U.S. patent application number 15/969109 was filed with the patent office on 2018-09-06 for compositions, formulations and methods for treating ocular diseases.
The applicant listed for this patent is AERPIO THERAPEUTICS, INC.. Invention is credited to John Janusz, Kevin Peters, Robert Shalwitz, Alexander Smith.
Application Number | 20180251457 15/969109 |
Document ID | / |
Family ID | 51529957 |
Filed Date | 2018-09-06 |
United States Patent
Application |
20180251457 |
Kind Code |
A1 |
Peters; Kevin ; et
al. |
September 6, 2018 |
COMPOSITIONS, FORMULATIONS AND METHODS FOR TREATING OCULAR
DISEASES
Abstract
Disclosed herein are compounds effective for activation of Tie-2
and inhibition of HPTP-beta. The compounds can provide effective
therapy for conditions associated with angiogenesis, for example,
ocular conditions. Formulations for increased solubility are
disclosed. Combination therapy with antibodies and PK/PD data are
also disclosed.
Inventors: |
Peters; Kevin; (Cincinnati,
OH) ; Shalwitz; Robert; (Bexley, OH) ; Janusz;
John; (West Chester, OH) ; Smith; Alexander;
(Apex, NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AERPIO THERAPEUTICS, INC. |
Cincinnati |
OH |
US |
|
|
Family ID: |
51529957 |
Appl. No.: |
15/969109 |
Filed: |
May 2, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15443622 |
Feb 27, 2017 |
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15969109 |
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15098955 |
Apr 14, 2016 |
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15443622 |
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13999670 |
Mar 14, 2014 |
9440963 |
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15098955 |
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61792868 |
Mar 15, 2013 |
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61792679 |
Mar 15, 2013 |
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61882056 |
Sep 25, 2013 |
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61882048 |
Sep 25, 2013 |
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61934570 |
Jan 31, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 47/26 20130101;
C07D 417/04 20130101; A61K 47/6951 20170801; A61P 27/00 20180101;
A61K 9/0051 20130101; C07D 277/28 20130101; A61K 47/40 20130101;
A61K 31/506 20130101; A61K 31/427 20130101; C07K 16/22 20130101;
C07D 277/56 20130101; A61K 2039/505 20130101; A61K 9/0019 20130101;
A61K 31/428 20130101; A61K 31/513 20130101; A61K 31/538 20130101;
C07D 277/64 20130101; A61K 38/179 20130101; A61K 31/4439 20130101;
A61K 2039/54 20130101; C07D 417/12 20130101; A61K 31/426 20130101;
A61K 31/433 20130101; A61P 27/02 20180101; C07D 277/60 20130101;
A61K 31/497 20130101; A61K 31/496 20130101; A61K 39/3955 20130101;
C07D 277/30 20130101; A61K 38/179 20130101; A61K 2300/00
20130101 |
International
Class: |
C07D 417/12 20060101
C07D417/12; C07D 277/56 20060101 C07D277/56; A61K 31/426 20060101
A61K031/426; A61K 38/17 20060101 A61K038/17; A61K 31/538 20060101
A61K031/538; A61K 31/513 20060101 A61K031/513; A61K 31/506 20060101
A61K031/506; A61K 39/395 20060101 A61K039/395; A61K 31/496 20060101
A61K031/496; A61K 31/4439 20060101 A61K031/4439; A61K 31/433
20060101 A61K031/433; A61K 31/428 20060101 A61K031/428; A61K 31/427
20060101 A61K031/427; A61K 31/497 20060101 A61K031/497; C07D 277/30
20060101 C07D277/30; C07D 277/60 20060101 C07D277/60; C07D 417/04
20060101 C07D417/04; C07D 277/64 20060101 C07D277/64 |
Claims
1-54. (canceled)
55. A method of treating an ocular edema in an eye of a subject in
need thereof, the method comprising intravitreally administering to
the subject a pharmaceutical formulation, wherein the
pharmaceutical formulation comprises a therapeutically-effective
amount of a Tie-2 activator, wherein the Tie-2 activator activates
Tie-2 in the eye of the subject, wherein the
therapeutically-effective amount of the Tie-2 activator is from
about 1 mg to about 10 mg; wherein after administration of the
pharmaceutical formulation to the subject, a visual acuity of the
subject increases; wherein the pharmaceutical formulation further
comprises a solubilizing agent; and wherein the method further
comprises inhibiting VEGF in the eye of the subject.
56. The method of claim 55, wherein the therapeutically-effective
amount of the Tie-2 activator is about 1.5 mg.
57. The method of claim 55, wherein the therapeutically-effective
amount of the Tie-2 activator is about 6 mg.
58. The method of claim 55, wherein the solubilizing agent is a
polysorbate.
59. The method of claim 55, wherein the ocular edema is diabetic
macular edema.
60. The method of claim 55, wherein a plasma concentration of the
Tie-2 activator is not less than about 1 ng/mL about 2 hours after
the administration of the pharmaceutical formulation.
61. A method of activating Tie-2 in an eye of a subject in need
thereof, the method comprising intravitreally administering to the
subject a pharmaceutical formulation, wherein the pharmaceutical
formulation comprises a therapeutically-effective amount of a Tie-2
activator, wherein the subject has an ocular edema; wherein the
therapeutically-effective amount of the Tie-2 activator is from
about 1 mg to about 10 mg; wherein after administration of the
pharmaceutical formulation to the subject, a visual acuity of the
subject increases; wherein the pharmaceutical formulation further
comprises a solubilizing agent; and wherein the method further
comprises inhibiting VEGF in the eye of the subject.
62. The method of claim 61, wherein the therapeutically-effective
amount of the Tie-2 activator is about 1.5 mg.
63. The method of claim 61, wherein the therapeutically-effective
amount of the Tie-2 activator is about 6 mg.
64. The method of claim 61, wherein the solubilizing agent is a
polysorbate.
65. The method of claim 61, wherein the ocular edema is diabetic
macular edema.
66. The method of claim 61, wherein a plasma concentration of the
Tie-2 activator is not less than about 1 ng/mL about 2 hours after
the administration of the pharmaceutical formulation.
Description
CROSS REFERENCE
[0001] This application claims the benefit of U.S. Provisional
Application No. 61/792,868, filed Mar. 15, 2013, U.S. Provisional
Application No. 61/792,679, filed Mar. 15, 2013, U.S. Provisional
Application No. 61/882,056, filed Sep. 25, 2013, U.S. Provisional
Application No. 61/882,048, filed Sep. 25, 2013 and U.S.
Provisional Application No. 61/934,570, filed Jan. 31, 2014, each
of which is incorporated herein by reference in its entirety.
FIELD
[0002] Disclosed herein are compositions, formulations, and methods
for treating ocular diseases, inter alia, diabetic macular edema,
age-related macular degeneration (wet form), choroidal
neovascularization, diabetic retinopathy, retinal vein occlusion
(central or branch), ocular trauma, surgery induced edema, surgery
induced neovascularization, cystoid macular edema, ocular ischemia,
uveitis, and the like. These diseases or conditions are
characterized by changes in the ocular vasculature whether
progressive or non-progressive, whether a result of an acute
disease or condition, or a chronic disease or condition.
INCORPORATION BY REFERENCE
[0003] Each patent, publication, and non-patent literature cited in
the application is hereby incorporated by reference in its entirety
as if each was incorporated by reference individually.
BACKGROUND
[0004] The eye comprises several structurally and functionally
distinct vascular beds, which supply ocular components critical to
the maintenance of vision. These include the retinal and choroidal
vasculatures, which supply the inner and outer portions of the
retina, respectively, and the limbal vasculature located at the
periphery of the cornea. Injuries and diseases that impair the
normal structure or function of these vascular beds are among the
leading causes of visual impairment and blindness. For example,
diabetic retinopathy is the most common disease affecting the
retinal vasculature, and is the leading cause of vision loss among
the working age population in the United States. Vascularization of
the cornea secondary to injury or disease is yet another category
of ocular vascular disease that can lead to severe impairment of
vision.
BRIEF DESCRIPTION OF THE DRAWINGS
[0005] FIG. 1 depicts the results of two phase three studies to
determine the effect of intravitreal injections of ranibizumab in
patients with diabetic macular edema.
[0006] FIG. 2 depicts the results of a study wherein 4 patients
received 5 mg of the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-
-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid
subcutaneously twice daily for 28 days and subsequently were
treated in one or both eyes (7 eyes total) with either ranibizumab
(0.3 or 0.5 mg) or aflibercept (2 mg) by intravitreal injection at
the discretion of the study investigator.
[0007] FIG. 3 depicts the results of phase three studies to
determine the effect of intravitreal injections of ranibizumab in
patients with diabetic macular edema.
[0008] FIG. 4 depicts the increased visual acuity of a study
wherein 4 patients received 5 mg of the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid subcutaneously twice
daily for 28 days and subsequently were treated with either
ranibizumab (0.3 or 0.5 mg) or aflibercept (2 mg) by intravitreal
injection.
[0009] FIG. 5 graphs changes in central foveal thickness over time
in an eye treated with a drug/antibody combination.
[0010] FIG. 6 graphs changes in central foveal thickness over time
in an eye treated with a drug/antibody combination.
[0011] FIG. 7 is a graphic representation of in vivo experiments
performed in 6 week old C57BL/6 mice.
[0012] FIG. 8A illustrates the extent of choroidal
neovascularization evident in a control sample stained with
FITC-labeled Griffonia simplicifolia (GSA) of the experiment of
FIG. 7.
[0013] FIG. 8B represents the extent of neovascularization in the
choroidal tissue of animals treated with aflibercept, stained with
FITC-labeled Griffonia simplicifolia (GSA).
[0014] FIG. 8C represents the extent of neovascularization in
tissue treated with a Tie-2 signaling enhancer, tissue stained with
FITC-labeled Griffonia simplicifolia (GSA).
[0015] FIG. 8D represents the extent of neovascularization present
in tissue receiving a combined therapy of aflibercept and the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid, stained with
FITC-labeled Griffonia simplicifolia (GSA).
[0016] FIG. 9 shows the plasma concentration of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid, pre-dose(0), 15
minutes, 1 hour, 2 hours, 3 hours and 4 hours after administration
after the first dose on day 14.
SUMMARY OF THE INVENTION
[0017] In some embodiments, the invention provides a method of
treating a condition in a subject in need thereof, the method
comprising administering to the subject a therapeutically-effective
amount of a compound that activates Tie-2, or a
pharmaceutically-acceptable salt thereof, and an agent that
increases solubility of the compound that activates Tie-2, or the
pharmaceutically-acceptable salt thereof as compared to solubility
in absence of the agent.
[0018] In some embodiments, the invention provides a method of
treating a condition in a subject in need thereof, the method
comprising administering to the subject a therapeutically-effective
amount of a compound that activates Tie-2, or a
pharmaceutically-acceptable salt thereof, wherein the
administration provides a plasma concentration in the subject of
the compound that activates Tie-2 or the
pharmaceutically-acceptable salt thereof of about 25 ng/mL to about
500 ng/mL.
[0019] In some embodiments, the invention provides a pharmaceutical
composition comprising: a) a compound that activates Tie-2, or a
pharmaceutically-acceptable salt thereof; and b) an agent that
improves the aqueous solubility of the compound that activates
Tie-2, or the pharmaceutically-acceptable salt thereof.
[0020] In some embodiments, the invention provides a pharmaceutical
composition comprising: a) a Tie-2 activator or a
pharmaceutically-acceptable salt thereof; and b) an antibody.
[0021] In some embodiments, the invention provides a kit
comprising: a) a Tie-2 activator or a pharmaceutically-acceptable
salt thereof; b) an antibody; and c) written instructions on use of
the kit in treatment of a condition.
[0022] In some embodiments, the invention provides a method of
treating a condition, the method comprising administering to a
subject in need thereof: a) a therapeutically-effective amount of a
Tie-2 activator or a pharmaceutically-acceptable salt thereof; and
b) a therapeutically-effective amount of an antibody.
[0023] In some embodiments, the invention provides a complex
comprising: a) a Tie-2 activator, or a pharmaceutically-acceptable
salt thereof; and b) a molecule comprising a channel, wherein the
compound that activates Tie-2, or the pharmaceutically-acceptable
salt thereof is held in the channel of the molecule by non-covalent
interactions.
[0024] In some embodiments, the invention provides a method of
treating a condition, the method comprising administering to a
subject in need thereof a therapeutically-effective amount of
complex comprising: a) a Tie-2 activator, or a
pharmaceutically-acceptable salt thereof; and b) a molecule
comprising a channel, wherein the compound that activates Tie-2, or
the pharmaceutically-acceptable salt thereof is held in the channel
of the molecule by non-covalent interactions.
DETAILED DESCRIPTION
[0025] Provided herein are compounds and methods of treating ocular
disorders that are characterized by vascular instability, vascular
leakage, and neovascularization. HPTP-.beta. is a member of the
receptor-like family of the protein tyrosine phosphatases
(PTPases). HPTP-.beta. is a transmembrane protein found primarily
in endothelial cells that displays structural and functional
similarity to cell adhesion molecules (CAMs). HPTP-.beta. is unique
among receptor-like PTPases in that it contains a single catalytic
domain. One of the main functions of HPTP-.beta. is to regulate
Tie-2 negatively.
[0026] Tie-2 is a receptor tyrosine kinase found almost exclusively
in endothelial cells. The principle regulators of Tie-2
phosphorylation are Angiopoietin-1 (Ang-1) and Angiopoietin-2
(Ang-2). Upon Angiopoietin-1 binding to Tie-2, the level of Tie-2
receptor phosphorylation increases. The duration of Tie-2 receptor
phosphorylation is regulated by HPTP-.beta., which cleaves off the
phosphate. Tie-2 receptor phosphorylation helps maintain
endothelial cell proximity; therefore, the duration of Tie-2
receptor phosphorylation is an important determinant of endothelial
cell proximity. For example, when severe inflammation occurs, the
capillary endothelial cells separate, allowing proteins, to enter
the interstitial space. Separation of the capillary endothelial
cells, and subsequent leak of proteins in the interstitial space,
is known as vascular leak and can lead to dangerous hypotension
(low blood pressure), edema, hemoconcentration, and
hypoalbuminemia. Inhibition of HPTP-.beta. leads to increased
levels and Tie-2 receptor phosphorylation, a process that can
maintain or restore capillary endothelial cell proximity.
[0027] The present disclosure relates to compositions and methods
for treating conditions, such as ocular diseases, for example,
those wherein neovasculatization and vascular leakage are present.
These diseases are sometimes characterized as diseases wherein
there is an elevated angiogenic response in the vessels associated
with the eye. The present disclosure provides a Human Protein
Tyrosine Phosphatase-beta (HPTP-.beta.) inhibitor that provides
vascular stabilization.
Human Protein Tyrosine Phosphatase-Beta (HPTP-.beta.)
Inhibitors.
[0028] Compounds disclosed herein can be effective as Tie-2
activators. The compounds can effect that activity, for example, by
binding or inhibiting HPTP-.beta. Such compounds can bind, for
example, by mimicking the binding mechanism of a native substrate,
such as a phosphorylated compound. A compound can be a phosphate
mimetic or bioisostere, for example, a sulfamic acid. The compound
could also be derived from an amino acid building block or comprise
an amino acid backbone for efficiency and economy of synthesis.
[0029] In some embodiments, a compound of the invention is a
compound of formula:
##STR00001##
wherein: Aryl.sup.1 is an aryl group which is substituted or
unsubstituted; Aryl.sup.2 is an aryl group which is substituted or
unsubstituted; X is alkylene, alkenylene, alkynylene, an ether
linkage, an amine linkage, an amide linkage, an ester linkage, a
thioether linkage, a carbamate linkage, a carbonate linkage, a
urethane linkage, a sulfone linkage, any of which is substituted or
unsubstituted, or a chemical bond; and Y is H, aryl, heteroaryl,
NH(aryl), NH(heteroaryl), NHSO.sub.2R.sup.g, or NHCOR.sup.g, any of
which is substituted or unsubstituted or
##STR00002##
wherein L.sup.2 is alkylene, alkenylene, or alkynylene, any of
which is substituted or unsubstituted, or together with the
nitrogen atom to which L is bound forms an amide linkage, a
carbamate linkage, a urethane linkage, or a sulfonamide linkage, or
a chemical bond, or together with any of R.sup.a, R.sup.b, R.sup.c,
and R.sup.d forms a ring that is substituted or unsubstituted.
R.sup.a is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl,
heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl,
any of which is substituted or unsubstituted, or together with any
of L.sup.2, R.sup.b, R.sup.c, and R.sup.d forms a ring that is
substituted or unsubstituted. R.sup.b is H, alkyl, alkenyl,
alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,
heteroaryl, or heteroarylalkyl, any of which is substituted or
unsubstituted, or together with any of L.sup.2, R.sup.a, R.sup.c,
and R.sup.d forms a ring that is substituted or unsubstituted.
R.sup.c is H or alkyl which is substituted or unsubstituted, or
together with any of L.sup.2, R.sup.a, R.sup.b, and R.sup.d forms a
ring that is substituted or unsubstituted. R.sup.d is H or alkyl
which is substituted or unsubstituted, or together with any of
L.sup.2, R.sup.a, R.sup.b, and R.sup.c forms a ring that is
substituted or unsubstituted, and R.sup.g is H, alkyl, alkenyl,
alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,
heteroaryl, or heteroarylalkyl, any of which is substituted or
unsubstituted, or a pharmaceutically-acceptable salt, tautomer, or
zwitterion thereof.
[0030] In some embodiments, aryl.sup.1 is substituted or
unsubstituted phenyl, aryl.sup.2 is substituted or unsubstituted
heteroaryl, and X is alkylene. In some embodiments, aryl.sup.1 is
substituted phenyl, aryl.sup.2 is substituted heteroaryl, and X is
methylene.
[0031] In some embodiments, a compound is of the formula:
##STR00003##
wherein wherein aryl.sup.1 is para-substituted phenyl, aryl.sup.2
is substituted heteroaryl, X is methylene. L.sup.2 is alkylene,
alkenylene, or alkynylene, any of which is substituted or
unsubstituted, or together with the nitrogen atom to which L is
bound forms an amide linkage, a carbamate linkage, a urethane
linkage, or a sulfonamide linkage, or a chemical bond. R.sup.a is
H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is
substituted or unsubstituted. R.sup.b is H, alkyl, alkenyl,
alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,
heteroaryl, or heteroarylalkyl, any of which is substituted or
unsubstituted. R.sup.c is H or alkyl which is substituted or
unsubstituted, and R.sup.d is H or alkyl which is substituted or
unsubstituted.
[0032] In some embodiments, aryl.sup.1 is para-substituted phenyl,
aryl.sup.2 is a substituted thiazole moiety. X is methylene,
L.sup.2 together with the nitrogen atom to which L is bound forms a
carbamate linkage, R.sup.a is alkyl, which is substituted or
unsubstituted, R.sup.b is arylalkyl, which is substituted or
unsubstituted, R.sup.c is H, and R.sup.d is H.
[0033] In some embodiments, Aryl.sup.2 is:
##STR00004##
wherein R.sup.e is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl,
alkynyl, an alkoxy group, an ether group, a carboxylic acid group,
a carboxaldehyde group, an ester group, an amine group, an amide
group, a carbonate group, a carbamate group, a urethane group, a
thioether group, a thioester group, a thioacid group, aryl,
arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or
heteroarylalkyl, any of which is substituted or unsubstituted, and
R.sup.f is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an
alkoxy group, an ether group, a carboxylic acid group, a
carboxaldehyde group, an ester group, an amine group, an amide
group, a carbonate group, a carbamate group, a urethane group, a
thioether group, a thioester group, a thioacid group, aryl,
arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or
heteroarylalkyl, any of which is substituted or unsubstituted.
[0034] In some embodiments, R.sup.e is H, OH, F, Cl, Br, I, alkyl,
an alkoxy group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,
heteroaryl, or heteroarylalkyl, any of which is substituted or
unsubstituted, and R.sup.f is H, OH, F, Cl, Br, I, alkyl, an alkoxy
group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,
heteroaryl, or heteroarylalkyl, any of which is substituted or
unsubstituted. In some embodiments, R.sup.e is H, OH, F, Cl, Br, I,
alkyl, or an alkoxy group, any of which is substituted or
unsubstituted and R.sup.f is alkyl, aryl, heterocyclyl, or
heteroaryl, any of which is substituted or unsubstituted. In some
embodiments, aryl.sup.1 is 4-phenylsulfamic acid, R.sup.a is alkyl,
which is substituted or unsubstituted, R.sup.b is arylalkyl, which
is substituted or unsubstituted, R.sup.e is H; and R.sup.f is
heteroaryl. In some embodiments, aryl.sup.1 is 4-phenylsulfamic
acid, R.sup.a is alkyl, which is substituted or unsubstituted,
R.sup.b is arylalkyl, which is substituted or unsubstituted,
R.sup.e is H; and R.sup.f is alkyl
[0035] In some embodiments, Aryl.sup.2 is:
##STR00005##
wherein R.sup.e is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl,
alkynyl, an alkoxy group, an ether group, a carboxylic acid group,
a carboxaldehyde group, an ester group, an amine group, an amide
group, a carbonate group, a carbamate group, a urethane group, a
thioether group, a thioester group, a thioacid group, aryl,
arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or
heteroarylalkyl, any of which is substituted or unsubstituted,
R.sup.f is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an
alkoxy group, an ether group, a carboxylic acid group, a
carboxaldehyde group, an ester group, an amine group, an amide
group, a carbonate group, a carbamate group, a urethane group, a
thioether group, a thioester group, a thioacid group, aryl,
arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or
heteroarylalkyl, any of which is substituted or unsubstituted. In
some embodiments, R.sup.e is H, OH, F, Cl, Br, I, alkyl, an alkoxy
group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,
heteroaryl, or heteroarylalkyl, any of which is substituted or
unsubstituted and R.sup.f is H, OH, F, Cl, Br, I, alkyl, an alkoxy
group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,
heteroaryl, or heteroarylalkyl, any of which is substituted or
unsubstituted. In some embodiments, R.sup.e is H, OH, F, Cl, Br, I,
alkyl, or an alkoxy group, any of which is substituted or
unsubstituted and R.sup.f is alkyl, aryl, heterocyclyl, or
heteroaryl, any of which is substituted or unsubstituted. In some
embodiments, aryl.sup.1 is 4-phenylsulfamic acid, R.sup.a is alkyl,
which is substituted or unsubstituted, R.sup.b is arylalkyl, which
is substituted or unsubstituted, R.sup.e is H; and R.sup.f is
heteroaryl.
[0036] In some embodiments, a substituted phenyl group is:
##STR00006##
wherein: each of R.sup.ph1, R.sup.ph2, R.sup.ph3, R.sup.ph4, and
R.sup.ph5 is independently H, OH, F, Cl, Br, I, CN, sulamic acid,
tosylate, mesylate, triflate, besylate, alkyl, alkenyl, alkynyl, an
alkoxy group, a sulfhydryl group, a nitro group, a nitroso group,
an azido group, a sulfoxide group, a sulfone group, a sulfonamide
group, an ether group, a carboxylic acid group, a carboxaldehyde
group, an ester group, an amine group, an amide group, a carbonate
group, a carbamate group, a urethane group, a thioether group, a
thioester group, a thioacid group, aryl, arylalkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl, or heteroarylalkyl
Optional Substituents for Chemical Groups.
[0037] Non-limiting examples of optional substituents include
hydroxyl groups, sulfhydryl groups, halogens, amino groups, nitro
groups, nitroso groups, cyano groups, azido groups, sulfoxide
groups, sulfone groups, sulfonamide groups, carboxyl groups,
carboxaldehyde groups, imine groups, alkyl groups, halo-alkyl
groups, alkenyl groups, halo-alkenyl groups, alkynyl groups,
halo-alkynyl groups, alkoxy groups, aryl groups, aryloxy groups,
aralkyl groups, arylalkoxy groups, heterocyclyl groups, acyl
groups, acyloxy groups, carbamate groups, amide groups, urethane
groups, and ester groups.
[0038] The following are non-limiting examples of units which can
substitute for hydrogen atoms: [0039] i) C.sub.1-C.sub.12 linear,
branched, or cyclic alkyl, alkenyl, and alkynyl; methyl (C.sub.1),
ethyl (C.sub.2), ethenyl (C.sub.2), ethynyl (C.sub.2), n-propyl
(C.sub.3), iso-propyl (C.sub.3), cyclopropyl (C.sub.3), 3-propenyl
(C.sub.3), 1-propenyl (also 2-methylethenyl) (C.sub.3), isopropenyl
(also 2-methylethen-2-yl) (C.sub.3), prop-2-ynyl (also propargyl)
(C.sub.3), propyn-1-yl (C.sub.3), n-butyl (C.sub.4), sec-butyl
(C.sub.4), iso-butyl (C.sub.4), tert-butyl (C.sub.4), cyclobutyl
(C.sub.4), buten-4-yl (C.sub.4), cyclopentyl (C.sub.5), cyclohexyl
(C.sub.6); [0040] ii) substituted or unsubstituted C.sub.6 or
C.sub.10 aryl; for example, phenyl, naphthyl (also referred to
herein as naphthylen-1-yl (C.sub.10) or naphthylen-2-yl
(C.sub.10)); [0041] iii) substituted or unsubstituted C.sub.6 or
C.sub.10 alkylenearyl; for example, benzyl, 2-phenylethyl,
naphthylen-2-ylmethyl; [0042] iv) substituted or unsubstituted
C.sub.1-C.sub.9 heterocyclic rings; [0043] v) substituted or
unsubstituted C.sub.1-C.sub.9 heteroaryl rings; [0044] vi)
--(CR.sup.102aR.sup.102b).sub.aOR.sup.101; for example, --OH,
--CH.sub.2OH, --OCH.sub.3, --CH.sub.2OCH.sub.3,
--OCH.sub.2CH.sub.3, --CH.sub.2OCH.sub.2CH.sub.3,
--OCH.sub.2CH.sub.2CH.sub.3, and
--CH.sub.2OCH.sub.2CH.sub.2CH.sub.3; [0045] vii)
--(CR.sup.102aR.sup.102b).sub.aC(O)R.sup.101; for example,
--COCH.sub.3, --CH.sub.2COCH.sub.3, --COCH.sub.2CH.sub.3,
--CH.sub.2COCH.sub.2CH.sub.3, --COCH.sub.2CH.sub.2CH.sub.3, and
--CH.sub.2COCH.sub.2CH.sub.2CH.sub.3; [0046] viii)
--(CR.sup.102aR.sup.102b).sub.aC(O)OR.sup.101; for example,
--CO.sub.2CH.sub.3, --CH.sub.2CO.sub.2CH.sub.3,
--CO.sub.2CH.sub.2CH.sub.3, --CH.sub.2CO.sub.2CH.sub.2CH.sub.3,
--CO.sub.2CH.sub.2CH.sub.2CH.sub.3, and
--CH.sub.2CO.sub.2CH.sub.2CH.sub.2CH.sub.3; [0047] ix)
--(CR.sup.102aR.sup.102b).sub.aC(O)N(R.sup.101).sub.2; for example,
--CONH.sub.2, --CH.sub.2CONH.sub.2, --CONHCH.sub.3,
--CH.sub.2CONHCH.sub.3, --CON(CH.sub.3).sub.2, and
--CH.sub.2CON(CH.sub.3).sub.2; [0048] x)
--(CR.sup.102aR.sup.102b).sub.aN(R.sup.101).sub.2; for example,
--NH.sub.2, --CH.sub.2NH.sub.2, --NHCH.sub.3, --CH.sub.2NHCH.sub.3,
--N(CH.sub.3).sub.2, and --CH.sub.2N(CH.sub.3).sub.2; [0049] xi)
halogen; --F, --Cl, --Br, and --I; [0050] xii)
--(CR.sup.102aR.sup.102b).sub.aCN; [0051] xiii)
--(CR.sup.102aR.sup.102b).sub.aNO.sub.2; [0052] xiv)
--CH.sub.jX.sub.k; wherein X is halogen, the index j is an integer
from 0 to 2, j+k=3; for example, --CH.sub.2F, --CHF.sub.2,
--CF.sub.3, --CCl.sub.3, or --CBr.sub.3; [0053] xv)
--(CR.sup.102aR.sup.102b).sub.aSR.sup.101; --SH, --CH.sub.2SH,
--SCH.sub.3, --CH.sub.2SCH.sub.3, --SC.sub.6H.sub.5, and
--CH.sub.2SC.sub.6H.sub.5; [0054] xvi)
--(CR.sup.102aR.sup.102b).sub.aSO.sub.2R.sup.101; for example,
--SO.sub.2H, --CH.sub.2SO.sub.2H, --SO.sub.2CH.sub.3,
--CH.sub.2SO.sub.2CH.sub.3, --SO.sub.2C.sub.6H.sub.5, and
--CH.sub.2SO.sub.2C.sub.6H.sub.5; and [0055] xvii)
--(CR.sup.102aR.sup.102b).sub.aSO.sub.3R.sup.101; for example,
--SO.sub.3H, --CH.sub.2SO.sub.3H, --SO.sub.3CH.sub.3,
--CH.sub.2SO.sub.3CH.sub.3, --SO.sub.3C.sub.6H.sub.5, and
--CH.sub.2SO.sub.3C.sub.6H.sub.5; wherein each R.sup.101 is
independently hydrogen, substituted or unsubstituted
C.sub.1-C.sub.6 linear, branched, or cyclic alkyl, phenyl, benzyl,
heterocyclic, or heteroaryl; or two R.sup.101 units can be taken
together to form a ring comprising 3-7 atoms; R.sup.102a and
R.sup.102b are each independently hydrogen or C.sub.1-C.sub.4
linear or branched alkyl; the index "a" is from 0 to 4.
[0056] Non-limiting examples of alkyl and alkylene groups include
straight, branched, and cyclic alkyl and alkylene groups. An alkyl
group can be, for example, a C.sub.1, C.sub.2, C.sub.3, C.sub.4,
C.sub.5, C.sub.6, C.sub.7, C.sub.8, C.sub.9, C.sub.10, C.sub.11,
C.sub.12, C.sub.13, C.sub.14, C.sub.15, C.sub.16, C.sub.17,
C.sub.18, C.sub.19, C.sub.20, C.sub.21, C.sub.22, C.sub.23,
C.sub.24, C.sub.25, C.sub.26, C.sub.27, C.sub.28, C.sub.29,
C.sub.30, C.sub.31, C.sub.32, C.sub.33, C.sub.34, C.sub.35,
C.sub.36, C.sub.37, C.sub.38, C.sub.39, C.sub.40, C.sub.41,
C.sub.42, C.sub.43, C.sub.44, C.sub.45, C.sub.46, C.sub.47,
C.sub.48, C.sub.49, or C.sub.50 group that is substituted or
unsubstituted.
[0057] Non-limiting examples of straight alkyl groups include
methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl,
and decyl.
[0058] Branched alkyl groups include any straight alkyl group
substituted with any number of alkyl groups. Non-limiting examples
of branched alkyl groups include isopropyl, isobutyl, sec-butyl,
and t-butyl.
[0059] Non-limiting examples of cyclic alkyl groups include
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptlyl, and
cyclooctyl groups. Cyclic alkyl groups also include fused-,
bridged-, and spiro-bicycles and higher fused-, bridged-, and
spiro-systems. A cyclic alkyl group can be substituted with any
number of straight, branched, or cyclic alkyl groups.
[0060] Non-limiting examples of alkenyl and alkenylene groups
include straight, branched, and cyclic alkenyl groups. The olefin
or olefins of an alkenyl group can be, for example, E, Z, cis,
trans, terminal, or exo-methylene. An alkenyl or alkenylene group
can be, for example, a C.sub.2, C.sub.3, C.sub.4, C.sub.5, C.sub.6,
C.sub.7, C.sub.8, C.sub.9, C.sub.10, C.sub.11, C.sub.12, C.sub.13,
C.sub.14, C.sub.15, C.sub.16, C.sub.17, C.sub.18, C.sub.19,
C.sub.20, C.sub.21, C.sub.22, C.sub.23, C.sub.24, C.sub.25,
C.sub.26, C.sub.27, C.sub.28, C.sub.29, C.sub.30, C.sub.31,
C.sub.32, C.sub.33, C.sub.34, C.sub.35, C.sub.36, C.sub.37,
C.sub.38, C.sub.39, C.sub.40, C.sub.41, C.sub.42, C.sub.43,
C.sub.44, C.sub.45, C.sub.46, C.sub.47, C.sub.48, C.sub.49, or
C.sub.50 group that is substituted or unsubstituted.
[0061] Non-limiting examples of alkynyl or alkynylene groups
include straight, branched, and cyclic alkynyl groups. The triple
bond of an alkylnyl or alkynylene group can be internal or
terminal. An alkylnyl or alkynylene group can be, for example, a
C.sub.2, C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.7, C.sub.8,
C.sub.9, C.sub.10, C.sub.11, C.sub.12, C.sub.13, C.sub.14,
C.sub.15, C.sub.16, C.sub.17, C.sub.18, C.sub.19, C.sub.20,
C.sub.21, C.sub.22, C.sub.23, C.sub.24, C.sub.25, C.sub.26,
C.sub.27, C.sub.28, C.sub.29, C.sub.30, C.sub.31, C.sub.32,
C.sub.33, C.sub.34, C.sub.35, C.sub.36, C.sub.37, C.sub.38,
C.sub.39, C.sub.40, C.sub.41, C.sub.42, C.sub.43, C.sub.44,
C.sub.45, C.sub.46, C.sub.47, C.sub.48, C.sub.49, or C.sub.50 group
that is substituted or unsubstituted.
[0062] Non-limiting examples of substituted and unsubstituted
acyclic hydrocarbyl include: [0063] 1) linear or branched alkyl,
non-limiting examples of which include, methyl (C.sub.1), ethyl
(C.sub.2), n-propyl (C.sub.3), iso-propyl (C.sub.3), n-butyl
(C.sub.4), sec-butyl (C.sub.4), iso-butyl (C.sub.4), tert-butyl
(C.sub.4), and the like; substituted linear or branched alkyl,
non-limiting examples of which includes, hydroxymethyl (C.sub.1),
chloromethyl (C.sub.1), trifluoromethyl (C.sub.1), aminomethyl
(C.sub.1), 1-chloroethyl (C.sub.2), 2-hydroxyethyl (C.sub.2),
1,2-difluoroethyl (C.sub.2), and 3-carboxypropyl (C.sub.3). [0064]
2) linear or branched alkenyl, non-limiting examples of which
include, ethenyl (C.sub.2), 3-propenyl (C.sub.3), 1-propenyl (also
2-methylethenyl) (C.sub.3), isopropenyl (also 2-methylethen-2-yl)
(C.sub.3), buten-4-yl (C.sub.4), and the like; substituted linear
or branched alkenyl, non-limiting examples of which include,
2-chloroethenyl (also 2-chlorovinyl) (C.sub.2), 4-hydroxybuten-1-yl
(C.sub.4), 7-hydroxy-7-methyloct-4-en-2-yl (C.sub.9), and
7-hydroxy-7-methyloct-3,5-dien-2-yl (C.sub.9). [0065] 3) linear or
branched alkynyl, non-limiting examples of which include, ethynyl
(C.sub.2), prop-2-ynyl (also propargyl) (C.sub.3), propyn-1-yl
(C.sub.3), and 2-methyl-hex-4-yn-1-yl (C.sub.7); substituted linear
or branched alkynyl, non-limiting examples of which include,
5-hydroxy-5-methylhex-3-ynyl (C.sub.7),
6-hydroxy-6-methylhept-3-yn-2-yl (C.sub.8), and
5-hydroxy-5-ethylhept-3-ynyl (C.sub.9).
[0066] Non-limiting examples of substituted and unsubstituted
cyclic hydrocarbyl include: rings comprising from 3 to 20 carbon
atoms, wherein the atoms which comprise said rings are limited to
carbon atoms, and further each ring can be independently
substituted with one or more moieties capable of replacing one or
more hydrogen atoms. The following are non-limiting examples of
substituted and unsubstituted carbocyclic rings:
i) carbocyclic rings having a single substituted or unsubstituted
hydrocarbon ring, non-limiting examples of which include,
cyclopropyl (C.sub.3), 2-methyl-cyclopropyl (C.sub.3),
cyclopropenyl (C.sub.3), cyclobutyl (C.sub.4),
2,3-dihydroxycyclobutyl (C.sub.4), cyclobutenyl (C.sub.4),
cyclopentyl (C.sub.5), cyclopentenyl (C.sub.5), cyclopentadienyl
(C.sub.5), cyclohexyl (C.sub.6), cyclohexenyl (C.sub.6),
cycloheptyl (C.sub.7), cyclooctanyl (C.sub.8),
2,5-dimethylcyclopentyl (C.sub.5), 3,5-dichlorocyclohexyl
(C.sub.6), 4-hydroxycyclohexyl (C.sub.6), and
3,3,5-trimethylcyclohex-1-yl (C.sub.6). ii) carbocyclic rings
having two or more substituted or unsubstituted fused hydrocarbon
rings, non-limiting examples of which include, octahydropentalenyl
(C.sub.8), octahydro-1H-indenyl (C.sub.9),
3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl (C.sub.9), decahydroazulenyl
(C.sub.10). iii) carbocyclic rings which are substituted or
unsubstituted bicyclic hydrocarbon rings, non-limiting examples of
which include, bicyclo-[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl,
bicyclo[3.1.1]heptanyl, 1,3-dimethyl[2.2.1]heptan-2-yl,
bicyclo[2.2.2]octanyl, and bicyclo[3.3.3]undecanyl.
[0067] Also included are C.sub.1-C.sub.6 tethered cyclic
hydrocarbyl units (whether carbocyclic units, C.sub.6 or C.sub.10
aryl units, heterocyclic units, or heteroaryl units) can be
connected to another moiety, unit, or core of the molecule by way
of a C.sub.1-C.sub.6 alkylene unit. Non-limiting examples of
tethered cyclic hydrocarbyl units include benzyl C.sub.1-(C.sub.6)
having the formula:
##STR00007##
wherein R.sup.a is optionally one or more independently chosen
substitutions for hydrogen. Further examples include other aryl
units, inter alia, (2-hydroxyphenyl)hexyl C.sub.6-(C.sub.6);
naphthalen-2-ylmethyl C.sub.1-(C.sub.10), 4-fluorobenzyl
C.sub.1-(C.sub.6), 2-(3-hydroxyphenyl)ethyl C.sub.2-(C.sub.6), as
well as substituted and unsubstituted C.sub.3-C.sub.10
alkylenecarbocyclic units, for example, cyclopropylmethyl
C.sub.1-(C.sub.3), cyclopentylethyl C.sub.2-(C.sub.5),
cyclohexylmethyl C.sub.1-(C.sub.6). Included within this category
are substituted and unsubstituted C.sub.1-C.sub.10
alkylene-heteroaryl units, for example a 2-picolyl
C.sub.1-(C.sub.6) unit having the formula:
##STR00008##
wherein R.sup.a is the same as defined above. In addition,
C.sub.1-C.sub.12 tethered cyclic hydrocarbyl units include
C.sub.1-C.sub.10 alkyleneheterocyclic units and alkylene-heteroaryl
units, non-limiting examples of which include, aziridinylmethyl
C.sub.1-(C.sub.2) and oxazol-2-ylmethyl C.sub.1-(C.sub.3).
[0068] A halo group can be any halogen atom, for example, fluorine,
chlorine, bromine, or iodine.
[0069] A halo-alkyl group can be any alkyl group substituted with
any number of halogen atoms, for example, fluorine, chlorine,
bromine, and iodine atoms. A halo-alkenyl group can be any alkenyl
group substituted with any number of halogen atoms. A halo-alkynyl
group can be any alkynyl group substituted with any number of
halogen atoms.
[0070] An alkoxy group can be, for example, an oxygen atom
substituted with any alkyl, alkenyl, or alkynyl group. An ether or
an ether group comprises an alkoxy group. Non-limiting examples of
alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, and
isobutoxy.
[0071] An aryl group can be heterocyclic or non-heterocyclic. An
aryl group can be monocyclic or polycyclic. An aryl group can be
substituted with any number of substituents described herein, for
example, hydrocarbyl groups, alkyl groups, alkoxy groups, and
halogen atoms. Non-limiting examples of aryl groups include phenyl,
toluyl, naphthyl, pyrrolyl, pyridyl, imidazolyl, thiophenyl, and
furyl.
[0072] Non-limiting examples of aryl groups can include: i) C.sub.6
or C.sub.10 substituted or unsubstituted aryl rings; phenyl and
naphthyl rings whether substituted or unsubstituted, non-limiting
examples of which include, phenyl (C.sub.6), naphthylen-1-yl
(C.sub.10), naphthylen-2-yl (C.sub.10), 4-fluorophenyl (C.sub.6),
2-hydroxyphenyl (C.sub.6), 3-methylphenyl (C.sub.6),
2-amino-4-fluorophenyl (C.sub.6), 2-(N,N-diethylamino)phenyl
(C.sub.6), 2-cyanophenyl (C.sub.6), 2,6-di-tert-butylphenyl
(C.sub.6), 3-methoxyphenyl (C.sub.6), 8-hydroxynaphthylen-2-yl
(C.sub.10), 4,5-dimethoxynaphthylen-1-yl (C.sub.10), and
6-cyano-naphthylen-1-yl (C.sub.10); and ii) C.sub.6 or C.sub.10
aryl rings fused with 1 or 2 saturated rings to afford
C.sub.8-C.sub.20 ring systems, non-limiting examples of which
include, bicyclo[4.2.0]octa-1,3,5-trienyl (C.sub.8), and indanyl
(C.sub.9).
[0073] An aryloxy group can be, for example, an oxygen atom
substituted with any aryl group, such as phenoxy.
[0074] An aralkyl group can be, for example, any alkyl group
substituted with any aryl group, such as benzyl.
[0075] An arylalkoxy group can be, for example, an oxygen atom
substituted with any aralkyl group, such as benzyloxy.
[0076] A heterocycle can be any ring containing a ring atom that is
not carbon, for example, N, O, S, P, Si, B, or any other
heteroatom. A heterocycle can be substituted with any number of
substituents, for example, alkyl groups and halogen atoms. A
heterocycle can be aromatic (heteroaryl) or non-aromatic.
Non-limiting examples of heterocycles include pyrrole, pyrrolidine,
pyridine, piperidine, succinamide, maleimide, morpholine,
imidazole, thiophene, furan, tetrahydrofuran, pyran, and
tetrahydropyran.
[0077] Non-limiting examples of heterocycles include: heterocyclic
units having a single ring containing one or more heteroatoms,
non-limiting examples of which include, diazirinyl (C.sub.1),
aziridinyl (C.sub.2), urazolyl (C.sub.2), azetidinyl (C.sub.3),
pyrazolidinyl (C.sub.3), imidazolidinyl (C.sub.3), oxazolidinyl
(C.sub.3), isoxazolinyl (C.sub.3), thiazolidinyl (C.sub.3),
isothiazolinyl (C.sub.3), oxathiazolidinonyl (C.sub.3),
oxazolidinonyl (C.sub.3), hydantoinyl (C.sub.3), tetrahydrofuranyl
(C.sub.4), pyrrolidinyl (C.sub.4), morpholinyl (C.sub.4),
piperazinyl (C.sub.4), piperidinyl (C.sub.4), dihydropyranyl
(C.sub.5), tetrahydropyranyl (C.sub.5), piperidin-2-onyl
(valerolactam) (C.sub.5), 2,3,4,5-tetrahydro-1H-azepinyl (C.sub.6),
2,3-dihydro-1H-indole (C.sub.8), and 1,2,3,4-tetrahydroquinoline
(C.sub.9); and ii) heterocyclic units having 2 or more rings one of
which is a heterocyclic ring, non-limiting examples of which
include hexahydro-1H-pyrrolizinyl (C.sub.7),
3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazolyl (C.sub.7),
3a,4,5,6,7,7a-hexahydro-1H-indolyl (C.sub.8),
1,2,3,4-tetrahydroquinolinyl (C.sub.9), and
decahydro-1H-cycloocta[b]pyrrolyl (C.sub.10).
[0078] Non-limiting examples of heteroaryl include: i) heteroaryl
rings containing a single ring, non-limiting examples of which
include, 1,2,3,4-tetrazolyl (C.sub.1), [1,2,3]triazolyl (CA),
[1,2,4]triazolyl (C.sub.2), triazinyl (C.sub.3), thiazolyl
(C.sub.3), 1H-imidazolyl (C.sub.3), oxazolyl (C.sub.3), isoxazolyl
(C.sub.3), isothiazolyl (C.sub.3), furanyl (C.sub.4), thiophenyl
(C.sub.4), pyrimidinyl (C.sub.4), 2-phenylpyrimidinyl (C.sub.4),
pyridinyl (C.sub.5), 3-methylpyridinyl (C.sub.5), and
4-dimethylaminopyridinyl (C.sub.5); and ii) heteroaryl rings
containing 2 or more fused rings one of which is a heteroaryl ring,
non-limiting examples of which include: 7H-purinyl (C.sub.5),
9H-purinyl (C.sub.5), 6-amino-9H-purinyl (C.sub.5),
5H-pyrrolo[3,2-d]pyrimidinyl (C.sub.6),
7H-pyrrolo[2,3-d]pyrimidinyl (C.sub.6), pyrido[2,3-d]pyrimidinyl
(C.sub.7), 2-phenylbenzo[d]thiazolyl (C.sub.7), 1H-indolyl
(C.sub.8), 4,5,6,7-tetrahydro-1-H-indolyl (C.sub.8), quinoxalinyl
(C.sub.8), 5-methylquinoxalinyl (C.sub.8), quinazolinyl (C.sub.8),
quinolinyl (C.sub.9), 8-hydroxy-quinolinyl (C.sub.9), and
isoquinolinyl (C.sub.9).
[0079] Non-limiting examples of heteroaryl include
1,2,3,4-tetrahydroquinoline having the formula:
##STR00009##
6,7-Dihydro-5H-cyclopentapyrimidine having the formula:
##STR00010##
and 1,2,3,4-tetrahydro-[1,8]naphthpyridine having the formula:
##STR00011##
[0080] An acyl group can be, for example, a carbonyl group
substituted with hydrocarbyl, alkyl, hydrocarbyloxy, alkoxy, aryl,
aryloxy, aralkyl, arylalkoxy, or a heterocycle. Non-limiting
examples of acyl include acetyl, benzoyl, benzyloxycarbonyl,
phenoxycarbonyl, methoxycarbonyl, and ethoxycarbonyl.
[0081] An acyloxy group can be an oxygen atom substituted with an
acyl group. An ester or an ester group comprises an acyloxy group.
A non-limiting example of an acyloxy group, or an ester group, is
acetate.
[0082] A carbamate group can be an oxygen atom substituted with a
carbamoyl group, wherein the nitrogen atom of the carbamoyl group
is unsubstituted, monosubstituted, or disubstituted with one or
more of hydrocarbyl, alkyl, aryl, heterocyclyl, or aralkyl. When
the nitrogen atom is disubstituted, the two substituents together
with the nitrogen atom can form a heterocycle.
Compounds of the Invention.
[0083] In some embodiments, a compound of the disclosure has
Formula (I):
##STR00012##
wherein the carbon atom having the amino unit has the
stereochemistry indicated in the following formula:
##STR00013##
The units which comprise R and Z can comprise units having any
configuration, and, as such, a compound of the disclosure can be a
single enantiomer, a diastereomer, or pairs or combinations
thereof. In addition, the compounds can be isolated as salts or
hydrates. In the case of salts, the compounds can comprise more
than one cation or anion. In the case of hydrates, any number of
water molecules, or fractional part thereof (for example, less than
1 water molecule present for each molecule of analogue) can be
present.
R Units
[0084] R is a substituted or unsubstituted thiazolyl unit having
the formula:
##STR00014##
R.sup.2, R.sup.3, and R.sup.4 are substituent groups that can be
independently chosen from a wide variety of non-carbon atom
containing units (for example, hydrogen, hydroxyl, amino, halogen,
and nitro) or organic substituent units, such as substituted and
unsubstituted acyclic hydrocarbyl and cyclic hydrocarbyl units as
described herein. The carbon comprising units can comprise, for
example, from 1 to 12 carbon atoms, or 1 to 10 carbon atoms, or 1
to 6 carbon atoms.
[0085] An example of compounds of Formula (I) include compounds
wherein R units are thiazol-2-yl units having the formula:
##STR00015##
wherein R.sup.2 and R.sup.3 are each independently chosen from:
[0086] i) hydrogen; [0087] ii) substituted or unsubstituted
C.sub.1-C.sub.6 linear, C.sub.3-C.sub.6 branched, or
C.sub.3-C.sub.6 cyclic alkyl; [0088] iii) substituted or
unsubstituted C.sub.2-C.sub.6 linear, C.sub.3-C.sub.6 branched, or
C.sub.3-C.sub.6 cyclic alkenyl; [0089] iv) substituted or
unsubstituted C.sub.2-C.sub.6 linear or C.sub.3-C.sub.6 branched
alkynyl; [0090] v) substituted or unsubstituted C.sub.6 or C.sub.10
aryl; [0091] vi) substituted or unsubstituted C.sub.1-C.sub.9
heteroaryl; [0092] vii) substituted or unsubstituted
C.sub.1-C.sub.9 heterocyclic; or [0093] viii) R.sup.2 and R.sup.3
can be taken together to form a saturated or unsaturated ring
having from 5 to 7 atoms; wherein from 1 to 3 atoms can optionally
be heteroatoms chosen from oxygen, nitrogen, and sulfur.
[0094] The following are non-limiting examples of units that can
substitute for one or more hydrogen atoms on the R.sup.2 and
R.sup.3 units. The following substituents, as well as others not
herein described, are each independently chosen from: [0095] i)
C.sub.1-C.sub.12 linear, C.sub.3-C.sub.12 branched, or
C.sub.3-C.sub.12 cyclic alkyl, alkenyl, and alkynyl; methyl
(C.sub.1), ethyl (C.sub.2), ethenyl (C.sub.2), ethynyl (C.sub.2),
n-propyl (C.sub.3), iso-propyl (C.sub.3), cyclopropyl (C.sub.3),
3-propenyl (C.sub.3), 1-propenyl (also 2-methylethenyl) (C.sub.3),
isopropenyl (also 2-methylethen-2-yl) (C.sub.3), prop-2-ynyl (also
propargyl) (C.sub.3), propyn-1-yl (C.sub.3), n-butyl (C.sub.4),
sec-butyl (C.sub.4), iso-butyl (C.sub.4), tert-butyl (C.sub.4),
cyclobutyl (C.sub.4), buten-4-yl (C.sub.4), cyclopentyl (C.sub.5),
cyclohexyl (C.sub.6); [0096] ii) substituted or unsubstituted
C.sub.6 or C.sub.10 aryl; for example, phenyl, naphthyl (also
referred to herein as naphthylen-1-yl (C.sub.10) or naphthylen-2-yl
(C.sub.10)); [0097] iii) substituted or unsubstituted C.sub.6 or
C.sub.10 alkylenearyl; for example, benzyl, 2-phenylethyl,
naphthylen-2-ylmethyl; [0098] iv) substituted or unsubstituted
C.sub.1-C.sub.9 heterocyclic rings; as described herein; [0099] v)
substituted or unsubstituted C.sub.1-C.sub.9 heteroaryl rings; as
described herein; [0100] vi)
--(CR.sup.21aR.sup.21b).sub.pOR.sup.20; for example, --OH,
--CH.sub.2OH, --OCH.sub.3, --CH.sub.2OCH.sub.3,
--OCH.sub.2CH.sub.3, --CH.sub.2OCH.sub.2CH.sub.3,
--OCH.sub.2CH.sub.2CH.sub.3, and
--CH.sub.2OCH.sub.2CH.sub.2CH.sub.3; [0101] vii)
--(CR.sup.21aR.sup.21b).sub.pC(O)R.sup.20; for example,
--COCH.sub.3, --CH.sub.2COCH.sub.3, --COCH.sub.2CH.sub.3,
--CH.sub.2COCH.sub.2CH.sub.3, --COCH.sub.2CH.sub.2CH.sub.3, and
--CH.sub.2COCH.sub.2CH.sub.2CH.sub.3; [0102] viii)
--(CR.sup.21aR.sup.21b).sub.pC(O)OR.sup.20; for example,
--CO.sub.2CH.sub.3, --CH.sub.2CO.sub.2CH.sub.3,
--CO.sub.2CH.sub.2CH.sub.3, --CH.sub.2CO.sub.2CH.sub.2CH.sub.3,
--CO.sub.2CH.sub.2CH.sub.2CH.sub.3, and
--CH.sub.2CO.sub.2CH.sub.2CH.sub.2CH.sub.3; [0103] ix)
--(CR.sup.21aR.sup.21b).sub.pC(O)N(R.sup.20).sub.2; for example,
--CONH.sub.2, --CH.sub.2CONH.sub.2, --CONHCH.sub.3,
--CH.sub.2CONHCH.sub.3, --CON(CH.sub.3).sub.2, and
--CH.sub.2CON(CH.sub.3).sub.2; [0104] x)
--(CR.sup.21aR.sup.21b).sub.pN(R.sup.20).sub.2; for example,
--NH.sub.2, --CH.sub.2NH.sub.2, --NHCH.sub.3, --CH.sub.2NHCH.sub.3,
--N(CH.sub.3).sub.2, and --CH.sub.2N(CH.sub.3).sub.2; [0105] xi)
halogen; --F, --Cl, --Br, and --I; [0106] xii)
--(CR.sup.21aR.sup.21b).sub.pCN; [0107] xiii)
--(CR.sup.21aR.sup.21b).sub.pNO.sub.2; [0108] xiv)
--(CH.sub.j'X.sub.k').sub.hCH.sub.jX.sub.k; wherein X is halogen,
the index j is an integer from 0 to 2, j+k=3, the index j' is an
integer from 0 to 2, j'+k'=2, the index h is from 0 to 6; for
example, --CH.sub.2F, --CHF.sub.2, --CF.sub.3, --CH.sub.2CF.sub.3,
--CHFCF.sub.3, --CCl.sub.3, or --CBr.sub.3; [0109] xv)
--(CR.sup.21R.sup.21b).sub.pSR.sup.20; --SH, --CH.sub.2SH,
--SCH.sub.3, --CH.sub.2SCH.sub.3, --SC.sub.6H.sub.5, and
--CH.sub.2SC.sub.6H.sub.5; [0110] xvi)
--(CR.sup.21aR.sup.21b).sub.pSO.sub.2R.sup.20; for example,
--SO.sub.2H, --CH.sub.2SO.sub.2H, --SO.sub.2CH.sub.3,
--CH.sub.2SO.sub.2CH.sub.3, --SO.sub.2C.sub.6H.sub.5, and
--CH.sub.2SO.sub.2C.sub.6H.sub.5; and [0111] xvii)
--(CR.sup.21aR.sup.21b).sub.pSO.sub.3R.sup.20; for example,
--SO.sub.3H, --CH.sub.2SO.sub.3H, --SO.sub.3CH.sub.3,
--CH.sub.2SO.sub.3CH.sub.3, --SO.sub.3C.sub.6H.sub.5, and
--CH.sub.2SO.sub.3C.sub.6H.sub.5; wherein each R.sup.20 is
independently hydrogen, substituted or unsubstituted
C.sub.1-C.sub.4 linear, C.sub.3-C.sub.4 branched, or
C.sub.3-C.sub.4 cyclic alkyl, phenyl, benzyl, heterocyclic, or
heteroaryl; or two R.sup.20 units can be taken together to form a
ring comprising 3-7 atoms; R.sup.21a and R.sup.21b are each
independently hydrogen or C.sub.1-C.sub.4 linear or C.sub.3-C.sub.4
branched alkyl; the index p is from 0 to 4.
[0112] An example of compounds of Formula (I) includes R units
having the formula:
##STR00016##
wherein R.sup.3 is hydrogen and R.sup.2 is a unit chosen from
methyl (C.sub.1), ethyl (C.sub.2), n-propyl (C.sub.3), iso-propyl
(C.sub.3), n-butyl (C.sub.4), sec-butyl (C.sub.4), iso-butyl
(C.sub.4), tert-butyl (C.sub.4), n-pentyl (C.sub.5), 1-methylbutyl
(C.sub.5), 2-methylbutyl (C.sub.5), 3-methylbutyl (C.sub.5),
cyclopropyl (C.sub.3), n-hexyl (C.sub.6), 4-methylpentyl (C.sub.6),
and cyclohexyl (C.sub.6).
[0113] An example of compounds of Formula (I) include R units
having the formula:
##STR00017##
wherein R.sup.2 is a unit chosen from methyl (C.sub.1), ethyl
(C.sub.2), n-propyl (C.sub.3), iso-propyl (C.sub.3), n-butyl
(C.sub.4), sec-butyl (C.sub.4), iso-butyl (C.sub.4), and tert-butyl
(C.sub.4); and R.sup.3 is a unit chosen from methyl (C.sub.1) or
ethyl (C.sub.2). Non-limiting examples of this aspect of R includes
4,5-dimethylthiazol-2-yl, 4-ethyl-5-methylthiazol-2-yl,
4-methyl-5-ethylthiazol-2-yl, and 4,5-diethylthiazol-2-yl.
[0114] An example of compounds of Formula (I) includes R units
wherein R.sup.3 is hydrogen and R.sup.2 is a substituted alkyl
unit, said substitutions chosen from: [0115] i) halogen: --F, --Cl,
--Br, and --I; [0116] ii) --N(R.sup.11).sub.2; and [0117] iii)
--OR.sup.11; wherein each R.sup.11 is independently hydrogen or
C.sub.1-C.sub.4 linear or C.sub.3-C.sub.4 branched alkyl.
Non-limiting examples of units that can be a substitute for a
R.sup.2 or R.sup.3 hydrogen atom on R units include --CH.sub.2F,
--CHF.sub.2, --CF.sub.3, --CH.sub.2CF.sub.3,
--CH.sub.2CH.sub.2CF.sub.3, --CH.sub.2Cl, --CH.sub.2OH,
--CH.sub.2OCH.sub.3, --CH.sub.2CH.sub.2OH,
--CH.sub.2CH.sub.2OCH.sub.3, --CH.sub.2NH.sub.2,
--CH.sub.2NHCH.sub.3, --CH.sub.2N(CH.sub.3).sub.2, and
--CH.sub.2NH(CH.sub.2CH.sub.3).
[0118] Further non-limiting examples of units that can be a
substitute for a R.sup.2 or R.sup.3 hydrogen atom on R units
include 2,2-difluorocyclopropyl, 2-methoxycyclohexyl, and
4-chlorocyclohexyl.
[0119] An example of compounds of Formula (I), R units include
units wherein R.sup.3 is hydrogen and R.sup.2 is phenyl or
substituted phenyl, wherein non-limiting examples of R.sup.2 units
include phenyl, 3,4-dimethylphenyl, 4-tert-butylphenyl,
4-cyclopropylphenyl, 4-diethylaminophenyl,
4-(trifluoromethyl)phenyl, 4-methoxyphenyl,
4-(difluoromethoxy)-phenyl, 4-(trifluoromethoxy)phenyl,
3-chloropheny, 4-chlorophenyl, and 3,4-dichloro-phenyl, which when
incorporated into the definition of R affords the following R units
4-phenylthiazol-2-yl, 3,4-dimethylphenylthiazol-2-yl,
4-tert-butylphenylthiazol-2-yl, 4-cyclopropylphenylthiazol-2-yl,
4-diethylaminophenylthiazol-2-yl,
4-(trifluoromethyl)-phenylthiazol-2-yl,
4-methoxyphenylthiazol-2-yl, 4-(difluoromethoxy)phenylthiazol-2-yl,
4-(trifluoromethoxy)phenylthiazol-2-yl, 3-chlorophenylthiazol-2-yl,
4-chlorophenylthiazol-2-yl, and 3,4-dichlorophenylthiazol-2-yl.
[0120] An example of compounds of Formula (I) includes R units
wherein R.sup.2 is chosen from hydrogen, methyl, ethyl, n-propyl,
and iso-propyl and R.sup.3 is phenyl or substituted phenyl. A
non-limiting example of a R unit according to the fifth aspect of
the first category of R units includes
4-methyl-5-phenylthiazol-2-yl and 4-ethyl-5-phenylthiazol-2-yl.
[0121] An example of compounds of Formula (I) includes R units
wherein R.sup.3 is hydrogen and R.sup.2 is a substituted or
unsubstituted heteroaryl unit chosen from 1,2,3,4-tetrazol-1-yl,
1,2,3,4-tetrazol-5-yl, [1,2,3]triazol-4-yl, [1,2,3]triazol-5-yl,
[1,2,4]triazol-4-yl, [1,2,4]triazol-5-yl, imidazol-2-yl,
imidazol-4-yl, pyrrol-2-yl, pyrrol-3-yl, oxazol-2-yl, oxazol-4-yl,
oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl,
[1,2,4]oxadiazol-3-yl, [1,2,4]oxadiazol-5-yl,
[1,3,4]oxadiazol-2-yl, furan-2-yl, furan-3-yl, thiophen-2-yl,
thiophen-3-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl,
thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, [1,2,4]thiadiazol-3-yl,
[1,2,4]thiadiazol-5-yl, and [1,3,4]thiadiazol-2-yl.
[0122] Further non-limiting example of compounds of Formula (I)
includes R units wherein R.sup.2 is substituted or unsubstituted
thiophen-2-yl, for example thiophen-2-yl, 5-chlorothiophen-2-yl,
and 5-methylthiophen-2-yl.
[0123] An example of compounds of Formula (I) includes R units
wherein R.sup.2 is substituted or unsubstituted thiophen-3-yl, for
example thiophen-3-yl, 5-chlorothiophen-3-yl, and
5-methylthiophen-3-yl.
[0124] An example of compounds of Formula (I) includes R units
wherein R.sup.2 and R.sup.3 are taken together to form a saturated
or unsaturated ring having from 5 to 7 atoms. Non-limiting examples
of the sixth aspect of the first category of R units include
5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl and
4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl.
[0125] Further examples of compounds of Formula (I) include R units
that are thiazol-4-yl or thiazol-5-yl units having the formula:
##STR00018##
[0126] wherein R.sup.4 is a unit chosen from: [0127] i) hydrogen;
[0128] ii) substituted or unsubstituted C.sub.1-C.sub.6 linear,
C.sub.3-C.sub.6 branched, or C.sub.3-C.sub.6 cyclic alkyl; [0129]
iii) substituted or unsubstituted C.sub.2-C.sub.6 linear,
C.sub.3-C.sub.6 branched, or C.sub.3-C.sub.6 cyclic alkenyl; [0130]
iv) substituted or unsubstituted C.sub.2-C.sub.6 linear or branched
alkynyl; [0131] v) substituted or unsubstituted C.sub.6 or C.sub.10
aryl; [0132] vi) substituted or unsubstituted C.sub.1-C.sub.9
heteroaryl; or [0133] vii) substituted or unsubstituted
C.sub.1-C.sub.9 heterocyclic.
[0134] The following are non-limiting examples of units that can
substitute for one or more hydrogen atoms on the R.sup.4 units. The
following substituents, as well as others not herein described, are
each independently chosen: [0135] i) C.sub.1-C.sub.12 linear,
C.sub.3-C.sub.12 branched, or C.sub.3-C.sub.12 cyclic alkyl,
alkenyl, and alkynyl; methyl (C.sub.1), ethyl (C.sub.2), ethenyl
(C.sub.2), ethynyl (C.sub.2), n-propyl (C.sub.3), iso-propyl
(C.sub.3), cyclopropyl (C.sub.3), 3-propenyl (C.sub.3), 1-propenyl
(also 2-methylethenyl) (C.sub.3), isopropenyl (also
2-methylethen-2-yl) (C.sub.3), prop-2-ynyl (also propargyl)
(C.sub.3), propyn-1-yl (C.sub.3), n-butyl (C.sub.4), sec-butyl
(C.sub.4), iso-butyl (C.sub.4), tert-butyl (C.sub.4), cyclobutyl
(C.sub.4), buten-4-yl (C.sub.4), cyclopentyl (C.sub.5), cyclohexyl
(C.sub.6); [0136] ii) substituted or unsubstituted C.sub.6 or
C.sub.10 aryl; for example, phenyl, naphthyl (also referred to
herein as naphthylen-1-yl (C.sub.10) or naphthylen-2-yl
(C.sub.10)); [0137] iii) substituted or unsubstituted C.sub.6 or
C.sub.10 alkylenearyl; for example, benzyl, 2-phenylethyl,
naphthylen-2-ylmethyl; [0138] iv) substituted or unsubstituted
C.sub.1-C.sub.9 heterocyclic rings; [0139] v) substituted or
unsubstituted C.sub.1-C.sub.9 heteroaryl rings; [0140] vi)
--(CR.sup.21aR.sup.21b).sub.pOR.sup.20; for example, --OH,
--CH.sub.2OH, --OCH.sub.3, --CH.sub.2OCH.sub.3,
--OCH.sub.2CH.sub.3, --CH.sub.2OCH.sub.2CH.sub.3,
--OCH.sub.2CH.sub.2CH.sub.3, and
--CH.sub.2OCH.sub.2CH.sub.2CH.sub.3; [0141] vii)
--(CR.sup.21aR.sup.21b).sub.pC(O)R.sup.20; for example,
--COCH.sub.3, --CH.sub.2COCH.sub.3, --COCH.sub.2CH.sub.3,
--CH.sub.2COCH.sub.2CH.sub.3, --COCH.sub.2CH.sub.2CH.sub.3, and
--CH.sub.2COCH.sub.2CH.sub.2CH.sub.3; [0142] viii)
--(CR.sup.21aR.sup.21b).sub.pC(O)OR.sup.20; for example,
--CO.sub.2CH.sub.3, --CH.sub.2CO.sub.2CH.sub.3,
--CO.sub.2CH.sub.2CH.sub.3, --CH.sub.2CO.sub.2CH.sub.2CH.sub.3,
--CO.sub.2CH.sub.2CH.sub.2CH.sub.3, and
--CH.sub.2CO.sub.2CH.sub.2CH.sub.2CH.sub.3; [0143] ix)
--(CR.sup.21aR.sup.21b).sub.pC(O)N(R.sup.20).sub.2; for example,
--CONH.sub.2, --CH.sub.2CONH.sub.2, --CONHCH.sub.3,
--CH.sub.2CONHCH.sub.3, --CON(CH.sub.3).sub.2, and
--CH.sub.2CON(CH.sub.3).sub.2; [0144] x)
--(CR.sup.21aR.sup.21b).sub.pN(R.sup.20).sub.2; for example,
--NH.sub.2, --CH.sub.2NH.sub.2, --NHCH.sub.3, --CH.sub.2NHCH.sub.3,
--N(CH.sub.3).sub.2, and --CH.sub.2N(CH.sub.3).sub.2; [0145] xi)
halogen; --F, --Cl, --Br, and --I; [0146] xii)
--(CR.sup.21aR.sup.21b).sub.pCN; [0147] xiii)
--(CR.sup.21aR.sup.21b).sub.pNO.sub.2; [0148] xiv)
--(CH.sub.j'X.sub.k').sub.hCH.sub.jX.sub.k; wherein X is halogen,
the index j is an integer from 0 to 2, j+k=3, the index j' is an
integer from 0 to 2, j'+k'=2, the index h is from 0 to 6; for
example, --CH.sub.2F, --CHF.sub.2, --CF.sub.3, --CH.sub.2CF.sub.3,
--CHFCF.sub.3, --CCl.sub.3, or --CBr.sub.3; [0149] xv)
--(CR.sup.21aR.sup.21b).sub.pSR.sup.20; --SH, --CH.sub.2SH,
--SCH.sub.3, --CH.sub.2SCH.sub.3, --SC.sub.6H.sub.5, and
--CH.sub.2SC.sub.6H.sub.5; [0150] xvi)
--(CR.sup.21aR.sup.21b).sub.pSO.sub.2R.sup.20; for example,
--SO.sub.2H, --CH.sub.2SO.sub.2H, --SO.sub.2CH.sub.3,
--CH.sub.2SO.sub.2CH.sub.3, --SO.sub.2C.sub.6H.sub.5, and
--CH.sub.2SO.sub.2C.sub.6H.sub.5; and [0151] xvii)
--(CR.sup.21aR.sup.21b).sub.pSO.sub.3R.sup.20; for example,
--SO.sub.3H, --CH.sub.2SO.sub.3H, --SO.sub.3CH.sub.3,
--CH.sub.2SO.sub.3CH.sub.3, --SO.sub.3C.sub.6H.sub.5, and
--CH.sub.2SO.sub.3C.sub.6H.sub.5; wherein each R.sup.20 is
independently hydrogen, substituted or unsubstituted
C.sub.1-C.sub.4 linear, C.sub.3-C.sub.4 branched, or
C.sub.3-C.sub.4 cyclic alkyl, phenyl, benzyl, heterocyclic, or
heteroaryl; or two R.sup.20 units can be taken together to form a
ring comprising 3-7 atoms; R.sup.21a and R.sup.21b are each
independently hydrogen or C.sub.1-C.sub.4 linear or C.sub.3-C.sub.4
branched alkyl; the index p is from 0 to 4.
