U.S. patent application number 12/868773 was filed with the patent office on 2010-12-23 for glucagon receptor antagonists, preparation and therapeutic uses.
This patent application is currently assigned to ELI LILLY AND COMPANY. Invention is credited to Scott Eugene CONNER, Jianke LI, Guoxin ZHU.
Application Number | 20100324140 12/868773 |
Document ID | / |
Family ID | 35219490 |
Filed Date | 2010-12-23 |
United States Patent
Application |
20100324140 |
Kind Code |
A1 |
CONNER; Scott Eugene ; et
al. |
December 23, 2010 |
GLUCAGON RECEPTOR ANTAGONISTS, PREPARATION AND THERAPEUTIC USES
Abstract
The present invention discloses novel compounds of Formula I, or
pharmaceutically acceptable salts thereof, which have glucagon
receptor antagonist or inverse agonist activity, as well as methods
for preparing such compounds. In another embodiment, the invention
discloses pharmaceutical compositions comprising compounds of
Formula I as well as methods of using them to treat diabetic and
other glucagon related metabolic disorders, and the like.
Inventors: |
CONNER; Scott Eugene;
(Indianapolis, IN) ; ZHU; Guoxin; (Carmel, IN)
; LI; Jianke; (Hamden, CT) |
Correspondence
Address: |
ELI LILLY & COMPANY
PATENT DIVISION, P.O. BOX 6288
INDIANAPOLIS
IN
46206-6288
US
|
Assignee: |
ELI LILLY AND COMPANY
Indianapolis
IN
|
Family ID: |
35219490 |
Appl. No.: |
12/868773 |
Filed: |
August 26, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11570449 |
Dec 12, 2006 |
7816557 |
|
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PCT/US2005/019901 |
Jun 8, 2005 |
|
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12868773 |
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60579362 |
Jun 14, 2004 |
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Current U.S.
Class: |
514/563 ;
562/450 |
Current CPC
Class: |
C07D 319/20 20130101;
C07C 255/54 20130101; C07C 235/42 20130101; C07D 295/096 20130101;
C07C 323/60 20130101; C07D 213/64 20130101; C07D 319/06 20130101;
A61P 43/00 20180101; C07D 213/30 20130101; C07D 213/65 20130101;
A61P 3/10 20180101; C07C 2601/14 20170501; C07C 323/62 20130101;
A61P 3/00 20180101; A61P 3/08 20180101; C07C 251/48 20130101; C07C
323/65 20130101; C07C 2601/02 20170501; C07D 213/89 20130101 |
Class at
Publication: |
514/563 ;
562/450 |
International
Class: |
A61K 31/197 20060101
A61K031/197; C07C 229/38 20060101 C07C229/38; A61P 3/10 20060101
A61P003/10 |
Claims
1-24. (canceled)
25. A compound of the formula ##STR00415## or a pharmaceutically
acceptable salt thereof.
26. A compound of claim 25 which is
3-{4-[1-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-4,4-dimethyl-p-
entyl]-benzoylamino}-propionic acid, Isomer 1, or a
pharmaceutically acceptable salt thereof, or
3-{4-[1-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-4,4-dimethyl-p-
entyl]-benzoylamino}-propionic acid, Isomer 2, or a
pharmaceutically acceptable salt thereof.
27. A compound of claim 25 which is
3-{4-[1-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-4,4-dimethyl-p-
entyl]-benzoylamino}-propionic acid, Isomer 1, or a
pharmaceutically acceptable salt thereof.
28. A mixture comprising
3-{4-[1-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-4,4-dimethyl-p-
entyl]-benzoylamino}-propionic acid, Isomer 1, or a
pharmaceutically acceptable salt thereof, or
3-{4-[1-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-4,4-dimethyl-p-
entyl]-benzoylamino}-propionic acid, Isomer 2, or a
pharmaceutically acceptable salt thereof.
29. A pharmaceutical composition which comprises a compound, or
pharmaceutically acceptable salt thereof, of claim 25, and a
pharmaceutically acceptable carrier.
30. A pharmaceutical composition which comprises a compound, or
pharmaceutically acceptable salt thereof, of claim 26, and a
pharmaceutically acceptable carrier.
31. A pharmaceutical composition which comprises a compound, or
pharmaceutically acceptable salt thereof, of claim 27, and a
pharmaceutically acceptable carrier.
32. A pharmaceutical composition which comprises a mixture of claim
28, and a pharmaceutically acceptable carrier.
Description
[0001] This patent application claims the benefit of U.S.
Provisional Patent Application No. 60/579,362 filed Jun. 14,
2004.
[0002] This invention relates to compounds that are antagonists or
inverse agonists of the glucagon receptor, and to pharmaceutical
compositions thereof, and the uses of these compounds and
compositions in the treatment of the human or animal body. The
present compounds show a high affinity and selective binding for
the glucagon receptor, and as such are useful in the treatment of
disorders responsive to the modulation of glucagon receptors, such
as diabetic and other glucagon related metabolic disorders, and the
like.
[0003] Glucagon is a key hormonal agent that, in cooperation with
insulin, mediates homeostatic regulation of the amount of glucose
in the blood. Glucagon primarily acts by stimulating certain cells
(important among these are liver cells) to release glucose when
blood glucose levels fall. The action of glucagon is opposite to
that of insulin, which stimulates cells to take up and store
glucose whenever blood glucose levels rise. Both glucagon and
insulin are peptide hormones. Glucagon is produced in the alpha
islet cells of the pancreas and insulin is produced in the beta
islet cells. Glucagon exerts its action by binding to and
activating its receptor, which is a member of the Glucagon-Secretin
branch of the 7-transmembrane G-protein coupled receptor family.
The receptor functions by activating the adenylyl cyclase second
messenger system resulting in an increase in cAMP levels. The
glucagon receptor, or naturally occurring variants of the receptor,
may possess intrinsic constitutive activity, invitro, as well as in
vivo (i.e. activity in the absence of an agonist). Compounds acting
as inverse agonists can inhibit this activity.
[0004] Diabetes mellitus is a common disorder of glucose
metabolism. The disease is characterized by hyperglycemia and may
be classified as type 1 diabetes, the insulin-dependent form, or
type 2 diabetes, which is non-insulin-dependent in character.
Subjects with type 1 diabetes are hyperglycemic and
hypoinsulinemic, and the conventional treatment for this form of
the disease is to provide insulin. However, in some patients with
type 1 or type 2 diabetes, absolute or relative elevated glucagon
levels have been shown to contribute to the hyperglycemic state.
Both in healthy control animals as well as in animal models of type
1 and type 2 diabetes, removal of circulating glucagon with
selective and specific antibodies has resulted in reduction of the
glycemic level. Mice with a homozygous deletion of the glucagon
receptor exhibit increased glucose tolerance. Also, inhibition of
glucagon receptor expression using antisense oligonucleotides
ameliorates diabetic syndrome in db/db mice. These studies suggest
that glucagon suppression or an action that antagonizes glucagon
could be a useful adjunct to conventional treatment of
hyperglycemia in diabetic patients. The action of glucagon can be
suppressed by providing an antagonist or an inverse agonist, i.e.
substances that inhibit or prevent constitutive, or
glucagon-induced, glucagon receptor mediated responses.
[0005] Several publications disclose peptides that are stated to
act as glucagon antagonists. Peptide antagonists of peptide
hormones are often potent; however they are generally known not to
be orally available because of degradation by physiological enzymes
and poor distribution in vivo. Therefore, orally available
non-peptide antagonists of peptide hormones are generally
preferred.
[0006] A number of publications have appeared in recent years
reporting non-peptide agents that act at the glucagon receptor. In
spite of the number of treatments for diseases that involve
glucagon, the current therapies suffer from one or more
inadequacies, including poor or incomplete efficacy, unacceptable
side effects, and contraindications for certain patient
populations. Thus, there remains a need for an improved treatment
using alternative or improved pharmaceutical agents that modulate
glucagon receptor activity and treat the diseases that could
benefit from glucagon receptor modulation. The present invention
provides such a contribution to the art based on the finding that a
novel class of compounds has a high affinity, selective, and potent
inhibitory activity at the glucagon receptor. The present invention
is distinct in the particular structures and their activities.
SUMMARY OF THE INVENTION
[0007] The present invention provides a compound structurally
represented by Formula I:
##STR00001##
or a pharmaceutically acceptable salt thereof wherein: [0008] Y is
--O-- or --S--; [0009] Q, D, X, and T independently represent
carbon (substituted with hydrogen or the optional substituents as
indicated herein), or nitrogen (optionally substituted with
oxygen), provided that no more than two of Q, D, X, and T are
nitrogen; [0010] R1 is --H, --OH, or -halogen; [0011] R2 is --H or
--(C.sub.1-C.sub.3) alkyl (optionally substituted with 1 to 3
halogens); [0012] R3 and R4 are independently [0013] --H, -halogen,
--CN, --OH, --(C.sub.1-C.sub.7)alkoxy, --(C.sub.1-C.sub.7)alkyl
(optionally substituted with 1 to 3 halogens), or
--(C.sub.2-C.sub.7)alkenyl; [0014] R5 is selected from the group
consisting of [0015] --H, --(C.sub.1-C.sub.12)alkyl (optionally
substituted with 1 to 3 halogens), --(C.sub.3-C.sub.12)cycloalkyl,
-phenyl, -phenyl-phenyl-(C.sub.1-C.sub.12)alkyl, -aryl,
-aryl-(C.sub.1-C.sub.12)alkyl, -heteroaryl,
-heteroaryl-(C.sub.1-C.sub.12)alkyl, --(C.sub.2-C.sub.12)alkenyl,
--(C.sub.3-C.sub.12)cycloalkenyl, -heterocycloalkyl,
-aryl-(C.sub.2-C.sub.10)alkenyl,
-heteroaryl-(C.sub.2-C.sub.10)alkenyl, --(C.sub.2-C.sub.12)alkynyl,
--(C.sub.3-C.sub.12)cycloalkynyl, -aryl-(C.sub.2-C.sub.12)alkynyl,
and -heteroaryl-(C.sub.2-C.sub.12)alkynyl, and wherein
--(C.sub.1-C.sub.12)alkyl, --(C.sub.3-C.sub.12)cycloalkyl, -phenyl,
-phenyl-phenyl-(C.sub.1-C.sub.12)alkyl, -aryl,
-aryl-(C.sub.1-C.sub.12)alkyl, -heteroaryl,
-heteroaryl-(C.sub.1-C.sub.12)alkyl, -heterocycloalkyl,
--(C.sub.2-C.sub.12)alkenyl, --(C.sub.3-C.sub.12)cycloalkenyl,
-aryl-(C.sub.2-C.sub.10)alkenyl,
-heteroaryl-(C.sub.2-C.sub.10)alkenyl, --(C.sub.2-C.sub.12)alkynyl,
--(C.sub.3-C.sub.12)cycloalkynyl, -aryl-(C.sub.2-C.sub.12)alkynyl,
-heteroaryl-(C.sub.2-C.sub.12)alkynyl, are each optionally
substituted with from one to three substituents each independently
selected from the group consisting of -hydrogen, -hydroxy, -cyano,
-nitro, -halo, -oxo, --(C.sub.1-C.sub.7)alkyl (optionally
substituted with 1 to 3 halogens), --(C.sub.1-C.sub.7)alkyl-COOR12,
--(C.sub.1-C.sub.7)alkoxy, --(C.sub.3-C.sub.7)cycloalkyl,
--C(O)R12, --COOR12, --OC(O)R12, --OS(O).sub.2R12, --N(R12).sub.2,
--NR12C(O)R12, --NR12SO.sub.2R12, --SR12, --S(O)R12,
--S(O).sub.2R12, and --S(O).sub.2N(R12).sub.2; [0016] R6 and R7 are
independently at each occurrence selected from the group consisting
of [0017] --H, -halogen, -hydroxy, --CN, --(C.sub.1-C.sub.7)alkoxy,
--(C.sub.2-C.sub.7)alkenyl, --(C.sub.1-C.sub.10)alkyl (optionally
substituted with 1 to 3 halogens), --(C.sub.3-C.sub.12)cycloalkyl,
tert-butoxyiminomethyl, 1,3-dioxan-2-yl, hydroxymethyl, formyl,
hydroxyiminomethyl, morphylino-4-yl-methyl, 4-methylpentyloxy, and
pentyloxy; [0018] provided however that wherein D is nitrogen, then
R6 or R7 are not attached to D, and provided that wherein T is
nitrogen, then R6 or R7 are not attached to T, and provided that
wherein Q is nitrogen, then R6 or R7 are not attached to Q, and
provided that wherein X is nitrogen, then R6 or R7 are not attached
to X; wherein R6 and R7 may optionally form a six membered ring
with the atoms to which they are attached, and the ring so formed
may optionally contain up to two oxygens, and further the ring so
formed may optionally be substituted with up to four halogens;
[0019] R8 and R9 are independently at each occurrence selected from
the group consisting of [0020] -hydrogen, -hydroxy, --CN, -nitro,
-halo, --(C.sub.1-C.sub.7)alkyl (optionally substituted with 1 to 3
halogens), --(C.sub.1-C.sub.7)alkoxy,
--(C.sub.3-C.sub.7)cycloalkyl, -aryl, -aryl-(C.sub.1-C.sub.7)alkyl,
-heteroaryl, -heteroaryl-(C.sub.1-C.sub.7)alkyl, -aryloxy,
--C(O)R12, --C(O)0R12, --OC(O)R12, --OS(O).sub.2R12,
--N(R12).sub.2, --NR12C(O)R12, --NR12SO.sub.2R12, --SR12,
--S(O)R12, --S(O).sub.2R12, --O(C.sub.2-C.sub.7)alkenyl, and
--S(O).sub.2N(R12).sub.2; and wherein --(C.sub.1-C.sub.7)alkyl,
--(C.sub.1-C.sub.7)alkoxy, --(C.sub.3-C.sub.7)cycloalkyl, -aryl,
-aryl-(C.sub.1-C.sub.7)alkyl, -heteroaryl,
-heteroaryl-(C.sub.1-C.sub.7)alkyl, -aryloxy, and
--O(C.sub.2-C.sub.7)alkenyl are each optionally substituted with
from one to three substituents independently selected from the
group consisting of -hydrogen, -hydroxy, -cyano, -nitro, -halo,
-oxo, --(C.sub.1-C.sub.7)alkyl, --(C.sub.1-C.sub.7)alkyl-C(O)OR12,
--(C.sub.1-C.sub.7)alkoxyl, --(C.sub.3-C.sub.7)cycloalkyl,
-heterocycloalkyl, --C(O)R12, --C(O)OR12, --OC(O)R12,
--OS(O).sub.2R12, --N(R12).sub.2, --NR12C(O)R12, --NR12SO.sub.2R12,
--SR12, --S(O)R12, --S(O).sub.2R12, and --S(O).sub.2N(R12).sub.2;
[0021] R10 is selected from the group consisting of [0022] --H,
halogen, --(C.sub.1-C.sub.12)alkyl (optionally substituted with 1
to 3 halogens), -cycloalkyl, -aryl, -aryl-(C.sub.1-C.sub.7)alkyl,
-heteroaryl, -heteroaryl-(C.sub.1-C.sub.7)alkyl,
--(C.sub.2-C.sub.12)alkenyl, --(C.sub.3-C.sub.12)cycloalkenyl,
-aryl-(C.sub.2-C.sub.10)alkenyl,
-heteroaryl-(C.sub.2-C.sub.10)alkenyl, --(C.sub.2-C.sub.12)alkynyl,
--(C.sub.3-C.sub.12)cycloalkynyl, -aryl-(C.sub.2-C.sub.12)alkynyl,
and -heteroaryl-(C.sub.2-C.sub.12)alkynyl; [0023] R11 is
independently at each occurrence selected from the group consisting
of [0024] --H, -halogen,
##STR00002##
[0024] wherein the zig-zag mark shows the point of attachment to
the parent molecule, wherein A, G, and E independently represent
carbon (substituted with hydrogen or the optional substituents as
indicated herein) or nitrogen, provided that no more than two of A,
G, and E are nitrogen; [0025] provided however that wherein A is
nitrogen, then R8, R9, and R14 are not attached to A, and provided
that wherein G is nitrogen, then R8, R9, and R14 are not attached
to G, and provided that wherein E is nitrogen, then R8, R9, and R14
are not attached to E,
##STR00003##
[0025] wherein the zig-zag mark shows the point of attachment to
the parent molecule, wherein m is an integer of 0, 1, 2, or 3, and
when m is 0, then (CH.sub.2)m is a bond, and
##STR00004##
wherein the zig-zag mark shows the point of attachment to the
parent molecule, [0026] provided however that wherein D is
nitrogen, then R11 is not attached to D, and provided that wherein
T is nitrogen, then R11 is not attached to T, and provided that
wherein Q is nitrogen, then R11 is not attached to Q, and provided
that wherein X is nitrogen, then R11 is not attached to X; [0027]
R12 is independently at each occurrence selected from the group
consisting of [0028] -hydrogen, --(C.sub.1-C.sub.7)alkyl
(optionally substituted with 1 to 3 halogens), and -aryl; [0029]
R13 is independently at each occurrence selected from the group
consisting of [0030] -hydrogen, -halogen, --(C.sub.1-C.sub.7)alkyl
(optionally substituted with 1 to 3 halogens), phenyl, and
--(C.sub.2-C.sub.7)alkenyl; and [0031] R14 is independently at each
occurrence [0032] --H, halogen, or --(C.sub.1-C.sub.7)alkyl
(optionally substituted with 1 to 3 halogens).
[0033] The present invention provides compounds that are useful as
glucagon receptor antagonists or inverse agonists. The present
invention further provides compounds that are selective antagonists
or inverse agonists of the glucagon receptor over the GLP-1
receptor. The present invention further provides a pharmaceutical
composition which comprises a compound of Formula I, or a
pharmaceutical salt thereof, and a pharmaceutically acceptable
carrier, diluent, or excipient.
[0034] Due to their interaction with the glucagon receptor, the
present compounds are useful in the treatment of a wide range of
conditions and disorders in which an interaction with the glucagon
receptor is beneficial. These disorders and conditions are defined
herein as "diabetic and other glucagon related metabolic
disorders". One of skill in the art is able to identify "diabetic
and other glucagon related metabolic disorders" by the involvement
of glucagon receptor mediated signaling either in the
pathophysiology of the disorder, or in the homeostatic response to
the disorder. Thus, the compounds may find use for example to
prevent, treat, or alleviate, diseases or conditions or associated
symptoms or sequelae, of the endocrinological system, the central
nervous system, the peripheral nervous system, the cardiovascular
system, the pulmonary system, and the gastrointestinal system,
while reducing and or eliminating one or more of the unwanted side
effects associated with the current treatments. "Diabetic and other
glucagon related metabolic disorders" include, but are not limited
to, diabetes, type 1 diabetes, type 2 diabetes, hyperglycemia,
hyper insulinemia, beta-cell rest, improved beta-cell function by
restoring first phase response, prandial hyperglycemia, preventing
apoptosis, impaired fasting glucose (IFG), metabolic syndrome,
hypoglycemia, hyper-/hypokalemia, normalizing glucagon levels,
improved LDL/HDL ratio, reducing snacking, eating disorders, weight
loss, polycystic ovarian syndrome (PCOS), obesity as a consequence
of diabetes, latent autoimmune diabetes in adults (LADA),
insulitis, islet transplantation, pediatric diabetes, gestational
diabetes, diabetic late complications, micro-/macroalbuminuria,
nephropathy, retinopathy, neuropathy, diabetic foot ulcers, reduced
intestinal motility due to glucagon administration, short bowel
syndrome, antidiarrheic, increasing gastric secretion, decreased
blood flow, erectile dysfunction, glaucoma, post surgical stress,
ameliorating organ tissue injury caused by reperfusion of blood
flow after ischemia, ischemic heart damage, heart insufficiency,
congestive heart failure, stroke, myocardial infarction, arrythmia,
premature death, anti-apoptosis, wound healing, impaired glucose
tolerance (IGT), insulin resistance syndromes, syndrome X,
hyperlipidemia, dyslipidemia, hypertriglyceridemia,
hyperlipoproteinemia, hypercholesterolemia, arteriosclerosis
including atherosclerosis, glucagonomas, acute pancreatitis,
cardiovascular diseases, hypertension, cardiac hypertrophy,
gastrointestinal disorders, obesity, diabetes as a consequence of
obesity, diabetic dyslipidemia, etc.
[0035] In addition, the present invention provides a compound of
Formula I, or a pharmaceutical salt thereof, or a pharmaceutical
composition which comprises a compound of Formula I, or a
pharmaceutical salt thereof, and a pharmaceutically acceptable
carrier, diluent, or excipient: for use in inhibiting the glucagon
receptor; for use in inhibiting a glucagon receptor mediated
cellular response in a mammal; for use in reducing the glycemic
level in a mammal; for use in treating a disease arising from
excessive glucagon; for use in treating diabetic and other glucagon
related metabolic disorders in a mammal; and for use in treating
diabetes, obesity, hyperglycemia, atheroscelerosis, ischemic heart
disease, stroke, neuropathy, and wound healing. Thus, the methods
of this invention encompass a prophylactic and therapeutic
administration of a compound of Formula I.
[0036] The present invention further provides the use of a compound
of Formula I, or a pharmaceutical salt thereof for the manufacture
of a medicament for inhibiting the glucagon receptor; for the
manufacture of a medicament for inhibiting a glucagon receptor
mediated cellular response in a mammal; for the manufacture of a
medicament for reducing the glycemic level in a mammal; for the
manufacture of a medicament for treating a disease arising from
excessive glucagon; for the manufacture of a medicament for
treating diabetic and other glucagon related metabolic disorders in
a mammal; and for the manufacture of a medicament for preventing or
treating diabetes, obesity, hyperglycemia, atheroscelerosis,
ischemic heart disease, stroke, neuropathy, and improper wound
healing.
[0037] The present invention further provides a method of treating
conditions resulting from excessive glucagon in a mammal; a method
of inhibiting the glucagon receptor in a mammal; a method of
inhibiting a glucagon receptor mediated cellular response in a
mammal; a method of reducing the glycemic level in a mammal; a
method of treating diabetic and other glucagon related metabolic
disorders in a mammal; a method of preventing or treating diabetes,
obesity, hyperglycemia, atheroscelerosis, ischemic heart disease,
stroke, neuropathy, and improper wound healing; said methods
comprising administering to a mammal in need of such treatment a
glucagon receptor-inhibiting amount of a compound of Formula I, or
a pharmaceutically acceptable salt thereof, or a pharmaceutical
composition which comprises a compound of Formula I, or a
pharmaceutical salt thereof, and a pharmaceutically acceptable
carrier, diluent, or excipient.
[0038] In addition, the present invention provides a pharmaceutical
composition which comprises a compound of Formula I, or a
pharmaceutical salt thereof, and a pharmaceutically acceptable
carrier, diluent, or excipient: adapted for use in inhibiting the
glucagon receptor; adapted for use in inhibiting glucagon receptor
mediated cellular responses; adapted for use in reducing the
glycemic level in a mammal; adapted for use in treating diabetic
and other glucagon related metabolic disorders in a mammal; and
adapted for use in preventing or treating diabetes, obesity,
hyperglycemia, atherosclerosis, ischemic heart disease, stroke,
neuropathy, and wound healing.
[0039] The compound or salt of the present invention further
provides a diagnostic agent for identifying patients having a
defect in the glucagon receptor, as a therapy to increase gastric
acid secretions, and to reverse intestinal hypomobility due to
glucagon administration. The invention also provides a method for
the treatment of disorders or diseases, wherein a glucagon
antagonistic action is beneficial, the method comprising
administering to a subject in need thereof an effective amount of a
compound according to the invention. In another embodiment of the
invention, the present compounds are used for the preparation of a
medicament for the treatment of any glucagon-mediated conditions
and diseases. In another embodiment of the invention, the present
compounds are used for the preparation of a medicament for the
treatment of hyperglycemia. In yet another embodiment of the
invention, the present compounds are used for the preparation of a
medicament for lowering blood glucose in a mammal. The present
compounds are effective in lowering the blood glucose, both in the
fasting and the postprandial stage. In still another embodiment of
the invention, the present compounds are used for the preparation
of a pharmaceutical composition for the treatment of IGT. In a
further embodiment of the invention, the present compounds are used
for the preparation of a pharmaceutical composition for the
treatment of type 2 diabetes. In yet a further embodiment of the
invention the present compounds are used for the preparation of a
pharmaceutical composition for the delaying or prevention of the
progression from IGT to type 2 diabetes. In yet another embodiment
of the invention the present compounds are used for the preparation
of a pharmaceutical composition for the delaying or prevention of
the progression from non-insulin requiring type 2 diabetes to
insulin requiring type 2 diabetes. In a further embodiment of the
invention the present compounds are used for the preparation of a
pharmaceutical composition for the treatment of type 1 diabetes.
Such treatment is normally accompanied by insulin therapy. In yet a
further embodiment of the invention the present compounds are used
for the preparation of a pharmaceutical composition for the
treatment of obesity. In still a further embodiment of the
invention the present compounds are used for the preparation of a
pharmaceutical composition for the treatment of disorders of the
lipid metabolism. In still another embodiment of the invention the
present compounds are used for the preparation of a pharmaceutical
composition for the treatment of an appetite regulation or energy
expenditure disorder. In a further embodiment of the invention,
treatment of a patient with the present compounds is combined with
diet and/or exercise.
DETAILED DESCRIPTION OF THE INVENTION
[0040] General terms used in the description of compounds,
compositions, and methods herein described, bear their usual
meanings. Throughout the instant application, the following terms
have the indicated meanings:
[0041] "GLP-1" means glucagon-like peptide 1. The term "glucagon
receptor" means one or more receptors that interact specifically
with glucagon to result in a biological signal. The term "GLP-1
receptor" means one or more receptors that interact specifically
with glucagon-like peptide 1 to result in a biological signal.
[0042] The term "glucagon receptor antagonist" means a compound of
the present invention with the ability to block cAMP production in
response glucagon.
[0043] The term "glucagon receptor inverse agonist" means a
compound of the present invention with the ability to inhibit the
constitutive activity of glucagon receptor.
[0044] The term "selective" antagonist or inverse agonist means a
compound having greater affinity for the glucagon receptor as
compared to the affinity for the GLP-1 receptor.
[0045] In the general formulae of the present document, the general
chemical terms have their usual meanings. For example;
[0046] "Halogen" or "halo" means fluoro, chloro, bromo and
iodo.
[0047] The term "alkyl," unless otherwise indicated, refers to
those alkyl groups of a designated number of carbon atoms of either
a straight or branched saturated configuration.
"(C.sub.1-C.sub.3)alkyl" are one to three carbon atoms, such as
methyl, ethyl, propyl, n-propyl, isopropyl, and the like and
branched or isomeric forms thereof, and optionally may be
substituted with one to three halogens or a designated number of
substituents as set forth in the embodiments recited herein,
"(C.sub.1-C.sub.7)alkyl" are one to seven carbon atoms such as
methyl, ethyl, propyl, n-propyl, isopropyl, n-butyl, isobutyl,
sec-butyl and tert-butyl, pentyl, isopentyl, hexyl, heptyl, and the
like, and branched or isomeric forms thereof, and optionally may be
substituted with one to three halogens or a designated number of
substituents as set forth in the embodiments recited herein, and
"(C.sub.1-C.sub.10)alkyl" are one to ten carbon atoms, such as
methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, nonyl, decyl,
and the like, and branched or isomeric forms thereof, and
optionally may be substituted with one to three halogens or a
designated number of substituents as set forth in the embodiments
recited herein. "(C.sub.1-C.sub.12)alkyl" are one to twelve carbon
atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl,
nonyl, decyl, and the like, and branched or isomeric forms thereof,
and optionally may be substituted with one to three halogens or a
designated number of substituents as set forth in the embodiments
recited herein.
[0048] The term "(C.sub.3-C.sub.12)cycloalkyl" refers to a
saturated or partially saturated carbocycle containing one or more
rings of from 3 to 12 carbon atoms, typically 3 to 7 carbon atoms
optionally substituted with up to three halogens. Examples of
(C.sub.3-C.sub.12)cycloalkyl include but are not limited to
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl,
and the like. "(C.sub.3-C.sub.7)cycloalkyl" means a ring with three
to seven carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl
and cyclohexyl, cycloheptyl, and the like, optionally substituted
with up to three halogens.
[0049] The term "(C.sub.1-C.sub.7)alkoxy" represents an alkyl group
of one to seven carbon atoms attached through an oxygen bridge,
such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy,
pentoxy, and the like, and may be optionally substituted with three
halogens or a designated number of substituents as set forth in the
embodiments recited herein.
[0050] The terms "(C.sub.2-C.sub.7)alkenyl",
"(C.sub.2-C.sub.10)alkenyl", "(C.sub.2-C.sub.10)alkylenyl",
"(C.sub.2-C.sub.12)alkenyl", or "(C.sub.2-C.sub.12)alkylenyl" means
hydrocarbon chains of the indicated number of carbon atoms of
either a straight or branched configuration having at least one
carbon-carbon double bond which may occur at any point along the
chain, such as ethenyl, propenyl, butenyl, pentenyl, vinyl, alkyl,
2-butenyl and the like, and may be optionally substituted with one
to three halogens or a designated number of substituents as set
forth in the embodiments recited herein.
[0051] The term "(C.sub.3-C.sub.12)cycloalkenyl" refers to a
partially saturated carbocycle containing one or more rings of from
3 to 12 carbon atoms, typically 3 to 7 carbon atoms optionally
substituted with up to three halogens.
[0052] The term "(C.sub.2-C.sub.12)alkynyl" means a hydrocarbon
chain of two to twelve carbon atoms of either a straight or
branched configuration and having at least one carbon-carbon triple
bond, which may occur at any point along the chain. Example of
alkynyl is acetylene. Alkynyl as defined above may be optionally
substituted with up to three halogens or the designated number of
substituents as set forth in the embodiments recited herein.
[0053] The term "(C.sub.3-C.sub.12)cycloalkynyl" refers to a
carbocycle containing one or more rings of from 3 to 12 carbon
atoms, typically 3 to 7 carbon atoms, having at least one
carbon-carbon triple bond which may occur at any point along the
chain or ring, optionally substituted with up to three halogens.
Cycloalkynyl as defined above may be optionally substituted with
the designated number of substituents as set forth in the
embodiments recited herein.
[0054] The term "aryl" includes carbocyclic aromatic ring systems
(e.g. phenyl), fused polycyclic aromatic ring systems (e.g.
naphthyl and anthracenyl), and aromatic ring systems fused to
carbocyclic non-aromatic ring systems (e.g.,
1,2,3,4-tetrahydronaphthyl). "Aryl" as defined above may be
optionally substituted with a designated number of substituents as
set forth in the embodiments recited herein.
[0055] The term "aryloxy" refers to an aryl group which is linked
to the parent molecule through an oxygen bridge.
[0056] The term "heteroaryl" group, as used herein, is an aryl ring
system having at least one heteroatom such as nitrogen, sulfur, or
oxygen, and includes monocyclic, bicyclic, or tricyclic aromatic
rings of 5 to 14 carbon atoms containing one or more heteroatoms
selected from the group consisting of O, N, and S. The "heteroaryl"
as defined above may be optionally substituted with a designated
number of substituents as set forth in the embodiments recited
herein. Examples of heteroaryl are, but are not limited to,
furanyl, indolyl, thienyl (also referred to herein as "thiophenyl")
thiazolyl, imidazolyl, isoxazoyl, oxazoyl, pyrazoyl, pyrrolyl,
pyrazinyl, pyridyl, pyrimidyl, pyrimidinyl and purinyl, cinnolinyl,
benzofuranyl, benzothienyl, benzotriazolyl, benzoxazolyl,
quinoline, isoxazolyl, isoquinoline, and the like.
[0057] The term "arylalkyl" refers to an aryl group which is linked
to the parent molecule through an alkyl moiety, and "arylalkyl" may
be further optionally substituted with a designated number of
substituents as set forth in the embodiments recited herein.
[0058] The term "heterocycloalkyl" refers to a non-aromatic ring
which contains one or more oxygen, nitrogen or sulfur and includes
a monocyclic, bicyclic or tricyclic non-aromatic ring of 5 to 14
carbon atoms containing one or more heteroatoms selected from O, N,
or S.
[0059] The term "optionally substituted," or "optional
substituents," as used herein, means that the groups in question
are either unsubstituted or substituted with one or more of the
substituents specified. When the groups in question are substituted
with more than one substituent, the substituents may be the same or
different. Furthermore, when using the terms "independently,"
"independently are," and "independently selected from" mean that
the groups in question may be the same or different. Certain of the
herein defined terms may occur more than once in the structural
formulae, and upon such occurrence each term shall be defined
independently of the other.
[0060] The term "patient" includes human and non-human animals such
as companion animals (dogs and cats and the like) and livestock
animals. Livestock animals are animals raised for food production.
Ruminants or "cud-chewing" animals such as cows, bulls, heifers,
steers, sheep, buffalo, bison, goats and antelopes are examples of
livestock. Other examples of livestock include pigs and avians
(poultry) such as chickens, ducks, turkeys and geese. Yet other
examples of livestock include fish, shellfish and crustaceans
raised in aquaculture. Also included are exotic animals used in
food production such as alligators, water buffalo and ratites
(e.g., emu, rheas or ostriches). The patient to be treated is
preferably a mammal, in particular a human being.
[0061] The term "a glucagon receptor mediated cellular response"
includes various responses by mammalian cells to glucagon
stimulation or glucagon receptor activity. For example "glucagon
receptor mediated cellular responses," include but are not limited
to, release of glucose from liver, or other cells, in response to
glucagon stimulation or glucagon receptor activity. One of ordinary
skill in the art can readily identify other cellular responses
mediated by glucagon receptor activity, for example by observing a
change in the responsive cellular endpoint after contacting the
cell with an effective dose of glucagon.
[0062] The terms "treatment", "treating" and "treat", as used
herein, include their generally accepted meanings, i.e., the
management and care of a patient for the purpose of preventing,
prohibiting, restraining, alleviating, ameliorating, slowing,
stopping, delaying, or reversing the progression or severity of a
disease, disorder, or pathological condition, described herein,
including the alleviation or relief of symptoms or complications,
or the cure or elimination of the disease, disorder, or
condition.
[0063] "Composition" means a pharmaceutical composition and is
intended to encompass a pharmaceutical product comprising the
active ingredient(s) including compound(s) of Formula I, and the
inert ingredient(s) that make up the carrier. Accordingly, the
pharmaceutical compositions of the present invention encompass any
composition made by admixing a compound of the present invention
and a pharmaceutically acceptable carrier.
[0064] The term "suitable solvent" refers to any solvent, or
mixture of solvents, inert to the ongoing reaction that
sufficiently solubilizes the reactants to afford a medium within
which to effect the desired reaction.
[0065] The term "unit dosage form" means physically discrete units
suitable as unitary dosages for human subjects and other non-human
animals, each unit containing a predetermined quantity of active
material calculated to produce the desired therapeutic effect, in
association with a suitable pharmaceutical carrier.
[0066] In one embodiment, the present invention provides compounds
of Formula I as described in detail herein. While all of the
compounds of the present invention are useful, certain of the
compounds are particularly interesting and are preferred. The
following listing sets out several groups of preferred compounds.
It will be understood that each of the listings may be combined
with other listings to create additional groups of preferred
embodiments. [0067] 1. wherein Y is --O--, [0068] 2. wherein Y is
--S--, [0069] 3. wherein D, Q, X, and T are carbon (substituted
with hydrogen or the optional substituents as indicated herein),
[0070] 4. wherein R1, R2, R3, R4 and R10 are hydrogen, [0071] 5.
wherein X is carbon and R11 is attached to X, [0072] 6. wherein D
is carbon and R11 is attached to D, [0073] 7. wherein X is carbon
and R11 is attached to X and R11 is
##STR00005##
[0073] wherein the zig-zag mark shows the point of attachment to
the parent molecule, and wherein A, G, and E independently
represent carbon (substituted with hydrogen or the optional
substituents as indicated herein) or nitrogen, provided that no
more than two of A, G, and E are nitrogen; [0074] 8. wherein X is
carbon and R11 is attached to X and R11 is
##STR00006##
[0074] wherein the zig-zag mark shows the point of attachment to
the parent molecule, and wherein A, G, and E independently
represent carbon (substituted with hydrogen or the optional
substituents as indicated herein) or nitrogen, provided that no
more than two of A, G, and E are nitrogen, and R8 and R9 are
independently at each occurrence selected from the group consisting
of -hydrogen, -hydroxy, --CN, -nitro, -halo,
--(C.sub.1-C.sub.7)alkyl (optionally substituted with 1 to 3
halogens), --(C.sub.1-C.sub.7)alkoxy,
--(C.sub.3-C.sub.7)cycloalkyl, -aryl, -aryl-(C.sub.1-C.sub.7)alkyl,
-heteroaryl, -heteroaryl-(C.sub.1-C.sub.7)alkyl, -aryloxy,
--C(O)R12, --C(O)OR12, --OC(O)R12, --OS(O).sub.2R12,
--N(R12).sub.2, --NR12C(O)R12, --NR12SO.sub.2R12, --SR12,
--S(O)R12, --S(O).sub.2R12, and --S(O).sub.2N(R12).sub.2, [0075] 9.
wherein X is carbon and R11 is attached to X and R11 is
##STR00007##
[0075] wherein the zig-zag mark shows the point of attachment to
the parent molecule, and wherein A, G, and E independently
represent carbon (substituted with hydrogen or the optional
substituents as indicated herein) or nitrogen, provided that no
more than two of A, G, and E are nitrogen, and R8 and R9 are
independently at each occurrence selected from the group consisting
of -hydrogen, -hydroxy, --CN, -nitro, -halo,
--(C.sub.1-C.sub.7)alkyl (optionally substituted with 1 to 3
halogens), --(C.sub.1-C.sub.7)alkoxy, and
--(C.sub.3-C.sub.7)cycloalkyl, [0076] 10. wherein X is carbon and
R11 is attached to X and R11 is
##STR00008##
[0076] wherein the zig-zag mark shows the point of attachment to
the parent molecule, and wherein A, G, and E are carbon
(substituted with hydrogen or the optional substituents as
indicated herein), [0077] 11. wherein X is carbon and R11 is
attached to X and R11 is
##STR00009##
[0077] wherein the zig-zag mark shows the point of attachment to
the parent molecule, and wherein A, G, and E are carbon
(substituted with hydrogen or the optional substituents as
indicated herein), and R8 and R9 are independently at each
occurrence selected from the group consisting of -hydrogen,
-hydroxy, --CN, -nitro, -halo, --(C.sub.1-C.sub.7)alkyl (optionally
substituted with 1 to 3 halogens), --(C.sub.1-C.sub.7)alkoxy,
--(C.sub.3-C.sub.7)cycloalkyl, -aryl, -aryl-(C.sub.1-C.sub.7)alkyl,
-heteroaryl, -heteroaryl-(C.sub.1-C.sub.7)alkyl, -aryloxy,
--C(O)R12, --C(O)OR12, --OC(O)R12, --OS(O).sub.2R12,
--N(R12).sub.2, --NR12C(O)R12, --NR12SO.sub.2R12, --SR12,
--S(O)R12, --S(O).sub.2R12, and --S(O).sub.2N(R12).sub.2, [0078]
12. wherein X is carbon and R11 is attached to X and R11 is
##STR00010##
[0078] wherein the zig-zag mark shows the point of attachment to
the parent molecule, and wherein A, G, and E are carbon
(substituted with hydrogen or the optional substituents as
indicated herein), and R8 and R9 are independently at each
occurrence selected from the group consisting of -hydrogen,
-hydroxy, --CN, -nitro, -halo, --(C.sub.1-C.sub.7)alkyl (optionally
substituted with 1 to 3 halogens), --(C.sub.1-C.sub.7)alkoxy, and
--(C.sub.3-C.sub.7)cycloalkyl, [0079] 13. wherein one of D, X, Q or
T is nitrogen, [0080] 14. wherein D is nitrogen, [0081] 15. wherein
X is nitrogen, [0082] 16. wherein Q is nitrogen, [0083] 17. wherein
T is nitrogen, [0084] 18. wherein two of D, X, Q and T are
nitrogen, [0085] 19. wherein D and T are nitrogen, [0086] 20.
wherein Q and X are nitrogen, [0087] 21. wherein R1 is hydrogen,
[0088] 22. wherein R1 is --OH, [0089] 23. wherein R1 is halogen,
[0090] 24. wherein R2 is hydrogen, [0091] 25. wherein R2 is
--(C.sub.1-C.sub.3)alkyl (optionally substituted with 1 to 3
halogens), [0092] 26. wherein R3 is hydrogen, [0093] 27. wherein R3
is halogen, [0094] 28. wherein R4 is hydrogen, [0095] 29. wherein
R4 is halogen, [0096] 30. wherein R3 is selected from the group
consisting of --(C.sub.1-C.sub.7)alkoxy, --(C.sub.1-C.sub.7)alkyl
(optionally substituted with 1 to 3 halogens), and
--(C.sub.2-C.sub.7)alkenyl, [0097] 31. wherein R4 is selected from
the group consisting of --(C.sub.1-C.sub.7)alkoxy,
--(C.sub.1-C.sub.7)alkyl (optionally substituted with 1 to 3
halogens), and --(C.sub.2-C.sub.7)alkenyl, [0098] 32. R5 is
selected from the group consisting of [0099] --H,
--(C.sub.1-C.sub.12)alkyl (optionally substituted with 1 to 3
halogens), --(C.sub.3-C.sub.12)cycloalkyl, -phenyl,
-phenyl-phenyl-(C.sub.1-C.sub.12)alkyl, -aryl,
-aryl-(C.sub.1-C.sub.12)alkyl, -heteroaryl,
-heteroaryl-(C.sub.1-C.sub.12)alkyl, --(C.sub.2-C.sub.12)alkenyl,
--(C.sub.3-C.sub.12)cycloalkenyl, -heterocycloalkyl,
-aryl-(C.sub.2-C.sub.10)alkenyl,
-heteroaryl-(C.sub.2-C.sub.10)alkenyl, --(C.sub.2-C.sub.12)alkynyl,
--(C.sub.3-C.sub.12)cycloalkynyl, -aryl-(C.sub.2-C.sub.12)alkynyl,
and -heteroaryl-(C.sub.2-C.sub.12)alkynyl, [0100] 33. R5 is
selected from the group consisting of [0101] --H,
--(C.sub.1-C.sub.12)alkyl (optionally substituted with 1 to 3
halogens), --(C.sub.3-C.sub.12)cycloalkyl, -phenyl,
-phenyl-phenyl-(C.sub.1-C.sub.12)alkyl,
--(C.sub.2-C.sub.12)alkenyl, --(C.sub.3-C.sub.12)cycloalkenyl,
-heterocycloalkyl, --(C.sub.2-C.sub.12)alkynyl, and
--(C.sub.3-C.sub.12)cycloalkynyl, [0102] 34. R5 is selected from
the group consisting of --(C.sub.1-C.sub.12)alkyl (optionally
substituted with 1 to 3 halogens), and
--(C.sub.3-C.sub.12)cycloalkyl, [0103] 35. wherein R6 and R7 are
methyl, [0104] 36. wherein R6 and R7 form a six membered ring with
the atoms to which they are attached, and the ring so formed may
optionally contain up to two oxygens, and further the ring so
formed may optionally be substituted with up to four halogens,
[0105] 37. wherein R8 is attached in the para position and is
tertbutyl or trifluoromethyl, [0106] 38. R10 is selected from the
group consisting of --H, halogen, --(C.sub.1-C.sub.12)alkyl
(optionally substituted with 1 to 3 halogens),
--(C.sub.3-C.sub.12)cycloalkyl, --(C.sub.2-C.sub.12)alkenyl,
--(C.sub.3-C.sub.12)cycloalkenyl, --(C.sub.2-C.sub.12)alkynyl,
--(C.sub.3-C.sub.12)cycloalkynyl, -aryl-(C.sub.2C.sub.12)alkynyl,
and -heteroaryl-(C.sub.2-C.sub.12)alkynyl, [0107] 39. R10 is
selected from the group consisting of --H, halogen, or
--(C.sub.1-C.sub.12)alkyl (optionally substituted with 1 to 3
halogens.
