one embodiment <700 nM, in another
embodiment <500 nM and in another embodiment <200 nM.
[0182] The present invention also provides a method of treating
diabetes comprising administering a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, to a subject in need
thereof.
[0183] In another embodiment, the invention provides a method of
treating a disease or condition mediated by the sodium D-glucose
co-transporter in a mammal, comprising administering to the mammal
in need thereof a therapeutically effective amount of a compound
according to formula (I), or a pharmaceutically acceptable salt
thereof.
[0184] The compounds of the present invention are useful as both
prophylactic and therapeutic treatments for diseases or conditions
related to the inhibition of SGLT-2 and/or SGLT-1.
[0185] 1. Diseases and conditions mediated by the sodium D-glucose
co-transporter The invention is useful for the treatment of a
disease or disorder mediated by the sodium D-glucose
co-transporter. Diseases and conditions mediated by the sodium
D-glucose co-transporter include: metabolic disorders, retinopathy,
nephropathy, diabetic foot, ulcers, macroangiopathies, metabolic
acidosis or ketosis, reactive hypoglycaemia, hyperinsulinaemia,
glucose metabolic disorder, insulin resistance, metabolic syndrome
(such as dyslipidemia, obesity, insulin resistance, hypertension,
microalbuminemia, hyperuricaemia, and hypercoagulability),
dyslipidaemias of different origins, atherosclerosis and related
diseases, high blood pressure, chronic heart failure, edema,
hyperuricaemia, Syndrome X, diabetes, insulin resistance, decreased
glucose tolerance (also known as impaired glucose tolerance, IGT),
non-insulin-dependent diabetes mellitus, Type II diabetes, Type I
diabetes, diabetic complications, body weight disorders, weight
loss, body mass index and leptin related diseases. In one
embodiment, the diseases and conditions include metabolic syndrome
(such as dyslipidemia, obesity, insulin resistance, hypertension,
microalbuminemia, hyperuricaemia, and hypercoagulability), Syndrome
X, diabetes, insulin resistance, decreased glucose tolerance (also
known as impaired glucose tolerance, IGT), non-insulin-dependent
diabetes mellitus, Type II diabetes, Type I diabetes, diabetic
complications, body weight disorders, weight loss, body mass index
and leptin related diseases. In one embodiment, the disease or
disorder is decreased glucose tolerance, Type II diabetes or
obesity.
[0186] Compounds of formula (I), or a pharmaceutically acceptable
salt thereof, may be also suitable for preventing beta-cell
degeneration such as apoptosis or necrosis of pancreatic beta
cells, for improving or restoring the functionality of pancreatic
cells, increasing the number and size of pancreatic beta cells, for
use as diuretics or antihypertensives and for the prevention and
treatment of acute renal failure.
[0187] As a further aspect, the invention relates to a method for
treating a disorder selected from type I and type II diabetes
mellitus, complications of diabetes, comprising administration of
an effective amount of a compound of formula (I) or a
pharmaceutically acceptable salt thereof.
[0188] As used herein a patient is suffering from "obesity" if the
patient exhibits at least one of: [0189] a body mass index (BMI),
i.e. the patient's mass (in kg) divided by the square of the
patient's height (in m), of 30 or more; [0190] an absolute waist
circumference of >102 cm in men or >88 cm in women; [0191] a
waist-to-hip ratio >0.9 in men or >0.85 in women; or [0192] a
percent body fat >25% in men or >30% in women.
[0193] As used herein a patient is suffering from "Type II
diabetes" if they meet the World Health Organisation criteria for
Diabetes diagnosis (Definition and diagnosis of diabetes mellitus
and intermediate hyperglycaemia, WHO, 2006), i.e. the patient
exhibits at least one of: [0194] a fasting plasma glucose 7.0
mmol/l (126 mg/dl); or [0195] a venous plasma glucose 11.1 mmol/l
(200 mg/dl) 2 hours after ingestion of 75 g oral glucose load.
[0196] As used herein a patient is suffering from "IGT" if they
meet the World Health Organisation criteria for IGT diagnosis
(Definition and diagnosis of diabetes mellitus and intermediate
hyperglycaemia, WHO, 2006), i.e. the patient exhibits both of:
[0197] a fasting plasma glucose <7.0 mmol/l (126 mg/dl); and
[0198] a venous plasma glucose 7.8 and <11.1 mmol/l (200 mg/dl)
2 hours after ingestion of 75 g oral glucose load.
Administration & Formulation
[0199] 1. General
[0200] For pharmaceutical use, the compounds of the invention may
be administered as a medicament by enteral or parenteral routes,
including intravenous, intramuscular, subcutaneous, transdermal,
airway (aerosol), oral, intranasal, rectal, vaginal and topical
(including buccal and sublingual) administration. The compounds of
Formula (I) should be assessed for their biopharmaceutical
properties, such as solubility and solution stability (across pH),
permeability, etc., in order to select the most appropriate dosage
form and route of administration for treatment of the proposed
indication. In one embodiment the compounds are administered
orally.
[0201] The compounds of the invention may be administered as
crystalline or amorphous products. The compounds of the invention
may be administered alone or in combination with one or more other
compounds of the invention or in combination with one or more other
drugs (or as any combination thereof). Generally, they will be
administered as a formulation in association with one or more
pharmaceutically acceptable excipients. The term "excipient"
includes any ingredient other than the compound(s) of the invention
which may impart either a functional (e.g drug release rate
controlling) and/or a non-functional (e.g. processing aid or
diluent) characteristic to the formulations. The choice of
excipient will to a large extent depend on factors such as the
particular mode of administration, the effect of the excipient on
solubility and stability, and the nature of the dosage form.
[0202] The present invention provides a pharmaceutical composition
comprising a compound according to Formula (I), or a
pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable excipient.
[0203] Typical pharmaceutically acceptable excipients or carriers
include: [0204] diluents, e.g. lactose, dextrose, sucrose,
mannitol, sorbitol, cellulose and/or glycine; [0205] lubricants,
e.g. silica, talcum, stearic acid, its magnesium or calcium salt
and/or polyethyleneglycol; [0206] binders, e.g. magnesium aluminum
silicate, starch paste, gelatin, tragacanth, methylcellulose,
sodium carboxymethylcellulose and/or polyvinylpyrrolidone; [0207]
disintegrants, e.g. starches, agar, alginic acid or its sodium
salt, or effervescent mixtures; and/or [0208] absorbants,
colorants, flavors and/or sweeteners.
[0209] A thorough discussion of pharmaceutically acceptable
excipients is available in Gennaro, Remington: The Science and
Practice of Pharmacy 2000, 20th edition (ISBN: 0683306472).
[0210] Accordingly, in one embodiment, the present invention
provides a pharmaceutical composition comprising a compound of
Formula (I), or a pharmaceutically acceptable salt thereof, and one
or more pharmaceutically acceptable carrier.
[0211] 2. Oral Administration
[0212] The compounds of the invention may be administered orally.
Oral administration may involve swallowing, so that the compound
enters the gastrointestinal tract, and/or buccal, lingual, or
sublingual administration by which the compound enters the blood
stream directly from the mouth.
[0213] Formulations suitable for oral administration include solid
plugs, solid microparticulates, semi-solid and liquid (including
multiple phases or dispersed systems) such as tablets; soft or hard
capsules containing multi- or nano-particulates, liquids (e.g.
aqueous solutions), emulsions or powders; lozenges (including
liquid-filled); chews; gels; fast dispersing dosage forms; films;
ovules; sprays; and buccal/mucoadhesive patches.
[0214] Formulations suitable for oral administration may also be
designed to deliver the compounds of Formula (I) in an immediate
release manner or in a rate-sustaining manner, wherein the release
profile can be delayed, pulsed, controlled, sustained, or delayed
and sustained or modified in such a manner which optimises the
therapeutic efficacy of the said compounds. Means to deliver
compounds in a rate-sustaining manner are known in the art and
include slow release polymers that can be formulated with the said
compounds to control their release.
[0215] Examples of rate-sustaining polymers include degradable and
non-degradable polymers that can be used to release the said
compounds by diffusion or a combination of diffusion and polymer
erosion. Examples of rate-sustaining polymers include hydroxypropyl
methylcellulose, hydroxypropyl cellulose, methyl cellulose, ethyl
cellulose, sodium carboxymethyl cellulose, polyvinyl alcohol,
polyvinyl pyrrolidone, xanthum gum, polymethacrylates, polyethylene
oxide and polyethylene glycol.
[0216] Liquid (including multiple phases and dispersed systems)
formulations include emulsions, suspensions, solutions, syrups and
elixirs. Such formulations may be presented as fillers in soft or
hard capsules (made, for example, from gelatin or
hydroxypropylmethylcellulose) and typically comprise a carrier, for
example, water, ethanol, polyethylene glycol, propylene glycol,
methylcellulose, or a suitable oil, and one or more emulsifying
agents and/or suspending agents. Liquid formulations may also be
prepared by the reconstitution of a solid, for example, from a
sachet.
[0217] The compounds of the invention may also be used in
fast-dissolving, fast-disintegrating dosage forms such as those
described in Liang and Chen, Expert Opinion in Therapeutic Patents
2001, 11(6): 981-986.
[0218] The formulation of tablets is discussed in H. Lieberman and
L. Lachman, Pharmaceutical Dosage Forms: Tablets 1980, vol. 1
(Marcel Dekker, New York).
[0219] 3. Parenteral Administration
[0220] The compounds of the invention can be administered
parenterally.
[0221] The compounds of the invention may be administered directly
into the blood stream, into subcutaneous tissue, into muscle, or
into an internal organ. Suitable means for administration include
intravenous, intraarterial, intrathecal, intraventricular,
intraurethral, intrasternal, intracranial, intramuscular,
intrasynovial and subcutaneous. Suitable devices for administration
include needle (including microneedle) injectors, needle-free
injectors and infusion techniques.
[0222] Parenteral formulations are typically aqueous or oily
solutions. Where the solution is aqueous, excipients such as sugars
(including but restricted to glucose, mannitol, sorbitol, etc.)
salts, carbohydrates and buffering agents (preferably to a pH of
from 3 to 9), but, for some applications, they may be more suitably
formulated as a sterile non-aqueous solution or as a dried form to
be used in conjunction with a suitable vehicle such as sterile,
pyrogen-free water (WFI).
[0223] Parenteral formulations may include implants derived from
degradable polymers such as polyesters (i.e. polylactic acid,
polylactide, polylactide-co-glycolide, polycapro-lactone,
polyhydroxybutyrate), polyorthoesters and polyanhydrides. These
formulations may be administered via surgical incision into the
subcutaneous tissue, muscular tissue or directly into specific
organs.
[0224] The preparation of parenteral formulations under sterile
conditions, for example, by lyophilisation, may readily be
accomplished using standard pharmaceutical techniques well known to
those skilled in the art.