[0152] An example of compounds of Formula (I) includes R units
wherein R.sup.4 is hydrogen.
[0153] An example of compounds of Formula (I) includes R units
wherein R.sup.4 is a unit chosen from methyl (C.sub.1), ethyl
(C.sub.2), n-propyl (C.sub.3), iso-propyl (C.sub.3), n-butyl
(C.sub.4), sec-butyl (C.sub.4), iso-butyl (C.sub.4), and tert-butyl
(C.sub.4). Non-limiting examples of this aspect of R includes
2-methylthiazol-4-yl, 2-ethylthiazol-4-yl,
2-(n-propyl)thiazol-4-yl, and 2-(iso-propyl)thiazol-4-yl.
[0154] An example of compounds of Formula (I) includes R units
wherein R.sup.4 is substituted or unsubstituted phenyl,
non-limiting examples of which include phenyl, 2-fluorophenyl,
2-chlorophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl,
3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl,
4-chlorophenyl, 4-methylphenyl, and 4-methoxyphenyl.
[0155] An example of compounds of Formula (I) includes R units
wherein R.sup.4 is substituted or unsubstituted heteroaryl,
non-limiting examples of which include thiophen-2-yl,
thiophen-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl,
2,5-dimethylthiazol-4-yl, 2,4-dimethylthiazol-5-yl,
4-ethylthiazol-2-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, and
3-methyl-1,2,4-oxadiazol-5-yl.
[0156] Another example of 5-member ring R units includes
substituted or unsubstituted imidazolyl units having the
formula:
##STR00019##
[0157] One example of imidazolyl R units includes imidazol-2-yl
units having the formula:
##STR00020##
wherein R.sup.2 and R.sup.3 are each independently chosen from:
[0158] i) hydrogen; [0159] ii) substituted or unsubstituted
C.sub.1-C.sub.6 linear, C.sub.3-C.sub.6 branched, or
C.sub.3-C.sub.6 cyclic alkyl; [0160] iii) substituted or
unsubstituted C.sub.2-C.sub.6 linear, C.sub.3-C.sub.6 branched, or
C.sub.3-C.sub.6 cyclic alkenyl; [0161] iv) substituted or
unsubstituted C.sub.2-C.sub.6 linear or branched alkynyl; [0162] v)
substituted or unsubstituted C.sub.6 or C.sub.10 aryl; [0163] vi)
substituted or unsubstituted C.sub.1-C.sub.9 heteroaryl; [0164]
vii) substituted or unsubstituted C.sub.1-C.sub.9 heterocyclic; or
[0165] viii) R.sup.2 and R.sup.3 can be taken together to form a
saturated or unsaturated ring having from 5 to 7 atoms; wherein
from 1 to 3 atoms can optionally be heteroatoms chosen from oxygen,
nitrogen, and sulfur.
[0166] The following are non-limiting examples of units that can
substitute for one or more hydrogen atoms on the R.sup.2 and
R.sup.3 units. The following substituents, as well as others not
herein described, are each independently chosen: [0167] i)
C.sub.1-C.sub.12 linear, C.sub.3-C.sub.12 branched, or
C.sub.3-C.sub.12 cyclic alkyl, alkenyl, and alkynyl; methyl
(C.sub.1), ethyl (C.sub.2), ethenyl (C.sub.2), ethynyl (C.sub.2),
n-propyl (C.sub.3), iso-propyl (C.sub.3), cyclopropyl (C.sub.3),
3-propenyl (C.sub.3), 1-propenyl (also 2-methylethenyl) (C.sub.3),
isopropenyl (also 2-methylethen-2-yl) (C.sub.3), prop-2-ynyl (also
propargyl) (C.sub.3), propyn-1-yl (C.sub.3), n-butyl (C.sub.4),
sec-butyl (C.sub.4), iso-butyl (C.sub.4), tert-butyl (C.sub.4),
cyclobutyl (C.sub.4), buten-4-yl (C.sub.4), cyclopentyl (C.sub.5),
cyclohexyl (C.sub.6); [0168] ii) substituted or unsubstituted
C.sub.6 or C.sub.10 aryl; for example, phenyl, naphthyl (also
referred to herein as naphthylen-1-yl (C.sub.10) or naphthylen-2-yl
(C.sub.10)); [0169] iii) substituted or unsubstituted C.sub.6 or
C.sub.10 alkylenearyl; for example, benzyl, 2-phenylethyl,
naphthylen-2-ylmethyl; [0170] iv) substituted or unsubstituted
C.sub.1-C.sub.9 heterocyclic rings; as described herein; [0171] v)
substituted or unsubstituted C.sub.1-C.sub.9 heteroaryl rings; as
described herein; [0172] vi)
--(CR.sup.21aR.sup.21b).sub.zOR.sup.20; for example, --OH,
--CH.sub.2OH, --OCH.sub.3, --CH.sub.2OCH.sub.3,
--OCH.sub.2CH.sub.3, --CH.sub.2OCH.sub.2CH.sub.3,
--OCH.sub.2CH.sub.2CH.sub.3, and
--CH.sub.2OCH.sub.2CH.sub.2CH.sub.3; [0173] vii)
--(CR.sup.21aR.sup.21b).sub.zC(O)R.sup.20; for example,
--COCH.sub.3, --CH.sub.2COCH.sub.3, --COCH.sub.2CH.sub.3,
--CH.sub.2COCH.sub.2CH.sub.3, --COCH.sub.2CH.sub.2CH.sub.3, and
--CH.sub.2COCH.sub.2CH.sub.2CH.sub.3; [0174] viii)
--(CR.sup.21aR.sup.21b).sub.zC(O)OR.sup.20; for example,
--CO.sub.2CH.sub.3, --CH.sub.2CO.sub.2CH.sub.3,
--CO.sub.2CH.sub.2CH.sub.3, --CH.sub.2CO.sub.2CH.sub.2CH.sub.3,
--CO.sub.2CH.sub.2CH.sub.2CH.sub.3, and
--CH.sub.2CO.sub.2CH.sub.2CH.sub.2CH.sub.3; [0175] ix)
--(CR.sup.21aR.sup.21b).sub.zC(O)N(R.sup.20).sub.2; for example,
--CONH.sub.2, --CH.sub.2CONH.sub.2, --CONHCH.sub.3,
--CH.sub.2CONHCH.sub.3, --CON(CH.sub.3).sub.2, and
--CH.sub.2CON(CH.sub.3).sub.2; [0176] x)
--(CR.sup.21aR.sup.21b).sub.zN(R.sup.20).sub.2; for example,
--NH.sub.2, --CH.sub.2NH.sub.2, --NHCH.sub.3, --CH.sub.2NHCH.sub.3,
--N(CH.sub.3).sub.2, and --CH.sub.2N(CH.sub.3).sub.2; [0177] xi)
halogen; --F, --Cl, --Br, and --I; [0178] xii)
--(CR.sup.21aR.sup.21b).sub.zCN; [0179] xiii)
--(CR.sup.21aR.sup.21b).sub.zNO.sub.2; [0180] xiv)
--(CH.sub.j'X.sub.k').sub.hCH.sub.jX.sub.k; wherein X is halogen,
the index j is an integer from 0 to 2, j+k=3, the index j' is an
integer from 0 to 2, j'+k'=2, the index h is from 0 to 6; for
example, --CH.sub.2F, --CHF.sub.2, --CF.sub.3, --CH.sub.2CF.sub.3,
--CHFCF.sub.3, --CCl.sub.3, or --CBr.sub.3; [0181] xv)
--(CR.sup.21aR.sup.21b).sub.zSR.sup.20; --SH, --CH.sub.2SH,
--SCH.sub.3, --CH.sub.2SCH.sub.3, --SC.sub.6H.sub.5, and
--CH.sub.2SC.sub.6H.sub.5; [0182] xvi)
--(CR.sup.21aR.sup.21b).sub.zSO.sub.2R.sup.20; for example,
--SO.sub.2H, --CH.sub.2SO.sub.2H, --SO.sub.2CH.sub.3,
--CH.sub.2SO.sub.2CH.sub.3, --SO.sub.2C.sub.6H.sub.5, and
--CH.sub.2SO.sub.2C.sub.6H.sub.5; and [0183] xvii)
--(CR.sup.21aR.sup.21b).sub.zSO.sub.3R.sup.20; for example,
--SO.sub.3H, --CH.sub.2SO.sub.3H, --SO.sub.3CH.sub.3,
--CH.sub.2SO.sub.3CH.sub.3, --SO.sub.3C.sub.6H.sub.5, and
--CH.sub.2SO.sub.3C.sub.6H.sub.5; wherein each R.sup.20 is
independently hydrogen, substituted or unsubstituted
C.sub.1-C.sub.4 linear, C.sub.3-C.sub.4 branched, or
C.sub.3-C.sub.4 cyclic alkyl, phenyl, benzyl, heterocyclic, or
heteroaryl; or two R.sup.20 units can be taken together to form a
ring comprising 3-7 atoms; R.sup.21a and R.sup.21b are each
independently hydrogen or C.sub.1-C.sub.4 linear or C.sub.3-C.sub.4
branched alkyl; the index p is from 0 to 4.
[0184] One example of R units includes compounds wherein R units
have the formula:
##STR00021##
wherein R.sup.3 is hydrogen and R.sup.2 is a unit chosen from
methyl (C.sub.1), ethyl (C.sub.2), n-propyl (C.sub.3), iso-propyl
(C.sub.3), n-butyl (C.sub.4), sec-butyl (C.sub.4), iso-butyl
(C.sub.4), and tert-butyl (C.sub.4).
[0185] Another example of R units includes compounds wherein
R.sup.2 is a unit chosen from methyl (C.sub.1), ethyl (C.sub.2),
n-propyl (C.sub.3), iso-propyl (C.sub.3), n-butyl (C.sub.4),
sec-butyl (C.sub.4), iso-butyl (C.sub.4), and tert-butyl (C.sub.4);
and R.sup.3 is a unit chosen from methyl (C.sub.1) or ethyl
(C.sub.2). Non-limiting examples of this aspect of R includes
4,5-dimethylimidazol-2-yl, 4-ethyl-5-methylimidazol-2-yl,
4-methyl-5-ethylimidazol-2-yl, and 4,5-diethylimidazol-2-yl.
[0186] An example of R units includes compounds wherein R.sup.3 is
hydrogen and R.sup.2 is a substituted alkyl unit chosen, said
substitutions chosen from: [0187] i) halogen: --F, --Cl, --Br, and
--I; [0188] ii) --N(R.sup.11).sub.2; and [0189] iii) --OR.sup.11;
wherein each R.sup.11 is independently hydrogen or C.sub.1-C.sub.4
linear or C.sub.3-C.sub.4 branched alkyl.
[0190] Non-limiting examples of units comprising this embodiment of
R includes: --CH.sub.2F, --CHF.sub.2, --CF.sub.3,
--CH.sub.2CF.sub.3, --CH.sub.2Cl, --CH.sub.2OH,
--CH.sub.2OCH.sub.3, --CH.sub.2CH.sub.2OH,
--CH.sub.2CH.sub.2OCH.sub.3, --CH.sub.2NH.sub.2,
--CH.sub.2NHCH.sub.3, --CH.sub.2N(CH.sub.3).sub.2, and
--CH.sub.2NH(CH.sub.2CH.sub.3).
[0191] An example of R units includes units wherein R.sup.3 is
hydrogen and R.sup.2 is phenyl.
[0192] An example of R units includes units wherein R.sup.3 is
hydrogen and R.sup.2 is a heteroaryl unit chosen from
1,2,3,4-tetrazol-1-yl, 1,2,3,4-tetrazol-5-yl, [1,2,3]triazol-4-yl,
[1,2,3]triazol-5-yl, [1,2,4]triazol-4-yl, [1,2,4]triazol-5-yl,
imidazol-2-yl, imidazol-4-yl, pyrrol-2-yl, pyrrol-3-yl,
oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl,
isoxazol-4-yl, isoxazol-5-yl, [1,2,4]oxadiazol-3-yl,
[1,2,4]oxadiazol-5-yl, [1,3,4]oxadiazol-2-yl, furan-2-yl,
furan-3-yl, thiophen-2-yl, thiophen-3-yl, isothiazol-3-yl,
isothiazol-4-yl, isothiazol-5-yl, thiazol-2-yl, thiazol-4-yl,
thiazol-5-yl, [1,2,4]thiadiazol-3-yl, [1,2,4]thiadiazol-5-yl, and
[1,3,4]thiadiazol-2-yl.
Z Units
[0193] Z is a unit having the formula:
-(L).sub.n-R.sup.1 [0194] R.sup.1 is chosen from: [0195] i)
hydrogen; [0196] ii) hydroxyl; [0197] iii) amino; [0198] iv)
substituted or unsubstituted C.sub.1-C.sub.6 linear,
C.sub.3-C.sub.6 branched or C.sub.3-C.sub.6 cyclic alkyl; [0199] v)
substituted or unsubstituted C.sub.1-C.sub.6 linear,
C.sub.3-C.sub.6 branched o C.sub.3-C.sub.6r cyclic alkoxy; [0200]
vi) substituted or unsubstituted C.sub.6 or C.sub.10 aryl; [0201]
vii) substituted or unsubstituted C.sub.1-C.sub.9 heterocyclic
rings; or [0202] viii) substituted or unsubstituted C.sub.1-C.sub.9
heteroaryl rings.
[0203] The following are non-limiting examples of units that can
substitute for one or more hydrogen atoms on the R.sup.1 units. The
following substituents, as well as others not herein described, are
each independently chosen: [0204] i) C.sub.1-C.sub.12 linear,
C.sub.3-C.sub.12 branched, or C.sub.3-C.sub.12 cyclic alkyl,
alkenyl, and alkynyl; methyl (C.sub.1), ethyl (C.sub.2), ethenyl
(C.sub.2), ethynyl (C.sub.2), n-propyl (C.sub.3), iso-propyl
(C.sub.3), cyclopropyl (C.sub.3), 3-propenyl (C.sub.3), 1-propenyl
(also 2-methylethenyl) (C.sub.3), isopropenyl (also
2-methylethen-2-yl) (C.sub.3), prop-2-ynyl (also propargyl)
(C.sub.3), propyn-1-yl (C.sub.3), n-butyl (C.sub.4), sec-butyl
(C.sub.4), iso-butyl (C.sub.4), tert-butyl (C.sub.4), cyclobutyl
(C.sub.4), buten-4-yl (C.sub.4), cyclopentyl (C.sub.5), cyclohexyl
(C.sub.6); [0205] ii) substituted or unsubstituted C.sub.6 or
C.sub.10 aryl; for example, phenyl, naphthyl (also referred to
herein as naphthylen-1-yl (C.sub.10) or naphthylen-2-yl
(C.sub.10)); [0206] iii) substituted or unsubstituted C.sub.6 or
C.sub.10 alkylenearyl; for example, benzyl, 2-phenylethyl,
naphthylen-2-ylmethyl; [0207] iv) substituted or unsubstituted
C.sub.1-C.sub.9 heterocyclic rings; as described herein; [0208] v)
substituted or unsubstituted C.sub.1-C.sub.9 heteroaryl rings; as
described herein; [0209] vi)
--(CR.sup.31aR.sup.31b).sub.qOR.sup.30; for example, --OH,
--CH.sub.2OH, --OCH.sub.3, --CH.sub.2OCH.sub.3,
--OCH.sub.2CH.sub.3, --CH.sub.2OCH.sub.2CH.sub.3,
--OCH.sub.2CH.sub.2CH.sub.3, and
--CH.sub.2OCH.sub.2CH.sub.2CH.sub.3; [0210] vii)
--(CR.sup.31aR.sup.31b).sub.qC(O)R.sup.30; for example,
--COCH.sub.3, --CH.sub.2COCH.sub.3, --COCH.sub.2CH.sub.3,
--CH.sub.2COCH.sub.2CH.sub.3, --COCH.sub.2CH.sub.2CH.sub.3, and
--CH.sub.2COCH.sub.2CH.sub.2CH.sub.3; [0211] viii)
--(CR.sup.31aR.sup.31b).sub.qC(O)OR.sup.30; for example,
--CO.sub.2CH.sub.3, --CH.sub.2CO.sub.2CH.sub.3,
--CO.sub.2CH.sub.2CH.sub.3, --CH.sub.2CO.sub.2CH.sub.2CH.sub.3,
--CO.sub.2CH.sub.2CH.sub.2CH.sub.3, and
--CH.sub.2CO.sub.2CH.sub.2CH.sub.2CH.sub.3; [0212] ix)
--(CR.sup.31aR.sup.31b).sub.qC(O)N(R.sup.30).sub.2; for example,
--CONH.sub.2, --CH.sub.2CONH.sub.2, --CONHCH.sub.3,
--CH.sub.2CONHCH.sub.3, --CON(CH.sub.3).sub.2, and
--CH.sub.2CON(CH.sub.3).sub.2; [0213] x)
--(CR.sup.31aR.sup.31b).sub.qN(R.sup.30).sub.2; for example,
--NH.sub.2, --CH.sub.2NH.sub.2, --NHCH.sub.3, --CH.sub.2NHCH.sub.3,
--N(CH.sub.3).sub.2, and --CH.sub.2N(CH.sub.3).sub.2; [0214] xi)
halogen; --F, --Cl, --Br, and --I; [0215] xii)
--(CR.sup.31aR.sup.31b).sub.qCN; [0216] xiii)
--(CR.sup.31aR.sup.31b).sub.qNO.sub.2; [0217] xiv)
--(CH.sub.j'X.sub.k').sub.hCH.sub.jX.sub.k; wherein X is halogen,
the index j is an integer from 0 to 2, j+k=3, the index j' is an
integer from 0 to 2, j'+k'=2, the index h is from 0 to 6; for
example, --CH.sub.2F, --CHF.sub.2, --CF.sub.3, --CH.sub.2CF.sub.3,
--CHFCF.sub.3, --CCl.sub.3, or --CBr.sub.3; [0218] xv)
--(CR.sup.31aR.sup.31b).sub.qSR.sup.30; --SH, --CH.sub.2SH,
--SCH.sub.3, --CH.sub.2SCH.sub.3, --SC.sub.6H.sub.5, and
--CH.sub.2SC.sub.6H.sub.5; [0219] xvi)
--(CR.sup.31aR.sup.31b).sub.qSO.sub.2R.sup.30; for example,
--SO.sub.2H, --CH.sub.2SO.sub.2H, --SO.sub.2CH.sub.3,
--CH.sub.2SO.sub.2CH.sub.3, --SO.sub.2C.sub.6H.sub.5, and
--CH.sub.2SO.sub.2C.sub.6H.sub.5; and [0220] xvii)
--(CR.sup.31aR.sup.31b).sub.qSO.sub.3R.sup.30; for example,
--SO.sub.3H, --CH.sub.2SO.sub.3H, --SO.sub.3CH.sub.3,
--CH.sub.2SO.sub.3CH.sub.3, --SO.sub.3C.sub.6H.sub.5, and
--CH.sub.2SO.sub.3C.sub.6H.sub.5; wherein each R.sup.30 is
independently hydrogen, substituted or unsubstituted
C.sub.1-C.sub.6 linear, C.sub.3-C.sub.6 branched, or
C.sub.3-C.sub.6 cyclic alkyl, phenyl, benzyl, heterocyclic, or
heteroaryl; or two R.sup.30 units can be taken together to form a
ring comprising 3-7 atoms; R.sup.31a and R.sup.31b are each
independently hydrogen or C.sub.1-C.sub.4 linear or C.sub.3-C.sub.4
branched alkyl; the index q is from 0 to 4.
[0221] One example of R.sup.1 units includes substituted or
unsubstituted phenyl (C.sub.6 aryl) units, wherein each
substitution is independently chosen from: halogen, C.sub.1-C.sub.4
linear, branched alkyl, or cyclic alkyl, --OR.sup.11, --CN,
--N(R.sup.11).sub.2, --CO.sub.2R.sup.11, --C(O)N(R.sup.11).sub.2,
--NR.sup.11C(O)R.sup.11, --NO.sub.2, and --SO.sub.2R.sup.11; each
R.sup.11 is independently hydrogen; substituted or unsubstituted
C.sub.1-C.sub.4 linear, C.sub.3-C.sub.4 branched, C.sub.3-C.sub.4
cyclic alkyl, alkenyl, or alkynyl; substituted or unsubstituted
phenyl or benzyl; or two R.sup.11 units can be taken together to
form a ring comprising from 3-7 atoms.
[0222] An example of R.sup.1 units includes substituted C.sub.6
aryl units chosen from phenyl, 2-fluorophenyl, 3-fluorophenyl,
4-fluorophenyl, 2,3-difluorophenyl, 3,4-difluorophenyl,
3,5-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,
2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl,
2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-methoxyphenyl,
3-methoxyphenyl, 4-methoxyphenyl, 2,3-dimethoxyphenyl,
3,4-dimethoxyphenyl, and 3,5-dimethoxyphenyl.
[0223] An example of R.sup.1 units includes substituted or
unsubstituted C.sub.6 aryl units chosen from 2,4-difluorophenyl,
2,5-difluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl,
2,3,5-trifluorophenyl, 2,3,6-trifluorophenyl,
2,4,5-trifluorophenyl, 2,4,6-trifluorophenyl, 2,4-dichlorophenyl,
2,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl,
2,3,4-trichlorophenyl, 2,3,5-trichlorophenyl,
2,3,6-trichlorophenyl, 2,4,5-trichlorophenyl,
3,4,5-trichlorophenyl, and 2,4,6-trichlorophenyl.
[0224] An example of R.sup.1 units includes substituted C.sub.6
aryl units chosen from 2-methylphenyl, 3-methylphenyl,
4-methylphenyl, 2,3-dimethylphenyl, 2,4-dimethylphenyl,
2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4-dimethylphenyl,
2,3,4-trimethylphenyl, 2,3,5-trimethylphenyl,
2,3,6-trimethylphenyl, 2,4,5-trimethylphenyl,
2,4,6-trimethylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl,
2,3-diethylphenyl, 2,4-diethylphenyl, 2,5-diethylphenyl,
2,6-diethylphenyl, 3,4-diethylphenyl, 2,3,4-triethylphenyl,
2,3,5-triethylphenyl, 2,3,6-triethylphenyl, 2,4,5-triethylphenyl,
2,4,6-triethylphenyl, 2-isopropylphenyl, 3-isopropylphenyl, and
4-isopropylphenyl.
[0225] An example of R.sup.1 units includes substituted C.sub.6
aryl units chosen from 2-aminophenyl, 2-(N-methylamino)phenyl,
2-(N,N-dimethylamino)phenyl, 2-(N-ethylamino)phenyl,
2-(N,N-diethylamino)phenyl, 3-aminophenyl, 3-(N-methylamino)phenyl,
3-(N,N-dimethylamino)phenyl, 3-(N-ethylamino)phenyl,
3-(N,N-diethylamino)phenyl, 4-aminophenyl, 4-(N-methylamino)phenyl,
4-(N,N-dimethylamino)phenyl, 4-(N-ethylamino)phenyl, and
4-(N,N-diethylamino)phenyl.
[0226] R.sup.1 can comprise heteroaryl units. Non-limiting examples
of C.sub.1-C.sub.9 heteroaryl units include:
##STR00022## ##STR00023##
[0227] R.sup.1 heteroaryl units can be substituted or
unsubstituted. Non-limiting examples of units that can substitute
for hydrogen include units chosen from: [0228] i) C.sub.1-C.sub.6
linear, C.sub.3-C.sub.6 branched, and C.sub.3-C.sub.6 cyclic alkyl;
[0229] ii) substituted or unsubstituted phenyl and benzyl; [0230]
iii) substituted of unsubstituted C.sub.1-C.sub.9 heteroaryl;
[0231] iv) --C(O)R.sup.9; and [0232] v) --NHC(O)R.sup.9; wherein
R.sup.9 is C.sub.1-C.sub.6 linear and branched alkyl;
C.sub.1-C.sub.6 linear and C.sub.3-C.sub.6 branched alkoxy; or
--NHCH.sub.2C(O)R.sup.10; R.sup.10 is chosen from hydrogen, methyl,
ethyl, and tert-butyl.
[0233] An example of R.sup.1 relates to units substituted by an
alkyl unit chosen from methyl, ethyl, n-propyl, iso-propyl,
n-butyl, iso-butyl, sec-butyl, and tert-butyl.
[0234] An example of R.sup.1 includes units that are substituted by
substituted or unsubstituted phenyl and benzyl, wherein the phenyl
and benzyl substitutions are chosen from one or more: [0235] i)
halogen; [0236] ii) C.sub.1-C.sub.3 alkyl; [0237] iii)
C.sub.1-C.sub.3 alkoxy; [0238] iv) --CO.sub.2R.sup.11; and [0239]
v) --NHCOR.sup.16; wherein R.sup.11 and R.sup.16 are each
independently hydrogen, methyl, or ethyl.
[0240] An example of R.sup.1 relates to phenyl and benzyl units
substituted by a carboxy unit having the formula --C(O)R.sup.9;
R.sup.9 is chosen from methyl, methoxy, ethyl, and ethoxy.
[0241] An example of R.sup.1 includes phenyl and benzyl units
substituted by an amide unit having the formula --NHC(O)R.sup.9;
R.sup.9 is chosen from methyl, methoxy, ethyl, ethoxy, tert-butyl,
and tert-butoxy.
[0242] An example of R.sup.1 includes phenyl and benzyl units
substituted by one or more fluoro or chloro units.
L Units
[0243] L is a linking unit which is present when the index n is
equal to 1, but is absent when the index n is equal to 0. L units
have the formula:
-[Q].sub.y[C(R.sup.5aR.sup.5b)].sub.x[Q.sup.1].sub.z[C(R.sup.6aR.sup.6b)-
].sub.w--
wherein Q and Q.sup.1 are each independently: [0244] i) --C(O)--;
[0245] ii) --NH--; [0246] iii) --C(O)NH--; [0247] iv) --NHC(O)--;
[0248] v) --NHC(O)NH--; [0249] vi) --NHC(O)O--; [0250] vii)
--C(O)O--; [0251] viii) --C(O)NHC(O)--; [0252] ix) --O--; [0253] x)
--S--; [0254] xi) --SO.sub.2--; [0255] xii) --C(.dbd.NH)--; [0256]
xiii) --C(.dbd.NH)NH--; [0257] xiv) --NHC(.dbd.NH)--; or [0258] xv)
--NHC(.dbd.NH)NH--. When the index y is equal to 1, Q is present.
When the index y is equal to 0, Q is absent. When the index z is
equal to 1, Q.sup.1 is present. When the index z is equal to 0,
Q.sup.1 is absent.
[0259] R.sup.5a and R.sup.5b are each independently: [0260] i)
hydrogen; [0261] ii) hydroxy; [0262] iii) halogen; [0263] iv)
substituted or unsubstituted C.sub.1-C.sub.6 linear or
C.sub.3-C.sub.6 branched alkyl; or [0264] v) a unit having the
formula:
[0264] --[C(R.sup.7aR.sup.7b)].sub.tR.sup.8
wherein R.sup.7a and R.sup.7b are each independently: [0265] i)
hydrogen; or [0266] ii) substituted or unsubstituted
C.sub.1-C.sub.6 linear, C.sub.3-C.sub.6 branched, or
C.sub.3-C.sub.6 cyclic alkyl.
R.sup.8 is:
[0266] [0267] i) hydrogen; [0268] ii) substituted or unsubstituted
C.sub.1-C.sub.6 linear, C.sub.3-C.sub.6 branched, or
C.sub.3-C.sub.6 cyclic alkyl; [0269] iii) substituted or
unsubstituted C.sub.6 or C.sub.10 aryl; [0270] iv) substituted or
unsubstituted C.sub.1-C.sub.9 heteroaryl; or [0271] v) substituted
or unsubstituted C.sub.1-C.sub.9 heterocyclic. R.sup.6a and
R.sup.6b are each independently: [0272] i) hydrogen; or [0273] ii)
C.sub.1-C.sub.4 linear or C.sub.3-C.sub.4 branched alkyl. The
indices t, w and x are each independently from 0 to 4.
[0274] The following are non-limiting examples of units that can
substitute for one or more hydrogen atoms on R.sup.5a, R.sup.5b,
R.sup.7a, R.sup.7b, and R.sup.8 units. The following substituents,
as well as others not herein described, are each independently
chosen: [0275] i) C.sub.1-C.sub.12 linear, branched, or cyclic
alkyl, alkenyl, and alkynyl; methyl (C.sub.1), ethyl (C.sub.2),
ethenyl (C.sub.2), ethynyl (C.sub.2), n-propyl (C.sub.3),
iso-propyl (C.sub.3), cyclopropyl (C.sub.3), 3-propenyl (C.sub.3),
1-propenyl (also 2-methylethenyl) (C.sub.3), isopropenyl (also
2-methylethen-2-yl) (C.sub.3), prop-2-ynyl (also propargyl)
(C.sub.3), propyn-1-yl (C.sub.3), n-butyl (C.sub.4), sec-butyl
(C.sub.4), iso-butyl (C.sub.4), tert-butyl (C.sub.4), cyclobutyl
(C.sub.4), buten-4-yl (C.sub.4), cyclopentyl (C.sub.5), cyclohexyl
(C.sub.6); [0276] ii) substituted or unsubstituted C.sub.6 or
C.sub.10 aryl; for example, phenyl, naphthyl (also referred to
herein as naphthylen-1-yl (C.sub.10) or naphthylen-2-yl
(C.sub.10)); [0277] iii) substituted or unsubstituted C.sub.6 or
C.sub.10 alkylenearyl; for example, benzyl, 2-phenylethyl,
naphthylen-2-ylmethyl; [0278] iv) substituted or unsubstituted
C.sub.1-C.sub.9 heterocyclic rings; as described herein below;
[0279] v) substituted or unsubstituted C.sub.1-C.sub.9 heteroaryl
rings; as described herein below; [0280] vi)
--(CR.sup.41aR.sup.41b).sub.rOR.sup.40; for example, --OH,
--CH.sub.2OH, --OCH.sub.3, --CH.sub.2OCH.sub.3,
--OCH.sub.2CH.sub.3, --CH.sub.2OCH.sub.2CH.sub.3,
--OCH.sub.2CH.sub.2CH.sub.3, and
--CH.sub.2OCH.sub.2CH.sub.2CH.sub.3; [0281] vii)
--(CR.sup.41aR.sup.41b).sub.rC(O)R.sup.40; for example,
--COCH.sub.3, --CH.sub.2COCH.sub.3, --COCH.sub.2CH.sub.3,
--CH.sub.2COCH.sub.2CH.sub.3, --COCH.sub.2CH.sub.2CH.sub.3, and
--CH.sub.2COCH.sub.2CH.sub.2CH.sub.3; [0282] viii)
--(CR.sup.41aR.sup.41b).sub.rC(O)OR.sup.40; for example,
--CO.sub.2CH.sub.3, --CH.sub.2CO.sub.2CH.sub.3,
--CO.sub.2CH.sub.2CH.sub.3, --CH.sub.2CO.sub.2CH.sub.2CH.sub.3,
--CO.sub.2CH.sub.2CH.sub.2CH.sub.3, and
--CH.sub.2CO.sub.2CH.sub.2CH.sub.2CH.sub.3; [0283] ix)
--(CR.sup.41aR.sup.41b).sub.rC(O)N(R.sup.40).sub.2; for example,
--CONH.sub.2, --CH.sub.2CONH.sub.2, --CONHCH.sub.3,
--CH.sub.2CONHCH.sub.3, --CON(CH.sub.3).sub.2, and
--CH.sub.2CON(CH.sub.3).sub.2; [0284] x)
--(CR.sup.41aR.sup.41b).sub.rN(R.sup.40).sub.2; for example,
--NH.sub.2, --CH.sub.2NH.sub.2, --NHCH.sub.3, --CH.sub.2NHCH.sub.3,
--N(CH.sub.3).sub.2, and --CH.sub.2N(CH.sub.3).sub.2; [0285] xi)
halogen; --F, --Cl, --Br, and --I; [0286] xii)
--(CR.sup.41aR.sup.41b).sub.rCN; [0287] xiii)
--(CR.sup.41aR.sup.41b).sub.rNO.sub.2; [0288] xiv)
--(CH.sub.j'X.sub.k').sub.hCH.sub.jX.sub.k; wherein X is halogen,
the index j is an integer from 0 to 2, j+k=3, the index j' is an
integer from 0 to 2, j'+k'=2, the index h is from 0 to 6; for
example, --CH.sub.2F, --CHF.sub.2, --CF.sub.3, --CH.sub.2CF.sub.3,
--CHFCF.sub.3, --CCl.sub.3, or --CBr.sub.3; [0289] xv)
--(CR.sup.41aR.sup.41b).sub.rSR.sup.40; --SH, --CH.sub.2SH,
--SCH.sub.3, --CH.sub.2SCH.sub.3, --SC.sub.6H.sub.5, and
--CH.sub.2SC.sub.6H.sub.5; [0290] xvi)
--(CR.sup.41aR.sup.41b).sub.rSO.sub.2R.sup.40; for example,
--SO.sub.2H, --CH.sub.2SO.sub.2H, --SO.sub.2CH.sub.3,
--CH.sub.2SO.sub.2CH.sub.3, --SO.sub.2C.sub.6H.sub.5, and
--CH.sub.2SO.sub.2C.sub.6H.sub.5; and [0291] xvii)
--(CR.sup.41aR.sup.41b).sub.rSO.sub.3R.sup.40; for example,
--SO.sub.3H, --CH.sub.2SO.sub.3H, --SO.sub.3CH.sub.3,
--CH.sub.2SO.sub.3CH.sub.3, --SO.sub.3C.sub.6H.sub.5, and
--CH.sub.2SO.sub.3C.sub.6H.sub.5; wherein each R.sup.40 is
independently hydrogen, substituted or unsubstituted
C.sub.1-C.sub.6 linear, C.sub.3-C.sub.6 branched, or
C.sub.3-C.sub.6 cyclic alkyl, phenyl, benzyl, heterocyclic, or
heteroaryl; or two R.sup.40 units can be taken together to form a
ring comprising 3-7 atoms; R.sup.41a and R.sup.41b are each
independently hydrogen or C.sub.1-C.sub.4 linear or C.sub.3-C.sub.4
branched alkyl; the index r is from 0 to 4.
[0292] One aspect of L units relates to units having the
formula:
--C(O)[C(R.sup.5aR.sup.5b)].sub.xNHC(O)--
wherein R.sup.5a is hydrogen, substituted or unsubstituted
C.sub.1-C.sub.4 alkyl, substituted or unsubstituted phenyl, and
substituted or unsubstituted heteroaryl; and the index x is 1 or 2.
Some embodiments relate to linking units having the formula: [0293]
i) --C(O)[C(R.sup.5aH)]NHC(O)O--; [0294] ii)
--C(O)[C(R.sup.5aH)][CH.sub.2]NHC(O)O--; [0295] ii)
--C(O)[CH.sub.2][C(R.sup.5aH)]NHC(O)O--; [0296] iv)
--C(O)[C(R.sup.5aH)]NHC(O)--; [0297] v)
--C(O)[C(R.sup.5aH)][CH.sub.2]NHC(O)--; or [0298] vi)
--C(O)[CH.sub.2][C(R.sup.5aH)]NHC(O)--; wherein R.sup.5a is: [0299]
i) hydrogen; [0300] ii) methyl; [0301] iii) ethyl; [0302] iv)
isopropyl; [0303] v) phenyl; [0304] vi) benzyl; [0305] vii)
4-hydroxybenzyl; [0306] viii) hydroxymethyl; or [0307] ix)
1-hydroxyethyl. When the index x is equal to 1, this embodiment
provides the following non-limiting examples of L units:
##STR00024##
[0308] When the index x is equal to 2, this embodiment provides the
following non-limiting examples of L units:
##STR00025##
[0309] Another embodiment of L units includes units wherein Q is
--C(O)--, the indices x and z are equal to 0, w is equal to 1 or 2,
a first R.sup.6a unit chosen from phenyl, 2-fluorophenyl,
3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl,
3,4-difluorophenyl, 3,5-difluorophenyl, 2-chlorophenyl,
3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl,
3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-hydroxyphenyl,
3-hydroxyphenyl, 4-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl,
4-methoxyphenyl, 2,3-dimethoxyphenyl, 3,4-dimethoxyphenyl, and
3,5-dimethoxyphenyl; a second R.sup.6a unit is hydrogen and
R.sup.6b units are hydrogen. For example a linking unit having the
formula:
##STR00026##
[0310] An example of this embodiment of L includes a first R.sup.6a
unit as depicted herein above that is a substituted or
unsubstituted heteroaryl unit as described herein above.
[0311] An example of this embodiment of L includes units having the
formula:
--C(O)[C(R.sup.6aR.sup.6b)].sub.w--;
wherein R.sup.6a and R.sup.6b are hydrogen and the index w is equal
to 1 or 2; said units chosen from: [0312] i) --C(O)CH.sub.2--; and
[0313] ii) --C(O)CH.sub.2CH.sub.2--.
[0314] Another embodiment of L units includes units having the
formula:
--C(O)[C(R.sup.5aR.sup.5b)].sub.xC(O)--;
wherein R.sup.5a and R.sup.5b are hydrogen and the index x is equal
to 1 or 2; said units chosen from: [0315] i) --C(O)CH.sub.2C(O)--;
and [0316] ii) --C(O)CH.sub.2CH.sub.2C(O)--.
[0317] Another embodiment of L units includes units having the
formula:
--C(O)NH[C(R.sup.5aR.sup.5b)].sub.x--;
wherein R.sup.5a and R.sup.5b are hydrogen and the index w is equal
to 0, 1 or 2; said units chosen from: [0318] ii) --C(O)NH--; [0319]
ii) --C(O)NHCH.sub.2--; and [0320] iii)
--C(O)NHCH.sub.2CH.sub.2--.
[0321] An example of L units includes units having the formula:
--SO.sub.2[C(R.sup.6aR.sup.6b)].sub.w--;
wherein R.sup.8a and R.sup.8b are hydrogen or methyl and the index
w is equal to 0, 1 or 2; said units chosen from: [0322] i)
--SO.sub.2--; [0323] ii) --SO.sub.2CH.sub.2--; and [0324] iii)
--SO.sub.2CH.sub.2CH.sub.2--.
Synthetic Schema.
[0325] Disclosed herein are categories of compounds useful for the
methods described herein, and pharmaceutically acceptable salt
forms thereof. For example, a compound having the formula:
##STR00027##
can form salts, for example, a salt of the sulfamic acid:
##STR00028##
[0326] The compounds can also exist in a zwitterionic form, for
example:
##STR00029##
or as a salt of a strong acid, for example:
##STR00030##
[0327] An aspect of Category I of the present disclosure relates to
compounds wherein R is a substituted or unsubstituted thiazol-2-yl
unit having the formula:
##STR00031##
one embodiment of which relates to inhibitors having the
formula:
##STR00032##
wherein R units are thiazol-2-yl units, that when substituted, are
substituted with R.sup.2 and R.sup.3 units. R and R.sup.5a units
are further described in Table I.
TABLE-US-00001 TABLE I No. R R.sup.5a A1 thiazol-2-yl (S)-benzyl A2
4-methylthiazol-2-yl (S)-benzyl A3 4-ethylthiazol-2-yl (S)-benzyl
A4 4-propylthiazol-2-yl (S)-benzyl A5 4-iso-propylthiazol-2-yl
(S)-benzyl A6 4-cyclopropylthiazol-2-yl (S)-benzyl A7
4-butylthiazol-2-yl (S)-benzyl A8 4-tert-butylthiazol-2-yl
(S)-benzyl A9 4-cyclohexylthiazol-2-yl (S)-benzyl A10
4-(2,2,2-trifluoroethyl)thiazol-2-yl (S)-benzyl A11
4-(3,3,3-trifluoropropyl)thiazol-2-yl (S)-benzyl A12
4-(2,2-difluorocyclopropyl)thiazol-2-yl (S)-benzyl A13
4-(methoxymethyl)thiazol-2-yl (S)-benzyl A14 4-(carboxylic acid
ethyl ester)thiazol-2-yl (S)-benzyl A15 4,5-dimethylthiazol-2-yl
(S)-benzyl A16 4-methyl-5-ethylthiazol-2-yl (S)-benzyl A17
4-phenylthiazol-2-yl (S)-benzyl A18 4-(4-chlorophenyl)thiazol-2-yl
(S)-benzyl A19 4-(3,4-dimethylphenyl)thiazol-2-yl (S)-benzyl A20
4-methyl-5-phenylthiazol-2-yl (S)-benzyl A21
4-(thiophen-2-yl)thiazol-2-yl (S)-benzyl A22
4-(thiophen-3-yl)thiazol-2-yl (S)-benzyl A23
4-(5-chlorothiophen-2-yl)thiazol-2-yl (S)-benzyl A24
5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl (S)-benzyl A25
4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl (S)-benzyl
[0328] The compounds encompassed within the first aspect of
Category I of the present disclosure can be prepared by the
procedure outlined in Scheme I and described in Example 1
below.
##STR00033## ##STR00034##
Example 1
4-{(S)-2-[(S)-2-(tert-Butoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethyl-
thiazol-2-yl)ethyl}phenylsulfamic acid (5)
Preparation of [1-(S)-carbamoyl-2-(4-nitrophenyl)ethyl-carbamic
acid tert-butyl ester (1)
[0329] To a 0.degree. C. solution of
2-(S)-tert-butoxycarbonylamino-3-(4-nitrophenyl)-propionic acid and
N-methylmorpholine (1.1 mL, 9.65 mmol) in DMF (10 mL) is added
dropwise iso-butyl chloroformate (1.25 mL, 9.65 mmol). The mixture
is stirred at 0.degree. C. for 20 minutes after which NH.sub.3 (g)
is passed through the reaction mixture for 30 minutes at 0.degree.
C. The reaction mixture is concentrated and the residue dissolved
in EtOAc, washed successively with 5% citric acid, water, 5%
NaHCO.sub.3, water and brine, dried (Na.sub.2SO.sub.4), filtered
and concentrated in vacuo to a residue that is triturated with a
mixture of EtOAc/petroleum ether to provide 2.2 g (74%) of the
desired product as a white solid.
Preparation of [2-(4-nitrophenyl)-1-(S)-thiocarbamoylethyl]carbamic
acid tert-butyl ester (2)
[0330] To a solution of
[1-(S)-carbamoyl-2-(4-nitrophenyl)ethyl-carbamic acid tert-butyl
ester, 1, (0.400 g, 1.29 mmol) in THF (10 mL) is added Lawesson's
reagent (0.262 g. 0.65 mmol). The reaction mixture is stirred for 3
hours and concentrated to a residue which is purified over silica
to provide 0.350 g (83%) of the desired product. .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 8.29 (s, 1H), 8.10 (d. J=8.4 Hz, 2H), 8.01
(s, 1H), 7.42 (d, J=8.4 Hz, 2H), 5.70 (d, J=7.2 Hz, 1H), 4.85 (d,
J=7.2 Hz, 1H), 3.11-3.30 (m, 1H), 1.21 (s, 9H).
Preparation of 1-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl
amine (3)
[0331] A mixture of
[2-(4-nitrophenyl)-1-(S)-thiocarbamoylethyl]-carbamic acid
tert-butyl ester, 2, (0.245 g, 0.753 mmol), 1-bromo-2-butanone
(0.125 g, 0.828 mmol) in CH.sub.3CN (5 mL) is refluxed 3 hours. The
reaction mixture is cooled to room temperature and diethyl ether is
added to the solution and the precipitate which forms is removed by
filtration. The solid is dried under vacuum to afford 0.242 g (90%
yield) of the desired product. ESI+ MS 278 (M+1).
Preparation of
{1-[1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethylcarbamoyl]-2-phenylethy-
l} carbamic acid tert-butyl ester (4)
[0332] To a solution of
1-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl amine
hydrobromide, 3, (0.393 g, 1.1 mmol),
(S)-(2-tert-butoxycarbonylamino)-3-phenylpropionic acid (0.220 g,
0.828 mmol) and 1-hydroxybenzotriazole (HOBt) (0.127 g, 0.828 mmol)
in DMF (10 mL) at 0.degree. C., is added
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0.159 g,
0.828 mmol) followed by diisopropylamine (0.204 g, 1.58 mmol). The
mixture is stirred at 0.degree. C. for 30 minutes then at room
temperature overnight. The reaction mixture is diluted with water
and extracted with EtOAc. The combined organic phase is washed with
1 N aqueous HCl, 5% aqueous NaHCO.sub.3, water and brine, and dried
over Na.sub.2SO.sub.4. The solvent is removed in vacuo to afford
0.345 g of the desired product which is used without further
purification. LC/MS ESI+525 (M+1).
Preparation of
4-{(S)-2-[(S)-2-(tert-butoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethy-
lthiazol-2-yl)ethyl}phenylsulfamic acid ammonium salt (5)
[0333]
{1-[1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethylcarbamoyl]-2-phen-
ylethyl} carbamic acid tert-butyl ester, 4, (0.345 g) is dissolved
in MeOH (4 mL). A catalytic amount of Pd/C (10% w/w) is added and
the mixture is stirred under a hydrogen atmosphere 2 hours. The
reaction mixture is filtered through a bed of CELITE.TM. and the
solvent is removed under reduced pressure. The crude product is
dissolved in pyridine (12 mL) and treated with SO.sub.3-pyridine
(0.314 g). The reaction is stirred at room temperature for 5
minutes after which a 7% solution of NH.sub.4OH (50 mL) is added.
The mixture is then concentrated and the resulting residue is
purified by reverse phase chromatography to afford 0.222 g of the
desired product as the ammonium salt. .sup.1H NMR (CD.sub.3OD
.delta. 7.50-6.72 (m, 10H), 5.44-5.42 (d, 1H, J=6.0 Hz), 4.34 (s,
1H), 3.34-2.79 (m, 4H), 2.83-2.76 (q, 2H, J=7.2 Hz), 1.40 (s, 9H),
1.31 (t, 3H, J=7.5 Hz).
[0334] The disclosed inhibitors can also be isolated as the free
acid. A non-limiting example of this procedure is described herein
below in Example 4.
[0335] The following is a non-limiting example of compounds
encompassed within this embodiment of the first aspect of Category
I of the present disclosure.
##STR00035##
4-{(S)-2-[(R)-2-(tert-butoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethy-
lthiazol-2-yl)ethyl}phenylsulfamic acid
[0336] .sup.1H NMR (CD.sub.3OD .delta. 7.22-7.02 (m, 10H), 5.39 (s,
1H), 4.34 (s, 1H), 3.24-2.68 (m, 6H), 1.37 (s, 9H), 1.30 (t, 3H,
J=7.5 Hz).
[0337] Another embodiment of this aspect of Category I relates to
inhibitors having the formula:
##STR00036##
wherein R units and R.sup.5a units further described in Table
II.
TABLE-US-00002 TABLE II No. R R.sup.5a B26 thiazol-2-yl (S)-benzyl
B27 4-methylthiazol-2-yl (S)-benzyl B28 4-ethylthiazol-2-yl
(S)-benzyl B29 4-propylthiazol-2-yl (S)-benzyl B30
4-iso-propylthiazol-2-yl (S)-benzyl B31 4-cyclopropylthiazol-2-yl
(S)-benzyl B32 4-butylthiazol-2-yl (S)-benzyl B33
4-tert-butylthiazol-2-yl (S)-benzyl B34 4-cyclohexylthiazol-2-yl
(S)-benzyl B35 4-(2,2,2-trifluoroethyl)thiazol-2-yl (S)-benzyl B36
4-(3,3,3-trifluoropropyl)thiazol-2-yl (S)-benzyl B37
4-(2,2-difluorocyclopropyl)thiazol-2-yl (S)-benzyl B38
4-(methoxymethyl)thiazol-2-yl (S)-benzyl B39 4-(carboxylic acid
ethyl ester)thiazol-2-yl (S)-benzyl B40 4,5-dimethylthiazol-2-yl
(S)-benzyl B41 4-methyl-5-ethylthiazol-2-yl (S)-benzyl B42
4-phenylthiazol-2-yl (S)-benzyl B43 4-(4-chlorophenyl)thiazol-2-yl
(S)-benzyl B44 4-(3,4-dimethylphenyl)thiazol-2-yl (S)-benzyl B45
4-methyl-5-phenylthiazol-2-yl (S)-benzyl B46
4-(thiophen-2-yl)thiazol-2-yl (S)-benzyl B47
4-(thiophen-3-yl)thiazol-2-yl (S)-benzyl B48
4-(5-chlorothiophen-2-yl)thiazol-2-yl (S)-benzyl B49
5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl (S)-benzyl B50
4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl (S)-benzyl
[0338] The compounds of this embodiment can be prepared according
to the procedure outlined above in Scheme I and described in
Example 1 by substituting the appropriate Boc-.beta.-amino acid for
(S)-(2-tert-butoxycarbonylamino)-3-phenylpropionic acid in step
(d).
[0339] The following are non-limiting examples of compounds
according to this embodiment.
##STR00037##
{1-[1-(4-Ethylthiazol-2-yl)-(S)-2-(4-sulfoaminophenyl)ethylcarbamoyl]-(S)-
-2-phenylethyl}methyl carbamic acid tert-butyl ester
[0340] .sup.1H NMR (300 MHz, MeOH-d.sub.4) .delta. 8.36 (d, J=8.1
Hz, 1H), 7.04-7.22 (m, 9H), 5.45 (s, 1H), 3.01-3.26 (m, 2H),
2.60-2.88 (m, 4H), 2.33 (s, 3H), 1.30 (s, 9H).
##STR00038##
{1-[1-(4-Phenylthiazol-2-yl)-(S)-2-(4-sulfoaminophenyl)ethylcarbamoyl]-(S-
)-2-phenylethyl}methyl carbamic acid tert-butyl ester
[0341] .sup.1H NMR (300 MHz, MeOH-d.sub.4) .delta. 8.20 (d, J=8.1
Hz, 1H), 7.96-7.99 (m, 2H), 7.48-7.52 (m, 3H), 7.00-7.23 (m, 7H),
6.89 (s, 1H), 5.28 (q, J=7.5 Hz, 1H), 4.33 (t, J=6.6 Hz, 1H),
3.09-3.26 (m, 2H), 3.34 (dd, J=13.2 and 8.4 Hz, 1H), 2.82 (dd,
J=13.2 and 8.4 Hz, 1H), 1.38 (s, 9H).
[0342] The second aspect of Category I of the present disclosure
relates to compounds wherein R is a substituted or unsubstituted
thiazol-4-yl having the formula:
##STR00039##
one embodiment of which relates to inhibitors having the
formula:
##STR00040##
wherein R units and R.sup.5a units further described in Table
III.
TABLE-US-00003 TABLE III No. R R.sup.5a C51 thiazol-4-yl (S)-benzyl
C52 2-methylthiazol-4-yl (S)-benzyl C53 2-ethylthiazol-4-yl
(S)-benzyl C54 2-propylthiazol-4-yl (S)-benzyl C55
2-iso-propylthiazol-4-yl (S)-benzyl C56 2-cyclopropylthiazol-4-yl
(S)-benzyl C57 2-butylthiazol-4-yl (S)-benzyl C58
2-tert-butylthiazol-4-yl (S)-benzyl C59 2-cyclohexylthiazol-4-yl
(S)-benzyl C60 2-(2,2,2-trifluoroethyl)thiazol-4-yl (S)-benzyl C61
2-(3,3,3-trifluoropropyl)thiazol-4-yl (S)-benzyl C62
2-(2,2-difluorocyclopropyl)thiazol-4-yl (S)-benzyl C63
2-phenylthiazol-4-yl (S)-benzyl C64 2-(4-chlorophenyl)thiazol-4-yl
(S)-benzyl C65 2-(3,4-dimethylphenyl)thiazol-4-yl (S)-benzyl C66
2-(thiophen-2-yl)thiazol-4-yl (S)-benzyl C67
2-(thiophen-3-yl)thiazol-4-yl (S)-benzyl C68
2-(3-chlorothiophen-2-yl)thiazol-4-yl (S)-benzyl C69
2-(3-methylthiophen-2-yl)thiazol-4-yl (S)-benzyl C70
2-(2-methylthiazol-4-yl)thiazol-4-yl (S)-benzyl C71
2-(furan-2-yl)thiazol-4-yl (S)-benzyl C72
2-(pyrazin-2-yl)thiazol-4-yl (S)-benzyl C73
2-[(2-methyl)pyridin-5-yl]thiazol-4-yl (S)-benzyl C74
2-(4-chlorobenzenesulfonylmethyl)thiazol-4-yl (S)-benzyl C75
2-(tert-butylsulfonylmethyl)thiazol-4-yl (S)-benzyl
[0343] The compounds encompassed within the second aspect of
Category I of the present disclosure can be prepared by the
procedure outlined in Scheme II and described in Example 2 herein
below.
##STR00041##
Example 2
4-{(S)-2-(S)-2-(tert-Butoxycarbonylamino)-3-phenylpropanamido-2-(2-phenylt-
hiazol-4-yl)}phenylsulfamic acid (9)
Preparation of
(S)-[3-diazo-1-(4-nitrobenzyl)-2-oxo-propyl]-carbamic acid
tert-butyl ester (6)
[0344] To a 0.degree. C. solution of
2-(S)-tert-butoxycarbonylamino-3-(4-nitrophenyl)-propionic acid
(1.20 g, 4.0 mmol) in THF (20 mL) is added dropwise triethylamine
(0.61 mL, 4.4 mmol) followed by iso-butyl chloroformate (0.57 mL,
4.4 mmol). The reaction mixture is stirred at 0.degree. C. for 20
minutes and filtered. The filtrate is treated with an ether
solution of diazomethane (.about.16 mmol) at 0.degree. C. The
reaction mixture is stirred at room temperature for 3 hours then
concentrated in vacuo. The resulting residue is dissolved in EtOAc
and washed successively with water and brine, dried
(Na.sub.2SO.sub.4), filtered and concentrated. The residue is
purified over silica (hexane/EtOAc 2:1) to afford 1.1 g (82% yield)
of the desired product as a slightly yellow solid. .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 8.16 (d, J=8.7 Hz, 2H), 7.39 (d, J=8.7 Hz,
2H), 5.39 (s, 1H), 5.16 (d, J=6.3 Hz, 1H), 4.49 (s, 1H), 3.25 (dd,
J=13.8 and 6.6, 1H), 3.06 (dd, J=13.5 and 6.9 Hz, 1H), 1.41 (s,
9H).
Preparation of (S)-tert-butyl
4-bromo-1-(4-nitrophenyl)-3-oxobutan-2-ylcarbamate (7)
[0345] To a 0.degree. C. solution of
(S)-[3-diazo-1-(4-nitrobenzyl)-2-oxo-propyl]-carbamic acid
tert-butyl ester, 6, (0.350 g, 1.04 mmol) in THF (5 mL) is added
dropwise 48% aq. HBr (0.14 mL, 1.25 mmol). The reaction mixture is
stirred at 0.degree. C. for 1.5 hours then the reaction is quenched
at 0.degree. C. with sat. Na.sub.2CO.sub.3. The mixture is
extracted with EtOAc (3.times.25 mL) and the combined organic
extracts are washed with brine, dried (Na.sub.2SO.sub.4), filtered
and concentrated to obtain 0.400 g of the product which is used in
the next step without further purification. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 8.20 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H),
5.06 (d, J=7.8 Hz, 1H), 4.80 (q, J=6.3 Hz, 1H), 4.04 (s, 2H), 1.42
(s, 9H).
Preparation of tert-butyl
(S)-1-(S)-2-(4-nitrophenyl)-1-(2-phenylthiazole-4-yl)ethylamino-1-oxo-3-p-
henylpropan-2-ylcarbamate (8)
[0346] A mixture of thiobenzamide (0.117 g, 0.85 mmol) and
(S)-tert-butyl 4-bromo-1-(4-nitrophenyl)-3-oxobutan-2-ylcarbamate,
7, (0.300 g, 0.77 mmol) in CH.sub.3CN (4 mL) is refluxed 2 hours.
The reaction mixture is cooled to room temperature and diethyl
ether is added to precipitate the intermediate
2-(nitrophenyl)-(S)-1-(4-phenylthiazol-2-yl)ethylamine which is
isolated by filtration as the hydrobromide salt. The hydrobromide
salt is dissolved in DMF (3 mL) together with diisoproylethylamine
(0.42 mL, 2.31 mmol), 1-hydroxybenzotriazole (0.118 g, 0.79 mmol)
and (S)-(2-tert-butoxycarbonyl-amino)-3-phenylpropionic acid (0.212
g, 0.80 mmol). The mixture is stirred at 0.degree. C. for 30
minutes then at room temperature overnight. The reaction mixture is
diluted with water and extracted with EtOAc. The combined organic
phase is washed with 1 N aqueous HCl, 5% aqueous NaHCO.sub.3, water
and brine, and dried over Na.sub.2SO.sub.4. The solvent is removed
in vacuo to afford 0.395 g (90% yield) of the desired product which
is used without further purification. LC/MS ESI+573 (M+1).
Preparation of
4-{(S)-2-(S)-2-(tert-butoxycarbonyl)-3-phenylpropaneamido-2-(2-phenylthia-
zole-4-yl)}phenylsulfamic acid (9)
[0347] tert-butyl
(S)-1-(S)-2-(4-nitrophenyl)-1-(2-phenylthiazole-4-yl)ethylamino-1-oxo-3-p-
henylpropan-2-ylcarbamate, 8, (0.360 g) is dissolved in MeOH (4
mL). A catalytic amount of Pd/C (10% w/w) is added and the mixture
is stirred under a hydrogen atmosphere 12 hours. The reaction
mixture is filtered through a bed of CELITE.TM. and the solvent is
removed under reduced pressure. The crude product is dissolved in
pyridine (12 mL) and treated with SO.sub.3-pyridine (0.296 g). The
reaction is stirred at room temperature for 5 minutes after which a
7% solution of NH.sub.4OH (10 mL) is added. The mixture is then
concentrated and the resulting residue is purified by reverse phase
chromatography to afford 0.050 g of the desired product as the
ammonium salt. .sup.1H NMR (300 MHz, MeOH-d.sub.4) .delta. 8.20 (d,
J=8.1 Hz, 1H), 7.96-7.99 (m, 2H), 7.48-7.52 (m, 3H), 7.00-7.23 (m,
7H), 6.89 (s, 1H), 5.28 (q, J=7.5 Hz, 1H), 4.33 (t, J=6.6 Hz, 1H),
3.09-3.26 (m, 2H), 3.34 (dd, J=13.2 and 8.4 Hz, 1H), 2.82 (dd,
J=13.2 and 8.4 Hz, 1H), 1.38 (s, 9H).
[0348] An aspect of Category II of the present disclosure relates
to compounds wherein R is a substituted or unsubstituted
thiazol-4-yl unit having the formula:
##STR00042##
one embodiment of which relates to inhibitors having the
formula:
##STR00043##
wherein R units are thiazol-4-yl units, that when substituted, are
substituted with R.sup.4 units. R and R.sup.5a units are further
described in Table IV.
TABLE-US-00004 TABLE IV No. R R.sup.5a D76 thiazol-4-yl (S)-benzyl
D77 2-methylthiazol-4-yl (S)-benzyl D78 2-ethylthiazol-4-yl
(S)-benzyl D79 2-propylthiazol-4-yl (S)-benzyl D80
2-iso-propylthiazol-4-yl (S)-benzyl D81 2-cyclopropylthiazol-4-yl
(S)-benzyl D82 2-butylthiazol-4-yl (S)-benzyl D83
2-tert-butylthiazol-4-yl (S)-benzyl D84 2-cyclohexylthiazol-4-yl
(S)-benzyl D85 2-(2,2,2-trifluoroethyl)thiazol-4-yl (S)-benzyl D86
2-(3,3,3-trifluoropropyl)thiazol-4-yl (S)-benzyl D87
2-(2,2-difluorocyclopropyl)thiazol-4-yl (S)-benzyl D88
2-phenylthiazol-4-yl (S)-benzyl D89 2-(4-chlorophenyl)thiazol-4-yl
(S)-benzyl D90 2-(3,4-dimethylphenyl)thiazol-4-yl (S)-benzyl D91
2-(thiophen-2-yl)thiazol-4-yl (S)-benzyl D92
2-(thiophen-3-yl)thiazol-4-yl (S)-benzyl D93
2-(3-chlorothiophen-2-yl)thiazol-4-yl (S)-benzyl D94
2-(3-methylthiophen-2-yl)thiazol-4-yl (S)-benzyl D95
2-(2-methylthiazol-4-yl)thiazol-4-yl (S)-benzyl D96
2-(furan-2-yl)thiazol-4-yl (S)-benzyl D97
2-(pyrazin-2-yl)thiazol-4-yl (S)-benzyl D98
2-[(2-methyl)pyridin-5-yl]thiazol-4-yl (S)-benzyl D99
2-(4-chlorobenzenesulfonylmethyl)thiazol-4-yl (S)-benzyl D100
2-(tert-butylsulfonylmethyl)thiazol-4-yl (S)-benzyl
[0349] The compounds encompassed within the second aspect of
Category II of the present disclosure can be prepared by the
procedure outlined in Scheme III and described in Example 3 herein
below.
##STR00044##
Example 3
4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthia-
zol-4-yl) ethyl}phenylsulfamic acid (13)
Preparation of methyl
(S)-1-[(S)-1-(2-ethylthiazole-4-yl)-2-(4-nitrophenyl)-ethyl]amino-1-oxo-3-
-phenylpropane-2-ylcarbamate (12)
[0350] A mixture of propanethioamide (69 mg, 0.78 mmol) and
(S)-tert-butyl 4-bromo-1-(4-nitrophenyl)-3-oxobutan-2-ylcarbamate,
7, (0.300 g, 0.77 mmol) in CH.sub.3CN (4 mL) is refluxed for 2
hours. The reaction mixture is cooled to room temperature and
diethyl ether is added to precipitate the intermediate
2-(nitrophenyl)-(S)-1-(4-ethylthiazol-2-yl)ethylamine which is
isolated by filtration as the hydrobromide salt. The hydrobromide
salt is dissolved in DMF (8 mL) together with diisoproylethylamine
(0.38 mL, 2.13 mmol), 1-hydroxybenzotriazole (107 mg, 0.71 mmol)
and (S)-(2-methoxycarbonyl-amino)-3-phenylpropionic acid (175 mg,
0.78 mmol). The mixture is stirred at 0.degree. C. for 30 minutes
then at room temperature overnight. The reaction mixture is diluted
with water and extracted with EtOAc. The combined organic phase is
washed with 1 N aqueous HCl, 5% aqueous NaHCO.sub.3, water and
brine, and dried over Na.sub.2SO.sub.4. The solvent is removed in
vacuo to afford 0.300 g (81% yield) of the desired product which is
used without further purification. LC/MS ESI+ MS 483 (M+1).
Preparation of
4-((S)-2-((S)-2-(methoxycarbonylamino)-3-phenylpropanamido)-2-(2-ethylthi-
azol-4-yl) ethyl)phenylsulfamic acid ammonium salt (13)
[0351] tert-Butyl
(S)-1-(S)-2-(4-nitrophenyl)-1-(2-ethylthiazole-4-yl)ethylamino-1-oxo-3-ph-
enylpropan-2-ylcarbamate, 12, (0.300 g) is dissolved in MeOH (4
mL). A catalytic amount of Pd/C (10% w/w) is added and the mixture
is stirred under a hydrogen atmosphere 18 hours. The reaction
mixture is filtered through a bed of CELITE.TM. and the solvent is
removed under reduced pressure. The crude product is dissolved in
pyridine (12 mL) and treated with SO.sub.3-pyridine (223 mg, 1.40
mmol). The reaction is stirred at room temperature for 5 minutes
after which a 7% solution of NH.sub.4OH (12 mL) is added. The
mixture is then concentrated and the resulting residue is purified
by reverse phase chromatography to afford 25 mg of the desired
product as the ammonium salt. .sup.1H NMR (300 MHz, MeOH-d.sub.4)
.delta. 7.14-7.24 (m, 6H), 6.97-7.0 (m, 4H), 6.62 (s, 1H),
5.10-5.30 (.mu., 1H), 4.36 (t, J=7.2 Hz, 1H), 3.63 (s, 3H), 3.14
(dd, J=13.5 and 6.3 Hz, 1H), 2.93-3.07 (m, 5H), 2.81 (dd, J=13.5
and 6.3 HZ, 1H), 1.39 (t, J=7.8 Hz, 3H).
[0352] In another iteration of the process of the present
disclosure, compound 13, as well as the other analogues which
comprise the present disclosure, can be isolated as the free acid
by adapting the procedure described herein below.
##STR00045## ##STR00046##
Example 4
4-((S)-2-((S)-2-(Methoxycarbonylamino)-3-phenylpropanamido)-2-(2-ethylthia-
zol-4-yl) ethyl)phenylsulfamic acid [Free Acid Form] (13)
Preparation of
{1-[2-(S)-(4-(S)-aminophenyl)-1-(2-ethylthiazol-4-yl)ethyl-carbamoyl]-2-p-
henylethyl}-carbamic acid methyl ester (12a)
[0353] A Parr hydrogenation vessel is charged with tert-butyl
(S)-1-(S)-2-(4-nitrophenyl)-1-(2-ethylthiazole-4-yl)ethylamino-1-oxo-3-ph-
enylpropan-2-ylcarbamate, 12, (18.05 g, 37.4 mmol, 1.0 eq) and Pd/C
(10% Pd on C, 50% wet, Degussa-type E101 NE/W, 2.68 g, 15 wt %) as
solids. MeOH (270 mL, 15 mL/g) is added to provide a suspension.
The vessel is put on a Parr hydrogenation apparatus. The vessel is
submitted to a fill/vacuum evacuate process with N.sub.2
(3.times.20 psi) to inert, followed by the same procedure with
H.sub.2 (3.times.40 psi). The vessel is filled with H.sub.2 and the
vessel is shaken under 40 psi H.sub.2 for .about.40 hr. The vessel
is evacuated and the atmosphere is purged with N.sub.2 (5.times.20
psi). An aliquot is filtered and analyzed by HPLC to insure
complete conversion. The suspension is filtered through a pad of
celite to remove the catalyst, and the homogeneous yellow filtrate
is concentrated by rotary evaporation to afford 16.06 g (95% yield)
of the desired product as a tan solid, which is used without
further purification.
Preparation of
4-((S)-2-((S)-2-(methoxycarbonyl)-3-phenylpropanamido)-2-(2-ethylthiazol--
4-yl) ethyl)phenylsulfamic acid (13)
[0354] A 100 mL RBF is charged with
{1-[2-(S)-(4-(S)-aminophenyl)-1-(2-ethylthiazol-4-yl)ethyl-carbamoyl]-2-p-
henylethyl}-carbamic acid methyl ester, 12a, (10.36 g, 22.9 mmol,
1.0 eq.) prepared in the step described herein above. Acetonitrile
(50 mL, 5 mL/g) is added and the yellow suspension is stirred at
room temperature. A second 3-necked 500 mL RBF is charged with
SO.sub.3.pyr (5.13 g, 32.2 mmol, 1.4 eq.) and acetonitrile (50 mL 5
mL/g) and the white suspension is stirred at room temperature. Both
suspensions are gently heated until the reaction solution
containing
{1-[2-(S)-(4-(S)-aminophenyl)-1-(2-ethylthiazol-4-yl)ethyl-carbamoyl]-2-p-
henylethyl}-carbamic acid methyl ester becomes red-orange in color
(typically for this example about 44.degree. C.). This substrate
containing solution is poured in one portion into the stirring
suspension of SO.sub.3.pyr at 35.degree. C. The resulting opaque
mixture (39.degree. C.) is stirred vigorously while allowed to
slowly cool to room temperature. After stirring for 45 min, the
reaction is determined to be complete by HPLC. H.sub.2O (200 mL, 20
mL/g) is added to the orange suspension to provide a yellow-orange
homogeneous solution having a pH of approximately 2.4. Concentrated
H.sub.3PO.sub.4 is added slowly over 12 minutes to lower the pH to
approximately 1.4. During this pH adjustment, an off-white
precipitate is formed and the solution is stirred at room
temperature for 1 hr. The suspension is filtered and the filter
cake is washed with the filtrate. The filter cake is air-dried on
the filter overnight to afford 10.89 g (89% yield) of the desired
product as a tan solid.
