U.S. patent application number 14/604173 was filed with the patent office on 2015-05-21 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, Sandeep Bhausaheb BHOSALE, Debnath BHUNIYA, Mark G. BOCK, Lili FENG, Atul Kashinath HAJARE, Suresh Eknath KURHADE, Jessica LIANG, P. Venkata PALLE, Dumbala Srinivas REDDY, Videsh SALUNKHE, Nadim S. SHAIKH, Vinod VYAVAHARE. Invention is credited to Gregory Raymond BEBERNITZ, Sandeep Bhausaheb BHOSALE, Debnath BHUNIYA, Mark G. BOCK, Lili FENG, Atul Kashinath HAJARE, Suresh Eknath KURHADE, Jessica LIANG, P. Venkata PALLE, Dumbala Srinivas REDDY, Videsh SALUNKHE, Nadim S. SHAIKH, Vinod VYAVAHARE.
Application Number | 20150141354 14/604173 |
Document ID | / |
Family ID | 43216622 |
Filed Date | 2015-05-21 |
United States Patent
Application |
20150141354 |
Kind Code |
A1 |
BEBERNITZ; Gregory Raymond ;
et al. |
May 21, 2015 |
GLYCOSIDE DERIVATIVES AND USES THEREOF
Abstract
This invention relates to compounds represented by formula (I):
##STR00001## wherein the variables are defined as herein above,
which are useful for treating diseases and conditions mediated by
the sodium D-glucose co-transporter (SGLT), e.g. diabetes. The
invention also provides methods of treating such diseases and
conditions, and compositions etc. for their treatment.
Inventors: |
BEBERNITZ; Gregory Raymond;
(Stow, MA) ; BOCK; Mark G.; (Boston, MA) ;
REDDY; Dumbala Srinivas; (Hyderabad, IN) ; HAJARE;
Atul Kashinath; (Ahmednagar, IN) ; VYAVAHARE;
Vinod; (Bangalore, IN) ; BHOSALE; Sandeep
Bhausaheb; (Pune, IN) ; KURHADE; Suresh Eknath;
(Pune, IN) ; SALUNKHE; Videsh; (Bangalore, IN)
; SHAIKH; Nadim S.; (Bangalore, IN) ; BHUNIYA;
Debnath; (Howrah, IN) ; PALLE; P. Venkata;
(Pune, IN) ; FENG; Lili; (Pine Brook, NJ) ;
LIANG; Jessica; (Annandale, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BEBERNITZ; Gregory Raymond
BOCK; Mark G.
REDDY; Dumbala Srinivas
HAJARE; Atul Kashinath
VYAVAHARE; Vinod
BHOSALE; Sandeep Bhausaheb
KURHADE; Suresh Eknath
SALUNKHE; Videsh
SHAIKH; Nadim S.
BHUNIYA; Debnath
PALLE; P. Venkata
FENG; Lili
LIANG; Jessica |
Stow
Boston
Hyderabad
Ahmednagar
Bangalore
Pune
Pune
Bangalore
Bangalore
Howrah
Pune
Pine Brook
Annandale |
MA
MA
NJ
NJ |
US
US
IN
IN
IN
IN
IN
IN
IN
IN
IN
US
US |
|
|
Assignee: |
NOVARTIS AG
Basel
CH
|
Family ID: |
43216622 |
Appl. No.: |
14/604173 |
Filed: |
January 23, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14291268 |
May 30, 2014 |
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14604173 |
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13614534 |
Sep 13, 2012 |
8828951 |
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14291268 |
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13425888 |
Mar 21, 2012 |
8466114 |
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13614534 |
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12906682 |
Oct 18, 2010 |
8163704 |
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13425888 |
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Current U.S.
Class: |
514/23 |
Current CPC
Class: |
A61P 3/06 20180101; A61K
31/7048 20130101; A61P 3/04 20180101; A61P 3/08 20180101; A61P 7/02
20180101; A61P 19/06 20180101; A61K 31/7052 20130101; A61P 3/10
20180101; C07D 407/10 20130101; A61K 31/706 20130101; A61P 9/12
20180101; C07H 7/04 20130101; A61P 3/00 20180101; C07D 405/10
20130101; C07D 413/10 20130101 |
Class at
Publication: |
514/23 |
International
Class: |
A61K 31/7048 20060101
A61K031/7048; A61K 31/706 20060101 A61K031/706 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 20, 2009 |
IN |
2173/DEL/09 |
Dec 23, 2009 |
IN |
2689/DELNP/09 |
Claims
1. A method of treating obesity, comprising administering to a
mammal in need thereof a therapeutically effective amount of the
compound: ##STR00140## or a pharmaceutically acceptable salt
thereof.
2. A method of treating obesity, comprising administering to a
mammal in need thereof a therapeutically effective amount of the
compound: ##STR00141## or a pharmaceutically acceptable salt
thereof.
3. A method of treating obesity, comprising administering to a
mammal in need thereof a therapeutically effective amount of the
compound: ##STR00142## or a pharmaceutically acceptable salt
thereof.
4. A method of treating obesity, comprising administering to a
mammal in need thereof a therapeutically effective amount of the
compound: ##STR00143## or a pharmaceutically acceptable salt
thereof.
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, U.S. Ser. No. 04/001,8998, WO 01/68660, WO
01/16147, WO 04/099230, WO 05/011592, U.S. Ser. No. 06/029,3252 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, U.S. Ser. No. 06/002,5349, 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 (U.S. Ser.
No. 06/000,9400, U.S. Ser. No. 06/001,9948, U.S. Ser. No.
06/003,5841, U.S. Ser. No. 06/007,4031, U.S. Ser. No. 08/002,7014
and WO 08/016132).
DESCRIPTION OF THE DRAWINGS
[0016] FIG. 1 is a differential scanning calorimetry thermogram of
a 1:1 L-proline co-crystal 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 prepared by
method 1.
[0017] FIG. 2 is a powder X-ray diffraction pattern for a 1:1
L-proline co-crystal 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 prepared by
method 1.
[0018] FIG. 3 is a differential scanning calorimetry thermogram of
a 2:1 L-proline co-crystal 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 prepared by
method 3.
[0019] FIG. 4 is a powder X-ray diffraction pattern for a 2:1
L-proline co-crystal 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 prepared by
method 3.
DETAILED DESCRIPTION OF THE INVENTION
[0020] This invention relates to compounds useful for treating
diseases and conditions mediated by the sodium D-glucose
co-transporter (SGLT), e.g. diabetes. The invention also provides
methods of treating such diseases and conditions, and compounds and
compositions etc. for their treatment.
[0021] The invention provides novel glycoside derivatives, their
polymorphs, stereoisomers, pro-drugs, solvates, pharmaceutically
acceptable salts and formulations thereof. The invention also
relates to processes for the preparation of the compounds of the
invention.
[0022] The compounds of the invention 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), 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.
[0023] The inventors have found compounds of Formula (I) that are
useful for inhibiting SGLT.
[0024] Accordingly, in a first aspect of the invention, there is
provided a compound represented by Formula (I):
##STR00002## [0025] wherein: [0026] Ring A is an C.sub.6-10aryl
which is optionally substituted with one or more substituents
independently selected from the group consisting of halo, hydroxy,
cyano, nitro, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6alkoxy, haloC.sub.1-6alkoxy, C.sub.3-7cycloalkyl,
C.sub.3-7cycloalkylC.sub.1-4alkyl, haloC.sub.1-6alkyl,
C.sub.6-10aryl, C.sub.6-10arylC.sub.1-4alkyl, --C(O)OR.sup.3,
--C(O)R.sup.3, --C(O)NR.sup.4R.sup.5, --NR.sup.4R.sup.5,
--CH.sub.2NR.sup.4R.sup.5, C.sub.1-6alkoxy, C.sub.3-7 cycloalkoxy,
--S(O).sub.pR.sup.3, --S(O).sub.2NR.sup.4R.sup.5,
--OS(O).sub.2R.sup.3, --CH.sub.2C(O)OR.sup.3,
--CH.sub.2C(O)NR.sup.4R.sup.5, --NR.sup.3C(O)NR.sup.4R.sup.5,
--NR.sup.3C(O)OR.sup.3, C.sub.6-10aryloxy, C.sub.2-10heterocyclyl,
C.sub.2-10heterocyclylC.sub.1-4alkyl,
C.sub.1-10heteroarylC.sub.1-4alkyl, C.sub.1-10heteroaryl,
C.sub.1-10heteroaryloxy and C.sub.1-10heterocycloxy; wherein the
alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl and
heteroaryl groups may be optionally substituted with one or more
substituents selected from the group consisting of halo, hydroxy,
cyano, nitro, C.sub.1-6alkyl, --S(O).sub.pR.sup.3, --C(O)OR.sup.3,
--C(O)R.sup.3, --C(O)NR.sup.4R.sup.5, --NR.sup.4R.sup.5,
--CH.sub.2NR.sup.4R.sup.5 and C.sub.1-6alkoxy; [0027] Ring A' is a
5-, 6- or 7-membered heterocycle, provided that Ring A' is not
1,3-dioxole; [0028] Y.sub.a is a bond or a
(C.sub.1-C.sub.6)alkylene which is optionally substituted with one
or more substituents independently selected from halo, hydroxy,
C.sub.1-4alkyl, C.sub.1-4alkoxy, haloC.sub.1-4alkyl; [0029] V is
hydrogen, halo or --OR.sup.b; [0030] n is 0, 1, 2, or 3; [0031] q
is 0, 1, 2, or 3; [0032] R.sup.1, R.sup.1a, R.sup.1b and R.sup.1c
are independently selected from 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; [0033] R.sup.2, for each occurrence, is
independently selected from the group consisting of halo, hydroxy,
cyano, nitro, C.sub.1-6alkyl, C.sub.3-7cycloalkyl,
C.sub.3-7cycloalkylC.sub.1-4alkyl, C.sub.6-10aryl,
C.sub.6-10arylC.sub.1-4alkyl, --C(O)OR.sup.3, --C(O)R.sup.3,
--C(O)NR.sup.4R.sup.5, --NR.sup.4R.sup.5,
--CH.sub.2NR.sup.4R.sup.5, C.sub.1-6alkoxy, C.sub.3-7 cycloalkoxy,
--S(O).sub.pR.sup.3, --S(O).sub.2NR.sup.4R.sup.5,
--OS(O).sub.2R.sup.3, --CH.sub.2C(O)OR.sup.3,
--CH.sub.2C(O)NR.sup.4R.sup.5, --NR.sup.3C(O)NR.sup.4R.sup.5,
--NR.sup.3C(O)OR.sup.3, C.sub.6-10aryloxy, C.sub.2-10heterocyclyl,
C.sub.2-10heterocyclylC.sub.1-4alkyl,
C.sub.1-10heteroarylC.sub.1-4alkyl, C.sub.1-10heteroaryl,
C.sub.1-10heteroaryloxy and C.sub.1-10heterocycloxy; wherein when
any portion of R.sup.2 is an alkyl, cycloalkyl, aryl, heterocyclyl
or heteroaryl, for each occurrence, it may be optionally
substituted with one or more substituents which are independently
selected from halo, hydroxy, C.sub.1-4alkyl, and C.sub.1-4alkoxy;
[0034] R.sup.2a, for each occurrence, is independently selected
from the group consisting of oxo, halo, hydroxy, cyano, nitro,
C.sub.1-6alkyl, C.sub.3-7cycloalkyl,
C.sub.3-7cycloalkylC.sub.1-4alkyl, C.sub.6-10aryl,
C.sub.6-10arylC.sub.1-4alkyl, --C(O)OR.sup.3, --C(O)R.sup.3,
--C(O)NR.sup.4R.sup.5, --NR.sup.4R.sup.5,
--CH.sub.2NR.sup.4R.sup.5, C.sub.1-6alkoxy, C.sub.3-7 cycloalkoxy,
--S(O).sub.pR.sup.3, --S(O).sub.2NR.sup.4R.sup.5,
--OS(O).sub.2R.sup.3, --CH.sub.2C(O)OR.sup.3,
--CH.sub.2C(O)NR.sup.4R.sup.5, --NR.sup.3C(O)NR.sup.4R.sup.5,
--NR.sup.3C(O)OR.sup.3, C.sub.6-10aryloxy, C.sub.2-10heterocyclyl,
C.sub.2-10heterocyclylC.sub.1-4alkyl,
C.sub.1-10heteroarylC.sub.1-4alkyl, C.sub.1-10heteroaryl,
C.sub.1-10heteroaryloxy and C.sub.1-10heterocycloxy; wherein when
any portion of R.sup.2a is an alkyl, cycloalkyl, aryl, heterocyclyl
or heteroaryl, for each occurrence, it may be optionally
substituted with one or more substituents which are independently
selected from halo, hydroxy, cyano, nitro, C.sub.1-6alkyl,
--S(O).sub.pR.sup.3, --C(O)OR.sup.3, --C(O)R.sup.3,
--C(O)NR.sup.4R.sup.5, --NR.sup.4R.sup.5, --CH.sub.2NR.sup.4R.sup.5
and C.sub.1-6alkoxy; or [0035] two R.sup.2a on adjacent atoms taken
together with the atoms to which they are attached may form a fused
C.sub.3-7cycloalkyl, C.sub.6aryl, 3- to 7-membered heterocyclyl, or
5- or 6-membered heteroaryl, wherein the fused cycloalkyl, aryl,
heterocyclyl, and heteroaryl may be optionally substituted with one
or more substituent independently selected from halo, hydroxy,
C.sub.1-4alkyl, and C.sub.1-4alkoxy; or [0036] two R.sup.2a on the
same carbon atom taken together may form a spiro 3- to 7-membered
heterocyclyl or a spiro C.sub.3-7cycloalkyl which may be optionally
substituted with one or more substituent independently selected
from halo, hydroxy, C.sub.1-4alkyl, and C.sub.1-4alkoxy; and [0037]
R.sup.3, for each occurrence, is independently selected from
hydrogen, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7
cycloalkylC.sub.1-4alkyl, C.sub.6-10aryl, C.sub.1-10heteroaryl, and
C.sub.2-10heterocyclyl; [0038] p is 0, 1 or 2; [0039] X is
[C(R.sup.6)(R.sup.7)].sub.t; [0040] Y is H, halo, C.sub.1-4 alkyl,
OR.sup.1c or NR.sup.4R.sup.5; [0041] t is 1, 2, or 3; [0042]
R.sup.6 and R.sup.7, for each occurrence, are independently
selected from hydrogen, C.sub.1-6 alkyl, OR.sup.1e, and
NR.sup.4R.sup.5; [0043] or when t is 1, R.sup.6 and R.sup.7
together may form an oxo group, [0044] or when R.sup.6 and R.sup.7
are on the same carbon they can be taken together to form a
C.sub.3-7cycloalkyl or a 3- to 7-membered heterocycle; [0045]
R.sup.1e, for each occurrence, is independently selected from
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; [0046] R.sup.4 and
R.sup.5, for each occurrence, are independently selected from
hydrogen, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7
cycloalkylC.sub.1-4alkyl, C.sub.6-10arylC.sub.1-4alkyl,
C.sub.6-10aryl, C.sub.1-10heteroaryl,
C.sub.1-10heteroarylC.sub.1-4alkyl, C.sub.2-10heterocyclyl, and
C.sub.2-10heterocyclylC.sub.1-4alkyl; or [0047] R.sup.4 and R.sup.5
taken together along with the nitrogen to which they are bound may
form a monocyclic or a bicyclic heteroaryl or heterocyclyl which
may be optionally substituted with one or more halo or
C.sub.1-4alkyl; or a pharmaceutically acceptable salt thereof.
[0048] In another aspect of the invention, the compound of Formula
(I) is of Formula (I-a):
##STR00003## [0049] wherein: [0050] Ring A is an C.sub.6-10aryl
which is optionally substituted with one or more substituents
independently selected from the group consisting of halo, hydroxy,
cyano, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6alkoxy, haloC.sub.1-6alkoxy, a 5-membered heteroaryl and a
6-membered heteroaryl; [0051] Ring A' is a 5- or 6-membered
heterocycle, provided that Ring A' is not 1,3-dioxole;
[0052] Y.sub.a is a bond or a (C.sub.1-C.sub.6)alkylene which is
optionally substituted with one or more substituents independently
selected from halo, C.sub.1-4alkyl, haloC.sub.1-4alkyl; [0053] V is
hydrogen, halo or --OR.sup.1b; [0054] n is 0, 1, 2, or 3; [0055] q
is 0, 1, 2, or 3; [0056] R.sup.1, R.sup.1a, R.sup.1b and
R.sup.1care independently selected from 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; [0057] R.sup.2, for each occurrence, is
independently selected from the group consisting of halo, hydroxy,
cyano, nitro, C.sub.1-6alkyl, C.sub.3-7cycloalkyl,
C.sub.3-7cycloalkylC.sub.1-4alkyl, C.sub.6-10aryl,
C.sub.6-10arylC.sub.1-4alkyl, --C(O)OR.sup.3, --C(O)R.sup.3,
--C(O)NR.sup.4R.sup.5, --NR.sup.4R.sup.5,
--CH.sub.2NR.sup.4R.sup.5, C.sub.1-6alkoxy, C.sub.3-7 cycloalkoxy,
--S(O).sub.pR.sup.3, --S(O).sub.2NR.sup.4R.sup.5,
--OS(O).sub.2R.sup.3, --CH.sub.2C(O)OR.sup.3,
--CH.sub.2C(O)NR.sup.4R.sup.5, --NR.sup.3C(O)NR.sup.4R.sup.5,
--NR.sup.3C(O)OR.sup.3, C.sub.6-10aryloxy, C.sub.2-10heterocyclyl,
C.sub.2-10heterocyclylC.sub.1-4alkyl,
C.sub.1-10heteroarylC.sub.1-4alkyl, C.sub.1-10heteroaryl,
C.sub.1-10heteroaryloxy and C.sub.1-10heterocycloxy; wherein
R.sup.2 may, for each occurrence, be optionally substituted with
one or more substituents which are independently selected from
halo, hydroxy, C.sub.1-4alkyl, and C.sub.1-4alkoxy; [0058]
R.sup.2a, for each occurrence, is independently selected from the
group consisting of oxo, halo, hydroxy, cyano, nitro,
C.sub.1-6alkyl, C.sub.3-7cycloalkyl,
C.sub.3-7cycloalkylC.sub.1-4alkyl, C.sub.6-10aryl,
C.sub.6-10arylC.sub.1-4alkyl, --C(O)OR.sup.3, --C(O)R.sup.3,
--C(O)NR.sup.4R.sup.5, --NR.sup.4R.sup.5,
--CH.sub.2NR.sup.4R.sup.5, C.sub.1-6alkoxy, C.sub.3-7 cycloalkoxy,
--S(O).sub.pR.sup.3, --S(O).sub.2NR.sup.4R.sup.5,
--OS(O).sub.2R.sup.3, --CH.sub.2C(O)OR.sup.3,
--CH.sub.2C(O)NR.sup.4R.sup.5, --NR.sup.3C(O)NR.sup.4R.sup.5,
--NR.sup.3C(O)OR.sup.3, C.sub.6-10aryloxy, C.sub.2-10heterocyclyl,
C.sub.2-10heterocyclylC.sub.1-4alkyl,
C.sub.1-10heteroarylC.sub.1-4alkyl, C.sub.1-10heteroaryl,
C.sub.1-10heteroaryloxy and C.sub.1-10heterocycloxy; wherein
R.sup.2a may, for each occurrence, be optionally substituted with
one or more substituents which are independently selected from
halo, hydroxy, C.sub.1-4alkyl, and C.sub.1-4alkoxy; or [0059] two
R.sup.2a on adjacent atoms taken together with the atoms to which
they are attached may form a fused C.sub.3-7cycloalkyl,
C.sub.6aryl, 3- to 7-membered heterocyclyl, or 5- or 6-membered
heteroaryl, wherein the fused cycloalkyl, aryl, heterocyclyl, and
heteroaryl may be optionally substituted with one or more
substituent independently selected from halo, hydroxy,
C.sub.1-4alkyl, and C.sub.1-4alkoxy; or [0060] two R.sup.2a on the
same carbon atom taken together may form a spiro 3- to 7-membered
heterocyclyl or a spiro C.sub.3-7cycloalkyl which may be optionally
substituted with one or more substituent independently selected
from halo, hydroxy, C.sub.1-4alkyl, and C.sub.1-4alkoxy; and [0061]
R.sup.3, for each occurrence, is independently selected from
hydrogen, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7
cycloalkylC.sub.1-4alkyl, C.sub.6-10aryl, C.sub.1-10heteroaryl, and
C.sub.2-10heterocyclyl; [0062] p is 0, 1 or 2; [0063] X is
[C(R.sup.6)(R.sup.7)].sub.t; [0064] Y is H, halo, C.sub.1-4 alkyl,
OR.sup.1c or NR.sup.4R.sup.5; [0065] t is 1, 2, or 3; [0066]
R.sup.6 and R.sup.7, for each occurrence, are independently
selected from hydrogen, C.sub.1-6 alkyl, OR.sup.1e, and
NR.sup.4R.sup.5; [0067] or when t is 1, R.sup.6 and R.sup.7
together may form an oxo group, [0068] or when R.sup.6 and R.sup.7
are on the same carbon they can be taken together to form a
C.sub.3-7cycloalkyl or a 3- to 7-membered heterocycle; [0069]
R.sup.1e, for each occurrence, is independently selected from
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; [0070] R.sup.4 and
R.sup.5, for each occurrence, are independently selected from
hydrogen, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7
cycloalkylC.sub.1-4alkyl, C.sub.6-10arylC.sub.1-4alkyl,
C.sub.6-10aryl, C.sub.1-10heteroaryl,
C.sub.1-10heteroarylC.sub.1-4alkyl, C.sub.2-10heterocyclyl, and
C.sub.2-10heterocyclylC.sub.1-4alkyl; or [0071] R.sup.4 and R.sup.5
taken together along with the nitrogen to which they are bound may
form a monocyclic or a bicyclic heteroaryl or heterocyclyl which
may be optionally substituted with one or more halo or
C.sub.1-4alkyl; or a pharmaceutically acceptable salt thereof.
[0072] In another aspect of the invention, the compound of Formula
(I) is of Formula (I-i):
##STR00004## [0073] wherein: [0074] Ring A is a C.sub.6-10aryl
which is optionally substituted with one or more substituents
independently selected from the group consisting of halo, hydroxy,
C.sub.1-3alkyl, C.sub.1-3alkoxy, haloC.sub.1-3alkoxy and 5-membered
heteroaryl; [0075] Ring A' is a 5- or 6-membered heterocycle
containing at least one O or N heteroatom, provided that Ring A' is
not 1,3-dioxole; [0076] Y.sub.a is a bond or a C.sub.1-3alkylene
which is optionally substituted with one or more substituents
independently selected from halo, C.sub.1-4alkyl, and
haloC.sub.1-4alkyl; [0077] V is hydrogen, halo or --OR.sup.1b;
[0078] n is 0, 1 or 2; [0079] q is 0, 1, 2, or 3; [0080] R.sup.1,
R.sup.1a, R.sup.1b and R.sup.1c are independently selected from
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; [0081] R.sup.2, for
each occurrence, is independently selected from the group
consisting of halo, hydroxy, cyano, nitro, C.sub.1-6alkyl,
C.sub.3-7cycloalkyl, C.sub.6-10aryl, C.sub.6-10arylC.sub.1-4alkyl,
--C(O)OR.sup.3, --C(O)R.sup.3, --C(O)NR.sup.4R.sup.5,
--NR.sup.4R.sup.5, --CH.sub.2NR.sup.4R.sup.5, C.sub.1-6alkoxy,
C.sub.3-7 cycloalkoxy, --CH.sub.2C(O)OR.sup.3,
--CH.sub.2C(O)NR.sup.4R.sup.5, --NR.sup.3C(O)NR.sup.4R.sup.5,
--NR.sup.3C(O)OR.sup.3, C.sub.6-10aryloxy, C.sub.2-10heterocyclyl,
C.sub.1-10heteroaryl, C.sub.1-10heteroaryloxy and
C.sub.1-10heterocycloxy; wherein R.sup.2 may, for each occurrence,
be optionally substituted with one or more substituents which are
independently selected from halo, hydroxy, C.sub.1-4alkyl, and
C.sub.1-4alkoxy; [0082] R.sup.2a, for each occurrence, is
independently selected from the group consisting of oxo, hydroxy,
C.sub.1-6alkyl, C.sub.3-7cycloalkylC.sub.1-4alkyl,
C.sub.6-10arylC.sub.1-4alkyl, --C(O)OR.sup.3, --C(O)R.sup.3,
--C(O)NR.sup.4R.sup.5 and CH.sub.2C(O)OR.sup.3; wherein R.sup.2a
may, for each occurrence, be optionally substituted with one or
more substituents which are independently selected from halo,
hydroxy, C.sub.1-4alkyl, and C.sub.1-4alkoxy; or [0083] two
R.sup.2a on adjacent atoms taken together with the atoms to which
they are attached may form a fused C.sub.3-7cycloalkyl,
C.sub.6aryl, 3- to 7-membered heterocyclyl, or 5-membered
heteroaryl, wherein the fused cycloalkyl, aryl, heterocyclyl, and
heteroaryl may be optionally substituted with one or more
substituent independently selected from halo, hydroxy,
C.sub.1-4alkyl, and C.sub.1-4alkoxy; or [0084] two R.sup.2a on the
same carbon atom taken together may form a spiro 3- to 7-membered
heterocyclyl or a spiro C.sub.3-7cycloalkyl which may be optionally
substituted with one or more substituent independently selected
from halo, hydroxy, C.sub.1-4alkyl, and C.sub.1-4alkoxy; and [0085]
R.sup.3, for each occurrence, is independently selected from
hydrogen, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7
cycloalkylC.sub.1-4alkyl, C.sub.6-10aryl, C.sub.1-10heteroaryl, and
C.sub.2-10heterocyclyl; [0086] X is [C(R.sup.6)(R.sup.7)].sub.t;
[0087] Y is H, halo, C.sub.1-4 alkyl, OR.sup.1c or NR.sup.4R.sup.5;
[0088] t is 1, 2, or 3; [0089] R.sup.6 and R.sup.7, for each
occurrence, are independently selected from hydrogen, C.sub.1-6
alkyl, OR.sup.1e, and NR.sup.4R.sup.5; [0090] or when t is 1,
R.sup.6 and R.sup.7 together may form an oxo group, [0091] or when
R.sup.6 and R.sup.7 are on the same carbon they can be taken
together to form a C.sub.3-7cycloalkyl or a 3- to 7-membered
heterocycle; [0092] R.sup.1e, for each occurrence, is independently
selected from 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; [0093] R.sup.4 and R.sup.5, for each
occurrence, are independently selected from hydrogen, C.sub.1-6
alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkylC.sub.1-4alkyl,
C.sub.6-10arylC.sub.1-4alkyl, C.sub.6-10aryl, C.sub.1-10heteroaryl,
C.sub.1-10heteroarylC.sub.1-4alkyl, C.sub.2-10heterocyclyl, and
C.sub.2-10heterocyclylC.sub.1-4alkyl; or [0094] R.sup.4 and R.sup.5
taken together along with the nitrogen to which they are bound may
form a monocyclic or a bicyclic heteroaryl or heterocyclyl which
may be optionally substituted with one or more halo or
C.sub.1-4alkyl; or a pharmaceutically acceptable salt thereof.
[0095] In another aspect of the invention, the compound of Formula
(I) is of Formula (I-ia):
##STR00005## [0096] wherein: [0097] Ring A is an C.sub.6-10aryl
which is optionally substituted with one or more substituents
independently selected from the group consisting of halo, hydroxy,
cyano, nitro, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6alkoxy, haloC.sub.1-6alkoxy, C.sub.3-7cycloalkyl,
C.sub.3-7cycloalkylC.sub.1-4alkyl, haloC.sub.1-6alkyl,
C.sub.6-10aryl, C.sub.6-10arylC.sub.1-4alkyl, --C(O)OR.sup.3,
--C(O)R.sup.3, --C(O)NR.sup.4R.sup.5, --NR.sup.4R.sup.5,
--CH.sub.2NR.sup.4R.sup.5, C.sub.1-6alkoxy, C.sub.3-7 cycloalkoxy,
--S(O).sub.pR.sup.3, --S(O).sub.2NR.sup.4R.sup.5,
--OS(O).sub.2R.sup.3, --CH.sub.2C(O)OR.sup.3,
--CH.sub.2C(O)NR.sup.4R.sup.5, --NR.sup.3C(O)NR.sup.4R.sup.5,
--NR.sup.3C(O)OR.sup.3, C.sub.6-10aryloxy, C.sub.2-10heterocyclyl,
C.sub.2-10heterocyclylC.sub.1-4alkyl,
C.sub.1-10heteroarylC.sub.1-4alkyl, C.sub.1-10heteroaryl,
C.sub.1-10heteroaryloxy and C.sub.1-10heterocycloxy; wherein the
alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl and
heteroaryl groups may be optionally substituted with one or more
substituents selected from the group consisting of halo, hydroxy,
cyano, nitro, C.sub.1-6alkyl, --S(O).sub.pR.sup.3, --C(O)OR.sup.3,
--C(O)R.sup.3, --C(O)NR.sup.4R.sup.5, --NR.sup.4R.sup.5,
--CH.sub.2NR.sup.4R.sup.5 and C.sub.1-6alkoxy; [0098] Ring A' is a
5- or 6-membered heterocycle containing at least one O or N
heteroatom, provided that Ring A' is not 1,3-dioxole; [0099]
Y.sub.a is a bond or a C.sub.1-3alkylene which is optionally
substituted with one or more substituents independently selected
from halo, C.sub.1-4alkyl, haloC.sub.1-4alkyl; [0100] V is
hydrogen, halo or --OR.sup.1b; [0101] n is 0, 1 or 2; [0102] q is
0, 1, 2, or 3; [0103] p is 0, 1 or 2; [0104] R.sup.1, R.sup.1a,
R.sup.1b and R.sup.1c are independently selected from 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; [0105] R.sup.2, for
each occurrence, is independently selected from the group
consisting of halo, hydroxy, cyano, nitro, C.sub.1-6alkyl,
C.sub.3-7cycloalkyl, C.sub.6-10aryl, C.sub.6-10arylC.sub.1-4alkyl,
--C(O)OR.sup.3, --C(O)R.sup.3, --C(O)NR.sup.4R.sup.5,
--NR.sup.4R.sup.5, --CH.sub.2NR.sup.4R.sup.5, C.sub.1-6alkoxy,
C.sub.3-7 cycloalkoxy, --CH.sub.2C(O)OR.sup.3,
--CH.sub.2C(O)NR.sup.4R.sup.5, --NR.sup.3C(O)NR.sup.4R.sup.5,
--NR.sup.3C(O)OR.sup.3, C.sub.6-10aryloxy, C.sub.2-10heterocyclyl,
C.sub.1-10heteroaryl, C.sub.1-10heteroaryloxy and
C.sub.1-10heterocycloxy; wherein R.sup.2 may, for each occurrence,
be optionally substituted with one or more substituents which are
independently selected from halo, hydroxy, C.sub.1-4alkyl, and
C.sub.1-4alkoxy; R.sup.2a, for each occurrence, is independently
selected from the group consisting of oxo, halo, hydroxy, cyano,
nitro, C.sub.1-6alkyl, C.sub.3-7cycloalkyl,
C.sub.3-7cycloalkylC.sub.1-4alkyl, C.sub.6-10aryl,
C.sub.6-10arylC.sub.1-4alkyl, --C(O)OR.sup.3, --C(O)R.sup.3,
--C(O)NR.sup.4R.sup.5, --NR.sup.4R.sup.5,
--CH.sub.2NR.sup.4R.sup.5, C.sub.1-6alkoxy, C.sub.3-7 cycloalkoxy,
--S(O).sub.pR.sup.3, --S(O).sub.2NR.sup.4R.sup.5,
--OS(O).sub.2R.sup.3, --CH.sub.2C(O)OR.sup.3,
--CH.sub.2C(O)NR.sup.4R.sup.5, --NR.sup.3C(O)NR.sup.4R.sup.5,
--NR.sup.3C(O)OR.sup.3, C.sub.6-10aryloxy, C.sub.2-10heterocyclyl,
C.sub.2-10heterocyclylC.sub.1-4alkyl,
C.sub.1-10heteroarylC.sub.1-4alkyl, C.sub.1-10heteroaryl,
C.sub.1-10heteroaryloxy and C.sub.1-10heterocycloxy; wherein
R.sup.2a may, for each occurrence, be optionally substituted with
one or more substituents which are independently selected from
halo, hydroxy, C.sub.1-4alkyl, and C.sub.1-4alkoxy; or [0106] two
R.sup.2a on adjacent atoms taken together with the atoms to which
they are attached may form a fused C.sub.3-7cycloalkyl,
C.sub.6aryl, 3- to 7-membered heterocyclyl, or 5-membered
heteroaryl, wherein the fused cycloalkyl, aryl, heterocyclyl, and
heteroaryl may be optionally substituted with one or more
substituent independently selected from halo, hydroxy,
C.sub.1-4alkyl, and C.sub.1-4alkoxy; or [0107] two R.sup.2a on the
same carbon atom taken together may form a spiro 3- to 7-membered
heterocyclyl or a spiro C.sub.3-7cycloalkyl which may be optionally
substituted with one or more substituent independently selected
from halo, hydroxy, C.sub.1-4alkyl, and C.sub.1-4alkoxy; and [0108]
R.sup.3, for each occurrence, is independently selected from
hydrogen, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7
cycloalkylC.sub.1-4alkyl, C.sub.6-10aryl, C.sub.1-10heteroaryl, and
C.sub.2-10heterocyclyl; [0109] X is [C(R.sup.6)(R.sup.7)].sub.t;
[0110] Y is H, halo, C.sub.1-4 alkyl, OR.sup.1c or NR.sup.4R.sup.5;
[0111] t is 1, 2, or 3; [0112] R.sup.6 and R.sup.7, for each
occurrence, are independently selected from hydrogen, C.sub.1-6
alkyl, OR.sup.1e, and NR.sup.4R.sup.5; [0113] or when t is 1,
R.sup.6 and R.sup.7 together may form an oxo group, [0114] or when
R.sup.6 and R.sup.7 are on the same carbon they can be taken
together to form a C.sub.3-7cycloalkyl or a 3- to 7-membered
heterocycle; [0115] R.sup.1e, for each occurrence, is independently
selected from 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; [0116] R.sup.4 and R.sup.5, for each
occurrence, are independently selected from hydrogen, C.sub.1-6
alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkylC.sub.1-4alkyl,
C.sub.6-10arylC.sub.1-4alkyl, C.sub.6-10aryl, C.sub.1-10heteroaryl,
C.sub.1-10heteroarylC.sub.1-4alkyl, C.sub.2-10heterocyclyl, and
C.sub.2-10heterocyclylC.sub.1-4alkyl; or [0117] R.sup.4 and R.sup.5
taken together along with the nitrogen to which they are bound may
form a monocyclic or a bicyclic heteroaryl or heterocyclyl which
may be optionally substituted with one or more halo or
C.sub.1-4alkyl; or a pharmaceutically acceptable salt thereof.
[0118] In another aspect of the invention, the compound of Formula
(I) is of Formula (I-ii):
##STR00006## [0119] wherein: [0120] Ring A is a C.sub.6-10aryl
which is optionally substituted with one or more substituents
independently selected from the group consisting of halo, hydroxy,
C.sub.1-3alkyl, C.sub.1-3alkoxy, haloC.sub.1-3alkoxy and 5-membered
heteroaryl; [0121] Ring A' is a 5- or 6-membered heterocycle
containing at least one O or N heteroatom, provided that Ring A' is
not 1,3-dioxole; [0122] Y.sub.a is a bond or a C.sub.1-3alkylene
which is optionally substituted with one or more substituents
independently selected from halo, C.sub.1-4alkyl,
haloC.sub.1-4alkyl; [0123] V is OH; [0124] n is 0, 1 or 2; [0125] q
is 0, 1, 2, or 3; [0126] R.sup.1 and R.sup.1a are each hydrogen;
[0127] R.sup.2, for each occurrence, is independently selected from
the group consisting of halo, hydroxy, cyano, nitro,
C.sub.1-6alkyl, C.sub.3-7cycloalkyl, C.sub.6-10aryl,
C.sub.6-10arylC.sub.1-4alkyl, --C(O)OR.sup.3, --C(O)R.sup.3,
--C(O)NR.sup.4R.sup.5, --NR.sup.4R.sup.5,
--CH.sub.2NR.sup.4R.sup.5, C.sub.1-6alkoxy, C.sub.3-7 cycloalkoxy,
--CH.sub.2C(O)OR.sup.3, --CH.sub.2C(O)NR.sup.4R.sup.5,
--NR.sup.3C(O)NR.sup.4R.sup.5, --NR.sup.3C(O)OR.sup.3,
C.sub.6-10aryloxy, C.sub.2-10heterocyclyl, C.sub.1-10heteroaryl,
C.sub.1-10heteroaryloxy and C.sub.1-10heterocycloxy; wherein
R.sup.2 may, for each occurrence, be optionally substituted with
one or more substituents which are independently selected from
halo, hydroxy, C.sub.1-4alkyl, and C.sub.1-4alkoxy; [0128]
R.sup.2a, for each occurrence, is independently selected from the
group consisting of oxo, hydroxy, C.sub.1-6alkyl,
C.sub.3-7cycloalkylC.sub.1-4alkyl, C.sub.6-10arylC.sub.1-4alkyl,
--C(O)OR.sup.3, --C(O)R.sup.3, --C(O)NR.sup.4R.sup.5 and
CH.sub.2C(O)OR.sup.3; wherein R.sup.2a may, for each occurrence, be
optionally substituted with one or more substituents which are
independently selected from halo, hydroxy, C.sub.1-4alkyl, and
C.sub.1-4alkoxy; or [0129] two R.sup.2a on adjacent atoms taken
together with the atoms to which they are attached may form a fused
C.sub.3-7cycloalkyl, C.sub.6aryl, 3- to 7-membered heterocyclyl, or
5-membered heteroaryl, wherein the fused cycloalkyl, aryl,
heterocyclyl, and heteroaryl may be optionally substituted with one
or more substituent independently selected from halo, hydroxy,
C.sub.1-4alkyl, and C.sub.1-4alkoxy; or [0130] two R.sup.2a on the
same carbon atom taken together may form a spiro 3- to 7-membered
heterocyclyl or a spiro C.sub.3-7cycloalkyl which may be optionally
substituted with one or more substituent independently selected
from halo, hydroxy, C.sub.1-4alkyl, and C.sub.1-4alkoxy; and [0131]
R.sup.3, for each occurrence, is independently selected from
hydrogen, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7
cycloalkylC.sub.1-4alkyl, C.sub.6-10aryl, C.sub.1-10heteroaryl, and
C.sub.2-10heterocyclyl; [0132] X is [C(R.sup.6)(R.sup.7)].sub.t;
[0133] Y is H or OH; [0134] t is 1; [0135] R.sup.6 and R.sup.7, for
each occurrence, are independently selected from hydrogen and
C.sub.1-3 alkyl; [0136] or when t is 1, R.sup.6 and R.sup.7
together may form an oxo group; [0137] R.sup.4 and R.sup.5, for
each occurrence, are independently selected from hydrogen,
C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7
cycloalkylC.sub.1-4alkyl, C.sub.6-10arylC.sub.1-4alkyl,
C.sub.6-10aryl, C.sub.1-10heteroaryl, C.sub.1-10
heteroarylC.sub.1-4alkyl, C.sub.2-10heterocyclyl, and
C.sub.2-10heterocyclylC.sub.1-4alkyl; or [0138] R.sup.4 and R.sup.5
taken together along with the nitrogen to which they are bound may
form a monocyclic or a bicyclic heteroaryl or heterocyclyl which
may be optionally substituted with one or more halo or
C.sub.1-4alkyl; or a pharmaceutically acceptable salt thereof.
