U.S. patent application number 14/306429 was filed with the patent office on 2014-10-02 for substituted aminopropionic derivatives as neprilysin inhibitors.
The applicant listed for this patent is Gary Mark COPPOLA, Yuki IWAKI, Rajeshri Ganesh KARKI, Toshio KAWANAMI, Gary Michael KSANDER, Muneto MOGI, Robert SUN. Invention is credited to Gary Mark COPPOLA, Yuki IWAKI, Rajeshri Ganesh KARKI, Toshio KAWANAMI, Gary Michael KSANDER, Muneto MOGI, Robert SUN.
Application Number | 20140296240 14/306429 |
Document ID | / |
Family ID | 42313042 |
Filed Date | 2014-10-02 |
United States Patent
Application |
20140296240 |
Kind Code |
A1 |
COPPOLA; Gary Mark ; et
al. |
October 2, 2014 |
SUBSTITUTED AMINOPROPIONIC DERIVATIVES AS NEPRILYSIN INHIBITORS
Abstract
The present invention provides a compound of formula I';
##STR00001## or a pharmaceutically acceptable salt thereof, wherein
R.sup.1, R.sup.2, R.sup.3, R.sup.5, B.sup.1, X and n are defined
herein. The invention also relates a method for manufacturing the
compounds of the invention, and its therapeutic uses. The present
invention further provides a combination of pharmacologically
active agents and a pharmaceutical composition.
Inventors: |
COPPOLA; Gary Mark; (Budd
Lake, NJ) ; IWAKI; Yuki; (Tokyo, JP) ; KARKI;
Rajeshri Ganesh; (Somerville, MA) ; KAWANAMI;
Toshio; (Boston, MA) ; KSANDER; Gary Michael;
(Amherst, NH) ; MOGI; Muneto; (Waltham, MA)
; SUN; Robert; (Natick, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
COPPOLA; Gary Mark
IWAKI; Yuki
KARKI; Rajeshri Ganesh
KAWANAMI; Toshio
KSANDER; Gary Michael
MOGI; Muneto
SUN; Robert |
Budd Lake
Tokyo
Somerville
Boston
Amherst
Waltham
Natick |
NJ
MA
MA
NH
MA
MA |
US
JP
US
US
US
US
US |
|
|
Family ID: |
42313042 |
Appl. No.: |
14/306429 |
Filed: |
June 17, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13688630 |
Nov 29, 2012 |
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14306429 |
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12788766 |
May 27, 2010 |
8394853 |
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13688630 |
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61324943 |
Apr 16, 2010 |
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61263145 |
Nov 20, 2009 |
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61181756 |
May 28, 2009 |
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Current U.S.
Class: |
514/237.8 ;
514/256; 514/274; 514/350; 514/460; 514/467; 514/533; 544/168;
544/316; 544/335; 546/298; 549/418; 549/449; 560/41 |
Current CPC
Class: |
A61K 45/00 20130101;
A61P 1/08 20180101; A61P 25/18 20180101; C07D 239/34 20130101; A61K
31/505 20130101; A61P 3/10 20180101; A61P 43/00 20180101; A61P
15/06 20180101; A61P 15/00 20180101; A61P 25/04 20180101; A61P
27/02 20180101; A61P 31/04 20180101; C07C 233/56 20130101; C07D
265/30 20130101; A61P 9/06 20180101; A61P 15/10 20180101; A61P
25/00 20180101; A61P 25/28 20180101; C07C 233/51 20130101; C07C
311/08 20130101; A61K 31/197 20130101; A61P 9/00 20180101; A61K
31/351 20130101; A61P 27/06 20180101; C07C 235/12 20130101; A61P
7/00 20180101; A61K 31/44 20130101; A61P 11/06 20180101; C07D
317/34 20130101; A61K 31/5375 20130101; A61K 31/325 20130101; A61P
25/08 20180101; C07D 309/32 20130101; A61P 7/10 20180101; A61P 1/00
20180101; C07C 271/22 20130101; A61P 13/02 20180101; C07D 257/04
20130101; A61K 31/357 20130101; A61P 17/00 20180101; A61K 31/216
20130101; C07C 2601/08 20170501; C07D 239/36 20130101; C07D 295/15
20130101; A61P 35/02 20180101; C07C 237/22 20130101; A61K 31/41
20130101; C07C 233/63 20130101; C07C 255/60 20130101; C07D 239/28
20130101; C07C 233/47 20130101; A61P 3/00 20180101; A61P 1/04
20180101; A61P 9/12 20180101; A61P 15/12 20180101; A61P 29/00
20180101; C07C 2601/14 20170501; C07D 271/06 20130101; A61K 31/421
20130101; A61P 17/02 20180101; C07D 213/82 20130101; A61P 5/24
20180101; A61P 3/14 20180101; A61P 13/12 20180101; A61K 45/06
20130101; C07C 275/24 20130101; C07C 237/16 20130101; A61P 15/08
20180101; A61P 9/04 20180101; C07C 233/49 20130101; C07D 263/32
20130101; A61P 3/04 20180101; C07C 235/78 20130101; C07C 2602/08
20170501; A61P 11/00 20180101; C07C 311/51 20130101; A61P 25/24
20180101; C07B 2200/05 20130101; A61P 9/10 20180101; C07D 261/18
20130101 |
Class at
Publication: |
514/237.8 ;
560/41; 514/533; 549/449; 514/467; 544/168; 544/335; 514/256;
544/316; 514/274; 546/298; 514/350; 549/418; 514/460 |
International
Class: |
C07D 317/34 20060101
C07D317/34; A61K 31/216 20060101 A61K031/216; A61K 31/357 20060101
A61K031/357; C07D 295/15 20060101 C07D295/15; A61K 31/5375 20060101
A61K031/5375; A61K 45/06 20060101 A61K045/06; A61K 31/505 20060101
A61K031/505; C07D 239/34 20060101 C07D239/34; C07D 213/82 20060101
C07D213/82; A61K 31/44 20060101 A61K031/44; C07D 309/32 20060101
C07D309/32; A61K 31/351 20060101 A61K031/351; C07C 235/78 20060101
C07C235/78; C07D 239/28 20060101 C07D239/28 |
Claims
1-19. (canceled)
20. A compound according to Formula VII or VIIA: ##STR00641##
wherein R.sup.1 is H; R.sup.2 is independently halo,
C.sub.1-7alkoxy, hydroxy, C.sub.1-7alkyl or halo-C.sub.1-7alkyl; n
is 0, 1 or 2; X is independently OH or --O--C.sub.1-7alkyl, A.sup.2
is a bond or CH.sub.2 or CH.sub.2--CH.sub.2; R4 is a 5- or
6-membered heteroaryl optionally substituted with one or more
substituents independently selected from the group consisting of
hydroxy, C.sub.1-7alkyl, C.sub.1-7alkoxy, halo, halo-C.sub.1-7alkyl
or benzyl.
21. The compound of claim 20 wherein R.sup.2 is meta-chloro or
meta-fluoro and the other optional R.sup.2 group is halo,
C.sub.1-7alkyl, halo-C.sub.1-7alkyl, hydroxy and C.sub.1-7alkoxy,
or a pharmaceutically acceptable salt thereof.
22. The compound according to claim 20 wherein R.sup.4 is a
6-membered ring heteroaryl selected from the group consisting of
pyrazinyl, pyridinyl, pyrimidinyl, pyranone, pyridinone,
pyrimidinone; or a pharmaceutically acceptable salt thereof.
23. The compound according to claim 21 wherein R.sup.4 is a
6-membered ring heteroaryl selected from the group consisting of
pyrazinyl, pyridinyl, pyrimidinyl, pyranone, pyridinone,
pyrimidinone; or a pharmaceutically acceptable salt thereof.
24. The compound according to claim 20 wherein R.sup.4 is a
5-membered ring heteroaryl selected from the group consisting of
oxazole, pyrrole, pyrazole, isooxazole, triazole, tetrazole,
oxadiazole, oxadiazolone, thiazole, isothiazole, thiophene,
imidazole and thiadiazole; or a pharmaceutically acceptable salt
thereof.
25. The compound according to claim 21 wherein R.sup.4 is a
5-membered ring heteroaryl selected from the group consisting of
oxazole, pyrrole, pyrazole, isooxazole, triazole, tetrazole,
oxadiazole, oxadiazolone, thiazole, isothiazole, thiophene,
imidazole and thiadiazole; or a pharmaceutically acceptable salt
thereof.
26. The compound according to claim 20 wherein R.sup.4 is selected
from the group consisting of: ##STR00642## or a pharmaceutically
acceptable salt thereof.
27. The compound according to claim 21 wherein R.sup.4 is selected
from the group consisting of: ##STR00643## or a pharmaceutically
acceptable salt thereof.
28. A pharmaceutical composition comprising a compound according to
claim 20 or a pharmaceutically acceptable salt thereof, and one or
more pharmaceutically acceptable carriers.
29. A combination comprising: a compound according to claim 20, or
a pharmaceutically acceptable salt thereof, and one or more
therapeutically active agents selected from HMG-Co-A reductase
inhibitor, an anigiotensin receptor blocker, angiotensin converting
enzyme Inhibitor, a calcium channel blocker, an endothelin
antagonist, a renin inhibitor, a diuretic, an ApoA-I mimic, an
anti-diabetic agent, an obesity-reducing agent, an aldosterone
receptor blocker, an endothelin receptor blocker, an aldosterone
synthase inhibitors, a CETP inhibitor and a phosphodiesterase of
type 5 (PDE5) inhibitor.
30. A method of inhibiting neutral endopeptidase EC. 3.4. 24.11.
activity in a subject in need thereof, comprising: administering to
the subject a therapeutically effective amount of the compound
according to claim 20, or a pharmaceutically acceptable salt
thereof.
31. The method according to claim 30, wherein the disorder or the
disease is selected from hypertension, pulmonary hypertension,
isolated systolic hypertension, resistant hypertension, peripheral
vascular disease, heart failure, congestive heart failure, left
ventricular hypertrophy, angina, renal insufficiency, renal
failure, diabetic nephropathy, non-diabetic nephropathy, nephroic
syndrome, glomerulonephritis, scleroderma, glomerular sclerosis,
proteinurea of primary renal disease, renal vascular hypertention,
diabetic retinopathy and end-stage renal disease (ESRD),
endothelial dysfunction, diastolic dysfunction, hypertrophic
cardiomyopathy, diabetic cardiac myopathy, supraventricular and
ventricular arrhythmias, atrial fibrillation (AF), cardiac
fibrosis, atrial flutter, detrimental vascular remodeling, plaque
stabilization, myocardial infarction (MI), renal fibrosis,
polycystic kidney disease (PKD), pulmonary arterial hypertension,
renal failure, cyclical oedema, Menieres disease,
hyperaldosteroneism hypercalciuria, ascites, glaucoma, menstrual
disorders, preterm labour, pre-eclampsia, endometriosis, and
reproductive disorders, asthma, obstructive sleep apnea,
inflammation, leukemia, pain, epilepsy, affective disorders,
depression, psychotic condition, dementia, geriatric confusion,
obesity and gastrointestinal disorders, wound healing, septic
shock, gastric acid secretion dysfunction, hyperreninaemia, cystic
fibrosis, restenosis, type-2 diabetes, metabolic syndrome, diabetic
complications, atherosclerosis, male and female sexual dysfunction.
Description
BACKGROUND OF THE INVENTION
[0001] Endogenous atrial natriuretic peptides (ANP), also called
atrial natriuretic factors (ANF) have diuretic, natriuretic and
vasorelaxant functions in mammals. The natural ANF peptides is
metabolically inactivated, in particular by a degrading enzyme
which has been recognized to correspond to the enzyme neutral
endopeptidase (NEP) EC 3.4.24.11, also responsible for e.g. the
metabolic inactivation of enkephalins.
[0002] Neutral endopeptidase (EC 3.4.24.11; enkephalinase;
atriopeptidase; NEP) is a zinc-containing metalloprotease that
cleaves a variety of peptide substrates on the amino side of
hydrophobic residues [see Pharmacol Rev, Vol. 45, p. 87 (1993)].
Substrates for this enzyme include, but are not limited to, atrial
natriuretic peptide (ANP, also known as ANF), brain natriuretic
peptide (BNP), met- and leu-enkephalin, bradykinin, neurokinin A,
endothelin-1 and substance P. ANP is a potent vasorelaxant and
natriuretic agent [see J Hypertens, Vol. 19, p. 1923 (2001)].
Infusion of ANP in normal subjects resulted in a reproducible,
marked enhancement of natriuresis and diuresis, including increases
in fractional excretion of sodium, urinary flow rate and glomerular
filtration rate [see J Clin Pharmacol, Vol. 27, p. 927 (1987)].
However, ANP has a short half-life in circulation, and NEP in
kidney cortex membranes has been shown to be the major enzyme
responsible for degrading this peptide [see Peptides, Vol. 9, p.
173 (1988)]. Thus, inhibitors of NEP (neutral endopeptidase
inhibitors, NEPi) should increase plasma levels of ANP and, hence,
are expected to induce natriuretic and diuretic effects.
[0003] This enzyme is involved in the breakdown of several
bioactive oligopeptides, cleaving peptide bonds on the amino side
of hydrophobic amino acid residues. The peptides metabolised
include atrial natriuretic peptides (ANP), bombesin, bradykinin,
calcitonin gene-related peptide, endothelins, enkephalins,
neurotensin, substance P and vasoactive intestinal peptide. Some of
these peptides have potent vasodilatory and neurohormone functions,
diuretic and natriuretic activity or mediate behaviour effects.
SUMMARY OF THE INVENTION
[0004] The aim of the present invention is to provide novel
compounds which are useful as neutral endopeptidase inhibitors,
e.g. as inhibitors of the ANF-degrading enzyme in mammals, so as to
prolong and potentiate the diuretic, natriuretic and vasodilator
properties of ANF in mammals, by inhibiting the degradation thereof
to less active metabolites. The compounds of this invention are
thus particularly useful for the treatment of conditions and
disorders responsive to the inhibition of neutral endopeptidase
(NEP) EC 3.4.24.11.
[0005] Thus, the compounds of the invention, by inhibiting the
neutral endopeptidase EC.3.4.24.11, can potentiate the biological
effects of bioactive peptides. Thus, in particular the compounds
have utility in the treatment of a number of disorders, including
hypertension, pulmonary hypertension, isolated systolic
hypertension, resistant hypertension, peripheral vascular disease,
heart failure, congestive heart failure, left ventricular
hypertrophy, angina, renal insufficiency (diabetic or
non-diabetic), renal failure (including edema and salt retension),
diabetic nephropathy, non-diabetic nephropathy, nephroic syndrome,
glomerulonephritis, scleroderma, glomerular sclerosis, proteinurea
of primary renal disease, renal vascular hypertention, diabetic
retinopathy and end-stage renal disease (ESRD), endothelial
dysfunction, diastolic dysfunction, hypertrophic cardiomyopathy,
diabetic cardiac myopathy, supraventricular and ventricular
arrhythmias, atrial fibrillation (AF), cardiac fibrosis, atrial
flutter, detrimental vascular remodeling, plaque stabilization,
myocardial infarction (MI), renal fibrosis, polycystic kidney
disease (PKD), pulmonary arterial hypertension, renal failure
(including edema and salt retension), cyclical oedema, Menieres
disease, hyperaldosteroneism (primary and secondary) and
hypercalciuria, ascites. In addition, because of their ability to
potentiate the effects of ANF the compounds have utility in the
treatment of glaucoma. As a further result of their ability to
inhibit the neutral endopeptidase E.C.3.4.24.11 the compounds of
the invention may have activity in other therapeutic areas
including for example the treatment of menstrual disorders, preterm
labour, pre-eclampsia, endometriosis, and reproductive disorders
(especially male and female infertility, polycystic ovarian
syndrome, implantation failure). Also the compounds of the
invention should treat asthma, obstructive sleep apnea,
inflammation, leukemia, pain, epilepsy, affective disorders such as
depression and psychotic condition such as dementia and geriatric
confusion, obesity and gastrointestinal disorders (especially
diarrhea and irritable bowel syndrome), wound healing (especially
diabetic and venous ulcers and pressure sores), septic shock, the
modulation of gastric acid secretion, the treatment of
hyperreninaemia, cystic fibrosis, restenosis, type-2 diabetes,
metabolic syndrome, diabetic complications and athereosclerosis,
male and female sexual dysfunction. In a preferred embodiment the
compounds of the invention are useful in the treatment of
cardiovascular disorders.
[0006] The invention pertains to the compounds, methods for using
them, and uses thereof as described herein. Examples of compounds
of the invention include the compounds according to anyone of
Formulae I' and I to VIIC, or a pharmaceutically acceptable salt
thereof, and the compounds of the examples.
[0007] The invention therefore provides a compound of the formula
(I'):
##STR00002##
or a pharmaceutically acceptable salt thereof, wherein: R.sup.1 is
H, C.sub.1-7alkyl, hydroxy, C.sub.1-7alkoxy, halogen, --SH,
--S--C.sub.1-7alkyl or NR.sup.aR.sup.b; R.sup.2 for each
occurrence, is independently C.sub.1-7alkyl, halo, NO.sub.2, CN,
C.sub.1-7alkanoylamino, C.sub.3-7cycloalkyl, hydroxy,
C.sub.1-7alkoxy, haloC.sub.1-7alkyl, --NR.sup.aR.sup.b,
C.sub.6-10aryl, heteroaryl or heterocyclyl; wherein R.sup.a and
R.sup.b for each occurrence are independently H or
C.sub.1-7alkyl;
R.sup.3 is A.sup.1-C(O)X.sup.1 or A.sup.2-R.sup.4;
[0008] R.sup.4 is C.sub.6-10aryl or a heteroaryl, which can be
monocyclic or bicyclic, and which can be optionally substituted
with one or more substituents independently selected from the group
consisting of hydroxy, hydroxyC.sub.1-7alkyl, nitro,
--NR.sup.aR.sup.b, --C(O)C.sub.1-7alkyl, C(O)--O--C.sub.1-7alkyl,
C.sub.1-7alkoxy, halo, C.sub.1-7alkyl, halo-C.sub.1-7alkyl,
C.sub.2-7alkenyl, C.sub.6-10aryl, heteroaryl,
--NHSO.sub.2--C.sub.1-7alkyl and benzyl; or R.sup.4 is a
heterocyclyl which can be optionally substituted with one or more
substituents independently selected from the group consisting of
oxo, hydroxy, hydroxyC.sub.1-7alkyl, amino,
C(O)--O--C.sub.1-7alkyl, C.sub.1-7alkoxy, halo, C.sub.1-7alkyl,
halo-C.sub.1-7alkyl, C.sub.6-10aryl, heteroaryl,
--NHSO.sub.2--C.sub.1-7alkyl and benzyl; R.sup.5 is H, halo,
hydroxy, C.sub.1-7alkoxy, halo, C.sub.1-7alkyl or
halo-C.sub.1-7alkyl; and X and X.sup.1 are independently OH,
--O--C.sub.1-7alkyl, --NR.sup.aR.sup.b,
--NHS(O).sub.2--C.sub.1-7alkyl, --NHS(O).sub.2-benzyl or
--O--C.sub.6-10aryl; wherein alkyl is optionally substituted with
one or more substituents independently selected from the group
consisting of C.sub.6-10aryl, heteroaryl, heterocyclyl,
C(O)NH.sub.2, C(O)NH--C.sub.1-6alkyl, and
C(O)N(C.sub.1-6alkyl).sub.2;
B.sup.1 is --C(O)NH-- or --NHC(O)--;
[0009] A.sup.1 is a bond or a linear or branched C.sub.1-7alkylene;
which is optionally substituted with one or more substituents
independently selected from the group consisting of halo,
C.sub.3-7cycloalkyl, C.sub.1-7alkoxy, hydroxy and O-acetate; in
which two geminal alkyl can optionally combine to form a
C.sub.3-7cycloalkyl; or A.sup.1 is a linear or branched
C.sub.1-7alkenylene; or A.sup.1 is a linear C.sub.1-4 alkylene
wherein one or more carbon atom(s) is/are replaced with an
heteroatom selected from O, NR.sup.c; and A.sup.1 is optionally
substituted with one or more substituents independently selected
from the group consisting of halo and C.sub.1-7alkyl; in which
R.sup.c for each occurrence, is independently H, C.sub.1-7alkyl,
--C(O)--O--C.sub.1-7alkyl or --CH.sub.2C(O)OH; or A.sup.1 is a
phenyl or a heteroaryl; each of which is optionally substituted
with one or more substituents independently selected from the group
consisting of C.sub.1-7alkyl, C.sub.3-7cycloalkyl,
halo-C.sub.1-7alkyl, hydroxy, C.sub.1-7alkoxy, halo,
--NR.sup.aR.sup.b, --OCH.sub.2CO.sub.2H, and
--OCH.sub.2C(O)NH.sub.2; or A.sup.1 is a C.sub.3-7cycloalkyl;
A.sup.1 is --C.sub.1-4alkylene-C.sub.6-10-aryl-,
--C.sub.1-4alkylene-heteroaryl- or
--C.sub.1-4alkylene-heterocyclyl-, wherein A.sup.1 may be in either
direction; and A.sup.2 is a bond or a linear or branched C.sub.1-7
alkylene; which is optionally substituted with one or more
substituents independently selected from the group consisting of
halo, C.sub.1-7alkoxy, hydroxy, O-Acetate and C.sub.3-7cycloalkyl;
n is 0, 1, 2, 3, 4 or 5;
[0010] wherein each heteroaryl is a monocyclic or bicyclic aromatic
ring comprising 5-10 ring atoms selected from carbon atoms and 1 to
5 heteroatoms, and
[0011] each heterocyclyl is a monocyclic saturated or partially
saturated but non-aromatic moiety comprising 4-7 ring atoms
selected from carbon atoms and 1-5 heteroatoms, wherein each
heteroatom of a heteroaryl or a heterocyclyl is independently
selected from O, N and S.
[0012] The invention therefore provides a compound of the formula
(I):
##STR00003##
or a pharmaceutically acceptable salt thereof, wherein: R.sup.1 is
H or C.sub.1-7alkyl; R.sup.2 for each occurrence, is independently
C.sub.1-7alkyl, halo, NO.sub.2, CN, C.sub.1-7alkanoylamino,
C.sub.3-7cycloalkyl, hydroxy, C.sub.1-7alkoxy, haloC.sub.1-7alkyl,
--NR.sup.aR.sup.b, C.sub.6-10aryl, heteroaryl or heterocyclyl;
wherein R.sup.a and R.sup.b for each occurrence are independently H
or C.sub.1-7alkyl;
R.sup.3 is A.sup.1-C(O)X.sup.1 or A.sup.2-R.sup.4;
[0013] R.sup.4 is C.sub.6-10aryl or a heteroaryl, which can be
monocyclic or bicyclic, and which can be optionally substituted
with one or more substituents independently selected from the group
consisting of hydroxy, hydroxyC.sub.1-7alkyl, amino,
C(O)--O--C.sub.1-7alkyl, C.sub.1-7alkoxy, halo, C.sub.1-7alkyl,
halo-C.sub.1-7alkyl, C.sub.6-10aryl, heteroaryl,
--NHSO.sub.2--C.sub.1-7alkyl and benzyl; or R.sup.4 is a
heterocyclyl which can be optionally substituted with one or more
substituents independently selected from the group consisting of
oxo, hydroxy, hydroxyC.sub.1-7alkyl, amino,
C(O)--O--C.sub.1-7alkyl, C.sub.1-7alkoxy, halo, C.sub.1-7alkyl,
halo-C.sub.1-7alkyl, C.sub.6-10aryl, heteroaryl,
--NHSO.sub.2--C.sub.1-7alkyl and benzyl; R.sup.5 is H, halo,
hydroxy, C.sub.1-7alkoxy, halo, C.sub.1-7alkyl or
halo-C.sub.1-7alkyl; and X and X.sup.1 are independently OH,
--O--C.sub.1-7alkyl, NR.sup.aR.sup.b, or --O--C.sub.6-10aryl;
wherein alkyl is optionally substituted with one or more
substituents independently selected from the group consisting of
C.sub.6-10aryl, heteroaryl, heterocyclyl, C(O)NH.sub.2,
C(O)NH--C.sub.1-6alkyl, and C(O)N(C.sub.1-6alkyl).sub.2;
B.sup.1 is --C(O)NH-- or --NHC(O)--;
[0014] A.sup.1 is a bond or a linear or branched C.sub.1-7alkylene;
which is optionally substituted with one or more substituents
independently selected from the group consisting of halo,
C.sub.3-7cycloalkyl, C.sub.1-7alkoxy, hydroxy and O-acetate; in
which two geminal alkyl can optionally combine to form a
C.sub.3-7cycloalkyl; or A.sup.1 is a phenyl or a heteroaryl; each
of which is optionally substituted with one or more substituents
independently selected from the group consisting of C.sub.1-7alkyl,
C.sub.3-7cycloalkyl, halo-C.sub.1-7alkyl, hydroxy, C.sub.1-7alkoxy,
halo, --NR.sup.aR.sup.b, --OCH.sub.2CO.sub.2H, and
--OCH.sub.2C(O)NH.sub.2; or A.sup.1 is a C.sub.3-7cycloalkyl;
A.sup.1 is --C.sub.1-4alkylene-C.sub.6-10-aryl-,
--C.sub.1-4alkylene-heteroaryl- or
--C.sub.1-4alkylene-heterocyclyl-, wherein A.sup.1 may be in either
direction; and A.sup.2 is a bond or a linear or branched C.sub.1-7
alkylene; which is optionally substituted with one or more
substituents independently selected from the group consisting of
halo, C.sub.1-7alkoxy, hydroxy, O-Acetate and C.sub.3-7cycloalkyl;
n is 0, 1, 2, 3, 4 or 5;
[0015] wherein each heteroaryl is a monocyclic or bicyclic aromatic
ring comprising 5-10 ring atoms selected from carbon atoms and 1 to
5 heteroatoms, and
[0016] each heterocyclyl is a monocyclic saturated or partially
saturated but non-aromatic moiety comprising 4-7 ring atoms
selected from carbon atoms and 1-5 heteroatoms, wherein each
heteroatom of a heteroaryl or a heterocyclyl is independently
selected from O, N and S.
[0017] In another embodiment, the invention pertains to a method
for treating a disorders or diseases responsive to the inhibition
of neutral endopeptidase EC 3.4. 24.11 (NEP), in a subject, by
administering to the subject a therapeutically effective amount of
a compound according to anyone of Formulae I' and I to VIIC, or a
pharmaceutically acceptable salt thereof, such that the disorder or
disease responsive to the inhibition of neutral endopeptidase EC
3.4. 24.11 (NEP) in the subject is treated.
[0018] In yet another embodiment, the invention pertains to a
method for treating hypertension, pulmonary hypertension, isolated
systolic hypertension, resistant hypertension, peripheral vascular
disease, heart failure, congestive heart failure, left ventricular
hypertrophy, angina, renal insufficiency (diabetic or
non-diabetic), renal failure (including edema and salt retension),
diabetic nephropathy, non-diabetic nephropathey, nephroic syndrome,
glomerulonephritis, scleroderma, glomerular sclerosis, proteinurea
of primary renal disease, renal vascular hypertention, diabetic
retinopathy and end-stage renal disease (ESRD), endothelial
dysfunction, diastolic dysfunction, hypertrophic cardiomyopathy,
diabetic cardiac myopathy, supraventricular and ventricular
arrhythmias, atrial fibrillation (AF), cardiac fibrosis, atrial
flutter, detrimental vascular remodeling, plaque stabilization,
myocardial infarction (MI), renal fibrosis, polycystic kidney
disease (PKD), pulmonary arterial hypertension, renal failure
(including edema and salt retension), cyclical oedema, Menieres
disease, hyperaldosteroneism (primary and secondary) and
hypercalciuria, ascites, glaucoma, menstrual disorders, preterm
labour, pre-eclampsia, endometriosis, and reproductive disorders
(especially male and female infertility, polycystic ovarian
syndrome, implantation failure), asthma, obstructive sleep apnea,
inflammation, leukemia, pain, epilepsy, affective disorders such as
depression and psychotic condition such as dementia and geriatric
confusion, obesity and gastrointestinal disorders (especially
diarrhea and irritable bowel syndrome), wound healing (especially
diabetic and venous ulcers and pressure sores), septic shock,
gastric acid secretion dysfunction, hyperreninaemia, cystic
fibrosis, restenosis, type-2 diabetes, metabolic syndrome, diabetic
complications and atherosclerosis, male and female sexual
dysfunction; comprising administering to the subject a
therapeutically effective amount of a compound according to anyone
of Formulae I' and I to VIIC, or a pharmaceutically acceptable salt
thereof, such that the subject is treated.
[0019] In yet another embodiment, the invention pertains to
pharmaceutical compositions, comprising of a compound according to
anyone of Formulae I' and I to VIIC, or a pharmaceutically
acceptable salt thereof, and one or more pharmaceutically
acceptable carriers.
[0020] In still another embodiment, the invention pertains to
combinations including a compound according to anyone of Formulae
I' and I-VIC, or a pharmaceutically acceptable salt thereof, and
pharmaceutical combinations of one or more therapeutically active
agents.
[0021] In another embodiment, the invention pertains to a method
for inhibiting neutral endopeptidase EC 3.4. 24.11 in a subject by
administering to the subject a therapeutically effective amount of
a compound according to anyone of Formulae I' and I to VIIC, or a
pharmaceutically acceptable salt thereof, such that neutral
endopeptidase EC 3.4. 24.11 is inhibited.
DETAILED DESCRIPTION OF THE INVENTION
Compounds of the Invention
[0022] References hereinafter to compounds of Formula I or I' apply
equally to compounds according to anyone of Formulae IA to
VIIC.
[0023] References hereinafter to embodiments of the invention apply
equally to compounds of Formula I or I' and compounds according to
anyone of Formulae IA to VIIC, insofar as the embodiments are
present.
[0024] Various embodiments of the invention are described herein.
It will be recognized that features specified in each embodiment
may be combined with other specified features to provide further
embodiments.
[0025] In one embodiment the invention provides a compound of the
Formula I or I', or a pharmaceutically acceptable salt thereof,
wherein:
R.sup.1 is H or C.sub.1-7alkyl; R.sup.2 for each occurrence, is
independently C.sub.1-7alkyl, halo, C.sub.3-7cycloalkyl, hydroxy,
C.sub.1-7alkoxy, haloC.sub.1-7alkyl, --NR.sup.aR.sup.b,
C.sub.6-10aryl, heteroaryl or heterocyclyl; wherein R.sup.a and
R.sup.b for each occurrence are independently H or
C.sub.1-7alkyl;
R.sup.3 is A.sup.1-C(O)X.sup.1 or A.sup.2-R.sup.4;
[0026] R.sup.4 is C.sub.6-10aryl or a heteroaryl, which can be
monocyclic or bicyclic and which can be optionally substituted with
one or more substituents independently selected from the group
consisting of hydroxy, C.sub.1-7alkoxy, halo, C.sub.1-7alkyl,
halo-C.sub.1-7alkyl C.sub.6-10aryl, heteroaryl,
--NHSO.sub.2--C.sub.1-7alkyl and benzyl;
R.sup.5 is H; and
[0027] X and X.sup.1 are independently OH, --O--C.sub.1-7alkyl or
NR.sup.aR.sup.b;
B.sup.1 is --C(O)NH-- or --NHC(O)--;
[0028] A.sup.1 is a linear or branched C.sub.1-7alkylene; which is
optionally substituted with one or more substituents independently
selected from the group consisting of halo, C.sub.3-7cycloalkyl,
C.sub.1-7alkoxy, hydroxy and O-acetate; in which two geminal alkyl
can optionally combine to form a C.sub.3-7cycloalkyl; or A.sup.1 is
a phenyl or a heteroaryl; each of which is optionally substituted
with one or more substituents independently selected from the group
consisting of C.sub.1-7alkyl, C.sub.3-7cycloalkyl,
halo-C.sub.1-7alkyl, hydroxy, C.sub.1-7alkoxy, halo,
--NR.sup.aR.sup.b, --OCH.sub.2CO.sub.2H, and
--OCH.sub.2C(O)NH.sub.2; and A.sup.2 is a bond or a linear or
branched C.sub.1-7 alkylene; which is optionally substituted with
one or more substituents independently selected from the group
consisting of halo, C.sub.1-7alkoxy, hydroxy, O-Acetate and
C.sub.3-7cycloalkyl; and n is 0, 1, 2, 3, 4 or 5;
[0029] wherein each heteroaryl is a monocyclic or bicyclic aromatic
ring comprising 5-10 ring atoms selected from carbon atoms and 1 to
5 heteroatoms, and
[0030] each heterocyclyl is a monocyclic saturated or partially
saturated but non-aromatic moiety comprising 4-7 ring atoms
selected from carbon atoms and 1-5 heteroatoms, wherein each
heteroatom of a heteroaryl or a heterocyclyl is independently
selected from O, N and S.
[0031] Certain compounds of Formula I or I' include compounds of
Formula IA wherein the stereochemistry at the carbon bearing the
biphenyl group is (R):
##STR00004##
or a pharmaceutically acceptable salt thereof, wherein X, R.sup.1,
R.sup.2, B.sup.1, R.sup.3 and n have the definitions of Formula I
or I', supra.
[0032] In one embodiment, the invention pertains to compounds of
Formula I or I' or a pharmaceutically acceptable salt thereof,
wherein n is 1, 2, 3, 4 or 5; R.sup.2 is halo and is attached to
the meta position and the other optional R.sup.2 groups are
independently C.sub.1-7alkyl, NO.sub.2, CN, halo,
C.sub.3-7cycloalkyl, hydroxy, C.sub.1-7alkoxy, halo-C.sub.1-7alkyl,
NR.sup.bR.sup.c, C.sub.6-10aryl, heteroaryl or heterocyclyl. This
embodiment is illustrated by compounds of Formulae IB and IC:
##STR00005##
or a pharmaceutically acceptable salt thereof, wherein X, R.sup.1,
R.sup.2, B.sup.1, R.sup.3 have the definitions of Formula I or I',
supra; p is 0, 1, 2, 3 or 4 and R.sup.2a is halo.
[0033] Certain compounds of Formula I or I' include compounds of
Formula II:
##STR00006##
or a pharmaceutically acceptable salt thereof, wherein X, X.sup.1,
A.sup.1, R.sup.1, R.sup.2 and n have the definitions of Formula I
or I', supra.
[0034] In a further embodiment, the invention pertains to compounds
of Formula II wherein the stereochemistry of the carbon bearing the
biphenyl groups is (R). This embodiment is illustrated by compounds
of Formula IIA:
##STR00007##
or a pharmaceutically acceptable salt thereof, wherein X, X.sup.1,
A.sup.1, R.sup.1, R.sup.2 and n have the definitions of Formula I
or I', supra.
[0035] Certain compounds of Formula I, I' or II include compounds
of Formula IIB or IIC:
##STR00008##
or a pharmaceutically acceptable salt thereof, wherein X, X.sup.1,
A.sup.1, R.sup.1, R.sup.2 have the definitions of Formula I or I',
supra; p is 0, 1, 2, 3 or 4 and R.sup.2a is halo.
[0036] Certain compounds of Formula I or I' include compounds of
Formula III:
##STR00009##
or a pharmaceutically acceptable salt thereof, wherein X, X.sup.1,
A.sup.1, R.sup.1, R.sup.2 and n have the definitions of Formula I
or I', supra.
[0037] In a further embodiment, the invention pertains to compounds
of Formula III wherein the stereochemistry of the carbon bearing
the biphenyl groups is (R). This embodiment is illustrated by
compounds of Formula IIA:
##STR00010##
or a pharmaceutically acceptable salt thereof, wherein X, X.sup.1,
A.sup.1, R.sup.1, R.sup.2 and n have the definitions of Formula I
or I', supra.
[0038] Certain compounds of Formula III include compounds of
Formula IIIB or IIIC:
##STR00011##
or a pharmaceutically acceptable salt thereof, wherein X, X.sup.1,
A.sup.1, R.sup.1, R.sup.2 have the definitions of Formula I or I',
supra; p is 0, 1, 2, 3 or 4 and R.sup.2a is halo.
[0039] In another embodiment the invention provides a compound
according to anyone of formulae I', I to IC, II to IIC and III to
IIIC or of any classes and subclasses described herein, or a
pharmaceutically acceptable salt or solvate thereof, wherein
A.sup.1 is a linear C.sub.1-7alkylene, which is optionally
substituted with one or more substituents independently selected
from the group consisting of halo, C.sub.1-7alkoxy, hydroxy,
O-acetate and C.sub.3-7cycloalkyl; in which two geminal alkyl can
optionally combine to form a C.sub.3-7cycloalkyl.
[0040] A further embodiment include compounds according to anyone
of Formulae I', I to IC, II to IIC and III to IIIC or of any
classes and subclasses described herein, or a pharmaceutically
acceptable salt thereof, wherein A.sup.1 is --CH.sub.2--,
--CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2-- or A.sup.1 has
the following formulae:
##STR00012##
in which R.sup.c1, R.sup.c2, R.sup.d1, R.sup.d2, R.sup.e1,
R.sup.e2, R.sup.e3 and R.sup.e4 are independently H, halo,
C.sub.3-7cycloalkyl, or C.sub.1-7alkyl; and alternatively R.sup.c1
and R.sup.c2 or R.sup.d1 and R.sup.d2 can form together with the
atoms to which they are attached a C.sub.3-7cycloalkyl. In one
aspect of this embodiment, A.sup.1 is one of the following:
##STR00013##
Yet another further embodiment includes compounds according to
anyone of Formulae I', I to IC, II to IIC and III to IIIC or of any
classes and subclasses described herein, or a pharmaceutically
acceptable salt thereof, wherein A.sup.1 has the following
formulae:
##STR00014##
in which R.sup.f1, R.sup.f2, R.sup.f3 and R.sup.f4 are
independently H, halo, O-acetate or C.sub.7-7alkyl. In a further
embodiment, A.sup.1 is one of the following:
##STR00015##
[0041] In yet another embodiment, the invention provides a compound
according to anyone of Formulae I', I to IC, II to IIC and III to
IIIC or of any classes and subclasses described herein, or a
pharmaceutically acceptable salt or solvate thereof, wherein
A.sup.1 is a C.sub.3-7cycloalkyl. Examples of this embodiment are
compounds of anyone of Formulae I', I to IC, II to IIC and III to
IIIC, wherein A1 is selected from the following:
##STR00016##
[0042] In yet another embodiment, the invention provides a compound
according to anyone of Formulae I', I to IC, II to IIC and III to
IIIC or of any classes and subclasses described herein, or a
pharmaceutically acceptable salt or solvate thereof, wherein
A.sup.1 is a linear or branched C.sub.2-7alkenylene. An example of
C.sub.2-7alkenylene is trans CH.dbd.CH.
[0043] In yet another embodiment, the invention provides a compound
according to anyone of Formulae I', I to IC, II to IIC and III to
IIIC or of any classes and subclasses described herein, or a
pharmaceutically acceptable salt or solvate thereof, wherein
A.sup.1 is a linear C.sub.1-4 alkylene wherein one or more carbon
atom(s) is/are replaced with an heteroatom selected from O,
NR.sup.c; and A.sup.1 is optionally substituted with one or more
substituents independently selected from the group consisting of
halo and C.sub.1-7alkyl; in which R.sup.c for each occurrence is
independently H, C.sub.1-7alkyl, --C(O)O C.sub.1-7alkyl or
CH.sub.2C(O)OH. One further embodiment includes compounds of
Formulae I', I to IC, II to IIC and III to IIIC wherein A.sup.1 is
one of the following:
##STR00017##
[0044] In yet another embodiment, the invention provides a compound
according to anyone of Formulae I', I to IC, II to IIC and III to
IIIC or of any classes and subclasses described herein, or a
pharmaceutically acceptable salt or solvate thereof, wherein
A.sup.1 is optionally substituted phenyl or heteroaryl, wherein
optional substituents are defined as in Formula I or Certain
compounds of the above embodiment include compounds according to
anyone of Formula I', I to IC, II to IIC and III to IIIC or a
pharmaceutically acceptable salt thereof, wherein A.sup.1 is a
5-membered ring heteroaryl. This embodiment is illustrated by
compounds of Formula IV:
##STR00018##
or a pharmaceutically acceptable salt thereof, wherein X, X.sup.1,
B.sup.1, R.sup.1, R.sup.2 and n have the definitions of Formula I
or I', supra and Y.sup.1, Y.sup.2 and Y.sup.3 are independently N,
NH, S, O or CH and form together with the ring atoms to which they
are attached a 5-membered heteroaryl ring.
[0045] In one aspect of this embodiment, the invention pertains to
compounds of Formula IVA:
##STR00019##
or a pharmaceutically acceptable salt thereof, wherein X, X.sup.1,
B.sup.1, R.sup.1, R.sup.2, Y.sup.1, Y.sup.2, Y.sup.3 and n have the
definitions of Formulae I, I' or IV, supra.
[0046] In one aspect of this embodiment, Y.sup.1, Y.sup.2 and
Y.sup.3 form together with the ring atoms to which they are
attached a 5-membered heteroaryl ring selected from furan,
thiophene, pyrrole, pyrazole, oxazole, thiazole, oxadiazole,
thiadiazole, and triazole. One further embodiment includes
compounds of Formula IV or VIA, or a pharmaceutically acceptable
salt thereof, wherein the 5-membered heteroaryl is one of the
following:
##STR00020##
[0047] In a further embodiment, the invention pertains to compounds
of Formula IV or IVA wherein n is 1, 2, 3, 4 or 5; R.sup.2 is halo
in the meta position and the other optional R.sup.2 groups are
independently C.sub.1-7alkyl, NO.sub.2, CN, halo,
C.sub.3-7cycloalkyl, hydroxy, C.sub.1-7alkoxy, halo-C.sub.1-7alkyl,
NR.sup.bR.sup.c, C.sub.6-10aryl, heteroaryl or heterocyclyl.
[0048] In yet another aspect of the above embodiment, the invention
pertains to compounds of Formula I', I to IC, II to IIC or III to
IIIC, or a pharmaceutically acceptable salt thereof, wherein
A.sup.1 is a 5-membered ring heteroaryl attached to the amide
B.sup.1 at a nitrogen atom. This embodiment is illustrated by
compounds of Formulae V or VA:
##STR00021##
[0049] or a pharmaceutically acceptable salt thereof, wherein X,
X.sup.1, B.sup.1, R.sup.1, R.sup.2 and n have the definitions of
Formula I or I', supra and each Y.sup.4 are independently N, S, O
or CH. In a further embodiment, the invention pertains to compounds
of Formula V or VA wherein n is 1, 2, 3, 4 or 5; R.sup.2 is halo in
the meta position and the other optional R.sup.2 groups are
independently C.sub.1-7alkyl, NO.sub.2, CN, halo,
C.sub.3-7cycloalkyl, hydroxy, C.sub.1-7alkoxy, halo-C.sub.1-7alkyl,
NR.sup.bR.sup.c, C.sub.6-10aryl, heteroaryl or heterocyclyl.
[0050] In yet another aspect of the above embodiment the invention
provides a compound according to anyone of Formulae I', I to IC, II
to IIC and III to IIIC or of any classes and subclasses described
herein, or a pharmaceutically acceptable salt or solvate thereof,
wherein A.sup.1 is a phenyl or a 6-membered ring heteroaryl in
which phenyl and heteroaryl are optionally substituted with
C.sub.1-7alkyl, C.sub.3-7cycloalkyl, halo-C.sub.1-7alkyl, hydroxy,
C.sub.1-7alkoxy, halo, NR.sup.aR.sup.b, --OCH.sub.2CO.sub.2H, or
--OCH.sub.2C(O)NH.sub.2. One aspect of this embodiment include
compounds according to anyone of Formulae I', I to IC, II to IIC
and III to IIIC, or pharmaceutically acceptable salt thereof,
wherein A.sup.1 is connected to the amide B.sup.1 and to the
C(O)X.sup.1 moieties in a para arrangement. Another aspect of this
embodiment include compounds according to anyone of Formula I', I
to IC, II to IIC and III to IIIC wherein A.sup.1 is connected to
the amide B.sup.1 and to the C(O)X.sup.1 moieties in a meta
arrangement. Compounds of this embodiment include compounds of
Formula VI:
##STR00022##
or a pharmaceutically acceptable salt thereof, wherein X, X.sup.1,
B.sup.1, R.sup.1, R.sup.2 and n have the definitions of Formula I
or I', supra and W.sup.1, W.sup.2, W.sup.3 and W.sup.4 are
independently N or CR.sup.e, in which each R.sup.e is independently
H, C.sub.1-7alkyl, C.sub.3-7cycloalkyl, halo-C.sub.1-7alkyl,
hydroxy, C.sub.1-7alkoxy, halo, --NR.sup.aR.sup.b,
--OCH.sub.2CO.sub.2H or --OCH.sub.2C(O)NH.sub.2. In one aspect of
this embodiment A.sup.1 is phenyl, pyridine or pyrimidine.
[0051] In a further embodiment, the invention pertains to compounds
of Formula VIA:
##STR00023##
[0052] or a pharmaceutically acceptable salt thereof, wherein X,
X.sup.1, B.sup.1, R.sup.1, R.sup.2, W.sup.1, W.sup.2, W.sup.3 and
W.sup.4 and n have the definitions of Formulae I, I' or VI,
supra.
[0053] One further embodiment includes compounds of Formula VI or
VIA, or a pharmaceutically acceptable salt thereof, wherein A.sup.1
is one of the following:
##STR00024##
[0054] In a further embodiment, the invention pertains to compounds
of Formula VI or VIA, or a pharmaceutically acceptable salt thereof
wherein n is 1, 2, 3, 4 or 5; R.sup.2 is halo in the meta position
and the other optional R.sup.2 groups are independently
C.sub.1-7alkyl, NO.sub.2, CN, halo, C.sub.3-7cycloalkyl, hydroxy,
C.sub.1-7alkoxy, halo-C.sub.1-7alkyl, NR.sup.bR.sup.c,
C.sub.6-10aryl, heteroaryl or heterocyclyl.
[0055] In one aspect of the previous embodiment, the invention
pertains to compounds according to anyone of Formulae I', I to IC,
IV to IV, V to VC and VI to VIC, or pharmaceutically acceptable
salt thereof, wherein B.sup.1 is --C(O)NH--. In another embodiment,
B.sup.1 is --NHC(O)--.
[0056] Certain compounds of the above embodiment include compounds
according to anyone of Formulae I', I to IC, II to IIC and III to
IIIC, or a pharmaceutically acceptable salt thereof, wherein
A.sup.1 is --C.sub.1-4alkylene-C.sub.6-10-aryl-,
--C.sub.1-4alkylene-heteroaryl- or
--C.sub.1-4alkylene-heterocyclyl-,
--C.sub.6-10aryl-C.sub.1-4-alkylene-, -heteroaryl-C.sub.1-4alkylene
or -heterocyclyl-C.sub.1-4alkylene-. In one aspect of this
embodiment, A.sup.1 is --C.sub.1-4alkylene-C.sub.6-10-aryl-,
--C.sub.1-4alkylene-heteroaryl- or
--C.sub.1-4alkylene-heterocyclyl-, wherein the alkylene portion is
attached to B.sup.1 amide group and the aryl, heteroaryl or
heterocyclyl moities are attached to C(O)X.sup.1. In another aspect
of this embodiment, A.sup.1 is --CH.sub.2-phenyl- or
-phenyl-CH.sub.2--. In another aspect of this embodiment, A.sup.1
is --CH.sub.2-heteroaryl or -heteroaryl-CH.sub.2--. In a further
embodiment, A.sup.1 is --CH.sub.2-heterocyclyl or
-heterocyclyl-CH.sub.2--. Representative examples of A.sup.1 are
the following:
##STR00025##
[0057] Certain compounds of Formula I or I' include compounds of
Formula VII:
##STR00026##
or a pharmaceutically acceptable salt thereof, wherein X, A.sup.2,
R.sup.1, R.sup.2, R.sup.4 and n have the definitions of Formula I
or I', supra. A further embodiment includes compounds of Formula
VIIA:
##STR00027##
[0058] or a pharmaceutically acceptable salt thereof, wherein X,
A.sup.2, R.sup.1, R.sup.2, R.sup.4 and n have the definitions of
Formula I or I', supra.
[0059] Certain compounds of Formula VII or VIIA have the formula
VIIB or VIIC:
##STR00028##
or a pharmaceutically acceptable salt thereof, wherein X, A.sup.2,
R.sup.1, R.sup.2, R.sup.4 have the definitions of Formula I or I',
supra; p is 0, 1, 2, 3 or 4 and R.sup.2a is halo.
[0060] A further aspect of this embodiment include compounds
according to anyone of Formulae VII to VIIC, or a pharmaceutically
acceptable salt thereof, wherein A.sup.2 is (CH.sub.2).sub.p and p
is 0, 1, 2, 3. In one aspect of this embodiment p is 0, therefore
A.sup.2 is a bond. In another aspect of this embodiment A.sup.2 is
CH.sub.2 or CH.sub.2--CH.sub.2.
[0061] In another aspect of this embodiment the invention provide
compounds according to anyone of Formulae VII to VIIC, or a
pharmaceutically acceptable salt thereof, wherein R.sup.4 is
optionally substituted C.sub.6-10aryl. Representative examples of
aryl are benzoimidazolone, benzoisothiazolone or phenyl. In one
further aspect of this embodiment, R.sup.4 is phenyl. Substituents
on the phenyl ring include for example, halo (e.g. F, Cl), hydroxy,
halo-C.sub.1-7alkyl (e.g. CF.sub.3),
--NHS(O).sub.2--C.sub.1-7alkyl, heteroaryl, C.sub.1-7alkoxy or
C.sub.1-7alkyl.
[0062] In yet another aspect of this embodiment the invention
provides compounds according to anyone of Formula VII to VIIC or a
pharmaceutically acceptable salt thereof, wherein R.sup.4 is an
optionally substituted bicyclic heteroaryl.
[0063] In yet another aspect of this embodiment the invention
provide compounds according to anyone of Formulae VII to VIIC or a
pharmaceutically acceptable salt thereof wherein R.sup.4 is
optionally substituted 5- or 6-membered heteroaryl. In one aspect
of this embodiment, R.sup.4 is a 6-membered ring heteroaryl
selected from the group consisting of pyrazinyl, pyridinyl,
pyrimidinyl, oxo-pyranyl (e.g. pyranone, optionally substituted
pyran-4-one, pyran-2-one such as 3-hydroxy-pyran-4-one,
3-hydroxy-pyran-2-one), and oxo-pyridinyl (e.g. pyridinone,
optionally substituted pyridin-4-one or pyridin-2-one such as for
example 3-hydroxy-1-methyl-pyridin-4-one or
1-benzyl-pyridin-2-one), or pyrimidinone (i.e oxo-pyrimidinyl). In
another aspect of this embodiment R.sup.4 is a 5-membered ring
heteroaryl selected from the group consisting of oxazole, pyrrole,
pyrazole, isooxazole, triazole, tetrazole, oxadiazole (e.g.
1-oxa-3,4-diazole, 1-oxa-2,4-diazole), oxadiazolone (e.g.
oxadiazol-2-one), thiazole, isothiazole, thiophene, imidazole and
thiadiazole. Other representative examples of R.sup.4 are
oxazolone, thiazolone, oxadiazolone, triazolone, oxazolone,
imidazolone, pyrazolone. In a further embodiment, the optional
substituents on C.sub.6-10aryl and heteroaryl are selected from
hydroxy, C.sub.1-7alkyl, C.sub.1-7alkoxy, halo, halo-C.sub.1-7alkyl
or benzyl.
[0064] In yet another aspect of the above embodiment the invention
provide compounds according to anyone of Formulae VII to VIIC or a
pharmaceutically acceptable salt thereof, wherein R.sup.4 is a
bicyclic heteroaryl. A further embodiment includes compounds
according to anyone of Formulae VII to VIIC, or a pharmaceutically
acceptable salt thereof, wherein R.sup.4 is indole, benzothiazole
or benzimidazole. Representative examples of R.sup.4 are the
following:
##STR00029## ##STR00030##
[0065] In yet another aspect of the above embodiment the invention
provide compounds according to anyone of Formulae VII to VIIC, or a
pharmaceutically acceptable salt thereof, wherein R.sup.4 is a
monocyclic saturated or partially saturated heterocyclyl, which
heterocyclyl contains at least one heteroatom selected from
nitrogen, sulfur and oxygen, and which heterocyclyl is optionally
substituted with one or more substituents independently selected
from the group consisting of oxo, hydroxy, C.sub.1-7alkoxy, halo,
C.sub.1-7alkyl, halo-C.sub.1-7alkyl, C.sub.6-10aryl, heteroaryl,
--NHSO.sub.2--C.sub.1-7alkyl and benzyl. In one particular aspect
of this embodiment, R.sup.4 is pyrrolidine or imidazolidine,
wherein the heterocyclyl may be linked to the carbonyl
(C(O)-A.sup.2) moiety via a carbon or a nitrogen and the
heterocyclyl is optionally substituted with oxo.
[0066] In one embodiment the invention provide compounds according
to anyone of Formulae I', I to IC, II to IIC, III to IIIC, IV, IVA,
V, VA, VI, VIA and VII to VIIC or a pharmaceutically acceptable
salt thereof, wherein R.sup.1 is H.
[0067] In another embodiment the invention provide compounds
according to anyone of Formulae I', I to IC, II to IIC, III to
IIIC, 1V, IVA, V, VA, VI, VIA and VII to VIIC, or a
pharmaceutically acceptable salt thereof, wherein each R.sup.2 is
independently halo, C.sub.1-7alkyl, C.sub.1-7alkoxy, hydroxy,
halo-C.sub.1-7alkyl and n is 0, 1 or 2. In a further embodiment n
is 1, 2, 3, 4 or 5, R.sup.2 is halo in the meta position and the
other optional R.sup.2 groups are independently halo,
C.sub.1-7alkyl, C.sub.1-7alkoxy, hydroxy or haloalkyl. In yet a
further embodiment, the invention provide compounds according to
anyone of Formulae I', I to IC, II to IIC, III to IIIC, 1V, IVA, V,
VA, VI, VIA and VII to VIIC, or a pharmaceutically acceptable salt
thereof, wherein n is 1 or 2, R.sup.2 is meta-chloro or meta-fluoro
and the other optional R.sup.2 group is halo, C.sub.1-7alkyl,
C.sub.1-7alkoxy, hydroxy or haloalkyl.
[0068] In yet another embodiment the invention provide compounds
according to anyone of Formulae I', I to IC, II to IIC, III to
IIIC, I, IVA, V, VA, VI, VIA and VII to VIIC, or a pharmaceutically
acceptable salt thereof, wherein X and X.sup.1 are independently OH
or --O--C.sub.1-7alkyl (e.g. --O-ethyl, --O-methyl or --O-nbutyl).
In one particular aspect of this embodiment X and X.sup.1 are OH.
In another aspect of this embodiment, X and X.sup.1 are
independently --O--C.sub.1-7alkyl in which alkyl is substituted
with C.sub.6-10aryl, heteroaryl, heterocyclyl, C(O)NH.sub.2,
C(O)NH--C.sub.1-6alkyl, or C(O)N(C.sub.1-6alkyl).sub.2.
Representative examples of X or X.sup.1 are
--O--CH.sub.2--C(O)N(CH.sub.3).sub.2,
--O--CH.sub.2--CH.sub.2-morpholine, --O--CH.sub.2-dioxolone or
--O-benzyl. In yet another aspect of this embodiment, X and X.sup.1
are --O--C.sub.6-10aryl. A representative examples of
--O--C.sub.6-10aryl is --O-(2,3-dihydro-1H-indene).
[0069] In another embodiment X, X.sup.1, B.sup.1, A.sup.1, A.sup.2,
R.sup.2, R.sup.1 and R.sup.4 groups are those defined by the X,
X.sup.1, A.sup.1, A.sup.2, B.sup.1, R.sup.2, R.sup.1 and R.sup.4
groups in the Examples section below.
[0070] In another embodiment individual compounds according to the
invention are those listed in the Examples section below, or a
pharmaceutically acceptable salt thereof.
DEFINITION
[0071] For purposes of interpreting this specification, the
following definitions will apply unless specified otherwise and
whenever appropriate, terms used in the singular will also include
the plural and vice versa.
[0072] As used herein, the term "alkyl" refers to a fully saturated
branched or unbranched (or straight chain or linear) hydrocarbon
moiety, comprising 1 to 20 carbon atoms. Preferably the alkyl
comprises 1 to 7 carbon atoms, and more preferably 1 to 4 carbon
atoms. Representative examples of alkyl include 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. The term
"C.sub.1-7alkyl" refers to a hydrocarbon having one to seven carbon
atoms. Moreover, the term alkenyl includes both "unsubstituted
alkyls" and "substituted alkyls". The term "alkylene" refers to a
divalent alkyl radical, wherein alkyl is as previously defined.
[0073] The term "alkenyl" refers to a branched or unbranched
hydrocarbon having at least one carbon-carbon double bond. The term
"C.sub.2-7alkenyl" refers to a hydrocarbon having two to seven
carbon atoms and comprising at least one carbon-carbon double bond.
Representative examples of alkenyl are vinyl, prop-1-enyl, allyl,
butenyl, isopropenyl or isobutenyl. The term "alkeylene" refers to
a divalent alkenyl radical, wherein alkenyl is as previously
defined.
[0074] As used herein, the term "haloalkyl" refers to an alkyl as
defined herein, that is substituted by one or more halo groups as
defined herein. Preferably the haloalkyl can be monohaloalkyl,
dihaloalkyl or polyhaloalkyl including perhaloalkyl. A
monohaloalkyl can have one iodo, bromo, chloro or fluoro within the
alkyl group. Dihaloalky and polyhaloalkyl groups can have two or
more of the same halo atoms or a combination of different halo
groups within the alkyl. Preferably, the polyhaloalkyl contains up
to 12, or 10, or 8, or 6, or 4, or 3, or 2 halo groups.
Representative examples of haloalkyl are fluoromethyl,
difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, pentafluoroethyl, heptafluoropropyl,
difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,
difluoropropyl, dichloroethyl and dichloropropyl. A perhaloalkyl
refers to an alkyl having all hydrogen atoms replaced with halo
atoms. The term "halo-C.sub.1-7alkyl" refers to a hydrocarbon
having one to seven carbon atoms and being substituted by one or
more halo groups.
[0075] 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 1-7, more preferably about 1-4 carbons.
[0076] As used herein, the term "cycloalkyl" refers to saturated or
unsaturated but non-aromatic monocyclic, bicyclic or tricyclic
hydrocarbon groups of 3-12 carbon atoms, preferably 3-8, or 3-7
carbon atoms. For bicyclic, and tricyclic cycloalkyl system, all
rings are non-aromatic. Exemplary monocyclic hydrocarbon groups
include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,
cyclohexyl and cyclohexenyl. Exemplary bicyclic hydrocarbon groups
include bornyl, decahydronaphthyl, bicyclo[2.1.1]hexyl,
bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2]octyl.
Exemplary tricyclic hydrocarbon groups include adamantyl. The term
"C.sub.3-7cycloakyl" refers to a cyclic hydrocarbon groups having 3
to 7 carbon atoms. The term "cycloalkylalkyl" refers to an alkyl
substituted with cycloalkyl.
[0077] The term "aryl" refers to monocyclic or bicyclic aromatic
hydrocarbon groups having 6-10 carbon atoms in the ring portion.
The term "aryl" also refer to a group in which the aromatic ring is
fused to a cycloalkyl ring, where the radical of attachment is on
the aromatic ring or on the fused cycloalkyl ring. Representative
examples of aryl are phenyl, naphthyl, hexahydroindyl, indanyl or
tetrahydronaphthyl. The term "C.sub.6-10 aryl" refers to an
aromatic hydrocarbon groups having 6 to 10 carbon atoms in the ring
portion.
[0078] The term "arylalkyl" is an alkyl substituted with aryl.
Representative examples of arylalkyl are benzyl or
Phenyl-CH.sub.2CH.sub.2--. The term also includes substituted
arylalkyl moiety.
[0079] The term "Heteroaryl" includes monocyclic or bicyclic
heteroaryl, containing from 5-10 ring members selected from carbon
atoms and 1 to 5 heteroatoms, and each heteroatoms is independently
selected from O, N or S wherein S and N may be oxidized to various
oxidation states. For bicyclic heteroaryl system, the system is
fully aromatic (i.e. all rings are aromatic).
[0080] Typical monocyclic heteroaryl groups include thienyl, furyl,
pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,
oxa-2,3-diazolyl, oxa-2,4-diazolyl, oxa-2,5-diazolyl,
oxa-3,4-diazolyl, thia-2,3-diazolyl, thia-2,4-diazolyl,
thia-2,5-diazolyl, thia-3,4-diazolyl, 3-, 4-, or 5-isothiazolyl,
2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or
5-1,2,4-triazolyl, 4- or 5-1,2,3-triazolyl, tetrazolyl, 2-, 3-, or
4-pyridyl, 3- or 4-pyridazinyl, 3-, 4-, or 5-pyrazinyl,
2-pyrazinyl, 2-4-, or 5-pyrimidinyl.
[0081] The term "heteroaryl" also refers to a group in which a
heteroaromatic ring is fused to one or more aryl, cycloaliphatic,
or heterocyclyl rings, where the radical or point of attachment is
on the heteroaromatic ring or on the fused aryl ring.
Representative examples of bicyclic heteroaryl are indolyl,
isoindolyl, indazolyl, indolizinyl, purinyl, quinolizinyl,
quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl,
naphthyridinyl, quinazolinyl, quinaxalinyl, thieno[2,3-b]furanyl,
furo[3,2-b]-pyranyl, 5H-pyrido[2,3-d]-o-oxazinyl,
1H-pyrazolo[4,3-d]-oxazolyl, 4H-imidazo[4,5-d]thiazolyl,
pyrazino[2,3-d]pyridazinyl, imidazo[2,1-b]thiazolyl,
imidazo[1,2-b][1,2,4]triazinyl, 7-benzo[b]thienyl, benzoxazolyl,
benzimidazolyl, benzothiazolyl, benzoxapinyl, benzoxazinyl,
1H-pyrrolo[1,2-b][2]benzazapinyl, benzofuryl, benzothiophenyl,
benzotriazolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-c]pyridinyl,
pyrrolo[3,2-c]pyridinyl, pyrrolo[3,2-b]pyridinyl,
imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl,
pyrazolo[4,3-d]pyridinyl, pyrazolo[4,3-c]pyridinyl,
pyrazolo[3,4-c]pyridinyl, pyrazolo[3,4-d]pyridinyl,
pyrazolo[3,4-b]pyridinyl, imidazo[1,2-a]pyridinyl,
pyrazolo[1,5-a]pyridinyl, pyrrolo[1,2-b]pyridazinyl,
imidazo[1,2-c]pyrimidinyl, pyrido[3,2-d]pyrimidinyl,
pyrido[4,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl,
pyrido[2,3-d]pyrimidinyl, pyrido[2,3-b]pyrazinyl,
pyrido[3,4-b]pyrazinyl, pyrimido[5,4-d]pyrimidinyl,
pyrazino[2,3-b]pyrazinyl, or pyrimido[4,5-d]pyrimidinyl.
When a heteroaryl moiety is substituted with hydroxy, the invention
also pertains to its oxo tautomeric. For example, an oxadiazole
substituted with hydroxy also includes oxo-oxadiazole or also known
as oxadiazolone. The tautomerisation is represented as follow:
##STR00031##
[0082] As used herein, the term "heterocyclyl" or "heterocyclo"
refers to an optionally substituted, saturated or unsaturated
non-aromatic (partially unsaturated) ring which is a 4-, 5-, 6-, or
7-membered monocyclic, 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. For bicyclic and tricyclic
heterocyclyl ring system, a non-aromatic ring system is defined as
being a non-fully or partially unsaturated ring system. Therefore
bicyclic and tricyclic heterocyclyl ring systems includes
heterocyclyl ring systems wherein one of the fused rings is
aromatic but the other(s) is (are) non-aromatic. In one embodiment,
heterocyclyl moiety represents a saturated monocyclic ring
containing from 5-7 ring atoms and optionally containing a further
heteroatom, selected from O, S or N. 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, dioxolanyl,
dioxanyl, dithianyl, piperazinyl, pyrrolidine, dihydropyranyl,
oxathiolanyl, dithiolane, oxathianyl, thiomorpholino, oxiranyl,
aziridinyl, oxetanyl, oxepanyl, azetidinyl, tetrahydrofuranyl,
tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl,
morpholino, piperazinyl, azepinyl, oxapinyl, oxaazepanyl,
oxathianyl, thiepanyl, azepanyl, dioxepanyl, and diazepanyl.