[0225] The solubility of compounds of Formula (I) used in the
preparation of parenteral solutions may be increased by the use of
appropriate formulation techniques, such as the incorporation of
co-solvents and/or solubility-enhancing agents such as surfactants,
micelle structures and cyclodextrins.
[0226] 4. Inhalation & Intranasal Administration
[0227] The compounds of the invention can be administered
intranasally or by inhalation, typically in the form of a dry
powder (either alone, as a mixture, for example, in a dry blend
with lactose, or as a mixed component particle, for example, mixed
with phospholipids, such as phosphatidylcholine) from a dry powder
inhaler, as an aerosol spray from a pressurised container, pump,
spray, atomiser (preferably an atomiser using electrohydrodynamics
to produce a fine mist), or nebuliser, with or without the use of a
suitable propellant, such as 1,1,1,2-tetrafluoroethane or
1,1,1,2,3,3,3-heptafluoropropane, or as nasal drops. For intranasal
use, the powder may comprise a bioadhesive agent, for example,
chitosan or cyclodextrin.
[0228] The pressurised container, pump, spray, atomizer, or
nebuliser contains a solution or suspension of the compound(s) of
the invention comprising, for example, ethanol, aqueous ethanol, or
a suitable alternative agent for dispersing, solubilising, or
extending release of the active, a propellant(s) as solvent and an
optional surfactant, such as sorbitan trioleate, oleic acid, or an
oligolactic acid.
[0229] Prior to use in a dry powder or suspension formulation, the
drug product is micronised to a size suitable for delivery by
inhalation (typically less than 5 microns). This may be achieved by
any appropriate comminuting method, such as spiral jet milling,
fluid bed jet milling, supercritical fluid processing to form
nanoparticles, high pressure homogenisation, or spray drying.
[0230] Capsules (made, for example, from gelatin or
hydroxypropylmethylcellulose), blisters and cartridges for use in
an inhaler or insufflator may be formulated to contain a powder mix
of the compound of the invention, a suitable powder base such as
lactose or starch and a performance modifier such as I-leucine,
mannitol, or magnesium stearate. The lactose may be anhydrous or in
the form of the monohydrate, preferably the latter. Other suitable
excipients include dextran, glucose, maltose, sorbitol, xylitol,
fructose, sucrose and trehalose.
[0231] Formulations for inhaled/intranasal administration may be
formulated to be immediate and/or modified release using, for
example, PGLA. Modified release formulations include delayed-,
sustained-, pulsed-, controlled-, targeted and programmed
release.
[0232] 5. Transdermal Administration
[0233] Suitable formulations for transdermal application include a
therapeutically effective amount of a compound of the invention
with carrier. Advantageous carriers include absorbable
pharmacologically acceptable solvents to assist passage through the
skin of the host. Characteristically, transdermal devices are in
the form of a bandage comprising a backing member, a reservoir
containing the compound optionally with carriers, optionally a rate
controlling barrier to deliver the compound of the skin of the host
at a controlled and predetermined rate over a prolonged period of
time, and means to secure the device to the skin.
[0234] Combination Therapy
[0235] A compound of formula (I), or a pharmaceutically acceptable
salt thereof, may be usefully combined with another
pharmacologically active compound, or with two or more other
pharmacologically active compounds, for use in therapy. For
example, a compound of the formula (I), or a pharmaceutically
acceptable salt thereof, as defined above, may be administered
simultaneously, sequentially or separately in combination with one
or more agents for the treatment of disorders previously
listed.
[0236] Therapeutic agents which are suitable for such a combination
include, for example, antidiabetic agents such as metformin,
sulphonylureas (e.g. glibenclamide, tolbutamide, glimepiride),
nateglinide, repaglinide, thiazolidinediones (e.g. rosiglitazone,
pioglitazone), PPAR-gamma-agonists (e.g. GI 262570) and
antagonists, PPAR-gamma/alpha modulators (e.g. KRP 297), alpha-
glucosidase inhibitors (e.g. acarbose, voglibose), DPPIV inhibitors
(e.g. LAF237, MK-431), alpha2-antagonists, insulin and insulin
analogues, GLP-1 and GLP-1 analogues (e.g. exendin-4) or amylin.
The list also includes inhibitors of protein tyrosinephosphatase 1,
substances that affect deregulated glucose production in the liver,
such as e.g. inhibitors of glucose-6-phosphatase, orfructose-1
,6-bisphosphatase, glycogen phosphorylase, glucagon receptor
antagonists and inhibitors of phosphoenol pyruvate carboxykinase,
glycogen synthase kinase or pyruvate dehydrokinase, lipid lowering
agents such as for example HMG-CoA-reductase inhibitors (e.g.
simvastatin, atorvastatin), fibrates (e.g. bezafibrate,
fenofibrate), nicotinic acid and the derivatives thereof,
PPAR-alpha agonists, PPAR-delta agonists, ACAT inhibitors (e.g.
avasimibe) or cholesterol absorption inhibitors such as, for
example, ezetimibe, bile acid-binding substances such as, for
example, cholestyramine, inhibitors of ileac bile acid transport,
HDL-raising compounds such as CETP inhibitors or ABC1 regulators or
active substances for treating obesity, such as sibutramine or
tetrahydrolipostatin, dexfenfluramine, axokine, antagonists of the
cannabinoidi receptor, MCH-1 receptor antagonists, MC4 receptor
agonists, NPY5 or NPY2 antagonists or .beta.3-agonists such as
SB-418790 or AD-9677 and agonists of the 5HT2c receptor.
[0237] Moreover, combinations with drugs for influencing high blood
pressure, chronic heart failure or atherosclerosis such as e.g.
A-II antagonists or ACE inhibitors, ECE inhibitors, diuretics,
.beta.-blockers, Ca-antagonists, centrally acting
antihypertensives, antagonists of the alpha-2- adrenergic receptor,
inhibitors of neutral endopeptidase, thrombocyte aggregation
inhibitors and others or combinations thereof are suitable.
Examples of angiotensin II receptor antagonists are candesartan
cilexetil, potassium losartan, eprosartan mesylate, valsartan,
telmisartan, irbesartan, EXP-3174, L-158809, EXP-3312, olmesartan,
medoxomil, tasosartan, KT-3-671 , GA-01 13, RU-64276, EMD-90423,
BR-9701 , etc. Angiotensin II receptor antagonists are preferably
used for the treatment or prevention of high blood pressure and
complications of diabetes, often combined with a diuretic such as
hydrochlorothiazide.
[0238] A combination with uric acid synthesis inhibitors or
uricosurics is suitable for the treatment or prevention of
gout.
[0239] A combination with GABA-receptor antagonists, Na-channel
blockers, topiramat, protein-kinase C inhibitors, advanced
glycation end product inhibitors or aldose reductase inhibitors may
be used for the treatment or prevention of complications of
diabetes. Such combinations may offer significant advantages,
including synergistic activity, in therapy.
[0240] The present invention thus provides:
[0241] The use of an agent selected from the group consisting of
insulin, insulin derivative or mimetic; insulin secretagogue;
insulinotropic sulfonylurea receptor ligand; PPAR ligand; insulin
sensitizer; biguanide; alpha-glucosidase inhibitors; GLP-1, GLP-1
analog or mimetic; DPPIV inhibitor; HMG-CoA reductase inhibitor;
squalene synthase inhibitor; FXR or LXR ligand; cholestyramine;
fibrates; nicotinic acid, and aspirin in the manufacture of a
medicament for the treatment of a disease or condition in a subject
mediated by the sodium D-glucose co-transporter, wherein the agent
is administered in combination with a compound according to Formula
(I), or a pharmaceutically acceptable salt thereof.
[0242] The use of a compound according to Formula (I), or a
pharmaceutically acceptable salt thereof, in the manufacture of a
medicament for the treatment of a disease or condition in a subject
mediated by the sodium D-glucose co-transporter, wherein the
compound is administered in combination with an agent selected from
the group consisting of insulin, insulin derivative, insulin
mimetic; insulin secretagogue; insulinotropic sulfonylurea receptor
ligand; PPAR ligand; insulin sensitizer; biguanide;
alpha-glucosidase inhibitors; GLP-1, GLP-1 analog, GLP-1 mimetic;
DPPIV inhibitor; HMG-CoA reductase inhibitor; squalene synthase
inhibitor; FXR ligand, LXR ligand; cholestyramine; fibrates;
nicotinic acid, and aspirin.
[0243] The use of a compound according to formula (I), or a
pharmaceutically acceptable salt thereof, in combination with an
agent selected from the group consisting of insulin, insulin
derivative, insulin mimetic; insulin secretagogue; insulinotropic
sulfonylurea receptor ligand; PPAR ligand; insulin sensitizer;
biguanide; alpha-glucosidase inhibitors; GLP-1, GLP-1 analog, GLP-1
mimetic; DPPIV inhibitor; HMG-CoA reductase inhibitor; squalene
synthase inhibitor; FXR ligand, LXR ligand; cholestyramine;
fibrates; nicotinic acid, and aspirin.
[0244] The present invention also provides a pharmaceutical
composition comprising a therapeutically effective amount of a
compound of Formula (I) in combination with a therapeutically
effective amount of insulin, insulin derivative, insulin mimetic;
insulin secretagogue; insulinotropic sulfonylurea receptor ligand;
PPAR ligand; insulin sensitizer; biguanide; alpha-glucosidase
inhibitors; GLP-1, GLP-1 analog, GLP-1 mimetic; DPPIV inhibitor;
HMG-CoA reductase inhibitor; squalene synthase inhibitor; FXR
ligand, LXR ligand; cholestyramine; fibrates; nicotinic acid, and
aspirin for simultaneous, separate or sequential use in
therapy.
[0245] Pharmaceutical compositions may contain a therapeutically
effective amount of a compound of the invention as defined above,
either alone or in a combination with another therapeutic agent,
e.g., each at an effective therapeutic dose as reported in the art.