[0355] The following are further non-limiting examples of the
second aspect of Category II of the present disclosure.
##STR00047##
4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(2-methylth-
iazol-4-yl)ethyl}phenylsulfamic acid
[0356] .sup.1H NMR (300 MHz, MeOH-d.sub.4) .delta. 8.15 (d, J=8.4
Hz, 1H), 7.16-7.25 (m, 5H), 6.97-7.10 (m, 4H), 6.61 (s, 1H),
5.00-5.24 (m, 1H), 4.36 (t, J=7.2 Hz, 1H), 3.64 (s, 3H), 3.11-3.19
(s, 1H), 2.92-3.04 (s, 2H), 2.81 (dd, J=13.5 and 8.1 Hz, 1H), 2.75
(s, 3H).
##STR00048##
4-{(S)-2-(2-Ethylthiazole-4-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylp-
ropan-amido]ethyl}phenylsulfamic acid
[0357] .sup.1H NMR (300 MHz, MeOH-d.sub.4) .delta. 7.16-7.29 (m,
5H), 7.02-7.12 (m, 4H), 6.83 (s, 1H), 5.10-5.35 (m, 1H), 3.52-3.67
(m, 3H), 3.18-3.25 (m, 2H), 3.05 (q, J=7.5 Hz, 2H), 2.82-2.95 (m,
2H), 2.65 (s, 3H), 1.39 (t, J=7.5 Hz, 3H).
##STR00049##
4-{(S)-2-(2-Isopropylthiazol-4-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phen-
ylpropan-amido]ethyl}phenylsulfamic acid
[0358] .sup.1H NMR (CD.sub.3OD) .delta. 8.16 (d, 1H, J=8.7 Hz),
7.22-7.13 (m, 3H), 7.07 (d, 1H, J=8.4 Hz), 6.96 (d, 1H, J=8.1 Hz),
6.62 (s, 1H), 5.19 (t, 1H, J=7.2 Hz), 4.36 (t, 1H, J=7.8 Hz), 3.63
(s, 3H), 3.08 (1H, A of ABX, J=3.6, 14.5 Hz), 2.99 (1H, B of ABX,
J=7.2, 13.8 Hz), 2.85-2.78 (m, 1H), 1.41 (d, 6H, J=6.9 Hz).
##STR00050##
4-{(S)-2-(2-Cyclopropylthiazol-4-yl)-2-[(S)-2-(methoxycarbonylamino)-3-ph-
enylpropanamido]ethyl}phenylsulfamic acid
[0359] .sup.1H NMR (CD.sub.3OD): .delta. 7.15-7.02 (m, 5H),
6.96-6.93 (d, 2H, J=8.4 Hz), 6.86-6.83 (d, 2H, J=8.3 Hz), 6.39 (s,
1H), 5.01 (t, 1H, J=5.0 Hz), 4.22 (t, 1H, J=7.4 Hz), 3.51 (s, 3H),
2.98-2.69 (m, 2H), 2.22-2.21 (m, 1H), 1.06-1.02 (m, 2H), 0.92-0.88
(m, 2H).
##STR00051##
4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropionamido]-2-(2-phenylt-
hiazole-4-yl)ethyl}phenylsulfamic acid
[0360] .sup.1H NMP (300 MHz, DMSO-d.sub.6) .delta. 7.96-7.99 (m,
2H), 7.51-7.56 (m, 3H), 7.13-7.38 (m, 6H), 6.92-6.95 (m, 4H),
5.11-5.16 (m, 1H), 4.32-4.35 (m, 1H), 3.51 (s, 3H), 3.39-3.40 (m,
2H), 3.09-3.19 (m, 1H), 2.92-3.02 (m, 2H), 2.75 (dd, J=10.5 Hz and
9.9 Hz, 1H).
##STR00052##
4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid
[0361] .sup.1H NMR (CD.sub.3OD): .delta. 7.61-7.56 (m, 2H),
7.25-7.01 (m, 10H), 6.75 (s, 1H), 5.24-5.21 (q, 1H, J=7.2 Hz), 4.38
(t, 1H, J=7.2 Hz), 3.60 (s, 3H), 3.23-3.14 (m, 1H), 3.08-3.00 (m,
2H), 2.87-2.80 (m, 1H).
##STR00053##
4-{(S)-2-[2-(3-Chlorothiophen-2-yl)thiazol-4-yl]-2-[(S)-2-(methoxycarbony-
lamino)-3-phenylpropanamido]ethyl}phenylsulfamic acid
[0362] .sup.1H NMR (CD.sub.3OD): .delta. 7.78-7.76 (d, 1H, J=5.4
Hz), 7.36-7.14 (m, 10H), 7.03 (s, 1H), 5.39 (t, 1H, J=6.9 Hz), 4.54
(t, 1H, J=7.3 Hz), 3.80 (s, 3H), 3.39-2.98 (m, 4H).
##STR00054##
4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(3-methy-
lthiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid
[0363] .sup.1H NMR (CD.sub.3OD): .delta. 7.38 (d, 1H, J=5.1 Hz),
7.15-6.93 (m, 10H), 6.73 (s, 1H), 5.17 (t, 1H, J=6.9 Hz), 4.31 (t,
1H, J=7.3 Hz), 3.57 (s, 3H), 3.18-3.11 (m, 1H), 3.02-2.94 (m, 2H),
2.80-2.73 (m, 1H), 2.46 (s, 3H).
##STR00055##
4-{[(S)-2-(2-(Furan-2-yl)thiazol-4-yl]-2-[(S)-2-(methoxycarbonylamino)-3--
phenylpropanamido]ethyl}phenylsulfamic acid
[0364] .sup.1H NMR (CD.sub.3OD): .delta. 7.54-7.46 (m, 1H),
7.02-6.79 (m, 10H), 6.55-6.51 (m, 1H), 6.44-6.41 (m, 1H), 5.02-5.00
(q, 1H, J=6.4 Hz), 4.16-4.14 (q, 1H, J=7.1 Hz), 3.43 (s, 3H),
2.96-2.58 (m, 4H).
##STR00056##
4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(2-methy-
lthiazole-4-yl)thiazole-4yl]ethyl}phenylsulfamic acid
[0365] .sup.1H NMR (300 MHz, MeOH-d.sub.4) .delta. 8.27 (d, J=5.4
Hz, 1H), 7.97 (s, 1H), 6.99-7.21 (m, 8H), 5.18-5.30 (m, 1H),
4.30-4.39 (m, 1H), 3.64 (s, 3H), 3.20 (dd, J=14.1 and 6.6 Hz, 1H),
2.98-3.08 (m, 2H), 2.84 (dd, J=14.1 and 6.6 Hz, 1H), 2.78 (s,
3H).
##STR00057##
4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[(2-pyrazin-
-2-yl)thiazole-4-yl]ethyl}phenylsulfamic acid
[0366] .sup.1H NMR (300 MHz, MeOH-d.sub.4) .delta. 9.34 (s, 1H),
8.65 (s, 2H), 8.34 (d, J=8.1 Hz, 1H), 7.00-5.16 (m. 9H), 5.30 (q,
J=7.2 Hz, 1H), 4.41 (t, J=7.2 Hz, 1H), 3.65 (s, 3H), 3.23 (dd,
J=13.8 and 6.9 Hz, 1H), 2.98-3.13 (m, 2H), 2.85 (dd, J=13.8 and 6.9
Hz, 1H).
##STR00058##
4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(6-methy-
lpyridin-3-yl)thiazol-4-yl]ethyl}phenylsulfamic acid
[0367] .sup.1H NMR (CD.sub.3OD): .delta. 8.90 (s, 1H), 8.19-8.13
(m, 1H), 7.39-7.36 (d, 1H, J=8.2 Hz), 7.07-6.88 (m, 9H), 6.79 (s,
1H), 5.17 (t, 1H, J=7.0 Hz), 4.29 (t, 1H, J=7.4 Hz), 3.54 (s, 3H),
3.10-2.73 (m, 4H), 2.53 (s, 3H).
##STR00059##
4-{(S)-2-{2-[(4-Chlorophenylsulfonyl)methyl]thiazol-4-yl}-2-[(S)-2-(metho-
xy-carbonylamino)-3-phenylpropanamido]ethyl}phenylsulfamic acid
[0368] .sup.1H NMR (CD.sub.3OD): .delta. 7.96-7.93 (d, 2H, J=8.6
Hz), 7.83-7.80 (d, 2H, J=8.6 Hz), 7.44-7.34 (m, 5H), 7.29-7.27 (d,
2H, J=8.4 Hz), 7.14-7.11 (d, 2H, J=8.4 Hz), 6.97 (s, 1H), 5.31 (t,
1H, J=6.8 Hz), 5.22-5.15 (m, 2H), 4.55 (t, 1H, J=7.3 Hz), 3.84 (s,
3H), 3.20-2.96 (m, 4H).
##STR00060##
4-{(S)-2-[2-(tert-Butylsulfonylmethyl)thiazol-4-yl]-2-[(S)-2-(methoxycarb-
onyl-amino)-3-phenylpropanamido]ethyl}phenylsulfamic acid
[0369] .sup.1H NMR (CD.sub.3OD): .delta. 7.40-7.30 (m, 5H),
7.21-7.10 (m, 4H), 7.02 (s, 1H), 5.37 (t, 1H, J=6.9 Hz), 5.01-4.98
(m, 2H), 4.51 (t, 1H, J=7.1 Hz), 3.77 (s, 3H), 3.34-2.91 (m, 4H),
1.58 (s, 9H).
[0370] Category III of the present disclosure relates to compounds
wherein R is a substituted or unsubstituted thiazol-2-yl unit
having the formula:
##STR00061##
one embodiment of which relates to inhibitors having the
formula:
##STR00062##
wherein R units are thiazol-2-yl units, that when substituted, are
substituted with R.sup.2 and R.sup.3 units. R and R.sup.5a units
are further described in Table V.
TABLE-US-00005 TABLE V No. R R.sup.5a E101 thiazol-2-yl (S)-benzyl
E102 4-methylthiazol-2-yl (S)-benzyl E103 4-ethylthiazol-2-yl
(S)-benzyl E104 4-propylthiazol-2-yl (S)-benzyl E105
4-iso-propylthiazol-2-yl (S)-benzyl E106 4-cyclopropylthiazol-2-yl
(S)-benzyl E107 4-butylthiazol-2-yl (S)-benzyl E108
4-tert-butylthiazol-2-yl (S)-benzyl E109 4-cyclohexylthiazol-2-yl
(S)-benzyl E110 4-(2,2,2-trifluoroethyl)thiazol-2-yl (S)-benzyl
E111 4-(3,3,3-trifluoropropyl)thiazol-2-yl (S)-benzyl E112
4-(2,2-difluorocyclopropyl)thiazol-2-yl (S)-benzyl E113
4-(methoxymethyl)thiazol-2-yl (S)-benzyl E114 4-(carboxylic acid
ethyl ester)thiazol-2-yl (S)-benzyl E115 4,5-dimethylthiazol-2-yl
(S)-benzyl E116 4-methyl-5-ethylthiazol-2-yl (S)-benzyl E117
4-phenylthiazol-2-yl (S)-benzyl E118 4-(4-chlorophenyl)thiazol-2-yl
(S)-benzyl E119 4-(3,4-dimethylphenyl)thiazol-2-yl (S)-benzyl E120
4-methyl-5-phenylthiazol-2-yl (S)-benzyl E121
4-(thiophen-2-yl)thiazol-2-yl (S)-benzyl E122
4-(thiophen-3-yl)thiazol-2-yl (S)-benzyl E123
4-(5-chlorothiophen-2-yl)thiazol-2-yl (S)-benzyl E124
5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl (S)-benzyl E125
4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl (S)-benzyl
[0371] The compounds encompassed within Category III of the present
disclosure can be prepared by the procedure outlined in Scheme IV
and described in Example 5 herein below.
##STR00063##
Example 5
4-[(S)-2-((S)-2-Acetamido-3-phenylpropanamido)-2-(4-ethylthiazol-2-yl)ethy-
l]phenylsulfamic acid (15)
Preparation of
(S)-2-acetamido-N--[(S)-1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)-ethyl]--
3-phenylpropanamide (14)
[0372] To a solution of
1-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl amine
hydrobromide, 3, (0.343 g, 0.957 mmol), N-acetyl-L-phenylalanine
(0.218 g), 1-hydroxybenzotriazole (HOBt) (0.161 g),
diisopropyl-ethylamine (0.26 g), in DMF (10 mL) at 0.degree., is
added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0.201
g). The mixture is stirred at 0.degree. C. for 30 minutes then at
room temperature overnight. The reaction mixture is diluted with
water and extracted with EtOAc. The combined organic phase is
washed with 1 N aqueous HCl, 5% aqueous NaHCO.sub.3, water and
brine, and dried over Na.sub.2SO.sub.4. The solvent is removed in
vacuo to afford 0.313 g (70% yield) of the desired product which is
used without further purification. LC/MS ESI+467 (M+1).
Preparation of
4-((S)-2-((S)-2-acetamido-3-phenylpropanamido)-2-(4-ethylthiazol-2-yl)eth-
yl)phenylsulfamic acid (15)
[0373]
(S)-2-Acetamido-N--[(S)-1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)et-
hyl]-3-phenylpropanamide, 14, (0.313 g) is dissolved in MeOH (4
mL). A catalytic amount of Pd/C (10% w/w) is added and the mixture
is stirred under a hydrogen atmosphere 2 hours. The reaction
mixture is filtered through a bed of CELITE.TM. and the solvent is
removed under reduced pressure. The crude product is dissolved in
pyridine (12 mL) and treated with SO.sub.3-pyridine (0.320 g). The
reaction is stirred at room temperature for 5 minutes after which a
7% solution of NH.sub.4OH (30 mL) is added. The mixture is then
concentrated and the resulting residue is purified by reverse phase
chromatography to afford 0.215 g of the desired product as the
ammonium salt. .sup.1H NMR (CD.sub.3OD) .delta. 7.23-6.98 (m, 10H),
5.37 (t, 1H), 4.64 (t, 1H, J=6.3 Hz), 3.26-2.74 (m, 6H), 1.91 (s,
3H), 1.29 (t, 3H, J=7.5 Hz).
[0374] The following are further non-limiting examples of compounds
encompassed within Category III of the present disclosure.
##STR00064##
4-[(S)-2-((S)-2-Acetamido-3-phenylpropanamido)-2-(4-tert-butylthiazol-2-y-
l)ethyl]phenylsulfamic acid
[0375] .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 7.22-7.17 (m,
5H), 7.06 (dd, J=14.1, 8.4 Hz, 4H), 6.97 (d, J=0.9 Hz, 1H), 5.39
(dd, J=8.4, 6.0 Hz, 1H), 4.65 (t, J=7.2 Hz, 1H), 3.33-3.26 (m, 1H),
3.13-3.00 (m, 2H), 2.80 (dd, J=13.5, 8.7 Hz, 1H), 1.91 (s, 3H),
1.36 (s, 9H).
##STR00065##
4-{(S)-2-((S)-2-Acetamido-3-phenylpropanamido)-2-[4-(thiophen-3-yl)thiazo-
l-2-yl]ethyl)phenylsulfamic acid
[0376] .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 8.58 (d, J=8.1
Hz, 1H), 7.83-7.82 (m, 1H), 7.57-7.46 (m, 3H), 7.28-6.93 (m, 11H),
5.54-5.43 (m, 1H), 4.69-4.55 (m, 2H), 3.41-3.33 (m, 1H), 3.14-3.06
(3H), 2.86-2.79 (m, 1H), 1.93 (s, 3H).
[0377] The first aspect of Category IV of the present disclosure
relates to compounds wherein R is a substituted or unsubstituted
thiazol-2-yl unit having the formula:
##STR00066##
one embodiment of which relates to inhibitors having the
formula:
##STR00067##
wherein R units and R.sup.5a units further described in Table
VI.
TABLE-US-00006 TABLE VI No. R R.sup.5a F126 thiazol-2-yl hydrogen
F127 4-methylthiazol-2-yl hydrogen F128 4-ethylthiazol-2-yl
hydrogen F129 4-propylthiazol-2-yl hydrogen F130
4-iso-propylthiazol-2-yl hydrogen F131 4-cyclopropylthiazol-2-yl
hydrogen F132 4-butylthiazol-2-yl hydrogen F133
4-tert-butylthiazol-2-yl hydrogen F134 4-cyclohexylthiazol-2-yl
hydrogen F135 4,5-dimethylthiazol-2-yl hydrogen F136
4-methyl-5-ethylthiazol-2-yl hydrogen F137 4-phenylthiazol-2-yl
hydrogen F138 thiazol-2-yl (S)-iso-propyl F139 4-methylthiazol-2-yl
(S)-iso-propyl F140 4-ethylthiazol-2-yl (S)-iso-propyl F141
4-propylthiazol-2-yl (S)-iso-propyl F142 4-iso-propylthiazol-2-yl
(S)-iso-propyl F143 4-cyclopropylthiazol-2-yl (S)-iso-propyl F144
4-butylthiazol-2-yl (S)-iso-propyl F145 4-tert-butylthiazol-2-yl
(S)-iso-propyl F146 4-cyclohexylthiazol-2-yl (S)-iso-propyl F147
4,5-dimethylthiazol-2-yl (S)-iso-propyl F148
4-methyl-5-ethylthiazol-2-yl (S)-iso-propyl F149
4-phenylthiazol-2-yl (S)-iso-propyl F150
4-(thiophen-2-yl)thiazol-2-yl (S)-iso-propyl
[0378] The compounds encompassed within Category IV of the present
disclosure can be prepared by the procedure outlined in Scheme V
and described in Example 6 herein below.
##STR00068##
Example 6
4-{(S)-2-[(S)-2-(tert-Butoxycarbonylamino)-3-methylbutanamido]-2-(4-ethylt-
hiazol-2-yl)ethyl}phenylsulfamic acid (17)
Preparation of tert-butyl
(S)-1-[(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethylamino]-3-methyl-1--
oxobutan-2-ylcarbamate (16)
[0379] To a solution of
1-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl amine
hydrobromide, 3, (0.200 g, 0.558 mmol),
(S)-(2-tert-butoxycarbonylamino)-3-methylbutyric acid (0.133 g) and
1-hydroxybenzo-triazole (HOBt) (0.094 g) in DMF (5 mL) at
0.degree., is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
(EDCI) (0.118 g) followed by diisopropylamine (0.151 g). The
mixture is stirred at 0.degree. C. for 30 minutes then at room
temperature overnight. The reaction mixture is diluted with water
and extracted with EtOAc. The combined organic phase is washed with
1 N aqueous HCl, 5% aqueous NaHCO.sub.3, water and brine, and dried
over Na.sub.2SO.sub.4. The solvent is removed in vacuo to afford
0.219 g (82% yield) of the desired product which is used without
further purification. LC/MS ESI+477 (M+1).
Preparation of
4-{(S)-2-[(S)-2-(tert-butoxycarbonylamino)-3-methylbutanamido]-2-(4-ethyl-
thiazol-2-yl)ethyl}phenylsulfamic acid (17)
[0380] tert-Butyl
(S)-1-[(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethylamino]-3-methyl-1--
oxobutan-2-ylcarbamate, 16, (0.219 g) is dissolved in MeOH (4 mL).
A catalytic amount of Pd/C (10% w/w) is added and the mixture is
stirred under a hydrogen atmosphere 2 hours. The reaction mixture
is filtered through a bed of CELITE.TM. and the solvent is removed
under reduced pressure. The crude product is dissolved in pyridine
(5 mL) and treated with SO.sub.3-pyridine (0.146 g). The reaction
is stirred at room temperature for 5 minutes after which a 7%
solution of NH.sub.4OH (30 mL) is added. The mixture is then
concentrated and the resulting residue is purified by reverse phase
chromatography to afford 0.148 g of the desired product as the
ammonium salt. .sup.1H NMR (CD.sub.3OD) .delta. 7.08 (s, 4H), 7.02
(s, 1H), 5.43 (s, 1H), 3.85 (s, 1H), 3.28-2.77 (m, 4H), 1.94 (hep,
1H), 1.46 (s, 9H), 1.29 (s, 3H, J=7.3 Hz), 0.83 (d, 6H).
[0381] The following are further non-limiting examples of the
second aspect of Category IV of the present disclosure.
##STR00069##
(S)-4-{2-[2-(tert-Butoxycarbonyl)acetamide]-2-(4-ethylthiazol-2-yl)ethyl}-
phenylsulfamic acid
[0382] .sup.1H NMR (CD.sub.3OD) .delta. 7.09-6.91 (m, 5H), 5.30 (t,
1H, J=8.4 Hz), 3.60-2.64 (m, 6H), 1.34 (s, 9H), 1.16 (t, 3H, J=7.5
Hz).
##STR00070##
4-{(S)-2-[(S)-2-(tert-Butoxycarbonylamino)-4-methylpentanamido]-2-(4-ethy-
lthiazol-2-yl)ethyl}phenylsulfamic acid
[0383] .sup.1H NMR (CD.sub.3OD) .delta. 7.19-7.00 (m, 5H),
5.50-5.40 (m, 1H), 4.13-4.06 (m, 1H), 3.32 (1H, A of ABX, J=7.5, 18
Hz), 3.12 (1H, B of ABX, J=8.1, 13.8 Hz), 2.79 (q, 2H, J=7.8, 14.7
Hz), 1.70-1.55 (m, 1H), 1.46 (s, 9H), 1.33 (t, 3H, J=2.7 Hz), 0.92
(q, 6H, J=6, 10.8 Hz).
##STR00071##
4-{(S)-2-[(S)-2-(tert-Butoxycarbonylamino)-4-methylpentanamido]-2-[2-(thi-
ophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid
[0384] .sup.1H NMR (CD3OD) .delta. 8.06 (d, 1H, J=8.4 Hz),
7.61-7.58 (m, 1H), 7.57 (s, 1H), 7.15 (t, 1H, J=0.6 Hz), 7.09-6.98
(m, 6H), 5.30-5.20 (m, 1H), 4.10-4.00 (m, 1H), 3.19-3.13 (m, 2H),
1.63-1.55 (m, 2H), 1.48-1.33 (m, 10H), 0.95-0.89 (m, 6H).
##STR00072##
(S)-4-{2-[2-(tert-Butoxycarbonyl)acetamide]-2-(4-ethylthiazol-2-yl)ethyl}-
-phenylsulfamic acid
[0385] .sup.1H NMR (CD.sub.3OD) .delta. 7.09-6.91 (m, 5H), 5.30 (t,
1H, J=8.4 Hz), 3.60-2.64 (m, 6H), 1.34 (s, 9H), 1.16 (t, 3H, J=7.5
Hz).
[0386] A further embodiment of Category IV relates to inhibitors
having the formula:
##STR00073##
wherein R units and R.sup.5a units further described in Table
VII.
TABLE-US-00007 TABLE VII No. R R.sup.5a G151 thiazol-2-yl hydrogen
G152 4-methylthiazol-2-yl hydrogen G153 4-ethylthiazol-2-yl
hydrogen G154 4-propylthiazol-2-yl hydrogen G155
4-iso-propylthiazol-2-yl hydrogen G156 4-cyclopropylthiazol-2-yl
hydrogen G157 4-butylthiazol-2-yl hydrogen G158
4-tert-butylthiazol-2-yl hydrogen G159 4-cyclohexylthiazol-2-yl
hydrogen G160 4,5-dimethylthiazol-2-yl hydrogen G161
4-methyl-5-ethylthiazol-2-yl hydrogen G162 4-phenylthiazol-2-yl
hydrogen G163 thiazol-2-yl (S)-iso-propyl G164 4-methylthiazol-2-yl
(S)-iso-propyl G165 4-ethylthiazol-2-yl (S)-iso-propyl G166
4-propylthiazol-2-yl (S)-iso-propyl G167 4-iso-propylthiazol-2-yl
(S)-iso-propyl G168 4-cyclopropylthiazol-2-yl (S)-iso-propyl G169
4-butylthiazol-2-yl (S)-iso-propyl G170 4-tert-butylthiazol-2-yl
(S)-iso-propyl G171 4-cyclohexylthiazol-2-yl (S)-iso-propyl G172
4,5-dimethylthiazol-2-yl (S)-iso-propyl G173
4-methyl-5-ethylthiazol-2-yl (S)-iso-propyl G174
4-phenylthiazol-2-yl (S)-iso-propyl G175
4-(thiophen-2-yl)thiazol-2-yl (S)-iso-propyl
[0387] The compounds encompassed within this embodiment of Category
IV can be made according to the procedure outlined in Scheme V and
described in Example 6 by substituting the corresponding
methylcarbamate for the Boc-protected reagent. The following are
non-limiting examples of this embodiment.
##STR00074##
4-{(S)-2-(4-Ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonyl)-4-methylpentana-
mido]ethyl}phenylsulfamic acid
[0388] .sup.1H NMR (CD3OD) .delta. 7.12-7.03 (m, 5H), 6.84 (d, 1H,
J=8.4 Hz), 5.40 (t, 1H, J=5.7 Hz), 4.16 (t, 1H, J=6.3 Hz), 3.69 (s,
3H), 3.61-3.55 (m, 1H), 3.29-3.27 (m, 1H), 3.14-3.07 (m, 1H), 2.81
(q, 2H, J=3.9, 11.2 Hz), 1.66-1.59 (m, 1H), 1.48-1.43 (m, 2H), 1.31
(t, 3H, J=4.5 Hz), 0.96-0.90 (m, 6H).
##STR00075##
(S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(methoxycarbonyl)acetamido]ethyl}-phe-
nylsulfamic acid
[0389] .sup.1H NMR (CD.sub.3OD) .delta. 7.12-7.07 (m, 4H), 7.03 (s,
1H), 5.42 (t, 1H, J=5.7 Hz), 3.83-3.68 (q, 2H, J=11.4 Hz), 3.68 (s,
3H), 3.34-3.04 (m, 2H), 2.83-2.76 (q, 2H, J=7.8 Hz), 1.31 (t, 3H,
J=7.5 Hz).
##STR00076##
4-{(S)-2-(4-Ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonyl)-3-methylbutanam-
ido]-ethyl}phenylsulfamic acid
[0390] .sup.1H NMR (CD.sub.3OD) .delta. 8.56 (d, 1H, J=7.8 Hz),
7.09 (s, 4H), 7.03 (s, 1H), 5.26-5.20 (m, 1H), 3.90 (d, 1H, J=7.8
Hz), 3.70 (s, 3H), 3.30 (1H, A of ABX, obscured by solvent), 3.08
(1H, B of ABX, J=9.9, 9 Hz), 2.79 (q, 2H, J=11.1, 7.2 Hz),
2.05-1.97 (m, 1H), 1.31 (t, 3H, J=7.5 Hz), 0.88 (s, 3H), 0.85 (s,
3H, 0.79-0.75 (m, 1H).
##STR00077##
4-{(S)-2-[(S)-2-(Methoxycarbonyl)-4-methylpentanamido]-2-[2-(thiophen-2-y-
l)thiazol-4-yl]ethyl}phenylsulfamic acid
[0391] .sup.1H NMR (CD.sub.3OD) .delta. 8.22 (d, 1H, J=9 Hz),
7.62-7.57 (m, H), 7.15 (t, 1H, J=0.6 Hz), 7.10-6.97 (m, 4H),
5.30-5.20 (m, 1H), 4.16-4.11 (m, 1H), 3.67 (s, 2H), 3.22 (1H, A of
ABX, J=6.9, 13.5 Hz), 3.11 (1H, B of ABX, J=7.8, 13.6 Hz),
1.65-1.58 (m, 1H), 1.50-1.45 (m, 2H), 0.95-0.88 (m, 6H).
[0392] Category IV of the present disclosure relates to compounds
having the formula:
##STR00078##
wherein R is a substituted or unsubstituted thiophen-2-yl or
thiophen-4-yl unit and non-limiting examples of R.sup.0 are further
described in Table VIII.
TABLE-US-00008 TABLE VIII No. R R.sup.8 H176 thiazol-2-yl
--OC(CH.sub.3).sub.3 H177 4-methylthiazol-2-yl --OC(CH.sub.3).sub.3
H178 4-ethylthiazol-2-yl --OC(CH.sub.3).sub.3 H179
4-cyclopropylthiazol-2-yl --OC(CH.sub.3).sub.3 H180
4-tert-butylthiazol-2-yl --OC(CH.sub.3).sub.3 H181
4-cyclohexylthiazol-2-yl --OC(CH.sub.3).sub.3 H182
4-(2,2,2-trifluoroethyl)thiazol-2-yl --OC(CH.sub.3).sub.3 H183
4-(3,3,3-trifluoropropyl)thiazol-2-yl --OC(CH.sub.3).sub.3 H184
4-(2,2-difluorocyclopropyl)thiazol-2-yl --OC(CH.sub.3).sub.3 H185
4,5-dimethylthiazol-2-yl --OC(CH.sub.3).sub.3 H186
4-methyl-5-ethylthiazol-2-yl --OC(CH.sub.3).sub.3 H187
4-phenylthiazol-2-yl --OC(CH.sub.3).sub.3 H188
4-(4-chlorophenyl)thiazol-2-yl --OC(CH.sub.3).sub.3 H189
4-(3,4-dimethylphenyl)thiazol-2-yl --OC(CH.sub.3).sub.3 H190
4-methyl-5-phenylthiazol-2-yl --OC(CH.sub.3).sub.3 H191
4-(thiophen-2-yl)thiazol-2-yl --OC(CH.sub.3).sub.3 H192
thiazol-4-yl --OC(CH.sub.3).sub.3 H193 4-methylthiazol-4-yl
--OC(CH.sub.3).sub.3 H194 4-ethylthiazol-4-yl --OC(CH.sub.3).sub.3
H195 4-cyclopropylthiazol-4-yl --OC(CH.sub.3).sub.3 H196
4-tert-butylthiazol-4-yl --OC(CH.sub.3).sub.3 H197
4-cyclohexylthiazol-4-yl --OC(CH.sub.3).sub.3 H198
4-(2,2,2-trifluoroethyl)thiazol-4-yl --OC(CH.sub.3).sub.3 H199
4-(3,3,3-trifluoropropyl)thiazol-4-yl --OC(CH.sub.3).sub.3 H200
4-(2,2-difluorocyclopropyl)thiazol-4-yl --OC(CH.sub.3).sub.3 H201
4,5-dimethylthiazol-4-yl --OC(CH.sub.3).sub.3 H202
4-methyl-5-ethylthiazol-4-yl --OC(CH.sub.3).sub.3 H203
4-phenylthiazol-4-yl --OC(CH.sub.3).sub.3 H204
4-(4-chlorophenyl)thiazol-4-yl --OC(CH.sub.3).sub.3 H205
4-(3,4-dimethylphenyl)thiazol-4-yl --OC(CH.sub.3).sub.3 H206
4-methyl-5-phenylthiazol-4-yl --OC(CH.sub.3).sub.3 H207
4-(thiophen-2-yl)thiazol-4-yl --OC(CH.sub.3).sub.3 H208
thiazol-2-yl --OCH.sub.3 H209 4-methylthiazol-2-yl --OCH.sub.3 H210
4-ethylthiazol-2-yl --OCH.sub.3 H211 4-cyclopropylthiazol-2-yl
--OCH.sub.3 H212 4-tert-butylthiazol-2-yl --OCH.sub.3 H213
4-cyclohexylthiazol-2-yl --OCH.sub.3 H214
4-(2,2,2-trifluoroethyl)thiazol-2-yl --OCH.sub.3 H215
4-(3,3,3-trifluoropropyl)thiazol-2-yl --OCH.sub.3 H216
4-(2,2-difluorocyclopropyl)thiazol-2-yl --OCH.sub.3 H217
4,5-dimethylthiazol-2-yl --OCH.sub.3 H218
4-methyl-5-ethylthiazol-2-yl --OCH.sub.3 H219 4-phenylthiazol-2-yl
--OCH.sub.3 H220 4-(4-chlorophenyl)thiazol-2-yl --OCH.sub.3 H221
4-(3,4-dimethylphenyl)thiazol-2-yl --OCH.sub.3 H222
4-methyl-5-phenylthiazol-2-yl --OCH.sub.3 H223
4-(thiophen-2-yl)thiazol-2-yl --OCH.sub.3 H224 thiazol-4-yl
--OCH.sub.3 H225 4-methylthiazol-4-yl --OCH.sub.3 H226
4-ethylthiazol-4-yl --OCH.sub.3 H227 4-cyclopropylthiazol-4-yl
--OCH.sub.3 H228 4-tert-butylthiazol-4-yl --OCH.sub.3 H229
4-cyclohexylthiazol-4-yl --OCH.sub.3 H230
4-(2,2,2-trifluoroethyl)thiazol-4-yl --OCH.sub.3 H231
4-(3,3,3-trifluoropropyl)thiazol-4-yl --OCH.sub.3 H232
4-(2,2-difluorocyclopropyl)thiazol-4-yl --OCH.sub.3 H233
4,5-dimethylthiazol-4-yl --OCH.sub.3 H234
4-methyl-5-ethylthiazol-4-yl --OCH.sub.3 H235 4-phenylthiazol-4-yl
--OCH.sub.3 H236 4-(4-chlorophenyl)thiazol-4-yl --OCH.sub.3 H237
4-(3,4-dimethylphenyl)thiazol-4-yl --OCH.sub.3 H238
4-methyl-5-phenylthiazol-4-yl --OCH.sub.3 H239
4-(thiophen-2-yl)thiazol-4-yl --OCH.sub.3 H240 thiazol-2-yl
--CH.sub.3 H241 4-methylthiazol-2-yl --CH.sub.3 H242
4-ethylthiazol-2-yl --CH.sub.3 H243 4-cyclopropylthiazol-2-yl
--CH.sub.3 H244 4-tert-butylthiazol-2-yl --CH.sub.3 H245
4-cyclohexylthiazol-2-yl --CH.sub.3 H246
4-(2,2,2-trifluoroethyl)thiazol-2-yl --CH.sub.3 H247
4-(3,3,3-trifluoropropyl)thiazol-2-yl --CH.sub.3 H248
4-(2,2-difluorocyclopropyl)thiazol-2-yl --CH.sub.3 H249
4,5-dimethylthiazol-2-yl --CH.sub.3 H250
4-methyl-5-ethylthiazol-2-yl --CH.sub.3 H251 4-phenylthiazol-2-yl
--CH.sub.3 H252 4-(4-chlorophenyl)thiazol-2-yl --CH.sub.3 H253
4-(3,4-dimethylphenyl)thiazol-2-yl --CH.sub.3 H254
4-methyl-5-phenylthiazol-2-yl --CH.sub.3 H255
4-(thiophen-2-yl)thiazol-2-yl --CH.sub.3 H256 thiazol-4-yl
--CH.sub.3 H257 4-methylthiazol-4-yl --CH.sub.3 H258
4-ethylthiazol-4-yl --CH.sub.3 H259 4-cyclopropylthiazol-4-yl
--CH.sub.3 H260 4-tert-butylthiazol-4-yl --CH.sub.3 H261
4-cyclohexylthiazol-4-yl --CH.sub.3 H262
4-(2,2,2-trifluoroethyl)thiazol-4-yl --CH.sub.3 H263
4-(3,3,3-trifluoropropyl)thiazol-4-yl --CH.sub.3 H264
4-(2,2-difluorocyclopropyl)thiazol-4-yl --CH.sub.3 H265
4,5-dimethylthiazol-4-yl --CH.sub.3 H266
4-methyl-5-ethylthiazol-4-yl --CH.sub.3 H267 4-phenylthiazol-4-yl
--CH.sub.3 H268 4-(4-chlorophenyl)thiazol-4-yl --CH.sub.3 H269
4-(3,4-dimethylphenyl)thiazol-4-yl --CH.sub.3 H270
4-methyl-5-phenylthiazol-4-yl --CH.sub.3 H271
4-(thiophen-2-yl)thiazol-4-yl --CH.sub.3
[0393] The compounds encompassed within Category IV of the present
disclosure can be prepared by the procedure outlined in Scheme VI
and described in Example 7 herein below.
##STR00079##
Example 7
[1-(S)-(Phenylthiazol-2-yl)-2-yl)-2-(4-sulfoaminophenyl)ethyl]-carbamic
acid tert-butyl ester (19)
Preparation of
[2-(4-nitrophenyl)-1-(S)-(4-phenylthiazol-2-yl)ethyl]-carbamic acid
tert-butyl ester (18)
[0394] A mixture of
[2-(4-nitrophenyl)-1-(S)-thiocarbamoylethyl]-carbamic acid
tert-butyl ester, 2, (0.343 g, 1.05 mmol), 2-bromoacetophenone
(0.231 g, 1.15 mmol), in CH.sub.3CN (5 mL) is refluxed 1.5 hour.
The solvent is removed under reduced pressure and the residue
re-dissolved in CH.sub.2Cl.sub.2 then pyridine (0.24 mL, 3.0 mmol)
and Boc.sub.2O (0.24 mL, 1.1 mmol) are added. The reaction is
stirred for 2 hours and diethyl ether is added to the solution and
the precipitate which forms is removed by filtration. The organic
layer is dried (Na.sub.2SO.sub.4), filtered, and concentrated to a
residue which is purified over silica to afford 0.176 g (39%) of
the desired product ESI+ MS 426 (M+1).
Preparation of
[1-(S)-(phenylthiazol-2-yl)-2-(4-sulfoaminophenyl)ethyl]-carbamic
acid tert-butyl ester (19)
[0395]
[2-(4-nitrophenyl)-1-(S)-(4-phenylthiazol-2-yl)ethyl]-carbamic acid
tert-butyl ester, 18, (0.176 g, 0.41 mmol) is dissolved in MeOH (4
mL). A catalytic amount of Pd/C (10% w/w) is added and the mixture
is stirred under a hydrogen atmosphere 12 hours. The reaction
mixture is filtered through a bed of CELITE.TM. and the solvent is
removed under reduced pressure. The crude product is dissolved in
pyridine (12 mL) and treated with SO.sub.3-pyridine (0.195 g, 1.23
mmol). The reaction is stirred at room temperature for 5 minutes
after which a 7% solution of NH.sub.4OH (10 mL) is added. The
mixture is then concentrated and the resulting residue is purified
by reverse phase chromatography to afford 0.080 g of the desired
product as the ammonium salt. .sup.1H NMR (300 MHz, MeOH-d.sub.4)
.delta. 7.93 (d, J=6.0 Hz, 2H), 7.68 (s, 1H), 7.46-7.42 (m, 3H),
7.37-7.32 (m, 1H), 7.14-7.18 (m, 3H), 5.13-5.18 (m, 1H), 3.40 (dd,
J=4.5 and 15.0 Hz, 1H), 3.04 (dd, J=9.6 and 14.1 Hz, 1H), 1.43 (s,
9H).
[0396] The following are further non-limiting examples of Category
IV of the present disclosure.
##STR00080##
(S)-4-(2-(4-Methylthiazol-2-yl)-2-pivalamidoethyl)phenylsulfamic
acid
[0397] .sup.1H NMR (CD.sub.3OD) .delta. 7.31 (s, 4H), 7.20 (s, 1H),
5.61-5.56 (m, 1H), 3.57-3.22 (m, 2H), 2.62 (s, 3H), 1.31 (s,
3H).
##STR00081##
(S)-4-(2-(4-Ethylthiazol-2-yl)-2-pivalamidoethyl)phenylsulfamic
acid
[0398] .sup.1H NMR (300 MHz, MeOH-d.sub.4) .delta. 7.92 (d, J=8.1
Hz, 1H), 7.12-7.14 (m, 4H), 7.03 (s, 1H), 5.38-5.46 (m, 1H),
3.3-3.4 (m, 1H), 3.08 (dd, J=10.2 and 13.8 Hz, 1H), 2.79 (q, J=7.2
Hz, 2H), 1.30 (t, J=7.2 Hz, 3H), 1.13 (s, 9H).
##STR00082##
(S)-4-(2-(4-(Hydroxymethyl)thiazol-2-yl)-2-pivalamidoethyl)phenylsulfamic
acid
[0399] .sup.1H NMR (300 MHz, MeOH-d.sub.4) .delta. 7.92 (d, J=8.1
Hz, 1H), 7.24 (s, 1H), 7.08 (d, J=8.7 Hz, 2H), 7.00 (d, J=8.7 Hz,
2H), 5.29-5.37 (m, 1H), 4.55 (s, 2H), 3.30 (dd, J=4.8 and 13.5 Hz,
1H), 2.99 (dd, J=10.5 and 13.5 Hz, 1H), 0.93 (s, 9H).
##STR00083##
(S)-4-(2-(4-(Ethoxycarbonyl)thiazol-2-yl)-2-pivalamidoethyl)phenylsulfami-
c acid
[0400] .sup.1H NMR (300 MHz, MeOH-d.sub.4) .delta. 8.30 (s, 1H),
8.04 (d, J=8.1 Hz, 1H), 7.13 (s, 4H), 5.41-5.49 (m, 1H), 4.41 (q,
J=7.2 Hz, 2H), 3.43 (dd, J=5.1 and 13.8 Hz, 1H), 3.14 (dd, J=5.7
and 9.9 Hz, 1H), 1.42 (t, J=7.2 Hz, 3H), 1.14 (s, 9H).
##STR00084##
(S)-4-(2-(4-Phenylthiazol-2-yl)-2-pivalamidoethyl)phenylsulfamic
acid
[0401] .sup.1H NMR (300 MHz, MeOH-d.sub.4) .delta. 7.94-8.01 (m,
3H), 7.70 (s, 1H), 7.42-7.47 (m, 2H), 7.32-7.47 (m, 1H), 7.13-7.20
(m, 3H), 5.48-5.55 (m, 1H), 3.50 (dd, J=5.1 and 14.1 Hz, 1H), 3.18
(dd, J=10.2 and 14.1 Hz, 1H), 1.17 (s, 9H).
##STR00085##
4-((S)-2-(4-(3-Methoxyphenyl)thiazol-2-yl)-2-pivalamidoethyl)phenylsulfam-
ic acid
[0402] .sup.1H NMR (CD.sub.3OD) .delta. 7.96-7.93 (d, 1H, J=8.1
Hz), 7.69 (s, 1H), 7.51-7.49 (d, 2H, J=7.9 Hz), 7.33 (t, 1H, J=8.0
Hz), 7.14 (s, 4H), 6.92-6.90 (d, 1H, J=7.8 Hz), 5.50 (t, 1H, J=5.1
Hz), 3.87 (s, 3H), 3.50-3.13 (m, 2H), 1.15 (s, 9H).
##STR00086##
4-((S)-2-(4-(2,4-Dimethoxyphenyl)thiazol-2-yl)-2-pivalamidoethyl)phenylsu-
lfamic acid
[0403] .sup.1H NMR (CD.sub.3OD) .delta. 8.11-8.09 (d, 1H, J=7.8
Hz), 7.96-7.93 (d, 1H, J=8.4 Hz), 7.74 (s, 1H), 7.18-7.16 (m, 4H),
6.67-6.64 (d, 2H, J=9.0 Hz), 5.55-5.47 (m, 1H), 3.95 (s, 3H), 3.87
(s, 3H), 3.52-3.13 (m, 2H), 1.17 (s, 9H).
##STR00087##
(S)-4-(2-(4-Benzylthiazol-2-yl)-2-pivalamidoethyl)phenylsulfamic
acid
[0404] .sup.1H NMR (CD.sub.3OD) .delta. 7.85 (d, 1H, J=8.4 Hz),
7.38-7.20 (m, 4H), 7.11-7.02 (m, 1H), 7.00 (s, 1H), 5.42-5.37 (m,
1H), 4.13 (s, 2H), 3.13-3.08 (m, 2H), 1.13 (s, 9H).
##STR00088##
(S)-4-(2-Pivalamido-2-(4-(thiophen-2-ylmethyl)thiazol-2-yl)ethyl)phenylsu-
lfamic acid
[0405] .sup.1H NMR (CD.sub.3OD) .delta. 7.88-7.85 (d, 1H),
7.38-7.35 (m, 1H), 7.10-7.01 (m, 4H), 7.02 (s, 1H), 5.45-5.38 (m,
1H), 4.13 (s, 2H), 3.13-3.05 (m, 2H), 1.13 (2, 9H).
##STR00089##
(S)-4-(2-(4-(3-Methoxybenzyl)thiazol-2-yl)-2-pivalamidoethyl)phenylsulfam-
ic acid
[0406] .sup.1H NMR (CD.sub.3OD) .delta. 7.85 (d, 1H, J=8.4 Hz),
7.25-7.20 (m, 1H), 7.11-7.02 (m, 4H), 7.01 (s, 1H), 6.90-6.79 (m,
2H), 5.45-5.40 (m, 1H), 4.09 (s, 2H), 3.79 (s, 3H), 3.12-3.08 (m,
2H), 1.10 (s, 9H).
##STR00090##
4-((S)-2-(4-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)thiazol-2-yl)-2-pivalami-
doethyl)-phenylsulfamic acid
[0407] .sup.1H NMR (CD.sub.3OD) .delta. 7.53 (s, 1H), 7.45 (s, 1H),
7.42-7.40 (d, 1H, J=8.4 Hz), 7.19-7.15 (m, 4H), 6.91-6.88 (d, 2H,
J=8.4 Hz), 5.51-5.46 (m, 1H), 4.30 (s, 4H), 3.51-3.12 (m, 2H), 1.16
(s, 9H).
##STR00091##
(S)-4-(2-(5-Methyl-4-phenylthiazol-2-yl)-2-pivalamidoethyl)phenylsulfamic
acid
[0408] .sup.1H NMR (CD.sub.3OD) .delta. 7.63-7.60 (d, 2H, J=7.1
Hz), 7.49-7.35 (m, 3H), 7.14 (s, 4H), 5.43-5.38 (m, 1H), 3.42-3.09
(m, 2H), 2.49 (s, 3H), 1.14 (s, 9H).
##STR00092##
(S)-4-(2-(4-(Biphen-4-yl)thiazol-2-yl)-2-pivalamidoethyl)phenylsulfamic
acid
[0409] .sup.1H NMR (CD.sub.3OD) .delta. 8.04-8.01 (m, 2H),
7.72-7.66 (m, 5H), 7.48-7.35 (m, 3H), 7.15 (s, 4H), 5.50 (t, 1H,
J=5.0 Hz), 3.57-3.15 (d, 2H), 1.16 (s, 9H).
##STR00093##
(S)-4-(2-tert-Butoxycarbonyl-2-(2-methylthaizol-4-yl)-phenylsulfamic
acid
[0410] .sup.1H NMR (300 MHz, D.sub.2O) .delta. 6.99-7.002 (m, 4H),
6.82 (s, 1H), 2.26 (dd, J=13.8 and 7.2 Hz, 1H), 2.76 (dd, J=13.8
and 7.2 Hz, 1H), 2.48 (s, 3H), 1.17 (s, 9H).
##STR00094##
(S)-4-(2-(tert-Butoxycarbonyl)-2-(4-propylthiazol-2-yl)ethyl)-phenyl
sulfamic acid
[0411] .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 7.18-7.02 (m,
5H), 5.06-5.03 (m, 1H), 3.26 (dd, J=13.8, 4.8 Hz, 1H), 2.95 (dd,
J=13.8, 9.3 Hz, 1H), 2.74 (dd, J=15.0, 7.2 Hz, 2H), 1.81-1.71 (m,
2H), 1.40 (s, 7H), 1.33 (bs, 2H), 0.988 (t, J=7.5 Hz 3H).
##STR00095##
(S)-4-(2-(tert-Butoxycarbonyl)-2-(4-tert-butylthiazol-2-yl)ethyl)-phenyl
sulfamic acid
[0412] .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 7.12 (s, 4H),
7.01 (s, 1H), 5.11-5.06 (m, 1H), 3.32-3.25 (m, 1H), 2.96 (m, 1H),
1.42 (s, 8H), 1.38 (s, 9H), 1.32 (s, 1H).
##STR00096##
(S)-4-(2-(tert-Butoxycarbonylamino)-2-(4-(methoxymethyl)thiazol-2-yl)ethy-
l)-phenyl sulfamic acid
[0413] .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 7.36 (s, 1H),
7.14-7.05 (m, 4H), 5.06 (dd, J=9.0, 5.1 Hz, 1H), 4.55 (s, 2H), 3.42
(s, 3H), 3.31-3.24 (m, 1H), 2.97 (dd, J=13.8, 9.9 Hz, 1H),
1.47-1.31 (m, 9H).
##STR00097##
(S)-4-(2-tert-Butoxycarbonylamino)-2-(4-(2-hydroxymethyl)thiazol-2-yl)eth-
yl)phenylsulfamic acid
[0414] .sup.1H NMR (300 MHz, MeOH-d.sub.4) .delta. 7.22-7.25 (m,
1H), 7.09-7.15 (m, 4H), 5.00-5.09 (m, 1H), 4.32-4.35 (m, 1H), 3.87
(t, J=6.6 Hz, 2H), 3.23-3.29 (m, 1H), 3.09-3.18 (m, 1H), 2.98 (t,
J=6.6 Hz, 2H), 1.41 (s, 9H).
##STR00098##
(S)-4-(2-tert-Butoxycarbonylamino)-2-(4-(2-ethoxy-2-oxoethyl)-thiazole-2--
yl)-ethyl)phenylsulfamic acid
[0415] .sup.1H NMR (300 MHz, MeOH-d.sub.4) .delta. 7.29 (s, 1H),
7.09-7.16 (m, 4H), 5.04-5.09 (m, 1H), 4.20 (q, J=6.9 Hz, 2H), 3.84
(s, 2H), 3.30 (dd, J=4.8 and 14.1 HZ, 1H), 2.97 (dd, J=9.6 Hz and
13.8 Hz, 1H), 1.41 (s, 9H), 1.29 (t, J=7.2 Hz, 3H).
##STR00099##
(S)-4-(2-(tert-Butoxycarbonylamino)-2-(4-(2-methoxy-2-oxoethyl)thiazol-2--
yl)ethyl)phenylsulfamic acid
[0416] .sup.1H NMR (300 MHz, MeOH-d.sub.4) .delta. 7.31 (s, 1H),
7.01-7.16 (m, 4H), 5.04-5.09 (m, 1H), 4.01 (s, 2H), 3.78 (s, 2H),
3.74 (s, 3H), 3.29 (dd, J=5.1 and 13.8 Hz, 1H), 2.99 (dd, J=9.3 and
13.8 Hz, 1H), 1.41 (s 9H).
##STR00100##
(S)-4-(2-(tert-Butoxycarbonylamino)-2-(5-phenylthiazol-2-yl)ethyl)-phenyl
sulfamic acid
[0417] .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 7.98 (s, 1H),
7.62 (d, J=7.2 Hz, 2H), 7.46-7.35 (m, 4H), 7.14 (s, 4H), 5.09 (bs,
1H), 3.07-2.99 (m, 2H), 1.43 (s, 9H).
##STR00101##
4-((S)-2-(tert-Butoxycarbonylamino)-2-(4-(3-(trifluoromethyl)phenyl)thiaz-
ol-2-yl)ethyl)phenyl sulfamic acid
[0418] .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 8.28 (s, 1H),
8.22-8.19 (m, 1H), 7.89 (s, 1H), 7.65 (d, J=5.1 Hz, 2H), 7.45 (d,
J=8.1 Hz, 1H), 7.15 (s, 4H), 5.17-5.14 (m, 1H), 3.43-3.32 (m, 1H),
3.05 (dd, J=14.1, 9.6 Hz, 1H), 1.42 (s, 9H).
##STR00102##
(S)-4-(2-(tert-Butoxycarbonylamino)-2-(4-phenylthiazol-2-yl)ethyl)-phenyl
sulfamic acid
[0419] .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 7.98 (s, 1H),
7.94 (d, J=7.2 Hz, 2H), 7.46-7.35 (m, 4H), 7.14 (s, 4H), 5.09 (bs,
1H), 3.07-2.99 (m, 2H), 1.43 (s, 9H).
##STR00103##
(S,S)-2-(2-{2-[2-tert-Butoxycarbonylamino-2-(4-sulfoaminophenyl)ethyl]thi-
azol-4-yl}acetylamido)-3-phenylpropionic acid methyl ester
[0420] .sup.1H NMR (300 MHz, MeOH-d.sub.4) .delta. 6.85-6.94 (m,
9H), 6.64 (s, 1H), 4.83 (s, 1H), 4.54-4.58 (m, 1H), 3.49 (s, 3H),
3.39 (s, 2H), 2.80-2.97 (m, 1H), 2.64-2.78 (m, 1H), 1.12 (s,
9H).
(S)-[1-{1-Oxo-4-[2-(1-phenyl-1H-tetrazol-5-sulfonyl)ethyl]-1H-1.lamda..sup-
.4-thiazol-2-yl}-2-(4-sulfamino-phenyl)-ethyl]-carbamic acid
tert-butyl ester
[0421] .sup.1H NMR (300 MHz, MeOH-d.sub.4) .delta. 7.22-7.75 (m,
2H), 7.62-7.69 (m, 2H), 7.55 (s, 1H), 7.10-7.20 (m, 5H), 5.25 (m,
1H), 4.27-4.36 (m, 1H), 4.11-4.21 (m, 1H), 3.33-3.44 (m, 4H),
2.84-2.90 (m, 1H), 1.33 (s, 9H).
##STR00104##
4-((S)-2-(tert-Butoxycarbonylamino)-2-(4-(thiophen-3-yl)thiazol-2-yl)ethy-
l)phenyl sulfamic acid
[0422] .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 7.84 (dd, J=3.0,
1.5 Hz, 1H), 7.57-7.55 (m, 2H), 7.47 (dd, J=4.8, 3.0 Hz, 1H), 7.15
(s, 4H), 5.15-5.10 (m, 1H), 3.39-3.34 (m, 1H), 3.01 (dd, J=14.1,
9.6 Hz, 1H), 1.42 (s, 8H), 1.32 (s, 1H).
##STR00105##
(S)-4-(2-(Benzo[d]thiazol-2-ylamino)-2-(tert-butoxycarbonyl)ethyl)phenyls-
ulfamic acid
[0423] .sup.1H NMR (CD.sub.3OD) .delta. 7.86-7.82 (m, 2H), 7.42 (t,
2H, J=7.1 Hz), 7.33 (t, 1H, J=8.2 Hz), 7.02 (s, 4H), 5.10-5.05 (m,
1H), 2.99-2.91 (m, 2H), 1.29 (s, 9H).
(S)-4-(2-tert-Butoxycarbonylamino)-2-(2-methylthiazol-4-yl)-phenylsulfamic
acid
[0424] .sup.1H NMR (300 MHz, D.sub.2O) .delta. 6.99-7.002 (m, 4H),
6.82 (s, 1H), 2.26 (dd, J=13.8 and 7.2 Hz, 1H), 2.76 (dd, J=13.8
and 7.2 Hz, 1H), 2.48 (s, 3H), 1.17 (s, 9H).
##STR00106##
(S)-4-(2-(tert-Butoxycarbonylamino)-2-(2-(pivaloyloxy)thiazol-4-yl)ethyl)-
-phenylsulfamic acid
[0425] .sup.1H NMR (300 MHz, D.sub.2O) .delta. 6.95 (s, 4H), 6.63
(s, 1H), 2.94 (dd, J=13.5 and 4.8 Hz, 1H), 2.75 (dd, J=13.5 and 4.8
Hz, 1H), 1.16 (s, 9H), 1.13 (s, 9H).
[0426] The first aspect of Category V of the present disclosure
relates to 2-(thiazol-2-yl) compounds having the formula:
##STR00107##
wherein R.sup.1, R.sup.2, R.sup.3, and L are further defined herein
in Table IX below.
TABLE-US-00009 TABLE IX No. L R.sup.1 R.sup.2 R.sup.3 I272
--CH.sub.2-- phenyl --CH.sub.3 --H I273 --CH.sub.2-- 2-fluorophenyl
--CH.sub.3 --H I274 --CH.sub.2-- 3-fluorophenyl --CH.sub.3 --H I275
--CH.sub.2-- 4-fluorophenyl --CH.sub.3 --H I276 --CH.sub.2--
2,3-difluorophenyl --CH.sub.3 --H I277 --CH.sub.2--
3,4-difluorophenyl --CH.sub.3 --H I278 --CH.sub.2--
3,5-difluorophenyl --CH.sub.3 --H I279 --CH.sub.2-- 2-chlorophenyl
--CH.sub.3 --H I280 --CH.sub.2-- 3-chlorophenyl --CH.sub.3 --H I281
--CH.sub.2-- 4-chlorophenyl --CH.sub.3 --H I282 --CH.sub.2--
2,3-dichlorophenyl --CH.sub.3 --H I283 --CH.sub.2--
3,4-dichlorophenyl --CH.sub.3 --H I284 --CH.sub.2--
3,5-dichlorophenyl --CH.sub.3 --H I285 --CH.sub.2-- 2-hydroxyphenyl
--CH.sub.3 --H I286 --CH.sub.2-- 3-hydroxyphenyl --CH.sub.3 --H
I287 --CH.sub.2-- 4-hydroxyphenyl --CH.sub.3 --H I288 --CH.sub.2--
2-methoxyphenyl --CH.sub.3 --H I289 --CH.sub.2-- 3-methoxyphenyl
--CH.sub.3 --H I290 --CH.sub.2-- 4-methoxyphenyl --CH.sub.3 --H
I291 --CH.sub.2-- 2,3-dimethoxyphenyl --CH.sub.3 --H I292
--CH.sub.2-- 3,4-dimethoxyphenyl --CH.sub.3 --H I293 --CH.sub.2--
3,5-dimethoxyphenyl --CH.sub.3 --H I294 --CH.sub.2-- phenyl
--CH.sub.2CH.sub.3 --H I295 --CH.sub.2-- 2-fluorophenyl
--CH.sub.2CH.sub.3 --H I296 --CH.sub.2-- 3-fluorophenyl
--CH.sub.2CH.sub.3 --H I297 --CH.sub.2-- 4-fluorophenyl
--CH.sub.2CH.sub.3 --H I298 --CH.sub.2-- 2,3-difluorophenyl
--CH.sub.2CH.sub.3 --H I299 --CH.sub.2-- 3,4-difluorophenyl
--CH.sub.2CH.sub.3 --H I300 --CH.sub.2-- 3,5-difluorophenyl
--CH.sub.2CH.sub.3 --H I301 --CH.sub.2-- 2-chlorophenyl
--CH.sub.2CH.sub.3 --H I302 --CH.sub.2-- 3-chlorophenyl
--CH.sub.2CH.sub.3 --H I303 --CH.sub.2-- 4-chlorophenyl
--CH.sub.2CH.sub.3 --H I304 --CH.sub.2-- 2,3-dichlorophenyl
--CH.sub.2CH.sub.3 --H I305 --CH.sub.2-- 3,4-dichlorophenyl
--CH.sub.2CH.sub.3 --H I306 --CH.sub.2-- 3,5-dichlorophenyl
--CH.sub.2CH.sub.3 --H I307 --CH.sub.2-- 2-hydroxyphenyl
--CH.sub.2CH.sub.3 --H I308 --CH.sub.2-- 3-hydroxyphenyl
--CH.sub.2CH.sub.3 --H I309 --CH.sub.2-- 4-hydroxyphenyl
--CH.sub.2CH.sub.3 --H I310 --CH.sub.2-- 2-methoxyphenyl
--CH.sub.2CH.sub.3 --H I311 --CH.sub.2-- 3-methoxyphenyl
--CH.sub.2CH.sub.3 --H I312 --CH.sub.2-- 4-methoxyphenyl
--CH.sub.2CH.sub.3 --H I313 --CH.sub.2-- 2,3-dimethoxyphenyl
--CH.sub.2CH.sub.3 --H I314 --CH.sub.2-- 3,4-dimethoxyphenyl
--CH.sub.2CH.sub.3 --H I315 --CH.sub.2-- 3,5-dimethoxyphenyl
--CH.sub.2CH.sub.3 --H I316 --CH.sub.2CH.sub.2-- phenyl --CH.sub.3
--H I317 --CH.sub.2CH.sub.2-- 2-fluorophenyl --CH.sub.3 --H I318
--CH.sub.2CH.sub.2-- 3-fluorophenyl --CH.sub.3 --H I319
--CH.sub.2CH.sub.2-- 4-fluorophenyl --CH.sub.3 --H I320
--CH.sub.2CH.sub.2-- 2,3-difluorophenyl --CH.sub.3 --H I321
--CH.sub.2CH.sub.2-- 3,4-difluorophenyl --CH.sub.3 --H I322
--CH.sub.2CH.sub.2-- 3,5-difluorophenyl --CH.sub.3 --H I323
--CH.sub.2CH.sub.2-- 2-chlorophenyl --CH.sub.3 --H I324
--CH.sub.2CH.sub.2-- 3-chlorophenyl --CH.sub.3 --H I325
--CH.sub.2CH.sub.2-- 4-chlorophenyl --CH.sub.3 --H I326
--CH.sub.2CH.sub.2-- 2,3-dichlorophenyl --CH.sub.3 --H I327
--CH.sub.2CH.sub.2-- 3,4-dichlorophenyl --CH.sub.3 --H I328
--CH.sub.2CH.sub.2-- 3,5-dichlorophenyl --CH.sub.3 --H I329
--CH.sub.2CH.sub.2-- 2-hydroxyphenyl --CH.sub.3 --H I330
--CH.sub.2CH.sub.2-- 3-hydroxyphenyl --CH.sub.3 --H I331
--CH.sub.2CH.sub.2-- 4-hydroxyphenyl --CH.sub.3 --H I332
--CH.sub.2CH.sub.2-- 2-methoxyphenyl --CH.sub.3 --H I333
--CH.sub.2CH.sub.2-- 3-methoxyphenyl --CH.sub.3 --H I334
--CH.sub.2CH.sub.2-- 4-methoxyphenyl --CH.sub.3 --H I335
--CH.sub.2CH.sub.2-- 2,3-dimethoxyphenyl --CH.sub.3 --H I336
--CH.sub.2CH.sub.2-- 3,4-dimethoxyphenyl --CH.sub.3 --H I337
--CH.sub.2CH.sub.2-- 3,5-dimethoxyphenyl --CH.sub.3 --H I338
--CH.sub.2CH.sub.2-- phenyl --CH.sub.2CH.sub.3 --H I339
--CH.sub.2CH.sub.2-- 2-fluorophenyl --CH.sub.2CH.sub.3 --H I340
--CH.sub.2CH.sub.2-- 3-fluorophenyl --CH.sub.2CH.sub.3 --H I341
--CH.sub.2CH.sub.2-- 4-fluorophenyl --CH.sub.2CH.sub.3 --H I342
--CH.sub.2CH.sub.2-- 2,3-difluorophenyl --CH.sub.2CH.sub.3 --H I343
--CH.sub.2CH.sub.2-- 3,4-difluorophenyl --CH.sub.2CH.sub.3 --H I344
--CH.sub.2CH.sub.2-- 3,5-difluorophenyl --CH.sub.2CH.sub.3 --H I345
--CH.sub.2CH.sub.2-- 2-chlorophenyl --CH.sub.2CH.sub.3 --H I346
--CH.sub.2CH.sub.2-- 3-chlorophenyl --CH.sub.2CH.sub.3 --H I347
--CH.sub.2CH.sub.2-- 4-chlorophenyl --CH.sub.2CH.sub.3 --H I348
--CH.sub.2CH.sub.2-- 2,3-dichlorophenyl --CH.sub.2CH.sub.3 --H I349
--CH.sub.2CH.sub.2-- 3,4-dichlorophenyl --CH.sub.2CH.sub.3 --H I350
--CH.sub.2CH.sub.2-- 3,5-dichlorophenyl --CH.sub.2CH.sub.3 --H I351
--CH.sub.2CH.sub.2-- 2-hydroxyphenyl --CH.sub.2CH.sub.3 --H I352
--CH.sub.2CH.sub.2-- 3-hydroxyphenyl --CH.sub.2CH.sub.3 --H I353
--CH.sub.2CH.sub.2-- 4-hydroxyphenyl --CH.sub.2CH.sub.3 --H I354
--CH.sub.2CH.sub.2-- 2-methoxyphenyl --CH.sub.2CH.sub.3 --H I355
--CH.sub.2CH.sub.2-- 3-methoxyphenyl --CH.sub.2CH.sub.3 --H I356
--CH.sub.2CH.sub.2-- 4-methoxyphenyl --CH.sub.2CH.sub.3 --H I357
--CH.sub.2CH.sub.2-- 2,3-dimethoxyphenyl --CH.sub.2CH.sub.3 --H
I358 --CH.sub.2CH.sub.2-- 3,4-dimethoxyphenyl --CH.sub.2CH.sub.3
--H I359 --CH.sub.2CH.sub.2-- 3,5-dimethoxyphenyl
--CH.sub.2CH.sub.3 --H
[0427] The compounds encompassed within the first aspect of
Category V of the present disclosure can be prepared by the
procedure outlined in Scheme VII and described in Example 8 herein
below.
##STR00108##
Example 8
{4-[2-(S)-(4-Ethylthiazol-2-yl)-2-(2-phenylacetylamido)ethyl]phenyl}sulfam-
ic acid (21)
Preparation of
N-[1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]-2-phenyl-acetamide
(20)
[0428] To a solution of
1-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl amine
hydrobromide, 3, (0.393 g, 1.1 mmol), phenylacetic acid (0.190 g,
1.4 mmol) and 1-hydroxybenzotriazole (HOBt) (0.094 g, 0.70 mmol) in
DMF (10 mL) at 0.degree., is added
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0.268 g, 1.4
mmol) followed by triethylamine (0.60 mL, 4.2 mmol). The mixture is
stirred at 0.degree. C. for 30 minutes then at room temperature
overnight. The reaction mixture is diluted with water and extracted
with EtOAc. The combined organic phase is washed with 1 N aqueous
HCl, 5% aqueous NaHCO.sub.3, water and brine, and dried over
Na.sub.2SO.sub.4. The solvent is removed in vacuo to afford 0.260 g
(60% yield) of the desired product which is used without further
purification. ESI+ MS 396 (M+1).
Preparation of
{4-[2-(S)-(4-ethylthiazol-2-yl)-2-(2-phenylacetylamido)ethyl]-phenyl}sulf-
amic acid (21)
[0429]
N-[1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]-2-phenyl-acetami-
de, 20, (0.260 g) is dissolved in MeOH (4 mL). A catalytic amount
of Pd/C (10% w/w) is added and the mixture is stirred under a
hydrogen atmosphere 18 hours. The reaction mixture is filtered
through a bed of CELITE.TM. and the solvent is removed under
reduced pressure. The crude product is dissolved in pyridine (12
mL) and treated with SO.sub.3-pyridine (0.177 g, 1.23). The
reaction is stirred at room temperature for 5 minutes after which a
7% solution of NH.sub.4OH (10 mL) is added. The mixture is then
concentrated and the resulting residue is purified by reverse phase
chromatography to afford 0.136 g of the desired product as the
ammonium salt. .sup.1H NMR (CD.sub.3OD) .delta. 8.60 (d, 1H, J=8.1
Hz), 7.33-7.23 (m, 3H), 7.16-7.00 (m, 6H), 5.44-5.41 (m, 1H), 3.28
(1H, A of ABX, obscured by solvent), 3.03 (1H, B of ABX, J=14.1,
9.6 Hz), 2.80 (q, 2H, J=10.5, 7.8 Hz) 1.31 (t, 3H, J=4.6 Hz).
[0430] The following are non-limiting examples of the first aspect
of Category V of the present disclosure.
##STR00109##
(S)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(2-fluorophenyl)acetamido)ethyl)pheny-
lsulfamic acid
[0431] .sup.1H NMR (CD.sub.3OD) .delta. 8.65 (d, 1H, J=8.4 Hz),
7.29-7.15 (m, 1H), 7.13-7.03 (m, 7H), 5.46-5.42 (m, 1H), 3.64-3.51
(m, 2H), 3.29 (1H), 3.04 (1H, B of ABX, J=13.8, 9.6 Hz), 2.81 (q,
2H, J=15.6, 3.9 Hz), 1.31 (t, 3H, J=7.8 Hz). .sup.19F NMR
(CD.sub.3OD) .delta. 43.64.