[0139] In another aspect of the invention, the compound of Formula
(I) is of Formula (I-iia):
##STR00007## [0140] wherein: [0141] Ring A is an C.sub.6-10aryl
which is optionally substituted with one or more substituents
independently selected from the group consisting of halo, hydroxy,
cyano, nitro, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6alkoxy, haloC.sub.1-6alkoxy, C.sub.3-7cycloalkyl,
C.sub.3-7cycloalkylC.sub.1-4alkyl, haloC.sub.1-6alkyl,
C.sub.6-10aryl, C.sub.6-10arylC.sub.1-4alkyl, --C(O)OR.sup.3,
--C(O)R.sup.3, --C(O)NR.sup.4R.sup.5, --NR.sup.4R.sup.5,
--CH.sub.2NR.sup.4R.sup.5, C.sub.1-6alkoxy, C.sub.3-7 cycloalkoxy,
--S(O).sub.pR.sup.3, --S(O).sub.2NR.sup.4R.sup.5,
--OS(O).sub.2R.sup.3, --CH.sub.2C(O)OR.sup.3,
--CH.sub.2C(O)NR.sup.4R.sup.5, --NR.sup.3C(O)NR.sup.4R.sup.5,
--NR.sup.3C(O)OR.sup.3, C.sub.6-10aryloxy, C.sub.2-10heterocyclyl,
C.sub.2-10heterocyclylC.sub.1-4alkyl,
C.sub.1-10heteroarylC.sub.1-4alkyl, C.sub.1-10heteroaryl,
C.sub.1-10heteroaryloxy and C.sub.1-10heterocycloxy; wherein the
alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl and
heteroaryl groups may be optionally substituted with one or more
substituents selected from the group consisting of halo, hydroxy,
cyano, nitro, C.sub.1-6alkyl, --S(O).sub.pR.sup.3, --C(O)OR.sup.3,
--C(O)R.sup.3, --C(O)NR.sup.4R.sup.5, --NR.sup.4R.sup.5,
--CH.sub.2NR.sup.4R.sup.5 and C.sub.1-6alkoxy; [0142] Ring A' is a
5- or 6-membered heterocycle containing at least one O or N
heteroatom, provided that Ring A' is not 1,3-dioxole; [0143]
Y.sub.a is a bond or a C.sub.1-3alkylene which is optionally
substituted with one or more substituents independently selected
from halo, C.sub.1-4alkyl, haloC.sub.1-4alkyl; [0144] V is OH;
[0145] n is 0, 1 or 2; [0146] q is 0, 1, 2, or 3; [0147] R.sup.1
and R.sup.1a are each hydrogen; [0148] R.sup.2, for each
occurrence, is independently selected from the group consisting of
halo, hydroxy, cyano, nitro, C.sub.1-6alkyl, C.sub.3-7cycloalkyl,
C.sub.6-10aryl, C.sub.6-10arylC.sub.1-4alkyl, --C(O)OR.sup.3,
--C(O)R.sup.3, --C(O)NR.sup.4R.sup.5, --NR.sup.4R.sup.5,
--CH.sub.2NR.sup.4R.sup.5, C.sub.1-6alkoxy, C.sub.3-7 cycloalkoxy,
--CH.sub.2C(O)OR.sup.3, --CH.sub.2C(O)NR.sup.4R.sup.5,
--NR.sup.3C(O)NR.sup.4R.sup.5, --NR.sup.3C(O)OR.sup.3,
C.sub.6-10aryloxy, C.sub.2-10heterocyclyl, C.sub.1-10heteroaryl,
C.sub.1-10heteroaryloxy and C.sub.1-10heterocycloxy; wherein
R.sup.2 may, for each occurrence, be optionally substituted with
one or more substituents which are independently selected from
halo, hydroxy, C.sub.1-4alkyl, and C.sub.1-4alkoxy; [0149]
R.sup.2a, for each occurrence, is independently selected from the
group consisting of oxo, halo, hydroxy, cyano, nitro,
C.sub.1-6alkyl, C.sub.3-7cycloalkyl,
C.sub.3-7cycloalkylC.sub.1-4alkyl, C.sub.6-10aryl,
C.sub.6-10arylC.sub.1-4alkyl, --C(O)OR.sup.3, --C(O)R.sup.3,
--C(O)NR.sup.4R.sup.5, --NR.sup.4R.sup.5,
--CH.sub.2NR.sup.4R.sup.5, C.sub.1-6alkoxy, C.sub.3-7 cycloalkoxy,
--S(O).sub.pR.sup.3, --S(O).sub.2NR.sup.4R.sup.5,
--OS(O).sub.2R.sup.3, --CH.sub.2C(O)OR.sup.3,
--CH.sub.2C(O)NR.sup.4R.sup.5, --NR.sup.3C(O)NR.sup.4R.sup.5,
--NR.sup.3C(O)OR.sup.3, C.sub.6-10aryloxy, C.sub.2-10heterocyclyl,
C.sub.2-10heterocyclylC.sub.1-4alkyl,
C.sub.1-10heteroarylC.sub.1-4alkyl, C.sub.1-10heteroaryl,
C.sub.1-10heteroaryloxy and C.sub.1-10heterocycloxy; wherein
R.sup.2a may, for each occurrence, be optionally substituted with
one or more substituents which are independently selected from
halo, hydroxy, C.sub.1-4alkyl, and C.sub.1-4alkoxy; or [0150] two
R.sup.2a on adjacent atoms taken together with the atoms to which
they are attached may form a fused C.sub.3-7cycloalkyl,
C.sub.6aryl, 3- to 7-membered heterocyclyl, or 5-membered
heteroaryl, wherein the fused cycloalkyl, aryl, heterocyclyl, and
heteroaryl may be optionally substituted with one or more
substituent independently selected from halo, hydroxy,
C.sub.1-4alkyl, and C.sub.1-4alkoxy; or [0151] two R.sup.2a on the
same carbon atom taken together may form a spiro 3- to 7-membered
heterocyclyl or a spiro C.sub.3-7cycloalkyl which may be optionally
substituted with one or more substituent independently selected
from halo, hydroxy, C.sub.1-4alkyl, and C.sub.1-4alkoxy; and [0152]
R.sup.3, for each occurrence, is independently selected from
hydrogen, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7
cycloalkylC.sub.1-4alkyl, C.sub.6-10aryl, C.sub.1-10heteroaryl, and
C.sub.2-10heterocyclyl; [0153] p is 0, 1 or 2; [0154] X is
[C(R.sup.6)(R.sup.7)].sub.t; [0155] Y is H or OH; [0156] t is 1;
[0157] R.sup.6 and R.sup.7, for each occurrence, are independently
selected from hydrogen and C.sub.1-3 alkyl; [0158] or when t is 1,
R.sup.6 and R.sup.7 together may form an oxo group; [0159] R.sup.4
and R.sup.5, for each occurrence, are independently selected from
hydrogen, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7
cycloalkylC.sub.1-4alkyl, C.sub.6-10arylC.sub.1-4alkyl,
C.sub.6-10aryl, C.sub.1-10heteroaryl, C.sub.1-10
heteroarylC.sub.1-4alkyl, C.sub.2-10heterocyclyl, and
C.sub.2-10heterocyclylC.sub.1-4alkyl; or [0160] R.sup.4 and R.sup.5
taken together along with the nitrogen to which they are bound may
form a monocyclic or a bicyclic heteroaryl or heterocyclyl which
may be optionally substituted with one or more halo or
C.sub.1-4alkyl; or a pharmaceutically acceptable salt thereof.
[0161] In another aspect of the invention, the compound of Formula
(I) is of Formula (I-iii):
##STR00008## [0162] wherein: [0163] Ring A is a phenyl ring which
is optionally substituted with one or more substituents
independently selected from the group consisting of chloro, fluoro,
hydroxy, methyl, methoxy, ethoxy, trifluoromethoxy and N-pyrazolyl;
[0164] the structure represented by the following formula:
##STR00009##
[0164] is selected from the group consisting of:
##STR00010##
wherein the hydrogen on each nitrogen may be optionally replaced
with R.sup.2a; [0165] Y.sub.a is CH.sub.2; [0166] V is OH; [0167] n
is 0 or 1; [0168] q is 0 or 1; [0169] R.sup.1 and R.sup.1a are each
hydrogen; [0170] R.sup.2 is halo; wherein R.sup.2 may, for each
occurrence, be optionally substituted with one or more substituents
which are independently selected from halo, hydroxy,
C.sub.1-4alkyl, and C.sub.1-4alkoxy;
[0171] R.sup.2a, for each occurrence, is independently selected
from the group consisting of hydroxy, C.sub.1-6alkyl,
C.sub.3-7cycloalkylC.sub.1-4alkyl; wherein R.sup.2a may, for each
occurrence, be optionally substituted with one or more substituents
which are independently selected from halo, hydroxy,
C.sub.1-4alkyl, and C.sub.1-4alkoxy; or [0172] two R.sup.2a on the
same carbon atom taken together may form a spiro
C.sub.3-7cycloalkyl which may be optionally substituted with one or
more substituent independently selected from halo, hydroxy,
C.sub.1-4alkyl, and C.sub.1-4alkoxy; [0173] X is CH.sub.2; [0174] Y
is OH; or a pharmaceutically acceptable salt thereof.
[0175] In another aspect of the invention, the compound of Formula
(I) is of Formula (I-iiia):
##STR00011## [0176] wherein: [0177] Ring A is a phenyl ring which
is optionally substituted with one or more substituents
independently selected from the group consisting of chloro, fluoro,
hydroxy, cyano, methyl, ethyl, isopropyl, ethynyl, methoxy, ethoxy,
trifluoromethoxy, amino, dimethylamino, methylsulfanyl,
methylsulfonyl, carbamoyl, cyclopropyl, cyclobutyl, phenyl, toulyl,
phenoxy, oxazolyloxy, and N-pyrazolyl; [0178] the structure
represented by the following formula:
##STR00012##
[0178] is selected from the group consisting of:
##STR00013##
wherein the hydrogen on each nitrogen may be optionally replaced
with R.sup.2a; R.sup.a, for each occurrence, is independently
selected from halo, hydroxy, cyano, nitro, C.sub.1-6alkyl,
--S(O).sub.pR.sup.3, --C(O)OR.sup.3, --C(O)R.sup.3,
--C(O)NR.sup.4R.sup.5, --NR.sup.4R.sup.5, --CH.sub.2NR.sup.4R.sup.5
and C.sub.1-6alkoxy; and m is 0 or an integer from 1-4; [0179]
Y.sub.a is CH.sub.2; [0180] V is OH; [0181] n is 0 or 1; [0182] q
is 0 or 1; [0183] R.sup.1 and R.sup.1a are each hydrogen; [0184]
R.sup.2 is halo; wherein R.sup.2 may, for each occurrence, be
optionally substituted with one or more substituents which are
independently selected from halo, hydroxy, C.sub.1-4alkyl, and
C.sub.1-4alkoxy;
[0185] R.sup.2a, for each occurrence, is independently selected
from the group consisting of oxo, halo, hydroxy, cyano, nitro,
C.sub.1-6alkyl, C.sub.3-7cycloalkyl,
C.sub.3-7cycloalkylC.sub.1-4alkyl, C.sub.6-10aryl,
C.sub.6-10arylC.sub.1-4alkyl, --C(O)OR.sup.3, --C(O)R.sup.3,
--C(O)NR.sup.4R.sup.5, --NR.sup.4R.sup.5,
--CH.sub.2NR.sup.4R.sup.5, C.sub.1-6alkoxy, C.sub.3-7 cycloalkoxy,
--S(O).sub.pR.sup.3, --S(O).sub.2NR.sup.4R.sup.5,
--OS(O).sub.2R.sup.3, --CH.sub.2C(O)OR.sup.3,
--CH.sub.2C(O)NR.sup.4R.sup.5, --NR.sup.3C(O)NR.sup.4R.sup.5,
--NR.sup.3C(O)OR.sup.3, C.sub.6-10aryloxy, C.sub.2-10heterocyclyl,
C.sub.2-10heterocyclylC.sub.1-4alkyl,
C.sub.1-10heteroarylC.sub.1-4alkyl, C.sub.1-10heteroaryl,
C.sub.1-10heteroaryloxy and C.sub.1-10heterocycloxy; wherein
R.sup.2a may, for each occurrence, be optionally substituted with
one or more substituents which are independently selected from
halo, hydroxy, C.sub.1-4alkyl, and C.sub.1-4alkoxy; or [0186] two
R.sup.2a on the same carbon atom taken together may form a spiro
C.sub.3-7cycloalkyl which may be optionally substituted with one or
more substituent independently selected from halo, hydroxy,
C.sub.1-4alkyl, and C.sub.1-4alkoxy; [0187] p is 0, 1 or 2; [0188]
X is CH.sub.2; [0189] Y is OH; or a pharmaceutically acceptable
salt thereof.
[0190] In another aspect of the invention, the compound of Formula
(I) is of Formula (I-iv):
##STR00014## [0191] wherein:
[0192] Ring A is a phenyl ring which is optionally substituted with
one substituent independently selected from the group consisting of
chloro, fluoro, methyl and methoxy; wherein Y.sub.a is situated
meta to the tetrahydropyran ring and the one substituent is
situated para to the tetrahydropyran ring; [0193] the structure
represented by the following formula:
##STR00015##
[0193] is selected from the group consisting of:
##STR00016##
wherein the hydrogen on each nitrogen may be optionally replaced
with R.sup.2a; [0194] Y.sub.a is CH.sub.2; [0195] V is OH; [0196] n
is 0 or 1; [0197] q is 0 or 1; [0198] R.sup.1 and R.sup.1a are each
hydrogen; [0199] R.sup.2 is halo; [0200] R.sup.2a, for each
occurrence, is independently selected from the group consisting of
unsubstituted hydroxy and unsubstituted C.sub.1-2alkyl; and [0201]
X is CH.sub.2; [0202] Y is OH; or a pharmaceutically acceptable
salt thereof.
[0203] In another aspect of the invention, the compound of Formula
(I) is of Formula (I-iva):
##STR00017## [0204] wherein: [0205] Ring A is a phenyl ring which
is optionally substituted with one substituent independently
selected from the group consisting of chloro, fluoro, hydroxy,
cyano, methyl, ethyl, isopropyl, ethynyl, methoxy, ethoxy,
trifluoromethoxy, amino, dimethylamino, methylsulfanyl,
methylsulfonyl, carbamoyl, cyclopropyl, cyclobutyl, phenyl, toulyl,
phenoxy, oxazolyloxy, and N-pyrazolyl; wherein Y.sub.a is situated
meta to the tetrahydropyran ring and the one substituent is
situated para to the tetrahydropyran ring; [0206] the structure
represented by the following formula:
##STR00018##
[0206] is selected from the group consisting of:
##STR00019##
wherein the hydrogen on each nitrogen may be optionally replaced
with R.sup.2a; R.sup.a, for each occurrence, is independently
selected from halo, hydroxy, cyano, nitro, C.sub.1-6alkyl,
--S(O).sub.pR.sup.3, --C(O)OR.sup.3, --C(O)R.sup.3,
--C(O)NR.sup.4R.sup.5, --NR.sup.4R.sup.5, --CH.sub.2NR.sup.4R.sup.5
and C.sub.1-6alkoxy; and m is 0 or an integer from 1-4; [0207] p is
0, 1, or 2; [0208] Y.sub.a is CH.sub.2; [0209] V is OH; [0210] n is
0 or 1; [0211] q is 0 or 1; [0212] R.sup.1 and R.sup.1a are each
hydrogen; [0213] R.sup.2 is halo; [0214] R.sup.2a, for each
occurrence, is independently selected from the group consisting of
oxo, halo, hydroxy, cyano, nitro, C.sub.1-6alkyl,
C.sub.3-7cycloalkyl, C.sub.3-7cycloalkylC.sub.1-4alkyl,
C.sub.6-10aryl, C.sub.6-10arylC.sub.1-4alkyl, --C(O)OR.sup.3,
--C(O)R.sup.3, --C(O)NR.sup.4R.sup.5, --NR.sup.4R.sup.5,
--CH.sub.2NR.sup.4R.sup.5, C.sub.1-6alkoxy, C.sub.3-7 cycloalkoxy,
--S(O).sub.pR.sup.3, --S(O).sub.2NR.sup.4R.sup.5,
--OS(O).sub.2R.sup.3, --CH.sub.2C(O)OR.sup.3,
--CH.sub.2C(O)NR.sup.4R.sup.5, --NR.sup.3C(O)NR.sup.4R.sup.5,
--NR.sup.3C(O)OR.sup.3, C.sub.6-10aryloxy, C.sub.2-10heterocyclyl,
C.sub.2-10heterocyclylC.sub.1-4alkyl,
C.sub.1-10heteroarylC.sub.1-4alkyl, C.sub.1-10heteroaryl,
C.sub.1-10heteroaryloxy and C.sub.1-10heterocycloxy; wherein
R.sup.2a may, for each occurrence, be optionally substituted with
one or more substituents which are independently selected from
halo, hydroxy, cyano, nitro, C.sub.1-6alkyl, --S(O).sub.pR.sup.3,
--C(O)OR.sup.3, --C(O)R.sup.3, --C(O)NR.sup.4R.sup.5,
--NR.sup.4R.sup.5, --CH.sub.2NR.sup.4R.sup.5 and C.sub.1-6alkoxy;
[0215] X is CH.sub.2; and [0216] Y is OH; or a pharmaceutically
acceptable salt thereof.
[0217] In another aspect of the invention, the compound of Formula
(I) is of Formula (V):
##STR00020## [0218] wherein: [0219] ring A is phenyl which is
substituted with one substituent selected from halo,
C.sub.1-4alkyl, and C.sub.3-7cycloalkyl; wherein Y.sub.a is
situated meta to the tetrahydropyran ring and the one substituent
is situated para to the tetrahydropyran ring; [0220] the structure
represented by the following formula:
##STR00021##
[0220] is selected from the group consisting of:
##STR00022## [0221] Y.sub.a is CH.sub.2; [0222] n is 0; [0223] q is
0; [0224] V is --OR.sup.1b; [0225] X is CH.sub.2; [0226] Y is
OR.sup.1c; [0227] R.sup.1, R.sup.1a, R.sup.1b and R.sup.1c are
hydrogen; [0228] or a pharmaceutically acceptable salt thereof.
Embodiments of the Compounds of Formulae (I), (I-a), (I-i), (I-ia),
(I-ii), (I-iia), (I-iii), (I-iiia), (I-iv), (I-iva), and (V)
General
[0229] Various embodiments of the invention are described herein.
It will be recognised that features specified in each embodiment
may be combined with other specified features to provide further
embodiments. Thus, combinations of the various features are herein
implicitly disclosed.
The Tetrahydropyran Ring and its Substituents
[0230] In one embodiment, V is OR.sup.1b. In a further embodiment,
V is OH.
[0231] In one embodiment, R.sup.1 and R.sup.1a are independently
selected from hydrogen, C.sub.1-3 alkyl,
C.sub.6-10aryl-C.sub.1-4alkyl, --C(O)C.sub.6-10aryl and
--C(O)C.sub.1-8alkyl. In a further embodiment, R.sup.1 is H. In a
further embodiment, R.sup.1a is H. In a further embodiment, R.sup.1
and R.sup.1a are both H.
[0232] In one embodiment, t is 1 or 2. In a further embodiment, t
is 1.
[0233] In one embodiment, X is CH.sub.2.
[0234] In one embodiment, Y is H or OR.sup.1c. In a further
embodiment, Y is H or OH. In a further embodiment, Y is OH. In a
further embodiment, Y is a halo. In a further embodiment, Y is
fluoro.
[0235] In one embodiment, the tetrahydropyran ring is a pyranose
ring of the structure:
##STR00023##
[0236] In a further embodiment, the pyranose ring has the following
stereochemistry:
##STR00024##
[0237] In one embodiment, R.sup.1b is selected from hydrogen,
C.sub.1-3 alkyl, C.sub.6-10aryl-C.sub.1-4alkyl,
--C(O)C.sub.6-10aryl and --C(O)C.sub.1-8alkyl. In a further
embodiment, R.sup.1b is H.
[0238] In one embodiment, R.sup.1c is selected from hydrogen,
C.sub.1-3 alkyl, C.sub.6-10aryl-C.sub.1-4alkyl,
--C(O)C.sub.6-10aryl and --C(O)C.sub.1-8alkyl. In a further
embodiment, R.sup.1c is H.
[0239] In one embodiment, R.sup.6 and R.sup.7, for each occurrence,
are independently selected from hydrogen, C.sub.1-3 alkyl,
OR.sup.1e, and NR.sup.4R.sup.5; or when t is 1, R.sup.6 and R.sup.7
together may form an oxo group; or when R.sup.6 and R.sup.7 are on
the same carbon they can be taken together to form a
C.sub.3-7cycloalkyl or a 3- to 7-membered heterocycle. In a further
embodiment, R.sup.6 and R.sup.7, for each occurrence, are
independently selected from hydrogen and C.sub.1-3 alkyl.
[0240] In one embodiment, R.sup.1e, for each occurrence, is
independently selected from hydrogen, C.sub.1-3 alkyl,
C.sub.6-10aryl-C.sub.1-4alkyl, --C(O)C.sub.6-10aryl and
--C(O)C.sub.1-6alkyl. In a further embodiment, R.sup.1e, for each
occurrence, is independently selected from hydrogen and C.sub.1-3
alkyl.
Ring A and its Substituents
[0241] In one embodiment, Ring A is substituted with one or more
substituents independently selected from the group consisting of
halo, hydroxy, C.sub.1-3alkyl, C.sub.1-3alkoxy, haloC.sub.1-3alkoxy
and 5-membered heteroaryl. In a further embodiment, Ring A is
substituted with one or more substituents independently selected
from the group consisting of halo, hydroxy, C.sub.1-3alkyl,
C.sub.3-7cycloalkyl, C.sub.1-3alkoxy, haloC.sub.1-3alkoxy and
5-membered heteroaryl. In a further embodiment, Ring A is
substituted with one or more substituents independently selected
from the group consisting of chloro, fluoro, hydroxy, methyl,
methoxy, ethoxy, trifluoromethoxy and N-pyrazolyl. In a further
embodiment, Ring A is substituted with one or more substituents
independently selected from the group consisting of chloro, fluoro,
hydroxy, methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy,
trifluoromethoxy and N-pyrazolyl. In a further embodiment, Ring A
is substituted with one or more substituents independently selected
from the group consisting of chloro, fluoro, methyl and methoxy. In
a further embodiment, Ring A is substituted with one or more chloro
substituents. In a further embodiment, Ring A is substituted with
one or more substituents independently selected from the group
consisting of chloro, ethyl, isopropyl, and cyclopropyl. In a
further embodiment, Ring A is substituted with one chloro. In a
further embodiment, Ring A is substituted with one ethyl. In a
further embodiment, Ring A is substituted with one isopropyl. In a
further embodiment, Ring A is substituted with one cyclopropyl.
[0242] In one embodiment, Ring A is naphthyl which is optionally
substituted.
[0243] In a one embodiment, Ring A is phenyl which is optionally
substituted.
[0244] In one embodiment, Y.sub.a is situated meta to the
tetrahydropyran ring.
[0245] In one embodiment, Ring A has one substituent. In one aspect
of this embodiment, Ring A has one substituent which is selected
from the group consisting of halo, hydroxy, C.sub.1-3alkyl,
C.sub.3-7cycloalkyl, C.sub.1-3alkoxy, haloC.sub.1-3alkoxy and
5-membered heteroaryl. In another aspect of this embodiment, Ring A
has one substituent which is selected from the group consisting of
chloro, fluoro, hydroxy, methyl, ethyl, isopropyl, cyclopropyl,
methoxy, ethoxy, trifluoromethoxy and N-pyrazolyl. In another
aspect of this embodiment, Ring A is substituted with one chloro.
In another aspect of this embodiment, Ring A is substituted with
one ethyl. In another aspect of this embodiment, Ring A is
substituted with one isopropyl. In another aspect of this
embodiment, Ring A is substituted with one cyclopropyl.
[0246] In a further embodiment, Ring A is unsubstituted.
[0247] In one embodiment, Ring A is phenyl with one substituent,
Y.sub.a is situated meta to the tetrahydropyran ring and the one
substituent is situated para to the tetrahydropyran ring. In one
aspect of this embodiment, the substituent on Ring A is selected
from the group consisting of halo, hydroxy, C.sub.1-3alkyl,
C.sub.3-7cycloalkyl, C.sub.1-3alkoxy, haloC.sub.1-3alkoxy and
5-membered heteroaryl. In another aspect of this embodiment, the
substituent on Ring A is selected from the group consisting of
chloro, fluoro, hydroxy, methyl, ethyl, isopropyl, cyclopropyl,
methoxy, ethoxy, trifluoromethoxy and N-pyrazolyl. In another
aspect of this embodiment, the substituent on Ring A is chloro. In
another aspect of this embodiment, the substituent on Ring A is
ethyl. In another aspect of this embodiment, the substituent on
Ring A is isopropyl. In another aspect of this embodiment, the
substituent on Ring A is cyclopropyl.
Linker Y.sub.a
[0248] In one embodiment, Y.sub.a is a bond or a
C.sub.1-3alkylene.
[0249] In one embodiment, Y.sub.a is unsubstituted.
[0250] In one embodiment, Y.sub.a is CH.sub.2.
The R.sup.2 Substituent(s)
[0251] In one embodiment, R.sup.2, for each occurrence, is
independently selected from the group consisting of halo, hydroxy,
cyano, nitro, C.sub.1-6alkyl, C.sub.3-7cycloalkyl, C.sub.6-10aryl,
C.sub.6-10arylC.sub.1-4alkyl, --C(O)OR.sup.3, --C(O)R.sup.3,
--C(O)NR.sup.4R.sup.5, --NR.sup.4R.sup.5,
--CH.sub.2NR.sup.4R.sup.5, C.sub.1-6alkoxy, C.sub.3-7 cycloalkoxy,
--CH.sub.2C(O)OR.sup.3, --CH.sub.2C(O)NR.sup.4R.sup.5,
--NR.sup.3C(O)NR.sup.4R.sup.5, --NR.sup.3C(O)OR.sup.3,
C.sub.6-10aryloxy, C.sub.2-10heterocyclyl, C.sub.1-10heteroaryl,
C.sub.1-10heteroaryloxy and C.sub.1-10heterocycloxy.
[0252] In a further embodiment, R.sup.2, for each occurrence, is
independently selected from the group consisting of halo, hydroxy,
cyano, nitro, C.sub.1-3alkyl, C.sub.3-7cycloalkyl, C.sub.6-10aryl,
C.sub.6-10arylC.sub.1-3alkyl, --C(O)OR.sup.3, --C(O)R.sup.3,
--C(O)NR.sup.4R.sup.5, --NR.sup.4R.sup.5,
--CH.sub.2NR.sup.4R.sup.5, C.sub.1-3alkoxy, C.sub.3-7 cycloalkoxy,
--CH.sub.2C(O)OR.sup.3, --CH.sub.2C(O)NR.sup.4R.sup.5,
--NR.sup.3C(O)NR.sup.4R.sup.5, --NR.sup.3C(O)OR.sup.3,
C.sub.6-10aryloxy, C.sub.2-6heterocyclyl, C.sub.5-7heteroaryl,
C.sub.5-7heteroaryloxy and C.sub.2-6heterocycloxy.
[0253] In one embodiment, n is 0, 1 or 2. In a further embodiment,
n is 0 or 1. In a further embodiment, n is 0.
[0254] In one embodiment, R.sup.2 is halo and n is 1. In a further
embodiment, R.sup.2 is fluoro and n is 1.
Ring A' and its Substituents
[0255] In one embodiment, Ring A' contains at least one O or N
heteroatom. In a further embodiment, Ring A' contains one or two
heteroatoms, wherein the heteroatoms are independently O or N.
[0256] In one embodiment, Ring A' contains at least one O, S or N
heteroatom. In a further embodiment, Ring A' contains one or two
heteroatoms, wherein the heteroatoms are independently O, S, or
N.
[0257] In one embodiment, Ring A' is selected from the group
consisting of a morpholine ring, a piperidine ring, a pyrrolidine
ring, a tetrahydropyran ring, a tetrahydrofuran ring and a
1,4-dioxane ring.
[0258] In one embodiment, Ring A' is selected from the group
consisting of a morpholine ring, a piperidine ring, and a
1,4-dioxane ring.
[0259] In one embodiment, the structure represented by the
following formula:
##STR00025##
is selected from the group consisting of:
##STR00026##
wherein the hydrogen on each nitrogen may be optionally replaced
with R.sup.2a.
[0260] In a further embodiment, the structure represented by the
following formula:
##STR00027##
is selected from the group consisting of:
##STR00028##
wherein the hydrogen on each nitrogen may be optionally replaced
with R.sup.2a.
[0261] In one embodiment, the structure represented by the
following formula:
##STR00029##
is selected from the group consisting of:
##STR00030##
wherein the hydrogen on each nitrogen may be optionally replaced
with R.sup.2a.
[0262] In a further embodiment, the structure represented by the
following formula:
##STR00031##
is selected from the group consisting of:
##STR00032##
[0263] In one embodiment, R.sup.2a, for each occurrence, is
independently selected from the group consisting of oxo, hydroxy,
C.sub.1-6alkyl, C.sub.3-7cycloalkylC.sub.1-4alkyl,
C.sub.6-10arylC.sub.1-4alkyl, --C(O)OR.sup.3, --C(O)R.sup.3,
--C(O)NR.sup.4R.sup.5 and CH.sub.2C(O)OR.sup.3; wherein R.sup.2a
may, for each occurrence, be optionally substituted with one or
more substituents which are independently selected from halo,
hydroxy, C.sub.1-4alkyl, and C.sub.1-4alkoxy; or [0264] two
R.sup.2a on adjacent atoms taken together with the atoms to which
they are attached may form a fused C.sub.3-7cycloalkyl,
C.sub.6aryl, 3- to 7-membered heterocyclyl, or 5-membered
heteroaryl, wherein the fused cycloalkyl, aryl, heterocyclyl, and
heteroaryl may be optionally substituted with one or more
substituent independently selected from halo, hydroxy,
C.sub.1-4alkyl, and C.sub.1-4alkoxy; or [0265] two R.sup.2a on the
same carbon atom taken together may form a spiro 3- to 7-membered
heterocyclyl or a spiro C.sub.3-7cycloalkyl which may be optionally
substituted with one or more substituent independently selected
from halo, hydroxy, C.sub.1-4alkyl, and C.sub.1-4alkoxy.
[0266] In a further embodiment, R.sup.2a, for each occurrence, is
independently selected from the group consisting of oxo, halo,
hydroxy, cyano, nitro, C.sub.1-6alkyl, C.sub.3-7cycloalkyl,
C.sub.3-7cycloalkylC.sub.1-4alkyl, C.sub.6-10aryl,
C.sub.6-10arylC.sub.1-4alkyl, --C(O)OR.sup.3, --C(O)R.sup.3,
--C(O)NR.sup.4R.sup.5, --NR.sup.4R.sup.5,
--CH.sub.2NR.sup.4R.sup.5, C.sub.1-6alkoxy, C.sub.3-7 cycloalkoxy,
--S(O).sub.pR.sup.3, --S(O).sub.2NR.sup.4R.sup.5,
--OS(O).sub.2R.sup.3, --CH.sub.2C(O)OR.sup.3,
--CH.sub.2C(O)NR.sup.4R.sup.5, --NR.sup.3C(O)NR.sup.4R.sup.5,
--NR.sup.3C(O)OR.sup.3, C.sub.6-10aryloxy, C.sub.2-10heterocyclyl,
C.sub.2-10heterocyclylC.sub.1-4alkyl,
C.sub.1-10heteroarylC.sub.1-4alkyl, C.sub.1-10heteroaryl,
C.sub.1-10heteroaryloxy and C.sub.1-10heterocycloxy; wherein
R.sup.2a may, for each occurrence, be optionally substituted with
one or more substituents which are independently selected from
halo, hydroxy, cyano, nitro, C.sub.1-6alkyl, --S(O).sub.pR.sup.3,
--C(O)OR.sup.3, --C(O)R.sup.3, --C(O)NR.sup.4R.sup.5,
--NR.sup.4R.sup.5, --CH.sub.2NR.sup.4R.sup.5 and C.sub.1-6alkoxy;
or [0267] two R.sup.2a on adjacent atoms taken together with the
atoms to which they are attached may form a fused
C.sub.3-7cycloalkyl, C.sub.6aryl, 3- to 7-membered heterocyclyl, or
5-membered heteroaryl, wherein the fused cycloalkyl, aryl,
heterocyclyl, and heteroaryl may be optionally substituted with one
or more substituent independently selected from halo, hydroxy,
C.sub.1-4alkyl, and C.sub.1-4alkoxy; or [0268] two R.sup.2a on the
same carbon atom taken together may form a spiro 3- to 7-membered
heterocyclyl or a spiro C.sub.3-7cycloalkyl which may be optionally
substituted with one or more substituent independently selected
from halo, hydroxy, C.sub.1-4alkyl, and C.sub.1-4alkoxy.
[0269] In a further embodiment, R.sup.2a, for each occurrence, is
independently selected from the group consisting of hydroxy,
C.sub.1-6alkyl, C.sub.3-7cycloalkylC.sub.1-4alkyl; wherein R.sup.2a
may, for each occurrence, be optionally substituted with one or
more substituents which are independently selected from halo,
hydroxy, C.sub.1-4alkyl, and C.sub.1-4alkoxy; or [0270] two
R.sup.2a on the same carbon atom taken together may form a spiro
C.sub.3-7cycloalkyl which may be optionally substituted with one or
more substituent independently selected from halo, hydroxy,
C.sub.1-4alkyl, and C.sub.1-4alkoxy.
[0271] In a further embodiment, R.sup.2a, for each occurrence, is
independently selected from the group consisting of unsubstituted
hydroxy and unsubstituted C.sub.1-2alkyl.
[0272] In one embodiment, q is 0, 1 or 2. In a further embodiment,
q is 0 or 1. In a further embodiment, q is 0.
Groups R.sup.3, R.sup.4 and R.sup.5
[0273] In one embodiment, R.sup.3, for each occurrence, is
independently selected from hydrogen, C.sub.1-3 alkyl, C.sub.3-7
cycloalkyl, C.sub.3-7 cycloalkylC.sub.1-3alkyl, C.sub.6-10aryl,
C.sub.1-7heteroaryl, and C.sub.2-8heterocyclyl. In a further
embodiment, R.sup.3, for each occurrence, is independently selected
from hydrogen and C.sub.1-3 alkyl.
[0274] In one embodiment, R.sup.4 and R.sup.5, for each occurrence,
are independently selected from hydrogen, C.sub.1-6 alkyl,
C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkylC.sub.1-4alkyl,
C.sub.6-10arylC.sub.1-4alkyl, C.sub.6-10aryl, C.sub.1-10heteroaryl,
C.sub.1-10heteroarylC.sub.1-4alkyl, C.sub.2-10heterocyclyl, and
C.sub.2-10heterocyclylC.sub.1-4alkyl; or R.sup.4 and R.sup.5 taken
together along with the nitrogen to which they are bound may form a
monocyclic or a bicyclic heteroaryl (with 5 to 14 members and
having 1 to 8 heteroatoms selected from N, O and S) or heterocyclyl
(which is a 4 to 7 membered monocyclic ring or a 7 to 12 membered
bicyclic ring or a 10 to 15 membered tricyclic ring having at least
one heteroatom selected from N, O and S) which may be optionally
substituted with one or more halo or C.sub.1-4alkyl
substituent.