[0083] The term "hydroxyalkyl" refers to alkyl groups, as described
above, in which the alkyl group is substituted with one or more
hydroxy.
[0084] The term "halogen" includes fluorine, bromine, chlorine and
iodine. The term "perhalogenated" generally refers to a moiety
wherein all hydrogens are replaced by halogen atoms.
[0085] The term "heteroatom" includes atoms of any element other
than carbon or hydrogen. Preferred heteroatoms are nitrogen,
oxygen, sulfur and phosphorus. In another embodiment, the
heteroatom is nitrogen, oxygen or sulfur.
[0086] It will be noted that the structure of some of the compounds
of this invention includes asymmetric carbon atoms. It is to be
understood accordingly that the isomers arising from such asymmetry
(e.g., all enantiomers and diastereomers) are included within the
scope of this invention, unless indicated otherwise. Such isomers
can be obtained in substantially pure form by classical separation
techniques and by stereochemically controlled synthesis.
Furthermore, the structures and other compounds and moieties
discussed in this application also include all tautomers
thereof.
[0087] As used herein, the term "isomers" refers to different
compounds that have the same molecular formula but differ in
arrangement and configuration of the atoms. Also as used herein,
the term "an optical isomer" or "a stereoisomer" refers to any of
the various stereo isomeric configurations which may exist for a
given compound of the present invention and includes geometric
isomers. It is understood that a substituent may be attached at a
chiral center of a carbon atom. Therefore, the invention includes
enantiomers, diastereomers or racemates of the compound.
"Enantiomers" are a pair of stereoisomers that are
non-superimposable mirror images of each other. A 1:1 mixture of a
pair of enantiomers is a "racemic" mixture. The term is used to
designate a racemic mixture where appropriate. "Diastereoisomers"
are stereoisomers that have at least two asymmetric atoms, but
which are not mirror-images of each other. The absolute
stereochemistry is specified according to the Cahn-Ingold-Prelog
R-S system. When a compound is a pure enantiomer the
stereochemistry at each chiral carbon may be specified by either R
or S. Resolved compounds whose absolute configuration is unknown
can be designated (+) or (-) depending on the direction (dextro- or
levorotatory) which they rotate plane polarized light at the
wavelength of the sodium D line. Certain of the compounds described
herein contain one or more asymmetric centers or axes and may thus
give rise to enantiomers, diastereomers, and other stereoisomeric
forms that may be defined, in terms of absolute stereochemistry, as
(R)- or (S)-. The present invention is meant to include all such
possible isomers, including racemic mixtures, optically pure forms
and intermediate mixtures. Optically active (R)- and (S)-isomers
may be prepared using chiral synthons or chiral reagents, or
resolved using conventional techniques. If the compound contains a
double bond, the substituent may be E or Z configuration. If the
compound contains a disubstituted cycloalkyl, the cycloalkyl
substituent may have a cis- or trans-configuration. All tautomeric
forms are also intended to be included.
[0088] Any asymmetric atom (e.g., carbon or the like) of the
compound(s) of the present invention can be present in racemic or
enantiomerically enriched, for example the (R)-, (S)- or
(R,S)-configuration. In certain embodiments, each asymmetric atom
has at least 50% enantiomeric excess, at least 60% enantiomeric
excess, at least 70% enantiomeric excess, at least 80% enantiomeric
excess, at least 90% enantiomeric excess, at least 95% enantiomeric
excess, or at least 99% enantiomeric excess in the (R)- or
(S)-configuration. Substituents at atoms with unsaturated bonds
may, if possible, be present in cis-(Z)- or trans-(E)-form.
[0089] Accordingly, as used herein a compound of the present
invention can be in the form of one of the possible isomers,
rotamers, atropisomers, tautomers or mixtures thereof, for example,
as substantially pure geometric (cis or trans) isomers,
diastereomers, optical isomers (antipodes), racemates or mixtures
thereof.
[0090] Any resulting mixtures of isomers can be separated on the
basis of the physicochemical differences of the constituents, into
the pure or substantially pure geometric or optical isomers,
diastereomers, racemates, for example, by chromatography and/or
fractional crystallization.
[0091] Any resulting racemates of final products or intermediates
can be resolved into the optical antipodes by known methods, e.g.,
by separation of the diastereomeric salts thereof, obtained with an
optically active acid or base, and liberating the optically active
acidic or basic compound. In particular, a basic moiety may thus be
employed to resolve the compounds of the present invention into
their optical antipodes, e.g., by fractional crystallization of a
salt formed with an optically active acid, e.g., tartaric acid,
dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O'-p-toluoyl
tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic
acid. Racemic products can also be resolved by chiral
chromatography, e.g., high pressure liquid chromatography (HPLC)
using a chiral adsorbent.
[0092] As used herein, the term "pharmaceutically acceptable salts"
refers to salts that retain the biological effectiveness and
properties of the compounds of this invention and, which are not
biologically or otherwise undesirable. In many cases, the compounds
of the present invention are capable of forming acid and/or base
salts by virtue of the presence of amino and/or carboxyl groups or
groups similar thereto. Pharmaceutically acceptable acid addition
salts can be formed with inorganic acids and organic acids, e.g.,
acetate, aspartate, benzoate, besylate, bicarbonate/carbonate,
bisulphate/sulphate, borate, camsylate, citrate, edisylate,
esylate, formate, fumarate, gluceptate, gluconate, glucuronate,
hexafluorophosphate, hibenzate, hydrochloride/chloride,
hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate,
malate, maleate, malonate, mesylate, methylsulphate, naphthylate,
2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate,
pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate,
saccharate, stearate, succinate, tartrate, tosylate and
trifluoroacetate salts. Inorganic acids from which salts can be
derived include, for example, hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid, and the like. Organic
acids from which salts can be derived include, for example, acetic
acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid,
maleic acid, malonic acid, succinic acid, fumaric acid, tartaric
acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,
methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,
salicylic acid, and the like. Pharmaceutically acceptable base
addition salts can be formed with inorganic and organic bases.
Inorganic bases from which salts can be derived include, for
example, sodium, potassium, lithium, ammonium, calcium, magnesium,
iron, zinc, copper, manganese, aluminum, and the like; particularly
preferred are the ammonium, potassium, sodium, calcium and
magnesium salts. Organic bases from which salts can be derived
include, for example, primary, secondary, and tertiary amines,
substituted amines including naturally occurring substituted
amines, cyclic amines, basic ion exchange resins, and the like,
specifically such as isopropylamine, trimethylamine, diethylamine,
triethylamine, tripropylamine, and ethanolamine. The
pharmaceutically acceptable salts of the present invention can be
synthesized from a parent compound, a basic or acidic moiety, by
conventional chemical methods. Generally, such salts can be
prepared by reacting free acid forms of these compounds with a
stoichiometric amount of the appropriate base (such as Na, Ca, Mg,
or K hydroxide, carbonate, bicarbonate, or the like), or by
reacting free base forms of these compounds with a stoichiometric
amount of the appropriate acid. Such reactions are typically
carried out in water or in an organic solvent, or in a mixture of
the two. Generally, non-aqueous media like ether, ethyl acetate,
ethanol, isopropanol, or acetonitrile are preferred, where
practicable. Lists of additional suitable salts can be found, e.g.,
in "Remington's Pharmaceutical Sciences", 20th ed., Mack Publishing
Company, Easton, Pa., (1985); and in "Handbook of Pharmaceutical
Salts: Properties, Selection, and Use" by Stahl and Wermuth
(Wiley-VCH, Weinheim, Germany, 2002).
[0093] Any formula given herein is also intended to represent
unlabeled forms as well as isotopically labeled forms of the
compounds. For example, any hydrogen represented by "H" in any of
the formulae herein is intended to represent all isotopic forms of
hydrogen (e.g. .sup.1H, .sup.2H or D, .sup.3H); any carbon
represented by "C" in any of the formulae herein is intended to
represent all isotopic forms of carbon (e.g. .sup.11C, .sup.13C,
.sup.14C); any nitrogen represented by "N" is intended to represent
all isotopic forms of nitrogen (e.g. .sup.14N, .sup.15N). Other
examples of isotopes that are included in the invention include
isotopes of oxygen, sulfur, phosphorous, fluorine, iodine and
chlorine, such as .sup.18F .sup.31P, .sup.32P, .sup.35S, .sup.36Cl,
.sup.125I. The invention includes various isotopically labeled
compounds as defined herein, for example those into which
radioactive isotopes, such as .sup.3H, .sup.13C, and .sup.14C are
present. In one embodiment, the atoms in the formulae herein occur
in their natural abundance. In another embodiment, one or more
hydrogen atom may be enriched in .sup.2H; or/and one or more carbon
atom may be enriched in .sup.11C, .sup.13C or .sup.14C; or/and one
or more nitrogen may be enriched in .sup.14N. Such isotopically
labelled compounds are useful in metabolic studies (with .sup.14C),
reaction kinetic studies (with, for example .sup.2H or .sup.3H),
detection or imaging techniques, such as positron emission
tomography (PET) or single-photon emission computed tomography
(SPECT) including drug or substrate tissue distribution assays, or
in radioactive treatment of patients. In particular, an .sup.18F or
labeled compound may be particularly desirable for PET or SPECT
studies. Isotopically labeled compounds of this invention and
prodrugs thereof can generally be prepared by carrying out the
procedures disclosed in the schemes or in the examples and
preparations described below by substituting a readily available
isotopically labeled reagent for a non-isotopically labeled
reagent.
[0094] Further, enrichment with heavier isotopes, particularly
deuterium (i.e., .sup.2H or D) may afford certain therapeutic
advantages resulting from greater metabolic stability, for example
increased in vivo half-life or reduced dosage requirements or an
improvement in therapeutic index. It is understood that deuterium
in this context is regarded as a substituent of a compound
according to anyone of the formulae I' and I to VIIC. The
concentration of such a heavier isotope, specifically deuterium,
may be defined by the isotopic enrichment factor. The term
"isotopic enrichment factor" as used herein means the ratio between
the isotopic abundance and the natural abundance of a specified
isotope. If a substituent in a compound of this invention is
denoted deuterium, such compound has an isotopic enrichment factor
for each designated deuterium atom of at least 3500 (52.5%
deuterium incorporation at each designated deuterium atom), at
least 4000 (60% deuterium incorporation), at least 4500 (67.5%
deuterium incorporation), at least 5000 (75% deuterium
incorporation), at least 5500 (82.5% deuterium incorporation), at
least 6000 (90% deuterium incorporation), at least 6333.3 (95%
deuterium incorporation), at least 6466.7 (97% deuterium
incorporation), at least 6600 (99% deuterium incorporation), or at
least 6633.3 (99.5% deuterium incorporation).
[0095] Isotopically-enriched compounds of formulae I' or I to VIIC
can generally be prepared by conventional techniques known to those
skilled in the art or by processes analogous to those described in
the accompanying Examples and Preparations using an appropriate
isotopically-enriched reagent in place of the non-enriched reagent
previously employed
[0096] Pharmaceutically acceptable solvates in accordance with the
invention include those wherein the solvent of crystallization may
be isotopically substituted, e.g. D.sub.2O, d.sub.6-acetone,
d.sub.6-DMSO.
[0097] Compounds of the invention, i.e. compounds according to
anyone of formulae I' and I to VIIC, that contain groups capable of
acting as donors and/or acceptors for hydrogen bonds may be capable
of forming co-crystals with suitable co-crystal formers. These
co-crystals may be prepared from compounds according to anyone of
formulae I' and I to VIIC by known co-crystal forming procedures.
Such procedures include grinding, heating, co-subliming,
co-melting, or contacting in solution compounds according to anyone
of formulae I' and I to VIIC with the co-crystal former under
crystallization conditions and isolating co-crystals thereby
formed. Suitable co-crystal formers include those described in WO
2004/078163. Hence the invention further provides co-crystals
comprising a compound according to anyone of formulae I' and I to
VIIC.
[0098] As used herein, the term "pharmaceutically acceptable
carrier" includes any and all solvents, dispersion media, coatings,
surfactants, antioxidants, preservatives (e.g., antibacterial
agents, antifungal agents), isotonic agents, absorption delaying
agents, salts, preservatives, drugs, drug stabilizers, binders,
excipients, disintegration agents, lubricants, sweetening agents,
flavoring agents, dyes, such like materials and combinations
thereof, as would be known to one of ordinary skill in the art
(see, for example, Remington's Pharmaceutical Sciences, 18th Ed.
Mack Printing Company, 1990, pp. 1289-1329). Except insofar as any
conventional carrier is incompatible with the active ingredient,
its use in the therapeutic or pharmaceutical compositions is
contemplated.
[0099] The term "a therapeutically effective amount" of a compound
of the present invention refers to an amount of the compound of the
present invention that will elicit the biological or medical
response of a subject, for example, reduction or inhibition of an
enzyme or a protein activity, or ameliorate symptoms, alleviate
conditions, slow or delay disease progression, or prevent a
disease, etc. In one non-limiting embodiment, the term "a
therapeutically effective amount" refers to the amount of the
compound of the present invention that, when administered to a
subject, is effective to (1) at least partially alleviating,
inhibiting, preventing and/or ameliorating a condition, or a
disorder or a disease (i) mediated by neutral endopeptidase EC 3.4.
24.11 or (ii) associated with neutral endopeptidase EC 3.4. 24.11
activity, or (iii) characterized by abnormal activity of neutral
endopeptidase EC 3.4. 24.11; or (2) reducing or inhibiting the
activity of neutral endopeptidase EC 3.4. 24.11; or (3) reducing or
inhibiting the expression of neutral endopeptidase EC 3.4. 24.11.
In another non-limiting embodiment, the term "a therapeutically
effective amount" refers to the amount of the compound of the
present invention that, when administered to a cell, or a tissue,
or a non-cellular biological material, or a medium, is effective to
at least partially reducing or inhibiting the activity of neutral
endopeptidase EC 3.4. 24.11; or at least partially reducing or
inhibiting the expression of neutral endopeptidase EC 3.4.
24.11.
[0100] As used herein, the term "subject" refers to an animal.
Preferably, the animal is a mammal. A subject also refers to for
example, primates (e.g., humans), cows, sheep, goats, horses, dogs,
cats, rabbits, rats, mice, fish, birds and the like. In a preferred
embodiment, the subject is a human.
[0101] As used herein, the term "inhibition" or "inhibiting" refers
to the reduction or suppression of a given condition, symptom, or
disorder, or disease, or a significant decrease in the baseline
activity of a biological activity or process.
[0102] As used herein, the term "treating" or "treatment" of any
disease or disorder refers in one embodiment, to ameliorating the
disease or disorder (i.e., slowing or arresting or reducing the
development of the disease or at least one of the clinical symptoms
thereof). In another embodiment "treating" or "treatment" refers to
alleviating or ameliorating at least one physical parameter
including those which may not be discernible by the patient. In yet
another embodiment, "treating" or "treatment" refers to modulating
the disease or disorder, either physically, (e.g., stabilization of
a discernible symptom), physiologically, (e.g., stabilization of a
physical parameter), or both. In yet another embodiment, "treating"
or "treatment" refers to preventing or delaying the onset or
development or progression of the disease or disorder.
[0103] As used herein, the term "a," "an," "the" and similar terms
used in the context of the present invention (especially in the
context of the claims) are to be construed to cover both the
singular and plural unless otherwise indicated herein or clearly
contradicted by the context.
[0104] The term "hypertension" refers to a condition where the
pressure of blood within the blood vessels is higher than normal as
it circulates through the body. When the systolic pressure exceeds
150 mmHg or the diastolic pressure exceeds 90 mmHg for a sustained
period of time, damage is done to the body. For example, excessive
systolic pressure can rupture blood vessels anywhere, and when it
occurs within the brain, a stroke results. Hypertension may also
cause thickening and narrowing of the blood vessels which
ultimately could lead to atherosclerosis.
[0105] The term "type 2 diabetes" including type 2 diabetes
associated with hypertension refers to a disease in which the
pancreas does not secrete sufficient insulin due to an impairment
of pancreatic beta-cell function and/or in which there is to
insensitivity to produced insulin (insulin resistance). Typically,
the fasting plasma glucose is less than 126 mg/dL, while
pre-diabetes is, e.g., a condition which is characterized by one of
following conditions: impaired fasting glucose (110-125 mg/dL) and
impaired glucose tolerance (fasting glucose levels less than 126
mg/dL and post-prandial glucose level between 140 mg/dL and 199
mg/dL). Type 2 diabetes mellitus can be associated with or without
hypertension. Diabetes mellitus occurs frequently, e.g., in African
American, Latino/Hispanic American, Native American, Native
American, Asian American and Pacific Islanders. Markers of insulin
resistance include HbA1C, HOMA IR, measuring collagen fragments,
TGF-.beta. in urine, PAI-1 and prorenin.
[0106] All methods described herein can be performed in any
suitable order unless otherwise indicated herein or otherwise
clearly contradicted by context. The use of any and all examples,
or exemplary language (e.g. "such as") provided herein is intended
merely to better illuminate the invention and does not pose a
limitation on the scope of the invention otherwise claimed.
[0107] Compounds of the present invention are either obtained in
the free form, as a salt thereof, or as prodrug derivatives
thereof.
[0108] When both a basic group and an acid group are present in the
same molecule, the compounds of the present invention may also form
internal salts, e.g., zwitterionic molecules.
[0109] The present invention also provides pro-drugs of the
compounds of the present invention that converts in vivo to the
compounds of the present invention. A pro-drug is an active or
inactive compound that is modified chemically through in vivo
physiological action, such as hydrolysis, metabolism and the like,
into a compound of this invention following administration of the
prodrug to a subject. The suitability and techniques involved in
making and using pro-drugs are well known by those skilled in the
art. Prodrugs can be conceptually divided into two non-exclusive
categories, bioprecursor prodrugs and carrier prodrugs. See The
Practice of Medicinal Chemistry, Ch. 31-32 (Ed. Wermuth, Academic
Press, San Diego, Calif., 2001). Generally, bioprecursor prodrugs
are compounds, which are inactive or have low activity compared to
the corresponding active drug compound that contain one or more
protective groups and are converted to an active form by metabolism
or solvolysis. Both the active drug form and any released metabolic
products should have acceptably low toxicity. Carrier prodrugs are
drug compounds that contain a transport moiety, e.g., that improve
uptake and/or localized delivery to a site(s) of action. Desirably
for such a carrier prodrug, the linkage between the drug moiety and
the transport moiety is a covalent bond, the prodrug is inactive or
less active than the drug compound, and any released transport
moiety is acceptably non-toxic. For prodrugs where the transport
moiety is intended to enhance uptake, typically the release of the
transport moiety should be rapid. In other cases, it is desirable
to utilize a moiety that provides slow release, e.g., certain
polymers or other moieties, such as cyclodextrins. Carrier prodrugs
can, for example, be used to improve one or more of the following
properties: increased lipophilicity, increased duration of
pharmacological effects, increased site-specificity, decreased
toxicity and adverse reactions, and/or improvement in drug
formulation (e.g., stability, water solubility, suppression of an
undesirable organoleptic or physiochemical property). For example,
lipophilicity can be increased by esterification of (a) hydroxyl
groups with lipophilic carboxylic acids (e.g., a carboxylic acid
having at least one lipophilic moiety), or (b) carboxylic acid
groups with lipophilic alcohols (e.g., an alcohol having at least
one lipophilic moiety, for example aliphatic alcohols).
[0110] Exemplary prodrugs are, e.g., esters of free carboxylic
acids and S-acyl derivatives of thiols and O-acyl derivatives of
alcohols or phenols, wherein acyl has a meaning as defined herein.
Preferred are pharmaceutically acceptable ester derivatives
convertible by solvolysis under physiological conditions to the
parent carboxylic acid, e.g., lower alkyl esters, cycloalkyl
esters, lower alkenyl esters, benzyl esters, mono- or
di-substituted lower alkyl esters, such as the .omega.-(amino,
mono- or di-lower alkylamino, carboxy, lower alkoxycarbonyl)-lower
alkyl esters, the .alpha.-(lower alkanoyloxy, lower alkoxycarbonyl
or di-lower alkylaminocarbonyl)-lower alkyl esters, such as the
pivaloyloxymethyl ester and the like conventionally used in the
art. In addition, amines have been masked as arylcarbonyloxymethyl
substituted derivatives which are cleaved by esterases in vivo
releasing the free drug and formaldehyde (Bundgaard, J. Med. Chem.
2503 (1989)). Moreover, drugs containing an acidic NH group, such
as imidazole, imide, indole and the like, have been masked with
N-acyloxymethyl groups (Bundgaard, Design of Prodrugs, Elsevier
(1985)). Hydroxy groups have been masked as esters and ethers. EP
039,051 (Sloan and Little) discloses Mannich-base hydroxamic acid
prodrugs, their preparation and use.
[0111] Furthermore, the compounds of the present invention,
including their salts, can also be obtained in the form of their
hydrates, or include other solvents used for their
crystallization.
General Synthetic Aspects
[0112] The compounds of the invention can be synthesized using the
methods described in the following schemes, examples, and by using
art recognized techniques. All compounds described herein are
included in the invention as compounds. Compounds of the invention
may be synthesized according to at least one of the methods
described in schemes 1-4.
[0113] Within the scope of this text, only a readily removable
group that is not a constituent of the particular desired end
product of the compounds of the present invention is designated a
"protecting group", unless the context indicates otherwise. The
protection of functional groups by such protecting groups, the
protecting groups themselves, and their cleavage reactions are
described for example in standard reference works, such as J. F. W.
McOmie, "Protective Groups in Organic Chemistry", Plenum Press,
London and New York 1973, in T. W. Greene and P. G. M. Wuts,
"Protective Groups in Organic Synthesis", Third edition, Wiley, New
York 1999.
[0114] 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.
[0115] 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.
[0116] 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.
[0117] 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.
[0118] The following applies in general to all processes mentioned
herein before and hereinafter.
[0119] 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.
[0120] 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".
[0121] 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.
[0122] 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.
[0123] 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.
[0124] 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).
[0125] The compounds of the invention according to anyone of
formulae I' and I to VIIC can be prepared by the procedure
described in the following sections.
ABBREVIATIONS
TABLE-US-00001 [0126] ATP: adenosine 5'-triphosphate AS:
Aldosterone Synthase Alloc: allyloxycarbonyl BOC: tertiary butyl
carboxy BOP: benzotriazole1-yloxy)tris(dimethylamino) BINAP:
racemic 2,2'-bis(diphenyl phosphonium hexafluorophosphate
phosphino)-1,1'-binaphthyl br: broad bs: broad singlet Ac: Acetyl
Atm: atmosphere Aq: aqueous calcd: calculated Bn: benzyl Cbz:
benzyloxycarbonyl Bu, i-bu and t-Bu: butyl, isobutyl and t-butyl Pr
and i-Pr: propyl and isopropyl CDI: 1,1'-carbonyldiimidazole COD:
1,5-cyclooctadiene DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene DCC:
1,3-dicyclohexylcarbodiimide DIAD: diisopropyl azodicarboxylate
DAST: (diethylamino)sulfur trifluoride d: doublet dd: doublet of
doublets DCM: dichloromethane DIEA: diethylisopropylamine DME:
1,4-dimethoxyethane DMF: N,N-dimethylformamide DMSO:
dimethylsulfoxide DIPEA: N,N-diisopropylethylamine DMAP:
N,N-dimethylaminopyridine Dppb: 1,2-bis(diphenylphosphino)butane
Dppe: 1,2-bis(diphenylphosphino) ethane DAD: diode array detector
DTT: dithiothreitol DPPA: diphenylphosphorylazide EDCI, EDIC:
N-Ethyl-N'-(3-dimethyl- aminopropyl)carbodiimide hydrochloride
EDTA: ethylenediamine tetraacetic acid ESI: electrospray ionization
Et and EtOAc: ethyl and ethyl acetate EDC: N-Ethyl-N'-(3-dimethyl-
aminopropyl)carbodiimide hydrochloride HATU:
O-(7-azobenzotriazol-1-yl)-1,1,3,3- HOBt:
1-hydroxy-7-azabenzotriazole tetramethyluroniumhexafluorophosphate
HPLC: high pressure liquid chromatography LC and LCMS: liquid
chromatography and liquid chromatography and mass spectrometry H:
Hour(s) HOAt: 1-hydroxy-7-azabezotriazole IR: infrared LDA: lithium
diisopropylamide KHMDS: potassium bis(trimethylsilyl)amide LHMDS:
lithium bis(trimethylsilyl)amide LTA: lead tetraacetate NHMDS:
sodium bis(trimethylsilyl)amide MeOD: methanol-d4 MeOH: methanol
MS: mass spectrometry m: multiplet min: minutes m/z: mass to charge
ratio Ms: mesyl Me: methyl M and mM: Molar and millimolar Mg:
milligram n.d.: not determined NMR: nuclear magnetic resonance ppm:
parts per million Pr and iPr: propyl and isopropyl Ph: Phenyl Pd/C:
Palladium on Carbom PyBOP: benzotriazol-1-yloxy RT: room
temperature Tripyrrolidinophosphoniumhexafluorophosphate PIDA:
iodobenzene bis(trifluoroacetate) PIFA: iodobenzene diacetate PS:
polymer supported RP: reverse phase s: singlet adn t: triplet Ts
tosyl TFA: trifluoroacetic acid THF: tetrahydrofuran Tf: triflate
tBu: tert-butyl TLC: thin layer chromatography Tris-HCl:
aminotris(hydroxymethyl) methane hydrochloride .mu.L, mL and L:
microlitre, millilitre and litre TMS: Trimethylsilyl WSC: water
soluble carbodiimide (N-Ethyl-N'- UV: ultraviolet
(3-dimethylaminopropyl)carbodiimide
[0127] The compounds of the invention of formula II can be prepared
by hydrolysis of intermediates A to C wherein X, X.sup.1, A.sup.1,
R.sup.1, R.sup.2 and n have the definition of Formula I or I',
supra; and P.sup.1 and P.sup.2 are appropriate protecting groups
selected from, but not limited to, methyl, ethyl, isopropyl,
tert-butyl, methoxybenzyl or benzyl.
##STR00032##
[0128] The compounds of the invention of formula III can be
prepared by hydrolysis of intermediate D, E or F wherein X,
X.sup.1, A.sup.1, R.sup.1, R.sup.2 and n have the definition of
Formula I or I', supra; and P.sup.1 and P.sup.2 can be appropriate
protecting groups selected from, but not limited to, methyl, ethyl,
isopropyl, tert-butyl, methoxybenzyl or benzyl.
##STR00033##
The compounds of the invention of formula VII can be prepared by
hydrolysis of intermediate G wherein A.sup.2, R.sup.1, R.sup.2,
R.sup.4 and n have the definition of Formula I or I', supra; and
P.sup.1 can be appropriate protecting group selected from, but not
limited to, methyl, ethyl, isopropyl, tert-butyl, methoxybenzyl or
benzyl.
##STR00034##
[0129] Standard methods can be applied for the hydrolysis of
Intermediates A to G using a base selected from, but not limited
to, NaOH, KOH or LiOH, or an acid selected from, but not limited
to, TFA or HCl. When P.sup.1 or P.sup.2 is benzyl or methoxybenzyl,
preferable method of deprotection is hydrogenation in the presence
of a catalyst such as, but not limited to, palladium-on-carbon
under hydrogen.
[0130] The intermediate A, B, C or G can be prepared using the
following process comprising: condensing an intermediate H or I
wherein X, P.sup.1, R.sup.1, R.sup.2 and n are as previously
described:
##STR00035##
with an intermediate J, K or L wherein X.sup.1, A.sup.1, A.sup.2,
R.sup.4 and P.sup.2 are previously described.
##STR00036##
Known condensation methods may be applied including, but not
limited to, conversion of the intermediate J, K or L to their
corresponding acid halide, using reagents such as thionyl chloride
or oxalyl chloride, or conversion of intermediate J, K or L to
mixed anhydride using reagents such as CIC(O)O-isobutyl or
2,4,6-trichlorobenzoyl chloride followed by reaction of the acid
halide or mixed anhydride with the intermediate H or I in a
presence or absence of a base such as tertiary amine (e.g.
triethylamine, DIPEA, or N-methylmorpholine) or pyridine derivative
(e.g. pyridine, 4-(dimethylamino)pyridine, or
4-pyrrolidinopyridine). Alternatively, the intermediate J, K, or L
can be coupled with H or I using coupling reagents such as DCC,
EDCI, PyBOP or BOP in presence or absence of a reagent such as
1-hydroxybenazotriazole, 1-hydroxy-7-azabenzotriazole or
pentafluorophenol.
[0131] Intermediate G wherein R.sup.4 is a tetrazole can be
synthesized according to Scheme 1:
##STR00037##
[0132] wherein A.sup.2, R.sup.1, R.sup.2, R.sup.4, P.sup.1, P.sup.2
and n are as previously defined above.
[0133] In step 1a, intermediate I is reacted with an appropriate
carboxylic acid using standard coupling reagents selected from, but
not limited to, DCC, EDCI, PyBOP or BOP in presence or absence of a
reagent such as 1-hydroxybenazotriazole,
1-hydroxy-7-azabenzotriazole or pentafluorophenol; followed by
removal of P.sup.2 protecting group in step 1c using a base
selected from, but not limited to, NaOH, KOH or LiOH, or an acid
selected from, but not limited to, TFA or HCl, or hydrogenation
with a catalyst such as, but not limited to, palladium-on-carbon
under hydrogen. Alternatively, intermediate I is reacted with an
appropriate anhydride in the presence of a base selected from, but
not limited to, pyridine, triethylamine or diisopropylethylamine
(step 1 b); followed by conversion of the carboxylic acid into a
tetrazole (step 1b) using similar method as described in Journal of
Medicinal Chemistry 1998, 41, 1513.
[0134] The intermediate D, E or F can be prepared using the
following process comprising: condensing an intermediate M wherein
X, P.sup.1, R.sup.1, R.sup.2 and n are as defined above;
##STR00038##
with an intermediate Q or S wherein X.sup.1, A.sup.1 and P.sup.2
have the meaning as defined above.
##STR00039##
[0135] Known condensation methods may be applied including, but not
limited to, conversion of the intermediate M or N to acid halide,
using reagents such as thionyl chloride or oxalyl chloride, or
conversion of intermediate M or N to mixed anhydride using reagents
such as CIC(O)O-isobutyl or 2,4,6-trichlorobenzoyl chloride
followed by reaction of the acid chloride or mixed anhydride with
the intermediate Q or S in a presence or absence of a base such as
tertiary amine (e.g. triethylamine, DIPEA, or N-methylmorpholine)
or pyridine derivative (e.g. pyridine, 4-(dimethylamino)pyridine,
or 4-pyrrolidinopyridine); Alternatively, the intermediate M or N
can be coupled with the intermediate Q or S using a reagent such as
DCC, EDCI, PyBOP or BOP in presence or absence of a reagent such as
1-hydroxybenazotriazole, 1-hydroxy-7-azabenzotriazole or
pentafluorophenol.
[0136] The intermediate M or N can be prepared according to the
following general procedures described in Scheme 2:
##STR00040##
wherein R.sup.1, R.sup.2, X and n are as defined above and wherein
m=0 or 1; P.sup.1 is a protecting group selected from, but not
limited to, hydrogen, methyl, ethyl, propyl, tert-butyl,
methoxymethyl, tert-butyldimethylsilyl, tetrahydrofuranyl, benzyl,
allyl or phenyl; R.sup.5 is for example hydrogen, methyl, ethyl,
isopropyl, benzyl or phenyl; R.sup.6 and R.sup.7 are independently
hydrogen, methyl, ethyl, isopropyl, benzyl or phenyl. Y is selected
from, but not limited to, chloro, bromo, iodo, benzotriazoloxy,
pyridinium, N,N-dimethylaminopyridinium, pentafluorophenoxy,
phenoxy, 4-chlorophenoxy, --OCO.sub.2Me, --OCO.sub.2Et,
tert-butoxycarbonyl or --OCC(O)O-isobutyl.
[0137] In step (2a), standard methods can be applied to prepare the
corresponding acid halide, such as the use of thionyl chloride,
oxalyl chloride; or standard methods to prepare the mixed anhydride
or the acyl pyridinium cation can be applied, such as the use of
pivaloyl chloride with a tertiary amine (e.g. triethylamine, DIPEA,
N-methylmorpholine) in the presence or absence of a pyridine
derivative (e.g. pyridine, 4-(dimethylamino)pyridine,
4-pyrrolidinopyridine), 2,4,6-trichlorobenzoyl chloride with a
tertiary amine (e.g. triethylamine, DIPEA, N-methylmorpholine) in
the presence or absence of a pyridine derivative (e.g. pyridine,
4-(dimethylamino)pyridine, 4-pyrrolidinopyridine), or CIC(O)O-1-Bu
with a tertiary amine (e.g. triethylamine, DIPEA,
N-methylmorpholine) in the presence or absence of a pyridine
derivative (e.g. pyridine, 4-(dimethylamino)pyridine,
4-pyrrolidinopyridine); or standard methods to prepare the
activated ester can be applied, such as the use of
1-hydroxybenazotriazole, 1-hydroxy-7-azabenzotriazole or
pentafluorophenol in the presence of a coupling reagent (e.g. DCC,
EDCI) or BOP.
[0138] In step (2b), standard methods to prepare the
N-acyloxazolidinones (m=0) can be employed. Illustrative examples
of this chemistry are outlined in Aldrichchimica Acta 1997, Vol.
30, pp. 3-12 and the references therein; or standard methods to
prepare the N-acyloxazinanone (m=1) can be employed. An
illustrative example of this chemistry is outlined in Organic and
Biomolecular Chemistry 2006, Vol. 4, No. 14, pp. 2753-2768. In step
(2c), standard methods for alkylation can be employed. An
illustrative example is outlined in Chemical Reviews 1996, 96(2),
835-876 and the references therein. In step (2d), standard methods
for cleavage of N-acyloxazolidinone or N-acyloxazinanone can be
employed. Illustrative examples of this chemistry are outlined in
Aldrichchimica Acta 1997, Vo. 30, pp. 3-12 and the references
therein.
[0139] The intermediate H or I can be prepared according to the
following general procedures described in Schemes 3 and 4:
##STR00041##
wherein R.sup.1, R.sup.2, X and n are as defined above and wherein
P.sub.3 is a protecting group selected from, but not limited to,
tert-butyl, benzyl, triphenylphosphynyl, tert-butoxycarbonyl,
benzyloxycarbonyl, allyloxycarbonyl, acetyl or trifluoroacetyl.
[0140] In step (3a), standard methods for introduction of the amine
part can be employed, such as using: either simultaneous treatment
with or stepwise treatment via the corresponding acyl azide
formation by using thionyl chloride (or ClCO.sub.2R.sup.8),
NaN.sub.3 (or TMSN.sub.3) and R.sup.9OH (wherein R.sup.6 and
R.sup.9 are hydrogen, methyl, ethyl, tert-butyl, allyl, benzyl or
4-methoxybenzyl); or either simultaneous treatment with or stepwise
treatment via the corresponding acyl azide formation with DPPA and
R.sup.9OH (wherein R.sup.9 is defined as above); or standard
methods for conversion to the corresponding carboxamide followed by
treatment with NH.sub.3 equivalent and either simultaneous
treatment with or stepwise treatment with LTA or hypervalent iodine
reagents (e.g. PIDA, PIFA, Phl(OH)OTs, PhlO) and R.sup.9OH (wherein
R.sup.9 is defined as above); or standard methods for conversion to
the corresponding carboxamide either simultaneous treatment with or
stepwise treatment with Br.sub.2 and MOH (wherein M is defined
herein e.g. Na, K, Ba or Ca); or standard methods for conversion to
the corresponding carboxamide and treatment with MOZ or NaBrO.sub.2
(wherein Z is defined herein e.g. Cl or Br); or standard methods
for conversion to the corresponding carboxamide and treatment with
Pb(OAc).sub.4 and R.sup.9OH (wherein R.sup.9 is defined as above);
or standard methods for conversion to the corresponding hydroxamic
acid followed by treatment with H.sub.2NOH or H.sub.2NOTMS and
treatment with Ac.sub.2O, Boc.sub.2O, R.sup.10COCl,
R.sup.10SO.sub.2Cl, R.sup.10PO.sub.2Cl (wherein R.sup.10 is defined
herein e.g. Me, Et, tBu or phenyl), thionyl chloride, EDCI, DCC, or
1-chloro-2,4-dinitrobenzene in the presence or absence of a base
(e.g. pyridine, Na.sub.2CO.sub.3aq, triethylamine, DIPEA) and
treatment with R.sup.9OH in the presence of a base (e.g. DBU, ZOH,
DIPEA) (wherein R.sup.9 and Z are defined as above).
[0141] In step (3b), standard methods for removing P.sub.3
protecting groups can be applied, such as base hydrolysis using
NaOH, KOH, or LiOH, acid hydrolysis using TFA or HCl, or
hydrogenation using palladium-on-carbon under hydrogen.
[0142] Scheme 4 describes an alternative synthesis of Intermediate
H or I:
##STR00042##
wherein LG is a leaving group selected from, but not limited to,
Cl, Br, I, OMs, OTs or OTf. In step (4a), standard methods for
Arndt-Eistert homologation can be employed. An illustrative example
of this chemistry is outlined in "Enantioselective synthesis of
.beta.-amino acids, 2.sup.nd Edition", John Wiley and Sons, Inc.,
NJ (2005), either directly or analogously. In step (4b), standard
methods for alkylation can be employed, such as using R.sup.1LG in
the presence of a base such as LDA, NHMDS, LHMDS or KHMDS. In step
(4c), standard methods to protect the carboxylic acid can be
employed, such as using TMSCHN.sub.2 (for methyl ester),
P.sup.1LG/base (e.g. K.sub.2CO.sub.3, NaHCO.sub.3, Cs.sub.2CO.sub.3
or K.sub.3PO.sub.4), thionyl chloride (or oxalyl
chloride)/R.sup.9OH, DCC (or EDCI)/DMAP/R.sup.9OH, BOP/R.sup.9OK
(or R.sup.9ONa), (R.sup.9O).sub.2CHNMe.sub.2, CDI/DBU/R.sup.9OH
wherein R.sup.9 has the same meaning as defined above, or
isobutylene/H.sub.2SO.sub.4 (for tert-butyl ester). In step (4d),
standard methods for Suzuki coupling reaction can be applied, such
as using a palladium (or nickel) species [e.g. Pd(PPh.sub.3).sub.4,
PdCl.sub.2(dppf), Pd(OAc).sub.2/a phosphine (e.g. PPh.sub.3, dppf,
PCy.sub.3, P(tBu).sub.3, XPhos), Pd/C, Pd.sub.2(dba).sub.3/a
phosphine (e.g. PPh.sub.3, dppf, PCy.sub.3, P(tBu).sub.3, XPhos),
Ni(COD).sub.2/a phosphine (or dppe, dppb, PCy.sub.3),
Ni(dppf)Cl.sub.2], a base (e.g. KF, CsF, K.sub.3PO.sub.4,
Na.sub.2CO.sub.3, K.sub.2CO.sub.3, Cs.sub.2CO.sub.3, NaOH, KOH,
NaO-t-Bu, KO-t-Bu), and (R.sup.2)n-PhB(OH).sub.2 [or
(R.sup.2)n-PhBF.sub.3K]. In step (4e), standard methods for
removing P.sub.3 protecting groups can be applied, such as base
hydrolysis using NaOH, KOH, or LiOH, acid hydrolysis using TFA or
HCl, or hydrogenation using palladium-on-carbon under hydrogen.
Alternatively, the intermediate H or I may be prepared be following
the synthetic routes outlined in Tetrahedron Letters, 2008, Vol.
49, No. 33, pp. 4977-4980 either directly or analogously and
converting the obtained boronic acid into a substituted biphenyl by
methods outlined in Organic Letters, 2002, Vol. 4, No. 22, pp.
3803-3805.
[0143] Alternatively, the intermediate H or I may be prepared be
following the synthetic routes outlined in Tetrahedron: Asymmetry,
2006, Vol. 17, No. 2, pp. 205-209 either directly or
analogously.
[0144] Alternatively, the intermediate H or I may be prepared by
methods of Mannich reaction. Illustrative examples of this
chemistry are outlined in "Enantioselective synthesis of
.beta.-amino acids, 2.sup.nd Edition", John Wiley and Sons, Inc.,
NJ (2005), either directly or analogously.
[0145] Alternatively, the intermediate H or I may be prepared by
enolate addition. Illustrative examples of this chemistry are
outlined in "Enantioselective synthesis of .beta.-amino acids,
2.sup.nd Edition", John Wiley and Sons, Inc., NJ (2005), either
directly or analogously.
[0146] Alternatively, the intermediate H or I may be prepared by
methods of aza-Michael reaction. Illustrative examples of this
chemistry are outlined in "Enantioselective synthesis of
.beta.-amino acids, 2.sup.nd Edition", John Wiley and Sons, Inc.,
NJ (2005), either directly or analogously.
[0147] Alternatively, the intermediate H or I may be prepared
following the synthetic route outlined in Synlett, 2006, No. 4, pp.
539-542, either directly or analogously.
[0148] The synthesis of intermediates J, K and L is also described
in US patent application of applicant docket number
PAT053600-US-USP3 which was filed on Apr. 16, 2010, which
application is incorporated herein by reference.
[0149] Scheme 5 illustrate the synthesis of a compound of Formula I
or I', or a salt thereof, wherein B.sup.1 is NHC(O), X is OH and
R.sup.3 is A.sup.1C(O)X.sup.1 wherein X.sup.1 is an
--O--C.sub.1-7alkyl.
##STR00043##
[0150] A compound of Formula 5a is converted into a compound of
Formula I or I' wherein B.sup.1 is NHC(O), X is OH and R.sup.3 is
A.sup.1C(O)X.sup.1 wherein X.sup.1 is an --O--C.sub.1-7alkyl or a
salt thereof, wherein R.sup.1, A.sup.1, R.sup.2 and n are as
defined in Formula I or I', according to the method described in
Scheme 5. Compound of Formula 5a undergoes Suzuki coupling reaction
with a boronic acid 5b, or an ester thereof, in the presence of a
catalyst and a base to generate a compound of Formula 5c or a salt
thereof. The Suzuki coupling reaction is well known in the art and
is carried out using standard procedures. Examples of Suzuki
coupling reaction are described in the exemplification section of
the description. Example of palladium catalyst which can be used
for the coupling are PdCl.sub.2(dppf).sub.2.CH.sub.2Cl.sub.2,
Pd(PPh.sub.3).sub.4, PdCl.sub.2(PPh.sub.3).sub.2, or other catalyst
as described in step (4d) of scheme 4. Example of a base which can
be used for the coupling are Na.sub.2CO.sub.3, K.sub.2CO.sub.3,
K.sub.3PO.sub.4 or other base described in step (4d) of Scheme 4.
The Suzuki coupling reaction can be carried out in a solvent.
Examples of a solvent are DME, DMF, CH.sub.2Cl.sub.2, ethanol,
methanol, dioxane, water or toluene, or a mixture thereof. One
example of Suzuki conditions is Pd(PPh.sub.3).sub.2Cl.sub.2 and
Na.sub.2CO.sub.3. In one embodiment the solvent is water or THF or
a mixture thereof.
[0151] Compound 5b or salt thereof, wherein R.sup.1, R.sup.2 and n
are as defined in Formula I or I', is then hydrolyzed to generate
the amine 5d or salt thereof. The hydrolysis can be carried out
under acidic condition. An example of hydrolysis condition is HCl
hydrolysis which generates the hydrochloric salt of compound 5d.
The HCl hydrolysis can be carried out in a solvent. Example of a
solvent is dioxane, water or THF or a mixture thereof. For example,
the HCl hydrolysis can be carried out using an HCl aqueous solution
in THF.
[0152] The amine 5d, or salt thereof, is then converted into a
compound of Formula I or I' wherein B.sup.1 is NHC(O), X is OH and
R.sup.3 is A.sup.1C(O)X.sup.1 wherein X.sup.1 is
--O--C.sub.1-7alkyl or a salt thereof, wherein R.sup.1, A.sup.1,
R.sup.2 and n are as defined in Formula I or I', by reaction with
an acyl chloride of Formula 5, in the presence or absence of a
base. Examples of a base are NaOH, Na.sub.2CO.sub.3,
K.sub.2CO.sub.3, KOH, LiOH or other base described supra for
reaction of an Intermediate H or I with an acid halide. The amide
formation can be carried out in a solvent. Examples of a solvent
are water, acetonitrile, THF or a mixture thereof.
For example, a HCl salt of compound 5d can be reacted with an acyl
chloride of Formula 5e in the presence of NaOH and
Na.sub.2CO.sub.3. An example of solvent is a mixture of
acetonitrile and water. Compounds of the invention of Examples
1-1
[0153] Compound of Formula 5e can be prepared from a compound of
Formula 6a, according to the method described in Scheme 6.
##STR00044##
[0154] Compound of Formula 6a is reacted with X.sup.1H wherein
X.sup.1 is --O--C.sub.1-7alkyl to generate the acid 6b or salt
thereof. The reaction can be carried out in a solvent. Examples of
a solvent are toluene, benzene or a mixture thereof. In one
embodiment the solvent is toluene. Examples of a reagent X.sup.1H
are methanol, ethanol, propanol or butanol. Compound of Formula 6b
is then converted to an acyl chloride 5e by reacting with thionyl
chloride, oxalyl chloride or sulfonyl chloride.
[0155] A compound of Formula I or I', or a salt thereof, wherein
B.sup.1 is NHC(O), X is --O--C.sub.1-7alkyl, and R.sup.3 is
A.sup.1C(O)X.sup.1 wherein X.sup.1 is an --OH and wherein R.sup.1,
A.sup.1, R.sup.2 and n are as defined in Formula I or I', can be
synthesized as outlined in Scheme 7:
##STR00045##
[0156] Compound of Formula 5c, or a salt thereof, wherein R.sup.1,
R.sup.2 and n are as defined in Formula I or I', is converted to
compound of Formula 7a, or a salt thereof; wherein R.sup.1, R.sup.2
and n are as defined in Formula I or I', and X is
--O--C.sub.1-7alkyl; by reaction with XH under acidic condition.
Examples of XH are methanol, ethanol, propanol or butanol.
[0157] Compound of Formula 5c, or salt thereof, is prepared as
described in Scheme 5.
[0158] Compound 7a is then converted to a compound of Formula I or
I', or salt thereof, wherein B.sup.1 is NHC(O), X is
--O--C.sub.1-7alkyl, and R.sup.3 is A.sup.1C(O)X.sup.1 wherein
X.sup.1 is an --OH, by reaction with anhydride reagent 6a.
Optionally a base can be used in the last step of Scheme 7. Example
of a base is NaOH, Na.sub.2CO.sub.3, K.sub.2CO.sub.3, KOH, LiOH or
other base described supra for reaction of an Intermediate H or I
with a mixed anhydride. In one particular example the reaction of
compound of Formula 7a with an anhydride of Formula 6a is carried
out in the presence of isopropyl acetate. Compounds of the
invention of Examples 1-1, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-9, 1-11,
1-12, 1-13, 1-17, 2-22, 2-23, 2-24, 3-25, 3-26, 3-28 and the like
can be prepared according to Schemes 5, 6 and 7.
[0159] The invention further includes any variant of the present
processes, in which an intermediate product obtainable at any stage
thereof is used as starting material and the remaining steps are
carried out, or in which the starting materials are formed in situ
under the reaction conditions, or in which the reaction components
are used in the form of their salts or optically pure
antipodes.
[0160] Compounds of the invention and intermediates can also be
converted into each other according to methods generally known per
se.
[0161] In another aspect, the present invention provides a
pharmaceutical composition comprising a compound of the present
invention or a pharmaceutically acceptable salt thereof, and one or
more pharmaceutically acceptable carriers. The pharmaceutical
composition can be formulated for particular routes of
administration such as oral administration, parenteral
administration, and rectal administration, etc. In addition, the
pharmaceutical compositions of the present invention can be made up
in a solid form including capsules, tablets, pills, granules,
powders or suppositories, or in a liquid form including solutions,
suspensions or emulsions. The pharmaceutical compositions can be
subjected to conventional pharmaceutical operations such as
sterilization and/or can contain conventional inert diluents,
lubricating agents, or buffering agents, as well as adjuvants, such
as preservatives, stabilizers, wetting agents, emulsifers and
buffers etc.
[0162] Typically, the pharmaceutical compositions are tablets and
gelatin capsules comprising the active ingredient together with
[0163] a) diluents, e.g., lactose, dextrose, sucrose, mannitol,
sorbitol, cellulose and/or glycine; [0164] b) lubricants, e.g.,
silica, talcum, stearic acid, its magnesium or calcium salt and/or
polyethyleneglycol; for tablets also [0165] c) binders, e.g.,
magnesium aluminum silicate, starch paste, gelatin, tragacanth,
methylcellulose, sodium carboxymethylcellulose and/or
polyvinylpyrrolidone; if desired [0166] d) disintegrants, e.g.,
starches, agar, alginic acid or its sodium salt, or effervescent
mixtures; and/or [0167] e) absorbents, colorants, flavors and
sweeteners.
[0168] Tablets may be either film coated or enteric coated
according to methods known in the art.
[0169] Suitable compositions for oral administration include an
effective amount of a compound of the invention in the form of
tablets, lozenges, aqueous or oily suspensions, dispersible powders
or granules, emulsion, hard or soft capsules, or syrups or elixirs.
Compositions intended for oral use are prepared according to any
method known in the art for the manufacture of pharmaceutical
compositions and such compositions can contain one or more agents
selected from the group consisting of sweetening agents, flavoring
agents, coloring agents and preserving agents in order to provide
pharmaceutically elegant and palatable preparations. Tablets
contain the active ingredient in admixture with nontoxic
pharmaceutically acceptable excipients which are suitable for the
manufacture of tablets. These excipients are, for example, inert
diluents, such as calcium carbonate, sodium carbonate, lactose,
calcium phosphate or sodium phosphate; granulating and
disintegrating agents, for example, corn starch, or alginic acid;
binding agents, for example, starch, gelatin or acacia; and
lubricating agents, for example magnesium stearate, stearic acid or
talc. The tablets are uncoated or coated by known techniques to
delay disintegration and absorption in the gastrointestinal tract
and thereby provide a sustained action over a longer period. For
example, a time delay material such as glyceryl monostearate or
glyceryl distearate can be employed. Formulations for oral use can
be presented as hard gelatin capsules wherein the active ingredient
is mixed with an inert solid diluent, for example, calcium
carbonate, calcium phosphate or kaolin, or as soft gelatin capsules
wherein the active ingredient is mixed with water or an oil medium,
for example, peanut oil, liquid paraffin or olive oil.
[0170] Certain injectable compositions are aqueous isotonic
solutions or suspensions, and suppositories are advantageously
prepared from fatty emulsions or suspensions. Said compositions may
be sterilized and/or contain adjuvants, such as preserving,
stabilizing, wetting or emulsifying agents, solution promoters,
salts for regulating the osmotic pressure and/or buffers. In
addition, they may also contain other therapeutically valuable
substances. Said compositions are prepared according to
conventional mixing, granulating or coating methods, respectively,
and contain about 0.1-75%, or contain about 1-50%, of the active
ingredient.
[0171] Suitable compositions for transdermal application include an
effective amount of a compound of the invention with carrier.
Carriers include absorbable pharmacologically acceptable solvents
to assist passage through the skin of the host. For example,
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.
[0172] Suitable compositions for topical application, e.g., to the
skin and eyes, include aqueous solutions, suspensions, ointments,
creams, gels or sprayable formulations, e.g., for delivery by
aerosol or the like. Such topical delivery systems will in
particular be appropriate for dermal application. They are thus
particularly suited for use in topical, including cosmetic,
formulations well-known in the art. Such may contain solubilizers,
stabilizers, tonicity enhancing agents, buffers and
preservatives.
[0173] As used herein a topical application may also pertain to an
inhalation or to an intranasal application. They are conveniently
delivered in the form of a dry powder (either alone, as a mixture,
for example a dry blend with lactose, or a mixed component
particle, for example with phospholipids) from a dry powder inhaler
or an aerosol spray presentation from a pressurised container,
pump, spray, atomizer or nebuliser, with or without the use of a
suitable propellant.
[0174] The present invention further provides anhydrous
pharmaceutical compositions and dosage forms comprising the
compounds of the present invention as active ingredients, since
water may facilitate the degradation of certain compounds.
[0175] Anhydrous pharmaceutical compositions and dosage forms of
the invention can be prepared using anhydrous or low moisture
containing ingredients and low moisture or low humidity conditions.
An anhydrous pharmaceutical composition may be prepared and stored
such that its anhydrous nature is maintained. Accordingly,
anhydrous compositions are preferably packaged using materials
known to prevent exposure to water such that they can be included
in suitable formulary kits. Examples of suitable packaging include,
but are not limited to, hermetically sealed foils, plastics, unit
dose containers (e.g., vials), blister packs, and strip packs.
[0176] The invention further provides pharmaceutical compositions
and dosage forms that comprise one or more agents that reduce the
rate by which the compound of the present invention as an active
ingredient will decompose. Such agents, which are referred to
herein as "stabilizers," include, but are not limited to,
antioxidants such as ascorbic acid, pH buffers, or salt buffers,
etc.
[0177] The compounds according to anyone of formulae I' and I to
VIIC in free form or in pharmaceutically acceptable salt form,
exhibit valuable pharmacological properties, e.g. neutral
endopeptidase EC 3.4. 24.11 modulating properties, e.g. as
indicated in in vitro and in vivo tests as provided in the next
sections and are therefore indicated for therapy.
[0178] Compounds of the invention, or a pharmaceutically acceptable
salt thereof, may be useful in the treatment of an indication
selected from: cardiovascular disorders, such hypertension,
pulmonary hypertension, isolated systolic hypertension, resistant
hypertension, peripheral vascular disease, heart failure,
congestive heart failure, left ventricular hypertrophy, angina,
renal insufficiency, renal failure (including edema and salt
retension), diabetic nephropathy, non-diabetic nephropathy,
cyclical oedema, Menieres disease, hyperaldosteroneism (primary and
secondary) and hypercalciuria, ascites, glaucoma, menstrual
disorders, preterm labour, pre-eclampsia, endometriosis, and
reproductive disorders (especially male and female infertility,
polycystic ovarian syndrome, implantation failure), asthma,
obstructive sleep apnea, inflammation, leukemia, pain, epilepsy,
affective disorders such as depression and psychotic condition such
as dementia and geriatric confusion, obesity and gastrointestinal
disorders (especially diarrhea and irritable bowel syndrome), wound
healing (especially diabetic and venous ulcers and pressure sores),
septic shock, the modulation of gastric acid secretion, the
treatment of hyperreninaemia, cystic fibrosis, restenosis, type-2
diabetes, diabetic complications and atherosclerosis, male and
female sexual dysfunction.
[0179] Thus, as a further embodiment, the present invention
provides the use of a compound according to anyone of formulae I'
and I to VIIC, or a pharmaceutically acceptable salt thereof. In a
further embodiment, the therapy is selected from a disease which is
ameliorated by inhibition of neutral endopeptidase EC 3.4. 24.11.
In another embodiment, the disease is selected from the
afore-mentioned list, suitably hypertension, pulmonary
hypertension, isolated systolic hypertension, resistant
hypertension, peripheral vascular disease, heart failure,
congestive heart failure, left ventricular hypertrophy, angina,
renal insufficiency, renal failure (including edema and salt
retension), diabetic nephropathy, non-diabetic nephropathy, type-2
diabetes, and diabetic complications and most suitably
cardiovascular disorders, such as hypertension, renal insufficiency
including edema and congestive heart failure.
[0180] In another embodiment, the invention provides a method of
treating a disease which is ameliorated by the inhibition of
neutral endopeptidase EC 3.4. 24.11 comprising administration of a
therapeutically acceptable amount of a compound according to anyone
of formulae I', I, IA, II, IIA, III, IIIA, IV, IVA, V, VA, VI, VIA
and VII to VIIC, or a pharmaceutically acceptable salt thereof. In
a further embodiment, the disease is selected from the
afore-mentioned list, suitably hypertension, pulmonary
hypertension, isolated systolic hypertension, resistant
hypertension, peripheral vascular disease, heart failure,
congestive heart failure, left ventricular hypertrophy, angina,
renal insufficiency, renal failure (including edema and salt
retension), diabetic nephropathy, non-diabetic nephropathy, type-2
diabetes, and diabetic complications and most suitably
cardiovascular disorders, such as hypertension, renal insufficiency
including edema and congestive heart failure.
[0181] The pharmaceutical composition or combination of the present
invention can be in unit dosage of about 1-1000 mg of active
ingredient(s) for a subject of about 50-70 kg, or about 1-500 mg or
about 1-250 mg or about 1-150 mg or about 0.5-100 mg, or about 1-50
mg of active ingredients. The therapeutically effective dosage of a
compound, the pharmaceutical composition, or the combinations
thereof, is dependent on the species of the subject, the body
weight, age and individual condition, the disorder or disease or
the severity thereof being treated. A physician, clinician or
veterinarian of ordinary skill can readily determine the effective
amount of each of the active ingredients necessary to prevent,
treat or inhibit the progress of the disorder or disease.
[0182] The above-cited dosage properties are demonstrable in vitro
and in vivo tests using advantageously mammals, e.g., mice, rats,
dogs, monkeys or isolated organs, tissues and preparations thereof.
The compounds of the present invention can be applied in vitro in
the form of solutions, e.g., preferably aqueous solutions, and in
vivo either enterally, parenterally, advantageously intravenously,
e.g., as a suspension or in aqueous solution. The dosage in vitro
may range between about 10.sup.-3 molar and 10.sup.-9 molar
concentrations. A therapeutically effective amount in vivo may
range depending on the route of administration, between about
0.1-500 mg/kg, or between about 1-100 mg/kg.
[0183] The activity of a compound according to the present
invention can be assessed by the following in vitro & in vivo
methods and/or by the following in vitro & in vivo methods
well-described in the art. See A fluorescence lifetime-based assay
for protease inhibitor profiling on human kallikrein 7 Doering K,
Meder G, Hinnenberger M, Woelcke J, Mayr L M, Hassiepen U Biomol
Screen. 2009 January; 14(1):1-9.
[0184] In particular, the in vitro inhibition of recombinant human
neutral endopeptidase (NEP, EC 3.4.24.11) can be determined as
follows:
[0185] Recombinant human neutral endopeptidase (expressed in insect
cells and purified using standard methods, final concentration 7
pM) is pre-incubated with test compounds at various concentrations
for 1 hour at room temperature in 10 mM sodium phosphate buffer at
pH 7.4, containing 150 mM NaCl and 0.05% (w/v) CHAPS. The enzymatic
reaction is started by the addition of a synthetic peptide
substrate Cys(PT14)-Arg-Arg-Leu-Trp-OH to a final concentration of
0.7 .mu.M. Substrate hydrolysis leads to an increase fluorescence
lifetime (FLT) of PT14 measured by the means of a FLT reader as
described by Doering et al. (2009). The effect of the compound on
the enzymatic activity was determined after 1 hour (t=60 min)
incubation at room temperature. The IC50 values, corresponding to
the inhibitor concentration showing 50% reduction of the FLT values
measured in absence of inhibitor, are calculated from the plot of
percentage of inhibition vs. inhibitor concentration using
non-linear regression analysis software.
[0186] Using the test assay (as described above) compounds of the
invention exhibited inhibitory efficacy in accordance to Table 1,
provided infra.
TABLE-US-00002 TABLE 1 Inhibitory Activity of Compounds Example #
Human NEP IC.sub.50 (nM) Example 3-25 18 Example 3-26 15 Example
3-27 15 Example 5-1 38 Example 5-4 7 Example 5-7 4 Example 5-11 3
Example 5-12 67 Example 5-36 42 Example 5-37 2.3 Example 5-39 0.7
Example 5-46 0.5 Example 5-47 2.7 Example 5-55 0.7 Example 6-1 75
Example 9-1 56 Example 11-1 1.1 Example 11-11 0.5 Example 11-14
0.07 Example 12-1 0.2 Example 14-1 0.8 Example 15-1 1.2
[0187] The compound of the present invention may be administered
either simultaneously with, or before or after, at least one other
therapeutic agent. The compound of the present invention may be
administered separately, by the same or different route of
administration, or together in the same pharmaceutical
composition.
[0188] In one embodiment, the invention provides a product
comprising a compound according to anyone of formulae I' and I to
VIIC, or a pharmaceutically acceptable salt thereof, and at least
one other therapeutic agent as a combined preparation for
simultaneous, separate or sequential use in therapy. In one
embodiment, the therapy is the treatment of a disease or condition
associated with neutral endopeptidase EC 3.4. 24.11 activity.
Products provided as a combined preparation include a composition
comprising the compound of formulae I' and I to VIIC and the other
therapeutic agent(s) together in the same pharmaceutical
composition, or the compound according to anyone of formulae I' and
I to VIIC, or a pharmaceutically acceptable salt thereof, and the
other therapeutic agent(s) in separate form, e.g. in the form of a
kit.
[0189] In one embodiment, the invention provides a pharmaceutical
composition comprising a compound according to anyone of formulae
I' and I to VIIC, or a pharmaceutically acceptable salt thereof,
and another therapeutic agent(s). Optionally, the pharmaceutical
composition may comprise a pharmaceutically acceptable excipient,
as described above.
[0190] In one embodiment, the invention provides a kit comprising
two or more separate pharmaceutical compositions, at least one of
which contains a compound according to anyone of formulae I' and I
to VIIC, or a pharmaceutically acceptable salt thereof. In one
embodiment, the kit comprises means for separately retaining said
compositions, such as a container, divided bottle, or divided foil
packet. An example of such a kit is a blister pack, as typically
used for the packaging of tablets, capsules and the like.
[0191] The kit of the invention may be used for administering
different dosage forms, for example, oral and parenteral, for
administering the separate compositions at different dosage
intervals, or for titrating the separate compositions against one
another. To assist compliance, the kit of the invention typically
comprises directions for administration.
[0192] In the combination therapies of the invention, the compound
of the invention, or a pharmaceutically acceptable salt thereof and
the other therapeutic agent may be manufactured and/or formulated
by the same or different manufacturers. Moreover, the compound of
the invention, or a pharmaceutically acceptable salt thereof, and
the other therapeutic may be brought together into a combination
therapy: (i) prior to release of the combination product to
physicians (e.g. in the case of a kit comprising the compound of
the invention and the other therapeutic agent); (ii) by the
physician themselves (or under the guidance of the physician)
shortly before administration; (iii) in the patient themselves,
e.g. during sequential administration of the compound of the
invention and the other therapeutic agent.
[0193] Accordingly, the invention provides the use of a compound
according to anyone of formulae I' and I to VIIC, or a
pharmaceutically acceptable salt thereof, in the manufacture of a
medicament for treating a disease or condition associated with
neutral endopeptidase EC 3.4. 24.11. activity, wherein the
medicament is prepared for administration with another therapeutic
agent. The invention also provides the use of another therapeutic
agent in the manufacture of medicament for treating a disease or
condition associated with neutral endopeptidase EC 3.4. 24.11.
activity, wherein the medicament is prepared for administration
with a compound according to anyone of formulae I' and I to VIIC,
or a pharmaceutically acceptable salt thereof.
[0194] The invention also provides a compound according to anyone
of formulae I' and I to VIIC, or a pharmaceutically acceptable salt
thereof, for use in a method of treating a disease or condition
associated with neutral endopeptidase EC 3.4. 24.11 activity,
wherein the compound according to anyone of formulae I' and I to
VIIC, or a pharmaceutically acceptable salt thereof, is prepared
for administration with another therapeutic agent. The invention
also provides another therapeutic agent for use in a method of
treating a disease or condition associated with neutral
endopeptidase EC 3.4. 24.11 activity, wherein the other therapeutic
agent is prepared for administration with a compound according to
anyone of formulae I' and I to VIIC, or a pharmaceutically
acceptable salt thereof. The invention also provides a compound
according to anyone of formulae I' and I to VIIC, or a
pharmaceutically acceptable salt thereof, for use in a method of
treating a disease or condition associated with neutral
endopeptidase EC 3.4. 24.11 activity, wherein the compound
according to anyone of formulae I' and I to VIIC, or a
pharmaceutically acceptable salt thereof, is administered with
another therapeutic agent. The invention also provides another
therapeutic agent for use in a method of treating a disease or
condition associated with neutral endopeptidase EC 3.4. 24.11
activity, wherein the other therapeutic agent is administered with
a compound according to anyone of formulae I' and I to VIIC, or a
pharmaceutically acceptable salt thereof.