Such therapeutic agents include:
[0246] a) antidiabetic agents, such as insulin, insulin derivatives
and mimetics; insulin secretagogues such as the sulfonylureas,
e.g., Glipizide, glyburide and Amaryl; insulinotropic sulfonylurea
receptor ligands such as meglitinides, e.g., nateglinide and
repaglinide; protein tyrosine phosphatase-1B (PTP-1B) inhibitors
such as PTP-112; GSK3 (glycogen synthase kinase-3) inhibitors such
as SB-517955, SB-4195052, SB-216763, NN-57-05441 and NN-57-05445;
RXR ligands such as GW-0791 and AGN-194204; sodium-dependent
glucose cotransporter inhibitors such as T-1095; glycogen
phosphorylase A inhibitors such as BAY R3401; biguanides such as
metformin; alpha-glucosidase inhibitors such as acarbose; GLP-1
(glucagon like peptide-1), GLP-1 analogs such as Exendin-4 and
GLP-1 mimetics; and DPPIV (dipeptidyl peptidase IV) inhibitors such
as vildagliptin;
[0247] b) hypolipidemic agents such as 3-hydroxy-3-methyl-glutaryl
coenzyme A (HMG-CoA) reductase inhibitors, e.g., lovastatin,
pitavastatin, simvastatin, pravastatin, cerivastatin, mevastatin,
velostatin, fluvastatin, dalvastatin, atorvastatin, rosuvastatin
and rivastatin; squalene synthase inhibitors; FXR (farnesoid X
receptor) and LXR (liver X receptor) ligands; cholestyramine;
fibrates; nicotinic acid bile acid binding resins such as
cholestyramine; fibrates; nicotinic acid and other GPR109 agonists;
cholesterol absorption inhibitors such as ezetimibe; CETP
inhibitors (cholesterol-ester-transfer-protein inhibitors), and
aspirin;
[0248] c) anti-obesity agents such as orlistat, sibutramine and
Cannabinoid Receptor 1 (CB1) antagonists e.g. rimonabant; and
[0249] d) anti-hypertensive agents, e.g., loop diuretics such as
ethacrynic acid, furosemide and torsemide; angiotensin converting
enzyme (ACE) inhibitors such as benazepril, captopril, enalapril,
fosinopril, lisinopril, moexipril, perinodopril, quinapril,
ramipril and trandolapril; inhibitors of the Na-K-ATPase membrane
pump such as digoxin; neutralendopeptidase (NEP) inhibitors;
ACE/NEP inhibitors such as omapatrilat, sampatrilat and fasidotril;
angiotensin II antagonists such as candesartan, eprosartan,
irbesartan, losartan, telmisartan and valsartan, in particular
valsartan; renin inhibitors such as ditekiren, zankiren,
terlakiren, aliskiren, RO 66-1132 and RO-66-1168; .beta.-adrenergic
receptor blockers such as acebutolol, atenolol, betaxolol,
bisoprolol, metoprolol, nadolol, propranolol, sotalol and timolol;
inotropic agents such as digoxin, dobutamine and milrinone; calcium
channel blockers such as amlodipine, bepridil, diltiazem,
felodipine, nicardipine, nimodipine, nifedipine, nisoldipine and
verapamil; aldosterone receptor antagonists; and aldosterone
synthase inhibitors.
[0250] e) agonists of peroxisome proliferator-activator receptors,
such as fenofibrate, pioglitazone, rosiglitazone, tesaglitazar,
BMS-298585, L-796449, the compounds specifically described in the
patent application WO 2004/103995 i.e. compounds of examples 1 to
35 or compounds specifically listed in claim 21, or the compounds
specifically described in the patent application WO 03/043985 i.e.
compounds of examples 1 to 7 or compounds specifically listed in
claim 19 and especially
(R)-1-{4[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-benzen-
esulfonyl}-2,3-dihydro-1H-indole-2-carboxylic or a salt
thereof.
[0251] Thus, the present invention provides a pharmaceutical
combination comprising: [0252] i) a compound according of Formula
(I), or a pharmaceutically acceptable salt thereof, [0253] ii) at
least one compound selected from [0254] a) antidiabetic agents,
[0255] b) hypolipidemic agents, [0256] c) anti-obesity agents,
[0257] d) anti-hypertensive agents, [0258] e) agonists of
peroxisome proliferator-activator receptors.
Biological Assays
[0259] The inhibitory effect on the sodium-dependent glucose
co-transporter SGLT (SGLT1 and SGLT2), of compounds of formula I
may be demonstrated using the following test procedures.
[0260] The ability of the substances to inhibit the SGLT-2 activity
may be demonstrated in a test set-up in which a CHO-K1 cell line
(ATCC No. CCL 6 1) or alternatively an HEK293 cell line (ATCC No.
CRL-1573) is stably transfected with an expression vector pZeoSV
(Invitrogen, EMBL accession number L36849) which contains the cDNA
for the coding sequence of the human sodium glucose co-transporter
2 (Genbank Ace. No.NM.sub.--003041) (CHO-hSGLT2 or HEK-hSGLT2).
These cell lines transport .sup.14C-labelled
alpha-methyl-glucopyranoside (.sup.14C-AMG, Amersham) into the
interior of the cell in sodium-dependent manner.
[0261] The SGLT-2 assay is carried out as follows: CHO-hSGLT2 cells
are cultivated in Ham's F12 Medium (BioWhittaker) with 10% foetal
calf serum and 250 .mu.g/mL zeocin (Invitrogen), and HEK293-hSGLT2
cells are cultivated in DMEM medium with 10% foetal calf serum and
250 .mu.g/mL zeocin (Invitrogen). The cells are detached from the
culture flasks by washing twice with PBS and subsequently treating
with trypsin/EDTA. After the addition of cell culture medium the
cells are centrifuged, resuspended in culture medium and counted in
a Casy cell counter. Then 40,000 cells per well are seeded into a
white, 96-well plate coated with poly-D-lysine and incubated
overnight at 37.degree. C., 5% CO2. The cells are washed twice with
250 .mu.l of assay buffer (Hanks Balanced Salt Solution, 137 mM
NaCl, 5.4 mM KCI, 2.8 mM CaCl2 , 1.2 mM MgSO4 and 10 mM HEPES (pH
7.4), 50 .mu.g/mL of gentamycin). 250 .mu.l of assay buffer and 5
.mu.l of test compound are then added to each well and the plate is
incubated for a further 15 minutes in the incubator. 5 .mu.l of 10%
DMSO are used as the negative control. The reaction is started by
adding 5 .mu.l of 14 C-AMG (0.05 .mu.Ci) to each well. After 2
hours' incubation at 37.degree. C., 5% CO2, the cells are washed
again with 250 .mu.l of PBS (200C) and then lysed by the addition
of 25 .mu.l of 0.1 N NaOH (5 min. at 37.degree. C.). 200 .mu.l of
MicroScint20 (Packard) are added to each well and incubation is
continued for a further 20 min at 37.degree. C. After this
incubation the radioactivity of the .sup.14C-AMG absorbed is
measured in a Topcount (Packard) using a .sup.14C scintillation
program.
[0262] To determine the selectivity with respect to human SGLT1 an
analogous test is set up in which the cDNA for hSGLTI (Genbank Ace.
No. NM000343) instead of hSGLT2 cDNA is expressed in CHO-K1 or
HEK293 cells.
[0263] The compounds according to the invention may for example
have IC.sub.50 values below 1000 nM, particularly below 100 nM,
most preferably below 10 nM for SGLT2. The title compounds of the
Examples were evaluated in the above described assays and the
results of which are collated in Table 1.
TABLE-US-00001 TABLE 1 Example SGLT2 IC.sub.50 SGLT1 IC.sub.50
Numbers nM (n = 1-4) nM (n = 1-4) 1 22.5 409.0 2 17.5 35.0 2a 97.0
308.0 2b 186.0 337.5 2c 27.0 197.0 2d -- -- 2e 89.0 188.0 2f 143.0
3443.0 2g 567.0 1000.0 3 >1000.0 814 3a >1000.0 5650 4 2.4
89.3
[0264] Since the compounds of the invention are prodrugs which are
metabolized in vivo to a parent compound, the inhibitory activity
against SGLT1 and SGLT2 of the parent compound is relevant to the
activity of the compounds of the invention in vivo. The parent
compound of each compound of the invention was evaluated in the
above described assays, the results of which are collated in Table
2.
TABLE-US-00002 TABLE 2 SGLT2 IC.sub.50 nM SGLT1 IC.sub.50 nM Ex.
Nos. Structure of Parent Compound (n = 1-4) (n = 1-4) 1, 2c, 2d,
2e, 2f, 2g, 3 and 4 ##STR00025##
(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-
benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-
phenyl]-6-hydroxymethyl-tetrahydro-pyran- 3,4,5-triol 0.5 22.0 2,
2a, 2b, and 3a ##STR00026##
(2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(2,3-
dihydro-benzo[1,4]dioxin-6-ylmethyl)-
phenyl]-6-hydroxymethyl-tetrahydro-pyran- 3,4,5-triol 2.2 9.0
[0265] It can be seen that the compounds of the invention are
useful as inhibitors of SGLT and therefore useful in the treatment
of diseases and conditions mediated by SGLT such as the metabolic
disorders disclosed herein.
Method of Preparation
[0266] The invention provides, in another aspect, a process for
preparing a compound of Formula (I). The schemes, outlined below,
show general routes for synthesizing compounds of Formula (I). In
general, compounds of the invention are prepared by modifying of
the primary alcohol group of the glycoside ring to form prodrugs.
The secondary alcohol groups of the glycoside ring may be protected
or they may be left unprotected taking advantage of the increased
reactivity of the primary alcohol over the three secondary alcohol
groups of the glycoside ring to modify only the primary alcohol.
Typically, alcohol groups may be protected with esters, trimethyl
silyl (TMS), tert-butyl dimethyl silyl (TBDMS), benzyl, etc.
[0267] Amino acid prodrugs may be prepared by using standard
methodology for forming ester bonds (see Scheme I). For example,
the amine group of an amino acid (ii) may be protected with, for
example, a tert-butyloxycarbonyl (BOC) protecting group. The
carboxylic acid group of the amino acid (ii) may then be reacted
with the primary alcohol of the glycoside (i) in the presence of a
coupling agent such as N,N'-dicyclohexylcarbodiimide,
N,N'-diisopropylcarbodiimide, or 1-ethyl-3-(3-dimethylaminopropyl)
carbodiimide in the presence of a base to form an amino acid
prodrug (iii). Protecting groups can be removed by methods known in
the art to form a compound of formula (I).
##STR00027##
[0268] Carbonate prodrugs can be prepared by reacting a
chloroformate (v) with a glycoside (iv) in the presense of a base
as shown in Scheme II.
##STR00028##
[0269] Phosphate ester prodrugs can be prepared by reacting by
reacting a glycoside (iv) with a alkyl chlorophosphate (vii) in the
presense of a base as shown in Scheme Ill.
##STR00029##
[0270] Phosphate prodrugs can be prepared by reacting by reacting a
glycoside (iv) with a phosphoramidic acid ester (ix) in the
presence of tetrazole followed by treatment with
meta-chloroperoxybenzoic acid as shown in Scheme IV. Treatment with
amberlyst 15 yields a phosphate prodrug.
##STR00030##
Synthesis of Starting Materials
[0271] Compounds of formula (xii), wherein Lg is a leaving group
such as halogen and all other symbols are defined herein above, may
be reacted with alkyl lithium or Mg to provide compounds of formula
(xiii) wherein M is selected from Li or Mg-Halogen, and all other
symbols are defined herein above. Compounds of formula (xiii) may
be reacted with compounds of formula (xiv) wherein PG is a
protecting group such as an acetyl. The resulting intermediate may
be dehydroxylated/dealkoxylated using reagent such as
triethylsilane BF.sub.3-etherate to provide compounds of Formula
(v) wherein all symbols are defined herein above.