[0108] Another embodiment is a compound of Formula I or a
pharmaceutically acceptable salt thereof wherein: [0109] Y is --O--
or --S--; [0110] Q, D, X, and T independently represent carbon or
nitrogen, provided that no more than two of Q, D, X, and T are
nitrogen; [0111] R1 is --H, --OH, or -halogen; [0112] R2 is --H or
--(C.sub.1-C.sub.3)alkyl; [0113] R3 and R4 are independently at
each occurrence selected from the group consisting of [0114] --H,
-halogen, --CN, --OH, --(C.sub.1-C.sub.7)alkoxy,
--(C.sub.1-C.sub.7)alkyl, --(C.sub.2-C.sub.7)alkenyl; [0115] R5 is
selected from the group consisting of [0116] --H,
--(C.sub.1-C.sub.12)alkyl, --(C.sub.3-C.sub.12)cycloalkyl, -phenyl,
-phenyl-phenyl-(C.sub.1-C.sub.12)alkyl, -aryl,
-aryl-(C.sub.1-C.sub.12)alkyl, -heteroaryl,
-heteroaryl-(C.sub.1-C.sub.12)alkyl, --(C.sub.2-C.sub.12)alkenyl,
--(C.sub.3-C.sub.12)cycloalkenyl, -heterocycloalkyl,
-aryl-(C.sub.2-C.sub.10)alkenyl,
-heteroaryl-(C.sub.2-C.sub.10)alkenyl, --(C.sub.2-C.sub.12)alkynyl,
--(C.sub.3-C.sub.12)cycloalkynyl, -aryl-(C.sub.2-C.sub.12)alkynyl,
and -heteroaryl-(C.sub.2-C.sub.12)alkynyl, and wherein
--(C.sub.1-C.sub.12)alkyl, --(C.sub.3-C.sub.12)cycloalkyl, -phenyl,
-phenyl-phenyl-(C.sub.1-C.sub.12)alkyl, -aryl,
-aryl-(C.sub.1-C.sub.12)alkyl, -heteroaryl,
-heteroaryl-(C.sub.1-C.sub.12)alkyl, -heterocycloalkyl,
--(C.sub.2-C.sub.12)alkenyl, --(C.sub.3-C.sub.12)cycloalkenyl,
-aryl-(C.sub.2-C.sub.10)alkenyl,
-heteroaryl-(C.sub.2-C.sub.10)alkenyl, --(C.sub.2-C.sub.12)alkynyl,
--(C.sub.3-C.sub.12)cycloalkynyl, -aryl-(C.sub.2-C.sub.12)alkynyl,
and -heteroaryl-(C.sub.2-C.sub.12)alkynyl, are each optionally
substituted with from one to three substituents each independently
selected from the group consisting of -hydrogen, -hydroxy, -cyano,
-nitro, -halo, -oxo, --(C.sub.1-C.sub.7)alkyl,
--(C.sub.1-C.sub.7)alkyl-COOR12, --(C.sub.1-C.sub.7)alkoxy,
--(C.sub.3-C.sub.7)cycloalkyl, -aryloxy, -aryl,
-aryl-(C.sub.1-C.sub.7)alkyl, -heteroaryl, -heterocycloalkyl,
--C(O)R12, --COOR12, --OC(O)R12, --OS(O).sub.2R12, --N(R12).sub.2,
--NR12C(O)R12, --NR12SO.sub.2R12, --SR12, --S(O)R12,
--S(O).sub.2R12, and --S(O).sub.2N(R12).sub.2; [0117] R6 and R7 are
independently at each occurrence selected from the group consisting
of [0118] --H, -halogen, -hydroxy, --CN, --(C.sub.1-C.sub.7)alkoxy,
--(C.sub.2-C.sub.7)alkenyl, and --(C.sub.1-C.sub.7)alkyl, provided
however that wherein D is nitrogen, then R6 or R7 are not attached
to D, and provided that wherein T is nitrogen, then R6 or R7 are
not attached to T, and provided that wherein Q is nitrogen, then R6
or R7 are not attached to Q, and provided that wherein X is
nitrogen, then R6 or R7 are not attached to X; wherein R6 and R7
may optionally form a six membered ring with the atoms to which
they are attached, and the ring so formed may optionally contain up
to two oxygens, and further the ring so formed may optionally be
substituted with up to four halogens; [0119] R8 and R9 are
independently at each occurrence selected from the group consisting
of [0120] -hydrogen, -hydroxy, --CN, -nitro, -halo,
--(C.sub.1-C.sub.7)alkyl, --(C.sub.1-C.sub.7)alkoxy,
--(C.sub.3-C.sub.7)cycloalkyl, -aryl, -aryl-(C.sub.1-C.sub.7)alkyl,
-heteroaryl, -heteroaryl-(C.sub.1-C.sub.7)alkyl, -aryloxy,
--C(O)R12, --COOR12, --OC(O)R12, --OS(O).sub.2R12, --N(R12).sub.2,
--NR12C(O)R12, --NR12SO.sub.2R12, --SR12, --S(O)R12,
--S(O).sub.2R12, and --S(O).sub.2N(R12).sub.2; and wherein
--(C.sub.1-C.sub.7)alkyl, --(C.sub.1-C.sub.7)alkoxy,
--(C.sub.3-C.sub.7)cycloalkyl, -aryl, -aryl-(C.sub.1-C.sub.7)alkyl,
-heteroaryl, -heteroaryl-(C.sub.1-C.sub.7)alkyl, -aryloxy, are each
optionally substituted with from one to three substituents
independently selected from the group consisting of -hydrogen,
-hydroxy, -cyano, -nitro, -halo, -oxo, --(C.sub.1-C.sub.7)alkyl,
--(C.sub.1-C.sub.7)alkyl-COOR12, --(C.sub.1-C.sub.7)alkoxyl,
--(C.sub.3-C.sub.7)cycloalkyl, -aryloxy, -aryl,
-aryl-(C.sub.1-C.sub.7)alkyl, -heteroaryl, -heterocycloalkyl,
--C(O)R12, --COOR12, --OC(O)R12, --OS(O).sub.2R12, --N(R12).sub.2,
--NR12C(O)R12, --NR12SO.sub.2R12, --SR12, --S(O)R12,
--S(O).sub.2R12, and --S(O).sub.2N(R12).sub.2; [0121] R10 is
selected from the group consisting of [0122] --H,
--(C.sub.1-C.sub.12)alkyl, -cycloalkyl, -aryl,
-aryl-(C.sub.1-C.sub.7)alkyl, -heteroaryl,
-heteroaryl-(C.sub.1-C.sub.7)alkyl, --(C.sub.2-C.sub.12)alkenyl,
--(C.sub.3-C.sub.12)cycloalkenyl, -aryl-(C.sub.2-C.sub.10)alkenyl,
-heteroaryl-(C.sub.2-C.sub.10)alkenyl, --(C.sub.2-C.sub.12)alkynyl,
--(C.sub.3-C.sub.12)cycloalkynyl, -aryl-(C.sub.2-C.sub.12)alkynyl,
and -heteroaryl-(C.sub.2-C.sub.12)alkynyl, and wherein
--(C.sub.1-C.sub.12)alkyl, -cycloalkyl, -aryl,
-aryl-(C.sub.1-C.sub.7)alkyl, -heteroaryl,
-heteroaryl-(C.sub.1-C.sub.7)alkyl, --(C.sub.2-C.sub.12)alkenyl,
--(C.sub.3-C.sub.12)cycloalkenyl, -aryl-(C.sub.2-C.sub.10)alkenyl,
-heteroaryl-(C.sub.2-C.sub.10)alkenyl, --(C.sub.2-C.sub.12)alkynyl,
--(C.sub.3-C.sub.12)cycloalkynyl, -aryl-(C.sub.2-C.sub.12)alkynyl,
and -heteroaryl-(C.sub.2-C.sub.12)alkynyl, are each optionally
substituted with from one to three substituents each independently
selected from the group consisting of -hydrogen, -hydroxy, -cyano,
-nitro, -halo, -oxo, --(C.sub.1-C.sub.7)alkyl,
--(C.sub.1-C.sub.7)alkyl-COOR12, --(C.sub.1-C.sub.7)alkoxyl,
--(C.sub.3-C.sub.7)cycloalkyl, -aryloxy, -aryl,
-aryl-C.sub.1-C.sub.7 alkyl, -heteroaryl, -heterocycloalkyl,
--C(O)R12, --COOR12, --OC(O)R12, --OS(O).sub.2R12, --N(R12).sub.2,
--NR12C(O)R12, --NR12SO.sub.2R12, --SR12, --S(O)R12,
--S(O).sub.2R12, and --S(O).sub.2N(R12).sub.2; [0123] R11 is
independently at each occurrence selected from the group consisting
of [0124] --H,
##STR00011##
[0124] wherein the zig-zag mark shows the point of attachment to
the parent molecule, wherein A, G, and E independently represent
carbon or nitrogen, provided that no more than two of A, G, and E
are nitrogen; provided however that wherein A is nitrogen, then R8
or R9 are not attached to A, and provided that wherein G is
nitrogen, then R8 or R9 are not attached to G, and provided that
wherein E is nitrogen, then R8 or R9 are not attached to E;
##STR00012##
wherein the zig-zag mark shows the point of attachment to the
parent molecule, wherein m is an integer of 0, 1, 2, or 3, and when
m is 0 m is a bond, [0125] provided however that wherein D is
nitrogen, then R11 is not attached to D, and provided that wherein
T is nitrogen, then R11 is not attached to T, and provided that
wherein Q is nitrogen, then R11 is not attached to Q, and provided
that wherein X is nitrogen, then R11 is not attached to X; [0126]
R12 is independently at each occurrence selected from the group
consisting of [0127] -hydrogen, --(C.sub.1-C.sub.7)alkyl, and
-aryl, [0128] R13 is independently at each occurrence selected from
the group consisting of -hydrogen, -halogen,
--(C.sub.1-C.sub.7)alkyl, and --(C.sub.2-C.sub.7)alkenyl.
[0129] Another preferred embodiment is a compound of Formula I, or
a pharmaceutically acceptable salt thereof, wherein: [0130] Y is
--O-- or --S--; [0131] Q, D, X, and T independently represent
carbon (substituted with hydrogen or the optional substituents as
indicated herein) or nitrogen, provided that no more than two of Q,
D, X, and T are nitrogen; [0132] R1 is --H, --OH, or -halogen;
[0133] R2 is --H or --(C.sub.1-C.sub.3)alkyl (optionally
substituted with 1 to 3 halogens); [0134] R3 and R4 are
independently [0135] --H, -halogen, --CN,
--(C.sub.1-C.sub.7)alkoxy, --(C.sub.1-C.sub.7)alkyl (optionally
substituted with 1 to 3 halogens), or --(C.sub.2-C.sub.7)alkenyl;
[0136] R5 is selected from the group consisting of [0137]
--(C.sub.1-C.sub.12)alkyl (optionally substituted with 1 to 3
halogens), --(C.sub.3-C.sub.12)cycloalkyl, -phenyl,
-phenyl-phenyl-(C.sub.1-C.sub.12)alkyl,
--(C.sub.2-C.sub.12)alkenyl, --(C.sub.3-C.sub.12)cycloalkenyl,
-heterocycloalkyl, --(C.sub.2-C.sub.12)alkynyl, and
--(C.sub.3-C.sub.12)cycloalkynyl, and wherein
--(C.sub.1-C.sub.12)alkyl, --(C.sub.3-C.sub.12)cycloalkyl, -phenyl,
-phenyl-phenyl-(C.sub.1-C.sub.12)alkyl, -heterocycloalkyl,
--(C.sub.2-C.sub.12)alkenyl, --(C.sub.3-C.sub.12)cycloalkenyl,
--(C.sub.2-C.sub.12)alkynyl, and --(C.sub.3-C.sub.12)cycloalkynyl,
are each optionally substituted with from one to three substituents
each independently selected from the group consisting of -hydrogen,
-hydroxy, -cyano, -nitro, -halo, -oxo, --(C.sub.1-C.sub.7)alkyl
(optionally substituted with 1 to 3 halogens); [0138] R6 and R7 are
independently at each occurrence selected from the group consisting
of [0139] --H, -halogen, -hydroxy, --CN, --(C.sub.1-C.sub.7)alkoxy,
--(C.sub.2-C.sub.7)alkenyl, --(C.sub.1-C.sub.10)alkyl (optionally
substituted with 1 to 3 halogens), --(C.sub.3-C.sub.12)cycloalkyl,
tert-butoxyiminomethyl, 1,3-dioxan-2-yl, hydroxymethyl, formyl,
hydroxyiminomethyl, morphylino-4-yl-methyl, 4-methylpentyloxy, and
pentyloxy; [0140] provided however that wherein D is nitrogen, then
R6 or R7 are not attached to D, and provided that wherein T is
nitrogen, then R6 or R7 are not attached to T, and provided that
wherein Q is nitrogen, then R6 or R7 are not attached to Q, and
provided that wherein X is nitrogen, then R6 or R7 are not attached
to X; [0141] wherein R6 and R7 may optionally form a six membered
ring with the atoms to which they are attached, and the ring so
formed may optionally contain up to two oxygens, and further the
ring so formed may optionally be substituted with up to four
halogens; [0142] R8 and R9 are independently at each occurrence
selected from the group consisting of [0143] -hydrogen, -hydroxy,
--CN, -nitro, -halo, --(C.sub.1-C.sub.7)alkyl (optionally
substituted with 1 to 3 halogens), --(C.sub.1-C.sub.7)alkoxy,
--(C.sub.3-C.sub.7)cycloalkyl, --C(O)R12, --C(O)OR12, --OC(O)R12,
--OS(O).sub.2R12, --N(R12).sub.2, --NR12C(O)R12, --NR12SO.sub.2R12,
--SR12, --S(O)R12, --S(O).sub.2R12, --O(C.sub.2-C.sub.7)alkenyl,
and --S(O).sub.2N(R12).sub.2; and wherein --(C.sub.1-C.sub.7)alkyl,
--(C.sub.1-C.sub.7)alkoxy, --(C.sub.3-C.sub.7)cycloalkyl, and
--O(C.sub.2-C.sub.7)alkenyl are each optionally substituted with
from one to three substituents independently selected from the
group consisting of -hydrogen, -hydroxy, -cyano, -nitro, -halo,
-oxo, and --(C.sub.1-C.sub.7)alkyl; [0144] R10 is selected from the
group consisting of [0145] --H, halogen, and
--(C.sub.1-C.sub.12)alkyl (optionally substituted with 1 to 3
halogens); [0146] R11 is independently at each occurrence selected
from the group consisting of [0147] --H, -halogen,
##STR00013##
[0147] wherein the zig-zag mark shows the point of attachment to
the parent molecule, wherein A, G, and E independently represent
carbon (substituted with hydrogen or the optional substituents as
indicated herein) or nitrogen, provided that no more than two of A,
G, and E are nitrogen; [0148] provided however that wherein A is
nitrogen, then R8, R9, and R14 are not attached to A, and provided
that wherein G is nitrogen, then R8, R9, and R14 are not attached
to G, and provided that wherein E is nitrogen, then R8, R9, and R14
are not attached to E,
##STR00014##
[0148] wherein the zig-zag mark shows the point of attachment to
the parent molecule, wherein m is an integer of 0, 1, 2, or 3, and
when m is 0 then (CH.sub.2)m is a bond, and
##STR00015##
wherein the zig-zag mark shows the point of attachment to the
parent molecule, [0149] provided however that wherein D is
nitrogen, then R11 is not attached to D, and provided that wherein
T is nitrogen, then R11 is not attached to T, and provided that
wherein Q is nitrogen, then R11 is not attached to Q, and provided
that wherein X is nitrogen, then R11 is not attached to X; [0150]
R12 is independently at each occurrence selected from the group
consisting of [0151] -hydrogen, and --(C.sub.1-C.sub.7)alkyl
(optionally substituted with 1 to 3 halogens); [0152] R13 is
independently at each occurrence selected from the group consisting
of [0153] -hydrogen, -halogen, --(C.sub.1-C.sub.7)alkyl (optionally
substituted with 1 to 3 halogens), phenyl, and
--(C.sub.2-C.sub.7)alkenyl; and [0154] R14 is independently at each
occurrence [0155] --H, halogen, or --(C.sub.1-C.sub.7)alkyl
(optionally substituted with 1 to 3 halogens).
[0156] Another preferred embodiment is a compound of Formula I, or
a pharmaceutically acceptable salt thereof, wherein: [0157] Y is
--O-- or --S--; [0158] Q, D, X, and T independently represent
carbon (substituted with hydrogen or the optional substituents as
indicated herein); [0159] R1 is --H, --OH, or -halogen; [0160] R2
is --H; [0161] R3 and R4 are independently --H, -halogen, or
--(C.sub.1-C.sub.7)alkyl (optionally substituted with 1 to 3
halogens); [0162] R5 is selected from the group consisting of
[0163] --(C.sub.1-C.sub.12)alkyl (optionally substituted with 1 to
3 halogens), and --(C.sub.3-C.sub.12)cycloalkyl (optionally
substituted with 1 to 3 halogens); [0164] R6 and R7 are
independently at each occurrence selected from the group consisting
of [0165] --H, -halogen, -hydroxy, --CN, --(C.sub.1-C.sub.7)alkoxy,
--(C.sub.2-C.sub.7)alkenyl, --(C.sub.1-C.sub.10)alkyl (optionally
substituted with 1 to 3 halogens), --(C.sub.3-C.sub.12)cycloalkyl,
tert-butoxyiminomethyl, 1,3-dioxan-2-yl, hydroxymethyl, formyl,
hydroxyiminomethyl, morphylino-4-yl-methyl, 4-methylpentyloxy, and
pentyloxy; [0166] provided however that wherein D is nitrogen, then
R6 or R7 are not attached to D, and provided that wherein T is
nitrogen, then R6 or R7 are not attached to T, and provided that
wherein Q is nitrogen, then R6 or R7 are not attached to Q, and
provided that wherein X is nitrogen, then R6 or R7 are not attached
to X; [0167] R8 and R9 are independently at each occurrence
selected from the group consisting of [0168] -hydrogen, -halogen,
--(C.sub.1-C.sub.7)alkyl (optionally substituted with 1 to 3
halogens), --(C.sub.1-C.sub.7)alkoxy,
--(C.sub.3-C.sub.7)cycloalkyl, --C(O)R12, --COOR12, --OC(O)R12,
--OS(O).sub.2R12, --SR12, --S(O)R12, --S(O).sub.2R12, and
--O(C.sub.2-C.sub.7)alkenyl; [0169] R10 is --H; [0170] R11 is
independently at each occurrence selected from the group consisting
of [0171] --H, -halogen, and
##STR00016##
[0171] wherein the zig-zag mark shows the point of attachment to
the parent molecule, wherein A, G, and E independently represent
carbon (substituted with hydrogen or the optional substituents as
indicated herein), [0172] provided however that wherein A is
nitrogen, then R8, R9, and R14 are not attached to A, and provided
that wherein G is nitrogen, then R8, R9, and R14 are not attached
to G, and provided that wherein E is nitrogen, then R8, R9, and R14
are not attached to E; [0173] R12 is independently at each
occurrence selected from the group consisting of [0174] -hydrogen,
and --(C.sub.1-C.sub.7)alkyl (optionally substituted with 1 to 3
halogens); [0175] R13 is independently at each occurrence selected
from the group consisting of [0176] -hydrogen, -halogen,
--(C.sub.1-C.sub.7)alkyl (optionally substituted with 1 to 3
halogens), and --(C.sub.2-C.sub.7)alkenyl; and [0177] R14 is
independently at each occurrence [0178] --H, halogen, or
--(C.sub.1-C.sub.7)alkyl (optionally substituted with 1 to 3
halogens).
[0179] As used herein, the term "stereoisomer" refers to a compound
made up of the same atoms bonded by the same bonds but having
different three-dimensional structures called configurations. As
used herein, the term "enantiomer" refers to two stereoisomers
whose molecules are nonsuperimposable mirror images of one another.
The term "chiral center" refers to a carbon atom to which four
different groups are attached. As used herein, the term
"diastereomers" refers to stereoisomers which are not enantiomers.
In addition, two diastereomers which have a different configuration
at only one chiral center are referred to herein as "epimers." The
terms "racemate," "racemic mixture" or "racemic modification" refer
to a mixture of equal parts of enantiomers.
[0180] The compounds of the present invention may be chiral, and it
is intended that any enantiomers, whether pure, partially purified,
or racemic mixtures, are included within the scope of the
invention. Furthermore, when a double bond or a fully or partially
saturated ring system or more than one center of asymmetry or a
bond with restricted rotatability is present in the molecule
diastereomers may be formed. It is intended that any diastereomers,
as separated, pure or partially purified diastereomers or mixtures
thereof are included within the scope of the invention.
Furthermore, some of the compounds of the present invention may
exist in different tautomeric forms and it is intended that any
tautomeric forms, which the compounds are able to form, are
included within the scope of the present invention. Thus, as one
skilled in the art knows, certain aryls may exist in tautomeric
forms. The invention also includes tautomers, enantiomers and other
stereoisomers of the compounds of Formula I. Such variations are
contemplated to be within the scope of the invention.
[0181] The terms "R" and "S" are used herein as commonly used in
organic chemistry to denote specific configuration of a chiral
center. The term "R" (rectus) refers to that configuration of a
chiral center with a clockwise relationship of group priorities
(highest to second lowest) when viewed along the bond toward the
lowest priority group. The term "S" (sinister) refers to that
configuration of a chiral center with a counterclockwise
relationship of group priorities (highest to second lowest) when
viewed along the bond toward the lowest priority group. The
priority of groups is based upon their atomic number (in order of
decreasing atomic number). A partial list of priorities and a
discussion of stereochemistry is contained in "Nomenclature of
Organic Compounds: Principles and Practice", (J. H. Fletcher, et
al., eds., 1974) at pages 103-120.
[0182] The designation "" refers to a bond that protrudes forward
out of the plane of the page. The designation "" refers to a bond
that protrudes backward out of the plane of the page. The
designation "" refers to a bond wherein the stereochemistry is not
defined.
[0183] The compounds of Formula I, when existing as a
diastereomeric mixture, may be separated into diastereomeric pairs
of enantiomers by, for example, fractional crystallization from a
suitable solvent, for example methanol or ethyl acetate or a
mixture thereof. The pair of enantiomers thus obtained may be
separated into individual stereoisomers by conventional means, for
example by the use of an optically active acid as a resolving
agent. Alternatively, any enantiomer of a compound of Formula I may
be obtained by stereospecific synthesis using optically pure
starting materials or reagents of known configuration or through
enantioselective synthesis.
[0184] The term "enantiomeric enrichment" as used herein refers to
the increase in the amount of one enantiomer as compared to the
other. A convenient method of expressing the enantiomeric
enrichment achieved is the concept of enantiomeric excess, or "ee,"
which is found using the following equation:
ee = E 1 - E 2 E 1 + E 2 .times. 100 ##EQU00001##
[0185] wherein E.sup.1 is the amount of the first enantiomer and
E.sup.2 is the amount of the second enantiomer. Thus, if the
initial ratio of the two enantiomers is 50:50, such as is present
in a racemic mixture, and an enantiomeric enrichment sufficient to
produce a final ratio of 70:30 is achieved, the ee with respect to
the first enantiomer is 40%. However, if the final ratio is 90:10,
the ee with respect to the first enantiomer is 80%. An ee of
greater than 90% is preferred, an ee of greater than 95% is most
preferred and an ee of greater than 99% is most especially
preferred. Enantiomeric enrichment is readily determined by one of
ordinary skill in the art using standard techniques and procedures,
such as gas or high performance liquid chromatography with a chiral
column. Choice of the appropriate chiral column, eluent and
conditions necessary to effect separation of the enantiomeric pair
is well within the knowledge of one of ordinary skill in the art.
In addition, the specific stereoisomers and enantiomers of
compounds of Formula I, can be prepared by one of ordinary skill in
the art utilizing well known techniques and processes, such as
those disclosed by J. Jacques, et al., "Enantiomers, Racemates, and
Resolutions," John Wiley and Sons, Inc., 1981, and E. L. Eliel and
S. H. Wilen, "Stereochemistry of Organic Compounds,"
(Wiley-Interscience 1994), and European Patent Application No.
EP-A-838448, published Apr. 29, 1998. Examples of resolutions
include recrystallization techniques or chiral chromatography.
Unless otherwise indicated, a compound indicated to be "isomer 1"
will be the first isomer eluted from the chiral separation column
and "isomer 2" will be the second.
[0186] In general, the term "pharmaceutical" when used as an
adjective means substantially non-toxic to living organisms. For
example, the term "pharmaceutical salt" as used herein, refers to
salts of the compounds of Formula I, which are substantially
non-toxic to living organisms. See, e.g., Berge, S. M, Bighley, L.
D., and Monkhouse, D. C., "Pharmaceutical Salts," J. Pharm. Sci.,
66:1, 1977. The present invention also encompasses pharmaceutically
acceptable salts of the present compounds. Such salts include
pharmaceutically acceptable acid addition salts, pharmaceutically
acceptable metal salts, ammonium and alkylated ammonium salts. Also
intended as pharmaceutically acceptable acid addition salts are any
hydrates that the present compounds are able to form. Furthermore,
the pharmaceutically acceptable salts comprise basic amino acid
salts such as lysine, arginine and ornithine. Typical
pharmaceutical salts include those salts prepared by reaction of
the compounds of Formula I, with an inorganic or organic acid or
base. Such salts are known as acid addition or base addition salts
respectively. These pharmaceutical salts frequently have enhanced
solubility characteristics compared to the compound from which they
are derived, and thus are often more amenable to formulation as
liquids or emulsions.
[0187] The term "acid addition salt" refers to a salt of a compound
of Formula I, prepared by reaction of a compound of Formula I, with
a mineral or organic acid. For exemplification of pharmaceutical
acid addition salts see, e.g., Berge, S. M, Bighley, L. D., and
Monkhouse, D. C., J. Pharm. Sci., 66:1, 1977. Since compounds of
this invention can be basic in nature, they accordingly react with
any of a number of inorganic and organic acids to form
pharmaceutical acid addition salts.
[0188] The acid addition salts may be obtained as the direct
products of compound synthesis. In the alternative, the free base
may be dissolved in a suitable solvent containing the appropriate
acid, and the salt isolated by evaporating the solvent or otherwise
separating the salt and solvent.
[0189] Acids commonly employed to form acid addition salts are
inorganic acids such as hydrochloric acid, hydrobromic acid,
hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and
organic acids, such as p-toluenesulfonic acid, ethanesulfonic acid,
methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid,
carbonic acid, succinic acid, citric acid, tartaric acid, benzoic
acid, acetic acid and the like. Preferred pharmaceutical acid
addition salts are those formed with mineral acids such as
hydrochloric acid, hydrobromic acid, and sulfuric acid, and those
formed with organic acids such as maleic acid, tartaric acid, and
methanesulfonic acid. Examples of such pharmaceutically acceptable
salts thus are the sulfate, pyrosulfate, bisulfate, sulfite,
bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate,
metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate,
propionate, decanoate, caprylate, acrylate, formate, isobutyrate,
caproate, heptanoate, propiolate, oxalate, malonate, succinate,
suberate, sebacate, fumarate, maleate, butyne-1,4-dioate,
hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,
dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate,
sulfonate, xylenesulfonate, phenylacetate, phenylpropionate,
phenylbutyrate, citrate, lactate, .beta.-hydroxybutyrate,
glycolate, tartrate, methanesulfonate, propanesulfonate,
naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the
like.
[0190] The skilled artisan would appreciate that some compounds of
Formula I, may be acidic in nature and accordingly react with any
of a number of inorganic and organic bases to form pharmaceutical
base addition salts. The term "base addition salt" refers to a salt
of a compound of Formula I, prepared by reaction of a compound of
Formula I, with a mineral or organic base. For exemplification of
pharmaceutical base addition salts see, e.g., Berge, S. M, Bighley,
L. D., and Monkhouse, D. C., J. Pharm. Sci., 66:1, 1977. Bases
commonly employed to form pharmaceutical base addition salts are
inorganic bases, such as ammonium or alkali or alkaline earth metal
hydroxides, carbonates, bicarbonates, and the like. Such bases
useful in preparing the salts of this invention thus include sodium
hydroxide, potassium hydroxide, ammonium hydroxide, potassium
carbonate, sodium carbonate, sodium bicarbonate, potassium
bicarbonate, calcium hydroxide, calcium carbonate, and the like.
Examples of pharmaceutical base addition salts are the ammonium,
lithium, potassium, sodium, calcium, magnesium, methylamino,
diethylamino, ethylene diamino, cyclohexylamino, and ethanolamino
salts, and the like of a compound of Formula I. The potassium and
sodium salt forms are particularly preferred. The present invention
also contemplates pharmaceutical base addition salts of compounds
of Formula I.
[0191] The pharmaceutical salts of the invention are typically
formed by reacting a compound of Formula I, with an equimolar or
excess amount of acid or base. The reactants are generally combined
in a mutual solvent such as diethylether, tetrahydrofuran,
methanol, ethanol, isopropanol, benzene, and the like for acid
addition salts, or water, an alcohol or a chlorinated solvent such
as dichloromethane for base addition salts. The salts normally
precipitate out of solution within about one hour to about ten days
and can be isolated by filtration or other conventional methods.
All pharmaceutically acceptable salts are contemplated in the
present invention. The compound or salt of the present invention
may form a solvate with low molecular weight solvents. Such
solvates are also contemplated as being within the scope of the
present invention.
[0192] The invention also encompasses prodrugs of the present
compounds, which on administration undergo chemical conversion by
metabolic processes before becoming pharmacologically active
substances. In general, such prodrugs will be functional
derivatives of present compounds, which are readily convertible in
vivo into a compound of the present invention. Conventional
procedures for the selection and preparation of suitable prodrug
derivatives are described, for example in "Design of Prodrugs", ed.
H. Bundgaard, Elsevier, 1985.
[0193] In a further aspect of the invention the present compounds
are administered in combination with one or more further active
substances in any suitable ratios. Such further active substances
may for example be selected from antidiabetics, antiobesity agents,
antihypertensive agents, agents for the treatment of complications
resulting from or associated with diabetes and agents for the
treatment of complications and disorders resulting from or
associated with obesity. The following listing sets out several
groups of combinations. It will be understood that each of the
agents named may be combined with other agents named to create
additional combinations.
[0194] Thus, in a further embodiment of the invention the present
compounds may be administered in combination with one or more
antidiabetics.
[0195] Suitable antidiabetic agents include insulin, insulin
analogues and derivatives such as those disclosed in EP 792 290
(Novo Nordisk A/S), for example N.sup..epsilon.B29-tetradecanoyl
des (B30) human insulin, EP 214 826 and EP 705 275 (Novo Nordisk
A/S), for example Asp.sup.B28 human insulin, U.S. Pat. No.
5,504,188 (Eli Lilly), for example Lys.sup.B28 Pro.sup.B29 human
insulin, EP 368 187 (Aventis), for example Lantus.RTM., which are
all incorporated herein by reference, GLP-1 and GLP-1 derivatives
such as those disclosed in WO 98/08871 (Novo Nordisk A/S), which is
incorporated herein by reference, as well as orally active
hypoglycemic agents.
[0196] The orally active hypoglycemic agents preferably comprise
imidazolines, sulphonylureas, biguanides, meglitinides,
oxadiazolidinediones, thiazolidinediones, insulin sensitizers,
insulin secretagogues, such as glimepiride, .alpha.-glucosidase
inhibitors, agents acting on the ATP-dependent potassium channel of
the .beta.-cells for example potassium channel openers such as
those disclosed in WO 97/26265, WO 99/03861 and WO 00/37474 (Novo
Nordisk A/S) which are incorporated herein by reference, or
mitiglinide, or a potassium channel blocker, such as BTS-67582,
nateglinide, glucagon antagonists such as those disclosed in WO
99/01423 and WO 00/39088 (Novo Nordisk A/S and Agouron
Pharmaceuticals, Inc.), which are incorporated herein by reference,
GLP-1 antagonists, DPP-IV (dipeptidyl peptidase-IV) inhibitors,
PTPase (protein tyrosine phosphatase) inhibitors, inhibitors of
hepatic enzymes involved in stimulation of gluconeogenesis and/or
glycogenolysis, glucose uptake modulators, activators of
glucokinase (GK) such as those disclosed in WO 00/58293, WO
01/44216, WO 01/83465, WO 01/83478, WO 01/85706, WO 01/85707, and
WO 02/08209 (Hoffman-La Roche) or those disclosed in WO 03/00262,
WO 03/00267 and WO 03/15774 (AstraZeneca), which are incorporated
herein by reference, GSK-3 (glycogen synthase kinase-3) inhibitors,
compounds modifying the lipid metabolism such as antilipidemic
agents such as HMG CoA inhibitors (statins), compounds lowering
food intake, PPAR (Peroxisome proliferator-activated receptor)
ligands including the PPAR-alpha, PPAR-gamma and PPAR-delta
subtypes, and RXR (retinoid X receptor) agonists, such as ALRT-268,
LG-1268 or LG-1069
[0197] In another embodiment, the present compounds are
administered in combination with insulin or an insulin analogue or
derivative, such as N.sup..epsilon.B29-tetradecanoyl des (B30)
human insulin, Asp.sup.B28 human insulin, Lys.sup.B28 Pro.sup.B29
human insulin, Lantus.RTM., or a mix-preparation comprising one or
more of these.
[0198] In a further embodiment of the invention the present
compounds are administered in combination with a sulphonylurea such
as glibenclamide, glipizide, tolbautamide, chloropamidem,
tolazamide, glimepride, glicazide and glyburide.
[0199] In another embodiment of the invention the present compounds
are administered in combination with a biguanide for example
metormin.
[0200] In yet another embodiment of the invention the present
compounds are administered in combination with a meglitinide for
example repaglinide or nateglinide.
[0201] In still another embodiment of the invention the present
compounds are administered in combination with a thiazolidinedione
insulin sensitizer for example troglitazone, ciglitazone,
piolitazone, rosiglitazone, isaglitazone, darglitazone,
englitazone, CS-011/CI-1037 or T 174 or the compounds disclosed in
WO 97/41097, WO 97/41119, WO 97/41120, WO 00/41121 and WO 98/45292
(Dr. Reddy's Research Foundation), which are incorporated herein by
reference.
[0202] In still another embodiment of the invention the present
compounds may be administered in combination with an insulin
sensitizer for example such as GI 262570, YM-440, MCC-555, JTT-501,
AR-H039242, KRP-297, GW-409544, CRE-16336, AR-H049020, LY510929,
MBX-102, CLX-0940, GW-501516 or the compounds disclosed in WO
99/19313, WO 00/50414, WO 00/63191, WO 00/63192, WO 00/63193 such
as ragaglitazar (NN 622 or (-)DRF 2725) (Dr. Reddy's Research
Foundation) and WO 00/23425, WO 00/23415, WO 00/23451, WO 00/23445,
WO 00/23417, WO 00/23416, WO 00/63153, WO 63196, WO 00/63209, WO
00/63190 and WO 00/63189 (Novo Nordisk A/S), which are incorporated
herein by reference.
[0203] In a further embodiment of the invention the present
compounds are administered in combination with an
.alpha.-glucosidase inhibitor for example voglibose, emiglitate,
miglitol or acarbose.
[0204] In another embodiment of the invention the present compounds
are administered in combination with an agent acting on the
ATP-dependent potassium channel of the .beta.-cells for example
tolbutamide, glibenclamide, glipizide, glicazide, BTS-67582 or
repaglinide.
[0205] In yet another embodiment of the invention the present
compounds may be administered in combination with nateglinide.
[0206] In still another embodiment of the invention the present
compounds are administered in combination with an antilipidemic
agent or antihyperlipidemic agent for example cholestyramine,
colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin,
simvastatin, pitavastatin, rosuvastatin, probucol, dextrothyroxine,
fenofibrate or atorvastin.
[0207] In still another embodiment of the invention the present
compounds are administered in combination with compounds lowering
food intake.
[0208] In another embodiment of the invention, the present
compounds are administered in combination with more than one of the
above-mentioned compounds for example in combination with metformin
and a sulphonylurea such as glyburide; a sulphonylurea and
acarbose; nateglinide and metformin; repaglinide and metformin,
acarbose and metformin; a sulfonylurea, metformin and troglitazone;
insulin and a sulfonylurea; insulin and metformin; insulin,
metformin and a sulfonylurea; insulin and troglitazone; insulin and
lovastatin; etc.
[0209] In a further embodiment of the invention the present
compounds may be administered in combination with one or more
antiobesity agents or appetite regulating agents.
[0210] Such agents may be selected from the group consisting of
CART (cocaine amphetamine regulated transcript) agonists, NPY
(neuropeptide Y) antagonists, MC4 (melanocortin 4) agonists, MC3
(melanocortin 3) agonists, orexin antagonists, TNF (tumor necrosis
factor) agonists, CRF (corticotropin releasing factor) agonists,
CRF BP (corticotropin releasing factor binding protein)
antagonists, urocortin agonists, .beta.3 adrenergic agonists such
as CL-316243, AJ-9677, GW-0604, LY362884, LY377267 or AZ-40140 MSH
(melanocyte-stimulating hormone) agonists, MCH
(melanocyte-concentrating hormone) antagonists, CCK
(cholecystokinin) agonists, serotonin re-uptake inhibitors such as
fluoxetine, seroxat or citalopram, serotonin and noradrenaline
re-uptake inhibitors, mixed serotonin and noradrenergic compounds,
5HT (serotonin) agonists, bombesin agonists, galanin antagonists,
growth hormone, growth factors such as prolactin or placental
lactogen, growth hormone releasing compounds, TRH (thyreotropin
releasing hormone) agonists, UCP 2 or 3 (uncoupling protein 2 or 3)
modulators, leptin agonists, DA agonists (bromocriptin, doprexin),
lipase/amylase inhibitors, PPAR (peroxisome proliferator-activated
receptor) modulators, RXR (retinoid X receptor) modulators, TR
.beta. agonists, AGRP (Agouti related protein) inhibitors, H3
histamine antagonists, opioid antagonists (such as naltrexone),
exendin-4, GLP-1 and ciliary neurotrophic factor (such as axokine),
cannaboid receptor antagonist for example CB-1 (such as
rimonabant). In another embodiment the antiobesity agent is
dexamphetamine or amphetamine. In another embodiment the
antiobesity agent is leptin. In another embodiment the antiobesity
agent is fenfluramine or exfenfluramine. In still another
embodiment the antiobesity agent is sibutramine. In a further
embodiment the antiobesity agent is orlistat. In another embodiment
the antiobesity agent is mazindol or phentermine. In still another
embodiment the antiobesity agent is phendimetrazine,
diethylpropion, fluoxetine, bupropion, topiramate or ecopipam.
[0211] Furthermore, the present compounds may be administered in
combination with one or more antihypertensive agents. Examples of
antihypertensive agents are .beta.-blockers such as alprenolol,
atenolol, timolol, pindolol, propranolol and metoprolol, SCE
(angiotensin converting enzyme) inhibitors such as benazepril,
captopril, enalapril, fosinopril, lisinopril, quinapril and
ramipril, calcium channel blockers such as nifedipine, felodipine,
nicardipine, isradipine, nimodipine, diltiazem and verapamil, and
.alpha.-blockers such as doxazosin, urapidil, prazosin and
terazosin. Further reference can be made to Remington: The Science
and Practice of Pharmacy, 19.sup.th Edition, Gennaro, Ed., Mack
Publishing Co., Easton, Pa., 1995.
[0212] The compounds of the present invention may be administered
in combination with FAS inhibitors.
[0213] The compounds of the present invention may also be
administered in combination with chemical uncouplers, hormone
sensitive lipase inhibitor, imidazolines, 11-.beta.-hydroxysteroid
dehydrogenase inhibitors, lipoprotein lipase activator, AMPK
activators, immunosuppresive drugs, nicotinamide, ASIS,
anti-androgens or carboxypeptidase inhibitors.
[0214] It should be understood that any suitable combination of the
compounds according to the invention with diet and/or exercise, one
or more of the above-mentioned compounds and optionally one or more
other active substances are considered to be within the scope of
the present invention.
[0215] The compounds of Formula I, can be prepared by one of
ordinary skill in the art following a variety of procedures, some
of which are illustrated in the procedures and schemes set forth
below. The particular order of steps required to produce the
compounds of Formula I is dependent upon the particular compound to
being synthesized, the starting compound, and the relative
liability of the substituted moieties. The reagents or starting
materials are readily available to one of skill in the art, and to
the extent not commercially available, are readily synthesized by
one of ordinary skill in the art following standard procedures
commonly employed in the art, along with the various procedures and
schemes set forth below.
[0216] The following Schemes, Preparations, Examples and Procedures
are provided to better elucidate the practice of the present
invention and should not be interpreted in any way as to limit the
scope of the same. Those skilled in the art will recognize that
various modifications may be made while not departing from the
spirit and scope of the invention. All publications mentioned in
the specification are indicative of the level of those skilled in
the art to which this invention pertains.
[0217] The optimal time for performing the reactions of the
Schemes, Preparations, Examples and Procedures can be determined by
monitoring the progress of the reaction via conventional
chromatographic techniques. Furthermore, it is preferred to conduct
the reactions of the invention under an inert atmosphere, such as,
for example, argon, or, particularly, nitrogen. Choice of solvent
is generally not critical so long as the solvent employed is inert
to the ongoing reaction and sufficiently solubilizes the reactants
to effect the desired reaction. The compounds are preferably
isolated and purified before their use in subsequent reactions.
Some compounds may crystallize out of the reaction solution during
their formation and then collected by filtration, or the reaction
solvent may be removed by extraction, evaporation, or decantation.
The intermediates and final products of Formula I may be further
purified, if desired by common techniques such as recrystallization
or chromatography over solid supports such as silica gel or
alumina.
[0218] The skilled artisan will appreciate that not all
substituents are compatible with all reaction conditions. These
compounds may be protected or modified at a convenient point in the
synthesis by methods well known in the art.
[0219] The terms and abbreviations used in the instant Schemes,
Preparations, Examples and Procedures have their normal meanings
unless otherwise designated. For example, as used herein, the
following terms have the meanings indicated: "eq" refers to
equivalents; "N" refers to normal or normality, "M" refers to molar
or molarity, "g" refers to gram or grams, "mg" refers to
milligrams; "L" refers to liters; "mL" refers to milliliters;
".mu.L" refers to microliters; "mol" refers to moles; "mmol" refers
to millimoles; "psi" refers to pounds per square inch; "min" refers
to minutes; "h" or "hr" refers to hours; ".degree. C." refers to
degrees Celsius; "TLC" refers to thin layer chromatography; "HPLC"
refers to high performance liquid chromatography; "R.sub.f" refers
to retention factor; "R.sub.t" refers to retention time; ".delta."
refers to part per million down-field from tetramethylsilane; "MS"
refers to mass spectrometry, Observed Mass indicates [M+H] unless
indicated otherwise. "MS(FD)" refers to field desorption mass
spectrometry, "MS(IS)" refers to ion spray mass spectrometry,
"MS(FIA)" refers to flow injection analysis mass spectrometry,
"MS(FAB)" refers to fast atom bombardment mass spectrometry,
"MS(EI)" refers to electron impact mass spectrometry, "MS(ES)"
refers to electron spray mass spectrometry, "UV" refers to
ultraviolet spectrometry, ".sup.1H NMR" refers to proton nuclear
magnetic resonance spectrometry. In addition, "IR" refers to infra
red spectrometry, and the absorption maxima listed for the IR
spectra are only those of interest and not all of the maxima
observed. "RT" refers to room temperature. "DEAD" refers to
diethylazodicarboxylate. "PPh.sub.3" refers to triphenylphosphine.
"ADDP" refers to 1,1'-(azodicarbonyl)dipiperidine. "PPBu.sub.3"
refers to tributylphosphine. "OTF" refers to triflate. "LAH" refers
to lithium aluminum hydride. "DIBAL-H" refers to diisobutylaluminum
hydride. "KOtBu" refers to potassium t-butoxide. "THF" refers to
tetrahydrofuran. "TBP" refers to tributylphosphine. "EDCI" refers
to 1-(3-dimethylaminopropyl)-3-ethylcarbodiamide hydrochloride.
"DMAP" refers to dimethylaminopyridine. "HNMe(OMe)" refers to
N,N,dimethylhydroxyamine. "CDMT" refers to
2-chloro-4,6-dimethoxy-[1,3,5]triazine. "NMM" refers to N-methyl
morpholine. "DCM" refers to dichloromethane. "DMSO" refers to
dimethylsulfoxide. "ET.sub.3N" refers to triethylamine. "DMF"
refers to dimethylformamide. "Et" in a formula refers to ethyl, for
example Et.sub.2O refers to diethylether, and EtOAc refers to
ethylacetate. "PyBOP" refers to bromo-tris-pyrrolidino-phosphonium
hexafluorophosphate. "Me" refers to methyl as in MeOH which is
methanol. "Pd/C" refers to 10% palladium on carbon. Unless
otherwise indicated, isomer 1 refers to the first isomer to be
eluted in a chiral separation and isomer 2 refers to the second
isomer to be eluted in a chiral separation.
[0220] Infrared spectra are recorded on a Perkin Elmer 781
spectrometer. .sup.1H NMR spectra are recorded on a Varian 400 MHz
spectrometer at ambient temperature. Data are reported as follows:
chemical shift in ppm from internal standard tetramethylsilane on
the .delta. scale, multiplicity (b=broad, s=singlet, d=doublet,
t=triplet, q=quartet, qn=quintet and m=multiplet), integration,
coupling constant (Hz) and assignment. .sup.13C NMR are recorded on
a Varian 400 MHz spectrometer at ambient temperature. Chemical
shifts are reported in ppm from tetramethylsilane on the .delta.
scale, with the solvent resonance employed as the internal standard
(CDCl.sub.3 at 77.0 ppm and DMSO-d.sub.6 at 39.5 ppm). Combustion
analyses are performed by Eli Lilly & Company Microanalytical
Laboratory. High resolution mass spectra are obtained on VG ZAB 3F
or VG 70 SE spectrometers. Analytical thin layer chromatography is
performed on EM Reagent 0.25 mm silica gel 60-F plates.
Visualization is accomplished with UV light.
General Schemes
[0221] Compounds of the present invention have been formed as
specifically described in the examples. Further, many compounds are
prepared as more generally using a) alkylation of a alcohol, phenol
or thiophenol with a halide, b) a Mitsunobu protocol (O. Mitsunobu,
1981 Synthesis, p1); c) and other methods known to the skilled
artisan. Alternative synthesis methods may also be effective and
known to the skilled artisan. Unless otherwise indicated, all
variables, such as Y', R1' to R15', etc., are as defined for
analogous variables (R1 to R15, etc.) in the summary of the
invention, and otherwise as defined herein.
[0222] For example, an intermediate like A is alkylated with an
alkylating agent B in the presence of a base (e.g. NaH,
K.sub.2CO.sub.3, Cs.sub.2CO.sub.3 etc.). Hydrolysis in the presence
of aqueous NaOH or LiOH gave the acid product.
##STR00017##
[0223] Alternatively, an intermediate like A is coupled with an
alcohol C under Mitsunobu reaction condition (DEAD/PPh.sub.3,
ADDP/PBu.sub.3 etc.). Hydrolysis in the presence of aqueous NaOH or
LiOH gave the acid product:
##STR00018##
[0224] Under certain circumstances, the synthetic sequence can be
altered, where an intermediate like D is coupled with an aryl
boronic acid or ester under Suzuki reaction conditions (Pd
catalyst, base). Hydrolysis in the presence of aqueous NaOH or LiOH
gave the acid product:
##STR00019##
The alcohol intermediates A and C can be made by A) reduction of
the ketone with or without chiral auxiliary or B) alkylation of
aldehyde with an organometallic reagent, e.g. Grignard reagent.
##STR00020##
The biaryl phenol analogs can be made by a palladium catalyzed
cross coupling reaction:
##STR00021##
[0225] The enantiomeric purified products are prepared either
through A) chiral chromatography or B) Mitsunobu coupling between a
phenol or thiophenol and a chiral alcohol that can be prepared
using the methods known to the art.
Preparations and Examples
[0226] The Examples provided herein are illustrative of the
invention claimed herein and are not intended to limit the scope of
the claimed invention in any way. Names of the preparations and
examples are derived using ChemDraw.