[0195] The invention also provides the use of a compound according
to anyone of formulae I' and I to VIIC, or a pharmaceutically
acceptable salt thereof, in the manufacture of a medicament for
treating a disease or condition associated with neutral
endopeptidase EC 3.4. 24.11 activity, wherein the patient has
previously (e.g. within 24 hours) been treated with another
therapeutic agent. The invention also provides the use of another
therapeutic agent in the manufacture of a medicament for treating a
disease or condition associated with neutral endopeptidase EC 3.4.
24.11 activity, wherein the patient has previously (e.g. within 24
hours) been treated with a compound according to anyone of formulae
I' and I to VIIC, or a pharmaceutically acceptable salt
thereof.
[0196] In one embodiment, the other therapeutic agent is selected
from: HMG-Co-A reductase inhibitor, an anigiotensin receptor
blocker (ARBs, angiotensin II receptor antagonist), angiotensin
converting enzyme (ACE) Inhibitor, a calcium channel blocker (CCB),
an endothelin antagonist, a renin inhibitor, a diuretic, an ApoA-I
mimic, an anti-diabetic agent, an obesity-reducing agent, an
aldosterone receptor blocker, an endothelin receptor blocker, an
aldosterone synthase inhibitors (ASI), a CETP inhibitor or a
phophodiesterase type 5 (PDE5) inhibitor.
[0197] The term "in combination with" a second agent or treatment
includes co-administration of the compound of the invention (e.g.,
a compound of Formulae I' or I-VIIC or a compound otherwise
described herein) with the second agent or treatment,
administration of the compound of the invention first, followed by
the second agent or treatment and administration of the second
agent or treatment first, followed by the compound of the
invention.
[0198] The term "second agent" includes any agent which is known in
the art to treat, prevent, or reduce the symptoms of a disease or
disorder described herein, e.g. a disorder or disease responsive to
the inhibition of neutral endopeptidase, such as for example,
hypertension, pulmonary hypertension, isolated systolic
hypertension, resistant hypertension, peripheral vascular disease,
heart failure, congestive heart failure, left ventricular
hypertrophy, angina, renal insufficiency (diabetic or
non-diabetic), renal failure (including edema and salt retension),
diabetic nephropathy, non-diabetic nephropathy, nephroic syndrome,
glomerulonephritis, scleroderma, glomerular sclerosis, proteinurea
of primary renal disease, renal vascular hypertention, diabetic
retinopathy and end-stage renal disease (ESRD), endothelial
dysfunction, diastolic dysfunction, hypertrophic cardiomyopathy,
diabetic cardiac myopathy, supraventricular and ventricular
arrhythmias, atrial fibrillation (AF), cardiac fibrosis, atrial
flutter, detrimental vascular remodeling, plaque stabilization,
myocardial infarction (MI), renal fibrosis, polycystic kidney
disease (PKD), pulmonary arterial hypertension, renal failure
(including edema and salt retension), cyclical oedema, Menieres
disease, hyperaldosteroneism (primary and secondary) and
hypercalciuria, ascites, glaucoma, menstrual disorders, preterm
labour, pre-eclampsia, endometriosis, and reproductive disorders
(especially male and female infertility, polycystic ovarian
syndrome, implantation failure), asthma, obstructive sleep apnea,
inflammation, leukemia, pain, epilepsy, affective disorders such as
depression and psychotic condition such as dementia and geriatric
confusion, obesity and gastrointestinal disorders (especially
diarrhea and irritable bowel syndrome), wound healing (especially
diabetic and venous ulcers and pressure sores), septic shock,
gastric acid secretion dysfunction, hyperreninaemia, cystic
fibrosis, restenosis, type-2 diabetes, metabolic syndrome, diabetic
complications and atherosclerosis, male and female sexual
dysfunction.
[0199] Examples of second agents include HMG-Co-A reductase
inhibitors, angiotensin II receptor antagonists, angiotensin
converting enzyme (ACE) Inhibitors, calcium channel blockers (CCB),
endothelin antagonists, renin inhibitors, diuretics, ApoA-I mimics,
anti-diabetic agents, obesity-reducing agents, aldosterone receptor
blockers, endothelin receptor blockers, aldosterone synthase
inhibitors (ASI) and CETP inhibitors.
[0200] The term "HMG-Co-A reductase inhibitor" (also called
beta-hydroxy-beta-methylglutaryl-co-enzyme-A reductase inhibitors)
includes active agents that may be used to lower the lipid levels
including cholesterol in blood. Examples include atorvastatin,
cerivastatin, compactin, dalvastatin, dihydrocompactin,
fluindostatin, fluvastatin, lovastatin, pitavastatin, mevastatin,
pravastatin, rivastatin, simvastatin, and velostatin, or,
pharmaceutically acceptable salts thereof.
[0201] The term "ACE-inhibitor" (also called angiotensin converting
enzyme inhibitors) includes molecules that interrupt the enzymatic
degradation of angiotensin I to angiotensin II. Such compounds may
be used for the regulation of blood pressure and for the treatment
of congestive heart failure. Examples include alacepril,
benazepril, benazeprilat, captopril, ceronapril, cilazapril,
delapril, enalapril, enaprilat, fosinopril, imidapril, lisinopril,
moveltopril, perindopril, quinapril, ramipril, spirapril,
temocapril, and trandolapril, or, pharmaceutically acceptables salt
thereof.
[0202] The term "endothelin antagonist" includes bosentan (cf. EP
526708 A), tezosentan (cf. WO 96/19459), or, pharmaceutically
acceptable salts thereof.
[0203] The term "renin inhibitor" includes ditekiren (chemical
name:
[1S-[1R*,2R*,4R*(1R*,2R*)]]-1-[(1,1-dimethylethoxy)carbonyl]-L-proly
1-L-phenylalanyl-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-
-[[(2-pyridinylmrthyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-N-alfa-me-
thyl-L-histidinamide); terlakiren (chemical name:
[R--(R*,S*)]-N-(4-morpholinylcarbonyl)-L-phenylalanyl-N-[1-(cyclohexylmet-
hyl)-2-hydroxy-3-(1-methylethoxy)-3-oxopropyl]-S-methyl-L-cysteineamide);
Aliskiren (chemical name:
(2S,4S,5S,7S)-5-amino-N-(2-carbamoyl-2,2-dimethylethyl)-4-hydroxy-7-{[4-m-
ethoxy-3-(3-methoxypropoxy)phenyl]methyl}-8-methyl-2-(propan-2-yl)nonanami-
de) and zankiren (chemical name:
[1S-[1R*[R*(R*)],2S*,3R*]]-N-[1-(cyclohexylmethyl)-2,3-dihydroxy-5-methyl
hexyl]-alfa-[[2-[[(4-methyl-1-piperazinyl)sulfonyl]methyl]-1-oxo-3-phenyl-
propyl]-amino]-4-thiazolepropanamide), or, hydrochloride salts
thereof, or, SPP630, SPP635 and SPP800 as developed by Speedel, or
RO 66-1132 and RO 66-1168 of Formula (A) and (B):
##STR00046##
pharmaceutically acceptable salts thereof.
[0204] The term "aliskiren", if not defined specifically, is to be
understood both as the free base and as a salt thereof, especially
a pharmaceutically acceptable salt thereof, most preferably a
hemi-fumarate salt thereof.
[0205] An angiotensin II receptor antagonist or a pharmaceutically
acceptable salt thereof is understood to be an active ingredient
which bind to the AT.sub.1-receptor subtype of angiotensin II
receptor but do not result in activation of the receptor. As a
consequence of the inhibition of the AT.sub.1 receptor, these
antagonists can, for example, be employed as antihypertensives or
for treating congestive heart failure.
[0206] The class of AT.sub.1 receptor antagonists comprises
compounds having differing structural features, essentially
preferred are the non-peptidic ones. For example, mention may be
made of the compounds which are selected from the group consisting
of valsartan, losartan, candesartan, eprosartan, irbesartan,
saprisartan, tasosartan, telmisartan, the compound with the
designation E-1477 of the following formula
##STR00047##
the compound with the designation SC-52458 of the following
formula
##STR00048##
and the compound with the designation ZD-8731 of the following
formula
##STR00049##
or, in each case, a pharmaceutically acceptable salt thereof.
Preferred AT.sub.1-receptor antagonist are those agents which have
been marketed, most preferred is valsartan or a pharmaceutically
acceptable salt thereof.
[0207] The term "calcium channel blocker (CCB)" includes
dihydropyridines (DHPs) and non-DHPs (e.g., diltiazem-type and
verapamil-type CCBs). Examples include amlodipine, felodipine,
ryosidine, isradipine, lacidipine, nicardipine, nifedipine,
niguldipine, niludipine, nimodipine, nisoldipine, nitrendipine, and
nivaldipine, and is preferably a non-DHP representative selected
from the group consisting of flunarizine, prenylamine, diltiazem,
fendiline, gallopamil, mibefradil, anipamil, tiapamil and
verapamil, or, pharmaceutically acceptable salts thereof. CCBs may
be used as anti-hypertensive, anti-angina pectoris, or
anti-arrhythmic drugs.
[0208] The term "diuretic" includes thiazide derivatives (e.g.,
chlorothiazide, hydrochlorothiazide, methylclothiazide, and
chlorothalidon).
[0209] The term "ApoA-I mimic" includes D4F peptides (e.g., formula
D-W-F-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F)
[0210] The term "anti-diabetic agent" includes insulin secretion
enhancers that promote the secretion of insulin from pancreatic
.beta.-cells. Examples include biguanide derivatives (e.g.,
metformin), sulfonylureas (SU) (e.g., tolbutamide, chlorpropamide,
tolazamide, acetohexamide,
4-chloro-N-[(1-pyrrolidinylamino)carbonyl]-benzensulfonamide
(glycopyramide), glibenclamide (glyburide), gliclazide,
1-butyl-3-metanilylurea, carbutamide, glibonuride, glipizide,
gliquidone, glisoxepid, glybuthiazole, glibuzole, glyhexamide,
glymidine, glypinamide, phenbutamide, and tolylcyclamide), or
pharmaceutically acceptable salts thereof. Further examples include
phenylalanine derivatives (e.g.,
nateglinide[N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine](cf.
EP 196222 and EP 526171) of the formula
##STR00050##
repaglinide[(S)-2-ethoxy-4-{2-[[3-methyl-1-[2-(1-piperidinyl)phenyl]butyl-
]amino]-2-oxoethyl}benzoic acid](cf. EP 589874, EP 147850 A2, in
particular Example 11 on page 61, and EP 207331 A1); calcium
(2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinlycarbonyl)-propionate
dihydrate (e.g., mitiglinide (cf. EP 507534)); and glimepiride (cf.
EP 31058). Further examples include DPP-IV inhibitors, GLP-1 and
GLP-1 agonists.
[0211] DPP-IV is responsible for inactivating GLP-1. More
particularly, DPP-IV generates a GLP-1 receptor antagonist and
thereby shortens the physiological response to GLP-1. GLP-1 is a
major stimulator of pancreatic insulin secretion and has direct
beneficial effects on glucose disposal.
[0212] The DPP-IV inhibitor can be peptidic or, preferably,
non-peptidic. DPP-IV inhibitors are in each case generically and
specifically disclosed e.g. in WO 98/19998, DE 196 16 486 A1, WO
00/34241 and WO 95/15309, in each case in particular in the
compound claims and the final products of the working examples, the
subject-matter of the final products, the pharmaceutical
preparations and the claims are hereby incorporated into the
present application by reference to these publications. Preferred
are those compounds that are specifically disclosed in Example 3 of
WO 98/19998 and Example 1 of WO 00/34241, respectively.
[0213] GLP-1 is an insulinotropic protein which is described, e.g.,
by W. E. Schmidt et al. in Diabetologia, 28, 1985, 704-707 and in
U.S. Pat. No. 5,705,483.
[0214] The term "GLP-1 agonists" includes variants and analogs of
GLP-1 (7-36)NH.sub.2 which are disclosed in particular in U.S. Pat.
No. 5,120,712, U.S. Pat. No. 5,118,666, U.S. Pat. No. 5,512,549, WO
91/11457 and by C. Orskov et al in J. Biol. Chem. 264 (1989) 12826.
Further examples include GLP-1(7-37), in which compound the
carboxy-terminal amide functionality of Arg.sup.36 is displaced
with Gly at the 37.sup.th position of the GLP-1(7-36)NH.sub.2
molecule and variants and analogs thereof including
GLN.sup.9-GLP-1(7-37), D-GLN.sup.9-GLP-1 (7-37), acetyl
LYS.sup.9-GLP-1(7-37), LYS.sup.18-GLP-1(7-37) and, in particular,
GLP-1(7-37)OH, VAL.sup.8-GLP-1(7-37), GLY.sup.8-GLP-1(7-37),
THR.sup.8-GLP-1(7-37), MET.sup.8-GLP-1(7-37) and
4-imidazopropionyl-GLP-1. Special preference is also given to the
GLP agonist analog exendin-4, described by Greig et al in
Diabetologia 1999, 42, 45-50.
[0215] Also included in the definition "anti-diabetic agent" are
insulin sensitivity enhancers which restore impaired insulin
receptor function to reduce insulin resistance and consequently
enhance the insulin sensitivity. Examples include hypoglycemic
thiazolidinedione derivatives (e.g., glitazone,
(S)-((3,4-dihydro-2-(phenyl-methyl)-2H-1-benzopyran-6-yl)methyl-thiazolid-
ine-2,4-dione (englitazone),
5-{[4-(3-(5-methyl-2-phenyl-4-oxazolyl)-1-oxopropyl)-phenyl]-methyl}-thia-
zolidine-2,4-dione (darglitazone),
5-{[4-(1-methyl-cyclohexyl)methoxy)-phenyl]methyl}-thiazolidine-2,4-dione
(ciglitazone),
5-{[4-(2-(1-indolyl)ethoxy)phenyl]methyl}-thiazolidine-2,4-dione
(DRF2189),
5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-ethoxy)]benzyl}-thiazolidine-2,4-d-
ione (BM-13.1246), 5-(2-naphthylsulfonyl)-thiazolidine-2,4-dione
(AY-31637), bis{4-[(2,4-dioxo-5-thiazolidinyl)methyl]phenyl}methane
(YM268),
5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-hydroxyethoxy]benzyl}-t-
hiazolidine-2,4-dione (AD-5075),
5-[4-(1-phenyl-1-cyclopropanecarbonylamino)-benzyl]-thiazolidine-2,4-dion-
e (DN-108)
5-{[4-(2-(2,3-dihydroindol-1-yl)ethoxy)phenyl]methyl}-thiazolid-
ine-2,4-dione,
5-[3-(4-chloro-phenyl])-2-propynyl]-5-phenylsulfonyl)thiazolidine-2,4-dio-
ne,
5-[3-(4-chlorophenyl])-2-propynyl]-5-(4-fluorophenyl-sulfonyl)thiazoli-
dine-2,4-dione,
5-{[4-(2-(methyl-2-pyridinyl-amino)-ethoxy)phenyl]methyl}-thiazolidine-2,-
4-dione (rosiglitazone),
5-{[4-(2-(5-ethyl-2-pyridyl)ethoxy)phenyl]-methyl}thiazolidine-2,4-dione
(pioglitazone),
5-{[4-((3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)me-
thoxy)-phenyl]-methyl}-thiazolidine-2,4-dione (troglitazone),
5-[6-(2-fluoro-benzyloxy)naphthalen-2-ylmethyl]-thiazolidine-2,4-dione
(MCC555),
5-{[2-(2-naphthyl)-benzoxazol-5-yl]-methyl}thiazolidine-2,4-dio- ne
(T-174) and
5-(2,4-dioxothiazolidin-5-ylmethyl)-2-methoxy-N-(4-trifluoromethyl-benzyl-
)benzamide (KRP297)).
[0216] Further anti-diabetic agents include, insulin signalling
pathway modulators, like inhibitors of protein tyrosine
phosphatases (PTPases), antidiabetic non-small molecule mimetic
compounds and inhibitors of glutamine-fructose-6-phosphate
amidotransferase (GFAT); compounds influencing a dysregulated
hepatic glucose production, like inhibitors of
glucose-6-phosphatase (G6Pase), inhibitors of
fructose-1,6-bisphosphatase (F-1,6-Bpase), inhibitors of glycogen
phosphorylase (GP), glucagon receptor antagonists and inhibitors of
phosphoenolpyruvate carboxykinase (PEPCK); pyruvate dehydrogenase
kinase (PDHK) inhibitors; inhibitors of gastric emptying; insulin;
inhibitors of GSK-3; retinoid X receptor (RXR) agonists; agonists
of Beta-3 AR; agonists of uncoupling proteins (UCPs); non-glitazone
type PPAR.gamma. agonists; dual PPAR.alpha./PPAR.gamma. agonists;
antidiabetic vanadium containing compounds; incretin hormones, like
glucagon-like peptide-1 (GLP-1) and GLP-1 agonists; beta-cell
imidazoline receptor antagonists; miglitol;
.alpha..sub.2-adrenergic antagonists; and pharmaceutically
acceptable salts thereof.
[0217] The term "obesity-reducing agent" includes lipase inhibitors
(e.g., orlistat) and appetite suppressants (e.g., sibutramine and
phentermine).
[0218] An aldosterone synthase inhibitor or a pharmaceutically
acceptable salt thereof is understood to be an active ingredient
that has the property to inhibit the production of aldosterone.
Aldosterone synthase (CYP11B2) is a mitochondrial cytochrome P450
enzyme catalyzing the last step of aldosterone production in the
adrenal cortex, i.e., the conversion of 11-deoxycorticosterone to
aldosterone. The inhibition of the aldosterone production with
so-called aldosterone synthase inhibitors is known to be a
successful variant to treatment of hypokalemia, hypertension,
congestive heart failure, atrial fibrillation or renal failure.
Such aldosterone synthase inhibition activity is readily determined
by those skilled in the art according to standard assays (e.g., US
2007/0049616).
[0219] The class of aldosterone synthase inhibitors comprises both
steroidal and non-steroidal aldosterone synthase inhibitors, the
later being most preferred.
[0220] Preference is given to commercially available aldosterone
synthase inhibitors or those aldosterone synthase inhibitors that
have been approved by the health authorities.
[0221] The class of aldosterone synthase inhibitors comprises
compounds having differing structural features. For example,
mention may be made of the compounds which are selected from the
group consisting of the non-steroidal aromatase inhibitors
anastrozole, fadrozole (including the (+)-enantiomer thereof), as
well as the steroidal aromatase inhibitor exemestane, or, in each
case where applicable, a pharmaceutically acceptable salt
thereof.
[0222] The most preferred non-steroidal aldosterone synthase
inhibitor is the (+)-enantiomer of the hydrochloride of fadrozole
(U.S. Pat. Nos. 4,617,307 and 4,889,861) of formula
##STR00051##
or, if appropriable, a pharmaceutically acceptable salt
thereof.
[0223] A preferred steroidal aldosterone antagonist is eplerenone
(cf. EP 122232 A) of the formula
##STR00052##
or Spironolactone; or, in each case, if appropriable, a
pharmaceutically acceptable salt thereof.
[0224] Aldosterone synthase inhibitors useful in said combination
are compounds and analogs generically and specifically disclosed
e.g. in US2007/0049616, in particular in the compound claims and
the final products of the working examples, the subject-matter of
the final products, the pharmaceutical preparations and the claims
are hereby incorporated into the present application by reference
to this publication. Preferred aldosterone synthase inhibitors
suitable for use in the present invention include, without
limitation
4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-methylbenzonitrile;
5-(2-chloro-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carbo-
xylic acid (4-methoxybenzyl)methylamide;
4'-fluoro-6-(6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepin-5-yl)biphenyl-3-c-
arbonitrile;
5-(4-Cyano-2-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carb-
oxylic acid butyl ester;
4-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-2-methoxybenzonitrile;
5-(2-Chloro-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carbo-
xylic acid 4-fluorobenzyl ester;
5-(4-Cyano-2-trifluoromethoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazo-
le-5-carboxylic acid methyl ester;
5-(4-Cyano-2-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carb-
oxylic acid 2-isopropoxyethyl ester;
4-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-2-methylbenzonitrile;
4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-fluorobenzonitrile;
4-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-2-methoxybenzonitrile;
3-Fluoro-4-(7-methylene-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzon-
itrile;
cis-3-Fluoro-4-[7-(4-fluoro-benzyl)-5,6,7,8-tetrahydro-imidazo[1,5-
-a]pyridin-5-yl]benzonitrile;
4'-Fluoro-6-(9-methyl-6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepin-5-yl)bip-
henyl-3-carbonitrile;
4'-Fluoro-6-(9-methyl-6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepin-5-yl)bip-
henyl-3-carbonitrile or in each case, the (R) or (S) enantiomer
thereof; or if appropriable, a pharmaceutically acceptable salt
thereof.
[0225] The term aldosterone synthase inhibitors also include
compounds and analogs disclosed in WO2008/076860, WO2008/076336,
WO2008/076862, WO2008/027284, WO2004/046145, WO2004/014914,
WO2001/076574.
[0226] Furthermore Aldosterone synthase inhibitors also include
compounds and analogs disclosed in U.S. patent applications
US2007/0225232, US2007/0208035, US2008/0318978, US2008/0076794,
US2009/0012068, US20090048241 and in PCT applications
WO2006/005726, WO2006/128853, WO2006128851, WO2006/128852,
WO2007065942, WO2007/116099, WO2007/116908, WO2008/119744 and in
European patent application EP 1886695. Preferred aldosterone
synthase inhibitors suitable for use in the present invention
include, without limitation
8-(4-Fluorophenyl)-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazine;
4-(5,6-Dihydro-8H-imidazo[5,1-c][1,4]oxazin-8-yl)-2-fluorobenzonitrile;
4-(5,6-Dihydro-8H-imidazo[5,1-c][1,4]oxazin-8-yl)-2,6-difluorobenzonitril-
e;
4-(5,6-Dihydro-8H-imidazo[5,1-c][1,4]oxazin-8-yl)-2-methoxybenzonitrile-
; 3-(5,6-Dihydro-8H-imidazo[5,1-c][1,4]oxazin-8-yl)benzonitrile;
4-(5,6-Dihydro-8H-imidazo[5,1-c][1,4]oxazin-8-yl)phthalonitrile;
4-(8-(4-Cyanophenyl)-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-8-yl)benzon-
itrile;
4-(5,6-Dihydro-8H-imidazo[5,1-c][1,4]oxazin-8-yl)benzonitrile;
4-(5,6-Dihydro-8H-imidazo[5,1-c][1,4]oxazin-8-yl)naphthalene-1-carbonitri-
le;
8-[4-(1H-Tetrazol-5-yl)phenyl]-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazi-
ne as developed by Speedel or in each case, the (R) or (S)
enantiomer thereof; or if appropriable, a pharmaceutically
acceptable salt thereof.
[0227] The term "endothelin receptor blocker" includes
bosentan.
[0228] The term "CETP inhibitor" refers to a compound that inhibits
the cholesteryl ester transfer protein (CETP) mediated transport of
various cholesteryl esters and triglycerides from HDL to LDL and
VLDL. Such CETP inhibition activity is readily determined by those
skilled in the art according to standard assays (e.g., U.S. Pat.
No. 6,140,343). Examples include compounds disclosed in U.S. Pat.
No. 6,140,343 and U.S. Pat. No. 6,197,786 (e.g.,
[2R,4S]-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethy-
l-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid
ethyl ester (torcetrapib); compounds disclosed in U.S. Pat. No.
6,723,752 (e.g.,
(2R)-3-{[3-(4-Chloro-3-ethyl-phenoxy)-phenyl]-[[3-(1,1,2,2-tetrafluoro-et-
hoxy)-phenyl]-methyl]-amino}-1,1,1-trifluoro-2-propanol); compounds
disclosed in U.S. patent application Ser. No. 10/807,838;
polypeptide derivatives disclosed in U.S. Pat. No. 5,512,548;
rosenonolactone derivatives and phosphate-containing analogs of
cholesteryl ester disclosed in J. Antibiot., 49(8): 815-816 (1996),
and Bioorg. Med. Chem. Lett.; 6:1951-1954 (1996), respectively.
Furthermore, the CETP inhibitors also include those disclosed in
WO2000/017165, WO2005/095409 and WO2005/097806.
[0229] A preferred PDE5 inhibitor is Sildenafil.
[0230] Second agent of particular interest include Endothelin
antagonists, renin inhibitors, angiotensin II receptor antagonists,
calcium channel blockers, diuretics, antidiabetic agents such as
DPPIV inhibitors, and aldosterone synthase inhibitors.
EXEMPLIFICATION OF THE INVENTION
[0231] All starting materials, building blocks, reagents, acids,
bases, dehydrating agents, solvents, and catalysts utilized to
synthesis 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 4th
Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21).
Further, the compounds of the present invention can be produced by
organic synthesis methods known to one of ordinary skill in the art
as shown in the following examples.
[0232] The following examples are intended to illustrate the
invention and are not to be construed as being limitations thereon.
Temperatures are given in degrees centigrade. If not mentioned
otherwise, all evaporations are performed under reduced pressure,
preferably between about 15 mm Hg and 100 mm Hg (=20-133 mbar). The
structure of final products, intermediates and starting materials
is confirmed by standard analytical methods, e.g., microanalysis
and spectroscopic characteristics, e.g., MS, IR, NMR. Abbreviations
used are those conventional in the art. The compounds in the
example 5-1 to 15-3 have been found to have IC.sub.50 values in the
range of about 0.01 nM to about 10,000 nM for NEP.
[0233] The conditions for measuring the retention times are as
follows:
[0234] HPLC condition A:
[0235] Column: INERTSIL C8-3, 3 .mu.m.times.33 mm.times.3.0 mm at
40.degree. C.
[0236] Flow rate: 2 ml/min
[0237] Mobile phase: A) 5 mM aqueous HCOONH4, B) MeOH/CH3CN (1/1,
v/v)
[0238] Gradient: linear gradient from 5% A to 95% B in 2 min
[0239] Detection: DAD-UV at 200-400 nm
[0240] HPLC condition B:
[0241] Column: INERTSIL C8-3, 3 .mu.m.times.33 mm.times.3.0 mm at
40.degree. C.
[0242] Flow rate: 2 ml/min
[0243] Mobile phase: A) 5 mM aqueous HCOONH4, B) MeOH/CH3CN (1/1,
v/v)
[0244] Gradient: linear gradient from 40% A to 95% B in 2 min
[0245] Detection: DAD-UV at 200-400 nm
[0246] HPLC condition C:
[0247] Column: INERTSIL C8-3, 3 .mu.m.times.33 mm.times.3.0 mm at
40.degree. C.
[0248] Flow rate: 2 ml/min
[0249] Mobile phase: A) (5 mM NH.sub.4.sup.+HCOO.sup.-)/water, B)
MeOH/CH.sub.3CN (1/1, v/v)
[0250] Gradient: linear gradient from 5 to 95% B in 2 min
[0251] Detection: DAD-UV at 200-400 nm
[0252] HPLC condition D:
[0253] Column: INERTSIL C8-3, 3 .mu.m.times.33 mm.times.3.0 mm at
40.degree. C.
[0254] Flow rate: 2 ml/min
[0255] Mobile phase: A) 0.1% aqueous Formic acid, B)
MeOH/CH.sub.3CN (1/1, v/v)
[0256] Gradient: linear gradient from 5% B to 95% B in 2 min
[0257] Detection: DAD-UV at 200-400 nm
[0258] HPLC condition E:
[0259] Column: Inertsil C8-3, 3 .mu.m.times.33 mm.times.3.0 mm at
40.degree. C.
[0260] Flow rate: 2 ml/min
[0261] Mobile phase: A) methanol/acetonitrile (1/1, v/v), B) 5 mM
aquesous HCOONH.sub.4
[0262] Gradient: linear gradient from 40% B to 95% A in 2 min
[0263] Detection: UV at 214 nm
[0264] The relative stereochemistry was determined using two
dimensional NMR. Under the reaction condition, it would be
unexpected that the stereocenter bearing the bisphenyl-methyl group
racemize. Therefore, the absolute stereochemistry was determined
based on the relative stereochemistry and the absolute
stereochemistry of the stereocenter bearing the bisphenyl-methyl
group.
Example 1-1
Synthesis of
(R)-4-(1-(biphenyl-4-yl)-4-ethoxy-4-oxobutan-2-ylamino)-4-oxobutanoic
acid
##STR00053##
[0266] To
(R)-ethyl-4-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)butanoat- e
(230.1 mg, 0.600 mmol) is added a solution of HCl in 1,4-dioxane
(3.00 mL, 12.00 mmol) at room temperature. After stirring for 1
hour, the reaction mixture is concentrated under reduced pressure
to give (R)-3-amino-4-biphenyl-4-yl-butyric acid ethyl ester
hydrochloride. A solution of (R)-3-amino-4-biphenyl-4-yl-butyric
acid ethyl ester hydrochloride, succinic anhydride (72.1 mg, 0.720
mmol) and DIPEA (0.126 mL, 0.720 mmol) in dichloromethane (4 mL) is
allowed to stir for 1 hour. The reaction is quenched with 10%
aqueous citric acid and extracted with dichloromethane. The organic
layer is separated and concentrated under reduced pressure. The
obtained residue is purified by flash column chromatography on
CN-modified silica gel (eluent: heptane/EtOAc=100:0 to 0:100) and
by RP-HPLC (SunFire C18, H.sub.2O (0.1% TFA)/CH.sub.3CN) to give
(R)-4-(1-(biphenyl-4-yl)-4-ethoxy-4-oxobutan-2-ylamino)-4-oxobutanoi-
c acid (148.2 mg). HPLC retention time=1.64 minutes (condition A);
MS (m+1)=384.1; 1H NMR (400 MHz, ACETONITRILE-d3) .delta. ppm 1.21
(t, J=7.07 Hz, 3H) 2.31-2.39 (m, 2H) 2.40-2.56 (m, 4H) 2.77-2.92
(m, 2H) 4.08 (q, J=7.24 Hz, 2H) 4.33-4.48 (m, 1H) 6.62 (d, J=8.34
Hz, 1H) 7.30 (d, J=8.08 Hz, 2H) 7.32-7.39 (m, 1H) 7.41-7.49 (m, 2H)
7.54-7.60 (m, 2H) 7.60-7.67 (m, 2H) 10.02 (br. s., 1H).
Example 1-2
Synthesis of
(R)-4-(1-(3'-chlorobiphenyl-4-yl)-4-ethoxy-4-oxobutan-2-ylamino)-4-oxobut-
anoic acid
##STR00054##
[0268] A solution of (R)-ethyl
3-amino-4-(3'-chlorobiphenyl-4-yl)butanoate hydrochloride (400 mg,
1.13 mmol), succinic anhydride (136 mg, 1.36 mmol) and DIPEA (0.237
mL, 1.36 mmol) in dichloromethane (5 mL) is allowed to stir for 2.5
hours. The reaction is quenched with 1 M aqueous HCl and extracted
with dichloromethane. The organic layer is separated and
concentrated under reduced pressure. The resulting residue is
purified by preparative HPLC using a gradient of 20% MeCN/water
(0.1% TFA) to 100% MeCN to give
(R)-4-(1-(3'-chlorobiphenyl-4-yl)-4-ethoxy-4-oxobutan-2-ylamino)-4-oxobut-
anoic acid (255 mg). HPLC retention time=1.15 minutes (condition
B); MS (m+1)=418.0; 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.29
(t, J=7.08 Hz, 3H) 2.46-2.58 (m, 4H) 2.64-2.67 (m, 2H) 2.87 (A of
ABX, J.sub.ab=13.6 Hz, J.sub.ax=7.8 Hz, 1H) 2.99 (B of ABX,
J.sub.ab=13.6 Hz, J.sub.bx=6.6 Hz, 1H) 4.12-4.24 (m, 2H) 4.47-4.55
(m, 1H) 6.50 (br d, J=8.8 Hz, 1H) 7.24-7.37 (m, 4H) 7.43-7.46 (m,
1H) 7.48-7.52 (m, 2H) 7.55-7.56 (m, 1H).
[0269] Chiral HPLC retention time=3.59 min. Column: Daicel
CHIRALPAK AD-H (4.6.times.100 mm); flow rate=1 ml/min.; eluent:
EtOH (containing 0.1% TFA)/heptane=4/6.
[0270] Following compounds are prepared using similar procedure as
described in example 1-2:
TABLE-US-00003 HPLC-RT MS Example # Product Starting Material
Condition (condition) (M + 1) Example 1-3 ##STR00055##
(R)-5-(1-(3'-chlorobiphenyl-4-yl)-4-ethoxy-4-oxobutan-
2-ylamino)-5-oxopentanoic acid ##STR00056## ##STR00057## DIPEA,
DCM, RT 1.57 min. (A) 432.1 Example 1-4 ##STR00058##
(R)-5-(4-ethoxy-1-(5'-fluoro-2'-methoxybiphenyl-4-yl)-4-
oxobutan-2-ylamino)-5-oxopentanoic acid ##STR00059## ##STR00060##
DIPEA, DCM, RT 0.93 min. (B) 446.3 Example 1-5 ##STR00061##
(R)-5-(1-(5'-chloro-2'-methoxybiphenyl-4-yl)-4-ethoxy-4-
oxobutan-2-ylamino)-5-oxopentanoic acid ##STR00062## ##STR00063##
DIPEA, DCM, RT 1.14 min. (B) 462.5 Example 1-6 ##STR00064##
(R)-4-(1-(2'-chloro-5'-fluorobiphenyl-4-yl)-4-ethoxy-4-
oxobutan-2-ylamino)-4-oxobutanoic acid ##STR00065## ##STR00066##
DIPEA, DCM, RT 0.97 min. (B) 436.2 Example 1-7 ##STR00067##
(R)-4-(4-ethoxy-1-(3'-fluorobiphenyl-4-yl)-4-oxobutan-
2-ylamino)-4-oxobutanoic acid ##STR00068## ##STR00069## DIPEA, DCM,
RT 1.23 min. (B) 402.0 Example 1-8 ##STR00070##
(R)-4-(4-(benzyloxy)-1-(3'-chlorobiphenyl-4-yl)-4-oxobutan-2-
ylamino)-4-oxobutanoic acid ##STR00071## ##STR00072## DIPEA, DCM,
RT 1.37 min. (B) 480.2 Example 1-9 ##STR00073## ##STR00074##
##STR00075## Pyridine, RT 1.32 min. (C) 490.2 Example 1-10
##STR00076## ##STR00077## ##STR00078## DIPEA, DCM, RT 1.52 min. (B)
506.4
Example 1-3
[0271] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.29 (t, J=7.2
Hz, 3H) 1.86-1.97 (m, 2H) 2.25-2.28 (m, 2H) 2.34 (t, J=7.0 Hz, 2H)
2.50 (A of ABX, J.sub.ab=16.2 Hz, Jax=5.6 Hz, 1H) 2.56 (B of ABX,
J.sub.ab=16.2 Hz, J.sub.bx=5.1 Hz, 1H) 2.88 (A of ABX,
J.sub.ab=13.6 Hz, J.sub.ax=7.8 Hz, 1H) 2.98 (B of ABX,
J.sub.ab=13.6 Hz, J.sub.bx=7.1 Hz, 1H) 4.12-4.23 (m, 2H) 4.50-4.58
(m, 1H) 6.32 (br d, J=8.8 Hz, 1H) 7.25-7.37 (m, 4H) 7.43-7.46 (m,
1H) 7.49-7.52 (m, 2H) 7.55-7.56 (m, 1H).
Example 1-4
[0272] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.29 (t, J=7.1
Hz, 3H) 1.86-1.97 (m, 2H) 2.25-2.28 (m, 2H) 2.34 (t, J=7.0 Hz, 2H)
2.54 (A of ABX, J.sub.ab=16.1 Hz, J.sub.ax=5.6 Hz, 1H) 2.58 (B of
ABX, J.sub.ab=16.1 Hz, J.sub.bx=5.2 Hz, 1H) 2.88 (A of ABX,
J.sub.ab=13.5 Hz, J.sub.ax=7.6 Hz, 1H) 2.97 (B of ABX,
J.sub.ab=13.5 Hz, J.sub.bx=7.0 Hz, 1H) 3.78 (s, 3H) 4.12-4.23 (m,
2H) 4.50-4.59 (m, 1H) 6.34 (br d, J=8.6 Hz, 1H) 6.88-6.91 (m, 1H)
6.96-7.04 (m, 2H) 7.23 (d, J=8.3 Hz, 2H) 7.44-7.47 (m, 2H).
Example 1-5
[0273] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.29 (t, J=7.1
Hz, 3H) 1.86-1.97 (m, 2H) 2.25-2.36 (m, 4H) 2.49-2.61 (m, 2H) 2.88
(A of ABX, J.sub.ab=13.6 Hz, J.sub.ax=7.6 Hz, 1H) 2.97 (B of ABX,
J.sub.ab=13.6 Hz, J.sub.bx=6.8 Hz, 1H) 3.79 (s, 3H) 4.12-4.23 (m,
2H) 4.50-4.59 (m, 1H) 6.34-6.36 (m, 1H) 6.89 (d, J=8.6 Hz, 1H)
7.21-7.28 (m, 3H) 7.43 (d, J=8.1 Hz, 2H).
Example 1-6
[0274] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.29 (t, J=7.1
Hz, 3H) 2.47-2.67 (m, 6H) 2.89 (A of ABX, J.sub.ab=13.7 Hz,
J.sub.ax=7.8 Hz, 1H) 3.00 (B of ABX, J.sub.ab=13.7 Hz, J.sub.bx=6.7
Hz, 1H) 4.12-4.24 (m, 2H) 4.49-4.57 (m, 1H) 6.51 (br d, J=8.6 Hz,
1H) 6.97-7.07 (m, 2H) 7.24-7.26 (m, 2H) 7.36-7.43 (m, 3H).
Example 1-7
[0275] 1H NMR (400 MHz, DMSO-d6) .delta. ppm 1.16 (t, J=7.1 Hz, 3H)
2.23-2.27 (m, 2H) 2.34-2.38 (m, 2H) 2.40-2.47 (m, 2H) 2.77 (d,
J=6.6 Hz, 2H) 3.99-4.06 (m, 2H) 4.21-4.30 (m, 1H) 7.14-7.19 (m, 1H)
7.29 (d, J=8.4 Hz, 2H) 7.46-7.52 (m, 3H) 7.63 (d, J=8.4 Hz, 2H)
7.91 (d, J=8.3 Hz, 1H) 12.04 (s, 1H).
Example 1-8
[0276] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 2.41-2.45 (m, 2H)
2.50-2.64 (m, 4H) 2.81-2.87 (m, 1H) 2.95-3.00 (m, 1H) 4.49-4.56 (m,
1H) 5.12 (A of AB, J=12.1 Hz, 1H) 5.18 (B of AB, J=12.1 Hz, 1H)
6.39 (d, J=8.1 Hz, 1H) 7.18-7.54 (m, 13H).
Example 1-9
[0277] 1H NMR (400 MHz, DMSO-d6): 1H NMR (400 MHz, DMSO-d6):
.delta. ppm 1.22-1.25 (t, J=7.07 Hz, 3H), 2.61-2.63 (m, 2H), 2.91
(d, J=7.07 Hz, 2H), 4.09 (q, J=7.07 Hz, 2H), 4.52-4.59 (m, 1H),
7.32-7.34 (m, 3H), 7.04 (t, J=7.83 Hz, 1H), 7.52-7.56 (m, 3H), 7.59
(t, J=2.02 Hz, 1H).
Example 1-10
[0278] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 2.03-2.13 (m,
2H), 2.44 (t, J=6.3 Hz, 2H), 2.64 (t, J=6.6 Hz, 2H), 2.70 (dd,
J=16.2, 5.6 Hz, 1H), 2.78 (dd, J=16.2, 5.1 Hz, 1H), 2.83-2.98 (m,
5H), 3.04 (dd, J=13.9, 6.8 Hz, 1H), 4.57-4.69 (m, 1H), 6.51 (d,
J=8.8 Hz, 1H), 6.79 (dd, J=8.1, 2.3 Hz, 1H), 6.90 (d, J=1.8 Hz,
1H), 7.18 (d, J=8.1 Hz, 1H), 7.26-7.31 (m, 3H), 7.34 (t, J=7.7 Hz,
1H), 7.43 (dt, J=7.3, 1.5 Hz, 1H), 7.49 (d, J=8.1 Hz, 2H), 7.54 (t,
J=1.8 Hz, 1H), 9.34 (br. s., 1H).
Example 1-11
Synthesis of
(R)-4-(1-(2',5'-dichlorobiphenyl-4-yl)-4-ethoxy-4-oxobutan-2-ylamino)-4-o-
xobutanoic acid
##STR00079##
[0280] To (R)-ethyl
3-(tert-butoxycarbonylamino)-4-(2',5'-dichlorobiphenyl-4-yl)butanoate
(1.09 g, 2.33 mmol) is added a solution of 4 M HCl in 1,4-dioxane
(5.81 mL, 23.3 mmol) at room temperature. After stirring for 2
hours, the reaction mixture is concentrated under reduced pressure
to give (R)-ethyl 3-amino-4-(2',5'-dichlorobiphenyl-4-yl)butanoate
hydrochloride. Next, a solution of the product, succinic anhydride
(280 mg, 2.80 mmol) and DIPEA (0.489 mL, 2.80 mmol) in
dichloromethane (15 mL) is allowed to stir for 2 hours. The
reaction is quenched with 1 M aqueous HCl and extracted with
dichloromethane. The organic layer is separated and concentrated
under reduced pressure. The resulting residue is purified by
preparative HPLC using a gradient of 20% MeCN/water (0.1% TFA) to
100% MeCN to give
(R)-4-(1-(2',5'-dichlorobiphenyl-4-yl)-4-ethoxy-4-oxobutan-2-ylamino)-4-o-
xobutanoic acid (553 mg) as a white solid; HPLC retention time=1.02
minutes (condition B); MS (m+1)=452.14; 1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 1.29 (t, J=7.2 Hz, 3H) 2.47-2.67 (m, 6H)
2.89 (A of ABX, J.sub.ab=13.7 Hz, J.sub.ax=7.8 Hz, 1H) 3.00 (B of
ABX, J.sub.ab=13.7 Hz, J.sub.bx=6.7 Hz, 1H) 4.12-4.24 (m, 2H)
4.49-4.57 (m, 1H) 6.53 (br d, J=8.8 Hz, 1H) 7.23-7.26 (m, 3H)
7.32-7.40 (m, 4H).
[0281] Following compounds are prepared using similar procedure as
described in example 1-11:
TABLE-US-00004 HPLC-RT MS Example Product Srating Material
(condition) (M + 1) Example 1-12 ##STR00080##
(R)-3-(3-Carboxy-propionylamino)-4-(3'-chloro-
biphenyl-4-yl)-butyric acid propyl ester ##STR00081## 1.24 min. (B)
432.3 Example 1-13 ##STR00082##
(R)-3-(3-Carboxy-propionylamino)-4-(3'-chloro-
biphenyl-4-yl)-butyric acid butyl ester ##STR00083## 1.34 min. (B)
446.2 Example 1-14 ##STR00084##
(R)-3-(3-Carboxy-propionylamino)-4-(3'-chloro-
biphenyl-4-yl)-butyric acid 5-methyl-2- oxo-[1,3]dioxol-4-yl methyl
ester ##STR00085## 1.12 min. (B) 502.2 Example 1-15 ##STR00086##
(R)-3-(3-Carboxy-propionylamino)-4-(3'-chloro-biphenyl-
4-yl)-butyric acid dimethylcarbamoylmethyl ester ##STR00087## 0.89
min. (B) 475.3 Example 1-16 ##STR00088##
(R)-3-(3-Carboxy-propionylamino)-4-(3'-chloro-biphenyl-
4-yl)-butyric acid 2-morpholin-4-yl-ethyl ester ##STR00089## 0.99
min. (B) 503.5
Example 1-12
[0282] 1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.87 (t, J=7.5
Hz, 3H), 1.49-1.61 (m, 2H), 2.22-2.29 (m, 2H), 2.32-2.39 (m, 2H),
2.45 (dd, J=6.9, 3.4 Hz, 2H), 2.78 (d, J=6.6 Hz, 2H), 3.94 (t,
J=6.6 Hz, 2H), 4.21-4.33 (m, 1H), 7.29 (d, J=8.3 Hz, 2H), 7.37-7.42
(m, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.58-7.65 (m, 3H), 7.69 (t, J=1.9
Hz, 1H), 7.92 (d, J=8.3 Hz, 1H).
Example 1-13
[0283] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.94 (t, J=7.3
Hz, 3H), 1.32-1.44 (m, 2H), 1.56-1.67 (m, 2H), 2.43-2.59 (m, 4H),
2.65 (t, J=6.4 Hz, 2H), 2.85 (dd, J=13.6, 8.1 Hz, 1H), 2.99 (dd,
J=13.6, 6.6 Hz, 1H), 4.03-4.18 (m, 2H), 4.43-4.56 (m, 1H), 6.57 (d,
J=8.6 Hz, 1H), 7.25 (d, J=8.3 Hz, 2H), 7.28-7.32 (m, 1H), 7.35 (t,
J=7.7 Hz, 1H), 7.41-7.46 (m, 1H), 7.48 (d, J=8.1 Hz, 2H), 7.55 (t,
J=1.8 Hz, 1H).
Example 1-14
[0284] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 2.17 (s, 3H),
2.44 (t, J=6.2 Hz, 2H), 2.48-2.57 (m, 1H), 2.57-2.73 (m, 3H), 2.87
(dd, J=13.6, 7.6 Hz, 1H), 2.98 (dd, J=13.9, 7.1 Hz, 1H), 4.47-4.58
(m, 1H), 4.84 (s, 2H), 6.32 (d, J=8.6 Hz, 1H), 7.23 (d, J=8.1 Hz,
2H), 7.30 (d, 1H), 7.35 (t, J=7.7 Hz, 1H), 7.44 (d, J=7.3 Hz, 1H),
7.49 (d, J=8.1 Hz, 2H), 7.54 (s, 1H).
Example 1-15
[0285] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 2.48-2.59 (m,
3H), 2.61-2.71 (m, 3H), 2.91-3.06 (m, 8H), 4.53-4.63 (m, 1H), 4.67
(d, J=14.7 Hz, 1H), 5.03 (d, J=14.7 Hz, 1H), 7.30 (dt, J=7.8, 1.8
Hz, 1H), 7.32-7.38 (m, 3H), 7.45 (dt, J=7.6, 1.5 Hz, 1H), 7.50 (d,
J=8.1 Hz, 2H), 7.55 (t, J=1.8 Hz, 1H), 8.08 (d, J=9.3 Hz, 1H).
Example 1-16
[0286] 1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 2.20-2.32 (m,
2H), 2.32-2.41 (m, 2H), 2.42-2.50 (m, 1H), 2.57 (dd, J=15.4, 5.6
Hz, 1H), 2.80 (d, J=36.1 Hz, 2H), 3.15 (br. s., 2H), 3.31-3.50 (m,
4H), 3.52-4.05 (m, 4H), 4.25-4.40 (m, 3H), 7.31 (d, J=8.3 Hz, 2H),
7.39-7.43 (m, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.60-7.67 (m, 3H), 7.70
(t, J=1.8 Hz, 1H), 8.02 (d, J=8.6 Hz, 1H), 10.06 (br. s., 1H),
12.17 (br. s., 1H).
Example 1-17
Synthesis of
(R)-4-(1-(5'-chloro-2'-fluorobiphenyl-4-yl)-4-ethoxy-4-oxobutan-2-ylamino-
)-4-oxobutanoic acid
##STR00090##
[0288] A solution of (R)-ethyl
3-amino-4-(5'-chloro-2'-fluorobiphenyl-4-yl)butanoate hydrochloride
(293 mg, 0.777 mmol), succinic anhydride (93 mg, 0.932 mmol) and
DIPEA (0.204 mL, 1.165 mmol) in dichloromethane (4 mL) is allowed
to stir for 1.5 hours. The reaction is quenched with 1 M aqueous
HCl and extracted with dichloromethane. The organic layer is
separated and concentrated under reduced pressure. The resulting
residue is purified by preparative HPLC using a gradient of 20%
MeCN/water (0.1% TFA) to 100% MeCN to give
(R)-4-(1-(5'-chloro-2'-fluorobiphenyl-4-yl)-4-ethoxy-4-oxobutan-2-ylamino-
)-4-oxobutanoic acid (294 mg). HPLC retention time=1.03 minutes
(condition B); MS (m+1)=436.2; 1H NMR (400 MHz, CHLOROFORM-d)
.delta. ppm 1.28 (t, J=7.07 Hz, 3H) 2.46-2.58 (m, 4H) 2.64-2.68 (m,
2H) 2.87 (A of ABX, J.sub.ab=13.64 Hz, J.sub.ax=7.83 Hz, 1H) 2.99
(B of ABX, J.sub.ab=13.64 Hz, J.sub.bx=6.57 Hz, 1H) 4.11-4.22 (m,
2H) 4.47-4.56 (m, 1H) 6.60 (br d, J=8.59 Hz, 1H) 7.05-7.10 (m, 1H)
7.23-7.27 (m, 3H) 7.39-7.41 (m, 1H) 7.44-7.46 (m, 2H).
[0289] Following compounds are prepared using similar procedure as
described in example 1-17:
TABLE-US-00005 Example HPLC-RT MS # Product Starting Material
Condition (condition) (M + 1) Example 1-18 ##STR00091##
(2S,3R)-3-(3- Carboxy- propionylamino)-4- (3'-chloro-biphenyl-
4-yl)-2-hydroxy- butyric acid methyl ester ##STR00092##
Intermediate 50 ##STR00093## Et.sub.3N, DCM 1.29 min. (A) 420.0
##STR00094## (2R,3R)-3-(3-Carboxy- propionylamino)-4-(3'-
chloro-biphenyl-4-yl)- 2-hydroxy-butyric acid methyl ester Example
1-19 ##STR00095## (2S,3R)-3-(3- Carboxy- propionylamino)-4-(3'-
chloro-biphenyl-4-yl)- 2-methoxy-butyric acid methyl ester
##STR00096## Intermediate 51 ##STR00097## DIPEA, DCM 1.21 min. (A)
434.2 ##STR00098## (2R,3R)-3-(3-Carboxy- propionylamino)-4-(3'-
chloro-biphenyl-4-yl)- 2-methoxy-butyric acid methyl ester Example
1-20 ##STR00099## (2S,3R)-3-(3- Carboxy- propionylamino)-4-(3'-
chloro-biphenyl-4-yl)- 2-methoxy-butyric acid ethyl ester
##STR00100## Intermediate 52 ##STR00101## DIPEA, DCM 1.57 min. (A)
448.3 ##STR00102## (2R,3R)-3-(3-Carboxy- propionylamino)-4-(3'-
chloro-biphenyl-4-yl)- 2-methoxy-butyric acid ethyl ester Example
1-21 ##STR00103## (2S,3R)-3-(3- Carboxy- propionylamino)-4-(3'-
chloro-biphenyl-4-yl)- 2-fluoro-butyric acid methy lester
##STR00104## Intermediate 53 ##STR00105## Et.sub.3N, DCM 0.83 min.
(B) 422.1 ##STR00106## (2R,3R)-3-(3-Carboxy- propionylamino)-4-(3'-
chloro-biphenyl-4-yl)- 2-fluoro-butyric acid methyl ester Example
1-22 ##STR00107## (R)-3-(3-Carboxy- propionylamino)-4-(3'-
chloro-biphenyl-4-yl)- 2-methyl-butyric acid ethyl ester
##STR00108## Intermediate 54 ##STR00109## Et.sub.3N, DCM 0.98 min.
(B) 432 Example 1-23 ##STR00110## (R)-3-(2-Carboxymethoxy-
acetylamino)-4-(3'- chloro-biphenyl-4-yl)- butyric acid ethyl ester
##STR00111## ##STR00112## Et.sub.3N, DCM 0.75 min. (B) 434
Example 1-20
[0290] 1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 1.15 (t, J=7.07 Hz,
3H), 2.24-2.34 (m, 4H), 2.74 (dd, J=8.59, 13.39 Hz), 2.88 (dd,
J=6.32, 13.39 Hz), 3.34 (s, 3H), 3.75 (d, J=2.78 Hz, 1H), 4.04 (dd,
J=7.07, 13.89 Hz, 2H), 4.33-4.43 (m, 1H), 7.31 (d, J=8.08 Hz, 2H),
7.38-7.43 (m, 1H), 7.48 (t, J=7.83 Hz, 1H), 7.63 (d, J=3.34 Hz),
7.71 (t, J=1.77 Hz, 1H), 7.95 (d, J=9.35 Hz, 1H).
Example 2-1
Synthesis of
(R)-3-(3-carboxy-propionylamino)-4-(4'-fluoro-biphenyl-4-yl)-butyric
acid ethyl ester
##STR00113##
[0292] A mixture of
(R)-4-(1-(4-bromophenyl)-4-ethoxy-4-oxobutan-2-ylamino)-4-oxobutanoic
acid (50 mg, 0.129 mmol), 4-fluorophenylboronic acid (27.2 mg,
0.194 mmol), Pd(Ph.sub.3P).sub.4 (14.96 mg, 0.013 mmol) and aqueous
Na2CO3 (0.129 mL, 0.259 mmol) in toluene (1 mL) is allowed to stir
at 95.degree. C. under nitrogen. After stirring for 13 hours, the
solution is cooled to ambient temperature and then quenched with
aqueous 1 M HCl. The products are extracted with ethyl acetate,
washed with brine, dried over MgSO.sub.4, filtered, and
concentrated under reduced pressure. The obtained residue is
purified by RP-HPLC (SunFire C18, H.sub.2O (0.1% TFA)/CH.sub.3CN),
and then lyophilized to give
(R)-3-(3-carboxy-propionylamino)-4-(4'-fluoro-biphenyl-4-yl)-butyric
acid ethyl ester (29.2 mg). HPLC retention time=1.26 minutes
(condition B); MS (m+1)=402.2; 1H NMR (400 MHz, CHLOROFORM-d)
.delta. ppm 1.29 (t, J=7 Hz, 3H) 2.47-2.67 (m, 6H) 2.87 (A of ABX,
Jab=13.7 Hz, Jax=7.9 Hz, 1H) 2.99 (B of ABX, Jab=13.7 Hz, Jbx=6.6
Hz, 1H) 4.12-4.23 (m, 2H) 4.47-4.55 (m, 1H) 6.52 (br d, J=8.6 Hz,
1H) 7.08-7.14 (m, 2H) 7.24 (d, J=8.4 Hz, 2H) 7.46-7.55 (m, 4H).
[0293] Following compounds are prepared using similar procedure as
described in example 2-1:
TABLE-US-00006 HPLC-RT MS Example Product Reagent (condition) (M +
1) Example 2-2 ##STR00114## Pd(PPh.sub.3).sub.4,
p-chlorophenylboronic acid, aq. 2M Na.sub.2CO.sub.3, (R)-4-(1-(4-
bromophenyl)-4- ethoxy-4-oxobutan-2- ylamino)-4- oxobutanoic acid
1.49 min. (B) 418.1 Example 2-3 ##STR00115## Pd(PPh.sub.3).sub.4,
m-fluorophenylboronic acid, aq. 2M Na.sub.2CO.sub.3, (R)-ethyl
4-(4- bromophenyl)-3-(4- methoxy-4- oxobutanamido)butan- oate. 1.24
min. (B) 416.1 Example 2-4 ##STR00116## Pd(PPh.sub.3).sub.4,
o-fluorophenylboronic acid, aq. 2M Na.sub.2CO.sub.3, (R)-ethyl
4-(4- bromophenyl)-3-(4- methoxy-4- oxobutanamido)butan- oate. 1.25
min. (B) 416.1 Example 2-5 ##STR00117## Pd(PPh.sub.3).sub.4,
o-chlorophenylboronic acid, aq. 2M Na2CO3, (R)-ethyl 4-(4-
bromophenyl)-3-(4- methoxy-4- oxobutanamido)butan- oate. 1.33 min.
(B) 432.1 Example 2-6 ##STR00118## Pd(PPh.sub.3).sub.4,
o-methoxyphenylboronic acid, aq. 2M Na.sub.2CO.sub.3, (R)-ethyl
4-(4- bromophenyl)-3-(4- methoxy-4- oxobutanamido)butan- oate. 1.22
min. (B) 428.2 Example 2-7 ##STR00119## Pd(PPh.sub.3).sub.4,
o-tolylboronic acid, aq. 2M Na.sub.2CO.sub.3, (R)-ethyl
4-(4-bromophenyl)-3- (4-methoxy-4- oxobutanamido)butan- oate. 1.35
min. (B) 412.2 Example 2-8 ##STR00120## Pd(PPh3)4, 2-chloro-5-
fluorophenylboronic acid, aq. 2M Na2CO3, (R)-ethyl 4-(4-
bromophenyl)-3-(4- methoxy-4- oxobutanamido)butan- oate. 1.28 min.
(B) 450.3 Example 2-9 ##STR00121## Pd(PPh3)4, m-tolylboronic acid,
aq. 2M Na2CO3, (R)- ethyl 4-(4- bromophenyl)-3-(4- methoxy-4-
oxobutanamido)butan- oate. 1.28 min. (B) 412.2 Example 2-10
##STR00122## Pd(PPh3)4, 3,5- difluorophenylboronic acid, aq. 2M
Na2CO3, (R)-ethyl 4-(4- bromophenyl)-3-(4- methoxy-4-
oxobutanamido)butan- oate. 1.23 min. (B) 434.2 Example 2-11
##STR00123## Pd(PPh3)4, 3-ethylphenylboronic acid, aq. 2M Na2CO3,
(R)-ethyl 4-(4- bromophenyl)-3-(4- methoxy-4- oxobutanamido)butan-
oate. 1.40 min. (B) 426.3 Example 2-12 ##STR00124## Pd(PPh3)4,
3-nitrophenylboronic acid, aq. 2M Na2CO3, (R)-ethyl 4-(4-
bromophenyl)-3-(4- methoxy-4- oxobutanamido)butan- oate. 1.16 min.
(B) 443.2 Example 2-13 ##STR00125## Pd(PPh3)4, 3-
(trifluoromethyl)phenyl- boronic acid, aq. 2M Na2CO3, (R)-ethyl 4-
(4-bromophenyl)-3-(4- methoxy-4- oxobutanamido)butan- oate. 1.39
min. (G) 466.1 Example 2-14 ##STR00126## Pd(PPh3)4, 3-
methoxyphenylboronic acid, aq. 2M Na2CO3, (R)-ethyl 4-(4-
bromophenyl)-3-(4- methoxy-4- oxobutanamido)butan- oate. 1.19 min.
(G) 428.2 Example 2-15 ##STR00127## Pd(PPh3)4, 3-
cyanobenzeneboronic acid, aq. 2M Na2CO3, (R)-ethyl 4-(4-
bromophenyl)-3-(4- methoxy-4- oxobutanamido)butan- oate. 0.98 min.
(B) 423.2 Example 2-16 ##STR00128## Pd(PPh3)4, 3-chloro-5-
fluorophenylboronic acid, aq. 2M Na2CO3, (R)-ethyl 4-(4-
bromophenyl)-3-(4- methoxy-4- oxobutanamido)butan- oate. 1.45 min.
(B) 450.1 Example 2-17 ##STR00129## Pd(PPh3)4, 2-
(trifluoromethyl)phenyl- boronic acid, aq. 2M Na2CO3, (R)-ethyl 4-
(4-bromophenyl)-3-(4- methoxy-4- oxobutanamido)butan- oate. 1.37
min. (B) 466.1 Example 2-18 ##STR00130## Pd(PPh3)4, 2-
cyanophenylboronic acid, aq. 2M Na2CO3, (R)-ethyl 4-(4-
bromophenyl)-3-(4- methoxy-4- oxobutanamido)butan- oate. 1.01 min.
(B) 423.2 Example 2-19 ##STR00131## Pd(PPh3)4, 2-
ethoxyphenylboronic acid, aq. 2M Na2CO3, (R)-ethyl 4-(4-
bromophenyl)-3-(4- methoxy-4- oxobutanamido)butan- oate. 1.29 min.
(B) 442.2 Example 2-20 ##STR00132## PdCl2(dppf).cndot.CH2Cl2
complex, phenyl-d5- boronic acid, aq. 2M Na2CO3, (R)-tert-butyl
4-(1-(4-bromophenyl)- 4-ethoxy-4-oxobutan-2- ylamino)-4-
oxobutanoate 1.42 min. (B) 445.2
Example 2-2
[0294] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.29 (t, J=7 Hz,
3H) 2.47-2.67 (m, 6H) 2.84-3.02 (m, 2H) 4.12-4.24 (m, 2H) 4.47-4.55
(m, 1H) 6.52 (br d, J=9.3 Hz, 1H) 7.24-7.26 (m, 2H) 7.39-7.41 (m,
2H) 7.48-7.51 (m, 4H).
Example 2-3
[0295] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.29 (t, J=7 Hz,
3H) 2.43-2.65 (m, 6H) 2.84-3.02 (m, 2H) 3.67 (s, 3H) 4.12-4.23 (m,
2H) 4.47-4.55 (m, 1H) 6.30 (br d, J=8.6 Hz, 1H) 7.00-7.05 (m, 1H)
7.26-7.29 (m, 3H) 7.34-7.41 (m, 2H) 7.51 (d, J=8.3 Hz, 2H).
Example 2-4
[0296] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.28 (t, J=7 Hz,
3H) 2.44-2.65 (m, 6H) 2.85-3.02 (m, 2H) 3.67 (s, 3H) 4.11-4.23 (m,
2H) 4.48-4.56 (m, 1H) 6.30 (br d, J=9.6 Hz, 1H) 7.11-7.22 (m, 2H)
7.25-7.33 (m, 3H) 7.40-7.45 (m, 1H) 7.48-7.50 (m, 2H).
Example 2-5
[0297] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.29 (t, J=7.2
Hz, 3H) 2.44-2.65 (m, 6H) 2.86-3.02 (m, 2H) 3.68 (s, 3H) 4.12-4.23
(m, 2H) 4.49-4.57 (m, 1H) 6.31 (br d, J=8.8 Hz, 1H) 7.24-7.34 (m,
5H) 7.37-7.39 (m, 2H) 7.45-7.47 (m, 1H).
Example 2-6
[0298] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.28 (t, J=7 Hz,
3H) 2.44-2.66 (m, 6H) 2.84-3.01 (m, 2H) 3.68 (s, 3H) 3.81 (s, 3H)
4.11-4.23 (m, 2H) 4.48-4.56 (m, 1H) 6.26 (br d, J=8.8 Hz, 1H)
6.97-7.04 (m, 2H) 7.22 (d, J=8.1 Hz, 2H) 7.29-7.33 (m, 2H)
7.46-7.48 (m, 2H).
Example 2-7
[0299] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.29 (t, J=7.1
Hz, 3H) 2.26 (s, 3H) 2.44-2.69 (m, 6H) 2.85-3.01 (m, 2H) 3.68 (s,
3H) 4.12-4.23 (m, 2H) 4.48-4.57 (m, 1H) 6.30 (br d, J=8.6 Hz, 1H)
7.21-7.26 (m, 8H).
Example 2-8
[0300] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.29 (t, J=7.2
Hz, 3H) 2.44-2.69 (m, 6H) 2.86-3.03 (m, 2H) 3.68 (s, 3H) 4.12-4.23
(m, 2H) 4.48-4.57 (m, 1H) 6.31 (br d, J=8.8 Hz, 1H) 6.90-7.01 (m,
1H) 7.05-7.08 (m, 1H) 7.25-7.27 (m, 2H) 7.36-7.43 (m, 3H).
Example 2-9
[0301] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.28 (t, J=7.2
Hz, 3H) 2.41-2.65 (m, 9H) 2.84-3.00 (m, 2H) 3.67 (s, 3H) 4.11-4.23
(m, 2H) 4.47-4.55 (m, 1H) 6.29 (br d, J=8.9 Hz, 1H) 7.16-7.39 (m,
6H) 7.50-7.53 (m, 2H).
Example 2-10
[0302] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.29 (t, J=7.2
Hz, 3H) 2.43-2.65 (m, 6H) 2.84-3.02 (m, 2H) 3.67 (s, 3H) 4.12-4.23
(m, 2H) 4.46-4.55 (m, 1H) 6.33 (br d, J=8.8 Hz, 1H) 6.76-6.80 (m,
1H) 7.06-7.12 (m, 2H) 7.26-7.27 (m, 2H) 7.48 (d, J=8.0 Hz, 2H).