##STR00110##
(S)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(3-fluorophenyl)acetamido)ethyl)pheny-
lsulfamic acid
[0432] .sup.1H NMR (CD3OD) .delta. 8.74 (d, 1H, J=8.4 Hz), 7.32 (q,
1H, J=6.6, 14.2 Hz), 7.10-6.91 (m, 8H), 5.47-5.40 (m, 1H), 3.53 (s,
2H), 3.30 (1H), 3.11 (1H, B of ABX, J=9.6, 14.1 Hz), 2.80 (q, 2H,
J=6.6, 15.1 Hz), 1.31 (t, 3H, J=7.8 Hz). 19F NMR .delta. 47.42.
##STR00111##
(S)-4-(2-(2-(2,3-Difluorophenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)--
phenylsulfamic acid
[0433] .sup.1H NMR (CD.sub.3OD) .delta. 7.16-7.05 (m, 5H),
6.85-6.80 (m, 1H), 5.48-5.43 (m, 1H), 3.63 (s, 2H), 3.38 (1H, A of
ABX, obscured by solvent), 3.03 (1H), 2.80 (q, H, J=15.1, 7.8 Hz),
1.31 (t, 3H, J=7.5 Hz).
##STR00112##
(S)-4-(2-(2-(3,4-Difluorophenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)--
phenylsulfamic acid
[0434] .sup.1H NMR (CD.sub.3OD) .delta. 8.75 (d, 1H, J=7.8 Hz),
7.23-7.04 (m, 6H), 6.88-6.84 (m, 1H), 5.44-5.40 (m, 1H), 3.49 (s,
2H), 3.34 (1H), 3.02 (1H, B of ABX, J=14.1, 9.9 Hz), 2.80 (q, 2H,
J=15.1, 7.8 Hz), 1.31 (t, 1H, J=7.5 Hz). 19F NMR (CD3OD) .delta.
22.18, 19.45.
##STR00113##
(S)-4-(2-(2-(2-Chlorophenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)pheny-
lsulfamic acid
[0435] .sup.1H NMR (CD3OD) .delta. 7.39-7.36 (m, 1H), 7.27-7.21 (m,
2H), 7.15-6.98 (m, 5H), 5.49-5.44 (m, 1H), 3.69 (d, 2H, J=11.7 Hz),
3.32 (1H), 3.04 (1H, B of ABX, J=9.3, 13.9 Hz), 2.80 (q, 2H, J=7.8,
15.3 Hz), 1.31 (t, 3H, J=7.5 Hz).
##STR00114##
(S)-4-(2-(2-(3-Chlorophenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)pheny-
lsulfamic acid
[0436] .sup.1H NMR (CD3OD) .delta. 7.33-7.23 (m, 3H), 7.13-7.03 (m,
5H), 5.43 (q, 1H, J=5.1, 9.6 Hz), 3.51 (s, 2H), 3.29 (1H), 3.03
(1H, B of ABX, J=9.9, 14.1 Hz), 2.80 (q, 2H, J=7.5, 15 Hz), 1.31
(t, 3H, J=7.8 Hz).
##STR00115##
(S)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(3-hydroxyphenyl)acetamido)ethyl)-phe-
nylsulfamic acid
[0437] .sup.1H NMR (CD.sub.3OD) .delta. 7.16-7.08 (m, 3H),
7.03-7.00 (m, 3H), 6.70-6.63 (m, 2H), 5.42-5.40 (m, 1H), 3.44 (s,
2H), 3.28 (1H, A of ABX, obscured by solvent), 3.04 (B of ABX,
J=14.1, 9.6 Hz), 2.89 (q, 2H, J=15, 7.5 Hz), 1.31 (t, 3H, J=7.5
Hz).
##STR00116##
(S)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(2-methoxyphenyl)acetamido)ethyl)-phe-
nylsulfamic acid
[0438] .sup.1H NMR (CD.sub.3OD) .delta. 8.00 (d, 1H, J=7.8 Hz),
7.26 (t, 1H, J=13.2 Hz), 7.09-7.05 (m, 4H), 7.01 (s, 1H), 6.91-6.89
(m, 4H), 5.44-5.39 (m, 1H), 3.71 (s, 3H), 3.52 (s, 2H), 3.26 (1H, A
of ABX, J=14.1, 5.1 Hz), 3.06 (1H B of ABX, J=13.8, 8.4 Hz), 2.80
(q, 2H, J=8.1, 15.6 Hz), 1.31 (t, 3H, J=1.2 Hz).
##STR00117##
(S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(3-methoxyphenyl)
acetamido]ethyl}-phenylsulfamic acid
[0439] .sup.1H NMR (CD.sub.3OD) .delta. 8.58 (d, 1H, J=8.1 Hz),
7.21 (t, 1H, J=7.8 Hz), 7.12-7.02 (m, 4H), 6.81 (s, 2H), 6.72 (d,
1H, J=7.5 Hz), 5.45-5.40 (m, 1H), 3.79 (s, 3H), 3.50 (s, 2H), 3.29
(1H, A of ABX, obscured by solvent), 3.08 (1H, B of ABX, J=11.8,
5.1 Hz), 2.80 (q, 2H, J=15, 7.5 Hz), 1.31 (t 3H, J=6.6 Hz).
##STR00118##
(S)-4-(2-(4-Ethylthiazol-2-yl)-2-(3-phenylpropanamido)ethyl)phenylsulfami-
c acid
[0440] .sup.1H NMR (CD.sub.3OD) .delta. 8.56 (d, 1H, J=8.4 Hz),
7.25-6.98 (m, 9H), 5.43-5.38 (m, 1H), 3.26 (1H, A of ABX, J=14.1,
9.6 Hz), 2.97 (1H, B of ABX, J=10.9, 3 Hz), 2.58-2.76 (m, 3H), 2.98
(q, 2H, J=13.8, 7.2 Hz), 1.29 (t, 3H, J=8.7 Hz).
##STR00119##
(S)-4-(2-(2-(3,4-Dimethoxyphenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)-
-phenylsulfamic acid
[0441] .sup.1H NMR (CD.sub.3OD) .delta. 7.12-7.03 (m, 3H), 6.91 (d,
1H, J=8.4 Hz), 6.82 (s, 1H), 6.66 (d, 1H, J=2.1 Hz), 6.63 (d, 1H,
J=2.1 Hz), 5.43 (m, 1H), 3.84 (s, 3H), 3.80 (s, 3H), 3.45 (s, 2H),
3.30 (1H), 3.03 (1H, B of ABX, J=14.1, 9.6 Hz), 2.79 (q, 2H,
J=15.1, 7.2 Hz), 1.30 (t, 3H, J=7.2 Hz).
##STR00120##
(S)-4-(2-(2-(2,3-Dimethoxyphenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)-
-phenylsulfamic acid
[0442] .sup.1H NMR (CD.sub.3OD) .delta. 8.31 (d, 1H, J=7.8 Hz),
7.11-6.93 (m, 6H), 6.68 (d, 1H, J=7.5 Hz), 5.49-5.40 (m, 1H), 3.87
(s, 3H), 3.70 (s, 3H), 3.55 (s, 2H), 3.26 (1H, A of ABX, obscured
by solvent), 3.06 (1H, B of ABX, J=13.9, 9 Hz), 2.80 (q, 2H,
J=14.8, 7.5 Hz), 1.31 (t, 3H, J=7.5 Hz).
##STR00121##
(S)-4-(2-(3-(3-Chlorophenyl)propanamido)-2-(4-ethylthiazol-2-yl)ethyl)phe-
nylsulfamic acid
[0443] .sup.1H NMR (CD3OD) .delta. 7.27-7.18 (m, 3H), 7.13-7.08 (m,
5H), 7.01 (s, 1H), 5.39 (q, 1H, J=5.1, 9.4 Hz), 3.28 (1H, A of ABX,
J=5.1, 14.1 Hz), 2.97 (1H, B of ABX, J=9.3, 13.9 Hz), 2.88-2.76 (m,
4H), 2.50 (t, 2H, J=8.1 Hz), 1.31 (t, 3H, J=7.8 Hz).
##STR00122##
(S)-4-(2-(4-Ethylthiazol-2-yl)-2-(3-(2-methoxyphenyl)propanamido)ethyl)-p-
henylsulfamic acid
[0444] .sup.1H NMR (CD.sub.3OD) .delta. 7.18-7.08 (m, 6H), 6.92 (d,
1H, J=8.1 Hz), 6.82 (t, 1H, J=7.5 Hz), 5.40-5.35 (m, 1H), 3.25 (1H,
A of ABX, J=15, 5.4 Hz), 3.00 (1H, B of ABX, J=10.5, 7.5 Hz),
2.88-2.76 (m, 4H), 2.47 (q, 2H, J=9.1, 6 Hz), 1.31 (t, 3H, J=7.8
Hz).
##STR00123##
(S)-4-(2-(4-Ethylthiazol-2-yl)-2-(3-(3-methoxyphenyl)propanamido)ethyl)-p-
henylsulfamic acid
[0445] .sup.1H NMR (CD.sub.3OD) .delta. 7.19-7.00 (m, 5H), 6.75 (s,
1H), 6.73 (s, 1H), 5.42-5.37 (m, 1H), 3.76 (s, 3H), 3.25 (1H, A of
ABX, J=13.9, 5.4 Hz), 2.98 (1H, B of ABX, J=14.1, 9.6 Hz),
2.86-2.75 (m, 4H), 2.48 (q, 2H, J=11.7, 1.2 Hz), 1.31 (t, 3H, J=7.5
Hz).
##STR00124##
(S)-4-(2-(4-Ethylthiazol-2-yl)-2-(3-(4-methoxyphenyl)propanamido)ethyl)-p-
henylsulfamic acid
[0446] .sup.1H NMR (CD.sub.3OD) .delta. 7.13-6.99 (m, 7H),
6.82-6.78 (m, 2H), 5.42-5.37 (m, 1H), 3.33 (s, 3H), 3.23 (1H), 2.97
(1H, B of ABX, J=13.3, 11.4 Hz), 2.83-2.75 (m, 4H), 2.49 (q, 2H,
J=6.4, 3.3 Hz), 1.31 (t, 3H, J=7.5 Hz).
##STR00125##
(S)-4-{2-[2-(4-Ethyl-2,3-dioxopiperazin-1-yl)acetamido]-2-(4-ethylthiazol-
-2-yl)ethyl}phenylsulfamic acid
[0447] .sup.1H NMR (CD.sub.3OD) .delta. 7.14 (s, 4H), 7.08 (s, 1H),
5.56-5.51 (m, 1H), 4.34 (d, 2H, J=16.2 Hz), 3.88 (d, 2H, J=17.6
Hz), 3.59-3.40 (m, 3H), 3.26-3.14 (m, 3H), 2.98 (1H, B of ABX,
J=10.8, 13.9 Hz), 2.82 (q, 2H, J=6.9, 15 Hz), 1.32 (t, 3H, J=7.5
Hz), 1.21 (t, 3H, J=7.2 Hz).
##STR00126##
(S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(5-methyl-2,4-dioxo-3,4-dihydropyrimi-
din-1(2H)-yl)acetamido]ethyl}phenylsulfamic acid
[0448] .sup.1H NMR (CD.sub.3OD) .delta. 7.13 (s, 1H), 7.06-7.02 (m,
4H), 6.95 (s, 1H), 5.42-5.31 (m, 1H), 4.43-4.18 (dd, 2H, J=16.5
Hz), 3.24-2.93 (m, 2H), 2.74-2.69 (q, 2H, J=7.3 Hz), 1.79 (s, 3H),
1.22 (t, 3H, J=7.5 Hz).
##STR00127##
(S)-4-[2-(benzo[d][1,3]dioxole-5-carboxamido)-2-(4-ethylthiazol-2-yl)ethy-
l]-phenylsulfamic acid
[0449] .sup.1H NMR (CD.sub.3OD) .delta. 7.25 (d, 1H, J=6.5 Hz),
7.13 (s, 1H), 7.06 (d, 2H, J=8.5 Hz), 7.00 (d, 2H, J=8.5 Hz), 6.91
(s, 1H), 6.76 (d, 1H, J=8.1 Hz), 5.90 (s, 2H), 5.48 (q, 1H, J=5.0
Hz), 3.32-3.24 (m, 2H), 3.07-2.99 (m, 2H), 2.72 (q, 2H, J=7.5 Hz),
1.21 (t, 3H, J=7.5 Hz).
##STR00128##
(S)-4-{2-[2-(2,5-Dimethylthiazol-4-yl)acetamido]-2-(4-ethylthiazol-2-yl)e-
thyl}-phenylsulfamic acid
[0450] .sup.1H NMR (CD.sub.3OD) .delta. 7.10-7.01 (m, 5H), 5.41 (t,
1H, J=6.9 Hz), 3.58 (s, 2H), 3.33-3.01 (m, 2H), 2.82-2.75 (q, 2H,
J=7.5 Hz), 2.59 (s, 3H), 2.23 (s, 3H), 1.30 (t, 3H, J=7.5 Hz).
##STR00129##
(S)-4-{2-[2-(2,4-Dimethylthiazol-5-yl)acetamido]-2-(4-methylthiazol-2-yl)-
ethyl}-phenylsulfamic acid
[0451] .sup.1H NMR (CD.sub.3OD): .delta. 8.71-8.68 (d, 1H, J=8.4
Hz), 7.10-7.03 (m, 4H), 7.01 (s, 1H), 5.41 (m, 1H), 3.59 (s, 1H),
3.34-2.96 (m, 2H), 2.59 (s, 3H), 2.40 (s, 3H), 2.23 (s, 3H).
##STR00130##
(S)-4-{2-(4-Ethylthiazol-2-yl)-2-[3-(thiazol-2-yl)propanamido]ethyl}pheny-
lsulfamic acid
[0452] .sup.1H NMR (CD.sub.3OD):
(S)-4-{2-[2-(2,5-Dimethylthiazol-4-yl)acetamido]-2-(4-ethylthiazol-2-yl)e-
thyl}-phenylsulfamic acid:
[0453] .sup.1H NMR (CD.sub.3OD) .delta. 7.10-7.01 (m, 5H), 5.41 (t,
1H, J=6.9 Hz), 3.58 (s, 2H), 3.33-3.01 (m, 2H), 2.82-2.75 (q, 2H,
J=7.5 Hz), 2.59 (s, 3H), 2.23 (s, 3H), 1.30 (t, 3H, J=7.5 Hz).
7.67-7.65 (m, 1H), 7.49-7.47 (m, 1H), 7.14-7.08 (m, 4H), 7.04 (s,
1H), 5.46-5.41 (q, 1H, J=5.1 Hz), 3.58 (s, 2H), 3.30-3.25 (m, 3H),
3.02-2.67 (m, 5H), 1.31 (t, 3H, J=7.5 Hz).
##STR00131##
(S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(4-ethylthiazol-2-yl)acetamido]ethyl}-
-phenylsulfamic acid
[0454] .sup.1H NMR (CD.sub.3OD) .delta. 7.04-6.91 (m, 6H), 5.32 (t,
1H, J=5.4 Hz), 3.25-2.90 (m, 2H), 2.71-2.61 (m, 4H) 1.93 (s, 2H)
1.22-1.14 (m, 6H).
[0455] The second aspect of Category V of the present disclosure
relates to 2-(thiazol-4-yl) compounds having the formula:
##STR00132##
wherein R.sup.1, R.sup.4, and L are further defined herein in Table
X below.
TABLE-US-00010 TABLE X No. L R.sup.1 R.sup.4 J360 --CH.sub.2--
phenyl methyl J361 --CH.sub.2-- phenyl ethyl J362 --CH.sub.2--
phenyl phenyl J363 --CH.sub.2-- phenyl thiophen-2-yl J364
--CH.sub.2-- phenyl thiazol-2-yl J365 --CH.sub.2-- phenyl
oxazol-2-yl J366 --CH.sub.2-- phenyl isoxazol-3-yl J367
--CH.sub.2-- 3-chlorophenyl methyl J368 --CH.sub.2-- 3-chlorophenyl
ethyl J369 --CH.sub.2-- 3-chlorophenyl phenyl J370 --CH.sub.2--
3-chlorophenyl thiophen-2-yl J371 --CH.sub.2-- 3-chlorophenyl
thiazol-2-yl J372 --CH.sub.2-- 3-chlorophenyl oxazol-2-yl J373
--CH.sub.2-- 3-chlorophenyl isoxazol-3-yl J374 --CH.sub.2--
3-methoxyphenyl methyl J375 --CH.sub.2-- 3-methoxyphenyl ethyl J376
--CH.sub.2-- 3-methoxyphenyl phenyl J377 --CH.sub.2--
3-methoxyphenyl thiophen-2-yl J378 --CH.sub.2-- 3-methoxyphenyl
thiazol-2-yl J379 --CH.sub.2-- 3-methoxyphenyl oxazol-2-yl J380
--CH.sub.2-- 3-methoxyphenyl isoxazol-3-yl J381 --CH.sub.2--
3-fluorophenyl methyl J382 --CH.sub.2-- 3-fluorophenyl ethyl J383
--CH.sub.2-- 3-fluorophenyl phenyl J384 --CH.sub.2-- 3-fluorophenyl
thiophen-2-yl J385 --CH.sub.2-- 3-fluorophenyl thiazol-2-yl J386
--CH.sub.2-- 3-fluorophenyl oxazol-2-yl J387 --CH.sub.2--
3-fluorophenyl isoxazol-3-yl J388 --CH.sub.2--
2,5-dimethylthiazol-4-yl methyl J389 --CH.sub.2--
2,5-dimethylthiazol-4-yl ethyl J390 --CH.sub.2--
2,5-dimethylthiazol-4-yl phenyl J391 --CH.sub.2--
2,5-dimethylthiazol-4-yl thiophen-2-yl J392 --CH.sub.2--
2,5-dimethylthiazol-4-yl thiazol-2-yl J393 --CH.sub.2--
2,5-dimethylthiazol-4-yl oxazol-2-yl J394 --CH.sub.2--
2,5-dimethylthiazol-4-yl isoxazol-3-yl J395 --CH.sub.2--
2,4-dimethylthiazol-5-yl methyl J396 --CH.sub.2--
2,4-dimethylthiazol-5-yl ethyl J397 --CH.sub.2--
2,4-dimethylthiazol-5-yl phenyl J398 --CH.sub.2--
2,4-dimethylthiazol-5-yl thiophen-2-yl J399 --CH.sub.2--
2,4-dimethylthiazol-5-yl thiazol-2-yl J400 --CH.sub.2--
2,4-dimethylthiazol-5-yl oxazol-2-yl J401 --CH.sub.2--
2,4-dimethylthiazol-5-yl isoxazol-3-yl J402 --CH.sub.2--
4-ethylthiazol-2-yl methyl J403 --CH.sub.2-- 4-ethylthiazol-2-yl
ethyl J404 --CH.sub.2-- 4-ethylthiazol-2-yl phenyl J405
--CH.sub.2-- 4-ethylthiazol-2-yl thiophen-2-yl J406 --CH.sub.2--
4-ethylthiazol-2-yl thiazol-2-yl J407 --CH.sub.2--
4-ethylthiazol-2-yl oxazol-2-yl J408 --CH.sub.2--
4-ethylthiazol-2-yl isoxazol-3-yl J409 --CH.sub.2--
3-methyl-1,2,4-oxadiazol-5-yl methyl J410 --CH.sub.2--
3-methyl-1,2,4-oxadiazol-5-yl ethyl J411 --CH.sub.2--
3-methyl-1,2,4-oxadiazol-5-yl phenyl J412 --CH.sub.2--
3-methyl-1,2,4-oxadiazol-5-yl thiophen-2-yl J413 --CH.sub.2--
3-methyl-1,2,4-oxadiazol-5-yl thiazol-2-yl J414 --CH.sub.2--
3-methyl-1,2,4-oxadiazol-5-yl oxazol-2-yl J415 --CH.sub.2--
3-methyl-1,2,4-oxadiazol-5-yl isoxazol-3-yl J416
--CH.sub.2CH.sub.2-- phenyl methyl J417 --CH.sub.2CH.sub.2-- phenyl
ethyl J418 --CH.sub.2CH.sub.2-- phenyl phenyl J419
--CH.sub.2CH.sub.2-- phenyl thiophen-2-yl J420 --CH.sub.2CH.sub.2--
phenyl thiazol-2-yl J421 --CH.sub.2CH.sub.2-- phenyl oxazol-2-yl
J422 --CH.sub.2CH.sub.2-- phenyl isoxazol-3-yl J423
--CH.sub.2CH.sub.2-- 3-chlorophenyl methyl J424
--CH.sub.2CH.sub.2-- 3-chlorophenyl ethyl J425 --CH.sub.2CH.sub.2--
3-chlorophenyl phenyl J426 --CH.sub.2CH.sub.2-- 3-chlorophenyl
thiophen-2-yl J427 --CH.sub.2CH.sub.2-- 3-chlorophenyl thiazol-2-yl
J428 --CH.sub.2CH.sub.2-- 3-chlorophenyl oxazol-2-yl J429
--CH.sub.2CH.sub.2-- 3-chlorophenyl isoxazol-3-yl J430
--CH.sub.2CH.sub.2-- 3-methoxyphenyl methyl J431
--CH.sub.2CH.sub.2-- 3-methoxyphenyl ethyl J432
--CH.sub.2CH.sub.2-- 3-methoxyphenyl phenyl J433
--CH.sub.2CH.sub.2-- 3-methoxyphenyl thiophen-2-yl J434
--CH.sub.2CH.sub.2-- 3-methoxyphenyl thiazol-2-yl J435
--CH.sub.2CH.sub.2-- 3-methoxyphenyl oxazol-2-yl J436
--CH.sub.2CH.sub.2-- 3-methoxyphenyl isoxazol-3-yl J437
--CH.sub.2CH.sub.2-- 3-fluorophenyl methyl J438
--CH.sub.2CH.sub.2-- 3-fluorophenyl ethyl J439 --CH.sub.2CH.sub.2--
3-fluorophenyl phenyl J440 --CH.sub.2CH.sub.2-- 3-fluorophenyl
thiophen-2-yl J441 --CH.sub.2CH.sub.2-- 3-fluorophenyl thiazol-2-yl
J442 --CH.sub.2CH.sub.2-- 3-fluorophenyl oxazol-2-yl J443
--CH.sub.2CH.sub.2-- 3-fluorophenyl isoxazol-3-yl J444
--CH.sub.2CH.sub.2-- 2,5-dimethylthiazol-4-yl methyl J445
--CH.sub.2CH.sub.2-- 2,5-dimethylthiazol-4-yl ethyl J446
--CH.sub.2CH.sub.2-- 2,5-dimethylthiazol-4-yl phenyl J447
--CH.sub.2CH.sub.2-- 2,5-dimethylthiazol-4-yl thiophen-2-yl J448
--CH.sub.2CH.sub.2-- 2,5-dimethylthiazol-4-yl thiazol-2-yl J449
--CH.sub.2CH.sub.2-- 2,5-dimethylthiazol-4-yl oxazol-2-yl J450
--CH.sub.2CH.sub.2-- 2,5-dimethylthiazol-4-yl isoxazol-3-yl J451
--CH.sub.2CH.sub.2-- 2,4-dimethylthiazol-5-yl methyl J452
--CH.sub.2CH.sub.2-- 2,4-dimethylthiazol-5-yl ethyl J453
--CH.sub.2CH.sub.2-- 2,4-dimethylthiazol-5-yl phenyl J454
--CH.sub.2CH.sub.2-- 2,4-dimethylthiazol-5-yl thiophen-2-yl J455
--CH.sub.2CH.sub.2-- 2,4-dimethylthiazol-5-yl thiazol-2-yl J456
--CH.sub.2CH.sub.2-- 2,4-dimethylthiazol-5-yl oxazol-2-yl J457
--CH.sub.2CH.sub.2-- 2,4-dimethylthiazol-5-yl isoxazol-3-yl J458
--CH.sub.2CH.sub.2-- 4-ethylthiazol-2-yl methyl J459
--CH.sub.2CH.sub.2-- 4-ethylthiazol-2-yl ethyl J460
--CH.sub.2CH.sub.2-- 4-ethylthiazol-2-yl phenyl J461
--CH.sub.2CH.sub.2-- 4-ethylthiazol-2-yl thiophen-2-yl J462
--CH.sub.2CH.sub.2-- 4-ethylthiazol-2-yl thiazol-2-yl J463
--CH.sub.2CH.sub.2-- 4-ethylthiazol-2-yl oxazol-2-yl J464
--CH.sub.2CH.sub.2-- 4-ethylthiazol-2-yl isoxazol-3-yl J465
--CH.sub.2CH.sub.2-- 3-methyl-1,2,4-oxadiazol-5-yl methyl J466
--CH.sub.2CH.sub.2-- 3-methyl-1,2,4-oxadiazol-5-yl ethyl J467
--CH.sub.2CH.sub.2-- 3-methyl-1,2,4-oxadiazol-5-yl phenyl J468
--CH.sub.2CH.sub.2-- 3-methyl-1,2,4-oxadiazol-5-yl thiophen-2-yl
J469 --CH.sub.2CH.sub.2-- 3-methyl-1,2,4-oxadiazol-5-yl
thiazol-2-yl J470 --CH.sub.2CH.sub.2--
3-methyl-1,2,4-oxadiazol-5-yl oxazol-2-yl J471 --CH.sub.2CH.sub.2--
3-methyl-1,2,4-oxadiazol-5-yl isoxazol-3-yl
[0456] The compounds encompassed within the second aspect of
Category I of the present disclosure can be prepared by the
procedure outlined in Scheme VIII and described in Example 9
below.
##STR00133##
Example 9
4-((S)-2-(2-(3-chlorophenyl)acetamido)-2-(2-(thiophen-2-yl)thiazol-4-yl)et-
hyl)phenylsulfamic acid (24)
Preparation of
(S)-2-(4-nitrophenyl)-1-[(thiophen-2-yl)thiazol-4-yl]ethanamine
hydrobromide salt (22)
[0457] A mixture of (S)-tert-butyl
4-bromo-1-(4-nitrophenyl)-3-oxobutan-2-ylcarbamate, 7, (7.74 g, 20
mmol), and thiophen-2-carbothioic acid amide (3.14 g, 22 mmol) in
CH.sub.3CN (200 mL) is refluxed for 5 hours. The reaction mixture
is cooled to room temperature and diethyl ether (50 mL) is added to
the solution. The precipitate which forms is collected by
filtration. The solid is dried under vacuum to afford 7.14 g (87%
yield) of the desired product. ESI+ MS 332 (M+1).
Preparation of
2-(3-chlorophenyl)-N--{(S)-2-(4-nitrophenyl)-1-[2-(thiophen-2-yl)thiazol--
4-yl]ethyl}acetamide (23)
[0458] To a solution of
2-(4-nitrophenyl)-1-(2-thiophene2-ylthiazol-4-yl)ethylamine, 22,
(0.41 g, 1 mmol) 3-chlorophenylacetic acid (0.170 g, 1 mmol) and
1-hydroxybenzotriazole (HOBt) (0.070 g, 0.50 mmol) in DMF (5 mL) at
0.degree. C., is added
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0.190 g, 1
mmol) followed by triethylamine (0.42 mL, 3 mmol). The mixture is
stirred at 0.degree. C. for 30 minutes then at room temperature
overnight. The reaction mixture is diluted with water and extracted
with EtOAc. The combined organic phase is washed with 1 N aqueous
HCl, 5% aqueous NaHCO.sub.3, water and brine, and dried over
Na.sub.2SO.sub.4. The solvent is removed in vacuo to afford 0.290 g
(60% yield) of the desired product which is used without further
purification. ESI- MS 482 (M-1).
Preparation of
{4-[2-(3-chlorophenyl)acetylamino]-2-(2-thiophen-2-ylthiazol-4-yl)ethyl]p-
henyl}sulfamic acid (24)
[0459]
2-(3-chlorophenyl)-N--{(S)-2-(4-nitrophenyl)-1-[2-(thiophene2-yl)th-
iazol-4-yl]ethyl}acetamide, 23, (0.290 g) is dissolved in MeOH (4
mL). A catalytic amount of Pd/C (10% w/w) is added and the mixture
is stirred under a hydrogen atmosphere 18 hours. The reaction
mixture is filtered through a bed of CELITE.TM. and the solvent is
removed under reduced pressure. The crude product is dissolved in
pyridine (12 mL) and treated with SO.sub.3-pyridine (0.157 g). The
reaction is stirred at room temperature for 5 minutes after which a
7% solution of NH.sub.4OH is added. The mixture is then
concentrated and the resulting residue is purified by reverse phase
chromatography to afford 0.078 g of the desired product as the
ammonium salt. .sup.1H NMR (CD3OD) .delta. 7.61 (d, 1H, J=3.6 Hz),
7.58 (d, 1H, J=5.1 Hz), 7.41-7.35 (m, 1H), 7.28-7.22 (m, 2H),
7.18-6.98 (m, 6H), 5.33 (t, 1H, J=6.6 Hz), 3.70 (d, 2H, J=3.9 Hz),
3.23 (1H, A of ABX, J=6.6, 13.8 Hz), 3.07 (1H, B of ABX, J=8.1,
13.5 Hz).
[0460] The following are non-limiting examples of compounds
encompassed within the second aspect of Category V of the present
disclosure.
##STR00134##
4-((S)-2-(2-(3-Methoxyphenyl)acetamide)-2-(2-(thiophene2-yl)thiazol-4-yl)-
ethyl)-phenylsulfamic acid
[0461] .sup.1H NMR (CD3OD) .delta. 8.35 (d, 1H, J=8.7 Hz),
7.61-7.57 (m, 2H), 7.25-7.20 (m, 2H), 7.25-7.20 (m, 2H), 7.09 (s,
1H), 7.05 (d, 2H, J=4.2 Hz), 6.99 (d, 1H, J=8.7 Hz), 6.81 (d, 1H,
J=7.8 Hz), 6.77 (s, 1H), 5.30-5.28 (m, 1H), 3.76 (s, 3H), 3.51 (s,
2H), 3.20 (1H, A of ABX, J=6.3, 13.6 Hz), 3.06 (1H, B of ABX,
J=8.1, 13.8 Hz).
##STR00135##
4-{(S)-2-(3-Phenylpropanamido)-2-[2-(thiophene2-yl)thiazol-4-yl]ethyl}-ph-
enylsulfamic acid
[0462] .sup.1H NMR (CD3OD) .delta. 8.30 (d, 1H, J=9 Hz), 7.61-7.56
(m, 2H), 7.26-7.14 (m, 7H), 7.12 (d, 1H, J=1.5 Hz), 7.09 (d, 1H,
J=2.1 Hz), 6.89 (s, 1H), 5.28-5.26 (m, 1H), 3.18 (1H, A of ABX,
J=6.2, 13.8 Hz), 2.96 (1H, B of ABX, J=8.4, 13.6 Hz).
##STR00136##
4-{(S)-2-(3-(3-Chlorophenyl)propanamido)-2-[2-(thiophene2-yl)thiazol-4-yl-
]ethyl}phenylsulfamic acid
[0463] .sup.1H NMR (CD.sub.3OD) .delta. 7.61-7.56 (m, 3H),
7.22-7.14 (m, 6H), 7.08 (d, 1H), 7.00 (d, 1H, J=77.5 Hz), 6.870 (s,
1H), 5.25 (t, 1H, J=7.8 Hz), 3.18 (1H, A of ABX, J=6.6, 13.8 Hz),
2.97 (1H, B of ABX, J=7.8, 13.8 Hz), 2.87 (t, 2H, J=7.5 Hz), 2.51
(t, 2H, J=7.2 Hz).
##STR00137##
4-{(S)-2-[2-(3-Fluorophenyl)acetamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]e-
thyl}phenylsulfamic acid
[0464] .sup.1H NMR (CD.sub.3OD) .delta. 7.61-7.57 (m, 2H),
7.32-7.28 (m, 1H), 7.19-7.16 (m, 2H), 7.08 (t, 1H, J=4.5 Hz),
7.02-6.95 (m, 6H), 5.29 (t, 1H, J=8.1 Hz), 3.53 (s, 2H), 3.22 (1H,
A of ABX, J=6.6, 13.9 Hz), 3.06 (1H, B of ABX, J=8.4, 13.6 Hz).
##STR00138##
(S)-4-{2-[2-(3-Methyl-1,2,4-oxadiazol-5-yl)acetamido]-2-(2-phenylthiazol--
4-yl)ethyl}phenylsulfamic acid
[0465] .sup.1H NMR (CD.sub.3OD): .delta. 7.98-7.95 (m, 2H),
7.48-7.46 (m, 3H), 7.23 (s, 1H), 7.09-7.05 (m, 4H), 5.33 (t, 1H,
J=7.2 Hz), 3.33-3.06 (m, 2H), 2.35 (s, 3H).
##STR00139##
4-{(S)-2-[2-(4-ethyl-2,3-dioxopiperazin-1-yl)acetamido]-2-[2-(thiophen-2--
yl)thiazol-4-yl]ethyl}phenylsulfamic acid
[0466] .sup.1H NMR (CD.sub.3OD) .delta. 7.62 (d, 1H, J=3 Hz), 7.58
(d, 1H, J=15.6 Hz), 7.27 (s, 1H), 7.16 (t, 1H, J=1.5 Hz), 5.42-5.32
(m, 1H), 4.31 (d, 1H, J=15.6 Hz), 3.91 (d, 1H, J=15.9 Hz),
3.60-3.50 (m, 4H), 3.30-3.23 (m, 2H), 2.98 (1H, B of ABX, J=9.9,
13.8 Hz), 1.21 (t, 3H, J=6.9 Hz).
[0467] The third aspect of Category V of the present disclosure
relates to compounds having the formula:
##STR00140##
wherein the linking unit L comprises a phenyl unit, said linking
group having the formula:
--C(O)[(CR.sup.5aH)][(CR.sup.6aH)]--
R.sup.1 is hydrogen, R.sup.6a is phenyl, R.sup.5a is phenyl or
substituted phenyl and non-limiting examples of the units R.sup.2,
R.sup.3, and R.sup.5a are further exemplified below in Table
XI.
TABLE-US-00011 TABLE XI No. R.sup.2 R.sup.3 R.sup.5a K472 methyl
hydrogen phenyl K473 methyl hydrogen 2-fluorophenyl K474 methyl
hydrogen 3-fluorophenyl K475 methyl hydrogen 4-fluorophenyl K476
methyl hydrogen 3,4-difluorophenyl K477 methyl hydrogen
2-chlorophenyl K478 methyl hydrogen 3-chlorophenyl K479 methyl
hydrogen 4-chlorophenyl K480 methyl hydrogen 3,4-dichlorophenyl
K481 methyl hydrogen 2-methoxyphenyl K482 methyl hydrogen
3-methoxyphenyl K483 methyl hydrogen 4-methoxyphenyl K484 ethyl
hydrogen phenyl K485 ethyl hydrogen 2-fluorophenyl K486 ethyl
hydrogen 3-fluorophenyl K487 ethyl hydrogen 4-fluorophenyl K488
ethyl hydrogen 3,4-difluorophenyl K489 ethyl hydrogen
2-chlorophenyl K490 ethyl hydrogen 3-chlorophenyl K491 ethyl
hydrogen 4-chlorophenyl K492 ethyl hydrogen 3,4-dichlorophenyl K493
ethyl hydrogen 2-methoxyphenyl K494 ethyl hydrogen 3-methoxyphenyl
K495 ethyl hydrogen 4-methoxyphenyl
[0468] The compounds encompassed within the third aspect of
Category V of the present disclosure can be prepared by the
procedure outlined in Scheme IX and described in Example 10 herein
below.
##STR00141##
Example 10
(S)-4-(2-(2,3-Diphenylpropanamido)-2-(4-ethylthiazol-2-yl)ethyl)-phenylsul-
famic acid (26)
Preparation of
(S)--N-[1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]-2,3-diphenyl-prop-
anamide (25)
[0469] To a solution of
1-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl amine
hydrobromide, 3, (0.95 g, 2.65 mmol), diphenylpropionic acid (0.60
g, 2.65 mmol) and 1-hydroxybenzotriazole (HOBt) (0.180 g, 1.33
mmol) in DMF (10 mL) at 0.degree., is added
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0.502 g, 2.62
mmol) followed by triethylamine (1.1 mL, 7.95 mmol). The mixture is
stirred at 0.degree. C. for 30 minutes then at room temperature
overnight. The reaction mixture is diluted with water and extracted
with EtOAc. The combined organic phase is washed with 1 N aqueous
HCl, 5% aqueous NaHCO.sub.3, water and brine, and dried over
Na.sub.2SO.sub.4. The solvent is removed in vacuo to afford 0.903 g
(70% yield) of the desired product which is used without further
purification.
Preparation of
(S)-4-(2-(2,3-diphenylpropanamido)-2-(4-ethylthiazol-2-yl)ethyl)phenylsul-
famic acid (26)
[0470]
(S)--N-[1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]-2,3-dipheny-
l-propanamide, 25, (0.903 g) is dissolved in MeOH (10 mL). A
catalytic amount of Pd/C (10% w/w) is added and the mixture is
stirred under a hydrogen atmosphere 18 hours. The reaction mixture
is filtered through a bed of CELITE.TM. and the solvent is removed
under reduced pressure. The crude product is dissolved in pyridine
(30 mL) and treated with SO.sub.3-pyridine (0.621 g). The reaction
is stirred at room temperature for 5 minutes after which a 7%
solution of NH.sub.4OH is added. The mixture is then concentrated
and the resulting residue is purified by reverse phase
chromatography to afford 0.415 g of the desired product as the
ammonium salt. .sup.1H NMR (CD.sub.3OD) .delta. 8.59-8.52 (m, 1H),
7.37-7.04 (m, 9H), 6.97-6.93 (m, 1H), 6.89-6.85 (m, 2H), 5.36-5.32
(m, 1H), 3.91-3.83 (m, 1H), 3.29 (1H, A of ABX, obscured by
solvent), 3.15 (1H, B of ABX, J=5.4, 33.8 Hz), 2.99-2.88 (m, 2H),
2.81-2.69 (m, 2H), 1.32-1.25 (m, 3H).
[0471] The following procedure illustrates an example of the
procedure which can be used to provide different R.sup.5a units
according to the present disclosure. Using the procedure outlined
in Scheme X and described in Example 11, one can achieve the
R.sup.5a units encompassed by the present disclosure.
##STR00142##
Example 11
2-(2-Methoxyphenyl)-3-phenylpropanoic acid (28)
Preparation of methyl 2-(2-methoxyphenyl)-3-phenylpropanoate
(27)
[0472] A 500 mL round-bottom flask is charged with methyl
2-(2-methoxyphenyl)acetate (8.496 g, 47 mmol, 1 eq) and THF (200
mL). The homogeneous mixture is cooled to 0.degree. C. in an ice
bath. Lithium diisopropyl amide (23.5 mL of a 2.0M solution in
heptane/THF) is added, maintaining a temperature less than
3.degree. C. The reaction is stirred 45 minutes at this reduced
temperature. Benzyl bromide (5.6 mL, 47 mmol, 1 eq) is added
dropwise. The reaction is allowed to gradually warm to room
temperature and is stirred for 18 hours. The reaction is quenched
with 1N HCl and extracted 3 times with equal portions of EtOAc. The
combined extracts are washed with H.sub.2O and brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The residue is
purified over silica to afford 4.433 g (35%) of the desired
compound. ESI+ MS 293 (M+Na).
Preparation of 2-(2-methoxyphenyl)-3-phenylpropanoic acid (28)
[0473] Methyl 2-(2-methoxyphenyl)-3-phenylpropanoate (4.433 g, 16
mmol, 1 eq) is dissolved in 100 mL of a 1:1 (v:v) mixture of THF
and methanol. Sodium hydroxide (3.28 g, 82 mmol, 5 eq) is added and
the reaction mixture is stirred 18 hours at room temperature. The
reaction is then poured into H.sub.2O and the pH is adjusted to 2
via addition of 1N HCl. A white precipitate forms which is removed
by filtration. The resulting solution is extracted with 3 portion
of diethyl ether. The extracts are pooled, washed with H.sub.2O and
brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated in
vacuo. The resulting residue is purified over silica to afford
2.107 g (51%) of the desired compound. ESI- MS 255 (M-1), 211
(M-CO.sub.2H).
[0474] Intermediate 28 can be carried forward according to the
procedure outlined in Scheme IX and described in Example 10 to
produce the following compound according to the third aspect of
Category V.
##STR00143##
(S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(2-methoxyphenyl)-3-phenylpropanamido-
]-ethyl}phenylsulfamic acid
[0475] .sup.1H NMR (CD.sub.3OD) .delta. 7.32-7.12 (m, 7H),
7.05-7.02 (m, 1H), 6.99-6.83 (m, 4H), 6.80-6.75 (m, 2H), 5.35-5.31
(m, 1H), 4.31-4.26 (m, 1H), 3.75 (s, 3H), 3.20-2.90 (m, 4H),
2.79-2.74 (m, 2H), 1.32-1.25 (m, 3H).
[0476] The following are further non-limiting examples of compounds
according to the third aspect of Category I of the present
disclosure.
##STR00144##
(S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(3-fluorophenyl)-3-phenylpropanamido]-
-ethyl}phenylsulfamic acid
[0477] .sup.1H NMR (CD.sub.3OD) .delta. 7.33-6.87 (m, 14H),
5.39-5.25 (m, 1H), 3.95-3.83 (m, 1H), 3.31-3.10 (m, 1H), 3.05-2.88
(m, 2H), 2.80-2.70 (m, 2H), 1.32-1.23 (m, 3H). .sup.19F NMR
.quadrature. 47.59.
##STR00145##
(S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(3-methoxyphenyl)-3-phenylpropanamido-
]-ethyl}phenylsulfamic acid
[0478] .sup.1H NMR (CD.sub.3OD) .delta. 7.85 (d, 1H, J=8.4 Hz),
7.25-7.20 (m, 1H), 7.11-7.02 (m, 4H), 7.01 (s, 1H), 6.90-6.79 (m,
2H), 5.45-5.40 (m, 1H), 4.09 (s, 2H), 3.79 (s, 3H), 3.12-3.08 (m,
2H), 1.10 (s, 9H).
[0479] The fourth aspect of Category V of the present disclosure
relates to compounds having the formula:
##STR00146##
wherein the linking unit L comprises a phenyl unit, said linking
group having the formula:
--C(O)[(CR.sup.5aH)][(CR.sup.6aH]--
R.sup.1 is hydrogen, R.sup.6a is phenyl, R.sup.5a is substituted or
unsubstituted heteroaryl and the units R.sup.2, R.sup.3, and
R.sup.5a are further exemplified herein below in Table XII.
TABLE-US-00012 TABLE XII No. R.sup.2 R.sup.3 R.sup.5a L496 methyl
hydrogen 3-methyl-1,2,4-oxadiazol-5-yl L497 methyl hydrogen
thiophen-2-yl L498 methyl hydrogen thiazol-2-yl L499 methyl
hydrogen oxazol-2-yl L500 methyl hydrogen isoxazol-3-yl L501 ethyl
hydrogen 3-methyl-1,2,4-oxadiazol-5-yl L502 ethyl hydrogen
thiophen-2-yl L503 ethyl hydrogen thiazol-2-yl L504 ethyl hydrogen
oxazol-2-yl L505 ethyl hydrogen isoxazol-3-yl L506 ethyl methyl
3-methyl-1,2,4-oxadiazol-5-yl L507 ethyl methyl thiophen-2-yl L508
ethyl methyl thiazol-2-yl L509 ethyl methyl oxazol-2-yl L510 ethyl
methyl isoxazol-3-yl L511 thiophen-2-yl hydrogen
3-methyl-1,2,4-oxadiazol-5-yl L512 thiophen-2-yl hydrogen
thiophen-2-yl L513 thiophen-2-yl hydrogen thiazol-2-yl L514
thiophen-2-yl hydrogen oxazol-2-yl L515 thiophen-2-yl hydrogen
isoxazol-3-yl L516 isoxazol-3-yl hydrogen
3-methyl-1,2,4-oxadiazol-5-yl L517 isoxazol-3-yl hydrogen
thiophen-2-yl L518 isoxazol-3-yl hydrogen thiazol-2-yl L519
isoxazol-3-yl hydrogen oxazol-2-yl L520 isoxazol-3-yl hydrogen
isoxazol-3-yl
[0480] The compounds encompassed within the fourth aspect of
Category V of the present disclosure can be prepared by the
procedure outlined in Scheme XI and described in Example 5 herein
below.
##STR00147## ##STR00148##
Example 12
4-{(S)-2-(4-Ethylthiazol-2-yl)-2-[2-(3-methyl-1,2,4-oxadiazol-5-yl)-3-phen-
ylpropanamido]ethyl}phenylsulfamic acid (31)
Preparation of
ethyl-2-benzyl-3-[(S)-1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)-ethylamin-
o]-3-oxopropanoate (29)
[0481] To a solution of
1-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl amine
hydrobromide, 3, (0.406 g, 1.13 mmol),
2-benzyl-3-ethoxy-3-oxopropanoic acid (0.277 g) and
1-hydroxybenzotriazole (HOBt) (0.191 g, 1.41 mmol) in DMF (10 mL)
at 0.degree., is added
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0.240 g, 1.25
mmol) followed by diisopropylethylamine (DIPEA) (0.306 g). The
mixture is stirred at 0.degree. C. for 30 minutes then at room
temperature overnight. The reaction mixture is diluted with water
and extracted with EtOAc. The combined organic phase is washed with
1 N aqueous HCl, 5% aqueous NaHCO.sub.3, water and brine, and dried
over Na.sub.2SO.sub.4. The solvent is removed in vacuo to afford
0.169 g (31% yield) of the desired product which is used without
further purification.
Preparation of
N--[(S)-1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]-2-(3-methyl-1,2,4-
-oxadiazol-5-yl)-3-phenylpropanamide (30)
[0482] Ethyl
2-benzyl-3-((S)-1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethylamino)-3-ox-
opropanoate is dissolved in toluene (5 mL) and heated to reflux.
Potassium carbonate (80 mg) and acetamide oxime (43 mg) are added.
and treated with 80 mg potassium carbonate and 43 mg acetamide
oxime at reflux. The reaction mixture is cooled to room
temperature, filtered and concentrated. The residue is
chromatographed over silica to afford 0.221 g (94%) of the desired
product as a yellow oil.
Preparation of
4-{(S)-2-(4-ethylthiazol-2-yl)-2-[2-(3-methyl-1,2,4-oxadiazol-5-yl)-3-phe-
nylpropanamido]ethyl}phenylsulfamic acid (31)
[0483]
N--[(S)-1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]-2-(3-methyl-
-1,2,4-oxadiazol-5-yl)-3-phenylpropanamide, 30, (0.221 g) and tin
(II) chloride (507 mg, 2.2 mmol) are dissolved in EtOH (25 mL) and
the solution is brought to reflux 4 hours. The solvent is removed
in vacuo and the resulting residue is dissolved in EtOAc. A
saturated solution of NaHCO.sub.3 (50 mL) is added and the solution
is stirred 1 hour. The organic layer is separated and the aqueous
layer extracted twice with EtOAc. The combined organic layers are
dried (Na.sub.2SO.sub.4), filtered and concentrated to a residue
which is dissolved in pyridine (0.143 g) and treated with
SO.sub.3-pyridine (0.143 g). The reaction is stirred at room
temperature for 5 minutes after which a 7% solution of NH.sub.4OH
is added. The mixture is then concentrated and the resulting
residue is purified by reverse phase chromatography to afford 0.071
g of the desired product as the ammonium salt. .sup.1H NMR
(CD.sub.3OD): .delta. 7.29-6.87 (m, 10H), 5.38-5.30 (m, 1H),
4.37-4.30 (m, 1H), 3.42-2.74 (m, 6H), 2.38-2.33 (m, 3H), 1.34-1.28
(m, 3H).
[0484] Category VI of the present disclosure relates to
2-(thiazol-2-yl) compounds having the formula:
##STR00149##
wherein R.sup.1, R.sup.2, and R.sup.3 are further defined herein in
Table XIII herein.
TABLE-US-00013 TABLE XIII No. R.sup.2 R.sup.3 R.sup.1 M521 ethyl
hydrogen thiophen-2-yl M522 ethyl hydrogen thiazol-2-yl M523 ethyl
hydrogen oxazol-2-yl M524 ethyl hydrogen isoxazol-3-yl M525 ethyl
hydrogen imidazol-2-yl M526 ethyl hydrogen isoxazol-3-yl M527 ethyl
hydrogen oxazol-4-yl M528 ethyl hydrogen isoxazol-4-yl M529 ethyl
hydrogen thiophen-4-yl M530 ethyl hydrogen thiazol-4-yl M531 ethyl
methyl methyl M532 ethyl methyl ethyl M533 ethyl methyl propyl M534
ethyl methyl iso-propyl M535 ethyl methyl butyl M536 ethyl methyl
phenyl M537 ethyl methyl benzyl M538 ethyl methyl 2-fluorophenyl
M539 ethyl methyl 3-fluorophenyl M540 ethyl methyl 4-fluorophenyl
M541 phenyl hydrogen methyl M542 phenyl hydrogen ethyl M543 phenyl
hydrogen propyl M544 phenyl hydrogen iso-propyl M545 phenyl
hydrogen butyl M546 phenyl hydrogen phenyl M547 phenyl hydrogen
benzyl M548 phenyl hydrogen 2-fluorophenyl M549 phenyl hydrogen
3-fluorophenyl M550 phenyl hydrogen 4-fluorophenyl M551
thiophen-2-yl hydrogen methyl M552 thiophen-2-yl hydrogen ethyl
M553 thiophen-2-yl hydrogen propyl M554 thiophen-2-yl hydrogen
iso-propyl M555 thiophen-2-yl hydrogen butyl M556 thiophen-2-yl
hydrogen phenyl M557 thiophen-2-yl hydrogen benzyl M558
thiophen-2-yl hydrogen 2-fluorophenyl M559 thiophen-2-yl hydrogen
3-fluorophenyl M560 thiophen-2-yl hydrogen 4-fluorophenyl
[0485] The compounds encompassed within Category VI of the present
disclosure can be prepared by the procedure outlined in Scheme XII
and described in Example 13 below.
##STR00150##
Example 13
(S)-4-[2-(4-Ethylthiazol-2-yl)-2-(4-oxo-4-phenylbutanamido)ethyl]-phenylsu-
lfamic acid (33)
Preparation of
(S)--N-[1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]-4-oxo-4-phenylbut-
anamide (32)
[0486] 3-Benzoylpropionic acid (0.250 g) is dissolved in
CH.sub.2Cl.sub.2 (5 mL), N-methyl imidazole (0.333 mL) is added and
the resulting solution is cooled to 0.degree. C. after which a
solution of thionyl chloride (0.320 g) in CH.sub.2Cl.sub.2 (2 mL)
is added dropwise. After 0.5 hours
(S)-1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethanamine, 3, (0.388
g) is added. The reaction is stirred for 18 hours at room
temperature and then concentrated in vacuo. The resulting residue
is dissolved in EtOAc and washed with 1N HCl and brine. The
solution is dried over Na.sub.2SO.sub.4, filtered, and concentrated
and the crude material purified over silica to afford 0.415 g of
the desired product.
Preparation of
(S)-4-[2-(4-ethylthiazol-2-yl)-2-(4-oxo-4-phenylbutanamido)-ethyl]phenyls-
ulfamic acid (33)
[0487]
(S)--N-[1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]-2,3-dipheny-
l-propanamide, 32, (0.2 g) is dissolved in MeOH (15 mL). A
catalytic amount of Pd/C (10% w/w) is added and the mixture is
stirred under a hydrogen atmosphere 18 hours. The reaction mixture
is filtered through a bed of CELITE.TM. and the solvent is removed
under reduced pressure. The crude product is dissolved in pyridine
(5 mL) and treated with SO.sub.3-pyridine (0.153 g). The reaction
is stirred at room temperature for 5 minutes after which a 7%
solution of NH.sub.4OH is added. The mixture is then concentrated
and the resulting residue is purified by reverse phase
chromatography to afford 0.090 g of the desired product as the
ammonium salt. .sup.1H NMR (CD.sub.3OD) .delta. 8.68 (d, 1H, J=8.2
Hz), 8.00 (d, 2H, J=7.2 Hz), 7.80-7.50 (m, 3H), 7.12 (s, 4H), 7.03
(s, 1H), 5.46-5.38 (m, 1H), 3.29-3.14 (m, 2H), 3.06-2.99 (m, 2H),
2.83 (q, 2H, J=7.5 Hz), 2.69-2.54 (m, 2H), 1.33 (t, 3H, J=7.5
Hz).
[0488] The following are non-limiting examples of compounds
encompassed within Category II of the present disclosure. The
intermediate nitro compounds of the following can be prepared by
coupling the appropriate 4-oxo-carboxcylic acid with intermediate 3
under the conditions described herein above for the formation of
intermediate 4 of scheme I.
##STR00151##
(S)-4-(2-(4-Ethylthiazol-2-yl)-2-(5-methyl-4-oxohexanamido)ethyl)phenylsu-
lfamic acid
[0489] .sup.1H NMR (CD.sub.3OD) .delta. 8.59 (d, 1H, J=8.1 Hz),
7.14 (s, 4H), 7.08 (t, 1H, J=13.0 Hz), 5.40-5.35 (m, 1H), 3.37-3.27
(m, 2H), 3.04-2.97 (m, 1H), 2.83-2.61 (m, 4H), 2.54-2.36 (m, 3H),
1.33 (t, 2H, J=7.3 Hz), 1.09 (dd, 6H, J=7.0, 2.2 Hz).
##STR00152##
(S)-4-{2-[4-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-4-oxobutanamido]--
2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamic acid
[0490] .sup.1H NMR (CD.sub.3OD) .delta. 8.64 (d, 1H, J=8.4 Hz),
.quadrature.7.60.quadrature..quadrature.d, 2H, J=10.6 Hz), 7.11 (s,
3H), 7.04 (d, 2H, J=5.5 Hz), 5.42-5.40 (m, 1H), 4.30-4.22 (m, 4H),
3.20-2.98 (m, 4H), 2.82 (q, 2H, J=7.3 Hz), 2.67-2.48 (m, 2H), 2.23
(t, 2H, J=5.5 Hz), 1.32 (t, 3H, J=7.3 Hz).
##STR00153##
(S)-4-{2-[4-(2,3-Dimethoxyphenyl)-4-oxobutanamido]-2-(4-ethylthiazol-2-yl-
)ethyl}phenylsulfamic acid
[0491] .sup.1H NMR (CD.sub.3OD), .delta. 8.64 (d, 1H, J=8.1 Hz),
7.21-7.11 (m, 7H), 7.02 (s, 1H), 5.42 (q, 1H, J=5.9 Hz), 3.90 (d,
3H, J=3.3 Hz), 3.88 (d, 3H, J=2.9 Hz), 3.22-3.18 (m, 2H), 3.07-2.99
(m, 2H), 2.83 (q, 2H, J=7.3 Hz), 2.63-2.54 (m, 2H), 1.34 (t, 3H,
J=7.69 Hz).
##STR00154##
(S)-4-{2-(4-Ethylthiazol-2-yl)-2-[4-oxo-4-(pyridin-2-yl)butanamido]ethyl}-
-phenylsulfamic acid
[0492] .sup.1H NMR (CD.sub.3OD) .delta. 8.60 (d, 1H, J=12.8 Hz),
7.91-7.81 (m, 2H), 7.48-7.44 (m, 1H), 7.22-7.21 (m, 1H), 6.99 (s,
3H), 6.91 (s, 1H), 5.30 (q, 1H, J=5.4 Hz), 3.36 (q, 2H, J=7.0 Hz),
3.21-3.15 (m, 1H), 2.91-2.85 (m, 1H), 2.74 (q, 2H, J=10.4 Hz),
2.57-2.50 (m, 2H), 1.20 (t, 3H, J=7.5 Hz).
##STR00155##
(S)-4-{2-[4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-oxobutanamido]-2-(4-e-
thylthiazol-2-yl)ethyl}phenylsulfamic acid
[0493] .sup.1H NMR (CD.sub.3OD) .delta. 7.52-7.47 (m, 2H), 7.11 (s,
4H), 7.03 (s, 1H), 6.95 (d, 1H, J=8.4 Hz), 5.41 (q, 1H, J=3.7 Hz),
4.31 (d, 4H, J=5.5 Hz), 3.24-3.12 (m, 2H), 3.06-2.98 (m, 2H), 2.83
(q, 2H, J=7.3 Hz), 2.62-2.53 (m, 2H), 1.33 (t, 3H, J=7.3 Hz).
##STR00156##
(S)-4-[2-(4-tert-butoxy-4-oxobutanamido)-2-(4-ethylthiazol-2-yl)ethyl]phe-
nylsulfamic acid
[0494] .sup.1H NMR (CD.sub.3OD), .delta. 7.10 (s 4H), 7.02 (s, 1H),
5.41 (q, 1H, J=3.7 Hz), 3.30-3.25 (m, 1H), 3.06-2.99 (m, 1H), 2.83
(q, 2H, J=7.3 Hz), 2.52-2.40 (m, 4H), 1.42 (s, 9H), 1.33 (t, 3H,
J=7.3 Hz).
##STR00157##
(S)-4-[2-(4-ethoxy-4-oxobutanamido)-2-(4-ethylthiazol-2-yl)ethyl]phenylsu-
lfamic acid
[0495] .sup.1H NMR (CD.sub.3OD) .delta. 8.62 (d, 1H, J=8.4 Hz),
7.10 (s, 4H), 7.02 (s, 1H), 5.40 (q, 1H, 3.7 Hz), 4.15 (q, 2H,
J=7.3 Hz), 3.28-3.25 (m, 1H), 3.05-3.02 (m, 1H), 2.82 (q, 2H, J=4.4
Hz), 2.54-2.48 (m, 2H), 1.33 (t, 3H, J=7.3 Hz), 1.24 (t, 3H, J=7.0
Hz).
[0496] The first aspect of Category VII of the present disclosure
relates to 2-(thiazol-2-yl) compounds having the formula:
##STR00158##
wherein non-limiting examples of R.sup.1, R.sup.2, and R.sup.3 are
further described below in Table XIV.
TABLE-US-00014 TABLE XIV No. R.sup.2 R.sup.3 R.sup.1 N561 methyl
hydrogen phenyl N562 methyl hydrogen benzyl N563 methyl hydrogen
2-fluorophenyl N564 methyl hydrogen 3-fluorophenyl N565 methyl
hydrogen 4-fluorophenyl N566 methyl hydrogen 2-chlorophenyl N567
methyl hydrogen 3-chlorophenyl N568 methyl hydrogen 4-chlorophenyl
N569 ethyl hydrogen phenyl N570 ethyl hydrogen benzyl N571 ethyl
hydrogen 2-fluorophenyl N572 ethyl hydrogen 3-fluorophenyl N573
ethyl hydrogen 4-fluorophenyl N574 ethyl hydrogen 2-chlorophenyl
N575 ethyl hydrogen 3-chlorophenyl N576 ethyl hydrogen
4-chlorophenyl N577 thiene-2-yl hydrogen phenyl N578 thiene-2-yl
hydrogen benzyl N579 thiene-2-yl hydrogen 2-fluorophenyl N580
thiene-2-yl hydrogen 3-fluorophenyl N581 thiene-2-yl hydrogen
4-fluorophenyl N582 thiene-2-yl hydrogen 2-chlorophenyl N583
thiene-2-yl hydrogen 3-chlorophenyl N584 thiene-2-yl hydrogen
4-chlorophenyl
[0497] The compounds encompassed within Category VII of the present
disclosure can be prepared by the procedure outlined in Scheme XIII
and described in Example 14 herein below.
##STR00159##
Example 14
(S)-4-(2-(3-Benzylureido)-2-(4-ethylthiazol-2-yl)ethyl)phenylsulfamic
acid (35)
Preparation of
(S)-1-benzyl-3-[1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]urea
(34)
[0498] To a solution of
1-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl amine
hydrobromide, 3, (0.360 g, 1 mmol) and Et.sub.3N (0.42 mL, 3 mmol)
in 10 mL CH.sub.2Cl.sub.2 is added benzyl isocyanate (0.12 mL, 1
mmol). The mixture is stirred at room temperature for 18 hours. The
product is isolated by filtration to afford 0.425 g (96% yield) of
the desired product which is used without further purification.
Preparation of
(S)-4-(2-(3-benzylureido)-2-(4-ethylthiazol-2-yl)ethyl)phenylsulfamic
acid (35)
[0499]
(S)-1-benzyl-3-[1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]urea-
, 34, (0.425 g) is dissolved in MeOH (4 mL). A catalytic amount of
Pd/C (10% w/w) is added and the mixture is stirred under a hydrogen
atmosphere 18 hours. The reaction mixture is filtered through a bed
of CELITE.TM. and the solvent is removed under reduced pressure.
The crude product is dissolved in pyridine (12 mL) and treated with
SO.sub.3-pyridine (0.220 g). The reaction is stirred at room
temperature for 5 minutes after which a 7% solution of NH.sub.4OH
is added. The mixture is then concentrated and the resulting
residue is purified by reverse phase chromatography to afford 0.143
g of the desired product as the ammonium salt. .sup.1H NMR
(CD.sub.3OD) .delta. 7.32-7.30 (m, 2H), 7.29-7.22 (m, 3H),
7.12-7.00 (m, 4H), 6.84 (d, 1H, J=8.1 Hz), 5.35-5.30 (m, 1H), 4.29
(s, 2H), 3.27-3.22 (m, 3H), 3.11-3.04 (m, 3H), 2.81 (q, 2H, J=10.2,
13.0 Hz), 1.31 (t, 3H, J=4.5 Hz).
[0500] The following is a non-limiting examples of compounds
encompassed within the first aspect of Category VII of the present
disclosure.
4-{[(S)-2-(2-Ethylthiazol-4-yl)-2-(3-(R)-methoxy-1-oxo-3-phenylpropan-2-yl-
)ureido]ethyl}phenylsulfamic acid
[0501] .sup.1H NMR (CD.sub.3OD) .delta. 7.36-7.26 (m, 3H),
7.19-7.17 (m, 2H), 7.10-7.06 (m, 2H), 6.90-6.86 (m, 3H), 5.12-5.06
(m, 1H), 4.60-4.55 (m, 1H), 3.69 (s, 3H) 3.12-2.98 (m, 6H),
1.44-1.38 (m, 3H).
[0502] The second aspect of Category VII of the present disclosure
relates to 2-(thiazol-4-yl) compounds having the formula:
##STR00160##
wherein non-limiting examples of R.sup.1 and R.sup.4 are further
described below in Table XV.
TABLE-US-00015 TABLE XV No. R.sup.1 R.sup.4 O585 Methyl methyl O586
Ethyl methyl O587 n-propyl methyl O588 iso-propyl methyl O589
Phenyl methyl O590 Benzyl methyl O591 2-fluorophenyl methyl O592
2-chlorophenyl methyl O593 thiophen-2-yl methyl O594 thiazol-2-yl
methyl O595 oxazol-2-yl methyl O596 isoxazol-3-yl methyl O597
Methyl ethyl O598 Ethyl ethyl O599 n-propyl ethyl O600 iso-propyl
ethyl O601 Phenyl ethyl O602 Benzyl ethyl O603 2-fluorophenyl ethyl
O604 2-chlorophenyl ethyl O605 thiophen-2-yl ethyl O606
thiazol-2-yl ethyl O607 oxazol-2-yl ethyl O608 isoxazol-3-yl ethyl
O609 Methyl thiophen-2-yl O610 Ethyl thiophen-2-yl O611 n-propyl
thiophen-2-yl O612 iso-propyl thiophen-2-yl O613 Phenyl
thiophen-2-yl O614 Benzyl thiophen-2-yl O615 2-fluorophenyl
thiophen-2-yl O616 2-chlorophenyl thiophen-2-yl O617 thiophen-2-yl
thiophen-2-yl O618 thiazol-2-yl thiophen-2-yl O619 oxazol-2-yl
thiophen-2-yl O620 isoxazol-3-yl thiophen-2-yl O621 Methyl
thiazol-2-yl O622 Ethyl thiazol-2-yl O623 n-propyl thiazol-2-yl
O624 iso-propyl thiazol-2-yl O625 Phenyl thiazol-2-yl O626 Benzyl
thiazol-2-yl O627 2-fluorophenyl thiazol-2-yl O628 2-chlorophenyl
thiazol-2-yl O629 thiophen-2-yl thiazol-2-yl O630 thiazol-2-yl
thiazol-2-yl O631 oxazol-2-yl thiazol-2-yl O632 isoxazol-3-yl
thiazol-2-yl O633 Methyl oxazol-2-yl O634 Ethyl oxazol-2-yl O635
n-propyl oxazol-2-yl O636 iso-propyl oxazol-2-yl O637 Phenyl
oxazol-2-yl O638 Benzyl oxazol-2-yl O639 2-fluorophenyl oxazol-2-yl
O640 2-chlorophenyl oxazol-2-yl O641 thiophen-2-yl oxazol-2-yl O642
thiazol-2-yl oxazol-2-yl O643 oxazol-2-yl oxazol-2-yl O644
isoxazol-3-yl oxazol-2-yl
[0503] The compounds encompassed within the second aspect of
Category VII of the present disclosure can be prepared by the
procedure outlined in Scheme XIV and described in Example 14
below.
##STR00161##
Example 15
4-{(S)-2-(3-Benzylureido)-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}-phenylsu-
lfamic acid (37)
Preparation of
1-benzyl-3-{(S)-2-(4-nitrophenyl)-1-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}-
urea (36)
[0504] To a solution of
(S)-2-(4-nitrophenyl)-1-[(2-thiophen-2-yl)thiazol-4-yl)ethan-amine
hydrobromide salt, 8, and Et.sub.3N (0.42 mL, 3 mmol) in 10 mL DCM
is added benzyl isocyanate (0.12 mL, 1 mmol). The mixture is
stirred at room temperature for 18 hours. The product is isolated
by filtration to afford 0.445 g (96% yield) of the desired product
which is used without further purification.
Preparation of
4-{(S)-2-(3-benzylureido)-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsu-
lfamic acid (37)
[0505]
1-Benzyl-3-{(S)-2-(4-nitrophenyl)-1-[2-(thiophen-2-yl)thiazol-4-yl]-
ethyl}urea, 36, (0.445 g) is dissolved in MeOH (10 mL) and
CH.sub.2Cl.sub.2 (5 mL). A catalytic amount of Pd/C (10% w/w) is
added and the mixture is stirred under a hydrogen atmosphere 18
hours. The reaction mixture is filtered through a bed of CELITE.TM.
and the solvent is removed under reduced pressure. The crude
product is dissolved in pyridine (12 mL) and treated with
SO.sub.3-pyridine (0.110 g). The reaction is stirred at room
temperature for 5 minutes after which a 7% solution of NH.sub.4OH
is added. The mixture is then concentrated and the resulting
residue is purified by reverse phase chromatography to afford 0.080
g of the desired product as the ammonium salt. .sup.1H NMR
(CD.sub.3OD) .delta. 7.61 (d, 1H, J=2.1 Hz), 7.58 (d, 1H, J=6 Hz),
7.33-7.22 (m, 4H), 7.17-7.14 (m, 1H), 7.09-6.94 (m, 6H), 5.16 (t,
1H, J=6.6 Hz), 4.13 (s, 2H), 3.14-3.11 (m, 2H).
[0506] Category VIII of the present disclosure relates to
2-(thiazol-4-yl) compounds having the formula:
##STR00162##
wherein R.sup.1, R.sup.4, and L are further defined herein in Table
XVI herein below.