[0227] Infrared spectra are recorded on a Perkin Elmer 781
spectrometer. 1H NMR spectra are recorded on a Varian 400 MHz
spectrometer at ambient temperature. Data are reported as follows:
chemical shift in ppm from internal standard tetramethylsilane on
the (scale, multiplicity (b=broad, s=singlet, d=doublet, t=triplet,
q=quartet, qn=quintet and m=multiplet), integration, coupling
constant (Hz) and assignment. 13C NMR are recorded on a Varian 400
MHz spectrometer at ambient temperature. Chemical shifts are
reported in ppm from tetramethylsilane on the (scale, with the
solvent resonance employed as the internal standard (CDCl3 at 77.0
ppm and DMSO-d6 at 39.5 ppm). Combustion analyses are performed by
Eli Lilly & Company Microanalytical Laboratory. High resolution
mass spectra are obtained on VG ZAB 3F or VG 70 SE spectrometers.
Analytical thin layer chromatography is performed on EM Reagent
0.25 mm silica gel 60-F plates. Visualization is accomplished with
UV light.
Preparation 1
Racemic 4-(1-Hydroxy-propyl)-benzoic acid methyl ester
##STR00022##
[0229] To a solution of 4-formyl-benzoic acid methyl ester (3.0 g,
18.3 mmol) in THF (10 mL) at 0.degree. C. is added ethylmagnesium
bromide (2M, 10 mL). After stirring at room temperature for 2
hours, it is quenched with saturated ammonium chloride, extracted
with EtOAc. The organic is concentrated to give the titled compound
as colorless oil: 2.2 g (62%).
[0230] The following compounds are made in a similar manner:
Preparation 2
Racemic 4-(1-Hydroxy-butyl)-benzoic acid methyl ester
##STR00023##
[0232] This compound is made from 4-formyl-benzoic acid methyl
ester and n-propylmagnesium chloride following the general method
exemplified in Preparation 1.
Preparation 3
Racemic 4-(1-Hydroxy-2-methyl-propyl)-benzoic acid methyl ester
##STR00024##
[0234] This compound is made from 4-formyl-benzoic acid methyl
ester and isopropylmagnesium chloride following the general method
exemplified in Preparation 1.
Preparation 4
Racemic 4-(1-Hydroxy-pentyl)-benzoic acid methyl ester
##STR00025##
[0236] This compound is made from 4-formyl-benzoic acid methyl
ester and n-butyl magnesium chloride following the general method
exemplified in Preparation 1.
Preparation 5
Racemic 4-(1-Hydroxy-3-methyl-butyl)-benzoic acid methyl ester
##STR00026##
[0238] This compound is made from 4-formyl-benzoic acid methyl
ester and isobutylmagnesium chloride following the general method
exemplified in Preparation 1.
Preparation 6
Racemic 4-(1-Hydroxy-hexyl)-benzoic acid methyl ester
##STR00027##
[0240] This compound is made from 4-formyl-benzoic acid methyl
ester and n-pentylmagnesium chloride following the general method
exemplified in Preparation 1.
Preparation 7
Racemic 4-(1-Hydroxy-heptyl)-benzoic acid methyl ester
##STR00028##
[0242] This compound is made from 4-formyl-benzoic acid methyl
ester and n-hexylmagnesium chloride following the general method of
Preparation 1.
Preparation 8
Racemic 4-(1-Hydroxy-4,4-dimethyl-pentyl)-benzoic acid methyl
ester
##STR00029##
[0244] This compound is made from 4-formyl-benzoic acid methyl
ester and 4,4-dimethylpentylmagnesium bromide following the general
method of Preparation 1.
Preparation 9
Racemic 4-(1-Hydroxy-butyl)-benzoic acid methyl ester
##STR00030##
[0245] Step A. N-Methoxy-N-methyl-terephthalamic acid methyl
ester
[0246] To a solution of Terephthalic acid monomethyl ester (5.4 g,
30 mmol) and 2-chloro-4,6-dimethoxy-[1,3,5]triazine (7.9 g, 45
mmol) in THF (300 mL) is added N-methyl morpholine (4.95 mL, 45
mmol), the mixture is stirred at room temperature overnight.
Additional N-methyl morpholine (4.95 mL, 45 mmol) is added,
followed by the addition of O,N-dimethyl-hydroxylamine HCl salt
(3.51 g, 45 mmol). The reaction mixture is stirred overnight, and
filtered through celite. The filtrate was concentrated and purified
by column chromatography on silica gel (hexane/ethyl acetate)
giving the title compound (6.8 g).
Step B. 4-Butyryl-benzoic acid methyl ester
[0247] To a solution of N-methoxy-N-methyl-terephthalamic acid
methyl ester (4.56 g, 20.4 mmol) in THF (100 mL) is added PrMgCl
(2.0M, 30.6 mmol) at 0.degree. C., the reaction is warmed to room
temperature, stirred overnight, quenched by NH.sub.4Cl aqueous
solution, extracted with ethyl acetate. The combined organic layers
are washed with brine, dried over sodium sulfate, concentrate.
Column chromatography on silica gel gives the title compound (1 g,
23.7%).
Step C. Racemic 4-(1-Hydroxy-butyl)-benzoic acid methyl ester
[0248] To a solution of 4-butyryl-benzoic acid methyl ester (400
mg, 1.94 mmol) in ethanol (5 mL) and THF (4 mL) is added sodium
borohydride (110 mg, 2.9 mmol), the mixture is stirred at room
temperature for 2 h. The reaction mixture is quenched by acetic
acid (0.5 mL) and water (10 mL), extracted with ethyl acetate.
Combined organic layers are washed with brine and dried over sodium
sulfate. Concentration and column chromatography on silica gel
gives the title compound (370 mg).
Preparation 10
Racemic 3-[4-(1-Hydroxy-nonyl)-benzoylamino]-propionic acid methyl
ester
##STR00031##
[0249] Step A. 3-(4-Formyl-benzoylamino)-propionic acid methyl
ester
[0250] 4-Formyl-benzoic acid, CDMT, and 4-methylmorpholine are
combined in anhydrous DCM under nitrogen. The reaction is allowed
to stir under nitrogen at room temperature overnight. The amine is
then added to the reaction mixture, and allowed to stir at room
temperature. Some water (<10% volume) is added to help
solubility. The reaction is monitored by HPLC, and upon complete
consumption of the acid, the reaction is diluted with DCM. The
reaction is diluted with water and rinsed with 1N HCl. Upon
acidification, a white solid precipitated from the biphasic
mixture. The solid was isolated by filtration and dried under
vacuum to afford the titled compound.
Step B. Racemic 3-[4-(1-Hydroxy-nonyl)-benzoylamino]-propionic acid
methyl ester
[0251] To a solution of 3-(4-formyl-benzoylamino)-propionic acid
methyl ester (1.2 g, 5 mmol) in THF (10 mL) at 0.degree. C. is
added ethylmagnesium bromide (2M, 1.1 mL). After stirring at room
temperature for 2 hours, it is quenched with saturated ammonium
chloride, extracted with EtOAc. The organic is concentrated to give
the titled compound as colorless oil: 270 mg (15%).
[0252] The following compound is made in a substantially similar
manner:
Preparation 11
Racemic
3-[4-(4,4,4-Trifluoro-1-hydroxy-butyl)-benzoylamino]-propionic acid
methyl ester
##STR00032##
[0254] This compound is made by the general method exemplified in
Preparation 10 using 3,3,3-trifluoropropylmagnesium bromide.
Preparation 12
Racemic
3-[4-(1-Hydroxy-4,4-dimethyl-pentyl)-benzoylamino]-propionic acid
methyl ester
##STR00033##
[0256] This compound is made by the general method exemplified in
Preparation 10 using 2,2-dimethylbutylmagnesium bromide.
Preparation 13
Racemic 3-[4-(1-Hydroxy-butyl)-benzoylamino]-propionic acid methyl
ester
##STR00034##
[0258] This compound is made by the general method exemplified in
Preparation 10 using n-propylmagnesium bromide.
Preparation 14
Racemic 3-[4-(1-Hydroxy-3-methyl-butyl)-benzoylamino]-propionic
acid methyl ester
##STR00035##
[0260] This compound is made by the general methods as exemplified
in Preparation 10 using isobutyl magnesium bromide as reagent.
Preparation 15
Racemic 3-[4-(1-Hydroxy-heptyl)-benzoylamino]-propionic acid methyl
ester
##STR00036##
[0262] This compound is made by the general methods as exemplified
in Preparation 10 using hexyl magnesium bromide as reagent.
Preparation 16
4'-Trifluoromethyl-biphenyl-4-ol
##STR00037##
[0264] 4-Bromophenol (5 g, 28.9 mmol), 4-trifluoromethyl phenyl
boronic acid (6.59 g, 34.7 mmol), potassium carbonate (12 g, 86.7
mmol) and palladium acetate (0.324 g, 1.445 mmol) are placed in
water (50 mL), and the resulting mixture is stirred at room
temperature over night under open air. The mixture is filtered
through celite and extracted with ethyl acetate (3.times.200 ml).
The combined organic layers are washed with water, 1N HCl, water,
brine, dried (MgSO4), concentrated and chromatographed to yield the
title compound as a white solid (6.0 g, 87%).
[0265] The following compound is made in a substantially similar
manner:
Preparation 17
4'-tert-Butyl-biphenyl-4-ol
##STR00038##
[0267] This compound is made by the general method exemplified in
Preparation 16 using 4-tert-butyl phenyl boronic acid as
reagent.
Preparation 18
4-(5-Trifluoromethyl-pyridin-2-yl)-phenol
##STR00039##
[0268] Step A.
2-(4-Benzyloxy-phenyl)-5-trifluoromethyl-pyridine
[0269] A mixture of 2-chloro-5-trifluoromethylpyridine (1.81 g, 10
mmol), 4-benzyloxyphenyl boronic acid (2.74 g, 12 mmol) and CsF
(5.32 g, 35 mmol) in dioxane (40 mL) is degassed and filled with
nitrogen. PdCl.sub.2(dppf) (200 mg) is added under nitrogen, the
reaction mixture is heated at 105.degree. C. overnight. The mixture
is cooled to room temperature, diluted with ethyl acetate (100 mL),
filtered through a pad of Celite. The filtrate is concentrated and
the residue is purified by column chromatography on silica gel
giving the title compound (2.55 g, 77.4%).
Step B. 4-(5-Trifluoromethyl-pyridin-2-yl)-phenol
[0270] To a solution of
2-(4-Benzyloxy-phenyl)-5-trifluoromethyl-pyridine (2.55 g) in
ethanol (100 mL) and THF (25 mL) is added Pd/C (5%, 0.253 g), the
mixture is stirred under 60 psi of hydrogen overnight. The catalyst
is filtered off, concentration of the filtrate gave the title
compound (1.25 g, 67.5%).
Preparation 19
Racemic 4-(1-Hydroxy-3,3-dimethyl-butyl)-benzoic acid methyl
ester
##STR00040##
[0272] This compound is made from 4-formyl-benzoic acid methyl
ester and 3,3-dimethyl-butanemagnesium bromide following the
general method exemplified in Preparation 1.
Preparation 20
Racemic 4-(Cyclopropyl-hydroxy-methyl)-benzoic acid methyl
ester
##STR00041##
[0274] This compound is made from 4-formyl-benzoic acid methyl
ester and Cyclopropyl magnesium bromide following the general
method exemplified in Preparation 1.
Preparation 21
Racemic 3-Fluoro-4-(1-hydroxy-3-methyl-butyl)-benzoic acid methyl
ester
##STR00042##
[0276] This compound is made from 3-Fluoro-4-formyl-benzoic acid
methyl ester and isobutylmagnesium bromide following the general
method exemplified in Preparation 1.
Preparation 22
Racemic 3-Fluoro-4-(1-hydroxy-heptyl)-benzoic acid methyl ester
##STR00043##
[0278] This compound is made from 3-Fluoro-4-formyl-benzoic acid
methyl ester and hexylmagnesium bromide following the general
method exemplified in Preparation 1.
Preparation 23
4-Bromo-3-[1,3]dioxan-2-yl-phenol
##STR00044##
[0280] To the solution of 2-bromo-5-methoxy-benzaldehyde (10 g,
46.5 mmol) at -78.degree. C. is added BBr.sub.3 (25 g, 93.75 mmol)
and allowed to warm to room temperature. After 2 h, the reaction is
quenched with water and extracted with ethyl acetate. The combined
organic layers are washed with water, brine, dried over MgSO.sub.4,
concentrated and purified by column chromatography to afford 3.6 g
of 2-bromo-5-hydroxy-benzaldehyde. To the solution of
2-bromo-5-hydroxy-benzaldehyde (1.45 g, 7.2 mmol in benzene (30 ml)
and THF (6 ml) is added 1,3-propanediol (2.74 g, 36 mmol) and TsOH
(37 mg, 0.22 mmol). The mixture is refluxed for 24. After cooling
down, the solvent is evaporated. The residue is loaded on silica
and purified by column chromatography to afford the titled compound
(2.3 g) as brown oil.
Preparation 24
6-Chloro-5-methyl-pyridin-3-ol
##STR00045##
[0282] 2-Chloro-3-methyl-5-nitro-pyridine (2 g, 11.6 mmol) and
SnCl.sub.2.(H.sub.2O).sub.2 (7.86 g, 34.8 mmol) are refluxed in
MeOH overnight. After cooled down, the mixture is diluted with
ethyl acetate, washed with water, brine, dried over MgSO.sub.4,
concentrated and purified by column chromatography to afford
6-chloro-5-methyl-pyridin-3-ylamine (1.7 g). To the solution of
6-chloro-5-methyl-pyridin-3-ylamine (1.7 g, 11.6 mmol) in 1N HCl is
added the solution of NaNO.sub.2 (960 mg, 13.92 mmol) in water (10
ml) slowly at 0.degree. C. After the addition, the solution is
stirred for 20 min and then heated to 90.degree. C. for 30 min. The
solution is cooled down, quenched with K.sub.2CO.sub.3, extracted
with ether, dried over MgSO.sub.4, and purified by column
chromatography to afford the titled compound (560 mg) as a yellow
solid.
Preparation 25
4'-Isopropyl-2-methyl-biphenyl-4-ol
##STR00046##
[0284] 4-Bromo-3-methylphenol (1.87 g, 10 mmol), 4-isopropyl phenyl
boronic acid (2.0 g, 12 mmol), potassium carbonate (4.1 g, 30 mmol)
and palladium acetate (0.112 g, 0.5 mmol) are placed in water (100
mL). And the resulting mixture is stirred at room temperature over
night under open air. The mixture is filtered through Celite and
extracted with ethyl acetate (3.times.200 ml). The combined organic
layers are washed with water, 1N HCl, water, brine, dried
(MgSO.sub.4), concentrated and chromatographed to yield the title
compound as a white solid (1.9 g).
Preparation 26
2-Bromo-5-hydroxy-benzaldehyde
##STR00047##
[0286] To 2-bromo-5-methoxy-benzaldehyde (10 g, 31.25 mmol) in
dichloromethane (30 ml) at -78.degree. C. is added BBr.sub.3 (25 g,
93.75 mmol) and allowed to warm to room temperature. After 2 h, the
reaction is quenched with water and extracted with ethyl acetate.
The combined organic layers are washed with water, brine, dried and
purified by the column chromatography to afford 3.6 g of the titled
compound.
Preparation 27
2-Bromo-5-hydroxy-benzaldehyde O-tert-butyl-oxime
##STR00048##
[0288] To the solution of 2-bromo-5-hydroxy-benzaldehyde (402 mg, 2
mmol) in methanol (10 ml) is added O-tert-butyl-hydroxylamine
hydrochloride (125 mg, 10 mmol). The mixture is stirred at room
temperature overnight. The resulting mixture is diluted with ethyl
acetate, washed with brine, dried over MgSO.sub.4, and evaporated
to afford the titled compound (360 mg) as colorless oil.
Preparation 28
4-Bromo-3,5-dimethyl-benzenethiol
##STR00049##
[0289] Step A. Dimethyl-thiocarbamic acid
O-(4-bromo-3,5-dimethyl-phenyl)ester
[0290] 4-Bromo-3,5-dimethyl-phenol (10.0 g, 50.01 mmol) is
dissolved into dry dioxane (200 mL) and combined with
4-dimethylamino pyridine (1.0 g, 5.2 mmol), triethylamine (12.77
mL, 100.1 mmol), and dimethylamino-thiocarbomoyl chloride (7.69 g,
62.51 mmol). The reaction is heated to reflux under nitrogen. The
reaction is monitored by TLC until all of the phenol is consumed,
approximately 20 h. After cooling to room temperature, the reaction
is diluted with ethyl acetate (200 mL). Water (75 mL) is added and
the two layers are separated. The organic layer is washed with
brine (75 mL) then dried-over anhydrous sodium sulfate. The solvent
is removed and the residue is purified by column chromatography,
(6.4 g or 55% yield).
Step B. Dimethyl-thiocarbamic acid
S-(4-bromo-3,5-dimethyl-phenyl)ester
[0291] Dimethyl-thiocarbamic acid
O-(4-bromo-3,5-dimethyl-phenyl)ester (6.4 g, 22.3 mmol) is diluted
with 50 mL of tetradecane and heated to reflux under nitrogen. The
reaction is monitored by TLC until all the conversion was complete,
approximately 20 h. The reaction is allowed to cool to room
temperature and then loaded onto silica gel column and purified
using flash column chromatography, yielding 5.78 g, or 90% of the
target product.
Step C. 4-Bromo-3,5-dimethyl-benzenethiol
[0292] Dimethyl-thiocarbamic acid
S-(4-bromo-3,5-dimethyl-phenyl)ester (5.78 g, 20.14 mmol) is
diluted with methanol (50 mL) and sodium methoxide (4.75 mL of
4.25M in methanol, 20.14 mmol) is added. The reaction is heated to
reflux under nitrogen and monitored by TLC. After complete
conversion, 20 hours, the reaction is allowed to cool to room
temperature. The reaction is neutralized with 1N hydrochloric acid
(7.5 mL) and diluted with ethyl acetate (150 mL). The two phases
are separated and the organic layer is washed with water (75 mL),
then brine (75 mL). The organic layer is dried over anhydrous
sodium sulfate, concentrated and loaded onto silica gel column. The
title compound is purified using flash column chromatography,
yielding 4.0 g, or 92%.
Preparation 29
(R,S) 4-(5,5,5-Trifluoro-1-hydroxy-pentyl)-benzoic acid methyl
ester
##STR00050##
[0294] This compound is made following the general method
exemplified in Preparation 1 using 4-formyl-benzoic acid methyl
ester and 1,1,1-trifluoro-butane-4-magnesium bromide.
Preparation 30
(R,S) 3-[4-(Cyclohexyl-hydroxy-methyl)-benzoylamino]-propionic acid
methyl ester
##STR00051##
[0296] This compound is made by the general method exemplified in
Preparation 10 using 3-(4-formyl-benzoylamino)-propionic acid
methyl ester and cyclohexylmagnesium bromide.
Preparation 31
(R,S) 3-[4-(1-Hydroxy-5-methyl-hexyl)-benzoylamino]-propionic acid
methyl ester
##STR00052##
[0298] This compound is made by the general method exemplified in
Preparation 10 using 3-(4-formyl-benzoylamino)-propionic acid
methyl ester and 4-methylpentane-1-magnesiumbromide.
Preparation 32
4'-tert-Butyl-2,6-dimethyl-biphenyl-4-ol
##STR00053##
[0300] This compound is made by the general method as exemplified
in Preparation 16 using 4-bromo-3,5-dimethyl-phenol and
4-tert-butyl phenyl boronic acid as reagents.
Preparation 33
2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-ol
##STR00054##
[0302] This compound is made by the general method as exemplified
in Preparation 16 using 4-bromo-3,5-dimethyl-phenol and
4-trifluoromethyl phenyl boronic acid as reagents.
Preparation 34
5-Methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ol
##STR00055##
[0303] Step A.
3-Methyl-5-nitro-2-(4-trifluoromethyl-phenyl)-pyridine
[0304] To a solution of 2-chloro-3-methyl-5-nitro-pyridine (5.0 g,
28.73 mmol) in toluene (50 mL) is added palladium tetrakis
triphenylphosphine (1.66 g, 1.44 mmol), 4-trifluoromethyl phenyl
boronic acid (10.92 g, 57.46 mmol), and potassium fluoride (3.34 g,
57.46 mmol). The reaction is purged with nitrogen three times and
heated to reflux under nitrogen. At reflux, water (25 mL) is added
to the reaction and the reaction is allowed to reflux under
nitrogen. The reaction is monitored by HPLC, and upon completion,
allowed to cool to room temperature. The reaction is diluted with
ethyl acetate and Celite is added, followed by water. This mixture
is then filtered through a pad of Celite. The solution is poured
into a separatory funnel and the organic layer is washed with water
and brine. The organic layer is dried over anhydrous sodium sulfate
and concentrated. The product is purified by flash column
chromatography (5.6 g, 19.71 mmol).
Step B. 5-Methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylamine
[0305] To a solution of the
3-methyl-5-nitro-2-(4-trifluoromethyl-phenyl)-pyridine (3.5 g,
10.56 mmol) in ethanol (50 mL) is added palladium (10%) on carbon
(0.700 g, 20% by wt.). The reaction is charged to 15 psi under a
hydrogen atmosphere and allowed to stir for 4 hours. The reaction
is diluted with ethyl acetate and Celite is added, followed by
water. This mixture is then filtered through a pad of celite. The
solution is concentrated, diluted with ethyl acetate, poured into a
separatory funnel and the organic layer is washed with water and
brine. The organic layer is dried over anhydrous sodium sulfate and
concentrated. The product is used directly in the next step (2.74
g, 10.87 mmol).
Step C. 5-Methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ol
[0306] 5-Methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylamine
(2.74 g, 10.87 mmol) is suspended in hydrochloric acid (21.74 mL,
5N) and the solution is cooled to -15.degree. C. in a brine/ice
bath. Sodium nitrate (0.9 g, 13.04 mmol) in water (10 mL) is added
slowly to the mixture. The reaction is allowed to stir at
-15.degree. C. for ten minutes after complete addition.
Hexafluorophosphoric acid (5 mL, 21.74 mmol of a 60% wt. solution
in water) is added slowly to the mixture. The resulting slurry is
filtered, rinsed with cold water, methanol, and diethyl ether, and
dried under vacuum. This solid is added in small portions to a
round bottom containing acetic acid (10 mL) at 105.degree. C. This
solution is cooled to room temperature then treated with sodium
hydroxide (25 mL, 5N) for 30 min. The pH of this solution is
adjusted to 6 with hydrochloric acid, extracted with ethyl acetate,
washed with brine, dried over anhydrous sodium sulfate, then
filtered and concentrated to provide the title product (2.2 g, 8.69
mmol).
Preparation 35
6-(4-tert-Butyl-phenyl)-5-methyl-pyridin-3-ol
##STR00056##
[0308] This compound is made by the general method exemplified in
Preparation 16 using 2-chloro-3-methyl-5-nitro-pyridine and
4-tbutyl phenyl boronic acid.
Example 1
Racemic
3-{4-[1-(4'-Trifluoromethyl-biphenyl-4-yloxy)-propyl]-benzoylamino-
}-propionic acid
##STR00057##
[0309] Step A.
4-[1-(4'-Trifluoromethyl-biphenyl-4-yloxy)-propyl]-benzoic acid
[0310] To a solution of 4-(1-hydroxy-propyl)-benzoic acid methyl
ester (300 mg, 1.55 mmol) in toluene (10 mL) is added
1,1'-(azodicarbonyl)dipiperidine (ADDP, 585 mg, 2.32 mmol) at
0.degree. C., followed by the addition of tributylphosphine (0.58
mL, 2.32 mmol) and 4'-trifluoromethyl-biphenyl-4-ol (442 mg, 1.86
mmol). The reaction mixture is warmed up to room temperature and
stirred overnight. The mixture is loaded on silica gel, eluted with
hexanes with a gradient from 0% of ethyl acetate to 50% of ethyl
acetate giving
4-[1-(4'-trifluoromethyl-biphenyl-4-yloxy)-propyl]-benzoic acid
methyl ester. The ester product is taken into ethanol (2 mL),
treated with sodium hydroxide (5N aqueous, 1 mL) for 3 hours at
room temperature. The mixture is concentrated, diluted with ethyl
acetate, acidified with 5 N HCl (1.1 mL), extracted with ethyl
acetate. The organic layers are dried and concentrated giving
4-[1-(4'-trifluoromethyl-biphenyl-4-yloxy)-propyl]-benzoic acid
(570 mg).
Step B. Racemic methyl
3-(4-{1-[6-(4-Trifluoromethyl-phenyl)-pyridin-3-yl]-heptyloxy}-benzoylami-
no)-propionoate
[0311] To a mixture of
4-[1-(4'-Trifluoromethyl-biphenyl-4-yloxy)-propyl]-benzoic acid
(270 mg, 0.68 mmol) in methylene chloride (7 mL) are added triethyl
amine (0.28 mL, 2.03 mmol), DMAP (5.0 mg), 3-amino-propionic acid
methyl ester (141 mg, 1.01 mmol) and EDCI (389 mg, 2.03 mmol) at
room temperature. The reaction mixture is stirred at room
temperature overnight, loaded on silica gel, eluted with eluted
with hexanes with a gradient from 0% of ethyl acetate to 100% of
ethyl acetate giving
3-{4-[1-(4'-trifluoromethyl-biphenyl-4-yloxy)-propyl]-benzoylamino}-propi-
onic acid methyl ester (215 mg).
Step C. Racemic
3-{4-[1-(4'-Trifluoromethyl-biphenyl-4-yloxy)-propyl]-benzoylamino}-propi-
onic acid
[0312] To a mixture of
3-{4-[1-(4'-Trifluoromethyl-biphenyl-4-yloxy)-propyl]-benzoylamino}-propi-
onic acid methyl ester (60 mg, 0.12 mmol) in methanol (2 mL) is
added sodium hydroxide (5 N aqueous, 0.5 mL) and stirred for 5
hours. The reaction mixture is concentrated and acidified by 5 N
HCl (0.5 mL), extracted with ethyl acetate. Combined organic layers
are washed with water and brine, dried over sodium sulfate.
Concentration gives the title compound (54 mg). MS (ES): 472.2
[M+H].sup.+.
Example 2
Racemic
3-{4-[3-Methyl-1-(4'-trifluoromethyl-biphenyl-4-yloxy)-butyl]-benz-
oylamino}-propionic acid
##STR00058##
[0314] This compound is made by the general method exemplified in
Example 1 using 4-(1-hydroxy-3-methylbutyl)-benzoic acid methyl
ester and 4'-trifluoromethyl-biphenyl-4-ol as starting materials.
MS (ES): 500.2 [M+H].sup.+.
Example 3
Racemic
3-{4-[1-(4-tert-Butyl-phenoxy)-3-methyl-butyl]-benzoylamino}-propi-
onic acid
##STR00059##
[0316] This compound is made by the general method exemplified in
Example 1 using 4-(1-hydroxy-3-methylbutyl)-benzoic acid methyl
ester and 4-tert-butyl-phenol as starting materials. MS (ES): 412.3
[M+H].sup.+.
Example 4
Racemic
3-{4-[1-(4'-tert-Butyl-biphenyl-4-yloxy)-4,4,4-trifluoro-butyl]-be-
nzoylamino}-propionic acid
##STR00060##
[0318] This compound is made by the general method exemplified in
Example 1 using 4-(1-hydroxy-4,4,4-trifluorobutyl)-benzoic acid
methyl ester and 4'-tert-butyl-biphenyl-4-ol as starting materials.
MS (ES): 526.2 [M+H].sup.+.
Example 5
Racemic
3-{4-[4,4,4-Trifluoro-1-(4'-trifluoromethyl-biphenyl-4-yloxy)-buty-
l]-benzoylamino}-propionic acid
##STR00061##
[0320] This compound is made by the general method exemplified in
Example 1 using 4-(1-hydroxy-4,4,4-trifluorobutyl)-benzoic acid
methyl ester and 4'-trifluoromethyl-biphenyl-4-ol as starting
materials. MS (ES): 538.3 [M+H].sup.+.
Example 6
Racemic
3-{4-[(4-Bromo-phenyl)-(4'-tert-butyl-biphenyl-4-yloxy)-methyl]-be-
nzoylamino}-propionic acid
##STR00062##
[0322] This compound is made by the general method exemplified in
Example 1 using 4-(1-hydroxy-1-(4-bromophenyl)-methyl)-benzoic acid
methyl ester and 4'-tbutyl-biphenyl-4-ol as starting materials. MS
(ES): 585.0.
Example 7
Racemic
3-{4-[2-Methyl-1-(4'-trifluoromethyl-biphenyl-4-yloxy)-propyl]-ben-
zoylamino}-propionic acid
##STR00063##
[0324] This compound is made by the general method exemplified in
Example 1 using 4-(1-hydroxy-2-methylpropyl)-benzoic acid methyl
ester and 4'-trifluoromethyl-biphenyl-4-ol as starting materials.
MS (ES): 486.2 [M+H].sup.+.
Example 8
Racemic
3-{4-[1-(4'-tert-Butyl-biphenyl-4-yloxy)-propyl]-benzoylamino}-pro-
pionic acid
##STR00064##
[0326] This compound is made by the general method exemplified in
Example 1 using 4-(1-hydroxy-propyl)-benzoic acid methyl ester and
4'-tert-butyl-biphenyl-4-ol as starting materials. MS (ES): 458.3
[M-H].sup.-.
Example 9
Racemic
3-{4-[1-(4'-tert-Butyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-pro-
pionic acid
##STR00065##
[0328] This compound is made by the general method exemplified in
Example 1 using 4-(1-hydroxy-heptyl)-benzoic acid methyl ester and
4'-tert-butyl-biphenyl-4-ol as starting materials. MS (ES): 516.3
[M+H].sup.+.
Example 10
Racemic
3-{4-[1-(4'-tert-Butyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylam-
ino}-propionic acid
##STR00066##
[0330] This compound is made by the general method exemplified in
Example 1 using 4-(1-hydroxy-3-methylbutyl)-benzoic acid methyl
ester and 4'-tbutyl-biphenyl-4-ol as starting materials. MS (ES):
488.3 [M+H].sup.+.
Example 11
Racemic
3-{4-[1-(4-Cyclohexyl-phenoxy)-hexyl]-benzoylamino}-propionic
acid
##STR00067##
[0332] This compound is made by the general method exemplified in
Example 1 using 4-(1-hydroxy-hexyl)-benzoic acid methyl ester and
4-cyclohexylphenol as starting materials. MS (ES): 452.3
[M+H].sup.+.
Example 12
Racemic
3-{4-[1-(4-Benzyloxy-phenoxy)-hexyl]-benzoylamino}-propionic
acid
##STR00068##
[0334] This compound is made by the general method exemplified in
Example 1 using 4-(1-hydroxy-hexyl)-benzoic acid methyl ester and
4-benzyloxyphenol as starting materials. MS (ES): 476.2
[M+H].sup.+.
Example 13
Racemic 3-[4-(1-Phenoxy-hexyl)-benzoylamino]-propionic acid
##STR00069##
[0336] This compound is made by the general method exemplified in
Example 1 using 4-(1-hydroxy-hexyl)-benzoic acid methyl ester and
phenol as starting materials. MS (ES): 370.3 [M+H].sup.+.
Example 14
Racemic
3-{4-[1-(4'-Trifluoromethyl-biphenyl-4-yloxy)-heptyl]-benzoylamino-
}-propionic acid
##STR00070##
[0338] This compound is made by the general method exemplified in
Example 1 using 4-(1-hydroxy-heptyl)-benzoic acid methyl ester and
4'-trifluoromethyl-biphenyl-4-ol as starting materials. MS (ES):
528.2 [M+H].sup.+.
Example 15
Racemic
3-{4-[1-(4'-Trifluoromethyl-biphenyl-4-ylsulfanyl)-heptyl]-benzoyl-
amino}-propionic acid
##STR00071##
[0340] This compound is made by the general method exemplified in
Example 1 using 4-(1-hydroxy-heptyl)-benzoic acid methyl ester and
4'-trifluoromethyl-biphenyl-4-mercaptol as starting materials. MS
(ES): 542.2 [M-H].sup.-.
Example 16
Racemic
3-{4-[1-(4'-Trifluoromethyl-biphenyl-4-yloxy)-pentyl]-benzoylamino-
}-propionic acid
##STR00072##
[0342] This compound is made by the general method exemplified in
Example 1 using 4-(1-hydroxy-pentyl)-benzoic acid methyl ester and
4'-trifluoromethyl-biphenyl-4-ol as starting materials. MS (ES):
498.2 [M-H].sup.-.
Example 17
Racemic
3-{4-[1-(4'-tert-Butyl-biphenyl-4-yloxy)-pentyl]-benzoylamino}-pro-
pionic acid
##STR00073##
[0344] This compound is made by the general method exemplified in
Example 1 using 4-(1-hydroxy-pentyl)-benzoic acid methyl ester and
4'-tbutyl-biphenyl-4-ol as starting materials. MS (ES): 486.3
[M-H].sup.-.
Example 18
Racemic
3-{4-[1-(4'-Trifluoromethyl-biphenyl-4-yloxy)-butyl]-benzoylamino}-
-propionic acid
##STR00074##
[0346] This compound is made by the general method exemplified in
Example 1 using 4-(1-hydroxy-butyl)-benzoic acid methyl ester and
4'-trifluoromethyl-biphenyl-4-ol as starting materials. MS (ES):
486.2 [M+H].sup.+.
Example 19
Racemic
3-{4-[1-(4'-tert-Butyl-biphenyl-4-yloxy)-butyl]-benzoylamino}-prop-
ionic acid
##STR00075##
[0348] This compound is made by the general method exemplified in
Example 1 using 4-(1-hydroxy-butyl)-benzoic acid methyl ester and
4'-tert-butyl-biphenyl-4-ol as starting materials. MS (ES): 475.2
[M+H].sup.+.
Example 20
Racemic
3-{4-[3-Methyl-1-(4'-trifluoromethyl-biphenyl-4-ylsulfanyl)-butyl]-
-benzoylamino}-propionic acid
##STR00076##
[0350] This compound is made by the general method exemplified in
Example 1 using 4-(1-hydroxy-3-methylbutyl)-benzoic acid methyl
ester and 4'-trifluoromethyl-biphenyl-4-mercaptol as starting
materials. MS (ES): 515.3 [M-H].sup.-.
Example 21
Racemic
3-{4-[1-(4'-Trifluoromethyl-biphenyl-4-yloxy)-nonyl]-benzoylamino}-
-propionic acid
##STR00077##
[0352] This compound is made by the general method exemplified in
Example 1 using 4-(1-hydroxy-nonyl)-benzoic acid methyl ester and
4'-trifluoromethyl-biphenyl-4-mercaptol as starting materials. MS
(ES): 554.2 [M-H].sup.-.
Example 22
Racemic
3-(4-{3-Methyl-1-[4-(6-trifluoromethyl-pyridin-3-yl)-phenoxy]-buty-
l}-benzoylamino)-propionic acid
##STR00078##
[0354] This compound is made by the general method exemplified in
Example 1 using 4-(1-hydroxy-3-methylbutyl)-benzoic acid methyl
ester and 4-(6-Trifluoromethyl-pyridin-3-yl)-phenol as starting
materials. MS (ES): 500.3 [M-H].sup.-.
Example 23
Racemic
3-(4-{2-Methyl-1-[4-(6-trifluoromethyl-pyridin-3-yl)-phenoxy]-prop-
yl}-benzoylamino)-propionic acid
##STR00079##
[0356] This compound is made by the general method exemplified in
Example 1 using 4-(1-hydroxy-2-methylpropyl)-benzoic acid methyl
ester and 4-(6-Trifluoromethyl-pyridin-3-yl)-phenol as starting
materials. MS (ES): 487.3 [M+H].sup.+.
Example 24
Racemic
3-(4-{1-[4'-trifluoromethoxy-biphenyl-4-ylsulfanyl]-3-methyl-butyl-
}-benzoylamino)-propionic acid
##STR00080##
[0357] Step A.
4-[1-(4-Bromo-phenylsulfanyl)-3-methyl-butyl]-benzoic acid
[0358] To a solution of 4-(1-hydroxy-3-methyl-butyl)-benzoic acid
methyl ester (1240 mg, 5.59 mmol) in toluene (10 mL) is added
1,1'-(azodicarbonyl)dipiperidine (ADDP, 2114 mg, 8.38 mmol) at
0.degree. C., followed by the additions of tributylphosphine (2.09
mL, 8.38 mmol) and 4-bromo-thiophenol (1267 mg, 6.7 mmol). The
reaction mixture is warmed up to room temperature and stirred
overnight. The mixture is loaded on silica gel, eluted with hexanes
with a gradient from 0% of ethyl acetate to 50% of ethyl acetate
giving 4-[1-(4-bromo-phenylsulfanyl)-3-methyl-butyl]-benzoic acid
methyl ester. 393 mg of the ester product is taken into ethanol (2
mL), treated with sodium hydroxide (5N aqueous, 1 mL) for 3 h at
room temperature. The mixture is concentrated, diluted with ethyl
acetate, acidified with 5 N HCl (1.1 mL), extracted with ethyl
acetate. The organic layers are dried and concentrated giving
4-[1-(4-bromo-phenylsulfanyl)-3-methyl-butyl]-benzoic acid (379
mg).
Step B. Racemic
3-{4-[1-(4-Bromo-phenylsulfanyl)-3-methyl-butyl]-benzoylamino}-propionic
acid methyl ester
[0359] To a mixture of
4-[1-(4-bromo-phenylsulfanyl)-3-methyl-butyl]-benzoic acid (379 mg,
1 mmol) in methylene chloride (10 mL) are added triethyl amine
(0.42 mL, 3 mmol), DMAP (5.0 mg), 3-amino-propionic acid methyl
ester (209 mg, 1.5 mmol) and EDCI (577 mg, 3.0 mmol) at room
temperature. The reaction mixture is stirred at room temperature
overnight, loaded on silica gel, eluted with eluted with hexanes
with a gradient from 0% of ethyl acetate to 100% of ethyl acetate
giving
3-{4-[1-(4-Bromo-phenylsulfanyl)-3-methyl-butyl]-benzoylamino}-propionic
acid methyl ester (350 mg).
Step C. Racemic
3-{4-[3-Methyl-1-(4'-trifluoromethoxy-biphenyl-4-ylsulfanyl)-butyl]-benzo-
ylamino}-propionic acid methyl ester
[0360]
3-{4-[1-(4-bromo-phenylsulfanyl)-3-methyl-butyl]-benzoylamino}-prop-
ionic acid methyl ester (350 mg, 0.75 mmol), potassium carbonate
(311 mg, 2.25 mmol), 4-triflouromethoxylphenyl boronic acid (311
mg, 1.5 mmol) and tetrakis-(triphenylphosphine)palladium (87 mg,
0.075 mmol) are place in a flask. After the reaction is purged with
N.sub.2 for several times, THF/H.sub.2O (20 ml/5 ml) is added. The
resulting solution is refluxed overnight, loaded on silica gel,
eluted with hexane and ethyl acetate to give
3-{4-[3-Methyl-1-(4'-trifluoromethoxy-biphenyl-4-ylsulfanyl)-butyl]--
benzoylamino}-propionic acid methyl ester (294 mg) as a yellow
solid.
Step D. Racemic
3-(4-{1-[4'-(1-Fluoro-ethoxy)-biphenyl-4-ylsulfanyl]-3-methyl-butyl}-benz-
oylamino)-propionic acid
[0361] To a mixture of
3-{4-[3-Methyl-1-(4'-trifluoromethoxy-biphenyl-4-ylsulfanyl)-butyl]-benzo-
ylamino}-propionic acid methyl ester (20 mg) in methanol (2 mL) is
added sodium hydroxide (5 N aqueous, 0.5 mL) and stirred for 5 h.
The reaction mixture is concentrated and acidified by 5 N HCl (0.5
mL), extracted with ethyl acetate. Combined organic layers are
washed with water and brine, dried over sodium sulfate.
Concentration gives the title compound (18 mg). MS (ES): 531.2
[M-H].sup.-.
[0362] The following compounds are made in a substantially similar
manner:
Example 25
Racemic
3-{4-[1-(3',4'-dimethyl-biphenyl-4-ylsulfanyl)-3-methyl-butyl]-ben-
zoylamino}-propionic acid
##STR00081##
[0364] This compound is made by the general method as exemplified
in Example 24 using 3,4-dimethylphenyl boronic acid as starting
material in step C. MS (ES): 477.2 [M+H].sup.+.
Example 26
Racemic
3-{4-[1-(4'-cyano-biphenyl-4-ylsulfanyl)-3-methyl-butyl]-benzoylam-
ino}-propionic acid
##STR00082##
[0366] This compound is made by the general method as exemplified
in Example 24 using 4-cyanophenyl boronic acid as starting material
in step C. MS (ES): 472.2 [M+H].sup.+.
Example 27
Racemic
3-{4-[1-(4'-Isobutyl-biphenyl-4-ylsulfanyl)-3-methyl-butyl]-benzoy-
lamino}-propionic acid
##STR00083##
[0368] This compound is made by the general method as exemplified
in Example 24 using 4-isobutylphenyl boronic acid in step C. MS
(ES): 505.2 [M+H].sup.+.
Example 28
Racemic
3-(4-{1-[4-(6-Methoxy-pyridin-3-yl)-phenylsulfanyl]-3-methyl-butyl-
}-benzoylamino)-propionic acid
##STR00084##
[0370] This compound is made by the general method as exemplified
in Example 24 using 4-methoxy-pyridin-3-yl boronic acid as starting
material in step C. MS (ES): 480.2 [M+H].sup.+.
Example 29
Racemic
3-{4-[1-(4'-Ethyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propioni-
c acid
##STR00085##
[0372] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-heptyl)-benzoic acid methyl ester
and 4-bromophenol as reagents in step A and 4-ethylphenyl boronic
acid in step C. MS (ES): 488.3 [M+H].sup.+.
Example 30
3-{4-[1-(4-Benzyloxy-phenoxy)-hexyl]-benzoylamino}-propionic acid,
Isomer 1
##STR00086##
[0374] Chiral Separation: The racemic
3-{4-[1-(4-Benzyloxy-phenoxy)-hexyl]-benzoylamino}-propionic acid
methyl ester was resolved on a Chiralpak AD column (4.6.times.150
mm). Eluted with Isopropyl Alcohol/Heptane (30/70) and concentrated
the fractions to provide a purified enantiomer ester (isomer 1,
100% ee). Hydrolysis of the purified enantiomer of the ester
provided the title compound as a white solid. MS (ES): 476.3
[M+H].sup.+.
[0375] The following enantiomerically purified compounds were
obtained by substantially similar chiral separation using Chiralpak
AD column (4.6.times.150 mm) or Chiralcel OJ column (4.6.times.250
mm):
Example 31
3-{4-[1-(4-Benzyloxy-phenoxy)-hexyl]-benzoylamino}-propionic acid,
Isomer 2
##STR00087##
[0377] This compound is made by the general method as exemplified
in Example 30 by resolving racemic
3-{4-[1-(4-Benzyloxy-phenoxy)-hexyl]-benzoylamino}-propionic acid
methyl ester on Chiralpak AD column (4.6.times.150 mm). MS (ES):
476.3 [M+H].sup.+.
Example 32
3-{4-[3-Methyl-1-(4'-trifluoromethyl-biphenyl-4-yloxy)-butyl]-benzoylamino-
}-propionic acid, Isomer 1 and
Example 33
3-{4-[3-Methyl-1-(4'-trifluoromethyl-biphenyl-4-yloxy)-butyl]-benzoylamino-
}-propionic acid, Isomer 2
##STR00088##
[0379] These compounds are made by the general method as
exemplified in Example 30 by resolving racemic
3-{4-[3-methyl-1-(4'-trifluoromethyl-biphenyl-4-yloxy)-butyl]-benzoylamin-
o}-propionic acid methyl ester on Chiralpak AD column
(4.6.times.150 mm). Isomer 1 MS (ES): 500.3 [M+H].sup.+. Isomer 2
MS (ES): 500.3 [M+H].sup.+.
Example 34
3-{4-[1-(4'-Trifluoromethyl-biphenyl-4-yloxy)-propyl]-benzoylamino}-propio-
nic acid, Isomer 1 and
Example 35
3-{4-[1-(4'-Trifluoromethyl-biphenyl-4-yloxy)-propyl]-benzoylamino}-propio-
nic acid, Isomer 2
##STR00089##
[0381] These compounds are made by the general method as
exemplified in Example 30 by resolving racemic
3-{4-[1-(4'-trifluoromethyl-biphenyl-4-yloxy)-propyl]-benzoylamino}-propi-
onic acid methyl ester on Chiralpak AD column (4.6.times.150 mm).
Isomer 1 MS (ES): 470.2 [M-H].sup.-. Isomer 2 MS (ES): 470.2
[M-H].sup.-.
Example 36
3-{4-[1-(4'-tert-Butyl-biphenyl-4-yloxy)-propyl]-benzoylamino}-propionic
acid, Isomer 1 and
Example 37
3-{4-[1-(4'-tert-Butyl-biphenyl-4-yloxy)-propyl]-benzoylamino}-propionic
acid, Isomer 2
##STR00090##
[0383] These compounds are made by the general method as
exemplified in Example 30 by resolving racemic
3-{4-[1-(4'-tert-butyl-biphenyl-4-yloxy)-propyl]-benzoylamino}-propionic
acid methyl ester on Chiralpak AD column (4.6.times.150 mm). Isomer
1 MS (ES): 458.3 [M-H].sup.-. Isomer 2 MS (ES): 458.3
[M-H].sup.-.
Example 38
3-{4-[1-(4'-tert-Butyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propionic
acid, Isomer 1 and
Example 39
3-{4-[1-(4'-tert-Butyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propionic
acid, Isomer 2
##STR00091##
[0385] These compounds are made by the general method as
exemplified in Example 30 by resolving racemic
3-{4-[1-(4'-tert-butyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propionic
acid methyl ester on Chiralpak AD column (4.6.times.150 mm). Isomer
1 MS (ES): 516.3 [M+H].sup.+. Isomer 2 MS (ES): 516.3
[M+H].sup.+.
Example 40
3-{4-[1-(4'-tert-Butyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylamino}-pro-
pionic acid, Isomer 1 and
Example 41
3-{4-[1-(4'-tert-Butyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylamino}-pro-
pionic acid, Isomer 2
##STR00092##
[0387] These compounds are made by the general method as
exemplified in Example 30 by resolving racemic
3-{4-[1-(4'-tert-butyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylamino}-pr-
opionic acid methyl ester on Chiralpak AD column (4.6.times.150
mm). Isomer 1 MS (ES): 488.3 [M+H].sup.+. Isomer 2 MS (ES): 488.3
[M+H].sup.+.