##STR00031##
[0272] Compounds of formula (xiii), wherein M is selected from Li
or Mg-Halogen and all other symbols are defined herein above, may
be reacted with compounds of formula (xvi) wherein Lg is a leaving
group such as halogen, mesylate, tosylate or
trifluoromethanesulfonyl and all other symbols are defined herein
above, to provide compounds of Formula (xv) wherein all symbols are
defined herein above.
##STR00032##
[0273] Intermediate (xii) can be prepared by reacting an acid
chloride (xvii) with an aromatic compound represented by A in the
presence of AlCl.sub.3 as shown in Scheme VII.
##STR00033##
[0274] It will be understood that the processes detailed above and
elsewhere herein are solely for the purpose of illustrating the
invention and should not be construed as limiting. A process
utilizing similar or analogous reagents and/or conditions known to
one skilled in the art may also be used to obtain a compound of the
invention.
[0275] Within the scope of this text, only a readily removable
group that is not a constituent of the particular desired end
product of the compounds of the present invention is designated a
"protecting group", unless the context indicates otherwise. The
protection of functional groups by such protecting groups, the
protecting groups themselves, and their cleavage reactions are
described for example in standard reference works, such as J. F. W.
McOmie, "Protective Groups in Organic Chemistry", Plenum Press,
London and New York 1973, in T. W. Greene and P. G. M. Wuts,
"Protective Groups in Organic Synthesis", Third edition, Wiley, New
York 1999, in "The Peptides"; Volume 3 (editors: E. Gross and J.
Meienhofer), Academic Press, London and New York 1981, in "Methoden
der organischen Chemie" (Methods of Organic Chemistry), Houben
Weyl, 4th edition, Volume 15/I, Georg Thieme Verlag, Stuttgart
1974, in H. -D. Jakubke and H. Jeschkeit, "Aminosauren, Peptide,
Proteine" (Amino acids, Peptides, Proteins), Verlag Chemie,
Weinheim, Deerfield Beach, and Basel 1982, and in Jochen Lehmann,
"Chemie der Kohlenhydrate: Monosaccharide and Derivate" (Chemistry
of Carbohydrates: Monosaccharides and Derivatives), Georg Thieme
Verlag, Stuttgart 1974. A characteristic of protecting groups is
that they can be removed readily (i.e. without the occurrence of
undesired secondary reactions) for example by solvolysis,
reduction, photolysis or alternatively under physiological
conditions (e.g. by enzymatic cleavage).
[0276] Any mixtures of final products or intermediates obtained can
be separated on the basis of the physico-chemical differences of
the constituents, in a known manner, into the pure final products
or intermediates, for example by chromatography, distillation,
fractional crystallisation, or by the formation of a salt if
appropriate or possible under the circumstances.
[0277] The following Examples are intended to illustrate the
invention and are not to be construed as being limitations thereon.
If not mentioned otherwise, all evaporations are performed under
reduced pressure. The structure of final products, intermediates
and starting materials have been confirmed by standard analytical
methods, e.g., microanalysis, melting point (m.p.) and
spectroscopic characteristics, e.g. MS and NMR. Abbreviations used
are those conventional in the art.
STARTING MATERIALS
Intermediate 1: Acetic acid
(2R,3R,4R,5S)-3,4,5-triacetoxy-6-[4-bromo-3-(2,3-dihydro-benzo[1,4]dioxin-
-6-ylmethy)-phenyl]tetrahydro-pyran-2-ylmethyl ester
##STR00034## ##STR00035##
[0279] Step I: To a stirred solution of 2-bromo-5-iodobenzoic acid
(25.0 g, 76.48 mmol) in dichloromethane (200 mL) was added
oxalylchloride (10.3 mL, 114.74 mmol) at 0.degree. C. followed by
DMF (0.9 mL). After complete addition, the reaction mixture was
stirred at room temperature for 3 h. Volatiles were evaporated
under reduced pressure to furnish 2-bromo-5-iodo-benzoyl chloride
(26.4 g). The crude product was used for the next step
immediately.
[0280] Step II: To a stirred solution of 2-bromo-5-iodo-benzoyl
chloride (26.4 g, 76.56 mmol) in dichloromethane (250 mL) was added
benzo(1,4)-dioxane (10.41 g, 76.26 mmol) at 0.degree. C. To this
reaction mixture, AlCl.sub.3 (40.78 g, 305.47 mmol) was added in
portions. After stirring overnight at room temperature, the
reaction mixture was poured into crushed ice. The resulting mixture
was extracted with dichloromethane (500 mL.times.2). The
dichloromethane layers were combined and washed with water (200
mL), saturated aqueous sodium bicarbonate solution (200
mL.times.2), and brine (200 mL), then dried over sodium sulfate and
concentrated. The solid product was triturated with hexanes, and
the triturated product was dried under vacuum to furnish
(2-bromo-5-iodo-phenyl)-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-metha-
none (30 g). .sup.1H NMR (400 MHz, DMSO-D.sub.6): .delta.4.29-4.37
(m, 4H), 7.02 (d, J=8.4 Hz, 1H), 7.16 (d, J=2.4 Hz, 1H), 7.18-7.19
(m, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.77-7.81 (m, 1H), 7.82 (d, J=2.0
Hz, 1H).
[0281] Step III: To a stirred solution of
(2-bromo-5-iodo-phenyl)-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-methanone
(30.0 g, 67.4 mmol) in trifluoroacetic acid (100 mL) was added
triethylsilane (86.2 mL, 539.3 mmol) followed by triflic acid (6.0
mL, 67.42 mmol) at room temperature. After stirring for 25 min at
room temperature, volatiles were evaporated under reduced pressure.
The resulting residue was taken up in ethyl acetate and washed with
saturated aqueous sodium bicarbonate solution (200 mL.times.2),
water (200 mL), and brine (200 mL), then dried over sodium sulfate,
concentrated and purified by silica gel column chromatography to
furnish 6-(2-bromo-5-iodo-benzyl)-2,3-dihydro-benzo[1,4]dioxine
(26.5 g).
[0282] .sup.1H NMR (400 MHz, DMSO-D.sub.6): .delta.3.90 (s, 4H),
4.2 (s, 2H), 6.65 (dd, J=8.4 Hz, J=2.0 Hz, 1H), 6.68 (d, J=2.0 Hz,
1H), 6.77 (d, J=8.4 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.50 (dd,
J=8.4 Hz, J=2.4 Hz 1H), 7.67 (d, J=2.8 Hz, 1H).
[0283] Step IV: To a stirred solution of
6-(2-bromo-5-iodo-benzyl)-2,3-dihydro-benzo[1,4]dioxine (26.5 g,
61.47 mmol) in THF:toluene 2:1 (300 mL) was added 1.6 M solution of
n-BuLi in hexanes (42.3 mL, 67.62 mmol) at -78.degree. C. The
reaction mixture was stirred for 1 h, and then transferred to a
stirred solution of
2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone (28.69 g, 61.47
mmol) in toluene (100 mL) at -78.degree. C. After stirring for 1 h,
0.6 N methanesulfonic acid in methanol (265 mL) was added dropwise
and stirred the reaction mixture for 16 h at room temperature.
Reaction was quenched by the addition of aq. NaHCO.sub.3 solution
(-75 mL) and extracted with ethyl acetate (250 mL.times.3), dried
over sodium sulfate, concentrated and purified by silica gel column
chromatography to furnish
(3R,4S,5S,6R)-2-[4-Bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phen-
yl]-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-3,4,5-triol (28.4
g)
[0284] Step V: To a stirred solution of
(3R,4S,5S,6R)-2-[4-bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phen-
yl]-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-3,4, 5-triol (28.4
g, 57.1 mmol) in acetonitrile-dichloromethane 1:1 (250 mL) was
added triethylsilane (36.5 mL, 228.4 mmol) and boron trifluoride
diethyletharate complex (14.1 mL, 114.2 mmol) at 10.degree. C.
After stirring for 4 h at 10.degree. C., the reaction was quenched
with saturated aqueous sodium bicarbonate (-100 mL). The organic
layer was separated, and the aqueous layer was extracted with ethyl
acetate (3.times.150 mL). The organic layers were combined and
dried over sodium sulfate, concentrated to furnish
(3R,4R,5S,6R)-2-[4-bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phen-
yl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (28.4 g). Crude
product was used for next reaction without purification.
[0285] Step VI: To a stirred solution of
(3R,4R,5S,6R)-2-[4-Bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phen-
yl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (28.4 g, 60.81
mmol) in dichloromethane (300 mL) was added pyridine (40 mL, 486.5
mmol), acetic anhydride (50 mL, 486.5 mmol) and DMAP (740 mg, 6.08
mmol) at room temperature. After stirring for 2 h, volatiles were
evaporated under reduced pressure. The resulting residue was taken
up in ethyl acetate (500 ml) and washed with 1N HCl (200
mL.times.2) followed by brine (200 ml), then dried over sodium
sulfate and concentrated. The resulting crude compound was
dissolved in ethanol (320 mL) at 65.degree. C. and allowed to cool
to room temperature while stirring. Light yellow solid formed was
filtered and washed with cold ethanol (150 mL) followed by hexane
(200 mL) to get acetic acid
(2R,3R,4R,5S)-3,4,5-triacetoxy-6-[4-bromo-3-(2,3-dihydro-benzo[1,4]dioxin-
-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylmethyl ester powder (22.5
g, purity 98%).
Intermediate 2:
(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-p-
henyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
##STR00036##
[0287] Step I: To a stirred solution of acetic acid
(2R,3R,4R,5S)-3,4,5-triacetoxy-6[4-bromo-3-(2,3-dihydro-benzo[1,4]dioxin--
6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylmethyl ester (Intermediate
1, 10.0 g, 15.74 mmol) in toluene (200 mL) was added
tricyclohexylphosphine (1.76 g, 6.29 mmol), a solution of potassium
phosphate tribasic (13.3 g, 62.9 mmol) in water (15 mL), and
ethylboronic acid (3.4 g, 47.2 mmol). The reaction mixture was
degassed for 45 min then palladium (II) acetate (529 mg, 2.3 mmol)
was added. After refluxing overnight, the reaction mixture was
cooled to room temperature, and water was added. The resulting
mixture was extracted with ethyl acetate, (2.times.200 mL), washed
with water and brine, then dried over sodium sulfate, concentrated
and purified by column chromatography to furnish acetic acid
(2R,3R,4R,5S)-3,4,5-triacetoxy-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmet-
hyl)-4-ethyl-phenyl]-tetrahydro-pyran-2-ylmethyl ester (5.4 g).
[0288] Step II: To a stirred solution of acetic acid
(2R,3R,4R,5S)-3,4,5-triacetoxy-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmet-
hyl)-4-ethyl-phenyl]-tetrahydro-pyran-2-ylmethyl ester (9.3 g, 15.9
mmol) in methanol:THF:water 3:2:1 (170 mL) was added lithium
hydroxide (764 mg, 19.1 mmol). After stirring for 2 h at room
temperature, the volatiles were evaporated under reduced pressure.