TABLE-US-00016 TABLE XVI No. R.sup.4 L R.sup.1 P645 methyl
--SO.sub.2-- methyl P646 ethyl --SO.sub.2-- methyl P647 phenyl
--SO.sub.2-- methyl P648 thiophen-2-yl --SO.sub.2-- methyl P649
methyl --SO.sub.2-- trifluoromethyl P650 ethyl --SO.sub.2--
trifluoromethyl P651 phenyl --SO.sub.2-- trifluoromethyl P652
thiophen-2-yl --SO.sub.2-- trifluoromethyl P653 methyl --SO.sub.2--
ethyl P654 ethyl --SO.sub.2-- ethyl P655 phenyl --SO.sub.2-- ethyl
P656 thiophen-2-yl --SO.sub.2-- ethyl P657 methyl --SO.sub.2--
2,2,2-trifluoroethyl P658 ethyl --SO.sub.2-- 2,2,2-trifluoroethyl
P659 phenyl --SO.sub.2-- 2,2,2-trifluoroethyl P660 thiophen-2-yl
--SO.sub.2-- 2,2,2-trifluoroethyl P661 methyl --SO.sub.2-- phenyl
P662 ethyl --SO.sub.2-- phenyl P663 phenyl --SO.sub.2-- phenyl P664
thiophen-2-yl --SO.sub.2-- phenyl P665 methyl --SO.sub.2--
4-fluorophenyl P666 ethyl --SO.sub.2-- 4-fluorophenyl P667 phenyl
--SO.sub.2-- 4-fluorophenyl P668 thiophen-2-yl --SO.sub.2--
4-fluorophenyl P669 methyl --SO.sub.2--
3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl P670 ethyl --SO.sub.2--
3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl P671 phenyl --SO.sub.2--
3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl P672 thiophen-2-yl
--SO.sub.2-- 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl P673 methyl
--SO.sub.2-- 1-methyl-1H-imidazol-4-yl P674 ethyl --SO.sub.2--
1-methyl-1H-imidazol-4-yl P675 phenyl --SO.sub.2--
1-methyl-1H-imidazol-4-yl P676 thiophen-2-yl --SO.sub.2--
1-methyl-1H-imidazol-4-yl P678 methyl --SO.sub.2--
4-acetamidophenyl P679 ethyl --SO.sub.2-- 4-acetamidophenyl P680
phenyl --SO.sub.2-- 4-acetamidophenyl P681 thiophen-2-yl
--SO.sub.2-- 4-acetamidophenyl P682 methyl --SO.sub.2CH.sub.2--
phenyl P683 ethyl --SO.sub.2CH.sub.2-- phenyl P684 phenyl
--SO.sub.2CH.sub.2-- phenyl P685 thiophen-2-yl --SO.sub.2CH.sub.2--
phenyl P686 methyl --SO.sub.2CH.sub.2--
(4-methylcarboxyphenyl)methyl P687 ethyl --SO.sub.2CH.sub.2--
(4-methylcarboxyphenyl)methyl P688 phenyl --SO.sub.2CH.sub.2--
(4-methylcarboxyphenyl)methyl P689 thiophen-2-yl
--SO.sub.2CH.sub.2-- (4-methylcarboxyphenyl)methyl P690 methyl
--SO.sub.2CH.sub.2-- (2-methylthiazol-4-yl)methyl P691 ethyl
--SO.sub.2CH.sub.2-- (2-methylthiazol-4-yl)methyl P692 phenyl
--SO.sub.2CH.sub.2-- (2-methylthiazol-4-yl)methyl P693
thiophen-2-yl --SO.sub.2CH.sub.2-- (2-methylthiazol-4-yl)methyl
P694 methyl --SO.sub.2CH.sub.2CH.sub.2-- phenyl P695 ethyl
--SO.sub.2CH.sub.2CH.sub.2-- phenyl P696 phenyl
--SO.sub.2CH.sub.2CH.sub.2-- phenyl P697 thiophen-2-yl
--SO.sub.2CH.sub.2CH.sub.2-- phenyl
[0507] The compounds encompassed within Category VIII of the
present disclosure can be prepared by the procedure outlined in
Scheme XV and described in Example 16 herein below.
##STR00163##
Example 16
{4-(S)-[2-Phenylmethanesulfonylamino-2-(2-thiophen-2-ylthiazol-4-yl)ethyl]-
phenyl}sulfamic acid (39)
Preparation of
(S)--N-{2-(4-nitrophenyl)-1-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}-1-pheny-
lmethanesulfonamide (38)
[0508] To a suspension of
2-(4-nitrophenyl)-1-(2-thiophene2-ylthiazol-4-yl)ethylamine, 8,
(330 mg, 0.80 mmol) in CH.sub.2Cl.sub.2 (6 mL) at 0.degree. C. is
added diisopropylethylamine (0.30 mL, 1.6 mmol) followed by
phenylmethanesulfonyl chloride (167 mg, 0.88 mmol). The reaction
mixture is stirred at room temperature for 14 hours. The mixture is
diluted with CH.sub.2Cl.sub.2 and washed with sat. NaHCO.sub.3
followed by brine, dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo. The resulting residue is purified over
silica to afford 210 mg of the desired product as a white
solid.
Preparation of
{4-(S)-[2-phenylmethanesulfonylamino-2-(2-thiophen-2-ylthiazol-4-yl)ethyl-
]phenyl}sulfamic acid (39)
[0509]
(S)--N-{2-(4-nitrophenyl)-1-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}-1-
-phenylmethanesulfonamide, 38, (210 mg, 0.41 mmol) is dissolved in
MeOH (4 mL). A catalytic amount of Pd/C (10% w/w) is added and the
mixture is stirred under a hydrogen atmosphere 18 hours. The
reaction mixture is filtered through a bed of CELITE.TM. and the
solvent is removed under reduced pressure. The crude product is
dissolved in pyridine (12 mL) and treated with SO.sub.3-pyridine
(197 mg, 1.23 mmol). The reaction is stirred at room temperature
for 5 minutes after which a 7% solution of NH.sub.4OH is added. The
mixture is then concentrated and the resulting residue is purified
by reverse phase chromatography to afford 0.060 g of the desired
product as the ammonium salt. .sup.1H NMR (300 MHz, MeOH-d.sub.4)
.delta. 7.52-7.63 (m, 6.70-7.28 (m, 11H), 4.75 (t, J=7.2 Hz, 1H),
3.95-4.09 (m, 2H), 3.20 (dd, J=13.5 and 7.8 Hz, 1H), 3.05 (dd,
J=13.5 and 7.8 Hz, 1H). 1013770
[0510] Intermediates for use in Step (a) of Scheme XV can be
conveniently prepared by the procedure outlined herein below in
Scheme XVI and described in Example 17.
##STR00164##
Example 17 (2-Methylthiazol-4-yl)methanesulfonyl chloride (41)
Preparation of sodium (2-methylthiazol-4-yl)methanesulfonate
(40)
[0511] 4-Chloromethyl-2-methylthiazole (250 mg, 1.69 mmol) is
dissolved in H.sub.2O (2 mL) and treated with sodium sulfite (224
mg, 1.78 mmol). The reaction mixture is subjected to microwave
irradiation for 20 minutes at 200.degree. C. The reaction mixture
is diluted with H.sub.2O (30 mL) and washed with EtOAc (2.times.25
mL). The aqueous layer is concentrated to afford 0.368 g of the
desired product as a yellow solid. LC/MS ESI+194 (M+1, free
acid).
Preparation of (2-methylthiazol-4-yl)methanesulfonyl chloride
(41)
[0512] Sodium (2-methylthiazol-4-yl)methanesulfonate, 40, (357 mg,
1.66 mmol) is dissolved in phosphorous oxychloride (6 mL) and is
treated with phosphorous pentachloride (345 mg, 1.66 mmol). The
reaction mixture is stirred at 50.degree. C. for 3 hours, then
allowed to cool to room temperature. The solvent is removed under
reduced pressure and the residue is re-dissolved in
CH.sub.2Cl.sub.2 (40 mL) and is washed with sat. NaHCO.sub.3 and
brine. The organic layer is dried over MgSO.sub.4, filtered, and
the solvent removed in vacuo to afford 0.095 g of the desired
product as a brown oil. LC/MS ESI+211 (M+1). Intermediates are
obtained in sufficient purity to be carried forward according to
Scheme IX without the need for further purification.
##STR00165##
4-{(S)-2-[(2-methylthiazol-4-yl)methylsulfonamido]-2-[2-(thiophen-2-yl)th-
iazol-4-yl]ethyl}phenylsulfamic acid
[0513] .sup.1H NMR (CD.sub.3OD): .delta. 7.71-7.66 (m, 2H),
7.27-7.10 (m, 7H), 4.87 (t, 1H, J=7.3 Hz), 4.30-4.16 (q, 2H, J=13.2
Hz), 3.34-3.13 (m, 2H), 2.70 (s, 3H).
[0514] The following are non-limiting examples of compounds
encompassed within Category VIII of the present disclosure.
##STR00166##
{4-(S)-[2-Phenylmethanesulfonylamino-2-(2-ethylthiazol-4-yl)ethyl]phenyl}-
-sulfamic acid
[0515] .sup.1H NMR (300 MHz, MeOH-d.sub.4) .delta. 7.27-7.32 (m,
3H), 7.16-7.20 (m, 3H), 7.05-7.6 (m, 2H), 6.96 (d, J=8.4 Hz, 2H),
4.70 (t, J=9.0 Hz, 1H), 3.91-4.02 (m, 2H), 2.95-3.18 (m, 4H), 1.41
(t, J=7.5 Hz, 3H).
##STR00167##
{4-(S)-[2-(3-Methoxyphenyl)methanesulfonylamino-2-(2-ethylthiazol-4-yl)et-
hyl]phenyl}sulfamic acid
[0516] .sup.1H NMR (300 MHz, MeOH-d.sub.4) .delta. 7.20 t, J=8.1
Hz. 1H), 6.94-7.08 (m, 4H), 6.88-6.94 (m, 3H), 6.75-6.80 (m, 1H),
4.67 (t, J=7.2 Hz, 1H), 3.90-4.0 (m, 2H), 3.76 (s, 3H), 2.95-3.16
(m, 4H), 1.40 (t, J=7.5 HZ, 3H).
##STR00168##
(S)-4-{[1-(2-Ethylthiazol-4-yl)-2-(4-sulfoaminophenyl)ethylsulfamoyl]meth-
yl}-benzoic acid methyl ester
[0517] .sup.1H NMR (300 MHz, MeOH-d.sub.4) .delta. 7.90-7.94-(m,
2H), 7.27-7.30 (m, 2H), 7.06-7.11 (m, 3H), 6.97-7.00 (m, 2H), 4.71
(t, J=7.2 Hz, 1H), 3.95-4.08 (4, 2H), 3.92 (s, 3H), 2.80-3.50 (m,
4H), 1.38-1.44 (m, 3H).
##STR00169##
(S)-4-[2-(2-Ethylthiazol-4-yl)-2-(1-methyl-1H-imidazol-4-sulfonamido)ethy-
l]-phenylsulfamic acid
[0518] .sup.1H NMR (300 MHz, MeOH-d.sub.4) .delta. 7.54 (s, 1H,
7.20 (s, 1H), 7.09 (s, 1H), 6.92-7.00 (m, 4H), 4.62 (t, J=5.4 Hz,
1H), 3.70 (s, 3H), 2.98-3.14 (m, 3H), 2.79 (dd, J=9.3 and 15.0 Hz,
1H), 1.39 (q, J=7.5 Hz, 3H).
##STR00170##
4-{(S)-2-[2-(Thiophen-2-yl)thiazol-4-yl]-2-(2,2,2-trifluoroethylsulfonami-
do)-ethyl}phenylsulfamic acid
[0519] .sup.1H NMR (CD.sub.3OD): .delta. 7.62-7.56 (m, 2H), 7.22
(s, 1H), 7.16-7.06 (m, 5H), 4.84 (t, 1H, J=7.6 Hz), 3.71-3.62 (m,
2H), 3.32-3.03 (m, 2H).
##STR00171##
{4-(S)-[2-(Phenylethanesulfonylamino)-2-(2thiophen-2-ylthiazol-4-yl)ethyl-
]-phenyl}sulfamic acid
[0520] .sup.1H NMR (300 MHz, MeOH-d.sub.4) 7.56-7.62 (m, 2H),
7.04-7.19 (m, 9H), 6.94-6.97 (m, 2H), 4.78 (t, J=7.8 Hz, 1H),
3.22-3.30 (m, 2H)), 3.11 (dd, J=13.5 and 7.8 Hz, 1H), 2.78-2.87 (m,
4H).
##STR00172##
{4-(S)-[3-(Phenylpropanesulfonylamino)-2-(2thiophen-2-ylthiazol-4-yl)ethy-
l]-phenyl}sulfamic acid
[0521] .sup.1H NMR (300 MHz, MeOH-d.sub.4) .delta. 7.56-7.62 (m,
2H), 6.99-7.17 (m, 10H), 4.72 (t, J=7.8 Hz, 1H), 3.21 (dd, J=13.5
and 7.2 Hz, 1H), 3.02 (dd, J=13.5 and 7.2 Hz, 1H), 2.39-2.64 (m,
4H), 1.65-1.86 (m, 2H).
##STR00173##
(S)-{4-[2-(4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-sulfonylamino)-2-(-
2-thiophen-2-ylthiazol-4-yl)ethyl]phenyl}sulfamic acid
[0522] .sup.1H NMR (300 MHz, MeOH-d.sub.4) .delta. 7.53 (d, J=5.1
Hz, 1H) 7.48 (d, J=5.1 Hz, 1H), 7.13-7.10 (m, 1H), 7.04 (d, J=8.4
Hz, 2H), 6.93-6.88 (m, 3H), 6.75 (d, J=8.1 Hz, 1H), 6.54 (d, J=8.1
Hz, 1H), 4.61 (t, J=7.5 Hz, 1H), 4.20-4.08 (m, 2H), 3.14-3.00 (m,
4H), 2.69 (s, 3H).
##STR00174##
4-{(S)-2-(4-acetamidophenylsulfonamido)-2-[2-(thiophen-2-yl)thiazol-4-yl]-
ethyl}phenylsulfamic acid
[0523] .sup.1H NMR (CD.sub.3OD): .delta. 7.67-7.52 (m, 6H),
7.24-7.23 (m, 1H), 7.12-7.09 (m, 3H), 7.02-6.99 (m, 2H), 4.70 (t,
1H, J=7.3 Hz), 3.25-3.00 (m, 2H), 2.24 (s, 3H).
[0524] The first aspect of Category IX of the present disclosure
relates to compounds having the formula:
##STR00175##
wherein R.sup.1 is a substituted or unsubstituted heteroaryl and
R.sup.4 is C.sub.1-C.sub.6 linear, branched, or cyclic alkyl as
further described herein below in Table XVII.
TABLE-US-00017 TABLE XVII No. R.sup.4 R.sup.1 Q698 --CH.sub.3
4-(methoxycarbonyl)thiazol-5-yl Q699 --CH.sub.3
4-[(2-methoxy-2-oxoethyl)carbamoyl]thiazol-5-yl Q700 --CH.sub.3
5-[1-N-(2-methoxy-2-oxoethyl)-1-H-indol-3-yl]oxazol-2-yl Q701
--CH.sub.3 5-(2-methoxyphenyl)oxazol-2-yl Q702 --CH.sub.3
5-[(S)-1-(tert-butoxycarbonyl)-2-phenylethyl]oxazol-2-yl Q703
--CH.sub.3 5-[4-(methylcarboxy)phenyl]oxazol-2-yl Q704 --CH.sub.3
5-(3-methoxybenzyl)oxazol-2-yl Q705 --CH.sub.3
5-(4-phenyl)oxazol-2-yl Q706 --CH.sub.3
5-(2-methoxyphenyl)thiazol-2-yl Q707 --CH.sub.3
5-(3-methoxyphenyl)thiazol-2-yl Q708 --CH.sub.3
5-(4-fluorophenyl)thiazol-2-yl Q709 --CH.sub.3
5-(2,4-difluorophenyl)thiazol-2-yl Q710 --CH.sub.3
5-(3-methoxybenzyl)thiazol-2-yl Q711 --CH.sub.3
4-(3-methoxyphenyl)thiazol-2-yl Q712 --CH.sub.3
4-(4-fluorophenyl)thiazol-2-yl Q713 --CH.sub.2CH.sub.3
4-(methoxycarbonyl)thiazol-5-yl Q714 --CH.sub.2CH.sub.3
4-[(2-methoxy-2-oxoethyl)carbamoyl]thiazol-5-yl Q715
--CH.sub.2CH.sub.3
5-[1-N-(2-methoxy-2-oxoethyl)-1-H-indol-3-yl]oxazol-2-yl Q716
--CH.sub.2CH.sub.3 5-(2-methoxyphenyl)oxazol-2-yl Q717
--CH.sub.2CH.sub.3
5-[(S)-1-(tert-butoxycarbonyl)-2-phenylethyl]oxazol-2-yl Q718
--CH.sub.2CH.sub.3 5-[4-(methylcarboxy)phenyl]oxazol-2-yl Q719
--CH.sub.2CH.sub.3 5-(3-methoxybenzyl)oxazol-2-yl Q720
--CH.sub.2CH.sub.3 5-(4-phenyl)oxazol-2-yl Q721 --CH.sub.2CH.sub.3
5-(2-methoxyphenyl)thiazol-2-yl Q722 --CH.sub.2CH.sub.3
5-(3-methoxyphenyl)thiazol-2-yl Q723 --CH.sub.2CH.sub.3
5-(4-fluorophenyl)thiazol-2-yl Q724 --CH.sub.2CH.sub.3
5-(2,4-difluorophenyl)thiazol-2-yl Q725 --CH.sub.2CH.sub.3
5-(3-methoxybenzyl)thiazol-2-yl Q726 --CH.sub.2CH.sub.3
4-(3-methoxyphenyl)thiazol-2-yl Q727 --CH.sub.2CH.sub.3
4-(4-fluorophenyl)thiazol-2-yl Q728 cyclopropyl
4-(methoxycarbonyl)thiazol-5-yl Q729 cyclopropyl
4-[(2-methoxy-2-oxoethyl)carbamoyl]thiazol-5-yl Q730 cyclopropyl
5-[1-N-(2-methoxy-2-oxoethyl)-1-H-indol-3-yl]oxazol-2-yl Q731
cyclopropyl 5-(2-methoxyphenyl)oxazol-2-yl Q732 cyclopropyl
5-[(S)-1-(tert-butoxycarbonyl)-2-phenylethyl]oxazol-2-yl Q733
cyclopropyl 5-[4-(methylcarboxy)phenyl]oxazol-2-yl Q734 cyclopropyl
5-(3-methoxybenzyl)oxazol-2-yl Q735 cyclopropyl
5-(4-phenyl)oxazol-2-yl Q736 cyclopropyl
5-(2-methoxyphenyl)thiazol-2-yl Q737 cyclopropyl
5-(3-methoxyphenyl)thiazol-2-yl Q738 cyclopropyl
5-(4-fluorophenyl)thiazol-2-yl Q739 cyclopropyl
5-(2,4-difluorophenyl)thiazol-2-yl Q740 cyclopropyl
5-(3-methoxybenzyl)thiazol-2-yl Q741 cyclopropyl
4-(3-methoxyphenyl)thiazol-2-yl Q742 cyclopropyl
4-(4-fluorophenyl)thiazol-2-yl
[0525] Compounds according to the first aspect of Category IX which
comprise a substituted or unsubstituted thiazol-4-yl unit for
R.sup.1 can be prepared by the procedure outlined in Scheme XVII
and described below in Example 18.
##STR00176## ##STR00177##
Example 18
(S)-4-(2-(2-Phenylthiazol-4-yl).sub.2-(4-(methoxycarbonyl)thiazole-5-ylami-
no)ethyl)phenylsulfamic acid (45)
Preparation of
(S)-2-(4-nitrophenyl)-1-(2-phenylthiazol-4-yl)ethanamine
hydrobromide salt (42)
[0526] A mixture of (S)-tert-butyl
4-bromo-1-(4-nitrophenyl)-3-oxobutan-2-ylcarbamate, 7, (1.62 g,
4.17 mmol) and thiobenzamide (0.63 g, 4.60 mmol) in CH.sub.3CN (5
mL) is refluxed for 24 hours. The reaction mixture is cooled to
room temperature and diethyl ether (50 mL) is added to the
solution. The precipitate which forms is collected by filtration.
The solid is dried under vacuum to afford 1.2 g (67% yield) of the
desired product. LC/MS ESI+326 (M+1).
Preparation of
(S)-4-(1-isothiocyanato-2-(4-nitrophenyl)ethyl)-2-phenylthiazole
(43)
[0527] To a solution of
(S)-2-(4-nitrophenyl)-1-(2-phenylthiazol-4-yl)ethanamine
hydrobromide salt, 42, (726 mg, 1.79 mmol) and CaCO.sub.3 (716 mg,
7.16 mmol) in H.sub.2O (2 mL) is added CCl.sub.4 (3 mL) followed by
thiophosgene (0.28 mL, 3.58 mmol). The reaction is stirred at room
temperature for 18 hours then diluted with CH.sub.2Cl.sub.2 and
water. The layers are separated and the aqueous layer extracted
with CH.sub.2Cl.sub.2. The combined organic layers are washed with
brine, dried (Na.sub.2SO.sub.4) and concentrated in vacuo to a
residue which is purified over silica (CH.sub.2Cl.sub.2) to afford
480 mg (73%) of the desired product as a yellow solid. .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 8.15 (d, J=8.7 Hz, 2H), 7.97-7.99 (m,
2H), 7.43-7.50 (m, 3H), 7.34 (d, J=8.7 Hz, 2H), 7.15 (d, J=0.9 Hz,
1H), 5.40-5.95 (m, 1H), 3.60 (dd, J=13.8 and 6.0 Hz, 1H), 3.46 (dd,
J=13.8 and 6.0 Hz).
Preparation of (S)-methyl
5-[1-(2-phenylthiazol-4-yl)-2-(4-nitrophenyl)-ethylamino]thiazole-4-carbo-
xylate (44)
[0528] To a suspension of potassium tert-butoxide (89 mg, 0.75
mmol) in THF (3 mL) is added methyl isocyanoacetate (65 .mu.L, 0.68
mmol) followed by
(S)-2-phenyl-4-(1-isothiocyanato-2-(4-nitrophenyl)ethyl)thiazole,
43, (250 mg, 0.68 mmol). The reaction mixture is stirred at room
temperature for 2 hours then poured into sat. NaHCO.sub.3. The
mixture is extracted with EtOAc (3.times.25 mL) and the combined
organic layers are washed with brine and dried (Na.sub.2SO.sub.4)
and concentrated in vacuo. The crude residue is purified over
silica to afford 323 mg (.about.100% yield) of the desired product
as a slightly yellow solid. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 8.09-8.13 (m, 2H), 7.95-7 98 (m, 3H), 7.84 (d, J=1.2 Hz,
1H), 7.44-7.50 (m, 3H), 7.28-7.31 (m, 2H), 7.96 (d, J=0.6 Hz, 1H),
4.71-4.78 (m, 1H), 3.92 (s, 3H), 3.60 (dd, J=13.8 and 6.0 Hz, 1H),
3.45 (dd, J=13.8 and 6.0 Hz, 1H).
Preparation of
(S)-4-(2-(2-phenylthiazol-4-yl).sub.2-(4-(methoxycarbonyl)thiazole-5-ylam-
ino)ethyl)phenylsulfamic acid (45)
[0529] (S)-methyl
5-[1-(2-phenylthiazol-4-yl)-2-(4-nitrophenyl)-ethylamino]thiazole-4-carbo-
xylate, 44, (323 mg, 0.68 mmol) and tin (II) chloride (612 mg, 2.72
mmol) are dissolved in EtOH and the solution is brought to reflux.
The solvent is removed in vacuo and the resulting residue is
dissolved in EtOAc. A saturated solution of NaHCO.sub.3 is added
and the solution is stirred 1 hour. The organic layer is separated
and the aqueous layer extracted twice with EtOAc. The combined
organic layers are dried (Na.sub.2SO.sub.4), filtered and
concentrated to a residue which is dissolved in pyridine (10 mL)
and treated with SO.sub.3-pyridine (130 mg, 0.82 mmol). The
reaction is stirred at room temperature for 5 minutes after which a
7% solution of NH.sub.4OH is added. The mixture is then
concentrated and the resulting residue is purified by reverse phase
chromatography to afford 0.071 g of the desired product as the
ammonium salt .sup.1H NMR (300 MHz, MeOH-d.sub.4) .delta. 7.97-8.00
(m, 3H), 7.48-7.52 (m, 3H), 7.22 (s, 1H), 7.03-7.13 (m, 4H), 4.74
(t, J=6.6 Hz, 1H), 3.88 (s, 3H), 3.28-3.42 (m, 2H).
[0530] Compounds according to the first aspect of Category IX which
comprise a substituted or unsubstituted thiazol-2-yl unit for
R.sup.1 can be prepared by the procedure outlined in Scheme XVIII
and described herein below in Example 19. Intermediate 46 can be
prepared according to Scheme II and Example 2 by substituting
cyclopropane-carbothioic acid amide for thiophen-2-carbothioic acid
amide.
##STR00178## ##STR00179##
Example 19
4-{(S)-2-(2-Cyclopropylthiazol-4-yl)-2-[4-(3-methoxyphenyl)thiazol-2-ylami-
no]ethyl}phenylsulfamic acid (50)
Preparation of
(S)-1-(1-(2-cyclopropylthiazol-4-yl)-2-(4-nitrophenyl)ethyl)-thiourea
(47)
[0531] To a solution of
(S)-1-(2-cyclopropylthiazol-4-yl)-2-(4-nitrophenyl)ethan-amine
hydrobromide hydrobromide salt, 32, (4.04 g, 10.9 mmol) and
CaCO.sub.3 (2.18 g, 21.8 mmol) in CCl.sub.4/water (25 mL/20 mL) is
added thiophosgene (1.5 g, 13.1 mmol). The reaction is stirred at
room temperature for 18 hours then diluted with CH.sub.2Cl.sub.2
and water. The layers are separated and the aqueous layer extracted
with CH.sub.2Cl.sub.2. The combined organic layers are washed with
brine, dried (Na.sub.2SO.sub.4) and concentrated in vacuo to a
residue which is subsequently treated with ammonia (0.5M in
1,4-dioxane, 120 mL) which is purified over silica to afford 2.90 g
of the desired product as a red-brown solid. LC/MS ESI- 347
(M-1).
Preparation of
(S)-4-(3-methoxybenzyl)-N-(1-(2-cyclopropylthiazol-4-yl)-2-(4-nitrophenyl-
)ethyl)thiazol-2-amine (48)
[0532]
(S)-1-(1-(2-Cyclopropylthiazol-4-yl)-2-(4-nitrophenyl)ethyl)-thiour-
ea, 47, (350 mg, 1.00 mmol) and 2-bromo-3'-methoxyacetophenone (253
mg, 1.10 mmol) are combined in 3 mL CH.sub.3CN and heated to reflux
for 24 hours. The mixture is concentrated and chromatographed to
afford 0.172 g of the product as a yellow solid. LC/MS ESI+479
(M+1).
Preparation of
4-{(S)-2-(2-cyclopropylthiazol-4-yl)-2-[4-(3-methoxyphenyl)-thiazol-2-yla-
mino]ethyl}phenylsulfamic acid (49)
[0533]
(S)-4-(3-methoxybenzyl)-N-(1-(2-cyclopropylthiazol-4-yl)-2-(4-nitro-
phenyl)ethyl)thiazol-2-amine, 48, (0.172 g) is dissolved in 10 mL
MeOH. A catalytic amount of Pd/C (10% w/w) is added and the mixture
is stirred under a hydrogen atmosphere for 18 hours. The reaction
mixture is filtered through a bed of CELITE.TM. and the solvent is
removed under reduced pressure. The crude product is dissolved in 5
mL pyridine and treated with SO.sub.3-pyridine (114 mg). The
reaction is stirred at room temperature for 5 minutes after which
10 mL of a 7% solution of NH.sub.4OH is added. The mixture is then
concentrated and the resulting residue is purified by reverse-phase
chromatography to afford 0.033 g of the desired product as the
ammonium salt. .sup.1H NMR (CD.sub.3OD): .delta. 7.33-7.22 (m, 3H),
7.10-6.97 (m, 5H), 6.84-6.80 (m, 2H), 5.02 (t, 1H, J=6.9 Hz), 3.82
(s, 1H), 3.18 (q, 2H, J=7.1 Hz), 2.36 (q, 1H, J=4.6 Hz), 1.20-1.13
(m, 2H), 1.04-0.99 (m, 2H).
[0534] The following are non-limiting examples of compounds
encompassed within the first aspect of Category IX.
##STR00180##
(S)-4-(2-(4-((2-Methoxy-2-oxoethyl)carbamoyl)thiazole-5-ylamino).sub.2-(2-
-ethylthiazole-4-yl)ethyl)phenylsulfamic acid
[0535] .sup.1H NMR (300 MHz, MeOH-d.sub.4) .delta. 7.91 (s, 1H),
7.08-7.10 (m, 3H), 6.99 (d, J=8.7 Hz, 2H), 4.58 (t, J=6.9 Hz, 1H),
4.11 (d, J=2.7 Hz, 2H), 3.78 (s, 3H), 3.14-3.28 (m, 2H), 3.06 (q,
J=7.5 Hz, 2H), 1.41 (t, J=7.5 Hz, 3H).
##STR00181##
(S)-4-(2-{5-[1-N-(2-Methoxy-2-oxoethylcarbamoyl)-1-H-indol-3-yl]oxazol-2--
ylamino}-2-(2-methylthiazol-4-yl)ethyl)phenylsulfamic acid
[0536] .sup.1H NMR (300 MHz, MeOH-d.sub.4) .delta. 7.63 (d, J=7.8
Hz, 1H), 7.37 (s, 1H), 7.18-7.29 (m, 4H), 7.02-7.16 (m, 4H), 6.85
(s, 1H), 5.04-5.09 (m, 1H), 4.85 (s, 3H), 3.27 (dd, J=13.5 and 8.1
Hz, 1H), 3.10 (m, J=13.5 and 8.1 Hz, 1H), 2.69 (s, 3H).
##STR00182##
4-((S)-2-(5-(2-Methoxyphenyl)oxazol-2-ylamino)-2-(2-methylthiazol-4-yl)et-
hyl)phenylsulfamic acid
[0537] .sup.1H NMR (300 MHz, MeOH-d.sub.4) .delta. 7.52 (dd, J=7.5
and 1.2 Hz, 1H), 6.95-7.24 (m, 10H), 5.04-5.09 (m, 1H), 3.92 (s,
3H), 3.26 (dd, J=13.8 and 8.4 Hz, 1H), 3.10 (dd, J=13.8 and 8.4 Hz,
1H), 2.72 (s, 3H).
##STR00183##
4-((S)-2-(5-((S)-1-(tert-Butoxycarbonyl)-2-phenylethyl)oxazole-2-ylamino)-
-2-(2-methylthiazole-4-yl)ethyl)phenylsulfamic acid
[0538] .sup.1H NMR (300 MHz, MeOH-d.sub.4) .delta. 7.03-7.27 (m,
10H), 6.50 (s, 1H), 4.95-5.00 (m, 1H), 4.76 (t, J=6.9 Hz, 1H), 3.22
(dd, J=14.1 and 6.9 Hz, 1H), 3.00-3.10 (m, 2H), 2.90 (dd, J=14.1
and 6.9 Hz, 1H), 2.72 (s, 3H), 1.37 (s, 9H).
##STR00184##
(S)-{4-{2-[5-(4-Methoxycarbonyl)phenyl]oxazol-2-ylamino}-2-(2-methylthiaz-
ol-4-yl)ethyl}phenylsulfamic acid
[0539] .sup.1H NMR (300 MHz, MeOH-d.sub.4) .delta. 7.99 (d, J=7.5
Hz, 2H), 7.56-7.59 (m, 2H), 7.23-7.24 (m, 1H), 7.08-7.14 (m, 4H),
6.83 (d, J=10.2 Hz, 1H), 5.08 (t, J=6.0 Hz, 1H), 3.91 (s, 3H),
3.25-3.35 (m, 1H), 3.09-3.13 (m, 1H), 2.73 (s, 3H).
##STR00185##
(S)-4-(2-(5-(3-Methoxybenzyl)oxazole-2-ylamino)-2-(2-methylthiazole-4-yl)-
ethyl)phenylsulfamic acid
[0540] .sup.1H NMR (300 MHz, MeOH-d.sub.4) .delta. 7.03-7.28 (m,
8H), 6.79-6.83 (m, 1H), 5.70 (s, 1H), 4.99-5.06 (m, 2H), 4.41 (d,
J=2.1 Hz, 2H), 3.80 (s, 3H), 3.27-3.37 (m, 1H), 3.03-3.15 (m, 1H),
2.71 (s, 3H).
##STR00186##
(S)-4-(2-(2-Methylthiazole-4-yl).sub.2-(5-phenyloxazole-2-ylamino)ethyl)p-
henylsulfamic acid
[0541] .sup.1H NMR (300 MHz, MeOH-d.sub.4) .delta. 7.45 (d, J=8.7
Hz, 2H), 7.33 (t, J=7.8 Hz, 2H), 7.18-7.22 (m, 1H), 7.10-7.14 (m,
6H), 7.04 (s, 1H), 5.04-5.09 (m, 1H), 3.26 (dd, J=13.8 and 6.3 Hz,
1H), 3.10 (dd, J=13.8 and 6.3 Hz, 1H), 2.70 (s, 3H).
##STR00187##
4-((S)-2-(2-Cyclopropylthiazol-4-yl)-2-(4-(3-methoxyphenyl)thiazol-2-ylam-
ino)-ethyl)phenylsulfamic acid
[0542] .sup.1H NMR (CD.sub.3OD): .delta. 7.33-7.22 (m, 3H),
7.10-6.97 (m, 5H), 6.84-6.80 (m, 2H), 5.02 (t, 1H, J=6.9 Hz), 3.82
(s, 1H), 3.18 (q, 2H, J=7.1 Hz), 2.36 (q, 1H, J=4.6 Hz), 1.20-1.13
(m, 2H), 1.04-0.99 (m, 2H).
##STR00188##
(S)-4-(2-(2-cyclopropylthiazol-4-yl)-2-(4-(4-fluorophenyl)thiazol-2-ylami-
no)ethyl)-phenylsulfamic acid
[0543] .sup.1H NMR (CD.sub.3OD): .delta. 7.79-7.74 (m, 2H),
7.14-7.03 (m, 7H), 7.21 (s, 1H), 6.79 (s, 1H), 5.08 (t, 1H, J=6.6
Hz), 3.29-3.12 (m, 2H), 2.40 (q, 2.40, J=5.1 Hz), 1.23-1.18 (m,
2H), 1.08-1.02 (m, 2H).
##STR00189##
4-((S)-2-(2-cyclopropylthiazol-4-yl)-2-(4-(2-methoxyphenyl)thiazol-2-ylam-
ino)-ethyl)phenylsulfamic acid
[0544] .sup.1H NMR (CD.sub.3OD): .delta. 7.89-7.87 (d, 1H, J=7.6
Hz), 7.28 (t, 1H, J=7.0 Hz), 7.10-6.96 (m, 8H), 5.03 (t, 1H, J=6.9
Hz), 3.90 (s, 1H), 3.19 (q, 2H, J=6.6 Hz), 2.38 (q, 1H, J=4.8 Hz),
1.21-1.14 (m, 2H), 1.06-1.00 (m, 2H).
##STR00190##
4-((S)-2-(2-cyclopropylthiazol-4-yl)-2-(4-(2,4-difluorophenyl)thiazol-2-y-
lamino)-ethyl)phenylsulfamic acid
[0545] .sup.1H NMR (CD.sub.3OD): .delta. 8.06-8.02 (q, 2H, J=6.9
Hz), 7.12-6.95 (m, 7H), 6.88 (s, 1H), 5.11 (t, 1H, J=6.9 Hz),
3.22-3.15 (m, 2H), 2.38 (q, 1H, J=4.8 Hz), 1.22-1.15 (m, 2H),
1.06-1.02 (m, 2H).
##STR00191##
(S)-4-(2-(4-(3-methoxybenzyl)thiazol-2-ylamino)-2-(2-cyclopropylthiazol-4-
-yl)ethyl)phenylsulfamic acid
[0546] .sup.1H NMR (CD.sub.3OD): .delta. 7.22-7.17 (m, 3H),
7.09-6.97 (m, 5H), 6.78-6.66 (m, 3H), 3.77 (s, 2H), 3.75 (s, 3H),
3.20-3.07 (m, 2H), 2.35 (q, 1H, J=4.8 Hz), 1.19-1.13 (m, 2H),
1.03-1.00 (m, 2H).
##STR00192##
(S)-{5-[1-(2-Ethylthiazol-4-yl)-2-(4-sulfoaminophenyl)ethylamino]-2-methy-
l-2H-[1,2,4]triazole-3-yl}carbamic acid methyl ester: .sup.1H NMR
(300 MHz, MeOH-d.sub.4) .delta. 6.97-7.08 (m, 5H), 3.71 (s, 3H),
3.51 (s, 3H), 3.15 (dd, J=13.5 and 6.3 Hz, 1H), 3.02-3.07 (m, 3H),
1.40 (t, J=6.6 Hz, 3H)
[0547] The second aspect of Category IX of the present disclosure
relates to compounds having the formula:
##STR00193##
wherein R.sup.1 is a substituted or unsubstituted heteroaryl and
R.sup.4 is substituted or unsubstituted phenyl and substituted or
unsubstituted heteroaryl as further described below in Table
XVIII.
TABLE-US-00018 TABLE XVIII No. R.sup.4 R.sup.1 R743 phenyl
4-(methoxycarbonyl)thiazol-5-yl R744 phenyl
4-[(2-methoxy-2-oxoethyl)carbamoyl]thiazol-5-yl R745 phenyl
5-[1-N-(2-methoxy-2-oxoethyl)-1-H-indol-3-yl]oxazol-2-yl R746
phenyl 5-(2-methoxyphenyl)oxazol-2-yl R747 phenyl
5-[(S)-1-(tert-butoxycarbonyl)-2-phenylethyl]oxazol-2-yl R748
phenyl 5-[4-(methylcarboxy)phenyl]oxazol-2-yl R749 phenyl
5-(3-methoxybenzyl)oxazol-2-yl R750 phenyl 5-(4-phenyl)oxazol-2-yl
R751 phenyl 5-(2-methoxyphenyl)thiazol-2-yl R752 phenyl
5-(3-methoxyphenyl)thiazol-2-yl R753 phenyl
5-(4-fluorophenyl)thiazol-2-yl R754 phenyl
5-(2,4-difluorophenyl)thiazol-2-yl R755 phenyl
5-(3-methoxybenzyl)thiazol-2-yl R756 phenyl
4-(3-methoxyphenyl)thiazol-2-yl R757 phenyl
4-(4-fluorophenyl)thiazol-2-yl R758 thiophen-2-yl
4-(methoxycarbonyl)thiazol-5-yl R759 thiophen-2-yl
4-[(2-methoxy-2-oxoethyl)carbamoyl]thiazol-5-yl R760 thiophen-2-yl
5-[1-N-(2-methoxy-2-oxoethyl)-1-H-indol-3-yl]oxazol-2-yl R761
thiophen-2-yl 5-(2-methoxyphenyl)oxazol-2-yl R762 thiophen-2-yl
5-[(S)-1-(tert-butoxycarbonyl)-2-phenylethyl]oxazol-2-yl R763
thiophen-2-yl 5-[4-(methylcarboxy)phenyl]oxazol-2-yl R764
thiophen-2-yl 5-(3-methoxybenzyl)oxazol-2-yl R765 thiophen-2-yl
5-(4-phenyl)oxazol-2-yl R766 thiophen-2-yl
5-(2-methoxyphenyl)thiazol-2-yl R767 thiophen-2-yl
5-(3-methoxyphenyl)thiazol-2-yl R768 thiophen-2-yl
5-(4-fluorophenyl)thiazol-2-yl R769 thiophen-2-yl
5-(2,4-difluorophenyl)thiazol-2-yl R770 thiophen-2-yl
5-(3-methoxybenzyl)thiazol-2-yl R771 thiophen-2-yl
4-(3-methoxyphenyl)thiazol-2-yl R772 thiophen-2-yl
4-(4-fluorophenyl)thiazol-2-yl R773 cyclopropyl
4-(methoxycarbonyl)thiazol-5-yl R774 cyclopropyl
4-[(2-methoxy-2-oxoethyl)carbamoyl]thiazol-5-yl R775 cyclopropyl
5-[1-N-(2-methoxy-2-oxoethyl)-1-H-indol-3-yl]oxazol-2-yl R776
cyclopropyl 5-(2-methoxyphenyl)oxazol-2-yl R777 cyclopropyl
5-[(S)-1-(tert-butoxycarbonyl)-2-phenylethyl]oxazol-2-yl R778
cyclopropyl 5-[4-(methylcarboxy)phenyl]oxazol-2-yl R779 cyclopropyl
5-(3-methoxybenzyl)oxazol-2-yl R780 cyclopropyl
5-(4-phenyl)oxazol-2-yl R781 cyclopropyl
5-(2-methoxyphenyl)thiazol-2-yl R782 cyclopropyl
5-(3-methoxyphenyl)thiazol-2-yl R783 cyclopropyl
5-(4-fluorophenyl)thiazol-2-yl R784 cyclopropyl
5-(2,4-difluorophenyl)thiazol-2-yl R785 cyclopropyl
5-(3-methoxybenzyl)thiazol-2-yl R786 cyclopropyl
4-(3-methoxyphenyl)thiazol-2-yl R787 cyclopropyl
4-(4-fluorophenyl)thiazol-2-yl
[0548] Compounds according to the second aspect of Category IX
which comprise a substituted or unsubstituted thiazol-4-yl unit for
R.sup.1 can be prepared by the procedure outlined in Schemes XIX,
XX, and XXI, and described below in Examples 20, 21, and 22.
##STR00194## ##STR00195## ##STR00196##
Example 20
(S)-4-(2-(5-Methyl-1,3,4-thiadiazol-2-ylamino)-2-(2-phenylthiazol-4-yl)eth-
yl)phenylsulfamic acid (55)
Preparation of [3-diazo-1-(4-nitrobenzyl)-2-oxo-propyl]-carbamic
acid tert-butyl ester (50)
[0549] To a 0.degree. C. solution of
2-(S)-tert-butoxycarbonylamino-3-(4-nitrophenyl)-propionic acid
(1.20 g, 4.0 mmol) in THF (20 mL) is added dropwise triethylamine
(0.61 mL, 4.4 mmol) followed by iso-butyl chloroformate (0.57 mL,
4.4 mmol). The reaction mixture is stirred at 0.degree. C. for 20
minutes then filtered. The filtrate is treated with an ether
solution of diazomethane (.about.16 mmol) at 0.degree. C. The
reaction mixture is stirred at room temperature for 3 hours and
concentrated. The residue is dissolved in EtOAc and washed
successively with water and brine, dried (Na.sub.2SO.sub.4),
filtered and concentrated in vacuo. The resulting residue is
purified over silica (hexane/EtOAc 2:1) to afford 1.1 g (82% yield)
of the desired product as a slightly yellow solid. .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 8.16 (d, J=8.7 Hz, 2H), 7.39 (d, J=8.7 Hz,
2H), 5.39 (s, 1H), 5.16 (d, J=6.3 Hz, 1H), 4.49 (s, 1H), 3.25 (dd,
J=13.8 and 6.6, 1H), 3.06 (dd, J=13.5 and 6.9 Hz, 1H), 1.41 (s,
9H).
Preparation of [3-bromo-1-(4-nitro-benzyl)-2-oxo-propyl]-carbamic
acid tert-butyl ester (51)
[0550] To a 0.degree. C. solution of
[3-diazo-1-(4-nitrobenzyl)-2-oxo-propyl]-carbamic acid tert-butyl
ester, 50, (0.350 g, 1.04 mmol) in THF (5 mL) is added dropwise 48%
aq. HBr (0.14 mL, 1.25 mmol). The reaction mixture is stirred at
0.degree. C. for 1.5 hours and quenched at 0.degree. C. with
saturated aqueous Na.sub.2CO.sub.3. The mixture is extracted with
EtOAc (3.times.25 mL) and the combined organic extracts are washed
with brine, dried (Na.sub.2SO.sub.4), filtered and concentrated in
vacuo to afford 0.400 g of the desired product that is used in the
next step without further purification. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 8.20 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H),
5.06 (d, J=7.8 Hz, 1H), 4.80 (q, J=6.3 Hz, 1H), 4.04 (s, 2H), 1.42
(s, 9H).
Preparation of
(S)-2-(4-nitrophenyl)-1-(2-phenylthiazol-4-yl)ethanamine
hydrobromide salt (52)
[0551] A mixture of
[3-bromo-1-(4-nitro-benzyl)-2-oxo-propyl]-carbamic acid tert-butyl
ester, 51, (1.62 g, 4.17 mmol) and benzothioamide (0.630 g, 4.59
mmol), in CH.sub.3CN (5 mL) is refluxed for 24 hours. The reaction
mixture is cooled to room temperature and diethyl ether (50 mL) is
added to the solution and the precipitate that forms is collected
by filtration. The solid is dried under vacuum to afford 1.059 g
(63%) of the desired product. ESI+ MS 326 (M+1).
Preparation of
(S)-4-[1-isothiocyanato-2-(4-nitrophenyl)-ethyl]-2-phenylthiazole
(53)
[0552] To a solution of
(S)-2-(4-nitrophenyl)-1-(2-phenylthiazol-4-yl)ethanamine
hydrobromide salt, 52, (2.03 g, 5 mmol) and CaCO.sub.3 (1 g, 10
mmol) in CCl.sub.4/water (10:7.5 mL) is added thiophosgene (0.46
mL, 6 mmol). The reaction is stirred at room temperature for 18
hours then diluted with CH.sub.2Cl.sub.2 and water. The layers are
separated and the aqueous layer extracted with CH.sub.2Cl.sub.2.
The combined organic layers are washed with brine, dried
(Na.sub.2SO.sub.4) and concentrated in vacuo to a residue that is
purified over silica (CH.sub.2Cl.sub.2) to afford 1.71 g (93%
yield) of the desired product. ESI+ MS 368 (M+1).
Preparation of
(S)-5-methyl-N-[2-(4-nitrophenyl)-1-(2-phenylthiazol-4-yl)ethyl]-1,3,4-th-
iadiazol-2-amine (54)
[0553] A solution of
(S)-4-[1-isothiocyanato-2-(4-nitrophenyl)-ethyl]-2-phenylthiazole,
53, (332 mg, 0.876 mmol) and acetic hydrazide (65 mg, 0.876 mmol)
in EtOH (5 mL) is refluxed for 2 hours. The solvent is removed
under reduced pressure, the residue is dissolved in POCl.sub.3 (3
mL) and the resulting solution is stirred at room temperature for
18 hours after which the solution is heated to 50.degree. C. for 2
hours. The solvent is removed in vacuo and the residue is dissolved
in EtOAc (40 mL) and the resulting solution is treated with 1N NaOH
until the pH remains approximately 8. The solution is extracted
with EtOAc. The combined aqueous layers are washed with EtOAc, the
organic layers combined, washed with brine, dried over MgSO.sub.4,
filtered, and concentrated in vacuo to afford 0.345 g (93% yield)
of the desired product as a yellow solid. .sup.1H NMR (CDCl.sub.3)
8.09 (d, J=8.4 Hz, 2H), 7.91 (m, 2H), 7.46 (m, 4H), 7.44 (s, 1H),
5.23 (m, 1H), 3.59 (m, 2H), 2.49 (s, 3H). ESI+ MS 424 (M+1).
Preparation of
(S)-4-[2-(5-methyl-1,3,4-thiadiazol-2-ylamino)-2-(2-phenylthiazol-4-yl)et-
hyl]phenylsulfamic acid (55)
[0554]
(S)-5-Methyl-N-[2-(4-nitrophenyl)-1-(2-phenylthiazol-4-yl)ethyl]-1,-
3,4-thiadiazol-2-amine, 54, (0.404 g, 0.954 mmol) is dissolved in
MeOH (5 mL). Pd/C (50 mg, 10% w/w) is added and the mixture is
stirred under a hydrogen atmosphere until the reaction is judged to
be complete. The reaction mixture is filtered through a bed of
CELITE.TM. and the solvent removed under reduced pressure. The
crude product is dissolved in pyridine (4 mL) and treated with
SO.sub.3-pyridine (0.304 g, 1.91 mmol). The reaction is stirred at
room temperature for 5 minutes after which a 7% solution of
NH.sub.4OH (50 mL) is added. The mixture is then concentrated and
the resulting residue is purified by reverse phase preparative HPLC
to afford 0.052 g (11% yield) of the desired product as the
ammonium salt. .sup.1H NMR (CD.sub.3OD): .delta. 8.00-7.97 (m, 2H),
7.51-7.47 (m, 3H), 7.23 (s, 1H), 7.11-7.04 (q, 4H, J=9.0 Hz), 5.18
(t, 1H, J=7.2 Hz), 3.34-3.22 (m, 2H), 2.50 (s, 3H). ESI- MS 472
(M-1).
##STR00197## ##STR00198##
Example 21
4-{(S)-2-[4-(2-Methoxyphenyl)thiazol-2-ylamino)-2-[2-(thiophen-2-yl)thiazo-
l-4-yl]ethyl}phenylsulfamic acid (58)
Preparation of
(S)-1-[1-(thiophen-2-ylthiazol-4-yl)-2-(4-nitrophenyl)ethyl]-thiourea
(56)
[0555] To a solution of
(S)-2-(4-nitrophenyl)-1-(thiophen-2-ylthiazol-4-yl)ethanamine
hydrobromide salt, 8, (1.23 g, 2.98 mmol) and CaCO.sub.3 (0.597 g,
5.96 mmol) in CCl.sub.4/water (10 mL/5 mL) is added thiophosgene
(0.412 g, 3.58 mmol). The reaction is stirred at room temperature
for 18 hours then diluted with CH.sub.2Cl.sub.2 and water. The
layers are separated and the aqueous layer extracted with
CH.sub.2Cl.sub.2. The combined organic layers are washed with
brine, dried (Na.sub.2SO.sub.4) and concentrated in vacuo to a
residue which is subsequently treated with ammonia (0.5M in
1,4-dioxane, 29.4 mL, 14.7 mmol) which is purified over silica to
afford 0.490 g of the desired product as a red-brown solid. ESI+ MS
399 (M+1).
Preparation of
4-(2-methoxyphenyl)-N--{(S)-2-(4-nitrophenyl)-1-[2-(thiophen-2-yl)thiazol-
-4-yl]ethyl}thiazol-2-amine (57)
[0556]
(S)-1-[1-(thiophen-2-ylthiazol-4-yl)-2-(4-nitrophenyl)ethyl]-thiour-
ea, 56, (265 mg, 0.679 mmol) is treated with
bromo-2'-methoxyacetophenone (171 mg, 0.746 mmol) to afford 0.221 g
of the product as a yellow solid. ESI+ MS 521 (M+1).
Preparation on
4-{(S)-2-[4-(2-methoxyphenyl)thiazol-2-ylamino)-2-[2-(thiophen-2-yl)thiaz-
ol-4-yl]ethyl}phenylsulfamic acid (58)
[0557]
4-(2-methoxyphenyl)-N--{(S)-2-(4-nitrophenyl)-1-[2-(thiophen-2-yl)t-
hiazol-4-yl]ethyl}thiazol-2-amine, 57, (0.229 g) is dissolved in 12
mL MeOH. A catalytic amount of Pd/C (10% w/w) is added and the
mixture is stirred under a hydrogen atmosphere for 18 hours. The
reaction mixture is filtered through a bed of CELITE.TM. and the
solvent is removed under reduced pressure. The crude product is
dissolved in 6 mL pyridine and treated with SO.sub.3-pyridine (140
mg). The reaction is stirred at room temperature for 5 minutes
after which 10 mL of a 7% solution of NH.sub.4OH is added. The
mixture is then concentrated and the resulting residue is purified
by reverse-phase chromatography to afford 0.033 g of the desired
product as the ammonium salt. .sup.1H NMR (CD.sub.3OD): .delta.
7.96-7.93 (m, 1H), 7.60-7.55 (m, 2H), 7.29-7.23 (m, 1H), 7.18-6.95
(m, 9H), 5.15 (t, 1H, J=6.9 Hz), 3.90 (s, 3H), 3.35-3.24 (m,
2H).
[0558] Compounds according to the second aspect of Category IX
which comprise a substituted or unsubstituted oxazol-2-yl unit for
R.sup.1 can be prepared by the procedure outlined in Scheme XXI and
described herein below in Example 22. Intermediate 39 can be
prepared according to Scheme XVII and Example 18.
##STR00199## ##STR00200##
Example 22
4-{(S)-2-[5-(3-Methoxyphenyl)oxazole-2-ylamino]-2-(2-phenylthiazole-4-yl)e-
thyl}phenylsulfamic acid (61)
Preparation of
[5-(3-methoxyphenyl)oxazol-2-yl]-[2-(4-nitrophenyl)-1-(2-phenylthiazole-4-
-yl) ethyl]amine (60)
[0559] A mixture of
(S)-4-(isothiocyanato-2-(4-nitrophenyl)ethyl)-2-phenylthiazole, 53,
(300 mg, 0.81 mmol), 1-azido-1-(3-methoxyphenyl)ethanone (382 mg,
2.0 mmol) and PPh.sub.3 (0.8 g, polymer bound, .about.3 mmol/g) in
dioxane (6 mL) is heated at 90.degree. C. for 20 minutes. The
reaction solution is cooled to room temperature and the solvent
removed in vacuo and the resulting residue is purified over silica
to afford 300 mg (74% yield) of the desired product as a yellow
solid. .sup.1H NMR (300 MHz, MeOH-d.sub.4) .delta. 8.02 (d, J=7.2
Hz, 2H), 7.92-7.99 (m, 2H), 7.42-7.47 (m, 3H), 7.22-7.27 (m, 3H),
6.69-7.03 (m, 4H), 6.75-6.78 (m, 1H), 5.26 (t, J=6.3 Hz, 1H), 3.83
(s, 4H), 3.42-3.45 (m, 2H).
Preparation of
4-{(S)-2-[5-(3-methoxyphenyl)oxazole-2-ylamino]-2-(2-phenylthiazole-4-yl)-
ethyl}phenylsulfamic acid (61)
[0560]
[5-(3-methoxyphenyl)oxazol-2-yl]-[2-(4-nitrophenyl)-1-(2-phenylthia-
zole-4-yl) ethyl]amine, 60, (300 mg, 0.60 mmol) is dissolved in
MeOH (15 mL). A catalytic amount of Pd/C (10% w/w) is added and the
mixture is stirred under a hydrogen atmosphere 18 hours. The
reaction mixture is filtered through a bed of CELITE.TM. and the
solvent is removed under reduced pressure. The crude product is
dissolved in pyridine (10 mL) and treated with SO.sub.3-pyridine
(190 mg, 1.2 mmol). The reaction is stirred at room temperature for
5 minutes after which a 7% solution of NH.sub.4OH is added. The
mixture is then concentrated and the resulting residue is purified
by reverse-phase chromatography to afford 0.042 g of the desired
product as the ammonium salt. .sup.1H NMR (300 MHz, MeOH-d.sub.4)
.delta. 7.99 d, J=7.5 Hz, 2H), 7.46-7.50 (m, 3H), 7.23-7.29 (m,
3H), 7.04-7.12 (m, 6H), 6.78 (dd, J=8.4 and 2.4 Hz, 1H), 5.16 (t,
J=6.6 Hz, 1H), 3.81 (s, 3H), 3.29-3.39 (m, 1H), 3.17 (dd, J=13.8
and 8.1 Hz, 1H).
[0561] The following are non-limiting examples of the second aspect
of Category IX of the present disclosure.
##STR00201##
(S)-4-(2-(5-Phenyl-1,3,4-thiadiazol-2-ylamino)-2-(2-phenylthiazol-4-yl)et-
hyl)-phenylsulfamic acid
[0562] .sup.1H NMR (CD.sub.3OD): .delta. 7.97-7.94 (m, 2H),
7.73-7.70 (m, 2H), 7.44-7.39 (m, 6H), 7.25 (s, 1H), 7.12 (s, 4H),
5.29 (t, 1H, J=6.9 Hz), 3.35-3.26 (m, 2H).
##STR00202##
4-((S)-2-(5-Propyl-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazo-
l-4-yl)ethyl)phenylsulfamic acid
[0563] .sup.1H NMR (CD.sub.3OD): .delta. 7.59-7.54 (m, 2H),
7.17-7.03 (m, 6H), 5.13 (t, 1H, J=7.2 Hz), 3.32-3.13 (m, 2H), 2.81
(t, 2H, J=7.4 Hz), 1.76-1.63 (h, 6H, J=7.4 Hz), 0.97 (t, 3H, J=7.3
Hz).
##STR00203##
4-((S)-2-(5-Benzyl-1,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazo-
l-4-yl)ethyl)phenylsulfamic acid
[0564] .sup.1H NMR (CD.sub.3OD): .delta. (m, 2H), 7.49-7.45 (m,
2H), 7.26-7.16 (m, 5H), 7.05-6.94 (m, 6H), 5.04 (t, 1H, J=7.1 Hz),
4.07 (s, 2H), 3.22-3.04 (m, 2H).
##STR00204##
4-((S)-2-(5-(Naphthalen-1-ylmethyl)-1,3,4-thiadiazol-2-ylamino)-2-(2-(thi-
ophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamic acid
[0565] .sup.1H NMR (CD.sub.3OD): .delta. 8.08-8.05 (m, 1H),
7.89-7.80 (m, 2H), 7.55-7.43 (m, 6H), 7.11-7.00 (m, 6H), 5.08 (t,
1H, J=7.1 Hz), 4.63 (s, 2H), 3.26-3.08 (m, 2H).
##STR00205##
4-((S)-2-(5-((Methoxycarbonyl)methyl)-1,3,4-thiadiazol-2-ylamino)-2-(2-(t-
hiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamic acid
[0566] .sup.1H NMR (CD.sub.3OD): .delta. 7.48-7.44 (m, 2H),
7.03-6.92 (m, 6H), 5.02 (t, 1H, J=7.2 Hz), 4.30 (s, 2H), 3.55 (s,
3H), 3.22-3.02 (m, 2H).
##STR00206##
4-((S)-2-(5-((2-Methylthiazol-4-yl)methyl)-1,3,4-thiadiazol-2-ylamino)-2--
(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfamic acid
[0567] .sup.1H NMR (CD.sub.3OD): .delta. 7.60-7.56 (m, 2H), 7.19
(s, 1H), 7.15-7.12 (m, 2H), 7.09-7.03 (q, 4H, J=8.7 Hz), 5.14 (t,
1H, J=7.2 Hz), 4.28 (s, 2H), 3.33-3.14 (m, 2H), 2.67 (s, 3H).
##STR00207##
4-{(S)-2-[4-(2,4-Difluorophenyl)thiazol-2-ylamino]-2-[2-(thiophen-2-yl)th-
iazol-4-yl]ethyl}phenylsulfamic acid
[0568] .sup.1H NMR (CD.sub.3OD): .delta. 8.06-8.02 (q, 1H, J=6.8
Hz), 7.59-7.54 (m, 2H), 7.16-7.08 (m, 6H), 7.01-6.88 (m, 4H), 5.20
(t, 1H, J=7.0 Hz), 3.36-3.17 (m, 2H).
##STR00208##
(S)-4-{2-[4-(Ethoxycarbonyl)thiazol-2-ylamino]-2-(2-phenylthiazol-4-yl)et-
hyl}phenylsulfamic acid
[0569] .sup.1H NMR (CD.sub.3OD): .delta. 8.02-7.99 (m, 2H),
7.54-7.45 (m, 4H), 7.26 (s, 1H), 7.08 (s, 4H), 5.26 (t, 1H, J=6.9
Hz), 4.35-4.28 (q, 2H, J=6.9 Hz), 3.38-3.18 (m, 2H), 1.36 (t, 3H,
J=7.2 Hz).
##STR00209##
(S)-4-{2-[4-(2-Ethoxy-2-oxoethyl)thiazol-2-ylamino]-2-(2-phenylthiazol-4--
yl)ethyl}phenylsulfamic acid
[0570] .sup.1H NMR (CD.sub.3OD): .delta. 7.96 (m, 2H), 7.50-7.46
(m, 3H), 7.21 (s, 1H), 7.10-7.04 (m, 4H), 6.37 (s, 1H), 5.09 (t,
1H, J=6.9 Hz), 4.17-4.10 (q, 2H, J=7.1 Hz), 3.54 (s, 2H), 3.35-3.14
(m, 2H), 1.22 (t, 3H, J=7.1 Hz).
##STR00210##
(S)-4-{2-[4-(4-acetamidophenyl)thiazol-2-ylamino]-2-(2-phenylthiazol-4-yl-
)ethyl}phenylsulfamic acid
[0571] .sup.1H NMR (CD.sub.3OD): .delta. 8.11 (m, 2H), 7.82-7.80
(m, 2H), 7.71-7.61 (m, 6H), 7.40 (s, 1H), 7.23 (s, 4H), 5.32 (t,
1H, J=7.0 Hz), 3.51-3.35 (m, 2H), 2.28 (s, 3H).
##STR00211##
(S)-4-[2-(4-phenylthiazol-2-ylamino)-2-(2-phenylthiazol-4-yl)ethyl]phenyl-
sulfamic acid
[0572] .sup.1H NMR (CD.sub.3OD): .delta. 8.03-7.99 (m, 2H),
7.75-7.72 (d, 2H, J=8.4 Hz), 7.53-7.48 (m, 3H), 7.42 (m, 4H), 7.12
(s, 4H), 6.86 (s, 1H), 5.23 (t, 1H, J=7.2 Hz), 3.40-3.27 (m,
2H).
##STR00212##
(S)-4-{2-[4-(4-(methoxycarbonyl)phenyl)thiazol-2-ylamino]-2-(2-phenylthia-
zol-4-yl)ethyl}phenylsulfamic acid
[0573] .sup.1H NMR (CD.sub.3OD): .delta. 8.04-8.00 (m, 4H),
7.92-7.89 (d, 2H, J=9.0 Hz), 7.53-7.49 (m, 3H), 7.30 (s, 1H), 7.15
(s, 4H), 7.05 (s, 1H), 5.28 (t, 1H, J=6.9 Hz), 3.93 (s, 3H),
3.35-3.24 (m, 2H).
##STR00213##
4-{(S)-2-[4-(Ethoxycarbonyl)thiazol-2-ylamino]-2-[2-(thiophen-2-yl)thiazo-
l-4-yl]ethyl}phenylsulfamic acid
[0574] .sup.1H NMR (CD.sub.3OD): .delta. 7.43-7.38 (m, 2H), 7.26
(s, 1H), 7.00-6.94 (m, 3H), 6.89 (s, 4H), 5.02 (t, 1H, J=7.0 Hz),
4.16-4.09 (q, 2H, J=7.1 Hz), 3.14-2.94 (m, 2H), 1.17 (t, 3H, J=7.1
Hz).
##STR00214##
(S)-4-[2-(4-(Methoxycarbonyl)thiazol-5-ylamino)-2-(2-phenylthiazole-4-yl)-
ethyl]phenylsulfamic acid
[0575] .sup.1H NMR (300 MHz, MeOH-d.sub.4) .delta. 7.97-8.00 (m,
3H), 7.48-7.52 (m, 3H), 7.22 (s, 1H), 7.03-7.13 (m, 4H), 4.74 (t,
J=6.6 Hz, 1H), 3.88 (s, 3H), 3.28-3.42 (m, 2H).
##STR00215##
(S)-4-[2-(5-Phenyloxazol-2-ylamino)-2-(2-phenylthiazol-4-yl)ethyl]-phenyl-
sulfamic acid
[0576] .sup.1H NMR (300 MHz, MeOH-d.sub.4) .delta. 7.94-7.96 (m,
2H), 7.45-7.49 (m, 5H), 7.32 (t, J=7.8 Hz, 2H), 7.12 (s, 1H), 7.19
(t, J=7.2 Hz, 1H), 7.12 (s, 4H), 7.05 (s, 1H), 5.15 (t, J=6.4 Hz,
1H), 3.34 (dd, J=14.1 and 8.4 Hz, 1H), 3.18 (dd, J=14.1 and 8.4 Hz,
1H).
##STR00216##
(S)-4-{2-[5-(4-Acetamidophenyl)oxazol-2-ylamino]-2-(2-phenylthiazol-4-yl)-
ethyl}phenylsulfamic acid
[0577] .sup.1H NMR (300 MHz, MeOH-d.sub.4) .delta. 7.92-7.94 (m,
2H), 7.55-7.58 (m, 2H), 7.39-7.50 (m, 5H), 7.26 (s, 1H), 7.12 (s,
4H), 7.02 (s, 1H0), 5.14 (t, J=7.8 Hz, 1H), 3.13-3.38 (m, 2H), 2.11
(s, 3H).
##STR00217##
4-((S)-2-(5-(2,4-Difluorophenyl)oxazole-2-ylamino)-2-(2-phenylthiazole-4--
yl)ethyl)phenylsulfamic acid
[0578] .sup.1H NMR (300 MHz, MeOH-d.sub.4) .delta. 7.97-7.99 (m,
2H), 7.54-7.62 (m, 1H), 7.45-7.50 (m, 3H), 7.28 (s, 1H), 7.12 (s,
4H), 6.97-7.06 (m, 3H), 5.15-5.20 (m, 1H), 3.28-3.40 (m, 1H), 3.20
(dd, J=13.8 and 8.4 Hz, 1H).
##STR00218##
4-{(S)-2-[5-(3-Methoxyphenyl)oxazol-2-ylamino]-2-[(2-thiophen-2-yl)thiazo-
le-4-yl]ethyl}phenylsulfamic acid
[0579] .sup.1H NMR (300 MHz, MeOH-d.sub.4) .delta. 7.55-7.60 (m,
2H), 7.26 (t, J=8.1 Hz, 1H), 7.21 (s, 1H), 7.04-7.15 (m, 8H),
6.77-6.81 (m, 1H), 5.10 (t, J=6.3 Hz, 1H), 3.81 (s, 3H), 3.29-3.36
(m, 1H), 3.15 (dd, J=14.1 and 8.4 Hz, 1H).
##STR00219##
(S)-4-[2-(4,6-Dimethylpyrimidin-2-ylamino)-2-(2-methylthiazole-4-yl)ethyl-
]phenylsulfamic acid
[0580] .sup.1H NMR (300 MHz, MeOH-d.sub.4) .delta. 7.00-7.10 (m,
5H), 6.44 (s, 1H), 5.50 (t, J=7.2 Hz, 1H), 3.04-3.22 (m, 2H), 2.73
(s, 3H), 2.27 (s, 6H).
##STR00220##
(S)-4-[2-(4-Hydroxy-6-methylpyrimidine-2-ylamino)-2-(2-methylthiazole-4-y-
l)ethyl]phenylsulfamic acid
[0581] .sup.1H NMR (300 MHz, MeOH-d4) .delta. 7.44 (d, J=8.4 Hz,
2H), 6.97-7.10 (m, 4H), 5.61 (s, 1H), 5.40-5.49 (m, 1H), 3.10-3.22
(m, 2H), 2.73 (s, 3H), 2.13 (s, 3H).
[0582] The first aspect of Category X of the present disclosure
relates to compounds having the formula:
##STR00221##
wherein R.sup.1 is heteroaryl and R.sup.4 is further described
below in Table XIX.