Example 42
3-{4-[1-(4'-Trifluoromethyl-biphenyl-4-ylsulfanyl)-heptyl]-benzoylamino}-p-
ropionic acid, Isomer 1 and
Example 43
3-{4-[1-(4'-Trifluoromethyl-biphenyl-4-ylsulfanyl)-heptyl]-benzoylamino}-p-
ropionic acid, Isomer 2
##STR00093##
[0389] These compounds are made by the general method as
exemplified in Example 30 by resolving racemic
3-{4-[1-(4'-Trifluoromethyl-biphenyl-4-ylsulfanyl)-heptyl]-benzoylamino}--
propionic acid methyl ester on Chiralcel OD column (4.6.times.150
mm). Isomer 1 MS (ES): 543.2 [M-H].sup.-. Isomer 2 MS (ES): 543.2
[M-H].sup.-.
Example 44
3-{4-[1-(4'-tert-Butyl-biphenyl-4-yloxy)-pentyl]-benzoylamino}-propionic
acid, Isomer 1 and
Example 45
3-{4-[1-(4'-tert-Butyl-biphenyl-4-yloxy)-pentyl]-benzoylamino}-propionic
acid, Isomer 2
##STR00094##
[0391] These compounds are made by the general method as
exemplified in Example 30 by resolving racemic
3-{4-[1-(4'-tert-Butyl-biphenyl-4-yloxy)-pentyl]-benzoylamino}-propionic
acid methyl ester on Chiralpak AD column (4.6.times.150 mm). Isomer
1 MS (ES): 489.44 [M+H].sup.+. Isomer 2 MS (ES): 489.44
[M+H].sup.+.
Example 46
3-{4-[2-Methyl-1-(4'-trifluoromethyl-biphenyl-4-yloxy)-propyl]-benzoylamin-
o}-propionic acid, Isomer 1 and
Example 47
3-{4-[2-Methyl-1-(4'-trifluoromethyl-biphenyl-4-yloxy)-propyl]-benzoylamin-
o}-propionic acid, Isomer 2
##STR00095##
[0393] These compounds are made by the general method as
exemplified in Example 30 by resolving racemic
3-{4-[2-Methyl-1-(4'-trifluoromethyl-biphenyl-4-yloxy)-propyl]-benzoylami-
no}-propionic acid methyl ester on Chiralpak AD column
(4.6.times.150 mm). Isomer 1 MS (ES): 486.2 [M+H].sup.+, Isomer 2
MS (ES): 486.2 [M+H].sup.+.
Example 48
3-{4-[1-(4'-Trifluoromethyl-biphenyl-4-yloxy)-pentyl]-benzoylamino}-propio-
nic acid, Isomer 1 and
Example 49
3-{4-[1-(4'-Trifluoromethyl-biphenyl-4-yloxy)-pentyl]-benzoylamino}-propio-
nic acid, Isomer 2
##STR00096##
[0395] This compound is made by the general method as exemplified
in Example 30 by resolving racemic
3-{4-[1-(4'-trifluoromethyl-biphenyl-4-yloxy)-pentyl]-benzoylamino}-propi-
onic acid methyl ester on Chiralcel OJ column (4.6.times.150 mm).
Isomer 1 MS (ES): 501.2 [M+H].sup.+. Isomer 2 MS (ES): 501.2
[M+H].sup.+.
Example 50
3-{4-[1-(4'-Trifluoromethyl-biphenyl-4-yloxy)-butyl]-benzoylamino}-propion-
ic acid, Isomer 1 and
Example 51
3-{4-[1-(4'-Trifluoromethyl-biphenyl-4-yloxy)-butyl]-benzoylamino}-propion-
ic acid, Isomer 2
##STR00097##
[0397] These compounds are made by the general method as
exemplified in Example 30 by resolving racemic
3-{4-[1-(4'-trifluoromethyl-biphenyl-4-yloxy)-butyl]-benzoylamino}-propio-
nic acid methyl ester on Chiralcel OJ column (4.6.times.150 mm).
Isomer 1 MS (ES): 486.2 [M+H].sup.+. Isomer 2 MS (ES): 486.2
[M+H].sup.+.
Example 52
3-{4-[1-(4'-tert-Butyl-biphenyl-4-yloxy)-butyl]-benzoylamino}-propionic
acid, Isomer 1 and
Example 53
3-{4-[1-(4'-tert-Butyl-biphenyl-4-yloxy)-butyl]-benzoylamino}-propionic
acid, Isomer 2
##STR00098##
[0399] These compounds are made by the general method as
exemplified in Example 30 by resolving racemic
3-{4-[1-(4'-tert-butyl-biphenyl-4-yloxy)-butyl]-benzoylamino}-propionic
acid methyl ester on Chiralpak AD column (4.6.times.150 mm). Isomer
1 MS (ES): 475.2 [M+H].sup.+. Isomer 2 MS (ES): 475.2
[M+H].sup.+.
Example 54
3-(4-{1-[4'-(1-Fluoro-1-methyl-ethyl)-biphenyl-4-ylsulfanyl]-3-methyl-buty-
l}-benzoylamino)-propionic acid, Isomer 1 and
Example 55
3-(4-{1-[4'-(1-Fluoro-1-methyl-ethyl)-biphenyl-4-ylsulfanyl]-3-methyl-buty-
l}-benzoylamino)-propionic acid, Isomer 2
##STR00099##
[0401] These compounds are made by the general method as
exemplified in Example 30 by resolving racemic
3-(4-{1-[4'-(1-fluoro-1-methyl-ethyl)-biphenyl-4-ylsulfanyl]-3-methyl-but-
yl}-benzoylamino)-propionic acid methyl ester on Chiralpak AD
column (4.6.times.150 mm). Isomer 1 MS (ES): 517.3 [M+H].sup.+.
Isomer 2 MS (ES): 517.3 [M+H].sup.+.
Example 56
3-(4-{3-Methyl-1-[4-(6-trifluoromethyl-pyridin-3-yl)-phenoxy]-butyl}-benzo-
ylamino)-propionic acid, Isomer 1 and
Example 57
3-(4-{3-Methyl-1-[4-(6-trifluoromethyl-pyridin-3-yl)-phenoxy]-butyl}-benzo-
ylamino)-propionic acid, Isomer 2
##STR00100##
[0403] These compounds are made by the general method as
exemplified in Example 30 by resolving racemic
3-(4-{3-methyl-1-[4-(6-trifluoromethyl-pyridin-3-yl)-phenoxy]-butyl}-benz-
oylamino)-propionic acid methyl ester on Chiralpak AD column
(4.6.times.150 mm). Isomer 1 MS (ES): 501.2 [M+H].sup.+. Isomer 2
MS (ES): 501.2 [M+H].sup.+.
Example 58
3-{4-[1-(4'-Trifluoromethyl-biphenyl-4-yloxy)-nonyl]-benzoylamino}-propion-
ic acid, Isomer 1 and
Example 59
3-{4-[1-(4'-Trifluoromethyl-biphenyl-4-yloxy)-nonyl]-benzoylamino}-propion-
ic acid, Isomer 2
##STR00101##
[0405] These compounds are made by the general method as
exemplified in Example 30 by resolving racemic
3-{4-[1-(4'-trifluoromethyl-biphenyl-4-yloxy)-nonyl]-benzoylamino}-propio-
nic acid methyl ester on Chiralpak AD column (4.6.times.150 mm).
Isomer 1 MS (ES): 554.2 [M-H].sup.-. Isomer 2 MS (ES): 554.2
[M-H].sup.-.
Example 60
3-{4-[1-(4'-Ethyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propionic
acid, Isomer 1 and
Example 61
3-{4-[1-(4'-Ethyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propionic
acid, Isomer 2
##STR00102##
[0407] These compounds are made by the general method as
exemplified in Example 30 by resolving racemic
3-{4-[1-(4'-ethyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propionic
acid methyl ester on Chiralpak AD column (4.6.times.150 mm). Isomer
1 MS (ES): 488.3 [M+H].sup.+. Isomer 2 MS (ES): 488.3
[M+H].sup.+.
Example 62
3-(4-{1-[6-(4-tert-Butyl-phenyl)-pyridin-3-yloxy]-4,4-dimethyl-pentyl}-ben-
zoylamino)-propionic acid, Isomer 1
##STR00103##
[0408] Step A. 3-(4-Formyl-benzoylamino)-propionic acid methyl
ester
[0409] 4-formyl-benzoic acid (20 g, 133 mmol), CDMT (24 g, 137
mmol), and 4-methyl-morpholine (15.4 mL, 140 mmol) are combined in
anhydrous dichloromethane (DCM) (300 mL) under nitrogen. The
reaction is allowed to stir under nitrogen at room temperature
overnight. Beta-alanine methyl ester hydrochloride (20.4 g, (147
mmol) is then added to the reaction mixture, followed by
4-methylmorpholine (15.4 mL, 140 mmol), and allowed to stir at room
temperature. Some water (<10% volume) is added to help
solubility. The reaction is monitored by HPLC, and upon complete
consumption of the acid, the reaction is diluted with DCM. The
reaction is diluted with water and extracted with 1N HCl. The
organic layer is washed with water and brine, followed by drying
over anhydrous sodium sulfate. The solution is filtered and
concentrated and further purified using flash column chromatography
(30 g, 128 mmol).
Step B.
3-[4-(1-Hydroxy-4,4-dimethyl-pentyl)-benzoylamino]-propionic acid
methyl ester
[0410] A solution of 3-(4-Formyl-benzoylamino)-propionic acid
methyl ester (4.8 g, 20.43 mmol) is dissolved in the anhydrous
tetrahydrofuran (THF) (75 mL) and cooled to 0.degree. C. under
nitrogen. 2,2-Dimethyl-butyl magnesium bromide (16.3 mL, 1.5M
solution in THF, 24.5 mmol) is then added slowly to the solution by
addition funnel. The reaction is allowed to stir at 0.degree. C.
for 1 hour and the ice bath is removed. The reaction is monitored
by TLC or HPLC to determine complete consumption of the aldehyde.
The reaction is cooled back down to 0.degree. C. and 1.0N hydrogen
chloride solution is dropped in to quench. The solids are dissolved
with enough water and the solution is diluted with ether. The two
phases are separated and the organic layer is washed with brine,
dried over anhydrous sodium sulfate and concentrated. The alcohol
(1.6 g, 4.98 mmol) is purified by column chromatography.
Step C.
3-{4-[1-(6-Chloro-pyridin-3-yloxy)-4,4-dimethyl-pentyl]-benzoylami-
no}-propionic acid methyl ester
[0411] 3-[4-(1-Hydroxy-4,4-dimethyl-pentyl)-benzoylamino]-propionic
acid methyl ester
[0412] (546 mg, 1.7 mmol) and 6-chloro-pyridin-3-ol (270 mg, 2.09
mmol) are combined in anhydrous toluene (10 mL), degassed, filled
with nitrogen for 3 times, and cooled in an ice bath.
Tributylphosphine (TBP) (630 uL, 2.55 mmol) is added to the
reaction mixture under nitrogen at 0.degree. C., followed by
addition of 1,1'-(azodicarbonyl)-dipiperidine(ADDP) (643 mg, 2.55
mmol). The reaction mixture is allowed to warm to room temperature
and stirred over night, the mixture is loaded on silica gel column.
Chromatography gave the title compound (722 mg, L67 mmol).
Step D.
3-(4-{1-[6-(4-tert-Butyl-phenyl)-pyridin-3-yloxy]-4,4-dimethyl-pen-
tyl}-benzoylamino)-propionic acid methyl ester
[0413] To a solution of
3-{4-[1-(6-chloro-pyridin-3-yloxy)-4,4-dimethyl-pentyl]-benzoylamino}-pro-
pionic acid methyl ester (84 mg, 0.19 mmol) in toluene:water (1:1)
(2 mL) is added palladium tetrakis triphenylphosphine (22.47 mg,
0.1 mol %), 4-tert-butylphenylboronic acid (58 mg, 0.39 mmol). The
reaction is purged with nitrogen and heated to reflux and the
potassium fluoride (23 mg, 0.39 mmol) is added. The reaction is
monitored by HPLC, and upon completion, allowed to cool to room
temperature. The reaction is diluted with ethyl acetate and then
Celite is added, followed by water. This mixture is then filtered
through a pad of Celite. The solution is separated in a seperatory
funnel and the organic layer is washed with 0.1N sodium hydoxide,
water, and brine. The organic layer is dried over anhydrous sodium
sulfate and concentrated. The
5-(4-{1-[6-(4-tert-butyl-phenyl)-pyridin-3-yloxy]-4,4-dimethyl-pentyl}-ph-
enyl)-5-oxo-pentanoic acid methyl ester (80 mg, 0.15 mmol) is
purified by flash column chromatography.
Step E. Chiral Separation
[0414] The racemic
3-(4-{1-[6-(4-tert-butyl-phenyl)-pyridin-3-yloxy]-4,4-dimethyl-pentyl}-ph-
enyl)-5-oxo-pentanoic acid methyl ester is resolved on a Chiralpak
AD-H column (4.6.times.150 mm). Fluted with Isopropyl
Alcohol/Heptane (30/70) and concentrated the fractions to provide a
purified enantiomer ester (isomer 1, 98.6% ee).
Step F.
3-(4-{1-[6-(4-tert-Butyl-phenyl)-pyridin-3-yloxy]-4,4-dimethyl-pen-
tyl}-benzoylamino)-propionic acid
[0415]
3-(4-{1-[6-(4-tert-Butyl-phenyl)-pyridin-3-yloxy]-4,4-dimethyl-pent-
yl}-benzoylamino)-propionic acid methyl ester (isomer 1, 80 mg,
0.15 mmol) is dissolved in the tetrahydrofuran (1 mL) and sodium
hydroxide solution (5 M, 1.0 mL, 5 mmol) is added. The reaction is
monitored by HPLC, and upon complete conversion, the reaction is
neutralized with 5N HCl, diluted with diethyl ether and water. The
two phases are separated, and the organic layer is washed, dried,
and concentrated. The title compound is used without further
purification. MS (ES): 515.2 [M-H].sup.-, the structure was also
confirmed by proton NMR.
Example 63
Racemic
3-(4-{1-[6-(4-Trifluoromethyl-phenyl)-pyridin-3-yloxy]-heptyl}-ben-
zoylamino)-propionic acid
##STR00104##
[0417] This compound is made by the general method as exemplified
in Example 62 using pentylmagnesium chloride in step B and
4-trifluromethyl phenyl boronic acid in step D as starting
materials, without chiral separation in step E. MS (ES): 527.3
[M-H].sup.-, the structure was also confirmed by proton NMR.
Example 64
Racemic
3-(4-{4,4,4-Trifluoro-1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl-
oxy]-butyl}-benzoylamino)-propionic acid
##STR00105##
[0419] This compound is made by the general method as exemplified
in Example 62 using 3,3,3-trifluropropylmagnesium bromide in step B
and 4-trifluromethyl phenyl boronic acid in step D as starting
materials, without chiral separation in step E. MS (ES): 539.2
[M-H].sup.-, the structure was also confirmed by proton NMR.
Example 65
Racemic
3-(4-{3-Methyl-1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-bu-
tyl}-benzoylamino)-propionic acid
##STR00106##
[0421] This compound is made by the general method as exemplified
in Example 62 using isobutylmagnesium chloride in step B and
4-trifluromethyl phenyl boronic acid in step D as starting
materials, and without chiral separation in step E. MS (ES): 499.3
[M-H].sup.-, the structure was also confirmed by proton NMR.
Example 66
Racemic
3-(4-{4,4-Dimethyl-1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy-
]-pentyl}-benzoylamino)-propionic acid
##STR00107##
[0423] This compound is made by the general method as exemplified
in Example 62 using 3,3-dimethylbutyl magnesium bromide in step B
and 4-trifluromethyl phenyl boronic acid in step D as starting
materials without chiral separation in step E. MS (ES): 527.2
[M-H].sup.-, the structure was also confirmed by proton NMR.
Example 67
Racemic
3-(4-{1-[6-(4-Trifluoromethyl-phenyl)-pyridin-3-yl]-butoxy}-benzoy-
lamino)-propionic acid
##STR00108##
[0425] This compound is made by the general method as exemplified
in Example 62 using pentylmagnesium chloride in step B and
4-trifluromethyl phenyl boronic acid in step D as starting
materials without chiral separation in step E. MS (ES): 485.2
[M-H].sup.-, the structure was also confirmed by proton NMR.
Example 68
Racemic
3-(4-{1-[6-(4-tert-Butyl-phenyl)-pyridin-3-yloxy]-4,4,4-trifluoro--
butyl}-benzoylamino)-propionic acid
##STR00109##
[0427] This compound is made by the general method as exemplified
in Example 62 using 3,3,3-trifluropropylmagnesium chloride in step
B and 4-tert-butylphenyl boronic acid in step D as starting
materials. MS (ES): 527.3 [M-H].sup.-, the structure was also
confirmed by proton NMR.
Example 69
Racemic
3-(4-{1-[6-(4-tert-Butyl-phenyl)-pyridin-3-yloxy]-3-methyl-butyl}--
benzoylamino)-propionic acid
##STR00110##
[0429] This compound is made by the general method as exemplified
in Example 62 using isobutylmagnesium chloride in step B and
4-tert-butylphenyl boronic acid in step D as starting materials. MS
(ES): 487.3 [M-H].sup.-, the structure was also confirmed by proton
NMR.
Example 70
3-(4-{1-[6-(4-tert-Butyl-phenyl)-pyridin-3-yloxy]-4,4-dimethyl-pentyl}-ben-
zoylamino)-propionic acid, enantiomer 2
##STR00111##
[0431] The racemic
3-(4-{1-[6-(4-tert-butyl-phenyl)-pyridin-3-yloxy]-4,4-dimethyl-pentyl}-be-
nzoylamino)-propionic acid methyl ester (80 mg, 0.15 mmol) is
resolved on a Chiralpak AD-H column (0.46.times.15 cm) with a flow
rate of 0.6 mL/min. and detection at 260 nm. Elute with isopropyl
alcohol in heptane and concentrate the fractions to provide a
purified enantiomer ester (isomer 2, 99.9% ee). Hydrolysis of the
enantiomer of the ester provided the title compound as a white
solid. MS (ES): 517.3 [M+H].sup.+, 515.2 [M-H].sup.-, the structure
was also confirmed by proton NMR.
Example 71
3-(4-{1-[6-(4-Trifluoromethyl-phenyl)-pyridin-3-yloxy]-heptyl}-benzoylamin-
o)-propionic acid, Isomer 1 and
Example 72
3-(4-{1-[6-(4-Trifluoromethyl-phenyl)-pyridin-3-yloxy]-heptyl}-benzoylamin-
o)-propionic acid, Isomer 2
##STR00112##
[0433] These compounds are made by the general method as
exemplified in Example 70 by resolving racemic
3-(4-{1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-heptyl}-benzoylami-
no)-propionic acid methyl ester on a Chiralpak AD-H column
(4.6.times.150 mm) with a flow rate of 0.6 mL/min. and detection at
260nm. Elute with acetonitrile in 3A alcohol (isomer 2, 99.9% ee).
Isomer 1MS (ES): 527.2 [M-H].sup.-, the structure was also
confirmed by proton NMR; Isomer 2 MS (ES): 527.2 [M-H].sup.-, the
structure was also confirmed by proton NMR.
Example 73
3-(4-{4,4,4-Trifluoro-[1-(6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-bu-
tyl}-benzoylamino)-propionic acid, Isomer 1 and
Example 74
3-(4-{4,4,4-Trifluoro-1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-but-
yl}-benzoylamino)-propionic acid, Isomer 2
##STR00113##
[0435] These compounds are made by the general method as
exemplified in Example 70 by resolving racemic
3-(4-{4,4,4-trifluoro-1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-bu-
tyl}-benzoylamino)-propionic acid methyl ester on a Chiralpak AD-H
column (4.6.times.150 mm) with a flow rate of 0.6 mL/min. and
detection at 260nm. Elute with acetonitrile in 3A alcohol (isomer
2, 99.8% ee). Isomer 1MS (ES): 539.2 [M-H].sup.-, the structure was
also confirmed by proton NMR; Isomer 2 MS (ES): 539.2 [M-H].sup.-,
the structure was also confirmed by proton NMR.
Example 75
3-(4-{1-[6-(4-tert-Butyl-phenyl)-pyridin-3-yloxy]-butyl}-benzoylamino)-pro-
pionic acid, Isomer 1 and
Example 76
3-(4-{1-[6-(4-tert-Butyl-phenyl)-pyridin-3-yloxy]-butyl}-benzoylamino)-pro-
pionic acid, Isomer 2
##STR00114##
[0437] These compounds are made by the general method as
exemplified in Example 70 by resolving racemic
3-(4-{1-[6-(4-tert-butyl-phenyl)-pyridin-3-yloxy]-butyl}-benzoylamino)-pr-
opionic acid methyl ester on a Chiralpak AD-H column (0.46.times.15
cm) with a flow rate of 0.6 mL/min. and detection at 260 nm. Eluted
with isopropyl alcohol in heptane (isomer 2, >99% ee). MS (ES):
473.2 [M-H].sup.-1, the structure was also confirmed by proton by
proton NMR; MS (ES): 473.2 [M-H].sup.-, the structure was also
confirmed by proton NMR.
Example 77
Racemic
3-(4-{1-[6-(4-Isobutyl-phenyl)-pyridin-3-yloxy]-butyl}-benzoylamin-
o)-propionic acid
##STR00115##
[0439] This compound is made by the general method as exemplified
in Example 62 using propylmagnesium chloride in step B and
4-isobuphenyl boronic acid in step D as starting materials, without
chiral separation in step E. MS (ES): 473.4 [M-H].sup.-, the
structure was also confirmed by proton NMR.
Example 78
Racemic
3-{4-[1-(3'-Trifluoromethyl-biphenyl-4-ylsulfanyl)-heptyl]-benzoyl-
amino}-propionic acid
##STR00116##
[0440] Step A. 4-[1-(4-Bromo-phenylsulfanyl)-3-methyl-butyl]benzoic
acid
[0441] To a solution of 4-(1-hydroxy-3-methyl-heptyl)-benzoic acid
methyl ester (1760 mg, 7.04 mmol) in toluene (70 mL) is added
1,1'-(azodicarbonyl)dipiperidine (ADDP, 2664 mg, 10.56 mmol) at
0.degree. C., followed by the additions of tributylphosphine (2.63
mL, 8.38 mmol) and 4-bromo-benzenethiol (1597 mg, 8.45 mmol). The
reaction mixture is warmed up to room temperature and stirred
overnight. The mixture is loaded on silica gel, eluted with hexanes
with a gradient from 0% of ethyl acetate to 50% of ethyl acetate
giving 4-[1-(4-bromo-phenylsulfanyl)-heptyl]-benzoic acid methyl
ester. 1700 mg of the ester product is taken into ethanol (5 mL),
treated with sodium hydroxide (5N aqueous, 2 mL) for 3 h at room
temperature. The mixture is concentrated, diluted with ethyl
acetate, acidified with 5 N HCl (2 mL), and extracted with ethyl
acetate. The organic layers are dried and concentrated giving
4-[1-(4-bromo-phenylsulfanyl)-3-methyl-heptyl]-benzoic acid (1700
mg).
Step B. Racemic
3-{4-[1-(4-Bromo-phenylsulfanyl)-3-methyl-heptyl]-benzoylamino}-propionic
acid methyl ester
[0442] To a mixture of
4-[1-(4-bromo-phenylsulfanyl)-3-methyl-hepyl]-benzoic acid (1700
mg, 4.18 mmol) in methylene chloride (42 mL) are added triethyl
amine (1.75 mL, 12.53 mmol), DMAP (5.0 mg), 3-amino-propionic acid
methyl ester (875 mg, 6.27 mmol) and EDCI (2408 mg, 12.53 mmol) at
room temperature. The reaction mixture is stirred at room
temperature overnight, loaded on silica gel, eluted with eluted
with hexanes with a gradient from 0% of ethyl acetate to 100% of
ethyl acetate giving
3-{4-[1-(4-(4-bromo-phenylsulfanyl)-3-methyl-heptyl]-benzoylamino}-propio-
nic acid methyl ester (1.640 mg). Step C. Racemic
3-{4-[3-Methyl-1-(4'-trifluoromethoxy-biphenyl-4-ylsulfanyl)-heptyl]-benz-
oylamino}-propionic acid
[0443]
3-{4-[1-(4-bromo-phenylsulfanyl)-3-methyl-heptyl]-benzoylamino}-pro-
pionic acid methyl ester (100 mg, 0.2 mmol), potassium carbonate
(83 mg, 0.6 mmol), 3-triflouromethoxylphenyl boronic acid (76 mg,
0.4 mmol) and tetrakis-(triphenylphosphine)palladium (23 mg, 0.02
mmol) are placed in a flask. After the reaction is purged with
N.sub.2 for several times, THF/H.sub.2O (20 ml/5 ml) is added. The
resulting solution is refluxed overnight, concentrated, diluted
with ethyl acetate, acidified with 1 N HCl (0.6 mL), extracted with
ethyl acetate. The organic layers are dried and purified with
reverse phase HPLC to afford the title compound (58 mg). MS (ES):
544.1 [M+H].sup.+.
Example 79
Racemic
3-{4-[1-(4'-Acetyl-biphenyl-4-ylsulfanyl)-heptyl]-benzoylamino}-pr-
opionic acid
##STR00117##
[0445] This compound is made in a substantially similar manner as
Example 78 using 4-acetylphenyl boronic acid as reagent in step C.
MS (ES): 518.3 [M+H].sup.+.
Example 80
Racemic
3-{4-[1-(4-(3',4'-dimethyl-biphenyl-4-ylsulfanyl)-heptyl]-benzoyla-
mino}-propionic acid
##STR00118##
[0447] This compound is made in a substantially similar manner as
Example 78 using 3,4-dimethylphenyl boronic acid as reagent in step
C. MS (ES): 504.3 [M+H].sup.+.
Example 81
Racemic
3-{4-[1-(4-(4'-methylsulfonyl-biphenyl-4-ylsulfanyl)-heptyl]-benzo-
ylamino}-propionic acid
##STR00119##
[0449] This compound is made in a substantially similar manner as
Example 78 using 4-methylsulfonylphenyl boronic acid as reagent in
step C. MS (ES): 554.3 [M+H].sup.+.
Example 82
Racemic
3-{4-[1-(4-(2',3'-dimethyl-biphenyl-4-ylsufanyl)-heptyl]-benzoylam-
ino}-propionic acid
##STR00120##
[0451] This compound is made in a substantially similar manner as
Example 78 using 2,3-dimethylphenyl boronic acid as reagent in step
C. MS (ES): 504.2 [M+H].sup.+.
Example 83
Racemic
3-{4-[1-(4-(2',6'-dimethyl-biphenyl-4-ylsulfanyl)-heptyl]-benzoyla-
mino}-propionic acid
##STR00121##
[0453] This compound is made in a substantially similar manner as
Example 78 using 2,6-dimethylphenyl boronic acid as reagent in step
C. MS (ES): 504.2 [M+1-1].sup.+.
Example 84
Racemic
3-{4-[1-(3'-isopropyl-biphenyl-4-ylsulfanyl)-heptyl]-benzoylamino}-
-propionic acid
##STR00122##
[0455] This compound is made in a substantially similar manner as
Example 78 using 3-isopropylphenyl boronic acid as reagent in step
C. MS (ES): 518.3 [M+H].sup.+.
Example 85
Racemic
3-{1-[1-(3'-acetyl-biphenyl-4-ylsufanyl)-heptyl]-benzoylamino}-pro-
pionic acid
##STR00123##
[0457] This compound is made in a substantially similar manner as
Example 78 using 3-acetylphenyl boronic acid as reagent in step C.
MS (ES): 518.3 [M+H].sup.+.
Example 86
Racemic
3-{4-[1-(4-(4'-pentyl-biphenyl-4-ylsulfanyl)-heptyl]-benzoylamino}-
-propionic acid
##STR00124##
[0459] This compound is made in a substantially similar manner as
Example 78 using 4-pentylphenyl boronic acid as reagent in step C.
MS (ES): 546.3 [M+H].sup.+.
Example 87
Racemic
3-{4-[1-(4'-cyclohexyl-biphenyl-4-ylsulfanyl)-heptyl]-benzoylamino-
}-propionic acid
##STR00125##
[0461] This compound is made in a substantially similar manner as
Example 78 using 4-cyclohexylphenyl boronic acid as reagent in step
C. MS (ES): 558.3 [M+H].sup.+.
Example 88
Racemic
3-{4-[1-(4-(4-Allyloxy-phenoxy)-heptyl]-benzoylamino}-propionic
acid
##STR00126##
[0463] This compound is made in a substantially similar manner as
Example 1 using 4-(1-hydroxy-heptyl)-benzoic acid methyl ester and
4-allyloxy-phenol as reagents in step A. MS (ES): 438.3
[M-H].sup.-.
Example 89
Racemic
3-{4-[1-(2,2,3,3-Tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-
-heptyl]-benzoylamino}-propionic acid
##STR00127##
[0465] This compound is made in a substantially similar manner as
Example 1 using 4-(1-hydroxy-heptyl)-benzoic acid methyl ester and
2,2,3,3-tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-6-ol as reagents
in step A. MS (ES): 514.2 [M+H].sup.+.
Example 90
Racemic
3-(4-{1-[4-(4-Trifluoromethyl-phenoxy)-phenoxy]-heptyl}-benzoylami-
no)-propionic acid
##STR00128##
[0467] This compound is made in a substantially similar manner as
Example 1 using 4-(1-hydroxy-heptyl)-benzoic acid methyl ester and
4-(4-trifluoromethyl-phenoxy)-phenol as reagents in step A. MS
(ES): 544.2 [M+H].sup.+.
Example 91
Racemic 3-{4-[1-(4-Pentyl-phenoxy)-heptyl]-benzoylamino}-propionic
acid
##STR00129##
[0469] This compound is made in a substantially similar manner as
Example 1 using 4-(1-hydroxy-heptyl)-benzoic acid methyl ester and
4-pentylphenol as reagents in step A. MS (ES): 454.2
[M+H].sup.+.
Example 92
Racemic
3-(4-{1-[4-(4-tert-Butyl-benzyloxy)-phenoxy]-heptyl}-benzoylamino)-
-propionic acid
##STR00130##
[0470] Step 1.
[0471] Racemic
3-{4-[1-(4-(4-Allyloxy-phenoxy)-heptyl]-benzoylamino}-propionic
acid methyl ester (1.59 g, 3.51 mmol) and triphenyl-phosphine
tetrakis palladium(203 mg, 0.18 mmol) are combined with anhydrous
tetrahydrofuran (10 mL) in a round bottom flask under nitrogen.
Diethyl amine (712 uL, 7.02 mmol) is added and the reaction is
allowed to stir under nitrogen at room temperature. The reaction is
monitored by HPLC, and upon complete conversion, the reaction is
quenched with water. The reaction is diluted with diethyl ether and
rinsed with 1N HCl, water, and brine. The ether layer is dried over
anhydrous sodium sulfate and concentrated. Racemic
3-{1-[1-(4-Allyloxy-phenoxy)-heptyl]-benzoylamino}-propionic acid
methyl ester (1.47 g, 3.50 mmol) is obtained pure after column
chromatography.
Step 2.
[0472] To
3-{4-[1-(4-(4-Hydroxy-phenoxy)-heptyl]-benzoylamino}-propionic acid
methyl ester (70 mg, 0.17 mmol) in anhydrous dimethyl formamide
(1.0 mL) is added cesium carbonate (110 mg, 0.34 mmol) in one
portion. The mixture is allowed to stir under nitrogen at room
temperature and 4-tert-butyl-benzyl bromide is added. The reaction
is allowed to stir at room temperature for several hours and is
monitored by HPLC. Upon complete consumption of starting material,
the reaction is carefully quenched with water, extracted with ethyl
acetate, washed, dried, and concentrated.
3-(4-{1-[4-(4-tert-Butyl-benzyloxy)-phenoxy]-heptyl}-benzoylamino)-propio-
nic acid methyl ester is purified by column chromatography.
Step 3.
[0473] The
3-(4-{1-[4-(4-tert-Butyl-benzyloxy)-phenoxy]-heptyl}-benzoylami-
no)-propionic acid methyl ester is dissolved in the THF (1.0 mL)
and 5N NaOH (1.0 mL) is added. The mixture is heated to reflux
under nitrogen and monitored by HPLC. Upon complete conversion, the
reaction is neutralized with 5N HCl (1.0 mL), diluted with diethyl
ether and water. The two phases are separated and the organic layer
is washed, dried, and concentrated to provide the title compound
(80 mg, 0.15 mmol). MS (ES): 544.2 [M-H].sup.-.
Example 93
Racemic
3-(4-{1-[4-(3,5-bistrifluoromethyl-benzyloxy)-phenoxy]-heptyl}-ben-
zoylamino)-propionic acid
##STR00131##
[0475] This compound is made in a manner substantially similar to
Example 92 using 3,5-bistrifluoromethyl-benzyl bromide. MS (ES):
624.2 [M-H].sup.-.
Example 94
Racemic
3-(4-{1-[4-(4-isopropyl-benzyloxy)-phenoxy]-heptyl}-benzoylamino)--
propionic acid
##STR00132##
[0477] This compound is made in a manner substantially similar to
Example 92 using 4-isopropylbenzyl bromide. MS (ES): 530.2
[M-H].sup.-.
Example 95
Racemic
3-(4-{1-[4-(4-chloro-benzyloxy)-phenoxy]-heptyl}-benzoylamino)-pro-
pionic acid
##STR00133##
[0479] This compound is made in a manner substantially similar to
Example 92 using 4-chlorobenzyl bromide. MS (ES): 522.2
[M-H].sup.-.
Example 96
Racemic
3-(4-{1-[4-(4-ethyl-benzyloxy)-phenoxy]-heptyl}-benzoylamino)-prop-
ionic acid
##STR00134##
[0481] This compound is,made in a manner substantially similar to
Example 92 using 4-ethylbenzyl bromide. MS (ES): 516.3
[M-H].sup.-.
Example 97
Racemic
3-(4-{1-[4-(4-bromo-benzyloxy)-phenoxy]-heptyl}-benzoylamino)-prop-
ionic acid
##STR00135##
[0483] This compound is made in a manner substantially similar to
Example 92 using 4-bromobenzyl bromide. MS (ES): 566.2
[M-H].sup.-.
Example 98
Racemic
3-(4-{1-[4-(4-fluoro-benzyloxy)-phenoxy]-heptyl}-benzoylamino)-pro-
pionic acid
##STR00136##
[0485] This compound is made in a manner substantially similar to
Example 92 using 4-fluorobenzyl bromide. MS (ES): 506.2
[M-H].sup.-.
Example 99
Racemic
3-(4-{1-[4-(4-trifluoromethyl-benzyloxy)-phenoxy]-heptyl}-benzoyla-
mino)-propionic acid
##STR00137##
[0487] This compound is made in a manner substantially similar to
Example 92 using 4-trifluoromethylbenzyl bromide. MS (ES): 556.3
[M-H].sup.-.
Example 100
Racemic
3-(4-{1-[4-(4-phenyl-benzyloxy)-phenoxy]-heptyl}-benzoylamino)-pro-
pionic acid
##STR00138##
[0489] This compound is made in a manner substantially similar to
Example 92 using 4-phenylbenzyl bromide. MS (ES): 564.3
[M-H].sup.-.
Example 101
Racemic
3-(4-{1-[4-(3-chloro-benzyloxy)-phenoxy]-heptyl}-benzoylamino)-pro-
pionic acid
##STR00139##
[0491] This compound is made in a manner substantially similar to
Example 92 using 3-chlorobenzyl bromide. MS (ES): 522.2
[M-H].sup.-.
Example 102
Racemic
3-(4-{1-[4-(3,4-dimethyl-benzyloxy)-phenoxy]-heptyl}-benzoylamino)-
-propionic acid
##STR00140##
[0493] This compound is made in a manner substantially similar to
Example 92 using 3,4-dimethylbenzyl bromide as reagent. MS (ES):
516.3 [M-H].sup.-.
Example 103
Racemic
3-(4-{1-[4-(4-isopropoxyphenoxy]-heptyl}-benzoylamino)-propionic
acid
##STR00141##
[0495] This compound is made in a manner substantially similar to
Example 92 using 4-isopropyl iodide. MS (ES): 440.2
[M-H].sup.-.
Example 104
Racemic
3-{1-[1-(3',5'-bistrifluoromethyl-biphenyl-4-yloxy)-heptyl]-benzoy-
lamino}-propionic acid
##STR00142##
[0497] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-heptyl)-benzoic acid methyl ester
and 4-bromophenol as reagents in Step A and
3,5-bitrifluoromethylphenyl boronic acid in Step C as starting
materials. MS (ES): 594.2 [M-H].sup.-.
Example 105
Racemic
3-{4-[1-(4'-tert-Butyl-biphenyl-4-yloxy)-4,4-dimethyl-pentyl]-benz-
oylamino}-propionic acid
##STR00143##
[0499] This compound is made by the general method as exemplified
in Example 1 using 4'-tert-butyl-biphenyl-4-ol and
4-(1-hydroxy-4,4-dimethyl-pentyl)-benzoic acid methyl ester in step
A as starting materials. MS (ES): 516.3 [M+H].sup.+.
Example 106
Racemic
3-{4-[1-(4-(4'-trifluoromethyl-biphenyl-4-yloxy)-4,4-dimethyl-pent-
yl]-benzoylamino}-propionic acid
##STR00144##
[0501] This compound is made by the general method as exemplified
in Example 1 using 4'-trifluoromethyl-biphenyl-4-ol and
4-(1-hydroxy-4,4-dimethyl-pentyl)-benzoic acid methyl ester in step
A as starting materials. MS (ES): 526.2 [M-H].sup.-.
Example 107
Racemic
3-{4-[1-(4'-tert-Butyl-biphenyl-4-yloxy)-2-methyl-propyl]-benzoyla-
mino}-propionic acid
##STR00145##
[0503] This compound is made by the general method as exemplified
in Example 1 using 4'-tert-butyl-biphenyl-4-ol and
4-(1-hydroxy-2-methyl-propyl)-benzoic acid methyl ester in step A
as starting materials. MS (ES): 474.2 [M+H].sup.+.
Example 108
Racemic
3-{4-[1-(4'-trifluoromethyl-biphenyl-4-yloxy)-hexyl]-benzoylamino}-
-propionic acid
##STR00146##
[0505] This compound is made by the general method as exemplified
in Example 1 using 4'-trifluoromethyl-biphenyl-4-ol and
4-(1-hydroxyhexyl)-benzoic acid methyl ester in step A as starting
materials. MS (ES): 512.3 [M-H].sup.-.
Example 109
3-{4-[1-(3',5'-bistrifluoromethyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}--
propionic acid, Isomer 1
##STR00147##
[0506] Chiral Separation:
[0507] The racemic
3-{4-[1-(4-benzyloxy-phenoxy)-hexyl]-benzoylamino}-propionic acid
methyl ester is resolved on a Chiralpak AD-H column (4.6.times.150
mm). Elute with Isopropyl Alcohol/Heptane (15/85) and concentrate
the fractions to provide a purified enantiomer ester (isomer 1,
>99% ee). Hydrolysis of the purified enantiomer of the ester
provided the title compound as a white solid. MS (ES): 594.2
[M-H].sup.-.
Example 110
3-{4-[1-(3',5'-bistrifluoromethyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}--
propionic acid, Isomer 2
##STR00148##
[0509] This compound is made by the general method as exemplified
in Example 109 by resolving racemic
3-{4-[1-(4-(3',5'-bistrifluoromethyl-biphenyl-4-yloxy)-heptyl]-benzoylami-
no}-propionic acid methyl ester on Chiralpak AD-H column
(4.6.times.150 mm) eluted with Isopropyl Alcohol/Heptane (15/85).
MS (ES): 594.2 [M-H].sup.-.
Example 111
3-{4-[1-(4-(4-tert-Butyl-phenoxy)-3-methyl-butyl]-benzoylamino}-propionic
acid, Isomer 1 and
Example 112
3-{4-[1-(4-tert-Butyl-phenoxy)-3-methyl-butyl]-benzoylamino}-propionic
acid, Isomer 2
##STR00149##
[0511] These compounds are made by the general method as
exemplified in Example 109 by resolving racemic
3-{4-[1-(4-tert-butyl-phenoxy)-3-methyl-butyl]-benzoylamino}-propionic
acid methyl ester on Chiralpak AD-H column (4.6.times.150 mm)
eluted with Methanol (100%). Isomer 1 MS (ES): 412.3 [M+H].sup.+;
Isomer 2 MS (ES): 412.3 [M+H].sup.+.
Example 113
3-{4-[1-(4'-tertbutyl-biphenyl-4-yloxy)-2-methyl-propyl]-benzoylamino}-pro-
pionic acid, Isomer 1 or
Example 114
3-{4-[1-(4'-tertbutyl-biphenyl-4-yloxy)-2-methyl-propyl]-benzoylamino}-pro-
pionic acid, Isomer 2
##STR00150##
[0513] These compounds are made by the general method as
exemplified in Example 109 by resolving racemic
3-{4-[1-(4'-tertbutyl-biphenyl-4-yloxy)-2-methyl-propyl]-benzoylamino}-pr-
opionic acid methyl ester on Chiralpak AD-H column (4.6.times.150
mm) eluted with Isopropyl Alcohol/Heptane (50/50). Isomer 1 MS
(ES): 474.2 [M+H].sup.+. Isomer 2 MS (ES): 474.2 [M+H].sup.+.
Example 115
3-{4-[1-(4-(4'-trifluoromethyl-biphenyl-4-yloxy)-4,4-dimethyl-pentyl]-benz-
oylamino}-propionic acid, Isomer 1 and
Example 116
3-{4-[1-(4-(4'-trifluoromethyl-biphenyl-4-yloxy)-4,4-dimethyl-pentyl]-benz-
oylamino}-propionic acid, Isomer 2
##STR00151##
[0515] These compounds are made by the general method as
exemplified in Example 109 by resolving racemic
3-{4-[1-(4-(4'-trifluoromethyl-biphenyl-4-yloxy)-4,4-dimethyl-pentyl]-ben-
zoylamino}-propionic acid methyl ester on Chiralpak AD-H column
(4.6.times.150 mm) eluted with Propyl Alcohol (100%). Isomer 1MS
(ES): 526.2 [M-H].sup.-. Isomer 2 MS (ES): 526.2 [M-H].sup.-.
Example 117
3-{4-[1-(4-(4'-Trifluoromethoxy-biphenyl-4-yloxy)-heptyl]-benzoylamino}-pr-
opionic acid, Isomer 1
##STR00152##
[0516] Step A. Racemic 4-[1-(4-(4-Bromo-phenoxyl)-heptyl]-benzoic
acid
[0517] To a solution of 4-(1-hydroxy-heptyl)-benzoic acid methyl
ester (1800 mg, 7.2 mmol) in toluene (72 mL) is added
1,1'-(azodicarbonyl)dipiperidine (ADDP, 2725 mg, 10.8 mmol) at
0.degree. C., followed by the additions of tributylphosphine (2.69
mL, 10.8 mmol) and 4-bromo-phenol (1503 mg, 8.64 mmol). The
reaction mixture is warmed up to room temperature and stirred
overnight. The mixture is loaded on silica gel, eluted with hexanes
with a gradient from 0% of ethyl acetate to 50% of ethyl acetate
giving 4-[1-(4-bromo-phenoxyl)-heptyl]-benzoic acid methyl ester.
1900 mg of the ester product is taken into ethanol (5 mL), treated
with sodium hydroxide (5N aqueous, 2 mL) for 3 h at room
temperature. The mixture is concentrated, diluted with ethyl
acetate, acidified with 5 N HCl (2 mL), and extracted with ethyl
acetate. The organic layers are dried and concentrated giving
4-[1-(4-(4-bromo-phenoxyl)-heptyl]-benzoic acid (1800 mg).
Step B. Racemic
3-{4-[1-(4-(4-Bromo-phenoxyl)-heptyl]-benzoylamino}-propionic acid
methyl ester
[0518] To a mixture of 4-[1-(4-bromo-phenoxyl)-heptyl]-benzoic acid
(1700 mg, 4.35 mmol) in methylene chloride (43 mL) are added
triethyl amine (1.82 mL, 13.4 mmol), DMAP (5.0 mg),
3-amino-propionic acid methyl ester (910 mg, 6.52 mmol) and EDCI
(2507 mg, 13.04 mmol) at room temperature. The reaction mixture is
stirred at room temperature overnight, loaded on silica gel, eluted
with eluted with hexanes with a gradient from 0% of ethyl acetate
to 100% of ethyl acetate giving racemic
3-{4-[1-(4-bromo-phenoxyl)-heptyl]-benzoylamino}-propionic acid
methyl ester (1660 mg).
Step C. 3-{4-[1-(4-Bromo-phenoxyl)-heptyl]-benzoylamino}-propionic
acid methyl ester, isomers 1 and 2
[0519] The racemic
3-{4-[1-(4-bromo-phenoxyl)-heptyl]-benzoylamino}-propionic acid
methyl ester was resolved on a Chiralpak AD-H column (4.6.times.150
mm). Elute with Isopropyl Alcohol/Heptane (50/50) and concentrated
the fractions to provide a purified enantiomer ester (isomer 1,
99.5% ee, isomer 2, 94.6% ee).
Step D.
3-{4-[1-(4'-Trifluoromethoxy-biphenyl-4-yloxy)-heptyl]-benzoylamin-
o}-propionic acid methyl ester, isomer 1
[0520] 3-{4-[1-(4-Bromo-phenoxyl)-heptyl]-benzoylamino}-propionic
acid methyl ester (isomer 1, 100 mg, 0.21 mmol), potassium
carbonate (85 mg, 0.63 mmol), 4-triflouromethoxylphenyl boronic
acid (86 mg, 0.42 mmol) and tetrakis-(triphenylphosphine)palladium
(24 mg, 0.021 mmol) are place in a flask. After the reaction is
purged with N.sub.2 for several times, THF/H.sub.2O (20 ml/5 ml) is
added. The resulting solution is refluxed overnight, concentrated
and acidified by 1 N HCl (0.6 mL), extracted with ethyl acetate.
Combined organic layers are washed with water and brine, dried over
sodium sulfate, purified by reverse phase HPLC to give the title
compound (40 mg). MS (ES): 526.2 [M-H].sup.-.