Example 2-11
[0303] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.27-1.30 (m, 6H)
2.44-2.57 (m, 4H) 2.62-2.74 (m, 4H) 2.84-3.00 (m, 2H) 3.67 (s, 3H)
4.13-4.23 (m, 2H) 4.47-4.55 (m, 1H) 6.30 (br d, J=7.6 Hz, 1H)
7.17-7.26 (m, 3H) 7.33-7.41 (m, 3H) 7.52 (d, J=7.8 Hz, 2H).
Example 2-12
[0304] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.30 (t, J=7.1
Hz, 3H) 2.41-2.65 (m, 6H) 2.67-2.92 (m, 1H) 3.00-3.05 (m, 1H) 3.68
(s, 3H) 4.14-4.22 (m, 2H) 4.48-4.56 (m, 1H) 6.33 (br d, J=8.6 Hz,
1H) 7.32 (d, J=8.3 Hz, 2H) 7.56-7.62 (m, 3H) 7.89-7.91 (m, 1H)
8.18-8.20 (m, 1H) 8.44 (t, J=8.0 Hz, 1H).
Example 2-13
[0305] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.29 (t, J=7.2
Hz, 3H) 2.44-2.65 (m, 6H) 2.86-2.91 (m, 1H) 2.98-3.03 (m, 1H) 3.67
(s, 3H) 4.13-4.22 (m, 2H) 4.47-4.56 (m, 1H) 6.33 (br d, J=8.8 Hz,
1H) 7.29 (d, J=8.2 Hz, 2H) 7.53 (d, J=8.2 Hz, 2H) 7.56-7.60 (m, 2H)
7.75 (d, J=7.6 Hz, 1H) 7.81 (s, 1H).
Example 2-14
[0306] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.28 (t, J=7.2
Hz, 3H) 2.43-2.65 (m, 6H) 2.84-2.89 (m, 1H) 2.96-3.01 (m, 1H) 3.67
(s, 3H) 3.86 (s, 3H) 4.11-4.23 (m, 2H) 4.47-4.55 (m, 1H) 6.30 (br
d, J=8.8 Hz, 1H) 6.87-6.90 (m, 1H) 7.10-7.11 (m, 1H) 7.15-7.17 (m,
1H) 7.24-7.26 (m, 2H) 7.34 (t, J=7.8 Hz, 2H) 7.51-7.53 (m, 2H).
Example 2-15
[0307] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.29 (t, J=7.1
Hz, 3H) 2.43-2.58 (m, 4H) 2.61-2.65 (m, 2H) 2.84-2.91 (m, 1H)
2.98-3.03 (m, 1H) 3.68 (s, 3H) 4.12-4.24 (m, 2H) 4.47-4.55 (m, 1H)
6.34 (br d, J=8.8 Hz, 1H) 7.30 (d, J=8.1 Hz, 2H) 7.50 (d, J=8.1 Hz,
2H) 7.51-7.63 (m, 2H) 7.78-7.81 (m, 1H) 7.85 (br s, 1H).
Example 2-16
[0308] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.29 (t, J=7.1
Hz, 3H) 2.43-2.57 (m, 4H) 2.61-2.64 (m, 2H) 2.87 (A of ABX,
J.sub.ab=13.6 Hz, J.sub.ax=7.8 Hz, 1H) 2.99 (B of ABX,
J.sub.ab=13.6 Hz, J.sub.bx=6.6 Hz, 1H) 3.68 (s, 3H) 4.12-4.23 (m,
2H) 4.46-4.55 (m, 1H) 6.34 (br d, J=8.6 Hz, 1H) 7.05 (dt, J=8.3 and
2.0 Hz, 1H) 7.15-7.19 (m, 1H) 7.26-7.28 (m, 3H) 7.35-7.36 (m, 1H)
7.45 (d, J=8.1 Hz, 2H).
Example 2-17
[0309] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.29 (t, J=7.1
Hz, 3H) 2.43-2.69 (m, 6H) 2.90 (A of ABX, J.sub.ab=13.6 Hz,
J.sub.ax=7.8 Hz, 1H) 2.99 (B of ABX, J.sub.ab=13.6 Hz, J.sub.bx=6.8
Hz, 1H) 3.68 (s, 3H) 4.12-4.23 (m, 2H) 4.49-4.57 (m, 1H) 6.31 (br
d, J=8.6 Hz, 1H) 7.20-7.26 (m, 4H) 7.32 (d, J=7.6 Hz, 1H) 7.44-7.47
(m, 1H) 7.53-7.57 (m, 1H) 7.73 (d, J=7.6 Hz, 2H).
Example 2-18
[0310] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.29 (t, J=7.2
Hz, 3H) 2.44-2.65 (m, 6H) 2.91 (A of ABX, J.sub.ab=13.6 Hz,
J.sub.ax=7.8 Hz, 1H) 3.01 (B of ABX, J.sub.ab=13.6 Hz, J.sub.bx=6.6
Hz, 1H) 3.68 (s, 3H) 4.12-4.24 (m, 2H) 4.48-4.57 (m, 1H) 6.34 (br
d, J=8.6 Hz, 1H) 7.32 (d, J=8.1 Hz, 2H) 7.41-7.56 (m, 2H) 7.62-7.66
(m, 1H) 7.75-7.77 (m, 1H) 7.81-7.84 (m, 2H).
Example 2-19
[0311] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.28 (t, J=7.2
Hz, 3H) 1.35 (t, J=6.9 Hz, 3H) 2.44-2.53 (m, 4H) 2.44-2.53 (m, 4H)
2.86 (A of ABX, J.sub.ab=13.6 Hz, J.sub.ax=8.1 Hz, 1H) 2.98 (B of
ABX, J.sub.ab=13.6 Hz, J.sub.bx=6.1 Hz, 1H) 3.67 (s, 3H) 3.99-4.23
(m, 4H) 4.48-4.56 (m, 1H) 6.27 (br d, J=8.6 Hz, 1H) 6.94-7.04 (m,
2H) 7.20-7.22 (m, 2H) 7.27-7.33 (m, 2H) 7.41-7.52 (m, 2H).
Example 2-20
[0312] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.28 (t, J=7.2
Hz, 3H) 1.43 (s, 9H) 2.36-2.56 (m, 6H) 2.84-3.01 (m, 4H) 4.11-4.22
(m, 2H) 4.47-4.56 (m, 1H) 6.30-6.35 (m, 1H) 7.25-7.27 (m, 2H)
7.51-7.54 (m, 2H).
Example 2-21
Synthesis of
(R)-4-(4-ethoxy-1-(5'-fluoro-2'-methoxybiphenyl-4-yl)-4-oxobutan-2-ylamin-
o)-4-oxobutanoic acid
##STR00133##
[0314] To a solution of (R)-tert-butyl
4-(1-(4-bromophenyl)-4-ethoxy-4-oxobutan-2-ylamino)-4-oxobutanoate,
intermediate 9, (100 mg, 0.23 mmol) and
5-fluoro-2-methoxyphenylboronic acid (57.6 mg, 0.34 mmol) in
toluene (1 mL) and EtOH (0.1 mL) is added Pd(PPh.sub.3).sub.4 (26.1
mg, 0.023 mmol) and Na.sub.2CO.sub.3 (47.9 mg, 0.45 mmol). After
stirring at 95.degree. C. under nitrogen for 18 hours, the solution
is cooled to ambient temperature and then quenched with aqueous 1 M
HCl. The crude is diluted with ethyl acetate, the organic layer is
washed with brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated under reduced pressure. The obtained residue is
purified by flash column chromatography on silica gel (eluent:
heptane/EtOAc=100:0 to 30:70) to give (R)-tert-butyl
4-(4-ethoxy-1-(5'-fluoro-2'-methoxybiphenyl-4-yl)-4-oxobutan-2-ylamino)-4-
-oxobutanoate (65 mg). HPLC retention time=1.44 minutes (condition
B); MS (m+1)=488.3; 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.32
(t, J=7.1 Hz, 3H) 1.48 (s, 9H) 2.41-2.48 (m, 2H) 2.51-2.63 (m, 4H)
2.90 (dd, J=13.6, 6 Hz, 1H) 3.02 (dd, J=13.6, 6 Hz, 1H) 3.81 (s,
3H) 4.14-4.29 (m, 2H) 4.49-4.63 (m, 1H) 6.44 (d, J=8.6 Hz, 1H)
6.89-6.97 (m, 1H) 6.98-7.05 (m, 1H) 7.05-7.11 (m, 1H) 7.27 (d,
J=8.1 Hz, 2H) 7.49 (d, J=8.1 Hz, 2H).
[0315] A solution of (R)-tert-butyl
4-(4-ethoxy-1-(5'-fluoro-2'-methoxybiphenyl-4-yl)-4-oxobutan-2-ylamino)-4-
-oxobutanoate, (65 mg, 0.13 mmol) in 4M HCl in 1,4-dioxane (671
.mu.L, 2.68 mmol) is stirred at room temperature. After stirring
for 1 hour, the reaction mixture is concentrated under reduced
pressure. The obtained residue is purified by RP-HPLC (SunFire C18,
H.sub.2O (0.1% TFA)/CH.sub.3CN), and then lyophilized to give
(R)-4-(4-ethoxy-1-(5'-fluoro-2'-methoxybiphenyl-4-yl)-4-oxobutan-2-ylamin-
o)-4-oxobutanoic acid (23 mg). HPLC retention time=1.66 minutes
(condition D); MS (m+1)=432.3; 1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 1.17 (t, J=7.1 Hz, 3H) 2.21-2.32 (m, 2H) 2.32-2.40 (m,
2H) 2.40-2.48 (m, 2H) 2.77 (d, J=6.8 Hz, 2H) 3.74 (s, 3H) 4.03 (q,
J=7.1 Hz, 2H) 4.19-4.33 (m, 1H) 7.04-7.20 (m, 3H) 7.23 (d, J=8.1
Hz, 2H) 7.43 (d, J=8.1 Hz, 2H) 7.93 (d, J=8.3 Hz, 1H)
[0316] Following compounds are prepared using similar procedure as
described in example 2-21:
TABLE-US-00007 LCMS-RT MS Example Product Reagent (condition) (M +
1) Example 2-22 ##STR00134##
(R)-4-(1-(5'-chloro-2'-methoxybiphenyl-4-yl)-
4-ethoxy-4-oxobutan-2-ylamino)-4-oxobutanoic acid
Pd(PPh.sub.3).sub.4, 5-chloro-2- methoxyphenylboronic acid, aq. 2M
Na.sub.2CO.sub.3, (R)-tert-butyl 4-(1-(4- bromophenyl)-4-
ethoxy-4-oxobutan-2- ylamino)-4- oxobutanoate. 1.63 min. (D) 448.2
Example 2-23 ##STR00135##
(R)-4-(4-ethoxy-1-(5'-fluoro-2'-hydroxybiphenyl-4-
yl)-4-oxobutan-2-ylamino)-4-oxobutanoic acid Pd(PPh.sub.3).sub.4,
5-fluoro-2- hydroxyphenylboronic acid, aq. 2M Na.sub.2CO.sub.3,
(R)-tert-butyl 4-(1-(4- bromophenyl)-4- ethoxy-4-oxobutan-2-
ylamino)-4- oxobutanoate. 1.29 min (A) 418.3 Example 2-24
##STR00136## (R)-4-(4-ethoxy-1-(2'-hydroxybiphenyl-4-
yl)-4-oxobutan-2-ylamino)-4-oxobutanoic acid Pd(PPh.sub.3).sub.4,
2- hydroxyphenylboronic acid, aq. 2M Na.sub.2CO.sub.3,
(R)-tert-butyl 4-(1-(4- bromophenyl)-4- ethoxy-4-oxobutan-2-
ylamino)-4- oxobutanoate. 1.65 min (D) 400.3
Example 2-22
[0317] 1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 1.23 (t, J=7.1 Hz,
3H) 2.36-2.58 (m, 6H) 2.85 (d, J=7.1 Hz, 2H) 3.76 (s, 3H) 4.10 (q,
J=7.1 Hz, 2H) 4.40-4.57 (m, 1H) 7.01 (d, J=8.6 Hz, 1H) 7.17-7.30
(m, 4H) 7.39 (d, J=8.1 Hz, 2H)
Example 2-23
[0318] 1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.16 (t, J=7.2
Hz, 1H) 2.23-2.30 (m, 2H) 2.34-2.40 (m, 2H) 2.40-2.45 (m, 2H) 2.75
(dd, J=6.6, 3.3 Hz, 2H) 4.02 (q, J=7.2 Hz, 2H) 4.19-4.30 (m, 1H)
6.87-6.94 (m, 1H) 6.93-7.02 (m, 1H) 7.07 (dd, J=9.7, 3.2 Hz, 1H)
7.22 (d, J=8.1 Hz, 2H) 7.49 (d, J=8.1 Hz, 2H) 7.94 (d, J=8.1 Hz,
1H) 9.52 (s, 1H)
Example 2-24
[0319] 1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.16 (t, J=7.1
Hz, 3H) 2.22-2.32 (m, 2H) 2.34-2.41 (m, 2H) 2.43 (dd, J=6.8, 3.3
Hz, 2H) 2.68-2.82 (m, 2H) 4.02 (q, J=7.1 Hz, 2H) 4.17-4.35 (m, 1H)
6.80-6.89 (m, 1H) 6.93 (d, J=7.1 Hz, 1H) 7.09-7.17 (m, 1H)
7.17-7.29 (m, 3H) 7.46 (d, J=8.3 Hz, 2H) 7.93 (d, J=8.1 Hz, 1H)
9.46 (br. s., 1H)
Example 3-1
Synthesis of
(R)-6-(1-(biphenyl-4-yl)-4-ethoxy-4-oxobutan-2-ylcarbamoyl)pyrimidine-4-c-
arboxylic acid
##STR00137##
[0321] To
(R)-ethyl-4-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)butanoat- e
(300 mg, 0.782 mmol) is added a solution of 4M HCl in 1,4-dioxane
(3.92 mL, 15.65 mmol) at room temperature. After stirring for 1
hour, the reaction mixture is concentrated under reduced pressure
to give (R)-3-amino-4-biphenyl-4-yl-butyric acid ethyl ester
hydrochloride.
[0322] Next, to a suspension of pyrimidine-4,6-dicarboxylic acid
(325 mg, 1.935 mmol), (R)-3-amino-4-biphenyl-4-yl-butyric acid
ethyl ester hydrochloride (250 mg, 0.774 mmol), WSC hydrochloride
(148 mg, 0.774 mmol) and HOAt (105 mg, 0.774 mmol) in DMF (4 mL)
and H.sub.2O (1 mL) is added DIPEA (0.135 mL, 0.774 mmol). After
stirring for 14 hours, the reaction is quenched with H.sub.2O, and
the products are extracted with EtOAc, washed with brine, dried
over Na2SO4, filtered, and concentrated under reduced pressure.
The obtained residue is purified by RP-HPLC (SunFire C18, H.sub.2O
(0.1% TFA)/CH.sub.3CN), and then lyophilized to give
(R)-6-(1-(biphenyl-4-yl)-4-ethoxy-4-oxobutan-2-ylcarbamoyl)pyrimidine-4-c-
arboxylic acid (84.8 mg). HPLC retention time=1.32 minutes
(condition B); MS (m+1)=434.1; 1H NMR (400 MHz, DMSO-d6) .delta.
ppm 1.12 (t, J=7.0 Hz, 3H) 2.65 (A of ABX, Jab=15.4 Hz, Jax=5.8 Hz,
1H) 2.73 (B of ABX, Jab=15.4 Hz, Jbx=7.9 Hz) 2.91 (A of ABX,
Jab=13.6 Hz, Jax=6.1 Hz, 1H) 3.01 (B of ABX, Jab=13.6 Hz, Jbx=8.2
Hz, 1H) 4.01 (q, J=7.0 Hz, 2H) 4.59-4.68 (m, 1H) 7.29-7.35 (m, 3H)
7.41-7.45 (m, 2H) 7.55-7.63 (m, 4H) 8.32 (d, J=1.35 Hz, 1H) 9.19
(d. J=9.1 Hz, 1H) 9.50 (d, J=1.35 Hz, 1H) 14.11 (br s, 1H).
[0323] Following compounds are prepared using similar procedure as
described in example 3-1:
TABLE-US-00008 HPLC-RT MS Example # Product Reagent (condition) (M
+ 1) Example 3-2 ##STR00138##
(R)-4-biphenyl-4-yl-3-[(2-hydroxy-pyrimidine-5-
carbonyl)-amino]-butyric acid ethyl ester ##STR00139## 1.56 min.
(A) 406.2 Example 3-3 ##STR00140##
(R)-4-biphenyl-4-yl-3-[(pyrimidine-4-carbonyl)- amino]-butyric acid
ethyl ester ##STR00141## 1.73 min. (A) 390 Example 3-4 ##STR00142##
(R)-ethyl 4-(biphenyl-4-yl)-3-(5-chloro-6-
hydroxynicotinamido)butanoate ##STR00143## PyBOP instead of
WSC.cndot.HCl and HOAt 1.69 min. (D) 439.0 Example 3-5 ##STR00144##
(R)-ethyl 4-(biphenyl-4-yl)-3-(6- hydroxynicotinamido)butanoate
##STR00145## PyBOP instead of WSC.cndot.HCl, HOAt 1.55 min. (B)
405.2 Example 3-6 ##STR00146## (R)-ethyl
4-(biphenyl-4-yl)-3-(5-hydroxy-4-oxo-4H-
pyran-2-carboxamido)butanoate ##STR00147## 1.65 min. (A) 422.2
Example 3-7 ##STR00148## (R)-ethyl
3-(2-aminopyrimidine-5-carboxamido)-4- (biphenyl-4-yl)butanoate
##STR00149## PyBOP instead of WSC.cndot.HCl and HOAt 1.58 min. (A)
405.8 Example 3-8 ##STR00150## (R)-ethyl
3-(6-aminonicotinamido)-4-(biphenyl-4- yl)butanoate ##STR00151##
PyBOP instead of WSC.cndot.HCl and HOAt 1.65 min. (A) 404.3
Example 3-2
[0324] 1H NMR (400 MHz, DMSO-d6) .delta. ppm 1.14 (t, J=7.1 Hz, 3H)
2.57 (d, J=7.1 Hz, 2H) 2.83-2.92 (m, 2H) 4.03 (q, J=7.1 Hz, 2H)
4.43-4.52 (m, 1H) 7.29-7.36 (m, 3H) 7.42-7.46 (m, 2H) 7.58-7.65 (m,
4H) 8.30 (d, J=8.4 Hz, 1H) 8.64 (br s, 1H).
Example 3-4
[0325] 1H NMR (400 MHz, DMSO-d6) .delta. ppm 1.13 (t, J=7.1 Hz, 3H)
2.55 (d, J=6.9 Hz, 2H) 2.82-2.92 (m, 2H) 4.00 (q, J=7.1 Hz, 2H)
4.43-4.52 (m, 1H) 7.29-7.35 (m, 3H) 7.42-7.46 (m, 2H) 7.58-7.65 (m,
4H) 7.93-7.96 (m, 1H) 8.10 (d, J=2.3 Hz, 1H) 8.25 (d, J=8.3 Hz, 1H)
12.53 (d, J=6.1 Hz, 1H).
Example 3-5
[0326] 1H NMR (400 MHz, DMSO-d6) .delta. ppm 1.13 (t, J=7.1 Hz, 3H)
2.55 (d, J=7.6 Hz, 2H) 2.81-2.92 (m, 2H) 4.02 (q, J=7.1 Hz, 2H)
4.43-4.52 (m, 1H) 7.29-7.36 (m, 3H) 7.42-7.46 (m, 2H) 7.57-7.65 (m,
4H) 7.78-7.81 (m, 1H) 7.92 (d, J=2.3 Hz, 1H) 8.16 (d, J=8.1 Hz, 1H)
11.92 (s, 1H).
Example 3-6
[0327] 1H NMR (400 MHz, DMSO-d6) .delta. ppm 1.13 (t, J=7 Hz, 3H)
2.55-2.67 (m, 2H) 2.83-2.94 (m, 2H) 4.02 (q, J=7 Hz, 2H) 4.46-4.55
(m, 1H) 6.82 (s, 1H) 7.28-7.35 (m, 3H) 7.42-7.46 (m, 2H) 7.59 (d,
J=8.3 Hz, 2H) 7.63 (d, J=7.0 Hz, 2H) 8.13 (s, 1H) 8.89 (d, J=8.6
Hz, 1H) 9.56 (s, 1H).
Example 3-7
[0328] 1H NMR (400 MHz, DMSO-d6) .delta. ppm 1.13 (t, J=7 Hz, 3H)
2.56-2.58 (m, 2H) 2.83-2.94 (m, 2H) 4.02 (q, J=7 Hz, 2H) 4.46-4.55
(m, 1H) 7.19 (s, 2H) 7.30-7.35 (m, 3H) 7.42-7.46 (m, 2H) 7.58-7.65
(m, 4H) 8.22 (d, J=8.1 Hz, 1H) 8.60 (s, 1H).
Example 3-9
Synthesis of (R)-benzyl
3-(4-butoxy-4-oxobutanamido)-4-(3'-chlorobiphenyl-4-yl)butanoate
##STR00152##
[0330] A mixture of (R)-benzyl
3-amino-4-(3'-chlorobiphenyl-4-yl)butanoate hydrochloride (150 mg,
0.360 mmol), 4-butoxy-4-oxobutanoic acid (107 mg, 0.540 mmol, 88%
purity), EDCI (104 mg, 0.540 mmol), DIPEA (0.094 ml, 0.540 mmol)
and HOAt (73.6 mg, 0.540 mmol) in DMF (2 ml) is allowed to stir at
room temperature for 1 hour. The reaction mixture is diluted with
water, and then the precipitated solid is collected on a funnel,
washed with H.sub.2O, and dried under reduced pressure to give
crude. The obtained residue is purified by silica gel flash column
chromatography (heptane/EtOAc=100:0 to 0:100) to give (R)-benzyl
3-(4-butoxy-4-oxobutanamido)-4-(3'-chlorobiphenyl-4-yl)butanoate
(178.9 mg); HPLC retention time=1.47 minutes (condition B); MS
(m+1)=536.42; 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.90-0.94
(m, 3H) 1.31-1.40 (m, 2H) 1.56-1.63 (m, 2H) 2.39-2.42 (m, 2H)
2.48-2.62 (m, 4H) 2.84 (A of ABX, J.sub.ab=13.6 Hz, J.sub.ax=8.1
Hz, 1H) 2.97 (B of ABX, J.sub.ab=13.6 Hz, J.sub.bx=6.6 Hz, 1H) 4.07
(t, J=6.7 Hz, 2H) 4.48-4.56 (m, 1H) 5.12 (A of AB, J=12.1 Hz, 1H)
5.18 (B of AB, J=12.1 Hz, 1H) 6.27 (br d, J=7.7 Hz, 1H) 7.20 (d,
J=8.3 Hz, 1H) 7.29-7.39 (m, 7H) 7.42-7.47 (m, 3H) 7.54-7.55 (m,
1H).
[0331] Following compounds are prepared using similar procedure as
described in example 3-8:
TABLE-US-00009 HPLC-RT MS Example # Product Starting Material
Condition (condition) (M + 1) Example 3-10 ##STR00153## (R)-methyl
6-(1-(3'-chlorobiphenyl-4-yl)-4-ethoxy-4-oxobutan-2-
ylamino)-6-oxohexanoate ##STR00154## ##STR00155## EDCl, HOAt,
DIPEA, DMF, RT 1.40 min. (B) 460.5 Example 3-11 ##STR00156##
(R)-ethyl 4-(3'-chlorobiphenyl-4-yl)-3-(3(pyridin-3-
yl)propanamido)butanoate ##STR00157## ##STR00158## EDCl, HOAt, DMF,
RT 1.56 min. (A) 451.3 Example 3-12 ##STR00159## (1S,4s)-methyl
4-((R)-1-(biphenyl-4-yl)-4-ethoxy-4-oxobutan-
2-ylcarbamoyl)cyclohexanecarboxylate ##STR00160## ##STR00161##
EDCl, HOAt, DIPEA, DMF, RT 1.42 min. (B) 452.2 Example 3-13
##STR00162## (1R,4r)-methyl
4-((R)-1-(biphenyl-4-yl)-4-ethoxy-4-oxobutan-
2-ylcarbamoyl)cyclohexanecarboxylate ##STR00163## ##STR00164##
EDCl, HOAt, DIPEA, DMF, RT 1.42 min. (B) 452.3 Example 3-14
##STR00165## (R)-ethyl 4-(3'-chlorobiphenyl-4-yl)-3-(3-(pyridin-2-
yl)propanamido)butanoate ##STR00166## ##STR00167## EDCl, HOAt,
DIPEA, DMF, RT 1.61 min. (A) 451.3 Example 3-16 ##STR00168##
(R)-benzyl 4-(3'-chlorobiphenyl-4-yl)-3-(4-ethoxy-4-
oxobutanamido)butanoate ##STR00169## ##STR00170## EDCl, HOAt,
DIPEA, DMF, RT 1.56 min. (B) 508.3 Example 3-17 ##STR00171##
(R)-ethyl
5-(4-(benzyloxy)-1-(3'-chlorobiphenyl-4-yl)-4-oxobutan-2-ylamino)-
5-oxopentanoate ##STR00172## ##STR00173## EDCl, HOAt, DIPEA, DMF,
RT 1.57 min. (B) 522.4 Example 3-18 ##STR00174## (R)-tert-butyl
2-(3-(1-(3'-chlorobiphenyl-4-yl)-4-ethoxy-4-
oxobutan-2-ylamino)-3-oxopropyl)-1H-benzo[d]imidazole-1-
carboxylate ##STR00175## ##STR00176## EDCl, HOAt, DIPEA, THF, RT
0.80 min. (B) 590.3 Example 3-19 ##STR00177## tert-butyl
4-(1-(3'-chloro-3-fluorobiphenyl-4-yl)-4-ethoxy-4-
oxobutan-2-ylamino)-4-oxobutanoate ##STR00178## ##STR00179## EDCl,
HOAt, DMF, RT 1.46 min. (B) 492.5
Example 3-10
[0332] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.29 (t, J=7.2
Hz, 3H) 1.58-1.64 (m, 4H) 2.14-2.18 (m, 2H) 2.28-2.32 (m, 2H) 2.49
(A of ABX, J.sub.ab=16.2 Hz, J.sub.ax=5.3 Hz, 1H) 2.53 (B of ABX,
J.sub.ab=16.2 Hz, J.sub.bx=5.3 Hz, 1H) 2.87 (A of ABX,
J.sub.ab=13.6 Hz, J.sub.ax=8.1 Hz, 1H) 2.99 (B of ABX,
J.sub.ab=13.6 Hz, J.sub.bx=6.8 Hz, 1H) 3.65 (s, 3H) 4.11-4.23 (m,
2H) 4.48-4.56 (m, 1H) 6.18 (br d, J=8.8 Hz, 1H) 7.26-7.37 (m, 4H)
7.43-7.52 (m, 3H) 7.56 (br t, J=1.8 Hz, 1H)
Example 3-11
[0333] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.27 (t, J=7.1
Hz, 3H) 2.40-2.51 (m, 4H) 2.77-2.83 (m, 1H) 2.91-2.97 (m, 3H)
4.08-4.20 (m, 2H) 4.46-4.54 (m, 1H) 6.22-6.24 (m, 1H) 7.18-7.23 (m,
3H) 7.29-7.37 (m, 2H) 7.43-7.49 (m, 3H) 7.55-7.57 (m, 2H) 8.44 (d,
J=4.8 Hz, 1H) 8.48 (s, 1H).
Example 3-12
[0334] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.29 (t, J=7.1
Hz, 3H) 1.53-2.20 (m, 9H) 2.46-2.57 (m, 3H) 2.86 (A of ABX,
J.sub.ab=13.6 Hz, J.sub.ax=7.8 Hz, 1H) 2.98 (B of ABX,
J.sub.ab=13.6 Hz, J.sub.bx=6.6 Hz, 1H) 3.65 (s, 3H) 4.11-4.23 (m,
2H) 4.47-4.55 (m, 1H) 6.23 (br d, J=8.6 Hz, 1H) 7.24-7.26 (m, 2H)
7.31-7.35 (m, 1H) 7.41-7.45 (m, 2H) 7.51-7.59 (m, 4H).
Example 3-13
[0335] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.29 (t, J=7.2
Hz, 3H) 1.36-1.51 (m, 4H) 1.84-1.94 (m, 2H) 1.98-2.06 (m, 3H)
2.24-2.32 (m, 1H) 2.50 (A of ABX, J.sub.ab=16.2 Hz, J.sub.ax=5.3
Hz, 1H) 2.53 (B of ABX, J.sub.ab=16.2 Hz, J.sub.bx=5.1 Hz, 1H) 2.86
(A of ABX, J.sub.ab=13.6 Hz, J.sub.ax=7.8 Hz, 1H) 2.98 (B of ABX,
J.sub.ab=13.6 Hz, J.sub.bx=6.6 Hz, 1H) 3.66 (s, 3H) 4.11-4.23 (m,
2H) 4.46-4.55 (m, 1H) 6.19 (br d, J=8.8 Hz, 1H) 7.24-7.26 (m, 2H)
7.31-7.36 (m, 1H) 7.41-7.45 (m, 2H) 7.51-7.58 (m, 4H).
Example 3-14
[0336] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.26 (t, J=7.2
Hz, 3H) 2.41-2.51 (m, 4H) 2.62-2.66 (m, 2H) 2.84 (A of ABX,
J.sub.ab=13.6 Hz, J.sub.ax=7.6 Hz, 1H) 2.92 (B of ABX,
J.sub.ab=13.6 Hz, J.sub.bx=6.6 Hz, 1H) 3.06-3.10 (m, 2H) 4.08-4.19
(m, 2H) 4.46-4.55 (m, 1H) 6.78 (d, J=8.9 Hz, 1H) 7.10-7.12 (m, 1H)
7.16 (d, J=7.8 Hz, 1H) 7.20-7.22 (m, 2H) 7.29-7.31 (m, 1H) 7.35 (t,
J=7.7 Hz, 1H) 7.42-7.47 (m, 3H) 7.54-7.59 (m, 2H) 8.48 (d, J=1.0
Hz, 1H).
Example 3-16
[0337] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.24 (t, J=7.1
Hz, 3H) 2.38-2.42 (m, 2H) 2.49-2.61 (m, 4H) 2.82-3.00 (m, 2H) 4.12
(q, J=7.1 Hz, 2H) 4.47-4.56 (m, 1H) 5.12 (A of AB, J=12.3 Hz, 1H)
5.18 (B of AB, J=12.3 Hz, 1H) 6.26 (br d, J=8.6 Hz, 1H) 7.20 (d,
J=8.3 Hz, 2H) 7.29-7.46 (m, 10H) 7.54-7.54 (m, 1H).
Example 3-17
[0338] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.23 (t, J=7.2
Hz, 3H) 1.86-1.92 (m, 2H) 2.14-2.18 (m, 2H) 2.24-2.28 (m, 2H)
2.50-2.63 (m, 2H) 2.82-2.99 (m, 2H) 4.11 (q, J=7.2 Hz, 2H)
4.53-4.54 (m, 1H) 5.12 (A of AB, J=12.1 Hz, 1H) 5.18 (B of AB,
J=12.1 Hz, 1H) 6.12-6.14 (m, 1H) 7.19-7.54 (m, 13H).
Example 3-18
[0339] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.26 (t, J=7.2
Hz, 3H) 1.67 (s, 9H) 2.46-2.57 (m, 2H) 2.74-2.96 (m, 4H) 3.41-3.45
(m, 2H) 4.09-4.17 (m, 2H) 4.50-4.59 (m, 1H) 6.95 (br d, J=8.6 Hz,
1H) 7.18 (d, J=8.1 Hz, 2H) 7.27-7.42 (m, 7H) 7.51 (t, J=1.8 Hz, 1H)
7.61-7.65 (m, 1H) 7.86-7.93 (m, 1H).
Example 3-19
[0340] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.28 (t, J=7.2
Hz, 3H) 1.43 (s, 9H) 2.37-2.40 (m, 2H) 2.50-2.59 (m, 4H) 2.98 (d,
J=7.3 Hz, 2H) 4.13-4.21 (m, 2H) 4.48-4.56 (m, 1H) 6.35 (br d, J=8.8
Hz, 1H) 7.22-7.44 (m, 6H) 7.54-7.54 (m, 1H).
Example 3-20
Synthesis of (R)-ethyl
4-(3'-aminobiphenyl-4-yl)-3-(4-methoxy-4-oxobutanamido)butanoate
##STR00180##
[0342] A suspension of (R)-ethyl
3-(4-methoxy-4-oxobutanamido)-4-(3'-nitrobiphenyl-4-yl)butanoate
(123 mg, 0.278 mmol) and Pd/C (59.2 mg, 0.028 mmol) in EtOH (2 ml)
is allowed to stir under hydrogen at room temperature for 5.5
hours. The reaction mixture is filtered, and the solution is
concentrated to give (R)-ethyl
4-(3'-aminobiphenyl-4-yl)-3-(4-methoxy-4-oxobutanamido)butanoate
(105 mg); HPLC retention time=0.84 minutes (condition B); MS
(m+1)=413.1; 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.28 (t,
J=7.2 Hz, 3H) 2.41-2.65 (m, 6H) 2.85-3.00 (m, 2H) 3.67 (s, 3H)
4.11-4.22 (m, 2H) 4.46-4.54 (m, 1H) 6.31 (br d, J=8.8 Hz, 1H)
6.71-6.74 (m, 1H) 6.95-7.02 (m, 2H) 7.21-7.25 (m, 3H) 7.48-7.50 (m,
2H).
[0343] Following compounds are prepared using similar procedure as
described in example 3-20:
TABLE-US-00010 Example HPLC-RT MS # Product Condition (condition)
(M + 1) Example 3-22 ##STR00181## (R)-benzyl
4-(3'-chlorobiphenyl-4-yl)-3-(4-(2,3-dihydro-
1H-inden-5-yloxy)-4-oxobutanamido)butanoate ##STR00182## Example
BB-13, PyBOP, indanol, DCM, RT 1.73 min. (B) 596.5
Example 3-22
[0344] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 2.03-2.11 (m, 2H)
2.48-2.62 (m, 4H) 2.81-2.90 (m, 7H) 2.95-3.00 (m, 1H) 4.49-4.58 (m,
1H) 5.07-5.18 (m, 2H) 6.23 (br d, J=8.6 Hz, 1H) 6.79-6.82 (m, 1H)
6.92 (s, 1H) 7.15-7.20 (m, 3H) 7.29-7.45 (m, 10H) 7.52-7.53 (m,
1H)
Example 3-23
Synthesis of (S)-benzyl
1-(2-((R)-1-(biphenyl-4-yl)-4-ethoxy-4-oxobutan-2-ylamino)-2-oxoethyl)pyr-
rolidine-2-carboxylate trifluoroacetic acid salt
##STR00183##
[0346] To a solution of (S)-benzyl
1-(2-tert-butoxy-2-oxoethyl)pyrrolidine-2-carboxylate (200 mg,
0.626 mmol) and triethylsilane (0.250 ml, 1.565 mmol) in DCM (3
ml), TFA (0.965 ml, 12.52 mmol) is added at room temperature. After
stirring for 24 hours, the reaction is concentrated to give
crude.
[0347] To a suspension of the crude, (R)-ethyl
3-amino-4-(biphenyl-4-yl)butanoate hydrochloride (266 mg, 0.832
mmol), WSC.HCl (0.180 g, 0.939 mmol) and HOAt (128 mg, 0.939 mmol)
in DMF (4 ml), DIPEA (0.328 ml, 1.878 mmol) is added. After
stirring for 4 hours, the reaction is diluted with H.sub.2O and
EtOAc. The products are extracted with EtOAc, washed with brine,
dried over Na.sub.2SO.sub.4, filtered, and concentrated. The crude
is subjected twice to column chromatography (heptane/EtOAc=100:0 to
0:100). Then, the obtained product is purified by preparative HPLC
using a gradient of 20% MeCN/water (0.1% TFA) to 100% MeCN to give
(S)-benzyl
1-(2-((R)-1-(biphenyl-4-yl)-4-ethoxy-4-oxobutan-2-ylamino)-2-oxoethyl)pyr-
rolidine-2-carboxylate trifluoroacetic acid salt (28.5 mg) as a
pale yellow solid; HPLC retention time=1.84 minutes (condition D);
MS (m+1)=529.3; 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm
1.25-1.28 (m, 3H) 1.74-1.85 (m, 2H) 1.91-1.98 (m, 1H) 2.09-2.19 (m,
1H) 2.35-2.41 (m, 1H) 2.46 (A of ABX, Jab=15.7 Hz, Jax=6.6 Hz, 1H)
2.59 (B of ABX, J.sub.ab=13.7 Hz, J.sub.bx=5.7 Hz, 1H) 2.78-2.83
(m, 1H) 2.86 (A of ABX, J.sub.ab=13.8 Hz, J.sub.ax=8.1 Hz, 1H) 2.99
(B of ABX, J.sub.ab=13.7 Hz, J.sub.bx=6.4 Hz, 1H) 3.08 (A of AB,
J=16.5 Hz, 1H) 3.35 (B of AB, J=16.5 Hz, 1H) 3.41 (dd, J=9.1 and
5.1 Hz, 1H) 4.11-4.20 (m, 2H) 4.46-4.55 (m, 1H) 5.10 (A of AB,
J=12.4 Hz, 1H) 5.13 (B of AB, J=12.4 Hz, 1H) 7.26-7.27 (m, 2H)
7.31-7.38 (m, 6H) 7.40-7.44 (m, 2H) 7.49-7.56 (m, 4H) 7.74 (br d,
J=8.6 Hz, 1H).
Example 3-24
Synthesis of (R)-ethyl
4-(3'-acetamidobiphenyl-4-yl)-3-(4-methoxy-4-oxobutanamido)butanoate
##STR00184##
[0349] A solution of (R)-ethyl
4-(3'-aminobiphenyl-4-yl)-3-(4-methoxy-4-oxobutanamido)butanoate
(70.5 mg, 0.171 mmol), Et.sub.3N (0.027 ml, 0.205 mmol) and
Ac.sub.2O (0.019 ml, 0.205 mmol) in DCM (1.7 ml) is allowed to stir
at room temperature for 65 hours. The reaction mixture is diluted
with water. The products are extracted with DCM in a phase
separator and concentrated to give crude (98 mg). The crude is
purified by silica gel flash column chromatography (eluent:
DCM/MeOH=10:1) to give (R)-ethyl
4-(3'-acetamidobiphenyl-4-yl)-3-(4-methoxy-4-oxobutanamido)butanoate
(71.5 mg); HPLC retention time=1.45 minutes (condition D); MS
(m+1)=455.4; 1H NMR (400 MHz, CD3CN, mixture of rotamers, data for
major rotamer) .delta. ppm 1.21 (t, J=7.1 Hz, 3H) 2.07 (s, 3H)
2.31-2.34 (m, 2H) 2.40-2.51 (m, 4H) 2.82-2.84 (m, 2H) 3.58 (s, 3H)
4.07 (q, J=7.1 Hz, 2H) 4.34-4.43 (m, 1H) 6.46 (br d, J=8.9 Hz, 1H)
7.28-7.39 (m, 4H) 7.52-7.54 (m, 3H) 7.80 (s, 1H) 8.37 (br s,
1H).
Example 3-25
Synthesis of
(R)-3-(4-butoxy-4-oxobutanamido)-4-(3'-chlorobiphenyl-4-yl)butanoic
acid
##STR00185##
[0351] A suspension of (R)-benzyl
3-(4-butoxy-4-oxobutanamido)-4-(3'-chlorobiphenyl-4-yl)butanoate
(178.9 mg, 0.334 mmol) and Pd/C (71.0 mg, 0.033 mmol) in EtOAc (3
ml) is allowed to stir under hydrogen at room temperature for 1.5
hours. The reaction mixture is filtered, and concentrated to give
crude. The resulting residue is purified by preparative HPLC using
a gradient of 20% MeCN/water (0.1% TFA) to 100% MeCN to give
(R)-3-(4-butoxy-4-oxobutanamido)-4-(3'-chlorobiphenyl-4-yl)butanoic
acid (90.7 mg) as a white solid; HPLC retention time=1.27 minutes
(condition B); MS (m+1)=446.24; 1H NMR (400 MHz, CHLOROFORM-d)
.delta. ppm 0.91 (t, J=7.5 Hz, 3H) 1.31-1.40 (m, 2H) 1.55-1.62 (m,
2H) 2.43-2.47 (m, 2H) 2.52-2.69 (m, 4H) 2.93 (A of ABX,
J.sub.ab=13.7 Hz, J.sub.ax=7.7 Hz, 1H) 3.00 (B of ABX,
J.sub.ab=13.7 Hz, J.sub.bx=6.8 Hz, 1H) 4.07 (t, J=6.7 Hz, 2H)
4.49-4.57 (m, 1H) 6.31 (br d, J=8.6 Hz, 1H) 7.26-7.37 (m, 4H)
7.43-7.46 (m, 1H) 7.49-7.52 (m, 2H) 7.55 (br t, J=1.8 Hz, 1H).
[0352] Chiral HPLC retention time=4.33 min. Column: Daicel
CHIRALPAK IA (4.6.times.100 mm); flow rate=1 ml/min.; eluent: EtOH
(containing 0.1% TFA)/heptane=10/90 to 70/30 in 10 min. (linear
gradient).
[0353] Following compounds are prepared using similar procedure as
described in example 3-24:
TABLE-US-00011 HPLC-RT MS Example # Product Condition (condition)
(M + 1) Example 3- 26 ##STR00186## (R)-4-(3'-
chlorobiphenyl-4-yl)-3- (5-ethoxy-5- oxopentanamido)butanoic acid
Pd/C, H.sub.2, EtOAc, RT 1.08 min. (B) 432.4 Example 3- 27
##STR00187## (R)-4-(3'- chlorobiphenyl-4-yl)-3- (4-(2,3-dihydro-1H-
inden-5-yloxy)-4- oxobutanamido)butanoic acid Pd/C, H.sub.2, EtOAc,
acetone, RT 1.36 min. (B) 506.4 Example 3- 28 ##STR00188##
(R)-4-(3'- chlorobiphenyl-4-yl)-3- (4-ethoxy-4-
oxobutanamido)butanoic acid Pd/C, H.sub.2, EtOAc, RT 1.00 min. (B)
418.4
Example 3-26
[0354] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.23 (t, J=7.1
Hz, 3H) 1.86-1.93 (m, 2H) 2.57 (A of ABX, J.sub.ab=16.3 Hz,
J.sub.ax=5.7 Hz, 1H) 2.64 (B of ABX, J.sub.ab=16.3 Hz, J.sub.bx=5.2
Hz, 1H) 2.94 (A of ABX, J.sub.ab=13.7 Hz, J.sub.ax=7.6 Hz, 1H) 2.99
(B of ABX, J.sub.ab=13.7 Hz, J.sub.bx=7.2 Hz, 1H) 4.10 (q, J=7.1
Hz, 2H) 4.51-4.60 (m, 1H) 6.17 (br d, J=8.6 Hz, 1H) 7.26-7.37 (m,
4H) 7.43-7.45 (m, 1H) 7.49-7.52 (m, 2H) 7.55 (br t, J=1.8 Hz,
1H).
Example 3-27
[0355] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 2.07 (quint,
J=7.4 Hz, 2H) 2.51-2.63 (m, 4H) 2.82-3.02 (m, 8H) 4.50-4.59 (m, 1H)
6.28 (d, J=8.6 Hz, 1H) 6.78-6.81 (m, 1H) 6.91 (d, J=1.8 Hz, 1H)
7.26-7.36 (m, 6H) 7.41-7.44 (m, 1H) 7.47-7.50 (m, 2H) 7.53-7.54 (m,
1H).
Example 3-28
[0356] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.24 (t, J=7.2
Hz, 3H) 2.44-2.69 (m, 6H) 2.93 (A of ABX, J.sub.ab=13.7 Hz,
J.sub.ax=7.8 Hz, 1H) 3.00 (B of ABX, J.sub.ab=13.7 Hz, J.sub.bx=6.7
Hz, 1H) 4.12 (q, J=7.2 Hz, 2H) 4.49-4.57 (m, 1H) 6.35 (br d, J=8.6
Hz, 1H) 7.26-7.37 (m, 4H) 7.43-7.46 (m, 1H) 7.49-7.52 (m, 2H) 7.55
(br t, J=1.6 Hz, 1H).
Example 3-29
Synthesis of
(R)-3-(4-(benzyloxy)-4-oxobutanamido)-4-(3'-chlorobiphenyl-4-yl)butanoic
acid
##STR00189##
[0358] A solution of succinic acid mono-benzyl ester (71.1 mg,
0.342 mmol), EDCI (65.5 mg, 0.342 mmol) and HOAt (46.5 mg, 0.342
mmol) in DMF (1 ml), which is allowed to stir at room temperature
for 1 hour, is added to a solution of
(R)-3-amino-4-(3'-chlorobiphenyl-4-yl)butanoic acid (66 mg, 0.228
mmol) and DIPEA (0.080 ml, 0.456 mmol) in a mixed solvent DMF (2
ml) and water (2 ml). The reaction mixture is allowed to stir for 3
hours, and then diluted with H.sub.2O. The products are extracted
twice with EtOAc. The combined organic layer is washed with brine,
dried over Na.sub.2SO.sub.4, filtered, and concentrated to give
crude. The resulting residue is purified by preparative HPLC using
a gradient of 20% MeCN/water (0.1% TFA) to 100% MeCN to give
(R)-3-(4-(benzyloxy)-4-oxobutanamido)-4-(3'-chlorobiphenyl-4-yl)butanoic
acid (42.4 mg) as a white solid; HPLC retention time=1.22 minutes
(condition B); MS (m+1)=480.35; 1H NMR (400 MHz, CHLOROFORM-d)
.delta. ppm 2.44-2.75 (m, 6H) 2.86-2.99 (m, 2H) 4.48-4.56 (m, 1H)
5.11 (s, 2H) 6.29 (br d, J=8.6 Hz, 1H) 6.97-7.07 (m, 10H) 7.25-7.36
(m, 2H) 7.42-7.50 (m, 2H) 7.54 (br t, J=1.6 Hz, 1H).
Example 3-30
Synthesis of
4-(biphenyl-4-yl)-3-(1-(carboxymethyl)cyclopentanecarboxamido)butanoic
acid
##STR00190##
[0360] To tert-butyl
4-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)butanoate (110 mg,
0.267 mmol), a solution of 4 M HCl in 1,4-dioxane (0.668 ml, 2.67
mmol) is added. After stirring for 1 h, the reaction mixture is
concentrated to give crude 3-amino-4-biphenyl-4-yl-butyric acid
tert-butyl ester hydrochloride.
[0361] Next, to a solution of EDCI (51.2 mg, 0.267 mmol),
1-hydroxy-7-azabenzotriazole (36.4 mg, 0.267 mmol) and 6:1 mixture
of 1-(2-(benzyloxy)-2-oxoethyl)cyclopentanecarboxylic acid and
2-(1-(benzyloxycarbonyl)cyclopentyl)acetic acid (65.6 mg, 0.214
mmol) in DMF (1 ml), which is stirred for 1.5 hours in advance, the
crude 3-amino-4-biphenyl-4-yl-butyric acid tert-butyl ester
hydrochloride and DIPEA (0.093 ml, 0.535 mmol) are added. After
stirring for 2.5 hours, the reaction mixture is diluted with
H.sub.2O, and the products are extracted with EtOAc. The organic
layer is washed with brine, dried over Na2SO4, filtered, and
concentrated. The obtained residue is purified by silica gel flash
column chromatography (heptane/EtOAc=100:0 to 0:100) to give crude
tert-butyl
3-(1-(2-(benzyloxy)-2-oxoethyl)cyclopentanecarboxamido)-4-(biphenyl-4-yl)-
butanoate (38 mg).
[0362] Next, to the solution of the crude tert-butyl
3-(1-(2-(benzyloxy)-2-oxoethyl)cyclopentanecarboxamido)-4-(biphenyl-4-yl)-
butanoate (38 mg) in DCM (0.7 ml), TFA (0.263 ml, 3.42 mmol) is
added. After stirring for 1 hour, the reaction mixture is
concentrated to give crude
3-(1-(2-(benzyloxy)-2-oxoethyl)cyclopentanecarboxamido)-4-(biphenyl-
-4-yl)butanoic acid (39 mg).
[0363] Next, A suspension of the crude (39 mg) and Pd/C (16.6 mg,
7.8 .mu.mol) in EtOH (1 ml) is allowed to stir under hydrogen at
room temperature for 4 hours. The reaction mixture is filtered, and
concentrated to give crude. The resulting residue is purified by
preparative HPLC using a gradient of 20% MeCN/water (0.1% TFA) to
100% MeCN to give
4-(biphenyl-4-yl)-3-(1-(carboxymethyl)cyclopentanecarboxamido)butanoic
acid (12.7 mg); HPLC retention time=1.16 minutes (condition B); MS
(m+1)=410.1; 1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.39-1.53
(m, 6H) 1.83-1.98 (m, 2H) 2.34-2.45 (m, 2H) 2.53 (s, 2H) 2.73-2.86
(m, 2H) 4.21-4.33 (m, 1H) 7.27 (d, J=8.1 Hz, 2H) 7.32-7.37 (m, 2H)
7.43-7.46 (m, 2H) 7.55-7.58 (m, 2H) 7.62-7.64 (m, 2H) 7.84 (br d,
J=8.9 Hz, 1H).
Example 3-31
Synthesis of (R)-ethyl
4-(3'-chlorobiphenyl-4-yl)-3-(2-oxo-2,3-dihydrooxazole-5-carboxamido)buta-
noate
##STR00191##
[0365] To a solution of (R)-ethyl
4-(3'-chlorobiphenyl-4-yl)-3-(2-methoxyoxazole-5-carboxamido)butanoate,
intermediate 14, (103 mg, 0.23 mmol) in dioxane (3 mL) is added 4 N
solution of HCl in dioxane (0.29 mL, 1.16 mmol). The crude was
stirred at room temperature for 2 hrs. The crude is concentrated
and is diluted in water and EtOAc. The organic layer is washed with
brine, dried over MgSO.sub.4, filtered, and concentrated. 50% of
the crude is purified via RP-HPLC (SunFire C18, H.sub.2O (0.1%
TFA)/CH.sub.3CN) to give (R)-ethyl
4-(3'-chlorobiphenyl-4-yl)-3-(2-oxo-2,3-dihydrooxazole-5-carboxamido)buta-
noate (38 mg) as a white solid. HPLC retention time=1.66 minutes
(condition A); MS (m+1)=429.4; 1H NMR (400 MHz, CHLOROFORM-d)
.delta. ppm 1.29 (t, J=7.1 Hz, 3H) 2.51-2.69 (m, 2H) 2.95 (dd, 1H)
3.05 (dd, 1H) 4.19 (q, 2H) 4.58-4.75 (m, 1H) 6.83 (d, J=8.8 Hz, 1H)
7.26-7.33 (m, 4H) 7.35 (t, J=7.7 Hz, 1H) 7.45 (dt, J=7.6, 1.5 Hz,
1H) 7.51 (d, J=8.3 Hz, 2H) 7.56 (t, J=1.8 Hz, 1H) 8.45 (br. s.,
1H).
Example 3-32
Synthesis of (R)-ethyl
4-(3'-chlorobiphenyl-4-yl)-3-(2-oxo-2,3-dihydrothiazole-5-carboxamido)but-
anoate
##STR00192##
[0367] To a solution of (R)-ethyl
4-(3'-chlorobiphenyl-4-yl)-3-(2-methoxythiazole-5-carboxamido)butanoate,
intermediate 13, (170 mg, 0.37 mmol) in dioxane (5 mL) is added a
solution of 4 M HCl in dioxane (0.5 mL, 2.00 mmol). The crude is
stirred at room temperature for 3 hrs. The crude is concentrated.
Part of the crude is purified via RP-HPLC (SunFire C18, H.sub.2O
(0.1% TFA)/CH.sub.3CN) to give (95 mg) of (R)-ethyl
4-(3'-chlorobiphenyl-4-yl)-3-(2-oxo-2,3-dihydrothiazole-5-carboxamido)but-
anoate as a white solid. HPLC retention time=1.82 minutes
(condition D); MS (m+1)=445.2. 1H NMR (400 MHz, CHLOROFORM-d)
.delta. ppm 1.29 (t, J=7.1 Hz, 3H) 2.46-2.70 (m, 2H) 2.78-2.97 (m,
1H) 3.07 (dd, J=13.0, 6.2 Hz, 1H) 4.11-4.28 (m, 2H) 4.51-4.69 (m,
1H) 6.64 (d, J=8.1 Hz, 1H), 7.19-7.42 (m, 5H) 7.44 (d, J=6.1 Hz,
1H) 7.48-7.62 (m, 3H), 9.54 (br. s., 1H).
Example 3-33
Synthesis of (R)-ethyl
4-(3'-chlorobiphenyl-4-yl)-3-(5-oxo-4,5-dihydro-1,3,4-oxadiazole-2-carbox-
amido)butanoate
##STR00193##
[0369] To a solution of (R)-ethyl
4-(3'-chlorobiphenyl-4-yl)-3-(2-hydrazinyl-2-oxoacetamido)butanoate,
intermediate 12, (289 mg, 0.72 mmol) in THF (8.5 mL) is added CDI
(139 mg, 0.86 mmol) at room temperature. After stirring for 18 hour
at room temperature, the reaction is quenched with H.sub.2O and 1M
HCl, and the crude is diluted with EtOAc. The organic layer is
washed with brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated under reduced pressure. The obtained residue is
purified by RP-HPLC (SunFire C18, H.sub.2O (0.1% TFA)/CH.sub.3CN)
and then lyophilized to give (R)-ethyl
4-(3'-chlorobiphenyl-4-yl)-3-(5-oxo-4,5-dihydro-1,3,4-oxadiazole-2-carbox-
amido)butanoate (100 mg). HPLC retention time=1.67 minutes
(condition A); MS (m+1)=430.2; 1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 1.14 (t, J=7.1 Hz, 3H) 2.52-2.70 (m, 2H) 2.84 (dd,
J=13.7, 8.4 Hz, 1H) 2.90 (dd, J=13.7, 8.4 Hz, 1H) 4.02 (q, J=7.1
Hz, 2H) 4.42-4.58 (m, 1H) 7.30 (d, J=8.1 Hz, 2H) 7.37-7.43 (m, 1H)
7.47 (t, J=7.8 Hz, 1H) 7.57-7.66 (m, 3H) 7.70 (t, J=1.9 Hz, 1H)
8.98 (d, J=8.8 Hz, 1H) 12.94 (s, 1H).
Example 3-34
Synthesis of
(R)-3-(3-Carboxymethyl-ureido)-4-(3'-chloro-biphenyl-4-yl)-butyric
acid ethyl ester
##STR00194##
[0371] To a solution of t-butyl 2-aminoacetate (19.08 mg, 0.145
mmol) and DIEA (18.8 mg, 0.145 mmol) in DMF (1 mL) is added
Intermediate 45 (50 mg, 0.145 mmol) and the mixture is stirred at
room temperature for 2 hours. The solvent is removed under reduced
pressure to give
(R)-3-(3-tert-butoxycarbonylmethyl-ureido)-4-(3'-chloro-biphenyl-4-yl)-bu-
tyric acid ethyl ester.
[0372] Next, to a solution of the above diester (70 mg, 0.147 mmol)
in methylene chloride (2 mL) is added TFA (4 mL) and the mixture is
stirred at room temperature for 18 hours. The solvents are removed
under reduced pressure and the residue is purified by preparative
HPLC using a gradient of 35% MeCN/water to 100% MeCN (+0.1% TFA).
Lyophilization of the proper fractions gives the title compound;
HPLC Retention time 1.42 minutes (condition C); MS 419.1 (M+1); 1H
NMR (400 MHz, DMSO-d.sub.6): .delta. ppm 1.17 (t, J=7.07 Hz, 3H),
2.41 (d, J=7.07 Hz, 2H), 2.77-2.79 (m, 2H), 3.66-3.68 (m, 2H), 4.04
(q, J=7.07 Hz, 2H), 4.08-4.15 (m, 1H), 6.13 (t, J=5.81 Hz, 1H),
6.24 (d, J=8.59 Hz, 1H), 7.28-7.30 (m, 2H), 7.39-7.42 (m, 1H), 7.48
(t, J=7.83 Hz, 1H), 7.62-7.64 (m, 3H), 7.71 (t, J=1.77 Hz, 1H),
12.42 (s, 1H).
Example 4-1
Synthesis of
(R)-4-biphenyl-4-yl-3-(2-1H-tetrazol-5-yl-acetylamino)-butyric acid
ethyl ester
##STR00195##
[0374] To a solution of
(R)-4-biphenyl-4-yl-3-tert-butoxycarbonylamino-butyric acid ethyl
ester (100 mg, 0.261 mmol) in DCM (3 mL) at room temperature is
added TFA (1 mL, 12.98 mmol) and the mixture is stirred at room
temperature for 0.5 hour. The mixture is concentrated under reduced
pressure to give (R)-3-amino-4-biphenyl-4-yl-butyric acid ethyl
ester trifluoroacetic salt. HPLC retention time=1.50 minutes
(condition C); MS (m+1)=384.
[0375] Next, to a suspension of (R)-3-amino-4-biphenyl-4-yl-butyric
acid ethyl ester trifluoroacetic salt (0.074 g, 0.261 mmol) in DCM
(10 mL) at room temperature is added 1H-tetrazole-5-acetic acid
(0.050 g, 0.392 mmol). To the mixture at ice bath temperature is
added bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.100 g, 0.392
mmol) and quickly followed by DIPEA (0.137 ml, 0.783 mmol). The
reaction mixture is slowly warmed up to room temperature and
stirred overnight. The reaction is extracted with DCM. The combined
organic layer is washed with saturated NaHCO.sub.3, saturated
NH.sub.4Cl, brine and dried over anhydrous sodium sulfate, filtered
and concentrated under reduced pressure to give
(R)-4-biphenyl-4-yl-3-(2-1H-tetrazol-5-yl-acetylamino)-butyric acid
ethyl ester. HPLC retention time=1.04 minutes (condition E); MS
(m+1)=394.
Example 4-2
Synthesis of (R)-ethyl
4-(biphenyl-4-yl)-3-(6-(methylsulfonamido)nicotinamido)butanoate
##STR00196##
[0377] To a solution of (R)-ethyl
3-amino-4-(3'-chlorobiphenyl-4-yl)butanoate hydrochloride (103 mg,
0.32 mmol) and 6-(methylsulfonamido)nicotinic acid, intermediate
15, (84 mg, 0.39 mmol) in CH.sub.2Cl.sub.2 (2 mL) and DMF (2 mL) is
added TEA (0.18 mL, 1.29 mmol) and HATU (159 mg, 0.42 mmol) at room
temperature. The crude is stirred at room temperature for 2 hrs.
The crude is quenched with saturated NaHCO.sub.3, diluted in EtOAc.
The organic layer is washed with six times with water, brine, dried
over MgSO.sub.4, filtered, and concentrated. The crude is purified
via RP-HPLC (SunFire C18, H.sub.2O (0.1% TFA)/CH.sub.3CN) to give
(R)-ethyl
4-(biphenyl-4-yl)-3-(6-(methylsulfonamido)nicotinamido)butanoate as
a white solid (4.1 mg). HPLC retention time=1.61 minutes (condition
A); MS (m+1)=482.3. 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.22
(t, J=7.2 Hz, 3H), 2.56 (t, J=4.8 Hz, 2H), 2.84-2.92 (m, 1H), 3.05
(dd, J=13.6, 6.1 Hz, 1H), 3.16 (s, 3H), 4.08-4.18 (m, 2H),
4.57-4.71 (m, 1H), 7.03 (d, J=8.3 Hz, 1H), 7.10 (d, J=8.3 Hz, 1H),
7.22 (d, J=8.3 Hz, 2H), 7.26-7.31 (m, 1H), 7.33-7.40 (m, 2H),
7.44-7.54 (m, 5H), 7.98 (dd, J=8.8, 2.3 Hz, 1H), 8.52 (s, 1H).
[0378] Following compounds are prepared using similar procedure as
described in example 4-2:
TABLE-US-00012 LCMS-RT MS Example # Product Reagent (condition) (M
+ 1) Example 4-3 ##STR00197## (R)-ethyl 4-(3'-
chlorobiphenyl-4-yl)-3-(4- (methylsulfonamido) benzamido)butanoate
##STR00198## EDCl and HOAt used instead of HATU 1.68 min (A) 515.2
Example 4-4 ##STR00199## (R)-ethyl 4-(3'-
chlorobiphenyl-4-yl)-3-(2- ethylthiazole-5- carboxamido)butanoate
##STR00200## intermediate 26 1.63 min (A) 457.2 Example 4-5
##STR00201## (R)-ethyl 3-(4-amino-4- oxobutanamido)-4-(3'-
chlorobiphenyl-4- yl)butanoalte ##STR00202## EDCl and HOAt used
instead of HATU 1.49 min (A) 417.3 Example 4-6 ##STR00203##
(R)-ethyl 4-(3'- chlorobiphenyl-4-yl)-3-(2- ethyloxazole-5-
carboxamido)butanoate ##STR00204## intermediate 23 1.60 min (A)
441.3 Example 4-7 ##STR00205## (R)-ethyl 4-(3'-
chlorobiphenyl-4-yl)-3-(3- hydroxy-1H-pyrazole-5-
carboxamido)butanoate ##STR00206## 1.82 min (A) 428.2 Example 4-8
##STR00207## (R)-ethyl 4-(3'- chlorobiphenyl-4-yl)-3-(5-
oxo-4,5-dihydro-1H- 1,2,4-triazole-3- carboxamido)butanoate
##STR00208## EDCl and HOAt used instead of HATU 1.86 min (D) 429.2
Example 4-9 ##STR00209## (R)-ethyl 4-(3'-
chlorobiphenyl-4-yl)-3-(6- hydroxypyridazine-3-
carboxamido)butanoate ##STR00210## EDCl and HOAt used instead of
HATU 1.82 min (D) 440.2 Example 4-10 ##STR00211## (R)-ethyl 4-(3'-
chlorobiphenyl-4-yl)-3-(3- hydroxyisothiazole-5-
carboxamido)butanoate ##STR00212## intermediate 20 EDCl and HOAt
used instead of HATU 1.56 min (A) 445.3 Example 4-11 ##STR00213##
(R)-ethyl 4-(3'- chlorobiphenyl-4-yl)-3-(2- oxo-2,3-dihydrooxazole-
4-carboxamido)butanoate ##STR00214## Intermediate 19 EDCl and HOAt
used instead of HATU 1.79 min (D) 429.1 Example 4-12 ##STR00215##
(R)-ethyl 4-(3'- chlorobiphenyl-4-yl)-3-(6- (methylsulfonamido)
nicotinamido)butanoate ##STR00216## intermediate 15 1.81 min. (D)
516.2
Example 4-3
[0379] 1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.13 (t, J=7.1
Hz, 3H) 2.52-2.67 (m, 2H) 2.88 (dd, J=13.3, 8.0 Hz, 1H) 2.95 (dd,
J=13.3, 8.0 Hz, 1H) 3.05 (s, 3H) 4.02 (q, J=7.1 Hz, 2H) 4.46-4.65
(m, 1H) 7.23 (d, J=8.8 Hz, 2H) 7.34 (d, J=8.1 Hz, 2H) 7.36-7.42 (m,
1H) 7.46 (t, J=7.8 Hz, 1H) 7.59-7.66 (m, 3H) 7.69 (t, J=1.8 Hz, 1H)
7.75 (d, J=8.6 Hz, 2H) 8.31 (d, J=8.3 Hz, 1H) 10.07 (s, 1H)
Example 4-4
[0380] 1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.13 (t, J=7.1
Hz, 3H) 1.28 (t, J=7.5 Hz, 3H) 2.59 (d, J=7.1 Hz, 2H) 2.81-2.94 (m,
2H) 2.97 (q, J=7.6 Hz, 2H) 4.03 (q, J=7.1 Hz, 2H) 4.40-4.55 (m, 1H)
7.32 (d, J=8.1 Hz, 2H) 7.36-7.42 (m, 1H) 7.46 (t, J=7.8 Hz, 1H)
7.58-7.65 (m, 3H) 7.69 (t, J=1.9 Hz, 1H) 8.18 (s, 1H) 8.52 (d,
J=8.3 Hz, 1H)
Example 4-5
[0381] 1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 1.24 (t, J=7.1 Hz,
3H) 2.38-2.60 (m, 6H) 2.78-2.94 (m, 2H) 4.10 (q, J=7.1 Hz, 2H)
4.42-4.55 (m, 1H) 7.32 (d, J=8.3 Hz, 2H) 7.40 (t, J=7.83 Hz, 1H)
7.50-7.53 (m, 4H) 7.60 (t, J=1.89 Hz, 1H)
Example 4-6
[0382] 1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.13 (t, J=7.2
Hz, 3H) 1.25 (t, J=7.6 Hz, 3H) 2.53-2.65 (m, 2H) 2.80 (q, J=7.6 Hz,
2H) 2.84-2.96 (m, 2H) 4.02 (q, J=7.1 Hz, 2H) 4.42-4.60 (m, 1H) 7.31
(d, J=8.3 Hz, 2H) 7.37-7.42 (m, 1H) 7.47 (t, J=7.8 Hz, 1H) 7.59 (s,
1H) 7.60-7.65 (m, 3H) 7.69 (t, J=1.9 Hz, 1H) 8.48 (d, J=8.6 Hz,
1H)
Example 4-7
[0383] 1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.13 (t, J=7.1
Hz, 3H) 2.52-2.65 (m, 2H) 2.85 (dd, J=13.6, 5.8 Hz, 1H) 2.91 (dd,
J=13.6, 5.8 Hz, 1H) 4.02 (q, J=7.1 Hz, 2H) 4.38-4.60 (m, 1H) 5.89
(s, 1H) 7.31 (d, J=8.3 Hz, 2H) 7.37-7.42 (m, 1H) 7.46 (t, J=7.8 Hz,
1H) 7.58-7.65 (m, 3H) 7.69 (t, J=1.8 Hz, 1H) 8.10 (d, J=8.6 Hz,
1H)
Example 4-8
[0384] 1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 1.22 (t, J=7.2 Hz,
3H) 2.56-2.72 (m, 2H) 2.95 (d, J=7.3 Hz, 2H) 4.11 (q, J=7.2 Hz, 2H)
4.53-4.73 (m, 1H) 7.28-7.36 (m, 3H) 7.39 (t, J=7.8 Hz, 1H)
7.48-7.55 (m, 3H) 7.58 (t, J=1.8 Hz, 1H)
Example 4-9
[0385] 1H NMR (400 MHz, DMSO-d.sub.2) .delta. ppm 1.13 (t, J=7.1
Hz, 3H) 2.53-2.71 (m, 2H) 2.85 (dd, J=13.7, 8.3 Hz, 1H) 2.96 (dd,
J=13.7, 8.3 Hz, 1H) 4.02 (q, J=7.1 Hz, 2H) 4.45-4.63 (m, 1H) 6.93
(dd, J=9.9, 2.3 Hz, 1H) 7.30 (d, J=8.1 Hz, 2H) 7.36-7.42 (m, 1H)
7.47 (t, J=7.8 Hz, 1H) 7.61 (d, J=8.3 Hz, 3H) 7.69 (t, J=1.8 Hz,
1H) 7.75 (d, J=9.9 Hz, 1H) 8.45 (d, J=9.1 Hz, 1H) 13.41 (d, J=2.0
Hz, 1H)
Example 4-10
[0386] 1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.13 (t, J=7.1
Hz, 3H) 2.60 (d, J=7.6 Hz, 2H) 2.90 (d, J=6.8 Hz, 2H) 4.02 (q,
J=7.2 Hz, 2H) 4.39-4.53 (m, 1H) 7.11 (s, 1H) 7.32 (d, J=8.1 Hz, 2H)
7.37-7.43 (m, 1H) 7.47 (t, J=7.8 Hz, 1H) 7.60-7.66 (m, 3H) 7.70 (t,
J=1.9 Hz, 1H) 8.72 (d, J=8.3 Hz, 1H) 11.76 (br. s., 1H)
Example 4-11
[0387] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.27 (t, J=7.1
Hz, 3H) 2.47-2.69 (m, 2H) 2.90 (dd, J=13.6, 7.8 Hz, 1H) 3.06 (dd,
J=13.6, 6.6 Hz, 1H) 3.06 (broad s, 1H) 4.07-4.28 (m, 2H) 4.52-4.74
(m, 1H) 7.21-7.37 (m, 5H) 7.38-7.44 (m, 1H) 7.48 (d, J=8.1 Hz, 2H)
7.53 (t, J=1.6 Hz, 1H) 9.50 (br. s., 1H).
