U.S. patent application number 10/838904 was filed with the patent office on 2004-12-02 for beta3 adrenergic agonists.
Invention is credited to Evers, Britta, Jesudason, Cynthia Darshini, Karanjawala, Rushad Eruch, Remick, David Michael, Ruehter, Gerd, Sall, Daniel Jon, Schotten, Theo, Siegel, Miles Goodman, Stenzel, Wolfgang, Stucky, Russell Dean, Werner, John Arnold.
Application Number | 20040242633 10/838904 |
Document ID | / |
Family ID | 27396478 |
Filed Date | 2004-12-02 |
United States Patent
Application |
20040242633 |
Kind Code |
A1 |
Evers, Britta ; et
al. |
December 2, 2004 |
Beta3 adrenergic agonists
Abstract
The present invention relates to a .beta..sub.3 adrenergic
receptor agonist of formula I: 1 or a pharmaceutical salt thereof;
which is capable of increasing lipolysis and energy expenditure in
cells and, therefore, is useful for treating Type II diabetes
and/or obesity. The compound can also be used to lower triglyceride
levels and cholesterol levels or raise high density lipoprotein
levels or to decrease gut motility. In addition, the compound can
be used to reduced neurogenic inflammation or as an antidepressant
agent. Compositions and methods for the use of the compounds in the
treatment of diabetes and obesity and for lowering triglyceride
levels and cholesterol levels or raising high density lipoprotein
levels or for decreasing gut motility are also disclosed.
Inventors: |
Evers, Britta; (Hamburg,
DE) ; Jesudason, Cynthia Darshini; (Indianapolis,
IN) ; Karanjawala, Rushad Eruch; (Zionsville, IN)
; Remick, David Michael; (Fishers, IN) ; Ruehter,
Gerd; (Hamburg, DE) ; Sall, Daniel Jon;
(Greenwood, IN) ; Schotten, Theo; (Vierhoefen,
DE) ; Siegel, Miles Goodman; (Indianapolis, IN)
; Stenzel, Wolfgang; (Reinbek, DE) ; Stucky,
Russell Dean; (Indianapolis, IN) ; Werner, John
Arnold; (Greenwood, IN) |
Correspondence
Address: |
ELI LILLY AND COMPANY
PATENT DIVISION
P.O. BOX 6288
INDIANAPOLIS
IN
46206-6288
US
|
Family ID: |
27396478 |
Appl. No.: |
10/838904 |
Filed: |
May 4, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10838904 |
May 4, 2004 |
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10311112 |
Dec 13, 2002 |
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6730792 |
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10311112 |
Dec 13, 2002 |
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PCT/US01/16519 |
Jul 9, 2001 |
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60217965 |
Jul 13, 2000 |
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60241614 |
Oct 19, 2000 |
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60292988 |
May 23, 2001 |
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Current U.S.
Class: |
514/318 ;
514/343; 514/408; 546/194; 546/205; 546/276.4; 548/577 |
Current CPC
Class: |
A61K 9/0095 20130101;
A61K 9/02 20130101; A61K 9/10 20130101; A61K 9/0014 20130101; A61K
9/08 20130101; C07D 213/30 20130101; C07D 333/16 20130101; A61K
9/0043 20130101; C07D 277/24 20130101; A61K 9/2054 20130101; A61P
43/00 20180101; C07D 405/12 20130101; A61P 3/04 20180101; A61K
9/0073 20130101; C07D 417/12 20130101; A61K 9/0031 20130101; A61K
9/12 20130101; A61P 3/10 20180101; C07D 413/12 20130101; C07D
213/84 20130101; A61K 9/0019 20130101; C07D 207/333 20130101; C07D
409/12 20130101; A61K 9/0056 20130101; A61K 9/107 20130101; C07D
401/12 20130101; C07D 213/82 20130101; C07D 261/08 20130101 |
Class at
Publication: |
514/318 ;
514/343; 546/194; 546/205; 546/276.4; 548/577; 514/408 |
International
Class: |
A61K 031/4545; A61K
031/4439; A61K 031/40; C07D 41/04 |
Claims
1. A compound of formula I: 171wherein: A.sup.1, A.sup.2 and
A.sup.3 are carbon or nitrogen provided that only one of A.sup.1,
A.sup.2 and A.sup.3 is nitrogen; Het is an optionally substituted,
optionally benzofused 5 or 6 membered heterocyclic ring; R.sup.1,
R.sup.1a and R.sup.1b are independently H, halo, hydroxy,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.4
haloalkyl, or SO.sub.2(C.sub.1-C.sub.6 alkyl); R.sup.2 is H or
C.sub.1-C.sub.6 alkyl; R.sup.3 is H or C.sub.1-C.sub.6 alkyl;
R.sup.4 is H or C.sub.1-C.sub.6 alkyl; or R.sup.3 and R.sup.4
combine with the carbon to which both are attached to form a
C.sub.3-C.sub.6 cyclic ring; or R.sup.4 and X.sup.1 combine with
the carbon to which both are attached to form a C.sub.3-C.sub.8
cyclic ring; or R.sup.4 combines with X.sup.1, the carbon to which
both are attached, and the phenyl group to which X.sup.1 is
attached to form: 172wherein: n and m are independently 0, 1, 2, or
3 provided that the sum of n+m is.ltoreq.4 and that R.sup.3 is H; X
is OCH.sub.2, SCH.sub.2 or a bond; X.sup.1 is a bond or a
C.sub.1-C.sub.5 divalent hydrocarbon moiety; X.sup.2 is O, S, NH,
NHSO.sub.2, SO.sub.2NH, CH.sub.2 or a bond; and X.sup.3 is
optionally substituted phenyl or an optionally substituted 5 or 6
membered heterocyclic ring; or a pharmaceutical salt thereof.
2. The compound of claim 1 wherein: A.sup.1, A.sup.2 and A.sup.3
are carbon; Het is optionally substituted one to three times
independently with halo, hydroxy, oxo, cyano, nitro, phenyl,
benzyl, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl,
C.sub.1-C.sub.4 alkoxy, COR.sup.8, CO.sub.2R.sup.8,
CONR.sup.8R.sup.8, NR.sup.8R.sup.8, NHCO(C.sub.1-C.sub.4 alkyl),
NHCO(phenyl), NHCO(benzyl), SR.sup.8, SO(C.sub.1-C.sub.4 alkyl),
SO.sub.2(C.sub.1-C.sub.4 alkyl), SO.sub.2(NR.sup.8R.sup.8),
OCO(C.sub.1-C.sub.4 alkyl), OCO.sub.2R.sup.8 or OCONR.sup.8R.sup.8
R.sup.1, R.sup.1a and R.sup.1b are independently H, halo,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4
haloalkyl, or SO.sub.2(C.sub.1-C.sub.4 alkyl); R.sup.2 is H or
C.sub.1-C.sub.4 alkyl; R.sup.3 and R.sup.4 are independently H or
C.sub.1-C.sub.4 alkyl; or R.sup.3 and R.sup.4 combine with the
carbon to which both are attached to form a C.sub.3-C.sub.6 cyclic
ring; or R.sup.4 and X.sup.1 combine with the carbon to which both
are attached to form a C.sub.3-C.sub.8 cyclic ring; or R.sup.4
combines with X.sup.1, the carbon to which both are attached, and
the phenyl group to which X.sup.1 is attached to form: 173X.sup.3
is optionally substituted one to three times independently with
halo, hydroxy, oxo, cyano, nitro, phenyl, benzyl, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxy,
COR.sup.8, CO.sub.2R.sup.8, CONR.sup.8R.sup.8, NR.sup.8R.sup.8,
NHCO(C.sub.1-C.sub.4 alkyl), NHCO(phenyl), NHCO(benzyl), SR.sup.8,
SO(C.sub.1-C.sub.4 alkyl), SO.sub.2(C.sub.1-C.sub.4 alkyl),
SO.sub.2(NR.sup.8R.sup.8), OCO(C.sub.1-C.sub.4 alkyl),
OCO.sub.2R.sup.8 or OCONR.sup.8R.sup.8; and R.sup.8 is
independently at each occurrence H or C.sub.1-C.sub.4 alkyl; or a
pharmaceutical salt thereof.
3. The compound of claim 2 of the formula: 174wherein: Het is
selected from furan; isothiazole; isoxazole; oxazole; and
thiophene; wherein said Het moieties are optionally substituted
once with fluorine, methyl, cyano, SO.sub.2NH.sub.2 or COCH.sub.3;
R.sup.3 and R.sup.4 are independently H or methyl; X.sup.3 is
phenyl, pyridyl or pyridazinyl wherein said X.sup.3 moieties are
substituted once or twice with chloro, cyano, CONH.sub.2 or
SO.sub.2CH.sub.3; or a pharmaceutical salt thereof.
4. The compound of claim 3 wherein Het is thien-2-yl optionally
substituted once with fluorine, methyl, cyano, SO.sub.2NH.sub.2 or
COCH.sub.3; R.sup.3 and R.sup.4 are both methyl; and X.sup.3 is
phenyl or pyridyl wherein said X.sup.3 moieties are substituted
once with cyano or CONH.sub.2; or a pharmaceutical salt
thereof.
5. The compound of claim 4 wherein X.sup.3 is pyridyl substituted
once with cyano or CONH.sub.2; or a pharmaceutical salt
thereof.
6. The compound of claim 5 which is selected from the group
consisting of: 175or a pharmaceutical salt thereof.
7. A compound of the formula: 176or a pharmaceutical salt
thereof.
8. The compound of claim 7 which is the hydrochloride salt.
9. The compound of claim 7 which is the hemi-fumarate, benzoate,
salicylate or R-mandelate salt.
10. Cancelled
11. A method of treating obesity comprising administering to a
patient in need thereof a compound of claim 3.
12. A method of treating Type II Diabetes comprising administering
to a patient in need thereof a compound of claim 3.
13. Cancelled
14. Cancelled
15. A compound of formula II: 177wherein: A.sup.1, A.sup.2 and
A.sup.3 are carbon or nitrogen provided that only one of A.sup.1,
A.sup.2 and A.sup.3 is nitrogen; Het is an optionally substituted,
optionally benzofused 5 or 6 membered heterocyclic ring; R.sup.1
and R.sup.1a are independently H, halo, hydroxy, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl, or
SO.sub.2 (C.sub.1-C.sub.6 alkyl); or a salt thereof.
16. The compound of claim 15 of the formula: 178wherein: Het is
selected from benzothiophene; furan; isothiazole; isoxazole;
oxazole; thiophene; and thiazole; wherein said Het moieties are
optionally substituted once with fluorine, chlorine, methyl, cyano,
SO.sub.2NH.sub.2 or COCH.sub.3; or a salt thereof.
17. A process for preparing a compound of claim 1 which comprises
reacting a compound of formula II: 179with a compound of formula
III: 180in the presence of a suitable solvent.
18. A method of treating obesity comprising administering to a
patient in need thereof a compound of claim 7.
19. A method of treating obesity comprising administering to a
patient in need thereof a compound of claim 8.
20. A method of treating obesity comprising administering to a
patient in need thereof a compound of claim 9.
Description
[0001] This application claims the benefit of U.S. Serial Nos.
60/217,965; 60/241,614; and 60/292,988.
FIELD OF THE INVENTION
[0002] The present invention is in the field of medicine,
particularly in the treatment of Type II diabetes and obesity. More
specifically, the present invention relates to .beta..sub.3
adrenergic receptor agonists useful in the treatment of Type II
diabetes and obesity.
BACKGROUND OF THE INVENTION
[0003] The current preferred treatment for Type II, non-insulin
dependent diabetes as well as obesity is diet and exercise, with a
view toward weight reduction and improved insulin sensitivity.
Patient compliance, however, is usually poor. The problem is
compounded by the fact that there are currently no approved
medications that adequately treat either Type II diabetes or
obesity.
[0004] One therapeutic opportunity that has recently been
recognized involves the relationship between adrenergic receptor
stimulation and anti-hyperglycemic effects. Compounds that act as
.beta..sub.3 receptor agonists have been shown to exhibit a marked
effect on lipolysis, thermogenesis and serum glucose levels in
animal models of Type II (non-insulin dependent) diabetes.
[0005] The .beta..sub.3 receptor, which is found in several types
of human tissue including human fat tissue, has roughly 50%
homology to the .beta..sub.1 and .beta..sub.2 receptor subtypes yet
is considerably less abundant. Stimulation of the .beta..sub.1 and
.beta..sub.2 receptors can cause adverse effects such as
tachycardia, arrhythmia, or tremors. An agonist that is selective
for the .beta..sub.3 receptor over the .beta..sub.1 and
.beta..sub.2 receptors is, therefore, more desirable for treating
Type II diabetes or obesity relative to a non-selective
agonist.
[0006] However, recent studies have suggested the presence of an
atypical beta receptor associated with atrial tachycardia in rats
(Br. J. of Pharmacol., 118:2085-2098, 1996). In other words,
compounds that are not agonists of the .beta..sub.1 and
.beta..sub.2 receptors can still modulate tachycardia through
activation of a yet to be discovered .beta..sub.4 or through some
other unknown pathway.
[0007] A large number of publications have appeared in recent years
reporting success in discovery of agents that stimulate the
.beta..sub.3 receptor. Despite these recent developments, there
remains a need to develop a selective .beta..sub.3 receptor agonist
which has minimal agonist activity against the .beta..sub.1 and
.beta..sub.2 receptors.
SUMMARY OF INVENTION
[0008] The present invention relates to a compound of formula I:
2
[0009] wherein:
[0010] A.sup.1, A.sup.2 and A.sup.3 are carbon or nitrogen provided
that only one of A.sup.1, A.sup.2 and A.sup.3 can be nitrogen;
[0011] Het is an optionally substituted, optionally benzofused 5 or
6 membered heterocyclic ring;
[0012] R.sup.1, R.sup.1a and R.sup.1b are independently H, halo,
hydroxy, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.4 haloalkyl, or SO.sub.2(C.sub.1-C.sub.6 alkyl);
[0013] R.sup.2 is H or C.sub.1-C.sub.6 alkyl;
[0014] R.sup.3 is H or C.sub.1-C.sub.6 alkyl;
[0015] R.sup.4 is H or C.sub.1-C.sub.6 alkyl;
[0016] or R.sup.3 and R.sup.4 combine with the carbon to which both
are attached to form a C.sub.3-C.sub.6 cyclic ring;
[0017] or R.sup.4 and X.sup.1 combine with the carbon to which both
are attached to form a C.sub.3-C.sub.8 cyclic ring;
[0018] or R.sup.4 combine the carbon to which both are attached,
and the phenyl group to which X.sup.1 is attached to form: 3
[0019] wherein:
[0020] n and m are independently 0, 1, 2, or 3 provided that the
sum of n+m is.ltoreq.4 and that R.sup.3 is H;
[0021] X is OCH.sub.2, SCH.sub.2 or a bond;
[0022] X.sup.1 is a bond or a C.sub.1-C.sub.5 divalent hydrocarbon
moiety;
[0023] x.sup.2 is O, S, NH, NHSO.sub.2, SO.sub.2NH, CH.sub.2 or a
bond; and
[0024] X.sup.3 is optionally substituted phenyl or an optionally
substituted 5 or 6 membered heterocyclic ring; or a pharmaceutical
salt thereof.
[0025] The present invention also relates to processes for
preparing, as well as novel pharmaceutical formulations containing,
a compound of formula I. In another embodiment, the pharmaceutical
formulations of the present invention may be adapted for use in
treating Type II diabetes and obesity and for agonizing the
.beta..sub.3 receptor.
[0026] The present invention also relates to methods for treating
Type II diabetes and obesity, as well as a method for agonizing the
.beta..sub.3 receptor employing a compound of formula I.
[0027] In addition, the present invention relates to a compound of
formula I for use in treating Type II diabetes and obesity as well
as a compound of formula I for use in agonizing the .beta..sub.3
receptor. The present invention is further related to the use of a
compound of formula I for the manufacture of a medicament for
treating Type II diabetes and obesity as a well as for agonizing
the .beta..sub.3 receptor.
[0028] The present invention is also related to a compound of
formula II: 4
[0029] which is useful as an intermediate to prepare a compound of
formula I.
DETAILED DESCRIPTION
[0030] For the purposes of the present invention, as disclosed and
claimed herein, the following terms are defined below.
[0031] The term "halo" represents fluoro, chloro, bromo, or
iodo.
[0032] The terms "C.sub.1-C.sub.6 alkyl" and "C.sub.1-C.sub.4
alkyl" represent a straight, branched or cyclic hydrocarbon moiety
having from one to six and one to four carbon atoms, respectively.
C.sub.1-C.sub.4 alkyl groups include methyl, ethyl, n-propyl,
isopropyl, cyclopropyl, n-butyl, isobutyl, secbutyl, t-butyl and
cyclobutyl. A "C.sub.1-C.sub.4 haloalkyl" group is a
C.sub.1-C.sub.4 alkyl moiety substituted with up to six halo atoms,
preferably one to three halo atoms. An example of a haloalkyl group
is trifluoromethyl. A "C.sub.1-C.sub.6 alkoxy" group is a
C.sub.1-C.sub.6 alkyl moiety connected through an oxy linkage.
[0033] The term "divalent hydrocarbon moiety" refers to a straight
or branched chain of carbon atoms that may optionally have one or
more points of unsaturation. Thus, a hydrocarbon diradical
according to the present invention includes alkylene, alkenylene
and alkylidene moieties. Examples include but are not intended to
be limited to methylene, ethylene, propylene, butylene,
--CH(CH.sub.3)CH.sub.2----CH(C.sub.2H.sub.- 5)CH.sub.2--,
--CH(CH.sub.3)CH(CH.sub.3)--, --CH.sub.2C(CH.sub.3).sub.2--,
--CH.sub.2CH(CH.sub.3)CH.sub.2--, --C(CH.sub.3).sub.2CH.sub.2--,
--CH.dbd.CHCH.sub.2--, --CH.dbd.CH--, --C.dbd.CCH.sub.2--, and the
like.
[0034] The term "optionally substituted" as used herein means an
optional substitution of one to three, preferably one or two groups
independently selected from oxo, nitro, cyano, phenyl, benzyl,
halo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 haloalkyl, COR.sup.5,
NR.sup.6R.sup.6, NR.sup.6COR.sup.5, NR.sup.6SO.sub.2R.sup.7,
OR.sup.6, OCOR.sup.5, OSO.sub.2R.sup.7, SR.sup.6, SOR.sup.7,
SO.sub.2R.sup.7 or SO.sub.2NR.sup.6R.sup.6; wherein
[0035] R.sup.5 is H, C.sub.1-C.sub.6 alkyl, phenyl, benzyl,
C.sub.1-C.sub.4 haloalkyl, NR.sup.6aR.sup.6a or OR.sup.6a;
[0036] R.sup.6 and R.sup.6a are independently H, C.sub.1-C.sub.6
alkyl or phenyl; or when two R.sup.6 or R.sup.6a groups are
attached to the same nitrogen atom, said R.sup.6 or R.sup.6a
groups, together with the nitrogen to which they are attached, may
combine to form a piperidine, pyrrolidine, hexamethyleneimine or
morpholine ring; and
[0037] R.sup.7 is C.sub.1-C.sub.6 alkyl or phenyl.