Example 118
3-{4-[1-(4'-Trifluoromethoxy-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propi-
onic acid, Isomer 2
##STR00153##
[0522] This compound is made in a substantially similar manner as
Example 117 using isomer 2 of
3-{4-[1-(4-bromo-phenoxyl)-heptyl]-benzoylamino}-propionic acid
methyl ester as starting material in step D. MS (ES): 526.2
[M-H].sup.-.
Example 119
3-{4-[1-(4'-Trifluoromethyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propio-
nic acid, Isomer 1 or
Example 120
3-{4-[1-(4'-Trifluoromethyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propio-
nic acid, Isomer 2
##STR00154##
[0524] These compounds are made by the general method as
exemplified in Example 117 using isomer 2 of
3-{4-[1-(4-bromo-phenoxyl)-heptyl]-benzoylamino}-propionic acid
methyl ester and trifiouromethylphenyl boronic acid as starting
materials in step D. Isomer 1 MS (ES): 528.3 [M+H].sup.+; Isomer 2
MS (ES): 528.3 [M+H].sup.+.
Example 121
3-{4-[1-(4-(2,2,3,3-Tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-hept-
yl]-benzoylamino}-propionic acid, Isomer 1 and
Example 122
3-{4-[1-(2,2,3,3-Tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-heptyl]-
-benzoylamino}-propionic acid, Isomer 2
##STR00155##
[0526] This compound is made by the general method as exemplified
in Example 109 by resolving racemic
3-{4-[1-(2,2,3,3-tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-heptyl-
]-benzoylamino}-propionic acid methyl ester on Chiralpak AD-H
column (4.6.times.150 mm) eluted with Propyl Alcohol/Heptane
(15/85). Isomer 1 MS (ES): 512.3 [M-H].sup.-; Isomer 2 MS (ES):
514.2 [M+H].sup.+.
Example 123
3-(4-{1-[4-(4-Trifluoromethyl-phenoxy)-phenoxy]-heptyl}-benzoylamino)-prop-
ionic acid, Isomer 1 and
Example 124
3-(4-{1-[4-(4-Trifluoromethyl-phenoxy)-phenoxy]-heptyl}-benzoylamino)-prop-
ionic acid, Isomer 2
##STR00156##
[0528] These compounds are made by the general method as
exemplified in Example 109 by resolving racemic
3-(4-{1-[4-(4-trifluoromethyl-phenoxy)-phenoxy]-heptyl}-benzoylamino)-pro-
pionic acid methyl ester on Chiralpak AD-H column (4.6.times.150
mm) eluted with Propyl Alcohol/Heptane (15/85). Isomer 1 MS (ES):
542.3 [M-H].sup.-. Isomer 2 MS (ES): 542.3 [M-H].sup.-.
Example 125
3-{4-[1-(4'-Trifluoromethyl-biphenyl-4-yloxy)-hexyl]-benzoylamino}-propion-
ic acid, Isomer 1 and
Example 126
3-{4-[1-(4'-Trifluoromethyl-biphenyl-4-yloxy)-hexyl]-benzoylamino}-propion-
ic acid, Isomer 2
##STR00157##
[0530] These compounds are made by the general method as
exemplified in Example 109 by resolving racemic
3-{4-[1-(4'-trifluoromethyl-biphenyl-4-yloxy)-hexyl]-benzoylamino}-propio-
nic acid methyl ester on Chiralcel OJ-H column (4.6.times.150 mm)
eluted with MeOH (100%). Isomer 1 MS (ES): 512.3 [M-H].sup.-.
Isomer 2 MS (ES): 512.3 [M-H].sup.-.
Example 127
3-(4-{1-[4'-isopropyl-biphenyl-4-ylsulfanyl]-butyl}-benzoylamino)-propioni-
c acid, Isomer 1
##STR00158##
[0532] This compound is made in a substantially similar manner as
Example 117 using 4-(1-hydroxy-butyl)-benzoic acid methyl ester as
starting material in step A and 4-isopropyphenylboronic acid as
reagent in step D. MS (ES): 460.2 [M+H].sup.+.
Example 128
Racemic
3-{4-[1-(2,6-Dimethyl-4'-trifluoromethoxy-biphenyl-4-yloxy)-heptyl-
]-benzoylamino}-propionic acid
##STR00159##
[0533] Step A. Racemic
4-[1-(4-Bromo-3,5-dimethyl-phenoxyl)-heptyl]-benzoic acid
[0534] To a solution of 4-(1-hydroxy-heptyl)-benzoic acid methyl
ester (1000 mg, 4.0 mmol) in toluene (40 mL) is added
1,1'-(azodicarbonyl)dipiperidine (ADDP, 1514 mg, 6.0 mmol) at
0.degree. C., followed by the additions of tributylphosphine (1.49
mL, 6.0 mmol) and 4-bromo-3,5-dimethyl-phenol (965 mg, 4.8 mmol).
The reaction mixture is warmed up to room temperature and stirred
overnight. The mixture is loaded on silica gel, eluted with hexanes
with a gradient from 0% of ethyl acetate to 50% of ethyl acetate
giving 4-[1-(4-bromo-phenoxyl)-heptyl]-benzoic acid methyl ester.
The ester product (1800 mg) is taken into ethanol (5 mL), treated
with sodium hydroxide (5N aqueous, 5 mL) for 3 h at room
temperature. The mixture is concentrated, diluted with ethyl
acetate, acidified with 5 N HCl (5 mL), extract with ethyl acetate.
The organic layers are dried and concentrated giving
4-[1-(4-bromo-3,5-dimethyl-phenoxyl)-heptyl]-benzoic acid (1790
mg).
Step B. Racemic
3-{4-[1-(4-Bromo-3,5-dimethyl-phenoxyl)-heptyl]-benzoylamino}-propionic
acid methyl ester
[0535] To a mixture of
4-[1-(4-bromo-3,5-dimethyl-phenoxyl)-heptyl]-benzoic acid (1790 mg,
4.27 mmol) in methylene chloride (43 mL) are added triethyl amine
(1.79 mL, 12.82 mmol), DMAP (5.0 mg), 3-amino-propionic acid methyl
ester (895 mg, 6.4 mmol) and EDCI (2463 mg, 12.8 mmol) at room
temperature. The reaction mixture is stirred at room temperature
overnight, loaded on silica gel, eluted with eluted with hexanes
with a gradient from 0% of ethyl acetate to 100% of ethyl acetate
giving racemic
3-{4-[1-(4-bromo-3,5-dimethyl-phenoxyl)-heptyl]-benzoylamino}-propionic
acid methyl ester (945 mg).
Step C. Racemic
3-{4-[1-(4-(2,6-Dimethyl-4'-trifluoromethoxy-biphenyl-4-yloxy)-heptyl]-be-
nzoylamino}-propionic acid
[0536]
3-{4-[1-(4-(4-Bromo-3,5-dimethyl-phenoxyl)-heptyl]-benzoylamino}-pr-
opionic acid methyl ester (isomer 1, 100 mg, 0.2 mmol), potassium
flouride (35 mg, 0.6 mmol), 4-triflouromethoxylphenyl boronic acid
(83 mg, 0.4 mmol) and tetrakis(triphenylphosphine)palladium (23 mg,
0.02 mmol) are place in a flask. After the reaction is purged with
N.sub.2 for several times, Toluene/H.sub.2O (20 ml/5 ml) is added.
The resulting solution is refluxed overnight, loaded on silica gel,
eluted with hexane and ethyl acetate to give
3-{4-[1-(2,6-Dimethyl-4'-trifluoromethoxy-biphenyl-4-yloxy)-heptyl]-benzo-
ylamino}-propionic acid, (105 mg).
Step D.
3-{4-[1-(4-(2,6-Dimethyl-4'-trifluoromethoxy-biphenyl-4-yloxy)-hep-
tyl]-benzoylamino}-propionic acid
[0537] To a mixture of
3-{4-[1-(2,6-Dimethyl-4'-trifluoromethoxy-biphenyl-4-yloxy)-heptyl]-benzo-
ylamino}-propionic acid methyl ester (105 mg) in methanol (2 mL) is
added sodium hydroxide (5 N aqueous, 0.5 mL) and stirred for 5 h.
The reaction mixture is concentrated and acidified by 5 N HCl (0.5
mL), extracted with ethyl acetate. Combined organic layers are
washed with water and brine, dried over sodium sulfate.
Concentration gives the title compound (114 mg). MS (ES): 572.3
[M+H].sup.+.
Example 129
Racemic
3-{4-[1-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-
-benzoylamino}-propionic acid
##STR00160##
[0539] This compound is made in a substantially similar manner as
Example 128 using 4-trifluoromethylphenyl boronic acid as reagent
in step C. MS (ES): 554.2 [M-E].sup.-.
Example 130
Racemic
3-{4-[1-(2,6-Dimethyl-4'-tertbutyl-biphenyl-4-yloxy)-heptyl]-benzo-
ylamino}-propionic acid
##STR00161##
[0541] This compound is made in a substantially similar manner as
Example 128 using 4-tertbutylphenyl boronic acid as reagent in step
C. MS (ES): 542.3 [M-H].sup.-.
Example 131
3-{4-[1-(4'-tert-Butyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylamino}-2(R-
)-hydroxy-propionic acid
##STR00162##
[0542] Step A.
4-[1-(4'-tertbutyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoic
acid
[0543] To a solution of racemic
4-(1-hydroxy-3-methyl-butyl)-benzoic acid methyl ester (300 mg,
1.35 mmol) in toluene (14 mL) is added
1,1'-(azodicarbonyl)dipiperidine (ADDP, 512 mg, 2.03 mmol) at
0.degree. C., followed by the addition of tributylphosphine (0.5
mL, 2.03 mmol) and 4'-tert butyl-biphenyl-4-ol (367 mg, 1.62 mmol).
The reaction mixture is warmed up to room temperature and stirred
overnight. The mixture is loaded on silica gel, eluted with hexanes
with a gradient from 0% of ethyl acetate to 50% of ethyl acetate
giving 4-[1-(4'-tertbutyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoic
acid methyl ester. The ester product is taken into ethanol (5 mL),
treated with sodium hydroxide (5N aqueous, 1 mL) for 3 h at room
temperature. The mixture is concentrated, diluted with ethyl
acetate, acidified with 5 N HCl (1 mL), extract with ethyl acetate.
The organic layers are dried and concentrated giving
4-[1-(4'-tertbutyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoic acid
(400 mg).
Step B.
3-{4-[1-(4'-tert-Butyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylam-
ino}-2(R)-hydroxy-propionic acid methyl ester
[0544] To a mixture of
4-[1-(4'-tertbutyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoic acid
(120 mg) in methylene chloride (3 mL) are added triethyl amine
(0.12 mL, 0.87 mmol), DMAP (5 mg), 3-Amino-2(R)-hydroxy-propionic
acid methyl ester (67.3 mg, 0.43 mmol) and EDCI (166 mg, 0.87 mmol)
at room temperature. The reaction mixture is stirred at room
temperature overnight, loaded on silica gel, eluted with eluted
with hexanes with a gradient from 0% of ethyl acetate to 100% of
ethyl acetate giving
3-{4-[1-(4'-tert-butyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylamino}-2(-
R)-hydroxy-propionic acid methyl ester (60 mg).
Step C.
3-{4-[1-(4'-tert-Butyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylam-
ino}-2(R)-hydroxy-propionic acid
[0545] To a mixture of
3-{4-[1-(4'-tert-butyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylamino}-2(-
R)-hydroxy-propionic acid methyl ester (60 mg, 0.12 mmol) in
methanol (2 mL) is added sodium hydroxide (5 N aqueous, 0.5 mL) and
stirred for 5 h. The reaction mixture is concentrated and acidified
by 5 N HCl (0.5 mL), extracted with ethyl acetate. Combined organic
layers are washed with water and brine, dried over sodium sulfate.
Concentration gives the title compound (63 mg). MS (ES): 504.3
[M+H].sup.+.
Example 132
3-{4-[1-(4'-tert-Butyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylamino}-2(S-
)-hydroxy-propionic acid
##STR00163##
[0547] This compound is made in a substantially similar manner as
Example 131 using 3-amino-2(S)-hydroxy-propionic acid methyl ester
as reagent in step B. MS (ES): 504.2 [M+H].sup.+.
Example 133
3-{4-[1-(4'-Pentyl-biphenyl-4-yloxy)-butyl]-benzoylamino}-propionic
acid, Isomer 1
##STR00164##
[0549] This compound is made in a substantially similar manner as
Example 117 using isomer 1 of
3-{4-[1-(4-bromo-phenoxy)-butyl]-benzoylamino}-propionic acid
methyl ester and 4-pentylphenylboronic acid as starting materials
in step D. MS (ES): 488.3 [M+H].sup.+.
Example 134
3-{4-[1-(4'-Isobutyl-biphenyl-4-yloxy)-butyl]-benzoylamino}-propionic
acid, Isomer 1
##STR00165##
[0551] This compound is made in a substantially similar manner as
Example 117 using isomer 1 of
3-{4-[1-(4-bromo-phenoxy)-butyl]-benzoylamino}-propionic acid
methyl ester and 4-isobutylphenylbronic acid as starting materials
in step D. MS (ES): 472.2 [M-H].sup.-.
Example 135
Racemic
3-{4-[1-(4-(6-chloro-pyridin-3-yloxy)-4,4,4-trifluoro-butyl]-benzo-
ylamino}-propionic acid
##STR00166##
[0553] The title compound is prepared in a manner substantially
similar to Example 62 starting from
3-{4-[1-(6-chloro-pyridin-3-yloxy)-4,4,4-trifluoro-butyl]-benzoylamino}-p-
ropionic acid methyl ester. MS: 429.2 [M-H].sup.-.
Example 136
3-{4-[1-(4-(4'-Acetyl-biphenyl-4-yloxy)-butyl]-benzoylamino}-propionic
acid, Isomer 1
##STR00167##
[0555] This compound is made in a substantially similar manner as
Example 117 using isomer 1 of
3-{4-[1-(4-bromo-phenoxy)-butyl]-benzoylamino}-propionic acid
methyl ester and 4-acetylphenylboronic acid as starting materials
in step D. MS (ES): 458.3 [M-H].sup.-.
Example 137
3-{4-[1-(3',5'-dichloro-biphenyl-4-yloxy)-butyl]-benzoylamino}-propionic
acid, Isomer 1 and
Example 138
3-{4-[1-(3',5'-dichloro-biphenyl-4-yloxy)-butyl]-benzoylamino}-propionic
acid, Isomer 2
##STR00168##
[0557] These compounds are made in a manner substantially similar
to Example 117 using isomer 1 of
3-{4-[1-(4-bromo-phenoxy)-butyl]-benzoylamino}-propionic acid
methyl ester and 3',5'-dichlorophenylboronic acid as starting
materials in step D. Isomer 1 MS (ES): 484.2 [M-H].sup.-; Isomer 2
MS (ES): 486.2 [M+H].sup.+.
Example 139
3-{4-[1-(2',3',4'-trifluoro-biphenyl-4-yloxy)-butyl]-benzoylamino}-propion-
ic acid, Isomer 1
##STR00169##
[0559] This compound is made in a substantially similar manner as
Example 117 using isomer 1 of
3-{4-[1-(4-(4-bromo-phenoxy)-butyl]-benzoylamino}-propionic acid
methyl ester and 2',3',4'-trifluorophenylboronic acid as starting
materials in step D. MS (ES): 472.2 [M+H].sup.+.
Example 140
3-{4-[1-(2',4'-dimethoxy-biphenyl-4-yloxy)-butyl]-benzoylamino}-propionic
acid, Isomer 1
##STR00170##
[0561] This compound is made in a substantially similar manner as
Example 117 using isomer 1 of
3-{4-[1-(4-bromo-phenoxy)-butyl]-benzoylamino}-propionic acid
methyl ester and 2',4'-dimethoxyphenylboronic acid as starting
materials in step D. MS (ES): 478.3 [M+H].sup.+.
Example 141
3-{4-[1-(4'-t-butyl-biphenyl-4-yloxy)-hexyl]-benzoylamino}-propionic
acid, Isomer 1 and
Example 142
3-{4-[1-(4'-t-butyl-biphenyl-4-yloxy)-hexyl]-benzoylamino}-propionic
acid, Isomer 2
##STR00171##
[0563] These compounds are made in a manner substantially similar
to Example 30 by resolving racemic
3-{4-[1-(4'-t-butyl-biphenyl-4-yloxy)-hexyl]-benzoylamino}-propionic
acid methyl ester on Chiralpak AD-H column (4.6.times.150 mm).
Isomer 1 MS (ES): 502.2 [M+H].sup.+; Isomer 2 MS (ES): 502.2
[M+H].sup.+.
Example 143
3-{4-[1-(4'-pentylphenyl-4-yloxy)-hexyl]-benzoylamino}-propionic
acid, Isomer 1 and
Example 144
3-{4-[1-(4'-pentylphenyl-4-yloxy)-hexyl]-benzoylamino}-propionic
acid, Isomer 2
##STR00172##
[0565] These compounds are made in a manner substantially similar
to Example 30 by resolving racemic
3-{4-[1-(4'-pentylphenyl-4-yloxy)-hexyl]-benzoylamino}-propionic
acid methyl ester on Chiralpak AD-H column (4.6.times.150 mm).
Isomer 1MS (ES): 454.2 [M+H].sup.+; Isomer 2 MS (ES): 454.2
[M+H].sup.+.
Example 145
3-(4-{1-[4-(1-Methyl-1-phenyl-ethyl)-phenoxy]-heptyl}-benzoylamino)-propio-
nic acid, Isomer 1 and
Example 146
3-(4-{1-[4-(1-Methyl-1-phenyl-ethyl)-phenoxy]-heptyl}-benzoylamino)-propio-
nic acid, Isomer 2
##STR00173##
[0567] These compounds are made in a manner substantially similar
to Example 30 by resolving racemic
3-(4-{1-[4-(1-methyl-1-phenyl-ethyl)-phenoxy]-heptyl}-benzoylamino)-propi-
onic acid methyl ester on Chiralpak AD-H column (4.6.times.150 mm).
Isomer 1 MS (ES): 502.2 [M+H].sup.+. Isomer 2 MS (ES): 502.2
[M+H].sup.+.
Example 147
3-{4-[1-(2',4',6'-trimethyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propio-
nic acid, Isomer 1
##STR00174##
[0569] This compound is made in a substantially similar manner as
Example 117 using isomer 1 of
3-{4-[1-(4-bromo-phenoxy)-heptyl]-benzoylamino}-propionic acid
methyl ester and 2',4',6'-trimethylphenylboronic acid as starting
materials in step D. MS (ES): 502.2 [M+H].sup.+.
Example 148
3-{4-[1-(4'-Fluoro-2'-methyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propi-
onic acid, Isomer 1
##STR00175##
[0571] This compound is made in a substantially similar manner as
Example 117 using isomer 1 of
3-{4-[1-(4-bromo-phenoxy)-heptyl]-benzoylamino}-propionic acid
methyl ester and 4-fluoro-2-methyl-phenylboronic acid as starting
materials in step D. MS (ES): 492.3 [M+H].sup.+.
Example 149
3-{4-[1-(4'-Trifluoromethoxy-biphenyl-4-yloxy)-hexyl]-benzoylamino}-propio-
nic acid, Isomer 1
##STR00176##
[0573] This compound is made in a substantially similar manner to
Example 117 using isomer 1 of
3-{4-[1-(4-bromo-phenoxy)-hexyl]-benzoylamino}-propionic acid
methyl ester and 4-trifluoromethoxy-phenylboronic acid as starting
materials in step D. MS (ES): 530.2 [M+H].sup.+.
Example 150
3-{4-[1-(4'-Fluoro-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propionic
acid, Isomer 1
##STR00177##
[0575] This compound is made in a substantially similar manner to
Example 117 using isomer 1 of
3-{4-[1-(4-bromo-phenoxy)-heptyl]-benzoylamino}-propionic acid
methyl ester and 4-trifluoromethoxy-phenylboronic acid as starting
materials in step D. MS (ES): 476.2 [M-H].sup.-.
Example 151
3-{4-[Cyclopropyl-(4'-trifluoromethyl-biphenyl-4-yloxy)-methyl]-benzoylami-
no}-propionic acid, Isomer 1 and
Example 152
3-{4-[Cyclopropyl-(4'-trifluoromethyl-biphenyl-4-yloxy)-methyl]-benzoylami-
no}-propionic acid, Isomer 2
##STR00178##
[0577] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
3-{4-[cyclopropyl-(4'-trifluoromethyl-biphenyl-4-yloxy)-methyl]-benzoylam-
ino}-propionic acid methyl ester on Chiralpak AD-H column
(4.6.times.150 mm). Isomer 1 MS (ES): 482.2 [M-H].sup.-; Isomer 2
MS (ES): 482.2 [M-H].sup.-.
Example 153
3-{4-[1-(4'-tert-Butyl-biphenyl-4-yloxy)-4,4,4-trifluoro-butyl]-benzoylami-
no}-propionic acid, Isomer 1 and
Example 154
3-{4-[1-(4'-tert-Butyl-biphenyl-4-yloxy)-4,4,4-trifluoro-butyl]-benzoylami-
no}-propionic acid, Isomer 2
##STR00179##
[0579] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
3-{4-[1-(4'-tert-butyl-biphenyl-4-yloxy)-4,4,4-trifluoro-butyl]-benzoylam-
ino}-propionic acid methyl ester on Chiralpak AD-H column
(4.6.times.150 mm). Isomer 1 MS (ES): 528.3 [M+H].sup.+. Isomer 2
MS (ES): 528.3 [M+H].sup.+.
Example 155
3-{4-[1-(4'-Chloro-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propionic
acid, Isomer 1
##STR00180##
[0581] This compound is made in a substantially similar manner to
Example 117 using isomer 1 of
3-{4-[1-(4-bromo-phenoxy)-heptyl]-benzoylamino}-propionic acid
methyl ester and 4-chlorophenylboronic acid as starting materials
in step D. MS (ES): 492.3 [M-H].sup.-.
Example 156
3-{4-[1-(4'-tert-Butyl-2-methyl-biphenyl-4-yloxy)-3-methyl-butyl]-3-fluoro-
-benzoylamino}-propionic acid, Isomer 1 and
Example 157
3-{4-[1-(4'-tert-Butyl-2-methyl-biphenyl-4-yloxy)-3-methyl-butyl]-3-fluoro-
-benzoylamino}-propionic acid, Isomer 2
##STR00181##
[0583] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
3-{4-[1-(4'-tert-butyl-2-methyl-biphenyl-4-yloxy)-3-methyl-butyl]-3-fluor-
o-benzoylamino}-propionic acid methyl ester on Chiralpak AD-H
column (4.6.times.150 mm). Isomer 1 MS (ES): 520.2 [M+H].sup.+;
Isomer 2 MS (ES): 520.2 [M+H].sup.+.
Example 158
3-{4-[1-(4'-tert-Butyl-biphenyl-4-yloxy)-heptyl]-3-fluoro-benzoylamino}-pr-
opionic acid, Isomer 1 and
Example 159
3-{4-[1-(4'-tert-Butyl-biphenyl-4-yloxy)-heptyl]-3-fluoro-benzoylamino}-pr-
opionic acid, Isomer 2
##STR00182##
[0585] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
3-{4-[1-(4'-tert-butyl-biphenyl-4-yloxy)-heptyl]-3-fluoro-benzoylamino}-p-
ropionic acid methyl ester on Chiralpak AD-H column (4.6.times.150
mm). Isomer 1 MS (ES): 534.2 [M+H].sup.+. Isomer 2 MS (ES): 534.2
[M+H].sup.+.
Example 160
3-{3-Fluoro-4-[1-(2-methyl-4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-be-
nzoylamino}-propionic acid, Isomer 1 and
Example 161
3-{3-Fluoro-4-[1-(2-methyl-4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-be-
nzoylamino}-propionic acid, Isomer 2
##STR00183##
[0587] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
3-{3-fluoro-4-[1-(4-(2-methyl-4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl-
]-benzoylamino}-propionic acid methyl ester on Chiralpak AD-H
column (4.6.times.150 mm). Isomer 1 MS (ES): 560.2 [M+H].sup.+;
Isomer 2 MS (ES): 560.2 [M+H].sup.+.
Example 162
3-{4-[1-(4'-tert-Butyl-biphenyl-4-yloxy)-3-methyl-butyl]-3-fluoro-benzoyla-
mino}-propionic acid, Isomer 1 and
Example 163
3-{4-[1-(4'-tert-Butyl-biphenyl-4-yloxy)-3-methyl-butyl]-3-fluoro-benzoyla-
mino}-propionic acid, Isomer 2
##STR00184##
[0589] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
3-{4-[1-(4'-tert-butyl-biphenyl-4-yloxy)-3-methyl-butyl]-3-fluoro-benzoyl-
amino}-propionic acid methyl ester on Chiralpak AD-H column
(4.6.times.150 mm). Isomer 1 MS (ES): 506.2 [M+H].sup.+; Isomer 2
MS (ES): 506.2 [M+H].sup.+.
Example 164
3-{4-[1-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-heptyl]-benzoylamino-
}-propionic acid, Isomer 1 and
Example 165
3-{4-[1-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-heptyl]-benzoylamino-
}-propionic acid, Isomer 2
##STR00185##
[0591] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
3-{4-[1-(4'-tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-heptyl]-benzoylamin-
o}-propionic acid methyl ester on Chiralpak AD-H column
(4.6.times.150 mm). Isomer 1 MS (ES): 544.2 [M+H].sup.+. Isomer 2
MS (ES): 544.2 [M+H].sup.+.
Example 166
3-{4-[1-(4'-tert-Butyl-2-methyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-pr-
opionic acid, Isomer 1 and
Example 167
3-{4-[1-(4'-tert-Butyl-2-methyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-pr-
opionic acid, Isomer 2
##STR00186##
[0593] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
3-{4-[1-(4'-tert-butyl-2-methyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-p-
ropionic acid methyl ester on Chiralpak AD-H column (4.6.times.150
mm). Isomer 1 MS (ES): 530.5 [M+H].sup.+. Isomer 2 MS (ES): 530.5
[M+H].sup.+.
Example 168
3-{4-[1-(4-(2-Methyl-4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-benzoyla-
mino}-propionic acid, Isomer 1 and
Example 169
3-{4-[1-(2-Methyl-4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-benzoylamin-
o}-propionic acid, Isomer 2
##STR00187##
[0595] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
3-{4-[1-(2-methyl-4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-benzoylami-
no}-propionic acid methyl ester on Chiralpak AD-H column
(4.6.times.150 mm). Isomer 1 MS (ES): 540.3 [M-H].sup.-. Isomer 2
MS (ES): 540.3 [M-H].sup.-.
Example 170
3-{4-[1-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-3-methyl-butyl]-benz-
oylamino}-propionic acid, Isomer 1 and
Example 171
3-{4-[1-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-3-methyl-butyl]-benz-
oylamino}-propionic acid, Isomer 2
##STR00188##
[0597] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
3-{4-[1-(4'-tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-3-methyl-butyl]-ben-
zoylamino}-propionic acid methyl ester on Chiralpak AD-H column
(4.6.times.150 mm). Isomer 1 MS (ES): 516.3 [M+H].sup.+. Isomer 2
MS (ES): 516.3 [M+H].sup.+.
Example 172
3-{4-[1-(4'-Isopropyl-2-methyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-pro-
pionic acid, Isomer 1 and
Example 173
3-{4-[1-(4'-Isopropyl-2-methyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-pro-
pionic acid, Isomer 2
##STR00189##
[0599] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
3-{4-[1-(4'-isopropyl-2-methyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-pr-
opionic acid methyl ester on Chiralpak AD-H column (4.6.times.150
mm). Isomer 1 MS (ES): 514.2 [M-H].sup.-. Isomer 2 MS (ES): 516.3
[M+H].sup.+.
Example 174
3-{4-[1-(4'-Fluoro-2-methyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propio-
nic acid, Isomer 1 and
Example 175
3-{4-[1-(4'-Fluoro-2-methyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propio-
nic acid, Isomer 2
##STR00190##
[0601] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
3-{4-[1-(4'-fluoro-2-methyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propi-
onic acid methyl ester on Chiralpak AD-H column (4.6.times.150 mm).
Isomer 1 MS (ES): 492.3 [M+H].sup.+. Isomer 2 MS (ES): 490.2
[M-H].sup.-.
Example 176
3-{4-[1-(4'-Ethyl-2-methyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propion-
ic acid, Isomer 1 and
Example 177
3-{4-[1-(4-(4'-Ethyl-2-methyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-prop-
ionic acid, Isomer 2
##STR00191##
[0603] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
3-{4-[1-(4'-ethyl-2-methyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-propio-
nic acid methyl ester on Chiralpak AD-H column (4.6.times.150 mm).
Isomer 1 MS (ES): 502.2 [M+H].sup.+; Isomer 2 MS (ES): 502.2
[M+H].sup.+.
Example 178
3-{4-[1-(2,6-Dimethyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylamino}-prop-
ionic acid, Isomer 1 and
Example 179
3-{4-[1-(2,6-Dimethyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylamino}-prop-
ionic acid, Isomer 2
##STR00192##
[0605] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
3-{4-[1-(2,6-dimethyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylamino}-pro-
pionic acid methyl ester on Chiralcel OJ column (4.6.times.250 mm).
Isomer 1 MS (ES): 458.3 [M-H].sup.-; Isomer 2 MS (ES): 458.3
[M-H].sup.-.
Example 180
3-{4-[1-(4'-Ethyl-2,6-dimethyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylam-
ino}-propionic acid, Isomer 1 and
Example 181
3-{4-[1-(4'-Ethyl-2,6-dimethyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylam-
ino}-propionic acid, Isomer 2
##STR00193##
[0607] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
3-{4-[1-(4'-ethyl-2,6-dimethyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoyla-
mino}-propionic acid methyl ester on Chiralcel OJ column
(4.6.times.250 mm). Isomer 1 MS (ES): 488.3 [M+H].sup.+; Isomer 2
MS (ES): 488.3 [M+H].sup.+.
Example 182
3-{4-[1-(4'-tert-Butyl-2-trifluoromethyl-biphenyl-4-yloxy)-3-methyl-butyl]-
-benzoylamino}-propionic acid, Isomer 1 and
Example 183
3-{4-[1-(4'-tert-Butyl-2-trifluoromethyl-biphenyl-4-yloxy)-3-methyl-butyl]-
-benzoylamino}-propionic acid, Isomer 2
##STR00194##
[0609] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
3-{4-[1-(4'-tert-butyl-2-trifluoromethyl-biphenyl-4-yloxy)-3-methyl-butyl-
]-benzoylamino}-propionic acid methyl ester on Chiralpak AD-H
column (4.6.times.150 mm). Isomer 1 MS (ES): 556.3 [M+H].sup.+.
Isomer 2 MS (ES): 556.3 [M+H].sup.+.
Example 184
3-{4-[1-(4'-tert-Butyl-2-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-benzoyl-
amino}-propionic acid, Isomer 1 and
Example 185
3-{4-[1-(4'-tert-Butyl-2-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-benzoyl-
amino}-propionic acid, Isomer 2
##STR00195##
[0611] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
3-{4-[1-(4'-tert-butyl-2-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-benzoy-
lamino}-propionic acid methyl ester on Chiralpak AD-H column
(4.6.times.150 mm). Isomer 1 MS (ES): 584.2 [M+H].sup.+; Isomer 2
MS (ES): 584.2 [M+H].sup.+.
Example 186
3-{4-[1-(4'-tert-Butyl-2-trifluoromethyl-biphenyl-4-yloxy)-pentyl]-benzoyl-
amino}-propionic acid, Isomer 1 and
Example 187
3-{4-[1-(4'-tert-Butyl-2-trifluoromethyl-biphenyl-4-yloxy)-pentyl]-benzoyl-
amino}-propionic acid, Isomer 2
##STR00196##
[0613] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
3-{4-[1-(4-(4'-tert-butyl-2-trifluoromethyl-biphenyl-4-yloxy)-pentyl]-ben-
zoylamino}-propionic acid methyl ester on Chiralpak AD-H column
(4.6.times.150 mm). Isomer 1 MS (ES): 556.3 [M+H].sup.+; Isomer 2
MS (ES): 556.3 [M+H].sup.+.
Example 188
3-{4-[1-(4'-tert-Butyl-2-trifluoromethyl-biphenyl-4-yloxy)-2-methyl-propyl-
]-benzoylamino}-propionic acid, Isomer 1 and
Example 189
3-{4-[1-(4'-tert-Butyl-2-trifluoromethyl-biphenyl-4-yloxy)-2-methyl-propyl-
]-benzoylamino}-propionic acid, Isomer 2
##STR00197##
[0615] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
3-{4-[1-(4'-tert-butyl-2-trifluoromethyl-biphenyl-4-yloxy)-2-methyl-propy-
l]-benzoylamino}-propionic acid methyl ester on Chiralpak AD-H
column (4.times.150 mm). Isomer 1 MS (ES): 542.3 [M+H].sup.+;
Isomer 2 MS (ES): 542.3 [M+H].sup.+.
Example 190
3-{4-[1-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-4,4-dimethyl-pe-
ntyl]-benzoylamino}-propionic acid, Isomer 1 and
Example 191
3-{4-[1-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-4,4-dimethyl-pe-
ntyl]-benzoylamino}-propionic acid, Isomer 2
##STR00198##
[0617] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
3-{4-[1-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-4,4-dimethyl-p-
entyl]-benzoylamino}-propionic acid methyl ester on Chiralpak AD-H
column (4.6.times.150 mm). Isomer 1 MS (ES): 556.3 [M+H].sup.+;
Isomer 2 MS (ES): 556.3 [M+H].sup.+.
Example 192
3-{4-[1-(4'-Isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-4,4-dimethyl-pentyl]--
benzoylamino}-propionic acid, Isomer 1 and
Example 193
3-{4-[1-(4'-Isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-4,4-dimethyl-pentyl]--
benzoylamino}-propionic acid, Isomer 2
##STR00199##
[0619] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
3-{4-[1-(4'-Isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-4,4-dimethyl-pentyl]-
-benzoylamino}-propionic acid methyl ester on Chiralpak AD-H column
(4.6.times.150 mm). Isomer 1 MS (ES): 530.5 [M+H].sup.+; Isomer 2
MS (ES): 530.2 [M+H].sup.+.
Example 194
3-{4-[1-(2-Cyano-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylami-
no}-propionic acid, Isomer 1 and Example 195
3-{4-[1-(2-Cyano-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylami-
no}-propionic acid, Isomer 2
##STR00200##
[0621] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
3-{4-[1-(2-cyano-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylam-
ino}-propionic acid methyl ester on Chiralpak AD-H column
(4.6.times.150 mm). Isomer 1 MS (ES): 499.2 [M+H].sup.+; Isomer 2
MS (ES): 499.2 [M+H].sup.+.
Example 196
3-{4-[1-(4'-Isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-2-methyl-propyl]-benz-
oylamino}-propionic acid, Isomer 1 and
Example 197
3-{4-[1-(4'-Isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-2-methyl-propyl]-benz-
oylamino}-propionic acid, Isomer 2
##STR00201##
[0623] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
3-{4-[1-(4'-isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-2-methyl-propyl]-ben-
zoylamino}-propionic acid methyl ester on Chiralpak AD-H column
(4.6.times.150 mm). Isomer 1 MS (ES): 488.3 [M+H].sup.+; Isomer 2
MS (ES): 488.3 [M+H].sup.+.
Example 198
3-{4-[1-(4-(2-Ethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-benzoylam-
ino}-propionic acid, Isomer 1 and
Example 199
3-{4-[1-(4-(2-Ethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-benzoylam-
ino}-propionic acid, Isomer 2
##STR00202##
[0625] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
3-{4-[1-(2-ethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-benzoylamin-
o}-propionic acid methyl ester on Chiralpak AD-H column
(4.6.times.150 mm). Isomer 1 MS (ES): 556.3 [M+H].sup.+; Isomer 2
MS (ES): 556.3 [M+H].sup.+.
Example 200
3-{4-[1-(4'-Chloro-2,6-dimethyl-biphenyl-4-yloxy)-4,4-dimethyl-pentyl]-ben-
zoylamino}-propionic acid, Isomer 1 and
Example 201
3-{4-[1-(4'-Chloro-2,6-dimethyl-biphenyl-4-yloxy)-4,4-dimethyl-pentyl]-ben-
zoylamino}-propionic acid, Isomer 2
##STR00203##
[0627] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
3-{4-[1-(4'-chloro-2,6-dimethyl-biphenyl-4-yloxy)-4,4-dimethyl-pentyl]-be-
nzoylamino}-propionic acid methyl ester on Chiralpak AD-H column
(4.6.times.150 mm). Isomer 1 MS (ES): 522.2 [M+H].sup.+; Isomer 2
MS (ES): 522.2 [M+H].sup.+.
Example 202
3-{4-[1-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-2-methyl-propyl]-ben-
zoylamino}-propionic acid, Isomer 1 and
Example 203
3-{1-[1-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-2-methyl-propyl]-ben-
zoylamino}-propionic acid, Isomer 2
##STR00204##
[0629] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
3-{4-[1-(4'-tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-2-methyl-propyl]-be-
nzoylamino}-propionic acid methyl ester on Chiralpak AD-H column
(4.6.times.150 ram). MS (ES): 502.2 [M+H].sup.+. MS (ES): 502.2
[M+H].sup.+.
Example 204
3-{4-[2-Methyl-1-(2-methyl-4'-trifluoromethoxy-biphenyl-4-yloxy)-propyl]-b-
enzoylamino}-propionic acid, Isomer 1 and
Example 205
3-{4-[2-Methyl-1-(2-methyl-4'-trifluoromethoxy-biphenyl-4-yloxy)-propyl]-b-
enzoylamino}-propionic acid, Isomer 2
##STR00205##
[0631] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
3-{4-[2-methyl-1-(2-methyl-4'-trifluoromethoxy-biphenyl-4-yloxy)-propyl]--
benzoylamino}-propionic acid methyl ester on Chiralpak AD-H column
(4.6.times.150 mm). Isomer 1 MS (ES): 516.3 [M+H].sup.+; Isomer 2
MS (ES): 516.3 [M+H].sup.+.
Example 206
3-{4-[1-(2-Chloro-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylam-
ino}-propionic acid, Isomer 1 and
Example 207
3-{4-[1-(2-Chloro-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylam-
ino}-propionic acid, Isomer 2
##STR00206##
[0633] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
3-{4-[1-(2-chloro-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoyla-
mino}-propionic acid methyl ester on Chiralpak AD-H column
(4.6.times.150 mm). Isomer 1 MS (ES): 508.3 [M+H].sup.+; Isomer 2
MS (ES): 508.3 [M+11].sup.+.
Example 208
3-{4-[1-(2-Chloro-4'-trifluoromethyl-biphenyl-4-yloxy)-3-methyl-butyl]-ben-
zoylamino}-propionic acid, Isomer 1 and
Example 209
3-{4-[1-(2-Chloro-4'-trifluoromethyl-biphenyl-4-yloxy)-3-methyl-butyl]-ben-
zoylamino}-propionic acid, Isomer 2
##STR00207##
[0635] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
3-{4-[1-(2-chloro-4t-trifluoromethyl-biphenyl-4-yloxy)-3-methyl-butyl]-be-
nzoylamino}-propionic acid methyl ester on Chiralpak AD-H column
(4.6.times.150 mm). Isomer 1 MS (ES): 534.2 [M+H].sup.+; Isomer 2
MS (ES): 534.2 [M+H].sup.+.
Example 210
3-{4-[2-Methyl-1-(2-methyl-4'-trifluoromethyl-biphenyl-4-yloxy)-propyl]-be-
nzoylamino}-propionic acid, Isomer 1 and
Example 211
3-{4-[2-Methyl-1-(2-methyl-4'-trifluoromethyl-biphenyl-4-yloxy)-propyl]-be-
nzoylamino}-propionic acid, Isomer 2
##STR00208##
[0637] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
3-{4-[2-Methyl-1-(2-methyl-4'-trifluoromethyl-biphenyl-4-yloxy)-propyl]-b-
enzoylamino}-propionic acid methyl ester on Chiralpak AD-H column
(4.6.times.150 mm). Isomer 1 MS (ES): 500.3 [M+H].sup.+; Isomer 2
MS (ES): 500.3 [M+H].sup.+.
Example 212
3-(4-{3-Methyl-1-[5-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-b-
utyl}-benzoylamino)-propionic acid, Isomer 1 and
Example 213
3-(4-{3-Methyl-1-[5-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-b-
utyl}-benzoylamino)-propionic acid, Isomer 2
##STR00209##
[0639] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
3-(4-{3-methyl-1-[5-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]--
butyl}-benzoylamino)-propionic acid methyl ester on Chiralpak AD-H
column (4.6.times.150 mm). Isomer 1 MS (ES): 515.2 [M+H].sup.+;
Isomer 2 MS (ES): 515.2 [M+H].sup.+.
Example 214
3-(4-{1-[6-(4-Isopropyl-phenyl)-5-methyl-pyridin-3-yloxy]-3-methyl-butyl}--
benzoylamino)-propionic acid, Isomer 1 and
Example 215
3-(4-{1-[6-(4-Isopropyl-phenyl)-5-methyl-pyridin-3-yloxy]-3-methyl-butyl}--
benzoylamino)-propionic acid, Isomer 2
##STR00210##
[0641] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
3-(4-{1-[6-(4-isopropyl-phenyl)-5-methyl-pyridin-3-yloxy]-3-methyl-butyl}-
-benzoylamino)-propionic acid methyl ester on Chiralpak AD-H column
(4.6.times.150 mm). Isomer 1 MS (ES): 489.2 [M+H].sup.+; Isomer 2
MS (ES): 489.2 [M+H].sup.+.
Example 216
3-(3-Fluoro-4-{3-methyl-1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-b-
utyl}-benzoylamino)-propionic acid, Isomer 1 and
Example 217
3-(3-Fluoro-4-{3-methyl-1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-b-
utyl}-benzoylamino)-propionic acid, Isomer 2
##STR00211##
[0643] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
3-(3-fluoro-4-{3-methyl-1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]--
butyl}-benzoylamino)-propionic acid methyl ester on Chiralpak AD-H
column (4.6.times.150 mm). Isomer 1 MS (ES): 519.2 [M+H].sup.+.
Isomer 2 MS (ES): 519.2 [M+H].sup.+.
Example 218
3-(4-{3-Methyl-1-[4-(5-trifluoromethyl-pyridin-2-yl)-phenoxy]-butyl}-benzo-
ylamino)-propionic acid, Isomer 1 and
Example 219
3-(4-{3-Methyl-1-[4-(5-trifluoromethyl-pyridin-2-yl)-phenoxy]-butyl}-benzo-
ylamino)-propionic acid, Isomer 2
##STR00212##
[0645] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
3-(4-{3-methyl-1-[4-(5-trifluoromethyl-pyridin-2-yl)-phenoxy]-butyl}-benz-
oylamino)-propionic acid methyl ester on Chiralpak AD-H column
(4.6.times.150 mm). MS (ES): 501.2 [M+H].sup.+; MS (ES): 501.2
[M+H].sup.+.
Example 220
3-{4-[1-(4-(4-tert-Butyl-phenoxy)-3-methyl-butyl]-benzoylamino}-propionic
acid, Isomer 1 and
Example 221
3-{4-[1-(4-(4-tert-Butyl-phenoxy)-3-methyl-butyl]-benzoylamino}-propionic
acid, Isomer 2
##STR00213##
[0647] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
3-{4-[1-(4-tert-butyl-phenoxy)-3-methyl-butyl]-benzoylamino}-propionic
acid methyl ester on Chiralpak AD-H column (4.6.times.150 mm).
Isomer 1 MS (ES): 412.3 [M+H].sup.+. Isomer 2 MS (ES): 412.3
[M+H].sup.+.
Example 222
2-Hydroxy-3-{4-[1-(4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-benzoylami-
no}-propionic acid, Isomer 1 and
Example 223
2-Hydroxy-3-{4-[1-(4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-benzoylami-
no}-propionic acid, Isomer 2
##STR00214##
[0649] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
2-hydroxy-3-{4-[1-(4-(4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-benzoy-
lamino}-propionic acid methyl ester on Chiralpak AD-H column
(4.6.times.150 mm). Isomer 1 MS (ES): 542.3 [M-H].sup.-; Isomer 2
MS (ES): 542.3 [M-H].sup.-.
Example 224
2-Hydroxy-3-{4-[1-(4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-benzoylami-
no}-propionic acid, Isomer 1 and
Example 225
2-Hydroxy-3-{4-[1-(4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-benzoylami-
no}-propionic acid, Isomer 2
##STR00215##
[0651] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
2-Hydroxy-3-{4-[1-(4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-benzoylam-
ino}-propionic acid methyl ester on Chiralpak AD-H column
(4.6.times.150 mm). Isomer 1 MS (ES): 542.3 [M-H].sup.-; Isomer 2
MS (ES): 542.3 [M-H].sup.-.
Example 226
3-(4-{1-[4-(1,1,3,3-Tetramethyl-butyl)-phenoxy]-heptyl}-benzoylamino)-prop-
ionic acid, Isomer 1 and
Example 227
3-(4-{1-[4-(1,1,3,3-Tetramethyl-butyl)-phenoxy]-heptyl}-benzoylamino)-prop-
ionic acid, Isomer 2
##STR00216##
[0653] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
3-(4-{1-[4-(1,1,3,3-tetramethyl-butyl)-phenoxy]-heptyl}-benzoylamino)-pro-
pionic acid methyl ester on Chiralpak AD-H column (4.6.times.150
mm). Isomer 1 MS (ES): 496.5 [M+H].sup.+; Isomer 2 MS (ES): 496.5
[M+H].sup.+.
Example 228
3-{4-[1-(2,2,3,3-Tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-heptyl]-
-benzoylamino}-propionic acid, Isomer 1 and
Example 229
3-{4-[1-(2,2,3,3-Tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-heptyl]-
-benzoylamino}-propionic acid, Isomer 2
##STR00217##
[0655] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
3-{4-[1-(2,2,3,3-tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-heptyl-
]-benzoylamino}-propionic acid methyl ester on Chiralpak AD-H
column (4.6.times.150 mm). Isomer 1 MS (ES): 514.2 [M+H].sup.+;
Isomer 2 MS (ES): 514.2 [M+H].sup.+.