The resulting residue was taken up in ethyl acetate (150 mL) and
washed with brine (75 mL), brine containing 5 mL of 5% aqueous
KHSO.sub.4 (75 mL), and brine (20 mL) again, then dried over sodium
sulfate and concentrated to furnish
(2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmet-
hyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (6.5
g)
[0289] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta.1.07 (t, J=7.6 Hz,
3H), 2.57 (q, J=7.6 Hz, 2H), 3.34-3.50 (m, 4H), 3.68 (dd, J=12.0,
5.6 Hz, 1H), 3.85-3.91 (m, 3H), 4.08 (d, J=9.6 Hz, 1H), 4.17 (s,
4H), 6.53-6.58 (m, 2H), 6.68 (d, J=8.4 Hz, 1H), 7.15-7.25 (m, 3H).
MS (ES) m/z 434.2 (M+18).
Intermediate 3:
(2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmet-
hyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
##STR00037##
[0291] Step I: To a stirred solution of acetic acid
(2R,3R,4R,5S)-3,4,5-triacetoxy-6-[4-bromo-3-(2,3-dihydro-benzo[1,4]dioxin-
-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylmethyl ester
(Intermediate 1, 10.0 g, 15.74 mmol) in toluene (100 mL) was added
tricyclohexylphosphine (1.76 g, 6.29 mmol), a solution of potassium
phosphate tribasic (13.3 g, 62.9 mmol) in water (15 mL), and
cyclopropylboronic acid (4.06 g, 47.2 mmol). The reaction mixture
was degassed for 45 min then palladium (II) acetate (529 mg, 2.3
mmol) was added. The reaction mixture was stirred at 90.degree. C.
overnight then cooled to room temperature and filtered through
celite, and the celite was washed with ethyl acetate (200 mL). The
organic layer of the filtrate was separated and washed with water
(100 mL) followed by brine (100 mL), then dried over sodium sulfate
and concentrated to give crude product which was further purified
by column chromatography to furnish acetic acid
(2R,3R,4R,5S)-3,4,5-triacetoxy-6[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]d-
ioxin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylmethyl ester (7.25
g, purity 98%) and this was recrystallized by absolute ethanol to
give white solid (5.25 g, purity>99%).
[0292] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.0.57-0.62 (m, 2H),
0.84-0.86 (m, 2H), 1.76 (s, 3H), 1.77-1.80 (m, 1H), 1.99 (s, 3H),
2.05 (s, 3H), 2.08 (s, 3H), 3.78-3.82 (m, 1H), 3.99-4.10 (ABq,
J=15.6 Hz, 2H), 4.14 (dd, J=12.4 Hz, 2.4 Hz, 1H), 4.22 (s, 4H),
4.26 (d, J=12.4 Hz, 4.8 Hz, 1H), 4.33 (d, J=9.6 Hz, 1H), 5.14 (t,
J=9.2 Hz, 1H), 5.22 (t, J=9.2 Hz, 1H), 5.30 (t, J=9.2 Hz, 1 H),
6.57-6.59 (m, 2H), 6.76 (dd, J=7.2 Hz, 2.0 Hz, 1 H), 6.98 (d, J=8.4
Hz, 1H), 7.02 (d, J=1.6 Hz, 1H), 7.17 (dd, J=8.0 Hz, 1.6 Hz, 1H).
MS (ES) m/z 597.3 (M+1).
[0293] Step II: To a stirred solution of acetic acid
(2R,3R,4R,5S)-3,4,5-triacetoxy-6[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]d-
ioxin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylmethyl ester (10.5
g, 17.61 mmol) in methanol:THF:water 3:2:1 (120 mL) was added
lithium hydroxide (813 mg, 19.37 mmol). After stirring for 2 h at
room temperature, the volatiles were evaporated under reduced
pressure. The resulting residue was taken up in ethyl acetate (150
mL) and washed with brine (75 mL), brine containing 10 mL of 5%
aqueous KHSO.sub.4 (75 mL), and brine (20 mL) again, then dried
over sodium sulfate and concentrated to furnish
(2S,3R,4R,5S,6R)-2[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmeth-
yl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (7.25
g)
[0294] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta.0.53-0.56 (m, 2H),
0.81-0.86 (m, 2H), 1.80-1.82 (m, 1H), 3.34-3.45 (m, 4H), 3.67 (dd,
J=12.0, 5.2 Hz, 1H), 3.86 (d, J=11.6 Hz, 1H), 3.99-4.09 (m, 3H),
4.17 (s, 4H), 6.58-6.62 (m, 2H), 6.68 (d, J=8.0 Hz, 1H), 6.96 (d,
J=7.6 Hz, 1H), 7.19 (m, 2H). MS (ES) m/z 446.2 (M+18).
EXAMPLE
Example 1
Synthesis of (R)-2-Amino-3-methyl-butyric Acid
(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-p-
henyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl Ester
##STR00038## ##STR00039##
[0296] STEP I: To a stirred solution of
(2S,3R,4R,5S,6R)-2-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-p-
henyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (Intermediate
2, 6.0 g, 14.40 mmol) in pyridine (60 ml) was added trityl chloride
(4.8 g, 17.28 mmol) followed by DMAP (0.18 g, 1.44 mmol) at room
temperature. Then the reaction mixture was heated at 80.degree. C.
After stirring for 16 h, pyridine was evaporated under reduced
pressure. Resulting residue was taken in ethyl acetate (100 ml),
washed with aq. copper sulfate solution (50 ml), brine (100 ml),
dried over sodium sulfate, concentrated and purified by silica gel
column chromatography to give 8.10 g of
(2S,3R,4R,5S,6R)-2-[3-(2,3-dihydro-benzo[1,4]dioxi
n-6-ylmethyl)-4-ethyl-phenyl]-6-trityloxymethyl-tetrahydro-pyran-3,4,5-tr-
iol as white solid.
[0297] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta.1.11 (t, J=7.6 Hz,
3H), 2.62 (q, J=7.6 Hz, 2H), 3.25-3.28 (m, 1H), 3.34-3.44 (m, 3H),
3.54 (d, J=4.8 Hz, 2H), 3.94 (s, 2H), 4.08-4.16 (m, 5H), 6.56-6.59
(m, 2H), 6.64 (d, J=8.0 Hz, 1H), 7.15-7.24 (m, 10H), 7.30-7.33 (m,
2H), 7.46-7.48 (m, 6H).
[0298] STEP II: To a stirred suspension of sodium hydride (60% in
mineral oil, 2.2 g, 54.64 mmol) in DMF (40 ml), was added a
solution of
(2S,3R,4R,5S,6R)-2[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-ph-
enyl]-6-trityloxymethyl-tetrahydro-pyran-3,4,5-triol (8.0 g, 12.14
mmol) in DMF (10 ml) at 0.degree. C. After stirring for 4 h at room
temperature, reaction mixture was cooled to 0.degree. C. and added
TBAI (0.45 g, 1.21 mmol) followed by benzyl bromide (5.1 ml, 42.50
mmol). Then it was allowed to attain room temperature and stirred
for overnight. Reaction mixture was poured into ice cold water and
extracted with ethyl acetate (2.times.80 ml). Combined organic
layers were washed with water (100 ml), brine (100 ml), dried over
sodium sulfate, concentrated and purified by silica gel column
chromatography to give 8.5 g of
6-[2-ethyl-5-((2S,3S,4R,5R,6R)-3,4,5-tris-benzyloxy-6-trityloxymethyl-tet-
rahydro-pyran-2-yl)-benzyl]-2,3-dihydro-benzo[1,4]dioxine as a
colorless oil.
[0299] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta.1.21 (t, J=7.2 Hz,
3H), 2.67 (q, J=7.6 Hz, 2H), 3.24 (d, J=8.0 Hz, 1H), 3.55 (d, J=9.2
Hz, 1H), 3.62 (t, J=10.0 Hz, 2H), 3.76 (t, J=9.2 Hz, 1H), 3.85-4.00
(m, 3H), 4.09-4.16 (m, 5H), 4.26 (d, J=9.2 Hz, 1H), 4.42 (d, J=10.4
Hz, 1H), 4.50 (d, J=10.0 Hz, 1H), 4.78 (d, J=9.6 Hz, 1H), 4.91 (dd,
J=14.8, 4.4 Hz, 2H), 6.56 (d, J=7.6 Hz, 1H), 6.61 (s, 1H), 6.67 (d,
J=8.4 Hz, 1H), 6.92 (d, J=6.4 Hz, 2H), 6.99-7.00 (m, 2H), 7.20-7.23
(m, 13H), 7.26 (s, 3H), 7.29-7.38 (m, 6H), 7.45 (d, J=8.0 Hz, 1 H),
7.54-7.55 (m, 6H).
[0300] STEP III : To a stirred solution of
6-[2-ethyl-5-((2S,3S,4R,5R,
6R)-3,4,5-tris-benzyloxy-6-trityloxymethyl-tetrahydro-pyran-2-yl)-benzyl]-
-2,3-dihydro-benzo[1,4]dioxine (8.0 g, 8.6 mmol) in DCM (80 ml),
was added a solution of aluminum chloride (1.72 g, 12.9 mmol) in
diethyl ether (50 ml) at 0.degree. C. This was stirred for 2 h at
room temperature. Reaction mixture was poured into ice cold water
and extracted with DCM (2.times.80 ml). Combined organic layers
were washed with aqueous sodium bicarbonate solution (100 ml),
brine (100 ml), dried over sodium sulfate, concentrated and
purified by silica gel column chromatography to give 5.56 g of
{(2R,3R,4R,5S,6S)-3,4,5-tris-benzyloxy-6-[3-(2,3-dihydro-benzo[-
1,4]d
ioxin-6-ylmethyl)-4-ethyl-phenyl]-tetrahydro-pyran-2-yl}-methanol
as a colorless oil.
[0301] .sup.1H NMR (400 MHz, CDCI.sub.3): .delta.1.16 (t, J=7.6 Hz,
3H), 2.63 (q, J=7.6 Hz, 2H), 3.47-3.51 (m, 1H), 3.54 (t, J=10.0 Hz,
1H), 3.67 (t, J=10.4 Hz, 1H), 3.72 (bs, 1H), 3.78-3.96 (m, 3H),
3.87-3.96 (m, 3H), 4.14-4.23 (m, 5H), 4.35 (d, J=10.8 Hz, 1H), 4.69
(d, J=10.8 Hz, 1H), 4.83-4.95 (m, 3H), 6.54 (d, J=8.4 Hz, 1H), 6.59
(s, 1H), 6.67 (d, J=8.4 Hz, 1H), 6.88-6.90 (m, 2H), 7.16-7.23 (m,
6H), 7.27-7.36 (m, 10H).