[0038] The term "heterocyclic ring" represents a stable, saturated,
partially unsaturated, fully unsaturated or aromatic ring, said
ring having from one to four heteroatoms that are independently
selected from the group consisting of sulfur, oxygen, and nitrogen.
The heterocycle may be attached at any point which affords a stable
structure. Representative heterocyclic rings include 1,3-dioxolane,
4,5-dihydro-1H-imidazole, 4,5-dihydrooxazole, furan, imidazole,
imidazolidine, isothiazole, isoxazole, morpholine, oxadiazole,
oxazole, oxazolidinedione, oxazolidone, piperazine, piperidine,
pyrazine, pyrazole, pyrazoline, pyridazine, pyridine, pyrimidine,
pyrrole, pyrrolidine, tetrazole, thiadiazole, thiazole, thiophene
and triazole. Representative "benzofused" heterocyclic rings
include benzoxazole, benzimidazole, benzofuran, benzothiophene,
benzothiazole, azaindole, and indole. Further specific examples of
benzofused and non-benzofused heterocycles are described below in
the Preparations and Examples sections.
[0039] 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.
[0040] 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 preferred patient of treatment
is a human.
[0041] The terms "treating" and "treat", as used herein, include
their generally accepted meanings, i.e., preventing, prohibiting,
restraining, alleviating, ameliorating, slowing, stopping, or
reversing the progression or severity of a pathological condition,
or sequela thereof, described herein.
[0042] The terms "preventing", "prevention of", "prophylaxis",
"prophylactic" and "prevent" are used herein interchangeably and
refer to reducing the likelihood that the recipient of a compound
of formula I will incur or develop any of the pathological
conditions, or sequela thereof, described herein.
[0043] As used herein, the term "effective amount" means an amount
of a compound of formula I that is capable of treating conditions,
or detrimental effects thereof, described herein or that is capable
of agonizing the .beta..sub.3 receptor.
[0044] The term "selective .beta..sub.3 receptor agonist" means a
compound that displays preferential agonism of the .beta..sub.3
receptor over agonism of the .beta..sub.1 or .beta..sub.2 receptor.
Thus, .beta..sub.3 selective compounds behave as agonists for the
.beta..sub.3 receptor at lower concentrations than that required
for similar agonism at the .beta..sub.1 and .beta..sub.2 receptors.
A .beta..sub.3 selective compound also includes compounds that
behave as agonists for the .beta..sub.3 receptor and as antagonists
for the .beta..sub.1 and .beta..sub.2 receptors.
[0045] The term "pharmaceutical" when used herein as an adjective
means substantially non-deleterious to the recipient patient.
[0046] The term "formulation", as in pharmaceutical formulation, is
intended to encompass a product comprising the active ingredient(s)
(compound of formula I), and the inert ingredient(s) that make up
the carrier, as well as any product which results, directly or
indirectly, from combination, complexation or aggregation of any
two or more of the ingredients, or from dissociation of one or more
of the ingredients, or from other types of reactions or
interactions of one or more of the ingredients. Accordingly, the
pharmaceutical formulations of the present invention encompass any
composition made by admixing a compound of the present invention
and a pharmaceutical carrier.
[0047] The term "unit dosage form" refers to 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.
[0048] Because certain compounds of the invention contain an acidic
moiety (e.g., carboxy), the compound of formula I may exist as a
pharmaceutical base addition salt thereof. Such salts include those
derived from inorganic bases such as ammonium and alkali and
alkaline earth metal hydroxides, carbonates, bicarbonates, and the
like, as well as salts derived from basic organic amines such as
aliphatic and aromatic amines, aliphatic diamines, hydroxy
alkamines, and the like.
[0049] Because certain compounds of the invention contain a basic
moiety (e.g., amino), the compound of formula I can also exist as a
pharmaceutical acid addition salt. Such salts include the
salicylate, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite,
phosphate, monohydrogenphosphate, dihydrogenphosphate,
metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate,
propionate, decanoate, caprylate, acrylate, formate, isobutyrate,
heptanoate, propiolate, oxalate, malonate, succinate, suberate,
sebacate, fumarate, maleate, 2-butyne-1,4 dioate, 3-hexyne-2,
5-dioate, benzoate, chlorobenzoate, hydroxybenzoate,
methoxybenzoate, phthalate, xylenesulfonate, phenylacetate,
phenylpropionate, phenylbutyrate, citrate, lactate, hippurate,
.beta.-hydroxybutyrate, glycolate, maleate, tartrate,
methanesulfonate, propanesulfonate, naphthalene-1-sulfonate,
naphthalene-2-sulfonate, mandelate and like salts. Preferred acid
addition salts include the hemifumarate, benzoate, salicylate,
R-mandelate, hydrochloride and glycolate salts.
[0050] It is recognized that various stereoisomeric forms of a
compound of formula I exist. The compounds may be prepared as
racemates and can be conveniently used as such. Therefore, the
racemates, individual enantiomers, diastereomers, or mixtures
thereof form part of the present invention. Unless otherwise
specified, whenever a compound is described or referenced in this
specification all the racemates, individual enantiomers,
diastereomers, or mixtures thereof are included in said reference
or description.
[0051] It is also recognized that various tautomeric forms of a
compound of formula I may exist, and all tautomeric forms are part
of the present invention. Unless otherwise specified, whenever a
compound is described or referenced in this specification all
tautomeric forms, or mixtures thereof, are included in said
reference or description.
[0052] Preferred Compounds of the Invention
[0053] Certain compounds of the invention 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 compounds.
[0054] a) A.sup.1, A.sup.2 and A.sup.3 are carbon;
[0055] b) Het is at the ortho-position relative to X;
[0056] c) Het is optionally substituted one to three times
independently with halo, hydroxy, oxo, cyano, nitro, phenyl,
benzyl, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl,
C.sub.1-C.sub.4 alkoxy, COR.sup.8, CO.sub.2R.sup.8,
CONR.sup.8R.sup.8, NR.sup.8R.sup.8, NHCO(C.sub.1-C.sub.4 alkyl),
NHCO(phenyl), NHCO(benzyl), SR.sup.8, SO(C.sub.1-C.sub.4 alkyl),
SO.sub.2(C.sub.1-C.sub.4 alkyl), SO.sub.2(NR.sup.8R.sup.8),
OCO(C.sub.1-C.sub.4 alkyl), OCO.sub.2R.sup.8 or OCONR.sup.8R.sup.8
where R.sup.8 is independently at each occurrence H or
C.sub.1-C.sub.4 alkyl;
[0057] d) Het is an optionally substituted 5-membered,
non-benzofused ring containing one or two heteroatoms that are
independently selected from the group consisting of sulfur, oxygen,
and nitrogen;
[0058] e) Het is selected from furan; isothiazole; isoxazole;
oxazole; and thiophene; wherein said Het moieties are optionally
substituted once with fluorine, methyl, cyano, SO.sub.2NH.sub.2 or
COCH.sub.3;
[0059] f) Het is selected from thien-2-yl; thien-3-yl;
thiazol-2-yl; isoxazol-3-yl; isoxazol-5-yl; and
isothiazol-5-yl;
[0060] g) Het is thien-2-yl optionally substituted once with
fluorine, methyl, cyano, SO.sub.2NH.sub.2 or COCH.sub.3;
[0061] h) Het is thien-2-yl;
[0062] i) R.sup.1, R.sup.1a and R.sup.1b are independently H, halo,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4
haloalkyl, or SO.sub.2(C.sub.1-C.sub.4 alkyl);
[0063] j) R.sup.1 is H, methyl, ethyl, CF.sub.3, chloro or
fluoro;
[0064] k) R.sup.1 is H, methyl, chloro or fluoro;
[0065] l) R.sup.1 is H or fluoro;
[0066] m) R.sup.1 is H;
[0067] n) R.sup.1a is H, methyl, ethyl, CF.sub.3, chloro or
fluoro;
[0068] o) R.sup.1a is H, methyl, chloro or fluoro;
[0069] p) R.sup.1a is H;
[0070] q) R.sup.1b is H, methyl, ethyl, CF.sub.3, chloro or
fluoro;
[0071] r) R.sup.1b is H, methyl, chloro or fluoro;
[0072] s) R.sup.1b is H;
[0073] t) R.sup.2 is H or C.sub.1-C.sub.4 alkyl;
[0074] u) R.sup.2 is H;
[0075] v) R.sup.3 and R.sup.4 are independently H or
C.sub.1-C.sub.4 alkyl;
[0076] w) R.sup.3 is H or methyl;
[0077] x) R.sup.4 is H or methyl;
[0078] y) R.sup.3 and R.sup.4 are both methyl;
[0079] z) R.sup.8 is independently at each occurrence H or
C.sub.1-C.sub.4 alkyl;
[0080] aa) X is OCH.sub.2;
[0081] bb) X.sup.1 is a bond, methylene or ethylene;
[0082] cc) X.sup.1 is methylene;
[0083] dd) X.sup.2 is at the para-position relative to X.sup.1;
[0084] ee) X.sup.2 is a bond or O;
[0085] ff) X.sup.2 is O or CH.sub.2;
[0086] gg) X.sup.2 is O;
[0087] hh) X.sup.3 is optionally substituted one to three times
independently with halo, hydroxy, oxo, cyano, nitro, phenyl,
benzyl, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl,
C.sub.1-C.sub.4 alkoxy, COR.sup.8, CO.sub.2R.sup.8,
CONR.sup.8R.sup.8, NR.sup.8R.sup.8, NHCO(C.sub.1-C.sub.4 alkyl),
NHCO(phenyl), NHCO(benzyl), SR.sup.8, SO(C.sub.1-C.sub.4 alkyl),
SO.sub.2(C.sub.1-C.sub.4 alkyl), SO.sub.2(NR.sup.8R.sup.8),
OCO(C.sub.1-C.sub.4 alkyl), OCO.sub.2R.sup.8 or
OCONR.sup.8R.sup.8;
[0088] ii) X.sup.3 is phenyl, pyridyl, thienyl or furanyl wherein
said X.sup.3 moieties are substituted one to three times with
fluoro, chloro, cyano, hydroxy, methyl, ethyl, trifluoromethyl,
methoxy, ethoxy, amino, CO.sub.2CH.sub.3, CO.sub.2CH.sub.2CH.sub.3,
CONR.sup.8R.sup.8, SCH.sub.3, SCH.sub.2CH.sub.3, SOCH.sub.3,
SOCH.sub.2CH.sub.3, SO.sub.2CH.sub.3 or
SO.sub.2CH.sub.2CH.sub.3;
[0089] jj) X.sup.3 is phenyl, pyridyl, thienyl or furanyl wherein
said X.sup.3 moieties are substituted one to three times with
fluoro, cyano, hydroxy, methyl, ethyl, methoxy, ethoxy, amino,
CO.sub.2CH.sub.3, CO.sub.2CH.sub.2CH.sub.3, CONH.sub.2, SCH.sub.3,
SCH.sub.2CH.sub.3, SOCH.sub.3, SOCH.sub.2CH.sub.3, SO.sub.2CH.sub.3
or SO.sub.2CH.sub.2CH.sub.3;
[0090] kk) X.sup.3 is phenyl, pyridyl, thienyl or furanyl wherein
said X.sup.3 moieties are substituted one to three times with
fluoro, amino, CO.sub.2CH.sub.3, CO.sub.2CH.sub.2CH.sub.3, cyano,
CONH.sub.2, SO.sub.2CH.sub.3 or SO.sub.2CH.sub.2CH.sub.3;
[0091] ll) X.sup.3 is phenyl, pyridyl or pyridazinyl wherein said
X.sup.3 moieties are substituted once or twice with chloro, cyano,
CONH.sub.2 or SO.sub.2CH.sub.3;
[0092] mm) X.sup.3 is phenyl, pyridyl, thienyl or furanyl wherein
said X.sup.3 moieties are substituted once with cyano or
CONH.sub.2;
[0093] nn) X.sup.3 is phenyl or pyridyl wherein said X.sup.3
moieties are substituted once with cyano or CONH.sub.2;
[0094] oo) X.sup.3 is pyridyl substituted once with cyano or
CONH.sub.2;
[0095] pp) X.sup.3 is 5-cyano or 5-carboxamido-pyrid-2-yl;
[0096] qq) X.sup.3 is 4-cyano or 4-carboxamido-phenyl;
[0097] rr) X.sup.3 is 3-cyano or 3-carboxamido-pyrid-2-yl;
[0098] ss) X.sup.3 is 2-cyano or 2-carboxamido-phenyl;
[0099] tt) the compound of formula I is an acid addition salt;
[0100] uu) the compound of formula I is the hydrochloride salt;
[0101] vv) the compound of formula I is the glycolate salt;
[0102] ww) the compound of formula I is the hemi-fumarate salt.
[0103] Synthesis
[0104] The compound of formula I may be prepared as described in
the following Schemes and Examples. 5
[0105] The reaction of Scheme 1 may be carried out under conditions
appreciated in the art for the amination of epoxides. For example,
the epoxide of formula II may be combined with an amine of formula
III in a lower alcohol, dimethylformamide, dimethylsulfoxide, or
acetone, preferably ethanol, isopropanol, n-butanol or t-butanal,
at room temperature to the reflux temperature of the reaction
mixture, preferably between 40.degree. C.-90.degree. C. The
reaction may also be carried out under conditions generally
described in Atkins, et al., Tet. Let., 27:2451, 1986. These
conditions include mixing the reagents in the presence of
trimethylsilyl acetamide in a polar aprotic solvent such as
acetonitrile, dimethylformamide, acetone, dimethylsulfoxide,
dioxane, diethylene glycol dimethyl ether, tetrahydrofuran, or
other polar aprotic solvents in which the reagents are soluble.
[0106] The compound of formula I may also be prepared via a Suzuki
coupling as shown in Scheme 2. 6
[0107] A compound of formula IV may be reacted with a compound of
formula III as described above in Scheme 1. The compound of formula
V (an aryl halide) may then be reacted with a heteroaryl boronic
acid, an aryl boronic ester, or an aryl boronic cyclic ester,
preferably an aryl boronic acid, under conditions appreciated in
the art for the coupling of aromatic halides with aryl boronic
acids and their derivatives. This coupling is known in the art
generally as a Suzuki coupling. The skilled artisan will recognize
that an aryl triflate may also be employed in the present Suzuki
coupling as an alternative to employing an aryl halide.
[0108] The epoxide starting materials employed in Schemes 1 and 2
may be prepared by techniques recognized and appreciated by one
skilled in the art. See, e.g., U.S. Pat. No. 4,663,334; European
Patent Application 171209; Korn, et al., J. Pharm. Sci.,
69(9):1010-13, 1980 and references cited below in the Preparations
section for representative and/or analogous procedures for
preparing the epoxides of formula II and IV. To illustrate,
epoxides of formula II, where X is OCH.sub.2 or SCH.sub.2, may be
prepared according to the procedure detailed in Scheme 3 wherein
R.sup.9 is OH or SH and X' is OCH.sub.2 or SCH.sub.2. 7
[0109] Equimolar amounts of a compound of formula VI and
(2S)-(+)-glycidyl 3-nitrobenzenesulfonate may be dissolved in an
inert solvent such as acetone and treated with a slight excess of a
weak base, such as potassium carbonate. The suspension may then be
heated at reflux for 16-20 hours with stirring to provide a
compound of formula II(a). Compounds of formula IV, where X is
OCH.sub.2 or SCH.sub.2, may be prepared in an analogous
fashion.
[0110] The amino starting materials employed in Schemes 1 and 2
(formula III compound) may also be prepared by techniques
recognized and appreciated by one skilled in the art. For example,
an amine of formula III, where X.sup.2 is , may be prepared
according to the procedure detailed in Scheme 4. 8
[0111] A compound of formula IX may be prepared by reacting an
arylalkyl alcohol of formula VII with excess (5 mol/equivalent)
formula VIII compound by methods well known in the art (see, e.g.,
Sh. Prikl. Kin., 45:1573-77, 1972). The reaction may also be
carried out by mixing the reagents in an aprotic solvent,
preferably diglyme, and adding potassium t-butoxide (0.5
mol/equivalent). The reaction is typically heated at reflux until
water present in the reaction mixture is removed (generally 2-8
hours). A compound of formula X may then be prepared by
hydrogenation of the corresponding compound of formula IX over a
precious metal catalyst. The hydrogenation can be affected at
between 20 and 60 psi of hydrogen (preferably 50 psi), and with a
variety of solvents (preferably methanol/acetic acid), temperatures
(preferably 50.degree. C.), and catalysts (preferably 5% palladium
on carbon wetted with ethanol denatured with toluene) well known in
the art.
[0112] A skilled artisan will appreciate that a compound of formula
X could be coupled with a wide variety of halides to yield the
claimed ethers. The coupling can be carried out according to
procedures well known in the art and is preferably performed by
mixing the starting materials in N,N-dimethylacetamide and toluene
in the presence of potassium carbonate. The reaction is typically
then heated to reflux for 5 to 24 hours to effect the reaction and
to remove water present in the reaction mixture.
[0113] Compounds of formula VI, VII and VIII are either
commercially available, known in the art, or can be prepared by
methods known in the art or described herein.
[0114] The following Preparations, Examples and Formulations are
provided so that the invention might be more fully understood. They
should not be construed as limiting the invention in any way.
Preparations
[0115] Epoxides of Formula II and IV
[0116] Epoxides 1-21, 23-54 and 56-74 are prepared for use as
described in Scheme 1. Epoxides 22 and 55 are prepared for use as
described in Scheme 2. These epoxides are pictured in Tables 1 and
2 below.
1TABLE 1 9 Het = 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26
27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48
49 50 51 52 53 54 55 56 57 58 59 60
[0117]
2TABLE 2 61 Y = 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78
79 80 81 82
Epoxide 1
[0118] A mixture of 2-(1-methylpyrazol-5-yl)phenol (4. mmol, 810
mg), (2S)-glycidyl 3-nitrobenzenesulfonate (5.58 mmol, 1.45 g),
potassium carbonate (5.58 mmol, 771 mg) and acetone (40 ml) are
refluxed for 16 hours, cooled to room temperature and the solids
removed via filtration. The filtrate is concentrated and the crude
product purified on silica gel (40% ethyl acetate/hexane) to give
956 mg of the title epoxide.