Example 230
3-{4-[1-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-3,3-dimethyl-bu-
tyl]-benzoylamino}-propionic acid, Isomer 1 and
Example 231
3-{4-[1-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-3,3-dimethyl-bu-
tyl]-benzoylamino}-propionic acid, Isomer 2
##STR00218##
[0657] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
3-{4-[1-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-3,3-dimethyl-b-
utyl]-benzoylamino}-propionic acid methyl ester on Chiralpak AD-H
column (4.6.times.150 mm). Isomer 1 MS (ES): 540.3 [M-H].sup.-;
Isomer 2 MS (ES): 542.3 [M+H].sup.+.
Example 232
3-{4-[1-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-3,3-dimethyl-butyl]--
benzoylamino}-propionic acid, Isomer 1 and
Example 233
3-{4-[1-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-3,3-dimethyl-butyl]--
benzoylamino}-propionic acid, Isomer 2
##STR00219##
[0659] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
3-{4-[1-(4'-tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-3,3-dimethyl-butyl]-
-benzoylamino}-propionic acid methyl ester on Chiralpak AD-H column
(4.6.times.150 mm). Isomer 1 MS (ES): 528.3 [M-H].sup.-; Isomer 2
MS (ES): 528.3 [M-H].sup.-.
Example 234
3-{4-[1-(4'-Isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-3,3-dimethyl-butyl]-b-
enzoylamino}-propionic acid, Isomer 1 and
Example 235
3-{4-[1-(4'-Isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-3,3-dimethyl-butyl]-b-
enzoylamino}-propionic acid, Isomer 2
##STR00220##
[0661] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
3-{4-[1-(4-(4'-isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-3,3-dimethyl-buty-
l]-benzoylamino}-propionic acid methyl ester on Chiralpak AD-H
column (4.6.times.150 mm). Isomer 1 MS (ES): 516.3 [M+H].sup.+;
Isomer 2 MS (ES): 516.3 [M+H].sup.+.
Example 236
3-(4-{3,3-Dimethyl-1-[5-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylox-
y]-butyl}-benzoylamino)-propionic acid, Isomer 1 and
Example 237
3-(4-{3,3-Dimethyl-1-[5-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylox-
y]-butyl}-benzoylamino)-propionic acid, Isomer 2
##STR00221##
[0663] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
3-(4-{3,3-dimethyl-1-[5-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylo-
xy]-butyl}-benzoylamino)-propionic acid methyl ester on Chiralpak
AD-H column (4.6.times.150 mm). Isomer 1MS (ES): 529.3 [M+H].sup.+;
Isomer 2 MS (ES): 529.3 [M+H].sup.+.
Example 238
3-{4-[1-(4'-Isopropyl-2-methoxy-biphenyl-4-yloxy)-3-methyl-butyl]-benzoyla-
mino}-propionic acid, Isomer 1 and
Example 239
3-{4-[1-(4-(4'-Isopropyl-2-methoxy-biphenyl-4-yloxy)-3-methyl-butyl]-benzo-
ylamino}-propionic acid, Isomer 2
##STR00222##
[0665] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
3-{4-[1-(4'-isopropyl-2-methoxy-biphenyl-4-yloxy)-3-methyl-butyl]-benzoyl-
amino}-propionic acid methyl ester on Chiralpak AD-H column
(4.6.times.150 mm). Isomer 1 MS (ES): 504.2 [M+H].sup.+; Isomer 2
MS (ES): 504.2 [M+H].sup.+.
Example 240
3-{4-[1-(4'-Isopropyl-2-methyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylam-
ino}-propionic acid, Isomer 1 and
Example 241
3-{4-[1-(4'-Isopropyl-2-methyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylam-
ino}-propionic acid, Isomer 2
##STR00223##
[0667] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
3-{4-[1-(4'-isopropyl-2-methyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoyla-
mino}-propionic acid methyl ester on Chiralpak AD-H column
(4.6.times.150 mm). Isomer 1 MS (ES): 488.3 [M+H].sup.+; Isomer 2
MS (ES): 488.3 [M+1-1].sup.+.
Example 242
3-{4-[1-(2,6-Dimethyl-4'-trifluoromethoxy-biphenyl-4-yloxy)-3,3-dimethyl-b-
utyl]-benzoylamino}-propionic acid, Isomer 1 and
Example 243
3-{4-[1-(2,6-Dimethyl-4'-trifluoromethoxy-biphenyl-4-yloxy)-3,3-dimethyl-b-
utyl]-benzoylamino}-propionic acid, Isomer 2
##STR00224##
[0669] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
3-{4-[1-(2,6-dimethyl-4'-trifluoromethoxy-biphenyl-4-yloxy)-3,3-dimethyl--
butyl]-benzoylamino}-propionic acid methyl ester on Chiralpak AD-H
column. (4.6.times.150 mm). Isomer 1 MS (ES): 558.3 [M+H].sup.+;
Isomer 2 MS (ES): 558.3 [M+H].sup.+.
Example 244
3-(4-{1-[2-(tert-Butoxyimino-methyl)-4'-trifluoromethyl-biphenyl-4-yloxy]--
3-methyl-butyl}-benzoylamino)-propionic acid, Isomer 1 and
Example 245
3-(4-{1-[2-(tert-Butoxyimino-methyl)-4'-trifluoromethyl-biphenyl-4-yloxy]--
3-methyl-butyl}-benzoylamino)-propionic acid, Isomer 2
##STR00225##
[0671] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
3-(4-{1-[2-(tert-butoxyimino-methyl)-4'-trifluoromethyl-biphenyl-4-yloxy]-
-3-methyl-butyl}-benzoylamino)-propionic acid methyl ester on
Chiralpak AD-H column (4.6.times.150 mm). Isomer 1 MS (ES): 599.2
[M+H].sup.+; Isomer 2 MS (ES): 599.2 [M+H].sup.+.
Example 246
3-{4-[1-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-3,3-dimethyl-butyl]--
benzoylamino}-2-hydroxy-propionic acid, Isomer 1 and
Example 247
3-{4-[1-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-3,3-dimethyl-butyl]--
benzoylamino}-2-hydroxy-propionic acid, Isomer 2
##STR00226##
[0673] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
3-{4-[1-(4'-tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-3,3-dimethyl-butyl]-
-benzoylamino}-2-hydroxy-propionic acid methyl ester on Chiralpak
AD-H column (4.6.times.150 mm). Isomer 1 MS (ES): 546.3
[M+H].sup.+; Isomer 2 MS (ES): 546.3 [M+H].sup.+.
Example 248
3-{4-[1-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-3,3-dimethyl-butyl]--
benzoylamino}-2-hydroxy-propionic acid, Isomer 1 and
Example 249
3-{4-[1-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-3,3-dimethyl-butyl]--
benzoylamino}-2-hydroxy-propionic acid, Isomer 2
##STR00227##
[0675] These compounds are made by the general method exemplified
in Example 30 by resolving racemic
3-{4-[1-(4'-tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-3,3-dimethyl-butyl]-
-benzoylamino}-2-hydroxy-propionic acid ethyl ester on Chiralpak
AD-H column (4.6.times.150 mm). Isomer 1 MS (ES): 546.3
[M+H].sup.+; Isomer 2 MS (ES): 546.3 [M+H].sup.+.
Example 250
3-{4-[1-(4'-Fluoro-2,6-dimethyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoyla-
mino}-propionic acid, Isomer 1
##STR00228##
[0677] This compound is made in a manner substantially similar to
Example 117 using isomer 1 of
3-{4-[1-(4-bromo-3,5-dimethyl-phenoxy)-3-methyl-butyl]-benzoylamino}-prop-
ionic acid methyl ester and 4-fluorophenylboronic acid as starting
materials in step D. MS (ES): 476.2 [M-H].sup.-.
Example 251
3-{4-[1-(4'-Fluoro-2,6,2'-trimethyl-biphenyl-4-yloxy)-heptyl]-benzoylamino-
}-propionic acid, Isomer 1
##STR00229##
[0679] This compound is made in a manner substantially similar to
Example 117 using isomer 1 of
3-{4-[1-(4-bromo-3,5-dimethyl-phenoxy)-heptyl]-benzoylamino}-propionic
acid methyl ester and 4-fluoro-2-methyl-phenylboronic acid as
starting materials in step D. MS (ES): 520.2 [M+H].sup.+.
Example 252
3-{4-[1-(4'-Chloro-2,6-dimethyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoyla-
mino}-propionic acid, Isomer 1
##STR00230##
[0681] This compound is made in a manner substantially similar to
Example 117 using isomer 1 of
3-{4-[1-(4-bromo-3,5-dimethyl-phenoxy)-3-methyl-butyl]-benzoylamino}-prop-
ionic acid methyl ester and 4-chloro-phenylboronic acid as starting
materials in step D. MS (ES): 492.3 [M+H].sup.+.
Example 253
3-{4-[1-(4'-Isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzo-
ylamino}-propionic acid, Isomer 1
##STR00231##
[0683] This compound is made in a manner substantially similar to
Example 117 using isomer 1 of
3-{4-[1-(4-bromo-3,5-dimethyl-phenoxy)-3-methyl-butyl]-benzoylamino}-prop-
ionic acid methyl ester and 4-isopropylphenylboronic acid as
starting materials in step D. MS (ES): 502.2 [M+H].sup.+.
Example 254
3-{4-[1-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-3-methyl-butyl]-
-benzoylamino}-propionic acid, Isomer 1 and
Example 255
3-{4-[1-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-3-methyl-butyl]-
-benzoylamino}-propionic acid, Isomer 2
##STR00232##
[0685] These compounds are made by the general method as
exemplified in Example 30 by resolving racemic
3-{4-[1-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-3-methyl-butyl-
]-benzoylamino}-propionic acid methyl ester on Chiralpak AD-H
column (4.6.times.150 mm). Isomer 1 MS (ES): 528.3 [M+H].sup.+;
Isomer 2MS (ES): 528.4 [M+H].sup.+.
Example 256
Racemic
3-{4-[1-(4'-tert-Butyl-biphenyl-4-yloxy)-hexyl]-benzoylamino}-prop-
ionic acid
##STR00233##
[0687] This compound is made by the general method exemplified in
Example 1 using 4-(1-hydroxy-hexyl)-benzoic acid methyl ester and
4'-tertbutyl-biphenyl-4-ol as starting materials. MS (ES): 502.2
[M+H].sup.+.
Example 257
Racemic
3-{4-[1-(4-(4'-tert-Butyl-biphenyl-4-yloxy)-heptyl]-3-fluoro-benzo-
ylamino}-propionic acid
##STR00234##
[0689] This compound is made by the general method as exemplified
in Example 1 using 3-fluoro-4-(1-hydroxy-heptyl)-benzoic acid
methyl ester and 4'-tertbutyl-biphenyl-4-ol as starting materials.
MS (ES): 534.2 [M+H].sup.+.
Example 258
Racemic
3-{4-[1-(4'-tert-Butyl-biphenyl-4-yloxy)-3-methyl-butyl]-3-fluoro--
benzoylamino}-propionic acid
##STR00235##
[0691] This compound is made by the general method as exemplified
in Example 1 using 3-fluoro-4-(1-hydroxy-3-methyl-butyl)-benzoic
acid methyl ester and 4'-tertbutyl-biphenyl-4-ol as starting
materials. MS (ES): 504.2 [M-H].sup.-.
Example 259
Racemic
3-{4-[1-(2-Cyano-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-butyl]-be-
nzoylamino}-propionic acid
##STR00236##
[0693] This compound is made by the general method as exemplified
in Example 1 using 4-(1-hydroxy-3-methyl-butyl)-benzoic acid methyl
ester and 4-hydroxy-4'-isopropyl-biphenyl-2-carbonitrile as
starting materials. MS (ES): 499.2 [M+H].sup.+.
Example 260
Racemic
3-{4-[1-(4'-Isopropyl-2-trifluoromethyl-biphenyl-4-yloxy)-heptyl]--
benzoylamino}-propionic acid
##STR00237##
[0695] This compound is made by the general method as exemplified
in Example 1 using 4-(1-hydroxy-heptyl)-benzoic acid methyl ester
and 4'-isopropyl-2-trifluoromethyl-biphenyl-4-ol as starting
materials. MS (ES): 570.2 [M+H].sup.+.
Example 261
Racemic
3-{4-[1-(2-Ethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-benz-
oylamino}-propionic acid
##STR00238##
[0697] This compound is made by the general method as exemplified
in Example 1 using 4-(1-hydroxy-heptyl)-benzoic acid methyl ester
and 2-ethyl-4'-trifluoromethyl-biphenyl-4-ol as starting materials.
MS (ES): 556.3 [M+H].sup.+.
Example 262
3-[4-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxymethyl)-benzoylamino]-pro-
pionic acid
##STR00239##
[0699] This compound is made by the general method as exemplified
in Example 1 using 4-hydroxymethyl-benzoic acid methyl ester and
4'-tert-butyl-2,6-dimethyl-biphenyl-4-ol as starting materials. MS
(ES): 460.2 [M+H].sup.+.
Example 263
3-[4-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxymethyl)-benzoylamino]-pro-
pionic acid
##STR00240##
[0701] This compound is made by the general method as exemplified
in Example 1 using 3-(4-hydroxymethyl-benzoic acid methyl ester and
4'-trifluoromethyl-2,6-dimethyl-biphenyl-4-ol as starting
materials. MS (ES): 472.2 [M+H].sup.+.
Example 264
Racemic
3-{4-[1-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-ethyl]--
benzoylamino}-propionic acid
##STR00241##
[0703] This compound is made by the general method as exemplified
in Example 1 using 4-(1-hydroxy-ethyl)-benzoic acid methyl ester
and 4'-trifluoromethyl-2,6-dimethyl-biphenyl-4-ol as starting
materials. MS (ES): 486.2 [M+H].sup.+.
Example 265
Racemic
3-{4-[1-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-ethyl]-benzo-
ylamino}-propionic acid
##STR00242##
[0705] This compound is made by the general method as exemplified
in Example 1 using 4-(1-hydroxy-ethyl)-benzoic acid methyl ester
and 4'-tert-butyl-2,6-dimethyl-biphenyl-4-ol as starting materials.
MS (ES): 474.2 [M+H].sup.+.
Example 266
Racemic
3-(3-Fluoro-4-{3-methyl-1-[6-(4-trifluoromethyl-phenyl)-pyridin-3--
yloxy]-butyl}-benzoylamino)-propionic acid
##STR00243##
[0707] This compound is made by the general method as exemplified
in Example 1 using 3-fluoro-4-(1-hydroxy-3-methyl-butyl)-benzoic
acid methyl ester and 6-(4-trifluoromethyl-phenyl)-pyridin-3-ol as
starting materials. MS (ES): 519.2 [M+H].sup.+.
Example 267
Racemic
3-(4-{1-[4-(1,1,3,3-Tetramethyl-butyl)-phenoxy]-heptyl}-benzoylami-
no)-propionic acid
##STR00244##
[0709] This compound is made by the general method as exemplified
in Example 1 using 4-(1-hydroxy-heptyl)-benzoic acid methyl ester
and 4-(1,1,3,3-tetramethyl-butyl)-phenol as starting materials. MS
(ES): 494.2 [M-H].sup.-.
Example 268
Racemic
3-(4-{3-Methyl-1-[4-(5-trifluoromethyl-pyridin-2-yl)-phenoxy]-buty-
l}-benzoylamino)-propionic acid
##STR00245##
[0711] This compound is made by the general method as exemplified
in Example 1 using 4-(1-hydroxy-3-methyl-butyl)-benzoic acid methyl
ester and 4-(5-trifluoromethyl-pyridin-2-yl)-phenol as starting
materials. MS (ES): 499.2 [M-H].sup.-.
Example 269
Racemic
3-{4-[1-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-3,3-dimethyl-
-butyl]-benzoylamino}-propionic acid
##STR00246##
[0713] This compound is made by the general method as exemplified
in Example 1 using 4-(1-hydroxy-3,3-dimethyl-butyl)-benzoic acid
methyl ester and 4'-tert-butyl-2,6-dimethyl-biphenyl-4-ol as
starting materials. MS (ES): 530.5 [M+H].sup.+.
Example 270
Racemic
3-{4-[1-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-3,3-dimethyl-
-butyl]-benzoylamino}-2-hydroxy-propionic acid
##STR00247##
[0715] This compound is made by the general method as exemplified
in Example 1 using 4-(1-hydroxy-3,3-dimethyl-butyl)-benzoic acid
methyl ester and 4'-tert-butyl-2,6-dimethyl-biphenyl-4-ol as
starting materials. MS (ES): 546.3 [M+H].sup.+.
Example 271
Racemic
3-{4-[1-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-3,3-dimethyl-
-butyl]-benzoylamino}-2-hydroxy-propionic acid
##STR00248##
[0717] This compound is made by the general method as exemplified
in Example 1 using 4-(1-hydroxy-3,3-dimethyl-butyl)-benzoic acid
methyl ester and 4'-tert-butyl-2,6-dimethyl-biphenyl-4-ol as
starting materials. MS (ES): 546.3 [M+H].sup.+.
Example 272
Chiral
3-{4-[1-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-3-methyl-
-butyl]-benzoylamino}-2-hydroxy-propionic acid, Isomer 1
##STR00249##
[0719] This compound is made by the general method as exemplified
in Example 1 using chiral 4-(1-hydroxy-3-methyl-butyl)-benzoic acid
methyl ester and 2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-ol as
starting materials. MS (ES): 544.2 [M+H].sup.+.
Example 273
Chiral
3-{4-[1-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-3-methyl-
-butyl]-benzoylamino}-2-hydroxy-propionic acid, Isomer 1
##STR00250##
[0721] This compound is made by the general method as exemplified
in Example 1 using chiral 4-(1-hydroxy-3-methyl-butyl)-benzoic acid
methyl ester and 2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-ol as
starting materials. MS (ES): 544.2 [M+H].sup.+.
Example 274
Racemic
3-{4-[1-(4-Bromo-3-[1,3]dioxan-2-yl-phenoxy)-3-methyl-butyl]-benzo-
ylamino}-propionic acid
##STR00251##
[0723] This compound is made by the general method as exemplified
in Example 1 using 4-(1-hydroxy-3-methyl-butyl)-benzoic acid methyl
ester and 4-bromo-3-[1,3]dioxan-2-yl-phenol as starting materials.
MS (ES): 521.3 [M+H].sup.+.
Example 275
Racemic
3-{4-[1-(4-tert-Butyl-phenoxy)-3-methyl-butyl]-benzoylamino}-propi-
onic acid
##STR00252##
[0725] This compound is made by the general method as exemplified
in Example 1 using 4-(1-hydroxy-3-methyl-butyl)-benzoic acid methyl
ester and 4-t-butyl-phenol as starting materials. MS (ES): 412.32
[M+H].sup.+.
Example 276
Racemic
3-{4-[1-(4'-tert-Butyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylam-
ino}-2-hydroxy-propionic acid
##STR00253##
[0727] This compound is made by the general method as exemplified
in Example 1 using 4-(1-hydroxy-3-methyl-butyl)-benzoic acid methyl
ester and 4'-tertbutyl-biphenol as starting materials. MS (ES):
504.2 [M+H].sup.+.
Example 277
Racemic
3-{4-[1-(4'-tert-Butyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylam-
ino}-2-hydroxy-propionic acid
##STR00254##
[0729] This compound is made by the general method as exemplified
in Example 1 using 4-(1-hydroxy-3-methyl-butyl)-benzoic acid methyl
ester and 4'-tertbutyl-biphenol as starting materials. MS (ES):
504.2 [M+H].sup.+.
Example 278
Racemic 3-{4-[1-(4-Pentyl-phenoxy)-heptyl]-benzoylamino}-propionic
acid
##STR00255##
[0731] This compound is made by the general method as exemplified
in Example 1 using 4-(1-hydroxy-heptyl)-benzoic acid methyl ester
and 4-pentyl-phenol as starting materials. MS (ES): 454.2
[M+H].sup.+.
Example 279
Racemic
3-(4-{1-[4-(1-Methyl-1-phenyl-ethyl)-phenoxy]-heptyl}-benzoylamino-
)-propionic acid
##STR00256##
[0733] This compound is made by the general method as exemplified
in Example 1 using 4-(1-hydroxy-heptyl)-benzoic acid methyl ester
and 4-(1-methyl-1-phenyl-ethyl)-phenol as starting materials. MS
(ES): 500.3 [M-H].sup.-.
Example 280
Racemic
2-Hydroxy-3-{4-[1-(4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-be-
nzoylamino}-propionic acid
##STR00257##
[0735] This compound is made by the general method as exemplified
in Example 1 using 4-(1-hydroxy-heptyl)-benzoic acid methyl ester
and 4-trifluoromethyl-biphenol as starting materials. MS (ES):
542.3 [M-H].sup.-.
Example 281
Racemic
2-Hydroxy-3-{4-[1-(4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-be-
nzoylamino}-propionic acid
##STR00258##
[0737] This compound is made by the general method as exemplified
in Example 1 using 4-(1-hydroxy-heptyl)-benzoic acid methyl ester
and 4-trifluoromethyl-biphenol as starting materials. MS (ES):
542.3 [M-H].sup.-.
Example 282
Racemic
3-{4-[1-(4'-Isopropyl-2-methyl-biphenyl-4-yloxy)-3-methyl-butyl]-b-
enzoylamino}-propionic acid
##STR00259##
[0739] This compound is made by the general method as exemplified
in Example 1 using 4-(1-hydroxy-3-methyl-butyl)-benzoic acid methyl
ester and 4t-isopropyl-2-methyl-biphenyl-4-ol as starting
materials. MS (ES): 488.3 [M+H].sup.+.
Example 283
Racemic
3-{4-[1-(4-Chloro-3-trifluoromethyl-phenoxy)-heptyl]-benzoylamino}-
-2-hydroxy-propionic acid
##STR00260##
[0741] This compound is made by the general method as exemplified
in Example 1 using 4-(1-hydroxy-heptyl)-benzoic acid methyl ester
and 4-chloro-3-trifluoromethyl-phenol as starting materials. MS
(ES): 486.2 [M+H].sup.+.
Example 284
Racemic
3-{4-[1-(3-Chloro-4-methyl-phenoxy)-3-methyl-butyl]-benzoylamino}--
propionic acid
##STR00261##
[0743] This compound is made by the general method as exemplified
in Example 1 using 4-(1-hydroxy-3-methyl-butyl)-benzoic acid methyl
ester and 3-chloro-4-methyl-phenol as starting materials. MS (ES):
404.2 [M+H].sup.+.
Example 285
Racemic
3-{4-[1-(2,2,3,3-Tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-
-heptyl]-benzoylamino}-propionic acid
##STR00262##
[0745] This compound is made by the general method as exemplified
in Example 1 using 4-(1-hydroxy-heptyl)-benzoic acid methyl ester
and 2,2,3,3-tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-6-ol as
starting materials. MS (ES): 514.2 [M+H].sup.+.
Example 286
[0746] Racemic
3-{4-[Cyclopropyl-(4'-trifluoromethyl-biphenyl-4-yloxy)-methyl]-benzoylam-
ino}-propionic acid
##STR00263##
[0747] This compound is made by the general method as exemplified
in Example 1 using 4-(cyclopropyl-hydroxy-methyl)-benzoic acid
methyl ester and 4'-trifluoromethyl-biphenyl-4-ol as starting
materials. MS (ES): 482.2 [M-H].sup.-.
Example 287
Racemic
3-{4-[1-(4'-Isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-heptyl]-benzo-
ylamino}-propionic acid
##STR00264##
[0749] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-heptyl)-benzoic acid methyl ester
and 4-bromo-3,5-dimethylphenol as reagents in step A and
4-isopropylphenyl boronic acid in step C as starting materials. MS
(ES): 530.5 [M+H].sup.+.
Example 288
Racemic
3-{4-[1-(4'-Acetyl-2,6-dimethyl-biphenyl-4-yloxy)-heptyl]-benzoyla-
mino}-propionic acid
##STR00265##
[0751] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-heptyl)-benzoic acid methyl ester
and 4-bromo-3,5-dimethylphenol as reagents in step A and
4-acetylphenyl boronic acid in step C as starting materials. MS
(ES): 530.2 [M+H].sup.+.
Example 289
Racemic
3-{4-[1-(4'-tert-Butyl-2-methyl-biphenyl-4-yloxy)-heptyl]-benzoyla-
mino}-propionic acid
##STR00266##
[0753] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-heptyl)-benzoic acid methyl ester
and 4-bromo-3-methylphenol as reagents in step A and
4-tertbutylphenyl boronic acid in step C as starting materials. MS
(ES): 528.3 [M-H].sup.-.
Example 290
Racemic
3-{4-[1-(2-Methyl-4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-ben-
zoylamino}-propionic acid
##STR00267##
[0755] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-heptyl)-benzoic acid methyl ester
and 4-bromo-3-methylphenol as reagents in step A and
4-trifluoromethylphenyl boronic acid in step C as starting
materials. MS (ES): 540.3 [M-H].sup.-.
Example 291
Racemic
3-(4-{1-[6-(4-Isopropyl-phenyl)-5-methyl-pyridin-3-yloxy]-4,4-dime-
thyl-pentyl}-benzoylamino)-propionic acid
##STR00268##
[0757] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-4,4-dimethyl-pentyl)-benzoic acid
methyl ester and 6-chloro-5-methyl-pyridin-3-ol as reagents in step
A and 4-isopropylphenyl boronic acid in step C as starting
materials. MS (ES): 517.3 [M+H].sup.+.
Example 292
Racemic
3-(4-{4,4-Dimethyl-1-[5-methyl-6-(4-trifluoromethyl-phenyl)-pyridi-
n-3-yloxy]-pentyl}-benzoylamino)-propionic acid
##STR00269##
[0759] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-4,4-dimethyl-pentyl)-benzoic acid
methyl ester and 6-chloro-5-methyl-pyridin-3-ol as reagents in step
A and 4-trifluoromethylphenyl boronic acid in step C as starting
materials. MS (ES): 529.3 [M+H].sup.+.
Example 293
Racemic
3-(4-{4,4-Dimethyl-1-[5-methyl-6-(4-trifluoromethoxy-phenyl)-pyrid-
in-3-yloxy]-pentyl}-benzoylamino)-propionic acid
##STR00270##
[0761] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-4,4-dimethyl-pentyl)-benzoic acid
methyl ester and 6-chloro-5-methyl-pyridin-3-ol as reagents in step
A and 4-trifluoromethoxyphenyl boronic acid in step C as starting
materials. MS (ES): 545.3 [M+H].sup.+.
Example 294
Racemic
3-{4-[1-(2,6-Dimethyl-4'-trifluoromethoxy-biphenyl-4-yloxy)-3,3-di-
methyl-butyl]-benzoylamino}-propionic acid
##STR00271##
[0763] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-3,3-dimethyl-butyl)-benzoic acid
methyl ester and 4-bromo-3,5-dimethyl-phenol as reagents in step A
and 4-trifluoromethoxyphenyl boronic acid in step C as starting
materials. MS (ES): 558.3 [M+H].sup.+.
Example 295
Racemic
3-{4-[1-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-3,3-dim-
ethyl-butyl]-benzoylamino}-2-hydroxy-propionic acid
##STR00272##
[0765] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-3,3-dimethyl-butyl)-benzoic acid
methyl ester and 4-bromo-3,5-dimethyl-phenol as reagents in step A
and 4-trifluoromethylphenyl boronic acid in step C as starting
materials. MS (ES): 558.3 [M+H].sup.+.
Example 296
Racemic
3-{4-[1-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-3,3-dim-
ethyl-butyl]-benzoylamino}-2-hydroxy-propionic acid
##STR00273##
[0767] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-3,3-dimethyl-butyl)-benzoic acid
methyl ester and 4-bromo-3,5-dimethyl-phenol as reagents in step A
and 4-trifluoromethylphenyl boronic acid in step C as starting
materials. MS (ES): 558.3 [M+H].sup.+.
Example 297
Racemic
2-Hydroxy-3-{4-[1-(4'-isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-3,3-
-dimethyl-butyl]-benzoylamino}-propionic acid
##STR00274##
[0769] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-3,3-dimethyl-butyl)-benzoic acid
methyl ester and 4-bromo-3,5-dimethyl-phenol as reagents in step A
and 4-trifluoromethylphenyl boronic acid in step C as starting
materials. MS (ES): 532.3 [M+H].sup.+.
Example 298
Racemic
3-{4-[1-(4'-Isopropyl-2-methoxy-biphenyl-4-yloxy)-3-methyl-butyl]--
benzoylamino}-propionic acid
##STR00275##
[0771] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-3-methyl-butyl)-benzoic acid
methyl ester and 4-bromo-3-methoxy-phenol as reagents in step A and
4-isopropylphenyl boronic acid in step C as starting materials. MS
(ES): 504.2 [M+H].sup.+.
Example 299
Racemic
3-{3-Fluoro-4-[1-(2-methyl-4'-trifluoromethyl-biphenyl-4-yloxy)-he-
ptyl]-benzoylamino}-propionic acid
##STR00276##
[0773] This compound is made by the general method as exemplified
in Example 24 using 3-fluoro-4-(1-hydroxy-heptyl)-benzoic acid
methyl ester and 4-bromo-3-methylphenol as reagents in step A and
4-trifluoromethylphenyl boronic acid in step C as starting
materials. MS (ES): 516.3 [M+H].sup.+.
Example 300
Racemic
3-{4-[1-(4'-tert-Butyl-2-chloro-biphenyl-4-yloxy)-heptyl]-benzoyla-
mino}-propionic acid
##STR00277##
[0775] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-heptyl)-benzoic acid methyl ester
and 4-bromo-3-chloro-phenol as reagents in step A and
4-tertbutylphenyl boronic acid in step C as starting materials. MS
(ES): 548.3 [M-H].sup.-.
Example 301
Racemic
3-{4-[1-(4'-trifluoromethyl-2-chloro-biphenyl-4-yloxy)-heptyl]-ben-
zoylamino}-propionic acid
##STR00278##
[0777] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-heptyl)-benzoic acid methyl ester
and 4-bromo-3-chloro-phenol as reagents in step A and
4-trifluoromethylphenyl boronic acid in step C as starting
materials. MS (ES): 560.2 [M-H].sup.-.
Example 302
Racemic
3-{4-[1-(2',4'-bistrifluoromethyl-2-chloro-biphenyl-4-yloxy)-hepty-
l]-benzoylamino}-propionic acid
##STR00279##
[0779] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-heptyl)-benzoic acid methyl ester
and 4-bromo-3-chloro-phenol as reagents in step A and
2,4-bistrifluoromethylphenyl boronic acid in step C as starting
materials. MS (ES): 628.3 [M-H].sup.-.
Example 303
Racemic
3-{4-[1-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-3-methy-
l-butyl]-benzoylamino}-propionic acid
##STR00280##
[0781] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-3-methyl-butyl)-benzoic acid
methyl ester and 4-bromo-3,5-dimethyl-phenol as reagents in step A
and 4-trifluoromethylphenyl boronic acid in step C as starting
materials. MS (ES): 526.2 [M-H].sup.-.
Example 304
Racemic
3-{4-[1-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-3-methyl-but-
yl]-benzoylamino}-propionic acid
##STR00281##
[0783] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-3-methyl-butyl)-benzoic acid
methyl ester and 4-bromo-3,5-dimethyl-phenol as reagents in step A
and 4-t-butylphenyl boronic acid in step C as starting materials.
MS (ES): 516.3 [M+H].sup.+.
Example 305
Racemic
3-{4-[1-(2-Hydroxy-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-butyl]--
benzoylamino}-propionic acid
##STR00282##
[0785] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-3-methyl-butyl)-benzoic acid
methyl ester and 4-bromo-benzene-1,3-diol as reagents in step A and
4-isopropylphenyl boronic acid in step C as starting materials. MS
(ES): 490.2 [M+H].sup.+.
Example 306
Racemic
3-{4-[1-(2-[1,3]Dioxan-2-yl-4'-isopropyl-biphenyl-4-yloxy)-3-methy-
l-butyl]-benzoylamino}-propionic acid
##STR00283##
[0787] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-3-methyl-butyl)-benzoic acid
methyl ester and 4-bromo-3-[1,3]dioxan-2-yl-phenol as reagents in
step A and 4-isopropylphenyl boronic acid in step C as starting
materials. MS (ES): 560.2 [M+H].sup.+.
Example 307
Racemic
3-(4-{1-[2-(tert-Butoxyimino-methyl)-4'-isopropyl-biphenyl-4-yloxy-
]-3-methyl-butyl}-benzoylamino)-propionic acid
##STR00284##
[0789] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-3-methyl-butyl)-benzoic acid
methyl ester and 2-bromo-5-hydroxy-benzaldehyde O-tert-butyl-oxime
as reagents in step A and 4-isopropylphenyl boronic acid in step C
as starting materials. MS (ES): 573.3 [M+H].sup.+.
Example 308
Racemic
3-(4-{1-[2-(tert-Butoxyimino-methyl)-4'-trifluoromethyl-biphenyl-4-
-yloxy]-3-methyl-butyl}-benzoylamino)-propionic acid
##STR00285##
[0791] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-3-methyl-butyl)-benzoic acid
methyl ester and 2-bromo-5-hydroxy-benzaldehyde O-tert-butyl-oxime
as reagents in step A and 4-trifluoromethylphenyl boronic acid in
step C as starting materials. MS (ES): 599.2 [M+H].sup.+.
Example 309
Racemic
3-{4-[1-(2,6-Dimethyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylami-
no}-propionic acid
##STR00286##
[0793] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-3-methyl-butyl)-benzoic acid
methyl ester and 4-bromo-3,5-dimethyl-phenol as reagents in step A
and phenyl boronic acid in step C as starting materials. MS (ES):
460.2 [M+H].sup.+.
Example 310
Racemic
3-{4-[1-(4'-Ethyl-2,6-dimethyl-biphenyl-4-yloxy)-3-methyl-butyl]-b-
enzoylamino}-propionic acid
##STR00287##
[0795] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-3-methyl-butyl)-benzoic acid
methyl ester and 4-bromo-3,5-dimethyl-phenol as reagents in step A
and 4-ethyl-phenyl boronic acid in step C as starting materials. MS
(ES): 486.2 [M-H].sup.-.
Example 311
Racemic
3-{4-[1-(2-Methyl-4'-trifluoromethoxy-biphenyl-4-yloxy)-heptyl]-be-
nzoylamino}-propionic acid
##STR00288##
[0797] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-heptyl)-benzoic acid methyl ester
and 4-bromo-3-methyl-phenol as reagents in step A and
4-trifluoromethoxy-phenyl boronic acid in step C as starting
materials. MS (ES): 556.3 [M-H].sup.-.
Example 312
Racemic
3-{4-[1-(4'-Isopropyl-2-methyl-biphenyl-4-yloxy)-heptyl]-benzoylam-
ino}-propionic acid
##STR00289##
[0799] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-heptyl)-benzoic acid methyl ester
and 4-bromo-3-methyl-phenol as reagents in step A and
4-isopropyl-phenyl boronic acid in step C as starting materials. MS
(ES): 516.3 [M+H].sup.+.
Example 313
Racemic
3-{4-[1-(2,6-Dimethyl-4'-trifluoromethoxy-biphenyl-4-yloxy)-3-meth-
yl-butyl]-benzoylamino}-propionic acid
##STR00290##
[0801] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-3-methyl-butyl)-benzoic acid
methyl ester and 4-bromo-3,5-dimethyl-phenol as reagents in step A
and 4-trifluoromethoxy -phenyl boronic acid in step C as starting
materials. MS (ES): 542.3 [M-H].sup.-.
Example 314
Racemic
3-{4-[1-(4'-ethyl-2-methyl-biphenyl-4-yloxy)-heptyl]-benzoylamino}-
-propionic acid
##STR00291##
[0803] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-heptyl)-benzoic acid methyl ester
and 4-bromo-3-methyl-phenol as reagents in step A and
4-ethyl-phenyl boronic acid in step C as starting materials. MS
(ES): 502.2 [M+H].sup.+.
Example 315
Racemic
3-{4-[1-(4'-acetyl-2-methyl-biphenyl-4-yloxy)-heptyl]-benzoylamino-
}-propionic acid
##STR00292##
[0805] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-heptyl)-benzoic acid methyl ester
and 4-bromo-3-methyl-phenol as reagents in step A and
4-acetyl-phenyl boronic acid in step C as starting materials. MS
(ES): 514.2 [M-H].sup.-.
Example 316
Racemic
3-{4-[1-(4'-fluoro-2-methyl-biphenyl-4-yloxy)-heptyl]-benzoylamino-
}-propionic acid
##STR00293##
[0807] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-heptyl)-benzoic acid methyl ester
and 4-bromo-3-methyl-phenol as reagents in step A and
4-fluoro-phenyl boronic acid in step C as starting materials. MS
(ES): 490.2 [M-H].sup.-.
Example 317
Racemic
3-{4-[1-(4'-tert-Butyl-2-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-
-benzoylamino}-propionic acid
##STR00294##
[0809] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-heptyl)-benzoic acid methyl ester
and 4-chloro-3-trifluoromethyl-phenol as reagents in step A and
4-tertbutyl-phenyl boronic acid in step C as starting materials. MS
(ES): 582.2 [M-H].sup.-.
Example 318
Racemic
3-{4-[1-(4'-tert-Butyl-2-trifluoromethyl-biphenyl-4-yloxy)-pentyl]-
-benzoylamino}-propionic acid
##STR00295##
[0811] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-pentyl)-benzoic acid methyl ester
and 4-chloro-3-trifluoromethyl-phenol as reagents in step A and
4-tertbutyl-phenyl boronic acid in step C as starting materials. MS
(ES): 554.2 [M-H].sup.-.
Example 319
Racemic
3-{4-[1-(4'-tert-Butyl-2-trifluoromethyl-biphenyl-4-yloxy)-2-methy-
l-propyl]benzoylamino}-propionic acid
##STR00296##
[0813] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-2-methyl-propyl)-benzoic acid
methyl ester and 4-chloro-3-trifluoromethyl-phenol as reagents in
step A and 4-t-butyl-phenyl boronic acid in step C as starting
materials. MS (ES): 540.3 [M-H].sup.-.
Example 320
Racemic
3-{4-[1-(4'-tert-Butyl-2-trifluoromethyl-biphenyl-4-yloxy)-3-methy-
l-butyl]-benzoylamino}-propionic acid
##STR00297##
[0815] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-3-methyl-butyl)-benzoic acid
methyl ester and 4-chloro-3-trifluoromethyl-phenol as reagents in
step A and 4-tertbutyl-phenyl boronic acid in step C as starting
materials. MS (ES): 554.2 [M-H].sup.-.
Example 321
Racemic
3-{4-[1-(3,5-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-
-benzoylamino}-propionic acid
##STR00298##
[0817] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-heptyl)-benzoic acid methyl ester
and 4-bromo-3,5-dimethyl-phenol as reagents in step A and
4-trifluoromethyl-phenyl boronic acid in step C as starting
materials. MS (ES): 554.2 [M-H].sup.-.
Example 322
Racemic
3-{4-[1-(4'-Chloro-3,5-dimethyl-biphenyl-4-yloxy)-heptyl]-benzoyla-
mino}-propionic acid
##STR00299##
[0819] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-heptyl)-benzoic acid methyl ester
and 4-bromo-3,5-dimethyl-phenol as reagents in step A and
4-chloro-phenyl boronic acid in step C as starting materials. MS
(ES): 522.2 [M+H].sup.+.
Example 323
Racemic
3-{4-[1-(4'-Chloro-3-methyl-biphenyl-4-yloxy)-heptyl]-benzoylamino-
}-propionic acid
##STR00300##
[0821] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-heptyl)-benzoic acid methyl ester
and 4-bromo-3-dimethyl-phenol as reagents in step A and
4-chloro-phenyl boronic acid in step C as starting materials. MS
(ES): 506.2 [M-H].sup.-.
Example 324
Racemic
3-{4-[1-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-3,3-dim-
ethyl-butyl]-benzoylamino}-propionic acid
##STR00301##
[0823] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-3,3-dimethyl-butyl)-benzoic acid
methyl ester and 4-bromo-3,5-dimethyl-phenol as reagents in step A
and 4-fluoromethyl-phenyl boronic acid in step C as starting
materials. MS (ES): 540.3 [M-H].sup.-.
Example 325
Racemic
3-{4-[1-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-4,4-dim-
ethyl-pentyl]-benzoylamino}-propionic acid
##STR00302##
[0825] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-4,4-dimethyl-pentyl)-benzoic acid
methyl ester and 4-bromo-3,5-dimethyl-phenol as reagents in step A
and 4-fluoromethyl-phenyl boronic acid in step C as starting
materials. MS (ES): 554.2 [M-H].sup.-.
Example 326
Racemic
3-{4-[1-(2,6-Dimethyl-4'-isopropyl-biphenyl-4-yloxy)-4,4-dimethyl--
pentyl]-benzoylamino}-propionic acid
##STR00303##
[0827] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-4,4-dimethyl-pentyl)-benzoic acid
methyl ester and 4-bromo-3,5-dimethyl-phenol as reagents in step A
and 4-isopropyl-phenyl boronic acid in step C as starting
materials. MS (ES): 530.2 [M+H].sup.+.
Example 327
Racemic
3-{4-[1-(4'-Isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-2-methyl-prop-
yl]-benzoylamino}-propionic acid
##STR00304##
[0829] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-2-methyl-propyl)-benzoic acid
methyl ester and 4-bromo-3,5-dimethyl-phenol as reagents in step A
and 4-isopropyl-phenyl boronic acid in step C as starting
materials. MS (ES): 488.3 [M+H].sup.+.
Example 328
Racemic
3-{4-[1-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-2-methy-
l-propyl]-benzoylamino}-propionic acid
##STR00305##
[0831] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-2-methyl-propyl)-benzoic acid
methyl ester and 4-bromo-3,5-dimethyl-phenol as reagents in step A
and 4-trifluoromethyl-phenyl boronic acid in step C as starting
materials. MS (ES): 514.2 [M+H].sup.+.
Example 329
Racemic
3-{4-[2-Methyl-1-(2-methyl-4'-trifluoromethyl-biphenyl-4-yloxy)-pr-
opyl]-benzoylamino}-propionic acid
##STR00306##
[0833] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-2-methyl-propyl)-benzoic acid
methyl ester and 4-bromo-3-methyl-phenol as reagents in step A and
4-trifluoromethyl-phenyl boronic acid in step C as starting
materials. MS (ES): 500.3 [M+H].sup.+.
Example 330
Racemic
3-{4-[1-(2,6-Dimethyl-4'-chloro-biphenyl-4-yloxy)-4,4-dimethyl-pen-
tyl]-benzoylamino}-propionic acid
##STR00307##
[0835] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-4,4-dimethyl-pentyl)-benzoic acid
methyl ester and 4-bromo-3,5-dimethyl-phenol as reagents in step A
and 4-chloro-phenyl boronic acid in step C as starting materials.
MS (ES): 522.2 [M+H].sup.+.
Example 331
Racemic
3-{4-[1-(4'-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-2-methyl-pro-
pyl]-benzoylamino}-propionic acid
##STR00308##
[0837] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-2-methyl-propyl)-benzoic acid
methyl ester and 4-bromo-3-methyl-phenol as reagents in step A and
4-tertbutyl-phenyl boronic acid in step C as starting materials. MS
(ES): 502.2 [M+H].sup.+.
Example 332
Racemic
3-{4-[1-(4'-Isopropyl-2-methyl-biphenyl-4-yloxy)-2-methyl-propyl]--
benzoylamino}-propionic acid
##STR00309##
[0839] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-2-methyl-propyl)-benzoic acid
methyl ester and 4-bromo-3-methyl-phenol as reagents in step A and
4-isopropyl-phenyl boronic acid in step C as starting materials. MS
(ES): 474.2 [M+H].sup.+.
Example 333
Racemic
3-{4-[1-(2,6-Difluoro-4'-trifluoromethyl-biphenyl-4-yloxy)-3-methy-
l-butyl]-benzoylamino}-propionic acid
##STR00310##
[0841] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-3-methyl-butyl)-benzoic acid
methyl ester and 4-bromo-3,5-difluoro-phenol as reagents in step A
and 4-trifluoromethyl-phenyl boronic acid in step C as starting
materials. MS (ES): 536.2 [M+H].sup.+.
Example 334
Racemic
3-{4-[1-(2,6-Difluoro-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-buty-
l]-benzoylamino}-propionic acid
##STR00311##
[0843] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-3-methyl-butyl)-benzoic acid
methyl ester and 4-bromo-3,5-difluoro-phenol as reagents in step A
and 4-isopropyl-phenyl boronic acid in step C as starting
materials. MS (ES): 510.2 [M+H].sup.+.
Example 335
Racemic
3-{4-[1-(2-Chloro-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-butyl]-b-
enzoylamino}-propionic acid
##STR00312##
[0845] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-3-methyl-butyl)-benzoic acid
methyl ester and 4-bromo-3-chloro-phenol as reagents in step A and
4-isopropyl-phenyl boronic acid in step C as starting materials. MS
(ES): 508.3 [M+H].sup.+.
Example 336
Racemic
3-{4-[1-(2-Chloro-4'-trifluoromethyl-biphenyl-4-yloxy)-3-methyl-bu-
tyl]-benzoylamino}-propionic acid
##STR00313##
[0847] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-3-methyl-butyl)-benzoic acid
methyl ester and 4-bromo-3-chloro-phenol as reagents in step A and
4-trifluoromethyl-phenyl boronic acid in step C as starting
materials. MS (ES): 534.2 [M+H].sup.+.
Example 337
Racemic
3-(4-{3-Methyl-1-[5-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3--
yloxy]-butyl}-benzoylamino)-propionic acid
##STR00314##
[0849] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-3-methyl-butyl)-benzoic acid
methyl ester and 6-chloro-5-methyl-pyridin-3-ol as reagents in step
A and 4-trifluoro-phenyl boronic acid in step C as starting
materials. MS (ES): 515.2 [M+H].sup.+.
Example 338
Racemic
3-(4-{1-[6-(4-Isopropyl-phenyl)-5-methyl-pyridin-3-yloxy]-3-methyl-
-butyl}-benzoylamino)-propionic acid
##STR00315##
[0851] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-3-methyl-butyl)-benzoic acid
methyl ester and 6-chloro-5-methyl-pyridin-3-ol as reagents in step
A and 4-isopropyl-phenyl boronic acid in step C as starting
materials. MS (ES): 489.2 [M+H].sup.+.