[0275] In a further embodiment, R.sup.4 and R.sup.5, for each
occurrence, are independently selected from hydrogen, C.sub.1-3
alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkylC.sub.1-3alkyl,
C.sub.6-10arylC.sub.1-4alkyl, C.sub.6-10aryl, C.sub.1-7heteroaryl,
C.sub.1-7heteroarylC.sub.1-3alkyl, C.sub.2-8heterocyclyl, and
C.sub.2-8heterocyclylC.sub.1-3alkyl; or R.sup.4 and R.sup.5 taken
together along with the nitrogen to which they are bound may form a
monocyclic or a bicyclic heteroaryl or heterocyclyl which may be
optionally substituted with one or more halo or C.sub.1-3alkyl. In
a further embodiment, R.sup.4 and R.sup.5, for each occurrence, are
independently selected from hydrogen and C.sub.1-3 alkyl.
Further Embodiments
[0276] In one embodiment, the moiety
##STR00033##
is selected from any one of structures i to xiv below.
##STR00034## ##STR00035##
[0277] In one embodiment, the moiety
##STR00036##
is selected from any one of structures (ii), (vii) and (xv)
below.
##STR00037##
[0278] In a further embodiment, the moiety
##STR00038##
is selected from any one of structures i, ii, vi, viii, ix and xi
to xiv above.
Specific Compounds
[0279] In another aspect of the invention, there is provided a
compound selected from compounds 1 to 72 below, or a
pharmaceutically acceptable salt thereof: [0280] 1.
(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-methyl-3,4-dihydro-2H
benzo[1,4]oxazin-7-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4-
,5-triol [0281] 2.
(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-ethyl-3,4-dihydro-2H-benzo[1,4]oxazin-7-
-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
[0282] 3.
(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-cyclopropyl-3,4-dihydro-2Hbenzo[1,4]oxa-
zin-7ylmethyl)-phenyl]-6-hydroxymethyltetrahydropyran3,4,5-triol
[0283] 4.
(2S,3R,4R,5S,6R)-2-[3-(4-Benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethy-
l)-4-chloro-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
[0284] 5.
(2S,3R,4R,5S,6R)-2-{4-Chloro-3-[4-(4-methoxy-benzyl)-3,4-dihydro-2H-benzo-
[1,4]oxazin-6-ylmethyl]-phenyl}-6-hydroxymethyltetrahydro-pyran-3,4,5-trio-
l [0285] 6.
(2S,3R,4R,5S,6R)-2-[3-(4-Benzyl-2,2-dimethyl-3,4-dihydro-2H-benzo[1,4]oxa-
zin-6-ylmethyl)-4-chloro-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-tr-
iol [0286] 7.
(2S,3R,4R,5S,6R)-2-[3-(4-benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethy-
l)-4-chloro-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
[0287] 8.
(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethy-
l)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol [0288] 9.
(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-ethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-
-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
[0289] 10.
(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-cyclopropylmethyl-3,4-dihydro-2H-benzo[-
1,4]oxazin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-trio-
l [0290] 11.
(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin--
6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
[0291] 12.
6-[2-Chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetr-
ahydro-pyran-2-yl)-benzyl]-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic
acid ethyl ester [0292] 13.
1-{6-[2-Chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetra-
hydro-pyran-2-yl)-benzyl]-2,3-dihydro-benzo[1,4]oxazin-4-yl}-ethanone
[0293] 14.
(2S,3R,4R,5S,6R)-2-{4-Chloro-3-[1-(4-methoxy-benzyl)-1,2,3,4-tetrahydro-q-
uinolin-6-ylmethyl]-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
[0294] 15.
(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(1,2,3,4-tetrahydro-quinolin-6-ylmethyl)-p-
henyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol [0295] 16.
(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(1,2,3,4-tetrahydro-quinolin-7-ylmethyl)-p-
henyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol [0296] 17.
(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(2,3-dihydro-1H-indol-5-ylmethyl)-phenyl]--
6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol [0297] 18.
(2S,3R,4R,5S,6R)-2-[3-(2-Benzyl-1,2,3,4-tetrahydro-isoquinolin-7-ylmethyl-
)-4-chloro-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
[0298] 19.
(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(1,2,3,4-tetrahydro-isoquinolin-7-ylmethyl-
)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol [0299] 20.
(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(2,2-dimethyl-3,4-dihydro-2H-benzo[1,4]oxa-
zin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
[0300] 21.
(2S,3R,4R,5S,6R)-2-(4-Chloro-3-chroman-6-ylmethyl-phenyl)-6-hydroxymethyl-
-tetrahydro-pyran-3,4,5-triol [0301] 22.
(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(2,3-dihydro-benzofuran-5-ylmethyl)-phenyl-
]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol [0302] 23.
(2R,3S,4R,5R,6S)-2-Hydroxymethyl-6-[4-methyl-3-(1,2,3,4-tetrahydro-quinol-
in-7-ylmethyl)-phenyl]-tetrahydro-pyran-3,4,5-triol [0303] 24.
(2S,3R,4R,5S,6R)-2-[3-(3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-fluo-
ro-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol [0304] 25.
(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-methoxy-
-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol [0305] 26.
(2R,3S,4R,5R,6S)-2-Hydroxymethyl-6-[4-methoxy-3-(1,2,3,4-tetrahydro-quino-
lin-6-ylmethyl)-phenyl]-tetrahydro-pyran-3,4,5-triol [0306] 27.
(2R,3S,4R,5R,6S)-2-Hydroxymethyl-6-[4-methoxy-3-(1,2,3,4-tetrahydro-quino-
lin-7-ylmethyl)-phenyl]-tetrahydro-pyran-3,4,5-triol [0307] 28.
(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(3,4-dihydro-2H-benzo[1,4]oxazin-7-ylmethy-
l)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol [0308] 29.
(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4,4-spiro-cyclopropyl-chroman-6-ylmethyl)-
-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol [0309] 30.
2S,3R,4R,5S,6R)-2-[5-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-2-ethoxy-p-
henyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol [0310] 31.
(2S,3R,4R,5S,6R)-2-[3-(3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-meth-
oxy-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol [0311] 32.
(2S,3R,4R,5S,6R)-2-(3-Chroman-6-ylmethyl-4-methoxy-phenyl)-6-hydroxymethy-
l-tetrahydro-pyran-3,4,5-triol [0312] 33.
(2S,3R,4R,5S,6R)-2-(3-Chroman-6-ylmethyl-4-trifluoromethoxy-phenyl)-6-hyd-
roxymethyl-tetrahydro-pyran-3,4,5-triol [0313] 34.
6-[2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahyd-
ro-pyran-2-yl)-benzyl]-chromen-4-one [0314] 35.
6-[2-Chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahyd-
ro-pyran-2-yl)-benzyl]-chroman-4-one [0315] 36.
(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-hydroxy-chroman-6-ylmethyl)-phenyl]-6-h-
ydroxymethyl-tetrahydro-pyran-3,4,5-triol [0316] 37.
(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(spiro[chromane-2,1'-cyclopentane]-6-ylmet-
hyl)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol [0317] 38.
(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(spiro[chromane-2,1'-cyclopentane]-6-ylmet-
hyl)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol [0318] 39.
6-[[2-Chloro-5-[(2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrah-
ydropyran-2-yl]phenyl]methyl]spiro[chromane-2,4'-piperidine]-4-one
[0319] 40.
6-(2-Methoxy-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6(benzyloxymet-
hyl)tetrahydro-2H-pyran-2-yl)benzyl)spiro[chroman-2,1'-cyclobutane
[0320] 41.
(2S,3R,4R,5S,6R)-2-[4-methoxy-3-(spiro[chromane-2,1'-cyclobutane]-6-y-
lmethyl)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol [0321]
42.
7-[2-Chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahyd-
ro-pyran-2-yl)-benzyl]-4H-benzo[1,4]oxazin-3-one [0322] 43.
7-[2-Methoxy-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahy-
dro-pyran-2-yl)-benzyl]-4H-benzo[1,4]oxazin-3-one [0323] 44.
(2S,3R,4R,5S,6R)-2-[4-chloro-3-(spiro[chromane-2,1'-cyclobutane]-6-ylmeth-
yl)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol [0324] 45.
[(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-chloro-3-[(2,2-dimethyl-3-oxo-4H--
1,4-benzoxazin-6-yl)methyl]phenyl]tetrahydropyran-2-yl]methyl
acetate [0325] 46.
6-[2-Chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahyd-
ro-pyran-2-yl)-benzyl]-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one
[0326] 47.
6-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahy-
dro-2H-pyran-2-yl)benzyl)-2H-benzo[b][1,4]oxazin-3(4H)-one [0327]
48.
(2S,3R,4R,5S,6R)-2-[3-[(4-benzylspiro[3H-1,4-benzoxazine-2,1'-cyclopropan-
e]-6-yl)methyl]-4-chloro-phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-tr-
iol [0328] 49.
(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(spiro[3,4-dihydro-1,4-benzoxazine-2,1'-cy-
clopropane]-6-ylmethyl)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-trio-
l [0329] 50. Acetic acid
(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-chloro-3-(2-cyano-3,4-dihydro-2H-b-
enzo[1,4]oxazin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylmethyl
ester [0330] 51.
6-[2-Chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahyd-
ro-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonitrile
[0331] 52.
6-[2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahyd-
ro-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid methyl ester [0332] 53.
6-[2-Chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahyd-
ro-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid [0333] 54.
6-[2-bromo-5-((3S,4R,5R,6R)-3,4,5-tris-benzyloxy-6-benzyloxymethyl-tetrah-
ydro-pyran-2-yl)-benzyl]-chroman [0334] 55.
6-[2-cyclopropyl-5-((3S,4R,5R,6R)-3,4,5-tris-benzyloxy-6-benzyloxymethyl--
tetrahydro-pyran-2-yl)-benzyl]-chroman [0335] 56.
(2S,3R,4R,5S,6R)-2-(3-Chroman-6-ylmethyl-4-cyclopropyl-phenyl)-6-hydroxym-
ethyl-tetrahydro-pyran-3,4,5-triol [0336] 57.
[(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-bromo-3-(2,3-dihydro-1,4-benzodio-
xin-6-ylmethyl)phenyl]tetrahydropyran-2-yl]methyl acetate [0337]
58.
[(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-bromo-3-(2,3-dihydro-1,4-benzodio-
xin-6-ylmethyl)phenyl]tetrahydropyran-2-yl]methyl acetate [0338]
59. Acetic acid
(2R,3R,4R,5S)-3,4,5-triacetoxy-6-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]-
dioxin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylmethyl ester [0339]
60.
(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 [0340]
61. 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 [0341] 62.
(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 [0342] 63.
4-Benzyl-6-[2-bromo-5-((2S,3S,4R,5R,6R)-3,4,5-tris-benzyloxy-6-benzyloxym-
ethyl-tetrahydro-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine
[0343] 64.
4-Benzyl-6-[2-cyclopropyl-5-((2S,3S,4R,5R,6R)-3,4,5-tris-benzyloxy-6-benz-
yloxymethyl-tetrahydro-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazin-
e [0344] 65.
(2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(3,4-dihydro-2H-benzo[1,4]oxazin-6-yl-
methyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol [0345]
66.
(2S,3R,4R,5S,6R)-2-[3-(3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-ethy-
l-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol [0346] 67.
(2S,3R,4R,5S,6R)-2-[2-(3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4'-met-
hyl-biphenyl-4-yl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
[0347] 68.
(2S,3R,4R,5S,6R)-2-[3-(4-Benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethy-
l)-4-isopropyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
[0348] 69.
(2S,3R,4R,5S,6R)-2-[3-(3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4--
isopropyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
[0349] 70.
(2S,3R,4R,5S,6R)-2-[3-(1-Benzyl-1,2,3,4-tetrahydro-quinolin-7-ylmethyl)-4-
-isopropyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
[0350] 71.
(2R,3S,4R,5R,6S)-2-Hydroxymethyl-6-[4-isopropyl-3-(1,2,3,4-tetrahydro-qui-
nolin-7-ylmethyl)-phenyl]-tetrahydro-pyran-3,4,5-triol [0351] 72.
(2R,3S,4R,5R,6S)-2-Hydroxymethyl-6-[4-isopropyl-3-(1,2,3,4-tetrahydro-qui-
nolin-6-ylmethyl)-phenyl]-tetrahydro-pyran-3,4,5-triol
[0352] In another aspect of the invention, there is provided a
compound selected from compounds 1 to 72 and compounds 73 to 126
below, or a pharmaceutically acceptable salt thereof: [0353] 73
(2S,3R,4R,5S,6R)-2-(3-Chroman-6-ylmethyl-4-methyl-phenyl)-6-hydroxymethyl-
-tetrahydro-pyran-3,4,5-triol [0354] 74
(2S,3R,4R,5S,6R)-2-(3-Chroman-6-ylmethyl-4-hydroxy-phenyl)-6-hydroxymethy-
l-tetrahydro-pyran-3,4,5-triol [0355] 75
(2S,3R,4R,5S,6R)-2-(3-Chroman-6-ylmethyl-4-ethoxy-phenyl)-6-hydroxymethyl-
-tetrahydro-pyran-3,4,5-triol [0356] 76
(2S,3R,4R,5S,6R)-2-(3-Chroman-6-ylmethyl-4-pyrazol-1-yl-phenyl)-6-hydroxy-
methyl-tetrahydro-pyran-3,4,5-triol [0357] 77
(2S,3R,4R,5S,6R)-2-(3-Chroman-6-ylmethyl-2-hydroxy-4-methyl-phenyl)-6-hyd-
roxymethyl-tetrahydro-pyran-3,4,5-triol [0358] 78
(2S,3R,4R,5S,6R)-2-[3-(3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-hydr-
oxy-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol [0359] 79
(2S,3R,4R,5S,6R)-2-[3-(3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-etho-
xy-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol [0360] 80
(2S,3R,4R,5S,6R)-2-[3-(3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-pyra-
zol-1-yl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
[0361] 81
2S,3R,4R,5S,6R)-2-[3-(3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-2-hydro-
xy-4-methyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
[0362] 82
(2S,3R,4R,5S,6R)-2-[3-(3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-2-hydr-
oxy-4-methyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
[0363] 83
(2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-[4-methyl-3-(spiro[chromane-4,1'--
cyclopropane]-6-ylmethyl)phenyl]tetrahydropyran-3,4,5-triol [0364]
84
(2S,3R,4R,5S,6R)-2-[4-ethoxy-3-(spiro[3,4-dihydro-1,4-benzoxazine-2,1'-cy-
clopentane]-6-ylmethyl)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-trio-
l [0365] 85
(2S,3R,4R,5S,6R)-2-[4-chloro-3-(spiro[3,4-dihydro-1,4-benzoxazine-2,1'-cy-
clopropane]-6-ylmethyl)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-trio-
l [0366] 86
(2R,3S,4R,5R,6S)-2-Hydroxymethyl-6-[4-methyl-3-(1-methyl-1,2,3,4-tetrahyd-
ro-quinolin-6-ylmethyl)-phenyl]-tetrahydro-pyran-3,4,5-triol [0367]
87
6-[2-Chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahyd-
ro-pyran-2-yl)-benzyl]-chroman-2-carboxylic acid amide [0368] 88
{6-[2-Chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahy-
dro-pyran-2-yl)-benzyl]-2,3-dihydro-benzo[1,4]oxazin-4-yl}-acetic
acid [0369] 89
(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(1-methyl-1,4-dihydro-chromeno[4-
,3-b]pyrrol-8-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-tri-
ol [0370] 90
(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(1,1a,2,7a-tetrahydro-7-oxa-cyclopropa[b]n-
aphthalen-4-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
[0371] 91
(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(8-fluoro-3,4-dihydro-2H-benzo[1-
,4]oxazin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
[0372] 92
(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(8-fluoro-2,3-dihydro-benzo[1,4]-
dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
[0373] 93
6-[2-Chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethy-
l-tetrahydro-pyran-2-yl)-benzyl]-1-methyl-3,4-dihydro-1H-quinolin-2-one
[0374] 94
(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(2-methyl-2,3-dihydro-1H-isoindo-
l-5-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
[0375] 95
(2S,3R,4R,5S,6R)-2-[4-chloro-3-(spiro[cyclopropane-1,4'-isochromane]-7-
'-ylmethyl)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol
[0376] 96
(2R,3S,4S,5R,6S)-2-methyl-6-[4-methyl-3-(spiro[chromane-4,1'-cyclopropane-
]-6-ylmethyl)phenyl]tetrahydropyran-3,4,5-triol [0377] 97
(2S,3R,4S,5S,6R)-2-[4-chloro-3-(spiro[chromane-2,3'-pyrrolidine]-6-ylmeth-
yl)phenyl]-6-methyl-tetrahydropyran-3,4,5-triol [0378] 98
(2S,3R,4S,5S,6R)-2-[4-chloro-3-(spiro[3,4-dihydro-1,4-benzoxazine-2,1'-cy-
clopentane]-6-ylmethyl)phenyl]-6-methyl-tetrahydropyran-3,4,5-triol
[0379] 99
(2S,3R,4R,5S,6S)-2-[4-chloro-3-(spiro[3,4-dihydro-1,4-benzoxazine-2,1'-
-cyclopentane]-6-ylmethyl)phenyl]-6-(fluoromethyl)tetrahydropyran-3,4,5-tr-
iol [0380] 100
(2S,3R,4R,5S,6R)-2-[4-chloro-3-(spiro[3,4-dihydro-1,4-benzoxazine-2,1'-cy-
clopropane]-6-ylmethyl)phenyl]-6-(1-hydroxyethyl)tetrahydropyran-3,4,5-tri-
ol [0381] 101
(2S,3R,4S,5S,6R)-2-[4-chloro-3-(2,4-dihydrochromeno[4,3-c]pyrazol-8-ylmet-
hyl)phenyl]-6-ethyl-tetrahydropyran-3,4,5-triol [0382] 102
(2S,3R,4S,5S,6R)-2-[4-chloro-3-(1H-phenoxazin-2-ylmethyl)phenyl]-6-methyl-
-tetra hydropyran-3,4,5-triol [0383] 103
(2S,3R,4R,5S,6R)-2-[3-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-isopropy-
l-phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol [0384] 104
(2S,3R,4R,5S,6R)-2-[3-(chroman-6-ylmethyl)-4-cyclobutyl-phenyl]-6-(hydrox-
ymethyl)tetrahydropyran-3,4,5-triol [0385] 105
(2S,3R,4R,5S,6R)-2-[4-ethyl-3-(1,2,3,4-tetrahydroquinolin-7-ylmethyl)phen-
yl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol [0386] 106
(2S,3R,4R,5S,6R)-2-[4-cyclopropyl-3-(1,2,3,4-tetrahydroquinolin-7-ylmethy-
l)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol [0387] 107
(2S,3R,4R,5S,6R)-2-[3-(3,4-dihydro-2H-1,4-benzothiazin-6-ylmethyl)-4-meth-
oxy-phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol [0388] 108
(2S,3R,4R,5S,6R)-2-[4-chloro-3-(3,4-dihydro-2H-1,4-benzothiazin-6-ylmethy-
l)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol [0389] 109
(2S,3R,4R,5S,6R)-2-[3-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-ethynyl--
phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol [0390] 110
(2S,3R,4R,5S,6R)-2-[4-ethyl-3-(1,2,3,4-tetrahydroquinolin-6-ylmethyl)phen-
yl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol [0391] 111
(2S,3R,4R,5S,6R)-2-[4-ethyl-3-(1,2,3,4-tetrahydroquinolin-6-ylmethyl)phen-
yl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol [0392] 112
(2S,3R,4R,5S,6R)-2-[3-(3,4-dihydro-2H-1,4-benzothiazin-6-ylmethyl)-4-meth-
oxy-phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol [0393] 113
(2S,3R,4R,5S,6R)-2-[4-chloro-3-(3,4-dihydro-2H-1,4-benzothiazin-6-ylmethy-
l)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol [0394] 114
(2S,3R,4R,5S,6R)-2-[3-(chroman-6-ylmethyl)-4-methylsulfanyl-phenyl]-6-(hy-
droxymethyl)tetrahydropyran-3,4,5-triol [0395] 115
(2S,3R,4R,5S,6R)-2-[3-(chroman-6-ylmethyl)-4-methylsulfonyl-phenyl]-6-(hy-
droxymethyl)tetrahydropyran-3,4,5-triol [0396] 116
(2S,3R,4R,5S,6R)-2-[4-cyclopropyl-3-(1,2,3,4-tetrahydroquinolin-6-ylmethy-
l)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol [0397] 117
(2S,3R,4R,5S,6R)-2-[3-(3,4-dihydro-2H-1,4-benzoxazin-6-ylmethyl)-4-dimeth-
ylamino-phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol [0398]
118
(2S,3R,4R,5S,6R)-2-[4-amino-3-(3,4-dihydro-2H-1,4-benzoxazin-6-ylmethyl)p-
henyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol [0399] 119
(2S,3R,4R,5S,6R)-2-[3-(3,4-dihydro-2H-1,4-benzothiazin-6-ylmethyl)-4-meth-
oxy-phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol [0400] 120
(2S,3R,4R,5S,6R)-2-[3-[(1,1-dioxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-y-
l)methyl]-4-methoxy-phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol
[0401] 121
3-chloro-2-(3,4-dihydro-2H-1,4-benzoxazin-6-ylmethyl)-6-[(2S,3R,4R,5S,6R)-
-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]benzamide
[0402] 122
2-(2,3-dihydro-1,4-benzodioxin-7-ylmethyl)-4-[(2S,3R,4R,5S,6R)-3,4,5--
trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]benzonitrile
[0403] 123
(2S,3R,4R,5S,6R)-2-[3-(2,3-dihydro-1,4-benzodioxin-7-ylmethyl)-4-ethynyl--
phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol [0404] 124
(2S,3R,4R,5S,6R)-2-[3-(3,4-dihydro-2H-1,4-benzoxazin-6-ylmethyl)-4-phenox-
y-phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol [0405] 125
(2S,3R,4R,5S,6R)-2-[3-(3,4-dihydro-2H-1,4-benzoxazin-6-ylmethyl)-4-oxazol-
-4-yloxy-phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol
[0406] 126 (1R,2R,3S,4S,6R)-4-[3-(9a,
10-dihydro-5aH-phenothiazin-3-ylmethyl)-4-chloro-phenyl]-6-(hydroxymethyl-
)cyclohexane-1,2,3-triol [0407] or a pharmaceutically acceptable
salt thereof.
[0408] Preferably, the compound is compound 40, 39, 30, 16, 14, 1,
7, 15, 13, 27, 20, 8, 10, 21 or 19, or a pharmaceutically
acceptable salt thereof.
[0409] More preferably, the compound is example 8, or a
pharmaceutically acceptable salt thereof.
[0410] More preferably, the compound is example 60, or a
pharmaceutically acceptable salt thereof.
[0411] More preferably, the compound is example 62, or a
pharmaceutically acceptable salt thereof.
[0412] More preferably, the compound is example 71, or a
pharmaceutically acceptable salt thereof.
Compounds of Formula (I), (I-a), (I-i), (I-ia), (I-ii), (I-iia),
(I-iii), (I-iiia), (I-iv), (I-iva), and (V) and Derivatives
Thereof
[0413] As used herein, the terms "compound of the invention" and
"compound of Formula (I)" etc. include pharmaceutically acceptable
derivatives thereof and polymorphs, isomers and isotopically
labelled variants thereof. Furthermore, the term "compounds of the
invention" and "compound of Formula (I)" etc. include compounds of
formulae (I), (I-a), (I-i), (I-ia), (I-ii), (I-iia), (I-iii),
(I-iiia), (I-iv), (I-iva), and (V), and the embodiments thereof
disclosed herein.
Pharmaceutically Acceptable Derivatives
[0414] The term "pharmaceutically acceptable derivative" includes
any pharmaceutically acceptable salt, solvate, or hydrate of a
compound of Formula (I).
Pharmaceutically Acceptable Salts
[0415] The term "pharmaceutically acceptable salt" includes a salt
prepared from pharmaceutically acceptable non-toxic acids or bases
including inorganic or organic acids and bases.
[0416] Compounds of Formula (I) which contain basic, e.g. amino,
groups are capable of forming pharmaceutically acceptable salts
with acids. In one embodiment, pharmaceutically acceptable acid
addition salts of the compounds of Formula (I) include, but are not
limited to, those of inorganic acids such as hydrohalic acids (e.g.
hydrochloric, hydrobromic and hydroiodic acid), sulfuric acid,
nitric acid, and phosphoric acids. In one embodiment,
pharmaceutically acceptable acid addition salts of the compounds of
Formula (I) include, but are not limited to, those of organic acids
such as aliphatic, aromatic, carboxylic and sulfonic classes of
organic acids, examples of which include: aliphatic monocarboxylic
acids such as formic acid, acetic acid, propionic acid or butyric
acid; aliphatic hydroxy acids such as lactic acid, citric acid,
tartaric acid or malic acid; dicarboxylic acids such as maleic acid
or succinic acid; aromatic carboxylic acids such as benzoic acid,
p-chlorobenzoic acid, phenylacetic acid, diphenylacetic acid or
triphenylacetic acid; aromatic hydroxyl acids such as
o-hydroxybenzoic acid, p-hydroxybenzoic acid,
1-hydroxynaphthalene-2-carboxylic acid or
3-hydroxynaphthalene-2-carboxylic acid; and sulfonic acids such as
methanesulfonic acid, ethanesulfonic acid or benzenesulfonic acid.
Other pharmaceutically acceptable acid addition salts of the
compounds of Formula (I) include, but are not limited to, those of
glycolic acid, glucuronic acid, furoic acid, glutamic acid,
anthranilic acid, salicylic acid, mandelic acid, embonic (pamoic)
acid, pantothenic acid, stearic acid, sulfanilic acid, algenic
acid, and galacturonic acid.
[0417] Compounds of Formula (I) which contain acidic, e.g.
carboxyl, groups are capable of forming pharmaceutically acceptable
salts with bases. In one embodiment, pharmaceutically acceptable
basic salts of the compounds of Formula (I) include, but are not
limited to, metal salts such as alkali metal or alkaline earth
metal salts (e.g. sodium, potassium, magnesium or calcium salts)
and zinc or aluminium salts. In one embodiment, pharmaceutically
acceptable basic salts of the compounds of Formula (I) include, but
are not limited to, salts formed with ammonia or pharmaceutically
acceptable organic amines or heterocyclic bases such as
ethanolamines (e.g. diethanolamine), benzylamines,
N-methyl-glucamine, amino acids (e.g. lysine) or pyridine.
[0418] Hemisalts of acids and bases may also be formed, e.g.
hemisulphate salts.
[0419] Pharmaceutically acceptable salts of compounds of Formula
(I) may be prepared by methods well-known in the art.
[0420] For a review of pharmaceutically acceptable salts, see Stahl
and Wermuth, Handbook of Pharmaceutical Salts: Properties,
Selection and Use (Wiley-VCH, Weinheim, Germany, 2002).
Solvates & hydrates
[0421] The compounds of the invention may exist in both unsolvated
and solvated forms. The term "solvate" includes molecular complexes
comprising a compound of the invention and one or more
pharmaceutically acceptable solvent molecules such as water or
C.sub.1-6 alcohols, e.g. ethanol. The term "hydrate" means a
"solvate" where the solvent is water. Thus, the compounds of the
present invention may exist as a hydrate, including a monohydrate,
dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and
the like, as well as the corresponding solvated forms. The compound
of the invention may be true solvates, while in other cases, the
compound of the invention may merely retain adventitious water or
be a mixture of water plus some adventitious solvent.
Amorphous & Crystalline Forms
[0422] The compounds of the invention may exist in solid states
from amorphous through to crystalline forms. All such solid forms
are included within the invention.
[0423] Co-Crystalline Forms
[0424] The compounds of the invention may exist as co-crystals. All
such co-crystalline forms are included within the invention. In one
embodiment, the compounds of the invention exist as co-crystals
with L-proline.
[0425] For the avoidance of doubt, the terms "L-proline co-crystal
of a compound of the invention", such as an L-proline co-crystal of
(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethy-
l)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol, an
L-proline co-crystal 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, an
L-proline co-crystal 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, or an
L-proline co-crystal of
(2R,3S,4R,5R,6S)-2-Hydroxymethyl-6-[4-isopropyl-3-(1,2,3,4-tetrahydro-qui-
nolin-7-ylmethyl)-phenyl]-tetrahydro-pyran-3,4,5-triol, refers to
all forms of association between L-proline and a compound of the
invention, including salt forms. In particular, these terms
encompass: (i) a non-ionic association between L-proline and a
compound of the invention (i.e. where no proton transfer has
occurred between L-proline and a compound of the invention); or
(ii) an ionic interaction where proton transfer between L-proline
and a compound of the invention has occurred to form an L-proline
salt of the compound of the invention, or (iii) mixtures of (i) and
(ii) above.
[0426] In a particular embodiment of the invention, the L-proline
co-crystal comprises is a non-ionic association between a compound
of the invention and L-proline (i.e. where no proton transfer has
occurred between L-proline and the compound of the invention).
[0427] In an alternative embodiment of the invention, the L-proline
co-crystal is an L-proline salt of the compound of the
invention.
[0428] In one embodiment, the invention provides a crystalline form
of L-proline co-crystal of
(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethy-
l)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol. In one
aspect, the crystalline form is non-ionic.
[0429] In another aspect, the crystalline form has differential
scanning calorimetry endotherms at about 64.degree. C., about
104.degree. C. and/or about 157.degree. C. In another aspect, the
crystalline form has a molar ratio of L-proline to
(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethy-
l)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol of 1:1. In
another aspect, the crystalline form has powder X-ray diffraction
peak(s) at about 19.3, about 23.2, about 17.0, and/or about 5.7
degrees 2.theta.. In one aspect, the crystalline form has powder
X-ray diffractions peaks substantially the same as those listed in
Table 1A.
[0430] In one embodiment, the invention provides a crystalline form
of L-proline co-crystal 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. In one
aspect, the crystalline form is non-ionic. In another aspect, the
crystalline form has differential scanning calorimetry endotherms
at about 151.degree. C. In another aspect, the crystalline form has
a molar ratio of L-proline to
(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 of 1:1.
In another aspect, the crystalline form has powder X-ray
diffraction peak(s) at about 16.7, about 19.9, about 17.6, and/or
about 21.9 degrees 2.theta.. In one aspect, the crystalline form
has powder X-ray diffractions peaks substantially the same as those
listed in Table 2A.
[0431] In one embodiment, the invention provides a crystalline form
of L-proline co-crystal 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. In one aspect,
the crystalline form is non-ionic. In another aspect, the
crystalline form has differential scanning calorimetry endotherms
at about 136.degree. C. In another aspect, the crystalline form has
a molar ratio of L-proline to
(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 of 1:1. In
another aspect, the crystalline form has powder X-ray diffraction
peak(s) at about 17.3, about 20.4, about 18.0, about 18.9, and/or
about 23.8 degrees 2.theta.. In one aspect, the crystalline form
has powder X-ray diffractions peaks substantially the same as those
listed in Table 3A. In another aspect, the crystalline form has a
powder X-ray diffraction spectrum substantially the same as the
spectrum shown in FIG. 2. In another aspect, the crystalline form
has a molar ratio of L-proline to
(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 of 2:1. In
another aspect, the crystalline form has differential scanning
calorimetry endotherms at about 176.degree. C.
[0432] In one embodiment, the invention provides a crystalline form
of L-proline co-crystal of
(2R,3S,4R,5R,6S)-2-Hydroxymethyl-6-[4-isopropyl-3-(1,2,3,4-tetrahydro-qui-
nolin-7-ylmethyl)-phenyl]-tetrahydro-pyran-3,4,5-triol. In one
aspect, the crystalline form is non-ionic. In another aspect, the
crystalline form has differential scanning calorimetry endotherms
at about 156.degree. C. and/or about 158.degree. C. In another
aspect, the crystalline form has a molar ratio of L-proline to
(2R,3S,4R,5R,6S)-2-Hydroxymethyl-6-[4-isopropyl-3-(1,2,3,4-tetrahydro-qui-
nolin-7-ylmethyl)-phenyl]-tetrahydro-pyran-3,4,5-triol of 1:1. In
one aspect, the crystalline form has powder X-ray diffractions
peaks substantially the same as those listed in Table 4.
[0433] In one embodiment, the invention provides a crystalline form
of L-proline co-crystal 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. In one aspect,
the crystalline form has a molar ratio of L-proline to
(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 of 2:1. In
another aspect, the crystalline form is non-ionic. In another
aspect, the crystalline form has a differential scanning
calorimetry endotherm at about 176.degree. C. In another aspect,
the crystalline form has powder X-ray diffraction peak(s) at about
6.1, 9.1, 12.8, 15.2, 16.5, 17.8, 18.9, 20.9, and/or 28.4. In
another aspect, the crystalline form has powder X-ray diffraction
pattern which is substantially the same as the powder X-ray
diffraction pattern shown in FIG. 4.
[0434] In the preceding paragraphs defining the molar ratio for a
crystalline forms of L-proline and a compound of the invention, the
phrase "a molar ratio of about 1:1" is used to indicate that the
crystalline form has between 0.9-1.1 moles of a compound of the
invention to 1 mole of L-proline. Likewise, the phrase "a molar
ratio of about 1:2" is used to indicate that the crystalline form
has between 0.9-1.1 moles of a compound of the invention to 2 moles
of L-proline.
[0435] When it is stated herein that the present invention relates
to a crystalline form of an L-proline co-crystal of a compound of
the invention such as,
(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethy-
l)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol,
(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,
(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, or
(2R,3S,4R,5R,6S)-2-Hydroxymethyl-6-[4-isopropyl-3-(1,2,3,4-tetrahydro-qui-
nolin-7-ylmethyl)-phenyl]-tetrahydro-pyran-3,4,5-triol, the degree
of crystallinity as determined by X-ray powder diffraction data is
conveniently greater than about 60%, more conveniently greater than
about 80%, preferably greater than about 90%.
[0436] In the preceding paragraphs defining the X-ray powder
diffraction peaks for a crystalline forms of L-proline and a
compound of the invention, the term "at about" is used to indicate
that the precise position of peaks (i.e. the recited 2-theta angle
values) should not be construed as being absolute values because,
as will be appreciated by those skilled in the art, the precise
position of the peaks may vary slightly between one machine and
another, from one sample to another, or as a result of slight
variations in measurement conditions utilized. It is also stated in
the preceding paragraphs that a crystalline form of a 1:1 L-proline
co-crystal of
(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethy-
l)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol, a 1:1
L-proline co-crystal 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, a 1:1
L-proline co-crystal 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, a 1:1
L-proline co-crystal of
(2R,3S,4R,5R,6S)-2-Hydroxymethyl-6-[4-isopropyl-3-(1,2,3,4-tetrahydro-qui-
nolin-7-ylmethyl)-phenyl]-tetrahydro-pyran-3,4,5-triol, and a 2:1
L-proline co-crystal 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 have powder
X-ray diffraction patterns that have substantially the same most
prominent peaks (2-theta angle values) shown in Tables 1A, 2A, 3A,
4, and 5, respectively; and that an L-proline co-crystal 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 which has about
a 1:1 molar ratio has substantially the same powder X-ray
diffraction spectrum as shown in FIG. 2 and that an L-proline
co-crystal 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 which has about
a 2:1 molar ratio has substantially the same powder X-ray
diffraction spectrum as shown in FIG. 4. It shall be appreciated
that the use of the term `substantially` in this context is also
intended to indicate that the 2-theta angle values of the powder
X-ray diffraction patterns may vary slightly from one machine to
another, from one sample to another, or as a result of slight
variations in measurement conditions utilized, so the peak
positions shown in the Table or in the specta are again not to be
construed as absolute values.
[0437] In this regard, it is known in the art that a powder X-ray
diffraction pattern may be obtained which has one or more
measurement errors depending on measurement conditions (such as
equipment, sample preparation or machine used). In particular, it
is generally known that intensities in an X-ray powder diffraction
pattern may fluctuate depending on measurement conditions and
sample preparation. For example, persons skilled in the art of
powder X-ray diffraction will realize that the relative intensity
of peaks can be affected by, for example, grains above 30 microns
in size and non-unitary aspect ratios, which may affect analysis of
samples. The skilled person will also realize that the position of
reflections can be affected by the precise height at which the
sample sits in the diffractometer and the zero calibration of the
diffractometer. The surface planarity of the sample may also have a
small effect. Hence a person skilled in the art will appreciate
that the diffraction pattern data presented herein is not to be
construed as absolute (for further information see Jenkins, R &
Snyder, R. L. `Introduction to X-Ray Powder Diffractometry` John
Wiley & Sons, 1996). Therefore, it shall be understood that the
crystalline form of the 1:1 L-proline co-crystal of
(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethy-
l)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol, the 1:1
L-proline co-crystal 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, the 1:1
L-proline co-crystal 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, the 1:1
L-proline co-crystal of
(2R,3S,4R,5R,6S)-2-Hydroxymethyl-6-[4-isopropyl-3-(1,2,3,4-tetrahydro-qui-
nolin-7-ylmethyl)-phenyl]-tetrahydro-pyran-3,4,5-triol, and the 2:1
L-proline co-crystal 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 of the present
invention is not limited to the crystals that provide powder X-ray
diffraction patterns having identical peaks as shown in Tables 1A,
2A, 3A, 4, and 5, respectively, and any crystals providing X-ray
powder diffraction patterns substantially the same as that shown in
Table 1A, 2A, 3A, 4, and 5, respectively, fall within the scope of
the present invention. Likewise, it shall be understood that the
crystalline form of an L-proline co-crystal 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 of the present
invention is not limited to the crystals that provide powder X-ray
diffraction spectra having identical peaks as shown in FIG. 2 or 4,
respectively, and any crystals providing X-ray powder diffraction
spectra substantially the same as that shown in FIG. 2 or 4, fall
within the scope of the present invention. A person skilled in the
art of powder X-ray diffraction is able to judge the substantial
identity of powder X-ray diffraction spectra.