Epoxide 2
[0119] Methyl hydrazine (23.2 mmol, 1.23 ml) is added to a solution
of 2-(3-hydroxy-2-propen-1-on-1yl)phenol (J. Am. Chem. Soc.,
72:3396, 1950), 15.4 mmol, 2.54 g) in methanol (7 ml) and the
mixture is heated at 100.degree. C. for one hour. After cooling,
the reaction mixture is diluted with water (100 ml) and stirred for
one hour. The precipitate is collected via filtration and purified
on silica gel (30% ethyl acetate/hexane) to give 811 mg of
2-(1-methylpyrazol-3-yl)phenol.
[0120] A mixture of 2-(1-methylpyrazol-3-yl)phenol (4.59 mmol, 800
mg), (2S)-glycidyl 3-nitrobenzenesulfonate (5.51 mmol, 1.42 g),
potassium t-butoxide (5.51 mmol, 515 mg) and tetrahydrofuran (30
ml) are refluxed for 16 hours, cooled to room temperature and
poured into saturated aqueous ammonium chloride. The aqueous layer
is extracted with ethyl acetate (3.times.) and the extracts washed
with brine, dried over magnesium sulfate, and concentrated in
vacuo. The crude product is purified on silica gel (40% ethyl
acetate/hexane) to give 785 mg of the title epoxide.
Epoxide 6
[0121] A mixture of 2-(pyrazol-5-yl)phenol (Catalan, et al., J. Am.
Chem. Soc., 114(13):5039-48, 1992, 10 mmol, 1. g), triethylamine
(40.0 mmol, 5.6 ml), and acetonitrile (55 ml) is cooled in an ice
bath under N.sub.2 and treated dropwise with chlorotrimethylsilane
(12.0 mmol, 1.52 ml). After the addition is complete, the cold bath
is removed and the reaction mixture stirred at ambient temperature
for 1 hour. The reaction mixture is then treated with trityl
chloride (10.0 mmol, 2.78 g) and stirred at ambient temperature
overnight, followed by refluxing for 1 hour. The reaction mixture
is concentrated, treated with saturated aqueous sodium bicarbonate,
and extracted with ethyl acetate (3.times.50 ml). The extracts are
dried over magnesium sulfate and concentrated to a viscous oil. The
oil is crystallized from 20% ethyl acetate/hexane to give 1.72 g of
N-trityl-2-(pyrazol-5-yl)phenol.
[0122] A solution of this intermediate phenol (4.27 mmol, 1.72 g)
is reacted with (2S)-glycidyl 3-nitrobenzenesulfonate (4.27 mmol,
1.11 g) substantially as decribed for epoxide 2 except that the
present reaction is refluxed for 48 hours and the crude product is
purified via crystallization from ethyl acetate to give 860 mg of
the title epoxide.
Epoxide 7
[0123] Phenylhydrazine (476 mmol, 51.5 g) and 2-hydroxyacetophenone
(476 mmol, 64.8 g) are stirred under reflux in dry ethanol (280 ml)
for 6 hours. After cooling, the crystals are filtered off, washed
with cold ethanol and dried under vacuum at 50.degree. C. to yield
73 g (68%) of the hydrazone, which is then mixed with nickel
chloride (7 g) and heated under a nitrogen atmosphere to
240.degree. C. for 3 hours. After cooling, the mixture is suspended
in dichloromethan (800 ml), salt is removed by filtration and the
filtrate is concentrated. The resulting crystals are filtered off,
washed with dichloromethane (50 ml) and dried in vacuo at
40.degree. C. to give 16.1 g of 2-(2-indolyl)phenol (24%). This
phenolic product is reacted with (2S)-glycidyl
3-nitrobenzenesulfonate substantially as described for Epoxide 1 to
yield the title epoxide.
Epoxide 8
[0124] 2-Hydroxyacetophenone (220 mmol, 30 g) is stirred in a
mixture of dimethylformamide-dimethyl acetal for 5 hours at
70.degree. C., cooled and recrystallised from diethylether. The
intermediate is dissolved in dry ethanol (200 ml) and formamidine
acetate (0.61 mmol, 63.5 g) is added. A solution of sodium (0.61
mol, 14 g) in ethanol (450 ml) is added in several portions and the
mixture is refluxed for 18 hours and evaporated. Recrystallisation
from diisopropylether yielded 3.6 g (10%) of
2-(pyrimidin-4-yl)phenol as a solid. This phenolic product is
reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as
described for Epoxide 1 to yield the title epoxide.
Epoxide 19
[0125] A mixture of 4-chloro-2-hydroxybenzoic acid hydrazide
(Chemical Abstracts, 93:7808, 475 mg, 2.55 mmol) and
triethylorthoformate (3.6 ml) is heated at 130.degree. C. for 3.5
hours. After cooling, a precipitate formed and is collected by
filtration. The filter cake is recrystallized from methanol to give
173 mg (35%) of 5-chloro-2-(1,3,4-oxadiazol-2-yl)ph- enol. This
phenolic product is reacted with (2S)-glycidyl
3-nitrobenzenesulfonate substantially as described for Epoxide 1 to
yield 170 mg (69%) of the titl epoxide.
Epoxide 20
[0126] A mixture of methyl 3-hydroxybenzoate (5.48 g, 36.0 mmol)
and 1,2-diaminoethane monotosylate (9.85 g, 42.4 mmol) is heated at
210.degree. C. for 7 hours. After cooling, the mixture is stirred
with aqueous 2N sodium hydroxide and extracted with ethyl acetate.
The precipitate which formed and is present in the aqueous layer is
collected by filtration and dried in vacuo to give 1.3 g (22%) of
2-(3-hydroxyphenyl)imidazoline.
[0127] To a solution of 2-(3-hydroxyphenyl)imidazoline (0.895 g,
5.52 mmol) in tetrahydrofuran (11 ml) is added water (11 ml),
potassium carbonate (1.5 g, 10.8 mmol), then di-t-butyl-dicarbonate
(1.2 g, 5.5 mmol). The resulting mixture is stirred over night
before additional di-t-butyl-dicarbonate (120 mg) is added and the
stirring is continued for several hours. The mixture is diluted
with water and extracted with ethyl acetate. The organic layer is
washed with brine, dried over sodium sulfate, and concentrated
under reduced pressure. The residue is purified via chromatography
on silica gel with dichloromethane/ethanol (gradient up to 20:1) to
give 615 mg of t-butyl (2-(3-hydroxyphenyl)imidazolin-1-yl-
)carboxylate (42%). This Boc-protected product (610 mg, 2.33 mmol)
is reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially
as described for Epoxide 1 to yield 720 mg (97%) of the title
epoxide.
Epoxide 22
[0128] A mixture of 2-iodophenol (5.00 g, 22.7 mmol), (2S)-glycidyl
3-nitrobenzenesulfonate (5.89 g, 22.7 mmol) and potassium carbonate
(3.44 g, 24.9 mmol) in methylethylketone (150 ml) is refluxed for
18 hours. After cooling, the salts are removed by filtration. The
filter cake is rinsed thoroughly with dichloromethane and the
collected filtrates are evaporated. The residue is purified via
flash chromatography on silica gel using a hexane-hexane/ethyl
acetate gradient (100 to 90:10).
Epoxide 23
[0129] Sodium (1.21 g, 52.6 mmol) is added to 200 ml methanol to
prepare a solution of sodium methoxide. After addition of guanidine
hydrochloride (12.41 g, 129.9 mmol) and
3-(dimethylamino)-1-(2-hydroxyphenyl)-2-propen-- 1-one (5.0 g,
26.15 mmol; J. Heterocyclic Chem., 14:345, 1977) the mixture is
heated at reflux over night. The reaction solvent is removed under
reduced pressure, and the residue treated with water. The resulting
precipitate is collected by filtration and dried in vacuo to give
4.25 g of 2-amino-4-(2-hydroxyphenyl)pyrimidine (87%). This
pyrimidine precursor is reacted with (2S)-glycidyl
3-nitrobenzenesulfonate substantially as described for Epoxide 1 to
give 2.05 g of the title epoxide (37.5%).
Epoxide 24
[0130] A mixture of 3-hydroxyacetophenone (20.0 g, 146.9 mmol) and
N,N-dimethylformamide dimethyl acetal (26.26 g, 220.4 mmol) is
heated over night at 100.degree. C. The excess of the acetal is
removed under reduced pressure and
3-(dimethylamino)-1-(3-hydroxyphenyl)-2-propen-1-one (10.3. g, 37%)
is obtained after chromatography on silica gel with
dichloromethane/ethanol 9:1. This intermediate enone is reacted
with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as
described for Epoxide 1 to give 5.02 g of the title epoxide
(78%).
Epoxide 25
[0131] A solution of
3-(dimethylamino)-1-(3-hydroxyphenyl)-2-propen-1-one (2.2 g, 11.5
mmol) and hydroxylamine hydrochloride (1.17 g, 16.8 mmol) in 45 ml
dioxane/water 1:1 is heated for 2 hours at 60.degree. C. The
reaction is poured into ice-water and the precipitate is collected
by filtration, washed with water, and dried in vacuo to give 1.4 g
of 3-(5-isoxazolyl)phenol (75.5%). This phenolic product is reacted
with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as
described for Epoxide 1 to give 1.33 g of the title epoxide
(70%).
Epoxide 26
[0132] 2-Amino-4-(3-hydroxyphenyl)pyrimidine, prepared
substantially as described for
2-amino-4-(2-hydroxyphenyl)pyrimidine, is reacted with
(2S)-glycidyl 3-nitrobenzenesulfonate substantially as described
for Epoxide 1 to give the title epoxide.
Epoxide 30
[0133] To dioxane (113 ml) is added 2-methoxy-5-fluorophenylboronic
acid (4.25 g, 24.9 mmol), 2-bromothiophene (3.65 g, 22.7 mmol, 0.9
eq.) and potassium carbonate (2M, 37 ml). Palladium (0)
tetrakistriphenylphoshine (0.03 eq.) is then added and th resulting
mixture is heated to 85.degree. C. for 3 hours. The reaction is
cooled to room temperature and poured into etl acetate and water.
The aqueous layer is extracted twice with ethyl acetate. The
organic layers are combined, and dried over sodium sulfate,
concentrated to a brown oil and the resulting residue is flash
chromatographed in 20% toluene/hexanes to afford 11.5 g of
2-(thien-2-yl)-4-fluoroanisole (90%).
[0134] The protected product from above (11.0 g, 52.8 mmol) is
demethylated with 110 grams of pyridine hydrochloride neat at 200
degrees for 3 hours. The reaction is poured into ice/water and
ethyl acetate is added. The layers are separated and the organic
layer is washed with water, dried over sodium sulfate and
concentrated to a brown solid. This is then flash chromatographed
with 1:3 ethyl acetate/hexanes to afford 7.82 g of
2-(thien-2-yl)-4-fluorophenol (77% yield). This phenolic product is
reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as
described for Epoxide 1 to yield the title epoxide.
Epoxide 31
[0135] Epoxide 31 is prepared from 2-methoxy-6-flourophenylboronic
acid and 2-bromothiophene by a procedure substantially similar to
that described for Epoxide 30.
Epoxide 33
[0136] A mixture of 2-methoxybenzaldehyde (10.0 g, 73.4 mmol),
tosylmethylisocyanide (14.34 g, 73.4 mmol) and potassium carbonate
(10.14 g, 73.4 mmol) in 220 ml methanol is heated at reflux for 6
hours. The solvent is removed under reduced pressure and the
residue poured into ice-water (800 ml). The precipitate is
collected by filtration, washed with water, and dried in vacuo to
give 9.05 g of 5 (2-methoxyphenyl)oxazole (70%).
[0137] Boron tribromide (1M in dichloromethane, 36 ml) is added
slowly to a cold solution (0.degree. C.) of the above oxazole (3.0
g, 17.1 mmol) in dichloromethane (215 ml). After stirring over
night at room temperature, ice-water (50 ml) is added carefully.
The aqueous layer is extracted with dichloromethane (50 ml), and
the combined organic layers are dried over sodium sulfate and
concentrated under reduced pressure. The precipitate which formed
after addition of dichloromethane (70 ml) is collected by
filtration, heated with dichloromethane (15 ml), and filtered again
to give 3.16 g of 2-(5-oxazolyl)phenol. This phenolic product is
reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as
described for Epoxide 1 to give 400 mg of the title epoxide
(9.5%).
Epoxide 34
[0138] 2-Methoxyphenylboronic acid (2 eq.) and pyrazole (1 eq.) are
coupled with copper(II) acetate catalysis as described in
Tetrahedron Lett. 39:2941-44, 1998 and the product is demethylated
by treatment with boron tribromide in dichloromethane (see, for
example, Synth. Commun. 27(20):3581-90, 1997) to yield
2-(pyrazol-1-yl)phenol. This phenolic product is reacted with
(2S)-glycidyl 3-nitrobenzenesulfonate substantially as described
for Epoxide 1 to give the title epoxide.
Epoxide 35
[0139] 2-(Imidazolidin-2-on-1-yl)anisole (Ger. Offen. 1977, DE
2528079) is demethylated with boron tribromide and the resulting
2-(imidazolidin-2-on-1-yl)phenol is reacte with (2S)-glycidyl
3-nitrobenzenesulfonate substantially s described for Epoxide 1 to
yield the title epoxide.
Epoxide 36
[0140] 2-(Imidazol-1-yl)anisole (L. M. Sitkina, A. M. Simonov,
Khim. Geterotsikl. Soedin 1966, 143) is demethylated with boron
tribromide and the resulting 2-(imidazol-1-yl)phenol is reacted
with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as
described for Epoxide 1 to give the title epoxide.
Epoxide 37
[0141] 3-(Dimethylamino)-1-(4-hydroxyphenyl)-2-propen-1-one is
prepared from 4-hydroxyacetophenone substantially in the same
manner as that described for
3-(dimethylamino)-1-(3-hydroxyphenyl)-2-propen-1-one (Epoxide 24).
4-(5-Isoxazolyl)phenol is prepared from
3-(dimethylamino)-1-(4-hydroxyphenyl)-2-propen-1-one substantially
in the same manner as that described for 3-(5-isoxazolyl)phenol
(Epoxide 25). This phenolic product is reacted with (2S)-glycidyl
3-nitrobenzenesulfonate substantially as described for Epoxide 1 to
yield the title epoxide.
Epoxide 45
[0142] 2-(3-Formyl-1-pyrrolyl)phenol (3 g, 16 mmol) and
triethylamine (17.6 mmol) are added to a suspension of
hydroxylamine hydrochloride (1.22 g, 17.6 mmol) in acetic anhydride
(7.7 ml) and the mixture is allowed to stir overnight at ambient
temperature. The mixture is refluxed for 5 hours, concentrated,
dissolved in 50 ml ethanol and stirred for 10 min with 50 ml 2 M
aqueous sodium hydroxie. After neutralisation with aqueous
hydrochloric acid, and extraction with ethylacetate, the organic
layer is dried and concentrated. The residue is purified by
chromatography (toluene/ethanol 9:1) to yield
2-(3-cyano-1-pyrrolyl)pheno- l (2.4 g, 92%). This phenolic product
is reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially
as described for Epoxide 1 to yield the title epoxide.
Epoxide 47
[0143] To 2-(3-formyl-1-pyrrolyl)phenol (2.9 g, 15.5 mmol) in 50 ml
dry tetrahydrofuran are added sodium cyanoborohydride (1.94 g, 31
mmol) and boron trifluoride diethyletherate (5.7 ml, 47 mmol). The
resulting solution is stirred for 3 hours at ambient temperature.
Saturated sodium bicarbonate (100 ml) is added and the resulting
mixture is stirred for 1 hour before extraction with
t-butylmethylether. The organic layer is dried and concentrated and
the residue is purified by chromatography (toluene/ethanol 9:1) to
yield 2-(3-methyl-1-pyrrolyl)phenol (300 mg, 11%). This phenolic
product is reacted with (2S)-glycidyl 3-nitrobenzenesulfonate
substantially as described for Epoxide 1 to yield the title
epoxide.
Epoxide 48
[0144] 2-Bromo-5-fluoro-phenol (0.87 ml, 7.9 mmol) and
2-thiopheneboronic acid (2.02 g, 15.8 mmol) are dissolved in 100 ml
dioxane. The resulting solution is flushed with argon before
tetrakis(triphenylphosphine)palladi- um (456 mg, 0.395 mmol) and 2
ml of aqueous 2M sodium carbonate solution (20 mmol) are added.
After flushing again with argon the mixture is refluxed for 15
hours at 100.degree. C. The solution is allowed to cool to room
temperature and the mixture is filtered. The filtrate is evaporated
and the residue is taken up in dichloromethane and extracted with
water. The organic layer is dried with sodium sulfate then
concentrated. The residue is purified by chromatography
(CH.sub.2Cl.sub.2/EtOH gradient 100:0 to 98:2) to yield 1.13 g of
2-(thien-2-yl)-5-fluorophenol (74%).
[0145] 2-(Thien-2-yl)-5-fluorophenol and (2S)-glycidyl
3-nitrobenzenesulfonate are reacted as described for the
preparation of Epoxide 1 to give the title epoxide.
Epoxides 49-51
[0146] 2-Bromo-5-fluorophenol is coupled with thiophene-3-boronic
acid; 2-bromo-4,5-difluorophenol is coupled with
thiophene-2-boronic acid; and 2-bromo-4,5-difluorophenol is coupled
with thiophene-3-boronic acid in Suzuki reactions substantially as
described for Epoxide 48, to yield 2-(thien-3-yl)-5-fluorophenol;
2-(thien-2-yl)-4,5-difluorophenol; and
2-(thien-3-yl)-4,5-difluorophenol, respectively. These phenolic
products are reacted with (2S)-glycidyl 3-nitrobenzenesulfonate
substantially as described for Epoxide 1 to yield the title
epoxides.
Epoxides 52 and 61
[0147] To a solution of 6-fluorochroman-4-one (21.0 g, 126 mmol) in
acetic acid (105 ml) is added bromine (6.5 ml, 126 mmol) at such a
rate as to not raise the temperature above 25.degree. C. After the
addition is complete, the reaction is allowed to stir for 2 hours
before pouring into 1 liter of ice. The resulting mixture is
stirred over night. The precipitate which formed is filtered and
placed in drying oven to produce 21 g of
3-bromo-6-fluorochroman-4-one.
[0148] The product from (14 g, 57 mmol) above is dissolved in
triethylamine (100 ml) and is stirred at refux for 2 hours. The
reaction is cooled and concentrated, taen up in chloroform, washed
with 2N aqueous hydrochloric acid and water. The organic layer is
dried over sodium sulfate and concentrated. The product residue is
crytallized from hot ethyl acetate.