TABLE-US-00019 TABLE XIX No. R.sup.4 R.sup.1 S788 phenyl
4-(methoxycarbonyl)thiazol-5-yl S789 phenyl
4-[(2-methoxy-2-oxoethyl)carbamoyl]thiazol-5-yl S790 phenyl
5-[1-N-(2-methoxy-2-oxoethyl)-1-H-indol-3-yl]oxazol-2-yl S791
phenyl 5-(2-methoxyphenyl)oxazol-2-yl S792 phenyl
5-[(S)-1-(tert-butoxycarbonyl)-2-phenylethyl]oxazol-2-yl S793
phenyl 5-[4-(methylcarboxy)phenyl]oxazol-2-yl S794 phenyl
5-(3-methoxybenzyl)oxazol-2-yl S795 phenyl 5-(4-phenyl)oxazol-2-yl
S796 phenyl 5-(2-methoxyphenyl)thiazol-2-yl S797 phenyl
5-(3-methoxyphenyl)thiazol-2-yl S798 phenyl
5-(4-fluorophenyl)thiazol-2-yl S799 phenyl
5-(2,4-difluorophenyl)thiazol-2-yl S800 phenyl
5-(3-methoxybenzyl)thiazol-2-yl S801 phenyl
4-(3-methoxyphenyl)thiazol-2-yl S802 phenyl
4-(4-fluorophenyl)thiazol-2-yl S803 thiophen-2-yl
4-(methoxycarbonyl)thiazol-5-yl S804 thiophen-2-yl
4-[(2-methoxy-2-oxoethyl)carbamoyl]thiazol-5-yl S805 thiophen-2-yl
5-[1-N-(2-methoxy-2-oxoethyl)-1-H-indol-3-yl]oxazol-2-yl S806
thiophen-2-yl 5-(2-methoxyphenyl)oxazol-2-yl S807 thiophen-2-yl
5-[(S)-1-(tert-butoxycarbonyl)-2-phenylethyl]oxazol-2-yl S808
thiophen-2-yl 5-[4-(methylcarboxy)phenyl]oxazol-2-yl S809
thiophen-2-yl 5-(3-methoxybenzyl)oxazol-2-yl S810 thiophen-2-yl
5-(4-phenyl)oxazol-2-yl S811 thiophen-2-yl
5-(2-methoxyphenyl)thiazol-2-yl S812 thiophen-2-yl
5-(3-methoxyphenyl)thiazol-2-yl S813 thiophen-2-yl
5-(4-fluorophenyl)thiazol-2-yl S814 thiophen-2-yl
5-(2,4-difluorophenyl)thiazol-2-yl S815 thiophen-2-yl
5-(3-methoxybenzyl)thiazol-2-yl S816 thiophen-2-yl
4-(3-methoxyphenyl)thiazol-2-yl S817 thiophen-2-yl
4-(4-fluorophenyl)thiazol-2-yl S818 cyclopropyl
4-(methoxycarbonyl)thiazol-5-yl S819 cyclopropyl
4-[(2-methoxy-2-oxoethyl)carbamoyl]thiazol-5-yl S820 cyclopropyl
5-[1-N-(2-methoxy-2-oxoethyl)-1-H-indol-3-yl]oxazol-2-yl S821
cyclopropyl 5-(2-methoxyphenyl)oxazol-2-yl S822 cyclopropyl
5-[(S)-1-(tert-butoxycarbonyl)-2-phenylethyl]oxazol-2-yl S823
cyclopropyl 5-[4-(methylcarboxy)phenyl]oxazol-2-yl S824 cyclopropyl
5-(3-methoxybenzyl)oxazol-2-yl S825 cyclopropyl
5-(4-phenyl)oxazol-2-yl S826 cyclopropyl
5-(2-methoxyphenyl)thiazol-2-yl S827 cyclopropyl
5-(3-methoxyphenyl)thiazol-2-yl S828 cyclopropyl
5-(4-fluorophenyl)thiazol-2-yl S829 cyclopropyl
5-(2,4-difluorophenyl)thiazol-2-yl S830 cyclopropyl
5-(3-methoxybenzyl)thiazol-2-yl S831 cyclopropyl
4-(3-methoxyphenyl)thiazol-2-yl S832 cyclopropyl
4-(4-fluorophenyl)thiazol-2-yl
[0583] Compounds according to the first aspect of Category X can be
prepared by the procedure outlined in Scheme XXII and described
below in Example 23.
##STR00222## ##STR00223##
Example 23
4-((S)-2-(2-(3-Chlorophenyl)acetamido)-2-(2-(thiophen-2-yl)oxazol-4-yl)eth-
yl)phenylsulfamic acid (64)
Preparation of
(S)-2-(4-nitrophenyl)-1-[(thiophen-2-yl)oxazol-4-yl]ethanamine
hydrobromide salt (62)
[0584] A mixture of (S)-tert-butyl
4-bromo-1-(4-nitrophenyl)-3-oxobutan-2-ylcarbamate, 7, (38.7 g, 100
mmol), and thiophen-2-carboxamide (14 g, 110 mmol) (available from
Alfa Aesar) in CH.sub.3CN (500 mL) is refluxed for 5 hours. The
reaction mixture is cooled to room temperature and diethyl ether
(200 mL) is added to the solution. The precipitate which forms is
collected by filtration. The solid is dried under vacuum to afford
the desired product which can be used for the next step without
purification.
Preparation of
2-(3-chlorophenyl)-N--{(S)-2-(4-nitrophenyl)-1-[2-(thiophen-2-yl)oxazol-4-
-yl]ethyl}acetamide (63)
[0585] To a solution of
(S)-2-(4-nitrophenyl)-1-[(thiophen-2-yl)oxazol-4-yl]ethanamine HBr,
47, (3.15 g, 10 mmol) 3-chlorophenyl-acetic acid (1.70 g, 10 mmol)
and 1-hydroxybenzotriazole (HOBt) (0.70 g, 5.0 mmol) in DMF (50 mL)
at 0.degree. C., is added
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (1.90 g, 10
mmol) followed by triethylamine (4.2 mL, 30 mmol). The mixture is
stirred at 0.degree. C. for 30 minutes then at room temperature
overnight. The reaction mixture is diluted with water and extracted
with EtOAc. The combined organic phase is washed with 1 N aqueous
HCl, 5% aqueous NaHCO.sub.3, water and brine, and dried over
Na.sub.2SO.sub.4. The solvent is removed in vacuo to afford the
desired product which is used without further purification.
Preparation of
--((S)-2-(2-(3-chlorophenyl)acetamido)-2-(2-(thiophen-2-yl)oxazol-4-yl)et-
hyl)phenylsulfamic acid (64)
[0586]
2-(3-chlorophenyl)-N--{(S)-2-(4-nitrophenyl)-1-[2-(thiophen-2-yl)ox-
azol-4-yl]ethyl}acetamide, 63, (3 g) is dissolved in MeOH (4 mL). A
catalytic amount of Pd/C (10% w/w) is added and the mixture is
stirred under a hydrogen atmosphere 18 hours. The reaction mixture
is filtered through a bed of CELITE.TM. and the solvent is removed
under reduced pressure. The crude product is dissolved in pyridine
(12 mL) and treated with SO.sub.3-pyridine (0.157 g). The reaction
is stirred at room temperature for 5 minutes after which a 7%
solution of NH.sub.4OH is added. The mixture is then concentrated
and the resulting residue can be purified by reverse phase
chromatography to afford the desired product as the ammonium
salt.
[0587] The second aspect of Category X of the present disclosure
relates to compounds having the formula:
##STR00224##
wherein R.sup.1 is aryl and R.sup.2 and R.sup.3 are further
described herein below in Table XX.
TABLE-US-00020 TABLE XX No. R.sup.2 R.sup.3 R.sup.1 T833 methyl
hydrogen phenyl T834 methyl hydrogen benzyl T835 methyl hydrogen
2-fluorophenyl T836 methyl hydrogen 3-fluorophenyl T837 methyl
hydrogen 4-fluorophenyl T838 methyl hydrogen 2-chlorophenyl T839
methyl hydrogen 3-chlorophenyl T840 methyl hydrogen 4-chlorophenyl
T841 ethyl hydrogen phenyl T842 ethyl hydrogen benzyl T843 ethyl
hydrogen 2-fluorophenyl T844 ethyl hydrogen 3-fluorophenyl T845
ethyl hydrogen 4-fluorophenyl T846 ethyl hydrogen 2-chlorophenyl
T847 ethyl hydrogen 3-chlorophenyl T848 ethyl hydrogen
4-chlorophenyl T849 thien-2-yl hydrogen phenyl T850 thien-2-yl
hydrogen benzyl T851 thien-2-yl hydrogen 2-fluorophenyl T852
thien-2-yl hydrogen 3-fluorophenyl T853 thien-2-yl hydrogen
4-fluorophenyl T854 thien-2-yl hydrogen 2-chlorophenyl T855
thien-2-yl hydrogen 3-chlorophenyl T856 thiene-2-yl hydrogen
4-chlorophenyl
[0588] Compounds according to the second aspect of Category X can
be prepared by the procedure outlined in Scheme XXIII and described
below in Example 24.
##STR00225## ##STR00226##
Example 24
{4-[2-(S)-(4-Ethyloxazol-2-yl)-2-phenylacetylaminoethyl]-phenyl}sulfamic
acid (67)
Preparation of
(S)-1-(4-ethyloxazol-2-yl)-2-(4-nitrophenyl)ethanamine (65)
[0589] A mixture of
[1-(S)-carbamoyl-2-(4-nitrophenyl)ethyl-carbamic acid tert-butyl
ester, 1, (10 g, 32.3 mmol) and 1-bromo-2-butanone (90%, 4.1 mL, 36
mmol) in CH.sub.3CN (500 mL) is refluxed for 18 hours. The reaction
mixture is cooled to room temperature and diethyl ether is added to
the solution and the precipitate which forms is removed by
filtration and is used without further purification.
Preparation of
N-[1-(4-ethyloxazol-2-yl)-2-(4-nitrophenyl)ethyl]-2-phenyl-acetamide
(66)
[0590] To a solution of
(S)-1-(4-ethyloxazol-2-yl)-2-(4-nitrophenyl)ethanamine, 65, (2.9 g,
11 mmol), phenylacetic acid (1.90 g, 14 mmol) and
1-hydroxybenzotriazole (HOBt) (0.94 g, 7.0 mmol) in DMF (100 mL) at
0.degree. C., is added
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (2.68 g, 14
mmol) followed by triethylamine (6.0 mL, 42 mmol). The mixture is
stirred at 0.degree. C. for 30 minutes then at room temperature
overnight. The reaction mixture is diluted with water and extracted
with EtOAc. The combined organic phase is washed with 1 N aqueous
HCl, 5% aqueous NaHCO.sub.3, water and brine, and dried over
Na.sub.2SO.sub.4. The solvent is removed in vacuo to afford the
desired product which is used without further purification.
Preparation of
{4-[2-(S)-(4-ethyloxazol-2-yl)-2-phenylacetylaminoethyl]-phenyl}sulfamic
acid (67)
[0591]
N-[1-(4-ethyloxazol-2-yl)-2-(4-nitrophenyl)ethyl]-2-phenyl-acetamid-
e, 66, (0.260 g) is dissolved in MeOH (4 mL). A catalytic amount of
Pd/C (10% w/w) is added and the mixture is stirred under a hydrogen
atmosphere 18 hours. The reaction mixture is filtered through a bed
of CELITE.TM. and the solvent is removed under reduced pressure.
The crude product is dissolved in pyridine (12 mL) and treated with
SO.sub.3-pyridine (0.177 g, 1.23). The reaction is stirred at room
temperature for 5 minutes after which a 7% solution of NH.sub.4OH
(10 mL) is added. The mixture is then concentrated and the
resulting residue is purified by reverse phase chromatography to
afford the desired product as the ammonium salt.
[0592] Non-limiting examples of the HPTP-.beta. IC.sub.50 .mu.M)
activity for illustrative compounds are listed in Table XXI.
HPTP-.beta. inhibition can be tested by any method chosen by the
formulator, for example, Amarasinge K. K. et al., "Design and
Synthesis of Potent, Non-peptidic Inhibitors of HPTPbeta" Bioorg
Med Chem Lett. 2006 Aug. 15; 16(16):4252-6. Epub 2006 Jun. 12.
Erratum in: Bioorg Med Chem Lett. 2008 Aug. 15; 18(16):4745.
Evidokimov, Artem G [corrected to Evdokimov, Artem G]: PMID:
16759857; and Klopfenstein S. R. et al.
"1,2,3,4-Tetrahydroisoquinolinyl Sulfamic Acids as Phosphatase
PTP1B Inhibitors" Bioorg Med Chem Lett. 2006 Mar. 15; 16(6):1574-8,
both of which are incorporated herein by reference in their
entirety.
TABLE-US-00021 TABLE XXI HPTP-.beta. No. Compound IC.sub.50 .mu.M
AA1 ##STR00227## 0.000157 AA2 ##STR00228## 0.004 AA3 ##STR00229##
0.031 AA4 ##STR00230## >5 .times. 10.sup.-8 AA5 ##STR00231##
<5 .times. 10.sup.-8 AA6 ##STR00232## 0.000162 AA7 ##STR00233##
0.006 AA8 ##STR00234## 0.001 AA9 ##STR00235## 0.0001 AA10
##STR00236## 0.0002 AA11 ##STR00237## 0.00001 AA12 ##STR00238##
<5 .times. 10.sup.-8 AA13 ##STR00239## 0.001 AA14 ##STR00240##
0.0001 AA15 ##STR00241## 0.0003 AA16 ##STR00242## 0.00008 AA17
##STR00243## 0.001 AA18 ##STR00244## 0.0002 AA19 ##STR00245##
0.0003 AA20 ##STR00246## <5 .times. 10.sup.-8 AA21 ##STR00247##
<2 .times. 10.sup.-6 AA22 ##STR00248## <5 .times. 10.sup.-8
AA23 ##STR00249## 0.00009 AA24 ##STR00250## 0.001 AA25 ##STR00251##
0.0004 AA26 ##STR00252## <5 .times. 10.sup.-8 AA27 ##STR00253##
0.00014 AA28 ##STR00254## 0.0001 AA29 ##STR00255## 0.001 AA30
##STR00256## 0.0002 AA31 ##STR00257## 0.00008 AA32 ##STR00258##
0.002 AA33 ##STR00259## 7 .times. 10.sup.-7 AA34 ##STR00260## 5
.times. 10.sup.-8 AA35 ##STR00261## <5 .times. 10.sup.-8 AA36
##STR00262## <5 .times. 10.sup.-8 AA37 ##STR00263## 0.0004 AA38
##STR00264## 0.003 AA39 ##STR00265## 0.001 AA40 ##STR00266## 0.0003
AA41 ##STR00267## 0.00024 AA42 ##STR00268## 0.006 AA43 ##STR00269##
0.028 AA44 ##STR00270## 0.020 AA45 ##STR00271## 0.003 AA46
##STR00272## 0.001 AA47 ##STR00273## 0.0003 AA48 ##STR00274##
0.0003 AA49 ##STR00275## <5 .times. 10.sup.-8 AA50 ##STR00276##
0.028 AA51 ##STR00277## 0.049 AA52 ##STR00278## 0.112 AA53
##STR00279## 0.085 AA54 ##STR00280## 0.266 AA55 ##STR00281## 0.584
AA56 ##STR00282## 0.042 AA57 ##STR00283## 0.110 AA58 ##STR00284##
0.086 AA59 ##STR00285## 0.113 AA60 ##STR00286## 0.132 AA61
##STR00287## 0.138 AA62 ##STR00288## 0.098 AA63 ##STR00289## 0.381
AA64 ##STR00290## 0.033 AA65 ##STR00291## 0.04 AA66 ##STR00292##
0.027 AA67 ##STR00293## 0.18 AA68 ##STR00294## 0.644 AA69
##STR00295## 0.167 AA70 ##STR00296## 0.132 AA71 ##STR00297## 0.555
AA72 ##STR00298## 0.308 AA73 ##STR00299## 0.253 AA74 ##STR00300##
0.045 AA75 ##STR00301## 0.05 AA76 ##STR00302## 0.012 AA77
##STR00303## 0.0003 AA78 ##STR00304## 0.028 AA79 ##STR00305## 0.075
AA80 ##STR00306## 0.056 AA81 ##STR00307## 0.033 AA82 ##STR00308##
0.04 AA83 ##STR00309## 0.014 AA84 ##STR00310## 0.008 AA85
##STR00311## 0.002 AA86 ##STR00312## 0.028 AA87 ##STR00313## 0.037
AA88 ##STR00314## 0.0002 AA89 ##STR00315## 0.003 AA90 ##STR00316##
0.01 AA91 ##STR00317## 0.006 AA92 ##STR00318## 0.002 AA93
##STR00319## 0.002 AA94 ##STR00320## 0.042 AA95 ##STR00321## 0.003
AA96 ##STR00322## 0.046 AA97 ##STR00323## 0.0002 AA98 ##STR00324##
0.0006 AA99 ##STR00325## 0.002 AA100 ##STR00326## 9 .times.
10.sup.-6
[0593] Non-limiting examples of compounds of the invention include:
[0594]
(S)-4-[2-Benzamido-2-(4-ethylthiazol-2-yl)ethyl]phenylsulfamic
acid; [0595]
(S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(2-fluorophenyl)acetamido]ethy-
l}phenylsulfamic acid; [0596]
(S)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(3-fluorophenyl)acetamido)ethyl)pheny-
lsulfamic acid; [0597]
(S)-4-(2-(2-(2,3-Difluorophenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)p-
henylsulfamic acid; [0598]
(S)-4-(2-(2-(3,4-Difluorophenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)p-
henylsulfamic acid; [0599]
(S)-4-(2-(2-(2-Chlorophenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)pheny-
lsulfamic acid; [0600]
(S)-4-(2-(2-(3-Chlorophenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)pheny-
lsulfamic acid; [0601]
(S)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(3-hydroxyphenyl)acetamido)ethyl)phen-
ylsulfamic acid; [0602]
(S)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(2-methoxyphenyl)acetamido)ethyl)phen-
ylsulfamic acid; [0603]
(S)-4-(2-(4-Ethylthiazol-2-yl)-2-(2-(3-methoxyphenyl)acetamido)ethyl)phen-
ylsulfamic acid; [0604]
(S)-4-(2-(4-Ethylthiazol-2-yl)-2-(3-phenylpropanamido)ethyl)phenylsulfami-
c acid; [0605]
(S)-4-(2-(2-(3,4-Dimethoxyphenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)-
-phenylsulfamic acid; [0606]
(S)-4-(2-(2-(2,3-Dimethoxyphenyl)acetamido)-2-(4-ethylthiazol-2-yl)ethyl)-
-phenylsulfamic acid; [0607]
(S)-4-(2-(3-(3-Chlorophenyl)propanamido)-2-(4-ethylthiazol-2-yl)ethyl)phe-
nylsulfamic acid; [0608]
(S)-4-(2-(4-Ethylthiazol-2-yl)-2-(3-(2-methoxyphenyl)propanamido)ethyl)ph-
enylsulfamic acid; [0609]
(S)-4-(2-(4-Ethylthiazol-2-yl)-2-(3-(3-methoxyphenyl)propanamido)ethyl)ph-
enylsulfamic acid; [0610]
(S)-4-(2-(4-Ethylthiazol-2-yl)-2-(3-(4-methoxyphenyl)propanamido)ethyl)ph-
enylsulfamic acid; [0611]
(S)-4-{2-[2-(4-Ethyl-2,3-dioxopiperazin-1-yl)acetamido]-2-(4-ethylthiazol-
-2-yl)ethyl}phenylsulfamic acid; [0612]
(S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(5-methyl-2,4-dioxo-3,4-dihydropyrimi-
din-1(2H)-yl)acetamide]ethyl}phenylsulfamic acid; [0613]
(S)-4-[2-(Benzo[d][1,3]dioxole-5-carboxamido)-2-(4-ethylthiazol-2-yl)ethy-
l]-phenylsulfamic acid; [0614]
4-((S)-2-(2-(2-Chlorophenyl)acetamido)-2-(2-(thiophene2-yl)thiazol-4-yl)e-
thyl)-phenylsulfamic acid; [0615]
4-((S)-2-(2-(3-Methoxyphenyl)acetamido)-2-(2-(thiophene2-yl)thiazol-4-yl)-
ethyl)-phenylsulfamic acid; [0616]
4-{(S)-2-(3-Phenylpropanamido)-2-[2-(thiophene2-yl)thiazol-4-yl]ethyl}phe-
nylsulfamic acid; [0617]
4-{(S)-2-(3-(3-Chlorophenyl)propanamido)-2-[2-(thiophene2-yl)thiazol-4-yl-
]ethyl}-phenylsulfamic acid; [0618]
4-{(S)-2-[2-(3-Fluorophenyl)acetamide]-2-[2-(thiophene2-yl)thiazol-4-yl]e-
thyl}-phenylsulfamic acid; [0619]
(S)-4-{2-[2-(2,5-Dimethylthiazol-4-yl)acetamide]-2-(4-ethylthiazol-2-yl]e-
thyl}-phenylsulfamic acid; [0620]
(S)-4-{2-[2-(2,4-Dimethylthiazol-5-yl)acetamide]-2-(4-methylthiazol-2-yle-
thyl}-phenylsulfamic acid; [0621]
(S)-4-{2-(4-Ethylthiazol-2-yl)-2-[3-(thiazol-2-yl)propanamido]ethyl}pheny-
lsulfamic acid; [0622]
(S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(4-ethylthiazol-2-yl)acetamide]ethyl}-
phenylsulfamic acid; [0623]
(S)-4-{2-[2-(3-Methyl-1,2,4-oxadiazol-5-yl)acetamide]-2-(2-phenylthiazol--
4-yl)ethyl}phenylsulfamic acid; [0624]
4-{(S)-2-[2-(4-Ethyl-2,3-dioxopiperazin-1-yl)acetamide]-2-[2-(thiophen-2--
yl)thiazol-4-yl]ethyl}phenylsulfamic acid; [0625]
(S)-4-(2-(2,3-Diphenylpropanamido)-2-(4-ethylthiazol-2-yl)ethyl)phenylsul-
famic acid; [0626]
(S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(2-methoxyphenyl)-3-phenylpropanamido-
]-ethyl)phenylsulfamic acid; [0627]
(S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(3-fluorophenyl)-3-phenylpropanamido]-
-ethyl}phenylsulfamic acid; [0628]
(S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(3-methoxyphenyl)-3-phenylpropanamido-
]-ethyl}phenylsulfamic acid; [0629]
4-{(S)-2-(4-Ethylthiazol-2-yl)-2-[2-(3-methyl-1,2,4-oxadiazol-5-yl)-3-phe-
nylpropanamido]ethyl}phenylsulfamic acid; [0630]
(S)-4-[2-(4-Ethylthiazol-2-yl)-2-(4-oxo-4-phenylbutanamido)-ethyl]phenyls-
ulfamic acid; [0631]
(S)-4-(2-(4-Ethylthiazol-2-yl)-2-(5-methyl-4-oxohexanamido)ethyl)phenylsu-
lfamic acid; [0632]
(S)-4-{2-[4-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-4-oxobutanamido]--
2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamic acid; [0633]
(S)-4-{2-[4-(2,3-Dimethoxyphenyl)-4-oxobutanamido]-2-(4-ethylthiazol-2-yl-
)ethyl}phenylsulfamic acid; [0634]
(S)-4-{2-(4-Ethylthiazol-2-yl)-2-[4-oxo-4-(pyridin-2-yl)butanamido]ethyl}-
phenylsulfamic acid; [0635]
(S)-4-{2-[4-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-4-oxobutanamido]-2-(4-e-
thylthiazol-2-yl)ethyl}phenylsulfamic acid; [0636]
(S)-4-[2-(4-tert-Butoxy-4-oxobutanamido)-2-(4-ethylthiazol-2-yl)ethyl]phe-
nylsulfamic acid; [0637]
(S)-4-[2-(4-Ethoxy-4-oxobutanamido)-2-(4-ethylthiazol-2-yl)ethyl]phenylsu-
lfamic acid; [0638]
(S)-4-(2-(3-Benzylureido)-2-(4-ethylthiazol-2-yl)ethyl)phenylsulfamic
acid; [0639]
4-{[(S)-2-(2-Ethylthiazol-4-yl)-2-(3-(R)-1methoxy-1-oxo-3-phenylpropan-2--
yl)ureido]ethyl}phenylsulfamic acid; [0640]
4-{(S)-2-(3-Benzylureido)-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsu-
lfamic acid; [0641]
{4-(S)-[2-Phenylmethanesulfonylamino-2-(2-thiophen-2-ylthiazol-4-yl)ethyl-
]-phenylsulfamic acid; [0642]
4-{(S)-2-[(2-Methylthiazol-4-yl)methylsulfonamido]-2-[2-(thiophen-2-yl)th-
iazol-4-yl]ethyl}phenylsulfamic acid; [0643]
{4-(S)-[2-Phenylmethanesulfonylamino-2-(2-ethylthiazol-4-yl)ethyl]phenyl}-
-sulfamic acid; [0644]
{4-(S)-[2-(3-Methoxyphenyl)methanesulfonylamino-2-(2-ethylthiazol-4-yl)et-
hyl]phenyl}sulfamic acid; [0645]
(S)-4-{[1-(2-Ethylthiazol-4-yl)-2-(4-sulfoaminophenyl)ethylsulfamoyl]meth-
yl}-benzoic acid methyl ester; [0646]
(S)-4-[2-(2-Ethylthiazol-4-yl)-2-(1-methyl-1H-imidazol-4-sulfonamido)ethy-
l]-phenylsulfamic acid; [0647]
4-{(S)-2-[2-(Thiophen-2-yl)thiazol-4-yl]-2-(2,2,2-trifluoroethylsulfonami-
do)-ethyl}phenylsulfamic acid; [0648]
{4-(S)-[2-(Phenylethanesulfonylamino)-2-(2thiophen-2-ylthiazol-4-yl)ethyl-
]-phenyl}sulfamic acid; [0649]
{4-(S)-[3-(Phenylpropanesulfonylamino)-2-(2thiophen-2-ylthiazol-4-yl)ethy-
l]-phenyl}sulfamic acid; [0650]
(S)-{4-[2-(4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-sulfonylamino)-2-(-
2-thiophen-2-ylthiazol-4-yl)ethyl]phenyl}sulfamic acid; [0651]
4-{(S)-2-(4-Acetamidophenylsulfonamido)-2-[2-(thiophen-2-yl)thiazol-4-yl]-
ethyl}phenylsulfamic acid; [0652]
4-{(S)-2-(2-cyclopropylthiazol-4-yl)-2-[4-(3-methoxyphenyl)-thiazol-2-yla-
mino]ethyl}phenylsulfamic acid; [0653]
(S)-4-(2-(4-((2-Methoxy-2-oxoethyl)carbamoyl)thiazole-5-ylamino)2-(2-ethy-
lthiazole-4-yl)ethyl)phenylsulfamic acid; [0654]
4-((S)-2-(5-(1-N-(2-Methoxy-2-oxoethyl)-1-H-indol-3-yl)oxazole-2-ylamino)-
-2-(2-methylthiazol-4-yl)ethyl))phenylsulfamic acid; [0655]
4-((S)-2-(5-(2-Methoxyphenyl)oxazol-2-ylamino)-2-(2-methylthiazol-4-yl)et-
hyl)-phenylsulfamic acid; [0656]
4-((S)-2-(5-((S)-1-(tert-Butoxycarbonyl)-2-phenylethyl)oxazole-2-ylamino)-
-2-(2-methylthiazole-4-yl)ethyl)phenylsulfamic acid; [0657]
(S)-4-(2-(5-(4-Methoxycarbonyl)phenyl)oxazole-2-ylamino)2-(2-methylthiazo-
le-4-yl)ethyl)phenylsulfamic acid; [0658]
(S)-4-(2-(5-(3-Methoxybenzyl)oxazole-2-ylamino)-2-(2-methylthiazole-4-yl)-
ethyl)-phenylsulfamic acid; [0659]
(S)-4-(2-(2-Methylthiazole-4-yl)2-(5-phenyloxazole-2-ylamino)ethyl)phenyl-
sulfamic acid; [0660]
4-((S)-2-(2-Cyclopropylthiazol-4-yl)-2-(4-(3-methoxyphenyl)thiazol-2-ylam-
ino)-ethyl)phenylsulfamic acid; [0661]
(S)-4-(2-(2-cyclopropylthiazol-4-yl)-2-(4-(4-fluorophenyl)thiazol-2-ylami-
no)ethyl)-phenylsulfamic acid; [0662]
4-((S)-2-(2-cyclopropylthiazol-4-yl)-2-(4-(2-methoxyphenyl)thiazol-2-ylam-
ino)-ethyl)phenylsulfamic acid; [0663]
4-((S)-2-(2-cyclopropylthiazol-4-yl)-2-(4-(2,4-difluorophenyl)thiazol-2-y-
lamino)-ethyl)phenylsulfamic acid; [0664]
(S)-4-(2-(4-(3-methoxybenzyl)thiazol-2-ylamino)-2-(2-cyclopropylthiazol-4-
-yl)ethyl)phenylsulfamic acid; [0665]
(S)-{5-[1-(2-Ethylthiazol-4-yl)-2-(4-sulfoaminophenyl)ethylamino]-2-methy-
l-2H-[1,2,4]triazole-3-yl}carbamic acid methyl ester; [0666]
4-{(S)-2-[4-(2-Methoxyphenyl)thiazol-2-ylamino)-2-[2-(thiophen-2-yl)thiaz-
ol-4-yl]ethyl}phenylsulfamic acid; [0667]
4-{(S)-2-[5-(3-Methoxyphenyl)oxazole-2-ylamino]-2-(2-phenylthiazole-4-yl)-
ethyl}phenylsulfamic acid; [0668]
4-{(S)-2-[4-(2,4-Difluorophenyl)thiazol-2-ylamino]-2-[2-(thiophen-2-yl)th-
iazol-4-yl]ethyl}phenylsulfamic acid; [0669]
(S)-4-{2-[4-(Ethoxycarbonyl)thiazol-2-ylamino]-2-(2-phenylthiazol-4-yl)et-
hyl}-phenylsulfamic acid; [0670]
(S)-4-{2-[4-(2-Ethoxy-2-oxoethyl)thiazol-2-ylamino]-2-(2-phenylthiazol-4--
yl)ethyl}phenylsulfamic acid; [0671]
(S)-4-{2-[4-(4-Acetamidophenyl)thiazol-2-ylamino]-2-(2-phenylthiazol-4-yl-
)ethyl}phenylsulfamic acid; [0672]
(S)-4-[2-(4-Phenylthiazol-2-ylamino)-2-(2-phenylthiazol-4-yl)ethyl]phenyl-
sulfamic acid; [0673]
(S)-4-{2-[4-(4-(Methoxycarbonyl)phenyl)thiazol-2-ylamino]-2-(2-phenylthia-
zol-4-yl)ethyl}phenylsulfamic acid; [0674]
4-{(S)-2-[4-(Ethoxycarbonyl)thiazol-2-ylamino]-2-[2-(thiophen-2-yl)thiazo-
l-4-yl]ethyl}phenylsulfamic acid; [0675]
(S)-4-[2-(4-(Methoxycarbonyl)thiazol-5-ylamino)-2-(2-phenylthiazole-4-yl)-
ethyl]-phenylsulfamic acid; [0676]
(S)-4-[2-(5-Phenyloxazole-2-ylamino)]-2-(2-phenylthiazole-4-yl)phenylsulf-
amic acid; [0677]
(S)-4-{2-[5-(4-Acetamidophenyl)oxazole-2-ylamino]-2-(2-phenylthiazole-4-y-
l)ethyl}phenylsulfamic acid; [0678]
4-((S)-2-(5-(2,4-Difluorophenyl)oxazole-2-ylamino)-2-(2-phenylthiazole-4--
yl)ethyl)phenylsulfamic acid; [0679]
4-{(S)-2-[5-(3-Methoxyphenyl)oxazol-2-ylamino]-2-[(2-thiophen-2-yl)thiazo-
le-4-yl]ethyl}phenylsulfamic acid; [0680]
(S)-4-[2-(4,6-Dimethylpyrimidene-2-ylamino)-2-(2-methylthiazole-4-yl)ethy-
l]-phenylsulfamic acid; [0681]
(S)-4-[2-(4-Hydroxy-6-methylpyrimidine-2-ylamino)-2-(2-methylthiazole-4-y-
l)ethyl]phenylsulfamic acid;
4-{(S)-2-[(S)-2-(tert-Butoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethy-
lthiazol-2-yl)ethyl}phenylsulfamic acid; [0682]
4-{(S)-2-[(R)-2-(tert-Butoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethy-
lthiazol-2-yl)ethyl}phenylsulfamic acid; [0683]
{1-[1-(5-Ethylthiazol-2-yl)-(S)-2-(4-sulfoaminophenyl)ethylcarbamoyl]-(S)-
-2-phenylethyl}methyl carbamic acid tert-butyl ester; [0684]
{(S)-2-Phenyl-1-[1-(4-phenylthiazol-2-yl)-(S)-2-(4-sulfoaminophenyl)ethyl-
carbamoyl]ethyl}carbamic acid tert-butyl ester; [0685]
4-{(S)-2-(S)-2-(tert-Butoxycarbonylamino)-3-phenylpropaneamido-2-(2-pheny-
lthiazole-4-yl)}phenylsulfamic acid; [0686]
4-{(S)-2-(4-Ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpr-
opanamido]ethyl}phenylsulfamic acid; [0687]
4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(thiazol-2--
yl)ethyl}phenylsulfamic acid; [0688]
4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(4-methylth-
iazol-2-yl)ethyl}phenylsulfamic acid; [0689]
4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(4-propylth-
iazol-2-yl)ethyl}phenylsulfamic acid; [0690]
4-{(S)-2-(4-tert-Butylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phe-
nylpropanamido]ethyl}phenylsulfamic acid; [0691]
4-{(S)-2-(4-Cyclopropylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-ph-
enylpropanamido]ethyl}phenylsulfamic acid; [0692]
4-{(S)-2-(4-Cyclohexylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phe-
nylpropanamido]ethyl}phenylsulfamic acid; [0693]
4-{(S)-2-(4,5-Dimethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phe-
nylpropanamido]ethyl}phenylsulfamic acid; [0694]
4-{(S)-2-Phenyl-1-[1-(2-phenylthiazol-4-yl)-(S)-2-(4-sulfoaminophenyl)eth-
ylcarbamoyl]ethyl}carbamic acid tert-butyl ester; [0695]
4-{(S)-2-(4-Ethyl-5-methylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-
-phenyl-propanamido]ethyl}phenylsulfamic acid; [0696]
4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[4-(2,2,2-t-
rifluoroethyl)thiazol-2-yl]ethyl}phenylsulfamic acid; [0697]
4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido)-2-[4-(3,3,3-t-
rifluoropropyl)thiazol-2-yl]ethyl}phenylsulfamic acid; [0698]
4-{(S)-2-[4-(2,2-Difluorocyclopropyl)thiazol-2-yl]-2-[(S)-2-(methoxycarbo-
nylamino)-3-phenylpropanamido]ethyl}phenylsulfamic acid; [0699]
4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[4-(methoxy-
methyl)thiazol-2-yl]ethyl}phenylsulfamic acid; [0700]
4-{(S)-2-(4-(Ethoxycarbonylamino)thiazol-2-yl)-2-[(S)-2-(methoxycarbonyla-
mino)-3-phenylpropanamido]ethyl}phenylsulfamic acid; [0701]
4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(5-phenylth-
iazol-2-yl))ethyl}phenylsulfamic acid; [0702]
4-{(S)-2-(4-tert-Butylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phe-
nylpropanamido]ethyl}phenylsulfamic acid; [0703]
4-{(S)-2-(4-Ethyl-5-phenylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-
-phenyl-propanamido]ethyl}phenylsulfamic acid; [0704]
4-{(S)-2-[4-(3,4-Dimethylphenyl)thiazol-2-yl]-2-[(S)-2-(methoxycarbonylam-
ino)-3-phenylpropanamido]ethyl}phenylsulfamic acid; [0705]
4-{(S)-2-[4-(4-Chlorophenyl)thiazol-2-yl]-2-[(S)-2-(methoxycarbonylamino)-
-3-phenylpropanamido]ethyl}phenylsulfamic acid; [0706]
4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(4-phenylth-
iazol-2-yl)ethyl}phenylsulfamic acid; [0707]
4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[4-(thiophe-
n-2-yl)thiazol-2-yl]ethyl}phenylsulfamic acid; [0708]
4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[4-(thiophe-
n-3-yl)thiazol-2-yl]ethyl}phenylsulfamic acid; [0709]
4-{(S)-2-(4-Ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbinyl)-3-phenylpropion-
amido]ethyl}phenylsulfamic acid; [0710]
4-{(S)-2-(5,6-Dihydro-4H-cyclopenta[d]thiazol-2-yl)-2-[(S)-2-(methoxy-car-
bonyl)-3-phenylpropanamido]ethyl}phenylsulfamic acid; [0711]
4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(4,5,6,7-te-
trahydrobenzo[d]thiazol-2-yl)ethyl}phenylsulfamic acid; [0712]
4-{(S)-2-[4-(5-Chlorothiophen-2-yl)thiazol-2-yl]-2-[(S)-2-(methoxycarbony-
lamino)-3-phenylpropanamido]ethyl}phenylsulfamic acid; [0713]
4-{(S)-2-[(S)-2-(Ethoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthia-
zol-2-yl)ethyl}phenylsulfamic acid; [0714]
4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthi-
azol-4-yl)ethyl}phenylsulfamic acid; [0715]
4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(2-methylth-
iazol-4-yl)ethyl}phenylsulfamic acid; [0716]
4-{(S)-2-(2-Ethylthiazole-4-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylp-
ropanamido]ethyl}phenylsulfamic acid; [0717]
4-{(S)-2-(2-Isopropylthiazol-4-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phen-
ylpropan-amido]ethyl}phenylsulfamic acid; [0718]
4-{(S)-2-(2-Cyclopropylthiazol-4-yl)-2-[(S)-2-(methoxycarbonylamino)-3-ph-
enylpropanamido]ethyl}phenylsulfamic acid; [0719]
4-{(S)-2-{2-[(4-Chlorophenylsulfonyl)methyl]thiazol-4-yl}-2-[(S)-2-(metho-
xycarbonyl)-3-phenylpropanamido]ethyl}phenylsulfamic acid; [0720]
4-{(S)-2-[2-(tert-Butylsulfonylmethyl)thiazol-4-yl]-2-[(S)-2-(methoxycarb-
onylamino)-3-phenylpropanamido]ethyl}phenylsulfamic acid; [0721]
4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropionamido]-2-(2-phenylt-
hiazole-4-yl)ethyl}phenylsulfamic acid; [0722]
4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid; [0723]
4-{(S)-2-[2-(3-Chlorothiophen-2-yl)thiazol-4-yl]-2-[(S)-2-(methoxycarbony-
lamino)-3-phenylpropanamido]ethyl}phenylsulfamic acid; [0724]
4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(3-methy-
lthiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid; [0725]
4-{[(S)-2-(2-(Furan-2-yl)thiazol-4-yl]-2-[(S)-2-(methoxycarbonylamino)-3--
phenylpropanamido]ethyl}phenylsulfamic acid;
[0726]
4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(-
2-methylthiazole-4-yl)thiazol-4yl]ethyl}phenylsulfamic acid; [0727]
4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-(2-pyrazine-
-2-yl)thiazole-4-yl}phenylsulfamic acid; [0728]
4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(6-methy-
lpyridin-3-yl)thiazol-4-yl]ethyl}phenylsulfamic acid; [0729]
4-[(S)-2-((S)-2-Acetamido-3-phenylpropanamido)-2-(4-ethylthiazol-2-yl)eth-
yl]-phenylsulfamic acid; [0730]
4-[(S)-2-((S)-2-Acetamido-3-phenylpropanamido)-2-(4-tert-butylthiazol-2-y-
l)ethyl]-phenylsulfamic acid; [0731]
4-{(S)-2-((S)-2-Acetamido-3-phenylpropanamido)-2-[4-(thiophen-3-yl)thiazo-
l-2-yl]ethyl)phenylsulfamic acid; [0732]
4-{(S)-2-[(S)-2-(tert-Butoxycarbonyl)-3-methylbutanamido]-2-(4-ethylthiaz-
ol-2-yl)ethyl}phenylsulfamic acid; [0733]
(S)-4-{2-[2-(tert-Butoxycarbonyl)acetamide]-2-(4-ethylthiazol-2-yl)ethyl}-
phenylsulfamic acid; [0734]
(S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(methoxycarbonyl)acetamido]ethyl}phen-
ylsulfamic acid; [0735]
4-{(S)-2-(4-Ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonyl)-3-methylbutanam-
ido]-ethyl}phenylsulfamic acid; [0736]
4-{(S)-2-[(S)-2-(tert-Butoxycarbonyl)-4-methylpentanamido]-2-(4-ethylthia-
zol-2-yl)ethyl}phenylsulfamic acid; [0737]
4-{(S)-2-(4-Ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonyl)-4-methylpentana-
mido]ethyl}phenylsulfamic acid; [0738]
4-((S)-2-(4-Ethylthiazol-2-yl)-2-{(S)-2-[2-(methoxycarbonyl)acetamide]-3--
phenylpropanamido}ethyl)phenylsulfamic acid; [0739]
4-{(S)-2-[(S)-2-(tert-Butoxycarbonyl)-4-methylpentanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid; [0740]
4-{(S)-2-[(S)-2-(Methoxycarbonyl)-4-methylpentanamido]-2-[2-(thiophen-2-y-
l)thiazol-4-yl]ethyl}phenylsulfamic acid; and [0741]
(S)-4-{2-[2-(tert-Butoxycarbonyl)acetamide]-2-(4-ethylthiazol-2-yl)ethyl}-
-phenylsulfamic acid.
Pharmaceutically-Acceptable Salts.
[0742] The invention provides the use of
pharmaceutically-acceptable salts of any compound described herein.
Pharmaceutically-acceptable salts include, for example,
acid-addition salts and base-addition salts. The acid that is added
to the compound to form an acid-addition salt can be an organic
acid or an inorganic acid. A base that is added to the compound to
form a base-addition salt can be an organic base or an inorganic
base. In some embodiments, a pharmaceutically-acceptable salt is a
metal salt. In some embodiments, a pharmaceutically-acceptable salt
is an ammonium salt.
[0743] Metal salts can arise from the addition of an inorganic base
to a compound of the invention. The inorganic base consists of a
metal cation paired with a basic counterion, such as, for example,
hydroxide, carbonate, bicarbonate, or phosphate. The metal can be
an alkali metal, alkaline earth metal, transition metal, or main
group metal. In some embodiments, the metal is lithium, sodium,
potassium, cesium, cerium, magnesium, manganese, iron, calcium,
strontium, cobalt, titanium, aluminum, copper, cadmium, or
zinc.
[0744] In some embodiments, a metal salt is a lithium salt, a
sodium salt, a potassium salt, a cesium salt, a cerium salt, a
magnesium salt, a manganese salt, an iron salt, a calcium salt, a
strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a
copper salt, a cadmium salt, or a zinc salt.
[0745] Ammonium salts can arise from the addition of ammonia or an
organic amine to a compound of the invention. In some embodiments,
the organic amine is triethyl amine, diisopropyl amine, ethanol
amine, diethanol amine, triethanol amine, morpholine,
N-methylmorpholine, piperidine, N-methylpiperidine,
N-ethylpiperidine, dibenzylamine, piperazine, pyridine, pyrrazole,
pipyrrazole, imidazole, pyrazine, or pipyrazine.
[0746] In some embodiments, an ammonium salt is a triethyl amine
salt, a diisopropyl amine salt, an ethanol amine salt, a diethanol
amine salt, a triethanol amine salt, a morpholine salt, an
N-methylmorpholine salt, a piperidine salt, an N-methylpiperidine
salt, an N-ethylpiperidine salt, a dibenzylamine salt, a piperazine
salt, a pyridine salt, a pyrrazole salt, a pipyrrazole salt, an
imidazole salt, a pyrazine salt, or a pipyrazine salt.
[0747] Acid addition salts can arise from the addition of an acid
to a compound of the invention. In some embodiments, the acid is
organic. In some embodiments, the acid is inorganic. In some
embodiments, the acid is hydrochloric acid, hydrobromic acid,
hydroiodic acid, nitric acid, nitrous acid, sulfuric acid,
sulfurous acid, a phosphoric acid, isonicotinic acid, lactic acid,
salicylic acid, tartaric acid, ascorbic acid, gentisinic acid,
gluconic acid, glucaronic acid, saccaric acid, formic acid, benzoic
acid, glutamic acid, pantothenic acid, acetic acid, propionic acid,
butyric acid, fumaric acid, succinic acid, methanesulfonic acid,
ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,
citric acid, oxalic acid, or maleic acid.
[0748] In some embodiments, the salt is a hydrochloride salt, a
hydrobromide salt, a hydroiodide salt, a nitrate salt, a nitrite
salt, a sulfate salt, a sulfite salt, a phosphate salt,
isonicotinate salt, a lactate salt, a salicylate salt, a tartrate
salt, an ascorbate salt, a gentisinate salt, a gluconate salt, a
glucaronate salt, a saccarate salt, a formate salt, a benzoate
salt, a glutamate salt, a pantothenate salt, an acetate salt, a
propionate salt, a butyrate salt, a fumarate salt, a succinate
salt, a methanesulfonate salt, an ethanesulfonate salt, a
benzenesulfonate salt, a p-toluenesulfonate salt, a citrate salt,
an oxalate salt, or a maleate salt.
Antibodies.
[0749] Compounds of the invention can be co-formulated or
co-administered with antibodies, for example, anti-VEGF agents.
Non-limiting examples of such antibodies include ranibizumab,
bevacizumab, and aflibercept.
[0750] An antibody can comprise a heavy chain and a light chain. In
some embodiments, the heavy chain comprises SEQ ID NO:1:
TABLE-US-00022 GluValGlnLeuValGluSerGlyGlyGlyLeuValGlnProGlyGly
SerLeuArgLeuSerCysAlaAlaSerGlyTyrAspPheThrHisTyr
GlyMetAsnTrpValArgGlnAlaProGlyLysGlyLeuGluTrpVal
GlyTrpIleAsnThrTyrThrGlyGluProThrTyrAlaAlaAspPhe
LysArgArgPheThrPheSerLeuAspThrSerLysSerThrAlaTyr
LeuGlnMetAsnSerLeuArgAlaGluAspThrAlaValTyrTyrCys
AlaLysTyrProTyrTyrTyrGlyThrSerHisTrpTyrPheAspVal
TrpGlyGlnGlyThrLeuValThrValSerSerAlaSerThrLysGly
ProSerValPheProLeuAlaProSerSerLysSerThrSerGlyGly
ThrAlaAlaLeuGlyCysLeuValLysAspTyrPheProGluProVal
ThrValSerTrpAsnSerGlyAlaLeuThrSerGlyValHisThrPhe
ProAlaValLeuGlnSerSerGlyLeuTyrSerLeuSerSerValVal
ThrValProSerSerSerLeuGlyThrGlnThrTyrIleCysAsnVal
AsnHisLysProSerAsnThrLysValAspLysLysValGluProLys
SerCysAspLysThrHisLeu.
[0751] In some embodiments, the heavy chain is SEQ ID NO:1.
[0752] In some embodiments, the light chain comprises SEQ ID
NO:2:
TABLE-US-00023 AspIleGlnLeuThrGlnSerProSerSerLeuSerAlaSerValGly
AspArgValThrIleThrCysSerAlaSerGlnAspIleSerAsnTyr
LeuAsnTrpTyrGlnGlnLysProGlyLysAlaProLysValLeuIle
TyrPheThrSerSerLeuHisSerGlyValProSerArgPheSerGly
SerGlySerGlyThrAspPheThrLeuThrIleSerSerLeuGlnPro
GluAspPheAlaThrTyrTyrCysGlnGlnTyrSerThrValProTrp
ThrPheGlyGlnGlyThrLysValGluIleLysArgThrValAlaAla
ProSerValPheIlePheProProSerAspGluGlnLeuLysSerGly
ThrAlaSerValValCysLeuLeuAsnAsnPheTyrProArgGluAla
LysValGlnTrpLysValAspAsnAlaLeuGlnSerGlyAsnSerGln
GluSerValThrGluGlnAspSerLysAspSerThrTyrSerLeuSer
SerThrLeuThrGlnSerSerGlyLeuTyrSerLeuSerSerValVal
ThrValProSerSerSerLeuGlyThrGlnThrTyrIleCysAsnVal
AsnHisLysProSerAsnThrLysValAspLysLysValGluProLys
SerCysAspLysThrHisLeu.
[0753] In some embodiments, the lgith chain is SEQ ID NO:2.
[0754] An antibody used herein can comprise one or both of SEQ ID
NOs: 1 and 2. An antibody used herein can consist of one or both of
SEQ ID NOs: 1 and 2.
Compositions
[0755] Disclosed are compositions and formulations for
administration to a subject having one or more conditions, for
example, one of the ocular diseases or ocular conditions as
described herein. The compositions can comprise, for example:
[0756] a) a compound herein or a pharmaceutically acceptable salt
thereof; and [0757] b) a solubilizing system.
[0758] The disclosed compositions can comprise from about 0.1 mg/mL
to about 100 mg/mL of a compound herein.
Solubilizing Systems
[0759] The disclosed solubilizing systems can comprise one or more
pharmaceutically acceptable agents, which alone or in combination
solubilize a compound herein or a pharmaceutically acceptable salt
thereof.
1. Alcohols
[0760] A non-limiting example of a solubilizing agent includes an
organic solvent. Non-limiting examples of organic solvents
includes: alcohols, for example, C.sub.1-C.sub.4 linear alkyl,
C.sub.3-C.sub.4 branched alkyl, for example, ethanol, glycerin,
2-hydroxypropanol, propylene glycol, maltitol, sorbitol, xylitol
and the like; substituted or unsubstituted C.sub.6 or C.sub.10
aryl; substituted or unsubstituted C.sub.7 or C.sub.14
alkylenearyl, for example, benzyl alcohol.
2. Cyclodextrins
[0761] A further non-limiting example of a solubilizing agent
relates to cyclodextrins: .beta.-cyclodextrin, .beta.-cyclodextrin
and .beta.-cyclodextrin and derivatives thereof. Non-limiting
examples of cyclodextrin derivatives includes methyl
.beta.-cyclodextrin, 2-hydroxypropyl-.beta.-cyclodextrin,
sulfobutyl ether-.beta.-cyclodextrin sodium salt, and
2-hydroxypropyl-.beta.-cyclodextirn. A cyclodextrin can possess a
large cyclic structure with a channel passing through the center of
the structure. The interior of the cyclodextrin can be hydrophobic,
and interact favorably with hydrophobic molecules. The exterior of
the cyclodextrin can be highly hydrophilic owing to the several
hydroxyl groups exposed to bulk solvent. Capture of a hydrophobic
molecule, such as a compound disclosed herein, in the channel of
the cyclodextrin can result in formation of a complex stabilized by
non-covalent hydrophobic interactions. The complex can be soluble
in water, and carry the captures hydrophobic molecule into the bulk
solvent.
3. Polyvinylpyrrolidione
[0762] Another non-limiting example of a solubilizing agent are the
polyvinylpyrrolidones (PVP) having the formula:
##STR00327##
wherein the index n is from about 40 to about 200. PVP's can have
an average molecular weight from about 5500 to about 28,000 g/mol.
One non-limiting example is PVP-10, having an average molecular
weight of approximately 10,000 g/mol.
4. Polyakyleneoxides
[0763] A further non-limiting example of solubilizing agents
includes polyalkyleneoxides, and polymers of alcohols or polyols.
Polymers can be mixed, or contain a single monomeric repeat
subunit. For example, polyethylene glycols having an average
molecular weight of from about 200 to about 20,000, for example,
PEG 200, PEG 400, PEG 600, PEG 1000, PEG 1450, PEG 1500, PEG 4000,
PEG 4600, and PEG 8000. In a further embodiment, the compositions
comprise one or more polyethylene glycols chosen from PEG 400, PEG
1000, PEG 1450, PEG 4600 and PEG 8000.
[0764] Other polyalkyleneoxides are polypropylene glycols having
the formula:
HO[CH(CH.sub.3)CH.sub.2O].sub.xH
wherein the index x represents the average number of propyleneoxy
units in the glycol polymer. As in the case of ethylene glycols,
for propylene glycols the index x can be represented by a whole
number or a fraction. For example, a polypropylene glycol having an
average molecular weight of 8,000 g/mole (PEG 8000) can be equally
represented by the formulae:
HO[CH(CH.sub.3)CH.sub.2O].sub.138H or
HO[CH(CH.sub.3)CH.sub.2O].sub.137.6H
or the polypropylene glycol can be represented by the common, short
hand notation: PEG 8000.
[0765] Another example of polypropylene glycols can have an average
molecular weight from about 1200 g/mol to about 20,000 g/mol, i.e.,
a polypropylene glycol having an average molecular weight of about
8,000 g/mol, for example, PEG 8000. Another solubilizing agent is
Polysorbate 80 (Tween.TM. 80) which is an oleate ester of sorbitol
and its anhydrides copolymerized with approximately 20 moles of
ethylene oxide for each mole of sorbitol and sorbitol anhydrides.
Polysorbate 80 is made up of sorbitan mono-9-octadecanoate
poly(oxy-1,2-ethandiyl) derivatives.
[0766] Solubilizing agents also include poloxamers having the
formula:
HO(CH.sub.2CH.sub.2).sub.y1(CH.sub.2CH.sub.2CH.sub.2O).sub.y2(CH.sub.2CH-
.sub.2O).sub.y3OH
which are nonionic block copolymers composed of a polypropyleneoxy
unit flanked by two polyethyleneoxy units. The indices y.sup.1,
y.sup.2, and y.sup.3 have values such that the poloxamer has an
average molecular weight of from about 1000 g/mol to about 20,000
g/mol (PLURONICS.TM.). These compound are commonly named with the
word Poloxamer followed by a number to indicate the specific
co-polymer, for example Poloxamer 407 having two PEG blocks of
about 101 units (y.sup.1 and y.sup.3 each equal to 101) and a
polypropylene block of about 56 units and poloxamer 185 [CAS No.
9003-11-6] wherein the indices y.sup.1, y.sup.2, and y.sup.3 have
the average values of 19, 30 and 10 respectively. Various
poloxamers are available under the trade name LUTROL.TM., for
example, LUTROL.TM. F-17. Pluronic F-68 is a commercially available
poloxamer. Other non-limiting examples of suitable poloxamers for
use are those such as poloxamer 188, Pluronic F-68, and the
like.
5. Polyoxyethylene Glycol Alkyl Ethers
[0767] Still further solubilizing agents relate to polyoxyethylene
glycol alkyl ethers having the formula:
RO(CH.sub.2CH.sub.2O).sub.nH
wherein R is a linear or branched alkyl group having from 6 to 20
carbon atoms and n is an integer of about 2 to about 20.
[0768] Examples of these compounds are ethoxylate alcohols such as
the NEODOL.TM. ethoxylated alcohols. NEODOL.TM. 23-1 is a mixture
of R units that are C.sub.12 and C.sub.13 in length with an average
of 1 ethoxy unit. Non-limiting examples of ethoxylated alcohols
include NEODOL.TM. 23-1, NEODOL.TM. 23-2, NEODOL.TM. 23-6.5,
NEODOL.TM. 25-3, NEODOL.TM. 25-5, NEODOL.TM. 25-7, NEODOL.TM. 25-9,
PLURONIC.TM. 12R3, and PLURONIC.TM. 25R2.
6. Polyoxypropylene Glycol Alkyl Ethers
[0769] Yet another example of a solubilizing agent includes
polyoxypropylene glycol alkyl ethers having the formula:
RO(CH.sub.2CH(CH.sub.3)O).sub.nH
wherein R is a linear or branched alkyl group having from 6 to 20
carbon atoms and n is an integer of about 2 to about 20.
[0770] The formulator, however, can use any solubilizing agent or
agents in combination to affect the solubility of a compound
herein.
[0771] One aspect of the disclosure relates to compositions and
formulations comprising the herein disclosed compounds or a
pharmaceutically acceptable salt thereof. Compositions containing
the disclosed inhibitors can comprise: [0772] a) a compound herein
or a pharmaceutically acceptable salt thereof; and [0773] b) a
solubilizing system.
[0774] Another aspect of the disclosed compositions relates to
Tie-2 activators or HPTP-.beta. inhibitors or a pharmaceutically
acceptable salt thereof having the formula:
##STR00328##
[0775] wherein R.sup.2 and R.sup.4 are chosen from: [0776] i)
hydrogen; [0777] ii) substituted or unsubstituted C.sub.1-C.sub.6
linear, C.sub.3-C.sub.6 branched, or C.sub.3-C.sub.6 cyclic alkyl;
[0778] iii) substituted or unsubstituted phenyl; or [0779] iv)
substituted or unsubstituted thiophenyl; [0780] R.sup.1 is
C.sub.1-C.sub.6 linear, C.sub.3-C.sub.6 branched, or
C.sub.3-C.sub.6 cyclic alkyl; [0781] R.sup.5a is chosen from:
[0782] i) hydrogen; [0783] ii) C.sub.1-C.sub.6 linear,
C.sub.3-C.sub.6 branched, or C.sub.3-C.sub.6 cyclic alkyl; or
[0784] iii) benzyl; or [0785] a pharmaceutically acceptable salt
thereof.
[0786] A non-limiting embodiment of this aspect relates to
HPTP-.beta. inhibitors having the formula:
##STR00329##
[0787] wherein R.sup.2 and R.sup.4 are chosen from: [0788] i)
hydrogen; [0789] ii) substituted or unsubstituted C.sub.1-C.sub.6
linear, C.sub.3-C.sub.6 branched, or C.sub.3-C.sub.6 cyclic alkyl;
[0790] iii) substituted or unsubstituted phenyl; or [0791] iv)
substituted or unsubstituted thiophenyl; [0792] R.sup.1 is
C.sub.1-C.sub.6 linear, C.sub.3-C.sub.6 branched, or
C.sub.3-C.sub.6 cyclic alkyl; or [0793] a pharmaceutically
acceptable salt.
[0794] An aspect of the disclosed compositions relates to
HPTP-.beta. inhibitors or a pharmaceutically acceptable salt
thereof having the formula:
##STR00330##
[0795] wherein R.sup.2 is chosen from: [0796] i) hydrogen; [0797]
ii) substituted or unsubstituted C.sub.1-C.sub.6 linear,
C.sub.3-C.sub.6 branched, or C.sub.3-C.sub.6 cyclic alkyl; [0798]
iii) substituted or unsubstituted thiophenyl; [0799] R.sup.1 is
C.sub.1-C.sub.3 alkyl substituted by one or more optionally
substituted phenyl; or [0800] a pharmaceutically acceptable salt
thereof.
[0801] In one iteration the substitutions for phenyl are chosen
from fluoro, chloro and methoxy.
[0802] An aspect of the disclosed compositions relates to
HPTP-.beta. inhibitors or a pharmaceutically acceptable salt
thereof having the formula:
##STR00331##
wherein R is chosen from, for example, benzyl, phenylethyl,
(2-methylthiazol-4-yl)methyl,
4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl,
(5-(4-chlorobenzamide)methyl)thiopen-2-yl, and
(5-(methoxycarbonyl)methyl)-1,3,4-thiadiazol-2-yl.
Formulation Example 1
[0803] In one non-limiting example, compositions of compounds
herein are prepared as follows. For example, about 100 mg of a
sterile powder of, for example,
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid is diluted in, for
example, about 100 mL water to form a first composition. To the
composition can be added, for example, 250 mg of hydroxypropyl beta
cyclodextrin (HP.beta.CD). Depending upon the formulation, the
administrator of the compound can withdraw a sufficient amount such
that the subject is injected subcutaneously with an amount that
provides from about 5 mg to about 50 mg of the compound. The
formulator, however, can prepare a composition having any
concentration convenient or desirable. Non-limiting examples
according to this embodiment include the following.
TABLE-US-00024 TABLE XXII Compound HP.beta.CD Water (mg) (mg) (mL)
50 250 25 50 250 50 50 250 75 50 250 100 100 250 25 100 250 50 100
250 75 100 250 100 50 250 200 50 250 300 50 250 400 50 250 500 100
250 200 100 250 300 100 250 400 100 250 500
Formulation Example 2
[0804] This formulation example relates to compositions comprising
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}-phenylsulfamic acid, having the
formula:
##STR00332##
and pharmaceutically acceptable salts thereof.
[0805] Formulation Example 2 comprises: [0806] a)
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof; [0807] b) a solubilizing system; and
[0808] c) a carrier system.
[0809] The compositions of Formulation Example 2 are formulated to
deliver an amount of
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid in the free acid form.
For example, a composition which comprises 10 mg/mL of
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid can have either 10
mg/mL of the free acid or an amount of a pharmaceutically
acceptable salt in an amount sufficient to deliver 10 mg/mL of the
free acid. As an example, a composition formulated to deliver 10
mg/mL of
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenyl-sulfamic acid can comprise either
10 mg/mL of
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiop-
hen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid or alternatively
10.4 mg/mL of the sodium salt, (sodium
(4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenyl-propanamido]-2-(2-(thiop-
hen-2-yl)thiazol-4-yl)ethyl}phenyl)sulfamate). Therefore, a
composition which delivers from about 0.1 mg/mL to about 60 mg/mL
of
(4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-(thioph-
en-2-yl)thiazol-4-yl)ethyl}phenyl)sulfamic acid can comprise an
amount of pharmaceutically acceptable salt thereof to deliver from
about 0.1 mg/mL to about 60 mg/mL of the compound.
[0810] Therefore, when a composition according to Formulation I
comprises an amount of
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid per mL, it is
understood that this amount is the amount of free acid that is
delivered and if a salt form of the compound is used in the
composition, the amount of the salt form can therefore reflect the
difference in molecular weight between the free acid and the salt
form. The following example demonstrates this equivalency.
[0811] A composition delivering 10 mg/mL of
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid, comprises: [0812] a)
10 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-
-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid; or about
10.4 mg/mL of sodium
(4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenyl-propanamido]-2-(2-(thiop-
hen-2-yl)thiazol-4-yl)ethyl}phenyl)sulfamate; or about 10.3 mg/mL
of ammonium
(4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(-
2-(thiophen-2-yl)thiazol-4-yl)ethyl}phenyl)sulfamate, and the like;
[0813] b) an amount of a solubilizing system; and [0814] c) a
carrier system.
[0815] The disclosed compositions according to Formulation Example
2 according to Formulation Example 2 comprise from about 0.1 mg/mL
to about 60 mg/mL of
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof.
[0816] In one aspect the disclosed compositions according to
Formulation Example 2 comprise from about 0.5 mg/mL to about 60
mg/mL of a compound herein or a pharmaceutically acceptable salt
thereof. In one embodiment, the composition comprises from about 5
mg/mL to about 40 mg/mL of a compound herein or a pharmaceutically
acceptable salt thereof. In another embodiment, the composition
comprises from about 10 mg/mL to about 40 mg/mL of a compound
herein or a pharmaceutically acceptable salt thereof. In a further
embodiment, the composition comprises from about 10 mg/mL to about
30 mg/mL of a compound herein or a pharmaceutically acceptable salt
thereof. In a still further embodiment, the composition comprises
from about 0.5 mg/mL to about 20 mg/mL of a compound herein or a
pharmaceutically acceptable salt thereof. In a further embodiment
the composition comprises from about 1 mg/mL to about 20 mg/mL
weight by volume of a compound herein or a pharmaceutically
acceptable salt thereof. In a further embodiment, the composition
comprises from about 15 mg/mL to about 30 mg/mL weight by volume of
a compound herein or a pharmaceutically acceptable salt thereof. In
another embodiment, the composition comprises from about 10 mg/mL
to about 50 mg/mL weight by volume of a compound herein or a
pharmaceutically acceptable salt thereof.
[0817] Particular embodiments of the disclosed compositions
according to Formulation Example 2, can comprise, for example, 1
mg/mL, 2 mg/mL, 3 mg/mL, 4 mg/mL, 5 mg/mL, 6 mg/mL, 7 mg/mL, 8
mg/mL, 9 mg/mL, 10 mg/mL, 11 mg/mL 12 mg/mL, 13 mg/mL, 14 mg/mL, 15
mg/mL, 16 mg/mL, 17 mg/mL, 18 mg/mL, 19 mg/mL, 20 mg/mL, 21 mg/mL,
22 mg/mL, 23 mg/mL, 24 mg/mL, 25 mg/mL, 26 mg/mL, 27 mg/mL, 28
mg/mL, 29 mg/mL, 30 mg/mL, 31 mg/mL 32 mg/mL, 33 mg/mL, 34 mg/mL,
35 mg/mL, 36 mg/mL, 37 mg/mL, 38 mg/mL, 39 mg/mL, 40 mg/mL, 41
mg/mL 42 mg/mL, 43 mg/mL, 44 mg/mL, 45 mg/mL, 46 mg/mL, 47 mg/mL,
48 mg/mL, 49 mg/mL, 50 mg/mL, 51 mg/mL 52 mg/mL, 53 mg/mL, 54
mg/mL, 55 mg/mL, 56 mg/mL, 57 mg/mL, 58 mg/mL, 59 mg/mL, and 60
mg/mL, about 1 mg/mL, about 2 mg/mL, about 3 mg/mL, about 4 mg/mL,
about 5 mg/mL, about 6 mg/mL, about 7 mg/mL, about 8 mg/mL, about 9
mg/mL, about 10 mg/mL, about 11 mg/mL about 12 mg/mL, about 13
mg/mL, about 14 mg/mL, about 15 mg/mL, about 16 mg/mL, about 17
mg/mL, about 18 mg/mL, about 19 mg/mL, about 20 mg/mL, about 21
mg/mL about 22 mg/mL, about 23 mg/mL, about 24 mg/mL, about 25
mg/mL, about 26 mg/mL, about 27 mg/mL, about 28 mg/mL, about 29
mg/mL, about 30 mg/mL, about 31 mg/mL about 32 mg/mL, about 33
mg/mL, about 34 mg/mL, about 35 mg/mL, about 36 mg/mL, about 37
mg/mL, about 38 mg/mL, about 39 mg/mL, about 40 mg/mL, about 41
mg/mL about 42 mg/mL, about 43 mg/mL, about 44 mg/mL, about 45
mg/mL, about 46 mg/mL, about 47 mg/mL, about 48 mg/mL, about 49
mg/mL, about 50 mg/mL, about 51 mg/mL about 52 mg/mL, about 53
mg/mL, about 54 mg/mL, about 55 mg/mL, about 56 mg/mL, about 57
mg/mL, about 58 mg/mL, about 59 mg/mL, and about 60 mg/mL of the
compound herein.
[0818] A formulation that is disclosed herein can be made more
soluble by the addition of an additive or agent. The improvement of
solubility of the formulation can increase by about 5%, about 10%,
about 15%, about 20%, about 25%, about 30%, about 35%, about 40%,
about 45%, about 50%, about 55%, about 60%, about 65%, about 70%,
about 75% about 80%, about 85%, about 90%, about 95%, about 100%,
about 110%, about 120%, about 130%, about 140%, about 150%, about
160%, about 170%, about 180%, about 190%, about 200%, about 225%,
about 250%, about 275%, about 300%, about 325%, about 350%, about
375%, about 400%, about 450%, or about 500%.
[0819] A formulation disclosed herein can be stable for about 1
day, about 2 days, about 3 days, about 4 days, about 5 days, about
6 days, about 7 days, about 8 days, about 9 days, about 10 days,
about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about
10 weeks, about 12 weeks, about 3 months, about 4 months, about 5
months, about 6 months, about 7 months, about 8 months, about 9
months, about 10 months, about 11 months, or about one year. A
formulation disclosed herein can be stable, for example, at about
0.degree. C., about 5.degree. C., about 10.degree. C., about
15.degree. C., about 20.degree. C., about 25.degree. C., about
30.degree. C., about 35.degree. C., about 40.degree. C., about
45.degree. C., about 50.degree. C., about 60.degree. C., about
70.degree. C., or about 80.degree. C.
Solubilizing Systems.
[0820] The disclosed compositions according to Formulation Example
2 can comprise, for example, from a ratio of about 1 part of a
compound herein or a pharmaceutically acceptable salt thereof to 4
parts solubilizing system (1:4) to about 1 part of the compound or
a pharmaceutically acceptable salt thereof to about 8 parts
solubilizing system (1:8). The disclosed solubilizing systems
comprise 2-hydroxypropyl-beta-cyclodextrin (HP.beta.-CD).
2-Hydroxypropyl-.beta.-cyclodextrin [CAS No. 128446-35-5] is
commercially available as Cavitron.TM..
2-Hydroxypropyl-.beta.-cyclodextrin, also described herein as
hydroxypropyl-.beta.-cyclodextrin,
2-hydroxypropyl-beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin
or HP.beta.CD, can be represented by either of the following
formulae:
##STR00333##
[0821] The average molecular weight of HP.beta.CD as provided under
the name Cavitron.TM., is approximately 1396 Da wherein the average
degree of substitution is from about 0.5 to about 1.3 units of
2-hydroxypropyl per ring glucose unit. For calculation purposes it
is convenient for the formulator to use 1400 Da as the molecular
weight of HP.beta.CD.
[0822] For example, a composition according to Formulation Example
2 comprising from about 0.1 mg/mL to about 60 mg/mL of the compound
or a pharmaceutically acceptable salt thereof can comprise from
about 0.25 mg/mL to about 500 mg/mL of HP.beta.CD. Stated another
way, a composition comprising about 10 mg/mL of a disclosed
composition can comprise from 40 mg/mL (1:4) to about 80 mg/mL
(1:8) of HP.beta.CD. The formulator can adjust the ratios of
compound to HP.beta.CD based upon composition parameters, for
example, choice and amount of a tonicity agent, pH, and the
like.