[0438] Generally, a measurement error of a diffraction angle in a
powder X-ray diffractogram is about 2.theta.=0.5 degrees or less
(or, more suitably, about 2.theta.=0.2 degrees or less) and such
degree of a measurement error should be taken into account when
interpreting the peak positions referred to the text above and in
Tables 1, 1A, 2, 2A, 3, 3A, 4, and 4A and in the spectra shown in
FIGS. 2 and 4. Therefore, where it is stated, for example, that the
co-crystal has an X-ray powder diffraction pattern with a peak at
about 2.theta.=17.3 degree (or any one of the other angles
mentioned above) then this can be interpreted as being
2.theta.=17.3 degree plus or minus 0.5 degree, or 2.theta.=17.3
degree plus or minus 0.2 degree.
Isomeric Forms
[0439] 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).
[0440] Accordingly, the invention provides: [0441] stereoisomeric
mixtures of compounds of Formula (I); [0442] a diastereomerically
enriched or diastereomerically pure isomer of a compound of Formula
(I); or [0443] an enantiomerically enriched or enantiomerically
pure isomer of a compound of Formula (I).
[0444] 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).
[0445] 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.
[0446] 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.
Isotopic Labeling
[0447] The invention includes pharmaceutically acceptable
isotopically-labelled compounds of Formula (I) wherein one or more
atoms are replaced by atoms having the same atomic number, but an
atomic mass or mass number different from the atomic mass or mass
number usually found in nature.
[0448] Examples of isotopes suitable for inclusion in the compounds
of the invention include isotopes of hydrogen, such as .sup.2H and
.sup.3H, carbon, such as .sup.11C, .sup.13C and .sup.14C, chlorine,
such as .sup.36Cl, fluorine, such as .sup.18F, iodine, such as
.sup.123I and .sup.125I, nitrogen, such as .sup.13N and .sup.15N,
oxygen, such as .sup.15O, .sup.17O and .sup.18O, phosphorus, such
as .sup.32P, and sulphur, such as .sup.35S. Certain
isotopically-labelled compounds of Formula (I), for example, those
incorporating a radioactive isotope, are useful in drug and/or
substrate tissue distribution studies. The radioactive isotopes
.sup.3H and .sup.14C are particularly useful for this purpose in
view of their ease of incorporation and ready means of
detection.
[0449] Substitution 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.
[0450] Isotopically-labelled 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-labelled reagent in place of the
non-labelled reagent previously employed.
Therapeutic Definitions
[0451] As used herein, "treatment" includes curative and
prophylactic treatment. As used herein, a "patient" means an
animal, preferably a mammal, preferably a human, in need of
treatment.
[0452] 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 and
a prophylactically effective amount where the compound or
derivative is used for the prevention of a disease or
condition.
[0453] The term "therapeutically effective amount" used herein
refers to the amount of compound needed to treat or ameliorate a
targeted disease or condition. The term "prophylactically effective
amount" used herein refers to the amount of compound needed to
prevent a targeted disease or condition. 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.
[0454] 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".
Treatment of Diseases and Conditions
[0455] 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.
[0456] The invention provides a compound of Formula (I) for use in
therapy. The invention further provides a pharmaceutical
composition comprising a compound of Formula (I) in combination
with a pharmaceutically acceptable excipient.
[0457] 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) to a
patient. The invention also provides the use of a compound of
Formula (I) 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) for use in treating a disease or condition mediated by the
sodium D-glucose co-transporter.
[0458] 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.
[0459] The present invention also provides a method of treating
diabetes comprising administering a compound of Formula (I) to a
subject in need thereof.
[0460] 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 claim 1.
[0461] 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 SGLT-1.
Diseases and Conditions Mediated by the Sodium D-Glucose
Co-Transporter
[0462] 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.
[0463] Compounds of formula (I) 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.
[0464] 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.
[0465] As used herein a patient is suffering from "obesity" if the
patient exhibits at least one of: [0466] 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; [0467] an absolute waist
circumference of >102 cm in men or >88 cm in women; [0468] a
waist-to-hip ratio >0.9 in men or >0.85 in women; or [0469] a
percent body fat >25% in men or >30% in women.
[0470] 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: [0471] a fasting plasma glucose >7.0
mmol/I (126 mg/dl); or [0472] a venous plasma glucose >11.1
mmol/I (200 mg/dl) 2 hours after ingestion of 75 g oral glucose
load.
[0473] 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:
[0474] a fasting plasma glucose <7.0 mmol/I (126 mg/dl); and
[0475] a venous plasma glucose >7.8 and <11.1 mmol/I (200
mg/dl) 2 hours after ingestion of 75 g oral glucose load.
Administration & Formulation
General
[0476] 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.
[0477] 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.
[0478] The present invention provides a pharmaceutical composition
comprising a compound according to Formula (I) and a
pharmaceutically acceptable excipient.
[0479] Typical pharmaceutically acceptable excipients include:
[0480] diluents, e.g. lactose, dextrose, sucrose, mannitol,
sorbitol, cellulose and/or glycine; [0481] lubricants, e.g. silica,
talcum, stearic acid, its magnesium or calcium salt and/or
polyethyleneglycol; [0482] binders, e.g. magnesium aluminum
silicate, starch paste, gelatin, tragacanth, methylcellulose,
sodium carboxymethylcellulose and/or polyvinylpyrrolidone; [0483]
disintegrants, e.g. starches, agar, alginic acid or its sodium
salt, or effervescent mixtures; and/or [0484] absorbants,
colorants, flavors and/or sweeteners.
[0485] A thorough discussion of pharmaceutically acceptable
excipients is available in Gennaro, Remington: The Science and
Practice of Pharmacy 2000, 20th edition (ISBN: 0683306472).
[0486] Accordingly, in one embodiment, the present invention
provides a pharmaceutical composition comprising a compound of
Formula (I) and a pharmaceutically acceptable excipient.
Oral Administration
[0487] 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.
[0488] 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.
[0489] 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.
[0490] 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.
[0491] 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.
[0492] 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.
[0493] The formulation of tablets is discussed in H. Lieberman and
L. Lachman, Pharmaceutical Dosage Forms: Tablets 1980, vol. 1
(Marcel Dekker, New York).
Parenteral Administration
[0494] The compounds of the invention can be administered
parenterally.
[0495] 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.
[0496] 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).
[0497] 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.
[0498] 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.
[0499] 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.
Inhalation & Intranasal Administration
[0500] 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.
[0501] 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.
[0502] 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.
[0503] 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.
[0504] 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.
Transdermal Administration
[0505] 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.
Combination Therapy
[0506] A compound of formula (I) of the present invention 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.
[0507] 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.
[0508] 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.
[0509] A combination with uric acid synthesis inhibitors or
uricosurics is suitable for the treatment or prevention of
gout.
[0510] 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.
[0511] Such combinations may offer significant advantages,
including synergistic activity, in therapy.
[0512] The present invention thus provides: [0513] The use of an
agent selected from the group consisting of insulin, insulin
derivative or mimetic; insulin secretagogue; insulinotropic
sulfonylurea receptor ligand;
[0514] 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); [0515] The
use of a compound according to Formula (I) 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 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,
and [0516] The use of a compound according to claim 1 in
combination with 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 treating a disease or condition in a subject
mediated by the sodium D-glucose co-transporter, [0517] Wherein the
diseases or conditions may be as described herein.
[0518] 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 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; or aspirin.
In another embodiment, the invention provides a product comprising
a compound of Formula (I) and 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
for simultaneous, separate or sequential use in therapy.
Chemical Definitions
[0519] 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.
[0520] "Alkylene" refers to a straight or branched divalent
hydrocarbon chain consisting solely of carbon and hydrogen atoms,
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.
[0521] "Halogen" or "halo" may be fluoro, chloro, bromo or
iodo.
[0522] The term "alkenyl" refers to a monovalent hydrocarbon having
at least one carbon-carbon double bond. The term
"C.sub.2-C.sub.6alkenyl" refers to a monovalent hydrocarbon having
two to six carbon atoms and comprising at least one carbon-carbon
double bond.
[0523] The term "alkynyl" refers to a monovalent hydrocarbon having
at least one carbon-carbon triple bond. The term
"C.sub.2-C.sub.6-alkynyl" refers to a monovalent hydrocarbon having
two to six carbon atoms and comprising at least one carbon-carbon
triple bond.
[0524] 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.
[0525] Alkyl, alkenyl, alkynyl, and alkoxy groups, containing the
requisite number of carbon atoms, can be unbranched or branched.
The requisite number of carbon may be represented as C.sub.1-6,
C.sub.1-4, etc.
[0526] The term "aryl" refers to monocyclic or bicyclic aromatic
hydrocarbon groups having 6-carbon atoms in the ring portion.
Non-limiting examples include phenyl and naphthyl.
[0527] The term "aryl" also refers to a group in which a aryl ring
is fused to one or more cycloalkyl or heterocyclyl rings, where the
radical or point of attachment is on the aryl ring. Nonlimiting
examples include 2,3-dihydro-1H-indene, 1,2,3,4-tetrahydronaphthyl
and 3,4-dihydro-2H-benzo[b][1,4]oxazinyl.
[0528] The term "arylalkyl" refers to an aryl group which is linked
to another moiety via an alkyl 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.
[0529] The term "aryloxy" refers to an aryl group which is linked
to another moiety through an oxygen atom, such as phenoxy.
[0530] 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 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]dioxolane, 1,4-dioxane, 1,4-dithiane,
piperazinyl, 1,3-dioxolane, imidazolidinyl, imidazolinyl,
pyrrolidine, dihydropyran, oxathiolane, dithiolane, 1,3-dioxane,
1,3-dithianyl, oxathianyl, thiomorpholinyl, oxiranyl, aziridinyl,
oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl,
tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, azepinyl,
oxapinyl, oxazepinyl and diazepinyl.
[0531] As used herein, the term "cycloalkyl" 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.
Exemplary tricyclic hydrocarbon groups include adamantyl.
[0532] The term "heterocycloxy" refers to a heterocyclyl which is
linked to another moiety through an oxygen atom, e.g.
piperazin-2-yloxy.
[0533] 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.
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, quinolyl, isoquinolyl indazolyl, indolinyl,
isoindolyl, indolizinyl, benzamidazolyl, and quinolinyl.
[0534] The term "heteroaryl" also refers to a group in which a
heteroaromatic ring is fused to one or more cycloalkyl, or
heterocyclyl rings, where the radical or point of attachment is on
the heteroaromatic ring. Nonlimiting examples include
5,6,7,8-tetrahydroquinoline and
6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidine.
[0535] A heteroaryl group may be mono-, bi-, tri-, or polycyclic,
preferably mono-, bi-, or tricyclic, more preferably mono- or
bicyclic.
[0536] The term "heteroarylalkyl" refers to an heteroaryl group
which is linked to another moiety via an alkyl 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.
[0537] The term "heteroaryloxy" refers to a heteroaryl group which
is linked to another moiety through an oxygen atom, such as
pyridin-3-lyoxy.
[0538] "Heteroaryl" and "heterocyclyl" is also intended to include
oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of tertiary
ring nitrogen.
[0539] 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.
[0540] An "amino" group as used herein refers to --NH.sub.2. The
term "N-(alkyl)amino" refers to an amino group in which one
hydrogen is replaced by an alkyl group. For example,
N--(C.sub.1-6alkyl)amino refers to an amino group in which one of
the hydrogens has been replaced with an alkyl group having from 1
to 6 carbon atoms. The term "N,N-di-(alkyl)amino" refers to an
amino group in which both hydrogens have been replaced by an alkyl
group which may be the same or different. For example,
N,N-di-(C.sub.1-6alkyl)amino refers to an amino group in which both
of the hydrogens have been replaced with an alkyl group which may
be the same or different having from 1 to 6 carbon atoms.
[0541] A "carbamoyl" group as used herein refers to --C(O)NH.sub.2.
The term "N-(alkyl)-carbamoyl" refers to a carbamoyl group in which
one hydrogen is replaced by an alkyl group. For example,
N--(C.sub.1-6alkyl)-carbamoyl refers to a carbamoyl group in which
one of the hydrogens has been replaced with an alkyl group having
from 1 to 6 carbon atoms. The term "N,N-di-(alkyl)-carbamoyl"
refers to a carbamoyl group in which both hydrogens have been
replaced by an alkyl group which may be the same or different. For
example, N,N-di-(C.sub.1-6alkyl)-carbamoyl refers to a carbamoyl
group in which both of the hydrogens have been replaced with an
alkyl group which may be the same or different having from 1 to 6
carbon atoms.
[0542] The term "alkanoyl" refers to a group having the formula
--C(O)--R, wherein R is an alkyl group. For example,
C.sub.1-6alkanoyl refers to an alkanoyl group which has from one to
six carbon atoms, such as acetyl, isopropyl-carbonyl, and the
like.
General
[0543] 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.
[0544] 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.
[0545] The term "about" in relation to a numerical value x means,
for example, x.+-.10%.
[0546] Whenever appropriate, terms used in the singular will also
include the plural and vice versa.
[0547] 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.
[0548] "Optional" or "optionally" means that the subsequently
described event of circumstances may or may not occur, and that the
description includes instances where said event or circumstance
occurs and instances in which it does not. For example, "optionally
substituted aryl" means that the aryl radical may or may not be
substituted and that the description includes both substituted aryl
radicals and aryl radicals having no substitution.
Synthesis
[0549] 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.
[0550] Salts of compounds of the present invention having at least
one salt-forming group may be prepared in a manner known per se.
For example, salts of compounds of the present invention having
acid groups may be formed, for example, by treating the compounds
with metal compounds, such as alkali metal salts of suitable
organic carboxylic acids, e.g. the sodium salt of 2-ethylhexanoic
acid, with organic alkali metal or alkaline earth metal compounds,
such as the corresponding hydroxides, carbonates or hydrogen
carbonates, such as sodium or potassium hydroxide, carbonate or
hydrogen carbonate, with corresponding calcium compounds or with
ammonia or a suitable organic amine, stoichiometric amounts or only
a small excess of the salt-forming agent preferably being used.
Acid addition salts of compounds of the present invention are
obtained in customary manner, e.g. by treating the compounds with
an acid or a suitable anion exchange reagent. Internal salts of
compounds of the present invention containing acid and basic
salt-forming groups, e.g. a free carboxy group and a free amino
group, may be formed, e.g. by the neutralisation of salts, such as
acid addition salts, to the isoelectric point, e.g. with weak
bases, or by treatment with ion exchangers.
[0551] Salts can be converted in customary manner into the free
compounds; metal and ammonium salts can be converted, for example,
by treatment with suitable acids, and acid addition salts, for
example, by treatment with a suitable basic agent.
[0552] Mixtures of isomers obtainable according to the invention
can be separated in a manner known per se into the individual
isomers; diastereoisomers can be separated, for example, by
partitioning between polyphasic solvent mixtures, recrystallisation
and/or chromatographic separation, for example over silica gel or
by e.g. medium pressure liquid chromatography over a reversed phase
column, and racemates can be separated, for example, by the
formation of salts with optically pure salt-forming reagents and
separation of the mixture of diastereoisomers so obtainable, for
example by means of fractional crystallisation, or by
chromatography over optically active column materials.
[0553] Intermediates and final products can be worked up and/or
purified according to standard methods, e.g. using chromatographic
methods, distribution methods, (re-) crystallization, and the
like.
[0554] The following applies in general to all processes mentioned
hereinbefore and hereinafter.
[0555] All the above-mentioned process steps can be carried out
under reaction conditions that are known per se, including those
mentioned specifically, in the absence or, customarily, in the
presence of solvents or diluents, including, for example, solvents
or diluents that are inert towards the reagents used and dissolve
them, in the absence or presence of catalysts, condensation or
neutralizing agents, for example ion exchangers, such as cation
exchangers, e.g. in the H+ form, depending on the nature of the
reaction and/or of the reactants at reduced, normal or elevated
temperature, for example in a temperature range of from about
-100.degree. C. to about 190.degree. C., including, for example,
from approximately -80.degree. C. to approximately 150.degree. C.,
for example at from -80 to -60.degree. C., at room temperature, at
from -20 to 40.degree. C. or at reflux temperature, under
atmospheric pressure or in a closed vessel, where appropriate under
pressure, and/or in an inert atmosphere, for example under an argon
or nitrogen atmosphere.
[0556] At all stages of the reactions, mixtures of isomers that are
formed can be separated into the individual isomers, for example
diastereoisomers or enantiomers, or into any desired mixtures of
isomers, for example racemates or mixtures of diastereoisomers, for
example analogously to the methods described under "Additional
process steps".
[0557] The solvents from which those solvents that are suitable for
any particular reaction may be selected include those mentioned
specifically or, for example, water, esters, such as lower
alkyl-lower alkanoates, for example ethyl acetate, ethers, such as
aliphatic ethers, for example diethyl ether, or cyclic ethers, for
example tetrahydrofuran or dioxane, liquid aromatic hydrocarbons,
such as benzene or toluene, alcohols, such as methanol, ethanol or
1- or 2-propanol, nitriles, such as acetonitrile, halogenated
hydrocarbons, such as methylene chloride or chloroform, acid
amides, such as dimethylformamide or dimethyl acetamide, bases,
such as heterocyclic nitrogen bases, for example pyridine or
N-methylpyrrolidin-2-one, carboxylic acid anhydrides, such as lower
alkanoic acid anhydrides, for example acetic anhydride, cyclic,
linear or branched hydrocarbons, such as cyclohexane, hexane or
isopentane, methycyclohexane, or mixtures of those solvents, for
example aqueous solutions, unless otherwise indicated in the
description of the processes. Such solvent mixtures may also be
used in working up, for example by chromatography or
partitioning.
[0558] The compounds, including their salts, may also be obtained
in the form of hydrates, or their crystals may, for example,
include the solvent used for crystallization. Different crystalline
forms may be present.
[0559] The invention relates also to those forms of the process in
which a compound obtainable as an intermediate at any stage of the
process is used as starting material and the remaining process
steps are carried out, or in which a starting material is formed
under the reaction conditions or is used in the form of a
derivative, for example in a protected form or in the form of a
salt, or a compound obtainable by the process according to the
invention is produced under the process conditions and processed
further in situ.
[0560] All starting materials, building blocks, reagents, acids,
bases, dehydrating agents, solvents and catalysts utilized to
synthesize the compounds of the present invention are either
commercially available or can be produced by organic synthesis
methods known to one of ordinary skill in the art (Houben-Weyl
4.sup.th Ed. 1952, Methods of Organic Synthesis, Thieme, Volume
21).
[0561] Typically, the compounds of Formula (I), (I-i), (I-ii),
(I-iii), (I-iv), (IA), (IIb), (IIc), (IId), (IIe), (IIf), (IIg),
(IIh) and (IIi), can be prepared according to the Schemes provided
infra.
Method of Preparation
[0562] 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
the reactions described in the schemes herein below, any reactive
group present, such as hydroxyl, amino, carbonyl or imino groups
may be protected during the reaction by conventional protecting
groups such as trimethylsilyl, tert-butyldimethylsilyl, benzyl,
acetal, ketal etc., which are cleaved again after the reaction.
##STR00039##
[0563] Compounds of formula (II), 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
(III) wherein M is selected from Li or Mg-Halogen, and all other
symbols are defined herein above. Compounds of formula (III) may be
reacted with compounds of formula (IV) wherein all symbols are
defined herein above. The resulting intermediate may be
dehydroxylated/dealkoxylated using reagent such as triethylsilane
BF.sub.3-etherate to provide compounds of Formula (I) wherein all
symbols are defined herein above.
##STR00040##
[0564] Compounds of formula (III), wherein M is selected from Li or
Mg-Halogen and all other symbols are defined herein above, may be
reacted with compounds of formula (V) 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 (I) wherein all symbols are defined herein above.
##STR00041##
[0565] Compounds of formula (VI), 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
(VII) wherein M is selected from Li or Mg-Halide and all other
symbols are defined herein above. Compounds of formula (VII) may be
reacted with compounds of formula (VIII) wherein all symbols are
defined herein above. The resulting intermediate may be
dehydroxylated using reagent such as triethylsilane
BF.sub.3-etherate or Pd--C in presence of hydrogen atmosphere to
provide compounds of Formula (I) wherein all symbols are defined
herein above.
##STR00042##
[0566] Compounds of formula (IX) wherein all symbols are defined
herein above may be reacted with acid of formula (X) or its
corresponding acid chloride wherein all symbols are defined herein
above. The reaction may be carried out in the presence of a Lewis
acid followed by treating the intermediate ketone with
triethylsilane BF.sub.3-etherate to provide compounds of Formula
(I) wherein all symbols are defined herein above.
##STR00043##
[0567] Compounds of formula (XI) wherein R.sup.11 is selected from
hydrogen, alkyl, acyl, trifluoromethanesulfonyl and all symbols are
defined herein above may be cyclised using OR.sup.11 to obtain
compounds of Formula (I) wherein ring A' has at least one `O` atom
and all other symbols are defined herein above.
[0568] Compounds of Formula (I) may be prepared from other
compounds of Formula (I) by methods well known to one skilled in
the art.
##STR00044##
[0569] Compounds of formula (XII) wherein Lg is a leaving group
such as halogen or triflate and all other symbols are defined
herein above may be converted under Suzuki coupling conditions or
Buchwald coupling conditions, to obtain compounds of Formula (I)
wherein ring A has at least one substituent and all other symbols
are defined herein above. Ring A' may be formed either before or
after the Suzuki coupling reaction from OR.sup.11 as shown in
Scheme 5.
Intermediate (II):
##STR00045##
[0571] Compounds of formula (IIa), wherein Lg is a leaving group
such as halogen and the remaining variables are as defined herein
above, may be reacted with compounds of formula (IIb) wherein M is
selected from lithium or magnesium halide and all other symbols are
defined herein above. The resulting intermediate may be
dehydroxylated/dealkoxylated using reagents such as triethylsilane
BF.sub.3-etherate or under hydrogenation conditions to provide
compounds of formula (II) wherein all symbols are defined herein
above.
##STR00046##
[0572] Compounds of formula (IIc), wherein Lg is a leaving group
such as halogen, Z is selected from OH, NH.sub.2 or SH, and the
remaining variables are as defined herein above, may be reacted
with compounds of formula (IId) wherein all symbols are defined
herein above to provide intermediate (II) wherein all symbols are
defined herein above. The reaction may be carried out in the
presence of a base.
##STR00047##
[0573] Compounds of formula (IIe) wherein Lg is a leaving group
such as halogen, and the remaining symbols are as defined herein
above, may be reacted with compounds of formula (IIf), wherein Z is
selected from OH, NH.sub.2 or SH and all other symbols are defined
herein above to provide intermediate (II) wherein the symbols are
defined herein above. The reaction may be carried out in the
presence of a base.
##STR00048##
[0574] Carboxylic acid of formula (IIg) or corresponding acid
halide, wherein Lg is a leaving group such as halogen and ring A is
as defined herein above, may be reacted with compounds of formula
(IIh), wherein all symbols are defined herein above, to provide
intermediate (II) wherein the symbols are defined herein above. The
reaction may be carried out in the presence of a Lewis acid
followed by reducing the intermediate ketone using reagent such as
triethylsilane BF.sub.3-etherate or under hydrogenation
conditions.
Intermediate (VIII) and (X)
##STR00049##
[0576] Compounds of formula (VIIIa) wherein the symbols are defined
herein above may be reacted with compounds of formula (VIIIb)
wherein M is selected from lithium or magnesium halide, to provide
intermediate of formula (VIIIc) which may be
dehydroxylated/dealkoxylated using reagent such as triethylsilane
BF.sub.3-etherate or Pd--C in presence of hydrogen atmosphere to
provide compounds of formula (VIIId).
[0577] Compounds of formula (VIIId) may be oxidized to provide
aldehyde of formula (VIII) which may be further oxidized to provide
acid of formula (X). The oxidations may be carried out with
processes known in the literature.
##STR00050##
[0578] Compounds of formula (VIIIa), wherein all symbols are
defined herein above, may be reacted with ketal of formula (VIIIe)
wherein M is selected from lithium or magnesium halide, to provide
compound of formula (VIIIf) which may be
dehydroxylated/dealkoxylated using reagent such as triethylsilane
BF.sub.3-etherate or Pd--C in presence of hydrogen atmosphere to
provide compounds of formula (VIIIg). Compounds of formula (VIIIg)
may be deprotected to provide aldehyde of formula (VIII) which may
be oxidized to provide acid of formula (X). The oxidation may be
carried out with processes known in the literature.
[0579] 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.
[0580] 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.
[0581] 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.
Intermediates
Intermediate 1
##STR00051##
[0583] Step I. To a stirred solution of 4H-Benzo[1,4]oxazin-3-one
(2.5 g, 16.77 mmol) in DMF (10 mL) was added potassium
tert-butoxide (2.81 g, 25.16 mmol) at 0.degree. C. After stirring
for 5 min, methyl iodide (3.54 g, 25.16 mmol) was added and the
reaction mixture was stirred for another 3 h. The reaction was
quenched by addition of water and extracted with ethyl acetate
(30.times.2 mL). The organic layer was washed with water (20 mL),
and evaporated to get a crude product 2.2 g.
[0584] Step II. To a stirred solution of
4-methyl-4H-benzo[1,4]oxazin-3-one (2.18 g, 13.37 mmol) in THF (5
mL) was added borane-tetrahydrofuran complex (4.02 g, 46.8 mmol) at
room temperature. After stirring the solution for 2 h, the reaction
mixture was refluxed for 4 h. After complete conversion, reaction
mixture was quenched by adding MeOH (10 mL) and evaporated the
solvents. The residue obtained was extracted with ethyl acetate
(30.times.2 mL) and the organic layer was washed with water (20
mL), brine (20 mL) and evaporation of solvent gave
4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine 2.0 g.
[0585] MS (ES) m/z 150.2 (M+1).
Intermediate 2
##STR00052##
[0587] Step I. To a stirred suspension LiAlH.sub.4 (7.6 g, 201
mmol) in THF at 0.degree. C. was added 4H-benzo[1,4]oxazin-3-one
(15 g, 100 mmol) in 30 mL of THF and stirred for 4 h at room
temperature. After cooling, excess of LiAlH.sub.4 was quenched by
the addition of EtOAc followed by aq. NH.sub.4Cl solution. The
residue was filtered through a celite bed and filtrate was
concentrated. The residue was diluted with water and extracted with
ethylacetate (200 mL.times.2), combined organic layer was washed
with water (100 mL) and brine (100 mL). Evaporation of the solvent
resulted in 3,4-dihydro-2H-benzo[1,4]oxazine (12 g) which was used
as such for the next step.
[0588] MS (ES) m/z 136 (M+1)
[0589] Step II: To a stirred solution of
3,4-dihydro-2H-benzo[1,4]oxazine (4.0 g, 29.6 mmol) in DMF (20 mL)
was added potassium carbonate (10.22 g, 74.0 mmol). After stirring
for five min. Iodo-ethane (3.5 mL, 44.4 mmol) was added and heated
to 60.degree. C. for overnight. Reaction mixture was cooled to room
temperature, quenched by the addition of water (20 mL), extracted
with ethyl acetate (3.times.25 mL). The organic layer was washed
with water (30 mL), brine (30 mL), dried over sodium sulfate,
concentrated and purified by silica gel column chromatoghraphy to
furnish 4-ethyl-3,4-dihydro-2H-benzo[1,4]oxazine (2.7 g).
[0590] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 1.10 (t, J=6.8
Hz, 3H), 3.26-3.33 (m, 4H), 4.16 (t, J=4.4 Hz, 2H), 4.40 (s, 2H),
6.52-6.58 (m, 1H), 6.60-6.80 (m, 3H).
[0591] MS (ES) m/z 163.2 (M+1)
[0592] Intermediate 3
##STR00053##
[0593] Step I. To a stirred solution of
3,4-dihydro-2H-benzo[1,4]oxazine (5 g, 37.0 mmol) in DMF (20 mL)
was added potassium tert-butoxide (6.22 g, 55.55 mmol) at 0.degree.
C. After stirring for 5 min, bromo-cyclopropane (4.44 mL, 55.55
mmol) was added and the reaction mixture was stirred for another 4
h at room temperature. The reaction was quenched by addition of
water and extracted with ethyl acetate (50.times.2 mL). The organic
layer was washed with water (20 mL), concentrated and purified by
silica gel column chromatoghraphy to furnish
4-Cyclopropyl-3,4-dihydro-2H-benzo[1,4]oxazine (4.42 g).
[0594] MS (ES) m/z 176 (M+1).
Intermediate 4
##STR00054##
[0596] Step I. To a stirred solution of 2-aminophenol (10 g, 9.2
mmol) in DCM (92 mL) at 0.degree. C. was added 2-bromoisobutyryl
bromide (11.4 mL, 9.17 mmol) followed by triethyl amine (12.7 mL,
9.2 mmol) and stirred the reaction mixture at 0.degree. C. for 4 h.
Reaction mixture was diluted with DCM 100 mL and then washed with
water 100 mL dried over sodium sulfate, concentrated on rotavap to
give 2-Bromo-N-(2-hydroxy-phenyl)-2-meth yl-propionamide (21.8 g)
brown solid which was used for next reaction without
purification
[0597] Step II. To a stirred solution of
2-Bromo-N-(2-hydroxy-phenyl)-2-methyl-propionamide (21.8 g, 84.4
mmol) in DMF (85 mL) at 25.degree. C. was added potassium carbonate
(23.32 g, 168.99 mmol) and stirred the reaction mixture at
80.degree. C. for 4 h. After TLC reaction mixture was filtered
through celite and diluted with ethyl acetate 500 mL and then
washed with water (100 mL.times.3), brine (100 mL), dried over
anhydrous sodium sulfate, concentrated to give
2,2-dimethyl-4H-benzo[1,4]oxazin-3-one (12.64 g) as brown solid
which was purified by column chromatography to furnish 8.5 g pure
compound.
[0598] MS (EI) m/z 178.2 (M+1)
[0599] Step III. To a stirred solution of LAH (3.01 g, 79.10 mmol)
in THF (80 mL) at 0.degree. C. was added
2,2-dimethyl-4H-benzo[1,4]oxazin-3-one (7.00 g, 39.5 mmol) in
portions and stirred the reaction mixture at 25.degree. C. for 1 h
and then 50.degree. C. for 3 h. Reaction mixture was quenched by
the addition cold saturated sodium sulfate solution and it was
filtered through celite and extracted with DCM (100 mL.times.2),
washed with brine (50 mL), dried over sodium sulfate, concentrated
to give 2,2-dimethyl-3,4-dihydro-2H-benzo[1,4]oxazine (6.09 g),
which was used as such for the next reaction without
purification
[0600] MS (EI) m/z 164.2 (M+1)
[0601] Step IV. To a stirred solution of
2,2-dimethyl-3,4-dihydro-2H-benzo[1,4]oxazine (6 g, 36.8 mmol) in
DCM (75 mL) at 0.degree. C. was added trifluoroacetic anhydride
(6.2 mL, 44.2 mmol) followed by triethyl amine (6.2 mL, 44.2 mmol)
and stirred the reaction mixture at 0.degree. C. for 2 h. Reaction
mixture was diluted with DCM (100 mL) and then washed with water
(100 mL.times.2), brine (100 mL), dried over anhydrous sodium
sulfate, concentrated on to give
1-(2,2-dimethyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-2,2,2-trifluoro-ethano-
ne (9.46 g) as brown solid which was purified by column
chromatography to furnish 8.7 g pure product.
[0602] MS (EI) m/z 260.2 (M+1)
[0603] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 1.38 (s, 6H),
3.65 (s, 2H), 6.86-6.96 (m, 2H), 7.12-7.16 (m, 1H), 7.97 (d,
1H).
Intermediate 5
##STR00055##
[0605] To a stirred solution of
6-bromo-1,2,3,4-tetrahydro-quinoline (3.00 g, 12.1 mmol) in
dimethylformamide (25 mL) was added potassium carbonate (3.3 g,
24.1 mmol), sodium iodide (0.905 g, 6.0 mmol) and 4-methoxybenzyl
chloride (2.5 mL, 18.1 mmol) and heated at 50.degree. C. After 18
h, reaction mixture was cooled to room temperature and quenched by
the addition of water and extracted with ethyl acetate (2.times.20
mL). The organic layer was washed with water (2.times.20 mL), brine
(20 mL), dried over sodium sulfate, concentrated and purified by
the silica gel column chromatography to furnish
6-bromo-1-(4-methoxy-benzyl)-1,2,3,4-tetrahydro-quinoline (2.5
g).
[0606] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 1.96-2.02 (m,
2H), 2.78 (t, J=6.0 Hz, 2H), 3.46 (t, J=5.2 Hz, 2H), 3.80 (s, 3H),
4.40 (s, 2H), 6.38 (d, J=8.4 Hz, 1H), 6.86 (d, J=8.4 Hz, 2H), 7.04
(d, J=8.8 Hz, 1H), 7.07 (s, 1H), 7.15 (d, J=8.4 Hz, 2H).
[0607] MS (ES) m/z 332.1, 334.1 (M+1)
EXAMPLES
Example 1
(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-methyl-3,4-dihydro-2H
benzo[1,4]oxazin-7-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4-
,5-triol
##STR00056##
[0609] Step I. To a stirred solution of
4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine (2.00 g, 13.4 mmol) in
dichloromethane (30 mL) was added 5-bromo-2-chlorobenzoyl chloride
(4.07 g, 16.1 mmol) in dichloromethane (20 mL) at 0.degree. C.
followed by addition of AlCl.sub.3 (2.14 g, 16.1 mmol). After 2 h,
the reaction mixture was brought to room temperature and stirred
overnight. The reaction was quenched by pouring over crushed ice
and extracted with dichloromethane (30.times.2 mL). The organic
layer was washed with aq. NaHCO.sub.3 (20 mL), H.sub.2O (20 mL) and
to obtain a crude product 3.0 g.
[0610] Step II. To the crude product (0.9 g, 2.45 mmol) in 1:2
mixture of 1,2-dichloroethane/MeCN (12 mL) was added Et.sub.3SiH
(0.83 mL, 5.16 mmol) and BF3.OEt2 (0.37 mL, 3.19 mmol)
simultaneously at 20.degree. C. After stirring overnight, the
reaction mixture was heated at 50.degree. C. for 2 h. The reaction
was quenched by the addition of aq. NaHCO.sub.3 (5 mL). The
volatiles were evaporated under reduced pressure; the resulting
mixture was extracted with dichloromethane (2.times.20 mL), washed
with brine (5 mL), dried over sodium sulfate, concentrated and
purified by silica gel column chromatography to furnish
7-(5-bromo-2-chloro-benzyl)-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine
(0.375 g).
[0611] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 2.89 (s, 3H),
3.27 (s, 2H), 3.93 (s, 2H), 4.32 (t, J=3.6 Hz, 2H), 6.61 (s, 1H),
6.64-6.74 (m, 2H) 7.19-7.32 (m, 3H).
[0612] MS (ES) m/z 351.8 (M+1)
[0613] Step III: To a stirred solution of
7-(5-bromo-2-chloro-benzyl)-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine
(0.37 g, 1.06 mmol) in THF toluene (5 mL of 1:2 mixture) was added
1.6 M solution of n BuLi in hexanes (0.68 mL, 1.06 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 (0.49 g, 1.06
mmol) in toluene (5 mL) at -78.degree. C. After stirring for 4 h,
0.6 N methanesulfonic acid in methanol (5 mL) was added and stirred
the reaction mixture for 12 h at room temperature. Reaction was
quenched by the addition of aq. NaHCO.sub.3 solution (5 mL) and
extracted with dichloromethane (3.times.10 mL), dried over sodium
sulfate, concentrated and purified by silica gel column
chromatography to furnish
(2S,3R,4S,5S,6R)-2-[4-chloro-3-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin--
7-ylmethyl)-phenyl]-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-3,4,5-triol
(0.178 g).
[0614] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 2.82 (s, 3H),
3.08 (s, 3H), 3.10 (d, J=10.0 Hz, 1H), 3.18 (t, J=4.0 Hz, 2H), 3.42
(t, J=9.6 Hz, 1H), 3.55-3.62 (m, 1H), 3.75 (t, J=9.2 Hz, 1H), 3.82
(dd, J=12.0, 5.6 Hz, 1H), 3.90 (d, J=14.8 Hz, 1H), 3.94 (d, J=10.4
Hz, 1H), 4.02 (d, J=15.2 Hz, 1H), 4.23 (t, J=4.4 Hz, 2H), 6.51 (s,
1H), 6.60-6.68 (m, 2H), 7.35 (d, J=8.4 Hz, 1H), 7.45 (d, J=8.4 Hz,
1H), 7.53 (s, 1H).
[0615] MS (ES) m/z 466.3 (M+1).
[0616] Step IV: To a stirred solution of
(2S,3R,4S,5S,6R)-2-[4-chloro-3-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin--
7-ylmethyl)-phenyl]-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-3,4,5-triol
(0.17 g, 0.37 mmol) in acetonitrile-dichloromethane mixture (1:1
mixture, 6 mL) was added boron trifluoride diethyletharate complex
(0.09 mL, 0.75 mmol), and triethylsilane (0.24 mL, 1.50 mmol) at
10.degree. C. After stirring for 4 h at the same temperature, the
reaction was quenched with aq. NaHCO.sub.3 (4 mL). The volatiles
were evaporated under reduced pressure; the resulting mixture was
extracted with dichloromethane (2.times.20 mL), washed with brine
(3 mL), dried over sodium sulfate, concentrated and purified by
preparative HPLC to furnish
(2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-methyl-3,4-dihydro-Hbenzo[1,4]oxazin-7--
ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (40
mg).