[0302] STEP IV: To a stirred solution of
(R)-2-tert-butoxycarbonylamino-3-methyl-butyric acid (6.3 g, 29.1
mmol) in DMF (40 ml) was added N,N'-dicyclohexylcarbodiimide (6.0
g, 29.1 mmol). After stirring for 30 min at room temperature,
reaction mixture was cooled to 0.degree. C., added a solution of
{(2R,3R,4R,5S,6S)-3,4,5-tris-benzyloxy-6[3-(2,3-dihydro-benzo[1,4]dioxin--
6-ylmethyl)-4-ethyl-phenyl]-tetrahydro-pyran-2-yl}-methanol (4.0 g,
5.8 mmol) in DMF (20 ml) followed by DMAP (360 mg, 2.9 mmol) and
stirred at ambient temperature for overnight. Reaction was quenched
by the addition of water (150 ml) and extracted with ethyl acetate
(2.times.80 ml). Combined organic layers were washed with water
(100 ml), brine (100 ml), dried over sodium sulfate, concentrated
and purified by silica gel column chromatography to give 4.5 g of
(R)-2-tert-butoxycarbonylamino-3-methyl-butyric acid
(2R,3R,4R,5S,6S)-3,4,5-tris-benzyloxy-6-[3-(2,
3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-tetrahydro-pyran-2-
-ylmethyl ester as a colorless oil.
[0303] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.0.76 (d, J=6.8 Hz,
3H), 0.89 (d, J=6.8 Hz, 3H), 1.12-1.17 (m, 3H), 1.42 (s, 9H),
1.90-1.92 (m, 1H), 2.59-2.63 (m, 2H), 3.51-3.57 (m, 1H), 3.60-3.65
(m, 2H), 3.77-3.95 (m, 5H), 4.15-4.18 (m, 5H), 4.26-4.40 (m, 4H),
4.61 (dd, J=10.8, 6.4 Hz, 1H), 4.85-4.93 (m, 3H), 6.52-6.59 (m,
2H), 6.68 (d, J=8.4 Hz, 1H), 6.89-6.91 (m, 2H), 7.15-7.23 (m, 7H),
7.28-7.35 (m, 9H).
[0304] STEP V: To a stirred solution of
(R)-2-tert-butoxycarbonylamino-3-methyl-butyric acid (2 R,3 R,4R,
5S,
6S)-3,4,5-tris-benzyloxy-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-
-ethyl-phenyl]-tetrahydro-pyran-2-yl methyl ester (4.5 g, 5.0 mmol)
in ethyl acetate: methanol (1:4 mixture, 50 ml) was added palladium
hydroxide (2.0 g). After stirring for overnight at room
temperature, reaction mixture was filtered through celite bed,
concentrated and purified by silica gel column chromatography to
give 3.12 g of (R)-2-tert-butoxycarbonylamino-3-methyl-butyric acid
(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-p-
henyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester as a
white solid.
[0305] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta.0.79 (d, J=6.8 Hz,
3H), 0.83 (d, J=7.2 Hz, 3H), 1.06 (t, J=7.2 Hz, 3H), 1.40 (s, 9H),
1.98-2.03 (m, 1H), 2.56 (q, J=7.6 Hz, 2H), 3.35-3.40 (m, 2H),
3.43-3.48 (m, 1H), 3.56-3.60 (m, 1H), 3.88 (s, 2H), 3.98-4.07 (m,
2H), 4.17 (s, 4H), 4.34 (dd, J=11.6, 6.4 Hz, 1H), 4.43-4.46 (m,
1H), 6.53-6.58 (m, 2H), 6.68 (d, J =8.4 Hz, 1H), 7.12-7.19 (m,
3H).
[0306] STEP VI: To a stirred solution of
(R)-2-tert-butoxycarbonylamino-3-methyl-butyric acid (2 R, 3S,4 R,
5R,
6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5--
trihydroxy-tetrahydro-pyran-2-ylmethyl ester (2.8 g, 4.6 mmol) in
methanol (30 ml) was added 3 N methanolic HCl (30 ml) at room
temperature. After refluxing for 2 h, volatiles were evaporated
under reduced pressure. The resulting residue was taken in ethyl
acetate (50 ml) and washed with aqueous saturated sodium
bicarbonate solution (15 ml), brine (15 ml), dried over sodium
sulfate, concentrated, and purified by preparative HPLC to give 410
mg of (R)-2-Amino-3-methyl-butyric acid
(2R,3S,4R,5R,6S)-6[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-ph-
enyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester as a white
solid.
[0307] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta.0.84 (d, J=6.8 Hz,
3H), 0.88 (d, J=7.8 Hz, 3H), 1.10 (t, J=8.0 Hz, 3H), 1.95-1.97 (m,
1H), 2.60 (q, J=8.0 Hz, 2H), 3.29-3.51 (m, 4H), 3.60-3.62 (m, 1H),
3.92 (s, 2H), 4.09 (d, J=9.2 Hz, 1H), 4.20 (s, 4H), 4.38-4.46 (m,
2H), 6.56-6.61 (m, 2H), 6.71 (d, J=8.0 Hz, 1H), 7.16-7.22 (m, 3H).
MS (ES) m/z 516.3 (M+1).
Example 2
Synthesis of Carbonic Acid
(2R,3S,4R,5R,6S)-6-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl
methyl)-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl Ester
Methyl Ester
##STR00040##
[0309] STEP I: To a stirred solution of
(2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmet-
hyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
[0310] (Intermediate 3, 890 mg, 2.1 mmol) in collidine (7 ml) was
added a solution of methyl chloroformate (0.21 ml, 2.5 mmol) in DCM
(0.5 ml) at -40.degree. C. After stirring for 1 h at same
temperature, it was stirred at room temperature for 1.5 h. Reaction
mixture was poured into ice cold 10% HCl solution and extracted
with ethyl acetate (2.times.10 ml). Combined organic layers were
washed with brine (10 ml), dried over sodium sulfate, concentrated
and purified by silica gel column chromatography to give 1.1 g of
carbonic acid (2 R, 3S,4 R, 5R,
6S)-6-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl
methyl)-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester
methyl ester as a white solid.
[0311] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta.0.54 (d, J=4.8 Hz,
2H), 0.81 (d, J=8.0 Hz, 2H), 1.76-1.83 (m, 1H), 3.32-3.33 (m, 1H),
3.92-3.43 (m, 2H), 3.52 (t, J=5.6 Hz, 1H), 3.70 (s, 3H), 4.01-4.06
(m, 3H), 4.15 (s, 4H), 4.26 (dd, J=11.2, 5.2 Hz, 1H), 4.43 (d,
J=11.2 Hz, 1H), 6.57-6.59 (m, 2H), 6.66 (d, J=8.4 Hz, 1H), 6.94 (d,
J=8.0 Hz, 1H), 7.12-7.14 (m, 2H). MS (ES) m/z 487.0 (M+1).
[0312] Following examples were prepared by using the procedures
described for example 2
TABLE-US-00003 Ex. No. Structure Analytical Data 2a ##STR00041##
Carbonic acid (2R,3S,4R,5R,6S)-6-[4-cyclopropyl-3-(2,3-dihydro-
benzo[1,4]dioxin-6-ylmethyl)-phenyl]-3,4,5-trihydroxy-
tetrahydro-pyran-2-ylmethyl ester ethyl ester .sup.1H NMR (400 MHz,
CD.sub.3OD): .delta. 0.53- 0.57 (m, 2H), 0.81-0.85 (m, 2H), 1.23
(t, J = 7.2 Hz, 3H), 1.79-1.82 (m, 1H), 3.34-3.46 (m, 3H),
3.52-3.58 (m, 1H), 4.03-4.08 (m, 3H), 4.13 (q, J = 6.8 Hz, 2H),
4.17 (s, 4H), 4.27 (dd, J = 12.0, 5.6 Hz, 1H), 4.43 (dd, J = 11.2,
2.0 Hz, 1H), 6.59-6.62 (m, 2H), 6.68 (d, J = 8.4 Hz, 1H), 6.96 (d,
J = 7.6 Hz, 1H), 7.15-7.17 (m, 2H). MS (ES) m/z 518.3 (M + 18). 2b
##STR00042## Carbonic acid
(2R,3S,4R,5R,6S)-6-[4-cyclopropyl-3-(2,3-dihydro-
benzo[1,4]dioxin-6-ylmethyl)-phenyl]-3,4,5-trihydroxy-
tetrahydro-pyran-2-ylmethyl ester isobutyl ester .sup.1H NMR (400
MHz, CD.sub.3OD): .delta. 0.53- 0.57 (m, 2H), 0.81-0.85 (m, 2H),
0.87 (d, J = 1.2 Hz, 3H), 0.89 (d, J = 1.6 Hz, 3H), 1.78-1.83 (m,
1H), 1.86-1.93 (m, 1H), 3.29-3.36 (m, 2H), 3.42-3.45 (m, 2H),
3.53-3.59 (m, 1H), 3.86 (d, J = 6.4 Hz, 2H), 4.03 (d, J = 5.2 Hz,
1H), 4.07 (d, J = 9.2 Hz, 1H), 4.16 (s, 4H), 4.28 (dd, J = 11.6,
5.6 Hz, 1H), 4.45 (dd, J = 11.6, 2.0 Hz, 1H), 6.59- 6.61 (m, 2H),
6.67-6.69 (m, 1H), 6.96 (d, J = 8.0 Hz, 1H), 7.15-7.17 (m, 2H). MS
(ES) m/z 529.3 (M + 1), 546.3 (M + 18). 2c ##STR00043## Carbonic
acid (2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-
6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-
ylmethyl ester ethyl ester .sup.1H NMR (400 MHz, CD.sub.3OD):
.delta. 1.07 (t, J = 8.0 Hz, 3H), 1.23 (t, J = 7.6 Hz, 3H), 2.57
(q, J = 8.0 Hz, 2H), 3.33- 3.33 (m, 3H), 3.53-3.55 (m, 1H), 3.89
(d, J = 2 Hz, 2H), 4.07-4.15 (m, 3H), 4.16 (s, 4H), 4.28 (dd, J =
12.0, 5.6 Hz, 1H), 4.44 (dd, J = 12.0, 2.4 Hz, 1H), 6.54-6.58 (m,
2H), 6.68 (d, J = 8.0 Hz, 1H), 7.14-7.21 (m, 3H). MS (ES) m/z 489.2
(M + 1), 506.2 (M + 18). 2d ##STR00044## Carbonic acid
(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-
6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-
ylmethyl ester isobutyl ester .sup.1H NMR (400 MHz, CD.sub.3OD):
.delta. 0.88 (dd, J = 6.8, 1.2 Hz, 6H), 1.06 (t, J = 7.6 Hz, 3H),
1.87-1.91 (m, 1H), 2.56 (q, J = 7.6 Hz, 2H), 3.33-3.37 (m, 1H),
3.42-3.45 (m, 2H), 3.54-3.57 (m, 1H), 3.85-3.88 (m, 4H), 4.08 (d, J
= 6.8 Hz, 1H), 4.16 (s, 4H), 4.29 (dd, J = 11.2, 5.6 Hz, 1H), 4.45
(dd, J = 11.6, 2.0 Hz, 1H), 6.54-6.57 (m, 2H), 6.67 (d, J = 8.4 Hz,
1H), 7.14-7.20 (m, 3H). MS (ES) m/z 517.3 (M + 1), 534.3 (M + 18).