[0149] The product from above (6-fluorochromen-4-one (5.25 g, 32.0
mmol) and hydroxylamine hydrochloride (4.65 g, 67.2 mmol) are
dissolved in ethanol (180 ml) and the resulting mixture is heated
to reflux. The reaction is allowed to stir for 18 hours before
cooling and concentrating. The residue is is taken up in toluene
and filtered to give 690 mg of 4-fluoro-2-(isoxazol-5-yl)phenol and
from the filtrate 594 mg of 4-fluoro-2-(isoxazol-3-yl)phenol. These
phenolic products are separately reacted with (2S)-glycidyl
3-nitrobenzenesulfonate substantially as described for Epoxide 1 to
yield the title epoxides.
Epoxide 53
[0150] 2-Fluoro-6-(thien-3-yl)anisole is prepared from
2-fluoro-6-iodoanisole (1.35 g, 5.36 mmol) by Suzuki coupling with
thiophene-3-boronic acid according to the general procedure
described in Representative Procedure 4(b) below; yield: 1.05 g
(94%).
[0151] 2-Fluoro-6-(thien-3-yl)phenol is obtained from the anisole
(1.0 g, 4.8 mmol) with an excess of boron tribromide in
dichloromethane by stirring over night. The crude phenol (1.1 g) is
used for the next step without further purification.
[0152] Sodium hydride (0.18 g, 4.5 mmol, 60% in oil) is washed
several times with hexane under argon and added to a solution of
2-fluoro-6-(thien-3-yl)phenol (0.44 g, 2.26 mmol) and (2S)-glycidyl
3-nitrobenzenesulfonate (0.587 g 2.26 mmol) in dry tetrahydrofuran
(20 ml). After stirri at room temperature over night, the mixture
is quenched wh ice-cold water, diluted with brine, and extracted
with ethl acetate. The organic layer is dried over sodium sulfate,
concentrated under reduced pressure, to give 65 mg (11%) of the
title epoxide after chromatography (silica gel,
dichloromethane).
Epoxide 54
[0153] A mixture of 2-bromo-1-(2-benzyloxyphenyl)ethanone (10.0 g,
32.77 mmol; prepared according to a procedure from J. Med. Chem.,
35:3045, 1992) and sodium formate (4.46 g, 65.6 mmol) in dry DMF
(100 ml) is stirred at room temperature over night. The mixture is
poured into water (400 ml) and extracted with dichloromethane
(2.times.100 ml). The combined extracts are dried over sodium
sulfate and concentrated under reduced pressure.
[0154] The residue is dissolved in acetic acid (100 ml), treated
with ammonium acetate (12.62 g, 163.7 mmol), and the mixture is
heated for 3 hours. After cooling, the mixture is diluted with
water (400 ml) and extracted with dichloromethane (2.times.100 ml).
The combined organic layers are washed with saturated aqueous
sodium bicarbonate solution (2.times.100 ml), dried over sodium
sulfate, and concentrated in vacuo. 4-(2-Benzyloxyphenyl)oxazole
(1.99 g, 24%) is obtained after chromatography (silica gel,
dichloromethane).
[0155] To a solution of the oxazole from above (1.99 g, 7.92 mmol)
in dichloromethane (20 ml) is added 10% palladium on carbon (1.99
g). The mixture is put under an atmosphere of hydrogen, stirred at
room temperature over night, then filtered through Celite. The
solvent is removed under reduced pressure to leave
2-(oxazol-4-yl)phenol (1.15 g, 90%), which is used for the next
step without further purification.
[0156] The title epoxide (1.05 g, 72%) is prepared from the above
phenol (1.08 g, 6.7 mmol) and (2S)-glycidyl 3-nitrobenzenesulfonate
substantially as described for Epoxide 1.
Epoxide 55
[0157] To a solution of 2-fluoro-6-iodoanisole (Justus Liebigs,
Ann. Chem., 746:134, 1971; 4.31 g, 17.1 mmol) in dichloromethane
(35 ml) is added a 1M solution of boron tribromide in
dichloromethane (18.2 ml). The mixture is kept under argon and
stirred for 4 hours at room temperature. The mixture is poured into
a saturated aqueous sodium bicarbonate solution and-the aqueous
layer is extracted with ethyl acetate. The combined organic layers
are dried over sodium sulfate and concentrated under reduced
pressure to give 2-fluoro-6-iodophenol (4.2 g).
[0158] The title epoxide (4.44 g, 86%) is prepared from the above
phenol and (2S)-glycidyl 3-nitrobenzenesulfonate substantiallly as
described for Epoxide 1 except using butanone as solvent.
Epoxides 56-60
[0159] Epoxides 56, 57, 58, 59 and 60 are prepared from
2-methoxy-5-fluorophenylboronic acid and 3-bromothiophene;
2-methoxy-6-fluorophenylboronic acid and 5-chloro-2-bromothiophene;
2-methoxyphenylboronic acid and 2-bromo-5-fluorothiophene;
(3-methoxypyrid-2-yl)boronic acid and 2-bromothiophene; and
2-methoxy-6-fluorophenyl and 3-bromothiophene, respectively, by a
procedure substantially similar to that described for Epoxide
30.
Epoxide 62
[0160] A slurry of 2-cyano phenol (25 g, 209.87 mmol),
triethylamine hydrochloride (43.3 g, 314.81 mmol), and sodium azide
(20.5 g, 314.81 mmol) in toluene (200 mL) is heated to the reflux
temperature of the mixture and then the mixture is allowed to stir
at reflux for 15 hours. The mixture is cooled and washed with water
(200 mL). The aqueous layer is washed with ether (100 mL), made
acidic with concentrated HCl, and the resulting solid is collected
by filtration. The solid is washed twice with water (200 mL) and
dried under vacuum at 100.degree. C. for 15 hours to give 33.05 g
of 2-(tetrazol-3-yl)phenol (97%).
[0161] 2-(Tetrazol-3-yl)phenol (32.8 g, 202.3 mmol) is dissolved in
dimethylformamide (100 mL) and water (25 mL) and cooled in ice.
Sodium hydroxide (8.49 g, 212.3 mmol) in water (20 mL) is added and
the solution is warmed to ambient temperature. After thirty
minutes, iodomethane (31.58 g, 222.5 mmol) is added neat. The
solution is stirred for 15 hours then diluted with ethyl acetate
(300 mL) and water (500 mL). The aqueous layer is washed three
times with ethyl acetate (300 mL) and the organic layers are
combined, washed three times with water (1 L), once with brine (1.2
L), dried over magnesium sulfate, filtered and concentrated in
vacuo. The solid is purified by flash column chromatography (80%
hexane:20% ethyl acetate gradient to 50% hexane:50% ethyl acetate
as an eluent) to give 23.5 g of 2-(1-methyltetrazol-3-yl)phenol
(66%).
[0162] 2-(1-Methyltetrazol-3-yl)phenol (0.25 g, 1.54 mmol),
(2S)-glycidyl 3-nitrobenzenesulfonate (0.42 g, 1.62 mmol), and
potassium carbonate (0.45 g, 3.23 mmol) is dissolved in methyl
ethyl ketone (2 mL), the mixture is heated to the reflux
temperature of the mixture, and then is allowed to stir at reflux
for 15 hours. The slurry is cooled, filtered and concentrated in
vacuo. The solid is purified by flash column chromatography (80%
hexane:20% ethyl acetate gradient to 50% hexane:50% ethyl acetate
as an eluent) to give 270 mg (75%) of the title epoxide. FDMS
m/e=233 (M.sup.++1).
Epoxide 63
[0163] The title epoxide is prepared from 2-hydroxybenzaldehyde and
glyoxal by the method described in Eur. J. Med. Chem., 33:181-187,
1998. This phenolic product is reacted with (2S)-glycidyl
3-nitrobenzenesulfonate substantially as described for Epoxide 1,
however, the title epoxide is used without purification as
described therein.
Epoxide 64
[0164] 2-Thienyl-1-methoxybenzene (10 g, 53 mmol) is cooled to
-78.degree. C. in dry tetrahydrofuran (265 ml) under nitrogen while
stirring. n-Butyl lithium in hexanes (1.6M, 37 ml, 59 mmol, 1.1
eq.) is added slowly and the resulting mixture is stirred cold for
an hour. Chloromethyl formate (4.1 ml, 53 mmol, 1.0 equivalent) is
added and the reaction is stirred cold for another hour. The
mixture is allowed to warm to room temperature before quenching
with saturated bicarbonate solution and ethyl acetate. The layers
are separated and the organic phase is washed with brine, dried
over sodium sulfate and concentrated. The residue is purified via
flash chromatography in 5% ethyl acetate/hexanes to afford 7.9 g of
2-(5-methoxycarbonylthien-2-yl)-1-methoxybenzene (61%).
[0165] 2-(5-Methoxycarbonylthien-2-yl)-1-methoxybenze is
demethylated with boron tribromide to give
1-(5-methoxycarbonylthien-2-yl)phenol. This phenolic product i
reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as
described for Epoxide 1 to yield the title epoxide.
Epoxide 65
[0166] A solution of 5-bromothiophene-2-carbonitrile (1.25 g, 6.65
mmol) in 50 ml of dioxane is degassed with argon,
tetrakis-(triphenylphosphine)- -palladium(0) (768 mg, 0.665 mmol)
is added and the mixture is stirred for 5 minutes. 2-Methoxybenzene
boronic acid (2.02 g, 13.3 mmol) and aqueous 2 N sodium carbonate
(13.3 ml) are successively added and the mixture is stirred for 16
hours at 85.degree. C. Extractive work-up (2.times.50 ml
dichloromethane and 2.times.30 ml water). The organic phase is
dried over sodium sulfate, filtrated and evaporated. The residue
(4.05 g) is purified via flash column on silica (eluent: 100%
hexane>hexane/ethyl acetate 96:4 gradient to give 1.37 g of
2-(5-cyanothien-2-yl)anisole (96%). M+=215.
[0167] An intimate mixture of 2-(5-cyanothien-2-yl)anisole (1.2 g,
5.9 mmol) and pyridinium hydrochloride (13.7 g, 119 mmol) is heated
for 1 hour to 210.degree. C. under argon. The mixture was cooled to
ambient temperature and a 1:1 mixture of water and ethyl acetate is
added to break and dissolve the solid cake formed during the
reaction. The slurry is then transferred to a separation funnel and
dichloromethane is added until the organic phase had a higher
density than the water phase (organic phase=lower phase). The
organic phase contains the desired product and is separated. The
remaining aqueous phase is additionally extracted twice with
dichloromethane and the collected organic phases are dried over
sodium sulfate and evaporated. The residue is purified via flash
column on silica (eluen 100% hexane>hexane/ethyl acetate 8:2
gradient) to give 973 mg of 2-(5-cyanothien-2-yl)phenol (87%).
M+=201.
[0168] To a solution of 2-(5-cyanothien-2-yl)phenol (970 mg, 4.819
mmol) in 20 ml of dry 2-butanone is added (2S)-glycidyl
3-nitrobenzenesulfonate (1.25 g, 4.82 mmol) and potassium carbonate
(732 mg, 5.30 mmol) successively. After stirring for 48 hours at
75.degree. C., the mixture is diluted with ethyl acetate and
extracted with 2N aqueous sodium hydroxide (2.times.30 ml) and
water (1.times.30 ml). (M+=257).
Epoxides 66-70
[0169] Epoxides 66-70 are prepared by a procedure substantially
similar to that described for Epoxide 65. The starting halogeno
thiophenes used to prepare Epoxides 65-70 are known from the
literature, see e.g., J. Mater. Chem., 5(4), 653-61, 1995; J. Chem.
Soc., Perkin Trans. 2, 5:625-30, 1982; Chem. Scr., 5(5), 217-26,
1974; Bull. Soc. Chim. Fr., 11:4115-20, 1967; Bull. Soc. Chim. Fr.,
11:4121-6, 1967; Bull. Inst. Chem. Res., 52(3):561-5, 1974; J. Med.
Chem., 43(16):3168-3185, 2000; Bioorg. Med. Chem. Lett.,
10(5):415-418, 2000; and JP 08311060.
Epoxide 73
[0170] A 25 ml 1-propanol solution of 2-methoxyphenyl boronic acid
(1.2 g, 7.5 mmol) and 5-bromothien-2-ylsulfonamide (1.2 g, 5 mmol)
is stirred under N.sub.2 at room temperature. Palladium(II) acetate
(56 mg, 0.25 mmol), triphenylphosphine (200 mg, 0.75 mmol), 2M
aqueous Na.sub.2CO.sub.3 (3 ml, 6 mmol), and 7 ml H.sub.2O are
added and the resulting mixture is refluxed (.about.88.degree. C.)
for 1 hour. The reaction is cooled, diluted with ethyl acetate,
washed with brine, and the brine back extracted with ethyl acetate.
The extract are combined, washed with aqueous NaHCO.sub.3, brine,
dried (Na.sub.2SO.sub.4), filtered, and the filtrate is
concentrated. The residue is purified by chromatography (SiO.sub.2,
ethyl acetate/hexane gradient) to give 943 mg (70%) of
5-(2-methoxyphenyl)thiophene-2-sulfonamide.
[0171] A 70 ml CH.sub.2Cl.sub.2 suspension of
5-(2-methoxyphenyl)thiophene- -2-sulfonamide (1.0 g, 3.7 mmol) is
stirred under N.sub.2 at -75.degree. C. as boron tribromide (1.1
ml, 12 mmol) is syringed into the reaction mixture. The amber
solution is stirred for 30 minutes at -75.degree. C., then at
0.degree. C. for 2-3 hours. The reaction is quenched with ice,
extracted with CH.sub.2Cl.sub.2. The extracts are washed with
brine, dried (Na.sub.2SO.sub.4), filtered, and the filtrate is
concentrated. The residue is purified by chromatography (SiO.sub.2,
ethyl acetate/hexane gradient) to give 720 mg of
5-(2-hydroxyphenyl)thiophene-2-sulfonamide (76%).
[0172] 5-(2-Hydroxyphenyl)thiophene-2-sulfonic acid amide (1.8 g,
7.1 mmol), K.sub.2CO.sub.3 (1.1 g, 8.5 mmol), and (2S)-glycidyl
3-nitrobenzenesulfonate (2.1 g, 7.8 mmol) are reacted as described
for the preparation of Epoxide 1 to give 1.5 g of the title epoxide
(70%).
Epoxide 74
[0173] (2-Methoxyphenyl)acetaldehyde is prepared by oxidation of
2-(2-methoxyphenyl)ethanol according to the procedure disclosed in
J. Org. Chem., 49:1720, 1999. A mixture of
(2-methoxyphenyl)acetaldehyde (3.8 g, 25.3 mmol) and
dimethylformamide dimethyl acetal (4.52 g, 37.9 mmol) is stirred at
room temperature for 1 hour. Excess of the acetal is removed under
reduced pressure to leave 4.68 g of 3-dimethylamino-2-(2-me-
thoxyphenyl)propenal (90%).
[0174] A solution of 3-dimethylamino-2-(2-methoxyphenyl)propenal
(4.68 g, 22.8 mmol) and hydrazine hydrate (6.7 ml) in ethanol (100
ml) is heated at reflux or 30 minutes. The solvent is removed in
vacuo and the residue is chromatographed (silica gel,
dichloromethane/ethanol 95:5) to give 2.69 g of
4-(2-methoxyphenyl)pyrazole (68%).
[0175] To a solution of 4-(2-methoxyphenyl)pyrazole (300 mg, 1.72
mmol) in dichloromethane (13 ml) is added a 1M solution of boron
tribromide (3.8 ml) in dichloromethane. The mixture is stirred at
room temperature over night then concentrated under reduced
pressure. The residue is chromatographed (silica gel,
dichloromethane/ethanol 9:1) to give 270 mg of
2-(pyrazol-4-yl)phenol (98%).
[0176] 2-(Pyrazol-4-yl)phenol and (2S)-glycidyl
3-nitrobenzenesulfonate are reacted as described for the
preparation of Epoxide 1 to give 180 mg of the title epoxide
(50%).
Epoxides 3-5, 9-18, 21, 27-29, 32, 38-41, 43, 46, 71 and 72
[0177] 2-(Thien-2-yl)phenol (J. Heterocycl. Chem., 22(6):1667-9,
1985); 2-(thiazol-2-yl)phenol (Arnold, et al., WO 94/22846);
2-(5-isoxazolyl)phenol; 2-(pyrrolidin-2-on-1-yl)phenol
(Tetrahedron, 26(17):4207-4212, 1970); 2-morpholinophenol;
2-piperidinophenol; 1-(2-hydroxyphenyl)piperazine;
2-(2-hydroxyphenyl)benzoxazole; 2-(2-hydroxyphenyl)benzothiazole;
2-(4,4-dimethyl-2-oxazolin-2-yl)phenol (Bioorg. Med. Chem. Lett.,
6(18):2173-76, 1996); 2-(1-pyrrolidino)phenol;
2-(pyrrol-1-yl)phenol (J. Het. Chem., 8:283-287, 1971);
2-(1,3,4-oxadiazol-2-yl)phenol (WO 94/22846);
2-(isoxazol-3-yl)phenol (J. Het. Chem., 8:283-287, 1971);
2-(isothiazol-5-yl)phenol (J. Chem. Res. (S), 349, 1988; J. Chem.
Res. (S), 163, 1992); 2-(1,3,4-thiadiazol-2-yl)p- henol (WO
94/22846); 2-(1,2,3-thiadiazol-4-yl)phenol; 2-(oxazol-2-yl)phenol
(WO 94/22846); 4-(2-hydroxyphenyl)-2(5H)-furanone (Ger. Offen.
DE2829414); 4-4-fluoro-2-hydroxyphenyl)-2(5H) -furanone (Ger.
Offen. DE2829414); 2-(furan-3-yl)phenol (Ger. Offen. DE2914166);
2-thiazol-4-yl-phenol (WO 94/22846); 2-(thiazol-4-yl)phenol (WO
94/22846); 2-(4,5-dimethylimidazol-2-yl)phenol (Eur. J. Med. Chem.,
33:181-187, 1998, using 4,5-dimethylimidazole instead of
imidazole); 2-(3-formylpyrrol-1-yl)phenol (J. Het. Chem., 283-287,
1971 using 2,5-dimethoxy-3-formyl-tetrahydrofuran instead of
2,5-dimethoxy-tetrahydr- ofuran); 2-(3-methylisoxazol-5-yl)phenol
(J. Org. Chem., 49:4419, 1984); and 2-(4-methylisoxazol-5-yl)phenol
(Pol. J. Chem., 56:501, 1982) are reacted with (2S)-glycidyl
3-nitrobenzenesulfonate substantially as described for Epoxide 1 to
yield the title epoxides.