Example 4-12
[0388] 1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.13 (t, J=7.1
Hz, 3H) 2.59 (d, J=7.3 Hz, 2H) 2.76-3.03 (m, 2H) 4.03 (q, J=7.1 Hz,
2H) 4.39-4.66 (m, 1H) 7.02 (d, 1H) 7.28-7.54 (m, 4H) 7.54-7.80 (m,
4H) 8.05 (dd, J=8.6, 2.3 Hz, 1H) 8.45 (d, J=8.3 Hz, 1H) 8.61 (br.
s., 1H).
Example 4-13
Synthesis of (R)-ethyl
4-(5'-fluoro-2'-methoxybiphenyl-4-yl)-3-(oxazole-5-carboxamido)butanoate
##STR00217##
[0390] To a solution of oxazole-5-carboxylic acid (70 mg, 0.61
mmol) in DMF (1.5 mL) and DCM (1.5 mL) is added (R)-ethyl
3-amino-4-(5'-fluoro-2'-methoxybiphenyl-4-yl)butanoate
hydrochloride, intermediate 10, (150 mg, 0.41 mmol), HATU (233 mg,
0.61 mmol), and TEA (284 .mu.L, 2.04 mmol). After stirring for 2
hours, the reaction is quenched with H.sub.2O, and the crude is
diluted with EtOAc, the organic layer is washed with brine, dried
over Na.sub.2SO.sub.4, filtered, and concentrated under reduced
pressure. The obtained residue is purified by RP-HPLC (SunFire C18,
H.sub.2O (0.1% TFA)/CH.sub.3CN), and then lyophilized to give
(R)-ethyl
4-(5'-fluoro-2'-methoxybiphenyl-4-yl)-3-(oxazole-5-carboxamido)butanoate
(157 mg). HPLC retention time=1.50 minutes (condition A); MS
(m+1)=427.4; 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.19 (t,
J=7.2 Hz, 3H) 2.46-2.62 (m, 2H) 2.86 (dd, J=13.6, 8.1 Hz, 1H) 3.02
(dd, J=13.6, 6.1 Hz, 1H) 3.67 (s, 3H) 4.05-4.15 (m, 2H) 4.52-4.69
(m, 1H) 6.76-6.82 (m, 1H) 6.83-6.96 (m, 2H) 7.11-7.21 (m, 3H) 7.37
(d, J=8.1 Hz, 2H) 7.61 (s, 1H) 7.80 (s, 1H)
[0391] Following compounds are prepared using similar procedure as
described in example 4-13:
TABLE-US-00013 Example 4- 14 ##STR00218## (R)-ethyl
4-(5'-fluoro-2'- methoxybiphenyl-4-yl-3- (3-hydroxyisoxazole-5-
carboxamido)butanoate ##STR00219## 1.43 min. (A) 443.3
Example 4-14
[0392] 1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 1.21 (t, J=7.1 Hz,
3H) 2.61-2.68 (m, 2H) 2.95 (d, J=7.1 Hz, 2H) 3.74 (s, 3H) 4.10 (q,
J=7.1 Hz, 2H) 4.60-4.73 (m, 1H) 6.43 (s, 1H) 6.98-7.06 (m, 3H) 7.27
(d, J=8.1 Hz, 2H) 7.38-7.48 (m, 2H) 8.78 (d, J=8.8 Hz, 1H)
Example 4-15
Synthesis of
5-[(R)-1-(3'-Chloro-biphenyl-4-ylmethyl)-2-ethoxycarbonyl-ethylcarbamoyl]-
-1H-pyrazole-3-carboxylic acid
##STR00220##
[0394] To a mixture of Intermediate 17-1 (130 mg, 0.367 mmol),
1H-pyrazole-3,5-dicarboxylic acid (74.5 mg, 0.477 mmol), EDCI (91
mg, 0.477 mmol) and HOBt (64.5 mg, 0.477 mmol) in DMF (3 mL) is
added triethylamine (149 mg, 0.203 mmol) and the mixture is stirred
at room temperature for 18 hours. Any insoluble material is removed
by filtration and the filtrate is chromatographed by HPLC using a
gradient of 10% MeCN/water to 100% MeCN (+0.1% TFA). Lyophilization
of the proper fractions gives the title compound; HPLC Retention
time 1.31 minutes (condition C); MS 456.2 (M+1); 1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.12 (t, J=7.07 Hz, 3H), 2.54-2.67 (m,
2H), 2.84-2.97 (m, 2H), 4.02 (q, J=7.07 Hz, 2H), 4.54 (m, 1H), 7.11
(s, broad, 1H), 7.32 (d, J=8.08 Hz, 2H), 7.39 (m, 1H), 7.46 (t,
1H), 7.62 (d, J=8.08 Hz, 3H), 7.69 (s, 1H), 8.41 (s, broad,
1H).
[0395] The following compounds are prepared using the procedure
described for Example 4-15.
TABLE-US-00014 HPLC-RT MS Example # Product Reagent (condition) (M
+ 1) Example 4-16 ##STR00221## 6-[(R)-1-(3'-Chloro-
biphenyl-4-ylmethyl)-2- ethoxycarbonyl- ethylcarbamoyl]-
pyrimidine-4-carboxylic acid ##STR00222## 1.31 min. (C) 468.2
Example 4-16
[0396] 1H NMR (400 MHz, DMSO-d.sub.6): .delta. ppm 1.11 (t, J=7.07
Hz, 3H), 2.59-2.79 (m, 2H), 2.87-2.92 (m, 1H), 2.98-3.04 (m, 1H),
4.01 (q, J=7.33 Hz, 2H), 4.57-4.66 (m, 1H), 7.30-7.32 (m, 2H),
7.37-7.40 (m, 1H), 7.45 (t, J=7.58 Hz, 1H), 7.59-7.61 (m, 3H), 7.68
(t, J=1.77 Hz, 1H), 8.16 (s, 1H), 9.10 (d, J=9.35 Hz, 1H), 9.31 (s,
1H).
Example 4-17
(R)-4-(3'-Chloro-biphenyl-4-yl)-3-[(3-hydroxy-isoxazole-5-carbonyl)-amino]-
-butyric acid ethyl ester
##STR00223##
[0398] To a solution of intermediate 16-1 (40.6 mg, 0.315 mmol) and
HATU (144 mg, 0.378 mmol) in DMF (2 mL) is added pyridine (74.7 mg,
0.76 mL, 0.944 mmol) and the mixture is stirred at room temperature
for 15 minutes. Then Intermediate 17-1 is added and stirring is
continued for 2 hours. Any insoluble is removed by filtration and
the filtrate is chromatographed by HPLC using a gradient of 10%
MeCN/water to 100% MeCN (+0.1% TFA). Lyophilization of the proper
fractions gives the title compound. HPLC Retention time 1.36
minutes (condition C); MS 429.1 (M+1); 1H NMR (400 MHz, DMSO-d6)
.delta. ppm 1.13 (t, J=7.07 Hz, 3H) 2.60 (dd, J=6.95, 3.66 Hz, 2H)
2.81-2.95 (m, 2H) 4.02 (q, J=7.24 Hz, 2H) 4.49 (d, J=7.83 Hz, 1H)
6.49 (s, 1H) 7.31 (d, J=8.34 Hz, 2H) 7.37-7.43 (m, 1H) 7.47 (t,
J=7.83 Hz, 1H) 7.59-7.66 (m, 3H) 7.70 (t, J=1.89 Hz, 1H) 8.83 (d,
J=8.84 Hz, 1H).
[0399] The following compounds are prepared using the procedure
described for Example 4-17
TABLE-US-00015 HPLC-RT MS Example # Product Reagent (condition) (M
+ 1) Example 4-18 ##STR00224## (R)-4-(3'-Chloro- biphenyl-4-yl)-3-
[(oxazole-5-carbonyl)- amino]-butyric acid ethyl ester ##STR00225##
1.48 min. (C) 413.1 Example 4-19 ##STR00226## (R)-4-(3'-Fluoro-
biphenyl-4-yl)-3-[(3- hydroxy-isoxazole-5- carbonyl)-amino]-
butyric acid ethyl ester ##STR00227## 1.22 min. (C) 413.1
Example 4-18
[0400] 1H NMR (400 MHz, DMSO-d6) .delta. ppm 1.12 (t, J=7.07 Hz,
3H) 2.60 (dd, J=6.95, 2.65 Hz, 2H) 2.82-2.96 (m, 2H) 4.02 (q,
J=7.07 Hz, 2H) 4.45-4.58 (m, 1H) 7.31 (d, J=8.34 Hz, 2H) 7.37-7.42
(m, 1H) 7.47 (t, J=7.83 Hz, 1H) 7.58-7.65 (m, 3H) 7.69 (t, J=1.77
Hz, 1H) 7.72 (s, 1H) 8.55 (s, 1H) 8.63 (d, J=8.59 Hz, 1H).
Example 4-19
[0401] 1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.13 (t, J=7.07
Hz, 3H) 2.54-2.75 (m, 2H) 2.76-3.02 (m, 2H) 4.02 (q, J=7.07 Hz, 2H)
4.29-4.70 (m, 1H) 6.49 (s, 1H) 6.96-7.23 (m, 1H) 7.30 (d, J=8.08
Hz, 2H) 7.44-7.58 (m, 3H) 7.64 (d, J=8.08 Hz, 2H) 8.83 (d, J=8.59
Hz, 1H) 11.68 (s, 1H).
Example 4-20
(R)-3-[(5-Carboxymethyl-furan-2-carbonyl)-amino]-4-(3'-chloro-biphenyl-4-y-
l)-butyric acid ethyl ester and
Example 4-21
(R)-3-[(5-Carboxymethyl-furan-2-carbonyl)-amino]-4-(3'-chloro-biphenyl-4-y-
l)-butyric acid
##STR00228##
[0403] The reaction is performed similar to Example 4-15 using
Intermediate 16-1 and Intermediate 44 to give
(R)-4-(3'-chloro-biphenyl-4-yl)-3-[(5-methoxycarbonylmethyl-furan-2-carbo-
nyl)-amino]-butyric acid ethyl ester. HPLC Retention time 1.38
minutes (condition C).
[0404] Next, to a solution of the above diester (235 mg, 0.486
mmol) in EtOH (5 mL) is added 1N NaoH (0.486 mL) and the mixture is
stirred at room temperature for 4 hours. The solvent is removed
under reduced pressure and water (4 mL) is added. The solution is
acidified with 1N HCl and the mixture is extracted with EtOAc. The
organic phase is dried over sodium sulfate and the solvent is
removed under reduced pressure. The residue is purified by
preparative HPLC using a gradient of 10% MeCN/water to 100% MeCN
(+0.1% TFA). Lyophilization of the proper fractions gives the title
compounds.
(R)-3-[(5-Carboxymethyl-furan-2-carbonyl)-amino]-4-(3'-chloro-biphenyl-4--
yl)-butyric acid ethyl ester. HPLC Retention time 1.35 minutes
(condition C); MS 470.0 (M+1); 1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 1.13 (t, J=7.07 Hz, 3H), 2.50-2.64 (m, 2H), 2.81-2.95
(m, 2H), 3.74 (s, 2H), 4.01 (q, J=7.07 Hz, 2H), 4.51 (m, 1H), 6.99
(d, J=3.28 Hz, 1H), 7.31 (d, J=8.34 Hz, 2H), 7.38-7.41 (m, 1H),
7.47 (t, 1H), 7.62 (d, J=8.08 Hz, 3H), 7.69 (t, 1H), 8.24 (d,
J=8.84 Hz, 1H).
[0405]
(R)-3-[(5-Carboxymethyl-furan-2-carbonyl)-amino]-4-(3'-chloro-biphe-
nyl-4-yl)-butyric acid. HPLC Retention time 0.94 minutes (condition
C); MS 442.0 (M+1); 1H NMR (400 MHz, DMSO-d6) .delta. ppm 2.44-2.58
(m, 2H), 2.81-2.94 (m, 2H), 3.74 (s, 2H), 4.48 (m, 1H), 6.39 (d,
J=3.28 Hz, 1H), 6.99 (d, J=3.54 Hz, 1H), 7.30 (d, J=8.34 Hz, 2H),
7.38-7.41 (m, 1H), 7.47 (t, 1H), 7.62 (d, J=8.34 Hz, 3H), 7.70 (t,
J=1.77 Hz, 1H), 8.22 (d, J=8.84 Hz, 1H).
Example 4-22
(R)-4-(3'-Chloro-biphenyl-4-yl)-3-[(2H-tetrazole-5-carbonyl)-amino]-butyri-
c acid ethyl ester
##STR00229##
[0407] To a solution of intermediate 16-1 in DCM (8 ml) at room
temperature is added 2-(4-methoxy-benzyl)-2H-tetrazole-5-carbonyl
chloride and followed by TEA (0.293 ml, 2.100 mmol). The reaction
is stirred at room temperature for 5 min. The reaction is quenched
by brine and is extracted with DCM. The combined organic layer is
washed with brine and dried over anhydrous sodium sulfate, filtered
and concentrated under reduced pressure. The residue is purified by
column chromatography (15% to 40% EtOAc/Heptane). The obtained
residue in TFA (5 ml, 64.9 mmol) is heated at 80.degree. C. for 0.5
hours. The reaction is concentrated under reduced pressure to give
(R)-4-(3'-chloro-biphenyl-4-yl)-3-[(2H-tetrazole-5-carbonyl)-amino]-butyr-
ic acid ethyl ester.
[0408] HPLC retention time=1.31 minutes (condition B); MS
(m+1)=414.1; 1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.11 (t,
J=7.1 Hz, 3H), 2.63 (dd, J=15.4, 5.6 Hz, 1H), 2.72 (dd, J=15.4, 8.3
Hz, 1H), 2.86-2.99 (m, 2H), 4.02 (q, J=7.1 Hz, 2H), 4.55-4.67 (m,
1H), 7.32 (d, J=8.1 Hz, 2H), 7.37-7.42 (m, 1H), 7.46 (t, J=7.8 Hz,
1H), 7.60 (d, J=8.1 Hz, 3H), 7.68 (t, J=1.8 Hz, 1H), 9.37 (d, J=8.8
Hz, 1H).
[0409] Following compounds are prepared using similar procedure as
described in example 4-22:
TABLE-US-00016 Depro- tection Example Condi- HPLC-RT MS # Product
Starting Material tion (condition) (M + 1) Example 4-23
##STR00230## (R)-4-(3'-Fluoro- biphenyl-4-yl)-3- [(2H-tetrazole-5-
carbonyl)-amino]- butyric acid ethyl ester ##STR00231##
##STR00232## 1 atm. H.sub.2, 10% Pd/C, EtOH, RT 1.12 min. (B) 398.2
Example 4-24 ##STR00233## (R)-4-(3'-Chloro- biphenyl-4-yl)-3-
[(2H-tetrazole-5- carbonyl)-amino]- butyric acid indan- 5-yl ester
##STR00234## ##STR00235## TFA, 80.degree. C. 1.68 min. (B)
502.3
Example 4-23
[0410] 1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.12 (t, J=7.2
Hz, 3H), 2.59-2.67 (m, J=15.4, 5.6 Hz, 1H), 2.72 (dd, J=15.4, 8.3
Hz, 1H), 2.85-3.01 (m, 2H), 4.02 (q, J=7.1 Hz, 2H), 4.55-4.67 (m,
1H), 7.11-7.19 (m, 1H), 7.32 (d, J=8.3 Hz, 2H), 7.42-7.51 (m, 3H),
7.61 (d, J=8.3 Hz, 2H), 9.34 (d, J=8.8 Hz, 1H).
Example 4-24
[0411] 1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.95-2.06 (m,
2H), 2.75-2.92 (m, 6H), 2.95 (dd, J=13.5, 5.9 Hz, 1H), 3.06 (dd,
J=13.6, 8.1 Hz, 1H), 4.64-4.76 (m, 1H), 6.78 (dd, J=8.1, 2.3 Hz,
1H), 6.88 (d, J=1.5 Hz, 1H), 7.17 (d, J=8.1 Hz, 1H), 7.34-7.41 (m,
3H), 7.46 (t, J=7.8 Hz, 1H), 7.59-7.65 (m, 3H), 7.70 (t, J=1.8 Hz,
1H), 8.43 (d, J=8.8 Hz, 1H).
Example 4-25
2-((R)-1-Biphenyl-4-ylmethyl-2-ethoxycarbonyl-ethylamino)-oxazole-4-carbox-
ylic acid ethyl ester
##STR00236##
[0413] To a suspension of (R)-4-biphenyl-4-yl-3-ureido-butyric acid
ethyl ester (169 mg, 0.518 mmol) in EtOH (5 ml) at ice bath is
added ethyl bromopyruvate (0.098 ml, 0.777 mmol). The reaction is
warmed up slowly to room temperature and stirred at reflux
overnight. The reaction is concentrated and the residue is taken up
in EtOAc and H.sub.2O. The combined organic layer is washed with
brine and dried over anhydrous sodium sulfate, filtered and
concentrated under reduced pressure to give
2-((R)-1-biphenyl-4-ylmethyl-2-ethoxycarbonyl-ethylamino)-oxazole-4-carbo-
xylic acid ethyl ester. HPLC retention time=1.42 minutes (condition
B); MS (m+1)=423.
Example 4-26
Synthesis of (R,E)-ethyl
4-(4-(benzyloxy)-1-(3'-chlorobiphenyl-4-yl)-4-oxobutan-2-ylamino)-4-oxobu-
t-2-enoate
##STR00237##
[0415] To (R)-benzyl 3-amino-4-(3'-chlorobiphenyl-4-yl)butanoate
(87.6 mg, 0.183 mmol) is added a solution of HCl in 1,4-dioxane
(0.456 mL, 1.825 mmol) at room temperature. After stirring for 3
hours, the reaction mixture is concentrated under reduced pressure
to give (R)-benzyl 3-amino-4-(3'-chlorobiphenyl-4-yl)butanoate
hydrochloride. A mixture of (R)-benzyl
3-amino-4-(3'-chlorobiphenyl-4-yl)butanoate hydrochloride, fumaric
acid monoethyl ester (33.4 mg, 0.220 mmol), EDCI (63.3 mg, 0.330
mmol), DIPEA (0.058 ml, 0.330 mmol) and HOAt (44.9 mg, 0.330 mmol)
in DMF (1.8 ml) is allowed to stir at room temperature for 3 hour.
The reaction mixture is diluted with water, and then the products
are extracted with EtOAc. The organic layer is washed with NH4OH,
1M HClaq and brine, dried over Na2SO4, filtered, and concentrated
to give crude. The obtained residue is purified by silica gel flash
column chromatography (heptane/EtOAc=100:0 to 0:100) to give
(R,E)-ethyl
4-(4-(benzyloxy)-1-(3'-chlorobiphenyl-4-yl)-4-oxobutan-2-ylamino)-4-oxobu-
t-2-enoate (72.9 mg); HPLC retention time=1.40 minutes (condition
B); MS (m+1)=506.3; 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.31
(t, J=7.1 Hz, 3H) 2.58 (A of ABX, J.sub.ab=16.4 Hz, J.sub.ax=5.3
Hz, 1H) 2.6 (B of ABX, J.sub.ab=16.4 Hz, J.sub.bx=5.1 Hz, 1H) 2.88
(A of ABX, J.sub.ab=13.6 Hz, J.sub.ax=8.1 Hz, 1H) 3.03 (B of ABX,
J.sub.ab=13.6 Hz, J.sub.bx=6.3 Hz, 1H) 4.24 (q, J=7.1 Hz, 2H)
4.56-4.64 (m, 1H) 5.12 (A of AB, J=12.1 Hz, 1H) 5.18 (B of AB,
J=12.1 Hz, 1H) 6.57 (br d, J=9.1 Hz, 1H) 6.77 (A of AB, J=15.4 Hz,
1H) 6.81 (B of AB, J=15.4 Hz, 1H) 7.19 (br d, J=8.1 Hz, 2H)
7.29-7.47 (m, 10H) 7.53-7.54 (m, 1H).
Example 4-27
Synthesis of (R)-ethyl
4-(3'-chlorobiphenyl-4-yl)-3-(2-(ethoxycarbonylamino)acetamido)butanoate
##STR00238##
[0417] A mixture of (R)-ethyl
3-amino-4-(3'-chlorobiphenyl-4-yl)butanoate hydrochloride (173 mg,
0.488 mmol), 2-(ethoxycarbonylamino)acetic acid (86 mg, 0.488
mmol), EDCI (140 mg, 0.732 mmol), DIPEA (0.128 ml, 0.732 mmol) and
HOAt (100 mg, 0.732 mmol) in DMF (2.5 ml) is allowed to stir at
room temperature for 1 hour. The reaction mixture is diluted with
water, and then the precipitated solid is collected on a funnel,
washed with H.sub.2O, and dried under reduced pressure to give
crude. The obtained residue is purified by silica gel flash column
chromatography (heptane/EtOAc=100:0 to 0:100) to give (R)-ethyl
4-(3'-chlorobiphenyl-4-yl)-3-(2-(ethoxycarbonylamino)acetamido)butanoate
(161 mg); HPLC retention time=1.16 minutes (condition B); MS
(m+1)=447.3; 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.25 (t,
J=7.07 Hz, 3H) 1.29 (t, J=7.07 Hz, 3H) 2.50 (A of ABX,
J.sub.ab=16.2 Hz, J.sub.ax=5.3 Hz, 1H) 2.54 (B of ABX,
J.sub.ab=16.2 Hz, J.sub.b=5.3 Hz, 1H) 2.89 (A of ABX, J.sub.ab=13.6
Hz, J.sub.ax=7.8 Hz, 1H) 2.99 (B of ABX, J.sub.ab=13.6 Hz,
J.sub.bx=6.6 Hz, 1H) 3.80 (be d, J=5.8 Hz, 2H) 4.12-4.23 (m, 4H)
4.48-4.56 (m, 1H) 5.15 (br s, 1H) 6.64 (br d, J=8.8 Hz, 1H)
7.25-7.27 (m, 2H) 7.29-7.38 (m, 2H) 7.43-7.46 (m, 1H) 7.49-7.52 (m,
2H) 7.55-7.56 (m, 1H).
[0418] Following compounds are prepared using similar procedure as
described in example 4-27:
TABLE-US-00017 HPLC-RT MS Example # Product Starting Material
Condition (condition) (M + 1) Example 4- 28 ##STR00239##
##STR00240## ##STR00241## 1.53 min. (A) 533.2 Example 4- 29
##STR00242## ##STR00243## ##STR00244## 1.00 min. (B) 416.1 Example
4- 30 ##STR00245## ##STR00246## ##STR00247## 1.64 min. (A) 476.2
Example 4- 31 ##STR00248## ##STR00249## ##STR00250## 1.66 min. (A)
426.1 Example 4- 32 ##STR00251## ##STR00252## ##STR00253## 1.69
min. (A) 443.2 Example 4- 33 ##STR00254## ##STR00255## ##STR00256##
1.66 min. (A) 438.2 Example 4- 34 ##STR00257## ##STR00258##
##STR00259## 1.71 min. (A) 427.1 Example 4- 35 ##STR00260##
##STR00261## ##STR00262## 1.75 min. (A) 431.1 Example 4- 36
##STR00263## ##STR00264## ##STR00265## 1.81 min. (A) 459.1 Example
4- 37 ##STR00266## ##STR00267## ##STR00268## 1.86 min. (A)
453.2
Example 4-29
[0419] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.31 (t, J=7.2
Hz, 3H) 2.64 (A of ABX, J.sub.ab=16.8 Hz, J.sub.ax=5.1 HZ, 1H) 2.68
(B of ABX, J.sub.ab=16.8 Hz, J.sub.bx=5.1 Hz, 1H) 2.97 (A of ABX,
J.sub.ab=13.7 Hz, J.sub.ax=8.1 HZ, 1H) 3.08 (B of ABX,
J.sub.ab=13.7 Hz, J.sub.bx=6.7 Hz, 1H) 4.25 (q, J=7.2 Hz, 2H)
4.58-4.67 (m, 1H) 6.66 (d, J=8.8 Hz, 1H) 6.80 (A of AB, J=15.4 Hz,
1H) 6.97 (B of AB, J=15.4 Hz, 1H) 7.27-7.37 (m, 4H) 7.43-7.45 (m,
1H) 7.51 (d, J=8.3 Hz, 2H) 7.55-7.56 (m, 1H).
Example 4-30
[0420] 1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 1.21 (t, J=7.2 Hz,
3H) 1.34 (t, J=7.6 Hz, 3H) 2.68 (d, J=6.8 Hz, 2H) 2.84-2.87 (m, 2H)
2.98-3.00 (m, 2H) 4.10 (q, J=7.1 Hz, 2H) 4.66-4.78 (m, 1H)
7.27-7.37 (m, 6H) 7.41-7.47 (m, 1H) 7.54 (s, 1H).
Example 4-31
[0421] 1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 1.20 (t, J=7.1 Hz,
3H) 2.28 (s, 3H) 2.62 (d, J=7.1 Hz, 2H) 2.93 (dd, J=13.6, 6.8 Hz,
1H) 3.00 (dd, J=13.6, 7.3 Hz, 1H) 4.09 (q, J=7.1 Hz, 2H) 4.60-4.76
(m, 1H) 6.45 (s, 1H) 7.24-7.40 (m, 4H) 7.42-7.51 (m, 3H) 7.54 (t,
J=1.8 Hz, 1H).
Example 4-32
[0422] 1H NMR (400 MHz, CD3OD) .delta. ppm 1.20 (t, J=7.2 Hz, 3H)
2.58-2.66 (m, 2H) 2.68 (s, 3H) 2.94 (dd, J=14.2, 7.8 Hz, 1H) 2.99
(dd, J=13.6, 6.8 Hz, 1H) 4.09 (q, J=7.2 Hz, 2H) 4.58-4.76 (m, 1H)
7.27-7.31 (m, 1H) 7.33 (d, J=8.3 Hz, 2H) 7.37 (t, J=7.8 Hz, 1H)
7.46-7.49 (m, 1H) 7.51 (d, J=8.1 Hz, 2H) 7.55 (t, J=1.9 Hz, 1H)
8.06 (s, 1H) 8.49 (d, J=8.6 Hz, 1H).
Example 4-33
[0423] 1H NMR (400 MHz, CD3OD) .delta. ppm 1.21 (t, J=7.1 Hz, 3H)
2.60-2.70 (m, 2H) 2.72 (s, 3H) 2.97 (dd, J=13.6, 8.1 Hz, 1H) 3.03
(dd, J=13.9, 6.6 Hz, 1H) 4.11 (q, J=7.2 Hz, 2H) 4.67-4.81 (m, 1H)
7.27-7.33 (m, 1H) 7.33-7.41 (m, 3H) 7.48-7.52 (m, 1H) 7.54 (d,
J=8.3 Hz, 2H) 7.57 (t, J=1.8 Hz, 1H) 8.70 (d, J=8.3 Hz, 1H) 8.92
(s, 2H).
Example 4-34
[0424] 1H NMR (400 MHz, CD3OD) .delta. ppm 1.21 (t, J=7.2 Hz, 3H)
2.43 (s, 3H) 2.63 (d, J=6.6 Hz, 2H) 2.94 (dd, J=13.9, 7.1 Hz, 1H)
2.99 (dd, J=13.6, 7.6 Hz, 1H) 4.10 (q, J=7.1 Hz, 2H) 4.62-4.74 (m,
1H) 7.26-7.30 (m, 1H) 7.30-7.39 (m, 3H) 7.43-7.51 (m, 3H) 7.53 (t,
J=1.8 Hz, 1H) 8.15 (s, 1H).
Example 4-35
[0425] 1H NMR (400 MHz, CD3OD) .delta. ppm 1.20 (t, J=7.1 Hz, 3H)
2.64 (dd, J=15.4, 7.3 Hz, 1H) 2.70 (dd, J=15.9, 6.3 Hz, 1H) 2.99
(d, J=7.3 Hz, 2H) 4.10 (q, J=7.2 Hz, 2H) 4.65-4.79 (m, 1H) 7.14
(dd, J=10.2, 8.7 Hz, 1H) 7.30 (ddd, J=8.8, 4.1, 2.8 Hz, 1H)
7.32-7.37 (m, 2H) 7.37-7.46 (m, 3H) 7.67 (s, 1H) 8.28 (s, 1H) 8.62
(d, J=8.6 Hz, 1H).
Example 4-36
[0426] 1H NMR (400 MHz, CD3OD) .delta. ppm 1.20 (t, J=7.2 Hz, 3H)
1.33 (t, J=7.7 Hz, 3H) 2.66 (d, J=6.8 Hz, 2H) 2.83 (q, J=7.6 Hz,
2H) 2.98 (d, J=7.1 Hz, 2H) 4.10 (q, J=7.1 Hz, 2H) 4.65-4.79 (m, 1H)
7.14 (dd, J=10.2, 8.7 Hz, 1H) 7.30 (ddd, J=8.8, 4.1, 2.8 Hz, 1H)
7.32-7.37 (m, 2H) 7.37-7.46 (m, 3H) 7.54 (s, 1H) 8.49 (d, J=8.8 Hz,
1H).
Example 4-37
[0427] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.33 (t, J=7.1
Hz, 3H) 2.22 (s, 3H) 2.57-2.72 (m, 2H) 2.99 (dd, J=13.6, 8.1 Hz,
1H) 3.16 (dd, J=13.6, 6.3 Hz, 1H) 4.15-4.33 (m, 2H) 4.60-4.82 (m,
1H) 5.55 (s, 1H) 6.10 (s, 1H) 7.15 (d, J=8.8 Hz, 1H) 7.34 (d, J=8.1
Hz, 3H) 7.39 (t, J=7.7 Hz, 1H) 7.48 (dt, J=7.6, 1.5 Hz, 1H) 7.54
(d, J=8.1 Hz, 2H) 7.58 (t, J=1.8 Hz, 1H) 7.72 (s, 1H).
Example 5-1
Synthesis of (R)-4-(biphenyl-4-yl)-3-(3-carboxypropanamido)butanoic
acid
##STR00269##
[0429] To a solution of
(R)-4-(1-(biphenyl-4-yl)-4-ethoxy-4-oxobutan-2-ylamino)-4-oxobutanoic
acid (61.2 mg, 0.160 mmol) in THF (1.6 mL) and methanol (0.2 mL),
aqueous 1M NaOH solution (0.638 mL, 0.638 mmol) is added at room
temperature. After stirring for 45 minutes, the reaction is
quenched with aqueous 0.1 M HCl and is extracted with ethyl
acetate. The organic layer is washed with brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure
to give (R)-4-(biphenyl-4-yl)-3-(3-carboxypropanamido)butanoic acid
(54.9 mg). HPLC retention time=1.33 minutes (condition A); MS
(m+1)=356.1; 1H NMR (400 MHz, CD3OD) .delta. ppm 2.40-2.56 (m, 6H)
2.83-2.94 (m, 2H) 4.43-4.50 (m, 1H) 7.29-7.32 (m, 3H) 7.41 (t, 2H,
J=7.7 Hz) 7.53-7.60 (m, 4H).
[0430] Following compounds are prepared using similar procedure as
described in example 5-1:
TABLE-US-00018 Hydroysis HPLC-RT MS Example # Product Starting
Material Condition (condition) (M + 1) Example 5-2 ##STR00270##
##STR00271## Aq. NaOH, THF, MeOH, rt 1.10 min. (A) 389.9 Example
5-3 ##STR00272## ##STR00273## Aq. NaOH, THF, MeOH, rt 0.87 min. (A)
373.9 Example 5-4 ##STR00274## ##STR00275## Aq. NaOH, THF, MeOH, rt
0.69 min. (B) 374.0 Example 5-5 ##STR00276## ##STR00277## Aq. NaOH,
THF, MeOH, rt 0.80 min. (B) 373.9 Example 5-6 ##STR00278##
##STR00279## Aq. NaOH, THF, MeOH, rt 0.74 min. (B) 390.0 Example
5-7 ##STR00280## ##STR00281## Aq. NaOH, THF, MeOH, rt 0.61 min. (B)
386.1 Example 5-8 ##STR00282## ##STR00283## Aq. NaOH, THF, MeOH, rt
0.94 min. (B) 370.0 Example 5-9 ##STR00284## ##STR00285## Aq. LiOH,
ETOH, rt. 0.67 min. (B) 362.0 Example 5- 10 ##STR00286##
##STR00287## aq. NaOH, MeOH, RT 1.19 min. (C) 366.0 Example 5- 11
##STR00288## ##STR00289## aq. NaOH, THF, MeOH, RT 1.28 min. (A)
377.9 Example 5- 12 ##STR00290## ##STR00291## aq. NaOH, THF, MeOH,
RT 0.80 min. (B) 406.0 Example 5- 13 ##STR00292## ##STR00293## aq.
NaOH, THF, MeOH, RT 0.74 min. (B) 408.2 Example 5- 14 ##STR00294##
##STR00295## aq. NaOH, THF, MeOH, RT 0.55 min. (B) 370.1 Example 5-
15 ##STR00296## ##STR00297## aq. NaOH, THF, MeOH, RT 0.46 min. (B)
392.1 Example 5- 16 ##STR00298## ##STR00299## aq. NaOH, THF, MeOH,
RT 0.70 min. (B) 384.3 Example 5- 17 ##STR00300## ##STR00301## aq.
NaOH, THF, MeOH, RT 1.40 min. (A) 411.2 Example 5- 18 ##STR00302##
##STR00303## aq. NaOH, THF, MeOH, RT 0.88 min. (A) 371.2 Example 5-
19 ##STR00304## ##STR00305## aq. NaOH, THF, MeOH, RT 1.41 min. (D)
401.2 Example 5- 20 ##STR00306## ##STR00307## aq. NaOH, THF, MeOH,
RT 1.59 min. (H) 424.2 Example 5- 21 ##STR00308## ##STR00309## aq.
NaOH, THF, MeOH, RT 1.44 min. (H) 386.2 Example 5- 22 ##STR00310##
##STR00311## aq. NaOH, THF, MeOH, RT 1.29 min. (B) 377.1 Example 5-
23 ##STR00312## ##STR00313## aq. NaOH, THF, MeOH, RT 0.49 min. (B)
381.1 Example 5- 24 ##STR00314## ##STR00315## aq. NaOH, THF, MeOH,
RT 1.36 min. (A) 394.0 Example 5- 26 ##STR00316## ##STR00317## aq.
NaOH, THF, MeOH, RT 1.20 min. (A) 411.2 Example 5- 27 ##STR00318##
##STR00319## aq. NaOH, THF, MeOH, RT 1.02 min. (B) 408.1 Example 5-
28 ##STR00320## ##STR00321## aq. NaOH, THF, MeOH, RT 0.82 min. (B)
410.1 Example 5- 29 ##STR00322## ##STR00323## aq. NaOH, THF, MeOH,
RT 0.53 min. (B) 424.0 Example 5- 30 ##STR00324## ##STR00325## aq.
NaOH, THF, MeOH, RT 1.36 min. (A) 377.0 Example 5- 31 ##STR00326##
##STR00327## aq. NaOH, THF, MeOH, RT 1.11 min. (A) 381.1 Example 5-
32 ##STR00328## ##STR00329## aq. NaOH, THF, MeOH, RT 0.61 min. (B)
410.1 Example 5- 33 ##STR00330## ##STR00331## aq. NaOH, THF, MeOH,
RT 1.28 min. (A) 376.2 Example 5- 34 ##STR00332## ##STR00333## aq.
NaOH, THF, MeOH, RT 1.51 min. (D) 400.5 Example 5- 35 ##STR00334##
##STR00335## aq. NaOH, THF, MeOH, RT 1.18 min. (D) 413.2 Example 5-
36 ##STR00336## ##STR00337## aq. NaOH, THF, MeOH, 50.degree. C.
0.68 min. (B) 361.2
Example 5-2
[0431] 1H NMR (400 MHz, CD3OD) .delta. ppm 2.38-2.42 (m, 2H)
2.45-2.54 (m, 4H) 2.82-2.94 (m, 2H) 4.42-4.48 (m, 1H) 7.12-7.16 (m,
2H) 7.31 (d, J=8.4 Hz, 2H) 7.41 (d, J=8.6 Hz, 2H) 7.54 (d, J=8.1
Hz, 2H) 7.58 (d, J=8.6 Hz, 2H).
Example 5-3
[0432] 1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 2.39-2.42 (m, 2H)
2.45-2.54 (m, 4H) 2.85 (A of ABX, Jab=13.6 Hz, Jax=7.6 HZ, 1H) 2.91
(B of ABX, Jab=13.6 Hz, Jbx=6.2 HZ, 1H) 4.42-4.48 (m, 1H) 7.12-7.16
(m, 2H) 7.31 (A of AB, J=8.2 Hz, 2H) 7.52 (B of AB, J=8.2 Hz, 2H)
7.58-7.62 (m, 2H)
Example 5-4
[0433] 1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 2.39-2.44 (m, 2H)
2.46-2.55 (m, 4H) 2.86 (A of ABX, Jab=13.6 Hz, Jax=7.6 HZ, 1H) 2.92
(B of ABX, Jab=13.6 Hz, Jbx=6.3 HZ, 1H) 4.42-4.49 (m, 1H) 7.01-7.06
(m, 1H) 7.32 (br d, J=8.1 Hz, 2H) 7.39-7.45 (m, 2H) 7.55 (d, J=8.1
Hz, 2H)
Example 5-5
[0434] 1H NMR (400 MHz, CD3OD) .delta. ppm 2.40-2.43 (m, 2H)
2.46-2.56 (m, 4H) 2.87 (A of ABX, Jab=13.5 Hz, Jax=7.7 HZ, 1H) 2.93
(B of ABX, Jab=13.5 Hz, Jbx=6.2 HZ, 1H) 4.43-4.50 (m, 1H) 7.13-7.18
(m, 1H) 7.20-7.24 (m, 1H) 7.31-7.35 (m, 3H) 7.44-7.48 (m, 3H) 7.99
(br d, J=8.3 Hz, 1H)
Example 5-6
[0435] 1H NMR (400 MHz, CD3OD) .delta. ppm 2.39-2.43 (m, 2H)
2.45-2.57 (m, 4H) 2.87 (A of ABX, Jab=13.6 Hz, Jax=7.6 HZ, 1H) 2.94
(B of ABX, Jab=13.6 Hz, Jbx=6.1 HZ, 1H) 4.44-4.51 (m, 1H) 7.28-7.35
(m, 7H) 7.46 (br d, J=7.9 Hz, 1H)
Example 5-7
[0436] 1H NMR (400 MHz, CD3OD) .delta. ppm 2.40-2.52 (m, 6H)
2.83-2.92 (m, 2H) 3.77 (s, 3H) 4.44-4.47 (m, 1H) 6.96-7.05 (m, 2H)
7.23-7.30 (m, 4H) 7.39-7.41 (m, 2H)
Example 5-8
[0437] 1H NMR (400 MHz, CD3OD) .delta. ppm 2.21 (s, 3H) 2.41-2.55
(m, 6H) 2.82-2.94 (m, 2H) 3.77 (s, 3H) 4.45-4.48 (m, 1H) 7.15-7.28
(m, 8H)
Example 5-9
[0438] 1H NMR (400 MHz, DMSO-d6) .delta. ppm 2.56 (dd, J=5.81,
15.92 Hz, 1H), 2.66 (dd, J=7.07, 15.92 Hz, 1H), 2.90 (dd, J=6.06,
13.64 Hz, 1H), 3.00 (dd, J=8.08, 13.64 Hz, 1H), 4.53-4.64 (m, 1H),
7.30 (d, J=8.34 Hz, 2H), 7.33 (t, J=7.58, 1H), 7.56 (d, J=8.34 Hz,
2H), 7.62 (d, J=7.07 Hz, 2H), 7.95 (dd, J=1.26, 5.05 Hz, 1H),
9.01-9.07 (m, 2H), 9.33 (d, J=1.52 Hz, 1H), 12.28 (s, 1H).
Example 5-10
[0439] 1H NMR (400 MHz, DMSO-d6) .delta. ppm 2.36-2.49 (m, 2H),
2.75-2.86 (m, 2H), 3.83 (s, 2H), 4.19-4.31 (m, 1H), 7.26 (d, J=8.3
Hz, 2H), 7.31-7.38 (m, 1H), 7.45 (t, J=7.6 Hz, 2H), 7.56 (d, J=8.3
Hz, 2H), 7.61-7.67 (m, 2H), 8.40 (d, J=8.1 Hz, 1H), 12.26 (br. s.,
1H), 16.02 (br. s., 1H).
Example 5-11
[0440] 1H NMR (400 MHz, DMSO-d6) .delta. ppm 2.46-2.59 (m, 2H),
2.86-2.88 (m, 2H), 4.41-4.49 (m, 1H), 7.29-7.36 (m, 3H), 7.42-7.46
(m, 2H), 7.58-7.65 (m, 4H), 8.26 (d, J=8 Hz, 1H), 8.64 (br s, 2H)
12.24 (br. s., 1H).
Example 5-12
[0441] 1H NMR (400 MHz, DMSO-d6) .delta. ppm 2.54-2.70 (m, 2H),
2.88-3.03 (m, 2H), 4.56-4.65 (m, 1H), 7.29-7.34 (m, 3H), 7.41-7.45
(m, 2H), 7.55-7.63 (m, 4H), 8.33 (s, 1H), 9.15 (d, J=9.1 Hz, 1H),
9.49 (s, 1H), 12.30 (br s, 1H), 14.11 (br s, 1H).
Example 5-13
[0442] 1H NMR (400 MHz, CD3OD) .delta. ppm 2.38-2.57 (m, 6H) 2.87
(A of ABX, Jab=13.6 Hz, Jax=7.6 Hz, 1H) 2.95 (B of ABX, Jab=13.6
Hz, Jbx=6.1 Hz, 1H) 4.44-4.51 (m, 1H) 7.06-7.14 (m, 2H) 7.31-7.37
(m, 5H) 7.48 (dd, J=8.8 and 5.1 Hz, 1H).
Example 5-14
[0443] 1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 2.39 (s, 3H)
2.39-2.55 (m, 6H) 2.85 (A of ABX, Jab=13.5 Hz, Jax=7.5 HZ, 1H) 2.90
(B of ABX, Jab=13.5 Hz, Jbx=6.4 Hz, 1H) 4.42-4.49 (m, 1H) 7.13 (br
d, J=7.3 Hz, 1H) 7.26-7.30 (m, 3H) 7.36-7.40 (m, 2H) 7.52 (d, J=8.3
Hz, 2H).
Example 5-15
[0444] 1H NMR (400 MHz, CD3OD) .delta. ppm 2.38-2.55 (m, 6H) 2.86
(A of ABX, Jab=13.6 Hz, Jax=7.8 HZ, 1H) 2.93 (B of ABX, Jab=13.6
Hz, Jbx=6.1 HZ, 1H) 4.42-4.49 (m, 1H) 6.86-6.92 (m, 1H) 7.19-7.25
(m, 2H) 7.33-7.35 (m, 2H) 7.55-7.58 (m, 2H).
Example 5-16
[0445] 1H NMR (400 MHz, CD3OD) .delta. ppm 1.27 (t, J=7.6 Hz, 3H)
2.39-2.55 (m, 6H) 2.70 (q, J=7.6 Hz, 2H) 2.85 (A of ABX, Jab=13.6
Hz, Jax=7.5 HZ, 1H) 2.90 (B of ABX, Jab=13.6 Hz, Jbx=6.4 HZ, 1H)
4.42-4.49 (m, 1H) 7.16 (br d, J=7.6 Hz, 1H) 7.28-7.33 (m, 3H)
7.38-7.42 (m, 2H) 7.52-7.54 (m, 2H).
Example 5-17
[0446] 1H NMR (400 MHz, DMSO-d6) .delta. ppm 2.47-2.50 (m, 2H)
2.82-2.91 (m, 2H) 4.40-4.49 (m, 1H) 7.29 (d, J=8.3 Hz, 2H)
7.31-7.36 (m, 1H) 7.42-7.46 (m, 2H) 7.59 (d, J=8.4 Hz, 2H)
7.63-7.65 (m, 2H) 7.95 (br d, J=2.3 Hz, 1H) 8.11 (br d, J=2.3 Hz,
1H) 8.25-8.27 (m, 1H) 12.24 (br s, 1H) 12.48 (br s, 1H).
Example 5-18
[0447] 1H NMR (400 MHz, CD3OD) .delta. ppm 2.38-2.55 (m, 6H) 2.86
(A of ABX, Jab=13.6 Hz, Jax=7.8 Hz, 1H) 2.92 (B of ABX, Jab=13.6
Hz, Jbx=6.3 Hz, 1H) 4.43-4.50 (m, 1H) 7.26 (br d, J=7.3 Hz, 1H)
7.35 (d, J=8.1 Hz, 2H) 7.51-7.58 (m, 4H) 7.64 (br d, J=7.8 Hz,
1H).
Example 5-19
[0448] 1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 2.39-2.42 (m, 2H)
2.45-2.56 (m, 4H) 2.88 (A of ABX, Jab=13.6 Hz, Jax=7.6 Hz, 1H) 2.95
(B of ABX, Jab=13.6 Hz, Jbx=6.2 Hz, 1H) 4.44-4.51 (m, 1H) 6.86-6.89
(m, 1H) 7.38-7.41 (m, 2H) 7.63-7.70 (m, 3H) 8.02-8.04 (m, 1H)
8.18-8.21 (m, 1H) 8.45 (br t, J=1.9 Hz, 1H).
Example 5-20
[0449] 1H NMR (400 MHz, CD3OD) .delta. ppm 2.39-2.56 (m, 6H) 2.87
(A of ABX, Jab=13.6 Hz, Jax=7.6 Hz, 1H) 2.93 (B of ABX, Jab=13.6
Hz, Jbx=6.3 Hz, 1H) 4.43-4.50 (m, 1H) 7.36 (d, J=8.3 Hz, 2H)
7.58-7.62 (m, 4H) 7.85-7.87 (m, 2H).
Example 5-21
[0450] 1H NMR (400 MHz, CD3OD) .delta. ppm 2.39-2.54 (m, 6H) 2.85
(A of ABX, Jab=13.6 Hz, Jax=7.5 Hz, 1H) 2.91 (B of ABX, Jab=13.6
Hz, Jbx=6.3 HZ, 1H) 3.84 (s, 3H) 4.42-4.49 (m, 1H) 6.86-6.89 (m,
1H) 7.11-7.17 (m, 2H) 7.29-7.34 (m, 3H) 7.52-7.54 (m, 2H).
Example 5-22
[0451] 1H NMR (400 MHz, DMSO-d6) .delta. ppm 2.43-2.46 (m, 2H),
2.81-2.91 (m, 2H) 4.40-4.49 (m, 1H) 6.33 (d, J=9.6 Hz, 1H)
7.28-7.35 (m, 3H) 7.42-7.46 (m, 2H) 7.58 (d, J=8.1 Hz, 2H)
7.63-7.65 (m, 2H) 7.81 (dd, J=9.6, 2.8 Hz, 1H) 7.93 (br s, 1H) 8.14
(d, J=8.3 Hz, 1H) 11.92 (br s, 1H) 12.19 (br s, 1H).
Example 5-23
[0452] 1H NMR (400 MHz, CD3OD) .delta. ppm 2.39-2.42 (m, 2H)
2.44-2.55 (m, 4H) 2.86 (A of ABX, Jab=13.6 Hz, Jax=7.6 Hz, 1H) 2.93
(B of ABX, Jab=13.6 Hz, Jbx=6.3 HZ, 1H) 4.43-4.50 (m, 1H) 7.36 (d,
J=8.3 Hz, 2H) 7.58-7.63 (m, 3H) 7.66-7.69 (m, 1H) 7.91-7.94 (m, 1H)
7.97 (br t, J=1.5 Hz, 1H).
Example 5-24
[0453] 1H NMR (400 MHz, DMSO-d6) .delta. ppm 2.50-2.61 (m, 2H)
2.83-2.94 (m, 2H) 4.43-4.52 (m, 1H) 6.82 (s, 1H) 7.28-7.35 (m, 3H)
7.44 (t, J=7.7 Hz, 2H) 7.58-7.65 (m, 4H) 8.12 (s, 1H) 8.86 (d,
J=8.3 Hz, 1H) 9.55 (s, 1H) 12.25 (br s, 1H).
Example 5-25
[0454] 1H NMR (400 MHz, DMSO-d6) .delta. ppm 1.66-2.47 (m, 10H)
2.71-2.83 (m, 2H) 3.31-3.46 (m, 3H) 4.18-4.49 (m, 2H) 7.26-7.28 (m,
2H) 7.32-7.36 (m, 1H) 7.43-7.47 (m, 2H) 7.57-7.66 (m, 4H) 7.86 (d,
J=8.3 Hz, 1H) 12.31 (br s, 2H).
Example 5-26
[0455] 1H NMR (400 MHz, DMSO-d6) .delta. ppm 1.80-2.03 (m, 3H)
2.27-2.31 (m, 1H) 2.39-2.52 (m, 2H) 2.75-2.81 (m, 1H) 2.85-2.89 (m,
1H) 2.95-3.03 (m, 1H) 3.41-3.78 (m, 2H) 3.90-3.99 (m, 1H) 4.14-4.20
(m, 1H) 4.28-4.35 (m, 1H) 7.28-7.37 (m, 3H) 7.44-7.48 (m, 2H)
7.58-7.65 (m, 2H) 8.45 (br s, 1H) 12.34 (br s, 1H).
Example 5-27
[0456] 1H NMR (400 MHz, CD3OD) .delta. ppm 2.38-2.54 (m, 6H) 2.86
(A of ABX, Jab=13.6 Hz, Jax=7.6 Hz, 1H) 2.93 (B of ABX, Jab=13.6
Hz, Jbx=6.2 HZ, 1H) 4.42-4.49 (m, 1H) 7.13-7.17 (m, 1H) 7.31-7.37
(m, 3H) 7.46-7.47 (m, 1H) 7.54-7.57 (m, 2H).
Example 5-28
[0457] 1H NMR (400 MHz, CD3OD) .delta. ppm 1.49-1.71 (m, 6H)
2.01-2.11 (m, 2H) 2.14-2.21 (m, 1H) 2.44-2.56 (m, 3H) 2.83 (A of
ABX, Jab=13.6 Hz, Jax=8.0 Hz, 1H) 2.91 (B of ABX, Jab=13.6 Hz,
Jbx=6.3 HZ, 1H) 4.43-4.51 (m, 1H) 7.28-7.32 (m, 3H) 7.38-7.42 (m,
2H) 7.52 (d, J=8.1 Hz, 2H) 7.56-7.59 (m, 2H) 7.71 (br d, J=8.6 Hz,
1H).
Example 5-29
[0458] 1H NMR (400 MHz, CD3OD) .delta. ppm 2.39-2.42 (m, 2H)
2.45-2.56 (m, 4H) 2.87 (A of ABX, Jab=13.6 Hz, Jax=7.8 Hz, 1H) 2.94
(B of ABX, Jab=13.6 Hz, Jbx=6.1 Hz, 1H) 4.44-4.51 (m, 1H) 7.23 (A
of AB, J=8.0 Hz, 2H) 7.28 (B of AB, J=8.0 Hz, 2H) 7.35 (d, J=7.6
Hz, 1H) 7.50-7.53 (m, 1H) 7.60-7.63 (m, 1H) 7.75 (d, J=7.8 Hz,
1H)
Example 5-30
[0459] 1H NMR (400 MHz, DMSO-d6) .delta. ppm 2.45-2.56 (m, 2H)
2.83-2.93 (m, 2H) 4.43-4.52 (m, 1H) 7.18 (s, 2H) 7.29-7.35 (m, 3H)
7.42-7.46 (m, 2H) 7.58-7.65 (m, 4H) 8.19 (d, J=8.1 Hz, 1H) 8.60 (s,
2H) 12.21 (br s, 1H).
Example 5-31
[0460] 1H NMR (400 MHz, CD3OD) .delta. ppm 2.39-2.43 (m, 2H)
2.46-2.57 (m, 4H) 2.90 (A of ABX, Jab=13.6 Hz, Jax=7.8 Hz, 1H) 2.97
(B of ABX, Jab=13.6 Hz, Jbx=6.1 Hz, 1H) 4.45-4.52 (m, 1H) 7.37-7.39
(m, 2H) 7.49-7.53 (m, 3H) 7.57-7.59 (m, 1H) 7.70-7.74 (m, 1H)
7.80-7.82 (m, 1H).
Example 5-32
[0461] 1H NMR (400 MHz, CD3OD) .delta. ppm 1.33-1.49 (m, 4H)
1.68-1.72 (m, 1H) 1.79-1.83 (m, 1H) 1.96-2.01 (m, 2H) 2.05-2.13 (m,
1H) 2.17-2.25 (m, 1H) 2.43-2.55 (m, 2H) 2.80-2.95 (m, 2H) 4.42-4.49
(m, 1H) 7.28-7.32 (m, 3H) 7.38-7.43 (m, 2H) 7.52-7.59 (m, 4H).
Example 5-33
[0462] 1H NMR (400 MHz, DMSO-d6) .delta. ppm 2.48-2.55 (m, 2H)
2.84-2.96 (m, 2H) 4.44-4.53 (m, 1H) 6.94 (br s, 1H) 7.30-7.35 (m,
3H) 7.42-7.46 (m, 2H) 7.57-7.64 (m, 4H) 8.17-8.60 (br m, 5H) 12.27
(br s, 1H).
Example 5-34
[0463] 1H NMR (400 MHz, CD3OD) .delta. ppm 1.30 (t, J=7.0 Hz, 3H)
2.39-2.56 (m, 6H) 2.82-2.93 (m, 2H) 4.02 (q, J=7.0 Hz, 2H)
4.42-4.49 (m, 1H) 6.96-7.03 (m, 2H) 7.23-7.28 (m, 4H) 7.44 (d,
J=8.4 Hz, 2H).
Example 5-35
[0464] 1H NMR (400 MHz, CD3OD) .delta. ppm 2.14 (s, 3H) 2.39-2.43
(m, 2H) 2.45-2.56 (m, 4H) 2.82-2.94 (m, 2H) 4.02 (q, J=7.0 Hz, 2H)
4.42-4.49 (m, 1H) 7.30-7.38 (m, 4H) 7.49-7.55 (m, 3H) 7.80 (br s,
1H).
Example 5-36
[0465] 1H NMR (400 MHz, CD3OD) .delta. ppm 2.39-2.55 (m, 6H) 2.85
(A of ABX, Jab=13.6 Hz, Jax=7.5 HZ, 1H) 2.90 (B of ABX, Jab=13.6
Hz, Jbx=6.3 HZ, 1H) 4.42-4.49 (m, 1H) 6.86-6.92 (m, 1H) 7.31 (d,
J=8.1 Hz, 2H) 7.53-7.55 (m, 2H).
Example 5-37
Synthesis of
(R)-4-(1-carboxy-3-(5'-fluoro-2'-methoxybiphenyl-4-yl)propan-2-ylamino)-4-
-oxobutanoic acid
##STR00338##
[0467] To a solution of
(R)-4-(4-ethoxy-1-(5'-fluoro-2'-methoxybiphenyl-4-yl)-4-oxobutan-2-ylamin-
o)-4-oxobutanoic acid (83 mg, 0.192 mmol) in MeOH (2 mL) is added
1N NaOH (4 mL, 4 mmol) After stirring at room temperature for 2
hours, the crude is concentrated under reduced pressure to remove
MeOH and is diluted with EtOAc. The organic layer is washed with
brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure. The obtained residue is purified by RP-HPLC
(SunFire C18, H.sub.2O (0.1% TFA)/CH.sub.3CN), and then lyophilized
to give
(R)-4-(1-carboxy-3-(5'-fluoro-2'-methoxybiphenyl-4-yl)propan-2-ylamino)-4-
-oxobutanoic acid (58 mg). HPLC retention time=1.46 minutes
(condition D); MS (m+1)=404.2; 1H NMR (400 MHz, CD.sub.3OD) .delta.
ppm 2.36-2.59 (m, 6H) 2.84 (dd, J=13.4, 6.3 Hz, 1H) 2.91 (dd,
J=13.4, 6.3 Hz, 1H) 3.75 (s, 3H) 4.34-4.56 (m, 1H) 6.95-7.08 (m,
3H) 7.26 (d, J=8.1 Hz, 2H) 7.42 (d, J=8.3 Hz, 2H)
[0468] Following compounds are prepared using similar procedure as
described in example 5-37:
TABLE-US-00019 Hydrolysis LCMS-RT MS Example # Product Starting
Material Condition (condition) (M + 1) Example 5- 38 ##STR00339##
##STR00340## Aq. NaOH, MeOH, rt 1.68 min. (D) 488.1 Example 5- 39
##STR00341## ##STR00342## Aq. NaOH, MeOH, rt 1.52 min. (D) 420.1
Example 5- 40 ##STR00343## ##STR00344## Aq. NaOH, MeOH, rt 1.57
min. (D) 487.2 Example 5- 41 ##STR00345## ##STR00346## Aq. NaOH,
MeOH, rt 1.65 min. (D) 429.1 Example 5- 42 ##STR00347##
##STR00348## Aq. NaOH, MeOH, rt 1.42 min. (D) 390.2 Example 5- 43
##STR00349## ##STR00350## Aq. NaOH, MeOH, rt 1.53 min. (D) 420.2
Example 5- 44 ##STR00351## ##STR00352## Aq. NaOH, MeOH, rt 1.45
min. (D) 378.1 Example 5- 45 ##STR00353## ##STR00354## Aq. NaOH,
MeOH, rt 1.26 min. (A) 389.3 Example 5- 46 ##STR00355##
##STR00356## Aq. NaOH, MeOH, rt 1.53 min. (D) 402.2 Example 5- 47
##STR00357## ##STR00358## Aq. NaOH, MeOH, rt 1.60 min. (D) 413.3
Example 5- 48 ##STR00359## ##STR00360## Aq. NaOH, MeOH, rt 1.38
min. (D) 427.2 Example 5- 49 ##STR00361## ##STR00362## Aq. NaOH,
MeOH, rt 1.37 min. (D) 399.3 Example 5- 50 ##STR00363##
##STR00364## Aq. NaOH, MeOH, rt 1.50 min. (D) 401.1 Example 5- 51
##STR00365## ##STR00366## Aq. NaOH, MeOH, rt 1.39 min. (D) 367.1
Example 5- 52 ##STR00367## ##STR00368## Aq. NaOH, MeOH, rt 1.57
min. (D) 440.1 Example 5- 53 ##STR00369## ##STR00370## Aq. NaOH,
MeOH, rt 1.37 min. (D) 401.3 Example 5- 54 ##STR00371##
##STR00372## Aq. NaOH, MeOH, rt 1.44 min. (D) 400.2 Example 5- 55
##STR00373## ##STR00374## Aq. NaOH, MeOH, rt 1.37 min. (D) 415.1
Example 5- 56 ##STR00375## ##STR00376## Aq. NaOH, MeOH, rt 1.52
min. (D) 400.2 Example 5- 57 ##STR00377## ##STR00378## Aq. NaOH,
MeOH, rt 1.77 min. (D) 368.2 Example 5- 58 ##STR00379##
##STR00380## Aq. NaOH, MeOH, rt 1.63 min. (D) 401.1 Example 5- 59
##STR00381## ##STR00382## Aq. NaOH, MeOH, rt 1.46 min. (D) 416.0
Example 5- 60 ##STR00383## ##STR00384## Aq. NaOH, MeOH, rt 1.41
min. (D) 440.0 Example 5- 61 ##STR00385## ##STR00386## Aq. NaOH,
MeOH, rt 1.16 min. (D) 372.2 Example 5- 62 ##STR00387##
##STR00388## Aq. NaOH, MeOH, rt 1.34 min. (D) 422.2 Example 5- 63
##STR00389## ##STR00390## Aq. NaOH, MeOH, rt 1.16 min. (D) 400.1
Example 5- 64 ##STR00391## ##STR00392## Aq. NaOH, MeOH, rt 1.29
min. (D) 404.1 Example 5- 65 ##STR00393## ##STR00394## Aq. NaOH,
MeOH, rt 1.43 min. (D) 356.2 Example 5- 66 ##STR00395##
##STR00396## Aq. NaOH, MeOH, rt 1.42 min. (D) 422.0 Example 5- 67
##STR00397## ##STR00398## Aq. NaOH, MeOH, rt 1.78 min. (D) 412.1
Example 5- 68 ##STR00399## ##STR00400## Aq. NaOH, MeOH, rt 1.53
min. (D) 417.1 Example 5- 69 ##STR00401## ##STR00402## Aq. NaOH,
MeOH, rt 1.79 min. (D) 401.2 Example 5- 70 ##STR00403##
##STR00404## Aq. NaOH, MeOH, rt 1.62 min. (D) 401.1 Example 5- 71
##STR00405## ##STR00406## Aq. NaOH, MeOH, rt 1.73 min. (D) 417.2
Example 5- 72 ##STR00407## ##STR00408## Aq. NaOH, MeOH, rt 1.49
min. (D) 454.2 Example 5- 73 ##STR00409## ##STR00410## Aq. NaOH,
EtOH, rt 1.28 min. (A) 367.0
Example 5-38
[0469] 1H NMR (400 MHz, CD3OD) .delta. ppm 2.65 (d, J=7.1 Hz, 2H)
2.91-3.07 (m, 2H) 3.26 (s, 3H) 4.70 (m, 1H) 7.04 (d, J=8.8 Hz, 1H)
7.26-7.33 (m, 1H) 7.33-7.44 (m, 3H) 7.47-7.56 (m, 3H) 7.57 (t,
J=1.9 Hz, 1H) 8.02 (dd, J=8.8, 2.5 Hz, 1H) 8.55 (d, J=1.78 Hz,
1H).