[0617] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 2.80 (s, 3H),
3.15 (t, J=4.4 Hz, 2H), 3.25-3.34 (m, 1H), 3.35-3.48 (m, 3H), 3.68
(dd, J=12.0, 5.6 Hz, 1H), 3.86 (d, J=8.4 Hz, 1H), 3.92 (Abq, J=15.2
Hz, 2H), 4.07 (d, J=9.6 Hz, 1H), 4.21 (t, J=4.4 Hz, 2H), 6.50 (d,
J=0.8 Hz, 1H), 6.66 (d, J=8.4 Hz, 1H), 6.64 (dd, J=8.4, 1.2 Hz,
1H), 7.24 (dd, J=8.0, 1.6 Hz, 1H), 7.29 (s, 1H), 7.33 (d, J=8.0,
1H).
[0618] MS (ES) m/z 436.0 (M+1).
[0619] Following examples were prepared by using the procedures
described for example 1.
TABLE-US-00001 Example No. Structure/IUPAC name Spectral data 2
##STR00057## (2S,3R,4R,5S,6R)-2-[4- Chloro-3-(4-ethyl-3,4-dihydro-
2H-benzo[1,4]oxazin- 7-ylmethyl)-phenyl]-6- hydroxymethyl-
tetrahydro-pyran-3,4,5-triol .sup.1H NMR (400 MHz, CD.sub.3OD):
.delta. 1.08 (t, J = 6.8 Hz, 3H), 3.15-3.48 (m, 8H), 3.66 (d, J =
11.2 Hz, 1H), 3.85 (d, J = 12.0 Hz, 1H), 3.90 (Abq, 15.2 Hz, 2H),
4.06 (d, J = 9.2 Hz, 1H), 4.14 (s, 2H), 6.49 (s, 1H), 6.60 (s, 2H),
7.23 (d, J = 8.0 Hz, 1H), 7.28 (s, 1H), 7.31 (d, J = 8.0 Hz, 1H), .
MS (ES) m/z 450.3 (M + 1). 3 ##STR00058## (2S,3R,4R,5S,6R)-2-[4-
Chloro-3-(4-cyclopropyl-3,4- dihydro-2Hbenzo[1,4]oxazin-
7ylmethyl)-phenyl]-6-hydroxy- methyltetrahydropyran3,4,5- triol
.sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 0.54 (s, 2H), 0.75 (d, J
= 2.0 Hz, 2H), 2.12 (m, 1H), 3.15-3.50 (m, 6H), 3.66 (dd, J = 11.6,
4.0 Hz, 1H), 3.85 (d, J = 10.8 Hz, 1H), 3.91 (Abq, 15.2 Hz, 2H),
4.05 (d, J = 9.2 Hz, 1H), 4.15 (s, 2H), 6.48 (s, 1H), 6.61 (d, J =
8.0 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H),
7.23 (s, 1H), 7.31 (d, J = 8.4 Hz, 1H),. MS (ES) m/z 462.3 (M +
1).
Example 4
(2S,3R,4R,5S,6R)-2-[3-(4-Benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl-
)-4-chloro-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
##STR00059##
[0621] Step I. To a stirred solution of
1-(2,3-dihydro-benzo[1,4]oxazin-4-yl)-2,2,2-trifluoro-ethanone (6.5
g, 28.1 mmol) in dichloromethane (45 mL) was added
5-bromo-2-chlorobenzoyl chloride (8.54 g, 33.7 mmol) in
dichloromethane (35 mL) and AlCl.sub.3 (5.61 g, 42.2 mmol) at
0.degree. C. After 2 h, the reaction mixture was brought to room
temperature and stirred overnight. The reaction was quenched by
pouring over crushed ice and extracted with dichloromethane
(2.times.50 mL). The organic layer was washed with aq. NaHCO.sub.3
(30 mL), H.sub.2O (20 mL), and the solvent evaporated to get the
crude product which was purified by silica gel column
chromatography to give
1-[6-(5-bromo-2-chloro-benzoyl)-2,3-dihydro-benzo[1,4]oxazin-4-yl]-2,2,2--
trifluoro-ethanone (10.0 g).
[0622] .sup.1H NMR (400 MHz, CDCl.sub.3): 4.03 (t, J=4.0 Hz, 2H),
4.48 (t, J=4.2 Hz, 2H), 7.04 (d, J=8.4 Hz, 1H), 7.34 (d, J=8.4 Hz,
1H), 7.50 (d, J=2.0 Hz, 1H), 7.55 (dd, J=8.4, 2.0 Hz, 1H), 7.68 (d,
J=8.4 Hz, 1H) 8.42 (broad s, 1H).
[0623] MS (ES) m/z 450 (M+2)
[0624] Step II. To a stirred solution of
1-[6-(5-bromo-2-chloro-benzoyl)-2,3-dihydro-benzo[1,4]oxazin-4-yl]-2,2,2--
trifluoro-ethanone (1.0 g, 2.23 mmol) in 1:2 of
1,2-dichloroethane/MeCN (12 mL) was added Et.sub.3SiH (0.755 mL,
4.68 mmol) and BF.sub.3.OEt.sub.2 (0.34 mL, 2.90 mmol)
simultaneously at 20.degree. C. The reaction mixture was heated at
50.degree. C. for 4 h and quenched by the addition of aq.
NaHCO.sub.3 (10 mL). The volatiles were evaporated under reduced
pressure; the resulting mixture was extracted with dichloromethane
(2.times.20 mL), washed with brine (5 mL), dried over sodium
sulfate, concentrated and was purified by silica gel column
chromatography to furnish
1-[6-(5-bromo-2-chloro-benzyl)-2,3-dihydro-benzo[1,4]oxazin-4-yl]-2,2,2-t-
rifluoro-ethanone (0.60 g).
[0625] .sup.1H NMR (400 MHz, DMSO): .delta. 3.96 (t, J=4.0 Hz, 2H),
3.99 (s, 2H), 4.37 (t, J=4.4 Hz, 2H), 6.69 (d, J=8.4 Hz, 1H), 7.03
(d, J=7.6 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.46 (dd, J=8.4, 2.0 Hz,
1H), 7.53 (d, J=2.4 Hz, 1H), 7.82 (broad s, 1H).
[0626] Step III: To a stirred solution of
1-[6-(5-bromo-2-chloro-benzyl)-2,3-dihydro-benzo[1,4]oxazin-4-yl]-2,2,2-t-
rifluoro-ethanone (8.6 g, 19.8 mmol) in ethanol (40 mL) was added
NaBH.sub.4 portion wise and the reaction mixture was stirred
overnight. The excess of NaBH.sub.4 was quenched by adding aq. HCl.
Ethanol was evaporated and the residue was partitioned between
dichloromethane and water. Organic layer was washed with brine,
water, dried over sodium sulfate followed by evaporation of solvent
furnished
6-(5-bromo-2-chloro-benzyl)-3,4-dihydro-2H-benzo[1,4]oxazine (6.1
g).
[0627] Step IV: To a stirred solution of
6-(5-bromo-2-chloro-benzyl)-3,4-dihydro-2H-benzo[1,4]oxazine (8.0
g, 23.66 mmol) in DMF (35 mL) was added potassium carbonate (6.53
g, 36.0 mmol), benzyl bromide (4.33 mL, 35.50 mmol) and heated to
50.degree. C. for 8 h. Reaction mixture was cooled to room
temperature, quenched by the addition of water (50 mL), extracted
with ethyl acetate (3.times.20 mL). The organic layer was washed
with water (50 mL), brine (50 mL), dried over sodium sulfate,
concentrated and purified by silica gel column chromatoghraphy to
furnish
4-benzyl-6-(5-bromo-2-chloro-benzyl)-3,4-dihydro-2H-benzo[1,4]oxazine
(7.0 g).
[0628] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 3.40 (t, J=4.4
Hz, 2H), 3.85 (s, 2H), 4.24 (t, J=4.4 Hz, 2H), 4.40 (s, 2H), 6.40
(dd, J=8.0, 2.0 Hz, 1H), 6.45 (d, J=2.0 Hz, 1H), 6.66 (d, J=8.0,
Hz, 1H), 7.20-7.36 (m, 8H).
[0629] MS (ES) m/z 429.9 (M+2).
[0630] Step V: To a stirred solution of
4-benzyl-6-(5-bromo-2-chloro-benzyl)-3,4-dihydro-2H-benzo[1,4]oxazine
(7.0 g, 16.3 mmol) in THF-toluene (40 mL of 1:2 mixture) was added
1.6 M solution of n-BuLi in hexanes (10.46 mL, 16.35 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 (7.62 g, 16.35
mmol) in toluene (25 mL) at -78.degree. C. After stirring for 4 h,
0.6 N methanesulfonic acid in methanol (50 mL) was added and
stirred for 12 h at room temperature. Reaction was quenched by the
addition of aq. saturated sodium bicarbonate solution (25 mL) and
extracted with dichloromethane (3.times.25 mL), dried over sodium
sulfate, concentrated and purified by silica gel column
chromatography to furnish
(2S,3R,4S,5S,6R)-2-[3-(4-benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-
-ylmethyl)-4-chloro-phenyl]-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-3,4-
,5-triol (5.0 g).
[0631] Step VI: To a stirred solution of
(2S,3R,4S,5S,6R)-2-[3-(4-benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethy-
l)-4-chloro-phenyl]-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-3,4,5-triol
(5.0 g, 9.24 mmol) in acetonitrile-dichloromethane mixture (1:1
mixture, 40 mL) was added boron trifluoride diethyletharate complex
(2.34 mL, 18.48 mmol), and triethylsilane (5.95 mL, 36.9 mmol) at
-10.degree. C. After stirring for 4 h at the same temperature, the
reaction was quenched with aq. saturated sodium bicarbonate
solution (15 mL). The volatiles were evaporated under reduced
pressure; the resulting mixture was extracted with dichloromethane
(2.times.30 mL). The organic layer was washed with brine (10 mL),
dried over sodium sulfate, concentrated and purified by preparative
HPLC to furnish
(2S,3R,4R,5S,6R)-2-[3-(4-benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethy-
l)-4-chloro-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
(3.5 g).
[0632] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 3.20-3.50 (m,
6H), 3.68 (dd, J=12.0, 4.4 Hz, 1H), 3.75-3.95 (m, 3H), 4.03 (d,
J=9.2 Hz, 1H), 4.16 (t, J=3.6 Hz, 2H), 4.35 (s, 2H), 6.37 (d, J=8.0
Hz, 1H), 6.54 (s, 1H), 6.57 (d, J=0.8 Hz, 1H), 7.15-7.62 (m,
8H).
[0633] MS (ES) m/z 511.8 (M+1).
[0634] Following examples were prepared by using the procedures
described for example 4.
TABLE-US-00002 Example No. Structure/IUPAC name Spectral data 5
##STR00060## (2S,3R,4R,5S,6R)-2-{4-Chloro-3-[4-
(4-methoxy-benzyl)-3,4-dihydro-2H- benzo[1,4]oxazin-6-ylmethyl]-
phenyl}-6-hydroxymethyltetrahydro- pyran-3,4,5-triol .sup.1H NMR
(400 MHz, CD.sub.3OD): .delta. 3.31 (s, 3H), 3.38-3.52 (m, 3H),
3.70 (dd, J = 11.2, 4.0 Hz, 1H), 3.78 (s, 3H), 3.88 (d, 11.6 Hz,
1H), 3.91 (Abq, 14.8 Hz, 2H), 4.08 (d, J = 9.2 Hz, 1H), 4.17 (s,
2H), 4.31 (s, 2H), 6.41 (d, J = 7.6 Hz, 1H), 6.59 (d, J = 7.6 Hz,
2H), 6.86 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 7.22-7.38
(m, 3H). MS (ES) m/z 541.8 (M + 1). 6 ##STR00061##
(2S,3R,4R,5S,6R)-2-[3-(4-Benzyl-2,2-
dimethyl-3,4-dihydro-2H-benzo[1,4]
oxazin-6-ylmethyl)-4-chloro-phenyl]-
6-hydroxymethyl-tetrahydro-pyran-3, 4,5-triol .sup.1H NMR (400 MHz,
CD.sub.3OD): .delta. 1.26 (s, 6H), 3.35-3.46 (m, 2H), 3.64- 3.70
(m, 1H), 3.80-3.91 (m, 3H), 4.05 (d, 1H), 4.38 (s, 2H), 4.56 (s,
4H), 6.46-6.52 (m, 1H), 6.54-6.57 (m, 2H), 7.19-7.28 (m, 8H). MS
(ES) m/z 540.2 (M + 1)
Examples 7-8
##STR00062## ##STR00063##
[0636] Step I. To a stirred suspension LiAlH.sub.4 (7.6 g, 201
mmol) in THF (70 mL) at 0.degree. C. was added
4H-benzo[1,4]oxazin-3-one (15 g, 100 mmol) in 30 mL of THF and the
mixture was stirred for 4 h at room temperature. After cooling,
excess of LiAlH.sub.4 was quenched by the addition of ethyl acetate
(30 mL) followed by aq. NH.sub.4Cl solution. The mixture was
filtered through a celite bed and the filtrate was concentrated
under reduced pressure and extracted with ethyl acetate (3.times.30
mL). The combined organic layers were washed with brine (30 mL) and
dried over Na.sub.2SO.sub.4. Evaporation of the solvent resulted in
benzoxazine (12 g) which was used as such for the next step.
[0637] MS (ES) m/z 136 (M+1)
[0638] Step II. To an ice-cold solution of benzoxazine (4.5 g, 33.3
mmol) in dichloromethane (25 mL) was added trifluoroacetic
anhydride (6.95 mL, 49.9 mmol) and the reaction mixture was stirred
for 2 h then quenched by the addition of aq. NaHCO.sub.3 solution.
The mixture was partitioned between dichloromethane and water. The
organic layer was separated, and the aqueous layer was extracted
with dichloromethane. The combined organic layers were washed with
brine, dried over Na.sub.2SO.sub.4, and concentrated to yield
1-(2,3-dihydro-benzo[1,4]oxazin-4-yl)-2,2,2-trifluoro-ethanone (6.5
g).
[0639] MS (ES) m/z 232 (M+1)
[0640] Step III: To a stirred solution of 2-bromo-5-chlorobenzoic
acid (8 g, 34.0 mmole) in dichloromethane (35 mL) was added DMF (1
mL) and oxalyl chloride (3.54 mL, 37.4 mmol) drop wise at 0.degree.
C. After complete addition, the reaction mixture was stirred at
room temperature for 3 h. The volatiles were evaporated under
reduced pressure to furnish 2-bromo-5-chloro-benzoyl chloride (8.5
g). The crude product was used without further purification.
[0641] To an ice cooled solution of 5-bromo-2-chlorobenzoyl
chloride in dichloromethane (35 mL) was added
1-(2,3-dihydro-benzo[1,4]oxazin-4-yl)-2,2,2-trifluoro-ethanone (6.5
g, 28.1 mmol) in dichloromethane (45 mL) followed by AlCl.sub.3
(5.61 g, 42.2 mmol) portion wise. After 2 h, the reaction mixture
was brought to room temperature and stirred overnight. The reaction
was quenched by pouring it over crushed ice. The resulting mixture
was extracted with dichloromethane. The organic layer was washed
with aq. NaHCO.sub.3 (100 mL) and water (100 mL), and the solvent
was evaporated to yield the crude product which was recrystallized
from hot ethylacetate to furnish
1-[6-(5-bromo-2-chloro-benzoyl)-2,3-dihydro-benzo[1,4]oxazin-4-yl]-2,2,2--
trifluoro-ethanone (10.0 g).
[0642] .sup.1H NMR (400 MHz, CDCl.sub.3): 4.03 (t, J=4.0 Hz, 2H),
4.48 (t, J=4.2 Hz, 2H), 7.04 (d, J=8.4 Hz, 1H), 7.34 (d, J=8.4 Hz,
1H), 7.50 (d, J=2.0 Hz, 1H), 7.55 (dd, J=8.4, 2.0 Hz, 1H), 7.68 (d,
J=8.4 Hz, 1H) 8.42 (broad s, 1H).
[0643] MS (ES) m/z 450 (M+2)
[0644] Step IV. To a stirred solution of
1-[6-(5-bromo-2-chloro-benzoyl)-2,3-dihydro-benzo[1,4]oxazin-4-yl]-2,2,2--
trifluoro-ethanone (36 g, 80.35 mmol) in 1,2-dichloroethane:MeCN
1:2 (180 mL) was added BF.sub.3.OEt.sub.2 (13.2 mL, 104 mmol) and
Et.sub.3SiH (26.9 mL, 168.7 mmol) at 0.degree. C. The reaction
mixture was stirred overnight at room temperature then quenched by
the addition of aq. NaHCO.sub.3 (.about.200 mL). The resulting
mixture was extracted with ethyl acetate (3.times.200 mL), and the
combined organic layers were washed with brine (200 mL) and dried
over sodium sulfate. Crude product obtained after evaporation of
solvent was purified by silica gel column chromatography to furnish
1-[6-(5-bromo-2-chloro-benzyl)-2,3-dihydro-benzo[1,4]oxazin-4-yl]-2,2,2-t-
rifluoro-ethanone (30 g).
[0645] .sup.1H NMR (400 MHz, DMSO): .delta. 3.96 (t, J=4.0 Hz, 2H),
3.99 (s, 2H), 4.37 (t, J=4.4 Hz, 2H), 6.69 (d, J=8.4 Hz, 1H), 7.03
(d, J=7.6 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.46 (dd, J=8.4, 2.0 Hz,
1H), 7.53 (d, J=2.4 Hz, 1H), 7.82 (br s, 1H).
[0646] Step V: To a stirred solution of
1-[6-(5-bromo-2-chloro-benzyl)-2,3-dihydro-benzo[1,4]oxazin-4-yl]-2,2,2-t-
rifluoro-ethanone (8.6 g, 19.8 mmol) in ethanol (40 mL) was added
NaBH.sub.4 (1.5 g, 39.0 mmol) portion wise and the reaction mixture
was stirred overnight. Excess of NaBH.sub.4 was quenched by adding
aq. NH.sub.4Cl, and ethanol was evaporated. The residue was
partitioned between ethyl acetate and water, and the organic layer
was separated, washed with brine (40 mL) and dried over sodium
sulphate. Crude product obtained after evaporation of solvent was
purified by silica gel column chromatography to furnish
6-(5-bromo-2-chloro-benzyl)-3,4-dihydro-2H-benzo[1,4]oxazine (6.1
g).
[0647] MS (ES) m/z 340 (M+2).
[0648] Step VI: To a stirred solution of
6-(5-bromo-2-chloro-benzyl)-3,4-dihydro-2H-benzo[1,4]oxazine (8.0
g, 23.66 mmol) in DMF (35 mL) was added potassium carbonate (6.53
g, 47.3 mmol), and benzyl bromide (4.33 mL, 35.50 mmol). The
reaction mixture was heated to 60.degree. C. for 8 h, then cooled
to room temperature and quenched by the addition of ice-cold water
(50 mL). The resulting mixture was extracted with ethyl acetate
(3.times.30 mL), and the combined organic layers were washed with
water (50 mL) and brine (50 mL), then dried over sodium sulfate.
The sodium sulfate was filtered off and the filtrate was
concentrated to crude product which was purified by silica gel
column chromatography to furnish
4-benzyl-6-(5-bromo-2-chloro-benzyl)-3,4-dihydro-2H-benzo[1,4]oxazine
(7.0 g).
[0649] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 3.40 (t, J=4.4
Hz, 2H), 3.85 (s, 2H), 4.24 (t, J=4.4 Hz, 2H), 4.40 (s, 2H), 6.40
(dd, J=8.0, 2.0 Hz, 1H), 6.45 (d, J=2.0 Hz, 1H), 6.66 (d, J=8.0,
Hz, 1H), 7.20-7.36 (m, 8H).
[0650] MS (ES) m/z 430 (M+2).
[0651] Step VII: To a stirred solution of
4-benzyl-6-(5-bromo-2-chloro-benzyl)-3,4-dihydro-2H-benzo[1,4]oxazine
(7.0 g, 16.3 mmol) in THF-toluene 1:2 (40 mL) was added 1.6 M
solution of n-BuLi in hexanes (10.46 mL, 16.35 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 (7.62 g, 16.35
mmol) in toluene (25 mL) at -78.degree. C. After stirring for 1 h,
0.6 N methanesulfonic acid in methanol (70 mL) was added and the
reaction mixture was stirred for 12 h at room temperature then
quenched by the addition of aq. saturated sodium bicarbonate
solution (-25 mL). The resulting mixture was extracted with ethyl
acetate (3.times.100 mL) and the combined organic layers were dried
over sodium sulfate, concentrated and purified by silica gel column
chromatography to furnish
(2S,3R,4S,5S,6R)-2-[3-(4-benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethy-
l)-4-chloro-phenyl]-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-3,4,5-triol
(5.0 g).
Example 7
(2S,3R,4R,5S,6R)-2-[3-(4-benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl-
)-4-chloro-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
[0652] Step VIII: To a stirred solution of
(2S,3R,4S,5S,6R)-2-[3-(4-benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethy-
l)-4-chloro-phenyl]-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-3,4,5-triol
(5.0 g, 9.24 mmol) in acetonitrile-dichloromethane mixture 1:1 (40
mL) was added boron trifluoride diethyletharate complex (2.34 mL,
18.48 mmol), and triethylsilane (5.95 mL, 36.9 mmol) at -5.degree.
C. After stirring for 4 h at the same temperature, the reaction was
quenched with aq. saturated sodium bicarbonate solution (15 mL).
The volatiles were evaporated under reduced pressure, and the
resulting mixture was extracted with dichloromethane (2.times.30
mL). The organic layers were combined and washed with brine (10
mL), dried over sodium sulfate, concentrated and purified by
preparative HPLC to furnish
(2S,3R,4R,5S,6R)-2-[3-(4-benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethy-
l)-4-chloro-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
(3.5 g).
[0653] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 3.20-3.50 (m,
6H), 3.68 (dd, J=12.0, 4.4 Hz, 1H), 3.75-3.95 (m, 3H), 4.03 (d,
J=9.2 Hz, 1H), 4.16 (t, J=3.6 Hz, 2H), 4.35 (s, 2H), 6.37 (d, J=8.0
Hz, 1H), 6.54 (s, 1H), 6.57 (d, J=0.8 Hz, 1H), 7.15-7.62 (m,
8H).
[0654] MS (ES) m/z 511.8 (M+1)
Example 8
(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl-
)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
[0655] Step IX: To a solution of
(2S,3R,4R,5S,6R)-2-[3-(4-benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethy-
l)-4-chloro-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
(2.4 g, 4.68 mmol) in methanol (15 mL) was added 10% palladium on
charcoal (240 mg) and 0.05 mL conc. HCl. The reaction mixture was
stirred under hydrogen atmosphere for 2 h then filtered through
celite bed (which was washed with methanol). The resulting filtrate
was concentrated to a residue which was purified by preparative
HPLC to furnish
(2S,3R,4R,5S,6R)-2-[4-chloro-3-(3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethy-
l)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (1.6
g).
[0656] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 3.24-3.34 (m,
2H), 3.35-3.49 (m, 4H), 3.69 (dd, J=12.0, 5.6 Hz, 1H), 3.88 (dd,
J=11.6, 2.0 Hz, 1H), 3.93 (ABq, J=15.2 Hz, 2H), 4.08 (d, J=9.6 Hz,
1H), 4.15 (t, J=4.4 Hz, 2H), 6.42-6.50 (m, 2H), 6.58 (d, J=8.0 Hz,
1H), 7.26 (dd, J=8.0, 2.4 Hz, 1H), 7.30 (d, J=2.0 Hz, 1H), 7.33 (d,
J=8.0 Hz, 1H).
Example 9
(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-ethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6--
ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
##STR00064##
[0658] To a stirred solution of
(2S,3R,4R,5S,6R)-2-[4-chloro-3-(3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethy-
l)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (0.1 g,
0.23 mmol) in DMF (2 mL) was added potassium carbonate (0.065 g,
0.47 mmol), ethyl iodide (0.028 mL, 0.35 mmol) and stirred the
solution at 20.degree. C. for 2 h. Reaction mixture was quenched by
the addition of water (2 mL), extracted with dichloromethane
(3.times.5 mL). The organic layer was washed with water (5 mL),
brine (5 mL), dried over sodium sulfate, concentrated and purified
by preparative HPLC to furnish
(2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-
-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (20
mg).
[0659] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 1.17 (t, J=6.8
Hz, 3H), 3.20-3.50 (m, 6H), 3.52-3.62 (m, 2H), 3.63 (dd, J=11.2,
5.6 Hz, 1H), 3.77 (d, J=11.2 Hz, 1H), 3.88 (abq, J=15.2 Hz, 2H),
4.06 (d, J=9.6 Hz, 1H), 4.15 (t, J=3.6 Hz, 2H), 6.43 (d, J=8.8 Hz,
1H), 6.46 (s, 1H), 6.57 (d, J=7.6 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H),
7.27 (s, 1H), 7.34 (d, J=8.4 Hz, 1H). MS (ES) m/z 450 (M+1).
[0660] Following examples were prepared using the procedures
described for example 9.
TABLE-US-00003 Example No. Structure/IUPAC name Spectral data 10
##STR00065## (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-
cyclopropylmethyl-3,4-dihydro-2H- benzo[1,4]oxazin-6-ylmethyl)-
phenyl]-6-hydroxymethyl-tetrahydro- pyran-3,4,5-triol .sup.1H NMR
(400 MHz, CD.sub.3OD): .delta. 0.118 (s, 2H), 0.51 (d, J = 6.8 Hz,
2H), 1.00-1.10 (m, 1H), 3.20- 3.60 (m, 8H), 3.60-3.75 (m, 1H), 3.82
(d, J = 10.0 Hz, 1H) 3.94 (abq, 15.2 Hz, 2H), 4.07 (d, J = 9.6 Hz,
1H), 4.15 (t, J = 4.0, 2H), 6.43 (d, J = 8.0 Hz, 1H), 6.45 (s, 1H),
6.58 (d, J = 8.0 Hz, 1H), 7.24 (dd, J = 8.0, 1.2 Hz, 1H), 7.25 (s,
1H) 7.34 (d, J = 8.0 Hz, 1H), . MS (ES) m/z 476.3 (M + 1). 11
##STR00066## (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-
methyl-3,4-dihydro-2H- benzo[1,4]oxazin-6-ylmethyl)-
phenyl]-6-hydroxymethyl-tetrahydro- pyran-3,4,5-triol .sup.1H NMR
(400 MHz, CD.sub.3OD): .delta. 3.20-3.32 (m, 3H), 3.37 (s, 3H),
3.40-3.55 (m, 3H), 3.61 (dd, J = 10.8, 5.2 Hz, 1H), 3.71 (d, J =
10.8 Hz, 1H), 3.93 (abq, 15.2 Hz, 2H), 4.06 (d, J = 9.6 Hz, 1H),
4.15 (t, J = 4.0, 2H), 6.43 (d, J = 8.8 Hz, 1H), 6.45 (s, 1H), 6.57
(d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.26 (s, 1H) 7.33
(d, J = 8.4 Hz, 1H),. MS (ES) m/z 435 (M + 1). 12 ##STR00067##
6-[2-Chloro-5-((2S,3R,4R,5S,6R)-3,4,
5-trihydroxy-6-hydroxymethyl-tetra-
hydro-pyran-2-yl)-benzyl]-2,3-dihydro-
benzo[1,4]oxazine-4-carboxylic acid ethyl ester .sup.1H NMR (400
MHz, CD.sub.3OD): .delta. 1.25 (t, J = 6.4 Hz, 3H), 3.30-3.50 (m,
3H), 3.66 (d, J = 11.6 Hz, 1H), 3.84 (d, J = 11.2 Hz, 3H), 3.99
(Abq, J = 15.2 Hz, 2H), 4.07 (d, J = 9.6 Hz, 1H), 4.12-4.26 (m,
3H), 6.58 (s, 2H), 6.72 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 7.6 Hz,
1H), 7.25 (d, J = 7.6 Hz, 1H), 7.32 (d, J = 6.4 Hz, 2H) 7.61 (s,
1H), . MS (ES) m/z 494.3 (M + 1). 13 ##STR00068##
1-{6-[2-Chloro-5-((2S,3R,4R,5S,6R)-
3,4,5-trihydroxy-6-hydroxymethyl-tetra-
hydro-pyran-2-yl)-benzyl]-2,3-di-
hydro-benzo[1,4]oxazin-4-yl}-ethanone .sup.1H NMR (400 MHz,
CD.sub.3OD): .delta. 2.25 (s, 3H), 3.25-3.55 (m, 4H), 3.71 (dd, J =
11.6, 4.4 Hz, 1H), 3.88 (d, J = 13.6 Hz, 3H), 4.06 (s, 2H), 4.12
(d, J = 9.6 Hz, 1H), 4.26 (s, 2H), 6.81 (d, J = 8.0 Hz, 2H), 6.98
(br s, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H),
7.39 (s, 1H) MS (ES) m/z 464.2 (M + 1).
Example 14
(2S,3R,4R,5S,6R)-2-{4-Chloro-3-[1-(4-methoxy-benzyl)-1,2,3,4-tetrahydro-qu-
inolin-6-ylmethyl]-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
##STR00069##
[0662] Step I: To a cooled solution of
6-bromo-1-(4-methoxy-benzyl)-1,2,3,4-tetrahydro-quinoline (2.5 g,
7.5 mmol) in THF (30 mL) was added 1.6 M n-butyl lithium in hexanes
(4.7 mL, 7.5 mmol) at -78.degree. C., stirred for 30 min. This was
transferred to a stirred solution of 5-bromo-2-chlorobenzaldehyde
(1.73 g, 7.9 mmol) in THF (30 mL) at -78.degree. C. After stirring
for 30 min, reaction was quenched by the addition of saturated
aqueous solution of ammonium chloride and extracted with ethyl
acetate (2.times.50 mL). The ethyl acetate layer was washed with
water, brine, dried over sodium sulphate, and concentrated. The
resulting residue was purified by silica gel column chromatography
to give
(5-bromo-2-chloro-phenyl)-[1-(4-methoxy-benzyl)-1,2,3,4-tetrahydro-quinol-
in-6-yl]-methanol (2.31 g).
[0663] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 1.95-2.10 (m,
3H), 2.77 (t, J=6.4 Hz, 2H), 3.33 (t, J=5.6 Hz, 2H), 3.78 (s, 3H),
4.39 (s, 2H), 5.96 (d, J=3.6 Hz, 1H), 6.46 (d, J=8.0 Hz, 1H), 6.84
(d, J=7.6 Hz, 2H), 6.91-7.91 (m, 7H). MS (ES) m/z 474.1 (M+2).
[0664] Step II: To an ice cold solution of
(5-bromo-2-chloro-phenyl)-[1-(4-methoxy-benzyl)-1,2,3,4-tetrahydro-quinol-
in-6-yl]-methanol (2.2 g, 4.7 mmol) in dichloromethane (50 mL) was
added Et.sub.3SiH (3.7 mL, 23.3 mmol) followed by
BF.sub.3.OEt.sub.2 (1.5 mL, 11.6 mmol). The reaction mixture was
stirred at room temperature overnight. The reaction was quenched by
the addition of aq. NaHCO.sub.3. The volatiles were evaporated
under reduced pressure; the resulting mixture was extracted with
dichloromethane (2.times.50 mL), washed with brine (10 mL), dried
over sodium sulfate, concentrated and. purified by silica gel
column chromatography to give
6-(5-Bromo-2-chloro-benzyl)-1-(4-methoxy-benzyl)-1,2,3,4-tetrahydro-quino-
line (1.48 g).
[0665] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 1.96-2.02 (m,
2H), 2.77 (t, J=6.0 Hz, 2H), 3.32 (t, J=5.6 Hz, 2H), 3.79 (s, 3H),
3.89 (s, 2H), 4.39 (s, 2H), 6.47-7.29 (m, 10H). MS (ES) m/z 458.1
(M+2).
[0666] Step III: To a stirred solution of
6-(5-bromo-2-chloro-benzyl)-1-(4-methoxy-benzyl)-1,2,3,4-tetrahydro-quino-
line (700 mg, 1.5 mmol) in THF-toluene (15 mL of 1:2 mixture) was
added 1.6 M solution of n-BuLi in hexanes (1.0 mL, 1.5 mmol) at
-78.degree. C. The reaction mixture was stirred for 30 min., and
then transferred to a stirred solution of
2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone (715 mg, 1.5
mmol) in toluene (10 mL) at -78.degree. C. After stirring for 40
min., 0.6 N methanesulfonic acid in methanol (30 mL) was added and
stirred for 20 h at room temperature. Reaction was quenched by the
addition of aq. saturated NaHCO.sub.3 (10 mL) and extracted with
ethyl acetate (3.times.20 mL), dried over sodium sulphate,
concentrated and purified by silica gel column chromatography to
furnish
(2S,3R,4S,5S,6R)-2-{4-chloro-3-[1-(4-methoxy-benzyl)-1,2,3,4-tetrahydro-q-
uinolin-6-ylmethyl]-phenyl}-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-3,4-
,5-triol (330 mg).
[0667] MS (ES) m/z 570.2 (M+1).
[0668] Step IV: To a stirred solution of
(2S,3R,4S,5S,6R)-2-{4-chloro-3-[1-(4-methoxy-benzyl)-1,2,3,4-tetrahydro-q-
uinolin-6-ylmethyl]-phenyl}-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-3,4-
,5-triol (325 mg, 0.6 mmol) in acetonitrile-dichloromethane mixture
(1:1 mixture, 14 mL) was added triethylsilane (0.4 mL, 2.2 mmol)
and boron trifluoride diethyletharate complex (0.15 mL, 1.1 mmol)
at -20.degree. C. After stirring for 4 h at 0.degree. C., reaction
was quenched with aq. saturated NaHCO.sub.3 solution (8 mL). The
volatiles were evaporated under reduced pressure; the resulting
mixture was extracted with ethyl acetate (3.times.20 mL). The
organic layer was washed with brine (5 mL), dried over sodium
sulphate, concentrated and purified by preparative HPLC to furnish
(2S,3R,4R,5S,6R)-2-{4-chloro-3-[1-(4-methoxy-benzyl)-1,2,3,4-tetrahydro-q-
uinolin-6-ylmethyl]-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
(160 mg).
[0669] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 1.91-1.96 (m,
J=5.6 Hz, 2H), 2.70 (t, J=6.4 Hz, 2H), 3.25-3.44 (m, 6H), 3.67 (dd,
J=12.0, 5.6 Hz, 1H), 3.74 (s, 3H), 3.84-3.95 (m, 3H), 4.06 (d,
J=9.6 Hz, 1H), 4.36 (s, 2H), 6.44 (d, J=9.2 Hz, 1H), 6.74 (d, J=7.2
Hz, 2H), 6.83 (d, J=8.8 Hz, 2H), 7.15 (d, J=8.8 Hz, 2H), 7.22-7.28
(m, 2H), 7.31 (d, J=8.0 Hz, 1H).
[0670] MS (ES) m/z 540.0 (M+1).
Example 15
(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(1,2,3,4-tetrahydro-quinolin-6-ylmethyl)-ph-
enyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
##STR00070##
[0672] To a solution of
(2S,3R,4R,5S,6R)-2-{4-chloro-3-[1-(4-methoxy-benzyl)-1,2,3,4-tetrahydro-q-
uinolin-6-ylmethyl]-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
(135 mg, 0.25 mmol) in methanol (5 mL) was added 10% palladium on
charcoal (60 mg), 0.05 mL conc. HCl and stirred under hydrogen
balloon pressure for 18 h. Reaction mixture was filtered through
celite bed, washed with methanol and concentrated. The resulting
residue was purified by preparative HPLC to furnish
(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(1,2,3,4-tetrahydro-quinolin-6-ylmethyl)-p-
henyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (74 mg).
[0673] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 1.84-1.90 (m,
2H), 2.67 (t, J=6.8 Hz, 2H), 3.17-3.20 (m, 2H), 3.25-3.46 (m, 4H),
3.65-3.69 (m, 1H), 3.84-3.96 (m, 3H), 4.06 (d, J=9.2 Hz, 1H), 6.43
(d, J=8.0 Hz, 1H), 6.73-6.76 (m, 2H), 7.23-7.28 (m, 2H), 7.32 (d,
J=8.4 Hz, 1H).
[0674] MS (ES) m/z 420.0 (M+1).
[0675] Following examples were prepared using the procedures
described for examples 14 or 15.
TABLE-US-00004 Example No. Structure/IUPAC name Spectral data 16
##STR00071## (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(1,2,
3,4-tetrahydro-quinolin-7-ylmethyl)-
phenyl]-6-hydroxymethyl-tetrahydro- pyran-3,4,5-triol .sup.1H NMR
(400 MHz, CD.sub.3OD): .delta. 1.84-1.89 (m, 2H), 2.68 (t, J = 6.4
Hz, 2H), 3.18 (t, J = 5.2 Hz, 2H), 3.26-3.46 (m, 4H), 3.67 (dd, J =
12.0, 4.8, 1H), 3.84-3.97 (m, 3H), 4.06 (d, J = 9.6 Hz, 1H), 6.34
(s, 1H), 6.40 (d, J = 7.6 Hz, 1H), 6.77 (d, J = 7.6 Hz, 1H),
7.24-7.33 (m, 3H). MS (ES) m/z 420.0 (M + 1). 17 ##STR00072##
(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(2,3-
dihydro-1H-indol-5-ylmethyl)-phenyl]-
6-hydroxymethyl-tetrahydro-pyran- 3,4,5-triol .sup.1H NMR (400 MHz,
CD.sub.3OD): .delta. 2.94 (t, J = 8.0 Hz, 2H), 3.26-3.45 (m, 6H),
3.66-3.70 (m, 1H), 3.86 (d, J = 11.2 Hz, 1H), 3.95 (d, J = 15.2,
1H), 4.01 (d, J = 15.2 Hz, 1H), 4.08 (d, J = 9.6 Hz, 1H), 6.62 (d,
J = 8.0 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.95 (s, 1H), 7.24-7.34
(m, 3H). MS (ES) m/z 406.0 (M + 1). 18 ##STR00073##
(2S,3R,4R,5S,6R)-2-[3-(2-Benzyl-1,2,
3,4-tetrahydro-isoquinolin-7-yl-
methyl)-4-chloro-phenyl]-6-hydroxy-
methyl-tetrahydro-pyran-3,4,5-triol .sup.1H NMR (400 MHz,
CD.sub.3OD): .delta. 2.82-2.89 (m, 4H), 3.25-3.47 (m, 4H),
3.66-3.70 (m, 3H), 3.77 (s, 2H), 3.85-3.88 (m, 1H), 3.98-4.08 (m,
3H), 6.84 (s, 1H), 6.98-7.40 (m, 10H). MS (ES) m/z 510.0 (M + 1).