[0178] Amines of Formula III
[0179] Amines 1-49 are prepared for use as described in Schemes 1
and 2. These amines are pictured in Tables 3-5 below.
3TABLE 3 83 X.sup.3 = 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98
99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115
116 117 118 119 120 121 122 123 124 125 126 127
[0180]
4TABLE 4 128 X.sup.3 = 129 130 131
[0181]
5TABLE 5 132 X.sup.3 = 133 134
[0182] Amines 1 and 10 may be prepared according to procedures
detailed in U.S. Ser. No. 09/068,192, the teachings of which are
herein incorporated by reference. Amines 11, 26 and 33 may be
prepared by a procedure substantially similar to that described for
Amine 1. Amines 2, 3, 8, and 9 may be prepared according to
procedures detailed in U.S. Pat. No. 5,977,154, the teachings of
which are herein incorporated by reference. Amines 27, 29 and 40
may be prepared by a procedure substantially similar to that
described for Amine 9.
Amine 4
[0183] 4-(2-Amino-2-methylpropyl)phenol (50.8 g, 225 mmol),
2-chloro-3-cyanopyridine (30.8 g, 222 mmol), potassium carbonate
(77.7 g, 562 mmol, powdered), N,N-dimethylacetamide (609 ml), and
isooctane (122 ml) are combined and heated to reflux. The water
formed during the reaction is removed azeotropically via a
Dean-Stark trap. After about 1-2 hours the reaction is complete.
The slurry is cooled to 30.degree. C. and filtered. The filter cake
is washed with N,N-dimethylacetamide (250 ml) and the combined
organic fractions are concentrated by rotary evaporation at
80.degree. C. The resulting dark green oil is dissolved in
dichloromethane (580 ml), and washed with water (160 ml). The
phases are separated and the organic phase washed with water (250
ml). Water (1 L) is added to the organic phase and the pH adjusted
to 1 with 12N aqueous hydrochloric acid (about 25 ml). The phases
are separated and the acidic aqueous layer is washed with
dichloromethane (250 ml). Dichloromethane (1 L) is added to the
acidic aqueous phase and the pH is adjusted to 12-13 with 5N
aqueous sodium hydroxide. The phases are separated and the organic
phase is dried over sodium sulfate. After filtration the solution
is concentrated to give 53 g of the title amine (88%).
Amine 6
[0184] 4-(2-Amino-2-methylpropyl)phenol (55.18 g, 244.9 mmol) is
added to 5.05N KOH (97.2 mmol). The mixture is warmed to 50.degree.
C. to give a homogeneous yellow solution. Chlorobenzene (1104 ml)
and N,N-dimethylacetamide (10.7 g, 122 mmol) is added and the
mixture is heated to reflux (about 100.degree. C.). The water is
removed azeotropically via a Dean-Stark trap. At about 125.degree.
C. a solid began to form. When the pot temperature reached
132.degree. C. the water has been removed and the reaction mixture
is a thick but stirable slurry (mechanical stirring required). The
Dean-Stark trap is removed and an additional 100 ml of
chlorobenzene is removed and discarded. Dry chlorobenzene (50 ml)
is added to the slurry, followed by ethyl 2-chloronicotinate (50.0
g, 269 mmol) in chlorobenzene (50 ml). The slurry is heated at
reflux until the reaction is complete (about 24 hours). After
cooling to room temperature, water (385 ml) and 1N NaOH (25 ml, 0.1
equiv) is added to the mixture and the phases are separated. The
organic phase is washed with water (285 ml) and the solution is
concentrated to a net weight of 700 g (89%).
Amine 7
[0185] 4-(2-Amino-2-methylpropyl)phenol (3.00 g, 18.2 mmol), methyl
6-chloronicotinate (3.27 g, 19.1 mmol), powdered potasssium
carbonate (3.76 g, 27.2 mmol, 300 mesh), N,N-dimethylacetamide (60
ml), and toluene (15 ml) are combined and heated to reflux. The
water formed during the reaction is removed azeotropically via a
Dean-Stark trap. After about 2 hours, the internal temperature
reached 154.degree. C. and the reaction is complete. The slurry is
cooled to 30.degree. C. and filtered. The filter cake is washed
with N,N-dimethylacetamide and the combined organic fractions
concentrated by rotary evaporation at 75.degree. C. The resulting
oil is dissolved in ethyl acetate (50 ml), and washed with water
(30 ml). The phases are separated and the aqueous phase is
extracted with ethyl acetate (20 ml) after some saturated aqueous
sodium chloride solution (10 ml) is added to facilitate phase
separation. The combined organic fractions are washed with water
(2.times.30 ml) and saturated aqueous sodium chloride (30 ml) and
then dried over sodium sulfate. After filtration the solution is
concentrated to give 4.60 g (80%) of the title amine.
Amine 12
[0186] 2-Cyano-3-chloropyridine (Bremner, et al., Syn. Comm.,
27:1535, 1997; Kaneda, et al., Chem. Pharm. Bull., 33:565, 1985) is
coupled to 4-(2-amino-2-methylpropyl)phenol to prepare the title
amine by a procedure substantially similar to that described above
for Amine 4.
Amine 24
[0187] Potassium tert-butoxide (58.6 ml, 58.6 mmol, 1M in
tetrahydrofuran) is added to a solution of 3,4-dichlorothiophenol
(10.0 g, 55.8 mmol) in tetrahydrofuran (300 ml) at 0.degree. C. and
the solution stirred for 30 minutes. Methyl iodide (8.32 g, 58.6
mmol) is added dropwise and the resulting slurry is stirred for 16
hours. The solvents are removed in vacuo and the residue is
dissolved in 150 ml each of methyl-t-butyl ether and 1M
NaHSO.sub.4. The phases are separated and the organic layer is
washed with 150 ml each of water and saturated aqueous sodium
chloride. The organic layer is dried over sodium sulfate, filtered
and concentrated in vacuo to give 9.67 g of 3,4-dichlorophenyl
methylsulfide (90%).
[0188] The sulfide from above is converted to the corresponding
sulfone as described below for Amine 38. The 3,4 dichloromethyl
sulfone is coupled to 4-(2-amino-2-methylpropyl)phenol to prepare
the title amine by a procedure substantially similar to that
described above for Amine 4.
Amine 31
[0189] To a 1 gallon autoclave is added 2,5-dichloropyridine (123
g, 830 mmol), palladium II acetate (5.6 g, 24.9 mmol),
1,3-bis(diphenylphosphine- )propane (20.5 g, 49.8 mmol),
1,1,1,3,3,3,-hexamethyldisilazane (700 ml), acetonitrile (1180 ml)
and dimethylformamide (295 ml). The autoclave is pressurized to 70
psi with carbon monoxide and heated to 80.degree. C. for 16 hours.
The reaction mixture is filtered and washed with acetonitrile. The
mixture is concentrated in vacuo to 590 g and 1L of water is added.
The resulting slurry is cooled to 0.degree. C. and filtered to give
102.6 g (79%) of 2-carboxamido-5-chloropyridine which is used
without further purification.
[0190] 2-Carboxamido-5-chloropyridine is coupled to
4-(2-amino-2-methylpropyl)phenol to prepare the title Amine by a
procedure substantially similar to that described above for Amine
4.
Amine 36
[0191] Oxalyl chloride (18.1 ml, 207 mmol) is added slowly to
dimethylformamide cooled to -25.degree. C. The resulting mixture is
cooled to -45.degree. C. and 2-carboxamido-5-chloropyridine (25 g,
160 mmol) is added portionwise. The reaction stirred for 30 minutes
and pyridine (14.2 ml, 176 mmol) is added. The reaction stirred for
5 hours, 20 minutes and is poured into 1.5 L of water and 1 L of
ethyl acetate is added. The phases are separated and the aqueous
layer is extracted with 100 ml of ethyl acetate. The combined
organics are washed with water (850 ml and 350 ml), saturated
aqueous sodium chloride (100 ml), dried over sodium sulfate,
filtered and concentrated in vacuo to give 19.95 g (92%) of
2-cyano-5-chloropyridine which is used without further
purification.
[0192] 2-Cyano-5-chloropyridine is coupled to
4-(2-amino-2-methylpropyl)ph- enol to prepare the title amine by a
procedure substantially similar to that described above for Amine
4.
Amine 38
[0193] To a solution of n-butyl lithium (0.544 mol) in
tetrahydrofuran (700 ml) at -78.degree. C. is added a solution of
3,4-difluorobromobenzen- e (100 g, 0.518 mol) in 200 ml of
tetrahydrofuran. After 10 minutes, a solution of dimethyl disulfide
in 100 ml of tetrahydrofuran is added and the resulting reaction
mixture is warmed to ambient temperature over 60 minutes. The
reaction is concentrated in vacuo and the resulting oil is
partitioned between 750 ml methyl-t-butyl ether and 300 ml water.
The phases are separated and the organic layer is washed with 300
ml of saturated aqueous sodium chloride, dried over magnesium
sulfate, filtered, and concentrated in vacuo. The resulting oil is
purified by vacuum distillation to provide 43.08 g of
3,4-difluorophenyl methylsulfide.
[0194] Metachloroperbenzoic acid (60.4 mmol) is added portionwise
to a solution of the sulfide (43 g, 26.8 mmol) in 1L of
dichloromethane at 0.degree. C. After 15 minutes, the reaction
mixture is warmed to ambient temperature and stirred for 1.25
hours. The solids are removed by filtration and the resulting
solution washed with 750 ml of 1M sodium bisulfite, 2L sodium
bicarbonate, 1L water, and 750 ml saturated aqueous sodium
chloride. The organic layer is dried over magnesium sulfate,
filtered and concentrated in vacuo to give 45.17 g (88%) of the
title amine.
Amine 41
[0195] The acetic acid salt of 4-(2-amino-2-methylpropyl)phenol (15
g, 66.5 mmol) is dissolved in 90 ml of hot water. 5N aqueous sodium
hydroxide (13.98 ml, 0.0699 mol) is added and the resulting mixture
is allowed to stir for one hour upon which a precipitate formed.
The reaction is then placed in the refrigerator to allow more
precipitation. The precipitate is filtered to afford 6.91 g of
4-(2-amino-2-methylpropyl- )phenol free base.
[0196] 4-(2-Amino-2-methylpropyl)phenol free base (6.91 g, 41.8
mmol) is dissolved in 100 ml of anhydrous tetrahydrofuran and the
solution is purged with nitrogen. Di-t-butyl-dicarbonate (10.56 ml,
46 mmol) is added and the resulting solution is allowed to stir
overnight. The reaction is concentrated, the residue dissolved in
ethyl acetate, and then washed with water. The organic layer is
dried over sodium sulfate, filtered and concentrated to a clear
oil. The oil is taken up in anhydrous tetrahydrofuran and
diisopropylethylamine (7.94 ml, 46 mmol) is added followed by
trifluoromethanesulfonic anhydride (7.67 ml, 45 mmol). The reaction
is allowed to stir for 3 hours, quenched with water, extracted with
ethyl acetate, dried over sodium sulfate and concentrated to a
clear solid.
[0197] A portion of the above solid (2.7 g, 6.8 mmol) is mixed with
3-cyanophenyl boronic acid (1.0 g, 6.8 mmol), aqueous potassium
carbonate (2M, 7.1 ml, 14.3 mmol), lithium chloride (288 mg, 6.8
mmol) and 60 ml of tetrahydrofuran. The reaction is fitted with a
condenser and purged with nitrogen before palladium(0)
tetrakistriphenylphoshine is added (37.9 mg, 0.34 mmol). The
reaction flask is covered with aluminum foil and the solution is
brought to reflux. After 16 hours, the reaction is poured into a
separatory funnel. Ethyl acetate (100 ml) is added and the organic
layer is washed with water, 1N aqueous HCl, water, 1N aqueous
sodium hydroxide and again with water. The organic layer is dried
over sodium sulfate and concentrated to a brown solid. The crude
product is purified on a silica flash column eluting with 20% ethyl
acetate/80% hexanes to give 900 mg of the amine protected title
amine.
[0198] The protected amine from above (1.025 g, 2.9 mmol) is placed
in a flask and stirred with trifluoroacetic acid (neat). After 10
minutes, the solution is concentrated and taken up in 10 ml of
methanol. This solution is then placed on a 10 g SCX column and
washed with methanol (2.times.10 ml). The product is eluted with
methanolic ammonia (2M) to give 735 mg of the title amine.
Amine 43
[0199] Carbonyldiimidazole (43.0 g, 265 mmol) is added in one
portion to a solution of 2-chloro-5-carboxythiophene (39.2 g, 241
mmol) in 400 ml of tetrahydrofuran. The resulting mixture is
allowed to stir for 60 minutes before aqueous ammonium hydroxide
(28%, 125 ml) is added in one portion. After stirring for 90
minutes, the mixture is concentrated in vacuo and the residue is
dissolved in ethyl acetate (750 ml). This organic solution is
washed with aqueous sodium hydroxide (1N, 100 ml) and then four
times with aqueous hydrochloric acid (1N, 100 ml). The organic
layer is dried over sodium sulfate, filtered, and concentrated in
vacuo, and dried overnight at 40.degree. C. in vacuo to give 22.6 g
of 2-chloro-5-carboxamidothiophene.
[0200] Oxalyl chloride (8.9 ml, 102 mmol) is added dropwise to a
cold solution (-40.degree. C.) of 2-chloro-5-carboxamidothiophene
(15 g, 92.8 mmol) in dimethylformamide (150 ml). After the addition
is complete, the reaction is allowed to stir for 2 hours before it
is diluted with ethyl acetate (500 ml). The resulting mixture is
washed four times with water (25 ml), dried over sodium sulfate,
and concentrated in vacuo to give 12.3 g of
2-chloro-5-cyanothiophene.
[0201] 2-Chloro-5-cyanothiophene (3.8 g, 26.6 mmol) and
4-(2-amino-2-methylpropyl)phenol (4.0 g, 17.8 mmol) are dissolved
in dimethylsulfoxide (15 ml). Sodium hydride (60% dispersion in
oil, 1.5 g) is added in portions over 2 hours. The first addition
(about half of the total) is done at room temperature. The reaction
is heated to 50.degree. C. and the remaining sodium hydride is
added in portions. After the additions are complete, the reaction
mixture is heated to 90.degree. C. and is allowed to stir for 44
hours. After allowing the reaction mixture to cool, it is diluted
with dichloromethane (45 ml) and water (90 ml). The layers are
separated and the organic layer is washed with water (15 ml). Water
(77 ml) is added to the organic layer and the pH of the aqueous
phase is adjusted to 1 with concentrated hydrochloric acid (1.9
ml). The aqueous layer is washed with dichloromethane (14 ml) and
then the pH is adjusted to 13 with aqueous sodium hydroxide (5N, 14
ml). The aqueous layer is extracted three times with
dichloromethane (90 ml, 2.times.45 ml). The extracts are combined,
dried over sodium sulfate, and concentrated in vacuo to give 3.5 g
of the title amine.
Amine 48
[0202] 2-Methyl-hydroxy-phenol (15.0 g, 0.12 mol), 2-nitro propane
(60.8 ml, 676 mmol)., potassium t-butoxide (6.77 g, 60 mmol) and
diglyme (150 ml) are mixed together in a reaction vessel and said
vessel is fitted with a Dean-Stark water trap. The reaction is
heated to 134.degree. C. until water and solvent began to collect
in the trap. The reaction is slowly heated to 149.degree. C. and
then is allowed to cool back down to 130.degree. C. at which point
the reaction is stirred for 3 hours. Reaction is cooled to room
temperature and water (20 ml) is added. After concentrating to
about half the volume, water (100 ml) is added and the mixture is
extracted with ethyl acetate (2.times.100 ml). The organic layer is
then washed with 1N aqueous hydrochloric acid and water, dried over
sodium sulfate and concentrated to a brown oil. A mixture of ethyl
acetate and hexanes, (300 ml, 1:4 ethyl acetate/hexanes) is added
and product is triturated.
[0203] The product from above (7.0 g) is taken up in methanol and
acetic acid and 5% palladium on carbon is added. Hydrogen gas is
injected into the reaction vessel up to 50 p.s.i. The mixture is
then heated to 50.degree. C. and shaken for 16 hours. The catalyst
is filtered and the reaction is concentrated. Ethyl acetate (400
ml) is added and product is filtered to give 7.55 g of
2-(2-amino-2-methylpropyl)phenol acetic acid salt.
2-(2-Amino-2-methylpropyl)phenol acetic acid salt is converted to
its free base form, the free base is reacted with
di-t-butyl-dicarbonate, and the protected amine is reacted with
4-cyanophenyl boronic acid to prepare the title amine substantially
as described above for Amine 41.
Amines 5, 13-23, 25, 28, 30, 32, 34, 35, 37, 39, 42, 44-47 and
49
[0204] Amines 5, 13-23, 25, 28, 30, 32, 34, 35, 37 and 39 are
prepared by procedures substantially similar to that described for
Amine 4. Amines 42 and 47 are prepared by procedures substantially
similar to that described for Amine 41. Amines 44-46 are prepared
by procedures substantially similar to that described for Amine 43.
Amine 49 is prepared by procedures substantially similar to that
described for Amine 48.
[0205] Aryl Halides of Formula V
[0206] Aryl halides 1-14 are prepared for use as described in
Scheme 2. These aryl halides are pictured below in Tables 6 and
7.
6TABLE 6 135 X.sup.3 = 136 137 138 139 140 141 142 143 144 145
[0207]
7TABLE 7 146 X.sup.3 = 147 148 149 150
[0208] Representative Procedure 1: Preparation of Aryl Halides
[0209] (2S)-1-(2-iodophenyloxy)-2,3-epoxypropane (Epoxide 22, 8
mmol) or (2S)-1-(2-iodo-6-fluorophenyloxy)-2,3-epoxypropane
(Epoxide 55) is reacted with an equimolar amount of an amine of
formula III (Amines 2-5, 9, 10, 12, 31, 36 or 40) in 100 ml of
refluxing dry ethanol overnight. After evaporation of the solvent
the residue is purified via flash chromatography on silica gel
using a dichloromethane-dichloromethane/etha- nolic ammonia
gradient (100 to 95:5).
[0210] Boronic Acids
[0211] The following boronic acids or cyclic esters are obtained
from commercial sources for use as described in Scheme 2.