Example 339
Racemic
3-{4-[1-(4'-tert-Butyl-biphenyl-3-yloxy)-3-methyl-butyl]-benzoylam-
ino}-propionic acid
##STR00316##
[0853] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-3-methyl-butyl)-benzoic acid
methyl ester and 3-bromo-phenol as reagents in step A and
4-tertbutyl-phenyl boronic acid in step C as starting materials. MS
(ES): 488.3 [M+H].sup.+.
Example 340
Racemic
3-{4-[3-Methyl-1-(4'-trifluoromethyl-biphenyl-3-yloxy)-butyl]-benz-
oylamino}-propionic acid
##STR00317##
[0855] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-3-methyl-butyl)-benzoic acid
methyl ester and 3-bromo-phenol as reagents in step A and
4-trifluoromethyl-phenyl boronic acid in step C as starting
materials. MS (ES): 500.3 [M+H].sup.+.
Example 341
Racemic
3-{4-[1-(4'-Isopropyl-biphenyl-3-yloxy)-3-methyl-butyl]-benzoylami-
no}-propionic acid
##STR00318##
[0857] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-3-methyl-butyl)-benzoic acid
methyl ester and 3-bromo-phenol as reagents in step A and
4-isopropyl-phenyl boronic acid in step C as starting materials. MS
(ES): 474.2 [M+H].sup.+.
Example 342
Racemic
3-{4-[3-Methyl-1-(4'-trifluoromethoxy-biphenyl-3-yloxy)-butyl]-ben-
zoylamino}-propionic acid
##STR00319##
[0859] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-3-methyl-butyl)-benzoic acid
methyl ester and 3-bromo-phenol as reagents in step A and
4-trifluoromethoxy-phenyl boronic acid in step C as starting
materials. MS (ES): 516.3 [M+H].sup.+.
Example 343
Racemic
3-{4-[3-Methyl-1-(6-methyl-4'-trifluoromethyl-biphenyl-3-yloxy)-bu-
tyl]-benzoylamino}-propionic acid
##STR00320##
[0861] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-3-methyl-butyl)-benzoic acid
methyl ester and 3-bromo-4-methyl-phenol as reagents in step A and
4-trifluoromethyl-phenyl boronic acid in step C as starting
materials. MS (ES): 514.2 [M+H].sup.+.
Example 344
Racemic
3-{4-[1-(4'-tert-Butyl-6-methyl-biphenyl-3-yloxy)-3-methyl-butyl]--
benzoylamino}-propionic acid
##STR00321##
[0863] This compound is made by the general method as exemplified
in Example 24 using 4-(1-hydroxy-3-methyl-butyl)-benzoic acid
methyl ester and 3-bromo-4-methyl-phenol as reagents in step A and
4-t-butyl-phenyl boronic acid in step C as starting materials. MS
(ES): 502.2 [M+H].sup.+.
Example 345
Racemic
3-{4-[1-(2-Hydroxymethyl-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-b-
utyl]-benzoylamino}-propionic acid
##STR00322##
[0864] and
Example 346
Racemic
3-{4-[1-(2-Formyl-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-butyl]-b-
enzoylamino}-propionic acid
##STR00323##
[0865] Step A.
4-[1-(4-Bromo-3-[1,3]dioxan-2-yl-phenoxy)-3-methyl-butyl]-benzoic
acid methyl ester
[0866] To a solution of 4-(1-hydroxy-3-methyl-butyl)-benzoic acid
methyl ester (1600 mg, 7.21 mmol) in toluene (72 mL) is added
1,1'-(azodicarbonyl)dipiperidine (ADDP, 2728 mg, 10.81 mmol) at
0.degree. C., followed by the additions of tributylphosphine (2.69
mL, 10.81 mmol) and 4-bromo-3-[1,3]dioxan-2-yl-phenol (2240 mg,
8.65 mmol). The reaction mixture is warmed up to room temperature
and stirred overnight. The mixture is loaded on silica gel, eluted
with hexanes with a gradient from 0% of ethyl acetate to 50% of
ethyl acetate giving the titled compound (1000 mg).
Step B.
4-[1-(4-Bromo-3-[1,3]dioxan-2-yl-phenoxy)-3-methyl-butyl]-benzoic
acid
[0867] To the solution of
4-[1-(4-bromo-3-[1,3]dioxan-2-yl-phenoxy)-3-methyl-butyl]-benzoic
acid methyl ester (1000 mg) in methanol (20 mL) is added sodium
hydroxide (5 N aqueous, 2 mL) and stirred for 4 h. The reaction
mixture is concentrated and acidified by 5 N HCl (2 mL), extracted
with ethyl acetate. Combined organic layers are washed with water
and brine, dried over sodium sulfate. Concentration gives the title
compound (940 mg) as a white solid.
Step C.
3-{4-[1-(4-Bromo-3-[1,3]dioxan-2-yl-phenoxy)-3-methyl-butyl]-benzo-
ylamino}-propionic acid methyl ester
[0868] To a mixture of
4-[1-(4-bromo-[1,3]dioxan-2-yl-phenoxy)-3-methyl-butyl]-benzoic
acid (940 mg, 2.09 mmol) in methylene chloride (21 mL) is added
triethyl amine (0.88mL, 6.28 mmol), DMAP (5.0 mg),
3-Amino-propionic acid methyl ester hydrochloride (438 mg, 3.14
mmol) and EDCI (1207 mg, 6.28 mmol) at room temperature. The
reaction mixture is stirred at room temperature overnight, loaded
on silica gel, eluted with eluted with hexanes with a gradient from
0% of ethyl acetate to 100% of ethyl acetate giving the titled
compound (670 mg).
Step D.
3-{4-[1-(2-[1,3]Dioxan-2-yl-4'-isopropyl-biphenyl-4-yloxy)-3-methy-
l-butyl]-benzoylamino}-propionic acid methyl ester
[0869]
3-{4-[1-(4-Bromo-3-[1,3]dioxan-2-yl-phenoxy)-3-methyl-butyl]-benzoy-
lamino}-propionic acid methyl ester (560 mg, 1.05 mmol), potassium
Fluoride (183 mg, 3.15 mmol), 4-isopropylphenyl boronic acid (344
mg, 2.1 mmol) and tetrakis(triphenylphosphine)palladium (121 mg,
0.105 mmol) are placed in a flask. After the reaction is purged
with N.sub.2 for several times, THF/H.sub.2O (20 ml/5 ml) is added.
The resulting solution is refluxed overnight, loaded on silica gel,
eluted with hexane and ethyl acetate to give the titled compound
(570 mg).
Step E. Racemic
3-{4-[1-(2-Formyl-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoyla-
mino}-propionic acid methyl ester, and
Racemic
3-{4-[1-(2-Formyl-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-butyl]-b-
enzoylamino}-propionic acid
[0870]
3-{4-[1-(2-[1,3]Dioxan-2-yl-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-
-butyl]-benzoylamino}-propionic acid methyl ester (570 mg) is taken
into THF (10 ml), treated with 5N HCl for 5 h, neutralfied with 5N
NaOH, extracted with ethyl actate, dried over MgSO.sub.4 and
concentrated. The residue is purified by column chromatography to
afford
3-{4-[1-(2-formyl-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoyla-
mino}-propionic acid methyl ester (36 mg) and
3-{4-[1-(2-formyl-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoyla-
mino}-propionic acid (228 mg). MS (ES): 502.2 [M+H].sup.+.
Step F.
3-{4-[1-(2-Hydroxymethyl-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-b-
utyl]-benzoylamino}-propionic acid
[0871] To the solution of
3-{4-[1-(2-formyl-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoyla-
mino}-propionic acid methyl ester (36 mg, 0.07 mmol) in methanol (5
ml) is added NaBH.sub.4 (3 mg, 0.07 mmol). After 2 h, the mixture
is diluted with ethyl actate, washed with 1N HCl, water, brine,
dried over MgSO.sub.4, and concentrated. The residue is taken into
methanol (20 mL), followed by the addition of sodium hydroxide (5 N
aqueous, 1 mL), stirred for 4 h. The reaction mixture is
concentrated and acidified by 5 N HCl (1 mL), extracted with ethyl
acetate. Combined organic layers are washed with water and brine,
dried over sodium sulfate. Concentration gives the title compound
(93 mg) as a white solid. MS (ES): 502.2 [M-H].sup.-.
Example 347
Racemic
3-(4-{1-[2-(Hydroxyimino-methyl)-4'-isopropyl-biphenyl-4-yloxy]-3--
methyl-butyl}-benzoylamino)-propionic acid
##STR00324##
[0873] To the solution of
3-{4-[1-(2-formyl-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoyla-
mino}-propionic acid (75 mg, 0.15 mmol) in methanol (10 ml) is
added hydroxylamine hydrochloride (104 mg, 1.5 mmol). After 4 h,
the mixture is diluted with ethyl actate, washed with 1N HCl,
water, brine, dried over MgSO.sub.4, and concentrated. The residue
is purified by column chromatography to afford 38 mg of
3-(4-{1-[2-(hydroxyimino-methyl)-4'-isopropyl-biphenyl-4-yloxy]-3-methyl--
butyl}-benzoylamino)-propionic acid methyl ester, which is
hydrolyzed by 5N NaOH to afford the titled compound (36 mg). MS
(ES): 517.2 [M+H].sup.+.
Example 348
Racemic
3-{4-[1-(4'-Isopropyl-2-morpholin-4-ylmethyl-biphenyl-4-yloxy)-3-m-
ethyl-butyl]-benzoylamino}-propionic acid
##STR00325##
[0875] To the solution of
3-{4-[1-(2-formyl-4'-isopropyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoyla-
mino}-propionic acid (240 mg, 0.48 mmol) and Morpholine (84 mg,
0.96 mmol) in dichlorometane (20 ml) is added NaBH(OAc).sub.3 (143
mg, 0.67 mmol) and acetic acid (58 mg, 0.96 mmol). The resulting
mixture is stirred overnight, diluted with ethyl actate, washed
with 1N HCl, water, brine, dried over MgSO.sub.4, and concentrated.
The residue is purified by column chromatography to afford 80 mg of
the titled compound as a white solid. MS (ES): 573.5
[M+H].sup.+.
Example 349
3-(4-{3,3-Dimethyl-1-[5-methyl-1-oxy-6-(4-trifluoromethoxy-phenyl)-pyridin-
-3-yloxy]-butyl}-benzoylamino)-propionic acid
##STR00326##
[0876] Step A.
4-[1-(6-Chloro-5-methyl-pyridin-3-yloxy)-3,3-dimethyl-butyl]-benzoic
acid methyl ester
[0877] To a solution of 4-(1-hydroxy-3,3-dimethyl-butyl)-benzoic
acid methyl ester (450 mg, 1.91 mmol) in toluene (19 mL) is added
1,1'-(azodicarbonyl)dipiperidine (ADDP, 722 mg, 2.86 mmol) at
0.degree. C., followed by the additions of tributylphosphine (0.71
mL, 2.86 mmol) and 6-chloro-5-methyl-pyridin-3-ol (327 mg, 2.29
mmol). The reaction mixture is warmed up to room temperature and
stirred overnight. The mixture is loaded on silica gel, eluted with
hexanes with a gradient from 0% of ethyl acetate to 50% of ethyl
acetate giving the titled compound (440 mg).
Step B.
4-[1-(6-Chloro-5-methyl-pyridin-3-yloxy)-3,3-dimethyl-butyl]-benzo-
ic acid
[0878] To the solution of
4-[1-(6-chloro-5-methyl-pyridin-3-yloxy)-3,3-dimethyl-butyl]-benzoic
acid methyl ester (440 mg) in methanol (30 mL) is added sodium
hydroxide (5 N aqueous, 2 mL) and stirred for 5 h. The reaction
mixture is concentrated and acidified by 5 N HCl (2 mL), extracted
with ethyl acetate. Combined organic layers are washed with water
and brine, dried over sodium sulfate. Concentration gives the
titled compound (414 mg).
Step C.
3-{4-[1-(6-Chloro-5-methyl-pyridin-3-yloxy)-3,3-dimethyl-butyl]-be-
nzoylamino}-propionic acid methyl ester
[0879] To a mixture of
4-[1-(6-chloro-5-methyl-pyridin-3-yloxy)-3,3-dimethyl-butyl]-benzoic
acid (414 mg, 1.19 mmol) in methylene chloride (12 mL) is added
triethyl amine (0.5 mL, 3.6 mmol), DMAP (5.0 mg), 3-Amino-propionic
acid methyl ester hydrochloride (250 mg, 1.8 mmol) and EDCI (688
mg, 3.6 mmol) at room temperature. The reaction mixture is stirred
at room temperature overnight, loaded on silica gel, eluted with
eluted with hexanes with a gradient from 0% of ethyl acetate to
100% of ethyl acetate giving the titled compound (400 mg).
Step D.
3-(4-{3,3-Dimethyl-1-[5-methyl-6-(4-trifluoromethoxy-phenyl)-pyrid-
in-3-yloxy]-butyl}-benzoylamino)-propionic acid methyl ester
[0880]
3-{4-[1-(6-Chloro-5-methyl-pyridin-3-yloxy)-3,3-dimethyl-butyl]-ben-
zoylamino}-propionic acid methyl ester (200 mg, 0.46 mmol),
potassium fluoride (80 mg, 1.38 mmol), 4-trifluoromethoxyphenyl
boronic acid (190 mg, 0.92 mmol) and
tetrakis(triphenylphosphine)palladium (53 mg, 0.046 mmol) are
placed in a flask. After the reaction is purged with N.sub.2 for
several times, THF/H.sub.2O (20 ml/5 ml) is added. The resulting
solution is refluxed overnight, loaded on silica gel, eluted with
hexane and ethyl acetate to give the titled compound (220 mg).
Step F.
3-(4-{3,3-Dimethyl-1-[5-methyl-1-oxy-6-(4-trifluoromethoxy-phenyl)-
-pyridin-3-yloxy]-butyl}-benzoylamino)-propionic acid
[0881] To the solution of
3-(4-{3,3-Dimethyl-1-[5-methyl-6-(4-trifluoromethoxy-phenyl)-pyridin-3-yl-
oxy]-butyl}-benzoylamino)-propionic acid methyl ester (200 mg, 0.36
mmol) in chloroform (20 mL) is added the solution of mCPBA (247 mg,
1.43 mmol) in chloroform (10 ml) dropwise. The resulting mixture is
stirred overnight. K.sub.2CO.sub.3 (200 mg) and MeOH (1 ml) are
added. The mixture is stirred for 30 min, filtrated. The solid
residue is washed with dichloromethane/MeOH(9/1). The filtrate is
concentrated and purified by column chromatography to afford
3-(4-{3,3-dimethyl-1-[5-methyl-1-oxy-6-(4-trifluoromethoxy-phenyl)-pyridi-
n-3-yloxy]-butyl}-benzoylamino)-propionic acid methyl ester (80
mg), which is hydrolyzed by sodium hydroxide (5 N aqueous, 1 mL)
giving the title compound (55 mg). MS (ES): 561.3 [M+H].sup.+.
Example 350
2-Hydroxy-3-{4-[1-(4'-isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-2-methyl-pr-
opyl]-benzoylamino}-propionic acid, Isomer 1
##STR00327##
[0882] Step A.
4-[1-(4-Bromo-3,5-dimethyl-phenoxy)-2-methyl-propyl]-benzoic acid
methyl ester
[0883] To a solution of 4-(1-hydroxy-2-methyl-propyl)-benzoic acid
methyl ester (5000 mg, 24.04 mmol) in toluene (240 mL) is added
1,1'-(azodicarbonyl)dipiperidine (ADDP, 9098 mg, 36.06 mmol) at
0.degree. C., followed by the additions of tributylphosphine (8.98
mL, 36.06 mmol) and 4-bromo-3,5-dimethyl-phenol (5798 mg, 28.85
mmol). The reaction mixture is warmed up to room temperature and
stirred overnight. The mixture is loaded on silica gel, eluted with
hexanes with a gradient from 0% of ethyl acetate to 50% of ethyl
acetate giving the titled compound (5540 mg).
Step B.
4-[1-(4-Bromo-3,5-dimethyl-phenoxy)-2-methyl-propyl]-benzoic acid
methyl ester, isomers 1 and 2
[0884] The racemic
4-[1-(4-bromo-3,5-dimethyl-phenoxy)-2-methyl-propyl]-benzoic acid
methyl ester was resolved on a Chiralcel OJ-H column (4.6.times.150
mm). Eluted with Methanol/DMEA (98/2) and concentrated the
fractions to provide a purified enantiomer ester (isomer 1, 98.4%
ee, isomer 2, >99% ee).
Step C.
4-[1-(4'-Isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-2-methyl-propyl]-
-benzoic acid methyl ester, isomer 1
[0885] Isomer 1 of
4-[1-(4-bromo-3,5-dimethyl-phenoxy)-2-methyl-propyl]-benzoic acid
methyl ester (500 mg, 1.28 mmol), potassium fluoride (223 mg, 3.84
mmol), 4-isopropylphenyl boronic acid (419 mg, 2.56 mmol) and
tetrakis-(triphenylphosphine)palladium (148 mg, 0.128 mmol) are
placed in a flask. After the reaction is purged with N.sub.2 for
several times, THF/H.sub.2O (20 ml/5 ml) is added. The resulting
solution is refluxed overnight, loaded on silica gel, eluted with
hexane and ethyl acetate to give the titled compound (510 mg).
Step D.
4-[1-(4'-Isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-2-methyl-propyl]-
-benzoic acid, isomers 1
[0886] To the solution of isomer 1 of
4-[1-(4'-isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-2-methyl-propyl]-benzoi-
c acid methyl ester (510 mg) in methanol (10 mL) is added sodium
hydroxide (5 N aqueous, 2 mL) and stirred for 4 h. The reaction
mixture is concentrated and acidified by 5 N HCl (2 mL), extracted
with ethyl acetate. Combined organic layers are washed with water
and brine, dried over sodium sulfate. Concentration gives the title
compound (450 mg) as a white solid.
Step E.
2-Hydroxy-3-{4-[1-(4'-isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-2-m-
ethyl-propyl]-benzoylamino}-propionic acid methyl ester, isomer
1
[0887] To a mixture of
4-[1-(4'-isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-2-methyl-propyl]-benzoi-
c acid (150 mg, 0.36 mmol) in methylene chloride (4 mL) is added
triethyl amine (0.15 mL, 1.08 mmol), DMAP (5.0 mg),
3-Amino-2-hydroxy-propionic acid methyl ester (83 mg, 0.54 mmol)
and EDCI (208 mg, 1.08 mmol) at room temperature. The reaction
mixture is stirred at room temperature overnight, loaded on silica
gel, eluted with eluted with hexanes with a gradient from 0% of
ethyl acetate to 100% of ethyl acetate giving the titled compound
(150 mg).
Step F.
2-Hydroxy-3-{4-[1-(4'-isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-2-m-
ethyl-propyl]-benzoylamino}-propionic acid, isomer 1
[0888] To the solution of isomer 1 of
2-Hydroxy-3-{4-[1-(4'-isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-2-methyl-p-
ropyl]-benzoylamino}-propionic acid methyl ester (150 mg) in
methanol (10 mL) is added sodium hydroxide (5 N aqueous, 1 mL) and
stirred for 4 h. The reaction mixture is concentrated and acidified
by 5 N HCl (1 mL), extracted with ethyl acetate. Combined organic
layers are washed with water and brine, dried over sodium sulfate.
Concentration gives the title compound (93 mg) as a white solid. MS
(ES): 504.2 [M+H].sup.+.
[0889] The following compounds are made in a manner substantially
similar to Example 350 using appropriate starting materials:
Example 351
2-Hydroxy-3-{4-[1-(4'-isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-2-methyl-pr-
opyl]-benzoylamino}-propionic acid, Isomer 2
##STR00328##
[0891] MS (ES): 504.2 [M+H].sup.+.
Example 352
2-Hydroxy-3-{4-[1-(4'-isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-2-methyl-pr-
opyl]-benzoylamino}-propionic acid, Isomer 1
##STR00329##
[0893] MS (ES): 504.2 [M+H].sup.+.
Example 353
2-Hydroxy-3-{4-[1-(4'-isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-2-methyl-pr-
opyl]-benzoylamino}-propionic acid, Isomer 2
##STR00330##
[0895] MS (ES): 504.2 [M+H].sup.+.
Example 354
3-{4-[1-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-2-methyl-propyl-
]-benzoylamino}-2-hydroxy-propionic acid, Isomer 1
##STR00331##
[0897] MS (ES): 530.2 [M+H].sup.+.
Example 355
3-{4-[1-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-2-methyl-propyl-
]-benzoylamino}-2-hydroxy-propionic acid, Isomer 2
##STR00332##
[0899] MS (ES): 530.2 [M+H].sup.+.
Example 356
3-{4-[1-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-2-methyl-propyl-
]-benzoylamino}-2-hydroxy-propionic acid, Isomer 1
##STR00333##
[0901] MS (ES): 530.2 [M+H].sup.+.
Example 357
3-{4-[1-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-2-methyl-propyl-
]-benzoylamino}-2-hydroxy-propionic acid, Isomer 2
##STR00334##
[0903] MS (ES): 530.2 [M+H].sup.+.
Example 358
Racemic
3-{4-[1-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-ylsulfanyl)-5,-
5,5-trifluoro-pentyl]-benzoylamino}-propionic acid
##STR00335##
[0904] Step A. Racemic
4-[1-(4-Bromo-3,5-dimethyl-phenylsulfanyl)-5,5,5-trifluoro-pentyl]-benzoi-
c acid methyl ester
[0905] A solution of the 4-bromo-3,5-dimethyl-benzenethiol (0.572
g, 2.26 mmol) and (R,S)
4-(5,5,5-trifluoro-1-hydroxy-pentyl)-benzoic acid methyl ester
(0.500 g, 1.81 mmol) in toluene(10 mL) is degassed and filled with
nitrogen three times. Tributylphosphine (0.670 mL, 2.72 mmol) is
added to the reaction mixture under nitrogen at 0.degree. C.,
followed by addition of 1,1'-(azodicarbonyl)-dipiperidine (0.685 g,
2.72 mmol). The reaction mixture is allowed to warm to room
temperature and stirred overnight, the mixture is concentrated and
purified by flash column chromatography (0.424 g, 0.89 mmol).
Step B. Racemic
4-[1-(4-Bromo-3,5-dimethyl-phenylsulfanyl)-5,5,5-trifluoro-pentyl]-benzoi-
c acid
[0906] Racemic
4-[1-(4-bromo-3,5-dimethyl-phenylsulfanyl)-5,5,5-trifluoro-pentyl]-benzoi-
c acid methyl ester (0.424 g, 0.890 mmol) is dissolved in the
tetrahydrofuran (2.5 mL) and sodium hydroxide (2.5 mL, 5N) is
added. The reaction is monitored by HPLC, and upon complete
conversion, the reaction is neutralized with hydrochloric acid (2.5
mL, 5N) and diluted with diethyl ether and water. The two phases
are separated, and the organic layer is washed, dried, and
concentrated. The title compound (0.380 g, 0.826 mmol) is used
without further purification.
Step C. Racemic
3-{4-[1-(4-Bromo-3,5-dimethyl-phenylsulfanyl)-5,5,5-trifluoro-pentyl]-ben-
zoylamino}-propionic acid ethyl ester
[0907] Racemic
4-[1-(4-bromo-3,5-dimethyl-phenylsulfanyl)-5,5,5-trifluoro-pentyl]-benzoi-
c acid(0.190 g, 0.410 mmol), 2-chloro-4,6-dimethoxy-1,3,5-triazine
(0.0747 g, 0.430 mmol) and 4-methylmorpholine (0.050 mL, 0.430
mmol) are combined in anhydrous dichloromethane(2.0 mL) under
nitrogen. The reaction is allowed to stir under nitrogen at room
temperature overnight. The beta alanine ethyl ester hydrochloride
(0.0695 g, 0.450 mmol) and 4-methylmorpholine (0.100 mL, 0.860
mmol) is added to the reaction mixture and allowed to stir at room
temperature. Some water (<10% volume) is added to help
solubility. The reaction is monitored by HPLC, and upon complete
consumption of the acid, the reaction is diluted with
dichloromethane. The reaction is diluted with water and rinsed with
1N hydrochloric acid. Upon acidification, the two layers are
separated. The organic layer is washed with brine, dried over
anhydrous sodium sulfate, and concentrated. Flash column
chromatography gave the title compound (0.200 g, 0.360 mmol).
Step D. Racemic
3-{4-[1-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-ylsulfanyl)-5,5,5-tri-
fluoro-pentyl]-benzoylamino}-propionic acid ethyl ester
[0908] To a solution of racemic
3-{4-[1-(4-bromo-3,5-dimethyl-phenylsulfanyl)-5,5,5-trifluoro-pentyl]-ben-
zoylamino}-propionic acid ethyl ester (0.200 g, 0.360 mmol) in
toluene(2 mL) is added palladium tetrakis triphenylphosphine
(0.0267 g, 0.020 mmol), 4-trifluoromethyl phenyl boronic acid(0.135
g, 0.720 mmol), and potassium fluoride (0.0416 g, 0.720 mmol). The
reaction is purged with nitrogen three times and heated to reflux
under nitrogen. At reflux, water (1.0 mL) is added to the reaction
and the reaction is allowed to reflux under nitrogen. The reaction
is monitored by HPLC, and upon completion, allowed to cool to room
temperature. The reaction is diluted with ethyl acetate and celite
is added, followed by water. This mixture is then filtered through
a pad of celite. The solution is poured into a separatory funnel
and the organic layer is washed with water and brine. The organic
layer is dried over anhydrous sodium sulfate and concentrated. The
product is purified by flash column chromatography (0.150 g, 0.240
mmol).
Step E. Racemic
3-{4-[1-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-ylsulfanyl)-5,5,5-tri-
fluoro-pentyl]-benzoylamino}-propionic acid
[0909] Racemic
3-{4-[1-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-ylsulfanyl)-5,5,5-tri-
fluoro-pentyl]-benzoylamino}-propionic acid ethyl ester (0.150 g,
0.240 mmol) is dissolved in tetrahydrofuran(1.0 mL) and sodium
hydroxide(1.0 mL, 5N) is added. The reaction is monitored by HPLC,
and upon complete conversion, the reaction is neutralized with
hydrochloric acid (1.0 mL, 5N) and diluted with diethyl ether and
water. The two phases are separated, and the organic layer is
washed, dried, and concentrated. The title compound is used without
further purification. MS (ES): 596.3 [M-H].sup.-.
Example 359
Racemic
3-{4-[1-(2,4,6-tri-t-butyl-phenoxy)-5,5,5-trifluoro-pentyl]-benzoy-
lamino}-propionic acid
##STR00336##
[0910] Step A. Racemic
4-[1-(4-Bromo-phenoxy)-5,5,5-trifluoro-pentyl]-benzoic acid methyl
ester
[0911] A solution of the 4-bromo-phenol (2.36 g, 13.61 mmol) and
(R,S) 4-(5,5,5-trifluoro-1-hydroxy-pentyl)-benzoic acid methyl
ester (3.00 g, 10.89 mmol) in toluene (50 mL) is degassed and
filled with nitrogen three times. Tributylphosphine (4.03 mL, 16.34
mmol) is added to the reaction mixture under nitrogen at 0.degree.
C., followed by addition of 1,1'-(azodicarbonyl)-dipiperidine (4.12
g, 16.34 mmol). The reaction mixture is allowed to warm to room
temperature and stirred overnight; the mixture is concentrated and
purified by flash column chromatography (3.0 g, 6.96 mmol).
Step B. Racemic
4-[1-(4-Bromo-phenoxy)-5,5,5-trifluoro-pentyl]-benzoic acid
[0912] Racemic
4-[1-(4-bromo-phenoxy)-5,5,5-trifluoro-pentyl]-benzoic acid methyl
ester (7.80 g, 18.1 mmol) is dissolved in the tetrahydrofuran (75
mL) and sodium hydroxide(25 mL, 5N) is added. The reaction is
heated to reflux under nitrogen. The reaction is monitored by HPLC,
and upon complete conversion, the reaction is neutralized with
hydrochloric acid (25 mL, 5N) and diluted with diethyl ether and
water. The two phases are separated, and the organic layer is
washed, dried, and concentrated. The title compound (7.46 g, 16.24
mmol) is used without further purification.
Step C. Racemic
3-{4-[1-(4-Bromo-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-propionic
acid methyl ester
[0913] Racemic
4-[1-(4-bromo-phenoxy)-5,5,5-trifluoro-pentyl]-benzoic acid (7.46
g, 17.89 mmol), 2-chloro-4,6-dimethoxy-1,3,5-triazine (3.23 g,
18.43 mmol) and 4-methylmorpholine (2.07 mL, 18.78 mmol) are
combined in anhydrous dichloromethane (100 mL) under nitrogen. The
reaction is allowed to stir under nitrogen at room temperature
overnight. Beta alanine methyl ester hydrochloride (2.76 g, 19.68
mmol) and 4-methylmorpholine (4.14 mL, 37.56 mmol) is added to the
reaction mixture and allowed to stir at room temperature. Some
water (<10% volume) is added to help solubility. The reaction is
monitored by HPLC, and upon complete consumption of the acid, the
reaction is diluted with dichloromethane. The reaction is diluted
with water and rinsed with 1N hydrochloric acid. Upon
acidification, the two layers are separated. The organic layer is
washed with brine, dried over anhydrous sodium sulfate, and
concentrated. Flash column chromatography gave the title compound
(7.07 g, 14.1 mmol).
Step D. Racemic
3-(4-{5,5,5-Trifluoro-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-
-phenoxy]-pentyl}-benzoylamino)-propionic acid methyl ester
[0914] To a solution of racemic
3-{4-[1-(4-bromo-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-propionic
acid methyl ester (2.20 g, 4.38 mmol) in dimethyl sulfoxide(15 mL)
is added
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II),
complex with dichloromethane (1:1) (0.178 g, 0.022 mmol),
bis(pinnocalado)diborane (2.22 g, 8.76 mmol), and potassium
acetate(0.860 g, 8.76 mmol). The reaction is purged with nitrogen
three times and heated to reflux under nitrogen. The reaction is
monitored by HPLC, and upon completion, allowed to cool to room
temperature. The reaction is diluted with ethyl acetate and celite
is added, followed by water. This mixture is then filtered through
a pad of celite. The solution is poured into a separatory funnel
and the organic layer is washed with water and brine. The organic
layer is dried over anhydrous sodium sulfate and concentrated. The
product is purified by flash column chromatography (1.78 g, 3.24
mmol).
Step E. Racemic
3-{4-[1-(2,4,6-tri-t-butyl-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-
-propionic acid methyl ester
[0915] To a solution of racemic
3-(4-{5,5,5-Trifluoro-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-
-phenoxy]-pentyl}-benzoylamino)-propionic acid methyl ester(0.300
g, 0.550 mmol) in toluene(3.0 mL) is added palladium tetrakis
triphenylphosphine(0.0316 g, 0.030 mmol),
2-bromo-1,3,5-tri-tert-butyl-benzene (0.353 g, 1.09 mmol), and
potassium fluoride(0.063 g, 1.09 mmol). The reaction is purged with
nitrogen three times and heated to reflux under nitrogen. At
reflux, water (1.0 mL) is added to the reaction and the reaction is
allowed to reflux under nitrogen. The reaction is monitored by
HPLC, and upon completion, allowed to cool to room temperature. The
reaction is diluted with ethyl acetate and celite is added,
followed by water. This mixture is then filtered through a pad of
celite. The solution is poured into a separatory funnel and the
organic layer is washed with water and brine. The organic layer is
dried over anhydrous sodium sulfate and concentrated. The product
is purified by flash column chromatography (0.333 g, 0.500
mmol).
Step F. Racemic
3-{4-[1-(2,4,6-tri-t-butyl-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-
-propionic acid
[0916] Racemic
3-{4-[1-(2,4,6-tri-t-butyl-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-
-propionic acid methyl ester (0.333 g, 0.500 mmol) is dissolved in
tetrahydrofuran(3.0 mL) and sodium hydroxide(3.0 mL, 5N) is added.
The reaction is monitored by HPLC, and upon complete conversion,
the reaction is neutralized with hydrochloric acid(3.0 mL, 5N) and
diluted with diethyl ether and water. The two phases are separated,
and the organic layer is washed, dried, and concentrated. The title
compound is used without further purification. MS (ES): 652.2
[M-H].sup.-.
Example 360
3-(4-{5,5,5-trifluoro-1-[5-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-y-
loxy]-pentyl}-benzoylamino)-propionic acid, Isomer 1 and
Example 361
3-(4-{5,5,5-trifluoro-1-[5-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-y-
loxy]-pentyl}-benzoylamino)-propionic acid, Isomer 2
##STR00337##
[0918] The title compounds are prepared in a manner substantially
similar to Example 1 starting from
4-(5,5,5-trifluoro-1-hydroxy-pentyl)-benzoic acid methyl ester and
5-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ol (Preparation
34). The isomers are resolved by methods described herein or known
to one skilled in the art. Isomer 1 MS: 567.3 [M-H].sup.-; Isomer 2
MS: 567.3 [M-H].sup.-.
Example 362
Racemic
3-(4-{1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-pentyl}-ben-
zoylamino)-propionic acid
##STR00338##
[0920] The title compound is prepared in a manner substantially
similar to Example 62 starting from
3-{4-[1-(6-chloro-pyridin-3-yloxy)-pentyl]-benzoylamino}-propionic
acid methyl ester and 4-trifluoromethyl phenyl boronic acid. MS:
499.2 [M-H].sup.-.
Example 363
Racemic
3-{4-[1-(4'-tert-butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl)-5,5,5-t-
rifluoro-pentyl]-benzoylamino}-propionic acid
##STR00339##
[0922] The title compound is prepared in a manner substantially
similar to Example 358 starting from
3-{4-[1-(4-bromo-3,5-dimethyl-phenylsulfanyl)-5,5,5-trifluoro-pentyl]-ben-
zoylamino}-propionic acid methyl ester and 4-tert-butyl phenyl
boronic acid. MS: 584.2 [M-H].sup.-.
Example 364
Racemic
3-{4-[1-(4-bromo-3,5-dimethyl-phenylsulfanyl)-5,5,5-trifluoro-pent-
yl]-benzoylamino}-propionic acid
##STR00340##
[0924] The title compound is prepared in a manner substantially
similar to Example 358 starting from
3-{4-[1-(4-bromo-3,5-dimethyl-phenylsulfanyl)-5,5,5-trifluoro-pentyl]-ben-
zoylamino}-propionic acid methyl ester. MS: 531.2 [M-H].sup.-.
Example 365
Racemic
3-(4-{5,5,5-trifluoro-1-[5-methyl-6-(4-trifluoromethyl-phenyl)-pyr-
idin-3-yloxy]-pentyl}-benzoylamino)-propionic acid
##STR00341##
[0926] The title compound is prepared in a manner substantially
similar to Example 1 starting from
4-(5,5,5-trifluoro-1-hydroxy-pentyl)-benzoic acid methyl ester and
5-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ol (Preparation
34). MS: 567.3 [M-H].sup.-.
Example 366
Racemic
3-(4-{4,4,4-trifluoro-1-[5-methyl-6-(4-trifluoromethyl-phenyl)-pyr-
idin-3-yloxy]-butyl}-benzoylamino)-propionic acid
##STR00342##
[0928] The title compound is prepared in a manner substantially
similar to Example 1 starting from
3-[4-(4,4,4-trifluoro-1-hydroxy-butyl)-benzoylamino]-propionic acid
methyl ester and
5-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ol(Preparation 34).
MS: 553.3 [M-H].sup.-.
Example 367
3-{4-[1-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-ylsulfanyl)-3-methyl-b-
utyl]-benzoylamino}-propionic acid, Isomer 1 and
Example 368
3-{4-[1-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-ylsulfanyl)-3-methyl-b-
utyl]-benzoylamino}-propionic acid, Isomer 2
##STR00343##
[0930] The title compound is prepared in a manner substantially
similar to Example 358 starting from enatiomerically purified
3-{4-[1-(4-bromo-3,5-dimethyl-phenylsulfanyl)-3-methyl-butyl]-benzoylamin-
o}-propionic acid methyl ester and 4-trifluoromethyl phenyl boronic
acid. Isomer 1 MS: 542.2 [M-H].sup.-; Isomer 2 MS: 542.2
[M-H].sup.-.
Example 369
3-{4-[1-(4'-tert-butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl)-3-methyl-butyl]-
-benzoylamino}-propionic acid, Isomer 1 and
Example 370
3-{4-[1-(4'-tert-butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl)-3-methyl-butyl]-
-benzoylamino}-propionic acid, Isomer 2
##STR00344##
[0932] The title compound is prepared in a manner substantially
similar to Example 367 starting from
3-{4-[1-(4-bromo-3,5-dimethyl-phenylsulfanyl)-3-methyl-butyl]-benzoylamin-
o}-propionic acid methyl ester and 4-tert-butyl phenyl boronic
acid. Isomer 1 MS: 530.2 [M-H].sup.-; Isomer 2 MS: 530.2
[M-H].sup.-.
Example 371
3-{4-[1-(4'-tert-butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl)-4,4,4-trifluoro-
-butyl]-benzoylamino}-propionic acid, Isomer 1 and
Example 372
3-{4-[1-(4'-tert-butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl)-4,4,4-trifluoro-
-butyl]-benzoylamino}-propionic acid, Isomer 2
##STR00345##
[0934] The title compounds are prepared in a manner substantially
similar to Example 367 starting from
3-{4-[1-(4-bromo-3,5-dimethyl-phenylsulfanyl)-4,4,4-trifluoro-butyl]-benz-
oylamino}-propionic acid methyl ester and 4-tert-butyl phenyl
boronic acid. Isomer 1 MS: 570.2 [M-H].sup.-; Isomer 2 MS: 570.2
[M-H].sup.-.
Example 373
3-{4-[1-(4-bromo-3,5-dimethyl-phenylsulfanyl)-4,4,4-trifluoro-butyl]-benzo-
ylamino}-propionic acid, Isomer 1 and
Example 374
3-{4-[1-(4-bromo-3,5-dimethyl-phenylsulfanyl)-4,4,4-trifluoro-butyl]-benzo-
ylamino}-propionic acid, Isomer 2
##STR00346##
[0936] The title compounds are prepared in a manner substantially
similar to Example 358 starting from
3-{4-[1-(4-bromo-3,5-dimethyl-phenylsulfanyl)-4,4,4-trifluoro-butyl]-benz-
oylamino}-propionic acid methyl ester. Isomer 1 MS: 517.3
[M-H].sup.-; Isomer 2 MS: 517.3 [M-H].sup.-.
Example 375
3-{4-[1-(4-bromo-3,5-dimethyl-phenylsulfanyl)-3-methyl-butyl]-benzoylamino-
}-propionic acid, Isomer 1 and
Example 376
3-{4-[1-(4-bromo-3,5-dimethyl-phenylsulfanyl)-3-methyl-butyl]-benzoylamino-
}-propionic acid, Isomer 2
##STR00347##
[0938] The title compounds are prepared in a manner substantially
similar to Example 358 starting from enatiomers of
3-{4-[1-(4-bromo-3,5-dimethyl-phenylsulfanyl)-3-methyl-butyl]-benzoylamin-
o}-propionic acid methyl ester. Isomer 1 MS: 477.2 [M-H].sup.-;
Isomer 2 MS: 477.2 [M-H].sup.-.
Example 377
3-{4-[1-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-5,5,5-trifluoro-
-pentyl]-benzoylamino}-propionic acid, Isomer 1 and
Example 378
3-{4-[1-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-5,5,5-trifluoro-
-pentyl]-benzoylamino}-propionic acid, Isomer 2
##STR00348##
[0940] The title compounds are prepared in a manner substantially
similar to Example 1 starting from
4-(6,6,6-trifluoro-1-hydroxy-hexyl)-benzoic acid methyl ester and
4'-tert-butyl-2,6-dimethyl-biphenyl-4-ol. The isomers are resolved
by methods described herein or known to one skilled in the art.
Isomer 1 MS: 580.2 [M-H].sup.-; Isomer 2 MS: 580.2 [M-H].sup.-.
Example 379
3-{4-[4,4,4-trifluoro-1-(4'-isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-butyl-
]-benzoylamino}-propionic acid, Isomer 1 and
Example 380
3-{4-[4,4,4-trifluoro-1-(4'-isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-butyl-
]-benzoylamino}-propionic acid, Isomer 2
##STR00349##
[0942] The title compounds are prepared in a manner substantially
similar to Example 128 starting from enatiomers of
3-{4-[1-(4-bromo-3,5-dimethyl-phenoxy)-4,4,4-trifluoro-butyl]-benzoylamin-
o}-propionic acid methyl ester and 4-isopropyl phenyl boronic acid.
Isomer 1 MS: 540.2 [M-H].sup.-, Isomer 2 MS: 540.2 [M-H].sup.-.
Example 381
Racemic
3-{4-[1-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-ylsulfanyl)-4,-
4,4-trifluoro-butyl]-benzoylamino}-propionic acid
##STR00350##
[0944] The title compound is prepared in a manner substantially
similar to Example 358 starting from
3-{4-[1-(4-bromo-3,5-dimethyl-phenylsulfanyl)-4,4,4-trifluoro-butyl]-benz-
oylamino}-propionic acid methyl ester and 4-trifluoromethyl phenyl
boronic acid. MS: 582.3 [M-H].sup.-.
Example 382
Racemic
3-{4-[1-(4'-tert-butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl)-4,4,4-t-
rifluoro-butyl]-benzoylamino}-propionic acid
##STR00351##
[0946] The title compound is prepared in a manner substantially
similar to Example 358 starting from
3-{4-[1-(4-bromo-3,5-dimethyl-phenylsulfanyl)-4,4,4-trifluoro-butyl]-benz-
oylamino}-propionic acid methyl ester and 4-tert-butyl phenyl
boronic acid. MS: 570.2 [M-H].sup.-.
Example 383
##STR00352##
[0948] The title compound is prepared in a manner substantially
similar to Example 358 starting from
3-{4-[1-(4-bromo-3,5-dimethyl-phenylsulfanyl)-3-methyl-butyl]-benzoylamin-
o}-propionic acid methyl ester and 4-trifluoromethyl phenyl boronic
acid. MS: 542.2 [M-H].sup.-.
Example 384
Racemic
3-{4-[1-(4'-tert-butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl)-3-methy-
l-butyl]-benzoylamino}-propionic acid
##STR00353##
[0950] The title compound is prepared in a manner substantially
similar to Example 358 starting from
3-{4-[1-(4-bromo-3,5-dimethyl-phenylsulfanyl)-3-methyl-butyl]-benzoylamin-
o}-propionic acid methyl ester and 4-tert-butyl phenyl boronic
acid. MS: 530.2 [M-H].sup.-.
Example 385
Racemic
3-{4-[1-(4-bromo-3,5-dimethyl-phenylsulfanyl)-4,4,4-trifluoro-buty-
l]-benzoylamino}-propionic acid
##STR00354##
[0952] The title compound is prepared in a manner substantially
similar to Example 358 starting from
3-{4-[1-(4-bromo-3,5-dimethyl-phenylsulfanyl)-4,4,4-trifluoro-butyl]-benz-
oylamino}-propionic acid methyl ester. MS: 517.3 [M-H].sup.-.
Example 386
Racemic
3-{4-[1-(4-bromo-3,5-dimethyl-phenylsulfanyl)-3-methyl-butyl]-benz-
oylamino}-propionic acid
##STR00355##
[0954] The title compound is prepared in a manner substantially
similar to Example 358 starting from
3-{4-[1-(4-bromo-3,5-dimethyl-phenylsulfanyl)-3-methyl-butyl]-benzoylamin-
o}-propionic acid methyl ester. MS: 477.2 [M-H].sup.-.
Example 387
3-{4-[1-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-benzoyl-
amino}-propionic acid, Isomer 1 and
Example 388
3-{4-[1-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-heptyl]-benzoyl-
amino}-propionic acid, Isomer 2
##STR00356##
[0956] The title compounds are prepared in a manner substantially
similar to Example 1 starting from 4-(1-hydroxy-heptyl)-benzoic
acid methyl ester and 4'-tert-butyl-2,6-dimethyl-biphenyl-4-ol. The
isomers are resolved by methods described herein or known to one
skilled in the art. Isomer 1 MS: 554.3 [M-H].sup.-; Isomer 2 MS:
554.3 [M-H].sup.-.
Example 389
3-{4-[3-methyl-1-(2,2',4'-trichloro-biphenyl-4-yloxy)-butyl]-benzoylamino}-
-propionic acid, Isomer 1 and
Example 390
3-{4-[3-methyl-1-(2,2',4'-trichloro-biphenyl-4-yloxy)-butyl]-benzoylamino}-
-propionic acid, isomer 2
##STR00357##
[0958] The title compounds are prepared in a manner substantially
similar to Example 24 starting from
3-{4-[1-(4-bromo-3-chloro-phenoxy)-3-methyl-butyl]-benzoylamino}-propioni-
c acid methyl ester and 2,4-dichlorophenyl boronic acid. The
isomers are resolved by methods described herein or known to one
skilled in the art. Isomer 1 MS: 533.2 [M-H].sup.-; Isomer 2 MS:
533.2 [M-H].sup.-.
Example 391
3-{4-[1-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-4,4,4-trifluoro-
-butyl]-benzoylamino}-propionic acid, Isomer 1 and
Example 392
3-{4-[1-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-4,4,4-trifluoro-
-butyl]-benzoylamino}-propionic acid, Isomer 2
##STR00358##
[0960] The title compounds are prepared in a manner substantially
similar to Example 1 starting from
4-(4,4,4-trifluoro-1-hydroxy-butyl)-benzoic acid methyl ester and
2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-ol. The isomers are
resolved by methods described herein or known to one skilled in the
art. Isomer 1 MS: 566.3 [M-H].sup.-; Isomer 2 MS: 566.3
[M-H].sup.-.
Example 393
3-{4-[1-(4'-tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-4,4,4-trifluoro-buty-
l]-benzoylamino}-propionic acid, Isomer 1 and
Example 394
3-{4-[1-(4'-tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-4,4,4-trifluoro-buty-
l]-benzoylamino}-propionic acid, Isomer 2
##STR00359##
[0962] The title compounds are prepared in a manner substantially
similar to Example 1 starting from
4-(4,4,4-trifluoro-1-hydroxy-butyl)-benzoic acid methyl ester and
4'-tert-butyl-2,6-dimethyl-biphenyl-4-ol. The isomers are resolved
by methods described herein or known to one skilled in the art.