Example 5-39
[0470] 1H NMR (400 MHz, CD3OD) .delta. ppm 2.36-2.60 (m, 6H) 2.84
(dd, J=13.4, 6.1 Hz, 1H) 2.91 (dd, J=13.4, 6.1 Hz, 1H) 3.77 (s, 3H)
4.34-4.58 (m, 1H) 7.03 (d, J=8.6 Hz, 1H) 7.18-7.31 (m, 4H) 7.39 (d,
J=8.1 Hz, 2H)
Example 5-40
[0471] 1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 2.51-2.70 (m, 2H)
2.79-2.99 (m, 2H) 3.05 (s, 3H) 4.41-4.62 (m, 1H) 7.22 (d, J=8.8 Hz,
2H) 7.33 (d, J=8.1 Hz, 2H) 7.36-7.43 (m, 1H) 7.46 (t, J=7.8 Hz, 1H)
7.56-7.66 (m, 3H) 7.69 (t, J=1.8 Hz, 1H) 7.76 (d, J=8.6 Hz, 2H)
8.30 (d, J=8.3 Hz, 1H) 10.09 (s, 1H) 12.24 (s, 1H)
Example 5-41
[0472] 1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.28 (t, J=7.6
Hz, 3H) 2.51-2.60 (m, 2H) 2.84-2.94 (m, 2H) 2.97 (q, J=7.6 Hz, 2H)
4.36-4.56 (m, 1H) 7.32 (d, J=8.3 Hz, 2H) 7.37-7.42 (m, 1H) 7.47 (t,
J=7.8 Hz, 1H) 7.60-7.66 (m, 3H) 7.70 (t, J=1.8 Hz, 1H) 8.23 (s, 1H)
8.60 (d, J=8.3 Hz, 1H) 12.30 (br. s., 1H)
Example 5-42
[0473] 1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 2.23-2.31 (m, 2H)
2.31-2.43 (m, 4H) 2.76 (d, J=6.6 Hz, 2H) 4.16-4.30 (m, 1H)
6.87-7.02 (m, 2H) 7.07 (dd, J=9.6, 3.0 Hz, 1H) 7.21 (d, J=8.3 Hz,
2H) 7.50 (d, J=8.1 Hz, 2H) 7.90 (d, J=8.1 Hz, 1H) 9.51 (br. s.,
1H)
Example 5-43
[0474] 1H NMR (400 MHz, CD3OD) .delta. ppm 2.33-2.60 (m, 6H) 2.85
(dd, J=13.7, 6.1 Hz, 1H) 2.94 (dd, J=13.7, 6.1 Hz, 1H) 3.45 (s, 3H)
4.35-4.57 (m, 1H) 7.14 (t, J=7.8 Hz, 1H) 7.21-7.34 (m, 3H) 7.38
(dd, J=8.0, 1.6 Hz, 1H) 7.47 (d, J=8.3 Hz, 2H)
Example 5-44
[0475] 1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 2.64 (d, J=5.8 Hz,
2H) 3.01 (d, J=6.8 Hz, 2H) 4.51-4.74 (m, 1H) 7.00 (br. s., 1H)
7.25-7.35 (m, 3H) 7.40 (t, J=7.6 Hz, 2H) 7.53 (d, J=8.1 Hz, 2H)
7.58 (d, J=8.1 Hz, 2H) 8.21 (br. s., 1H)
Example 5-45
[0476] 1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 2.38-2.55 (m, 6H)
2.85 (dd, J=13.6, 6.3, Hz, 1H) 2.93 (dd, J=13.6, 6.3, Hz, 1H)
4.40-4.56 (m, 1H) 7.27-7.37 (m, 3H) 7.40 (t, J=7.8 Hz, 1H)
7.54-7.56 (m, 3H) 7.60 (t, J=1.8 Hz, 1H)
Example 5-46
[0477] 1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 2.51-2.63 (m, 2H)
2.84 (dd, J=13.6, 8.3 Hz, 1H) 2.89 (dd, J=13.6, 8.3 Hz, 1H)
4.40-4.55 (m, 1H) 7.30 (d, J=8.3 Hz, 2H) 7.37-7.42 (m, 1H) 7.47 (t,
J=7.8 Hz, 1H) 7.58-7.66 (m, 3H) 7.70 (t, J=1.9 Hz, 1H) 8.95 (d,
J=8.6 Hz, 1H) 12.93 (s, 1H)
Example 5-47
[0478] 1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.25 (t, J=7.6
Hz, 3H) 2.51-2.59 (m, 2H) 2.80 (q, J=7.6 Hz, 2H) 2.84-2.94 (m, 2H)
4.41-4.56 (m, 1H) 7.31 (d, J=8.1 Hz, 2H) 7.37-7.42 (m, 1H) 7.47 (t,
J=7.8 Hz, 1H) 7.59 (s, 1H) 7.63 (d, J=8.3 Hz, 3H) 7.70 (t, J=1.9
Hz, 1H) 8.45 (d, J=8.6 Hz, 1H) 12.27 (br. s., 1H)
Example 5-48
[0479] 1H NMR (400 MHz, CD3OD) .delta. ppm 1.33 (t, J=7.6 Hz, 3H)
2.64 (d, J=6.8 Hz, 2H) 2.84 (q, J=7.6 Hz, 2H) 2.98 (d, J=7.01 Hz,
2H) 3.72 (s, 3H) 4.62-4.75 (m, 1H) 6.94-7.06 (m, 3H) 7.27 (d, J=8.1
Hz, 2H) 7.40 (d, J=8.3 Hz, 2H) 7.54 (s, 1H)
Example 5-49
[0480] 1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 2.51-2.62 (m, 2H)
2.84 (dd, J=13.7, 7.9 Hz, 1H) 2.91 (dd, J=13.7, 7.9 Hz, 1H) 3.73
(s, 3H) 4.42-4.55 (m, 1H) 7.05-7.19 (m, 3H) 7.25 (d, J=8.1 Hz, 2H)
7.42 (d, J=8.1 Hz, 2H) 7.73 (s, 1H) 8.55 (s, 1H) 8.63 (d, J=8.6 Hz,
1H)
Example 5-50
[0481] 1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 2.69 (d, J=6.8 Hz,
2H) 2.95-3.10 (m, 2H) 4.68-4.79 (m, 1H) 7.21-7.33 (m, 1H) 7.33-7.47
(m, 4H) 7.49-7.65 (m, 4H) 7.76-7.97 (m, 2H) 8.20-8.42 (m, 1H)
Example 5-51
[0482] 1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 2.62 (d, J=6.6 Hz,
2H) 2.96 (d, J=7.3 Hz, 2H) 4.54-4.68 (m, 1H) 7.28-7.36 (m, 3H) 7.40
(t, J=7.7 Hz, 2H) 7.56 (dd, J=17.2, 7.8 Hz, 4H)
Example 5-52
[0483] 1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 2.34-2.45 (m, 2H)
2.45-2.59 (m, 4H) 2.86 (dd, J=13.4, 6.0 Hz, 1H) 2.93 (dd, J=13.4,
6.0 Hz, 1H) 4.40-4.55 (m, 1H) 7.19-7.26 (m, 1H) 7.34 (d, J=8.1 Hz,
2H) 7.46-7.49 (m, 1H) 7.51 (t, J=8.0 Hz, 1H) 7.56 (d, J=8.3 Hz, 2H)
7.61 (d, J=7.8 Hz, 1H)
Example 5-53
[0484] 1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 2.04-2.26 (m, 2H)
2.31-2.46 (m, 2H) 2.69-2.88 (m, 2H) 2.94-3.21 (m, 2H) 4.18-4.37 (m,
1H) 7.28 (d, J=7.1 Hz, 2H) 7.35-7.43 (m, 1H) 7.43-7.54 (m, 2H) 7.63
(d, J=8.2 Hz, 3H) 7.70 (t, J=1.9 Hz, 1H) 7.98 (dd, J=8.3, 2.3 Hz,
1H) 12.22 (br. s., 1H)
Example 5-54
[0485] 1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 2.57 (s, 3H) 2.68
(d, J=6.6 Hz, 2H) 2.92-3.08 (m, 2H) 4.64-4.74 (m, 1H) 7.25-7.33 (m,
1H) 7.33-7.44 (m, 3H) 7.44-7.55 (m, 3H) 7.57 (t, J=1.8 Hz, 1H)
Example 5-55
[0486] 1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 2.64 (d, J=6.3 Hz,
2H) 2.97 (d, J=7.1 Hz, 2H) 3.74 (s, 3H) 4.58-4.73 (m, 1H) 6.43 (s,
1H) 6.96-7.08 (m, 3H) 7.27 (d, J=8.1 Hz, 2H) 7.42 (d, J=8.1 Hz, 2H)
8.71 (d, J=8.3 Hz, 1H)
Example 5-56
[0487] 1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 2.52-2.67 (m, 2H)
2.80-2.96 (m, 2H) 4.38-4.54 (m, 1H) 5.90 (br. s., 1H) 7.30 (d,
J=8.1 Hz, 2H) 7.35-7.42 (m, 1H) 7.46 (t, J=7.8 Hz, 1H) 7.61 (d,
J=8.3 Hz, 3H) 7.69 (t, J=1.9 Hz, 1H) 8.08 (br. s., 1H)
Example 5-57
[0488] 1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 2.48-2.55 (m, 1H)
2.64 (d, J=6.8 Hz, 1H) 2.88-3.00 (m, 2H) 4.32-4.69 (m, 1H)
7.26-7.35 (m, 3H) 7.41 (t, J=7.5 Hz, 2H) 7.49-7.65 (m, 4H)
Example 5-58
[0489] 1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 2.62 (d, J=6.6 Hz,
2H) 2.92-3.01 (m, 2H) 4.59-4.64 (m, 1H) 7.28-7.43 (m, 4H) 7.48-7.56
(m, 3H) 7.59 (t, J=1.9 Hz, 1H)
Example 5-59
[0490] 1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 2.64 (d, J=6.6 Hz,
2H) 3.01 (d, J=7.1 Hz, 2H) 4.63-4.75 (m, 1H) 7.05 (d, J=8.1 Hz, 1H)
7.26-7.32 (m, 1H) 7.35 (d, J=8.3 Hz, 2H) 7.37-7.43 (m, 2H) 7.44 (d,
J=1.0 Hz, 1H) 7.48 (dd, J=8.1, 1.77 Hz, 1H) 7.52-7.60 (m, 4H)
Example 5-60
[0491] 1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 2.30-2.44 (m, 2H)
2.44-2.64 (m, 4H) 2.87 (dd, J=13.7, 6.4 Hz, 1H) 2.95 (dd, J=13.7,
6.4 Hz, 1H) 4.42-4.53 (m, 1H) 7.27-7.52 (m, 8H)
Example 5-61
[0492] 1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 2.22-2.32 (m, 2H)
2.32-2.44 (m, 4H) 2.76 (d, J=6.6 Hz, 2H) 4.16-4.29 (m, 1H)
6.82-6.88 (m, 1H) 6.89-6.97 (m, 1H) 7.08-7.17 (m, 1H) 7.17-7.28 (m,
3H) 7.47 (d, J=8.1 Hz, 2H) 7.90 (d, J=8.1 Hz, 1H) 9.47 (br. s., 1H)
12.14 (br. s., 1H)
Example 5-62
[0493] 1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 2.22-2.31 (m, 2H)
2.33-2.42 (m, 4H) 2.72-2.85 (m, 2H) 3.72 (s, 3H) 4.16-4.34 (m, 1H)
6.92 (ddd, J=9.4, 3.79, 1.8 Hz, 1H) 7.21-7.33 (m, 4H) 7.34-7.45 (m,
1H) 7.92 (d, J=8.1 Hz, 1H) 12.14 (br. s., 2H)
Example 5-63
[0494] 1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 2.42-2.48 (m, 2H)
2.85 (d, J=6.8 Hz, 2H) 4.30-4.46 (m, 1H) 6.99 (s, 1H) 7.30 (d,
J=8.1 Hz, 2H) 7.36-7.42 (m, 1H) 7.47 (t, J=7.8 Hz, 1H) 7.63 (d,
J=8.1 Hz, 3H) 7.67-7.77 (m, 2H) 10.13 (br. s., 1H) 10.22 (br. s.,
1H) 12.26 (br. s., 1H)
Example 5-64
[0495] 1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 2.35-2.60 (m, 6H)
2.85 (dd, J=13.7, 6.4 Hz, 1H) 2.93 (dd, J=13.7, 6.4 Hz, 1H) 3.65
(s, 3H) 4.37-4.58 (m, 1H) 7.05-7.18 (m, 3H) 7.30 (d, J=8.1 Hz, 2H)
7.44 (d, J=8.3 Hz, 2H)
Example 5-65
[0496] 1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 2.38-2.56 (m, 6H)
2.85 (dd, J=13.4, 7.3 Hz, 1H) 2.89 (dd, J=13.4, 7.3 Hz, 1H)
4.40-4.52 (m, 1H) 7.26-7.35 (m, 3H) 7.36-7.46 (m, 2H) 7.52-7.61 (m,
3H)
Example 5-66
[0497] 1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 2.31-2.58 (m, 6H)
2.68-2.99 (m, 2H) 3.63 (s, 3H) 4.33-4.56 (m, 1H) 6.92-7.18 (m, 3H)
7.30-7.38 (m, 1H) 7.38-7.46 (m, 2H)
Example 5-67
[0498] 1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 2.51-2.65 (m, 2H)
2.86 (dd, J=13.7, 8.1 Hz, 1H) 2.95 (dd, J=13.7, 8.1 Hz, 1H)
4.42-4.61 (m, 1H) 6.89-6.99 (m, 1H) 7.30 (d, J=8.3 Hz, 2H)
7.37-7.42 (m, 1H) 7.42-7.51 (m, 1H) 7.62 (d, J=8.1 Hz, 3H) 7.69 (t,
J=1.8 Hz, 1H) 7.76 (d, J=9.9 Hz, 1H) 8.41 (d, J=9.1 Hz, 1H) 12.26
(br. s., 1H) 13.40 (s, 1H)
Example 5-68
[0499] 1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 2.51-2.57 (m, 2H)
2.90 (d, J=6.8 Hz, 2H) 4.34-4.52 (m, 1H) 7.15 (s, 1H) 7.31 (d,
J=8.1 Hz, 2H) 7.39 (dd, J=7.6, 1.77 Hz, 1H) 7.47 (t, J=7.8 Hz, 1H)
7.59-7.66 (m, 3H) 7.70 (t, J=1.8 Hz, 1H) 8.74 (d, J=8.6 Hz, 1H)
Example 5-69
[0500] 1H NMR (400 MHz, CD3OD) .delta. ppm 2.61 (d, J=6.6 Hz, 2H)
2.89-3.02 (m, 2H) 4.53-4.71 (m, 1H) 7.16-7.37 (m, 4H) 7.39 (t,
J=7.8 Hz, 1H) 7.45-7.57 (m, 3H) 7.59 (t, J=1.8 Hz, 1H) 8.20 (d,
1H).
Example 5-70
[0501] 1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 2.41-2.57 (m, 2H)
2.73-2.96 (m, 2H) 4.35-4.46 (m, 1H) 7.30 (d, J=8.3 Hz, 2H)
7.35-7.44 (m, 1H) 7.47 (t, J=7.8 Hz, 1H) 7.57-7.67 (m, 4H) 7.70 (t,
J=1.9 Hz, 1H) 8.23 (d, J=8.3 Hz, 1H) 11.14 (s, 1H) 12.29 (br. s.,
1H).
Example 5-71
[0502] 1H NMR (400 MHz, CD3OD) .delta. ppm 2.58 (dd, J=6.8, 1.8 Hz,
2H) 2.95 (dd, J=7.0, 3.4 Hz, 2H) 4.53-4.66 (m, 1H) 7.27-7.36 (m,
3H) 7.36-7.43 (m, 2H), 7.49-7.57 (m, 3H) 7.59 (t, J=1.7 Hz,
1H).
Example 5-72
[0503] 1H NMR (400 MHz, CD3OD) .delta. ppm 2.60-2.71 (m, 2H), 3.03
(dd, J=6.9, 4.7 Hz, 2H), 3.28 (s, 3H), 4.65-4.76 (m, 1H), 7.06 (d,
J=8.8 Hz, 1H), 7.23-7.38 (m, 3H), 7.38-7.47 (m, 2H), 7.50-7.64 (m,
5H), 8.03 (dd, J=8.8, 2.3 Hz, 1H), 8.17 (d, 1H), 8.56 (br. s.,
1H).
Example 5-73
[0504] 1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 2.43-2.59 (m,
2H), 2.82-2.95 (m, 2H), 4.04-4.16 (m, 1H), 7.30 (d, J=8.3 Hz, 2H),
7.34 (t, J=7.3 Hz, 1H), 7.45 (t, J=7.6 Hz, 2H), 7.59 (d, J=8.1 Hz,
3H), 7.64 (d, J=8.6 Hz, 2H), 8.03 (s, 1H), 12.45 (br. s., 2H).
Example 6-1
Synthesis of
(R)-3-(biphenyl-4-ylmethyl)-4-(2-carboxyethylamino)-4-oxobutanoic
acid
##STR00411##
[0506] To a solution of
(R)-3-(biphenyl-4-ylmethyl)-4-(3-methoxy-3-oxopropylamino)-4-oxobutanoic
acid (22.1 mg, 0.060 mmol) in THF (0.6 mL) and methanol (0.1 mL),
aqueous 1M NaOH (0.12 mL, 0.12 mmol) is added at room temperature.
After stirring for 3 hours, additional aqueous 1M NaOH (0.12 mL,
0.12 mmol) is added. The reaction mixture is allowed to stir for 30
minutes and quenched with 0.5 mL of aqueous 1M HCl and 0.5 mL of
brine. The mixture is extracted twice with ethyl acetate, and the
organic layer is concentrated under reduced pressure to give
(R)-3-(biphenyl-4-ylmethyl)-4-(2-carboxyethylamino)-4-oxobutanoic
acid (16.4 mg). HPLC retention time=1.04 minutes (condition A); MS
(m+1)=356.1; 1H NMR (400 MHz, DMSO-d6) .delta. ppm 2.13-2.31 (m,
3H) 2.59-2.65 (m, 1H) 2.81-2.90 (m, 2H) 3.12-3.27 (m, 2H) 7.26 (d,
2H, J=8 Hz) 7.34 (t, 1H, J=7.4 Hz) 7.45 (t, 2H, J=7.7 Hz) 7.57 (d,
2H, J=8.1 Hz) 7.63-7.65.
Example 7-1
Synthesis of (R)-3-biphenyl-4-ylmethyl-N-carboxymethyl-succinamic
acid
##STR00412##
[0508] A solution of (R)-tert-butyl
3-(biphenyl-4-ylmethyl)-4-(2-tert-butoxy-2-oxoethylamino)-4-oxobutanoate
(40 mg, 0.088 mmol) and TFA (0.5 mL, 6.49 mmol) in DCM (1.5 mL) is
allowed to stir for 2 hours at room temperature. The reaction is
concentrated under reduced pressure, and the obtained residue is
suspended in DCM (0.5 mL) and heptane (2 mL), and collected on a
funnel, giving (R)-3-biphenyl-4-ylmethyl-N-carboxymethyl-succinamic
acid (9.6 mg). HPLC retention time=1.26 minutes (condition A); MS
(m+1)=342.0; 1H NMR (400 MHz, CD3OD) .delta. ppm 2.39 (dd, J=16.67,
5.31 Hz, 1H) 2.63-2.82 (m, 2H) 2.98-3.14 (m, 2H) 3.84 and 3.95 (AB,
2H, J=17.8 Hz) 7.26-7.33 (m, 3H) 7.40 (t, J=7.71 Hz, 2H) 7.56 (dd,
J=19.96, 8.08 Hz, 4H).
[0509] Following compounds are prepared using similar procedure as
described in example 7-1:
TABLE-US-00020 Hydrolysis HPLC-RT MS Example # Product Starting
Material Condition (condition) (M + 1) Example 7-2 ##STR00413##
##STR00414## TFA, DCM, rt 1.35 min. (A) 370.0
Example 7-2
[0510] 1H NMR (400 MHz, DMSO-d6) .delta. ppm 1.51-1.58 (m, 2H)
2.12-2.21 (m, 3H) 2.49-2.65 (m, 2H) 2.81-2.89 (m, 2H) 2.94-3.08 (m,
2H) 7.26 (d, 2H, J=8.1 Hz) 7.32-7.36 (m, 1H) 7.43-7.46 (m, 2H) 7.57
(d, 2H, J=8.0 Hz) 7.63-7.65 (m, 2H).
Example 8-1
Synthesis of
(R)-4-(2-biphenyl-4-ylmethyl-3-carboxy-propionylamino)-2-methyl-pentanoic
acid
##STR00415##
[0512] To a stirred solution of 2-biphenyl-4-ylmethyl-succinic acid
4-tert-butyl ester (100 mg, 0.29 mmol) in DMF (10 mL) is added HOBt
(45 mg, 0.29 mmol) and EDCI (56 mg, 0.29 mmol) and the mixture is
stirred at room temperature for 10 minutes then
(2R,4R)-4-amino-2-methyl-pentanoic acid ethyl ester
trifluoroacetate (47 mg, 0.29 mmol) and triethylamine (89 mg, 0.87
mmol) is added and the mixture is stirred at room temperature for 5
hours. The mixture is quenched with water and extracted with ethyl
acetate. The organic layer is washed with water, brine, dried over
magnesium sulfate and filtered. The solvent is removed under
reduced pressure to give
(2R,4R)-7-biphenyl-4-ylmethyl-2,4-dimethyl-6-oxo-nonanedioic acid
9-tert-butyl ester 1-ethyl ester.
[0513] Next, to a solution of
(2R,4R)-7-biphenyl-4-ylmethyl-2,4-dimethyl-6-oxo-nonanedioic acid
9-tert-butyl ester 1-ethyl ester EtOH (4 mL) is added aqueous 1M
NaOH (4 mL) and the mixture is stirred at room temperature for 30
minutes. The mixture is acidified to pH 2-3 with aqueous 1M HCl and
is extracted with ethyl acetate. The solvent is removed under
reduced pressure and the residue is purified by preparative HPLC
using a gradient of 10-100% MeCN/water (0.1% TFA). Lyophilization
of the proper fractions furnished
(R)-4-(2-biphenyl-4-ylmethyl-3-carboxy-propionylamino)-2-methyl-pentanoic
acid. HPLC retention time=1.13 minutes (condition C); MS 398.2
(M+1); .sup.1H-NMR (400 MHz, DMSO-d6) .delta. ppm 0.93 (m, 6H),
1.23 (m, 1H), 1.59 (m, 1H), 2.17 (m, 1H), 2.63 (m, 1H), 2.82 (m,
1H), 3.72 (m, 1H), 7.27 (m, 2H), 7.33 (m, 1H), 7.45 (m, 2H), 7.56
(m, 2H), 7.62 (m, 2H), 7.71 (m, 1H), 12.07 (s, 1H).
Example 9-1
Synthesis of
(R)-4-biphenyl-4-yl-3-[(1H-tetrazole-5-carbonyl)-amino]-butyric
acid
##STR00416##
[0515] To a mixture of
(R)-3-[(1-benzyl-1H-tetrazole-5-carbonyl)-amino]-4-biphenyl-4-yl-butyric
acid ethyl ester and
(R)-3-[(2-benzyl-2H-tetrazole-5-carbonyl)-amino]-4-biphenyl-4-yl-butyric
acid ethyl ester (180 mg, 0.383 mmol) in EtOH (1 mL) and THF (1 mL)
is added aqueous 1M LiOH (2 mL). After stirring for 0.5 hour, the
reaction mixture is acidified with aqueous 1M HCl. The mixture is
extracted with ethyl acetate, dried over Na.sub.2SO.sub.4, and
concentrated under reduced pressure. The residue is dissolved in
MeOH and hydrogenated with 10% Pd/C at room temperature for 3 hours
and at 40.degree. C. for 2 hours. The reaction mixture is
concentrated and purified by reverse phase HPLC to give
(R)-4-biphenyl-4-yl-3-[(1H-tetrazole-5-carbonyl)-amino]-butyric
acid. HPLC retention time=1.18 minutes (condition D); MS (m+1)=352;
.sup.1H NMR (400 MHz, DMSO-d6) ppm 2.56 (dd, J=5.81, 15.92 Hz, 1H),
2.67 (dd, J=7.58, 15.92 Hz, 1H), 2.85-2.99 (m, 2H), 4.55-4.64 (m,
1H), 7.26-7.35 (m, 3H), 7.43 (dd, J=7.83, 7.83 Hz, 2H), 7.56 (d,
J=8.08 Hz, 2H), 7.62 (d, J=7.07 Hz, 2H), 9.28 (d, 8.84 Hz, 1H),
12.28 (s, 1H).
Example 10-1
(R)-4-biphenyl-4-yl-3-(3-1H-tetrazol-5-yl-propionylamino)-butyric
acid
##STR00417##
[0517] To a solution of
(R)-4-biphenyl-4-yl-3-{3-[1-(2-cyano-ethyl)-1H-tetrazol-5-yl]-propionylam-
ino}-butyric acid ethyl ester (137 mg, 0.297 mmol) in DCM (8 mL) at
room temperature is added DBU (1.507 mL, 10.00 mmol) and the
mixture is stirred at room temperature for 2 hours. The reaction is
extracted with DCM. The combined organic layer is washed with
saturated NH.sub.4Cl, brine and dried over anhydrous sodium
sulfate, filtered and concentrated under reduced. The obtained
residue is purified by flash chromatography (silica gel, 2% to 10%
EtOH/DCM) to give
(R)-4-biphenyl-4-yl-3-(3-1H-tetrazol-5-yl-propionylamino)-butyric
acid ethyl ester (37 mg). To the obtained ester in EtOH (2 mL) at
room temperature is added aqueous 1M NaOH (1 mL, 1.0 mmol) and the
mixture is stirred at room temperature for 1 hour. To the reaction
is added 1 mL of aqueous 1M HCl to pH=4, and the mixture is
purified by reverse phase HPLC [30% to 60% acetonitrile-H.sub.2O
(0.1% TFA)] to give
(R)-4-biphenyl-4-yl-3-(3-1H-tetrazol-5-yl-propionylamino)-butyric
acid. HPLC retention time=1.24 minutes (condition C); MS (m+1)=380;
1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 2.37 (dd, J=6.7, 2.1 Hz,
2H), 2.53 (t, J=7.6 Hz, 2H), 2.69-2.82 (m, 2H), 3.02 (t, J=7.7 Hz,
2H), 4.17-4.29 (m, 1H), 7.22 (d, J=8.3 Hz, 2H), 7.34 (tt, J=7.3,
1.3 Hz, 1H), 7.42-7.48 (m, 2H), 7.57 (d, J=8.3 Hz, 2H), 7.64 (dd,
J=8.2, 1.1 Hz, 2H), 8.00 (d, J=8.1 Hz, 1H), 12.21 (br. s., 1H),
15.92 (br. s., 1H). Chiral HPLC retention time=5.64 min. Column:
Daicel CHIRALCEL OJ-H (4.6.times.100 mm); flow rate=1 ml/min.;
eluent: EtOH (containing 0.1% TFA)/heptane=2/8.
Example 11-1
Synthesis of
(R)-4-(1-carboxy-3-(3'-chlorobiphenyl-4-yl)propan-2-ylamino)-4-oxobutanoi-
c acid
##STR00418##
[0519] To a solution of
(R)-4-(1-(biphenyl-4-yl)-4-ethoxy-4-oxobutan-2-ylamino)-4-oxobutanoic
acid (110 mg, 0.263 mmol) in THF (2 mL) and methanol (0.2 mL),
aqueous 1M NaOH solution (1.053 mL, 1.053 mmol) is added at room
temperature. After stirring for 1 hour, the reaction is quenched
with 0.1 M aqueous HCl, and the solution is diluted with DCM (15
ml) and allowed to stir for 1.5 hours. The precipitated solid is
collected on a funnel, washed with water, DCM, heptane and then DCM
in that order, and dried under reduced pressure to
(R)-4-(1-carboxy-3-(3'-chlorobiphenyl-4-yl)propan-2-ylamino)-4-oxobutanoi-
c acid (66 mg). HPLC retention time=0.87 minutes (condition B); MS
(m+1)=390.0; 1H NMR (400 MHz, CD3OD) .delta. ppm 2.39-2.55 (m, 6H)
2.86 (A of ABX, J.sub.ab=13.6 Hz, J.sub.ax=7.6 Hz, 1H) 2.92 (B of
ABX, J.sub.ab=13.6 Hz, J.sub.bx=6.2 Hz, 1H) 4.42-4.49 (m, 1H)
7.30-7.34 (m, 3H) 7.40 (t, J=7.4 Hz, 1H) 7.51-7.56 (m, 3H) 7.60 (t,
J=1.8 Hz, 1H).
[0520] Following compounds are prepared using similar procedure as
described in example 11-1:
TABLE-US-00021 Example Hydrolysis HPLC-RT MS # Product Starting
Material Condition (condition) (M + 1) Example 11-2 ##STR00419##
##STR00420## Aq. NaOH, THF, MeOH, RT 0.79 min. (B) 404.1 Example
11-3 ##STR00421## ##STR00422## Aq. NaOH, THF, MeOH, RT 0.65 min.
(B) 418.2 Example 11-4 ##STR00423## ##STR00424## Aq. NaOH, THF,
MeOH, RT 0.63 min. (B) 434.3 Example 11-5 ##STR00425## ##STR00426##
Aq. NaOH, THF, MeOH, RT 1.40 min. (A) 418.3 Example 11-6
##STR00427## ##STR00428## Aq. NaOH, THF, MeOH, RT 1.40 min. (A)
423.3 Example 11-7 ##STR00429## ##STR00430## Aq. NaOH, THF, MeOH,
RT 1.39 min. (A) 423.3 Example 11-9 ##STR00431## ##STR00432## Aq.
NaOH, THF, MeOH, RT 1.50 min. (B) 462.3 Example 11-10 ##STR00433##
##STR00434## Aq. NaOH, THF, MeOH, 50.degree. C. 0.72 min. (B) 408.2
Example 11-11 ##STR00435## ##STR00436## Aq. NaOH, EtOH, rt 1.16
min. (C) 462.2 Example 11-12 ##STR00437## ##STR00438## Aq. NaOH,
EtOH, rt 1.34 min. (C) 440.2 Example 11-13 ##STR00439##
##STR00440## Aq. NaOH, EtOH, 50.degree. C. 1.09 min. (C) 428.2
Example 11-14 ##STR00441## ##STR00442## Aq. NaOH, EtOH, rt 1.17
min. (C) 401.0 Example 11-15 ##STR00443## ##STR00444## Aq. NaOH,
EtOH, rt 1.12 min. (C) 385.2 Example 11-16 ##STR00445##
##STR00446## BCl.sub.3, DCM, rt 1.15 min. (C) 385.1 Example 11-17
##STR00447## ##STR00448## Aq. NaOH, EtOH, 50.degree. C. 1.18 min.
(C) 384.3 Example 11-18 ##STR00449## ##STR00450## Aq. NaOH, EtOH,
50.degree. C. 1.08 min. (C) 428.2 Example 11-19 ##STR00451##
##STR00452## Aq. NaOH, EtOH, rt 1.04 min. (C) 439.3 Example 11-20
##STR00453## ##STR00454## Aq. NaOH, EtOH, rt 1.03 min. (C) 439.2
Example 11-21 ##STR00455## ##STR00456## Aq. NaOH, EtOH, rt 0.89
min. (C) 440.1 Example 11-22 ##STR00457## ##STR00458## Aq. NaOH,
EtOH, rt 1.09 min. (C) 427.3 Example 11-23 ##STR00459##
##STR00460## Aq. NaOH, EtOH, rt 0.9 min. (C) 362.1 Example 11-24
##STR00461## ##STR00462## Aq. NaOH, EtOH, 50.degree. C. 0.96 min.
(C) 412.1 Example 11-25 ##STR00463## ##STR00464## Aq. NaOH, EtOH,
rt 0.97 min. (C) 424.4 Example 11-26 ##STR00465## ##STR00466## Aq.
NaOH, EtOH, rt 0.83 min. (C) 385.1 Example 11-27 ##STR00467##
##STR00468## Aq. NaOH, EtOH, rt 1.22 min. (C) 436.2 Example 11-28
##STR00469## ##STR00470## Aq. NaOH, EtOH, 50.degree. C. 0.98 min.
(C) 424.0 Example 11-29 ##STR00471## ##STR00472## Aq. NaOH, MeOH,
rt 1.52 min. (D) 448.1 Example 11-30 ##STR00473## ##STR00474## Aq.
NaOH, THF, MeOH, rt 1.12 min. (A) 388.3 Example 11-31 ##STR00475##
##STR00476## Aq. NaOH, MeOH, rt 1.52 min. (D) 398.1 Example 11-32
##STR00477## ##STR00478## Aq. NaOH, MeOH, rt 1.56 min. (D) 415.0
Example 11-33 ##STR00479## ##STR00480## Aq. NaOH, MeOH, rt 1.56
min. (D) 410.1 Example 11-34 ##STR00481## ##STR00482## Aq. NaOH,
MeOH, rt 1.75 min. (D) 425.1 Example 11-35 ##STR00483##
##STR00484## Aq. NaOH, MeOH, rt 1.63 min. (D) 399.1 Example 11-36
##STR00485## ##STR00486## Aq. NaOH, MeOH, rt 1.62 min. (D) 403.0
Example 11-37 ##STR00487## ##STR00488## Aq. NaOH, MeOH, rt 1.73
min. (D) 431.1 Example 11-38 ##STR00489## ##STR00490## Aq. NaOH,
THF, MeOH, rt 0.80 min. (B) 419.2 Example 11-39 ##STR00491##
##STR00492## Aq. NaOH, THF, MeOH, rt 0.66 min. (B) 408.1 Example
11-40 ##STR00493## ##STR00494## ##STR00495## Aq. NaOH, MeOH, rt
1.07 min. (A) 406.0 Example 11-41 ##STR00496## ##STR00497##
##STR00498## Aq. NaOH, MeOH, rt 1.04 min. (A) 406.0 Example 11-42
##STR00499## ##STR00500## ##STR00501## Aq. NaOH, MeOH, rt 0.97 min.
(A) 420.1 Example 11-43 ##STR00502## ##STR00503## ##STR00504## Aq.
NaOH, MeOH, rt 0.96 min. (A) 420.1 Example 11-44 ##STR00505##
##STR00506## ##STR00507## ##STR00508## Aq. NaOH, MeOH, rt 1.07 min.
(A) 408.1 Example 11-45 ##STR00509## ##STR00510## Aq. NaOH, MeOH,
rt 0.53 min. (B) 404 Example 11-46 ##STR00511## ##STR00512## Aq.
NaOH, MeOH, rt 0.37 min. (B) 406
Example 11-2
[0521] 1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 1.76-1.83 (m, 2H)
2.15-2.21 (m, 4H) 2.49 (A of ABX, J.sub.ab=15.7 Hz, J.sub.ax=7.3
Hz, 1H) 2.53 (B of ABX, J.sub.ab=15.7 Hz, J.sub.bx=6.1 Hz, 1H) 2.83
(A of ABX, J.sub.ab=13.6 Hz, J.sub.ax=8.3 Hz, 1H) 2.93 (B of ABX,
J.sub.ab=13.6 Hz, J.sub.bx=5.8 Hz, 1H) 4.46-4.53 (m, 1H) 7.30-7.33
(m, 3H) 7.39 (t., J=7.8 Hz, 1H) 7.51-7.55 (m, 3H) 7.59-7.60 (m,
1H).
Example 11-3
[0522] 1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 1.77-1.84 (m, 2H)
2.16-2.23 (m, 4H) 2.39-2.42 (m, 2H) 2.49 (A of ABX, J.sub.ab=15.6
Hz, J.sub.ax=7.5 Hz, 1H) 2.53 (B of ABX, J.sub.ab=15.6 Hz,
J.sub.bx=6.1 Hz, 1H) 2.83 (A of ABX, J.sub.ab=13.6 Hz, J.sub.ax=6.1
Hz, 1H) 2.91 (B of ABX, J.sub.ab=13.6 Hz, J.sub.bx=6.3 Hz, 1H) 3.75
(s, 3H) 4.46-4.53 (m, 1H) 6.97-7.04 (m, 2H) 7.26 (d, J=8.1 Hz, 2H)
7.42 (d, J=8.1 Hz, 2H).
Example 11-4
[0523] 1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 1.77-1.84 (m, 2H)
2.16-2.24 (m, 4H) 2.49 (A of ABX, J.sub.ab=15.6 Hz, J.sub.ax=7.5
Hz, 1H) 2.54 (B of ABX, J.sub.ab=15.6 Hz, J.sub.bx=6.1 Hz, 1H) 2.83
(A of ABX, J.sub.ab=13.6 Hz, J.sub.ax=8.2 Hz, 1H) 2.91 (B of ABX,
J.sub.ab=13.6 Hz, J.sub.bx=6.1 Hz, 1H) 3.77 (s, 3H) 4.45-4.52 (m,
1H) 7.03 (d, J=8.6 Hz, 1H) 7.24-7.28 (m, 3H) 7.39-7.41 (m, 2H).
Example 11-5
[0524] 1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 1.49-1.56 (m, 4H)
2.13 (t, J=6.8 Hz, 2H) 2.23 (t, J=6.9 Hz, 2H) 2.45-2.56 (m, 2H)
2.80-2.86 (m, 1H) 2.91-2.96 (m, 1H) 4.46-4.53 (m, 1H) 7.31-7.33 (m,
3H) 7.40 (t, J=8.0 Hz, 1H) 7.52-7.55 (m, 3H) 7.59 (br t, J=1.8 Hz,
1H).
Example 11-6
[0525] 1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 2.39-2.57 (m, 4H)
2.80 (A of ABX, J.sub.ab=13.6 Hz, J.sub.ax=8.1 Hz, 1H) 2.89 (B of
ABX, J.sub.ab=13.6 Hz, J.sub.bx=6.1 Hz, 1H) 3.04 (t, J=7.1 Hz, 2H)
3.75 (s, 3H) 4.40-4.47 (m, 1H) 7.27-7.29 (m, 2H) 7.32-7.35 (m, 1H)
7.41 (t, J=7.8 Hz, 1H) 7.51-7.54 (m, 3H) 7.59-7.60 (m, 1H)
7.83-7.84 (m, 1H) 8.28 (br d, J=7.1 Hz, 1H) 8.55 (d, J=5.6 Hz, 1H)
8.62 (s, 1H).
Example 11-7
[0526] 1H NMR (400 MHz, CD3OD) .delta. ppm 2.47 (A of ABX,
J.sub.ab=15.7 Hz, J.sub.ax=7.7 HZ, 1H) 2.54 (B of ABX,
J.sub.ab=15.7 Hz, J.sub.bx=5.8 Hz, 1H) 2.64-2.75 (m, 2H) 2.80 (A of
ABX, J.sub.ab=13.7 Hz, J.sub.ax=8.3 Hz, 1H) 2.92 (B of ABX,
J.sub.ab=13.7 Hz, J.sub.b=5.9 Hz, 1H) 3.17-3.21 (m, 2H) 4.43-4.50
(m, 1H) 7.28-7.35 (m, 3H) 7.39-7.43 (m, 1H) 7.51-7.54 (m, 3H) 7.59
(br t, J=1.9 Hz, 1H) 7.69-7.75 (m, 2H) 8.29-8.32 (m, 1H) 8.61 (d,
J=4.6 Hz, 1H).
Example 11-8
[0527] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.82-1.89 (m, 2H)
2.29 (t, J=7.3 Hz, 2H) 2.56 (A of ABX, J.sub.ab=16.4 Hz,
J.sub.ax=5.6 Hz, 1H) 2.64 (B of ABX, J.sub.ab=16.4 Hz, J.sub.bx=5.1
Hz, 1H) 2.95 (A of ABX, J.sub.ab=13.8 Hz, J.sub.ax=7.6 Hz, 1H) 2.99
(B of ABX, J.sub.ab=13.8 Hz, J.sub.bx=7.2 Hz, 1H) 3.30 (s, 3H) 3.38
(t, J=5.9 Hz, 2H) 4.10 (q, J=7.1 Hz, 2H) 4.52-4.57 (m, 1H) 6.59 (br
d, J=8.6 Hz, 1H) 7.26-7.37 (m, 4H) 7.42-7.45 (m, 1H) 7.48-7.52 (m,
2H) 7.55 (br t, J=1.6 Hz, 1H).
Example 11-9
[0528] 1H NMR (400 MHz, CD.sub.3CN+D.sub.2O) .delta. ppm 2.43-2.56
(m, 2H) 2.71-2.91 (m, 4H) 3.21-3.34 (m, 2H) 4.39-4.46 (m, 1H) 7.27
(d, J=8.3 Hz, 2H) 7.34-7.49 (m, 7H) 7.55-7.56 (m, 1H) 7.65-7.70 (m,
2H).
Example 11-10
[0529] 1H NMR (400 MHz, CD3OD) .delta. ppm 2.38-2.41 (m, 2H)
2.47-2.58 (m, 4H) 2.85-2.90 (m, 1H) 2.99-3.04 (m, 1H) 4.48-4.55 (m,
1H) 7.32-7.44 (m, 5H) 7.53-7.56 (m, 1H) 7.62-7.63 (m, 1H).
Example 11-11
[0530] 1H NMR (400 MHz, DMSO-d6): 1H NMR (400 MHz, DMSO-d6):
.delta. ppm 2.44-2.52 (m, 2H), 2.83-2.85 (d, J=6.82 Hz, 2H),
4.29-4.38 (m, 1H), 7.28-7.30 (d, J=8.34 Hz, 2H), 7.40-7.43 (t,
J=7.83 Hz, 1H), 7.62-7.65 (m, 3H), 7.71-7.72 (t, J=1.77 Hz, 1H),
9.42-9.45 (M, 1H), 12.32 (s, 1H).
Example 11-12
[0531] 1H NMR (400 MHz, DMSO-d6) .delta. ppm 2.54-2.59 (m, 1H),
2.64-2.70 (m, 1H), 2.88-2.93 (m, 1H), 2.98-3.03 (m, 1H), 4.56-4.63
(m, 1H), 7.30-7.32 (m, 2H), 7.37-7.40 (m, 1H), 7.43-7.47 (t, J=7.83
Hz, 1H), 7.59-7.61 (m, 3H), 7.67-7.68 (t, J=2.02 Hz, 1H), 8.32 (d,
J=1.26 Hz, 1H), 9.17-9.19 (d, J=9.09 Hz, 1H), 9.50 (d, J=1.52 Hz,
1H), 12.34 (s, 1H), 14.14 (s, 1H).
Example 11-13
[0532] 1H NMR (400 MHz, DMSO-d6) .delta. ppm 2.46-2.60 (m, 2H),
2.84-2.96 (m, 2H), 4.51 (m, 1H), 7.31 (d, J=8.34 Hz, 2H), 7.38-7.41
(m, 1H), 7.46 (t, 1H), 7.62 (d, J=8.34 Hz, 3H), 7.69 (t, 1H).
Example 11-14
[0533] 1H NMR (400 MHz, DMSO-d6) .delta. ppm) 2.75-2.99 (m, 1H)
4.47 (d, J=7.58 Hz, 1H) 6.49 (s, 1H) 7.30 (d, J=8.34 Hz, 1H)
7.37-7.43 (m, 1H) 7.47 (t, J=7.83 Hz, 1H) 7.63 (d, J=8.08 Hz, 2H)
7.70 (t, J=1.77 Hz, 1H) 8.80 (d, J=8.59 Hz, 1H) 11.69 (s, 1H)
12.04-12.58 (m, 1H).
Example 11-15
[0534] 1H NMR (400 MHz, DMSO-d6) .delta. ppm 2.81-2.96 (m, 2H)
4.42-4.55 (m, 1H) 7.31 (d, J=8.34 Hz, 2H) 7.36-7.43 (m, 1H) 7.47
(t, J=7.83 Hz, 1H) 7.63 (d, J=8.34 Hz, 4H) 7.69 (t, J=1.77 Hz, 1H)
7.72 (s, 1H) 8.54 (s, 1H) 8.60 (d, J=8.59 Hz, 1H) 12.29 (br. s.,
1H).
Example 11-16
[0535] 1H NMR (400 MHz, DMSO-d6) .delta. ppm 2.53-2.64 (m, 2H)
2.84-2.93 (m, 2H) 4.41-4.59 (m, 1H) 7.00 (d, J=2.02 Hz, 1H) 7.31
(d, J=8.08 Hz, 2H) 7.37-7.42 (m, 1H) 7.47 (t, J=7.83 Hz, 1H)
7.58-7.65 (m, 3H) 7.70 (t, J=1.77 Hz, 1H) 8.72 (d, J=1.77 Hz, 1H)
8.95 (d, J=8.59 Hz, 1H) 12.31 (br. s., 1H).
Example 11-17
[0536] 1H NMR (400 MHz, DMSO-d6) .delta. ppm 2.46-2.60 (m, 2H),
2.83-2.98 (m, 2H), 4.52 (m, 1H), 6.61 (d, J=2.27 Hz, 1H), 7.31 (d,
J=8.34 Hz, 2H), 7.37-7.42 (m, 1H), 7.46 (t, 1H), 7.62 (d, J=8.34
Hz, 3H), 7.69 (t, 1H), 7.74 (d, J=2.02 Hz, 1H), 8.13 (d, J=8.84 Hz,
1H).
Example 11-18
[0537] 1H NMR (400 MHz, DMSO-d6) .delta. ppm 2.48-2.62 (m, 2H),
2.84-2.96 (m, 2H), 4.52 (m, 1H), 7.16 (d, J=3.54 Hz, 1H), 7.27 (d,
J=3.79 Hz, 1H), 7.31 (d, J=8.34 Hz, 2H), 7.38-7.41 (m, 1H), 7.47
(t, 1H), 7.63 (d, J=8.34 Hz, 3H), 7.70 (t, 1H), 8.59 (d, J=8.59 Hz,
1H).
Example 11-19
[0538] 1H NMR (400 MHz, DMSO-d6): 1H NMR (400 MHz, DMSO-d.sub.6):
.delta. ppm 2.54-2.67 (m, 2H), 2.88-2.92 (m, 1H), 2.99-3.05 (m,
1H), 4.53-4.62 (m, 1H), 7.31-7.33 (m, 2H), 7.37-7.39 (m, 1H),
7.43-7.47 (t, J=7.58 Hz, 1H), 7.60-7.62 (m, 3H), 7.68 (m, 1H),
7.86-7.87 (d, J=4.55 Hz, 1H), 8.30 (s, 1H), 8.62-8.63 (d, J=4.80
Hz, 1H), 8.80-8.83 (d, J=9.09 Hz, 1H).
Example 11-20
[0539] 1H NMR (400 MHz, DMSO-d6): 1H NMR (400 MHz, DMSO-d.sub.6):
.delta. ppm 2.50-2.53 (m, 1H), 2.56-2.59 (t, J=6.32 Hz, 1H),
2.90-2.98 (m, 2H), 4.51-4.58 (m, 1H), 7.33-7.35 (d, J=8.34 Hz, 2H),
7.39-7.42 (m, 1H), 7.45-7.49 (t, J=7.83 Hz, 1H), 7.61-7.65 (m, 3H),
7.69-7.70 (t, J=1.77 Hz, 1H), 7.90-7.91 (dd, J=1.77 Hz, 5.05 Hz,
1H), 8.38-8.39 (m, 1H), 8.83-8.85 (dd, J=0.76 Hz, 5.05 Hz, 1H),
8.91-8.93 (d, J=8.34 Hz, 1H).
Example 11-21
[0540] 1H NMR (400 MHz, DMSO-d6): 1H NMR (400 MHz, DMSO-d6):
.delta. ppm 2.45-2.55 (m, 1H), 2.59-2.67 (m, 1H), 2.88-2.93 (m,
1H), 2.99-3.05 (m, 1H), 4.51-4.61 (m, 1H), 7.32-7.34 (d, J=8.08 Hz,
2H), 7.37-7.40 (m, 1H), 7.44-7.48 (t, J=7.58 Hz, 1H), 7.60-7.62 (t,
J=7.83 Hz, 2H), 7.69 (s, 1H), 7.77 (s, 1H), 8.86-8.87 (d, J=4.04
Hz, 1H), 9.06 (s, 1H).
Example 11-22
[0541] 1H NMR (400 MHz, DMSO-d6): .delta. ppm 2.49-2.53 (m, 2H),
2.90-2.92 (d, J=6.82 Hz, 2H), 4.42-4.51 (m, 1H), 6.72-6.73 (d,
J=2.27 Hz, 2H), 7.32-7.34 (m, 2H), 7.39-7.42 (m, 1H), 7.45-7.49 (t,
J=7.83 Hz, 1H), 7.62-7.66 (m, 3H), 7.70-7.71 (t, J=1.77 Hz, 1H),
8.27-8.29 (d, J=8.08 Hz, 1H), 11.96 (s, 1H), 12.33 (s, 1H), 12.75
(s, 1H).
Example 11-23
[0542] 1H NMR (400 MHz, DMSO-d6): 1H NMR (400 MHz, DMSO-d6):
.delta. ppm 2.44-2.55 (m, 2H), 2.79-2.89 (m, 2H), 4.29-4.38 (m,
1H), 7.27-7.29 (d, J=8.08 Hz, 2H), 7.39-7.42 (m, 1H), 7.45-7.49 (t,
J=8.08 Hz, 1H), 7.62-7.64 (d, J=8.08 Hz, 3H), 7.70-7.71 (m, 1H),
8.85-8.87 (d, J=9.09 Hz, 1H), 12.30 (s, 1H).
Example 11-24
[0543] 1H NMR (400 MHz, DMSO-d6) .delta. ppm 2.46-2.60 (m, 2H),
2.84-2.96 (m, 2H), 4.51 (m, 1H), 7.15 (m, 2H), 7.44-7.52 (m, 3H),
7.62 (d, J=8.34 Hz, 2H), 8.38 (d, broad, J=7.58 Hz, 1H).
Example 11-25
[0544] 1H NMR (400 MHz, DMSO-d6): .delta. ppm 2.54-2.59 (m, 1H),
2.64-2.70 (m, 1H), 2.88-2.93 (m, 1H), 2.98-3.03 (m, 1H), 4.56-4.65
(m, 1H), 7.13-7.18 (m, 1H), 7.30-7.32 (d, J=8.34 Hz, 2H), 7.45-7.48
(m, 3H), 7.60-7.62 (d, J=8.34 Hz, 2H), 8.31-8.32 (d, J=1.26 Hz,
1H), 8.17-8.19 (d, J=9.09 Hz, 1H), 8.49 (d, J=1.26 Hz, 1H), 12.32
(s, 1H), 14.10 (s, 1H).
Example 11-26
[0545] 1H NMR (400 MHz, DMSO-d6) .delta. ppm 2.52-2.62 (m, 2H)
2.83-2.92 (m, 2H) 4.47 (d, J=7.07 Hz, 1H) 6.49 (s, 1H) 7.11-7.21
(m, 1H) 7.30 (d, J=8.34 Hz, 2H) 7.42-7.55 (m, 3H) 7.64 (d, J=8.34
Hz, 2H) 8.80 (d, J=8.59 Hz, 1H) 11.68 (br. s., 1H) 12.30 (br. s.,
1H).
Example 11-27
[0546] 1H NMR (400 MHz, DMSO-d6) .delta. ppm 2.51-2.57 (m, 1H),
2.64-2.70 (m, 1H), 2.84-2.89 (dd, J=6.06 Hz, 1H), 2.96-3.01 (dd,
J=7.83 Hz, 1H), 3.72 (s, 3H), 4.54-4.63 (m, 1H), 6.96-7.00 (m, 1H),
7.06-7.08 (dd, J=0.76 Hz, 1H), 7.22-7.24 (m, 3H), 7.28-7.32 (m,
1H), 7.35-7.38 (m, 2H), 8.33-8.34 (d, J=1.26 Hz, 1H), 9.16-9.18 (d,
J=9.09 Hz, 1H), 9.49 (d, J=1.52 Hz, 1H), 12.31 (s, 1H), 14.13 (s,
1H).
Example 11-28
[0547] 1H NMR (400 MHz, DMSO-d6) .delta. ppm 2.52-2.60 (m, 2H),
2.73 (s, 1H), 2.89 (s, 1H), 2.81-2.95 (m, 2H), 3.74 (s, 3H), 4.50
(m, 1H), 7.00 (t, 1H), 7.08 (d, J=8.34 Hz, 1H), 7.15 (s, broad,
1H), 7.23-7.26 (m, 3H), 7.29-7.33 (m, 1H), 7.38 (d, J=8.08 Hz, 2H),
8.39 (d, broad, J=7.07 Hz, 1H).
Example 11-29
[0548] 1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 1.33 (t, J=7.6 Hz,
3H) 2.66 (d, J=6.8 Hz, 2H) 2.84 (q, J=7.6 Hz, 2H) 2.98 (dd, J=13.6,
8.1 Hz, 1H) 3.03 (dd, J=13.6, 6.6 Hz, 1H) 4.64-4.76 (m, 1H)
7.24-7.37 (m, 6H) 7.40-7.45 (m, 1H) 7.53 (s, 1H).
Example 11-30
[0549] 1H NMR (400 MHz, DMSO-d6) .delta. ppm 2.40-2.51 (m, 2H)
2.79-2.90 (m, 2H) 4.29-4.38 (m, 1H) 6.47 (d, J=15.7 Hz, 1H) 6.88
(d, J=15.7 Hz 1H) 7.28-7.30 (m, 2H) 7.39-7.41 (m, 1H) 7.47 (t,
J=8.0 Hz, 1H) 7.62-7.65 (m, 2H) 7.70-7.71 (m, 1H) 8.54 (d, J=8.1
Hz, 1H) 7.31 (d, J=8.3 HZ, 2H) 7.40-7.43 (m, 1H) 7.47-7.50 (m, 1H)
7.62-7.65 (m, 3H) 7.69-7.71 (m, 1H) 8.54 (d, J=8.1 Hz, 1H)
Example 11-31
[0550] 1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 2.22 (s, 3H)
2.43-2.49 (m, 1H) 2.52-2.60 (m, 1H) 2.84 (dd, J=13.6, 6.1 Hz, 1H)
2.94 (dd, J=13.6, 8.1 Hz, 1H) 4.39-4.58 (m, 1H) 6.33 (s, 1H) 7.30
(d, J=8.3 Hz, 2H) 7.36-7.42 (m, 1H) 7.46 (t, J=7.8 Hz, 1H) 7.61 (d,
J=8.3 Hz, 3H) 7.69 (t, J=1.9 Hz, 1H) 8.02 (d, J=7.8 Hz, 1H).
Example 11-32
[0551] 1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 2.51-2.56 (m, 2H)
2.89 (d, J=6.8 Hz, 2H) 3.31 (s, 3H) 4.33-4.57 (m, 1H) 7.31 (d,
J=8.1 Hz, 2H) 7.37-7.42 (m, 1H) 7.46 (t, J=7.8 Hz, 1H) 7.60-7.66
(m, 3H) 7.69 (t, J=1.8 Hz, 1H) 8.15 (s, 1H) 8.50 (d, J=8.3 Hz, 1H)
12.24 (br. s., 1H).
Example 11-33
[0552] 1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 2.52-2.60 (m, 2H)
2.66 (s, 3H) 2.93 (d, J=6.8 Hz, 2H) 4.43-4.63 (m, 1H) 7.33 (d,
J=8.1 Hz, 2H) 7.36-7.42 (m, 1H) 7.46 (t, J=7.8 Hz, 1H) 7.58-7.66
(m, 3H) 7.69 (t, J=1.8 Hz, 1H) 8.74 (d, J=8.3 Hz, 1H) 8.98 (s, 2H)
12.28 (br. s., 1H).
Example 11-34
[0553] 1H NMR (400 MHz, MeOD) .delta. ppm 2.15 (s, 3H) 2.67 (d,
J=6.6 Hz, 2H) 2.98 (dd, J=13.9, 8.3 Hz, 1H) 3.03 (dd, J=14.1, 6.8
Hz, 1H) 4.62-4.77 (m, 1H) 5.57 (s, 1H) 6.16 (s, 1H) 7.27-7.32 (m,
1H) 7.32-7.41 (m, 3H) 7.46-7.54 (m, 3H) 7.56 (t, J=1.8 Hz, 1H) 7.65
(s, 1H) 8.55 (d, J=8.6 Hz, 1H).
Example 11-35
[0554] 1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 2.42 (s, 3H) 2.63
(d, J=6.3 Hz, 2H) 2.99 (d, J=7.1 Hz, 2H) 4.59-4.73 (m, 1H)
7.25-7.30 (m, 1H) 7.30-7.37 (m, 3H) 7.41-7.50 (m, 3H) 7.53 (t,
J=1.8 Hz, 1H) 8.15 (s, 1H).
Example 11-36
[0555] 1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 2.51-2.61 (m, 2H)
2.87 (dd, J=13.1, 5.6 Hz, 1H) 2.94 (dd, J=13.4, 7.6 Hz, 1H)
4.41-4.60 (m, 1H) 7.29-7.38 (m, 3H) 7.45 (ddd, J=8.7, 4.2, 2.8 Hz,
1H) 7.49 (d, J=6.8 Hz, 2H) 7.56 (dd, J=6.8, 2.5 Hz, 1H) 7.71 (s,
1H) 8.53 (s, 1H) 8.59 (d, J=8.6 Hz, 1H) 12.26 (br. s., 1H).
Example 11-37
[0556] 1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 1.32 (t, J=7.6 Hz,
3H) 2.66 (d, J=6.8 Hz, 2H) 2.83 (q, J=7.6 Hz, 2H) 2.98 (dd, J=13.6,
7.8 Hz, 1H) 3.03 (dd, J=14.7, 6.8 Hz, 1H) 4.61-4.80 (m, 1H) 7.13
(dd, J=18.9, 10.1 Hz, 1H) 7.25-7.32 (m, 1H) 7.32-7.37 (m, 2H)
7.37-7.45 (m, 3H) 7.54 (s, 1H).
Example 11-38
[0557] 1H NMR (400 MHz, DMSO-d6) .delta. ppm 1.15 (t, J=7.73 Hz,
3H) 2.39 (d, J=6.8 Hz, 2H) 2.79 (d, J=6.8 Hz, 2H) 3.46-3.56 (m, 2H)
3.91-4.01 (m, 2H) 4.21-4.29 (m, 1H) 7.14-7.17 (m, 1H) 7.28 (d,
J=8.3 Hz, 2H) 7.39-7.42 (m, 1H) 7.48 (t, J=7.83 Hz, 1H) 7.61-7.64
(m, 3H) 7.69-7.70 (m, 1H) 7.84 (d, J=8.4 Hz, 1H) 12.23 (br s,
1H).
Example 11-39
[0558] 1H NMR (400 MHz, Methanol-d4) .delta. ppm 2.39-2.56 (m, 6H)
2.87 (A of ABX, J.sub.ab=13.6 Hz, J.sub.ax=7.6 Hz, 1H) 2.94 (B of
ABX, J.sub.ab=13.6 Hz, J.sub.bx=6.1 Hz, 1H) 4.43-4.50 (m, 1H)
7.15-7.20 (m, 1H) 7.31-7.35 (m, 3H) 7.45-7.48 (m, 3H).
Example 11-40
[0559] 1H NMR (400 MHz, DMSO-d6) .delta. ppm 2.24-2.37 (m, 4H),
2.73 (dd, 1H, J=7.83, 13.4 Hz), 2.88 (dd, 1H, J=7.33, 13.4 Hz),
3.93 (s, 1H), 4.26-4.36 (m, 1H), 5.35 (bs, 1H), 7.33 (d, 2H, J=8.08
Hz), 7.38-7.43 (m, 1H), 7.48 (t, 1H, J=7.83 Hz), 7.63 (d, 3H,
J=8.34 Hz), 7.70 (t, 1H, J=2.02 Hz), 7.73 (d, 1H, J=9.09 Hz), 12.26
(bs, 2H).
Example 11-41
[0560] 1H NMR (400 MHz, DMSO-d6) .delta. ppm 2.21-2.33 (m, 4H),
2.65-2.81 (m, 2H), 4.02 (d, 1H, J=4.04 Hz), 4.24-4.32 (m, 1H), 5.56
(bs, 1H), 7.27 (d, 2H, J=8.34 Hz), 7.37-7.42 (m, 1H), 7.47 (t, 1H,
J=7.83 Hz), 7.58 (d, 2H, J=8.34 Hz), 7.60-7.64 (m, 1H), 7.69 (t,
1H, J=1.77 Hz), 7.96 (d, 1H, J=8.84 Hz), 12.03 (bs, 1H), 12.60 (bs,
1H).
Example 11-42
[0561] 1H NMR (400 MHz, DMSO-d6) .delta. ppm 2.22-2.37 (m, 4H),
2.74 (dd, 1H, J=8.34, 13.4 Hz), 2.86 (dd, 1H, J=6.82, 13.4 Hz),
3.34 (s, 3H), 3.62 (d, 1H, J=2.78 Hz), 4.34-4.44 (m, 1H), 7.31 (d,
2H, J=8.34 Hz), 7.38-7.43 (m, 1H), 7.48 (t, 1H, J=7.83 Hz), 7.63
(d, 3H, J=8.34 Hz), 7.71 (s, 1H), 7.89 (d, 1H, J=9.35 Hz).
Example 11-43
[0562] 1H NMR (400 MHz, DMSO-d6) .delta. ppm 2.17-2.37 (m, 4H),
2.64-2.81 (m, 2H), 3.37 (s, 3H), 3.77 (d, 1H, J=4.04 Hz), 4.25-4.34
(m, 1H), 7.25 (d, 2H, J=8.08 Hz), 7.38-7.42 (m, 1H), 7.47 (t, 1H,
J=7.83 Hz), 7.56-7.64 (m, 3H), 7.68 (t, 1H, J=1.77 Hz), 8.05 (d,
1H, J=8.84 Hz), 12.05 (bs, 1H), 12.89 (bs, 1H).
Example 11-44
[0563] 1H NMR (400 MHz, DMSO-d6) .delta. ppm 2.20-2.39 (m, 4H),
2.65-2.87 (m, 2H), 4.37-4.56 (m, 1H), 4.91 (d, 0.5H, J=2.78 Hz),
5.04 (d, 0.5H, J=3.03 Hz), 7.29 (d, 2H, J=8.34 Hz), 7.38-7.43 (m,
1H), 7.47 (t, 1H, J=7.83 Hz), 7.58-7.65 (m, 3H), 7.69 (t, 1H,
J=1.77 Hz), 8.27 (d, 1H, J=8.59 Hz), 12.05 (bs, 1H), 13.57 (bs,
1H).
Example 11-45
[0564] 1H NMR (400 MHz, DMSO-d6) .delta. ppm 1.10 (d, J=7.1 Hz,
3H), 2.17-2.37 (m, 4H), 2.57-2.78 (m, 3H), 4.19-4.31 (m, J=9.2,
9.2, 4.5, 4.3 Hz, 1H), 7.30 (d, J=8.1 Hz, 2H), 7.37-7.42 (m, 1H),
7.47 (t, J=7.8 Hz, 1H), 7.57-7.65 (m, 3H), 7.70 (t, J=1.8 Hz, 1H),
7.86 (d, J=8.8 Hz, 1H), 12.21 (br. s., 2H).