2e ##STR00045## Carbonic acid tert-butyl ester
(2R,3S,4R,5R,6S)-6-[3-(2,3-
dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5-
trihydroxy-tetrahydro-pyran-2-ylmethyl ester .sup.1HNMR (400 MHz,
CD.sub.3OD): .delta. 1.06 (t, J = 7.3 Hz, 3H), 1.42 (s, 9H), 2.56
(q, J = 7.3 Hz, 2H), 3.30-3.38 (m, 1H), 3.43 (t, 7.3 Hz, 2H),
3.51-3.52 (m, 1H), 3.89 (q, J = 3.4 Hz, 2H), 4.07 (d, J = 9.3 Hz,
1H), 4.16 (s, 4H), 4.20- 4.23 (m, 1H), 4.39 (d, J = 9.3 Hz, 1H),
6.55-6.57 (m, 2H), 6.68 (d, J = 8.3 Hz, 1H), 7.14-7.21 (m, 3H). MS
(ES) m/z 534.3 (M + 1). 2f ##STR00046## Carbonic acid
bicyclo[2.2.1]hept-2-ylmethyl ester
(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-
ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-
ylmethyl ester .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 1.07 (t,
J = 7.3 Hz, 3H), 1.12-1.14 (m, 1H), 1.24-1.32 (m, 4H), 1.41-1.53
(m, 2H), 1.63-1.69 (m, 1H), 2.15-2.18 (m, 3H), 2.56 (q, J = 7.3 Hz,
2H), 3.30-3.37 (m, 1H), 3.46 (t, J = 6.4 Hz, 2H), 3.54- 3.57 (m,
1H), 3.89 (s, 2H), 3.94-3.99 (m, 1H), 4.07-4.09 (m, 2H), 4.17 (s,
4H), 4.29 (dd, J = 11.8, 5.3 Hz, 1H), 4.45 (d, J = 11.2 Hz, 1H),
6.55-6.58 (m, 2H), 6.68 (d, J = 7.9 Hz, 1H), 7.15-7.16 (m, 2H),
7.19-7.21 (m, 1H). MS (ES) m/z 586.3 (M + 18). 2g ##STR00047##
Carbonic acid (2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-
6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-
ylmethyl ester (S)-1-phenyl-ethyl ester .sup.1H NMR (400 MHz,
CD.sub.3OD): .delta. 1.07 (t, J = 7.3 Hz, 3H), 1.48 (d, J = 6.3 Hz,
3H), 2.56 (q, J = 7.3 Hz, 2H), 3.30-3.36 (m, 1H), 3.42 (t, J = 7.4
Hz, 2H), 3.51-3.55 (m, 1H), 3.87 (s, 2H), 4.06 (d, J = 9.3 Hz, 1H),
4.15 (s, 4H), 4.30 (dd, J = 11.7, 5.8 Hz, 1H) 4.40 (d, J = 11.7 Hz,
1H), 5.65 (q, J = 6.4 Hz, 1H), 6.55-6.57 (m, 2H), 6.67 (d, J = 8.3
Hz, 1H), 7.13-7.20 (m, 4H), 7.24-7.32 (m, 4H). MS (ES) m/z 582.3 (M
+ 18).
Example 3
Synthesis of Phosphoric Acid
(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl
methyl)-4-ethyl
-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl Ester Diethyl
Ester
##STR00048##
[0314] To a stirred solution of
(2S,3R,4R,5S,6R)-2-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-p-
henyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (Intermediate
2, 500 mg, 1.2 mmol) in pyridine (5 ml) was added
diethylchlorophosphate (0.27 ml, 1.9 mmol) at -40.degree. C. After
stirring for 1 h at same temperature, reaction was quenched with
the addition of 1N HCl and extracted with ethyl acetate (2.times.10
ml). Combined organic layers were washed with brine (10 ml), dried
over sodium sulfate, concentrated and purified by preparative HPLC
to give 220 mg of phosphoric acid
(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-p-
henyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester diethyl
ester as a white solid.
[0315] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta.1.07 (t, J=7.6 Hz,
3H), 1.15 (td J=7.2, 1.2 Hz, 3H), 1.22 (td, J=6.8, 0.8 Hz, 3H),
2.57 (q, J=7.6 Hz, 2H), 3.36-3.46 (m, 3H), 3.53-3.55 (m, 1H),3.89
(s, 2H), 3.96-4.11 (m, 5H), 4.17 (s, 4H), 4.18-4.22 (m 1H),
4.30-4.34 (m, 1H), 6.52 (d, J=2.0 Hz, 1H),6.57 (dd, J=8.4, 2.4 Hz,
1H), 6.68 (d, J=8.4 Hz, 1H), 7.15-7.22 (m, 3H). MS (ES) m/z 553.3
(M+1).
[0316] Following example was prepared by using the procedures
described for example 3
TABLE-US-00004 Ex. No. Structure Analytical Data 3a ##STR00049##
Phosphoric acid (2R,3S,4R,5R,6S)-6-[4-cyclopropyl-3-(2,3-dihydro-
benzo[1,4]dioxin-6-ylmethyly phenyl]-3,4,5-trihydroxy-tetrahydro-
pyran-2-yl methyl ester diethyl ester .sup.1H NMR (400 MHz,
CD.sub.3OD): .delta. 0.53- 0.57 (m, 2H), 0.81-0.86 (m, 2H), 1.15
(td J = 6.8, 0.8 Hz, 3H), 1.22 (td, J = 6.8, 0.8 Hz, 3H), 1.79-1.84
(m, 1H), 3.35-3.48 (m, 3H), 3.52-3.56 (m, 1H), 3.96-4.10 (m, 7H),
4.16 (s, 4H), 4.18- 4.22 (m, 1H), 4.29-4.34 (m, 1H), 6.56- 6.61 (m,
2H), 6.68 (d, J = 8.4 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 7.16-7.18
(m, 2H). MS (ES) m/z 565.2 (M + 1).
Example 4
Synthesis of Disodium Salt of Phosphoric Acid
Mono-{(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-e-
thyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl}
ester
##STR00050##
[0318] To a stirred solution of
(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-p-
henyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (Intermediate
2, 1.0 g, 2.4 mmol) in THF (15 ml) was added a solution of
Diethyl-phosphoramidic acid di-tert-butyl ester (780 mg, 3.12 mmol)
in THF (5 ml) at 0.degree. C. followed by a solution of tetrazole
(435 mg, 6.2 mmol) in DCM (12.5 ml). After stirring for 5 min at
same temperature, it was stirred at room temperature for 20 min.
Reaction mixture was cooled to -40 .degree. C. and added a solution
of m-CPBA (830 mg, 4.8 mmol) in DCM (5 ml). The reaction mixture
was stirred at same temperature for 5 min and then at room
temperature for 2 h. Reaction mixture was cooled to 0.degree. C.
and quenched by the addition of 10% sodium bisulfite solution (5
ml). This was extracted with ether (3.times.10 ml). Combined
organic layer was washed with brine (5 ml), dried over sodium
sulfate and concentrated to give 700 mg of phosphoric acid
di-tert-butyl ester
(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-e-
thyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl
ester.
[0319] To the stirred solution of phosphoric acid di-tert-butyl
ester (2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]d
ioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylm-
ethyl ester (500 mg) in methanol (20 ml) was added amberlyst 15 ion
exchange resin (250 mg) and refluxed for overnight. Reaction
mixture was cooled to room temperature, filtered through celite bed
and filtrate was concentrated to give 300 mg of phosphoric acid
mono-{(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-e-
thyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl} ester.
The crude material was taken up for next reaction.
[0320] To a solution of phosphoric acid
mono-{(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-e-
thyl-phenyl]-3,4, 5-tri hydroxy-tetrahydro-pyran-2-ylmethyl} ester
(300 mg, 0.6 mmol) in methanol (5 ml) was added 1N sodium
bicarbonate solution (80 mg, 0.7 mmol) in water. After stirring at
room temperature for 2 h, the volatiles were evaporated under
reduced pressure. The resulting solid was triturated with diethyl
ether. The resulting residue was purified by preparative HPLC to
give 95 mg of disodium salt of phosphoric acid
mono-{(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-e-
thyl-phenyl]-3,4, 5-trihydroxy-tetrahydro-pyran-2-ylmethyl}
ester.
[0321] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta.1.06 (t, J=7.4 Hz,
3H), 2.56 (q, J=7.3 Hz, 2H), 3.34-3.41 (m, 2H), 3.49 (t, J=8.8 Hz,
1H), 3.81-3.88 (m, 3H), 3.92-3.99 (m, 1H), 4.05 (d, J=9.3 Hz, 1H),
4.16 (s, 4H), 4.20-4.25 (m, 1H), 6.54 (m, 2H), 6.67 (d, J=7.8 Hz,
1H), 7.12-7.21 (m, 3H). MS (ES) m/z 497.1 (M+1) for phosphoric
acid.
[0322] The following are further embodiments of the invention:
[0323] Embodiment 1: A compound represented by structural formula
(I):
##STR00051##
[0324] or a pharmaceutiacally acceptable salt thereof, wherein:
[0325] A is selected from the group consisting of
[0325] ##STR00052## [0326] V is hydrogen, halo or --OR.sup.1b;
[0327] R.sup.1, R.sup.1a and R.sup.1b are independently selected
from the group consisting of hydrogen, C.sub.1-6 alkyl,
C.sub.6-10aryl-C.sub.1-4alkyl, --C(O)C.sub.6-10aryl and
--C(O)C.sub.1-6alkyl; [0328] R.sup.2 and R.sup.2a, for each
occurrence, are independently selected from the group consisting of
halo, hydroxy, C.sub.1-6alkyl, and C.sub.1-6alkoxy; [0329] R.sup.3
is halo, hydroxy, C.sub.1-6alkyl, haloC.sub.1-6alkyl,
C.sub.3-10cycloalkyl, C.sub.1-6alkoxy, or haloC.sub.1-3alkoxy;
[0330] R.sup.4 is selected from the group consisting of:
[0330] ##STR00053## [0331] R.sup.5 is an amino acid sidechain;
[0332] R.sup.6 is a C.sub.1-6 alkyl, C.sub.3-10carbocyclyl,
C.sub.3-10carbocyclyl-C.sub.1-4alkyl, 3- to 10-membered
heterocyclyl, (3- to 10-membered heterocyclyl)-C.sub.1-4alkyl,
C.sub.6-10aryl, C.sub.6-10aryl-C.sub.1-4alkyl, 5- to 10-membered
heteroaryl, or (5- to 10-membered heteroaryl)-C.sub.1-4alkyl;
[0333] R.sup.7, for each occurrence, is independently hydrogen,
C.sub.1-6alkyl, C.sub.3-10carbocyclyl,
C.sub.3-10carbocyclyl-C.sub.1-4alkyl, 3- to 10-membered
heterocyclyl, (3- to 10-membered heterocyclyl)-C.sub.1-4alkyl,
C.sub.6-10aryl, C.sub.6-10aryl-C.sub.1-4alkyl, 5- to 10-membered
heteroaryl, or (5- to 10-membered heteroaryl)-C.sub.1-4alkyl;
[0334] n is 0, 1, 2, or 3; and [0335] q is 0, 1, or 2.