19 ##STR00074## (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(1,2,
3,4-tetrahydro-isoquinolin-7-yl- methyl)-phenyl]-6-hydroxymethyl-
tetrahydro-pyran-3,4,5-triol .sup.1H NMR (400 MHz, CD.sub.3OD):
.delta. 3.08 (t, J = 6.0 Hz, 2H), 3.27-3.49 (m, 6H), 3.71 (dd, J =
11.6, 4.8 Hz, 1H), 3.88-3.91 (m, 1H), 4.06-4.15 (m, 3H), 4.29 (s,
2H), 7.04 (s, 1H), 7.16 (s, 2H), 7.31-7.37 (m, 3H). MS (ES) m/z
419.9 (M + 1). 20 ##STR00075## (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(2,2-
dimethyl-3,4-dihydro-2H-benzo[1,4]
oxazin-6-ylmethyl)-phenyl]-6-hydroxy-
methyl-tetrahydro-pyran-3,4,5-triol .sup.1H NMR (400 MHz,
CD.sub.3OD): .delta. 1.26 (s, 6H), 2.98 (s, 2H), 3.37-3.44 (m, 4H),
3.65-3.70 (m, 1H), 3.85-3.98 (m, 3H), 4.08 (d, J = 9.48 Hz, 1H),
6.43 (d, J = 8.16 Hz, 1H), 6.46 (s, 1H), 6.54 (d, J = 7.94 Hz, 1H),
7.25 (d, J = 8.16 Hz, 1H), 7.30-7.34 (m, 2H). MS (ES) m/z 450.0 (M
+ 1) 21 ##STR00076## (2S,3R,4R,5S,6R)-2-(4-Chloro-3-
chroman-6-ylmethyl-phenyl)-6- hydroxymethyl-tetrahydro-pyran-
3,4,5-triol .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 1.93-1.96
(m, 2H), 2.71 (t, J = 6.40 Hz, 2H), 3.26-3.44 (m, 4H), 3.66-3.70
(m, 1H), 3.87 (d, J = 11.20 Hz, 1H), 3.90 (d, J = 15.2 Hz, 1H),
3.99 (d, J = 14.8 Hz, 1H), 4.06-4.12 (m, 3H), 6.60 (d, J = 8.16 Hz,
1H), 6.84-6.87 (m, 2H), 7.26 (dd, J = 8.16 Hz, 1.98 Hz 1H), 7.30
(d, J = 1.98 Hz, 1H), 7.33 (d, J = 8.16 Hz, 1H). MS (ES) m/z 420.9
(M + 1), 4437.9 (M + 18) 22 ##STR00077##
(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(2,3-
dihydro-benzofuran-5-ylmethyl)-phenyl]-
6-hydroxymethyl-tetrahydro-pyran- 3,4,5-triol .sup.1H NMR (400 MHz,
CD.sub.3OD): .delta. 3.17 (t, J = 8.56 Hz, 2H), 3.30-3.46 (m, 4H),
3.66-3.70 (m, 1H), 3.85- 3.88 (m, 1H), 3.98 (d, J = 15.2 Hz, 1H),
4.02 (d, J = 14.8 Hz, 1H), 4.07 (d, J = 9.2 Hz, 1H), 4.48 (t, J =
8.56 Hz, 2H), 6.60 (d, J = 8.3 Hz, 1H), 6.91 (d, J = 8.1 Hz, 1H),
7.02 (s, 1H), 7.26 (dd, J = 8.1 Hz, 2.0 Hz 1H), 7.31 (d, J = 1.7
Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H). MS (ES) m/z 424.0 (M + 18) 23
##STR00078## (2R,3S,4R,5R,6S)-2-Hydroxymethyl-
6-[4-methyl-3-(1,2,3,4- tetrahydroquinolin-7-ylmethyl)-
phenyl]-tetrahydro-pyran-3,4,5-triol .sup.1H NMR (400 MHz,
CD.sub.3OD): .delta. 1.84-1.90 (m, 2H), 2.18 (s, 3H), 2.67 (t, J =
6.0 Hz, 2H), 3.16-3.19 (m, 2H), 3.35-3.48 (m, 4H), 3.68 (dd, J =
12.0, 5.2, 1H), 3.78-3.88 (m, 3H), 4.06 (d, 8.8 Hz, 1H), 6.27 (d, J
= 1.6 Hz, 1H), 6.36 (dd, J = 7.6, 1.6 Hz, 1H), 6.76 (d, J = 7.6 Hz,
1H), 7.00 (d, J = 7.2 Hz, 1H), 7.15-7.18 (m, 2H). MS (ES) m/z 400.3
(M + 1). 24 ##STR00079## (2S,3R,4R,5S,6R)-2-[3-(3,4-Dihydro-
2H-benzo[1,4]oxazin-6-ylmethyl)-4-
fluoro-phenyl]-6-hydroxymethyl-tetra- hydro-pyran-3,4,5-triol
.sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 3.29-3.48 (m, 6H), 3.71
(dd, J = 12.0, 5.2 Hz, 1H), 3.79-3.91 (m, 3H), 4.10 (d, J = 9.2,
1H), 4.17 (t, J = 4.4 Hz, 2H), 6.46- 6.52 (m, 2H), 6.59 (d, J = 8.0
Hz, 1H), 7.01-7.31 (m, 3H). MS (ES) m/z 406.3 (M + 1). 25
##STR00080## (2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-
benzo[1,4]dioxin-6-ylmethyl)-4- methoxy-phenyl]-6-hydroxymethyl-
tetrahydro-pyran-3,4,5-triol .sup.1H NMR (400 MHz, CD.sub.3OD):
.delta. 3.27-3.45 (m, 4H), 3.66-3.70 (dd, J = 12.0, 5.6 Hz, 1H),
3.76-3.89 (m, 6H), 4.05 (d, J = 9.6, 1H), 4.18 (s, 4H), 6.64-6.67
(m, 3H), 6.92 (d, J = 8.4 Hz, 1H), 7.17 (d, J = 2.0 Hz, 1H), 7.25
(dd, J = 8.0, 2.0 Hz, 1H). MS (ES) m/z 436.0 (M + 18). 26
##STR00081## (2R,3S,4R,5R,6S)-2-Hydroxymethyl-
6-[4-methoxy-3-(1,2,3,4-tetrahydro- quinolin-6-ylmethyl)-phenyl]-
tetrahydro-pyran-3,4,5-triol .sup.1H NMR (400 MHz, CD.sub.3OD):
.delta. 1.84-1.88 (m, 2H), 2.67 (d, J = 6.4 Hz, 2H), 3.17 (t, J =
6.4 Hz, 2H), 3.25-3.44 (m, 4H), 3.65 (dd, J = 12.0, 4.8, 1H),
3.74-3.86 (m, 6H), 4.01 (d, J = 9.2 Hz, 1H), 6.41 (d, J = 8.0 Hz,
1H), 6.73-6.75 (m, 2H) 6.89 (d, J = 8.8 Hz, 1H), 7.12 (d, J = 1.6
Hz, 1H), 7.21 (dd, J = 8.4, 2.0 Hz, 1H). MS (ES) m/z 416.0 (M + 1).
27 ##STR00082## (2R,3S,4R,5R,6S)-2-Hydroxymethyl-
6-[4-methoxy-3-(1,2,3,4-tetrahydro- quinolin-7-ylmethyl)-phenyl]-
tetrahydro-pyran-3,4,5-triol .sup.1H NMR (400 MHz, CD.sub.3OD):
.delta. 1.84-1.88 (m, 2H), 2.66 (d, J = 6.4 Hz, 2H), 3.17 (t, J =
6.4 Hz, 2H), 3.25-3.43 (m, 4H), 3.65 (dd, J = 12.0, 5.2, 1H),
3.72-3.86 (m, 6H), 4.01 (d, J = 9.2 Hz, 1H), 6.36-6.42 (m, 2H),
6.73 (d, J = 7.6 Hz, 1H) 6.89 (d, J = 8.8 Hz, 1H), 7.14 (d, J = 2.0
Hz, 1H), 7.21 (dd, J = 8.4, 2.0 Hz, 1H). MS (ES) m/z 416.1 (M + 1).
28 ##STR00083## (2S,3R,4R,5S,6R)-2-[4-Chloro-3-
(3,4-dihydro-2H-benzo[1,4]oxazin-7-
ylmethyl)-phenyl]-6-hydroxymethyl- tetrahydro-pyran-3,4,5-triol
.sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 3.26-3.47 (m, 6H),
3.66-3.70 (m, 1H), 3.85-3.96 (m, 3H), 4.07 (d, J = 9.5 Hz, 1H),
4.15 (t, J = 4.4 Hz, 2H), 6.40-6.45 (m, 2H), 6.56 (d, J = 8.0 Hz,
1H), 7.24-7.30 (m, 2H), 7.32 (d, J = 8.4 Hz, 1H),. MS (ES) m/z
421.9 (M + 1). 29 ##STR00084## (2S,3R,4R,5S,6R)-2-[4-Chloro-3-
(4,4-spiro-cyclopropyl-chroman-6- ylmethylyphenyl]-6-hydroxymethyl-
tetrahydro-pyran-3,4,5-triol .sup.1H NMR (400 MHz, CD.sub.3OD):
.delta. 0.80-0.83 (m, 2H), 0.96-0.99 (m, 2H), 1.82 (t, J = 5.1 Hz,
2H), 3.27-3.45 (m, 4H), 3.66- 3.70 (m, 1H), 3.87 (d, J = 11.7 Hz,
1H), 3.92 (d, J = 15.2 Hz, 1H), 3.97 (d, J = 15.2 Hz, 1H), 4.07 (d,
J = 9.2 Hz, 1H), 4.20 (t, J = 5.1 Hz, 2H), 6.55 (d, J = 2.2 Hz,
1H), 6.61 (d, J = 8.3 Hz, 1H), 6.81 (dd, J = 8.3 Hz, J = 2.2 Hz,
1H), 7.25-7.27 (m, 2H),7.33 (d, J = 8.1 Hz, 1H). MS (ES) m/z 447.2
(M + 1). 30 ##STR00085## 2S,3R,4R,5S,6R)-2-[5-(2,3-Dihydro-
benzo[1,4]dioxin-6-ylmethyl)-2- ethoxy-phenyl]-6-hydroxymethyl-
tetrahydro-pyran-3,4,5-triol .sup.1H NMR (400 MHz, CD.sub.3OD):
.delta. 1.38 (t, J = 6.8 Hz, 3H), 3.25-3.28 (m, 1H), 3.36-3.47 (m,
2H), 3.56- 3.67 (m, 3H), 3.76 (s, 2H), 3.84 (d, J = 11.6 Hz, 1H),
4.01-4.05 (m, 2H), 4.17 (s, 3H), 4.65 (d, J = 8.4 Hz, 1H), 6.62 (d,
J = 6.4 Hz, 2H), 6.69 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 2.1 Hz,
1H), 7.04 (d, J = 8.4 Hz, 1H), 7.24 (s, 1H). MS (ES) m/z 449.9 (M +
18). 31 ##STR00086## (2S,3R,4R,5S,6R)-2-[3-(3,4-Dihydro-
2H-benzo[1,4]oxazin-6-ylmethyl)-4- methoxy-phenyl]-6-hydroxymethyl-
tetrahydro-pyran-3,4,5-triol .sup.1H NMR (400 MHz, CD.sub.3OD):
.delta. 3.25-3.28 (m, 1H), 3.3-3.88 (m, 3H), 3.67- 3.75 (m, 2H),
3.76 (d, J = 10.8 Hz, 1H), 3.79 (s, 3H), 3.80-3.88 (m, 2H), 4.02
(d, J = 9.2 Hz, 1H), 4.13 (t, J = 4.4 Hz, 2H), 6.43 (dd, J = 8.0
& 1.6 Hz, 2H), 6.46 (s, 1H), 6.53 (d, J = 8.0 Hz, 1H), 6.90 (d,
J = 4.8 Hz, 1H), 7.14 (d, J = 2.0 Hz, 1H), 7.22 (dd, J = 8.4 &
2.0 Hz, 1H). MS (ES) m/z 418.0 (M + 1). 32 ##STR00087##
(2S,3R,4R,5S,6R)-2-(3-Chroman-6- ylmethyl-4-methoxy-phenyl)-6-
hydroxymethyl-tetrahydro-pyran- 3,4,5-triol .sup.1H NMR (400 MHz,
CD.sub.3OD): .delta. 1.94-1.97 (m, 2H), 2.71 (t, J = 6.4 Hz, 2H),
3.27-3.28 (m, 1H), 3.31-3.44 (m, 3H), 3.66- 3.70 (m, 1H), 3.75 (d,
J = 6.4 Hz, 1H), 3.81 (s, 3H), 3.83-3.89 (m, 3H), 4.04 (d, J = 9.2
Hz, 1H), 4.11 (t, J = 5.2 Hz, 1H), 6.58 (d, J = 8.0 Hz, 1H),
6.85-6.89 (m, 2H), 6.92 (d, J = 8.4 Hz, 1H), 7.16 (d, J = 2.0 Hz,
1H), 7.25 (dd, J = 8.4 & 2.4 Hz, 1H). MS (ES) m/z 434.1 (M +
18). 33 ##STR00088## (2S,3R,4R,5S,6R)-2-(3-Chroman-6-
ylmethyl-4-trifluoromethoxy-phenyl)-
6-hydroxymethyl-tetrahydro-pyran- 3,4,5-triol .sup.1H NMR (400 MHz,
CD.sub.3OD): .delta. 1.91-1.97 (m, 2H), 2.71 (t, J = 6.8 Hz, 2H),
3.20-3.28 (m, 1H), 3.35-3.44 (m, 3H), 3.66- 3.70 (m, 1H), 3.84-3.94
(m, 3H), 4.09-4.11 (m, 3H), 6.60 (d, J = 8.0 Hz, 1H), 6.84 (d, J =
8.3 Hz, 2H), 7.23 (dd, J = 8.4 &1.2 Hz, 1H), 7.33 (d, J = 6.0
Hz, 1H), 7.36 (dd, J = 2.0 & 8.4 Hz, 1H). MS (ES) m/z 471.0 (M
+ 1).
Examples 34-35
##STR00089##
[0677] Step I: To a stirred solution of acetic acid
(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-
-tetrahydro-pyran-2-ylmethyl ester (13.00 g, 22.56 mmol) prepared
using the procedures described in J. Med. Chem. 2008,
51(5),1145-49, in 1,2-dichloroethane (130 mL) was added acetyl
chloride at 0.degree. C. Subsequently, AlCl.sub.3 (9.03 g, 67.68
mmol) was added over 30 min at a rate to ensure that the
temperature did not exceed 4.degree. C. After 1 h, the reaction
mixture was taken to room temperature and stirred at 50.degree. C.
overnight. The reaction was quenched by pouring over ice and the
resulting suspension was diluted with water (100 mL) and extracted
with dichloromethane (100.times.2 mL). The organic layer was washed
with water (50 mL), brine (50 mL) and dried over anhydrous sodium
sulfate. Solvent was removed under reduced pressure to get a crude
product (12 g).
[0678] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 1.70 (s, 3H),
1.97 (s, 3H), 2.0 (s, 6H), 2.61 (s, 3H), 3.96-4.0 (m, 1H),
4.07-4.17 (m, 3H), 4.31 (dd, J=12.4 Hz, 4.9 Hz, 1H), 4.54 (d, J=9.8
Hz, 1H), 5.03 (t, J=9.8 Hz, 1H), 5.16 (t, J=9.5 Hz, 1H), 5.37 (t,
J=9.5 Hz, 1H), 6.88 (d, J=8.5 Hz, 1H), 7.26 (dd, J=8.3 Hz, 1.95 Hz,
1H), 7.32-7.39 (m, 2H), 7.40 (d, J=8.3 Hz, 1H), 7.68 (d, J=2.2 Hz,
1H).
[0679] MS (ES) m/z 590.9 (M+1)
[0680] Step II: To acetic acid
(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[3-(3-acetyl-4-hydroxy-benzyl)-4-chlo-
ro-phenyl]-tetrahydro-pyran-2-ylmethylester (12.00 g, 20.32 mmol)
was added N,N-dimethyl formamide dimethyl acetal (3.0 mL, 22.35
mmol). The reaction mixture was stirred at 90.degree. C. overnight.
The reaction was quenched by the addition of water (30 mL) and
extracted with ethyl acetate (150 mL.times.3), solvent was removed
under reduced pressure to get a crude product (8.12 g). The crude
product was used for next reaction without any purification.
[0681] MS (ES) m/z 477.9 (M+1)
Example 34
6-[2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahydr-
o-pyran-2-yl)-benzyl]-chromen-4-one
[0682] Step III: To
(E)-1-{5-[2-Chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-t-
etrahydro-pyran-2-yl)-benzyl]-2-hydroxy-phenyl}-3-dimethylamino-propenone
(8.00 g, 16.77 mmol) in chloroform (80 mL) was added conc. HCl (3
mL). The reaction mixture was refluxed overnight. The reaction was
quenched by the addition of water (50 mL) and extracted with ethyl
acetate (150 mL.times.3), solvent was removed under reduced
pressure to get a crude product (4.0 g).
[0683] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 3.28-3.47 (m,
5H), 3.70 (dd, J=12.0 Hz, 7.5 Hz, 1H), 3.90 (d, J=11.5 Hz, 1H),
4.14 (d, J=9.5 Hz, 1H), 4.26 (d, J=3.9 Hz, 1H), 6.35 (d, J=5.8 Hz,
1H), 7.34-7.41 (m, 2H), 7.45 (d, J=2.0 Hz, 1H), 7.53 (d, J=8.8 Hz,
1H), 7.65 (dd, J=8.8 Hz, 2.2 Hz, 1H), 7.93 (d, J=2.2 Hz, 1H), 8.16
(d, J=5.8 Hz, 1H).
[0684] MS (ES) m/z 432.8 (M+1)
Example 35
6-[2-Chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahydr-
o-pyran-2-yl)-benzyl]-chroman-4-one
[0685] Step IV: To a stirred solution of
6-[2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahyd-
ro-pyran-2-yl)-benzyl]-chromen-4-one (0.10 g, 0.2315 mmol) in ethyl
acetate (2.5 mL) was added 10% Palladium on C (20 mg, 20% w/w)
followed by methanol (2.5 mL). After stirring for for 18 h under
hydrogen atmosphere, the reaction mixture was filtered through
celite and concentrated to furnish the crude product, which was
further purified by Preparative HPLC to yield the title compound
(41 mg)
[0686] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 2.78 (t, J=6.6
Hz, 2H), 3.27-3.49 (m, 4H), 3.71 (dd, J=12.0 Hz, 7.5 Hz, 1H), 3.90
(d, J=11.5 Hz, 1H), 4.04-4.13 (m, 3H), 4.51 (t, J=7.0 Hz, 2H), 6.92
(d, J=8.5 Hz, 1H), 7.30-7.41 (m, 4H), 7.65 (d, J=2.2 Hz, 1H).
[0687] MS (ES) m/z 434.9 (M+1)
Example 36
(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-hydroxy-chroman-6-ylmethyl)-phenyl]-6-hy-
droxymethyl-tetrahydro-pyran-3,4,5-triol
##STR00090##
[0689] To a solution of
6-[2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahyd-
ro-pyran-2-yl)-benzyl]-chroman-4-one (0.1 g, 0.23 mmol) in methanol
(3 mL) was added sodium borohydride (0.017 g, 0.46 mmol). The
reaction mixture was stirred for 2 h and quenched by the addition
of water (10 mL) and extracted with ethyl acetate (150 mL.times.3),
solvent was removed under reduced pressure to get crude
(2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-hydroxy-chroman-6-ylmethyl)-phenyl]-6-h-
ydroxymethyl-tetrahydro-pyran-3,4,5-triol which was further
purified by preparative HPLC (Yield=30 mg).
[0690] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 1.95-2.06 (m,
2H), 3.26-3.46 (m, 5H), 3.68 (dd, J=11.9 Hz, 5.1 Hz, 1H), 3.87 (d,
J=11.5 Hz, 1H), 3.97-4.02 (m, 1H), 4.08 (d, J=9.2 Hz, 1H),
4.15-4.20 (m, 2H), 4.65 (t, J=4.4 Hz, 1H), 6.66 (d, J=8.3 Hz, 1H),
7.00 (d, J=8.8 Hz, 1H), 7.15 (s, 1H), 7.23-7.32 (m, 2H), 7.33 (d,
J=8.3 Hz, 1H).
[0691] MS (ES) m/z 453.9 (M+18)
Example 37
(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(spiro[chromane-2,1'-cyclopentane]-6-ylmeth-
yl)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol
##STR00091##
[0693] Step I: To the acetic acid
(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[3-(3-acetyl-4-hydroxy-benzyl)-4-chlo-
ro-phenyl]-tetrahydro-pyran-2-ylmethylester (0.1 g, 0.17 mmol) was
added cyclopentanone (0.015 mL, 0.17 mmol) followed by pyrrolidine
(0.056 mL, 0.34 mmol). The reaction mixture was subjected to
microwave irradiation for 4 min. Reaction mixture was quenched with
water (3 mL), extracted with ethyl acetate (5 mL.times.3), and
solvent was removed under reduced pressure to get a crude product
(0.1 g) which was used for next reaction as such.
[0694] Step II: To a stirred solution of the crude product obtained
in step 1 in THF:MeOH (3:2, 5 mL) was added lithium hydroxide (0.02
g, 0.52 mmol) in water (1 mL). The reaction mixture was stirred for
3 h at room temperature, diluted with water (3 mL), extracted with
ethyl acetate (5 mL.times.3), solvent was removed under reduced
pressure to get a crude product, which was purified by column
chromatography to yield the title compound (20 mg).
[0695] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 1.64-1.86 (m,
6H), 2.00-2.04 (m, 2H), 2.81 (s, 2H), 3.26-3.47 (m, 4H), 3.69 (dd,
J=11.7 Hz, 4.9 Hz, 1H), 3.87 (d, J=11.9 Hz, 1H), 4.02-4.12 (m, 3H),
6.85 (d, J=8.3 Hz, 1H), 7.29-7.39 (m, 4H), 7.60 (d, J=2.0 Hz,
1H).
[0696] MS (ES) m/z 489.4 (M+1)
Example 38
(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(spiro[chromane-2,1'-cyclopentane]-6-ylmeth-
yl)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol
##STR00092##
[0698] To
6-[2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-
-tetrahydro-pyran-2-yl)-benzyl]-2,2-spirocyclopentyl-chroman-4-one
(0.125 g, 0.26 mmol) in acetonitrile/1,2-dichloroethane (1:1
mixture, 2 mL) was added triethylsilane (0.15 mL, 1 mmol) followed
by borontrifluoride diethyletherate (0.06 mL, 0.5 mmol) at
0.degree. C. The reaction mixture was stirred at room temperature
for 18 h and then heated to 60.degree. C. for 2 h, quenched with
saturated NaHCO.sub.3 (5 mL) extracted with dichloromethane (10 mL
x 3), solvent was removed under reduced pressure to get the crude
product which was further purified by preparative HPLC to yield the
title compound (Yield=5 mg).
[0699] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 1.61-1.70 (m,
6H), 1.86-1.89 (m, 6H), 2.75 (t, J=6.6 Hz, 2H), 3.27-3.46 (m, 2H),
3.68-3.71 (m, 1H), 3.88 (d, J=11.4 Hz, 1H), 3.99 (q, J=15.1 Hz,
2H), 4.11 (d, J=9.3 Hz, 1H), 6.59 (d, J=8.8 Hz, 1H), 6.88-6.90 (m,
2H), 7.28 (d, J=7.8 Hz, 1H), 7.33-7.36 (m, 2H).
[0700] MS (ES) m/z 475.0 (M+1)
[0701] Following example was prepared by using the analogous
procedures described for example 38.
TABLE-US-00005 Example No. Structure/IUPAC name Spectral data 39
##STR00093## 6-[[2-Chloro-5-[(2S,3R,4R,5S,6R)- 3,4,5-trihydroxy-6-
(hydroxymethyl)tetrahydropyran-2-yl]
phenyl]methyl]spiro[chromane-2,4'- piperidine]-4-one .sup.1H NMR
(400 MHz, CD.sub.3OD): .delta. 1.85-1.95 (m, 2H), 2.25 (d, J = 14
Hz, 2H), 2.82 (s, 2H), 3.25-3.47 (m, 9H), 3.69 (dd, J = 11.7 &
4.6 Hz, 1H), 3.87 (d, J = 11.5. Hz, 1H), 4.03-4.12 (m, 2H), 7.03
(d, J = 8.5 Hz, 1H), 7.29-7.47 (m, 3H), 7.45 (d, J = 8.5 Hz, 1H),
7.64 (s, 1H). MS (ES) m/z 503.9 (M + 1)
Example 40-41
##STR00094## ##STR00095##
[0703] Step I: To a stirred solution of
5-bromo-2-methoxybenzaldehyde (5.0 g, 23.25 mmol) in toluene (50
mL) was added ethylene glycol (2.6 mL, 46.5 mmol) and
p-toluenesulfonic acid monohydrate (0.45 g, 2.32 mmol) and the
reaction mixture was azeotroped for 2 h, quenched with sat.
NaHCO.sub.3 (50 mL). Reaction mixture was concentrated under
reduced pressure, extracted with ethyl acetate (2.times.100 mL),
washed with water, brine, dried over sodium sulfate, concentrated
and purified by silica gel column chromatography to furnish
2-(5-bromo-2-methoxy-phenyl)-[1,3]dioxolane (3.75 g).
[0704] Step II: To a stirred solution of compound prepared in step
I (3.50 g, 13.51 mmol) in THF (20 mL) was added n-butyl lithium
(8.5 mL, 13.51 mmol) at -78.degree. C. and stirred for 1 h.
Ttetra-OBn-glucaranolactone (7.25 g, 13.51 mmol) in toluene (20 mL)
was cooled to -78.degree. C. and Ithium salt prepared above was
added to this at -78.degree. C. and stirred for 1 h, quenched with
sat. NH.sub.4Cl soln. (10 mL) and extracted with ethyl acetate
(2.times.70 mL). The ethyl acetate layer was washed with water,
brine, dried over sodium sulphate, concentrated and purified by
silica gel column chromatography to furnish
(3R,4S,5R,6R)-3,4,5-Tris-benzyloxy-6-benzyloxymethyl-2-(3-[1,3]dioxolan-2-
-yl-4-methoxy-phenyl)-tetrahydro-pyran-2-ol (4.8 g).
[0705] Step II: To a stirred solution of compound prepared in step
II (4.80 g, 6.68 mmol) in THF (20 mL) was added 6N HCl (10 mL) and
stirred for 16 h. This reaction mixture was concentrated under
reduced pressure, diluted with ethyl acetate (100 mL) washed with
sat. NH.sub.4Cl (20 mL), dried over sodium sulfate, concentrated
and purified by silica gel column chromatography to furnish
2-Methoxy-5-((3R,4S,5R,6R)-3,4,5-tris-benzyloxy-6-benzyloxymethyl-2-hydro-
xy-tetrahydro-pyran-2-yl)-benzaldehyde (3.2 g).
[0706] Step IV: To a stirred solution of
6-bromospiro[chromane-2,1'-cyclobutane](0.563 g, 2.23 mmol) in THF
(3 mL) at -78.degree. C. was added n-butyl lithium (1.45 mL, 2.23
mmol) and stirred for 1 h. Compound obtained in step III (0.3 g,
0.45 mmol) in toluene (3 mL) was cooled to -78.degree. C. and
Ithium salt prepared above was added to this at -78.degree. C. This
reaction mixture was stirred for 1 h, quenched with sat. NH.sub.4Cl
(10 mL) and extracted with ethyl acetate (2.times.20 mL). The ethyl
acetate layer was washed with water, brine, dried over sodium
sulphate, concentrated and purified by silica gel column
chromatography to furnish
[2-methoxy-5-[(3R,4S,5R,6R)-3,4,5-tribenzyloxy-6-(benzyloxymethyl)-2-hydr-
oxytetrahydropyran-2-yl]phenyl]-spiro[chromane-2,1'-cyclobutane]-6-yl-meth-
anone (0.250 g).
Example 40
6-(2-Methoxy-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6(benzyloxymethyl)t-
etrahydro-2H-pyran-2-yl)benzyl)spiro[chroman-2,1'-cyclobutane
[0707] Step V: To a stirred solution of compound obtained in step
IV (0.250 g, 0.29 mmol) in DCE (2 mL) and acetonitrile (2 mL) at
-30.degree. C. was added triethylsilane (0.28 g, 1.03 mmol)
followed by borntrifluoride.diethyletherate (0.13 g, 1.76 mmol) and
stirred at -30.degree. C. for 5 h and then at 25.degree. C. for 16
h. Reaction was quenched with sat. NaHCO.sub.3 (20 mL), the
volatiles were evaporated under reduced pressure; the resulting
mixture was extracted with dichloromethane (2.times.20 mL), washed
with brine (5 mL), dried over sodium sulfate, concentrated and
purified by silica gel column chromatography to furnish the titled
compound (Yield=0.21 g).
Example 41
(2S,3R,4R,5S,6R)-2-[4-methoxy-3-(spiro[chromane-2,1'-cyclobutane]-6-ylmeth-
yl)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol
[0708] Step VI: To a stirred solution of (0.21 g, 0.25 mmol) in
ethyl acetate (5 mL) was added Palladium on C 10% w/w (50 mg)
followed by a drop of conc.HCl was added. The reaction was stirred
for 18 h under hydrogen atmosphere. Reaction mixture was filtered
through celite and concentrated to furnish the crude titled
compound which was purified by preparative HPLC (22 mg).
[0709] Following examples were prepared by using the analogous
procedures described for examples 40-41.
TABLE-US-00006 Example no. Structure/IUPAC name Spectral data 42
##STR00096## 7-[2-Chloro-5-((2S,3R,4R,5S,6R)-
3,4,5-trihydroxy-6-hydroxymethyl-
tetrahydro-pyran-2-yl)-benzyl]-4H- benzo[1,4]oxazin-3-one .sup.1H
NMR (400 MHz, DMSO- D6): .delta. 3.09-3.26 (m, 3H), 3.43-3.46 (m,
1H), 3.66- 3.71 (m, 1H), 3.92-3.97 (m, 2H), 4.00 (d, J = 9.2 Hz,
1H), 4.10-4.12 (m, 1H), 4.46 (t, J +32 6.0 Hz, 1H), 4.52 (s, 2H),
4.86 (d, J = 6.0 Hz, 1H), 4.97-4.97 (m, 2H), 6.76-6.80 (m, 3H),
7.24 (dd, J +32 8.0 Hz, 1.6 Hz, 1H), 7.34 (d, J = 1.6 Hz, 1H), 7.38
(d, J = 8.0 Hz, 1H), 10.64 (s, 1H). MS (ES) m/z 436.0 (M + 1). 43
##STR00097## 7-[2-Methoxy-5-((2S,3R,4R,5S,6R)-
3,4,5-trihydroxy-6-hydroxymethyl-
tetrahydro-pyran-2-yl)-benzyl]-4H- benzo[1,4]oxazin-3-one .sup.1H
NMR (400 MHz, CD.sub.3OD): .delta. 3.30-3.44 (m, 5H), 3.67 (dd,
1H), 3.79 (s, 3H), 3.80-3.86 (m, 2H), (d, J = 9.0 Hz, 1H), 4.49 (s,
2H), 6.73-6.90 (m, 3H), 6.91 (d, J = 8.0 Hz, 1H), 7.18 (s, 1H),
7.25 (dd, J = 8.31, 1.7 Hz, 1H) MS (ES) m/z 432.1 (M + 1) 44
##STR00098## (2S,3R,4R,5S,6R)-2-[4-chloro-3-
(spiro[chromane-2,1'-cyclobutane]-6- ylmethyl)phenyl]-6-
(hydroxymethyl)tetrahydropyran-3,4,5- triol .sup.1H NMR (400 MHz,
DMSO- D6): .delta. 1.88 (t, J = 6.4 Hz, 2H), 1.99-2.05 (m, 2H),
2.09-2.13 (m, 2H), 2.70 (t, J = 6.8 Hz, 2H), 3.11-3.27 (m, 5H),
3.39-3.47 (m, 2H), 3.68-3.71 (m, 1H), 3.88- 3.97 (m, 2H), 3.99 (d,
J = 9.2 Hz, 1H), 4.46 (t, J = 5.6 Hz, 1H), 4.85 (d, J = 6.0 Hz,
1H), 4.96-4.98 (m, 2H), 6.63 (d, J = 8.8 Hz, 1H), 6.86-6.88 (m,
2H), 7.23 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 7.32 (d, J = 2.0 Hz, 1H),
7.38 (d, J = 8.0 Hz, 1H), MS (ES) m/z 461.0 (M + 1)
##STR00099## ##STR00100##
[0710] Step I: To a stirred solution of acetic acid
(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-
-tetrahydro-pyran-2-ylmethyl ester (4.0 g, 6.93 mmol) prepared
using the procedures described in J. Med. Chem. 2008, 51(5),
1145-49, in dichloromethane (40 mL) was added 1 molar solution of
BBr.sub.3 (34.6 mL, 34.6 mmol) at -78.degree. C. under nitrogen
atmosphere. Reaction was stirred at -78.degree. C. for 1.5 h and
-30.degree. C. for 1 h. Reaction mixture was poured over ice and
neutralized with sat. NaHCO.sub.3 (20 mL), extracted with
dichloromethane, concentrated and purified by silica gel column
chromatography to furnish acetic acid
(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-chloro-3-(4-hydroxy-benzyl)-phenyl-
]-tetrahydro-pyran-2-ylmethyl ester (2.9 g).
[0711] Step II: To a stirred solution of compound prepared in step
I (2 g, 3.64 mmol) in dichloroethane (20 mL) was added TBAB (117
mg, 0.364 mmol), 6% aqueous nitric acid (20 mmol) at 0-5.degree. C.
and stirred at room temperature for 4 h. Organic layer was
separated, washed with water and brine and concentrated to furnish
crude acetic acid
(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-chloro-3-(4-hydroxy-3-nitro-benzyl-
)-phenyl]-tetrahydro-pyran-2-ylmethyl ester which was further
purified by column chromatography (1.5 g)
[0712] Step III: To a stirred solution of compound prepared in step
11 (0.70 g, 1.178 mmol) in anhydrous acetonitrile (10 mL) was added
anhydrous Cs.sub.2CO.sub.3 (1.5 g, 4.71 mmol) and
2-bromo-2-methyl-propionic acid ethyl ester (0.6 mL, 5.89 mmol).
Reaction was heated to reflux under nitrogen atmosphere for 15 h.
Additional amount of 2-bromo-2-methyl-propionic acid ethyl ester
(0.6 mL, 5.89 mmol) was added at room temperature and heating
continued for 15 h. Reaction mixture was filtered, residue was
washed with anhydrous acetonitrile and concentrated to obtain crude
product, which contains varying amounts of products resulting from
partial hydrolyses of acetates. The crude product was reacetylated
by using acetic anhydride, pyridine and DMAP in dichloromethane.
Reaction was quenched with aq. ammonium chloride, extracted with
ethyl acetate (2.times.20 mL), washed with dil HCl, water, dried
over sodium sulfate, concentrated and purified by column
chromatography furnished
2-{4-[2-Chloro-5-((2S,3S,4R,5R,6R)-3,4,5-triacetoxy-6-acetoxymethyl-tetra-
hydro-pyran-2-yl)-benzyl]-2-nitro-phenoxy}-2-methyl-propionic acid
ethyl ester (515 mg).
Example 45
[(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-chloro-3-[(2,2-dimethyl-3-oxo-4H-1-
,4-benzoxazin-6-yl)methyl]phenyl]tetrahydropyran-2-yl]methyl
acetate
[0713] Step IV: To a stirred solution of compound prepared in step
III (515 mg, 0.73 mmol) in glacial acetic acid (8 mL) was added
iron powder (400 mg, 7.1 mmol) and stirred at 60.degree. C.
overnight. Reaction mixture was cooled to room temperature, diluted
with EtOAc (15 mL) and filtered through celite. Filtrate was
concentrated and purified by column chromatography to furnish
[(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-chloro-3-[(2,2-dimethyl-3-oxo-4H--
1,4-benzoxazin-6-yl)methyl]phenyl]tetrahydropyran-2-yl]methyl
acetate (365 mg)
Example 46
6-[2-Chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahydr-
o-pyran-2-yl)-benzyl]-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one
[0714] Step V: To a stirred solution of compound prepared in step
IV (141 mg, 0.22 mmol) in methanol (6 mL) was added NaOMe (70 mg,
1.29 mmol) and stirred at room temperature for 3 h. The solvent was
evaporated and the crude product was purified by silica gel column
chromatography to obtain the title compound (50 mg)
[0715] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 1.42 (s, 6H),
3.27-2.49 (m, 4H), 3.63-3.73 (m, 1H), 3.86-3.92 (m, 1H), 4.04 (d,
J=5.2 Hz, 2H), 4.09-4.14 (m, 1H), 6.70-6.74 (m, 1H), 6.81-6.85 (m,
2H), 7.28-7.33 (m, 1H), 7.35-7.40 (m, 2H)
[0716] MS (ES) m/z 464.0 (M+1)
[0717] Following example was prepared by using the analogous
procedures described for examples 45-46.