8TABLE 8 151 152 153 154 155 156 157 158 159 160
EXAMPLES
[0212] Representative Procedure 2: Amination of Epoxide
[0213] A vial is charged with a solution of single amine of formula
III (0.2M in ethanol or t-butanol, 90 micromolar) and a solution of
a single epoxide of formula II (0.2M in dimethylsulfoxide, 80
micromolar). The vial is sealed and heated to 80.degree. C. for
24-48 hours. The solution is cooled to room temperature, diluted
with methanol, and passed over a cation exchange column, eluting
the basic material with 1N methanolic ammonia.
[0214] Representative Procedure 3: Amination of Epoxide
[0215] A stirred mixture of an epoxide of formula II (1 equivalent)
and an amine of formula III (1-2 equivalents) in ethanol, methanol,
n-butanol or t-butanol is heated at 70-80.degree. C. for 2-72
hours. The solvent is evaporated to dryness to give a crude oil
that is optionally diluted with methanol or ethanol and passed over
a cation exchange column (eluting the free base product with 1N
methanolic ammonia) before further purification.
[0216] The final products prepared via Representative Procedure 2
or 3 may be further purified by flash or radial chromatography.
Typical chromatography conditions include: a) using a variable
mixture of 25:5:1 chloroform/methanol/ammonium hydroxide and 9:1
chloroform/methanol; b) a variable mixture of 90:10:1
CH.sub.2Cl.sub.2/ethanolic NH.sub.3 gradient; c)
dichloromethane/6-12% methanol, 0.15-0.35M ammonia in
dichloromethane gradient; d) methylene chloride with a step
gradient to 2-8% methanol; e) chloroform/2.0M ammonia in methanol,
from 0-10% to 6-20% gradient elution or f) isocratic 6-8% 2M
ammonia in methanol: 92-94% dichloromethane.
[0217] Alternatively, the final products may be purified on C18
bonded silica gel using either mass guided or UV guided reverse
phase liquid chromatography (acetonitrile/water with 0.01%
hydrochloric acid or 0.1% trifluoroacetic acid). When purification
of a compound of the present invention results in production of a
free base, the free base thus prepared may be salified, e.g., by
dissolution of the free base in CH.sub.2Cl.sub.2 or diethylether,
adding 1M ethanolic HCl or a solution of HCl in diethylether, and
evaporating the volatiles, or as described in more detail
below.
[0218] For example, a hydrochloride salt may be prepared by
dissolving the free base in dichloromethane, diethylether, or a
mixture of ethyl acetate and methanol and adding 1M ethanolic HCl,
a solution of HCl in diethylether, or 0.5M ammonium chloride. The
resulting mixture is allowed to stir for a short time, e.g., for
five minutes, before evaporating the volatiles and optionally
triturating in diethyl ether to give the hydrochloride salt.
[0219] The oxalate salts may be prepared by dissolving the free
base in a small amount of ethyl acetate, optionally adding methanol
for solubitity. The resulting solution is treated with 1 equivalent
of a 0.5M solution of oxalic acid in ethyl acetate. The reaction
mixture is either concentrated in vacuo or centrifuged, separated,
and the solids are dried, to give the oxalate salt.
[0220] To prepare a succinate salt, the free base may be dissolved
in a small amount of ethyl acetate or methanol and then treated
with 1 equivalent of succinic acid in methanol. The resulting
slurry is dissolved in the minimum amount of methanol then
concentrated in vacuo to give the succinate salt.
[0221] For products synthesized from Epoxide 6, the cde products
are treated with 1N HCl/dioxane for 2 hours at room temperature and
concentrated before purifying on C18 bonde silica gel as described
above to give a compound of the formula: 161
[0222] For products synthesized from Epoxide 20, the title
compounds are prepared by removal of the Boc-protecting group from
the imidazoline ring by stirring a solution of the crude protected
product in dichloromethane/2N HCl 10:1.
[0223] For products synthesized from Epoxide 24, the intermediate
N,N-dimethyl s are treated with hydrazine hydrate in ethanol to
give a compound of the formula: 162
[0224] The table below sets out representative combinations of
Amines and Epoxides that are reacted as described above in
Representative Procedure 2 or 3. Preparation of desired product is
confirmed via mass spectral analysis (MSA). Emax.+-.Standard Error
Mean (SEM) data, discussed in the "Demonstration of Function"
section below, is also included for said compounds where available.
The Emax values represent the average of at least 3 runs except as
otherwise indicated.
9TABLE 9 E.g. Epoxide Amine MSA Isolated Form Emax (%) .+-. SEM 1 3
1 475.2 Trifluoro Acetate 58.1 .+-. 2.6 2 5 1 460.2 Trifluoro
Acetate 43.6 .+-. 9.7 3 1 2 498.3 Free Base <10 4 2 4 498.3 Free
Base 55.0 .+-. 1.3 5 3 2 500.3 Free Base 66.1 .+-. 4.8 6 4 2 501.3
Free Base 58.7 .+-. 1.8 7 5 2 485.0 Free Base 48.8 .+-. 2.5 8 6 2
484.1 Free Base 33.7 .+-. n = 1 9 7 2 533.4 Free Base 23.7 .+-.
10.0 10 8 2 496.6 Free Base 35.1 .+-. 0.9 11 9 2 501.4 Free Base
18.0 .+-. 6.5 12 21 2 485.2 Hydrochloride 64.8 .+-. 6.3 13 33 2
485.3 Hydrochloride 54.8 .+-. 1.7 14 1 3 516.3 Free Base 16.9 .+-.
n = 1 15 2 5 516.3 Free Base 70.9 .+-. 3.0 16 3 3 518.3 Free Base
67.6 .+-. 4.7 17 4 3 519.3 Free Base 62.9 .+-. 2.2 18 5 3 503.0
Free Base 49.1 .+-. 2.9 19 6 3 502.1 Free Base 31.3 .+-. n = 1 20 7
3 551.5 Free Base 30.4 .+-. 2.5 21 7 5 551.4 Free Base 48.0 .+-.
2.0 22 9 3 519.3 Free Base 22.0 .+-. 5.3 23 10 3 521.4
Di-Hydrochloride 29.9 .+-. 3.2 24 11 3 519.5 Di-Hydrochloride 17.3
.+-. 3.2 25 12 3 520.4 Tri-Hydrochloride 13.7 .+-. 3.5 26 13 3
553.3 Free Base 41.4 .+-. 6.6 27 14 3 569.3 Free Base 20.8 .+-. 8.5
28 15 3 533.3 Free Base 83.4 .+-. 7.2 29 17 3 501.3 Hydrochloride
48.4 .+-. 5.9 30 18 3 504.5 Free Base 51.7 .+-. 2.7 31 19 3 538.3
Free Base 12.1 .+-. n = 1 32 21 3 503.3 Hydrochloride 54.2 .+-. 5.0
33 23 3 529.3 Free Base 26.2 .+-. 4.3 34 24 3 502.4 Free Base
<10 35 25 3 503.3 Free Base 28.9 .+-. n = 1 36 37 3 503.3 Free
Base 17.5 .+-. n = 1 37 5 3 489.2 Trifluoro Acetate 41.5 .+-. 0.5
38 26 3 529.3 Free Base 20.5 .+-. n = 1 39 27 3 519.2 Oxalate 67.1
.+-. 0.7 40 27 3 500.3 Trifluoro Acetate 79.5 .+-. 6.7 41 38 3
518.3 Hydrochloride 33.5 .+-. 4.2 42 28 3 520.2 Oxalate 43.3 .+-.
2.7 43 40 3 502.4 Hydrochloride 61.9 .+-. 2.5 44 29 3 520.2 Oxalate
22.1 .+-. 3.3 45 32 3 503.3 Free Base 66.5 .+-. 3.9 46 33 3 503.3
Hydrochloride 64.7 .+-. 1.3 47 34 3 502.4 Hydrochloride 35.5 .+-.
5.5 48 1 4 498.3 Free Base 14.4 .+-. n = 1 49 2 2 498.3 Free Base
59.1 .+-. n = 1 50 3 4 500.3 Free Base 78.9 .+-. 2.5 51 3 4 499.9
Hydrochloride 74.1 .+-. 3.3 52 4 4 501.3 Free Base 70.1 .+-. 3.3 53
5 4 485.0 Free Base 74.5 .+-. 12.5 54 5 4 484.9 Hydrochloride 66.8
.+-. 6.8 55 6 4 484.1 Free Base 37.5 .+-. n = 1 56 7 4 533.3 Free
Base 30.1 .+-. 2.1 57 8 4 496.4 Free Base 41.8 .+-. 5.6 58 9 4
501.3 Free Base 21.0 .+-. 3.4 59 20 3 504.3 Free Base <10 60 21
4 485.2 Hydrochloride 70.8 .+-. 3.1 61 23 4 511.4 Free Base 32.8
.+-. 4.3 62 37 4 485.3 Trifluoro Acetate 24.7 .+-. 5.2 63 30 4
518.2 Oxalate 52.6 .+-. 2.5 64 31 4 518.2 Trifluoro Acetate 30.5
.+-. 6.8 65 33 4 485.3 Hydrochloride 55.9 .+-. 5.8 66 1 5 516.3
Free Base 26.6 .+-. n = 1 67 2 3 516.3 Free Base 77.4 .+-. n = 1 68
3 5 518.3 Free Base 83.7 .+-. 3.0 69 3 5 517.9 Hydrochloride 80.7
.+-. 4.4 70 4 5 519.3 Free Base 73.8 .+-. 6.0 71 4 5 518.9
Hydrochloride 65.6 .+-. 1.3 72 5 5 503.0 Free Base 67.6 .+-. 7.1 73
5 5 502.9 Hydrochloride 69.5 .+-. 0.1 74 6 5 502.1 Free Base 36.8
.+-. n = 1 75 8 3 514.5 Free Base 40.3 .+-. 3.7 76 8 5 514.3 Free
Base 48.8 .+-. 5.5 77 9 5 519.3 Free Base 22.4 .+-. 4.6 78 10 5
521.4 Di-Hydrochloride 30.3 .+-. 5.1 79 11 5 519.3 Di-Hydrochloride
21.3 .+-. 3.3 80 12 5 520.4 Tri-Hydrochloride 12.3 .+-. 0.2 81 13 5
553.3 Free Base 60.4 .+-. 5.1 82 14 5 569.2 Free Base 45.9 .+-.
10.7 83 15 5 533.3 Hydrochloride 83.5 .+-. 4.4 84 16 5 505.3 Free
Base 72.1 .+-. 6.2 85 17 5 501.2 Hydrochloride 69.2 .+-. 12.1 86 18
5 504.3 Free Base 64.6 .+-. 3.3 87 19 5 538.1 Free Base 14.2 .+-. n
= 1 88 20 5 504.3 Free Base <10 89 21 5 503.3 Hydrochloride 71.8
.+-. 2.5 90 23 5 529.5 Free Base 31.5 .+-. 2.8 91 26 5 529.3 Free
Base 24.9 .+-. 9.3 92 24 5 502.4 Free Base 14.4 .+-. n = 1 93 25 5
503.3 Free Base <10 94 37 5 503.3 Free Base <10 95 39 5 536.3
Hydrochloride 13.9 .+-. 0.1 96 27 5 519.2 Oxalate 78.1 .+-. 6.6 97
28 5 520.2 Oxalate 52.4 .+-. 0.8 98 29 5 520.2 Oxalate 39.2 .+-.
4.0 99 30 5 536.2 Oxalate 59.1 .+-. 0.6 100 31 5 536.2 Trifluoro
Acetate 31.4 .+-. 5.0 101 33 5 503.3 Hydrochloride 67.4 .+-. 4.0
102 34 5 502.4 Hydrochloride 46.1 .+-. 4.5 103 35 5 520.5 Free Base
21.1 .+-. 0.1 104 36 5 502.4 Hydrochloride 36.0 .+-. 5.0 105 1 6
545.4 Free Base <10 106 2 6 545.3 Free Base 53.2 .+-. 2.4 107 3
6 547.3 Free Base 84.3 .+-. 5.3 108 3 6 547.2 Trifluoro Acetate
87.1 .+-. 11.9 109 4 6 548.3 Free Base 61.4 .+-. 4.4 110 5 6 532.0
Free Base 60.3 .+-. 3.9 111 6 6 531.1 Free Base 23.6 .+-. n = 1 112
5 6 532.2 Trifluoro Acetate 56.9 .+-. 8.6 113 1 7 531.3 Free Base
20.7 .+-. n = 1 114 2 7 531.3 Free Base 56.6 .+-. n = 1 115 3 7
533.3 Free Base 61.9 .+-. 7.0 116 4 7 534.3 Free Base 58.2 .+-. 7.2
117 5 7 518.0 Free Base 32.2 .+-. 6.5 118 6 7 517.1 Free Base 29.5
.+-. n = 1 119 3 8 499.2 Trifluoro Acetate 55.2 .+-. 3.6 120 4 8
500.2 Trifluoro Acetate 35.8 .+-. 4.6 121 5 8 484.3 Trifluoro
Acetate 38.9 .+-. 7.1 122 27 8 505.3 Trifluoro Acetate 61.9 .+-.
5.3 123 3 9 516.2 Trifluoro Acetate 73.6 .+-. 8.2 124 4 9 518.2
Trifluoro Acetate 46.7 .+-. 3.6 125 5 9 502.2 Trifluoro Acetate
40.3 .+-. 7.9 126 27 9 518.2 Trifluoro Acetate 62.2 .+-. 1.3 127 1
10 550.3 Free Base <10 128 2 10 550.3 Free Base 40.6 .+-. n = 1
129 3 10 552.2 Trifluoro Acetate 53.2 .+-. 4.8 130 4 10 553.3 Free
Base 49.5 .+-. 3.4 131 4 10 552.9 Trifluoro Acetate 43.5 .+-. 1.4
132 5 10 537.0 Free Base 34.6 .+-. 7.8 133 6 10 536.1 Free Base
21.4 .+-. n = 1 134 21 10 537.4 Hydrochloride 47.7 .+-. 6.5 135 5
10 537.2 Trifluoro Acetate 35.2 .+-. 4.3 136 39 10 570.2
Hydrochloride <10 137 1 11 564.3 Free Base <10 138 2 11 564.3
Free Base 41.7 .+-. n = 1 139 3 11 566.3 Free Base 62.2 .+-. 7.4
140 4 11 567.3 Free Base 48.9 .+-. 2.5 141 5 11 551.0 Free Base
48.3 .+-. 9.9 142 6 11 550.1 Free Base 20.2 .+-. n = 1 143 3 12
500.2 Trifluoro Acetate 67.2 .+-. 4.8 144 4 12 501.2 Trifluoro
Acetate 55.9 .+-. 1.1 145 4 36 501.2 Trifluoro Acetate 44.6 .+-.
6.2 146 5 12 484.2 Trifluoro Acetate 58.7 .+-. 2.9 147 27 12 501.2
Trifluoro Acetate 58.9 .+-. 3.6 148 30 12 536.2 Trifluoro Acetate
51.6 .+-. 9.7 149 31 12 518.2 Trifluoro Acetate 26.9 .+-. 4.0 150 3
13 476.2 Trifluoro Acetate 69.8 .+-. 6.0 151 4 13 477.2 Trifluoro
Acetate 73.1 .+-. 3.8 152 5 13 461.2 Trifluoro Acetate 45.3 .+-.
4.2 153 3 14 476.2 Trifluoro Acetate 66.8 .+-. 5.5 154 4 14 477.3
Trifluoro Acetate 61.1 .+-. 7.7 155 5 14 461.2 Trifluoro Acetate
46.6 .+-. 4.2 156 3 15 577.1 Trifluoro Acetate 84.9 .+-. 0.2 157 4
15 578.1 Trifluoro Acetate 73.3 .+-. 6.6 158 5 15 562.1 Trifluoro
Acetate 73.0 .+-. 3.0 159 3 16 577.2 Trifluoro Acetate 76.9 .+-.
7.4 160 5 16 562.2 Trifluoro Acetate 56.3 .+-. 1.4 161 3 17 533.2
Trifluoro Acetate 52.5 .+-. 4.7 162 4 17 428.2 Trifluoro Acetate
36.2 .+-. 2.6 163 5 17 518.2 Trifluoro Acetate 44.6 .+-. 4.3 164 3
18 551.2 Trifluoro Acetate 67.3 .+-. 3.5 165 4 18 552.2 Trifluoro
Acetate 49.7 .+-. 3.9 166 5 18 536.2 Trifluoro Acetate 58.3 .+-.
9.5 167 3 19 509.2 Trifluoro Acetate 57.3 .+-. 3.5 168 4 19 510.2
Trifluoro Acetate 56.1 .+-. 4.5 169 5 19 494.2 Trifluoro Acetate
43.3 .+-. 6.8 170 3 20 576.2 Trifluoro Acetate 55.0 .+-. 4.8 171 4
20 * Trifluoro Acetate 47.9 .+-. 6.5 172 5 20 561.2 Trifluoro
Acetate 40.4 .+-. 8.8 173 3 21 543.2 Trifluoro Acetate 87.9 .+-.
4.5 174 5 21 528.2 Trifluoro Acetate 59.3 .+-. 3.2 175 3 22 509.2
Trifluoro Acetate 67.4 .+-. 3.9 176 4 22 510.2 Trifluoro Acetate
57.0 .+-. 7.6 177 5 22 494.2 Trifluoro Acetate 46.0 .+-. 1.7 178 3
23 509.2 Trifluoro Acetate 64.4 .+-. 5.2 179 4 23 510.2 Trifluoro
Acetate 62.2 .+-. 8.6 180 5 23 494.2 Trifluoro Acetate 52.4 .+-.
6.9 181 3 24 586.2 Trifluoro Acetate 66.2 .+-. 1.6 182 4 24 587.1
Trifluoro Acetate 57.6 .+-. 7.1 183 5 24 571.2 Trifluoro Acetate
53.7 .+-. 4.3 184 3 25 564.2 Trifluoro Acetate 64.1 .+-. 3.2 185 4
25 565.2 Trifluoro Acetate 45.1 .+-. 2.6 186 5 25 549.2 Trifluoro
Acetate 41.1 .+-. 8.2 187 3 26 517.2 Trifluoro Acetate 45.1 .+-.
1.5 188 4 26 518.2 Trifluoro Acetate 38.3 .+-. 5.7 189 5 26 502.2
Trifluoro Acetate 35.1 .+-. 5.2 190 3 27 535.2 Trifluoro Acetate
54.5 .+-. 3.3 191 4 27 536.2 Trifluoro Acetate 49.5 .+-. 1.5 192 5
27 520.2 Trifluoro Acetate 40.3 .+-. 6.9 193 3 28 543.2 Trifluoro
Acetate 73.5 .+-. 3.2 194 4 28 544.2 Trifluoro Acetate 56.6 .+-.