Isomer 1 MS: 554.2 [M-H].sup.-; Isomer 2 MS: 554.2 [M-H].sup.-.
Example 395
3-{4-[5,5,5-trifluoro-1-(4'-isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-penty-
l]-benzoylamino}-propionic acid, Isomer 1 and
Example 396
3-{4-[5,5,5-trifluoro-1-(4'-isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-penty-
l]-benzoylamino}-propionic acid, Isomer 2
##STR00360##
[0964] The title compounds are prepared in a manner substantially
similar to Example 128 starting from
3-{4-[1-(4-bromo-3,5-dimethyl-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylami-
no}-propionic acid methyl ester and 4-isopropyl phenyl boronic
acid. Isomer 1 MS: 554.2 [M-H].sup.-; Isomer 2 MS: 554.2
[M-H].sup.-.
Example 397
Racemic
3-{4-[5,5,5-trifluoro-1-(4'-isopropyl-2,6-dimethyl-biphenyl-4-ylox-
y)-pentyl]-benzoylamino}-propionic acid
##STR00361##
[0966] The title compound is prepared in a manner substantially
similar to Example 128 starting from
3-{4-[1-(4-bromo-3,5-dimethyl-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylami-
no}-propionic acid methyl ester and 4-isopropyl phenyl boronic
acid. MS: 554.2 [M-H].sup.-.
Example 398
3-{4-[1-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-5-methyl-hexyl]-
-benzoylamino}-propionic acid, Isomer 1 and
Example 399
3-{4-[1-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-5-methyl-hexyl]-
-benzoylamino}-propionic acid, Isomer 2
##STR00362##
[0968] The title compounds are prepared in a manner substantially
similar to Example 1 starting from
4-(1-hydroxy-5-methyl-hexyl)-benzoic acid methyl ester and
2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-ol. The isomers are
resolved by methods described herein or known to one skilled in the
art. Isomer 1 MS:554.2 [M-H].sup.-; Isomer 2
MS:554.2[M-H].sup.-.
Example 400
3-{4-[5-methyl-1-(4'-trifluoromethyl-biphenyl-4-yloxy)-hexyl]-benzoylamino-
}-propionic acid, Isomer 1 and
Example 401
3-{4-[5-methyl-1-(4'-trifluoromethyl-biphenyl-4-yloxy)-hexyl]-benzoylamino-
}-propionic acid, Isomer 2
##STR00363##
[0970] The title compounds are prepared in a manner substantially
similar to Example 1 starting from
4-(1-hydroxy-5-methyl-hexyl)-benzoic acid methyl ester and
4'-trifluoromethyl-biphenyl-4-ol. The isomers are resolved by
methods described herein or known to one skilled in the art. Isomer
1 MS: 526.2 [M-H].sup.-; Isomer 2 MS: 526.2 [M-H].sup.-.
Example 402
3-(4-{1-[6-(4-tert-butyl-phenyl)-pyridin-3-yloxy]-5-methyl-hexyl}-benzoyla-
mino)-propionic acid, Isomer 1 and
Example 403
3-(4-{1-[6-(4-tert-butyl-phenyl)-pyridin-3-yloxy]-5-methyl-hexyl}-benzoyla-
mino)-propionic acid, Isomer 2
##STR00364##
[0972] The title compounds are prepared in a manner substantially
similar to Example 62 starting from
3-{4-[1-(6-chloro-pyridin-3-yloxy)-5-methyl-hexyl]-benzoylamino}-propioni-
c acid methyl ester and 4-tert-butyl phenyl boronic acid. Isomer 1
MS: 515.2 [M-H].sup.-; Isomer 2 MS: 515.2 [M-H].sup.-.
Example 404
Racemic
3-(4-{5-methyl-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-hexy-
l}-benzoylamino)-propionic acid
##STR00365##
[0974] The title compound is prepared in a manner substantially
similar to Example 62 starting from
3-{4-[1-(6-chloro-pyridin-3-yloxy)-5-methyl-hexyl]-benzoylamino}-propioni-
c acid methyl ester and 4-trifluoromethyl phenyl boronic acid. MS:
527.2[M-H].sup.-.
Example 405
Racemic
3-{4-[1-(6-chloro-pyridin-3-yloxy)-5-methyl-hexyl]-benzoylamino}-p-
ropionic acid
##STR00366##
[0976] The title compound is prepared in a manner substantially
similar to Example 62 starting from
3-{4-[1-(6-chloro-pyridin-3-yloxy)-5-methyl-hexyl]-benzoylamino}-propioni-
c acid methyl ester. MS: 417.3 [M-H].sup.-.
Example 406
Racemic
3-{4-[1-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-5-methy-
l-hexyl]-benzoylamino}-propionic acid
##STR00367##
[0978] The title compound is prepared in a manner substantially
similar to Example 1 starting from
4-(1-hydroxy-5-methyl-hexyl)-benzoic acid methyl ester and
2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-ol. MS: 554.2
[M-H].sup.-.
Example 407
Racemic
3-(4-{1-[6-(4-tert-butyl-phenyl)-pyridin-3-yloxy]-5-methyl-hexyl}--
benzoylamino)-propionic acid
##STR00368##
[0980] The title compound is prepared in a manner substantially
similar to Example 62 starting from
3-{4-[1-(6-chloro-pyridin-3-yloxy)-5-methyl-hexyl]-benzoylamino}-propioni-
c acid methyl ester and 4-tert-butyl phenyl boronic acid. MS: 515.2
[M-H].sup.-.
Example 408
Racemic
3-{4-[5-methyl-1-(4'-trifluoromethyl-biphenyl-4-yloxy)-hexyl]-benz-
oylamino}-propionic acid
##STR00369##
[0982] The title compound is prepared in a manner substantially
similar to Example 1 starting from
4-(1-hydroxy-5-methyl-hexyl)-benzoic acid methyl ester and
4'-trifluoromethyl-biphenyl-4-ol. MS: 526.2 [M-H].sup.-.
Example 409
Racemic
3-{4-[1-(4'-tert-butyl-biphenyl-4-yloxy)-5-methyl-hexyl]-benzoylam-
ino}-propionic acid
##STR00370##
[0984] The title compound is prepared in a manner substantially
similar to Example 1 starting from
4-(1-hydroxy-5-methyl-hexyl)-benzoic acid methyl ester and
4'-tert-butyl-biphenyl-4-ol. MS: 514.2 [M-H].sup.-.
Example 410
3-(4-{1-[6-(4-tert-butyl-phenyl)-pyridin-3-yloxy]-5,5,5-trifluoro-pentyl}--
benzoylamino)-propionic acid, Isomer 1 and
Example 411
3-(4-{1-[6-(4-tert-butyl-phenyl)-pyridin-3-yloxy]-5,5,5-trifluoro-pentyl}--
benzoylamino)-propionic acid, Isomer 2
##STR00371##
[0986] The title compounds are prepared in a manner substantially
similar to Example 62 starting from
4-[1-(6-chloro-pyridin-3-yloxy)-5,5,5-trifluoro-pentyl]-benzoic
acid methyl ester and 4-tert-butyl phenyl boronic acid. Isomer 1
MS: 541.3 [M-H].sup.-; Isomer 2 MS: 541.3 [M-H].sup.-.
Example 412
3-(4-{1-[6-(4-tert-butyl-phenyl)-pyridin-3-yloxy]-4,4,4-trifluoro-butyl}-b-
enzoylamino)-propionic acid, Isomer 1 and
Example 413
3-(4-{1-[6-(4-tert-butyl-phenyl)-pyridin-3-yloxy]-4,4,4-trifluoro-butyl}-b-
enzoylamino)-propionic acid, Isomer 2
##STR00372##
[0988] The title compounds are prepared in a manner substantially
similar to Example 62 starting from
4-[1-(6-chloro-pyridin-3-yloxy)-4,4,4-trifluoro-butyl]-benzoic acid
methyl ester and 4-tert-butyl phenyl boronic acid. Isomer 1 MS:
527.2 [M-H].sup.-; Isomer 2 MS: 527.2 [M-H].sup.-.
Example 414
Racemic
3-{4-[(4'-tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-cyclohexyl-met-
hyl]-benzoylamino}-propionic acid
##STR00373##
[0990] The title compound is prepared in a manner substantially
similar to Example 1 starting from
4-(cyclohexyl-hydroxy-methyl)-benzoic acid methyl ester and
4'-tert-butyl-biphenyl-4-ol. MS: 540.3 [M-H].sup.-.
Example 415
Racemic
3-{4-[1-(4'-tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-4,4,4-triflu-
oro-butyl]-benzoylamino}-propionic acid
##STR00374##
[0992] The title compound is prepared in a manner substantially
similar to Example 1 starting from
4-(4,4,4-trifluoro-1-hydroxy-butyl)-benzoic acid methyl ester and
4'-tert-butyl-biphenyl-4-ol. MS: 554.2 [M-H].sup.-.
Example 416
3-{4-[4,4,4-trifluoro-1-(4'-trifluoromethyl-biphenyl-4-yloxy)-butyl]-benzo-
ylamino}-propionic acid, Isomer 1 and
Example 417
3-{4-[4,4,4-trifluoro-1-(4'-trifluoromethyl-biphenyl-4-yloxy)-butyl]-benzo-
ylamino}-propionic acid, Isomer 2
##STR00375##
[0994] The title compounds are prepared in a manner substantially
similar to Example 1 starting from
4-(4,4,4-trifluoro-1-hydroxy-butyl)-benzoic acid methyl ester and
4'-trifluoromethyl-biphenyl-4-ol. The isomers are resolved by
methods described herein or known to one skilled in the art. Isomer
1 MS: 538.3 [M-H].sup.-; Isomer 2 MS: 538.3 [M-H].sup.-.
Example 418
Racemic
3-(4-{4,4,4-trifluoro-1-[6-(4-isopropyl-phenyl)-pyridin-3-yloxy]-b-
utyl}-benzoylamino)-propionic acid
##STR00376##
[0996] The title compound is prepared in a manner substantially
similar to Example 62 starting from
4-[1-(6-chloro-pyridin-3-yloxy)-4,4,4-trifluoro-butyl]-benzoic acid
methyl ester and 4-isopropyl phenyl boronic acid. MS: 513.2
[M-H].sup.-.
Example 419
Racemic
3-(4-{5,5,5-trifluoro-1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl-
oxy]-pentyl}-benzoylamino)-propionic acid
##STR00377##
[0998] The title compound is prepared in a manner substantially
similar to Example 62 starting from
4-[1-(6-chloro-pyridin-3-yloxy)-5,5,5-trifluoro-pentyl]-benzoic
acid methyl ester and 4-trifluoromethyl phenyl boronic acid. MS:
553.3 [M-H].sup.-.
Example 420
Racemic
3-(4-{[6-(4-tert-butyl-phenyl)-pyridin-3-yloxy]-cyclohexyl-methyl}-
-benzoylamino)-propionic acid
##STR00378##
[1000] The title compound is prepared in a manner substantially
similar to Example 62 starting from
4-[(6-chloro-pyridin-3-yloxy)-cyclohexyl-methyl]-benzoic acid
methyl ester and 4-tert-butyl phenyl boronic acid. MS: 513.2
[M-H].sup.-.
Example 421
Racemic
3-(4-{5,5,5-trifluoro-1-[6-(4-isopropyl-phenyl)-pyridin-3-yloxy]-p-
entyl}-benzoylamino)-propionic acid
##STR00379##
[1002] The title compound is prepared in a manner substantially
similar to Example 62 starting from
4-[1-(6-chloro-pyridin-3-yloxy)-5,5,5-trifluoro-pentyl]-benzoic
acid methyl ester and 4-isopropyl phenyl boronic acid. MS: 527.2
[M-H].sup.-.
Example 422
Racemic
3-{4-[1-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-4,4,4-t-
rifluoro-butyl]-benzoylamino}-propionic acid
##STR00380##
[1004] The title compound is prepared in a manner substantially
similar to Example 128 starting from
3-{4-[1-(4-bromo-3,5-dimethyl-phenoxy)-4,4,4-trifluoro-butyl]-benzoylamin-
o}-propionic acid methyl ester and 4-trifluoromethyl phenyl boronic
acid. MS: 566.2 [M-H].sup.-.
Example 423
Racemic
3-(4-{cyclohexyl-[6-(4-isopropyl-phenyl)-pyridin-3-yloxy]-methyl}--
benzoylamino)-propionic acid
##STR00381##
[1006] The title compound is prepared in a manner substantially
similar to Example 62 starting from
4-[(6-chloro-pyridin-3-yloxy)-cyclohexyl-methyl]-benzoic acid
methyl ester and 4-isopropyl phenyl boronic acid. MS: 499.2
[M-H].sup.-.
Example 424
Racemic
3-{4-[cyclohexyl-(4'-isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-meth-
yl]-benzoylamino}-propionic acid
##STR00382##
[1008] The title compound is prepared in a manner substantially
similar to Example 128 starting from
3-{4-[(4-bromo-3,5-dimethyl-phenoxy)-cyclohexyl-methyl]-benzoylamino}-pro-
pionic acid methyl ester and 4-isopropyl phenyl boronic acid. MS:
526.2 [M-H].sup.-.
Example 425
Racemic
3-{4-[4,4,4-trifluoro-1-(4'-isopropyl-2,6-dimethyl-biphenyl-4-ylox-
y)-butyl]-benzoylamino}-propionic acid
##STR00383##
[1010] The title compound is prepared in a manner substantially
similar to Example 128 starting from
3-{4-[1-(4-bromo-3,5-dimethyl-phenoxy)-4,4,4-trifluoro-butyl]-benzoylamin-
o}-propionic acid methyl ester and 4-isopropyl phenyl boronic acid.
MS: 540.3 [M-H].sup.-.
Example 426
3-{4-[cyclohexyl-(4'-trifluoromethyl-biphenyl-4-yloxy)-methyl]-benzoylamin-
o}-propionic acid, Isomer 1 and
Example 427
3-{4-[cyclohexyl-(4'-trifluoromethyl-biphenyl-4-yloxy)-methyl]-benzoylamin-
o}-propionic acid, Isomer 2
##STR00384##
[1012] The title compound is prepared in a manner substantially
similar to Example 128 starting from
3-{4-[(4-bromo-phenoxy)-cyclohexyl-methyl]-benzoylamino}-propionic
acid methyl ester and 4-trifluoromethyl phenyl boronic acid. The
isomers are resolved by methods described herein or known to one
skilled in the art. Isomer 1 MS: 524.3 [M-H].sup.-; Isomer 2 MS:
524.3 [M-H].sup.-.
Example 428
3-{4-[5,5,5-trifluoro-1-(4'-isopropyl-biphenyl-4-yloxy)-pentyl]-benzoylami-
no}-propionic acid, Isomer 1 and
Example 429
3-{4-[5,5,5-trifluoro-1-(4'-isopropyl-biphenyl-4-yloxy)-pentyl]-benzoylami-
no}-propionic acid, Isomer 2
##STR00385##
[1014] The title compound is prepared in a manner substantially
similar to Example 128 starting from
3-{4-[1-(4-bromo-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-propionic
acid methyl ester and 4-isopropyl phenyl boronic acid. The isomers
are resolved by methods described herein or known to one skilled in
the art. Isomer 1 MS: 526.2 [M-H].sup.-; Isomer 2 MS: 526.2
[M-H].sup.-.
Example 430
Racemic
3-{4-[(4'-tert-butyl-biphenyl-4-yloxy)-cyclohexyl-methyl]-benzoyla-
mino}-propionic acid
##STR00386##
[1016] The title compound is prepared in a manner substantially
similar to Example 128 starting from
3-{4-[(4-bromo-phenoxy)-cyclohexyl-methyl]-benzoylamino}-propionic
acid methyl ester and 4-tert-butyl phenyl boronic acid. MS: 512.3
[M-H].sup.-.
Example 431
Racemic
3-{4-[5,5,5-trifluoro-1-(2'-3'-fluoro-4'-trifluoromethyl-biphenyl--
4-yloxy)-pentyl]-benzoylamino}-propionic acid
##STR00387##
[1018] The title compound is prepared in a manner substantially
similar to Example 359 starting from
3-(4-{5,5,5-trifluoro-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-
-phenoxy]-pentyl}-benzoylamino)-propionic acid methyl ester and
1-bromo-2,3-difluoro-4-trifluoromethyl-benzene. MS: 588.3
[M-H].sup.-.
Example 432
Racemic
3-{4-[cyclohexyl-(4'-trifluoromethyl-biphenyl-4-yloxy)-methyl]-ben-
zoylamino}-propionic acid
##STR00388##
[1020] The title compound is prepared in a manner substantially
similar to Example 128 starting from
3-{4-[(4-bromo-phenoxy)-cyclohexyl-methyl]-benzoylamino}-propionic
acid methyl ester and 4-trifluoromethyl phenyl boronic acid. MS:
524.3 [M-H].sup.-.
Example 433
Racemic
3-{4-[5,5,5-trifluoro-1-(4'-isopropyl-biphenyl-4-yloxy)-pentyl]-be-
nzoylamino}-propionic acid
##STR00389##
[1022] The title compound is prepared in a manner substantially
similar to Example 128 starting from
3-{4-[1-(4-bromo-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-propionic
acid methyl ester and 4-isopropyl phenyl boronic acid. MS: 526.2
[M-H].sup.-.
Example 434
Racemic
3-{4-[1-(4'-ethyl-biphenyl-4-yloxy)-5,5,5-trifluoro-pentyl]-benzoy-
lamino}-propionic acid
##STR00390##
[1024] The title compound is prepared in a manner substantially
similar to Example 128 starting from
3-{4-[1-(4-bromo-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-propionic
acid methyl ester and 4-ethyl phenyl boronic acid. MS: 572.3
[M-H].sup.-.
Example 435
Racemic
3-{4-[5,5,5-trifluoro-1-(3'-fluoro-4'-trifluoromethyl-biphenyl-4-y-
loxy)-pentyl]-benzoylamino}-propionic acid
##STR00391##
[1026] The title compound is prepared in a manner substantially
similar to Example 359 starting from
3-(4-{5,5,5-trifluoro-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-
-phenoxy]-pentyl}-benzoylamino)-propionic acid methyl ester and
4-bromo-2-fluoro-1-trifluoromethyl-benzene. MS: 570.2
[M-H].sup.-.
Example 436
Racemic
3-{4-[1-(2,4,6-triisopropyl-phenoxy)-5,5,5-trifluoro-pentyl]-benzo-
ylamino}-propionic acid
##STR00392##
[1028] The title compound is prepared in a manner substantially
similar to Example 359 starting from
3-(4-{5,5,5-trifluoro-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-
-phenoxy]-pentyl}-benzoylamino)-propionic acid methyl ester and
2-bromo-1,3,5-triisopropyl-benzene. MS: 610.2 [M-H].sup.-.
Example 437
Racemic
3-{4-[1-(2,3,4,5,6-pentamethyl-phenoxy)-5,5,5-trifluoro-pentyl]-be-
nzoylamino}-propionic acid
##STR00393##
[1030] The title compound is prepared in a manner substantially
similar to Example 359 starting from
3-(4-{5,5,5-trifluoro-1-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)--
phenoxy]-pentyl}-benzoylamino)-propionic acid methyl ester and
1-bromo-2,3,4,5,6-pentamethyl-benzene. MS: 554.2 [M-H].sup.-.
Example 438
Racemic
3-{4-[1-(2,4,6-tri-t-butyl-phenoxy)-5,5,5-trifluoro-pentyl]-benzoy-
lamino}-propionic acid
##STR00394##
[1032] The title compound is prepared in a manner substantially
similar to Example 359 starting from
3-(4-{5,5,5-trifluoro-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-
-phenoxy]-pentyl}-benzoylamino)-propionic acid methyl ester and
2-bromo-1,3,5-tri-tert-butyl-benzene. MS: 652.2 [M-H].sup.-.
Example 439
Racemic
3-{4-[1-(3,5-dimethyl-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamin-
o}-propionic acid
##STR00395##
[1034] The title compound is prepared in a manner substantially
similar to Example 128 starting from
3-{4-[1-(4-bromo-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-propionic
acid methyl ester. MS: 436.2 [M-H].sup.-.
Example 440
3-{4-[1-(4'-tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-5,5,5-trifluoro-pent-
yl]-benzoylamino}-propionic acid, Isomer 1 and
Example 441
3-{4-[1-(4'-tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-5,5,5-trifluoro-pent-
yl]-benzoylamino}-propionic acid, isomer 2
##STR00396##
[1036] The title compounds are prepared in a manner substantially
similar to Example 128 starting from
3-{4-[1-(4-bromo-3,5-dimethyl-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylami-
no}-propionic acid methyl ester and 4-tert-butyl phenyl boronic
acid. Isomer 1 MS: 568.2 [M-H].sup.-; Isomer 2 MS: 568.2
[M-H].sup.-.
Example 442
Racemic
3-{4-[1-(4-ethyl-3,5-dimethyl-phenoxy)-5,5,5-trifluoro-pentyl]-ben-
zoylamino}-propionic acid
##STR00397##
[1038] The title compound is prepared in a manner substantially
similar to Example 128 starting from
3-{4-[1-(4-bromo-3,5-dimethyl-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylami-
no}-propionic acid methyl ester and ethyl boronic acid. MS: 464.2
[M-H].sup.-.
Example 443
Racemic
3-{4-[1-(2,6-dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-5,5,5-t-
rifluoro-pentyl]-benzoylamino}-propionic acid
##STR00398##
[1040] The title compound is prepared in a manner substantially
similar to Example 128 starting from
3-{4-[1-(4-bromo-3,5-dimethyl-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylami-
no}-propionic acid methyl ester and 4-trifluoromethyl phenyl
boronic acid. MS: 580.3 [M-H].sup.-.
Example 444
Racemic
3-(4-{1-[4-(4-methyl-pentyloxy)-phenoxy]-heptyl}-benzoylamino)-pro-
pionic acid
##STR00399##
[1042] The title compound is prepared in a manner substantially
similar to Example 92 starting from
3-{4-[1-(4-hydroxy-phenoxy)-heptyl]-benzoylamino}-propionic acid
methyl ester and 1-bromo-4-methyl-pentane. MS: 484.2
[M-H].sup.-.
Example 445
Racemic
3-{4-[1-(4-pentyloxy-phenoxy)-heptyl]-benzoylamino}-propionic
acid
##STR00400##
[1044] The title compound is prepared in a manner substantially
similar to Example 92 starting from
3-{4-[1-(4-hydroxy-phenoxy)-heptyl]-benzoylamino}-propionic acid
methyl ester and 1-bromo-pentane. MS: 468.2 [M-H].sup.-.
Example 446
3-{4-[5,5,5-trifluoro-1-(4'-trifluoromethyl-biphenyl-4-yloxy)-pentyl]-benz-
oylamino}-propionic acid, Isomer 1 and
Example 447
3-{4-[5,5,5-trifluoro-1-(4'-trifluoromethyl-biphenyl-4-yloxy)-pentyl]-benz-
oylamino}-propionic acid, Isomer 2
##STR00401##
[1046] The title compound is prepared in a manner substantially
similar to Example 128 starting from
3-{4-[1-(4-bromo-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-propionic
acid methyl ester and 4-trifluoromethyl phenyl boronic acid. Isomer
1 MS: 552.2 [M-H].sup.-; Isomer 2 MS: 552.2 [M-H].sup.-.
Example 448
Racemic
3-{4-[1-(4'-tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-5,5,5-triflu-
oro-pentyl]-benzoylamino}-propionic acid
##STR00402##
[1048] The title compound is prepared in a manner substantially
similar to Example 128 starting from
3-{4-[1-(4-bromo-3,5-dimethyl-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylami-
no}-propionic acid methyl ester and 4-tert-butyl phenyl boronic
acid. MS: 568.2 [M-H].sup.-.
Example 449
Racemic
3-{4-[1-(4-bromo-3,5-dimethyl-phenoxy)-5,5,5-trifluoro-pentyl]-ben-
zoylamino}-propionic acid
##STR00403##
[1050] The title compound is prepared in a manner substantially
similar to Example 128 starting from
3-{4-[1-(4-bromo-3,5-dimethyl-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylami-
no}-propionic acid methyl ester. MS: 516 [M-H].sup.-.
Example 450
3-{4-[1-(4'-tert-butyl-biphenyl-4-yloxy)-5,5,5-trifluoro-pentyl]-benzoylam-
ino}-propionic acid, Isomer 1 and
Example 451
3-{4-[1-(4'-tert-butyl-biphenyl-4-yloxy)-5,5,5-trifluoro-pentyl]-benzoylam-
ino}-propionic acid, Isomer 2
##STR00404##
[1052] The title compounds are prepared in a manner substantially
similar to Example 128 starting from
3-{4-[1-(4-bromo-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-propionic
acid methyl ester and 4-tert-butyl phenyl boronic acid. Isomer 1
MS: 540.3 [M-H].sup.-; Isomer 2 MS: 540.3 [M-H].sup.-.
Example 452
3-(4-{1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-hexyl}-benzoylamino-
)-propionic acid, Isomer 1 and
Example 453
3-(4-{1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-hexyl}-benzoylamino-
)-propionic acid, Isomer 2
##STR00405##
[1054] The title compounds are prepared in a manner substantially
similar to Example 62 starting from
3-{4-[1-(6-chloro-pyridin-3-yloxy)-hexyl]-benzoylamino}-propionic
acid methyl ester and 4-trifluoromethyl phenyl boronic acid. Isomer
1 MS: 513.3 [M-H].sup.-; Isomer 2 MS: 513.3 [M-H].sup.-.
Example 454
3-(4-{1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-pentyl}-benzoylamin-
o)-propionic acid, Isomer 1 and
Example 455
3-(4-{1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-pentyl}-benzoylamin-
o)-propionic acid, Isomer 2
##STR00406##
[1056] The title compounds are prepared in a manner substantially
similar to Example 62 starting from
3-{4-[1-(6-chloro-pyridin-3-yloxy)-pentyl]-benzoylamino}-propionic
acid methyl ester and 4-trifluoromethyl phenyl boronic acid. Isomer
1 MS: 499.2 [M-H].sup.-; Isomer 2 MS: 499.2 [M-H].sup.-.
Example 456
Racemic
3-{4-[5,5,5-trifluoro-1-(4'-trifluoromethyl-biphenyl-4-yloxy)-pent-
yl]-benzoylamino}-propionic acid
##STR00407##
[1058] The title compound is prepared in a manner substantially
similar to Example 128 starting from
3-{4-[1-(4-bromo-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-propionic
acid methyl ester and 4-trifluoromethyl phenyl boronic acid. MS:
552.2[M-H].sup.-.
Example 457
Racemic
3-{4-[1-(4'-tert-butyl-biphenyl-4-yloxy)-5,5,5-trifluoro-pentyl]-b-
enzoylamino}-propionic acid
##STR00408##
[1060] The title compound is prepared in a manner substantially
similar to Example 128 starting from
3-{4-[1-(4-bromo-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-propionic
acid methyl ester and 4-tert-butyl phenyl boronic acid. MS:
540.3[M-H].sup.-.
Example 458
Racemic
3-{4-[1-(4-bromo-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-pr-
opionic acid
##STR00409##
[1062] The title compound is prepared in a manner substantially
similar to Example 128 starting from
3-{4-[1-(4-bromo-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-propionic
acid methyl ester. MS: 488 [M-H].sup.-.
Example 459
Racemic 3-{4-[1-(4-hydroxy-phenoxy)-heptyl]-benzoylamino}-propionic
acid
##STR00410##
[1064] The title compound is prepared in a manner substantially
similar to Example 92 starting from
3-{4-[1-(4-hydroxy-phenoxy)-heptyl]-benzoylamino}-propionic acid
methyl ester. MS: 398.3 [M-H].sup.-.
Example 460
3-{4-[1-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-2-methyl-propyl-
]-benzoylamino}-propionic acid, isomer 1
Example 461
3-{4-[1-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-2-methyl-propyl-
]-benzoylamino}-propionic acid, isomer 1
##STR00411##
[1066] The racemic
3-{4-[1-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yloxy)-2-methyl-propy-
l]-benzoylamino}-propionic acid is resolved on a Chiralpak OJ-H
column (0.46.times.15 cm) with a flow rate of 0.6 mL/min. and
detection at 250 nm. Elute with Methanol and concentrate the
fractions to provide a purified enantiomer ester isomer 1 (100% ee)
and enantiomer ester isomer 2 (99.3% ee). Hydrolysis of the
purified enantiomer of the ester provided the title compound as a
white solid. The structure was confirmed by proton NMR.
Example 462
3-{4-[1-(2,6-Dimethyl-4'-trifluoromethoxy-biphenyl-4-yloxy)-heptyl]-benzoy-
lamino}-propionic acid, isomer 1
Example 463
3-{4-[1-(2,6-Dimethyl-4'-trifluoromethoxy-biphenyl-4-yloxy)-heptyl]-benzoy-
lamino}-propionic acid, isomer 1
##STR00412##
[1068] The racemic
3-{4-[1-(2,6-Dimethyl-4'-trifluoromethoxy-biphenyl-4-yloxy)-heptyl]-benzo-
ylamino}-propionic acid is resolved on a Chiralpak OJ-H column
(0.46.times.15 cm) with a flow rate of 0.6 mL/min. and detection at
250 nm. Elute with Methanol and concentrate the fractions to
provide a purified enantiomer ester isomer 1 (100% ee) and
enantiomer ester isomer 2 (99.2% ee). Hydrolysis of the purified
enantiomer of the ester provided the title compound as a white
solid. The structure was confirmed by proton NMR.
[1069] The compound of Formula I is preferably formulated in a unit
dosage form prior to administration. Therefore, yet another
embodiment of the present invention is a pharmaceutical composition
comprising a compound of Formula I and one or more pharmaceutically
acceptable carriers, diluents or excipients.
[1070] The present pharmaceutical compositions are prepared by
known procedures using well-known and readily available
ingredients. In making the formulations of the present invention,
the active ingredient (Formula I compound) will usually be mixed
with a carrier, or diluted by a carrier, or enclosed within a
carrier which may be in the form of a capsule, sachet, paper or
other container. When the carrier serves as a diluent, it may be a
solid, semisolid or liquid material that acts as a vehicle,
excipient, or medium for the active ingredient. Thus, the
compositions can be in the form of tablets, pills, powders,
lozenges, sachets, cachets, elixirs, suspensions, emulsions,
solutions, syrups, aerosol (as a solid or in a liquid medium), soft
and hard gelatin capsules, suppositories, sterile injectable
solutions and sterile packaged powders.
[1071] Some examples of suitable carriers, excipients, and diluents
include lactose, dextrose, sucrose, sorbitol, mannitol, starches,
gum acacia, calcium phosphate, alginates, tragacanth, gelatin,
calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone,
cellulose, water syrup, methyl cellulose, methyl and
propylhydroxybenzoates, talc, magnesium stearate and mineral oil.
The formulations can additionally include lubricating agents,
wetting agents, emulsifying and suspending agents, preserving
agents, sweetening agents or flavoring agents. The compositions of
the invention may be formulated so as to provide quick, sustained
or delayed release of the active ingredient after administration to
the patient.
[1072] The compositions of the present invention may be formulated
in sustained release form to provide the rate controlled release of
any one or more of the components or active ingredients to optimize
the therapeutic effects, i.e., antihistaminic activity and the
like. Suitable dosage forms for sustained release include layered
tablets containing layers of varying disintegration rates or
controlled release polymeric matrices impregnated with the active
components and shaped in tablet form or capsules containing such
impregnated or encapsulated porous polymeric matrices.
[1073] Liquid form preparations include solutions, suspensions and
emulsions. As an example may be mentioned water or water-propylene
glycol solutions for parenteral injections or addition of
sweeteners and opacifiers for oral solutions, suspensions and
emulsions. Liquid form preparations may also include solutions for
intranasal administration.
[1074] Aerosol preparations suitable for inhalation may include
solutions and solids in powder form, which may be in combination
with a pharmaceutically acceptable carrier such as inert compressed
gas, e.g. nitrogen.
[1075] For preparing suppositories, a low melting wax such as a
mixture of fatty acid glycerides such as cocoa butter is first
melted, and the active ingredient is dispersed homogeneously
therein by stirring or similar mixing. The molten homogeneous
mixture is then poured into convenient sized molds, allowed to cool
and thereby solidify.
[1076] Also included are solid form preparations which are intended
to be converted, shortly before use, to liquid form preparations
for either oral or parenteral administration. Such liquid forms
include solutions, suspensions and emulsions.
[1077] The compounds of the invention may also be deliverable
transdemially. The transdermal compositions may take the form of
creams, lotions, aerosols and/or emulsions and can be included in a
transdermal patch of the matrix or reservoir type as a re
conventional in the art for this purpose.
[1078] Preferably the compound is administered orally.
[1079] Preferably, the pharmaceutical preparation is in a unit
dosage form. In such form, the preparation is subdivided into
suitably sized unit doses containing appropriate quantities of the
active components, e.g., an effective amount to achieve the desired
purpose.
[1080] The quantity of the inventive active composition in a unit
dose of preparation may be generally varied or adjusted from about
0.01 milligrams to about 1,000 milligrams, preferably from about
0.01 to about 950 milligrams, more preferably from about 0.01 to
about 500 milligrams, and typically from about 1 to about 250
milligrams, according to the particular application. The actual
dosage employed may be varied depending upon the patient's age,
sex, weight and severity of the condition being treated. Such
techniques are well known to those skilled in the art. Generally,
the human oral dosage form containing the active ingredients can be
administered 1 or 2 times per day.
[1081] There is increasing evidence that glucagon plays an
important role in glucose homeostasis. Compounds of Formula I are
effective as antagonists or inverse agonists of the glucagon
receptor, and thus inhibit the activity of the glucagon receptor.
More particularly, these compounds are selective antagonists or
inverse agonists of the glucagon receptor. As selective antagonists
or inverse agonists, the compounds of Formula I are useful in the
treatment of diseases, disorders, or conditions responsive to the
inactivation of the glucagon receptor, including but not limited to
diabetic and other glucagon related disorder. It is postulated that
selective antagonists or inverse agonists of the glucagon receptor
will lower plasma glucose levels and thus prevent or treat diabetic
and other glucagon related metabolic disorders.
Pharmacological Methods
[1082] In the following section binding assays as well as
functional assays useful for evaluating the efficiency of the
compounds of the invention are described.
[1083] Binding of compounds to the glucagon receptor may be
determined in a competition binding assay using the cloned human
glucagon receptor, and selectivity against the hG1p1 receptor.
Antagonism may be determined as the ability of the compounds to
inhibit the amount of cAMP formed in in the assay in the presence
of 5 nM glucagon.
[1084] Glucagon Receptor (hGlucR) Binding Assay
[1085] The receptor binding assay used cloned human glucagon
receptor (Lok S, Kuijper J L, Jelinek L J, Kramer J M, Whitmore T
E, Sprecher C A, Mathewes S, Grant F J, Biggs S H, Rosenberg G B,
et al. Gene 140 (2), 203-209 (1994)) isolated from 293HEK
membranes. The hGlucR cDNA was subcloned into the expression
plasmid phD (Trans-activated expression of fully gamma-carboxylated
recombinant human protein C, an antithrombotic factor. Grinnell, B.
W., Berg, D. T., Walls, J. and Yan, S. B. Bio/Technology 5:
1189-1192 (1987)). This plasmid DNA was transfected into 293 HEK
cells and selected with 200 ug/mL Hygromycin.
[1086] Crude plasma membranes are prepared using cells from
suspension culture. The cells are lysed on ice in hypotonic buffer
containing 25 mM Tris HCL, pH 7.5, 1 mM MgCl2, DNAse1, 20 u/mL, and
Roche Complete Inhibitors-without EDTA. The cell suspension is
homogenized with a glass dounce homogenizer using a Teflon pestle
for 25 strokes. The homogenate is centrifuged at 4 degrees C. at
1800.times.g for 15 mins. The supernate is collected and the pellet
is resuspended in hypotonic buffer and rehomogenized. The mixture
is centrifuged at 1800.times.g for 15 mins. The second supernate is
combined with the first supernate. The combined supernates are
recentrifuged at 1800.times.g for 15 mins to clarify. The clarified
supernate is transferred to high speed tubes and centrifuged at
25000.times.g for 30 minutes at 4 degrees C. The membrane pellet is
resuspended in homogenization buffer and stored as frozen aliquots
at -80 degree C. freezer until needed.
[1087] Glucagon is radioiodinated by I-125-lactoperoxidase
procedure and purified by reversed phase HPLC at Perkin-Elmer/NEN
(NEX207). The specific activity is 2200 Ci/mmol. Kd determination
is performed by homologous competition instead of saturation
binding due to high propanol content in the 1-125 glucagon
material. The Kd is estimated to be 3 nM and is used to calculate
Ki values for all compounds tested.
[1088] The binding assays are carried out using a Scintillation
Proximity Assay (Amersham) with WGA beads previously blocked with
1% fatty acid free BSA (ICN). The binding buffer contains 25 mM
Hepes, pH 7.4, 2.5 mM CaCl2, 1 mM MgCl2, 0.1% fatty acid free BSA,
(ICN), 0.003% tween-20, and Roche Complete Inhibitors without EDTA.
Glucagon is dissolved in 0.01 N HCl at 1 mg/mL and immediately
frozen at -80 degrees C. in 30 ul aliquots. The glucagon aliquot is
diluted and used in binding assays within an hour. Test compounds
are dissolved in DMSO and serially diluted in DMSO. 10 ul diluted
compounds or DMSO is transferred into Coming 3632, opaque clear
bottom assay plates containing 90 ul assay binding buffer or cold
glucagon (NSB at 1 uM final). 50 ul of 1-125 glucagon (0.15 nM
final in reaction), 50 ul of membranes (300 ug/well), and 40 ul of
WGA beads (150 ugs/well) are added, covered, and mixed end over
end. Plates are read with a MicroBeta after 14 hours of settling
time at room temp.
[1089] Results are calculated as a percent of specific
I-125-glucagon binding in the presence of compound. The absolute
EC50 dose of compound is derived by non-linear regression of
percent specific binding of I-125-glucagon vs. the dose of compound
added. The EC50 dose is converted to Ki using the Cheng-Prusoff
equation (Cheng Y., Prusoff W. H., Biochem. Pharmacol. 22,
3099-3108, 1973).
Glucagon-Like-Peptide 1 (Glp1-R) Receptor Binding Assay
[1090] The receptor binding assay used cloned human glucagon-like
peptide 1 receptor (hGlp1-R). (Graziano M P, Hey P J, Borkowski D,
Chicchi G G, Strader C D, Biochem Biophys Res Commun. 1993 Oct. 15;
196(1):141-6) isolated from 293HEK membranes. The hGlp1-R cDNA was
subcloned into the expression plasmid phD (Trans-activated
expression of fully gamma-carboxylated recombinant human protein C,
an antithrombotic factor. Grinnell, B. W., Berg, D. T., Walls, J.
and Yan, S. B. Bio/Technology 5: 1189-1192 (1987)). This plasmid
DNA was transfected into 293 HEK cells and selected with 200 ug/mL
Hygromycin.
[1091] Crude plasma membrane is prepared using cells from
suspension culture. The cells are lysed on ice in hypotonic buffer
containing 25 mM Tris HCl, pH 7.5, 1 mM MgCl2, DNAse, 20 u/mL, and
Roche Complete Inhibitors without EDTA. The cell suspension is
homogenized with a glass dounce homogenizer using a Teflon pestle
for 25 strokes. The homogenate is centrifuged at 4 degrees C. at
1800.times.g for 15 mins. The supernate is collected and the pellet
is resuspended in hypotonic buffer and rehomogenized. The mixture
is centrifuged at 1800.times.g for 15 mins. The second supernate is
combined with the first supernate. The combined supernates are
recentrifuged at 1800.times.g for 15 mins to clarify. The clarified
supernate is transferred to high speed tubes and centrifuged at
25000.times.g for 30 minutes at 4 degrees C. The membrane pellet is
resuspended in homogenization buffer and stored as frozen aliquots
in -80 degree C. freezer until use.
[1092] Glucagaon-like peptide 1 (Glp-1) is radioiodinated by the
I-125-lactoperoxidase procedure and purified by reversed phase HPLC
at Perkin-Elmer/NEN (NEX308). The specific activity is 2200
Ci/mmol. Kd determination is performed by homologous competition
instead of saturation binding due to high propanol content in the
I-125 Glp-1 material. The Kd is estimated to be 3 nM and is used to
calculate Ki values for all compounds tested.
[1093] The binding assays are carried out using a Scintillation
Proximity Assay (Amersham) with wheat germ agglutinin (WGA) beads
previously blocked with 1% fatty acid free BSA (ICN). The binding
buffer contains 25 mM Hepes, pH 7.4, 2.5 mM CaCl2, 1 mM MgCl2, 0.1%
fatty acid free BSA, (ICN), 0.003% tween-20, and Roche Complete
Inhibitors without EDTA. Glucagon-like peptide 1 is dissolved in
PBS at 1 mg/mL and immediately frozen at -80 degrees C. in 30 ul
aliquots. The glucagon-like peptide aliquot is diluted and used in
binding assays within an hour. Test compounds are dissolved in DMSO
and serially diluted in DMSO. 10 ul diluted compounds or DMSO is
transferred into Corning 3632, opaque clear bottom assay plates
containing 90 ul assay binding buffer or cold glucagon-like peptide
1 (NSB at 1 uM final). 50 ul of I-125 glucagon-like peptide 1 (0.15
nM final in reaction), 50 ul of membranes (600 ug/well), and 40 ul
of WGA beads (150 ugs/well) are added, covered, and mixed end over
end. Plates are read with a MicroBeta after 14 hours of settling
time at room temp.
[1094] Results are calculated as a percent of specific
I-125-glucagon-like peptide 1 binding in the presence of compound.
The absolute EC50 dose of compound is derived by non-linear
regression of percent specific binding of I-125-glucagon-like
peptide 1 vs. the dose of compound added. The EC50 dose is
converted to Ki using the Cheng-Prusoff equation (Cheng Y., Prusoff
W. H., Biochem. Pharmacol. 22, 3099-3108, 1973).
Glucagon-Stimulated cAMP Functional Antagonist Assay
[1095] The cAMP functional assay uses the same cloned human
glucagon receptor cell line isolated for the hGlucR binding assay
described above. Cells are stimulated with a mixture of an EC80
dose of glucagon in the presence of compound. The cAMP generated
within the cell is quantitated using an Amplified Luminescent
Proximity Homogeneous Assay, Alpha Screen, from Perkin Elmer
(6760625R).
[1096] Briefly, cAMP within the cell competes for binding of
biotinylated cAMP from the kit to a coated anti-cAMP antibody
Acceptor bead and a strepavidin coated Donor bead. As the cAMP
level within the cell increases, a disruption of the Acceptor
bead-biotinlyated cAMP-Donor bead complex occurs and decreases the
signal.
[1097] Glucagon is dissolved in 0.01 N HCl at 1 mg/mL and
immediately frozen at -80 degrees C. in 30 ul aliquots. The
glucagon aliquot is diluted and used in the functional assay within
an hour. Cells are harvested from sub-confluent tissue culture
dishes with Enzyme-Free Cell Dissociation Solution, (Specialty
Media 5-004-B). The cells are pelleted at low speed and washed 3
times with assay buffer [25 mM Hepes in HBSS-with Mg and Ca (GIBCO,
14025-092) with 0.1% Fatty Acid Free BSA (ICN)] then diluted to a
final concentration of 250,000 cells per mL. Compounds are serially
diluted into DMSO then diluted into assay buffer with a 3.times.
concentration of glucagon and 3% DMSO. The EC80 of glucagon is
pre-determined from a full glucagon dose response and represents
the dose at which glucagons produces an 80% of the maximal glucagon
response. A mixture of biotinylated cAMP (1 unit/well final) from
the Alpha Screen Kit and 3.times. IBMX (1500 uM) is prepared in
Assay Buffer.
[1098] The functional assay is performed in 96 well, low-volume,
white, poylstyrene Costar Plates (3688). The biotinylated cAMP/IBMX
mixture, 0.02 mLs, is placed into each well, followed by addition
of 0.02 mLs of glucagon dose response, cAMP standard curve, or
compound/glucagon mixtures. The reaction is started by addition of
0.02 mLs of cells (5000/well final). After 60 minutes at room
temperature, the reaction is stopped by the addition of 0.03 mLs of
Lysis Buffer [10 mM Hepes, pH 7.4, 1% NP40, and 0.01% fatty acid
free BSA (ICN) containing 1 unit each/well of Acceptor and Donor
beads from the Alpha Screen Kit]. Lysis Buffer addition is
performed under a green light to prevent bleaching of the detection
beads. The plates are wrapped in foil and left to equilibrate
overnight at room temperature. The plates are read on a Packard
Fusion.TM.-.quadrature.Instrument.
[1099] Alpha screen units are converted to pmoles cAMP generated
per well based upon the cAMP standard curve. The pmoles cAMP
produced in the presence of compound are converted to % of a
maximal response with the EC80 dose of glucagon alone. With each
experiment, the dose of glucagon needed to produce a 50% response
of pmoles cAMP is determined. This EC50 dose is used to normalize
results to a Kb using a modified Cheng-Prusoff equation (Cheng Y.,
Prusoff W. H., Biochem. Pharmacol. 22, 3099-3108, 1973), where
Kb=(EC50 compound)/[1+(pM glucagon used/EC50 in pM for glucagon
dose response)].
[1100] The compounds according to the invention preferably have a
Ki value of no greater than 50 .mu.M as determined by the Glucagon
Receptor (hGlucR) Binding Assay disclosed herein. More preferably,
the compounds according to the invention have a Ki value of less
than 5 .mu.M, preferably of less than 500 nM and even more
preferred of less than 100 nM as determined by the Glucagon
Receptor (hGlucR) Binding Assay disclosed herein. Generally, the
compounds according to the invention show a higher affinity for the
glucagon receptor compared to the GLP-1 receptor, and preferably
have a higher binding affinity to the glucagon receptor than to the
GLP-1 receptor.
[1101] The results are given below for the indicated compound.
TABLE-US-00001 TABLE 1 Example Ki (nM) ##STR00413## 265
##STR00414## 254
[1102] From the above description, one skilled in the art can
ascertain the essential characteristics of the present invention,
and without departing from the spirit and scope thereof, can make
various changes and modifications of the invention to adapt it to
various usages and conditions. Thus, other embodiments are also
within the claims.
* * * * *