TABLE-US-00007 Example No. Structure/IUPAC name Spectral data 47
##STR00101## 6-(2-chloro-5-((2S,3R,4R,5S,6R)- 3,4,5-trihydroxy-6-
(hydroxymethyl)tetrahydro-2H-pyran-
2-yl)benzyl)-2H-benzo[b][1,4]oxazin- 3(4H)-one .sup.1H NMR (400
MHz, DMSO- D6): .delta. 3.09-3.26 (m, 5H), 3.33-3.46 (m, 2H), 3.66-
3.71 (m, 1H), 3.85-4.03 (m, 3H), 4.40-4.46 (m, 1H), 4.49 (s, 2H),
4.82-4.97 (m, 2H), 6.69-6.75 (m, 2H), 6.83 (d, J = 8.4 Hz, 1H),
7.23 (dd, J = 8 & 2 Hz, 1H), 7.30 (d, J = 1.6 Hz, 1H), 7.36 (d,
J = 8.4 Hz, 1H). MS (ES) m/z 436.0 (M + 1).
Example 48-49
##STR00102## ##STR00103##
[0719] Step I. To a stirred solution of ethyl-1-hydroxycyclopropane
carboxylate (2.93 g, 20.5 mmol) in THF (50 mL) was added sodium
hydride (60% in mineral oil, 981 mg, 24.5 mmol) under argon
atmosphere. After 10 min, 15-crown-5 (0.2 mL) followed by
4-bromo-2-nitro-fluorphenol (4.5 g, 20.5 mmol) were added. The
reaction mixture was stirred at room temperature overnight then
quenched by the addition of methanol (1.5 mL) and diluted with
ethyl acetate. The mixture was washed with brine, and the organic
layer was dried over anhydrous sodium sulfate, concentrated and
purified by silica gel column chromatography to give
1-(4-bromo-2-nitro-phenoxy)-cyclopropanecarboxylic acid ethyl ester
(3.51 g).
[0720] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 1.20 (t, J=6.8
Hz, 3H), 1.95-1.42 (m, 2H), 1.65-1.69 (m, 2H), 4.19 (q, J=6.8 Hz,
2H), 7.05 (d, J=8.8 Hz, 1H), 7.58 (dd, J=8.8, 2.8 Hz, 1H), 7.96 (d,
J=2.4 Hz, 1H).
[0721] MS (ES) m/z 329.9 (M+1).
[0722] Step II. To a stirred solution of
1-(4-bromo-2-nitro-phenoxy)-cyclopropanecarboxylic acid ethyl ester
(3.5 g, 10.6 mmol) in glacial acetic acid (40 mL) was added iron
powder (5.9 g, 106.1 mmol) at room temperature and the reaction
mixture was heated at 60.degree. C. for 3 h. The mixture was cooled
to room temperature, diluted with ethyl acetate, and filtered
through celite bed. The filtrate was concentrated, and the
resulting residue was taken in ethyl acetate and washed with water
and saturated sodium bicarbonate solution, then the organic layer
was dried over sodium sulfate, concentrated and the resulting
residue was purified by silica gel column chromatography to furnish
6-bromospiro[4H-1,4-benzoxazine-2,1'-cyclopropane]-3-one (2.51
g).
[0723] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 1.14-1.25 (m,
4H), 6.82 (d, J=8.4 Hz, 1H), 7.03-7.06 (m, 2H), 10.86 (s, 1H).
[0724] MS (ES) m/z 256.2 (M+1).
[0725] Step III. To a stirred solution of
6-bromospiro[4H-1,4-benzoxazine-2,1'-cyclopropane]-3-one (2.6 g,
10.2 mmol) in THF (20 mL) was added 1 M solution of
borane-tetrahydrofuran complex in THF (51.0 mL, 51.2 mmol). After
refluxing for 6 h, the reaction mixture was cooled to room
temperature and quenced by the addtion of methanol. Volatiles were
evaporated under reduced pressure, and the resulting residue was
taken up in ethyl actate and washed with saturated aq. sodium
bicarbonate solution, water, and brine. The organic layer was dried
over sodium sulfate, concentrated, and the resulting residue was
purified by silica gel column chromatography to furnish
6-bromospiro[3,4-dihydro-1,4-benzoxazine-2,1'-cyclopropane](2.3
g).
[0726] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 0.68-0.71 (m,
2H), 1.02-1.06 (m, 2H), 3.31 (s, 2H), 3.87 (bs, 1H), 6.57 (d, J=8.8
Hz, 1H), 6.72 (dd, J=8.4, 2.4 Hz, 1H), 6.77 (d, J=2.4 Hz, 1H).
[0727] MS (ES) m/z 240.1 (M+1).
[0728] Step IV. To a stirred solution of
6-bromospiro[3,4-dihydro-1,4-benzoxazine-2,1'-cyclopropane](3.11 g,
12.9 mmol) in DMF (20 mL) was added potassium carbonate (3.6 g,
26.0 mmol) and benzyl bromide (1.61 mL, 13.6 mmol). The reaction
mixture was heated at 60.degree. C. for 6 h then cooled to room
temperature and quenched by the addition of water. The reaction
mixture was extracted with ethylacetate (2.times.50 mL) and the
combined organic layers were washed with water (20 mL) and brine
(20 mL), then dried over sodium sulfate, filtered and concentrated.
The crude product was purified by silica gel column chromatography
to furnish
4-benzyl-6-bromo-spiro[3H-1,4-benzoxazine-2,1'-cyclopropane](1.13
g).
[0729] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 0.62-0.65 (m,
2H), 1.02-1.05 (m, 2H), 3.26 (s, 2H), 4.44 (s, 2H), 6.59 (d, J=8.4
Hz, 1H), 6.69 (dd, J=8.4, 2.4 Hz, 1H), 6.79 (d, J=2.0 Hz, 1H),
7.27-7.36 (m, 5H).
[0730] MS (ES) m/z 330.0 (M+1).
[0731] Step V. To a stirred solution of
4-benzyl-6-bromo-spiro[3H-1,4-benzoxazine-2,1'-cyclopropane](1.12
g, 3.4 mmol) in THF (10 mL) was added 1.6 M solution of n-BuLi in
hexanes (2.12 mL, 3.4 mmol) at -78.degree. C. The reaction mixture
was stirred for 30 min, and then transferred to a stirred solution
of 5-bromo-2-chlorobenzaldehyde (745 mg, 3.4 mmol) in THF (10 mL)
at -78.degree. C. After stirring for 1 h, the reaction was quenched
by the addition of saturated ammonium chloride solution and
extracted with ethyl acetate. The ethyl acetate layer was washed
with water, brine, dried over sodium sulphate, and concentrated.
The resulting residue was purified by silica gel column
chromatography to furnish
(4-benzylspiro[3H-1,4-benzoxazine-2,1'-cyclopropane]-6-yl)-(5-bromo-2-chl-
oro-phenyl)methanol (790 mg).
[0732] MS (ES) m/z 470.0 (M+1).
[0733] Step VI. To an ice cold solution of
(4-benzylspiro[3H-1,4-benzoxazine-2,1'-cyclopropane]-6-yl)-(5-bromo-2-chl-
oro-phenyl)methanol (780 mg, 1.7 mmol) in trifluoroacetic acid (4
mL) was added triethylsilane (1.32 mL, 8.3 mmol) followed by
triflic acid (0.15 mL, 1.7 mmol). After heating the mixture for 15
min at 50.degree. C., the reaction was cooled to room temperature.
Trifluoroacetic acid was evaporated under reduced pressure, and the
resulting residue was taken in saturated aq. sodium bicarbonate
solution and extracted with ethyl acetate. The organic layer was
washed with water, brine, dried over sodium sulfate, and
concentrated. The resulting residue was purified by silica gel
column chromatography to furnish
4-benzyl-6-[(5-bromo-2-chloro-phenyl)methyl]spiro[3H-1,4-benzoxazine-2,1'-
-cyclopropane](715 mg).
[0734] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 0.64-0.67 (m,
2H), 1.04-1.07 (m, 2H), 3.28 (s, 2H), 3.88 (s, 2H), 4.42 (s, 2H),
6.42 (d, J=8.0 Hz, 1H), 6.51 (s, 1H), 6.68 (d, J=8.0 Hz, 1H),
7.17-7.35 (m, 8H).
[0735] MS (ES) m/z 448.0 (M+1).
[0736] Step VII. To a stirred solution of
4-benzyl-6-[(5-bromo-2-chloro-phenyl)methyl]spiro[3H-1,4-benzoxazine-2,1'-
-cyclopropane](710 mg, 1.6 mmol) in THF-toluene (20 mL of 1:2
mixture) was added 1.6 M solution of n-BuLi in hexanes (1.6 mL, 1.6
mmol) at -78.degree. C. The reaction mixture was stirred for 30
min, and then transferred to a stirred solution of
2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone (730 mg, 1.6
mmol) in toluene (15 mL) at -78.degree. C. After stirring for 40
min, 0.6 N methanesulfonic acid in methanol (7 mL) was added and
stirred for 20 h at room temperature. The reaction was quenched by
the addition of saturated aq. sodium bicarbonate solution (8 mL)
then extracted with ethyl acetate (3.times.10 mL). The organic
layer was dried over sodium sulphate and concentrated. The
resulting residue was purified by silica gel column chromatography
to furnish
(3R,4S,5S,6R)-2-[3-[(4-benzylspiro[3H-1,4-benzoxazine-2,1'-cyclopropane]--
6-yl)methyl]-4-chloro-phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran--
3,4,5-triol (350 mg).
[0737] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 0.67-0.66 (m,
2H), 0.87-0.92 (m, 2H), 3.00 (s, 3H), 306 (d, J=9.6 Hz, 1H), 3.29
(s, 2H), 3.38-3.43 (m, 1H), 3.53-3.57 (m, 1H), 3.71-3.98 (m, 5H),
4.38 (ABq, J=16.0, 4.0 Hz, 2H), 6.38 (dd, J=8.4, 2.0 Hz, 1H), 6.52
(d, J=8.0 Hz, 1H), 6.55 (d, J=1.6 Hz, 1H), 7.20-7.31 (m, 6H), 7.41
(dd, J=8.8, 2.0 Hz, 1H), 7.50 (d, J=2.4 Hz, 1H).
[0738] MS (ES) m/z 558.2 (M+1).
Example 48
(2S,3R,4R,5S,6R)-2-[3-[(4-benzylspiro[3H-1,4-benzoxazine-2,1'-cyclopropane-
]-6-yl)methyl]-4-chloro-phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-tri-
ol
[0739] Step VIII. To a stirred solution of
(3R,4S,5S,6R)-2-[3-[(4-benzylspiro[3H-1,4-benzoxazine-2,1'-cyclopropane]--
6-yl)methyl]-4-chloro-phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran--
3,4,5-triol (340 mg, 0.6 mmol) in acetonitrile-dichloromethane (6
mL, 1:1 mixture) was added triethylsilane (0.4 mL, 2.4 mmol) and
boron trifluoride diethyletharate complex (0.15 mL, 1.2 mmol) at
-5.degree. C. After stirring for 4 h at 0.degree. C., the reaction
was quenched with saturated aq. sodium bicarbonate solution (5 mL).
The volatiles were evaporated under reduced pressure, and the
resulting mixture was extracted with ethyl acetate (3.times.10 mL).
The ethyl acetate layers were combined and washed with brine (10
mL), dried over sodium sulphate, and concentrated. The resulting
residue was purified by silica gel column chromatography to furnish
(2S,3R,4R,5S,6R)-2-[3-[(4-benzylspiro[3H-1,4-benzoxazine-2,1'-cyclopropan-
e]-6-yl)methyl]-4-chloro-phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-tr-
iol (300 mg).
[0740] MS (ES) m/z 538.0 (M+1).
Example 49
(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(spiro[3,4-dihydro-1,4-benzoxazine-2,1'-cyc-
lopropane]-6-ylmethyl)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol
[0741] Step IX. To a solution of
(2S,3R,4R,5S,6R)-2-[3-[(4-benzylspiro[3H-1,4-benzoxazine-2,1'-cyclopropan-
e]-6-yl)methyl]-4-chloro-phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-tr-
iol (300 mg) in methanol (3 mL), was added ethyl acetate (0.5 mL),
10% palladium on charcoal (40 mg), and 0.3 mL conc. HCl. The
reaction mixture was stirred under hydrogen balloon pressure for 2
h then filtered through a celite bed which was washed with
methanol, and the resulting filtrate was concentrated to a residue
which was purified by preparative HPLC to furnish
(2S,3R,4R,5S,6R)-2-[4-chloro-3-(spiro[3,4-dihydro-1,4-benzoxazine-
-2,1'-cyclopropane]-6-ylmethyl)phenyl]-6-(hydroxymethyl)tetrahydropyran-3,-
4,5-triol (56 mg).
[0742] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 0.65-0.68 (m,
2H), 0.89-0.92 (m, 2H), 3.20 (s, 2H), 3.28-3.46 (m, 4H), 3.68 (dd,
J=12.0, 5.6 Hz, 1H), 3.85-3.99 (m, 3H), 4.07 (d, J=9.6 Hz, 1H),
6.44 (dd, J=8.0, 2.0 Hz, 1H), 6.50-6.52 (m, 2H), 7.25 (dd, J=8.0,
2.0 Hz, 1H), 7.31-7.34 (m, 2H).
[0743] MS (ES) m/z 448.0 (M+1).
Example 50-51
##STR00104## ##STR00105##
[0745] Step I. To a stirred solution of acetic acid
(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-
-tetrahydro-pyran-2-ylmethyl ester (3.0 g, 5.2 mmol, prepared using
the procedures described in J. Med. Chem. 2008, 51(5), 1145-49) in
dichloromethane (30 mL) was added boron tribromide solution (1.0 M
in DCM, 26.0 mL, 26.0 mmol) at -78.degree. C. After stirring at
-15.degree. C. for 1 h, the reaction mixture was poured onto an
ice-cold saturated aqueous sodium bicarbonate solution. The mixture
was extracted with dichloromethane (2.times.50 mL), and the
combined organic layers were washed with water (20 mL) and brine
(20 mL), then dried over sodium sulfate and concentrated to a
residue which was purified by silica gel column chromatography to
furnished
(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-chloro-3-(4-hydroxy-benzyl)-phenyl-
]-tetrahydro-pyran-2-ylmethyl ester (2.1 g).
[0746] MS (ES) m/z 549.3 (M+1).
[0747] Step II. To a stirred solution of
(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-chloro-3-(4-hydroxy-benzyl)-phenyl-
]-tetrahydro-pyran-2-ylmethyl ester (5.4 g) in ethylenedichloride
(55 mL) was added 6% HNO.sub.3 (22.2 mL) and tetra-butyl ammonium
bromide (324 mg). The reaction mixture was heated at 50.degree. C.
for 15 min. then cooled and diluted with dichloromethane. The
mixture was washed with water, saturated aqueous sodium bicarbonate
solution, brine, and the organic layer was dried over anhydrous
sodium sulfate then concentrated. The resulting residue was
purified by silica gel column chromatography to furnish acetic acid
(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-chloro-3-(4-hydroxy-3-nitro-benzyl-
)-phenyl]-tetrahydro-pyran-2-ylmethyl ester (4.2 g)
[0748] MS (ES) m/z 593.8 (M+1).
[0749] Step III. To a stirred solution of acetic acid
(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-chloro-3-(4-hydroxy-3-nitro-benzyl-
)-phenyl]-tetrahydro-pyran-2-ylmethyl ester (1.71 g, 2.9 mmol) in
glacial acetic acid (15 mL) was added iron powder (3.22 g, 57.7
mmol). After stirring at 60.degree. C. for 15 min, the reaction
mixture was filtered through a celite bed. The filtrate was
concentrated under reduced pressure, and the resulting residue was
taken up in ethyl acetate and the solution was washed with water,
saturated aqueous sodium bicarbonate solution, and brine. The
organic layer was dried over anhydrous sodium sulfate and
concentrated to a residue which was purified by silica gel column
chromatography to furnish acetic acid
(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[3-(3-amino-4-hydroxy-benzyl)-4-chlor-
o-phenyl]-tetrahydro-pyran-2-ylmethyl ester (1.3 g)
[0750] MS (ES) m/z 563.9 (M+1).
Example 50
Acetic acid
(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-chloro-3-(2-cyano-3,4-dihydro-2H-b-
enzo[1,4]oxazin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylmethyl
ester
[0751] Step IV. To a stirred solution of acetic acid
(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[3-(3-amino-4-hydroxy-benzyl)-4-chlor-
o-phenyl]-tetrahydro-pyran-2-ylmethyl ester (1.8 g, 3.2 mmol) in
acetonitrile (15 mL) was added 2-chloroacrylonitrile (0.35 mL, 4.5
mmol) and potassium carbonate (882 mg, 6.4 mmol). After the
reaction was refluxed overnight, the mixture was filtered through a
celite bed. The filtrate was concentrated and purified by silica
gel column chromatography to furnish acetic acid
(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-chloro-3-(2-cyano-3,4-dihydro-2H-b-
enzo[1,4]oxazin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylmethyl
ester (440 mg).
[0752] MS (ES) m/z 615.2 (M+1).
Example 51
6-[2-Chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahydr-
o-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonitrile
[0753] Step V. To a stirred solution of acetic acid
(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-chloro-3-(2-cyano-3,4-dihydro-2H-b-
enzo[1,4]oxazin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylmethyl
ester (430 mg) in THF Methanol:water (2:1:1 mixture, 4 mL) was
added lithium hydroxide (20 mg). After stirring at room temperature
overnight, the reaction mixture was concentrated. The resulting
residue was taken up in 50% methanol in ethyl acetate then filtered
through celite bed. The filtrate was concentrated, and the residue
was purified by preparative HPLC to furnish
6-[2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahyd-
ro-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonitrile
(35 mg).
[0754] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 3.26-3.50 (m,
6H), 3.68 (dd, J=12.0 Hz, 4.8 Hz, 1H), 3.85-3.97 (m, 3H), 4.08 (d,
J=9.2 Hz, 1H), 5.25 (t, J=2.8 Hz, 1H), 6.48-6.51 (m, 2H), 6.68 (d,
J=8.0 Hz, 1H), 7.26 (dd, J=8.4 Hz, 2.4 Hz, 1H), 7.32-7.34 (m,
2H).
[0755] MS (ES) m/z 447.1 (M+1).
Examples 52-53
##STR00106##
[0756] Example 52
6-[2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahydr-
o-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid methyl ester
[0757] Step I. To a stirred solution of acetic acid
(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-chloro-3-(2-cyano-3,4-dihydro-2H-b-
enzo[1,4]oxazin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylmethyl
ester (180 mg) in methanol (2 mL) was added sodium methoxide (20
mg). After stirring at room temperature overnight, the reaction
mixture was concentrated to furnish
6-[2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl--
tetrahydro-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxyl-
ic acid methyl ester. The resulting crude material was taken for
the further conversion (195 mg).
[0758] MS (ES) m/z 480.1 (M+1).
Example 53
6-[2-Chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahydr-
o-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid
[0759] Step II. To a stirred solution of
6-[2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahyd-
ro-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid methyl ester (190 mg) in THF: Methanol: water (1:1:1 mixture,
1.5 mL) was added lithium hydroxide (17 mg). After stirring at room
temperature overnight, the reaction mixture was concentrated, and
the resulting residue was taken up in 50% methanol in ethyl
acetate. The solution was filtered through a celite bed, and the
filtrate was concentrated to a residue which was purified by
preparative HPLC to furnish
6-[2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahyd-
ro-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic
acid (23 mg).
[0760] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 3.19-3.44 (m,
5H), 3.56 (dd, J=11.6 Hz, 2.8 Hz, 1H), 3.68 (dd, J=12.0 Hz, 5.2 Hz,
1H), 3.84-3.97 (m, 3H), 4.07 (d, J=9.2 Hz, 1H), 4.33 (dd, J=8.0,
2.4 Hz, 1H), 6.42-6.45 (m, 2H), 6.71 (d, J=8.0 Hz, 1H), 7.24 (dd,
J=8.4 Hz, 2.4 Hz, 1H), 7.29-7.32 (m, 2H).
[0761] MS (ES) m/z 466.0 (M+1).
Examples 54-56
##STR00107## ##STR00108##
[0763] Step I. To a stirred solution of 2-bromo-5-iodobenzoic acid
(1.0 g, 3.06 mmol) in DCM (5 mL) was added DMF (0.2 mL) and oxalyl
chloride (0.44 mL, 4.59 mmol) at 0.degree. C. After complete
addition, the reaction mixture was stirred at room temperature for
3 h. The volatiles were evaporated under reduced pressure, and the
crude product was dissolved in DCM (4 mL) and added to chroman (488
mg, 3.67 mmol) which had been cooled to 0.degree. C. To this
mixture was added aluminum chloride (488 mg, 3.67 mmol) in
portions. After stirring for 4 h, the reaction was quenched by
pouring it into crushed ice. This was extracted with
dichloromethane (50 mL.times.2). The dichloromethane layers were
combined and washed with water (20 mL), saturated aqueous sodium
bicarbonate solution (20 mL.times.2), and brine (20 mL), then dried
over sodium sulfate, and concentrated. The crude product was
purified by column chromatography to furnish
(2-bromo-5-iodo-phenyl)-chroman-6-yl-methanone (1.2 g).
[0764] Step II. To a stirred solution of
(2-bromo-5-iodo-phenyl)-chroman-6-yl-methanone (2.0 g, 4.51 mmol)
in acetonitrile:dichloromethane (2:1 mixture, 9 mL) was added
triethylsilane (2.52 mL, 15.78 mmol) and boron trifluoride diethyl
etherate complex (1.11 mL, 9.02 mmol) at 0.degree. C. After
stirring overnight at room temperature, reaction was quenched by
the addition of saturated aqueous sodium bicarbonate solution.
Volatiles were evaporated under reduced pressure. The aqueous layer
was extracted with ethyl acetate (2.times.20 mL). Ethyl acetate
layer was washed with water, brine, dried over sodium sulfate,
concentrated and purified by silica gel column chromatography to
furnish 6-(2-bromo-5-iodo-benzyl)-chroman (1.5 g).
[0765] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 2.03 (m, 2H),
2.77 (t, J=6.4 Hz, 2H), 3.93 (s, 2H), 4.18 (t, J=5.2 Hz, 2H), 6.73
(d, J=8.4 Hz, 1H), 6.83 (s, 1H), 6.89 (dd, J=8.4 Hz, 1.6 Hz, 1H),
7.28 (s, 1H), 7.39 (dd, J=8.4 Hz, 2.0 Hz, 1H), 7.44 (d, J=2.0 Hz,
1H).
[0766] Step III. To a stirred solution of
6-(2-bromo-5-iodo-benzyl)-chroman (1.0 g, 2.33 mmol) in dry THF (6
mL) was added n-BuLi (1.6 M in hexane, 1.45 mL, 2.33 mmol) at
-78.degree. C.
[0767] After stirring for 45 min, the reaction mixture was
transferred to a cooled solution of
2,3,4,6-tetrakis-O-(benzyl)-D-glucopyranone (1.66 g, 2.56 mmol) in
THF (6 mL) at -78.degree. C. After stirring for 1 h, a solution of
methane sulfonic acid (0.3 mL) in methanol (6 mL) was added, and
the reaction was allowed to attain room temperature. After stirring
overnight, the reaction was quenched by the addition of a saturated
sodium bicarbonate solution (10 mL), and the resulting mixture was
extracted with ethyl acetate (50 mL.times.3). The organic layers
were combined and dried over sodium sulfate, concentrated and
purified by silica gel column chromatography to furnish
6-[2-bromo-5-((3R,4S,5R,6R)-3,4,5-tris-benzyloxy-6-benzyloxymethyl-2-meth-
oxy-tetrahydro-pyran-2-yl)-benzyl]-chroman (900 mg).
Example 54
6-[2-bromo-5-((3S,4R,5R,6R)-3,4,5-tris-benzyloxy-6-benzyloxymethyl-tetrahy-
dro-pyran-2-yl)-benzyl]-chroman
[0768] Step IV. To a stirred solution of
6-[2-bromo-5-((3R,4S,5R,6R)-3,4,5-tris-benzyloxy-6-benzyloxymethyl-2-meth-
oxy-tetrahydro-pyran-2-yl)-benzyl]-chroman (900 mg, 1.05 mmol) in
acetonitrile:dichloromethane (1:1 mixture, 6 mL) was added
triethylsilane (0.34 mL, 2.1 mmol) and boron trifluoride
diethyletharate complex (0.19 mL, 1.58 mmol), at 0.degree. C. After
stirring for 2 h, the reaction was quenched with saturated aqueous
sodium bicarbonate solution. The volatiles were evaporated under
reduced pressure; the resulting mixture was extracted with ethyl
acetate (2.times.10 mL). The organic layers were combined and dried
over sodium sulfate then concentrated to a residue which was
purified by silica gel column chromatography to furnish
6-[2-bromo-5-((3S,4R,5R,6R)-3,4,5-tris-benzyloxy-6-benzyloxymethyl-tetrah-
ydro-pyran-2-yl)-benzyl]-chroman (600 mg).
Example 55
6-[2-cyclopropyl-5-((3S,4R,5R,6R)-3,4,5-tris-benzyloxy-6-benzyloxymethyl-t-
etrahydro-pyran-2-yl)-benzyl]-chroman
[0769] Step V. To a stirred solution of
6-[2-bromo-5-((3S,4R,5R,6R)-3,4,5-tris-benzyloxy-6-benzyloxymethyl-tetrah-
ydro-pyran-2-yl)-benzyl]-chroman (300 mg, 0.363 mmol) in toluene
(1.6 mL) was added tricyclohexylphosphine (10 mg), potassium
phosphate (346 mg, 1.63 mmol), water (81 .mu.l), cyclopropylboronic
acid (93 mg, 1.09 mmol). The reaction mixture was degassed for 45
min then palladium (II) acetate (4 mg) was added. After heating
overnight at 100.degree. C., the reaction mixture was cooled to
room temperature and was filtered through celite. The celite was
washed with an additional ethyl acetate (30 mL) and the organic
layer of the filtrate was separated and washed with water (20 mL)
followed by brine (20 mL), then dried over sodium sulfate and
concentrated to give crude product which was further purified by
column chromatography to furnish
6-[2-cyclopropyl-5-((3S,4R,5R,6R)-3,4,5-tris-benzyloxy-6-benzyloxymethyl--
tetrahydro-pyran-2-yl)-benzyl]-chroman (250 mg).
Example 56
(2S,3R,4R,5S,6R)-2-(3-Chroman-6-ylmethyl-4-cyclopropyl-phenyl)-6-hydroxyme-
thyl-tetrahydro-pyran-3,4,5-triol
[0770] Step VI. To a stirred solution of
6-[2-cyclopropyl-5-((3S,4R,5R,6R)-3,4,5-tris-benzyloxy-6-benzyloxymethyl--
tetrahydro-pyran-2-yl)-benzyl]-chroman (650 mg) in THF (5 mL) was
added 10% palladium charcoal activated (dry) (100 mg), methanol (5
mL), and conc. HCl (0.2 mL). The reaction mixture was stirred under
hydrogen atmosphere (bladder pressure) overnight then filtered
through a celite bed. The filtrate was concentrated and purified by
preparative HPLC to furnish
(2S,3R,4R,5S,6R)-2-(3-chroman-6-ylmethyl-4-cyclopropyl-phenyl)-6--
hydroxymethyl-tetrahydro-pyran-3,4,5-triol (63 mg).
[0771] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 0.52-0.56 (m,
2H), 0.81-0.89 (m, 2H), 1.80-1.85 (m, 1H), 1.90-1.96 (m, 2H), 2.69
(t, J=6.0 Hz, 2H), 3.29-3.47 (m, 3H), 3.67 (dd, J=12.0 Hz, 5.0 Hz,
1H), 3.87 (dd, J=12.0 Hz, 1.6 Hz, 1H), 4.07 (d, J=8.8 Hz, 2H),
4.11-4.09 (m, 4H), 6.58 (d, J=8.0 Hz, 1H), 6.80-6.84 (m, 2H), 6.96
(d, J=8.0 Hz, 1H), 7.10-7.22 (m, 2H).
[0772] MS (ES) m/z 444.1 (M+18).
Examples 57-58
##STR00109## ##STR00110##
[0774] 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.
[0775] 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).
[0776] .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).
[0777] 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).
[0778] .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).
[0779] 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
(.about.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)
Example 57
[(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-bromo-3-(2,3-dihydro-1,4-benzodiox-
in-6-ylmethyl)phenyl]tetrahydropyran-2-yl]methyl acetate
[0780] 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 (.about.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.
Example 58
[(2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-bromo-3-(2,3-dihydro-1,4-benzodiox-
in-6-ylmethyl)phenyl]tetrahydropyran-2-yl]methyl acetate
[0781] Step V: 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%).
Examples 59-60
##STR00111##
[0782] Example 59
Acetic acid
(2R,3R,4R,5S)-3,4,5-triacetoxy-6-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]-
dioxin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylmethyl ester
[0783] 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 (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 (11) 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]-
dioxin-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%).
[0784] .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, 1H),
6.57-6.59 (m, 2H), 6.76 (dd, J=7.2 Hz, 2.0 Hz, 1H), 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).
[0785] MS (ES) m/z 597.3 (M+1).
Example 60
(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
[0786] 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]-
dioxin-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-ylmet-
hyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (7.25
g)
[0787] .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 61-62
##STR00112##
[0788] Example 61
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
[0789] 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 (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).
Example 62
(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-ph-
enyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
[0790] 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)
[0791] .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).
[0792] MS (ES) m/z 434.2 (M+18).
Examples 63-65
##STR00113## ##STR00114##
[0794] Step I. To a stirred solution of
1-(2,3-dihydro-benzo[1,4]oxazin-4-yl)-2,2,2-trifluoro-ethanone (9.2
g, 39.77 mmol) in dichloromethane (70 mL) was added
5-iodo-2-bromobenzoyl chloride (13.7 g, 39.77 mmol) in
dichloromethane (30 mL) at 0.degree. C. followed by addition of
AlCl.sub.3 (13.3 g, 99.41 mmol). After 3 h, the reaction mixture
was brought to room temperature and stirred overnight. The reaction
was quenched by pouring it over crushed ice and the resultanting
mixture was extracted with dichloromethane (100.times.2 mL). The
organic layers were combined and washed with aq. sodium bicarbonate
(20 mL) and water (20 mL) then concentrated to furnish
6-(2-bromo-5-iodo-benzoyl)-4-(2,2,2-trifluoro-acetyl)-4H-benzo[1,4]oxazin-
-3-one (16.1 g).
[0795] MS (ES) m/z: 539.7 [M(.sup.79Br)+1], 541.7
[M(.sup.81Br)+1]
[0796] Step II. To a stirred solution of
6-(2-bromo-5-iodo-benzoyl)-4-(2,2,2-trifluoro-acetyl)-4H-benzo[1,4]oxazin-
-3-one (16.0 g, 29.252 mmol) in 1,2-dichloroethane/MeCN (1:2
mixture, 60 mL) was added triethylsilane (9.9 mL, 62.43 mmol) and
borontrifluoride diethyletherate complex (4.9 mL, 38.51 mmol)
simultaneously at -10.degree. C. After stirring overnight at room
temperature, the reaction was heated at 50.degree. C. for 3 h. The
reaction was quenched by the addition of aq. sodium bicarbonate (50
mL). Volatiles were evaporated under reduced pressure, and the
resulting residue was extracted with ethyl acetate (2.times.100
mL). The organic layers were combined and washed with water and
brine, then dried over sodium sulfate and concentrated to a residue
which was purified by silica gel column chromatography to furnish
1-[6-(2-bromo-5-iodo-benzyl)-2,3-dihydro-benzo[1,4]oxazin-4-yl]-2,2,2-tri-
fluoro-ethanone (12.1 g).
[0797] MS (ES) m/z 544.7 (M+18)
[0798] Step III. To a stirred solution of
1-[6-(2-bromo-5-iodo-benzyl)-2,3-dihydro-benzo[1,4]oxazin-4-yl]-2,2,2-tri-
fluoro-ethanone (12.0 g, 22.81 mmol) in methanol (100 mL) and THF
(20 mL) was added sodium borohydride (1.73 g, 45.62 mmol) portion
wise and the reaction mixture was stirred at room temperature for 1
h. The excess of sodium borohydride was quenched by adding 1N HCl.
Methanol was evaporated and the residue was partitioned between
dichloromethane and water. The organic layer was washed with water,
and brine, then concentrated to furnish the crude product which was
purified by silica gel column chromatography to provide
6-(2-bromo-5-iodo-benzyl)-3,4-dihydro-2H-benzo[1,4]oxazine (9.45
g).
[0799] MS (ES) m/z: 429.8 [M(.sup.79Br)+1], 431.8
[M(.sup.81Br)+1]
[0800] Step IV. To a stirred solution of
6-(2-bromo-5-iodo-benzyl)-3,4-dihydro-2H-benzo[1,4]oxazine (9.4 g,
21.86 mmol) in DMF (50 mL) was added potassium carbonate (6.04 g,
43.71 mmol), benzyl bromide (3.2 mL, 26.23 mmol) and the mixture
was heated to 50.degree. C. overnight. The reaction mixture was
cooled to room temperature, quenched by the addition of water (100
mL), then extracted with ethyl acetate (3.times.50 mL). The organic
layers were combined then washed with water (50 mL), brine (50 mL),
dried over sodium sulfate, and concentrated to a residue which was
purified by silica gel column chromatography to furnish
4-benzyl-6-(2-bromo-5-iodo-benzyl)-3,4-dihydro-2H-benzo[1,4]oxazine
(10.5 g).
[0801] MS (ES) m/z: 519.8 [M(.sup.79Br)+1], 521.8
[M(.sup.81Br)+1]
[0802] Step V. To a stirred solution of
4-benzyl-6-(2-bromo-5-iodo-benzyl)-3,4-dihydro-2H-benzo[1,4]oxazine
(2.0 g, 3.85 mmol) in THF (20 mL) was added n-Butyl lithium (2.4
mL, 3.85 mmol) at -78.degree. C. and the mixture was stirred for 1
h. This was transferred to a solution of
2,3,4,6-tetrakis-O-(benzyl)-D-glucopyranone (2.07 g, 3.85 mmol) in
THF (18 mL) at -78.degree. C. After stirring for 1 h, the reaction
was quenched with Sat. ammonium chloride (20 mL), and the resulting
mixture was extracted with ethyl acetate (2.times.20 mL), washed
with water and brine, then dried over sodium sulfate, concentrated
and purified by silica gel column chromatography to furnish
(3R,4S,5R,6R)-2-[3-(4-benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)--
4-bromo-phenyl]-3,4,5-tris-benzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2--
ol (1.62 g).
[0803] MS (ES) m/z: 931.9 [M(.sup.79Br)+1], 934.0
[M(.sup.81Br)+1]
Example 63
4-Benzyl-6-[2-bromo-5-((2S,3S,4R,5R,6R)-3,4,5-tris-benzyloxy-6-benzyloxyme-
thyl-tetrahydro-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine
[0804] Step VI. To a stirred solution of
(3R,4S,5R,6R)-2-[3-(4-benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)--
4-bromo-phenyl]-3,4,5-tris-benzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2--
ol (1.60 g, 1.72 mmol) in acetonitrile-dichloromethane mixture (3:1
mixture, 7 mL) was added triethylsilane (0.82 mL, 5.15 mmol)
followed by boron trifluoride diethyletharate complex (0.42 mL,
3.43 mmol) at -30.degree. C. After stirring for 2 h at 0.degree.
C., the reaction was quenched with aq. sodium bicarbonate (4 mL).
The volatiles were evaporated under reduced pressure, and the
resulting mixture was extracted with dichloromethane (2.times.20
mL). The organic layers were combined and washed with brine (3 mL),
dried over sodium sulfate, then concentrated to a residue which was
purified by column chromatography to furnish
4-benzyl-6-[2-bromo-5-((2S,3S,4R,5R,6R)-3,4,5-tris-benzyloxy-6-be-
nzyloxymethyl-tetrahydro-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxaz-
ine (1.10 g).
[0805] MS (ES) m/z: 917.1 [M(.sup.79Br)+1], 919.1
[M(.sup.81Br)+1]
Example 64
4-Benzyl-6-[2-cyclopropyl-5-((2S,3S,4R,5R,6R)-3,4,5-tris-benzyloxy-6-benzy-
loxymethyl-tetrahydro-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine
[0806] Step VII. To a stirred solution of
4-benzyl-6-[2-bromo-5-((2S,3S,4R,5R,6R)-3,4,5-tris-benzyloxy-6-benzyloxym-
ethyl-tetrahydro-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine
(0.35 g, 0.38 mmol) in toluene:water (10:1 mixture, 10 mL) was
added cyclopropylboronic acid (49.2 mg, 0.5731 mmol)
tricyclohexylphosphine (26.7 mg, 0.0955 mmol), and potassium
phosphate (0.28 g, 1.34 mmol). The reaction mixture was degassed
for 45 min then palladium (II) acetate (8.5 mg, 0.03821 mmol) was
added. After heating overnight at 100.degree. C., the reaction
mixture was cooled to room temperature and water (20 mL) was added.