4.2 195 5 28 528.2 Trifluoro Acetate 48.1 .+-. 3.8 196 3 29 518.2
Trifluoro Acetate 74.4 .+-. 3.3 197 4 29 519.2 Trifluoro Acetate
67.7 .+-. 2.7 198 5 29 503.2 Trifluoro Acetate 48.1 .+-. 6.5 199 27
29 519.3 Trifluoro Acetate 83.0 .+-. 4.0 200 30 29 518.2 Trifluoro
Acetate 59.5 .+-. 3.7 201 31 29 517.2 Trifluoro Acetate 26.8 .+-.
4.2 202 3 30 475.2 Trifluoro Acetate 59.1 .+-. 6.0 203 4 30 476.2
Trifluoro Acetate 57.8 .+-. 3.1 204 3 37 580.2 Trifluoro Acetate
67.6 .+-. 4.0 205 3 31 518.2 Trifluoro Acetate 70.3 .+-. 0.3 206 4
31 519.2 Trifluoro Acetate 64.2 .+-. 8.1 207 27 31 519.2 Trifluoro
Acetate 70.5 .+-. 4.9 208 3 32 510.2 Trifluoro Acetate 92.4 .+-.
7.3 209 4 32 511.2 Trifluoro Acetate 88.3 .+-. 8.0 210 5 32 *
Trifluoro Acetate 89.1 .+-. 2.7 211 27 32 511.2 Trifluoro Acetate
88.5 .+-. 9.3 212 5 33 484.7 Trifluoro Acetate 68.9 .+-. 3.1 213 27
33 500.2 Trifluoro Acetate 63.0 .+-. 3.2 214 30 33 517.2 Trifluoro
Acetate 42.4 .+-. 9.4 215 31 33 535.2 Trifluoro Acetate 28.1 .+-.
4.5 216 3 34 533.2 Trifluoro Acetate 85.4 .+-. 4.9 217 5 34 518.2
Trifluoro Acetate 76.2 .+-. 8.3 218 3 35 551.2 Trifluoro Acetate
76.5 .+-. 1.7 219 5 35 536.2 Trifluoro Acetate 50.4 .+-. 6.3 220 3
36 500.3 Trifluoro Acetate 56.0 .+-. 2.9 221 5 36 484.2 Trifluoro
Acetate 40.8 .+-. 8.3 222 4 37 581.2 Trifluoro Acetate 59.0 .+-.
10.0 223 3 38 570.2 Trifluoro Acetate 63.7 .+-. 3.1 224 4 38 571.2
Trifluoro Acetate 37.0 .+-. 0.3 225 3 39 571.2 Trifluoro Acetate
59.5 .+-. 4.3 226 4 39 572.2 Trifluoro Acetate 37.8 .+-. 9.2 227 30
40 535.2 Trifluoro Acetate 51.3 .+-. 10.8 228 31 40 535.2 Trifluoro
Acetate 28.9 .+-. 3.4 229 5 41 468.2 Oxalate 34.7 .+-. 4.3 230 5 42
468.2 Oxalate 30.8 .+-. 6.0 231 3 43 505.2 Trifluoro Acetate 65.9
.+-. 4.2 232 5 43 490.2 Trifluoro Acetate 37.4 .+-. 2.8 233 3 44
523.2 Trifluoro Acetate 71.0 .+-. 4.7 234 5 44 508.2 Trifluoro
Acetate 44.0 .+-. 4.4 235 3 45 * Trifluoro Acetate 60.5 .+-. 5.6
236 5 45 474.2 Trifluoro Acetate 36.8 .+-. 1.6 237 3 46 507.2
Trifluoro Acetate 57.7 .+-. 1.1 238 5 46 492.2 Trifluoro Acetate
47.6 .+-. 2.4 239 41 4 501.2 Hydrochloride 49.8 .+-. 4.5 240 41 5
519.2 Hydrochloride 65.7 .+-. 3.8 241 41 12 501.2 Hydrochloride
47.0 .+-. 2.5 242 41 29 519.2 Hydrochloride 55.9 .+-. 4.0 243 41 33
500.2 Hydrochloride 47.9 .+-. 3.5 244 41 40 518.2 Hydrochloride
66.6 .+-. 5.7 245 41 34 534.2 Hydrochloride 56.1 .+-. 2.9 246 41 35
552.2 Hydrochloride 52.1 .+-. 2.4 247 41 2 501.2 Hydrochloride 45.4
.+-. 3.4 248 41 3 519.2 Hydrochloride 47.5 .+-. 4.8 249 41 10 553.2
Hydrochloride 35.9 .+-. 2.9 250 41 38 571.2 Hydrochloride 31.6 .+-.
3.1 251 41 39 572.2 Hydrochloride 33.4 .+-. 5.7 252 41 27 536.2
Hydrochloride 38.4 .+-. 3.8 253 41 18 552.2 Hydrochloride 37.6 .+-.
2.7 254 41 16 578.2 Hydrochloride 50.5 .+-. 0.8 255 41 22 510.2
Hydrochloride 41.4 .+-. 3.9 256 41 14 477.3 Hydrochloride 50.6 .+-.
1.8 257 41 13 477.2 Hydrochloride 49.9 .+-. 3.4 258 41 43 506.2
Hydrochloride 48.4 .+-. 5.6 259 41 44 524.2 Hydrochloride 54.1 .+-.
3.9 260 41 45 490.2 Hydrochloride 38.2 .+-. 2.0 261 41 46 508.2
Hydrochloride 52.3 .+-. 6.6 262 43 5 530.2 Dihydrochloride 63.6
.+-. 4.3 263 17 4 486.6 Hydrochloride 64.3 .+-. 9.6 264 17 2 486.6
Hydrochloride 39.4 .+-. 10.1 265 17 10 535.7 Hydrochloride 42.7
.+-. 9.4 266 17 31 501.6 Hydrochloride 36.7 .+-. 6.8 267 17 36
486.6 Hydrochloride 37.1 .+-. 2.5 268 17 12 483.6 Hydrochloride
54.6 .+-. 8.2 269 17 9 500.6 Hydrochloride 41.3 .+-. 4.2 270 17 40
500.6 Hydrochloride 56.4 .+-. 8.3 271 45 5 526.6 Hydrochloride 39.0
.+-. 0.6 272 45 3 526.6 Hydrochloride 35.7 .+-. 2.8 273 46 5 529.6
Free Base 40.3 .+-. 0.5 274 46 3 529.6 Free Base 38.8 .+-. 1.4 275
47 5 514.6 Hydrochloride 47.0 .+-. 1.4 276 47 3 514.6 Hydrochloride
53.8 .+-. 2.0 277 48 3 536.6 Hydrochloride 42.3 .+-. 11.1 278 48 5
536.6 Hydrochloride 27.5 .+-. 2.7 279 49 3 536.6 Hydrochloride 17.0
.+-. 2.7 280 49 5 536.6 Hydrochloride 38.4 .+-. 5.1 281 50 3 554.6
Hydrochloride 15.6 .+-. 0.1 282 50 5 554.6 Hydrochloride 17.4 .+-.
2.1 283 51 3 554.6 Hydrochloride <10 284 51 5 554.6
Hydrochloride 10.8 .+-. 0.3 285 3 2 500.2 Oxalate 24.6 .+-. 3.8 286
3 33 499.1 Trifluoroacetate 72.1 .+-. 4.5 287 5 30 *
Trifluoroacetate 39.9 .+-. 4.9 288 5 37 * Trifluoroacetate 52.9
.+-. 7.4 289 5 47 468.2 Oxalate 37.4 .+-. 7.2 290 5 48 468.2
Hydrochloride 22.7 .+-. 1.7 291 5 49 468.2 Hydrochloride 18.4 .+-.
n = 1 292 52 4 503.3 Trifluoroacetate 43.5 .+-. 9.8 293 52 5 521.3
Trifluoroacetate 50.1 .+-. 5.6 294 52 12 503.3 Trifluoroacetate
43.9 .+-. 4.4 295 52 33 502.3 Trifluoroacetate 39.7 .+-. 8.7 296 52
40 520.2 Trifluoroacetate 47.9 .+-. 4.4 297 21 12 485.3
Hydrochloride 74.5 .+-. 6.7 298 21 31 503.4 Hydrochloride 54.5 .+-.
0.8 299 21 9 502.4 Hydrochloride 45.9 .+-. 3.9 300 21 36 485.3
Hydrochloride 52.2 .+-. 5.9 301 21 40 502.4 Hydrochloride 69.2 .+-.
1.2 302 39 3 536.3 Hydrochloride 12.8 .+-. n = 1 303 40 5 502.4
Hydrochloride 67.9 .+-. 6.1 304 40 10 536.3 Hydrochloride 44.8 .+-.
4.9 305 40 2 484.3 Hydrochloride 68.8 .+-. 6.5 306 40 4 484.4
Hydrochloride 82.4 .+-. 4.0 307 40 12 484.3 Hydrochloride 74.4 .+-.
1.8 308 32 5 503.3 Hydrochloride 71.2 .+-. 5.8 309 54 3 503.3
Hydrochloride 67.1 .+-. 1.2 310 54 5 503.3 Hydrochloride 72.7 .+-.
3.4 311 54 2 485.2 Trifluoroacetate 51.5 .+-. 1.7 312 54 4 485.4
Trifluoroacetate 59.8 .+-. 3.1 313 53 5 535.9 Trifluoroacetate 29.3
.+-. 4.1 314 60 12 518.3 Trifluoroacetate 42.0 .+-. 2.0 315 60 29
535.9 Trifluoroacetate 39.9 .+-. 2.5 316 60 40 535.3
Trifluoroacetate 58.8 .+-. 3.1 317 56 40 535.2 Trifluoroacetate
56.4 .+-. 5.0 318 56 33 517.2 Trifluoroacetate 41.8 .+-. 3.8 319 56
12 518.2 Trifluoroacetate 49.9 .+-. 3.9 320 56 5 536.2
Trifluoroacetate 51.4 .+-. 2.1 321 56 4 518.2 Trifluoroacetate 42.5
.+-. 2.3 322 57 4 552.1 Trifluoroacetate 27.6 .+-. 3.9 323 57 5
570.1 Trifluoroacetate 33.8 .+-. 3.8 324 57 12 570.2
Trifluoroacetate 38.5 .+-. 6.7 325 57 33 569.2 Trifluoroacetate
31.6 .+-. 7.8 326 57 40 569.2 Trifluoroacetate 30.4 .+-. 2.1 327 4
46 508.2 Trifluoroacetate 56.7 .+-. 2.1 328 4 43 506.1
Trifluoroacetate 57.4 .+-. 6.5 329 4 44 524.2 Trifluoroacetate 60.2
.+-. 3.0 330 4 45 490.2 Trifluoroacetate 55.9 .+-. 2.8 331 58 4
518.2 Hydrochloride 72.9 .+-. 2.0 332 58 5 537.2 Hydrochloride 80.6
.+-. 2.4 333 58 12 518.2 Hydrochloride 72.4 .+-. 3.0 334 58 33
517.0 Hydrochloride 77.8 .+-. 3.0 335 59 4 501.2 Hydrochloride 66.5
.+-. 1.8 336 59 5 519.2 Hydrochloride 68.8 .+-. 2.4 337 59 12 501.2
Hydrochloride 52.8 .+-. 3.7 338 59 33 500.2 Hydrochloride 65.5 .+-.
3.9 339 63 5 502.3 Hydrochloride 40.5 .+-. 1.2 340 43 3 530.3
Di-Hydrochloride 28.1 .+-. 2.3 341 63 3 502.3 Free Base 46.2 .+-.
6.3 342 3 34 533.2 Hydrochloride Not Tested 343 5 34 518.2
Hydrochloride Not Tested 344 27 5 519.2 Hydrochloride Not Tested
345 64 5 576.1 Oxalate 72.1 .+-. 4.2 346 64 29 576.1 Oxalate 57.3
.+-. 6.3 347 65 5 543.3 Hydrochloride 84.8 .+-. 3.4 348 66 5 532.3
Trifluoro Acetate 72.6 .+-. 5.5 349 67 5 543.3 Trifluoro Acetate
57.4 .+-. 3.3 350 68 5 532.3 Trifluoro Acetate 45.8 .+-. 1.9 351 69
5 543.3 Trifluoro Acetate 64.3 .+-. 1.3 352 70 5 532.0 Trifluoro
Acetate 68.5 .+-. 2.5 353 73 5 597.3 Hydrochloride 96.5 .+-. 9.7
354 74 5 502.4 Hydrochloride 73.5 .+-. 2.5 355 32 31 503.3
Trifluoroacetate 66.6 .+-. 3.3 356 54 9 502.4 Trifluoroacetate 65.2
.+-. 1.9 357 54 31 503.2 Trifluoroacetate 65.4 .+-. 2.6 358 54 40
502.1 Trifluoroacetate 68.4 .+-. 1.5 359 72 3 517.6
Trifluoroacetate 31.2 .+-. 4.4 360 72 5 517.3 Trifluoroacetate 49.9
.+-. 3.5 361 32 9 502.4 Trifluoroacetate 70.1 .+-. 2.2 362 54 12
485.3 Trifluoroacetate 56.2 .+-. 2.9 363 54 36 485.3
Trifluoroacetate 50.1 .+-. 4.9 364 32 36 485.0 Trifluoroacetate
69.2 .+-. 2.5 365 32 40 502.0 Trifluoroacetate 80.2 .+-. 5.6 366 71
3 517.2 Trifluoroacetate 47.9 .+-. 3.5 367 71 5 517.2
Trifluoroacetate 69.5 .+-. 4.6 368 71 2 499.3 Trifluoroacetate 48.4
.+-. 2.5 369 71 4 499.4 Trifluoroacetate 59.3 .+-. 3.1 *Preparation
of product not confirmed by MSA
[0225] Representative Procedure 4: Suzuki Coupling
[0226] Procedure 4(a)
[0227] A compound of formula V (6.4 mmol) is dissolved in 50 ml of
dry dioxane and thoroughly flushed with argon. Palladium(0)
tetrakis(triphenylphosphine) (750 mg, 0.64 mmol) is added under
argon and stirred at ambient temperature until the mixture becomes
homogenous. The clear solution is divided into aliquots of 2 ml,
and each testing tube is charged with 2 equivalents of an aryl
boronic acid of formula IV and 500 .mu.l of 2M aqueous sodium
carbonate under argon. The testing tubes are sealed and heated in a
microwave oven (MLS ETHOS 1600) for 35 minutes and 100.degree. C.
at 1000 W. After complete conversion the samples are diluted with 2
ml of water and extracted with 3 ml of dichloromethane. Extraction
is repeated with 2 ml of dichloromethane. The organic solutions are
collected and dried over sodium sulfate. The organic filtrate is
treated with pre-treated Amberlyst 15 (3 to 4 g each). (Prior to
use Amberlyst 15 is prewashed with dichloromethane, ethanol then
dichloromethane until the filtrate is colorless). The suspensions
are shaken for 30 minutes on an orbital shaker and filtered. The
Amberlyst is repeatedly rinsed with dichloromethane/ethanol 1:1
(4.times.3 ml) and then repeatedly treated with
dichloromethane/ethanolic ammonia 1:1. Finally the resin is treated
with ethanolic ammonia overnight. The alkaline filtrates are
collected and evaporated.
[0228] Procedure 4(b)
[0229] A mixture of an aryl halide of formula V (1.2 mmol), a
boronic acid of formula IV (2.4 mmol), palladium(0)
tetrakis(triphenylphosphine) (0.06 mmol), and 2M aqueous sodium
carbonate (1.5 ml) in dioxane (20 ml) is heated over night at
100.degree. C. in a sealed tube. The mixture is poured into water
and extracted two times with ethyl acetate. The combined organic
layers are washed with brine, dried over sodium sulfate, and
concentrated under reduced pressure.
[0230] The final products prepared via Suzuki coupling may be
purified by normal phase chromatography (silica gel,
dichloromethane/ethanolic ammonia) providing the free bases or by
reverse phase chromatography (acetonitrile/0.1% trifluoroacetic
acid or 0.01% HCl in water) providing the trifluoro acetate or
hydrochloride salts. The final products existing as salts may also
be prepared in a separate salification step by dissolution of the
free base in ethanol or dichloromethane and treatment of the
solution with acid, e.g., 1N ethanolic HCl. Removal of all
volatiles under reduced pressure, affords the desired salt.
[0231] The table below sets out representative combinations of aryl
halides and boronic acids that are reacted as described above.
Preparation of desired product is confirmed via mass spectral
analysis (MSA). Emax.+-.Standard Error Mean (SEM) data, discussed
in the "Demonstration of Function" section below, is also included
for said compounds where available. The Emax values represent the
average of at least 3 runs except as otherwise indicated.
10TABLE 10 Aryl Boronic E.g. Halide Acid MSA Salt Form Emax (%)
.+-. SEM 370 2 1 552.3 Free Base 40.3 .+-. 2.8 371 3 1 534.2 Free
Base 38.9 .+-. 3.9 372 4 1 552.3 Free Base 56.3 .+-. 4.8 373 1 2
495.7 Free Base 29.0 .+-. 6.8 374 2 2 513.5 Free Base 49.3 .+-. 0.3
375 3 2 495.8 Free Base 35.1 .+-. 7.3 376 4 2 513.5 Free Base 48.2
.+-. 6.7 377 5 2 547.2 Di-Hydrochloride 33.0 .+-. 4.2 378 1 3 500.5
Free Base 60.2 .+-. 3.2 379 2 3 518.5 Free Base 37.7 .+-. 1.6 380 3
3 500.3 Free Base 57.4 .+-. 4.1 381 4 3 518.3 Trifluoro Acetate
58.5 .+-. 6.9 382 5 3 552.3 Hydrochloride 32.3 .+-. 1.9 383 5 10
552.1 Hydrochloride 52.1 .+-. 5.4 384 1 4 550.6 Free Base 45.4 .+-.
5.6 385 2 4 568.3 Free Base 43.1 .+-. 4.3 386 3 4 550.7 Free Base
46.9 .+-. 6.7 387 4 4 568.2 Trifluoro Acetate 78.7 .+-. 14.9 388 1
5 495.8 Free Base <10 389 2 5 513.5 Free Base 20.3 .+-. 2.0 390
3 5 495.8 Free Base 14.4 .+-. 1.7 391 4 5 513.5 Free Base 22.5 .+-.
1.5 392 5 5 547.4 Di-Hydrochloride 17.6 .+-. 0.4 393 5 6 586.0
Hydrochloride 50.0 .+-. 3.6 394 5 7 594.3 Hydrochloride 76.9 .+-.
5.0 395 5 8 536.3 Hydrochloride 46.6 .+-. 5.9 396 5 9 566.1
Hydrochloride 50.5 .+-. 1.9 397 6 10 518.4 Hydrochloride 29.9 .+-.