[0336] Embodiment 2: The compound of Embodiment 1, or a
pharmaceutically acceptable salt thereof, wherein n is 0.
[0337] Embodiment 3: The compound of Embodiment 1 or 2, or a
pharmaceutically acceptable salt thereof, wherein q is 0.
[0338] Embodiment 4: The compound of anyone of Embodiments 1-3, or
a pharmaceutically acceptable salt thereof, wherein A is
##STR00054##
[0339] Embodiment 5: The compound of anyone of the preceding
embodiments, or a pharmaceutically acceptable salt thereof, wherein
V is --OR.sup.1b.
[0340] Embodiment 6: The compound of anyone of the preceding
embodiments, or a pharmaceutically acceptable salt thereof, wherein
R.sup.1, R.sup.1a, and R.sup.1b are hydrogen.
[0341] Embodiment 7: The compound of anyone of the preceding
embodiments, or a pharmaceutically acceptable salt thereof, wherein
R.sup.3 is C.sub.1-4alkyl or C.sub.3-6cycloalkyl,
[0342] Embodiment 8: The compound of anyone of the preceding
embodiments, or a pharmaceutically acceptable salt thereof, wherein
R.sup.3 is ethyl or cyclopropyl.
[0343] Embodiment 9: The compound of anyone of the preceding
embodiments, or a pharmaceutically acceptable salt thereof, wherein
R.sup.3 is ethyl
[0344] Embodiment 10: The compound of anyone of the preceding
embodiments, or a pharmaceutically acceptable salt thereof, wherein
R.sup.4 is
##STR00055##
[0345] Embodiment 11: The compound of Embodiment 10, or a
pharmaceutically acceptable salt thereof, wherein R.sup.5 is a
naturally occurring amino acid sidechain selected from the group
consisting of the sidechain of glycine, alanine, cysteine,
asparagine, glutamine, glutamic acid, arginine, aspartic acid,
histidine, lysine, isoleucine, leucine, methionine, phenylalanine,
proline, serine, threonine, tryptophane, tyrosine, and valine.
[0346] Embodiment 12: The compound of Embodiment 11, or a
pharmaceutically acceptable salt thereof, wherein R.sup.5 is the
sidechain of valine.
[0347] Embodiment 13: The compound of Embodiment 10, or a
pharmaceutically acceptable salt thereof, wherein R.sup.5 is a
non-standard amino acid sidechain selected from the group
consisting of the sidechain of 3,5-dibromotyrosine,
3,5-diiodotyrosine, gem-dimethylglycine, hydroxylysine,
.alpha.-aminobutyric acid, hydroxyproline, lanthionine, thyroxine,
ornithine, and citrulline.
[0348] Embodiment 14: The compound of anyone of Embodiments 1-9, or
a pharmaceutically acceptable salt thereof, wherein R.sup.4 is
##STR00056##
[0349] Embodiment 15: The compound of Embodiment 14, or a
pharmaceutically acceptable salt thereof, wherein R.sup.6 is
C.sub.1-6alkyl, C.sub.3-8carbocyclyl-C.sub.1-4alkyl, or
phenyl-C.sub.1-4alkyl.
[0350] Embodiment 16: The compound of Embodiment 15, or a
pharmaceutically acceptable salt thereof, wherein R.sup.6 is
methyl, ethyl, isobutyl, tert-butyl,
bicyclo[2.2.1]heptan-2-ylmethyl, or 1-phenyl-ethan-1-yl.
[0351] Embodiment 17: The compound of anyone of Embodiments 1-9, or
a pharmaceutically acceptable salt thereof, wherein R.sup.4 is
##STR00057##
[0352] Embodiment 18: The compound of Embodiment 17, or a
pharmaceutically acceptable salt thereof, wherein R.sup.7, for each
occurrence, is independently hydrogen or a C.sub.1-6alkyl.
[0353] Embodiment 19: The compound of Embodiment 18, or a
pharmaceutically acceptable salt thereof, wherein each R.sup.7 is
ethyl.
[0354] Embodiment 20: The compound of Embodiment 18, or a
pharmaceutically acceptable salt thereof, wherein each R.sup.7 is
hydrogen.
[0355] Embodiment 21: The compound of Embodiment 1, or a
pharmaceutically acceptable salt thereof, wherein the compound is
selected from the group consisting of: [0356]
(R)-2-amino-3-methyl-butyric acid
(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-p-
henyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester; [0357]
carbonic acid
(2R,3S,4R,5R,6S)-6-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6--
ylmethyl)-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl
ester methyl ester; [0358] carbonic acid
(2R,3S,4R,5R,6S)-6-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmet-
hyl)-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester
ethyl ester; [0359] carbonic acid
(2R,3S,4R,5R,6S)-6-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmet-
hyl)-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester
isobutyl ester; [0360] carbonic acid
(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-p-
henyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester ethyl
ester; [0361] carbonic acid
(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-p-
henyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester isobutyl
ester; [0362] Carbonic acid tert-butyl ester
(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-p-
henyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester; [0363]
carbonic acid bicyclo[2.2.1]hept-2-ylmethyl ester
(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-p-
henyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester; [0364]
carbonic acid
(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-et-
hyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester
(S)-1-phenyl-ethyl ester; [0365] phosphoric acid
(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-p-
henyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester diethyl
ester; [0366] phosphoric acid
(2R,3S,4R,5R,6S)-6-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmet-
hyl)-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester
diethyl ester; [0367] phosphoric acid
mono-{(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-e-
thyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl}
ester.
[0368] Embodiment 22: A pharmaceutical composition comprising a
therapeutically effective amount of a compound according to any one
of Embodiments 1 to 21, or a pharmaceutically acceptable salt
thereof, and one or more pharmaceutically acceptable carrier.
[0369] Embodiment 23: A combination comprising a therapeutically
effective amount of a compound according to any one of Embodiments
1 to 21, or a pharmaceutically acceptable salt thereof, and one or
more therapeutically active co-agents.
[0370] Embodiment 24: A method of inhibiting sodium D-glucose
co-transporter activity in a subject, wherein the method comprises
administering to the subject a therapeutically effective amount of
the compound according to any one of Embodiments 1 to 21, or a
pharmaceutically acceptable salt thereof.
[0371] Embodiment 25: A method of treating diabetes comprising
administering a compound according to any one of Embodiments 1 to
21, or a pharmaceutically acceptable salt thereof, to a subject in
need thereof.
[0372] Embodiment 26: A method of treating a disease or condition
mediated by the sodium D-glucose co-transporter in a subject,
comprising administering to the mammal in need thereof a
therapeutically effective amount of a compound according to any one
of Embodiments 1 to 21, or a pharmaceutically acceptable salt
thereof.
[0373] Embodiment 27: The method according to Embodiment 26,
wherein the disease or condition is metabolic syndrome, Syndrome X,
diabetes, insulin resistance, decreased glucose tolerance,
non-insulin-dependent diabetes mellitus, Type II diabetes, Type I
diabetes, diabetic complications, a body weight disorder, obesity,
or a leptin related disease.
[0374] Embodiment 28: The method according to Embodiment 27,
wherein the disease or condition is dyslipidemia, obesity, insulin
resistance, hypertension, microalbuminemia, hyperuricaemia, or
hypercoagulability.
[0375] Embodiment 29: A compound of any one of Embodiments 1 to 21,
or a pharmaceutically acceptable salt thereof, for use as a
medicament.
[0376] Embodiment 30: A compound of any one of Embodiments 1 to 21,
or a pharmaceutically acceptable salt thereof, for use in treating
diabetes.
[0377] Embodiment 31: A compound of any one of Embodiments 1 to 21,
or a pharmaceutically acceptable salt thereof, for use in treating
a disease or condition in a subject mediated by sodium D-glucose
co-transporter.
[0378] Embodiment 32: The compound according to any one of
Embodiment 31, or a pharmaceutically acceptable salt thereof,
wherein the disease or condition ismetabolic syndrome, Syndrome X,
diabetes, insulin resistance, decreased glucose tolerance,
non-insulin-dependent diabetes mellitus, Type II diabetes, Type I
diabetes, diabetic complications, a body weight disorder, obesity,
or a leptin related disease.
[0379] Embodiment 33: The compound according to Embodiment 32, or a
pharmaceutically acceptable salt thereof, wherein the disease or
condition is dyslipidemia, obesity, insulin resistance,
hypertension, microalbuminemia, hyperuricaemia, or
hypercoagulability.
[0380] Embodiment 34: Use of a compound according to any one of
Embodiments 1 to 21, or a pharmaceutically acceptable salt thereof,
in the manufacture of a medicament for the treatment of
diabetes.
[0381] Embodiment 35: Use of a compound according to any one of
Embodiments 1 to 21, or a pharmaceutically acceptable salt thereof,
in the manufacture of a medicament for the treatment of a disorder
or disease mediated by sodium D-glucose co-transporter.
[0382] Embodiment 32: Use of a compound according to Embodiment 35,
or a pharmaceutically acceptable salt thereof, wherein the disease
or condition ismetabolic syndrome, Syndrome X, diabetes, insulin
resistance, decreased glucose tolerance, non-insulin-dependent
diabetes mellitus, Type II diabetes, Type I diabetes, diabetic
complications, a body weight disorder, obesity, or a leptin related
disease.
[0383] Embodiment 33: Use of a compound according to Embodiment 32,
or a pharmaceutically acceptable salt thereof, wherein the disease
or condition is dyslipidemia, obesity, insulin resistance,
hypertension, microalbuminemia, hyperuricaemia, or
hypercoagulability.
[0384] Embodiment 34: A pharmaceutical compositions comprising a
therapeutically effective amount of a compound according to any one
of Embodiments 1 to 21, or a pharmaceutically acceptable salt
thereof, in combination with a therapeutically effective amount of
another therapeutic agent.
[0385] Embodiment 35: A pharmaceutical combination comprising:
[0386] i) a compound according to any one of Embodiments 1 to 21,
or a pharmaceutically acceptable salt thereof, [0387] ii) at least
one compound selected from [0388] a) antidiabetic agents, [0389] b)
hypolipidemic agents, [0390] c) anti-obesity agents, [0391] d)
anti-hypertensive agents, [0392] e) agonists of peroxisome
proliferator-activator receptors.
* * * * *