Example 11-46
[0565] 1H NMR (400 MHz, DMSO-d6) .delta. ppm 2.45 (dd, J=6.6, 3.5
Hz, 1H), 2.82 (d, J=7.1 Hz, 1H), 3.88 (dd, J=20.2, 15.2 Hz, 1H),
4.03 (s, 1H), 4.29-4.41 (m, 1H), 7.29 (d, J=8.3 Hz, 1H), 7.37-7.43
(m, 1H), 7.48 (t, J=8.0 Hz, 1H), 7.62 (d, J=8.3 Hz, 2H), 7.70 (t,
J=1.8 Hz, 1H), 7.89 (d, J=8.8 Hz, 1H), 11.65-13.45 (m, 1H).
Example 11-47/48
(R)-3-[(S)-2-(Carboxymethyl-amino)-propionylamino]-4-(3'-chloro-biphenyl-4-
-yl)-butyric acid and
(R)-3-[(R)-2-(Carboxymethyl-amino)-propionylamino]-4-(3'-chloro-biphenyl--
4-yl)-butyric acid
##STR00513##
[0567] To a solution of
(R)-3-[2-(tert-butoxycarbonyl-ethoxycarbonylmethyl-amino)-propionylamino]-
-4-(3'-chloro-biphenyl-4-yl)-butyric acid ethyl ester (290 mg,
0.504 mmol) in THF (3 ml) and MeOH (0.5 ml) at room temperature is
added 2M NaOH (1.009 ml, 2.017 mmol). The reaction is stirred at
room temperature over night. The mixture is concentrated to dryness
and the crude i taken up in DCM (3.00 ml), to which is added TFA
(3.89 ml, 50.4 mmol) and the mixture is stirred at room temperature
for 2 hr. The reaction is concentrated for HPLC purification.
Reverse phase HPLC [25 to 50% ACN--H.sub.2O (0.1% TFA) over 10 min
by Sunfire C18 column] give
(R)-3-[(S)-2-(Carboxymethyl-amino)-propionylamino]-4-(3'-chloro-biphenyl--
4-yl)-butyric acid and
(R)-3-[(R)-2-(Carboxymethyl-amino)-propionylamino]-4-(3'-chloro-biphenyl--
4-yl)-butyric acid.
[0568]
(R)-3-[(S)-2-(Carboxymethyl-amino)-propionylamino]-4-(3'-chloro-bip-
henyl-4-yl)-butyric acid: 1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.28 (d, J=7.1 Hz, 3H), 2.40 (dd, J=15.7, 8.3 Hz, 1H),
2.51-2.56 (m, 1H), 2.76 (dd, J=13.4, 8.1 Hz, 1H), 2.87 (dd, J=13.4,
5.3 Hz, 1H), 3.43-3.52 (m, 3H), 3.67 (q, J=6.7 Hz, 1H), 4.25-4.36
(m, 1H), 7.30 (d, J=8.3 Hz, 2H), 7.38-7.43 (m, 1H), 7.48 (t, J=7.8
Hz, 1H), 7.59-7.65 (m, 3H), 7.70 (t, J=1.8 Hz, 1H), 8.41 (d, J=8.3
Hz, 1H). HRMS: Calcd for C.sub.21H.sub.23ClN.sub.2O.sub.5:
418.1295. found: m/z 418.1307. LCMS (condition A): 419 (M+1);
retention time=0.93 min;
(R)-3-[(R)-2-(Carboxymethyl-amino)-propionylamino]-4-(3'-chloro-biphenyl--
4-yl)-butyric acid: 1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.17
(d, J=6.8 Hz, 3H), 2.41-2.49 (m, 0H), 2.51-2.57 (m, 1H), 2.73 (dd,
J=13.4, 9.1 Hz, 1H), 2.91 (dd, J=13.4, 4.8 Hz, 1H), 3.55-3.67 (m,
2H), 3.67-3.74 (m, 1H), 4.26-4.40 (m, 1H), 7.29 (d, J=8.3 Hz, 2H),
7.39-7.44 (m, 0H), 7.48 (t, J=7.8 Hz, 0H), 7.59-7.65 (m, 3H), 7.69
(t, J=1.8 Hz, 1H), 8.43 (d, J=8.6 Hz, 1H). HRMS: Calcd for
C.sub.21H.sub.23ClN.sub.2O.sub.5: 418.1295. found: m/z 418.1305.
LCMS (condition A): 419 (M+1); retention time=0.99 min.
[0569] Following compounds are prepared using similar procedure as
described in example 11-47/48:
TABLE-US-00022 HPLC-RT MS Example # Product Starting material
(condition) (M + 1) Example 11- 49 ##STR00514## (R)-3-[2-
(Carboxymethyl- amino)-acetylamino]- 4-(3'-chloro-biphenyl-
4-yl)-butyric acid ##STR00515## 1.12 min. (A) 405.2
Example 11-49
[0570] 1H NMR (400 MHz, DMSO-d6) .delta. ppm 2.39-2.50 (m, 2H)
2.77-2.89 (m, 2H) 3.61-3.71 (m, 2H) 3.81 (s, 2H) 4.26-4.35 (m, 1H)
7.31 (d, J=8.3 HZ, 2H) 7.40-7.43 (m, 1H) 7.47-7.50 (m, 1H)
7.62-7.65 (m, 3H) 7.69-7.70 (m, 1H) 8.49 (d, J=7.3 Hz, 1H).
Example 12-1
Synthesis of
(R)-4-(1-carboxy-3-(3'-chlorobiphenyl-4-yl)propan-2-ylamino)-4-oxobutanoi-
c acid
##STR00516##
[0572] To a solution of
(R)-4-(1-(2',5'-dichlorobiphenyl-4-yl)-4-ethoxy-4-oxobutan-2-ylamino)-4-o-
xobutanoic acid (106 mg, 0.234 mmol) in THF (2 ml) and MeOH (0.1
ml), 1M aqueous NaOH solution (1.406 mL, 1.406 mmol) is added at
room temperature. After stirring for 4.5 hours, the reaction is
quenched with 0.1 M aqueous HCl (3 ml), and the products are
extracted with EtOAc. The combined organic layer is washed with
brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated
under reduced pressure. The crude is triturated in DCM. The
precipitates are collected on a funnel, washed with DCM, and dried
under reduced pressure to give
(R)-4-(1-carboxy-3-(3'-chlorobiphenyl-4-yl)propan-2-ylamino)-4-oxobutanoi-
c acid (64.0 mg) as white solid; HPLC retention time=1.24 minutes
(condition A); MS (m+1)=424.07; 1H NMR (400 MHz, CD3OD) .delta. ppm
2.38-2.42 (m, 2H) 2.45-2.57 (m, 4H) 2.87 (A of ABX, J.sub.ab=13.6
Hz, J.sub.ax=7.6 Hz, 1H) 2.95 (B of ABX, J.sub.ab=13.6 Hz,
J.sub.bx=6.1 Hz, 1H) 4.44-4.51 (m, 1H) 7.30-7.37 (m, 6H) 7.47 (d,
J=8.4 Hz, 1H).
Example 13-1
Synthesis of
(R)-4-(1-(biphenyl-4-yl)-3-carboxypropan-2-ylcarbamoyl)picolinic
acid
Example 13-2
Synthesis of
(R)-2-(1-(biphenyl-4-yl)-3-carboxypropan-2-ylcarbamoyl)isonicotinic
acid
##STR00517##
[0574] To a solution of (R)-ethyl
3-amino-4-(biphenyl-4-yl)butanoate hydrochloride (200 mg, 0.625
mmol), 2,4-pyridinedicarboxylic acid hydrate (151 mg, 0.813 mmol),
EDCI (132 mg, 0.688 mmol) and 1-hydroxy-7-azabenzotriazole (94 mg,
0.688 mmol) in DMF (6 ml), DIPEA (0.164 ml, 0.938 mmol) is added.
The reaction mixture is allowed to stir for 3 hours. Then, the
reaction mixture is diluted with H.sub.2O. The precipitated solid
is collected on a funnel and dried under reduced pressure. To a
solution of the crude in THF (8 ml) and MeOH (1 ml), 1 M aqueous
NaOH (2.5 ml, 2.5 mmol) is added. After stirring for 1 hour, the
reaction is quenched with 5% citric acid and brine, and the
products are extracted with EtOAc. The organic layer is washed with
brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated. The
resulting residue is purified by preparative HPLC using a gradient
of 20% MeCN/water (0.1% TFA) to 100% MeCN to give
(R)-4-(1-(biphenyl-4-yl)-3-carboxypropan-2-ylcarbamoyl)picolinic
acid and
(R)-2-(1-(biphenyl-4-yl)-3-carboxypropan-2-ylcarbamoyl)isonicotinic
acid as white solids, respectively (Example 13-1: 33 mg; Example
13-2: 36 mg). Example 13-1, HPLC retention time=1.50 minutes
(condition D); MS (m+1)=405.1; 1H NMR (400 MHz, DMSO-d6) .delta.
ppm 2.53-2.62 (m, 2H) 2.88-2.97 (m, 2H) 4.50-4.59 (m, 1H) 7.31-7.35
(m, 3H) 7.42-7.45 (m, 2H) 7.57-7.64 (m, 4H) 7.89 (dd, J=5, 1.6 Hz,
1H) 8.83 (dd, J=5, 0.8 Hz, 1H) 8.37 (dd, J=1.6, 0.8 Hz) 8.89 (d,
J=8.3 Hz, 1H). Example 13-2, HPLC retention time=1.24 minutes
(condition A); MS (m+1)=405.1; 1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 2.52-2.68 (m, 2H) 2.91 (A of ABX, J.sub.ab=13.6 Hz,
J.sub.ax=6.1 Hz, 1H) 3.01 (B of ABX, J.sub.ab=13.6 Hz, J.sub.bx=8.1
Hz, 1H) 4.56-4.65 (m, 1H) 7.29-7.34 (m, 3H) 7.41-7.45 (m, 2H)
7.55-7.64 (m, 4H) 7.99 (dd, J=5, 1.6 Hz, 1H) 8.34 (dd, J=1.6, 0.8
Hz, 1H) 8.84 (dd, J=5, 0.8 Hz, 1H) 8.90 (d, J=9.1 Hz, 1H) 12.26 (br
s, 1H) 13.87 (br s, 1H).
[0575] Following compounds are prepared using similar procedure as
described in example 13-1 and 13-2:
TABLE-US-00023 HPLC-RT MS Example # Product Condition (condition)
(M + 1) Example 13- 3 ##STR00518## (R)-3-(2- aminopyrimidine-4-
carboxamido)-4- (biphenyl-4-yl)butanoic acid ##STR00519## PyBOP,
DIPEA, DMF, RT; aq. NaOH, THF, MeOH, RT 1.37 min. (A) 377.0
Example 13-3
[0576] 1H NMR (400 MHz, DMSO-d6) .delta. ppm 2.55 (d, J=6.6 Hz, 2H)
2.91 (A of ABX, J.sub.ab=13.6 Hz, J.sub.ax=6.3 Hz, 1H) 2.96 (B of
ABX, J.sub.ab=13.6 Hz, J.sub.bx=7.6 Hz, 1H) 4.46-4.55 (m, 1H) 6.86
(br s, 2H) 7.02 (d, J=4.8 Hz, 1H) 7.28-7.36 (m, 3H) 7.42-7.46 (m,
2H) 7.58-7.65 (m, 4H) 8.39 (d, J=9.1 Hz, 1H) 8.45 (d, J=4.8 Hz,
1H).
Example 14-1
Synthesis of
(R)-3-(3-Carboxymethyl-ureido)-4-(3'-chloro-biphenyl-4-yl)-butyric
acid
##STR00520##
[0578] To a solution of Intermediate 16-1 (90 mg, 0.254 mmol) and
ethyl isocyanatoacetate (39.4 mg, 0.305 mmol) in DMF (3 mL) is
added pyridine (2.93 g, 37.1 mmol) and the mixture is stirred at
room temperature for 2 hours. The solvent is removed under reduced
pressure and the residue is used directly in the next step.
[0579] Next, the above residue is dissolved in EtOH (1 mL) and 1N
NaOH (3 mL, 3 mmol) is added. The mixture is stirred at room
temperature for 2 hours then is acidified with 1N HCl. The mixture
is extracted with EtOAc and the organic phase is washed with water,
brine then dried over sodium sulfate. The solvent is removed under
reduced pressure and the residue purified by preparative HPLC using
a gradient of 10% MeCN/water to 100% MeCN (+0.1% TFA).
Lyophilization of the proper fractions gives the title compound;
HPLC Retention time 0.98 minutes (condition C); MS 391.3 (M+1); 1H
NMR (400 MHz, DMSO-d6): .delta. ppm 2.34 (d, J=7.33 Hz, 2H), 2.79
(d, J=6.57 Hz, 2H), 3.67 (d, J=5.56 Hz, 2H), 4.04-4.12 (m, 1H),
6.15 (t, J=5.81 Hz, 1H), 6.23 (d, J=8.34 Hz, 1H), 7.28-7.30 (m,
2H), 7.39-7.42 (m, 1H), 7.48 (t, J=7.83 Hz, 1H), 7.62-7.65 (m, 3H),
7.71 (t, J=1.77 Hz, 1H), 12.32 (s, br, 2H).
Example 15-1
(R)-4-(3'-Chloro-biphenyl-4-yl)-3-[(2H-tetrazole-5-carbonyl)-amino]-butyri-
c acid
##STR00521##
[0581] To a suspension of the starting material in MeOH (5 ml) at
room temperature is added NaOH (2 mL, 6.00 mmol) and the mixture is
stirred until the reaction was completed. The reaction mixture is
acidified to pH<4 and purified by HPLC (15% to 60%
acetonitrile-H.sub.2O with 0.1% TFA) to give
(R)-4-(3'-chloro-biphenyl-4-yl)-3-[(2H-tetrazole-5-carbonyl)-amino]-butyr-
ic acid (80 mg).
[0582] HPLC retention time=0.95 minutes (condition B); MS
(m+1)=386.1; 1H NMR (400 MHz, DMSO-d.sub.6) d ppm 2.52-2.61 (m,
1H), 2.61-2.72 (m, 1H), 2.84-2.99 (m, 2H), 4.51-4.64 (m, 1H), 7.31
(d, J=8.1 Hz, 2H), 7.36-7.41 (m, 1H), 7.46 (t, J=7.8 Hz, 1H), 7.61
(d, J=8.3 Hz, 3H), 7.68 (t, J=1.9 Hz, 1H), 9.31 (d, J=8.8 Hz, 1H),
12.32 (br. s., 1H).
[0583] Following compounds are prepared using similar procedure as
described in example 15-1:
TABLE-US-00024 Starting material and hydrolysis HPLC-RT MS Example
# Product condition (condition) (M + 1) Example 15- 2 ##STR00522##
(R)-4-(3'-Fluoro- biphenyl-4-yl)-3-[(2H- tetrazole-5-carbonyl)-
amino]-butyric acid ##STR00523## 1 atm. H2, Pd/C, EtOH, RT Followed
by aq. NaOH and EtOH 1.26 min. (A) 370.2 Example 15- 3 ##STR00524##
(R)-4-(2'-Methoxy- biphenyl-4-yl)-3-[(2H- tetrazole-5-carbonyl)-
amino]-butyric acid ##STR00525## 1 atm. H2, Pd/C, EtOH, RT Followed
by aq. NaOH and EtOH 1.24 min. (A) 382.2
Example 15-2
[0584] 1H NMR (400 MHz, DMSO-d.sub.6) d ppm 2.52-2.72 (m, 2H),
2.86-3.00 (m, 2H), 4.52-4.65 (m, 1H), 7.11-7.20 (m, 1H), 7.31 (d,
J=8.1 Hz, 2H), 7.43-7.51 (m, 3H), 7.61 (d, J=8.3 Hz, 2H), 9.28 (d,
J=8.8 Hz, 1H), 12.29 (br. s., 1H).
Example 15-3
[0585] 1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 2.52-2.60 (m,
J=15.9, 5.8 Hz, 1H), 2.67 (dd, J=15.9, 7.8 Hz, 1H), 2.87 (dd,
J=13.6, 5.8 Hz, 1H), 2.95 (dd, J=13.6, 8.3 Hz, 1H), 3.73 (s, 3H),
4.52-4.64 (m, 1H), 7.00 (td, J=7.4, 1.1 Hz, 1H), 7.08 (d, J=9.1 Hz,
1H), 7.22-7.27 (m, 3H), 7.28-7.34 (m, 1H), 7.37 (d, J=8.3 Hz, 2H),
9.30 (d, J=8.8 Hz, 1H), 12.28 (br. s., 1H).
Example 16-1
N--[(R)-1-(3'-chloro-biphenyl-4-ylmethyl)-3-methanesulfonylamino-3-oxo-pro-
pyl]-succinamic acid
##STR00526##
[0587]
[(R)-1-(3'-Chloro-biphenyl-4-ylmethyl)-3-methanesulfonylamino-3-oxo-
-propyl]-carbamic acid tert-butyl ester (150 mg, 0.321 mmol) is
treated with 4M HCl in dioxane. After being stirred at room
temperature for 1 h, the reaction mixture is concentrated in vacuo.
To this residue in DCM (2 mL) are added succinic anhydride (48.2
mg, 0.482 mmol) and triethylamine (0.112 mL, 0.803 mmol). After
being stirred at room temperature for 2 h, the reaction mixture is
diluted with EtOAc and washed with 1M HCl and brine. The organic
layer is dried over Na.sub.2SO.sub.4 and concentrated. The residue
is purified by reverse phase HPLC (SunFire C18, 0.1% TFA in
H.sub.2O/CH.sub.3CN) to give
N--[(R)-1-(3'-chloro-biphenyl-4-ylmethyl)-3-methanesulfonylamino-3-oxo-pr-
opyl]-succinamic acid (63 mg). HPLC retentions time=1.32 minutes
(condition A); MS (m+1)=467; 1H NMR (400 Mz, DMSO-d6) .delta. ppm
2.22-2.29 (m, 2H), 2.32-2.54 (m, 4H), 2.77 (d, 2H, J=6.82 Hz), 3.17
(s, 3H), 4.31 (dt, 1H, J=7.33, 13.9 Hz), 7.28 (d, 2H, J=8.08 Hz),
7.38-7.43 (m, 1H), 7.48 (t, 1H, J=7.83 Hz), 7.62 (d, 3H, J=8.34
Hz), 7.70 (t, 1H, J=2.02 Hz), 7.89 (d, 1H, J=8.34 Hz), 11.70 (s,
1H), 12.04 (s, 1H).
[0588] Following compounds are prepared using similar procedure as
described in example 16-1:
TABLE-US-00025 HPLC-RT MS Example # Product Starting material
(condition) (M + 1) Example 16- 2 ##STR00527## N-[(R)-1-(3'-Chloro-
biphenyl-4-ylmethyl)-3- oxo-3-(propane-1- sulfonylamino)-propyl]-
succinamic acid ##STR00528## 1.26 min. (condition A) 495 Example
16- 3 ##STR00529## N-[(R)-1-(3'-Chloro- biphenyl-4-ylmethyl)-3-
oxo-3- phenylmethanesulfonyl amino-propyl]- succinamic acid
##STR00530## 1.34 min. (condition A) 543 Example 16- 4 ##STR00531##
N-[(R)-2-Carbamoyl-1- (3'-chloro-biphenyl-4- ylmethyl)-ethyl]-
succinamic acid ##STR00532## 1.33 min. (condition A) 389
Example 16-2
[0589] 1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.96 (t, 3H,
J=7.33 Hz), 1.66 (dd, 2H, J=7.33, 15.2 Hz), 2.25 (t, 2H, J=7.07
Hz), 2.31-2.45 (m, 4H), 2.76 (d, 2H, J=6.82 Hz), 3.25-3.32 (m, 2H),
4.30 (dd, 1H, J=7.83, 14.7 Hz), 7.28 (d, 2H, J=8.34 Hz), 7.38-7.43
(m, 1H), 7.48 (t, 1H, J=7.83 Hz), 7.63 (d, 3H, J=8.08 Hz), 7.70 (t,
1H, J=1.77 Hz), 7.89 (d, 1H, J=8.34 Hz), 11.61 (s, 1H), 12.04 (s,
1H).
Example 16-3
[0590] 1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 2.24-2.31 (m,
2H), 2.34-2.40 (m, 2H), 2.44 (d, 2H, J=6.82 Hz), 2.78 (d, 2H,
J=6.82 Hz), 4.26-4.36 (m, 1H), 4.67 (s, 2H), 7.25-7.33 (m, 4H),
7.34-7.43 (m, 4H), 7.48 (t, 1H, J=7.58 Hz), 7.63 (d, 3H, J=8.34
Hz), 7.70 (t, 1H, J=1.77 Hz), 7.92 (d, 1H, J=8.34 Hz), 11.60 (s,
1H), 12.05 (s, 1H).
Example 16-4
[0591] 1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 2.19-2.29 (m,
4H), 2.36 (dd, 2H, J=6.57, 6.57 Hz), 2.72 (dd, 1H, J=7.83, 13.6
Hz), 2.81 (dd, 1H, J=5.31, 13.6 Hz), 4.17-4.27 (m, 1H), 6.83 (s,
1H), 7.28 (d, 3H, J=8.34 Hz), 7.38-7.43 (m, 1H), 7.47 (t, 1H,
J=7.83 Hz), 7.58-7.65 (m, 3H), 7.69 (t, 1H, J=1.77 Hz), 7.78 (d,
1H, J=8.34 Hz), 12.05 (s, 1H).
Example 16-5
Synthesis of
N--[(R)-1-(3'-chloro-biphenyl-4-ylmethyl)-3-methanesulfonylamino-3-oxo-pr-
opyl]-succinamic acid butyl ester
##STR00533##
[0593] To a solution of
N--[(R)-1-(3'-chloro-biphenyl-4-ylmethyl)-3-methanesulfonylamino-3-oxo-pr-
opyl]-succinamic acid (50 mg, 0.107 mmol) in n-butanol (2 mL) is
added thionyl chloride (9.38 .mu.L, 0.128 mmol). The reaction
mixture is warmed to 50.degree. C. and stirred for 1 h. After
cooling to room temperature, the reaction mixture is concentrated
and purified by reverse phase HPLC (SunFire C18, 0.1% TFA in
H.sub.2O/CH.sub.3CN) to give
N--[(R)-1-(3'-chloro-biphenyl-4-ylmethyl)-3-methanesulfonylamino-3-oxo-pr-
opyl]-succinamic acid butyl ester (32 mg). HPLC retentions
time=1.56 minutes (condition A); MS (m+1)=523; 1H NMR (400 Mz,
DMSO-d.sub.6) .delta. ppm 0.86 (t, 3H, J=7.33 Hz), 1.22-1.34 (m,
2H), 1.45-1.55 (m, 2H), 2.23-2.33 (m, 2H), 2.35-2.44 (m, 3H),
2.45-2.55 (m, 3H), 2.71-2.83 (m, 1H), 3.18 (s, 3H), 3.96 (t, 2H,
J=6.57 Hz), 4.27-4.38 (m, 1H), 7.28 (d, 2H, J=8.08 Hz), 7.37-7.43
(m, 1H), 7.48 (t, 1H J=7.83 Hz), 7.62 (d, 3H, J=8.34 Hz), 7.70 (s,
1H), 7.91 (d, 1H, J=8.34 Hz), 11.71 (s, 1H).
Example 17
(R)-3-(2-acetyloxazole-5-carboxamido)-4-(3'-chlorobiphenyl-4-yl)butanoic
acid
##STR00534##
[0595] To a solution of
(R)-4-(3'-chlorobiphenyl-4-yl)-3-(2-(prop-1-en-2-yl)oxazole-5-carboxamido-
)butanoic acid (60 mg, 0.14 mmol) in DCM (2 mL) and MeOH (2 mL) at
-78.degree. C. is bubbled ozone for 30 seconds. After 30 seconds
ozone is removed and oxygen is bubbled for 10 minutes. After
bubbling oxygen for 10 minutes the -78.degree. C. bath is removed
and the reaction is quenched with polymer supported
triphenylphosphine and the reaction is stirred at room temperature
for 2 hours. After 2 hours the reaction is filtered to remove
triphenylphosphineoxide on supported polymer and the filtrate is
collected and concentrated under reduced pressure. The obtained
residue is purified by RP-HPLC (SunFire C18, H.sub.2O (0.1%
TFA)/CH.sub.3CN), and then lyophilized to give
(R)-3-(2-acetyloxazole-5-carboxamido)-4-(3'-chlorobiphenyl-4-yl)butanoic
acid (13 mg). HPLC retention time=1.67 minutes (condition D); MS
(m+1)=427.0; 1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 2.53-2.59
(m, 2H) 2.60 (s, 3H) 2.87 (dd, J=10.9, 3.3 Hz, 1H) 2.94 (dd,
J=10.9, 5.1 Hz, 1H) 4.46-4.60 (m, 1H) 7.31 (d, J=8.1 Hz, 2H)
7.36-7.43 (m, 1H) 7.47 (t, J=7.8 Hz, 1H) 7.62 (d, J=8.3 Hz, 3H)
7.69 (t, J=1.9 Hz, 1H) 7.94 (s, 1H) 8.86 (d, J=8.6 Hz, 1H) 12.31
(br. s., 1H).
[0596] Starting materials or intermediates are prepared in
following manner:
Intermediate 1: (R)-ethyl
4-(4-bromophenyl)-3-(4-methoxy-4-oxobutanamido)butanoate
##STR00535##
[0598] To
(R)-ethyl-4-(4-bromophenyl-4-yl)-3-(tert-butoxycarbonylamino)but-
anoate (2.02 g, 5.23 mmol) is added a solution of 4M HCl in
1,4-dioxane (13.1 mL, 52.3 mmol) at room temperature. After
stirring for 1 hour, the reaction mixture is concentrated under
reduced pressure to give (R)-3-amino-4-bromophenyl-4-yl-butyric
acid ethyl ester hydrochloride. To a solution of
(R)-3-amino-4-bromophenyl-4-yl-butyric acid ethyl ester
hydrochloride is added succinic anhydride (0.707 g, 7.06 mmol) and
DIPEA (2.06 mL, 11.8 mmol) in dichloromethane (20 mL) and allowed
to stir for 4 hours. The reaction is quenched with 0.1 M aqueous
HCl. The products are extracted with ethyl acetate and washed with
brine. The organic layer is dried over Na2.sub.SO.sub.4, filtered,
and concentrated under reduced pressure to give
(R)-4-(1-(4-bromophenyl)-4-ethoxy-4-oxobutan-2-ylamino)-4-oxobutanoic
acid (2.26 g). To a solution of the obtained residue (2.26 g) in
toluene (25 mL) and MeOH (25 mL), TMSCHN.sub.2 in hexanes (5.85 ml,
11.70 mmol) is added portionwise at room temperature under
nitrogen. The reaction mixture is allowed to stir for 1.5 hour,
then quenched with AcOH (0.5 mL; 8.78 mmol), and the solution is
stirred for 10 minutes. The solution is concentrated, and the
obtained residue is purified by flash column chromatography on 40 g
silica gel (eluent: heptane/EtOAc=100:0 to 0:100) to give (R)-ethyl
4-(4-bromophenyl)-3-(4-methoxy-4-oxobutanamido)butanoate (1.92 g).
HPLC retention time=1.04 minutes (condition B); MS (ES+)=400 (m+1),
402.0 (m+3; 100%); 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.28
(t, J=7.2 Hz, 3H) 2.40-2.53 (m, 4H) 2.60-2.64 (m, 2H) 2.79 (A of
ABX, Jab=13.7 Hz, Jax=7.85 Hz, 1H) 2.90 (B of ABX, Jab=13.7 Hz,
Jbx=6.65 Hz, 1H) 3.68 (s, 3H) 4.10-4.22 (m, 2H) 4.39-4.47 (m, 1H)
6.29 (br d, J=8.6 Hz, 1H) 7.06 (d, J=8.4 Hz, 2H) 7.40-7.42 (m,
2H).
Intermediate 2: (R)-ethyl
4-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)butanoate
##STR00536##
[0600] A mixture of (R)-ethyl
4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoate (1.5 g,
3.88 mmol), phenylboronic acid (0.710 g, 5.82 mmol), Pd(Ph3P).sub.4
(0.449 g, 0.388 mmol) and aqueous Na.sub.2CO.sub.3 (3.88 mL, 7.77
mmol) in toluene (25 mL) is allowed to stir at 95.degree. C. under
nitrogen for 14 hours. The reaction mixture is cooled to room
temperature and quenched with brine. The mixture is extracted twice
with ethylacetate, and the combined organic layer is washed with
brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated
under reduced pressure. The obtained residue is purified by silica
gel flash column chromatography (heptane/EtOAc=100:0 to 50:50) to
give (R)-ethyl
4-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)butanoate (1.30 g);
HPLC retention time=1.61 minutes (condition B); MS (ES+)=328.0
(m-tBu+2); 284.1 (m-Boc+2; 100%); 1H NMR (400 MHz, CHLOROFORM-d)
.delta. ppm 1.28 (t, J=7.1 Hz, 3H) 2.48 (A of ABX, Jab=16.1 Hz,
Jax=5.9 Hz, 1H) 2.53 (B of ABX, Jab=16.0 Hz, Jbx=5.3 Hz, 1H)
2.83-3.00 (m, 2H) 4.14-4.19 (m, 3H) 5.06 (br s) 7.26-7.27 (m, 2H)
7.31-7.35 (m, 2H) 7.43 (t, J=7.6 Hz, 2H) 7.52-7.58 (m, 4H).
[0601] Following intermediates are prepared using similar procedure
as described for intermediate 2:
TABLE-US-00026 MS HPLC-RT (ES+; Intermediate # Product Condition
(condition) 100%) Intermediate 2-2 ##STR00537## (R)-ethyl 3-(tert-
butoxycarbonylamino)-4-(3'- fluorobiphenyl-4- yl)butanoate
Pd(PPh3)4, 3- fluorobenzeneboronic acid, aq. 2M Na2CO3, toluene,
95.degree. C. 1.61 min. (B) 302.1 (m-BOC + 2) Intermediate 2-3
##STR00538## (R)-ethyl 3-(tert- butoxycarbonylamino)-
4-(5'-chloro-2'- methoxybiphenyl-4- yl)butanoate
PdCl.sub.2(dppf).cndot.CH2Cl.sub.2 complex, 5-chloro-2-
methoxyphenylboronic acid, aq. 2M Na2CO3, toluene, 95.degree. C.
1.58 min. (B) 348.1 (m-BOC + 2) Intermediate 2-4 ##STR00539##
(R)-ethyl 3-(tert- butoxycarbonylamino)- 4-(5'-fluoro-2'-
methoxybiphenyl-4- yl)butanoate
PdC.sub.2(dppf).cndot.CH.sub.2Cl.sub.2 complex, 5-fluoro-2-
methoxyphenylboronic acid, aq. 2M Na.sub.2CO.sub.3, toluene,
95.degree. C 1.42 min. (B) 332.2 (m-BOC + 2) Intermediate 2-5
##STR00540## (R)-ethyl 3-(tert- butoxycarbonylamino)-
4-(2'-chloro-5'- fluorobiphenyl-4- yl)butanoate
Pd(PPh.sub.3).sub.4, 2-chloro-5- fluorophenylboronic acid, aq. 2M
Na.sub.2CO.sub.3, toluene, 95.degree. C 1.49 min. (B) 336.1 (m-BOC
+ 2) Intermediate 2-6 ##STR00541## (R)-ethyl 3-(tert-
butoxycarbonylamino)- 4-(5'-chloro-2'- fluorobiphenyl-4-
yl)butanoate Pd(PPh.sub.3).sub.4, 5-chloro-2- fluorophenylboronic
acid, aq. 2M Na2CO3, DME, 95.degree. C 1.47 min. (B) 336.1 (m-BOC +
2)
Intermediate 3:
(R)-4-(1-(biphenyl-4-yl)-4-tert-butoxy-4-oxobutan-2-ylamino)-4-oxobutanoi-
c acid
##STR00542##
[0603] To (R)-tert-butyl
4-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)butanoate (26.4 mg,
0.064 mmol) is added 4M HCl in 1,4-dioxane (0.321 ml, 1.283 mmol)
at room temperature. The reaction mixture is stirred for 45 minutes
and concentrated under reduced pressure. To a solution of the
obtained residue in dichloromethane (0.4 mL) is added succinic
anhydride (7.70 mg, 0.077 mmol) and DIPEA (0.013 mL, 0.077 mmol).
The reaction mixture is allowed to stir at room temperature for 14
hours and concentrated under reduced pressure. The obtained residue
is purified by RP-HPLC (SunFire C-18, H.sub.2O (0.1%
TFA)/CH.sub.3CN) to give
(R)-4-(1-(biphenyl-4-yl)-4-tert-butoxy-4-oxobutan-2-ylamino)-4-oxobutanoi-
c acid (9.5 mg). HPLC retention time=1.70 minutes (condition A); MS
(ES+)=412.1 (m+1); 356.0 (m-tBu+2; 100%); 1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 1.48 (s, 9H) 2.36-2.51 (m, 4H) 2.64-2.67
(m, 2H) 2.87 (A of ABX, Jab=13.5 Hz, Jax=5.7 Hz, 1H), 2.97
(Jab=13.5 Hz, Jbx=6.2 Hz, 1H) 7.24-7.26 (m, 2H) 7.31-7.35 (m, 1H)
7.43 (t, J=7.75 Hz, 2H) 7.53 (d, J=8.0 Hz, 2H) 7.57 (d, J=7.6 HZ,
2H).
[0604] Following intermediates are prepared using similar procedure
as described in intermediate 3:
TABLE-US-00027 HPLC-RT MS Intermediate # Product Starting Material
(condition) (M + 1) Intermediate 3-2 ##STR00543## (R)-4-(4-Bromo-
phenyl)-3-(3- carboxy- propionylamino)- butyric acid ethyl ester
##STR00544## 0.90 min. (B) 385.9
Intermediate 4: (R)-tert-butyl
4-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)butanoate
##STR00545##
[0606] A solution of
(R)-2-(biphenyl-4-ylmethyl)-4-tert-butoxy-4-oxobutanoic acid (100
mg, 0.294 mmol), DPPA (0.076 mL, 0.353 mmol) and Et.sub.3N (0.049
mL, 0.353 mmol) in Toluene (1.5 mL) is allowed to stir at
100.degree. C. under nitrogen for 2 hours. tBuOH (0.281 ml, 2.94
mmol) is added and the mixture is refluxed for 5 hours at the same
temperature. The reaction is cooled to room temperature, and the
solvent is removed. Ethyl acetate is added to the obtained residue,
and the organic layer is washed with 5% aqueous citric acid,
H.sub.2O, saturated aqueous NaHCO.sub.3, and brine. The organic
layer is dried over Na.sub.2SO.sub.4, filtered, and concentrated
under reduced pressure. The obtained residue is purified by flash
column chromatography on 40 g of silica gel (heptane/EtOAc=100:0 to
50:50) to give the corresponding isocyanate (35.7 mg). The obtained
isocyanate is dissolved in tBuOH (0.3 mL) and the solution is
allowed to stir at 80.degree. C. for 20 hours. The reaction mixture
is concentrated, and the residue is purified by flash column
chromatography on 12 g of silica gel (heptane/EtOAc=100:0 to 70:30)
to give (R)-tert-butyl
4-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)butanoate (26.4 mg,
22%). HPLC retention time=1.74 minutes (condition B); MS
(ES+)=356.0 (m-tBu+2) 300.0 (m-tBux2+3; 100%); 1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 1.41 (s, 9H) 1.47 (s, 9H) 2.36 (A of ABX,
Jab=15.6 Hz, Jax=6.2 Hz, 1H) 2.44 (B of ABX, Jab=15.5 Hz, Jbx=5.45
Hz) 2.82-2.97 (m, 2H) 4.15 (br s) 5.09 (br d) 7.6-7.35 (m, 3H)
7.41-7.45 (m, 2H) 7.51-7.56 (m, 4H).
Intermediate 5: (R)-ethyl
4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoate
##STR00546##
[0608] To a suspension of
(R)-4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoic acid
(9.98 g, 27.9 mmol) and NaHCO.sub.3 (4.68 g, 55.7 mmol) in DMF (45
mL) is added Ethyl iodide (6.75 mL, 84 mmol) at room temperature
under nitrogen. After stirring for 71 hours, the reaction is
quenched with H.sub.2O (300 mL), and then precipitated solid is
collected and washed with H.sub.2O (500 mL) to give (R)-ethyl
4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoate (10.25 g,
94%). HPLC retention time=1.48 minutes (condition B); MS
(ES+)=329.9 (m-tBu+2); 286.0 (m-Boc+2; 100%); 1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 1.27 (t, J=7.2 Hz, 3H) 1.40 (s, 9H), 2.43
(A of ABX, Jab=15.8 Hz, Jax=5.7 Hz, 1H) 2.50 (B of ABX, Jab=15.8
Hz, Jbx=5.4 Hz, 1H) 2.74-2.90 (m, 2H) 4.11 (br s) 4.15 (q, J=7.1
Hz, 2H) 5.04 (br d) 7.07 (d, J=8.3 Hz, 2H) 7.40-7.43 (m, 2H).
[0609] Following intermediates are prepared using similar procedure
as described for intermediate 5:
TABLE-US-00028 MS HPLC-RT (ES+; Intermediate # Product Condition
(condition) 100%) Intermediate 5-2 ##STR00547## (R)-benzyl 4-(4-
bromophenyl)-3- butoxycarbonylamino) butanoate BnBr, NaHCO.sub.3,
DMF, RT 1.56 min. (B) 348 (m-MOC + 2) Intermediate 5-3 ##STR00548##
(R)-4-(4-Bromo- phenyl)-3-tert- butoxycarbonylamino- butyric acid
propyl ester n-propyl iodide, NaHCO.sub.3, DMF, RT 1.47 min. (B)
400 (m + 1) Intermediate 5-4 ##STR00549## (R)-4-(4-Bromo-
phenyl)-3-tert- butoxycarbonylamino- butyric acid butyl ester
n-butyl iodide, NaHCO.sub.3) DMF, RT 1.55 min. (B) 414 (m + 1)
Intermediate 5-5 ##STR00550## (R)-4-(4-Bromo- phenyl)-3-tert-
butoxycarbonylamino- butyric acid 5- methyl-2-oxo- [1,3]dioxol-4-
ylmethyl ester ##STR00551## K.sub.2CO.sub.3, DMF, RT 1.28 min. (B)
470 (m + 1) Intermediate 5-6 ##STR00552## (R)-4-(4-Bromo-
phenyl)-3-tert- butoxycarbonylamino- butyric acid dimethylcarbamoyl
methyl ester ##STR00553## K.sub.2CO.sub.3, DMF, RT 1.65 min. (B)
444 (m + 1) Intermediate 5-7 ##STR00554## (R)-4-(4-Bromo-
phenyl)-3-tert- butoxycarbonylamino- butyric acid 2-
morpholin-4-yl- ethyl ester ##STR00555## K.sub.2CO.sub.3, DMF, RT
1.19 min. (B) 471 (m + 1)
Intermediate 5-2: (R)-benzyl
4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoate
##STR00556##
[0611] To a suspension of
(R)-4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoic acid
(5.02 g, 14.01 mmol) and NaHCO.sub.3 (3.53 g, 42.0 mmol) in DMF (20
mL) is added Benzyl bromide (5.10 mL, 42 mmol) at room temperature
under nitrogen. After stirring for 46 hours, the reaction is
diluted with H.sub.2O (200 mL), and then precipitated solid is
collected and washed with H.sub.2O (500 mL) and then with heptane
(200 ml) to give (R)-benzyl
4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoate (5.61 g,
89%). HPLC retention time=1.56 minutes (condition B); MS
(ES+)=392.1 (m-tBu+2); 348.1 (m-Boc+2; 100%); 1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 1.39 (s, 9H) 2.48 (A of ABX, Jab=15.9 Hz,
Jax=5.6 Hz, 1H) 2.54 (B of ABX, Jab=15.9 Hz, Jbx=5.3 Hz, 1H)
2.72-2.88 (m, 2H) 4.11 (br s, 1H) 5.02 (br s, 1H) 5.10 (A of AB,
J=12.1 Hz, 1H) 5.16 (A of AB, J=12.1 Hz, 1H) 7.00 (d, J=8.1 Hz, 2H)
7.34-7.39 (m, 7H).
Intermediate 6:
(R)-3-(biphenyl-4-ylmethyl)-4-(3-methoxy-3-oxopropylamino)-4-oxobutanoic
acid
##STR00557##
[0613] To a solution of (R)-tert-butyl
3-(biphenyl-4-ylmethyl)-4-(3-methoxy-3-oxopropylamino)-4-oxobutanoate
(40 mg, 0.094 mmol) in DCM (0.5 mL), TFA (0.15 mL) is added at room
temperature. The mixture is allowed to stir for 2 hours, and then
concentrated under reduced pressure to give
(R)-3-(biphenyl-4-ylmethyl)-4-(3-methoxy-3-oxopropylamino)-4-oxobutanoic
acid (33.5 mg, 96%). HPLC retention time=1.20 minutes (condition
A); MS (m+1)=370.1; 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm
2.21-2.29 (m, 1H) 2.38-2.45 (m, 1H) 2.62-2.66 (m, 1H) 2.75-3.00 (m,
4H) 3.29-3.37 (m, 1H) 3.45-3.53 (m, 4H) 6.12 (br s, 1H) 7.23 (d,
J=8 Hz, 2H) 7.32-7.35 (m, 1H) 7.41-7.45 (m, 2H) 7.53 (d, J=8.1 Hz,
2H) 7.56-7.59 (m, 2H).
Intermediate 7: (R)-tert-butyl
3-(biphenyl-4-ylmethyl)-4-(3-methoxy-3-oxopropylamino)-4-oxobutanoate
##STR00558##
[0615] A solution of
(R)-2-(biphenyl-4-ylmethyl)-4-tert-butoxy-4-oxobutanoic acid (142
mg, 0.417 mmol), 3-amino-propionic acid methyl ester hydrochloride
(76 mg, 0.542 mmol), WSC hydrochloride (120 mg, 0.626 mmol),
1-hydroxy-7-azabenzotriazole (85 mg, 0.626 mmol) and DIPEA (0.219
ml, 1.251 mmol) in DMF (4 mL) is allowed to stir at room
temperature under nitrogen for 13 hours. The reaction is quenched
with H.sub.2O. The products are extracted with ethyl acetate,
washed with aqueous 1M HCl and then with brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated under reduced
pressure. The obtained residue is purified by flash column
chromatography on 12 g of silica gel (heptane/EtOAc=70:30 to 0:100)
to give (R)-tert-butyl
3-(biphenyl-4-ylmethyl)-4-(3-methoxy-3-oxopropylamino)-4-oxobutanoate
(164 mg, 91%). HPLC retention time=1.59 minutes (condition A); MS
(ES+)=425.4 (m); 369.4 (m-tBu+1; 100%); 1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 2.24-2.44 (m, 2H) 2.67-2.79 (m, 3H)
2.89-2.96 (m, 1H) 3.28-3.36 (m, 1H) 3.45-3.53 (m, 1H) 7.23 (d,
J=5.8 Hz, 2H) 7.33 (t, J=7.35 Hz, 1H) 7.41-7.44 (m, 2H) 7.51 (d,
J=8.1 Hz, 2H) 7.58 (d, J=7.4 Hz, 2H).
[0616] Following intermediates are prepared using similar procedure
as described in intermediate 7:
TABLE-US-00029 Starting HPLC-RT MS Intermediate # Product Material
Condition (condition) (M + 1) Intermediate 7-2 ##STR00559##
(R)-3-Biphenyl-4- ylmethyl-N-tert- butoxycarbonylmethyl- succinamic
acid tert-butyl ester ##STR00560## ##STR00561## WSC.cndot.HCl,
HOAt, DIPEA, DMF, rt 1.64 min. (B) 454.1 Intermediate 7-3
##STR00562## (R)-3-Biphenyl-4- ylmethyl-N-(3- carboxy-propyl)-
succinamic acid tert-butyl ester ##STR00563## ##STR00564##
WSC.cndot.HCl, HOAt, DIPEA, DMF, rt 1.71 min. (B) 426.1
Intermediate 8:
(R)-3-[(1-benzyl-1H-tetrazole-5-carbonyl)-amino]-4-biphenyl-4-yl-butyric
acid ethyl ester and
(R)-3-[(2-benzyl-2H-tetrazole-5-carbonyl)-amino]-4-biphenyl-4-yl-butyric
acid ethyl ester
##STR00565##
[0618] (R)-ethyl
4-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)butanoate (117 mg,
0.305 mmol) is treated with 4M HCl dioxane solution (2 mL). After
stirring for 0.5 hour, the reaction mixture is concentrated under
reduced pressure. To a solution of the obtained residue and
Et.sub.3N (0.106 mL, 0.763 mmol) in DCM (3 mL) is added
benzyl-H-tetrazole-5-carbonyl chloride (mixture of 1 and 2-benzyl
isomers, 82 mg, 0.366 mmol, prepared according to J. Med. Chem.
1986, 29, 538-549). After stirring for 10 minutes, Et.sub.3N (0.106
mL, 0.763 mmol) and the acid chloride (82 mg, 0.366 mmol) are
added. After stirring for 0.5 hour, the reaction mixture is diluted
with ethyl acetate, washed with H.sub.2O and brine, dried over
Na.sub.2SO.sub.4, and concentrated under reduced pressure. The
residue is purified by silica gel column chromatography to give
(R)-3-[(1-benzyl-1H-tetrazole-5-carbonyl)-amino]-4-biphenyl-4-yl-butyric
acid ethyl ester and
(R)-3-[(2-benzyl-2H-tetrazole-5-carbonyl)-amino]-4-biphenyl-4-yl-butyric
acid ethyl ester. HPLC retention time=1.51 minutes (condition D);
MS=470.0 (m+1); 1H NMR (400 MHz, CDCl3) .delta. ppm 1.27 (t,
J=7.07, 7.07 Hz, 3H), 2.57-2.70 (m, 2H), 3.00 (dd, J=7.58, 13.77
Hz, 1H), 3.12 (dd, J=6.57, 13.77 Hz, 1H), 4.12-4.23 (m, 2H),
4.71-4.80 (m, 1H), 5.80 (s, 2H), 7.27-7.45 (m, 9H), 7.52 (d, J=8.34
Hz, 2H), 7.56 (d, J=8.46 Hz, 2H), 7.75 (d, J=7.33 Hz, 1H).
Intermediate 9:
(R)-4-biphenyl-4-yl-3-{3-[1-(2-cyano-ethyl)-1H-tetrazol-5-yl]-propionylam-
ino}-butyric acid ethyl ester
##STR00566##
[0620] To a solution of
(R)-4-biphenyl-4-yl-3-tert-butoxycarbonylamino-butyric acid ethyl
ester (400 mg, 1.04 mmol) in DCM (10 mL) at room temperature is
added TFA (2.009 mL, 26.1 mmol) and the mixture is stirred at room
temperature for 1 hour. The mixture is concentrated under reduced
pressure. To the obtained TFA salt in DCM (10 mL) at ice bath
temperature is added succinic anhydride (125 mg, 1.25 mmol) and
followed by TEA (0.363 mL, 2.61 mmol). The reaction is stirred at
room temperature for 16 hours. The mixture is concentrated under
reduced pressure. The obtained residue is purified by flash
chromatography (silica gel, 2% to 5% EtOH/DCM) give
(R)-4-biphenyl-4-yl-3-(3-carboxy-propionylamino)-butyric acid ethyl
ester (200 mg). HPLC retention time=1.53 minutes (condition C);
MS=384 (m+1).
[0621] Next, to a solution of
(R)-4-biphenyl-4-yl-3-(3-carboxy-propionylamino)-butyric acid ethyl
ester (200 mg, 0.522 mmol) in THF (10 mL) at room temperature is
added EDC HCl (120 mg, 0.626 mmol) and HOBT (96 mg, 0.626 mmol).
The reaction is stirred at room temperature for 10 minutes then
added 3-aminopropionitrile (0.046 ml, 0.626 mmol) and TEA (0.087
ml, 0.626 mmol). After 1 hour, 0.5 equivalent of EDC HCl, HOBT, and
3-aminopropionitrile are added and stirred for 16 hours. The
reaction mixture is quenched by brine and is extracted with
ethylacetate. The combined organic layer is washed with brine and
dried over anhydrous sodium sulfate, filtered and concentrated
under reduced pressure. The obtained residue is purified by flash
chromatography (silica gel, 2% to 5% EtOH/DCM) to give
(R)-4-biphenyl-4-yl-3-[3-(2-cyano-ethylcarbamoyl)-propionylamino]-butyric
acid ethyl ester (218 mg, 96% yield). HPLC retention time=0.77
minutes (condition E); MS=436 (m+1).
[0622] Next, to a solution of
(R)-4-biphenyl-4-yl-3-[3-(2-cyano-ethylcarbamoyl)-propionylamino]-butyric
acid ethyl ester (204 mg, 0.468 mmol) in THF (10 mL) at room
temperature is added Ph.sub.3P (307 mg, 1.17 mmol) and the mixture
is stirred at room temperature for 10 minutes. Then to the mixture
at ice bath temperature is added DIAD (0.228 ml, 1.171 mmol) and
trimethylsilyl azide (0.155 ml, 1.171 mmol). The resulting mixture
is slowly warmed up to room temperature and stirred for 16 hours.
The reaction mixture is concentrated under reduced pressure. The
obtained residue is purified by flash chromatography (silica gel,
1% to 3% EtOH/DCM) to give
(R)-4-biphenyl-4-yl-3-{3-[1-(2-cyano-ethyl)-1H-tetrazol-5-yl]-propionylam-
ino}-butyric acid ethyl ester (137 mg, 64% yield). HPLC retention
time=1.61 minutes (condition C); MS=461 (m+1).
Intermediate 10:
(R)-2-(biphenyl-4-ylmethyl)-4-tert-butoxy-4-oxobutanoic acid
##STR00567##
[0624] To a stirred solution of (R)-tert-butyl
4-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(biphenyl-4-ylmethyl)-4-oxobutano-
ate (1.20 g, 2.402 mmol) in a mixed solvent of THF (20 mL) and
water (5 mL), a solution of aqueous H.sub.2O.sub.2(0.960 mL, 9.61
mmol) and aqueous LiOH (4.80 ml, 4.80 mmol) is added at 0.degree.
C. during 5 minutes. After stirring for 1.5 hour, the reaction is
quenched with saturated aqueous Na.sub.2SO.sub.3 (10 mL) at
0.degree. C., and allowed to stir for 10 minutes at the same
temperature. The reaction mixture is warmed up to ambient
temperature while stirring for 0.5 hour. Then, saturated aqueous
NaHCO.sub.3 and brine are added to the mixture. The product is
extracted with ethyl acetate, washed with aqueous 1M HCl, dried
over MgSO.sub.4, filtered, and concentrated under reduced pressure.
The obtained residue is purified by flash column chromatography on
120 g of silica gel (heptane/EtOAc=75:25 to 0:100) to give
(R)-2-(biphenyl-4-ylmethyl)-4-tert-butoxy-4-oxobutanoic acid (765
mg, 93%). HPLC retention time=1.63 minutes (condition D); MS=338.6
(m-1); 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.43 (s, 9H) 2.41
(A of ABX, J.sub.ab=16.67 Hz, J.sub.ax=4.55 Hz, 1H) 2.52-2.67 (B of
ABX, Jab=16.75 Hz, Jbx=8.45 Hz, 1H) 2.74-2.89 (m, 1H) 3.06-3.22 (m,
2H) 7.22-7.29 (m, 2H) 7.30-7.37 (m, 1H) 7.43 (t, J=7.58 Hz, 2H)
7.53 (d, J=8.1 Hz, 2H) 7.57 (d, J=7.8 Hz, 2H).
Intermediate 11: Synthesis of (R)-tert-butyl
4-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(biphenyl-4-ylmethyl)-4-oxobutano-
ate
##STR00568##
[0626] A stirred solution of
(S)-4-benzyl-3-(3-(biphenyl-4-yl)propanoyl)oxazolidin-2-one
(intermediate 12: 5.01 g, 13.00 mmol) in THF (180 mL) is cooled to
-73.8.degree. C., and 1M THF solution of sodium
hexamethyldisilylamide (14.30 mL, 14.30 mmol) is added during 5
minutes. After 30 minutes, a solution of tert-butyl bromoacetate
(2.495 mL, 16.90 mmol) in THF (20 mL) is added dropwise during 5
minutes. The solution is stirred at -74.degree. C. for 1 hour, and
the reaction is quenched with saturated aqueous NH.sub.4Cl (100
mL), and warmed up to ambient temperature. The precipitated solid
is filtered off and washed with ethyl acetate (50 mL). The organic
phase is separated, washed with brine, dried over MgSO.sub.4, and
concentrated under reduced pressure. The obtained residue is
suspended in MeOH (70 mL) and then filtered to collect the solid
(5.9 g) as a mixture of the desired product and the starting
material. The mixture is purified by flash column chromatography on
120 g of silica gel (heptane/EtOAc=90:10 to 50:50) to give
(R)-tert-butyl
4-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(biphenyl-4-ylmethyl)-4-oxobutano-
ate (2.40 g, 37%). HPLC retention time=1.74 minutes (condition B);
MS=499.4 (m+); 443.4 (m-tBu+1; 100%); 1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 1.41 (s, 9H) 2.42 (dd, J=16.67, 4.04 Hz,
1H) 2.71 (ddd, J=16.55, 13.26, 9.60 Hz, 2H) 2.87 (dd, J=16.93,
10.86 Hz, 1H) 3.04 (dd, J=13.14, 6.32 Hz, 1H) 3.32 (dd, J=13.39,
3.03 Hz, 1H) 3.92 (t, J=8.34 Hz, 1H) 4.07 (dd, J=8.97, 2.15 Hz, 1H)
4.48-4.58 (m, 2H) 7.20-7.30 (m, 3H) 7.30-7.36 (m, 5H) 7.42 (t,
J=7.58 Hz, 2H) 7.52 (d, J=8.1 Hz, 2H) 7.56 (d, J=7.8 Hz, 2H).
Intermediate 12:
(S)-4-benzyl-3-(3-(biphenyl-4-yl)propanoyl)oxazolidin-2-one
##STR00569##
[0628] To a 1.6 M solution of n-BuLi in hexane (12.1 mL, 19.3 mmol)
is added dropwise a solution of (S)-(-)-4-benzyl-2-oxazolidinone
(3.26 g, 18.4 mmol) in dry THF (80 mL) at -71.6.degree. C. under
nitrogen over 10 minutes. The solution is warmed up to
-60.5.degree. C. while the addition, and allowed to stir for 1 hour
in dry ice/MeOH bath. 3-(Biphenyl-4-yl)propanoyl chloride
(intermediate 13: 5.46 g, 22.31 mmol) in dry THF (20 mL) is added
dropwise at -72.degree. C. over 5 minutes. The solution is warmed
up to -56.5.degree. C. while the addition. After stirring 10
minutes at the same temperature, the reaction mixture is allowed to
warm to room temperature and stirring is continued for 3 hours. The
reaction mixture is filtered, and the collected precipitate is
washed with 20 mL (10 mL.times.2) of MeOH and then with 150 mL of
H.sub.2O to give the desired product (4.26 g). The products in the
mother liquor is extracted with ethyl acetate, washed with brine,
dried over MgSO.sub.4, filtered, and concentrated under reduced
pressure. The obtained residue is suspended in 80 mL of MeOH, and
the suspension is filtered and washed with 20 mL of MeOH (1.79 g).
The two fractions are mixed to give
(S)-4-benzyl-3-(3-(biphenyl-4-yl)propanoyl)oxazolidin-2-one (6.05
g, 85% in 2 steps). Retention time=1.77 minutes (condition A); MS
(m+1)=387.3; 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 2.77 (dd,
J=13.39, 9.35 Hz, 1H) 2.99-3.15 (m, 2H) 3.20-3.43 (m, 3H) 4.09-4.24
(m, 2H), 4.68 (dddd, J=9.76, 6.73, 3.47, 3.28 Hz, 1H) 7.18 (d,
J=7.07 Hz, 2H) 7.23-7.37 (m, 6H) 7.42 (t, J=7.58 Hz, 2H) 7.53 (d,
J=8.1 Hz, 2H), 7.57 (d, J=7.8 Hz, 2H).
Intermediate 13: 3-(biphenyl-4-yl)propanoyl chloride
##STR00570##
[0630] A mixture of 3-(4-biphenylyl)propionic acid (5 g, 22.10
mmol) and SOCl.sub.2 (4.03 ml, 55.2 mmol) is refluxed under
nitrogen at 85.degree. C. for 1.5 hour. The reaction mixture is
concentrated under reduced pressure to give
3-(biphenyl-4-yl)propanoyl chloride (5.46 g). The material is used
in the next step without further purification.
Intermediate 14: (2R,4R)-4-Amino-2-methyl-pentanoic acid ethyl
ester trifluoroacetate
##STR00571##
[0632] To a stirred solution of
2-(triphenylphosphanylidene)-propionic acid ethyl ester (3.11 g,
8.57 mmol) in methylene chloride (20 mL) is added a solution of
3,3-dimethyl-N--((R)-1-methyl-2-oxo-ethyl)-butyramide (J. Med.
Chem. 41, 6 (1998) (1.35 g, 7.79 mmol) in methylene chloride (20
mL) and the mixture is stirred at room temperature for 2 hours. The
solvent is removed under reduced pressure and the residue is
purified by column chromatography using a gradient of 10-50%
heptane/EtOAc to give
(E)-(R)-4-tert-butoxycarbonylamino-2-methyl-pent-2-enoic acid ethyl
ester. .sup.1H-NMR (400 MHz, CDCl.sub.3); .delta. ppm 1.22 (d,
J=6.44 Hz, 3H), 1.30 (t, 3H), 1.43 (s, 9H), 1.91 (s, 3H), 4.19 (q,
2H), 6.51 (d, broad, J=7.45 Hz, 1H).
[0633] Next, a solution of
(E)-(R)-4-tert-butoxycarbonylamino-2-methyl-pent-2-enoic acid ethyl
ester (1.83 g, 7.11 mmol) in ethyl acetate (75 mL) is hydrogenated
over 10% Pt/C (183 mg) at 1 atm for 18 hours. The catalyst is
filtered through Celite and the solvent is removed under reduced
pressure. The residue is purified by chiral HPLC to afford
(2R,4R)-4-tert-butoxycarbonylamino-2-methyl-pentanoic acid ethyl
ester, .sup.1H-NMR (400 MHz, CDCl.sub.3); .delta. ppm 1.13 (t, 3H),
1.18 (m, 3H), 1.26 (t, 3H), 1.43 (s, 9H), 1.81 (s, 1H), 2.50 (m,
1H), 3.72 (m broad, 1H), 4.14 (m, 2H), 4.33 (m broad, 1H).
[0634] Next, (2R,4R)-4-tert-butoxycarbonylamino-2-methyl-pentanoic
acid ethyl ester (142 mg, 0.548 mmol) is added to trifluoroacetic
acid (5 mL). After 10 minutes, the solvent is removed under reduced
pressure. Methylene chloride is added and the solvent is removed
under reduced pressure to give (2R,4R)-4-amino-2-methyl-pentanoic
acid ethyl ester trifluoroacetate. This material is used directly
in the subsequent coupling reaction.
Intermediate 15: 2-Biphenyl-4-ylmethyl-succinic acid 1-methyl
ester
##STR00572##
[0636] To a solution of (triphenylphosphanylidene)-acetic acid
methyl ester (2.26 g, 6.77 mmol) in methylene chloride (25 mL) is
added t-butyl bromoacetate (1.32 g, 6.77 mmol) and the mixture is
stirred at room temperature for 48 hours. The solvent is removed
under reduced pressure and the residue is purified by column
chromatography using a gradient of 80-100% heptane/EtOAc to afford
2-(triphenylphosphanylidene)-succinic acid 4-tert-butyl ester
1-methyl ester. MS 449.3 (M+1).
[0637] Next, a mixture of 2-(triphenylphosphanylidene)-succinic
acid 4-tert-butyl ester 1-methyl ester (700 mg, 1.561 mmol) and
biphenyl-4-carboxaldehyde (278 mg, 1.419 mmol) in toluene (20 mL)
is refluxed for 4 days. The solvent is removed under reduced
pressure and the residue is purified by column chromatography using
a gradient of 0-30% heptane/EtOAc to give
2-[1-biphenyl-4-yl-meth-(Z)-ylidene]-succinic acid 4-tert-butyl
ester 1-methyl ester as an oil, .sup.1H-NMR (400 MHz, CDCl.sub.3);
.delta. ppm 1.47 (s, 9H), 3.52 (s, 2H), 3.84 (s, 3H), 7.37 (t, 1H),
7.46 (t, 4H), 7.62 (t, 4H), 7.89 (s, 1H).
[0638] A solution of 2-[1-biphenyl-4-yl-meth-(Z)-ylidene]-succinic
acid 4-tert-butyl ester 1-methyl ester (410 mg, 1.163 mmol) in
ethyl acetate (20 mL) is hydrogenated over Pt/C (40 mg) at 1 atm
for 18 hours. The catalyst is filtered through Celite and the
solvent is removed under reduced pressure to give
2-biphenyl-4-ylmethyl-succinic acid 4-tert-butyl ester 1-methyl
ester.
[0639] The enantiomers are separated by chiral HPLC.
[0640] Next, 2-biphenyl-4-ylmethyl-succinic acid 4-tert-butyl ester
1-methyl ester (160 mg, 0.451 mmol) is added to trifluoroacetic
acid (5 mL). After 10 minutes, the solvent is removed under reduced
pressure. Methylene chloride is added and the solvent is removed
under reduced pressure to give 2-biphenyl-4-ylmethyl-succinic acid
1-methyl ester. This material is used directly in the subsequent
coupling reaction.
Intermediate 16-1: Synthesis of (R)-ethyl
3-amino-4-(3'-chlorobiphenyl-4-yl)butanoate hydrochloride
##STR00573##
[0642] To (R)-ethyl
3-(tert-butoxycarbonylamino)-4-(3'-chlorobiphenyl-4-yl)butanoate
(3.33 g, 7.97 mmol) is added a solution of 4 M HCl in 1,4-dioxane
(19.9 mL, 18.0 mmol) at room temperature. After stirring for 0.5
hours, the reaction mixture is concentrated under reduced pressure
to give (R)-ethyl 3-amino-4-(3'-chlorobiphenyl-4-yl)butanoate
hydrochloride (2.90 g). HPLC retention time=0.70 minutes (condition
B); MS (m+1)=318.26; 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm
1.19-1.24 (m, 3H) 2.73-2.78 (m, 1H) 2.84-2.91 (m, 1H) 3.05-3.11 (m,
1H) 3.50-3.54 (m, 1H) 3.92 (br s, 1H) 4.14-4.17 (m, 2H) 7.29-7.53
(m, 8H) 8.73 (br. s., 3H).
[0643] Following intermediates are prepared using similar procedure
as described for intermediate 16-1:
TABLE-US-00030 Intermediate HPLC-RT MS # Product Starting Material
Condition (condition) (M + 1) Intermediate 16-2 ##STR00574##
(R)-ethyl 3-amino-4- (biphenyl-4- yl)butanoate hydrochloride
##STR00575## Intermediate 2 4M HCl/1,4- dioxane 0.89 min. (B) 284.1
Intermediate 16-3 ##STR00576## (R)-ethyl 3-amino-4-
(3'-fluorobiphenyl-4- yl)butanoate hydrochloride ##STR00577##
Intermediate 2-2 4M HCl/1,4- dioxane 0.94 min. (B) 302.1
Intermediate 16-4 ##STR00578## (R)-ethyl 3-amino-4- (5'-chloro-2'-
methoxybiphenyl-4- yl)butanoate hydrochloride ##STR00579##
Intermediate 2-3 4M HCl/1,4- dioxane 0.94 min. (B) 348.2
Intermediate 16-5 ##STR00580## (R)-ethyl 3-amino-4- (5'-fluoro-2'-
methoxybiphenyl-4- yl)butanoate hydrochloride ##STR00581##
Intermediate 2-4 4M HCl/1,4- dioxane 1.38 min. (A) 332.2
Intermediate 16-6 ##STR00582## (R)-ethyl 3-amino-4- (2'-chloro-5'-
fluorobiphenyl-4- yl)butanoate hydrochloride ##STR00583##
Intermediate 2-5 4M HCl/1,4- dioxane 0.93 min. (B) 336.1
Intermediate 16-7 ##STR00584## (R)-benzyl 3-amino-
4-(3'-chlorobiphenyl- 4-yl)butanoate ##STR00585## Intermediate 17-2
4M HCl/1,4- dioxane 1.20 min. (B) 380.2 Intermediate 16-8
##STR00586## (R)-ethyl 3-amino-4- (5'-chloro-2'- fluorobiphenyl-4-
yl)butanoate ##STR00587## Intermediate 2-6 4M HCl/1,4- dioxane 0.88
min. (B) 336.1
Intermediate 16-7: (R)-benzyl
3-amino-4-(3'-chlorobiphenyl-4-yl)butanoate hydrochloride
##STR00588##
[0645] To (R)-benzyl
3-(tert-butoxycarbonylamino)-4-(3'-chlorobiphenyl-4-yl)butanoate
(3.561 g, 7.42 mmol) is added a solution of 4 M HCl in 1,4-dioxane
(18.55 mL, 74.2 mmol) at room temperature. After stirring for 4
hours, the reaction mixture is concentrated under reduced pressure
to give (R)-benzyl 3-amino-4-(3'-chlorobiphenyl-4-yl)butanoate
hydrochloride (3.11 g). HPLC retention time=1.07 minutes (condition
B); MS (m+1)=380.1; 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 2.81
(A of ABX, J.sub.ab=17.4 Hz, J.sub.ax=4.5 Hz, 1H) 2.93 (B of ABX,
J.sub.ab=17.4 Hz, J.sub.bx=7.6 Hz, 1H) 3.03-3.09 (m, 1H) 3.50 (dd,
J=4.9 and 13.5 Hz, 1H) 3.98 (br s, 1H) 5.09 (s, 2H) 7.24-7.22 (m,
9H) 7.35-7.38 (m, 1H) 7.42 (d, J=8.1 Hz, 2H) 7.48-7.49 (m, 1H) 8.78
(br s, 3H).