The resulting mixture was extracted with ethyl acetate (2
25.times.25 mL), washed with water and brine, then dried over
sodium sulfate, concentrated and purified by column chromatography
to furnish
4-benzyl-6-[2-cyclopropyl-5-((2S,3S,4R,5R,6R)-3,4,5-tris-benzyloxy-6-benz-
yloxymethyl-tetrahydro-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazin-
e (317 mg). The product was taken up for the next step without
characterization.
Example 65
(2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(3,4-dihydro-2H-benzo[1,4]oxazin-6-ylm-
ethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
[0807] Step VIII. To a solution of
4-benzyl-6-[2-cyclopropyl-5-((2S,3S,4R,5R,6R)-3,4,5-tris-benzyloxy-6-benz-
yloxymethyl-tetrahydro-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazin-
e (0.42 g, 0.4783 mmol) in THF (4.7 mL) was added 10% palladium on
charcoal (80 mg), 0.1 mL conc. HCl followed by methanol (4.7 mL)
and the mixture was stirred under hydrogen atmosphere for 18 h. The
reaction mixture was filtered through a celite bed, washed with
methanol and concentrated. The resulting residue was purified by
preparative HPLC to furnish
(2S,3R,4R,5S,6R)-2-[4-cyclopropyl-3-(3,4-dihydro-2H-benzo[1,4]oxa-
zin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
(34 mg).
[0808] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 0.53-0.57 (m,
2H), 0.82-0.86 (m, 2H), 1.81-1.88 (m, 1H), 3.27 (t, J=11.0 Hz, 2H),
3.43-3.47 (m, 3H), 3.68 (dd, J=12.0 Hz, 5.6 Hz, 1H), 3.86 (d,
J=11.6 Hz, 1H), 3.99 (Abq, J=15.6 Hz, 2H), 4.08 (d, J=9.2 Hz, 1H),
4.13 (t, J=11.0 Hz, 2H), 6.39-6.41 (m, 2H), 6.54 (d, J=8.0 Hz, 1H),
6.95 (d, J=8.4 Hz, 1H), 7.17-7.21 (m, 2H).
[0809] MS (ES) m/z 428.1 (M+1).
[0810] Following example was prepared by using the procedures
described for examples 63-65.
TABLE-US-00008 Example No. Structure/IUPAC name Spectral data 66
##STR00115## (2S,3R,4R,5S,6R)-2-[3-(3,4-Dihydro-
2H-benzo[1,4]oxazin-6-ylmethyl)-4- ethyl-phenyl]-6-hydroxymethyl-
tetrahydro-pyran-3,4,5-triol .sup.1H NMR (400 MHz, CD.sub.3OD):
.delta. 1.07 (t, J = 7.6 Hz, 3H), 2.58 (q, J = 7.6 Hz, 2H),
3.26-3.48 (m, 6H), 3.66-3.70 (m, 1H), 3.80-3.89 (m, 3H), 4.07 (d, J
= 9.2 Hz, 1H), 4.13 (t, J = 4.4 Hz, 2H), 6.34-6.37 (m, 2H), 6.54
(dd, J = 7.6, 0.8 Hz, 1H), 7.14 (d, J = 7.8 Hz, 1H), 7.18 (d, J =
1.6 Hz, 1H), 7.22 (dd, J = 7.6, 1.6 Hz, 1H) MS (ES) m/z 416.4 (M +
1). 67 ##STR00116## (2S,3R,4R,5S ,6R)-2-[2-(3,4-Dihydro-
2H-benzo[1,4]oxazin-6-ylmethyl)-4'- methyl-biphenyl-4-yl]-6-
hydroxymethyl-tetrahydro-pyran- 3,4,5-triol .sup.1H NMR (400 MHz,
CD.sub.3OD): .delta. 2.36 (s, 3H), 3.26 (t, J = 4.4 Hz, 2H),
3.37-3.45 (m, 5H), 3.65-3.80 (m, 3H), 3.88 (d, J = 11.4 Hz, 1H),
4.12 (t, J = 4.4 Hz, 2H), 6.18 (dd, J = 8.1 Hz, 1.7 Hz, 1H), 6.25
(s, 1H), 6.48 (d, J = 8.1 Hz, 1H), 7.07 (d, J = 8.0 Hz, 2H), 7.16
(d, J = 7.8 Hz, 3H), 7.28-7.32 (m, 2H). MS (ES) m/z 4478.2 (M +
1).
Example 68-69
##STR00117##
[0812] Step I: To a solution of 2-bromoisopropyl benzene (2.0 g,
10.0 mmole) in dry THF (20 mL), nBuLi (1.6 M in hexane), (6.9 mL,
11.05 mmole) was added at -78.degree. C. and the mixture was
stirred at same temperature for one hour. DMF (0.9 g, 12.0 mmole)
was added and the mixture was stirred at -78.degree. C. for half an
hour then allowed to stir at 0.degree. C. for 15 min. The reaction
mixture was diluted with saturated aqueous ammonium chloride (10
mL) and extracted with EtOAc (3.times.30 mL). The organic layers
were combined and washed with brine, dried over sodium sulfate, and
concentrated to yield 2-isopropyl benzaldehyde (1.4 g).
[0813] Step II: A solution of 2-isopropyl benzaldehyde (1.5 g,
10.13 mmole) in DCM (10 mL) was added to a solution of AlCl.sub.3
(2.6 g, 20.26 mmole) in DCM (10 mL) at 0.degree. C. followed by
addition of a dilute solution of Br.sub.2 (0.67 mL, 13.1 mmole in
20 mL DCM) to the reaction mixture. The solution was stirred at
0.degree. C. for 6 hours then stirred overnight at room
temperature. The reaction mixture was basified using saturated
aqueous sodium bicarbonate and extracted with DCM (30.times.2 mL).
The organic layers were combined and the crude product was obtained
by evaporation of the solvent. The crude product was purified by
column chromatography using 1% EtOAc in Hexane to yield
5-bromo-2-isopropylbenzaldehyde (800 mg).
[0814] Step III: To a solution of
4-Benzyl-6-bromo-3,4-dihydro-2H-benzo[1,4]oxazine (1.5 g, 4.93
mmol) in THF (20 mL) was added 1.6 M n-butyl lithium in hexanes
(3.0 mL, 74.93 mmol) at -78.degree. C. The reaction was stirred for
30 min. then transferred to a stirred solution of
5-bromo-2-isopropylbenzaldehyde (1.12 g, 4.93 mmol) in THF (15 mL)
at -78.degree. C. After stirring for 30 min, the reaction was
quenched by the addition of saturated aqueous solution of ammonium
chloride. The resulting mixture was extracted with ethyl acetate
(3.times.30 mL), and the combined organic layers were washed with
water (25 mL) and brine (25 mL), then dried over sodium sulfate,
concentrated and purified using neutral alumina column
chromatography to give
(4-Benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-(5-bromo-2-isopropyl-phen-
yl)-methanol (1.3 g).
[0815] Step IV: To an ice cold solution of
(4-Benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-(5-bromo-2-isopropyl-phen-
yl)-methanol (1.3 g, 2.87 mmol) in dichloromethane (25 mL) was
added Et.sub.3SiH (4.8 mL, 5.70 mmol) followed by
BF.sub.3.OEt.sub.2 (0.74 mL, 5.7 mmol). The reaction mixture was
stirred at room temperature overnight then quenched by the addition
of aq. NaHCO.sub.3. The reaction mixture was extracted with ethyl
acetate (3.times.30 mL), and the combined organic layers were
washed with brine (30 mL) and dried over sodium sulfate. Crude
product obtained after evaporation of the solvent was purified by
silica gel column chromatography to furnish
4-Benzyl-6-(5-bromo-2-isopropyl-benzyl)-3,4-dihydro-2H-benzo[1,4]oxazine
(1.0 g).
[0816] Step V: To a stirred solution of
4-Benzyl-6-(5-bromo-2-isopropyl-benzyl)-3,4-dihydro-2H-benzo[1,4]oxazine
(1.0 g, 2.29 mmol) in THF-toluene (15 mL of 1:2 mixture) was added
1.6 M solution of n-BuLi in hexanes (1.40 mL, 1.40 mmol) at
-78.degree. C. The reaction mixture was stirred for 30 min. then
transferred to a stirred solution of
2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone (1.0 g, 2.29
mmol) in toluene (10 mL) at -78.degree. C. After stirring for 40
min., 0.6 N methanesulfonic acid in methanol (10 mL) was added and
the reaction was stirred for 20 h at room temperature then quenched
by the addition of aq. saturated NaHCO.sub.3 (10 mL). The resulting
mixture was extracted with ethyl acetate (3.times.20 mL), and the
organic layers were combined and dried over sodium sulphate, and
concentrated to a residue which was purified by silica gel column
chromatography to furnish
(3R,4S,5S,6R)-2-[3-(4-Benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)--
4-isopropyl-phenyl]-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-3,4,5-triol
(600 mg).
Example 68
(2S,3R,4R,5S,6R)-2-[3-(4-Benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl-
)-4-isopropyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
[0817] Step VI: To a stirred solution of
(3R,4S,5S,6R)-2-[3-(4-Benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)--
4-isopropyl-phenyl]-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-3,4,5-triol
(600 mg, 1.09 mmol) in acetonitrile-dichloroethane mixture (1:1
mixture, 10 mL) was added triethylsilane (0.7 mL, 4.4 mmol) and
boron trifluoride diethyletharate complex (0.27 mL, 2.18 mmol) at
-20.degree. C. After stirring for 4 h at 0.degree. C., the reaction
was quenched with aq. saturated NaHCO.sub.3 solution (8 mL). The
volatiles were evaporated under reduced pressure; the resulting
mixture was extracted with ethyl acetate (3.times.20 mL). The
organic layers were combined and washed with brine (5 mL), dried
over sodium sulphate, concentrated to a residuer which was purified
by column chromatography to furnish
(2S,3R,4R,5S,6R)-2-[3-(4-Benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethy-
l)-4-isopropyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
(520 mg).
Example 69
(2S,3R,4R,5S,6R)-2-[3-(3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-isopr-
opyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
[0818] Step VII: To a solution
(2S,3R,4R,5S,6R)-2-[3-(4-benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethy-
l)-4-isopropyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
(520 mg, 1.0 mmol) in methanol (5 mL) was added 10% palladium on
charcoal (150 mg), 0.05 mL conc. HCl and the mixture was stirred
under hydrogen balloon pressure for 18 h. The reaction mixture was
filtered through a celite bed, and the celite was washed with
methanol. The resulting filtrate was concentrated to a residue
which was purified by preparative HPLC to furnish
(2S,3R,4R,5S,6R)-2-[3-(3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethyl-
)-4-isopropyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
(70 mg).
[0819] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 1.06 (s, 3H),
1.08 (s, 3H), 3.10-3.180 (m, 1H), 3.26-3.30 (m, 2H), 3.34-3.48 (m,
4H), 3.66-3.70 (m, 1H), 3.83-3.89 (m, 3H), 4.07 (d, J=9.20 Hz, 1H),
4.11-4.13 (m, 2H), 6.32 (dd, J=2.4 Hz, J=8.4 Hz, 1H), 6.36 (d,
J=1.6 Hz, 1H), 6.53 (d, J=8.4 Hz, 1H), 7.18 (s, 1H), 7.24-7.28 (m,
2H). MS (ES) m/z 430.3 (M+1).
Examples 70-71
##STR00118##
[0821] Step I: To a solution of 2-bromoisopropyl benzene (2.0 g,
10.0 mmole) in dry THF (20 mL), nBuLi (1.6 M in hexanes) (6.9 mL,
11.05 mmole) was added at -78.degree. C. and the mixture was
stirred at same temperature for one hour. DMF (0.9 g, 12.0 mmole)
was added and the mixture was stirred at -78.degree. C. for an
additional half an hour, then allowed to stir at 0.degree. C. for
15 min. The reaction mixture was diluted with saturated aqueous
ammonium chloride (10 mL) and extracted with ethyl acetate
(3.times.30 mL). The combined organic layers were washed with brine
and dried over sodium sulfate. The solvent was evaporated to yield
2-isopropyl benzaldehyde (1.4 g).
[0822] Step II: To a solution of trifluoroacetic acid (50 ml) and
2-isopropylbenzaldehyde (2.0 g, 13.5 mmol) was added conc.
sulphuric acid (98%) (10 ml) at room temperature, followed by
N-bromosuccinamide (NBS, 3.6 g 20.2 mmol) in portions. After 2 hrs,
the mixture was poured into ice water and extracted with
dichloromethane (3.times.30 mL). The organic layers were combined
and neutralized with saturated aqueous sodium bicarbonate, washed
with brine (30 mL), dried over sodium sulfate and concentrated. The
resulting residue was purified by column chromatography to furnish
5-bromo-2-isopropylbenzaldehyde (1.80 g).
[0823] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 1.30 (d, J=6.8
Hz, 6H), 3.84-3.91 (m, 1H), 7.33 (d, J=8.4 Hz, 1H), 7.65 (dd,
J=2.0, J=8.4 Hz, 1H), 7.93 (d, J=2.0 Hz, 1H), 10.3 (s, 1H).
##STR00119##
[0824] Step I: To a stirred solution of
7-bromo-1,2,3,4-tetrahydroquinoline (7.0 g, 33.0 mmol) in DMF (50
mL) was added potassium carbonate (13.6 g, 99.0 mmol), and benzyl
bromide (4.33 mL, 36.3 mmol), and the mixture was heated to
60.degree. C. for 12 h, then cooled to room temperature and
quenched by the addition of ice-cold water (150 mL). The resulting
mixture was extracted with ethyl acetate (3.times.50 mL), and the
organic layers were combined and washed with water (50 mL) and
brine (50 mL), then dried over sodium sulfate, concentrated and
purified by silica gel column chromatography to furnish
1-benzyl-7-bromo-1,2,3,4-tetrahydro-quinoline (7.1 g).
[0825] Step II: To a solution of
1-benzyl-7-bromo-1,2,3,4-tetrahydro-quinoline (2.50 g, 8.27 mmol)
in THF (20 mL) was added 1.6 M n-butyl lithium in hexanes (5.14 mL,
8.27 mmol) at -78.degree. C. The mixture was stirred for 45 min.
then transferred to a stirred solution of
5-bromo-2-isopropylbenzaldehyde (1.87 g, 8.27 mmol) in THF (15 mL)
at -78 15.degree. C. After stirring for 30 min, the reaction was
quenched by the addition of saturated aqueous solution of ammonium
chloride, and the resulting mixture was extracted with ethyl
acetate (3.times.30 mL). The organic layers were combined and
washed with water (25 mL) and brine (25 mL), then dried over sodium
sulfate, concentrated and purified using neutral alumina column
chromatography to furnish
(1-benzyl-1,2,3,4-tetrahydro-quinolin-7-yl)-(5-bromo-2-isopropyl--
phenyl)-methanol (2.64 g).
[0826] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 0.85 (d, J=7.2
Hz, 3H), 1.11 (d, J=6.8 Hz, 3H), 1.97-2.03 (m, 2H), 2.78 (t, J=6.4
Hz, 2H), 2.92-2.99 (m, 1H), 3.40 (t, J=5.6 Hz, 2H), 4.40 (s, 2H),
5.85 (d, J=3.2 Hz, 1H), 6.36 (s, 1H), 6.47 (d, J=1.2 Hz, 1H), 6.91
(d, J=7.6 Hz, 1H), 7.04 (d, J=8.0 Hz, 1H), 7.14-7.34 (m, 7H), 7.62
(d, J=2.0 Hz, 1H).
[0827] MS (ES) m/z 452 (M+2).
[0828] Step III: To a solution of
(1-benzyl-1,2,3,4-tetrahydro-quinolin-7-yl)-(5-bromo-2-isopropyl-phenyl)--
methanol (2.61 g, 5.79 mmol) in TFA (7.0 mL), Et.sub.3SiH (4.63 mL,
28.95 mmol) was added followed by triflic acid (1.0 mL, 11.5 mmol)
at room temperature. The reaction mixture was stirred at room
temperature for 30 min. The reaction was evaporated to dryness and
neutralized by adding saturated aqueous NaHCO.sub.3 (15 mL). The
resulting mixture was extraction with dichloromethane (3.times.30
mL). Crude product obtained after evaporation solvent was purified
by using neutral alumina column chromatography to furnish
1-benzyl-7-(5-bromo-2-isopropyl-benzyl)-1,2,3,4-tetrahydro-quinoline
(1.80 g).
[0829] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 1.05 (d, J=7.2
Hz, 6H), 1.96-2.02 (m, 2H), 2.76 (t, J=6.0 Hz, 2H), 2.98-3.04 (m,
1H), 3.35 (t, J=5.6 Hz, 2H), 3.80 (s, 2H), 4.37 (s, 2H), 6.19 (s,
1H), 6.27 (d, J=7.6 Hz, 1H), 6.85 (d, J=7.6 Hz, 1H), 7.07 (d,
J=8.80 Hz, 1H), 7.14-7.29 (m, 7H).
[0830] MS (ES) m/z 436 (M+2).
[0831] Step IV: To a stirred solution of
1-benzyl-7-(5-bromo-2-isopropyl-benzyl)-1,2,3,4-tetrahydro-quinoline
(1.50 g, 3.45 mmol) in THF-toluene 1:2 (15 mL) was added 1.6 M
solution of n-BuLi in hexanes (2.16 mL, 3.45 mmol) at -78.degree.
C. The reaction mixture was stirred for 45 min., and then
transferred to a stirred solution of
2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone (1.60 g, 3.45
mmol) in toluene (10 mL) at -78.degree. C. After stirring for 45
min., 0.6 N methanesulfonic acid in methanol (15 mL) was added and
the mixture was stirred for 20 h at room temperature. The reaction
was quenched by addition of aq. saturated NaHCO.sub.3 (10 mL) and
the resulting mixture was extracted with ethyl acetate (3.times.20
mL). The organic layers were combined and dried over sodium
sulphate, concentrated and purified by silica gel column
chromatography to furnish
(2S,3R,4S,5S,6R)-2-[3-(1-Benzyl-1,2,3,4-tetrahydro-quinolin-7-ylmethyl)-4-
-isopropyl-phenyl]-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-3,4,5-triol
(1.27 g).
Example 70
(2S,3R,4R,5S,6R)-2-[3-(1-Benzyl-1,2,3,4-tetrahydro-quinolin-7-ylmethyl)-4--
isopropyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
[0832] Step V: To a stirred solution of
(2S,3R,4S,5S,6R)-2-[3-(1-benzyl-1,2,3,4-tetrahydro-quinolin-7-ylmethyl)-4-
-isopropyl-phenyl]-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-3,4,5-triol
(1.20 g, 2.19 mmol) in acetonitrile-dichloroethane 1:1 (20 mL) was
added triethylsilane (1.39 mL, 8.76 mmol) at room temperature, then
the reaction mixture cooled to -50 to -60.degree. C. and boron
trifluoride diethyletharate complex (0.55 mL, 4.38 mmol) was added
dropwise, and the reaction mixture was stirred at same temperature
and allowed to stir at below -30.degree. C. for 2 hours and at
-20.degree. C. for 1 hour and then below 0.degree. C. for 1 hour.
The reaction was quenched with aq. saturated NaHCO.sub.3 solution
(20 mL). The volatiles were evaporated under reduced pressure, and
the resulting mixture was extracted with ethyl acetate (3.times.20
mL). The organic layers were combined and washed with brine (5 mL),
dried over sodium sulphate, and concentrated to furnish
(2S,3R,4R,5S,6R)-2-[3-(1-Benzyl-1,2,3,4-tetrahydro-quinolin-7-ylm-
ethyl)-4-isopropyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
(1.0 g). Crude product was used for next step without
purification.
Example 71
(2R,3S,4R,5R,6S)-2-Hydroxymethyl-6-[4-isopropyl-3-(1,2,3,4-tetrahydro-quin-
olin-7-ylmethyl)-phenyl]-tetrahydro-pyran-3,4,5-triol
[0833] Step-VI: To a solution
(2S,3R,4R,5S,6R)-2-[3-(1-benzyl-1,2,3,4-tetrahydro-quinolin-7-ylmethyl)-4-
-isopropyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
(1.0 g, 1.0 mmol) in methanol (20 mL) was added 10% dry palladium
on charcoal (200 mg) and conc. HCl (0.2 mL), and the mixture was
stirred under hydrogen balloon pressure for 18 h. The reaction
mixture was filtered through a celite bed which was washed with
methanol and the filtrate was concentrated. The resulting residue
was purified by preparative HPLC to furnish
(2R,3S,4R,5R,6S)-2-Hydroxymethyl-6-[4-isopropyl-3-(1,2,3,4-tetrah-
ydro-quinolin-7-ylmethyl)-phenyl]-tetrahydro-pyran-3,4,5-triol (320
mg).
[0834] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 1.07 (s, 3H),
1.08 (s, 3H), 1.84-1.88 (m, 2H), 2.67 (t, J=6.4 Hz, 2H), 3.17 (t,
J=5.6 Hz, 3H), 3.37-3.46 (m, 5H), 3.65-3.70 (m, 1H), 3.83-3.88 (m,
2H), 4.08 (d, J=9.2 HZ, 1H), 6.26 (s, 1H), 6.32 (d, J=8.0 Hz, 1H),
6.74 (d, J=7.60 Hz, 1H), 7.19 (s, 1H), 7.22-7.26 (m, 2H).
[0835] MS (ES) m/z 428.1 (M+1).
[0836] Following example was prepared by using the procedures
described for examples 70-71.
TABLE-US-00009 Example No. Structure/IUPAC name Spectral data 72
##STR00120## (2R,3S,4R,5R,6S)-2-Hydroxymethyl-
6[4-isopropyl-3-(1,2,3,4-tetrahydro- quinolin-6-ylmethyl)-phenyl]-
tetrahydro-pyran-3,4,5-triol. .sup.1H NMR (400 MHz, CD.sub.3OD):
.delta. 1.06 (s, 3H), 1.07 (s, 3H), 1.82- 1.88 (m, 2H), 2.65 (t, J
= 6.8 Hz, 2H), 3.12 (m, 1H), 3.16 (t, J = 10.20 Hz, 2H), 3.38-3.46
(m, 4H), 3.66 (dd, J = 4.4 Hz, J = 12.0 Hz, 1H), 3.84-3.88 (m, 3H),
4.08 (d, J = 9.2 HZ, 1H), 6.43 (d, J = 8.0 Hz, 1H), 6.63-6.70 (m,
2H), 7.18 (s, 1H), 7.24-7.26 (m, 2H). MS (ES) m/z 428.1 (M +
1).
[0837] The below list of examples, but not limited to these, can
also be synthesized following the general synthesis described
herein above:
##STR00121## ##STR00122## ##STR00123## ##STR00124## ##STR00125##
##STR00126## ##STR00127## ##STR00128## ##STR00129## ##STR00130##
##STR00131## ##STR00132## ##STR00133## ##STR00134## ##STR00135##
##STR00136## ##STR00137## ##STR00138## ##STR00139##
[0838] 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.
[0839] 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 14 C-labelled
alpha-methyl-glucopyranoside (14 C-AMG, Amersham) into the interior
of the cell in sodium-dependent manner.
[0840] 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 KCl, 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 14 C-AMG absorbed is measured
in a Topcount (Packard) using a 14 C scintillation program.
[0841] 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.
[0842] The compounds according to the invention may for example
have EC50 values below 1000 nM, particularly below 100 nM, most
preferably below 10 nM. The title compounds of the above Examples
were evaluated in the above described assay and the results of
which are collated in Table 1.
TABLE-US-00010 TABLE 1 Example SGLT2 IC.sub.50 SGLT1 IC.sub.50
Number nM (n = 1-4) nM (n = 1-4) 1 2.7 655 2 11.1 2500 3 16 -- 4 65
-- 8 0.25 725 9 7.2 -- 10 18 -- 11 1.4 -- 14 5.5 800 15 0.2 650 16
0.15 750 17 0.8 480 20 0.55 >3700 21 0.2 1100 22 0.4 -- 24 1.3
31000 25 1.5 40 28 0.33 1000 29 84.5 7000 31 1.2 404 33 11 157 35
9.5 1100 36 28 -- 38 14.4 -- 41 16.2 1620 42 0.35 105 43 3.9 59 46
14 >3900 47 16.5 >3200 60 2.2 9 62 0.5 22 65 2.7 170 66 0.9
100 69 1.2 37 71 1.5 19
[0843] 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.
Co-Crystal of the Compounds of the Invention
[0844] Method 1: 1:1 Co-Crystals of Compounds of the Invention with
L-Proline Proline co-crystals were prepared from Examples 8, 60, 62
and 71, by the following method. The procedure given below pertains
to the preparation of about 543 mg of the co-crystals for Examples
73-76.
[0845] Example 8, 60, 62 or 71 (about 4.28 mg) and L-proline (1.15
g) were taken in 1:1 molar ratio in 10 ml of ethanol in a 25 ml
round bottom flask and refluxed for one hour at 90.degree. C. The
ethanol was then removed under vacuum (using rotatory vacuum
evaporator) to yield a gummy paste. This gummy paste was stirred in
20 ml of hexane at room temperature for 5 hrs (for Examples 60 and
62), overnight for Example 8 and 2 days for Example 71. The hexane
was then decanted to yield a free flowing solid. Characterization
data for co-crystals prepared by this method is shown in Examples
73-76.
[0846] Powder x-ray diffraction patterns for Examples 73-76 were
measured using the following conditions:
Scanning Axis: Gonio
Start Position (.degree.2 Th.): 2.5167
End Position (.degree.2 Th.): 49.9707
Step Size (.degree.2 Th.): 0.0330
[0847] Scan Step Time (sec): 10.1600
Scan Type: Continuous
PSD Mode: Scanning
PSD Length (.degree.2 Th.): 2.12
Offset (.degree.2 Th.): 0.0000
Divergence Slit Type: Automatic
Irradiated Length (mm): 10.00
Specimen Length (mm): 10.00
Measurement Temperature (.degree. C.): 25.00
Anode Material: Cu
K-Alpha1 (.ANG.): 1.54060
K-Alpha2 (.ANG.): 1.54443
K-Beta (.ANG.): 1.39225
K-A2/K-A1 Ratio: 0.50000
Generator Settings: 40 mA, 45 kV
Goniometer Radius (mm): 240.00
[0848] Dist. Focus-Diverg. Slit (mm): 100.00
Incident Beam Monochromator: No
Spinning: Yes
Example 73
1:1 Proline Co-crystal with
(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethy-
l)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
[0849]
(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(3,4-dihydro-2H-benzo[1,4]oxazin-6-y-
lmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
(Example 8) was completely amorphous initially but formed a
crystalline complex with proline. This was confirmed by powder
X-ray diffraction (PXRD) analysis. The stoichiometry of Example 8
and L-proline in the co-crystal prepared by the above method was
found to be 1:1 by NMR spectroscopy & HPLC. Characterization
data for co-crystals of Example 8 and proline prepared by method 1
is shown in Table 1. Relative intensities of the most prominent
powder x-ray diffraction peaks for co-crystals of Example 8 and
proline are shown in Table 1A.
TABLE-US-00011 TABLE 1 1:1 Co-crystal of Example 8 and Example 8
Proline proline IR 3337, 2875, 1613, 3053, 2983, 2777, 3585, 3208,
2914, (cm-1) 1594, 1513, 1478, 2369, 1617, 1560, 1622, 1591, 1513,
1352, 1315, 1289, 1449, 1405, 1377, 1480, 1457, 1406, 1211, 1083,
1039, 1294, 1256, 1169, 1369, 1317, 1291, 886, 819 1085, 1035, 983,
1214, 1127, 1075, 849 1034, 959, 922, 883, 836, 793 MP 74-126 205
decomposes 85-87 (.degree. C.) PXRD amorphous 15.14, 18.04, 19.57,
5.7, 12.9, 16.6, (2 .theta.) 24.80, 30.57, 32.16, 17.0, 19.3, 20.6,
39.79, 36.56, 37.65, 22.3, 23.2, 25.2, 37.65 25.7, 26.5, 27.6 DSC
Broad peak Sharp peak Three peaks were (.degree. C.) observed from
observed at observed at 74-126 205 63.78, 104.34 and 155.53
TABLE-US-00012 TABLE 1A Relative Angle (2-Theta) Intensity (%) 5.7
28.37 12.9 12.28 16.6 16.69 17.0 33.15 19.3 100.00 20.6 13.03 22.3
13.34 23.2 55.29 25.2 25.48 25.7 12.95 26.5 20.58 27.6 16.72
Example 74
1:1 Proline Co-crystal with
(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
[0850]
(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
(Example 60) was completely amorphous initially but formed a
crystalline complex with proline. This was confirmed by powder
X-ray diffraction (PXRD) analysis. The stoichiometry of Example 60
and L-proline in the co-crystal prepared by method 1 was found to
be 1:1 by NMR spectroscopy & HPLC. Characterization data for
co-crystals of Example 60 and proline prepared by the above method
is shown in Table 2. Relative intensities of the most prominent
powder x-ray diffraction peaks for co-crystals of Example 60 and
proline are shown in Table 2A.
TABLE-US-00013 TABLE 2 1:1 Co-crystal of Example 60 and Example 60
Proline proline IR 3349, 2930, 2875, 3053, 2983, 2777, 3334, 2918,
2880, (cm-1) 1589, 1506, 1458, 2369, 1617, 1560, 1613, 1589, 1505,
1429, 1360, 1284, 1449, 1405, 1377, 1455, 1427, 1402, 1258, 1203,
1124, 1294, 1256, 1169, 1374, 1310, 1279, 1086, 1068, 1020, 1085,
1035, 983, 1262, 1199, 1165, 917, 886 849 1124, 1083, 1068, 1041,
1019, 954 MP 75-118 205 decomposes 148-158 (.degree. C.) PXRD
amorphous 15.14, 18.04, 19.57, 4.07, 15.41, 15.80, (2 .theta.)
24.80, 30.57, 32.16, 16.16, 16.68, 17.04, 39.79, 36.56, 37.65,
17.59, 18.16, 18.67, 37.65 19.53, 19.91, 20.36, 21.47, 21.88,
22.23, 23.84, 26.98, 32.32 DSC Broad peak Sharp peak Sharp peak
(.degree. C.) observed from observed at observed at 75-118 205
150.58
TABLE-US-00014 TABLE 2A Relative Angle (2-Theta) Intensity (%) 4.07
25.22 15.41 19.85 15.80 44.90 16.16 87.61 16.68 100.00 17.04 36.50
17.59 81.41 18.16 51.31 18.67 36.27 19.53 32.80 19.91 76.22 20.36
52.35 21.47 34.08 21.88 48.13 22.23 27.34 23.84 25.74 26.98 19.61
32.32 15.11
Example 75
1:1 Proline Co-crystal with
(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
[0851]
(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-e-
thyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (Example
62) was completely amorphous initially but formed a crystalline
complex with proline. This was confirmed by powder X-ray
diffraction (PXRD) analysis. The stoichiometry of Example 62 and
L-proline in the co-crystal prepared by method 1 was found to be
1:1 by NMR spectroscopy & HPLC. Characterization data for
co-crystals of Example 62 and proline prepared by method 1 is shown
in Table 3. Relative intensities of the most prominent powder x-ray
diffraction peaks for co-crystals of Example 62 and proline are
shown in Table 3A.
TABLE-US-00015 TABLE 3 1:1 Co-crystal of Example 62 and Example 62
Proline proline IR 3340, 2966, 2931, 3053, 2983, 2777, 3316, 3198,
2965, (cm-1) 2874, 1589, 1506, 2369, 1617, 1560, 2913, 2873, 2679,
1456, 1429, 1358, 1449, 1405, 1377, 1605, 1505, 1455, 1285, 1258,
1202, 1294, 1256, 1169, 1427, 1409, 1358, 1124, 1085, 1068, 1085,
1035, 983, 1311, 1286, 1257, 955, 917, 885, 849 1201, 1127, 1085,
833 1069, 1018, 1004, 918, 884 MP 76-123 205 decomposes 146-151
(.degree. C.) PXRD amorphous 15.14, 18.04, 19.57, 3.70, 9.68,
11.07, (2 .theta.) 24.80, 30.57, 32.16, 14.26, 14.80, 15.40, 39.79,
36.56, 37.65, 16.12, 16.59, 17.31, 37.65 17.98, 18.36, 18.88,
20.42, 21.18, 22.50, 23.78, 24.56, 25.79, 27.46, 31.97, 32.46 DSC
Broad peak Sharp peak Two peaks were (.degree. C.) observed from
observed at observed at 75-118 205 152.15 and 163.81
TABLE-US-00016 TABLE 3A Relative Angle (2-Theta) Intensity (%) 3.70
15.78 9.68 10.68 11.07 21.21 14.26 14.81 14.80 22.97 15.40 4.98
16.12 8.45 16.59 18.78 17.31 100.0 17.60 20.35 17.98 47.20 18.36
25.18 18.88 36.33 20.42 69.29 21.18 27.94 22.50 12.25 23.78 33.08
24.56 6.92 25.79 21.69 27.46 8.90 31.97 7.65 32.46 5.98
Example 76
1:1 Proline Co-crystal with
(2R,3S,4R,5R,6S)-2-Hydroxymethyl-6-[4-isopropyl-3-(1,2,3,4-tetrahydro-qui-
nolin-7-ylmethyl)-phenyl]-tetrahydro-pyran-3,4,5-triol
[0852]
(2R,3S,4R,5R,6S)-2-Hydroxymethyl-6-[4-isopropyl-3-(1,2,3,4-tetrahyd-
ro-quinolin-7-ylmethyl)-phenyl]-tetrahydro-pyran-3,4,5-triol
(Example 71) was completely amorphous initially but formed a
crystalline complex with proline. This was confirmed by powder
X-ray diffraction (PXRD) analysis. The stoichiometry of Example 71
and L-proline in the co-crystal prepared by method 1 was found to
be 1:1 by NMR spectroscopy & HPLC. Characterization data for
co-crystals of Example 71 and proline prepared by method 1 is shown
in Table 4.
TABLE-US-00017 TABLE 4 1:1 Co-crystal of Example 71 and Example 71
Proline proline IR 3318, 2959, 2928, 3053, 2983, 2777, 3311, 2959,
2926, (cm-1) 1659, 1614, 1578, 2369, 1617, 1560, 1613, 1579, 1499,
1498, 1464, 1446, 1449, 1405, 1377, 1406, 1361, 1314, 1361, 1313,
1180, 1294, 1256, 1169, 1170, 1084, 1045, 1084, 1010, 886, 1085,
1035, 983, 1010, 833, 785 832, 786 849 PXRD Amorphous 15.14, 18.04,
19.57, 5.7, 8.8, 16.4, (2 .theta.) 24.80, 30.57, 32.16, 19.1, 2.3,
23.6, 39.79, 36.56 37.65, 24.5 37.65 MP 76-120 205 decomposes
145-148 (.degree. C.) DSC Broad peak Sharp peak Two peaks (.degree.
C.) observed at observed at observed at 76-120 205 156.29 and
158.38
Example 77
1:1 Proline Co-crystal with
(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
[0853] Method 2: 1:1 Co-Crystals of Example 62 with L-Proline
[0854]
(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-e-
thyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (Example
62, 1500 mg, 3.6 mmol), L-proline (415 mg, 3.6 mmol) and ethanol
(23 mL) were added to a 50 mL 3-neck round bottom flask equipped
with nitrogen purging, magnetic stirring bar, thermometer pocket
& calcium chloride guard tube and the mixture was stirred at
25-30.degree. C. for 30 min., then heat to reflux. A clear solution
was observed which was refluxed for 30 min., then slowly cool to
25-30.degree. C. causing percipitation. Di-isopropyl ether (DIPE,
23 mL) was added while maintaining the mixture at 25-30.degree. C.
and stirring continuously for additional one to two hours at the
same temperature. The precipitate was collected by filtration using
vacuum (Nitrogen atmosphere), and the filter cake was washed with
ethanol-DIPE mixture (1:1 v/v, 10 ml) followed by DIPE (23 mL). The
product was vacuum dried at 65-70.degree. C. for 5-6 hrs.
[0855] A melting point 136.degree. C. (.DELTA.H 53 J/g) was
observed by differential scanning calorimetry (DSC) and is shown in
FIG. 1. A powder X-ray diffraction (PXRD) spectrum is shown in FIG.
2.
Example 78
2:1 Proline Co-crystal with
(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
[0856] Method 3: 1:2 Co-Crystals of Example 62 with L-Proline
[0857]
(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-e-
thyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (Example
62, 1 kg) was added to 15 L of ethanol with agitation while
maintaining the mixture at 20-25.degree. C. The mixture was stirred
for 10 min at 20-25.degree. C., then L-proline (537 gm) was added
while maintaining the mixture at 20-25.degree. C. The mixture was
stirred at this temperature for 30 min., then heated to reflux and
refluxed for 30 min. The mixture was slowly cooled to 25-30.degree.
C. then stirred for 1 hr. DIPE (15 L) was added while maintaining
the temperature at 25-30.degree. C. and the mixture was stirred at
this temperature for 1 hr. The precipitated product was collected
by filtration and the product was washed with DIPE (5 L). The
product was air dried at 65-70.degree. C. to yield 1.22 kg (79%) of
a 1:2 co-crystal of Example 62: L-proline. A melting point
176.degree. C. (.DELTA.H 85 J/g) was observed by differential
scanning calorimetry (DSC) and is shown in FIG. 3. A powder X-ray
diffraction (PXRD) spectrum is shown in FIG. 4. Relative
intensities of the most prominent powder x-ray diffraction peaks
for the 1:2 co-crystals of Example 62 and proline are shown in
Table 5.
TABLE-US-00018 TABLE 5 Relative Angle (2-Theta) Intensity (%) 6.1
28.1 9.1 53.9 12.8 22.7 15.2 34.4 16.5 28.3 17.8 100.0 18.9 39.0
20.9 39.5 28.4 20.4 -- --
[0858] It will be understood that the invention has been described
by way of example only and modifications may be made whilst
remaining within the scope and spirit of the invention.
* * * * *