[0823] The following are non-limiting examples of ratios of
compound or a pharmaceutically acceptable salt and HP.beta.CD: 1:4,
1:4.1, 1:4.2, 1:4.3, 1:4.4; 1:4.5, 1:4.6, 1:4.7, 1:4.8, 1:4.9, 1:5,
1:5.1, 1:5.2, 1:5.3, 1:5.4; 1:5.5, 1:5.6, 1:5.7, 1:5.8, 1:5.9, 1:6,
1:6.1, 1:6.2, 1:6.3, 1:6.4; 1:6.5, 1:6.6, 1:6.7, 1:6.8, 1:6.9, 1:7,
1:7.1, 1:7.2, 1:7.3, 1:7.4; 1:7.5, 1:7.6, 1:7.7, 1:7.8, 1:7.9, and
1:8, or alternatively, about 1:4, about 1:4. about 1, about 1:4.2,
about 1:4.3, about 1:4.4; about 1:4.5, about 1:4.6, about 1:4.7,
about 1:4.8, about 1:4.9, about 1:5, about 1:5. about 1, about
1:5.2, about 1:5.3, about 1:5.4; about 1:5.5, about 1:5.6, about
1:5.7, about 1:5.8, about 1:5.9, about 1:6, about 1:6.1, about
1:6.2, about 1:6.3, about 1:6.4; about 1:6.5, about 1:6.6, about
1:6.7, about 1:6.8, about 1:6.9, about 1:7, about 1:7.1, about
1:7.2, about 1:7.3, about 1:7.4; about 1:7.5, about 1:7.6, about
1:7.7, about 1:7.8, about 1:7.9, and about 1:8.
[0824] As such, the compositions can comprise an amount of
HP.beta.CD suitable for achieving the desired properties of the
composition, i.e., concentration of a compound, such as
4-{(S)-2-[(S)-2-methoxy-carbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid, the desired
viscosity, and the desired osmolarity. The amount of HP.beta.CD can
vary depending upon the amount of the compound that the formulator
desires to deliver in a single dose.
Carrier System
[0825] The disclosed compositions according to Formulation Example
2 comprise from about 1.35% to about 90% weight by volume of a
carrier system. The amount of carrier system present is based upon
several different factors or choices made by the formulator, for
example, the final concentration of the compound and the amount of
solubilizing agent.
[0826] The following is a non-limiting example of a composition
comprising 15 mg/mL of
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid: [0827] a) 15 mg of
the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid; [0828] b) 93.75 mg of
2-hydroxypropyl-beta-cyclodextrin; and [0829] c) the balance a
carrier system to a volume of 1 mL.
[0830] In one aspect, the carrier system comprises: [0831] i) one
or more tonicity agents; and [0832] ii) water.
[0833] Non-limiting examples of tonicity agents include dextrose,
mannitol and glycerin. The formulator can utilize more than one
tonicity agent when formulating the disclosed compositions
according to Formulation Example 2. The tonicity agent can comprise
from about 0.5% to about 5% weight by volume of the final
composition. In non-limiting examples, when preparing the final
composition, the tonicity agent may be combined with
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid before mixing with the
carrier system. Alternately, when reconstituting the final
composition the formulator can use commercially available solutions
containing a tonicity agent, for example, 5% Dextrose Injection,
USP.
[0834] The osmolarity of the disclosed compositions according to
Formulation Example 2 can be within any range chosen by the
formulator. In one aspect the osmolarity is from about 250 to about
350 mOsm/L. In one embodiment of this aspect of the disclosed
osmolarity is from about 270 to about 310 mOsm/L.
[0835] The pH of the disclosed compositions according to
Formulation Example 2 can be from about 6 to about 8. If the pH is
outside the range desired by the formulator, the pH can be adjusted
by using sufficient pharmaceutically-acceptable acids and
bases.
[0836] One aspect of the disclosed compositions according to
Formulation Example 2 relates to compositions comprising
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid or pharmaceutically
acceptable salts thereof.
[0837] One embodiment of this aspect of the disclosed compositions
according to Formulation Example 2 comprises: [0838] a) from about
9.5 mg/mL to about 10.5 mg/mL of the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof; [0839] b) from about 59 mg/mL to about
65.5 mg/mL of 2-hydroxypropyl-.beta.-cyclodextrin; and [0840] c) a
carrier system.
[0841] A non-limiting iteration of this embodiment of the disclosed
compositions according to Formulation Example 2 comprises: [0842]
a) about 10 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid; [0843] b) about 62.5
mg/mL of 2-hydroxypropyl-.beta.-cyclodextrin; and [0844] c) a
carrier system.
[0845] One specific example of a composition according to this
iteration comprises: [0846] a) 10 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid; [0847] b) 62.5 mg/mL
of 2-hydroxypropyl-.beta.-cyclodextrin; and [0848] c) a carrier
system containing: [0849] i) 2% weight to volume of the composition
dextrose; and [0850] ii) water. [0851] c) a carrier system
containing: [0852] i) dextrose; and [0853] ii) water [0854] wherein
the dextrose is present in an amount such that the concentration of
dextrose in the final composition is 2%.
[0855] Another embodiment of this aspect of the disclosed
compositions according to Formulation Example 2 comprises: [0856]
a) from about 14 mg/mL to about 16 mg/mL of the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof; [0857] b) from about 87.5 mg/mL to about
100 mg/mL of 2-hydroxypropyl-.beta.-cyclodextrin; and [0858] c) a
carrier system.
[0859] A non-limiting iteration of this embodiment of the disclosed
compositions according to Formulation Example 2 comprises: [0860]
a) about 15 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid; [0861] b) about
93.75 mg/mL of 2-hydroxypropyl-.beta.-cyclodextrin; and [0862] c) a
carrier system.
[0863] One specific example of a composition according to this
iteration comprises: [0864] a) 15 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid; [0865] b) 93.75
mg/mL of 2-hydroxypropyl-.beta.-cyclodextrin; and [0866] c) a
carrier system containing: [0867] i) 2% weight to volume of the
composition dextrose; and [0868] ii) water.
[0869] A further embodiment of this aspect of the disclosed
compositions according to Formulation Example 2 comprises: [0870]
a) from about 18.5 mg/mL to about 21.5 mg/mL of the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof; [0871] b) from about 115.6 mg/mL to about
134.5 mg/mL of 2-hydroxypropyl-.beta.-cyclodextrin; and [0872] c) a
carrier system.
[0873] A non-limiting iteration of this embodiment of the disclosed
compositions according to Formulation Example 2 comprises: [0874]
a) about 20 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid; [0875] b) about 125
mg/mL of 2-hydroxypropyl-.beta.-cyclodextrin; and [0876] c) a
carrier system.
[0877] One specific example of a composition according to this
iteration comprises: [0878] a) 20 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid; [0879] b) 125 mg/mL
of 2-hydroxypropyl-.beta.-cyclodextrin; and [0880] c) a carrier
system containing: [0881] i) 2% weight to volume of the composition
dextrose; and [0882] ii) water.
[0883] A further embodiment of this aspect of the disclosed
compositions according to Formulation Example 2 comprises: [0884]
a) from about 24 mg/mL to about 26 mg/mL of the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof; [0885] b) from about 150 mg/mL to about
162.5 mg/mL of 2-hydroxypropyl-.beta.-cyclodextrin; and [0886] c) a
carrier system.
[0887] A non-limiting iteration of this embodiment of the disclosed
compositions according to Formulation Example 2 comprises: [0888]
a) about 25 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid; [0889] b) about
156.25 mg/mL of 2-hydroxypropyl-.beta.-cyclodextrin; and [0890] c)
a carrier system.
[0891] One specific example of a composition according to this
iteration comprises: [0892] a) 25 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid; [0893] b) 156.25
mg/mL of 2-hydroxypropyl-.beta.-cyclodextrin; and [0894] c) a
carrier system containing: [0895] i) 2% weight to volume of the
composition dextrose; and [0896] ii) water.
[0897] A further embodiment of this aspect of the disclosed
compositions according to Formulation Example 2 comprises: [0898]
a) from about 27.5 mg/mL to about 32 mg/mL of the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof; [0899] b) from about 170 mg/mL to about
200 mg/mL of 2-hydroxypropyl-.beta.-cyclodextrin; and [0900] c) a
carrier system.
[0901] A non-limiting iteration of this embodiment of the disclosed
compositions according to Formulation Example 2 comprises: [0902]
a) about 30 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid; [0903] b) about
187.5 mg/mL of 2-hydroxypropyl-.beta.-cyclodextrin; and [0904] c) a
carrier system.
[0905] One specific example of a composition according to this
iteration comprises: [0906] a) 30 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid; [0907] b) 187.5
mg/mL of 2-hydroxypropyl-.beta.-cyclodextrin; and [0908] c) a
carrier system containing: [0909] i) 2% weight to volume of the
composition dextrose; and [0910] ii) water.
[0911] Another embodiment of this aspect of the disclosed
compositions according to Formulation Example 2 comprises: [0912]
a) from about 34 mg/mL to about 36 mg/mL of the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof; [0913] b) from about 212.5 mg/mL to about
223.5 mg/mL of 2-hydroxypropyl-.beta.-cyclodextrin; and [0914] c) a
carrier system.
[0915] A non-limiting iteration of this embodiment of the disclosed
compositions according to Formulation Example 2 comprises: [0916]
a) about 35 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid; [0917] b) about
218.75 mg/mL of 2-hydroxypropyl-.beta.-cyclodextrin; and [0918] c)
a carrier system.
[0919] One specific example of a composition according to this
iteration comprises: [0920] a) 35 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid; [0921] b) 218.75
mg/mL of 2-hydroxypropyl-.beta.-cyclodextrin; and [0922] c) a
carrier system containing: [0923] i) 2% weight to volume of the
composition dextrose; and [0924] ii) water.
[0925] Another embodiment of this aspect of the disclosed
compositions according to Formulation Example 2 comprises: [0926]
a) from about 38 mg/mL to about 42 mg/mL of the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof; [0927] b) from about 237.5 mg/mL to about
262.5 mg/mL of 2-hydroxypropyl-.beta.-cyclodextrin; and [0928] c) a
carrier system.
[0929] A non-limiting iteration of this embodiment of the disclosed
compositions according to Formulation Example 2 comprises: [0930]
a) about 40 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid; [0931] b) about 250
mg/mL of 2-hydroxypropyl-.beta.-cyclodextrin; and [0932] c) a
carrier system.
[0933] One specific example of a composition according to this
iteration comprises: [0934] a) 40 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid; [0935] b) 250 mg/mL
of 2-hydroxypropyl-.beta.-cyclodextrin; and [0936] c) a carrier
system containing: [0937] i) 2% weight to volume of the composition
dextrose; and [0938] ii) water.
Example 25
[0939] To a 100 mL volumetric flask containing water (85 mL) was
charged HP.beta.CD (10 g) and dextrose (1.5 g). The solution was
stirred for 1 hour at 20.degree. C. then the volume made up to 100
mL with additional distilled water. The resulting solution
comprised 10% HP.beta.CD and 1.5% dextrose.
[0940] In a like manner, solutions comprising 15% HP.beta.CD/1.5%
dextrose and 17.5% HP.beta.CD/1.5% dextrose were prepared. These
stock solutions were used for the following experiments.
[0941] In a 25 mL volumetric flask is added the stock solution
comprising 10% HP.beta.CD/1.5% dextrose followed by the addition of
sodium
4-{(S)-2-[(S)-2-(methoxy-carbonylamino)-3-phenylpropanamido]-2-[2-(thioph-
en-2-yl)thiazol-4-yl]ethyl}phenyl-sulfamate (550 mg). The total
volume was made up to 25 mL by the addition of distilled water. The
resulting solution had a nominal concentration of
4-{(S)-2-[(S)-2-methoxy-carbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid of 20 mg/mL after
applying a molecular weight correction factor.
[0942] Similarly, to a stock solution comprising 10%
HP.beta.CD/1.5% dextrose was added
4-{(S)-2-[(S)-2-(methoxy-carbonylamino)-3-phenylpropanamido]-2-[2-(thioph-
en-2-yl)thiazol-4-yl]ethyl}phenyl-sulfamate (687 mg). After
dilution to 25 mL the resulting solution had a nominal
concentration of
4-{(S)-2-[(S)-2-methoxy-carbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}phenyl-sulfamic acid of 25 mg/mL after
applying a molecular weight correction factor.
[0943] Compositions comprising 15% HP.beta.CD/1.5% dextrose and 687
mg and 825 mg of
4-{(S)-2-[(S)-2-(methoxy-carbonylamino)-3-phenylpropanamido]-2--
[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenyl-sulfamate were also
prepared. Likewise, compositions comprising 17.5% HP.beta.CD/1.5%
dextrose and 825 mg and 962.5 mg of Compound A-Na were also
prepared.
[0944] The following Table XXIII describes the test compositions
each totaling 25 mL wherein
4-{(S)-2-[(S)-2-(methoxy-carbonylamino)-3-phenylpropanamido]-2-[2-(thioph-
en-2-yl)thiazol-4-yl]ethyl}phenyl-sulfamate is listed as Compound
A-Na.
TABLE-US-00025 TABLE XXIII Stock Solution 10% 15% 17.5% HP.beta.CD/
HP.beta.CD/ HP.beta.CD/ 1.5% dex. 1.5% dex. 1.5% dex. Comp 550 687
687 825 825 962.5 A-Na (mg) Comp A 20 25 25 30 30 35 mg/mL
[0945] To 3 one-dram vials was transferred approximately 3 mL of
each of the 6 solutions above. One vial of each was held at
4.degree. C., 20.degree. C. and 40.degree. C. The vials were
evaluated weekly for one month then monthly for three months.
[0946] After 3 months none of the vials appeared hazy or had any
precipitate or flocculent. The above compositions where then
further processed and submitted for in vivo testing.
Preparation of Compositions for Subcutaneous Deliver Via 0.75 mL
Single Use Syringes
Example 26
[0947] To 200 mL of Mille-Q water was added
2-hydroxypropyl-.beta.-cyclodextrin (50 g) (Ashland/ISP Cavitron
W7HP7) with stirring. Next, dextrose (96%) (1.3 g) (Sigma Aldrich)
was added and the solution was stirred until all the solids were
dissolved. Sodium
(4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-(2-thio-
phen-2-yl)thiazol-4-yl)ethyl}phenyl)-sulfamate (10.82 g) was added
and the solution was stirred until the solids were dissolved. The
resulting solution had a pH value of 7.26 and a density of 1.07
g/mL. Final solution filtered through Millipore.TM. MilliPak
20-0.22 micron PVDF filter. A calibrated peristaltic pump was used
to dispense 0.75 mL of the final solution into HYpak 0.75 mL
syringes having 27 g staked needles and Hypak FluroTec
stoppers.
Example 27
[0948] To 200 mL of Milli-Q water was added
2-hydroxypropyl-.beta.-cyclodextrin (43.75 g) (Ashland/ISP Cavitron
W7HP7) with stirring. Next, Dextrose (96%) (2.61 g) (Sigma Aldrich)
was added and the solution was stirred until all the solids were
dissolved. Sodium
(4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2--
(2-thiophen-2-yl)thiazol-4-yl)ethyl}phenyl)-sulfamate (10.85 g) was
added and the solution was stirred until the solids were dissolved.
The resulting solution had a pH value of 7.32 which was adjusted to
7.04 with 1N HCl (0.5 mL). The final solution had a density of
1.064 g/mL. Final solution filtered through Millipore.TM. MilliPak
20-0.22 micron PVDF filter. A calibrated peristaltic pump was used
to dispense 0.75 mL of the final solution into HYpak 0.75 mL
syringes having 27 g staked needles and Hypak FluroTec
stoppers.
Example 28
[0949] To 200 mL of Milli-Q water was added
2-hydroxypropyl-.beta.-cyclodextrin (56.25 g) (Ashland/ISP Cavitron
W7HP7) with stirring. Next, Dextrose (96%) (1.3 g) (Sigma Aldrich)
was added and the solution was stirred until all the solids were
dissolved. Sodium
(4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2--
(2-thiophen-2-yl)thiazol-4-yl)ethyl}phenyl)-sulfamate (10.86 g) was
added and the solution was stirred until the solids were dissolved.
The resulting solution had a pH value of 7.24 and a density of
1.074 g/mL. Final solution filtered through Millipore.TM. MilliPak
20-0.22 micron PVDF filter. A calibrated peristaltic pump was used
to dispense 0.75 mL of the final solution into HYpak 0.75 mL
syringes having 27 g staked needles and Hypak FluroTec
stoppers.
[0950] In the above examples, the formulator can alternatively heat
the solution to about 40.degree. C. to aid in solubilizing the
components. In addition, the formulator can filter the solutions at
any point in the process to remove any undissolved material.
[0951] The following is a non-limiting example of the process for
preparing a pharmaceutical composition suitable for subcutaneous
delivery of the disclosed compositions according to Formulation
Example 2 comprising
4-{(S)-2-[(S)-2-methoxy-carbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt to humans.
Step-Wise Manufacturing Process: 20 mg of
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid Per mL Solution
[0952] 1. Add approximately 16.0 kg of United States Pharmacopeia
(USP) Sterile Water for Injection to an appropriately-sized glass
vessel. [0953] 2. Add 2812.5 g of
2-hydroxylpropyl-beta-cyclodextrin (HP.beta.CD) (USP) to the glass
flask and mix for a minimum of 5 minutes or until dissolved. [0954]
3. Add 450 g of
4-{(S)-2-[(S)-2-methoxy-carbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}phenyl-sulfamic acid (as the sodium salt
factored for purity, volatiles and water) to the glass flask and
mix for a minimum of 30 minutes or until all of the solids are
dissolved. [0955] 4. Add 450 g of D-glucose (Dextrose) Anhydrous
(USP) to the glass flask and mix for a minimum of 5 minutes or
until all of the solids are dissolved. [0956] 5. Transfer the
solution to a 36 L glass formulation vessel using a peristaltic
pump. [0957] 6. QS the formulation to 22.7 kg by adding Sterile
Water for Injection, USP and mix for a minimum of 30 minutes or
until dissolved. [0958] 7. Adjust the pH to obtain a pH of 6.6-7.0.
[0959] 8. Add sufficient quantities of Sterile Water for Injection,
USP to the batch to obtain the final batch weight of 23.7 kg (22.5
L*1.052 g/mL-specific gravity) and mix for a minimum of 10 minutes
or until all of the solids are dissolved. [0960] 9. Filter through
two filters (Sartopore 2 XLG Midicap filters) connected in series
into a similar 36 L glass fill vessel. [0961] 10. Fill into various
syringes: i.e., 0.75 mL syringe (to deliver 15 mg of
4-{(S)-2-[(S)-2-methoxy-carbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}phenyl-sulfamic acid), 1 mL syringe (20
mg of
4-{(S)-2-[(S)-2-methoxy-carbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}phenyl-sulfamic acid), etc.
Dry Compositions
[0962] The disclosed compositions according to Formulation Example
2 can be re-constituted from a dry or solid composition. As such
the dry or solid compositions comprise: [0963] a)
4-{(S)-2-[(S)-2-methoxy-carbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}phenyl-sulfamic acid or a
pharmaceutically acceptable salt thereof; and [0964] b)
HP.beta.CD.
[0965] The dry compositions are prepared such that upon
re-constitution with a carrier system described herein, the
resulting aqueous composition delivers from about 0.5 mg/mL to
about 60 mg/mL of the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof.
[0966] As in the aqueous compositions described herein, the ratio
of the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid to HP.beta.CD is from
about 1:4 to about 1:8. The amount of dry material in a container
that can be reconstituted can vary depending upon the number of
doses of dry material desired. For example, a single 15 mg/mL dose
of the compound can be sealed or otherwise placed in a container
that has an exact volume such that when the composition is
re-constituted, an amount of composition that is reconstituted has
15 mg/mL of a compound.
[0967] In another embodiment, the dry compositions comprise: [0968]
a)
4-{(S)-2-[(S)-2-methoxy-carbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}phenyl-sulfamic acid or a
pharmaceutically acceptable salt thereof; [0969] b) HP.beta.CD; and
[0970] c) a tonicity agent; wherein the ratio of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid to HP.beta.CD is from
about 1:4 to about 1:8 and the tonicity agent is present in an
amount such that the re-constituted formula comprises from about
0.5% to about 5% weight to volume of the tonicity agent.
[0971] The use of further solubilizing agents was examined. In a
first test of further solubilizing agents, polyvinylpyrrolidone
(PVP) having the formula:
##STR00334##
wherein the index n is from about 40 to about 200 was tested. PVP's
have an average molecular weight from about 5500 to about 28,000
g/mol. One non limiting example is PVP-10 having an average
molecular weight of approximately 10,000 g/mol available from
Sigma-Aldrich.
[0972] The follow experiments were undertaken to determine the
suitability of formulating a composition comprising PVP and
HP.beta.CD as a solubilizing system for sodium
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}phenylsulfamate. The following is a
non-limiting example.
Example 29
[0973] To a 25 mL volumetric flask containing 20 mL of distilled
water is charged hydroxylpropyl-.beta.-cyclodextrin (2.5 g) and
polyvinylpyrrolidone, PVP-10, (0.125 g) and the solution stirred at
room temperature for 0.5 hours. Additional water was added to bring
the final volume to 25 mL. The following compositions were prepared
according to this procedure.
TABLE-US-00026 TABLE XXIV Experiment HP.beta.CD PVP-10 No.
Concentration (g) (g) 1 10% HP.beta.CD + 0.5% PVP 2.5 0.125 2 10%
HP.beta.CD + 1.0% PVP 2.5 0.25 3 10% HP.beta.CD + 2.0% PVP 2.5 0.5
4 15% HP.beta.CD + 0.5% PVP 3.75 0.125 5 15% HP.beta.CD + 1.0% PVP
3.75 0.25 6 15% HP.beta.CD + 2.0% PVP 3.75 0.5
[0974] To each solution was added sodium
(4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-(thioph-
en-2-yl)thiazol-4-yl)ethyl}-phenyl)sulfamate (1300 mg) was added to
solutions 1, 2 and 3 and stirred for 6 hours at room temperature to
provide a nominal concentration of 52 mg/mL. Similarly, the
compound (1500 mg) was added to solutions 4 5, and 6 and stirred
for 6 hours at room temperature to provide a nominal concentration
of 60 mg/mL. Table XXV lists the solution obtained herein
below.
TABLE-US-00027 TABLE XXV Experiment Comp. A-Na HP.beta.CD PVP-10
No. mg/mL mg/mL mg/mL 7 52 100 5 8 52 100 10 9 52 100 20 10 60 150
5 11 60 150 10 12 60 150 20
Summary of Results
[0975] All compositions comprising polyvinylpyrrolidones were hazy
upon 2 hours of standing or yielded a suspension. Experiments 10,
11 and 12 yielded a gel upon standing. Compositions formulated in
the manner of Example 30 having only a PVP (no HP.beta.CD) formed a
hazy initial solution that setup as a gel and remained such upon
standing for 3 days.
[0976] In one aspect of the disclosed compositions according to
Formulation Example 2, the compositions do not comprise
poylvinylpyrrolidone or a derivative thereof. Compositions which
gel upon standing cannot be injected parentally, e.g.,
subcutaneously and, therefore, are incompatible with the disclosed
compositions according to Formulation Example 2. This is because
the temperature during shipment and storage of the compositions
result in physical properties, i.e., formation of a gel that cannot
be administered by the artisan.
[0977] In a further aspect of the disclosed compositions according
to Formulation Example 26, the compositions do not comprise
poylvinylpyrrolidone or a derivative thereof in combination with
2-hydroxypropyl-.beta.-cyclodextrin.
[0978] The follow experiments were undertaken to determine the
suitability of formulating a composition comprising a quaternary
ammonium salt, PVP and HP.beta.CD as a solubilizing system for
sodium
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamate. The following is a
non-limiting example.
Preparation of Stock Solution
[0979] Benzalkonium chloride (BAC; alkylbenzyldimethylammonium
chloride, alkyl: C.sub.8-C.sub.18 available from Sigma-Aldrich)
(36.3 mg) was added to water (200 mL) in a 250 mL volumetric flask.
The mixture was stirred for 10 hours in a 35.degree. C. water bath
until the solution was clear. 2-Hydroxy-propyl-.beta.-cyclodextrin
(27.5 g) was added and the volume made up to 250 mL with the
addition of more water.
Example 30
[0980] To a 25 mL volumetric flask is added the stock solution
(22.8 mL followed by polyvinylpyrrolidone (Povidone 437190.TM. ex
Sigma-Aldrich) (0.25 g) and sodium
(4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-(2-(thi-
ophen-2-yl)thiazol-4-yl)ethyl}phenyl)-sulfamate (1.14 g). The
volume was made up to 25 mL with the addition of more stock
solution. The resulting suspension was stirred for 1 hour at
20.degree. C. The solution was filtered through 0.65 micron then
0.45 micron filter paper and 5 mL of the filtrate was transferred
to 3 separate vials. One vial was held at each of the following
temperatures 4.degree. C., 20.degree. C. and 40.degree. C.
Example 31
[0981] To a 25 mL volumetric flask is added the stock solution
(22.8 mL followed by polyvinylpyrrolidone (Povidone 437190.TM. ex
Sigma-Aldrich) (0.375 g) and sodium
(4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-(2-(thi-
ophen-2-yl)thiazol-4-yl)ethyl}phenyl)-sulfamate (1.14 g). The
volume was made up to 25 mL with the addition of more stock
solution. The resulting suspension was stirred for 1 hour at
20.degree. C. The solution was filtered through 0.65 micron then
0.45 micron filter paper, however, the flow rate was extremely
slow. 5 mL of the filtrate was transferred to 3 separate vials. One
vial was held at each of the following temperatures 4.degree. C.,
20.degree. C. and 40.degree. C.
Example 32
[0982] To a 25 mL volumetric flask is added the stock solution
(22.8 mL followed by polyvinylpyrrolidone (Povidone 437190.TM. ex
Sigma-Aldrich) (0.5 g) and sodium
(4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-(2-(thi-
ophen-2-yl)thiazol-4-yl)ethyl}phenyl)-sulfamate (1.43 g). The
volume was made up to 25 mL with the addition of more stock
solution. The resulting suspension was stirred for 1 hour at
20.degree. C. Attempt to filter solution through 0.65 micron then
0.45 micron filter paper and 5 mL of the filtrate was unsuccessful.
Example 9 was abandoned.
[0983] Table XXVI below outlines the compositions of Examples 7-9:
sodium
4-{(S)-2-[(S)-2-methoxy-carbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}phenylsulfamate is referred to as Compd
A-Na in the table.
TABLE-US-00028 TABLE XXVI Ex. 11 Ex. 12 Ex. 13 Components (mg/mL)
(mg/mL) (mg/mL) Compd A-Na 40 40 50 PVP 10 15 20 BAC 0.13 0.13 0.13
HP.beta.CD 100 100 100
Summary of Results
[0984] Example 7: 4.degree. C. sample gelled and remained so for 8
days. [0985] 20.degree. C. a suspension was observed. [0986]
40.degree. C. solution remained clear for 8 days.
[0987] Example 8: 4.degree. C. sample gelled and remained so for 8
days. [0988] 20.degree. C. the solution appeared hazy. [0989]
40.degree. C. solution remained clear for 8 days.
[0990] In some embodiments of the disclosed compositions according
to Formulation Example 2, the compositions do not comprise
benzalkonium chloride or other quaternary ammonium salt. In some
embodiments of the disclosed compositions according to Formulation
Example 2, the compositions do comprise benzalkonium chloride or
other quaternary ammonium salt.
[0991] In a further aspect of the disclosed compositions according
to Formulation Example 2, in some embodiments, the compositions do
comprise benzalkonium chloride or other quaternary ammonium salt in
combination with 2-hydroxy-propyl-.beta.-cyclodextrin, and in some
embodiments, the compositions do not comprise benzalkonium chloride
or other quaternary ammonium salt in combination with
2-hydroxy-propyl-.beta.-cyclodextrin.
[0992] In a still further aspect of the disclosed compositions
according to Formulation Example 2, in some embodiments, the
compositions do comprise benzalkonium chloride or other quaternary
ammonium salt in combination with polyvinylpyrrolidone or a
derivative thereof, and in some embodiments, the compositions do
not comprise benzalkonium chloride or other quaternary ammonium
salt in combination with polyvinylpyrrolidone or a derivative
thereof.
[0993] In a yet further aspect of the disclosed compositions
according to Formulation Example 2, in the some embodiments, the
compositions do comprise benzalkonium chloride or other quaternary
ammonium salt in combination with polyvinylpyrrolidone or a
derivative thereof and 2-hydroxypropyl-.beta.-cyclodextrin, and in
some embodiments, the compositions do not comprise benzalkonium
chloride or other quaternary ammonium salt in combination with
polyvinylpyrrolidone or a derivative thereof and
2-hydroxypropyl-.beta.-cyclodextrin.
[0994] Some embodiments do, and some embodiments do not contain
polyethylene glycol. Non-limiting examples of polyethylene glycols
include those having an average molecular weight of from about 200
to about 20,000, for example, PEG 200, PEG 400, PEG 600, PEG 1000,
PEG 1450, PEG 1500, PEG 4000, PEG 4600, and PEG 8000. In a further
embodiment, the compositions comprise one or more polyethylene
glycols chosen from PEG 400, PEG 1000, PEG 1450, PEG 4600 and PEG
8000. Non-limiting examples include any disclosed herein.
[0995] The disclosed compositions according to Formulation Example
2 optionally comprise from about 0.001% to about 0.5%, or from
about 0.001% to about 1% weight by volume pharmaceutically
acceptable preservatives. One non-limiting example of a suitable
preservative is benzyl alcohol.
[0996] In some embodiments, the compositions according to Formula
Example 1 consists essentially of
4-{(S)-2-[(S)-2-methoxy-carbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof, a solubilizing system and a carrier
system.
[0997] In some embodiments, the compositions according to Formula
Example 1 consists of
4-{(S)-2-[(S)-2-methoxy-carbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof, a solubilizing system and a carrier
system.
[0998] In some embodiments, the compositions according to Formula
Example 1 consists essentially of
4-{(S)-2-[(S)-2-methoxy-carbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof, a solubilizing system and a carrier
system, wherein the solubilizing system consists of HP.beta.CD.
[0999] In still other embodiments, the compositions according to
Formula Example 1 consists essentially of
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenyl-sulfamic acid or a pharmaceutically
acceptable salt thereof, a solubilizing system and a carrier system
wherein the carrier system consists of water and a tonicity
agent.
[1000] In yet other embodiments, the compositions according to
Formula Example 1 consists essentially of
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenyl-sulfamic acid or a pharmaceutically
acceptable salt thereof, a solubilizing system and a carrier
system, wherein the solubilizing system consists of HP.beta.CD and
wherein the carrier system consists of water and a tonicity
agent.
[1001] In still other embodiments, the compositions according to
Formula Example 1 consists essentially of
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenyl-sulfamic acid or a pharmaceutically
acceptable salt thereof, HP.beta.CD, a tonicity agent, water and
optionally a preservative.
[1002] In a particular embodiment the compositions according to
Formula Example 1 consists of
4-{(S)-2-[(S)-2-methoxy-carbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof, HP.beta.CD, a tonicity agent, water and
optionally a preservative.
[1003] The disclosed compositions according to Formulation Example
2 can further comprise from about 0.01% to about 1% weight by
volume pharmaceutically acceptable preservatives. One non-limiting
example of a suitable preservative is benzyl alcohol, for example,
0.9% benzyl alcohol.
Excipients.
[1004] A pharmaceutical composition of the invention can be a
combination of any pharmaceutical compounds described herein with
other chemical components, such as carriers, stabilizers, diluents,
dispersing agents, suspending agents, thickening agents, and/or
excipients. The pharmaceutical composition facilitates
administration of the compound to an organism. Pharmaceutical
compositions can be administered in therapeutically-effective
amounts as pharmaceutical compositions by various forms and routes
including, for example, intravenous, subcutaneous, intramuscular,
oral, rectal, aerosol, parenteral, ophthalmic, pulmonary,
transdermal, vaginal, otic, nasal, and topical administration.
[1005] A pharmaceutical composition can be administered in a local
or systemic manner, for example, via injection of the compound
directly into an organ, optionally in a depot or sustained release
formulation. Pharmaceutical compositions can be provided in the
form of a rapid release formulation, in the form of an extended
release formulation, or in the form of an intermediate release
formulation. A rapid release form can provide an immediate release.
An extended release formulation can provide a controlled release or
a sustained delayed release.
[1006] For oral administration, pharmaceutical compositions can be
formulated readily by combining the active compounds with
pharmaceutically-acceptable carriers or excipients. Such carriers
can be used to formulate tablets, powders, pills, dragees,
capsules, liquids, gels, syrups, elixirs, slurries, suspensions and
the like, for oral ingestion by a subject.
[1007] Pharmaceutical preparations for oral use can be obtained by
mixing one or more solid excipient with one or more of the
compounds described herein, optionally grinding the resulting
mixture, and processing the mixture of granules, after adding
suitable auxiliaries, if desired, to obtain tablets or dragee
cores. Cores can be provided with suitable coatings. For this
purpose, concentrated sugar solutions can be used, which can
contain an excipient such as gum arabic, talc,
polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or
titanium dioxide, lacquer solutions, and suitable organic solvents
or solvent mixtures. Dyestuffs or pigments can be added to the
tablets or dragee coatings, for example, for identification or to
characterize different combinations of active compound doses.
[1008] Pharmaceutical preparations which can be used orally include
push-fit capsules made of gelatin, as well as soft, sealed capsules
made of gelatin and a plasticizer, such as glycerol or sorbitol. In
some embodiments, the capsule comprises a hard gelatin capsule
comprising one or more of pharmaceutical, bovine, and plant
gelatins. A gelatin can be alkaline-processed. The push-fit
capsules can contain the active ingredients in admixture with
filler such as lactose, binders such as starches, and/or lubricants
such as talc or magnesium stearate and, stabilizers. In soft
capsules, the active compounds can be dissolved or suspended in
suitable liquids, such as fatty oils, liquid paraffin, or liquid
polyethylene glycols. Stabilizers can be added. All formulations
for oral administration are provided in dosages suitable for such
administration.
[1009] For buccal or sublingual administration, the compositions
can be tablets, lozenges, or gels.
[1010] Parental injections can be formulated for bolus injection or
continuous infusion. The pharmaceutical compositions can be in a
form suitable for parenteral injection as a sterile suspension,
solution or emulsion in oily or aqueous vehicles, and can contain
formulatory agents such as suspending, stabilizing and/or
dispersing agents. Pharmaceutical formulations for parenteral
administration include aqueous solutions of the active compounds in
water-soluble form. Suspensions of the active compounds can be
prepared as oily injection suspensions. Suitable lipophilic
solvents or vehicles include fatty oils such as sesame oil, or
synthetic fatty acid esters, such as ethyl oleate or triglycerides,
or liposomes. Aqueous injection suspensions can contain substances
which increase the viscosity of the suspension, such as sodium
carboxymethyl cellulose, sorbitol, or dextran. The suspension can
also contain suitable stabilizers or agents which increase the
solubility of the compounds to allow for the preparation of highly
concentrated solutions. Alternatively, the active ingredient can be
in powder form for constitution with a suitable vehicle, e.g.,
sterile pyrogen-free water, before use.
[1011] The active compounds can be administered topically and can
be formulated into a variety of topically administrable
compositions, such as solutions, suspensions, lotions, gels,
pastes, medicated sticks, balms, creams, and ointments. Such
pharmaceutical compositions can contain solubilizers, stabilizers,
tonicity enhancing agents, buffers and preservatives.
[1012] Formulations suitable for transdermal administration of the
active compounds can employ transdermal delivery devices and
transdermal delivery patches, and can be lipophilic emulsions or
buffered aqueous solutions, dissolved and/or dispersed in a polymer
or an adhesive. Such patches can be constructed for continuous,
pulsatile, or on demand delivery of pharmaceutical compounds.
Transdermal delivery can be accomplished by means of iontophoretic
patches. Additionally, transdermal patches can provide controlled
delivery. The rate of absorption can be slowed by using
rate-controlling membranes or by trapping the compound within a
polymer matrix or gel. Conversely, absorption enhancers can be used
to increase absorption. An absorption enhancer or carrier can
include absorbable pharmaceutically acceptable solvents to assist
passage through the skin. For example, transdermal devices can be
in the form of a bandage comprising a backing member, a reservoir
containing compounds and carriers, a rate controlling barrier to
deliver the compounds to the skin of the subject at a controlled
and predetermined rate over a prolonged period of time, and
adhesives to secure the device to the skin or the eye.
[1013] For administration by inhalation, the active compounds can
be in a form as an aerosol, a mist, or a powder. Pharmaceutical
compositions are conveniently delivered in the form of an aerosol
spray presentation from pressurized packs or a nebuliser, with the
use of a suitable propellant, for example, dichlorodifluoromethane,
trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide
or other suitable gas. In the case of a pressurized aerosol, the
dosage unit can be determined by providing a valve to deliver a
metered amount. Capsules and cartridges of, for example, gelatin
for use in an inhaler or insufflator can be formulated containing a
powder mix of the compounds and a suitable powder base such as
lactose or starch.
[1014] The compounds can also be formulated in rectal compositions
such as enemas, rectal gels, rectal foams, rectal aerosols,
suppositories, jelly suppositories, or retention enemas, containing
conventional suppository bases such as cocoa butter or other
glycerides, as well as synthetic polymers such as
polyvinylpyrrolidone and PEG. In suppository forms of the
compositions, a low-melting wax such as a mixture of fatty acid
glycerides or cocoa butter can be used.
[1015] In practicing the methods of treatment or use provided
herein, therapeutically-effective amounts of the compounds
described herein are administered in pharmaceutical compositions to
a subject having a disease or condition to be treated. In some
embodiments, the subject is a mammal such as a human. A
therapeutically-effective amount can vary widely depending on the
severity of the disease, the age and relative health of the
subject, the potency of the compounds used, and other factors. The
compounds can be used singly or in combination with one or more
therapeutic agents as components of mixtures.
[1016] Pharmaceutical compositions can be formulated using one or
more physiologically-acceptable carriers comprising excipients and
auxiliaries, which facilitate processing of the active compounds
into preparations that can be used pharmaceutically. Formulation
can be modified depending upon the route of administration chosen.
Pharmaceutical compositions comprising a compounds described herein
can be manufactured, for example, by mixing, dissolving,
granulating, dragee-making, levigating, emulsifying, encapsulating,
entrapping, or compression processes.
[1017] The pharmaceutical compositions can include at least one
pharmaceutically acceptable carrier, diluent, or excipient and
compounds described herein as free-base or
pharmaceutically-acceptable salt form. The methods and
pharmaceutical compositions described herein include the use
crystalline forms (also known as polymorphs), and active
metabolites of these compounds having the same type of
activity.
[1018] Methods for the preparation of compositions comprising the
compounds described herein include formulating the compounds with
one or more inert, pharmaceutically-acceptable excipients or
carriers to form a solid, semi-solid, or liquid composition. Solid
compositions include, for example, powders, tablets, dispersible
granules, capsules, cachets, and suppositories. Liquid compositions
include, for example, solutions in which a compound is dissolved,
emulsions comprising a compound, or a solution containing
liposomes, micelles, or nanoparticles comprising a compound as
disclosed herein. Semi-solid compositions include, for example,
gels, suspensions and creams. The compositions can be in liquid
solutions or suspensions, solid forms suitable for solution or
suspension in a liquid prior to use, or as emulsions. These
compositions can also contain minor amounts of nontoxic, auxiliary
substances, such as wetting or emulsifying agents, pH buffering
agents, and other pharmaceutically-acceptable additives.
[1019] Non-limiting examples of dosage forms suitable for use in
the invention include feed, food, pellet, lozenge, liquid, elixir,
aerosol, inhalant, spray, powder, tablet, pill, capsule, gel,
geltab, nanosuspension, nanoparticle, microgel, suppository
troches, aqueous or oily suspensions, ointment, patch, lotion,
dentifrice, emulsion, creams, drops, dispersible powders or
granules, emulsion in hard or soft gel capsules, syrups,
phytoceuticals, nutraceuticals, and any combination thereof.
[1020] Non-limiting examples of pharmaceutically-acceptable
excipients suitable for use in the invention include granulating
agents, binding agents, lubricating agents, disintegrating agents,
sweetening agents, glidants, anti-adherents, anti-static agents,
surfactants, anti-oxidants, gums, coating agents, coloring agents,
flavouring agents, coating agents, plasticizers, preservatives,
suspending agents, emulsifying agents, anti-microbial agents, plant
cellulosic material and spheronization agents, and any combination
thereof.
[1021] A composition of the invention can be, for example, an
immediate release form or a controlled release formulation. An
immediate release formulation can be formulated to allow the
compounds to act rapidly. Non-limiting examples of immediate
release formulations include readily dissolvable formulations. A
controlled release formulation can be a pharmaceutical formulation
that has been adapted such that drug release rates and drug release
profiles can be matched to physiological and chronotherapeutic
requirements or, alternatively, has been formulated to effect
release of a drug at a programmed rate. Non-limiting examples of
controlled release formulations include granules, delayed release
granules, hydrogels (e.g., of synthetic or natural origin), other
gelling agents (e.g., gel-forming dietary fibers), matrix-based
formulations (e.g., formulations comprising a polymeric material
having at least one active ingredient dispersed through), granules
within a matrix, polymeric mixtures, and granular masses.
[1022] The disclosed compositions can optionally comprise from
about 0.001% to about 0.005% weight by volume pharmaceutically
acceptable preservatives. One non-limiting example of a suitable
preservative is benzyl alcohol.
[1023] In some, a controlled release formulation is a delayed
release form. A delayed release form can be formulated to delay a
compound's action for an extended period of time. A delayed release
form can be formulated to delay the release of an effective dose of
one or more compounds, for example, for about 4, about 8, about 12,
about 16, or about 24 hours.
[1024] A controlled release formulation can be a sustained release
form. A sustained release form can be formulated to sustain, for
example, the compound's action over an extended period of time. A
sustained release form can be formulated to provide an effective
dose of any compound described herein (e.g., provide a
physiologically-effective blood profile) over about 4, about 8,
about 12, about 16 or about 24 hours.
[1025] Non-limiting examples of pharmaceutically-acceptable
excipients can be found, for example, in Remington: The Science and
Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing
Company, 1995); Hoover, John E., Remington's Pharmaceutical
Sciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A.
and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker,
New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug
Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins
1999), each of which is incorporated by reference in its
entirety.
[1026] The disclosed methods include administration of a
HPTP-.beta. inhibitor or a pharmaceutically acceptable salt thereof
in combination with a pharmaceutically acceptable carrier. The
carrier can be selected to minimize any degradation of the active
ingredient and to minimize any adverse side effects in the
subject.
[1027] In another aspect, the 4 HPTP-.beta. inhibitor or a
pharmaceutically acceptable salt thereof can be used
prophylactically, i.e., as a preventative agent after treatment
with an anti-VEGF agent has stopped. The HPTP-.beta. inhibitor or a
pharmaceutically acceptable salt thereof herein can be conveniently
formulated into pharmaceutical compositions composed of one or more
pharmaceutically acceptable carriers. See e.g., Remington's
Pharmaceutical Sciences, latest edition, by E.W. Martin Mack Pub.
Co., Easton, Pa., which discloses typical carriers and conventional
methods of preparing pharmaceutical compositions that can be used
in conjunction with the preparation of formulations of the compound
described herein and which is incorporated by reference herein.
Such pharmaceutical can be standard carriers for administration of
compositions to humans and non-humans, including solutions such as
sterile water, saline, and buffered solutions at physiological pH.
Other compositions can be administered according to standard
procedures used by those skilled in the art. For example,
pharmaceutical compositions can also include one or more additional
active ingredients such as antimicrobial agents, anti-inflammatory
agents, anesthetics, and the like.
[1028] Non-limiting examples of pharmaceutically-acceptable
carriers include, but are not limited to, saline, Ringer's solution
and dextrose solution. The pH of the solution can be from about 5
to about 8, and can be from about 7 to about 7.5. Further carriers
include sustained release preparations such as semipermeable
matrices of solid hydrophobic polymers containing the HPTP-.beta.
inhibitor or a pharmaceutically-acceptable salt thereof, which
matrices are in the form of shaped articles, e.g., films,
liposomes, microparticles, or microcapsules.
[1029] The disclosed methods relate to administering the
HPTP-.beta. inhibitor or a pharmaceutically acceptable salt thereof
as part of a pharmaceutical composition. Compositions suitable for
topical administration can be used (see, for example, US Patent
Application 2005/0059639 included herein by reference in its
entirety). In various embodiments, compositions of the invention
can comprise a liquid comprising an active agent in solution, in
suspension, or both. Liquid compositions can include gels. In one
embodiment, the liquid composition is aqueous. Alternatively, the
composition can take form of an ointment. In another embodiment,
the composition is an in situ gellable aqueous composition. In
iteration, the composition is an in situ gellable aqueous solution.
Such a composition can comprise a gelling agent in a concentration
effective to promote gelling upon contact with the eye or lacrimal
fluid in the exterior of the eye. Aqueous compositions of the
invention have ophthalmically compatible pH and osmolality. The
composition can comprise an ophthalmic depot formulation comprising
an active agent for subconjunctival administration. The
microparticles comprising active agent can be embedded in a
biocompatible pharmaceutically acceptable polymer or a lipid
encapsulating agent. The depot formulations may be adapted to
release all or substantially all the active material over an
extended period of time. The polymer or lipid matrix, if present,
may be adapted to degrade sufficiently to be transported from the
site of administration after release of all or substantially all
the active agent. The depot formulation can be a liquid
formulation, comprising a pharmaceutical acceptable polymer and a
dissolved or dispersed active agent. Upon injection, the polymer
forms a depot at the injections site, e.g. by gelifying or
precipitating. The composition can comprise a solid article that
can be inserted in a suitable location in the eye, such as between
the eye and eyelid or in the conjuctival sac, where the article
releases the active agent. Solid articles suitable for implantation
in the eye in such fashion generally comprise polymers and can be
bioerodible or non-bioerodible.
[1030] Pharmaceutical formulations can include additional carriers,
as well as thickeners, diluents, buffers, preservatives, surface
active agents and the like in addition to the compounds disclosed
herein. Pharmaceutical formulations can also include one or more
additional active ingredients such as antimicrobial agents,
anti-inflammatory agents, anesthetics, and the like.
[1031] An excipient can fill a role as simple and direct as being
an inert filler, or an excipient as used herein may be part of a pH
stabilizing system or coating to insure delivery of the ingredients
safely to the stomach. The formulator can also take advantage of
the fact the compounds of the present disclosure have improved
cellular potency, pharmacokinetic properties, as well as improved
oral bioavailability.
[1032] The HPTP-.beta. inhibitor or a pharmaceutically acceptable
salt thereof can also be present in liquids, emulsions, or
suspensions for delivery of active therapeutic agents in aerosol
form to cavities of the body such as the nose, throat, or bronchial
passages. The ratio of HPTP-.beta. inhibitor or a pharmaceutically
acceptable salt thereof to the other compounding agents in these
preparations can vary as the dosage form requires.
[1033] Depending on the intended mode of administration, the
pharmaceutical compositions administered as part of the disclosed
methods can be in the form of solid, semi-solid or liquid dosage
forms, such as, for example, tablets, suppositories, pills,
capsules, powders, liquids, suspensions, lotions, creams, gels, or
the like, for example, in unit dosage form suitable for single
administration of a precise dosage. The compositions can, as noted
above, an effective amount of the HPTP-.beta. inhibitor or a
pharmaceutically acceptable salt thereof in combination with a
pharmaceutically acceptable carrier and, in addition, can include
other medicinal agents, pharmaceutical agents, carriers, adjuvants,
diluents, etc.
[1034] For solid compositions, conventional nontoxic solid carriers
include, for example, pharmaceutical grades of mannitol, lactose,
starch, magnesium stearate, sodium saccharin, talc, cellulose,
glucose, sucrose, magnesium carbonate, and the like. In one
embodiment, a composition comprising the HPTP-.beta. inhibitor or a
pharmaceutically acceptable salt thereof in an amount of
approximately 5 mg per 0.1 mL liquid is prepared. The liquid phase
comprises sterile water and an appropriate amount of a saccharide
or polysaccharide.
Methods of Administration and Treatment Methods.
[1035] Pharmaceutical compositions containing compounds described
herein can be administered for prophylactic and/or therapeutic
treatments. In therapeutic applications, the compositions can be
administered to a subject already suffering from a disease or
condition, in an amount sufficient to cure or at least partially
arrest the symptoms of the disease or condition, or to cure, heal,
improve, or ameliorate the condition. Compounds can also be
administered to lessen a likelihood of developing, contracting, or
worsening a condition. Amounts effective for this use can vary
based on the severity and course of the disease or condition,
previous therapy, the subject's health status, weight, and response
to the drugs, and the judgment of the treating physician.
[1036] Multiple therapeutic agents can be administered in any order
or simultaneously. If simultaneously, the multiple therapeutic
agents can be provided in a single, unified form, or in multiple
forms, for example, as multiple separate pills. The compounds can
be packed together or separately, in a single package or in a
plurality of packages. One or all of the therapeutic agents can be
given in multiple doses. If not simultaneous, the timing between
the multiple doses may vary to as much as about a month.
[1037] Compounds and compositions of the invention can be packaged
as a kit. In some embodiments, a kit includes written instructions
on the use of the compounds and compositions.
[1038] Compounds described herein can be administered before,
during, or after the occurrence of a disease or condition, and the
timing of administering the composition containing a compound can
vary. For example, the compounds can be used as a prophylactic and
can be administered continuously to subjects with a propensity to
conditions or diseases in order to lessen a likelihood of the
occurrence of the disease or condition. The compounds and
compositions can be administered to a subject during or as soon as
possible after the onset of the symptoms. The administration of the
compounds can be initiated within the first 48 hours of the onset
of the symptoms, within the first 24 hours of the onset of the
symptoms, within the first 6 hours of the onset of the symptoms, or
within 3 hours of the onset of the symptoms. The initial
administration can be via any route practical, such as by any route
described herein using any formulation described herein. A compound
can be administered as soon as is practicable after the onset of a
disease or condition is detected or suspected, and for a length of
time necessary for the treatment of the disease, such as, for
example, from about 1 month to about 3 months. The length of
treatment can vary for each subject.
[1039] Pharmaceutical compositions described herein can be in unit
dosage forms suitable for single administration of precise dosages.
In unit dosage form, the formulation is divided into unit doses
containing appropriate quantities of one or more compounds. The
unit dosage can be in the form of a package containing discrete
quantities of the formulation. Non-limiting examples are packaged
injectables, vials, or ampoules. Aqueous suspension compositions
can be packaged in single-dose non-reclosable containers.
Multiple-dose reclosable containers can be used, for example, in
combination with or without a preservative. Formulations for
parenteral injection can be presented in unit dosage form, for
example, in ampoules, or in multi-dose containers with a
preservative.
[1040] A compound described herein can be present in a composition
in a range of from about 1 mg to about 2000 mg; from about 5 mg to
about 1000 mg, from about 10 mg to about 25 mg to 500 mg, from
about 50 mg to about 250 mg, from about 100 mg to about 200 mg,
from about 1 mg to about 50 mg, from about 50 mg to about 100 mg,
from about 100 mg to about 150 mg, from about 150 mg to about 200
mg, from about 200 mg to about 250 mg, from about 250 mg to about
300 mg, from about 300 mg to about 350 mg, from about 350 mg to
about 400 mg, from about 400 mg to about 450 mg, from about 450 mg
to about 500 mg, from about 500 mg to about 550 mg, from about 550
mg to about 600 mg, from about 600 mg to about 650 mg, from about
650 mg to about 700 mg, from about 700 mg to about 750 mg, from
about 750 mg to about 800 mg, from about 800 mg to about 850 mg,
from about 850 mg to about 900 mg, from about 900 mg to about 950
mg, or from about 950 mg to about 1000 mg.
[1041] A compound described herein can be present in a composition
in an amount of about 1 mg, about 2 mg, about 3 mg, about 4 mg,
about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg,
about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg,
about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg,
about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg,
about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 250
mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about
500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg,
about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950
mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg,
about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about
1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600
mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg,
about 1850 mg, about 1900 mg, about 1950 mg, or about 2000 mg.
Kits
[1042] The present disclosure further relates to kits containing
compositions according to Formulation Example 2 for use by medical
or other trained personnel, as well as for use by trained subjects
for delivery of the disclosed compositions according to Formulation
Example 2 to a subject. In general the disclosed kits comprise:
[1043] A) an aqueous composition as described herein containing
from about 1 mg/mL to about 60 mg/mL of the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid; and [1044] B) a means
for delivering the composition to a subject.
[1045] The compositions according to Formulation Example 2 can
comprise the following concentrations of the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid: 1 mg/mL, 2 mg/mL, 3
mg/mL, 4 mg/mL, 5 mg/mL, 6 mg/mL, 7 mg/mL, 8 mg/mL, 9 mg/mL, 10
mg/mL, 11 mg/mL, 12 mg/mL, 13 mg/mL, 14 mg/mL, 15 mg/mL, 16 mg/mL,
17 mg/mL, 18 mg/mL, 19 mg/mL, 20 mg/mL, 21 mg/mL, 22 mg/mL, 23
mg/mL, 24 mg/mL, 25 mg/mL, 26 mg/mL, 27 mg/mL, 28 mg/mL, 29 mg/mL,
30 mg/mL, 31 mg/mL, 32 mg/mL, 33 mg/mL, 34 mg/mL, 35 mg/mL, 36
mg/mL, 37 mg/mL, 38 mg/mL, 39 mg/mL, 40 mg/mL, 41 mg/mL, 42 mg/mL,
43 mg/mL, 44 mg/mL, 45 mg/mL, 46 mg/mL, 47 mg/mL, 48 mg/mL, 49
mg/mL, 50 mg/mL, 51 mg/mL, 52 mg/mL, 53 mg/mL, 54 mg/mL, 55 mg/mL,
56 mg/mL, 57 mg/mL, 58 mg/mL, 59 mg/mL, and 60 mg/mL.
[1046] The disclosed compositions according to Formulation Example
2 can be administered to a subject. Non-limiting examples of routes
of administration include parenteral delivery, i.e., intravenous,
subcutaneous, and intramuscular. Delivery can be by, for example,
syringes, needles, infusion pumps, injectors. Syringes and
injectors can be, for example, single-dose, multi-dose, fixed-dose
or variable-dose. Examples of injectors include, but are not
limited to, pen injectors, auto-injectors, and electronic patch
injector systems. One convenient means for delivering the disclosed
compositions according to Formulation Example 2 is by single use
disposable auto injectors. One non-limiting example is a single use
injector configured like the single injector sold under the
Tradename MOLLY.TM.. Non-limiting examples of injectors are
described in U.S. Pat. No. 7,442,185; U.S. Pat. No. 8,038,649; U.S.
Pat. No. 8,062,255; U.S. Pat. No. 8,075,517; U.S. Pat. No.
8,235,952; U.S. Pat. No. 8,277,412; U.S. Pat. Nos. 8,529,510; and
8,551,054.
[1047] The kits can comprise suitable components for the
administration of a compound of the invention to a subject. In some
embodiments a compound of the invention is present in the kit as a
unit dosage form. For example, the kit may comprise a delivery
device that is capable of holding a single dose volume of 0.75 mL
is capable of delivering 15 mg/mL of compound when the
concentration of the compound is 20 mg/mL. As such, the formulator
can provide delivery devices having a higher concentration of
compound and adjust the delivered volume to provide an amount of
compound that is less than the amount in the entire solution. In
another embodiment the kit comprises a delivery device that
contains a sufficient amount of a composition to allow for
administration of multiple doses from the delivery device.
[1048] In some embodiments, a kit of the invention comprises:
[1049] A) a composition for delivering a HPTP-.beta. inhibitor or a
pharmaceutically acceptable salt; and [1050] B) a composition for
delivering an anti-VEGF agent.
[1051] The kits can be modified to fit the dosing regimen
prescribed for the subject being treated. The following is a
non-limiting example of a kit for use with a patient receiving an
intravenously delivered composition comprising the disclosed
compounds and an intravireally administered anti-VEGF agent. This
particular example provides dosing of the disclosed compounds twice
daily for 3 months and for an injection of ranibizumab at week 12.
[1052] A. 3 packages, each package containing 4 vials. Each vial
comprising a sufficient amount of a HPTP-.beta. inhibitor or a
pharmaceutically acceptable salt to provide 2 daily injections of 5
mg of the disclosed compounds for 7 days; and [1053] B. a vial of
ranibizumab for injection at the end of week 12 which provides 0.5
mg of ranibizumab.
[1054] The artisan, however, can provide kits that comprise any
combination of elements. In addition, when the disclosed
HPTP-.beta. inhibitors or a pharmaceutically acceptable salt
provided orally, a single container with sufficient doses of the
disclosed compounds can be supplied with the kit.
[1055] Also included with each kit labels providing instructions
for use and disposal can be included, as well as instructions for
use of the compositions to be delivered. The instructions can be
modified from kit to kit to reflect the dosing regime prescribed.
The instructions can describe any therapy, compounds, excipients,
or method of administration described herein.
[1056] The following are additional non-limiting examples of
compositions according to Formulation Example 2 that can comprise
the disclosed kits.
[1057] One example is a kit comprising: [1058] A) an aqueous
composition containing: [1059] a) 10 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}-phenylsulfamic acid; [1060] b) 62.5
mg/mL of 2-hydroxypropyl-.beta.-cyclodextrin; and [1061] c) a
carrier system, comprising: [1062] i) a tonicity agent; and [1063]
ii) water [1064] wherein the tonicity agent is present in an amount
such that the concentration in the final composition is from about
1% to about 5% weight to volume and the carrier system is present
in an amount such that the concentration of the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid has a concentration of
10 mg/mL; and [1065] B) a component for delivering the aqueous
composition.
[1066] In one non-limiting example, the kit comprises: [1067] A) 1
mL of an aqueous composition containing: [1068] a) 10 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}-phenylsulfamic acid; [1069] b) 62.5
mg/mL of 2-hydroxypropyl-.beta.-cyclodextrin; and [1070] c) the
balance 2% weight to volume of aqueous dextrose; and [1071] B) a
component for delivering the aqueous composition; [1072] wherein
the component for delivery is a single use syringe.
[1073] In another non-limiting example, the kit comprises: [1074]
A) 0.75 mL of an aqueous composition containing: [1075] a) 10 mg/mL
of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}-phenylsulfamic acid; [1076] b) 62.5
mg/mL of 2-hydroxypropyl-.beta.-cyclodextrin; and [1077] c) the
balance 2% weight to volume of aqueous dextrose; and [1078] B) a
component for delivering the aqueous composition; [1079] wherein
the component for delivery is a single use syringe.
[1080] One example is a kit comprising: [1081] A) an aqueous
composition containing: [1082] a) 15 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}-phenylsulfamic acid; [1083] b) 93.75
mg/mL of 2-hydroxypropyl-.beta.-cyclodextrin; and [1084] c) a
carrier system, comprising: [1085] i) a tonicity agent; and [1086]
ii) water [1087] wherein the tonicity agent is present in an amount
such that the concentration in the final compositions is from about
1% to about 10% weight to volume and the carrier system is present
in an amount such that the concentration of the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid is 15 mg/mL; and
[1088] B) a component for delivering the aqueous composition.
[1089] In one non-limiting example, the kit comprises: [1090] A) 1
mL of an aqueous composition containing: [1091] a) 15 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}-phenylsulfamic acid; [1092] b) 93.75
mg/mL of 2-hydroxypropyl-.beta.-cyclodextrin; and [1093] c) the
balance 2% weight to volume of aqueous dextrose; and [1094] B) a
component for delivering the aqueous composition; [1095] wherein
the component for delivery is a single use syringe.
[1096] In another non-limiting example, the kit comprises: [1097]
A) 0.75 mL of an aqueous composition containing: [1098] a) 15 mg/mL
of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}-phenylsulfamic acid; [1099] b) 93.75
mg/mL of 2-hydroxypropyl-.beta.-cyclodextrin; and [1100] c) the
balance 2% weight to volume of aqueous dextrose; and [1101] B) a
component for delivering the aqueous composition; [1102] wherein
the component for delivery is a single use syringe.
[1103] In a further aspect the kits comprising a composition
according to Formulation Example 2 is a kit, comprising: [1104] A)
an aqueous composition containing: [1105] a) 20 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}-phenylsulfamic acid; [1106] b) 125 mg/mL
of 2-hydroxypropyl-.beta.-cyclodextrin; and [1107] c) a carrier
system, comprising: [1108] i) a tonicity agent; and [1109] ii)
water [1110] wherein the tonicity agent is present in an amount
such that the concentration in the final composition is from about
1% to about 10% weight to volume; and [1111] B) a component for
delivering the aqueous composition.
[1112] In another aspect the kits comprising a composition
according to Formulation Example 2 is a pharmaceutical kit,
comprising: [1113] A) a 0.75 mL single dose syringe, the syringe
containing a composition, comprising: [1114] a) 20 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}-phenylsulfamic acid; [1115] b) 125 mg/mL
of 2-hydroxypropyl-.beta.-cyclodextrin; and [1116] c) a carrier
system, comprising: [1117] i) 2% weight to volume of dextrose of
the composition; and [1118] ii) water; and [1119] B) instructions
for use of the kit.
[1120] A further aspect of the compositions according to
Formulation Example 2 relates to kits which comprise a solid
composition for reconstitution. The amount of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}-phenylsulfamic acid or a
pharmaceutically acceptable salt thereof in the container of dry
composition can be in any convenient amount. For example, a
container comprising 20 mg of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}-phenylsulfamic acid or a
pharmaceutically acceptable salt thereof can have a demarcation
line indicating a final volume of 1 mL. The user can then
reconstitute the composition by adding sufficient carrier to create
a composition comprising 20 mg/mL of the compound. The formulator
also has options for use according to the instructions. For
example, the instructions can direct the user to withdrawn a
sufficient amount according to the prescribed dose. If the
prescribed dose is 15 mg/mL the user can withdraw 0.75 mL's of the
20 mg/mL solution for delivery to the subject. Therefore,
instructions for re-constitution can afford the user with the
proper method of reconstitution, as well as the amount of
re-constituted formula to be delivered to a subject.
[1121] The following is a non-limiting example of a kit containing
a solid composition: [1122] A) a solid or dry composition,
comprising: [1123] a)
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thio-
phen-2-yl)thiazol-4-yl]ethyl}-phenylsulfamic acid or a
pharmaceutically acceptable salt thereof; and [1124] b) HP.beta.CD;
wherein the ratio of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}-phenylsulfamic acid to HP.beta.CD is
from about 1:4 to about 1:8 and the tonicity agent is present in an
amount such that the re-constituted formula comprises from about
0.5% to about 10% weight to volume of the tonicity agent
[1125] In another iteration the dry compositions for reconstitution
can comprise: [1126] a)
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}-phenylsulfamic acid or a
pharmaceutically acceptable salt thereof; [1127] b) HP.beta.CD; and
[1128] c) a tonicity agent; wherein the ratio of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}-phenylsulfamic acid to HP.beta.CD is
from about 1:4 to about 1:8 and the tonicity agent is present in an
amount such that the re-constituted formula comprises from about
0.5% to about 10% weight to volume of the tonicity agent.
[1129] A set of instructions can be included in any of the herein
described kits. The instructions can relate to the dosing amount,
timing of dosing, and reconstitution of the composition when the
kit contains a dry composition, methods of disposal of delivery
means and unused composition, and the like.
[1130]
4-{(S)-2-[(S)-2-(Methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(t-
hiophen-2-yl)thiazol-4-yl]ethyl}-phenylsulfamic acid can be
prepared by the procedure outlined in Scheme XXIV and describe in
Example 25 herein below.
##STR00335## ##STR00336## ##STR00337## ##STR00338##
Example 33
4-{(S)-2-[(S)-2-Methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen--
2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid (72)
Preparation of
(S)-[3-diazo-1-(4-nitrobenzyl)-2-oxo-propyl]-carbamic acid
tert-butyl ester (6)
[1131] To a 0.degree. C. solution of
2-(S)-tert-butoxycarbonylamino-3-(4-nitrophenyl)-propionic acid, 1,
(1.20 g, 4.0 mmol) in THF (20 mL) was added dropwise triethylamine
(0.61 mL, 4.4 mmol) followed by iso-butyl chloroformate (0.57 mL,
4.4 mmol). The reaction mixture was stirred at 0.degree. C. for 20
minutes and filtered. The filtrate was treated with an ether
solution of diazomethane (.about.16 mmol) at 0.degree. C. The
reaction mixture was stirred at room temperature for 3 hours then
concentrated in vacuo. The resulting residue was dissolved in EtOAc
and washed successively with water and brine, dried
(Na.sub.2SO.sub.4), filtered and concentrated. The residue was
purified over silica (hexane/EtOAc 2:1) to afford 1.1 g (82% yield)
of the desired product as a slightly yellow solid. .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 8.16 (d, J=8.7 Hz, 2H), 7.39 (d, J=8.7 Hz,
2H), 5.39 (s, 1H), 5.16 (d, J=6.3 Hz, 1H), 4.49 (s, 1H), 3.25 (dd,
J=13.8 and 6.6, 1H), 3.06 (dd, J=13.5 and 6.9 Hz, 1H), 1.41 (s,
9H).
Preparation of (S)-tert-butyl
4-bromo-1-(4-nitrophenyl)-3-oxobutan-2-ylcarbamate (7)
[1132] To a 0.degree. C. solution of
(S)-[3-diazo-1-(4-nitrobenzyl)-2-oxo-propyl]-carbamic acid
tert-butyl ester, 6, (0.350 g, 1.04 mmol) in THF (5 mL) is added
dropwise 48% aq. HBr (0.14 mL, 1.25 mmol). The reaction mixture was
stirred at 0.degree. C. for 1.5 hours then the reaction was
quenched at 0.degree. C. with sat. Na.sub.2CO.sub.3. The mixture is
extracted with EtOAc (3.times.25 mL) and the combined organic
extracts are washed with brine, dried (Na.sub.2SO.sub.4), filtered
and concentrated to obtain 0.400 g of the product which was used in
the next step without further purification. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 8.20 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H),
5.06 (d, J=7.8 Hz, 1H), 4.80 (q, J=6.3 Hz, 2H), 4.04 (s, 2H), 1.42
(s, 9H).
Preparation of
(S)-2-(4-Nitrophenyl)-1-(2-(thiophen-2-yl)thiazol-4-yl)ethanamine
hydrobromide (65)
[1133] Thiophene-2-carbothioamide in acetonitrile (4 vol. with
respect to 7) was stirred at 15 to 25.degree. C. for 30 to 60
minutes. To remove residual sulfur, the resulting mixture was
filtered through Celite.RTM. and the reaction flask and filter cake
are rinsed with acetonitrile (2.times.1 vol). The filtrate was then
added to the reactor containing and (S)-tert-butyl
4-bromo-1-(4-nitrophenyl)-3-oxobutan-2-ylcarbamate, 7, (0.98 eq)
under a nitrogen atmosphere. Additional ACN was added and the
resulting bright yellow slurry was heated to 80.degree. C. over 6
hours. The reaction mixture was refluxed for 6 to 16 hours. The
reaction mixture was cooled to 65 to 70.degree. C. over 1 hour and
stirred for an additional 1 to 4 hours. The reaction mixture was
then cooled to 50 to 60.degree. C. over 1 hour. The reaction
mixture was aged for an additional 1 to 2 hours at 50 to 60.degree.
C. The reaction mixture was then cooled to 20 to 25.degree. C. over
1 hour. The reaction mixture was aged for an additional 4 to 16
hours at 20 to 25.degree. C. The resulting slurry was filtered and
the filter cake was washed with ACN. The wet cake was dried under
vacuum at 40 to 45.degree. C. to afford the desired product.
Preparation of methyl
(S)-1-(S)-2-(4-nitrophenyl)-1-(2-(thiophen-2-yl)thiazol-4-yl)ethylamino-1-
-oxo-3-phenylpropan-2-ylcarbamate (68)
[1134] A solution of
(S)-2-[(methoxy-carbonyl)amino]-3-phenylpropanoic acid (66) (1.07
eq.) was added to a reactor containing
(S)-2-(4-nitrophenyl)-1-(2-(thiophen-2-yl)thiazol-4-yl)ethanamine
(67) (1.0 eq.) under a nitrogen atmosphere.