Intermediate 17-1: Synthesis of (R)-ethyl
3-(tert-butoxycarbonylamino)-4-(3'-chlorobiphenyl-4-yl)butanoate
##STR00589##
[0647] A mixture of (R)-ethyl
4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoate (4.89 g,
12.66 mmol), 3-chlorophenylboronic acid (2.97 g, 18.99 mmol),
Pd(PPh.sub.3).sub.4 (1.463 g, 1.266 mmol) and 2 M aqueous
Na.sub.2CO.sub.3 (12.66 ml, 25.3 mmol) in 1,2-dimethoxyethane (100
ml) is allowed to stir at 95.degree. C. under nitrogen for 3 hours.
The reaction mixture is cooled to room temperature and quenched
with brine. The two phases are separated. The mixture is extracted
twice with ethyl acetate from the aqueous layer. The combined
organic layer is washed with brine, dried over MgSO.sub.4,
filtered, and concentrated under reduced pressure. The obtained
residue is purified by silica gel flash column chromatography
(heptane/EtOAc=100:0 to 70:30) to give (R)-ethyl
3-(tert-butoxycarbonylamino)-4-(3'-chlorobiphenyl-4-yl)butanoate
(3.33 g); HPLC retention time=1.44 minutes (condition B); MS
(ES+)=318.26 (m-BOC+2; 100%); 1H NMR (400 MHz, CHLOROFORM-d)
.delta. ppm 1.28 (t, J=7.2 Hz, 3H) 1.41 (s, 9H) 2.47 (A of ABX,
J.sub.ab=15.8 Hz, J.sub.ax=5.9 Hz, 1H) 2.52 (B of ABX,
J.sub.ab=15.8 Hz, J.sub.bx=5.4 Hz, 1H) 2.83-2.89 (m, 1H) 2.95-3.00
(m, 1H) 4.17 (q, J=7.2 Hz, 2H) 4.18 (br s, 1H) 5.07 (br s, 1H)
7.26-7.37 (m, 4H) 7.43-7.51 (m, 3H) 7.55 (br t, J=1.8 Hz, 1H).
[0648] Following intermediates are prepared using similar procedure
as described for intermediate 17-1:
TABLE-US-00031 MS HPLC-RT (ES+; Intermediate # Product Condition
(condition) 100%) Intermediate 17-2 ##STR00590## (R)-benzyl
3-(tert- butoxycarbonylamino)- 4-(3'- chlorobiphenyl-4-
yl)butanoate Pd(PPh.sub.3).sub.4, 3- chlorophenylboronic acid, aq.
2M Na2CO3, toluene, 95.degree. C. 1.74 min. (B) 380.2 (m-BOC + 2)
Intermediate 17-3 ##STR00591## (R)-3-tert- Butoxycarbonylamino-
4-(3'-chloro- biphenyl-4-yl)- butyric acid propyl ester
Pd(PPh.sub.3).sub.4, 3- chlorophenylboronic acid, aq. 2M Na2CO3,
toluene, 95.degree. C. 1.66 min. (B) 432 (m + 1) Intermediate 17-4
##STR00592## (R)-3-tert- Butoxycarbonylamino- 4-(3'-chloro-
biphenyl-4-yl)- butyric acid butyl ester Pd(PPh.sub.3).sub.4, 3-
chlorophenylboronic acid, aq. 2M Na2CO3, toluene, 95.degree. C.
1.73 min. (B) 446 (m + 1) Intermediate 17-5 ##STR00593##
(R)-3-tert- Butoxycarbonylamino- 4-(3'-chloro- biphenyl-4-yl)-
butyric acid 5- methyl-2-oxo- [1,3]dioxol-4- ylmethyl ester
Pd(OAc).sub.2, dicyclohexyl-(2',6'- dimethoxy- biphenyl-2-yl)-
phosphane, 3- chlorophenylboronic acid, K.sub.3PO.sub.4, toluene,
95.degree. C. 1.53 min. (B) 502 (m + 1) Intermediate 17-6
##STR00594## (R)-3-tert- Butoxycarbonylamino- 4-(3'-chloro-
biphenyl-4-yl)- butyric acid dimethylcarbamoyl methyl ester
Pd(PPh.sub.3).sub.4, 3- chlorophenylboronic acid, K.sub.3PO.sub.4,
DMF, 95.degree. C. 1.51 min. (B) 475 (m + 1) Intermediate 17-7
##STR00595## (R)-3-tert- Butoxycarbonylamino- 4-(3'-chloro-
biphenyl-4-yl)- butyric acid 2- morpholin-4-yl- ethyl ester
Pd(PPh.sub.3).sub.4, 3- chlorophenylboronic acid, K.sub.3PO.sub.4,
DMF, 95.degree. C. 1.51 min. (B) 503 (m + 1)
Intermediate 17-2: (R)-benzyl
3-(tert-butoxycarbonylamino)-4-(3'-chlorobiphenyl-4-yl)butanoate
##STR00596##
[0650] A suspension of give (R)-benzyl
4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoate (2.00 g,
4.46 mmol), 3-chlorophenylboronic acid (1.046 g, 6.69 mmol),
Pd(PPh.sub.3).sub.4 (0.515 g, 0.446 mmol) and Na2CO3aq (4.46 ml,
8.92 mmol) in Toluene (30 ml) is allowed to stir under nitrogen at
95.degree. C. for 19 hr. The reaction mixture is cooled to ambient
temperature, and diluted with brine and EtOAc. The products are
extracted twice with EtOAc, washed with brine, dried over MgSO4,
filtered, and concentrated. The residue is purified by flash column
chromatography on 90 g silica gel (eluent: heptane/EtOAc=100:0 to
65:35) to give (R)-benzyl
3-(tert-butoxycarbonylamino)-4-(3'-chlorobiphenyl-4-yl)butanoate
(1.03 g); HPLC retention time=1.74 minutes (condition B); MS
(ES+)=380.2 (m-BOC+2; 100%); 1H NMR (400 MHz, CHLOROFORM-d) .delta.
ppm 1.40 (s, 9H) 2.52 (A of ABX, J.sub.ab=15.9 Hz, J.sub.ax=5.8 Hz,
1H) 2.58 (B of ABX, J.sub.ab=15.9 Hz, J.sub.bx=5.6 Hz, 1H)
2.81-2.98 (m, 2H) 4.19 (br s, 1H) 5.07 (br d, 1H) 5.12 (A of AB,
J=12.3 Hz, 1H) 5.17 (A of AB, J=12.3 Hz, 1H) 7.20-7.22 (m, 2H)
7.28-7.39 (m, 7H) 7.42-7.47 (m, 3H) 7.53-7.54 (m, 1H).
Intermediate 18: Synthesis of (S)-benzyl
1-(2-tert-butoxy-2-oxoethyl)pyrrolidine-2-carboxylate
##STR00597##
[0652] To a suspension of (S)-benzyl pyrrolidine-2-carboxylate
hydrochloride (700 mg, 2.90 mmol) and K.sub.2CO.sub.3 (1201 mg,
8.69 mmol) in DMF (7 ml), t-butyl bromoacetate (0.535 ml, 3.62
mmol) is added. After stirring for 71 hours, aqueous K2CO3 (1.5 g
of K.sub.2CO.sub.3/40 ml of H.sub.2O) is added to the reaction
mixture. The products are extracted with EtOAc. The organic layer
is washed twice with water and once with brine, dried over
K.sub.2CO.sub.3, filtered, and concentrated to give (S)-benzyl
1-(2-tert-butoxy-2-oxoethyl)pyrrolidine-2-carboxylate (458 mg);
HPLC retention time=1.38 minutes (condition D); MS (m+1)=320.2; 1H
NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.44 (s, 9H) 1.81-2.03 (m,
3H) 2.13-2.14 (m, 1H) 2.82-2.88 (m, 1H) 3.13-3.17 (m, 1H) 3.46 (A
of AB, J=17.3 Hz, 1H) 3.49 (B of AB, J=17.3 Hz, 1H) 3.73 (dd, J=8.8
and 4.8 Hz, 1H) 5.15 (A of AB, J=12.4 Hz, 1H) 5.17 (B of AB, J=12.4
Hz, 1H) 7.29-7.38 (m, 5H).
Intermediate 19: Synthesis of (R)-ethyl
3-(tert-butoxycarbonylamino)-4-(2',5'-dichlorobiphenyl-4-yl)butanoate
##STR00598##
[0654] A mixture of (R)-ethyl
4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoate (1.005 g,
2.60 mmol), 2,5-dichlorophenylboronic acid (0.745 g, 3.90 mmol),
Pd(PPh3)4 (0.301 g, 0.260 mmol) and 2 M aqueous Na.sub.2CO.sub.3
(2.60 ml, 5.20 mmol) in 1,2-dimethoxyethane (20 ml) is allowed to
stir at 95.degree. C. under nitrogen for 3 hours. The reaction
mixture is cooled to room temperature and diluted with brine. The
two phases are separated. The products are extracted twice with
ethyl acetate (2.times.100 ml) from the aqueous layer. The combined
organic layer is washed with brine, dried over MgSO.sub.4,
filtered, and concentrated under reduced pressure. The obtained
residue is purified by silica gel flash column chromatography
(heptane/EtOAc=100:0 to 70:30) to give (R)-ethyl
3-(tert-butoxycarbonylamino)-4-(2',5'-dichlorobiphenyl-4-yl)butanoate
(1.09 g); HPLC retention time=1.50 minutes (condition B); MS
(ES+)=352.00 (m-BOC+2; 100%); 1H NMR (400 MHz, CHLOROFORM-d)
.delta. ppm 1.28 (t, J=7.1 Hz, 3H) 1.41 (s, 9H) 2.45-2.58 (m, 2H)
2.85-3.00 (m, 2H) 4.17 (t, J=7.1 Hz, 2H) 4.20 (br s, 1H) 5.06-5.08
(m, 1H) 7.23-7.28 (m, 3H) 7.31-7.40 (m, 4H).
Intermediate 20: Synthesis of
(R)-3-amino-4-(3'-chlorobiphenyl-4-yl)butanoic acid
hydrochloride
##STR00599##
[0656] A solution of (R)-benzyl
3-(tert-butoxycarbonylamino)-4-(3'-chlorobiphenyl-4-yl)butanoate
(152 mg, 0.317 mmol) and 1 M aqueous NaOH (1.583 ml, 1.583 mmol) in
a mixed solvent of MeOH (0.3 ml) and THF (3 ml) is allowed to stir
for 2 hours. The reaction is quenched with 1M aqueous HCl (2.5 ml).
The products are extracted with EtOAc. The organic layer is dried
over Na.sub.2SO.sub.4, filtered, and concentrated to give
crude.
[0657] To the crude, a solution of 4 M HCl in 1,4-dioxane (1.583
ml, 6.33 mmol) is added. After stirring for 1 h, the precipitated
solid is collected, and dried under reduced pressure to give
(R)-3-amino-4-(3'-chlorobiphenyl-4-yl)butanoic acid hydrochloride
(60.2 mg) as a white solid; HPLC retention time=0.52 minutes
(condition B); MS (m+1)=290.22; 1H NMR (400 MHz, CD.sub.3OD)
.delta. ppm 2.58-2.74 (m, 2H) 2.99-3.11 (m, 2H) 3.80-3.85 (m, 1H)
7.34-7.45 (m, 4H) 7.54-7.57 (m, 1H) 7.62-7.65 (m, 3H).
Intermediate 21: Synthesis of a mixture of
1-(2-(benzyloxy)-2-oxoethyl)cyclopentanecarboxylic acid and
2-(1-(benzyloxycarbonyl)cyclopentyl)acetic acid
##STR00600##
[0659] A solution of 2-oxaspiro[4.4]nonane-1,3-dione (3 g, 19.46
mmol) and benzyl alcohol (2.023 ml, 19.46 mmol) in toluene (2 ml)
is allowed to stir at 100.degree. C. for 19 hours. The reaction
mixture is cooled to ambient temperature and concentrated to give
6:1 mixture of 1-(2-(benzyloxy)-2-oxoethyl)cyclopentanecarboxylic
acid and 2-(1-(benzyloxycarbonyl)cyclopentyl)acetic acid (4.89 g);
1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.60-1.78 (m, 6H)
2.19-2.24 (m, 2H) 2.75 (s, 2H) 5.11 (s, 2H, major isomer) 5.13 (s,
2H, minor isomer) 7.30-7.37 (m, 5H).
Intermediate 22: Synthesis of tert-butyl
4-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)butanoate
##STR00601##
[0661] A solution of
4-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)butanoic acid (250
mg, 0.703 mmol), tBuOH (0.135 ml, 1.407 mmol), EDCI (270 mg, 1.407
mmol) and 4-dimethylaminopyridine (86.0 mg, 0.704 mmol) in DCM (7
ml) is allowed to stir at room temperature under nitrogen for 62
hours. The reaction is quenched with water, and the organic layer
is separated and concentrated. The residue is purified by flash
column chromatography on silica gel to give tert-butyl
4-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)butanoate (110 mg);
HPLC retention time=1.77 minutes (condition B); MS (ES+)=412.1
(m+1) 300.0 (m-tBux2+3; 100%); 1H NMR (400 MHz, CHLOROFORM-d)
.delta. ppm 1.41 (s, 9H) 1.47 (s, 9H) 2.36 (A of ABX, J.sub.ab=15.5
Hz, J.sub.ax=6.2 Hz, 1H) 2.44 (B of ABX, J.sub.ab=15.5 Hz,
J.sub.bx=5.6 Hz) 2.82-2.94 (m, 2H) 4.11-4.17 (m, 1H) 5.08-5.10 (m,
1H) 7.25-7.34 (m, 3H) 7.41-7.44 (m, 2H) 7.51-7.58 (m, 4H).
Intermediate 23: Synthesis of ethyl
3-amino-4-(3'-chloro-3-fluorobiphenyl-4-yl)butanoate
##STR00602##
[0663] A suspension of zinc (479 mg, 7.33 mmol) and
1,2-dibromoethane (0.032 ml, 0.366 mmol) in THF (8 ml) is heated at
70.degree. C. under nitrogen then a few drops of ethyl bromoacetate
is added. After stirring for 20 min, a solution of
2-(3'-chloro-3-fluorobiphenyl-4-yl)acetonitrile (300 mg, 1.221
mmol) in THF (2 ml) is added in one portion. The remaining
bromoacetate is added dropwise over 50 min (total amount of ethyl
bromoacetate: 4.88 mmol). After stirring for 15 min at the same
temperature, the reaction mixture is cooled to ambient temperature.
To the reaction mixture, sodium triacetoxyborohydride (2588 mg,
12.22 mmol) and AcOH (8 ml) are added. The reaction mixture is
allowed to stir for 13 hours, and concentrated to give crude. The
crude is diluted with EtOAc, and 2M aqueous Na.sub.2CO.sub.3 is
added to be pH of 10. The products are extracted with EtOAc. The
organic layer is dried over K2CO3, filtered, and concentrated to
give crude. The resulting residue is purified by preparative HPLC
using a gradient of 20% MeCN/water (0.1% NH.sub.4OH) to 100% MeCN
to give ethyl 3-amino-4-(3'-chloro-3-fluorobiphenyl-4-yl)butanoate
(148 mg) as orange oil; HPLC retention time=0.85 minutes (condition
B); MS (m+1)=336.13; 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm
1.27 (t, J=7.1 Hz, 3H) 2.36 (A of ABX, J.sub.ab=15.9 Hz,
J.sub.ax=8.8 Hz, 1H) 2.52 (B of ABX, J.sub.ab=15.9 Hz, J.sub.bx=4.0
Hz, 1H) 2.71-2.76 (m, 1H) 2.82-2.87 (m, 1H) 3.51-3.57 (m, 1H) 4.15
(d, J=7.1 Hz, 2H) 7.24-7.39 (m, 5H) 7.42-7.44 (m, 1H) 7.54-7.55 (m,
1H).
Intermediate 24: Synthesis of
2-(3'-chloro-3-fluorobiphenyl-4-yl)acetonitrile
##STR00603##
[0665] A suspension of 4-bromo-2-fluorobenzyl cyanide (3.50 g,
16.35 mmol), 3-chlorobenzeneboronic acid (2.68 g, 17.17 mmol),
Pd(OAc).sub.2 (0.110 g, 0.491 mmol), K.sub.2CO.sub.3 (5.65 g, 40.9
mmol) and tetrabutylammonium bromide (5.80 g, 17.99 mmol) in water
(14 ml) is allowed to stir under nitrogen at 70.degree. C. for 1
hour. The reaction mixture is cooled to room temperature, and
diluted with EtOAc. The two phases are separated. The organic layer
is washed with brine, dried over MgSO.sub.4, filtered and
concentrated. The obtained residue is purified by silica gel flash
column chromatography (heptane/EtOAc=100:0 to 70:30) to give
2-(3'-chloro-3-fluorobiphenyl-4-yl)acetonitrile (3.52 g); HPLC
retention time=1.17 minutes (condition B); 1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 3.81 (s, 2H) 7.29-7.45 (m, 5H) 7.50-7.55
(m, 2H).
Intermediate 25: (R)-tert-butyl
4-(1-(4-bromophenyl)-4-ethoxy-4-oxobutan-2-ylamino)-4-oxobutanoate
##STR00604##
[0667] To a solution of 4-tert-butoxy-4-oxobutanoic acid (2.38 g,
13.64 mmol) in DMF (30 mL) and DCM (30 mL) is added (R)-ethyl
3-amino-4-(4-bromophenyl)butanoate hydrochloride (4 g, 12.4 mmol),
HATU (5.19 g, 13.64 mmol), and TEA (6.91 mL, 49.6 mmol). After
stirring at room temperature for 2 hours, the reaction is quenched
with H.sub.2O, and the crude is diluted with EtOAc, the organic
layer is washed with brine, dried over Na.sub.2SO.sub.4, filtered,
and concentrated under reduced pressure to give (R)-tert-butyl
4-(1-(4-bromophenyl)-4-ethoxy-4-oxobutan-2-ylamino)-4-oxobutanoate
(4.0 g). HPLC retention time=1.70 minutes (condition A); MS
(m+1)=444.1.
Intermediate 26:
(R)-3-amino-4-(5'-fluoro-2'-methoxy-biphenyl-4-yl)-butyric acid
ethyl ester hydrochloride salt
##STR00605##
[0669] To a solution of (R)-ethyl
4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoate, (3.12 g,
8.08 mmol), and 5-fluoro-2-methoxyphenylboronic acid (2.2 g, 12.93
mmol) in toluene (52 mL) and is added
PdCl.sub.2(dppf)CH.sub.2Cl.sub.2 adduct (0.66 g, 0.81 mmol) and 2M
aq. Na.sub.2CO.sub.3 (8.1 mL, 16.16 mmol). After stirring at
95.degree. C. under nitrogen for 4 hours, the solution is cooled to
ambient temperature and then quenched with ice water. The crude is
diluted with ethyl acetate. The organic layer is washed with brine,
dried over Na.sub.2SO.sub.4, filtered, and concentrated under
reduced pressure. The obtained residue is purified by flash column
chromatography on silica gel (eluent: heptane/EtOAc=100:0 to 50:50)
to give (R)-ethyl
3-(tert-butoxycarbonylamino)-4-(5'-fluoro-2'-methoxybiphenyl-4-yl)butanoa-
te (2.86 g). HPLC retention time=1.80 minutes (condition A); MS
(m+1)=432.2; 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.31 (t,
J=7.1 Hz, 3H) 1.45 (s, 9H) 2.45-2.65 (m, 2H) 2.83-2.94 (m, 1H)
2.94-3.09 (m, 1H) 3.80 (s, 3H) 4.20 (q, J=7.2 Hz, 2H) 4.24-4.33 (m,
1H) 5.11 (br. s., 1H) 6.90-6.96 (m, 1H) 7.00 (dd, J=7.8, 3.3 Hz,
1H) 7.06 (dd, J=9.2, 3.2 Hz, 1H) 7.27 (d, J=7.8 Hz, 2H) 7.49 (d,
J=7.8 Hz, 2H)
[0670] A solution of (R)-ethyl
3-(tert-butoxycarbonylamino)-4-(5'-fluoro-2'-methoxybiphenyl-4-yl)butanoa-
te, (2.86 g, 6.62 mmol) in 4M HCl in 1,4-dioxane (33.1 ml, 132
mmol) is stirred at room temperature. After stirring for 1 hour,
the reaction mixture is concentrated under reduced pressure to give
(R)-ethyl 3-amino-4-(5'-fluoro-2'-methoxybiphenyl-4-yl)butanoate
hydrochloride salt (2.44 g). HPLC retention time=1.46 minutes
(condition A); MS (m+1)=332.3; 1H NMR (400 MHz, CHLOROFORM-d)
.delta. ppm 1.15 (t, J=6.4 Hz, 3H) 2.66-2.77 (m, 1H) 2.78-2.91 (m,
1H) 2.94-3.10 (m, 1H) 3.42-3.53 (m, 1H) 3.67 (s, 3H) 3.83-3.96 (m,
1H) 4.07 (q, J=6.8 Hz, 2H) 6.77-6.84 (m, 1H) 6.87-6.96 (m, 2H) 7.23
(d, J=7.1 Hz, 2H) 7.38 (d, J=7.1 Hz, 2H) 8.64 (br. s., 2H)
Intermediate 27: (R)-ethyl
4-(3'-chlorobiphenyl-4-yl)-3-(2-ethoxy-2-oxoacetamido)butanoate
##STR00606##
[0672] To a solution of (R)-ethyl
3-amino-4-(3'-chlorobiphenyl-4-yl)butanoate hydrochloride (500 mg,
1.57 mmol) in DMF (11 mL) is added TEA (0.23 mL, 1.65 mmol) and
ethyl 2-chloro-2-oxoacetate (0.18 mL, 1.57 mmol) at room
temperature. After stirring for 1 hour at room temperature, the
reaction is quenched with H.sub.2O, and the crude is diluted with
EtOAc. The organic layer is washed with brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated under reduced
pressure. The obtained residue is purified by flash column
chromatography on silica gel (eluent: heptane/EtOAc=70:30 to 50:50)
to give (R)-ethyl
4-(3'-chlorobiphenyl-4-yl)-3-(2-ethoxy-2-oxoacetamido)butanoate
(550 mg). HPLC retention time=1.88 minutes (condition A); MS
(m+1)=418.3
Intermediate 28: (R)-ethyl
4-(3'-chlorobiphenyl-4-yl)-3-(2-hydrazinyl-2-oxoacetamido)butanoate
##STR00607##
[0674] To a solution of (R)-ethyl
4-(3'-chlorobiphenyl-4-yl)-3-(2-ethoxy-2-oxoacetamido)butanoate
(450 mg, 1.08 mmol) in MeOH (24 mL) is added a solution of 50% wt
hydrazine (0.068 ml, 1.08 mmol) in MeOH (10 mL) at -20.degree. C.
After stirring for 18 hours at room temperature, the reaction
mixture is concentrated under reduced pressure to give (R)-ethyl
4-(3'-chlorobiphenyl-4-yl)-3-(2-hydrazinyl-2-oxoacetamido)butanoate
(412 mg). HPLC retention time=1.76 minutes (condition A); MS
(m+1)=404.1
Intermediate 29: (R)-ethyl
4-(3'-chlorobiphenyl-4-yl)-3-(2-methoxythiazole-5-carboxamido)butanoate
##STR00608##
[0676] To a solution of 2-methoxythiazole-5-carboxylic acid (80 mg,
0.50 mmol) and (R)-ethyl
3-amino-4-(3'-chlorobiphenyl-4-yl)butanoate hydrochloride (160 mg,
0.45 mmol) in DMF (5 mL) is added HATU (207 mg, 0.55 mmol) and TEA
(276 mg, 2.73 mmol). The crude is stirred at room temperature for 2
hrs. The crude is neutralized with 1 N HCl and diluted in water and
EtOAc. The organic layer is washed with brine, dried over
MgSO.sub.4, filtered, and concentrated. The crude is purified via
flash chromatography using 30% EtOAc/heptane to 70% EtOAc/heptane
to give (R)-ethyl
4-(3'-chlorobiphenyl-4-yl)-3-(2-methoxythiazole-5-carboxamido)b-
utanoate (170 mg). HPLC retention time=1.97 minutes (condition D);
MS (m+1)=459.1. 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.29 (t,
J=7.1 Hz, 3H) 2.49-2.69 (m, 2H) 2.93 (dd, J=13.6, 8.1 Hz, 1H) 3.10
(dd, J=13.5, 6.2 Hz, 1H) 4.09 (s, 3H) 4.00-4.15 (m, 2H) 4.53-4.69
(m, 1H) 6.78 (d, J=8.6 Hz, 1H) 7.25-7.32 (m, 3H) 7.35 (t, J=7.71
Hz, 1H) 7.44 (dt, J=7.6, 1.5 Hz, 1H) 7.48-7.54 (m, 3H) 7.55 (t,
J=1.8 Hz, 1H).
Intermediate 30: (R)-ethyl
4-(3'-chlorobiphenyl-4-yl)-3-(2-methoxyoxazole-5-carboxamido)butanoate
##STR00609##
[0678] To a solution of 2-methoxyoxazole-5-carboxylic acid,
intermediate 16, (98 mg, 0.69 mmol) and (R)-ethyl
3-amino-4-(3'-chlorobiphenyl-4-yl)butanoate hydrochloride (210 mg,
0.57 mmol) in DMF (10 mL) and CH.sub.2Cl.sub.2 (4 mL) is added HATU
(272 mg, 0.72 mmol) and TEA (0.50 mL, 3.58 mmol). The crude is
stirred at room temperature for 2 hrs. The crude is quenched with
water and diluted in EtOAc. The organic layer is washed with water
3.times., brine, dried over MgSO.sub.4, filtered, and concentrated.
The crude is purified via flash chromatography using 30%
EtOAc/heptane to 70% EtOAc/heptane to give (R)-ethyl
4-(3'-chlorobiphenyl-4-yl)-3-(2-methoxyoxazole-5-carboxamido)bu-
tanoate (122 mg). HPLC retention time=1.89 minutes (condition A);
MS (m+1)=443.2; 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.28 (t,
J=7.1 Hz, 3H), 2.52-2.66 (m, 2H), 2.94 (dd, 1H), 3.08 (dd, J=13.6,
6.3 Hz, 1H), 4.12 (s, 3H), 4.14-4.23 (m, 2H), 4.60-4.71 (m, 1H),
6.81 (d, J=8.8 Hz, 1H), 7.25-7.32 (m, 3H), 7.35 (t, J=7.7 Hz, 1H),
7.42 (s, 1H), 7.43-7.47 (m, 1H), 7.48-7.54 (m, 2H), 7.55 (t, J=1.6
Hz, 1H).
Intermediate 31: 6-(methylsulfonamido)nicotinic acid
##STR00610##
[0680] To a solution of methyl 6-aminonicotinate (1.0 g, 6.57 mmol)
in CH.sub.2Cl.sub.2 (50 mL) with TEA (0.96 mL, 6.90 mmol) cooled in
an ice bath is added MsCl (0.54 mL, 6.90 mmol) slowly.
[0681] The crude is allowed to stir at room temperature for 2 hrs.
The crude is then concentrated. The crude is dissolved in MeOH (20
mL) and to the crude is added 1 N NaOH (30 mL, 30 mmol). The crude
is stirred at room temperature for 18 hrs. The crude is quenched
with 1N HCl (32 mL, 32 mmol). The crude is concentrated to remove
MeOH and some water is removed as well. The crude is diluted in
CH.sub.2Cl.sub.2 and basified with 1 N NaOH (30 mL). The aq. layer
is extracted with CH.sub.2Cl.sub.2. The aq. layer is acidified with
concentrated HCl to bring the PH to 1 via PH paper indicator. The
crude is diluted in EtOAc and the aq. layer is extracted with
EtOAc. The combined organic layer is washed with brine, dried over
MgSO4, filtered, and concentrated to give
6-(methylsulfonamido)nicotinic acid (421 mg) as a yellow solid.
HPLC retention time=0.40 minutes (condition D); MS (m+1)=217.2.
Intermediate 32: 2-methoxyoxazole-5-carboxylic acid
##STR00611##
[0683] To a solution of ethyl 2-chlorooxazole-5-carboxylate (510
mg, 2.90 mmol) in anhdryous MeCN (10 mL) and anhydrous MeOH (10 mL)
is added NaOMe (628 mg, 11.62 mmol). The crude is stirred at reflux
for 2 hrs. To this crude is added additional MeOH. The crude is
refluxed for another 4 hrs. The crude is concentrated and is
redissolved in MeOH (10 mL). To this crude is added 1 N NaOH (10
ml). The crude is stirred at room temperature for 3 hrs. The crude
is quenched with concentrated HCl, PH adjusted to 7 via PH paper
indicator. The crude is concentrated and diluted in water. The aq.
layer is acidified with concentrated HCl and diluted in EtOAc. The
organic layer is washed with water, brine, dried over MgSO.sub.4,
filtered, and concentrated to give 2-methoxyoxazole-5-carboxylic
acid (290 mg). HPLC retention time=0.58 minutes (condition D); MS
(m+1)=144.0.
Intermediate 33: ethyl
5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxylate
##STR00612##
[0685] To a solution of ethyl 2-(hydroxyamino)-2-iminoacetate (2 g,
15.14 mmol) in dioxane (15.00 mL) is added CDI (2.7 g, 16.65 mmol)
and DBU (2.5 ml, 16.65 mmol) at room temperature. After stirring
for 1 hour at 80.degree. C., the reaction is quenched with 1N HCl,
and the crude is diluted with EtOAc. The organic layer is washed
with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure to give ethyl
5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxylate (2.4 g). HPLC
retention time=0.72 minutes (condition D); MS 159.1 (M+1).
Intermediate 34: 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxylic
acid
##STR00613##
[0687] To a solution of crude ethyl
5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxylate (2.4 g, 15.14
mmol) in MeOH (2 mL) is added aqueous 1N NaOH (4 mL, 4 mmol) at
room temperature. After stirring for 5 hours at room temperature
the reaction is quenched with 1N HCl (5 mL, 5 mmol), the crude is
concentrated under reduced pressure to remove MeOH. The crude is
diluted with EtOAc, the organic layer is washed with brine, dried
over Na.sub.2SO.sub.4, filtered and concentrated under reduced
pressure to give 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxylic
acid (1.9 g).
Intermediate 35: 2-oxo-2,3-dihydrooxazole-4-carboxylic acid
##STR00614##
[0689] This intermediate is prepared according to: Okonya, J. F.;
Hoffman, R. V.; Johnson, M. C.; J. Org. Chem. 2002, 67,
1102-1108.
Intermediate 36: 3-hydroxyisothiazole-5-carboxylic acid
##STR00615##
[0691] To a solution of methyl 3-hydroxyisothiazole-5-carboxylate
(300 mg, 1.73 mmol) in MeOH (2 mL) is added 1N NaOH (6 mL, 6 mmol).
After stirring at room temperature for 2 hours, the crude is
concentrated under reduced pressure to remove MeOH and is diluted
with EtOAc. The organic layer is washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to give 3-hydroxyisothiazole-5-carboxylic acid (250 mg).
Intermediate 37: ethyl 2-vinyloxazole-5-carboxylate
##STR00616##
[0693] To a solution of tributyl(vinyl)stannane (1.1 mL, 3.83 mmol)
and ethyl 2-chlorooxazole-5-carboxylate (546 mg, 3.11 mmol) in
dioxane (37 mL) is added Pd(PPh.sub.3).sub.2Cl.sub.2 (222 mg, 0.32
mmol) at room temperature. After stirring at 100.degree. C. under
nitrogen for 4 hours, the solution is cooled to ambient temperature
and then quenched with H.sub.2O. The crude is diluted with EtOAc,
the organic layer is washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The obtained residue is purified by flash column chromatography
(eluent: heptane/EtOAc=90:10 to 80:20) to give ethyl
2-vinyloxazole-5-carboxylate (470 mg). HPLC retention time=0.39
minutes (condition B); MS (m+1)=168.2; 1H NMR (400 MHz, CD.sub.3OD)
.delta. ppm 1.38 (t, J=7.1 Hz, 3H) 4.38 (q, J=7.2 Hz, 2H) 5.88 (d,
J=11.4 Hz, 1H) 6.39 (d, J=17.7 Hz, 1H) 6.69 (dd, J=17.6, 11.2 Hz,
1H) 7.83 (s, 1H)
Intermediate 38: ethyl 2-ethyloxazole-5-carboxylate
##STR00617##
[0695] To a solution of ethyl 2-vinyloxazole-5-carboxylate (470 mg,
2.81 mmol) in MeOH (7 mL) is added 10% wt. Pd/C (100 mg, 0.094
mmol) at room temperature. After stirring at room temperature under
a balloon of hydrogen for 1 hour, the crude is filtered to remove
Pd/C. The filtrate is collected and concentrated to give ethyl
2-ethyloxazole-5-carboxylate (470 mg). HPLC retention time=1.09
minutes (condition A); MS (m+1)=170.3; 1H NMR (400 MHz, CD.sub.3OD)
.delta. ppm 1.35 (t, J=7.6 Hz, 3H) 1.36 (t, J=7.2 Hz, 3H) 2.87 (q,
J=7.7 Hz, 2H) 4.35 (q, J=7.2 Hz, 2H) 7.71 (s, 1H)
Intermediate 39: 2-ethyloxazole-5-carboxylic acid
##STR00618##
[0697] To a solution of 2-ethyloxazole-5-carboxylate (470 mg, 2.81
mmol) in MeOH (10 mL) is added 1N NaOH (6 mL, 6 mmol). After
stirring at room temperature for 18 hours, the crude is
concentrated under reduced pressure to remove MeOH and is diluted
with EtOAc. The organic layer is washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to give 2-ethyloxazole-5-carboxylic acid (244 mg). 1H NMR (400 MHz,
CD.sub.3OD) .delta. ppm 1.36 (t, J=7.7 Hz, 3H) 2.89 (q, J=7.6 Hz,
2H) 5.15 (br. s., 1H) 7.69 (s, 1H)
Intermediate 40: ethyl 2-vinylthiazole-5-carboxylate
##STR00619##
[0699] To a solution of tributyl(vinyl)stannane (0.92 mL, 3.14
mmol) and ethyl 2-bromothiazole-5-carboxylate (0.38 mL, 2.54 mmol)
in dioxane (33 mL) is added Pd(PPh.sub.3).sub.2Cl.sub.2 (182 mg,
0.26 mmol) at room temperature. After stirring at 100.degree. C.
under nitrogen for 4 hours, the solution is cooled to ambient
temperature and then quenched with H.sub.2O. The crude is diluted
with EtOAc, the organic layer is washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The obtained residue is purified by flash column chromatography on
silica gel (eluent: heptane/EtOAc=90:10 to 80:20) to give ethyl
2-vinylthiazole-5-carboxylate (418 mg). HPLC retention time=0.45
minutes (condition B); MS (m+1)=184.1; 1H NMR (400 MHz, CD.sub.3OD)
.delta. ppm 1.37 (t, J=7.2 Hz, 3H) 4.35 (q, J=7.1 Hz, 2H) 5.71 (d,
J=10.9 Hz, 1H) 6.24 (d, J=17.4 Hz, 1H) 6.93 (dd, J=17.4, 10.9 Hz,
1H) 8.29 (s, 1H)
Intermediate 41: ethyl 2-ethylthiazole-5-carboxylate
##STR00620##
[0701] To a solution of ethyl 2-vinylthiazole-5-carboxylate (400
mg, 2.18 mmol) in MeOH (7 mL) is added 10% wt. Pd/C (267 mg, 0.25
mmol) at room temperature. After stirring at room temperature under
a balloon of hydrogen for 1 hour, the crude is filtered to remove
Pd/C. The filtrate is concentrated to give ethyl
2-ethylthiazole-5-carboxylate (404 mg). HPLC retention time=0.60
minutes (condition B); MS (m+1)=186.3; 1H NMR (400 MHz, CD3OD)
.delta. ppm 1.35 (t, J=7.3 Hz, 2H) 1.39 (t, J=7.20 Hz, 2H) 3.07 (q,
J=7.58 Hz, 2H) 4.35 (q, J=7.16 Hz, 2H) 8.22 (s, 1H)
Intermediate 42: 2-ethylthiazole-5-carboxylic acid
##STR00621##
[0703] To a solution of ethyl 2-ethylthiazole-5-carboxylate (400
mg, 2.159 mmol) in MeOH (10 mL) is added 1N NaOH (6 mL, 6 mmol)
After stirring at room temperature for 18 hours, the crude is
concentrated under reduced pressure to remove MeOH. The crude is
diluted with EtOAc, the organic layer is washed with brine, dried
over Na.sub.2SO.sub.4, filtered and concentrated under reduced
pressure to give 2-ethylthiazole-5-carboxylic acid (282.4 mg). HPLC
retention time=0.78 minutes (condition D); MS (m+3)=160.4; 1H NMR
(400 MHz, CD3OD) .delta. ppm 1.40 (t, J=7.6 Hz, 3H) 3.07 (q, J=7.6
Hz, 2H) 5.08 (br. s., 1H) 8.20 (s, 1H).
Intermediate 43: 3-Hydroxy-isoxazole-5-carboxylic acid
##STR00622##
[0705] To a solution of 3-hydroxy-isoxazole-5-carboxylic acid
methyl ester (286 mg, 2.0 mmol) in methanol (7 mL) is added 1N NaOH
(4.0 mL, 4.0 mmol) and the mixture is stirred at room temperature
for 18 hrs. The solvent is removed under reduced pressure and 4.0
mL of 1N HCl is added to the residue. The resulting solution is
lyophilized to give the product which is used as is in subsequent
reactions.
Intermediate 44: 5-Methoxycarbonylmethyl-furan-2-carboxylic
acid
##STR00623##
[0707] To a solution of 5-methoxycarbonylmethyl-furan-2-carboxylic
acid methyl ester (250 mg, 1.26 mmol) in methanol (5 mL) is added
1N NaOH (2.78 mL, 2.78 mmol) and the mixture is stirred at room
temperature for 18 hours. The solvent is removed under reduced
pressure and 2.78 mL of 1N HCl is added to the residue. The
resulting solution is lyophilized to give
5-carboxymethyl-furan-2-carboxylic acid.
[0708] Next, to a solution of the above diacid (220 mg, 1.29 mmol)
in methanol (8 mL) is added Amberlyst-15 resin (50 mg) and the
mixture is stirred at room temperature for 18 hours. The resin is
filtered and the solvent is removed under reduced pressure to give
the product which is used as is in subsequent reactions. 1H NMR
(400 MHz, CHLOROFORM-d) .delta. ppm 3.75 (s, 3H), 3.82 (s, 2H),
6.45 (d, J=3.54 Hz, 1H), 7.29 (d, J=3.54 Hz, 1H), 10.17 (s, broad,
1H).
Intermediate 45:
(R)-4-(3'-Chloro-biphenyl-4-yl)-3-isocyanato-butyric acid ethyl
ester
##STR00624##
[0710] To a vigorously stirred mixture of 8% aqueous sodium
bicarbonate (3 mL) and methylene chloride (3 mL) at 0.degree. C. is
added triphosgene (28.1 mg, 0.095 mmol) and the mixture is stirred
at 0.degree. C. for 5 minutes then Intermediate 17-1 (100 mg, 0.284
mmol) is added and stirring is continued for an additional 15
minutes. The organic layer is separated and dried over sodium
sulfate. The solvent is removed under reduced pressure to give the
title compound. This is used as is in subsequent reactions.
Intermediate 46: 2-(4-Methoxy-benzyl)-2H-tetrazole-5-carbonyl
chloride
##STR00625##
[0712] To a solution of 1H-tetrazole-5-carboxylic acid ethyl ester
sodium salt (500 mg, 3.05 mmol) in DMF (5 ml) at room temperature
is added 4-methoxybenzyl chloride (747 .mu.l, 5.48 mmol) and TEA
(1500 .mu.l, 10.76 mmol). The reaction mixture is stirred at room
temperature overnight. The reaction is added water and extracted
with EtOAc. The combined organic layer is washed with brine and
dried over anhydrous sodium sulfate, filtered and concentrated
under reduced pressure. The residue is purified by column
chromatography (10% to 30% EtOAc/Heptane). To a solution of the
purified residue in EtOH (2 ml) at room temperature is added NaOH
(2 ml, 2.000 mmol) and the mixture is stirred at room temperature.
After stirring for 1 hour, the mixture is concentrated under
reduced pressure to remove EtOH and extracted with EtOAC after
being acidified to pH<5. The combined organic layer is washed
with brine and dried over anhydrous sodium sulfate, filtered and
concentrated under reduced pressure to give
2-(4-methoxy-benzyl)-2H-tetrazole-5-carboxylic acid.
[0713] Next, to a mixture of
2-(4-methoxy-benzyl)-2H-tetrazole-5-carboxylic acid in Toluene (15
ml) at room temperature is added SOCl.sub.2 (1 ml, 13.70 mmol) and
the mixture is heated at 80.degree. C. for 3 hr. The reaction
mixture is concentrated under reduced pressure to give the crude
product, which is used without further purification.
Intermediate 47: (R)-3-Amino-4-(3'-chloro-biphenyl-4-yl)-butyric
acid indan-5-yl ester
##STR00626##
[0715] To a suspension of
boc-(R)-3-amino-4-(4-bromo-phenyl)-butanoic acid (500 mg, 1.396
mmol) in THF (12 ml) at room temperature is added 5-indanol (187
mg, 1.396 mmol) and Ph.sub.3P (403 mg, 1.535 mmol). To the mixture
at ice bath is added DIAD (0.326 ml, 1.675 mmol) and the mixture is
stirred from ice bath to room temperature overnight. The reaction
is concentrated under reduced pressure and purified by column
chromatography (5% to 20% EtOAc/Heptane) to give 450 mg of solid.
To a solution of the obtained solid (200 mg, 0.422 mmol) in DMF (5
ml) at room temperature is added 3-chlorophenylboronic acid (79 mg,
0.506 mmol), tripotassium phosphate (134 mg, 0.632 mmol) and
Pd(PPh.sub.3).sub.4 (48.7 mg, 0.042 mmol). The reaction is stirred
at 100.degree. C. overnight. The reaction is quenched by brine and
is extracted with EtOAc. The combined organic layer is washed with
brine and dried over anhydrous sodium sulfate, filtered and
concentrated under reduced pressure. The residue is purified by
column chromatography (5% to 30% EtOAc/Heptane). To the obtained
residue (143 mg, 0.283 mmol) in DCM (1 ml) at room temperature is
added TFA (1 mL, 12.98 mmol) and the mixture is stirred at room
temperature for 2 hours. The mixture is concentrated to give the
crude salt which is used directly without further purification.
HPLC retention time=1.27 minutes (condition B); MS (m+1)=406.
[0716] Intermediate 48: (R)-4-Biphenyl-4-yl-3-ureido-butyric acid
ethyl ester
##STR00627##
[0717] To a suspension of (R)-3-amino-4-biphenyl-4-yl-butyric acid
ethyl ester (200 mg, 0.625 mmol) in THF (10 ml) at 0.degree. C. was
added phenyl chloroformate (0.087 ml, 0.688 mmol) and pyridine
(0.126 ml, 1.563 mmol). The mixture is stirred at 0.degree. C. for
5 min then is warmed up to room temperature. LCMS monitored the
reaction until it is complete. The reaction is extracted with
EtOAc. The combined organic layer is washed with 1N HCl, H.sub.2O,
sat. aq. NaHCO.sub.3 and brine and dried over anhydrous sodium
sulfate, filtered and concentrated to give the crude residue.
[0718] Next, to a solution of the obtained residue (0.252 g, 0.625
mmol) in DMSO (1.5 ml) at room temperature is added ammonium
hydroxide (0.027 ml, 0.688 mmol). The reaction is stirred at room
temperature. 30 min LCMS showed small desired product with big
starting material so more ammonium hydroxide is added and the
reaction is stirred at room temperature overnight until the
reaction is complete. The reaction is extracted with EtOAc. The
combined organic layer is washed with H.sub.2O, 1N HCl, H.sub.2O, 1
N NaOH and brine and dried over anhydrous sodium sulfate, filtered
and concentrated under reduced pressure. The residue is purified by
column chromatography (2% to 6% EtOH/DCM) to give
(R)-4-biphenyl-4-yl-3-ureido-butyric acid ethyl ester (169 mg).
HPLC retention time=1.04 minutes (condition B); MS (m+1)=327.
Intermediate 49:
(R)-3-amino-4-(3'-chloro-biphenyl-4-yl)-2-hydroxy-butyric acid
methyl ester hydrochloride
##STR00628##
[0720] (R)-3-(4-Bromo-phenyl)-2-tert-butoxycarbonylamino-propionic
acid (4.0 g, 11.6 mmol), 3-chlorophenylboronic acid (2.36 g, 15.11
mmol), Pd(PPh.sub.3).sub.4 (0.067 g, 0.058 mmol) and 2M
Na.sub.2CO.sub.3 aqueous solution (8.0 mL) are refluxed in
1,2-dimethoxyethane (70 mL) for 2.5 h under N.sub.2 atmosphere.
After cooling to room temperature, the reaction mixture is diluted
with EtOAc and washed with 1M HCl and brine. The organic layer is
dried over Na.sub.2SO.sub.4 and concentrated. The residue is
purified by flash column chromatography (silica gel, DCM/10% MeOH
in DCM=100:0 to 0:100). to give
(R)-2-tert-butoxycarbonylamino-3-(3'-chloro-biphenyl-4-yl)-propionic
acid (containing impurities). HPLC retention time=1.56 minutes
(condition A): MS (m+1)=376.
[0721] This is dissolved in 1,2-dimethoxyethane (40 mL) and
Et.sub.3N (1.46 mL, 10.5 mmol) and ethyl chloroformate (1.00 mL,
10.5 mmol) are added. After being stirred at room temperature for
0.5 h, the resultant precipitate is removed by filtration. To the
filtrate is slowly added NaBH.sub.4 (0.44 g, 11.6 mmol) in H.sub.2O
(5 mL). After being stirred for 2 h, the reaction mixture is
diluted with EtOAc and washed with H.sub.2O and brine. The organic
layer is dried over Na.sub.2SO.sub.4, concentrated and purified by
flash column chromatography (silica gel, eluent;
heptane/EtOAc=100:0 to 0:100) to give
[(R)-2-(3'-chloro-biphenyl-4-yl)-1-hydroxymethyl-ethyl]-carbamic
acid tert-butyl ester (2.8 g). HPLC retention time=1.26 minutes
(condition A): MS (m+1-Boc)=262. 1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 1.43 (s, 9H), 2.90 (d, 2H, J=7.33 Hz), 3.60 (dd, 1H,
J=5.05, 10.86 Hz), 3.72 (dd, 1H, J=3.79, 11.12 Hz), 3.91 (bs, 1H),
4.75 (bs, 1H), 7.29-7.34 (m, 3H), 7.37 (t, 1H, J=7.83 Hz),
7.44-7.48 (m, 1H), 7.51 (d, 2H, J=8.08 Hz), 7.57 (t, 1H, J=1.77
Hz).
[0722] Next, to a solution of
[(R)-2-(3'-chloro-biphenyl-4-yl)-1-hydroxymethyl-ethyl]-carbamic
acid tert-butyl ester (2.0 g, 5.53 mmol) in DCM (30 mL) is added
Dess-Martin periodinane (2.81 g, 6.63 mmol). After being stirred at
room temperature for 2 h, the reaction mixture is diluted with
EtOAc and washed with saturated NaHCO.sub.3 aqueous solution and
brine. The organic layer is dried over Na.sub.2SO.sub.4 and
concentrated. The residue is purified by flash column
chromatography (silica gel, eluent; heptane/EtOAc=100:0 to 0:100)
to give [(R)-2-(3'-chloro-biphenyl-4-yl)-1-formyl-ethyl]-carbamic
acid tert-butyl ester (1.05 g). HPLC retention time=1.27 minutes
(condition A): MS (m+1)=360.
[0723] This is dissolved in MeOH (20 mL) and AcOH (0.199 mL, 3.47
mmol). To this solution KCN (0.226 g, 3.47 mmol) in H.sub.2O (4 mL)
is slowly added. After being stirred at room temperature overnight,
the reaction mixture is diluted with EtOAc and washed with
saturated NaHCO.sub.3 aqueous solution, H.sub.2O and brine. The
organic layer is dried over Na.sub.2SO.sub.4 and concentrated. This
is treated with 4M HCl in dioxane (20 mL) and MeOH (10 mL) at room
temperature. After being stirred overnight, the reaction mixture is
concentrated. The residue is dissolved in MeOH and treated with
SOCl.sub.2 (0.211 mL, 2.89 mmol). After being stirred at 50.degree.
C. for 5 h, the reaction mixture is concentrated to dryness. The
residue is dissolved in THF (10 mL) and treated with saturated
NaHCO.sub.3 aqueous solution (5 mL) and Boc.sub.2O (0.631 g, 2.89
mmol). After being stirred at room temperature for 2 h, the
reaction mixture is diluted with EtOAc and washed with brine. The
organic layer is dried over MgSO.sub.4 and concentrated. The
residue is purified by flash column chromatography (silica gel,
eluent; heptane/EtOAc=100:0 to 0:100) to give
(R)-3-tert-butoxycarbonylamino-4-(3'-chloro-biphenyl-4-yl)-2-hydr-
oxy-butyric acid methyl ester (0.61 g). HPLC retention time=1.01,
1.06 minutes (condition B): MS (m+1-Boc)=320. 1H-NMR (400 MHz,
CDCl.sub.3) .delta. ppm 1.40 (s, 9H), 2.77-3.05 (m, 2H), 3.63 (s,
0.7H), 3.77 (s, 2.3H), 4.11 (s, 0.8H), 4.25-4.40 (m, 1.2H),
4.78-4.95 (m, 1H), 7.27-7.40 (m, 4H), 7.42-7.58 (m, 4H).
[0724]
(R)-3-tert-butoxycarbonylamino-4-(3'-chloro-biphenyl-4-yl)-2-hydrox-
y-butyric acid methyl ester (113 mg, 0.269 mmol) is treated with 4M
HCl in dioxane (2 mL). After being stirred at room temperature for
1 h, the reaction mixture is concentrated. The residue is used for
a next step without further purification. HPLC retention time=1.22,
1.29 minutes (condition A): MS (m+1)=320.
Intermediate 50:
(R)-3-amino-4-(3'-chloro-biphenyl-4-yl)-2-methoxy-butyric acid
methyl ester hydrochloride
##STR00629##
[0726] To a solution of
(R)-3-tert-butoxycarbonylamino-4-(3'-chloro-biphenyl-4-yl)-2-hydroxy-buty-
ric acid methyl ester (610 mg, 1.45 mmol) in CH.sub.3CN (20 mL) are
added iodomethane (0.545 mL, 8.72 mmol) and silver oxide (1.35 g,
5.81 mmol). After being stirred at room temperature for 16 h,
additional iodomethane (0.545 mL, 8.72 mmol) and silver oxide (1.35
g, 5.81 mmol) are added and stirred for 3 days. The reaction
mixture is filtered through celite pad and the filtrate is washed
with brine. The organic layer is dried over MgSO.sub.4 and
concentrated. The residue is purified by flash column
chromatography (silica gel, eluent; heptane/EtOAc=100:0 to 0:100)
to give
(R)-3-tert-butoxycarbonylamino-4-(3'-chloro-biphenyl-4-yl)-2-methoxy-buty-
ric acid methyl ester (500 mg). HPLC retention time=1.20, 1.25
minutes (condition B): MS (m+1-Boc)=334. 1H-NMR (400 MHz,
CDCl.sub.3) .delta. ppm 1.37, 1.41 (s, 9H), 2.72-3.03 (m, 2H),
3.43, 3.71 (s, 3H), 3.63-3.82 (m, 1H), 4.27-4.41 (m, 1H), 4.68-5.04
(m, 1H), 7.28-7.40 (m, 4H), 7.41-7.61 (m, 4H).
[0727]
(R)-3-tert-butoxycarbonylamino-4-(3'-chloro-biphenyl-4-yl)-2-methox-
y-butyric acid methyl ester (200 mg, 0.461 mmol) is treated with 4M
HCl in dioxane (3 mL). After being stirred at room temperature for
1 h, the reaction mixture is concentrated. The residue is used for
a next step without further purification. HPLC retention time=1.26,
1.33 minutes (condition A): MS (m+1)=334.
Intermediate 51:
(R)-3-amino-4-(3'-chloro-biphenyl-4-yl)-2-methoxy-butyric acid
ethyl ester hydrochloride
##STR00630##
[0729] To a solution of
(R)-3-amino-4-(3'-chloro-biphenyl-4-yl)-2-methoxy-butyric acid
methyl ester (500 mg, 1.15 mmol) in MeOH (5 mL) is added 2M NaOH
aqueous solution (5 mL). After being stirred at room temperature
for 2 h, the reaction mixture is acidified with 2M HCl and
extracted with EtOAc. The organic layer is dried over
Na.sub.2SO.sub.4 and concentrated. The residue is dissolved in EtOH
(5 mL) and treated with SOCl.sub.2 (0.252 mL, 3.26 mmol). After
being stirred at 55.degree. C., the reaction mixture was
concentrated. The residue is used for a next step without further
purification. HPLC retention time=1.49 minutes (condition A): MS
(m+1)=348.2
Intermediate 52:
(R)-3-Amino-4-(3'-chloro-biphenyl-4-yl)-2-fluoro-butyric acid
methyl ester hydrochloride
##STR00631##
[0731] To a solution of
(R)-3-tert-butoxycarbonylamino-4-(3'-chloro-biphenyl-4-yl)-2-hydroxy-buty-
ric acid methyl ester (220 mg, 0.524 mmol) is added DAST (0.083 mL,
0.629 mmol) at 0.degree. C. The reaction mixture is gradually
warmed to room temperature and stirred for 1 h. Additional DAST
(0.083 mL, 0.629 mmol) is added and stirred at room temperature for
2 h. The reaction mixture is diluted with EtOAc and washed with
saturated NaHCO.sub.3 aqueous solution and brine. The organic layer
is dried over Na.sub.2SO.sub.4 and concentrated. The residue is
purified by flash column chromatography (silica gel, eluent;
heptane/EtOAc=100:0 to 0:100) to give
(R)-3-tert-butoxycarbonylamino-4-(3'-chloro-biphenyl-4-yl)-2-fluoro-butyr-
ic acid methyl ester (63 mg). HPLC retention time=1.36 minutes
(condition B): MS (m+1-Boc)=322.1H-NMR (400 MHz, CDCl.sub.3)
.delta. ppm 1.39 (s, 9H), 2.84-2.95 (m, 2H), 3.06 (bs, 0.5H), 3.69
(s, 3H), 4.43-4.61 (m, 1H), 4.72-4.80 (m, 0.5H), 5.00 (s, 0.5H),
5.12 (s, 0.5H), 7.28-7.34 (m, 3H), 7.37 (t, 1H, J=7.58 Hz),
7.42-7.47 (m, 1H), 7.48-7.53 (m, 1H), 7.55 (t, 1H, J=2.02 Hz).
19F-NMR (377 MHz, CDCl.sub.3) .delta. ppm -204.18.
[0732]
(R)-3-tert-butoxycarbonylamino-4-(3'-chloro-biphenyl-4-yl)-2-fluoro-
-butyric acid methyl ester (60 mg, 0.142 mmol) is treated with 4M
HCl in dioxane (1.5 mL). After being stirred at room temperature
for 1 h, the reaction mixture is concentrated. The residue is used
for a next step without further purification. HPLC retention
time=0.88 minutes (condition B): MS (m+1)=322.
Intermediate 53-1:
[(R)-1-(3'-chloro-biphenyl-4-ylmethyl)-3-methanesulfonylamino-3-oxo-propy-
l]-carbamic acid tert-butyl ester
##STR00632##
[0734]
(R)-3-tert-butoxycarbonylamino-4-(3'-chloro-biphenyl-4-yl)-butyric
acid ethyl ester (250 mg, 0.598 mmol) is treated with 2M NaOH
aqueous solution (1 mL) in THF (1 mL) and EtOH (2 mL). After being
stirred for 1 h, the reaction mixture is acidified with 1M HCl and
extracted with EtOAc. The organic layer is washed with brine, dried
over Na.sub.2SO.sub.4 and concentrated in vacuo. To a solution of
this residue in DMF (2 mL) are added methylsulfonamide (85 mg,
0.897 mmol), EDC (172 mg, 0.897 mmol), HOAt (98 mg, 0.718 mmol),
and Et.sub.3N (0.125 mL, 0.897 mmol). After being stirred at room
temperature overnight, the reaction mixture is diluted with EtOAc,
washed with 1M HCl and brine. The organic layer is dried over
Na.sub.2SO.sub.4 and concentrated. The residue is purified by flash
column chromatography (silica gel, eluent: DCM/10% MeOH in
DCM=100:0 to 0:100) to give
[(R)-1-(3'-chloro-biphenyl-4-ylmethyl)-3-methanesulfonylamino-3-oxo-propy-
l]-carbamic acid tert-butyl ester (244 mg). HPLC retentions
time=1.30 minutes (condition B); MS (m+1)=467; 1H NMR (400 Mz,
DMSO-d6) .delta. ppm 1.30 (s, 9H), 2.41-2.48 (m, 2H), 2.70-2.78 (m,
2H), 3.18 (s, 3H), 3.99-4.11 (m, 1H), 7.28 (d, 2H, J=8.34 Hz),
7.38-7.44 (m, 1H), 7.48 (t, 1H, J=7.83 Hz), 7.59-7.66 (m, 3H), 7.69
(s, 1H).
[0735] Following compounds are prepared using similar procedure as
described in example 53-1:
TABLE-US-00032 HPLC-RT Example Product Reagent (condition) MS (M +
1) Example 53-2 ##STR00633## ##STR00634## 1.22 min. (condition B)
496 Example 53-3 ##STR00635## ##STR00636## 1.33 min. (condition B)
544 Example 53-4 ##STR00637## NH.sub.4Cl 1.17 min. (condition B)
389
Intermediate 54-1:
(R)-3-[2-(tert-butoxycarbonyl-ethoxycarbonylmethyl-amino)-propionylamino]-
-4-(3'-chloro-biphenyl-4-yl)-butyric acid ethyl ester
##STR00638##
[0737] To a suspension of
2-(tert-butoxycarbonyl-ethoxycarbonylmethyl-amino)-propionic acid
TFA salt (197 mg, 0.714 mmol) in THF (10 ml) at room temperature is
added EDCI (219 mg, 1.142 mmol) and HOBT (164 mg, 1.071 mmol). The
mixture is stirred at room temperature for 10 mins and then was
added a solution of (R)-3-amino-4-(3'-chloro-biphenyl-4-yl)-butyric
acid ethyl ester (202 mg, 0.571 mmol) in THF and TEA (0.199 ml,
1.428 mmol). The mixture is stirred at room temperature. Reverse
phase HPLC [30 to 90% ACN--H.sub.2O (0.1% TFA) over 10 min by
X-Bridge phenyl column] give the title compound (290 mg, 71%
yield). LCMS (condition B): 575 (M+1); retention time=1.52 min.
Intermediate 54-2:
2-(tert-Butoxycarbonyl-ethoxycarbonylmethyl-amino)-propionic
acid
##STR00639##
[0739] To a solution of H-DL-Ala-OBzl.p-tosylate (2.88 g, 8.20
mmol) in THF (80 ml) at room temperature was added TEA (3.43 ml,
24.60 mmol) and followed by ethyl bromoacetate (1.096 ml, 9.84
mmol). The reaction was stirred at room temperature over night.
There were some white solid in the reaction. The reaction mixture
was filtered off the white solid and concentrated for purification.
Flash chromatography (silica gel, 2 to 4% EtOH/DCM) gave the title
compound as an oil (1.7 g, 78% yield). LCMS (condition B): 266
(M+1); retention time=0.70 min.
[0740] Next, to a solution of
2-(ethoxycarbonylmethyl-amino)-propionic acid benzyl ester (1.7 g,
6.41 mmol) in DCM (80 ml) at 0.degree. C. was added BOC-anhydride
(2.232 ml, 9.61 mmol) and followed by TEA (2.68 ml, 19.22 mmol).
The reaction mixture was slowly warmed up to room temperature and
stirred over night. The reaction was quenched by brine and was
extracted with DCM. The combined organic layer was washed with
brine and dried over anhydrous sodium sulfate, filtered and
concentrated to give the crude. Flash chromatography (silica gel, 5
to 10% acetone/heptane) gave the title compound as an oil (1.66 g,
71% yield). LCMS (condition B): 366 (M+1); retention time=1.13
min.
[0741] Next, a solution of
2-(tert-butoxycarbonyl-ethoxycarbonylmethyl-amino)-propionic acid
benzyl ester in EtOAc was hydrogenated under H.sub.2 balloon by
catalyst 10% Pd/C wet for 1 hr. The reaction was filtered off the
catalyst and concentrated to give the crude for the next
reaction.
Intermediate 55:
(R)-3-Amino-4-(3'-chloro-biphenyl-4-yl)-2-methyl-butyric acid ethyl
ester trifluoroacetate
##STR00640##
[0743] To a solution of
(R)-3-tert-butoxycarbonylamino-4-(3'-chloro-biphenyl-4-yl)-butyric
acid ethyl ester (300 mg, 0.718 mmol) in THF (10 ml) at -78.degree.
C. is added LiHMDS/THF (1M) (1.579 ml, 1.579 mmol). The reaction
mixture is stirred at -78.degree. C. for 50 min and then to this
mixture is added methyl iodine (0.054 ml, 0.861 mmol) and the
reaction is slowly warmed up to room temperature and stirred over
night. The reaction is quenched by sat. NH.sub.4Cl and is extracted
with EtOAc. The combined organic layer is washed with brine and
dried over anhydrous sodium sulfate, filtered and concentrated to
give the crude. Reverse phase HPLC [20 to 90% ACN--H.sub.2O (0.1%
TFA) over 10 min by Sunfire C18] give
(R)-3-tert-butoxycarbonylamino-4-(3'-chloro-biphenyl-4-yl)-2-methyl-butyr-
ic acid ethyl ester. LCMS (condition B): 432 (M+1); retention
time=1.55 min. To a solution of
(R)-3-tert-butoxycarbonylamino-4-(3'-chloro-biphenyl-4-yl)-2-methyl-butyr-
ic acid ethyl ester (240 mg, 0.556 mmol) in DCM (2 ml) at room
temperature was added TFA (1.070 ml, 13.89 mmol) and the mixture is
stirred at room temperature. 1 hr the reaction is done so the
mixture is concentrated to give
(R)-3-amino-4-(3'-chloro-biphenyl-4-yl)-2-methyl-butyric acid ethyl
ester trifluoroacetate. LCMS (condition B): 332 (M+1); retention
time=1.00 min.
[0744] It can be seen that the compounds of the invention are
useful as inhibitors of Neutral endopeptidase (EC 3.4.24.11)
activity and therefore useful in the treatment of diseases and
conditions associated with Neutral endopeptidase (EC 3.4.24.11)
activity such as the diseases disclosed herein.
[0745] 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.
* * * * *