4.4 398 6 3 518.4 Hydrochloride 22.1 .+-. 1.7 399 7 10 536.3
Hydrochloride 37.3 .+-. 3.7 400 7 3 536.3 Hydrochloride 26.0 .+-.
3.5 401 8 10 518.4 Hydrochloride 46.3 .+-. 6.8 402 8 3 518.4
Trifluoroacetate 31.1 .+-. 3.3 403 9 10 536.3 Hydrochloride 57.9
.+-. 11.2 404 9 3 536.3 Hydrochloride 40.4 .+-. 7.8 405 1 9 514.3
Hydrochloride 64.4 .+-. 7.1 406 1 6 534.0 Trifluoroacetate 55.8
.+-. 7.1 407 1 7 542.2 Hydrochloride 79.7 .+-. 7.6 408 1 8 484.3
Hydrochloride 74.0 .+-. 6.5 409 2 9 532.2 Hydrochloride 71.3 .+-.
3.9 410 2 6 552.3 Hydrochloride 76.0 .+-. 5.0 411 2 7 560.3
Trifluoroacetate 78.2 .+-. 9.9 412 2 8 502.4 Hydrochloride 74.4
.+-. 7.0 413 3 9 514.3 Hydrochloride 66.9 .+-. 9.2 414 3 6 534.3
Trifluoroacetate 65.7 .+-. 11.4 415 3 7 542.3 Trifluoroacetate 80.6
.+-. 5.7 416 3 8 484.3 Hydrochloride 68.9 .+-. 6.7 417 4 9 532.2
Hydrochloride 79.3 .+-. 2.4 418 4 6 552.4 Hydrochloride 74.4 .+-.
6.5 419 4 7 560.2 Trifluoroacetate 87.5 .+-. 1.8 420 4 8 502.4
Hydrochloride 78.9 .+-. 2.3 421 10 3 517.3 Hydrochloride 53.4 .+-.
6.9 422 10 9 531.3 Hydrochloride 60.1 .+-. 8.2 423 10 6 551.4
Hydrochloride 63.1 .+-. 4.7 424 10 7 559.1 Hydrochloride 71.2 .+-.
7.9 425 10 8 501.3 Hydrochloride 67.1 .+-. 3.0 426 11 3 517.3
Hydrochloride 61.0 .+-. 7.1 427 11 9 531.3 Hydrochloride 72.4 .+-.
6.9 428 11 6 551.3 Hydrochloride 75.5 .+-. 6.9 429 11 7 559.3
Trifluoroacetate 84.7 .+-. 12.3 430 11 8 501.3 Hydrochloride 77.4
.+-. 9.0 431 12 3 500.3 Hydrochloride 50.3 .+-. 7.8 432 12 9 514.3
Hydrochloride 60.7 .+-. 8.4 433 12 6 534.2 Hydrochloride 56.5 .+-.
11.0 434 12 7 542.3 Trifluoroacetate 73.1 .+-. 5.1 435 12 8 484.3
Hydrochloride 61.4 .+-. 6.1 436 13 3 518.4 Hydrochloride 57.5 .+-.
12.0 437 13 9 532.2 Hydrochloride 72.0 .+-. 10.5 438 13 6 552.3
Hydrochloride 64.3 .+-. 12.4 439 13 7 560.1 Trifluoroacetate 75.0
.+-. 9.6 440 13 8 502.4 Hydrochloride 73.4 .+-. 4.4 441 14 3 500.3
Hydrochloride 64.2 .+-. 7.0 442 14 9 514.3 Hydrochloride 61.5 .+-.
3.0 443 14 6 534.2 Hydrochloride 56.1 .+-. 11.2 444 14 7 542.3
Trifluoroacetate 83.8 .+-. 11.4 445 14 8 484.3 Hydrochloride 74.5
.+-. 14.1 446 4 3 518.5 Hydrochloride 64.0 .+-. 6.0
Example 447
[0232] 163
[0233] A solution of Amine 4 (300 mg, 1.130 mmol) and
trimethylsilyl acetamide (TMSA) (210 mg, 1.614 mmol) is dissolved
in acetonitrile (1.5 mL) and stirred for 30 minutes. To this
solution is added Epoxide 62 (250 mg, 1.076 mmol) in acetonitrile
(3 mL) and ytterbium triflate (13 mg, 0.215 mmol). The solution is
heated at 80.degree. C. for 24 hours and concentrated in vacuo. The
resulting solid is purified by flash column chromatography (99%
dichloromethane:1% methanol gradient to (95% dichloromethane:5%
methanol as eluent) to give 135 mg of the title compound (25%).
FDMS m/e=500 (M.sup.++1). Emax (.+-.SEM)=74.5 (4.0).
Example 448
[0234] 164
[0235] The compound of Example 346 is hydrolized with 1.0
equivalent of lithium hydroxide (1M), in tetrahydrofuran at room
temperature overnight, and then concentrated to a crude residue
which is purified via HPLC as the trifluoroacetic acid salt as
described above in Representative Procedure 2 and 3. MS 562.2. Emax
(.+-.SEM)=79.9 (5.5).
Example 449
[0236] 165
[0237] The title compound is prepared from the compound of Example
345 as described in Example 448. MS 562.2. Emax (.+-.SEM)=74.2
(2.2).
Example 450
[0238] 166
[0239] The compound of Example 345 in dimethylformamide is treated
with 1.0 equivalent of sodium ethoxide and 4.0 equivalents of
formamide. The mixture is heated to 100.degree. C. for 4 hours,
cooled to room temperature then concentrated. The residue is
purified via HPLC as the trifluoroacetic acid salt as described
above in Representative Procedure 2 and 3. MS 561.2. Emax
(.+-.SEM)=67.4 (2.1).
Example 451
[0240] 167
[0241] The compound of Example 50 (250 mg) and 0.5 molar
equivalents (29 mg) of fumaric acid are suspended in 5 mL of
ethanol denatured with toluene and the mixture is heated mildly to
effect dissolution. After approximately five minutes, the solution
begins to precipitate. The temperature of the crystal slurry is
maintained at the crystallization temperature (56-57.degree. C.)
for about one hour. The heat source is then turned off and the
slurry is allowed to cool with stirring overnight. Ethanol
denatured with toluene (2 mL) is added and the solids are isolated
by vacuum filtration. The filter cake is washed with ethanol
denatured with toluene (5 mL) and air dried to give 230 mg of the
title compound. mp=147-149.degree. C. (measured by differential
scanning calorimetry (DSC) with a scan rate of 10.degree.
C./minute).
Example 452
[0242] 168
[0243] The compound of Example 50 (57.7 mg) is dissolved in 2.5 mL
of absolute ethanol and the solution is stirred at room
temperature. To the stirred solution is added benzoic acid (1
equivalent, 14.1 mg) dissolved in 200 microliters of methanol. The
resulting mixture is stirred at room temperature for 3.5 to 4
hours. Precipitation occurrs in approximately 30-60 minutes. The
precipitate is isolated by vacuum filtration and the filter cake is
collected and air-dried overnight. mp=148-150.degree. C. (measured
by DSC with a scan rate of 5.degree. C./minute).
Example 453
[0244] 169
[0245] The compound of Example 50 (200 mg) is dissolved in 1 mL of
acetone and the solution is stirred at room temperature. To the
stirred solution is added R-mandelic acid (1 equivalent, 61 mg) in
acetone (1 ml). The resulting, mixture is stirred at room
temperature and the precipitate is isolated by vacuum filtration.
The filter cake is collected and air dried overnight. mp=138-140
.degree. C. (measured by DSC with a scan rate of 5.degree.
C./minute).
Example 454
[0246] 170
[0247] The compound of Example 50 (106 mg) is dissolved in 1 mL of
ethyl acetate and the solution is stirred at room temperature. To
the stirred solution is added salicylic acid (1 equivalent, 29 mg)
in 150 microliters of methanol. The resulting mixture is stirred at
room temperature and then heated up to 50.degree. C. Hexane is
added to the mixture as an antisolvent at elevated temperature
until cloud point (approxiamtely 1 ml ethyl acetate:l ml of
hexane). The slurry is allowed to slowly cool to room temperature.
The precipitate is isolated by vacuum filtration and the filter
cake is collected and air dried overnight. mp=124.degree. C. (peak
max) (measured by DSC with a scan rate of 5.degree. C./minute).
[0248] Demonstration of Function
[0249] The genes encoding the human .beta..sub.1-adrenergic
receptor (Frielle et al., Proc. Natl. Acad. Sci., 84:7920-7924,
1987), the human .beta..sub.2-adrenergic receptor (Kobika et al.,
Proc. Natl. Acad. Sci., 84:46-50, 1987, Emorine et al., Proc. Natl.
Acad. Sci., 84:6995-6999, 1987) and the human .beta.3 adrenergic
receptor (Granneman et al., Molecular Pharmacology, 44(2):264-70,
1993) are individually subcloned into a phd expression vector
(Grinnell et al., Bio/Technology, 5:1189-1192, 1987) and
transfected into the DXB-11 Chinese hamster ovary (CHO) cell line
by calcium phosphate precipitation methodology. The stably
transfected cells are grown to 95% confluency in 95% Dulbecco's
modified Eagles Medium (DMEM), 5% fetal bovine serum and 0.01%
proline. Media is removed and the cells are washed with phosphate
buffered (pH 7.4) saline (without magnesium and calcium). Cells are
then lifted using an enzyme free cell dissociation solution
(Specialty Media, Lavallette, N.J.) and pelleted by
centrifugation.
[0250] Cells from each of the above cell lines are resuspended and
added (20,000/well) to a 96-well plate. Cells are incubated at
37.degree. C. with representative compounds of the invention for 20
minutes in buffer (Hank's balanced salt solution, 10 mM HEPES, 0.1%
BSA, 1 mM L-ascorbic acid, 0.2% dimethyl sulfoxide, 1 mM
3-isobutyl-1-methylxanthine, pH 7.4). After halting the incubation
with quench buffer (50 mM Na Acetate, 0.25% Triton X-100, pH 5.8),
the c-AMP level is quantified by scintillation proximity assay
(SPA) using a modification of the commercially available c-AMP kit
(Amersham, Arlington Heights, Ill.) with rabbit anti-cAMP antibody
(ICN Biomedicals, Aurora, Ohio) for the kit.
[0251] Sigmoidal dose response curves, from the whole cell receptor
coupled c-AMP assay are fit to a four parameter logistic equation
using non linear regression: y=(a-d)/(1+(Dose/c).sup.b)+d where a
and d are responses at zero and maximal dose, b is the slope factor
and c is the EC.sub.50 as previously described (DeLean et al., Am.
J. Physiol., 235, E97-E102, 1978). EC.sub.50 is assessed as the
concentration producing 50% of the maximum response to each
agonist.
[0252] Isoproterenol is accepted in the art as a non-selective
.beta..sub.3 agonist and is widely used as a comparator-in
evaluating the activity of compounds. See Trends in Pharm. Sci.,
15:3, 1994. The % intrinsic activity (E.sub.max) of representative
compounds of the invention is assessed relative to isoproterenol by
the compound's maximal response divided by the isoproterenol
maximal response times 100.
[0253] In vitro Rat Atrial Tachycardia
[0254] Male rats (250-350 g) (Harlan Sprague Dawley, Indianapolis,
Ind., USA) are killed by cervical dislocation. Hearts are removed
and the left and right atria are dissected and mounted with thread
in tissue baths containing 10 mls of modified Krebs' solution.
Initial resting tension is 1.5-2.0 g at the outset of the
experiment (Naunyn-Schmied Arch. Pharmacol., 320:145, 1982).
Tissues are allowed to equilibrate approximately 30 minutes with
vigorous oxygenation before exposure to a compound of the
invention.
[0255] To evaluate the ability of test compounds to increase heart
rate, representative compounds of the present invention are added
cumulatively once the atrial rate reached a steady state from the
previous addition. Compound addition is continued until no further
increase in atrial rate occurred or until a concentration of
10.sup.-4M is reached. The increase in beats per minute (bpm) is
measured for each concentration of test compound by means of a
BioPac System (Br. J. of Pharmacol., 126:1018-1024, 1999).
[0256] Utilities
[0257] As agonists of the .beta..sub.3 receptor, a compound of the
present invention is useful in treating conditions in human and
non-human animals in which the .beta..sub.3 receptor has been
demonstrated to play a role. The diseases, disorders or conditions
for which compounds of the present invention are useful in treating
or preventing include, but are not limited to, (1) diabetes
mellitus, (2) hyperglycemia, (3) obesity, (4) hyperlipidemia, (5)
hypertriglyceridemia, (6) hypercholesterolemia, (7) atherosclerosis
of coronary, cerebrovascular and peripheral arteries, (8)
gastrointestinal disorders including peptid ulcer, esophagitis,
gastritis and duodenitis, (including that induced by H. pylori),.
intestinal ulcerations (including inflammatory bowel disease,
ulcerative colitis, Crohn's disease and proctitis) and
gastrointestinal ulcerations, (9) neurogenic inflammation of
airways, including cough, asthma, (10) depression, (11) prostate
diseases such as benign prostate hyperplasia, (12) irritable bowel
syndrome and other disorders needing decreased gut motility, (13)
diabetic retinopathy, (14) neuropathic bladder dysfunction, (15)
elevated intraocular pressure and glaucoma and (16) non-specific
diarrhea dumping syndrome.
[0258] In treating non-human, non-companion animals, the compounds
of the present invention are useful for increasing weight gain
and/or improving the feed utilization efficiency and/or increasing
lean body mass and/or decreasing birth mortality rate and
increasing post/natal survival rate.
[0259] Formulation
[0260] 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 formulation
comprising a compound of formula I and a pharmaceutical
carrier.
[0261] The present pharmaceutical formulations 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 which 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.
[0262] 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.
Formulation Examples
Formulation 1
Tablets
[0263]
11 Ingredient Quantity (mg/tablet) Active Ingredient 5-500
Cellulose, microcrystalline 200-650 Silicon dioxide, fumed 10-650
Stearate acid 5-15
[0264] The components are blended and compressed to form
tablets.
Formulation 2
Suspensions
[0265]
12 Ingredient Quantity (mg/5 ml) Active Ingredient 5-500 mg Sodium
carboxymethyl cellulose 50 mg Syrup 1.25 mg Benzoic acid solution
0.10 ml Flavor q.v. Color q.v. Purified water to 5 ml
[0266] The medicament is passed through a No. 45 mesh U.S. sieve
and mixed with the sodium carboxymethyl cellulose and syrup to form
a smooth paste. The benzoic acid solution, flavor, and color are
diluted with some of the water and added, with stirring. Sufficient
water is then added to produce the required volume.
Formulation 3
Intravenous Solution
[0267]
13 Ingredient Quantity Active Ingredient 25 mg Isotonic saline
1,000 ml
[0268] The solution of the above ingredients is intravenously
administered to a patient at a rate of about 1 ml per minute.
[0269] Dose
[0270] The specific dose administered is determined by the
particular circumstances surrounding each situation. These
circumstances include, the route of administration, the prior
medical history of the recipient, the pathological condition or
symptom being treated, the severity of the condition/symptom being
treated, and the age and sex of the recipient. However, it will be
understood that the therapeutic dosage administered will be
determined by the physician in the light of the relevant
circumstances.
[0271] Generally, an effective minimum daily dose of a compound of
formula I is about 5, 10, 15, or 20 mg. Typically, an effective
maximum dose is about 500, 100, 60, 50, or 40 mg. Most typically,
the dose ranges between 15 mg and 60 mg. The exact dose may be
determined, in accordance with the standard practice in the medical
arts of "dose titrating" the recipient; that is, initially
administering a low dose of the compound, and gradually increasing
the does until the desired therapeutic effect is observed.
[0272] Route of Administration
[0273] The compounds can be administered by a variety of routes
including the oral, rectal, transdermal, subcutaneous, topical,
intravenous, intramuscular or intranasal routes.
[0274] Combination Therapy
[0275] A compound of formula I may be used in combination with
other drugs that are used in the treatment/prevention/suppression
or amelioration of the diseases or conditions for which compounds
of formula I are useful. Such other drug(s) may be administered, by
a route and in an amount commonly used therefor, contemporaneously
or sequentially with a compound of formula I. When a compound of
formula I is used contemporaneously with one or more other drugs, a
pharmaceutical unit dosage form containing such other drugs in
addition to the compound of formula I is preferred. Accordingly,
the pharmaceutical compositions of the present invention include
those that also contain one or more other active ingredients, in
addition to a compound of formula I. Examples of other active
ingredients that may be combined with a compound of formula I,
either administered separately or in the same pharmaceutical
compositions, include, but are not limited to:
[0276] (a) insulin sensitizers including (i) PPAR.gamma. agonists
such as the glitazones (e.g. troglitazone, pioglitazone,
englitazone, MCC-555, BRL49653 and the like), and compounds
disclosed in WO97/27857, 97/28115, 97/28137 and 97/27847; (ii)
biguanides such as metformin and phenformin;
[0277] (b) insulin or insulin mimetics;
[0278] (c) sulfonylureas such as tolbutamide and glipizide;
[0279] (d) alpha-glucosidase inhibitors (such as acarbose);
[0280] (e) cholesterol lowering agents such as
[0281] i. HMG-CoA reductase inhibitors (lovastatin, simvastatin and
pravastatin, fluvastatin, atorvastatin, and other statins),
[0282] ii. sequestrants (cholestyramine, colestipol and a
dialkylaminoalkyl derivatives of a cross-linked dextran),
[0283] iii. nicotinyl alcohol nicotinic acid or a salt thereof,
[0284] iv. proliferator-activator receptor a agonists such as
fenofibric acid derivatives (gemfibrozil, clofibrat, fenofibrate
and benzafibrate),
[0285] v.inhibitors of cholesterol absorption for example
beta-sitosterol and (acyl CoA:cholesterol acyltransferase)
inhibitors for example melinamide,
[0286] vi. probucol,
[0287] vii. vitamin E, and
[0288] viii. thyromimetics;
[0289] (f) PPAR.delta. agonists such as those disclosed in
WO97/28149;
[0290] (g) antiobesity compounds such as fenfluramine,
dexfenfluramine, phentermine, sibutramine, orlistat, and other
.beta..sub.3 adrenergic receptor agonists;
[0291] (h) feeding behavior modifying agents such as neuropeptide Y
antagonists (e.g. neuropeptide Y5) such as those disclosed in WO
97/19682, WO 97/20820, WO 97/20821, WO 97/20822 and WO
97/20823;
[0292] (i) PPAR.alpha. agonists such as described in WO 97/36579 by
Glaxo;
[0293] (j) PPAR.gamma. antagonists as described in WO97/10813;
and
[0294] (k) serotonin reuptake inhibitors such as fluoxetine and
sertraline.
* * * * *