2-Chloro-4,6-dimethoxy-1,3,5-triazine (1.07 eq) was added to the
stirred reaction mixture followed by tetrahydrofuran (THF) (ca. 13
vol. with respect to 67). The temperature was adjusted to 19 to
25.degree. C. and N-methylmorpholine (NMM) (0.4 eq) was added at a
rate such that the temperature was maintained between 20 and
30.degree. C. The reaction mixture was stirred at 19 to 25.degree.
C. for 50 to 70 minutes. Additional NMM (0.4 eq) was added at a
rate such that the temperature was maintained between 20 and
30.degree. C. The resulting reaction mixture was stirred at 19 to
25.degree. C. for 50 to 70 minutes. Additional NMM (0.2 eq) was
added at a rate such that the temperature was maintained between 20
and 30.degree. C. The resulting reaction mixture was stirred at 19
to 25.degree. C. for 50 to 70 minutes. Additional NMM (1.2 eq) was
added at a rate such that the temperature was maintained between 20
and 30.degree. C. The resulting reaction mixture was stirred at 19
to 25.degree. C. for 90 to 120 minutes. The reaction mixture was
further stirred at 19 to 25.degree. C. for 2 to 3 hours. A sample
of reaction mixture was tested to determined chemical purity. The
reaction mixture was then stirred at 19 to 25.degree. C. for
minimum 8 hours. The resulting slurry was filtered and the filter
cake washed with THF (2.times.1 vol,). The wet cake was added back
to the reactor and de-ionized water (40 vol.) was added.
Tetrahydrofuran (20 vol.) was added to the stirred reaction mixture
and stirring was continued for 4 to 16 hours at 19 to 25.degree. C.
The solids are collected by filtration. The filter cake was washed
with a 2:1 (v/v) water/THF mixture. The wet cake was further dried
under vacuum at room temperature or 40-50.degree. C. for minimum 12
hours to afford the desired product.
Preparation of methyl
((S)-1-(((S)-2-(4-aminophenyl)-1-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)ami-
no)-1-oxo-3-phenylpropan-2-yl)carbamate (69)
[1135] To a reactor purged with nitrogen was added methyl
(S)-1-(S)-2-(4-nitrophenyl)-1-(2-(thiophen-2-yl)thiazol-4-yl)ethylamino-1-
-oxo-3-phenylpropan-2-ylcarbamate (68), the catalyst, Pd/C (10%)
(0.2:1 ratio of catalyst to 68 by weight), and tetrahydrofuran
(THF). The reactor was pressurized to 45 psi with nitrogen for
minimum 5 minutes then depressurized to approximately 5 psi
nitrogen. This procedure was repeated three times before reactor
was finally pressurized to 30 to 36 psi with hydrogen. The
resulting mixture was stirred for a minimum of 24 hours while
maintaining the pressure at 30 to 36 psi with hydrogen. The reactor
was then depressurized and purged with nitrogen for testing of
reaction completion. The reaction mixture was filtered through a
bed of Celite.RTM. filter aid to remove the catalyst and the filter
cake was washed with THF. The combined filtrate and washes were
concentrated under reduced pressure at 30 to 50.degree. C. to
approximately 3 volumes. The reaction mixture was cooled to 19 to
25.degree. C. and methyl t-butyl ether (MTBE) (2.5 vol.) was added
over 30 minutes. The resulting reaction mixture was stirred at 19
to 25.degree. C. for 60 to 120 minutes during which time the
product begins to precipitate. Additional MTBE (9.5 vol.) was added
over a period of 60 to 90 minutes. The resulting slurry was aged at
19 to 25.degree. C. for a period of 6 to 16 hours. The solids are
collected by filtration and the filter cake was washed with MTBE.
The wet cake was then dried under vacuum at room temperature or
40-50.degree. C. to afford the desired product.
Preparation of trimethylammonium
(4-((S)-2-((S)-2-((methoxycarbonyl)amino)-3-phenylpropanamido)-2-(2-(thio-
phen-2-yl)thiazol-4-yl)ethyl)phenyl)sulfamate (70)
[1136]
((S)-1-(((S)-2-(4-aminophenyl)-1-(2-(thiophen-2-yl)thiazol-4-yl)eth-
yl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate (69), trimethylamine
sulfur trioxide complex (1.71 eq.) and tetrahydrofuran (THF) (7.1
vol.) were added to a reactor purged with nitrogen. The reaction
mixture was stirred and triethylamine (0.106 eq.) was added at 19
to 25.degree. C. The stirred reaction mixture was warmed to 35 to
40.degree. C. and stirred for 4 to 8 hours. The reaction mixture
was cooled to 19 to 25.degree. C. and stirring was continued for 1
to 2 hours. The reaction mixture was filtered and the filter cake
was washed with THF. The combined filtrate and washes are added to
a stirred reactor containing methyl t-butyl ether (MTBE) (10 vol.)
over a minimum of 2 hour period. On completion of the addition, the
reaction mixture was stirred at 19 to 25.degree. C. for 4 to 16
hours. The solids are collected by filtration and the wet cake was
washed with MTBE. The wet cake was dried under vacuum at 20 to
25.degree. C. for 2 hours to afford the desired product.
Preparation of sodium
(4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropan-amido]-2-(2-(thiop-
hen-2-yl)thiazol-4-yl)ethyl}phenyl)sulfamate (71)
[1137] trimethyl-ammonium
(4-((S)-2-((S)-2-((methoxycarbonyl)amino)-3-phenylpropanamido)-2-(2-(thio-
phen-2-yl)thiazol-4-yl)ethyl)-phenyl)sulfamate (70) was added to a
stirred reactor containing methanol (MeOH) (4.87 vol.) and sodium
methoxide (25% solution in MeOH) (0.093 eq.). Sodium methoxide (25%
solution in MeOH) (1.08 eq.) was added over 5 minutes while
maintaining the temperature at 19 to 25.degree. C. The resulting
mixture was stirred at 19-25.degree. C. for 30 to 60 minutes then 2
portions of sodium methoxide (25% solution in MeOH) (0.14 eq. and
0.07 eq.) are added over 30 minutes while maintaining the
temperature at 19 to 25.degree. C. The resulting mixture was
stirred for 30 to 60 minutes while maintaining the temperature at
19 to 25.degree. C. The reaction mixture was then filtered and the
filter cake washed with methanol (MeOH). The filtrates and cake
washes are concentrated under reduced pressure at 30 to 40.degree.
C. to approximately 8 volumes. The reaction mixture was cooled to
19 to 25.degree. C. and methyl t-butyl ether (10 vol) was then
added. The reaction mixture was then stirred for 15 to 20 minutes.
The resulting solids are isolated by filtration and the filter cake
was washed with MTBE. The wet cake was dried under vacuum at room
temperature or 35-40.degree. C. for a minimum of 2 hours to afford
the desired product.
Preparation of
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid (72)
[1138] sodium
(4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropan-amido]-2-(2-(thiop-
hen-2-yl)thiazol-4-yl)ethyl}phenyl)-sulfamate 71) (97.0 gm, 0.16
mol) was slowly added to distilled water (1.0 L) and acetone (200
mL) in a three-neck 5-L round bottom flask equipped with an
overhead mechanical stirrer, a thermometer and an addition funnel
at ambient temperature. To the resulting suspension 85%
H.sub.3PO.sub.4 (20.33 g, 1.1 eq.) diluted with water (100 mL) was
slowly added through the addition funnel over 15 minutes. No
apparent temperature change was observed. A considerable amount of
a free-flowing suspension formed in 10-15 minutes after the
addition was complete. The suspension was stirred at ambient
temperature for 2 hours and filtered. The solid cake was rinsed
with 20% acetone in water (2.times.50 mL). The solid was removed
and dried under vacuum to afford 88.05 g (93.8% yield) of the
desired product as a light-yellow solid which HPLC analysis
indicated had a purity of 99.26%. .sup.1H (CD.sub.3OD): .delta.
7.61-7.56 (m, 2H), 7.25-7.01 (m, 10H), 6.75 (s, 1H), 5.24-5.21 (q,
1H, J=7.2 Hz), 4.38 (t, 1H, J=7.2 Hz), 3.60 (s, 3H), 3.23-3.14 (m,
1H), 3.08-3.00 (m, 2H), 2.87-2.80 (m, 1H).
Formulation Example 3
[1139] This formulation example relates to compositions comprising
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthi-
azol-4-yl)ethyl}phenylsulfamic acid having the formula:
##STR00339##
and pharmaceutically acceptable salts thereof.
[1140] Formulation Example 3 comprises: [1141] a)
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthi-
azol-4-yl)ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof; [1142] b) a solubilizing system; and
[1143] c) a carrier system.
[1144] The compositions of Formulation Example 3 are formulated to
deliver an amount of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthi-
azol-4-yl)ethyl}phenylsulfamic acid in the free acid form. For
example, a composition which comprises 10 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthi-
azol-4-yl)ethyl}phenylsulfamic acid can have either 10 mg/mL of the
free acid or an amount of a pharmaceutically acceptable salt in an
amount sufficient to deliver 10 mg/mL of the free acid. As an
example, a composition formulated to deliver 10 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthi-
azol-4-yl)ethyl}phenylsulfamic acid can comprise either 10 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthi-
azol-4-yl)ethyl}phenylsulfamic acid or alternatively 10.4 mg/mL of
the sodium salt, (sodium
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthi-
azol-4-yl)ethyl}phenylsulfamate). Therefore, a composition which
delivers from about 10 mg/mL to about 100 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthi-
azol-4-yl)ethyl}phenylsulfamic acid can comprise an amount of
pharmaceutically acceptable salt thereof to deliver from about 10
mg/mL to about 100 mg/mL of the compound
[1145] Therefore, when a composition according to Formulation
Example 3 comprises an amount of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthi-
azol-4-yl)ethyl}phenylsulfamic acid per mL, it is understood that
this amount is the amount of free acid that is delivered and if a
salt form of the compound is used in the composition, the amount of
the salt form can therefore reflect the difference in molecular
weight between the free acid and the salt form. The following
example demonstrates this equivalency.
[1146] A composition delivering 10 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthi-
azol-4-yl)ethyl}phenylsulfamic acid, comprises: [1147] a) 10 mg/mL
of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthi-
azol-4-yl)ethyl}phenylsulfamic acid; or about 10.4 mg/mL of sodium
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthi-
azol-4-yl)ethyl}phenylsulfamate; or about 10.3 mg/mL, of ammonium
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthi-
azol-4-yl)ethyl}phenylsulfamate, and the like; [1148] b) an amount
of 2-hydroxypropyl-.beta.-cyclodextrin as defined herein; and
[1149] c) a carrier system.
[1150] The disclosed compositions according to Formulation Example
3 according to Formulation Example 3 comprise from about 10 mg/mL
to about 100 mg/mL of the
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthi-
azol-4-yl)ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof.
[1151] In one aspect the disclosed compositions according to
Formulation Example 3 comprise from about 20 mg/mL to about 100
mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthi-
azol-4-yl)ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof. In one embodiment, the composition
comprises from about 15 mg/mL to about 60 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthi-
azol-4-yl)ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof. In another embodiment, the composition
comprises from about 40 mg/mL to about 90 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthi-
azol-4-yl)ethyl}-phenylsulfamic acid or a pharmaceutically
acceptable salt thereof. In a further embodiment, the composition
comprises from about 10 mg/mL to about 30 mg/mL of
4-{(S)-2-[(S)-2-(methoxy-carbonylamino)-3-phenylpropanamido]-2-(2-ethylth-
iazol-4-yl)ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof. In a still further embodiment, the
composition comprises from about 40 mg/mL to about 80 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonyl-1amino)-3-phenylpropanamido]-2-(2-ethylt-
hiazol-4-yl)ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof. In a yet further embodiment the
composition comprises from about 10 mg/mL to about 20 mg/mL weight
by volume of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthi-
azol-4-yl)ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof. In a still yet further embodiment, the
composition comprises from about 60 mg/mL to about 90 mg/mL weight
by volume of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthi-
azol-4-yl)ethyl}phenyl-sulfamic acid or a pharmaceutically
acceptable salt thereof. In still another embodiment, the
composition comprises from about 50 mg/mL to about 100 mg/mL weight
by volume of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthi-
azol-4-yl)ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof.
[1152] Particular embodiments of the disclosed compositions
according to Formulation Example 3, comprise 1 mg/mL, 2 mg/mL, 3
mg/mL, 4 mg/mL, 5 mg/mL, 6 mg/mL, 7 mg/mL, 8 mg/mL, 9 mg/mL, 10
mg/mL, 11 mg/mL 12 mg/mL, 13 mg/mL, 14 mg/mL, 15 mg/mL, 16 mg/mL,
17 mg/mL, 18 mg/mL, 19 mg/mL, 20 mg/mL, 21 mg/mL, 22 mg/mL, 23
mg/mL, 24 mg/mL, 25 mg/mL, 26 mg/mL, 27 mg/mL, 28 mg/mL, 29 mg/mL,
30 mg/mL, 31 mg/mL 32 mg/mL, 33 mg/mL, 34 mg/mL, 35 mg/mL, 36
mg/mL, 37 mg/mL, 38 mg/mL, 39 mg/mL, 40 mg/mL, 41 mg/mL 42 mg/mL,
43 mg/mL, 44 mg/mL, 45 mg/mL, 46 mg/mL, 47 mg/mL, 48 mg/mL, 49
mg/mL, 50 mg/mL, 51 mg/mL 52 mg/mL, 53 mg/mL, 54 mg/mL, 55 mg/mL,
56 mg/mL, 57 mg/mL, 58 mg/mL, 59 mg/mL, 60 mg/mL, 61 mg/mL 62
mg/mL, 63 mg/mL, 64 mg/mL, 65 mg/mL, 66 mg/mL, 67 mg/mL, 68 mg/mL,
69 mg/mL, 70 mg/mL, 71 mg/mL 72 mg/mL, 73 mg/mL, 74 mg/mL, 75
mg/mL, 76 mg/mL, 77 mg/mL, 78 mg/mL, 79 mg/mL, 80 mg/mL, 81 mg/mL
82 mg/mL, 83 mg/mL, 84 mg/mL, 85 mg/mL, 86 mg/mL, 87 mg/mL, 88
mg/mL, 89 mg/mL, 90 mg/mL, 91 mg/mL 92 mg/mL, 93 mg/mL, 94 mg/mL,
95 mg/mL, 96 mg/mL, 97 mg/mL, 98 mg/mL, 99 mg/mL, and 100 mg/mL,
about 1 mg/mL, about 2 mg/mL, about 3 mg/mL, about 4 mg/mL, about 5
mg/mL, about 6 mg/mL, about 7 mg/mL, about 8 mg/mL, about 9 mg/mL,
about 10 mg/mL, about 11 mg/mL about 12 mg/mL, about 13 mg/mL,
about 14 mg/mL, about 15 mg/mL, about 16 mg/mL, about 17 mg/mL,
about 18 mg/mL, about 19 mg/mL, about 20 mg/mL, about 21 mg/mL
about 22 mg/mL, about 23 mg/mL, about 24 mg/mL, about 25 mg/mL,
about 26 mg/mL, about 27 mg/mL, about 28 mg/mL, about 29 mg/mL,
about 30 mg/mL, about 31 mg/mL, about 32 mg/mL, about 33 mg/mL,
about 34 mg/mL, about 35 mg/mL, about 36 mg/mL, about 37 mg/mL,
about 38 mg/mL, about 39 mg/mL, about 40 mg/mL, about 41 mg/mL,
about 42 mg/mL, about 43 mg/mL, about 44 mg/mL, about 45 mg/mL,
about 46 mg/mL, about 47 mg/mL, about 48 mg/mL, about 49 mg/mL,
about 50 mg/mL, about 51 mg/mL, about 52 mg/mL, about 53 mg/mL,
about 54 mg/mL, about 55 mg/mL, about 56 mg/mL, about 57 mg/mL,
about 58 mg/mL, about 59 mg/mL, about 60 mg/mL, about 61 mg/mL,
about 62 mg/mL, about 63 mg/mL, about 64 mg/mL, about 65 mg/mL,
about 66 mg/mL, about 67 mg/mL, about 68 mg/mL, about 69 mg/mL,
about 70 mg/mL, about 71 mg/mL, about 72 mg/mL, about 73 mg/mL,
about 74 mg/mL, about 75 mg/mL, about 76 mg/mL, about 77 mg/mL,
about 78 mg/mL, about 79 mg/mL, about 80 mg/mL, about 81 mg/mL,
about 82 mg/mL, about 83 mg/mL, about 84 mg/mL, about 85 mg/mL,
about 86 mg/mL, about 87 mg/mL, about 88 mg/mL, about 89 mg/mL,
about 90 mg/mL, about 91 mg/mL, about 92 mg/mL, about 93 mg/mL,
about 94 mg/mL, about 95 mg/mL, about 96 mg/mL, about 97 mg/mL,
about 98 mg/mL, about 99 mg/mL, and about 100 mg/mL of a compound
disclosed herein, for example,
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropan-amido]-2-(2-ethylth-
iazol-4-yl)ethyl}phenylsulfamic acid.
Solubilizing Systems
[1153] In one embodiment, a formulation disclosed herein can
comprise a ratio of about 20 parts of a compound herein or a
pharmaceutically acceptable salt thereof to about 1 part
solubilizing system (about 20:about 1), to about 1 part of the
compound herein or a pharmaceutically acceptable salt thereof to
about 20 parts solubilizing system (about 1:about 20). For example,
a formulation containing about 100 mg of a compound herein or a
pharmaceutically acceptable salt thereof can contain from about 5
mg to about 2000 mg of a solubilizing agent, such as a
cyclodextrin. In another embodiment, the ratio can be based on
number, or moles, or compound compared to number, or moles, of
solubilizing system.
[1154] The disclosed solubilizing systems can comprise
cyclodextrins: .beta.-cyclodextrin, .beta.-cyclodextrin and
.beta.-cyclodextrin and derivatives thereof. Non-limiting examples
of cyclodextrin derivatives includes methyl-.beta.-cyclodextrin,
2-hydroxypropyl-.beta.-cyclodextrin, sulfobutyl
ether-.beta.-cyclodextrin sodium salt, and
2-hydroxypropyl-.beta.-cyclodextirn.
[1155] The following are non-limiting examples of ratios of a
compound herein and a solubilizing agent, such as a cyclodextrin.
The following examples alternatively describe the ratio of a
solubilizing agent, such as a cyclodextrin, and a compound herein.
The ratio can be: about 20:about 1; about 19.9:about 1; about
19.8:about 1; about 19.7:about 1; about 19.6:about 1; about
19.5:about 1; about 19.4:about 1; about 19.3:about 1; about
19.2:about 1; about 19.1:about 1; about 19:about 1; about
18.9:about 1; about 18.8:about 1; about 18.7:about 1; about
18.6:about 1; about 18.5:about 1; about 18.4:about 1; about
18.3:about 1; about 18.2:about 1; about 18.1:about 1; about
18:about 1; about 17.9:about 1; about 17.8:about 1; about
17.7:about 1; about 17.6:about 1; about 17.5:about 1; about
17.4:about 1; about 17.3:about 1; about 17.2:about 1; about
17.1:about 1; about 17:about 1; about 16.9:about 1; about
16.8:about 1; about 16.7:about 1; about 16.6:about 1; about
16.5:about 1; about 16.4:about 1; about 16.3:about 1; about
16.2:about 1; about 16.1:about 1; about 16:about 1; about
15.9:about 1; about 15.8:about 1; about 15.7:about 1; about
15.6:about 1; about 15.5:about 1; about 15.4:about 1; about
15.3:about 1; about 15.2:about 1; about 15.1:about 1; about
15:about 1; about 14.9:about 1; about 14.8:about 1; about
14.7:about 1; about 14.6:about 1; about 14.5:about 1; about
14.4:about 1; about 14.3:about 1; about 14.2:about 1; about
14.1:about 1; about 14:about 1; about 13.9:about 1; about
13.8:about 1; about 13.7:about 1; about 13.6:about 1; about
13.5:about 1; about 13.4:about 1; about 13.3:about 1; about
13.2:about 1; about 13.1:about 1; about 13:about 1; about
12.9:about 1; about 12.8:about 1; about 12.7:about 1; about
12.6:about 1; about 12.5:about 1; about 12.4:about 1; about
12.3:about 1; about 12.2:about 1; about 12.1:about 1; about
12:about 1; about 11.9:about 1; about 11.8:about 1; about
11.7:about 1; about 11.6:about 1; about 11.5:about 1; about
11.4:about 1; about 11.3:about 1; about 11.2:about 1; about
11.1:about 1; about 11:about 1; about 10.9:about 1; about
10.8:about 1; about 10.7:about 1; about 10.6:about 1; about
10.5:about 1; about 10.4:about 1; about 10.3:about 1; about
10.2:about 1; about 10.1:about 1; about 10:about 1; about 9.9:about
1; about 9.8:about 1; about 9.7:about 1; about 9.6:about 1; about
9.5:about 1; about 9.4:about 1; about 9.3:about 1; about 9.2:about
1; about 9.1:about 1; about 9:about 1; about 8.9:about 1; about
8.8:about 1; about 8.7:about 1; about 8.6:about 1; about 8.5:about
1; about 8.4:about 1; about 8.3:about 1; about 8.2:about 1; about
8.1:about 1; about 8:about 1; about 7.9:about 1; about 7.8:about 1;
about 7.7:about 1; about 7.6:about 1; about 7.5:about 1; about
7.4:about 1; about 7.3:about 1; about 7.2:about 1; about 7.1:about
1; about 7:about 1; about 6.9:about 1; about 6.8:about 1; about
6.7:about 1; about 6.6:about 1; about 6.5:about 1; about 6.4:about
1; about 6.3:about 1; about 6.2:about 1; about 6.1:about 1; about
6:about 1; about 5.9:about 1; about 5.8:about 1; about 5.7:about 1;
about 5.6:about 1; about 5.5:about 1; about 5.4:about 1; about
5.3:about 1; about 5.2:about 1; about 5.1:about 1; about 5:about 1;
about 4.9:about 1; about 4.8:about 1; about 4.7:about 1; about
4.6:about 1; about 4.5:about 1; about 4.4:about 1; about 4.3:about
1; about 4.2:about 1; about 4.1:about 1; about 4:about 1; about
3.9:about 1; about 3.8:about 1; about 3.7:about 1; about 3.6:about
1; about 3.5:about 1; about 3.4:about 1; about 3.3:about 1; about
3.2:about 1; about 3.1:about 1; about 3:about 1; about 2.9:about 1;
about 2.8:about 1; about 2.7:about 1; about 2.6:about 1; about
2.5:about 1; about 2.4:about 1; about 2.3:about 1; about 2.2:about
1; about 2.1:about 1; about 2:about 1; about 1.9:about 1; about
1.8:about 1; about 1.7:about 1; about 1.6:about 1; about 1.5:about
1; about 1.4:about 1; about 1.3:about 1; about 1.2:about 1; about
1.1:about 1; or about 1:about 1.
[1156] As such, the compositions can comprise an amount of
HP.beta.CD suitable for achieving the desired properties of the
composition, i.e., concentration of
4-{(S)-2-[(S)-2-(methoxycarbonyl-amino)-3-phenylpropanamido]-2-(2-ethylth-
iazol-4-yl)ethyl}phenylsulfamic acid, the desired viscosity, the
desired osmolarity and the like. The amount of HP.beta.CD can vary
depending upon the amount of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthi-
azol-4-yl)ethyl}phenylsulfamic acid the formulator desires to
deliver in a single dose.
Carrier System
[1157] The disclosed compositions according to Formulation Example
3 comprise from about 1.5% to about 90% weight by volume of a
carrier system. The amount of carrier system present is based upon
several different factors or choices made by the formulator, for
example, the final concentration of the compound and the amount of
solubilizing agent.
[1158] The following is a non-limiting example of a composition
comprising 60 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthi-
azol-4-yl)ethyl}-phenylsulfamic acid: [1159] a) 60 mg of the
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthi-
azol-4-yl)ethyl}phenylsulfamic acid; [1160] b) 5 mg of
2-hydroxypropyl-beta-cyclodextrin; and [1161] c) the balance a
carrier system to a volume of 1 mL.
[1162] In one aspect, the carrier system comprises: [1163] i) one
or more tonicity agents; and [1164] ii) water.
[1165] Non-limiting examples of tonicity agents include dextrose,
mannitol and glycerin. The formulator can utilize more than one
tonicity agent when formulating the disclosed compositions
according to Formulation Example 3. The tonicity agent can comprise
from about 0.5% to about 5% weight by volume of the final
composition. In non-limiting examples, when preparing the final
composition, the tonicity agent may be combined with
4-{(S)-2-[(S)-2-(methoxycarbonyl-amino)-3-phenylpropanamido]-2-(2-ethylth-
iazol-4-yl)ethyl}phenylsulfamic acid before mixing with the carrier
system. Alternately, when reconstituting the final composition the
formulator can use commercially available solutions containing a
tonicity agent, for example, 5% Dextrose Injection, USP.
[1166] The osmolarity of the disclosed compositions according to
Formulation Example 3 can be within any range chosen by the
formulator. In one aspect the osmolarity is from about 250 to about
350 mOsm/L. In one embodiment of this aspect of the disclosed
osmolarity is from about 270 to about 310 mOsm/L.
[1167] The pH of the disclosed compositions according to
Formulation Example 3 can be from about 6 to about 8. If the pH is
outside the range desired by the formulator, the pH can be adjusted
by using sufficient pharmaceutically acceptable acids and
bases.
[1168] One aspect of the disclosed compositions according to
Formulation Example 3 relates to compositions comprising
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthi-
azol-4-yl)ethyl}phenylsulfamic acid or pharmaceutically acceptable
salts thereof.
[1169] One embodiment of this aspect of the disclosed compositions
according to Formulation Example 3 comprises: [1170] a) from about
42 mg/mL to about 48 mg/mL of the
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthi-
azol-4-yl)ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof; [1171] b) from about 4.2 mg/mL to about
4.8 mg/mL of 2-hydroxypropyl-.beta.-cyclodextrin; and [1172] c) a
carrier system.
[1173] A non-limiting iteration of this embodiment of the disclosed
compositions according to Formulation Example 3 comprises: [1174]
a) about 45 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid; [1175] b) about 4.5
mg/mL of 2-hydroxypropyl-.beta.-cyclodextrin; and [1176] c) a
carrier system.
[1177] One specific example of a composition according to this
iteration comprises: [1178] a) 45 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid; [1179] b) 45 mg/mL
of 2-hydroxypropyl-.beta.-cyclodextrin; and [1180] c) a carrier
system containing: [1181] i) 2% weight to volume of the composition
dextrose; and [1182] ii) water.
[1183] Another embodiment of this aspect of the disclosed
compositions according to Formulation Example 3 comprises: [1184]
a) from about 55 mg/mL to about 65 mg/mL of the
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthi-
azol-4-yl)ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof; [1185] b) from about 110 mg/mL to about 6
mg/mL of 2-hydroxypropyl-.beta.-cyclodextrin; and [1186] c) a
carrier system.
[1187] A non-limiting iteration of this embodiment of the disclosed
compositions according to Formulation Example 3 comprises: [1188]
a) about 60 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid; [1189] b) about 600
mg/mL of 2-hydroxypropyl-.beta.-cyclodextrin; and [1190] c) a
carrier system.
[1191] One specific example of a composition according to this
iteration comprises: [1192] a) 60 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid; [1193] b) 60 mg/mL
of 2-hydroxypropyl-.beta.-cyclodextrin; and [1194] c) a carrier
system containing: [1195] i) 2% weight to volume of the composition
dextrose; and [1196] ii) water.
[1197] A further embodiment of this aspect of the disclosed
compositions according to Formulation Example 3 comprises: [1198]
a) from about 85 mg/mL to about 95 mg/mL of the
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthi-
azol-4-yl)ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof; [1199] b) from about 20 mg/mL to about 30
mg/mL of 2-hydroxypropyl-.beta.-cyclodextrin; and [1200] c) a
carrier system.
[1201] A non-limiting iteration of this embodiment of the disclosed
compositions according to Formulation Example 3 comprises: [1202]
a) about 90 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid; [1203] b) about 1000
mg/mL of 2-hydroxypropyl-.beta.-cyclodextrin; and [1204] c) a
carrier system.
[1205] One specific example of a composition according to this
iteration comprises: [1206] a) 90 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid; [1207] b) 500 mg/mL
of 2-hydroxypropyl-.beta.-cyclodextrin; and [1208] c) a carrier
system containing: [1209] i) 2% weight to volume of the composition
dextrose; and [1210] ii) water.
Formulation Example 4
[1211] This formulation example relates to compositions comprising
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthi-
azol-2-yl)ethyl}phenylsulfamic acid having the formula:
##STR00340##
and pharmaceutically acceptable salts thereof.
[1212] Formulation Example 4 comprises: [1213] a)
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthi-
azol-2-yl)ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof; [1214] b) a solubilizing system; and
[1215] c) a carrier system.
[1216] The compositions of Formulation Example 4 are formulated to
deliver an amount of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthi-
azol-2-yl)ethyl}-phenylsulfamic acid in the free acid form. For
example, a composition which comprises 10 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthi-
azol-2-yl)ethyl}phenylsulfamic acid can have either 10 mg/mL of the
free acid or an amount of a pharmaceutically acceptable salt in an
amount sufficient to deliver 10 mg/mL of the free acid. As an
example, a composition formulated to deliver 10 mg/mL of
4-{(S)-2-[(S)-2-(methoxy-carbonylamino)-3-phenylpropanamido]-2-(4-ethylth-
iazol-2-yl)ethyl}phenylsulfamic acid can comprise either 10 mg/mL
of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthi-
azol-2-yl)ethyl}phenylsulfamic acid or alternatively 10.4 mg/mL of
the sodium salt, (sodium
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthi-
azol-2-yl)ethyl}phenylsulfamate). Therefore, a composition which
delivers from about 0.1 mg/mL to about 90 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthi-
azol-2-yl)ethyl}phenylsulfamic acid can comprise an amount of
pharmaceutically acceptable salt thereof to deliver from about 0.1
mg/mL to about 90 mg/mL of the compound
[1217] Therefore, when a composition according to Formulation
Example 4 comprises an amount of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthi-
azol-2-yl)ethyl}phenylsulfamic acid per mL, it is understood that
this amount is the amount of free acid that is delivered and if a
salt form of the compound is used in the composition, the amount of
the salt form can therefore reflect the difference in molecular
weight between the free acid and the salt form. The following
example demonstrates this equivalency.
[1218] A composition delivering 10 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthi-
azol-2-yl)ethyl}phenylsulfamic acid, comprises: [1219] a) 10 mg/mL
of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthi-
azol-2-yl)ethyl}phenylsulfamic acid; or about 10.4 mg/mL of sodium
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthi-
azol-2-yl)ethyl}phenylsulfamate; or about 10.3 mg/mL, of ammonium
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthi-
azol-2-yl)ethyl}phenylsulfamate, and the like; [1220] b) an amount
of 2-hydroxypropyl-.beta.-cyclodextrin as defined herein; and
[1221] c) a carrier system.
[1222] The disclosed compositions according to Formulation Example
4 according to Formulation Example 4 comprise from about 10 mg/mL
to about 90 mg/mL of the
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[4-ethylthi-
azol-2-yl]ethyl}phenyl-sulfamic acid or a pharmaceutically
acceptable salt thereof.
[1223] In one aspect the disclosed compositions according to
Formulation Example 4 comprise from about 20 mg/mL to about 100
mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[4-ethylthi-
azol-2-yl]ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof. In one embodiment, the composition
comprises from about 15 mg/mL to about 60 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[4-ethylthi-
azol-2-yl]ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof. In another embodiment, the composition
comprises from about 40 mg/mL to about 90 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthi-
azol-2-yl)ethyl}-phenylsulfamic acid or a pharmaceutically
acceptable salt thereof. In a further embodiment, the composition
comprises from about 10 mg/mL to about 30 mg/mL of
4-{(S)-2-[(S)-2-(methoxy-carbonylamino)-3-phenylpropanamido]-2-(4-ethylth-
iazol-2-yl)ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof. In a still further embodiment, the
composition comprises from about 40 mg/mL to about 80 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonyl-1amino)-3-phenylpropanamido]-2-(4-ethylt-
hiazol-2-yl)ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof. In a yet further embodiment the
composition comprises from about 10 mg/mL to about 20 mg/mL weight
by volume of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[4-ethylthi-
azol-2-yl]ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof. In a still yet further embodiment, the
composition comprises from about 60 mg/mL to about 90 mg/mL weight
by volume of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthi-
azol-2-yl)ethyl}phenyl-sulfamic acid or a pharmaceutically
acceptable salt thereof. In still another embodiment, the
composition comprises from about 50 mg/mL to about 80 mg/mL weight
by volume of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthi-
azol-2-yl)ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof.
[1224] Particular embodiments of the disclosed compositions
according to Formulation Example 4, comprise 1 mg/mL, 2 mg/mL, 3
mg/mL, 4 mg/mL, 5 mg/mL, 6 mg/mL, 7 mg/mL, 8 mg/mL, 9 mg/mL, 10
mg/mL, 11 mg/mL 12 mg/mL, 13 mg/mL, 14 mg/mL, 15 mg/mL, 16 mg/mL,
17 mg/mL, 18 mg/mL, 19 mg/mL, 20 mg/mL, 21 mg/mL, 22 mg/mL, 23
mg/mL, 24 mg/mL, 25 mg/mL, 26 mg/mL, 27 mg/mL, 28 mg/mL, 29 mg/mL,
30 mg/mL, 31 mg/mL 32 mg/mL, 33 mg/mL, 34 mg/mL, 35 mg/mL, 36
mg/mL, 37 mg/mL, 38 mg/mL, 39 mg/mL, 40 mg/mL, 41 mg/mL 42 mg/mL,
43 mg/mL, 44 mg/mL, 45 mg/mL, 46 mg/mL, 47 mg/mL, 48 mg/mL, 49
mg/mL, 50 mg/mL, 51 mg/mL 52 mg/mL, 53 mg/mL, 54 mg/mL, 55 mg/mL,
56 mg/mL, 57 mg/mL, 58 mg/mL, 59 mg/mL, 60 mg/mL, 61 mg/mL 62
mg/mL, 63 mg/mL, 64 mg/mL, 65 mg/mL, 66 mg/mL, 67 mg/mL, 68 mg/mL,
69 mg/mL, 70 mg/mL, 71 mg/mL 72 mg/mL, 73 mg/mL, 74 mg/mL, 75
mg/mL, 76 mg/mL, 77 mg/mL, 78 mg/mL, 79 mg/mL, 80 mg/mL, 81 mg/mL
82 mg/mL, 83 mg/mL, 84 mg/mL, 85 mg/mL, 86 mg/mL, 87 mg/mL, 88
mg/mL, 89 mg/mL, and 90 mg/mL, about 1 mg/mL, about 2 mg/mL, about
3 mg/mL, about 4 mg/mL, about 5 mg/mL, about 6 mg/mL, about 7
mg/mL, about 8 mg/mL, about 9 mg/mL, about 10 mg/mL, about 11 mg/mL
about 12 mg/mL, about 13 mg/mL, about 14 mg/mL, about 15 mg/mL,
about 16 mg/mL, about 17 mg/mL, about 18 mg/mL, about 19 mg/mL,
about 20 mg/mL, about 21 mg/mL about 22 mg/mL, about 23 mg/mL,
about 24 mg/mL, about 25 mg/mL, about 26 mg/mL, about 27 mg/mL,
about 28 mg/mL, about 29 mg/mL, about 30 mg/mL, about 31 mg/mL,
about 32 mg/mL, about 33 mg/mL, about 34 mg/mL, about 35 mg/mL,
about 36 mg/mL, about 37 mg/mL, about 38 mg/mL, about 39 mg/mL,
about 40 mg/mL, about 41 mg/mL, about 42 mg/mL, about 43 mg/mL,
about 44 mg/mL, about 45 mg/mL, about 46 mg/mL, about 47 mg/mL,
about 48 mg/mL, about 49 mg/mL, about 50 mg/mL, about 51 mg/mL,
about 52 mg/mL, about 53 mg/mL, about 54 mg/mL, about 55 mg/mL,
about 56 mg/mL, about 57 mg/mL, about 58 mg/mL, about 59 mg/mL,
about 60 mg/mL, about 61 mg/mL, about 62 mg/mL, about 63 mg/mL,
about 64 mg/mL, about 65 mg/mL, about 66 mg/mL, about 67 mg/mL,
about 68 mg/mL, about 69 mg/mL, about 70 mg/mL, about 71 mg/mL,
about 72 mg/mL, about 73 mg/mL, about 74 mg/mL, about 75 mg/mL,
about 76 mg/mL, about 77 mg/mL, about 78 mg/mL, about 79 mg/mL,
about 80 mg/mL, about 81 mg/mL, about 82 mg/mL, about 83 mg/mL,
about 84 mg/mL, about 85 mg/mL, about 86 mg/mL, about 87 mg/mL,
about 88 mg/mL, about 89 mg/mL, and about 90 mg/mL of a compound
herein, such as
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropan-amido]-2-(4-ethylth-
iazol-2-yl)ethyl}phenylsulfamic acid.
Solubilizing Systems
[1225] In one embodiment, the disclosed compositions according to
Formulation Example 4 can comprise from a ratio of about 20 parts
of the compound herein or a pharmaceutically acceptable salt
thereof to about 1 part solubilizing system (about 20:about 1) to
about 1 part of the compound herein or a pharmaceutically
acceptable salt thereof to about 20 parts solubilizing system
(about 1:about 20). The disclosed solubilizing systems can comprise
cyclodextrins, non-limiting examples of which include:
.beta.-cyclodextrin, .beta.-cyclodextrin and .beta.-cyclodextrin
and derivatives thereof. Non-limiting examples of cyclodextrin
derivatives includes methyl-.beta.-cyclodextrin,
2-hydroxypropyl-.beta.-cyclodextrin, sulfobutyl
ether-.beta.-cyclodextrin sodium salt, and
2-hydroxypropyl-.beta.-cyclodextrin.
[1226] The formulator can adjust the ratios of the compound to
HP.beta.CD based upon composition parameters, for example, choice
and amount of a tonicity agent and pH. Suitable ratios are
described above. As such, the compositions can comprise an amount
of solubilizing system suitable for achieving the desired
properties of the composition, i.e., concentration of compound, the
desired viscosity, and the desired osmolarity. The amount of
HP.beta.CD can vary depending upon the amount of compound that the
formulator desires to deliver in a single dose.
Carrier System
[1227] The disclosed compositions according to Formulation Example
4 can comprise from about 1.5% to about 90% weight by volume of a
carrier system. The amount of carrier system present is based upon
several different factors or choices made by the formulator, for
example, the final concentration of the compound and the amount of
solubilizing agent.
[1228] The following is a non-limiting example of a composition
comprising 60 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthi-
azol-2-yl)ethyl}-phenylsulfamic acid: [1229] a) 60 mg of the
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthi-
azol-2-yl)ethyl}phenylsulfamic acid; [1230] b) 360 mg of
2-hydroxypropyl-beta-cyclodextrin; and [1231] c) the balance a
carrier system to a volume of 1 mL.
[1232] In one aspect, the carrier system comprises: [1233] i) one
or more tonicity agents; and [1234] ii) water.
[1235] Non-limiting examples of tonicity agents include dextrose,
mannitol and glycerin. The formulator can utilize more than one
tonicity agent when formulating the disclosed compositions
according to Formulation Example 4. The tonicity agent can comprise
from about 0.5% to about 5% weight by volume of the final
composition. In non-limiting examples, when preparing the final
composition, the tonicity agent may be combined with
4-{(S)-2-[(S)-2-(methoxycarbonyl-amino)-3-phenylpropanamido]-2-(4-ethylth-
iazol-2-yl)ethyl}phenylsulfamic acid before mixing with the carrier
system. Alternately, when reconstituting the final composition the
formulator can use commercially available solutions containing a
tonicity agent, for example, 5% Dextrose Injection.
[1236] The osmolarity of the disclosed compositions according to
Formulation Example 4 can be within any range chosen by the
formulator. In one aspect the osmolarity is from about 250 to about
350 mOsm/L. In one embodiment of this aspect of the disclosed
osmolarity is from about 270 to about 310 mOsm/L.
[1237] The pH of the disclosed compositions according to
Formulation Example 4 can be from about 6 to about 8. If the pH is
outside the range desired by the formulator, the pH can be adjusted
by using sufficient pharmaceutically acceptable acids and
bases.
[1238] One aspect of the disclosed compositions according to
Formulation Example 4 relates to compositions comprising
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthi-
azol-2-yl)ethyl}phenylsulfamic acid or pharmaceutically acceptable
salts thereof.
[1239] One embodiment of this aspect of the disclosed compositions
according to Formulation Example 4 comprises: [1240] a) from about
40 mg/mL to about 45 mg/mL of the
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[4-ethylthi-
azol-2-yl]ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof; [1241] b) from about 120 mg/mL to about
5.2 mg/mL of 2-hydroxypropyl-.beta.-cyclodextrin; and [1242] c) a
carrier system.
[1243] A non-limiting iteration of this embodiment of the disclosed
compositions according to Formulation Example 4 comprises: [1244]
a) about 40 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid; [1245] b) about 240
mg/mL of 2-hydroxypropyl-.beta.-cyclodextrin; and [1246] c) a
carrier system.
[1247] One specific example of a composition according to this
iteration comprises: [1248] a) 40 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid; [1249] b) 240 mg/mL
of 2-hydroxypropyl-.beta.-cyclodextrin; and [1250] c) a carrier
system containing: [1251] i) 2% weight to volume of the composition
dextrose; and [1252] ii) water.
[1253] Another embodiment of this aspect of the disclosed
compositions according to Formulation Example 4 comprises: [1254]
a) from about 55 mg/mL to about 65 mg/mL of the
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[4-ethylthi-
azol-2-yl]ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof; [1255] b) from about 5.5 mg/mL to about
650 mg/mL of 2-hydroxypropyl-.beta.-cyclodextrin; and [1256] c) a
carrier system.
[1257] A non-limiting iteration of this embodiment of the disclosed
compositions according to Formulation Example 4 comprises: [1258]
a) about 60 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[4-ethylthi-
azol-2-yl]ethyl}phenylsulfamic acid; [1259] b) about 30 mg/mL of
2-hydroxypropyl-.beta.-cyclodextrin; and [1260] c) a carrier
system.
[1261] One specific example of a composition according to this
iteration comprises: [1262] a) 60 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[4-ethylthi-
azol-2-yl]ethyl}phenylsulfamic acid; [1263] b) 30 mg/mL of
2-hydroxypropyl-.beta.-cyclodextrin; and [1264] c) a carrier system
containing: [1265] i) 2% weight to volume of the composition
dextrose; and [1266] ii) water.
[1267] A further embodiment of this aspect of the disclosed
compositions according to Formulation Example 4 comprises: [1268]
a) from about 70 mg/mL to about 77 mg/mL of the
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[4-ethylthi-
azol-2-yl]ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof; [1269] b) from about 20 mg/mL to about
1000 mg/mL of 2-hydroxypropyl-.beta.-cyclodextrin; and [1270] c) a
carrier system.
[1271] A non-limiting iteration of this embodiment of the disclosed
compositions according to Formulation Example 4 comprises: [1272]
a) about 74 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[4-ethylthi-
azol-2-yl]ethyl}phenylsulfamic acid; [1273] b) about 225 mg/mL of
2-hydroxypropyl-.beta.-cyclodextrin; and [1274] c) a carrier
system.
[1275] One specific example of a composition according to this
iteration comprises: [1276] a) 74 mg/mL of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[4-ethylthi-
azol-2-yl]ethyl}phenylsulfamic acid; [1277] b) 225 mg/mL of
2-hydroxypropyl-.beta.-cyclodextrin; and [1278] c) a carrier system
containing: [1279] i) 2% weight to volume of the composition
dextrose; and [1280] ii) water.
[1281]
4-{(S)-2-(4-Ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-ph-
enylpropanamido]-ethyl}phenylsulfamic acid can be prepared by the
procedure outlined in Scheme XXV and described in Example 34 herein
below.
##STR00341## ##STR00342##
Example 34
4-{(S)-2-(4-Ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpro-
panamido]ethyl}phenylsulfamic acid (75)
Preparation of Methyl
(S)-1-((S)-1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethylamino)-1-oxo-3-p-
henylpropan-2-ylcarbamate (73)
[1282] To a solution of
1-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl) ethyl amine (3) (307
g, 82%, 1.1 mol), (S)-(2-methoxycarbonylamino)-3-phenylpropionic
acid (333 g, 89%, 1.33 mol, 1.2 eq) and 1-hydroxybenzotriazole
(HOBt) (180 g, 1.33 mol, 1.2 eq) in DMF (5 L) at 0.degree. C., was
added 1-(3-dimethylaminopropyl-3-ethylcarbodiimide (EDCI) (255 g,
1.33 mol, 1.2 eq) followed by diisopropylamine (285 g, 2.2 mol, 2
eq). The mixture was stirred at 0.degree. C. for 30 minutes then at
room temperature overnight. The reaction mixture was diluted with
water (20 L) and extracted with EtOAc (30 L.times.3). The combined
organic phase was washed with 1 N aqueous HCl, 5% aqueous
NaHCO.sub.3, brine and dried over Na.sub.2SO.sub.4. The solvent was
removed in vacuo and the crude product was washed with a small
amount of EtOAc to afford 245 g of the desired product with 94%
HPLC purity. Yield: 56%. LC/MS (M+1): 483; .sup.1H NMR (300 MHz,
CD.sub.3OD): .delta. 8.14-8.11 (d, 2H, J=8.4 Hz), 7.50-7.47 (d, 2H,
J=8.4 Hz), 7.20-7.17 (m, 5H), 7.03 (s, 1H), 5.52-5.47 (m, 1H),
4.35-4.30 (t, 1H, J=7.8 Hz), 3.67-3.54 (m, 4H), 3.25-3.17 (m, 1H),
3.02-2.95 (m, 1H), 2.81-2.74 (m, 3H), 1.31-1.26 (t, 3H, J=7.5
Hz).
Preparation of Methyl
(S)-1-((S)-2-(4-aminophenyl)-1-(4-ethylthiazol-2-yl)ethylamino)-1-oxo-3-p-
henylpropan-2-ylcarbamate (74)
[1283] Methyl
(S)-1-((S)-1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethylamino)-1-oxo-3-p-
henylpropan-2-ylcarbamate (73) (220 g, 0.45 mol) was dissolved in
4.5 L of ethanol. FeCl.sub.3 (15.0 g, 0.09 mol, 0.2 equiv.) and
activated carbon (96.8 g) were added to the above solution. The
resulting mixture was then refluxed while hydrated hydrazine (440
mL, 7.04 mol) was added dropwise during 1 h. The mixture was
refluxed for another 2 h and then cooled down to rt. The activated
carbon was filtered. Filtrate was concentrated under reduced
pressure, diluted with 1 L water and extracted with ethyl acetate,
washed with brine, dried over Na.sub.2SO.sub.4. The combined
organic layer was concentrated and washed with ethyl ether to
afford 10 as off-white solid (163 g, yield: 78.6%). LC/MS (M+1):
453; H NMR (300 MHz, CD.sub.3OD) .delta.: 7.21-6.98 (m, 10H),
5.40-5.38 (t, 1H, J=7.5 Hz), 4.38-4.33 (t, 1H, J=7.5 Hz), 3.70 (s,
3H), 3.24-3.22 (m, 1H), 3.11-3.01 (m, 2H), 2.81-2.72 (m, 3H),
1.32-1.26 (t, 3H, J=7.5 Hz). HPLC: 96.5%.
Preparation of
4-((S)-2-(4-ethylthiazol-2-yl)-2-((S)-2-(methoxycarbonylamino)-3-phenylpr-
opanamido)ethyl)phenylsulfamic acid (75)
[1284] Methyl
(S)-1-((S)-2-(4-aminophenyl)-1-(4-ethylthiazol-2-yl)ethylamino)-1-oxo-3-p-
henylpropan-2-ylcarbamate (74) (123 g, 0.272 mol) and
N-methylmorpholine (50 g, 0.495 mol) were dissolved in 1.1 L of
THF. Me.sub.3NSO.sub.3 complex (58 g, 0.417 mol) was added in one
portion. The resulting mixture was warmed up to 50.degree. C. for 3
hours and then concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (DCM/MeOH=20/1 to
DCM/MeOH=10/1) to give the desired product 11 (150 g, yield: 104%),
which contained a small amount of Me.sub.3N and MeOSO.sub.3H. LC/MS
(M-1): 531; H NMR (300 MHz, CD.sub.3OD) .delta.: 7.21-6.99 (m,
10H), 5.39-5.34 (t, 1H, J=6.0 Hz), 4.39-4.34 (t, 1H, J=8.1 Hz),
3.61 (s, 3H), 3.25-3.23 (m, 1H), 3.10-3.00 (m, 2H), 2.81-2.74 (m,
3H), 1.31-1.26 (t, 3H, J=7.2 Hz); HPLC: 98.1%.
Preparation of sodium
4-{(S)-2-(4-Ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonyl-amino)-3-phenyl--
propanamido]ethyl}phenylsulfamate (76)
[1285] To a solution of
4-((S)-2-(4-ethylthiazol-2-yl)-2-((S)-2-(methoxycarbonylamino)-3-phenylpr-
opanamido)ethyl)-phenylsulfamic acid (75) (150 g, 0.272 mmol) in
methanol (1.2 L) was added 50% NaOH (11.3 g, 0.272 mol, 1.0 equiv.)
at room temperature. The resulting mixture was stirred at rt for 30
min and then concentrated under reduced pressure to give the crude
product, which contained a small amount of Me.sub.3N and
MeOSO.sub.3Na. To a stirred slurry of the crude product (75 g) in
H.sub.2O (150 mL) was added aq. NaOH (2 g, 0.05 mol, in 50 mL
H.sub.2O) in dropwise at room temperature. The slurry was continued
to stir for 20 min, filtered and washed with water (10 mL) and
ethyl ether (50 mL). Then the filter cake was dried under reduced
pressure at 50.degree. C. to give 62 g (83%) of the desired
compound. LC/MS (M-1): 531; H-NMR (300 MHz, CD.sub.3OD) .delta.:
7.21-6.98 (m, 10H), 5.40-5.36 (t, 1H, J=6.9 Hz), 4.38-4.34 (t, 1H,
J=7.5 Hz), 3.61 (s, 3H), 3.24-3.23 (m, 1H), 3.11-3.01 (m, 2H),
2.81-2.74 (m, 3H), 1.31-1.26 (t, 3H, J=7.5 Hz); HPLC: 98.5%.
Methods
[1286] Disclosed are methods for the treatment of diseases or
conditions of the eye, especially diabetic macular edema,
age-related macular degeneration (wet form), choroidal
neovascularization, diabetic retinopathy, ocular ischemia, uveitis,
retinal vein occlusion (central or branch), ocular trauma, surgery
induced edema, surgery induced neovascularization, cystoid macular
edema, ocular ischemia, uveitis, and the like. These diseases or
conditions are characterized by changes in the ocular vasculature
whether progressive or non-progressive, whether a result of an
acute disease or condition, or a chronic disease or condition.
These diseases can be characterized by an increased level of plasma
Vascular Endothelial Growth Factor.
[1287] In some embodiments, the disclosed methods relate to the
administration of the HPTP-.beta. inhibitor or a pharmaceutically
acceptable salt thereof, as well as compositions comprising the
HPTP-.beta. inhibitor or a pharmaceutically acceptable salt
thereof.
[1288] In some embodiments, the methods of the disclosure are drawn
towards co-administration of a HPTP-.beta. inhibitor or a
pharmaceutically acceptable salt thereof which stabilizes the
vasculature against leakage and one or more anti-VEGF agents.
[1289] In some embodiments, the methods of the disclosure are drawn
towards co-administration of a HPTP-.beta. inhibitor or a
pharmaceutically acceptable salt thereof which stabilizes the
vasculature against neovascularization and one or more anti-VEGF
agents.
[1290] In some embodiments, the inhibitor stabilizes the
vasculature against leakage and neovascularization.
[1291] In one embodiment of the disclosed methods, a human subject
with at least one visually impaired eye is treated with from about
0.1 mg to about 100 mg of the HPTP-.beta. inhibitor or a
pharmaceutically acceptable salt thereof via subcutaneous or
intravitreal injection. Improvement of clinical symptoms can be
monitored by one or more methods known to the art, for example,
indirect ophthalmoscopy, fundus photography, fluorescein
angiopathy, electroretinography, external eye examination, slit
lamp biomicroscopy, applanation tonometry, pachymetry, optical
coherence tomography and autorefaction. As described herein, the
dosing can occur at any frequency determined by the administrator.
After cessation of the anti-VEGF agent treatment, subsequent doses
can be administered weekly or monthly, e.g., with a frequency of
2-8 weeks or 1-12 months apart depending upon the response.
[1292] One aspect of the disclosed methods relates to diseases that
are a direct or indirect result of diabetes, inter alia, diabetic
macular edema and diabetic retinopathy. The ocular vasculature of
the diabetic becomes unstable over time leading to conditions such
as non-proliferative retinopathy, macular edema, and proliferative
retinopathy. As fluid leaks into the center of the macula, the part
of the eye where sharp, straight-ahead vision occurs, the buildup
of fluid and the associated protein begin to deposit on or under
the macula. This results in swelling that causes the subject's
central vision to gradually become distorted. This condition is
referred to as "macular edema." Another condition that may occur is
non-proliferative retinopathy in which vascular changes, such as
microaneurysms, outside the macular region of the eye may be
observed.
[1293] These conditions may or may not progress to diabetic
proliferative retinopathy which is characterized by increased
neovascularization. These new blood vessels are fragile and are
susceptible to bleeding. The result is scaring of the retina, as
well as occlusion or total blockage of the light pathway through
the eye due to the over formation of new blood vessels. Typically
subjects having diabetic macular edema are suffering from the
non-proliferative stage of diabetic retinopathy; however, it is not
uncommon for subjects to only begin manifesting macular edema at
the onset of the proliferative stage.
[1294] Diabetic retinopathy is the most common cause of vision loss
in working-aged Americans (Klein R et al., "The Wisconsin
Epidemiologic Study of Diabetic Retinopathy. II. Prevalence and
risk of diabetic retinopathy when age at diagnosis is less than 30
years," Arch. Ophthalmol. 1984, 102:520-526). Severe vision loss
occurs due to tractional retinal detachments that complicate
retinal neovascularization (NV), but the most common cause of
moderate vision loss is diabetic macular edema (DME). The
pathogenesis of diabetic macular edema is not completely
understood, but hypoxia is a contributing factor (Nguyen Q D et
al., "Supplemental inspired oxygen improves diabetic macular edema;
a pilot study," Invest. Ophthalmol. Vis. Sci. 2003, 45:617-624).
Vascular endothelial growth factor (Vegf) is a hypoxia-regulated
gene and VEGF levels are increased in hypoxic or ischemic retina.
Injection of VEGF into mouse eyes causes breakdown of the inner
blood-retinal barrier (See, Derevjanik N L et al. Quantitative
assessment of the integrity of the blood-retinal barrier in mice,
Invest. Ophthalmol. Vis. Sci. 2002, 43:2462-2467) and sustained
release of VEGF in the eyes of monkeys causes macular edema (Ozaki
H et al., "Intravitreal sustained release of VEGF causes retinal
neovascularization in rabbits and breakdown of the blood-retinal
barrier in rabbits and primates," Exp Eye Res 1997, 64:505-517).
This combination of observations in patients and animal models led
to the hypothesis that VEGF plays an important role in the
pathogenesis of diabetic macular edema. This hypothesis has been
confirmed by several clinical trials that have shown that VEGF
antagonists reduce foveal thickening and improve vision in patients
with diabetic macular edema (Nguyen Q D et al., "Vascular
endothelial growth factor is a critical stimulus for diabetic
macular edema," Am. J. Ophthalmol. 2006, 142:961-969; and Nguyen Q
D et al. "Primary End Point (Six Months) Results of the Ranibizumab
for Edema of the mAcula in Diabetes (READ-2) Study," Ophthalmology
2009, 116:2175-2181).
[1295] The effects of VEGF on vascular endothelial cells are
modulated by Tie2 receptors, which are selectively expressed on
vascular endothelial cells and are required for embryonic vascular
development (Dumont D J et al., "Dominant-negative and targeted
null mutations in the endothelial receptor tyrosine kinase, tek,
reveal a critical role in vasculogenesis of the embryo," Genes Dev.
1994, 8:1897-1909). Angiopoietin 1 (Ang1) binds Tie2 with high
affinity and initiates phosphorylation and downstream signaling
(Davis S et al., "Isolation of angiopoietin-1, a ligand for the
TIE2 receptor, by secretion-trap expression cloning," Cell 1996,
87:1161-1169). Mice deficient in Ang1 die around E12.5 with
vascular defects similar to, but less severe than those seen in
Tie2-deficient mice. Angiopoietin 2 (Ang2) binds Tie2 with high
affinity, but does not stimulate phosphorylation in cultured
endothelial cells. It acts as a competitive inhibitor of Ang1 and
transgenic mice overexpressing Ang2 have a phenotype similar to
Ang1-deficient mice. Several lines of evidence indicate that Ang2
is a developmentally- and hypoxia-regulated permissive factor for
VEGF-induced neovascularization in the retina (Hackett S F et al.,
"Angiopoietin 2 expression in the retina: upregulation during
physiologic and pathologic neovascularization," J. Cell. Physiol.
2000, 184:275-284). Double transgenic Tet/opsin/ang2 and
Tet/opsin/ang1 mice with inducible expression of Ang2 or Ang1,
respectively, have also helped to elucidate the role of Tie2 in the
retina (Nambu H et al., "Angiopoietin 1 inhibits ocular
neovascularization and breakdown of the blood-retinal barrier,"
Gene Ther. 2004, 11:865-873). In mice with ischemic retinopathy,
increased expression of Ang2 when VEGF is high (P12-17) increases
retinal neovascularization, but increased expression at P20 when
VEGF levels have come down, hastens regression of retinal
neovascularization and findings were similar in other models of
ocular neovascularization. In contrast, increased expression of
Ang1 suppressed neovascularization and reduced vascular leakage in
several models. Therefore, Ang2 reduces stabilizing signals from
the matrix making endothelial cells dependent upon VEGF and other
soluble stimulators; when VEGF is high, neovascularization is
stimulated and when VEGF is low, neovascularization regresses. In
contrast, Ang1 increases stabilizing signals from the matrix and
makes the vasculature unresponsive to soluble stimulators like
VEGF.
[1296] Angiopoietin 2 binds Tie2, but does not stimulate
phosphorylation and therefore acts as an antagonist under most
circumstances. In the eye, angiopoietin 2 is upregulated at sites
of neovascularization and acts as a permissive factor for VEGF.
Increased expression of VEGF in the retina does not stimulate
sprouting of neovascularization from the superficial or
intermediate capillary beds of the retina or the choriocapillaris,
but does stimulate sprouting from the deep capillary bed where
there is constitutive expression of angiopoietin 2 (Hackett S F et
al., "Angiopoietin-2 plays an important role in retinal
angiogenesis," J. Cell. Physiol. 2002, 192:182-187). Co-expression
of VEGF and angiopoietin 2 at the surface of the retina causes
sprouting of neovascularization from the superficial retinal
capillaries (Oshima Y et al., "Angiopoietin-2 enhances retinal
vessel sensitivity to vascular endothelial growth factor," J. Cell.
Physiol. 2004, 199:412-417). In double transgenic mice with
inducible expression of angiopoietin 2 in the retina, expression of
angiopoietin 2 when VEGF levels were high markedly enhanced
neovascularization and expression of angiopoietin 2 when VEGF
levels were low caused regression of neovascularization. In double
transgenic mice with inducible expression of angiopoietin 1, the
induced expression of angiopoietin 1 in the retina strongly
suppressed VEGF-induced vascular leakage or neovascularization
(Nambu H et al., "Angiopoietin 1 inhibits ocular neovascularization
and breakdown of the blood-retinal barrier," Gene Ther. 2004,
11:865-873). In fact, in mice with high expression of VEGF in the
retina which develop severe NV and retinal detachment, angiopoietin
1 is able to prevent the VEGF-induced detachments.
[1297] Regulation of Tie2 also occurs through an
endothelial-specific phosphatase, vascular endothelial protein
tyrosine phophatase (VE-PTP) in mice (Fachinger G et al.,
"Functional interaction of vascular endothelial-protein-tyrosine
phosphatase with the angiopoietin receptor Tie-2," Oncogene 1999,
18:5948-5943) and its human orthologue human protein tyrosine
phosphatase-.beta. (HPTP-.beta.) (Krueger N X et al., "Structural
diversity and evolution of human receptor-like protein tyrosine
phosphatases," EMBO J. 1990, 9:3241-3252). Mice deficient in VE-PTP
die at E10 with severe defects in vascular remodeling and
maturation of developing vasculature. Silencing of HPTP-.beta. in
cultured human endothelial cells, enhances Ang1-induced
phosphorylation of Tie2 and survival-promoting activity while
hypoxia increases expression of HPTP-.beta. and reduces
Ang1-induced phosphorylation of Tie2 (Yacyshyn O K et al.,
"Thyrosine phosphatase beta regulates angiopoietin-Tie2 signaling
in human endothelial cells," Angiogenesis 2009, 12:25-33).
[1298] Macular degeneration is a condition characterized by a
gradual loss or impairment of eyesight due to cell and tissue
degeneration of the yellow macular region in the center of the
retina. Macular degeneration is often characterized as one of two
types, non-exudative (dry form) or exudative (wet form). Although
both types are bilateral and progressive, each type may reflect
different pathological processes. The wet form of age-related
macular degeneration (AMD) is the most common form of choroidal
neovascularization and a leading cause of blindness in the elderly.
AMD affects millions of Americans over the age of 60, and is the
leading cause of new blindness among the elderly.
[1299] Choroidal neovascular membrane (CNVM) is a problem that is
related to a wide variety of retinal diseases, but is most commonly
linked to age-related macular degeneration. With CNVM, abnormal
blood vessels stemming from the choroid (the blood vessel-rich
tissue layer just beneath the retina) grow up through the retinal
layers. These new vessels are very fragile and break easily,
causing blood and fluid to pool within the layers of the
retina.
[1300] Diabetes (diabetes mellitus) is a metabolic disease caused
by the inability of the pancreas to produce insulin or to use the
insulin that is produced. The most common types of diabetes are
type 1 diabetes (often referred to as Juvenile Onset Diabetes
Mellitus) and type 2 diabetes (often referred to as Adult Onset
Diabetes Mellitus). Type 1 diabetes results from the body's failure
to produce insulin due to loss of insulin producing cells, and
presently requires the person to inject insulin. Type 2 diabetes
generally results from insulin resistance, a condition in which
cells fail to use insulin properly.
[1301] Diabetes can be correlated to a large number of other
conditions, including conditions or diseases of the eye including
diabetic retinopathy (DR) and diabetic macular edema (DME) which
are leading causes of vision loss and blindness in most developed
countries. The increasing number of individuals with diabetes
worldwide suggests that DR and DME continues to be major
contributors to vision loss and associated functional impairment
for years to come.
[1302] Diabetic retinopathy is a complication of diabetes that
results from damage to the blood vessels of the light-sensitive
tissue at the back of the eye (retina). At first, diabetic
retinopathy may cause no symptoms or only mild vision problems.
Eventually, however, diabetic retinopathy can result in blindness.
Diabetic retinopathy can develop in anyone who has type 1 diabetes
or type 2 diabetes.
[1303] At its earliest stage, non-proliferative retinopathy,
microaneurysms occur in the retina's tiny blood vessels. As the
disease progresses, more of these blood vessels become damaged or
blocked and these areas of the retina send signals into the
regional tissue to grow new blood vessels for nourishment. This
stage is called proliferative retinopathy. The new blood vessels
grow along the retina and along the surface of the clear, vitreous
gel that fills the inside of the eye. By themselves, these blood
vessels do not cause symptoms or vision loss. However, they have
thin, fragile walls and without timely treatment, these new blood
vessels can leak blood (whole blood or some constituents thereof)
which can result in severe vision loss and even blindness. Also,
fluid can leak into the center of the macula, the part of the eye
where sharp, straight-ahead vision occurs. The fluid and the
associated protein begin to deposit on or under the macula swell
the patient's central vision becomes distorted. This condition is
called macular edema. It can occur at any stage of diabetic
retinopathy, although it is more likely to occur as the disease
progresses. About half of the people with proliferative retinopathy
also have macular edema.
[1304] Uveitis is a condition in which the uvea becomes inflamed.
The eye is shaped much like a tennis ball, hollow on the inside
with three different layers of tissue surrounding a central cavity.
The outermost is the sclera (white coat of the eye) and the
innermost is the retina. The middle layer between the sclera and
the retina is called the uvea. The uvea contains many of the blood
vessels that nourish the eye. Complications of uveitis include
glaucoma, cataracts or new blood vessel formation
(neovascularization).
[1305] Ocular trauma is any sort of physical or chemical injury to
the eye. Ocular trauma can affect anyone and major symptoms include
redness or pain in the affected eye. Neither symptom may occur if
tiny projectiles are the cause of the trauma.
[1306] Surgery-induced edema is the development of swelling in the
eye tissues following surgery on the retina or other part of the
eye. Cystoid macular edema (CME) is an example of this phenomenon.
CME can occur not only in people who have had cataract surgery, but
also those with diabetes, retinitis pigmentosa, AMD, or conditions
that cause chronic inflammation in the eye. The major symptoms of
CME are blurred or decreased central vision.
[1307] Ocular ischemic syndrome (OIS) encompasses the signs and
symptoms that result from chronic vascular insufficiency. It is
caused by ocular hypoperfusion due to occlusion or stenosis of the
common or internal carotid arteries. OIS generally affects those
between the ages of 50-80 and they may also have systemic diseases
such as hypertension or diabetes. The major symptoms of OIS are
orbital pain, vision loss, changes of the visual field, asymmetric
cataract, and sluggish reaction to light, among a variety of other
symptoms.
[1308] Retinal vein occlusion (RVO) is the most common retinal
vascular disease after diabetic retinopathy. Depending on the area
of retinal venous drainage effectively occluded, it is broadly
classified as either central retinal vein occlusion (CRVO),
hemispheric retinal vein occlusion (HRVO), or branch retinal vein
occlusion (BRVO). It has been observed that each of these has two
subtypes. Presentation of RVO in general is with variable painless
visual loss with any combination of fundal findings consisting of
retinal vascular tortuosity, retinal hemorrhages (blot and flame
shaped), cotton wool spots, optic disc swelling and macular edema.
In a CRVO, retinal hemorrhages can be found in all four quadrants
of the fundus, whilst these are restricted to either the superior
or inferior fundal hemisphere in a HRVO. In a BRVO, hemorrhages are
largely localized to the area drained by the occluded branch
retinal vein. Vision loss occurs secondary to macular edema or
ischemia.
[1309] Angiogenesis, the process of creating new blood vessels from
pre-existing vessels, is essential to a wide range of physiological
and pathological events including embryological development,
menstruation, wound healing, and tumor growth. Most, if not all,
tumors require angiogenesis to grow and proliferate. VEGF has been
shown to a major factor in angiogenesis where it can increase
vessel permeability and capillary number. Due to the essential
function of angiogenesis in tumor development, much effort has been
put forth to develop therapies that target regulators of
angiogenesis, including VEGF.
[1310] Vascular endothelial growth factor (VEGF) is a protein that
is primarily found in endothelial cells and has functions in
vasculogenesis, angiogenesis, and permeabilization of blood
vessels. The expression of VEGF is induced by hypoxia, activated
oncogenes, and cytokines. It has been found that VEGF activation
not only leads to angiogenesis in normal human cells and tissues,
but also angiogenesis in tumors, allowing for tumor progression and
growth. Inhibition of VEGF inhibits tumor growth leading to tumor
regression. A variety of retinopathies are associated with
increased levels of VEGF; ischemia in the eye leads to an induction
of VEGF production due to lack of oxygen. This increase in VEGF can
cause hyperproliferation of blood vessels in the retina, eventually
leading to blindness. The disclosed HPTP-.beta. inhibitors act to
stabilize ocular vasculature and, in some embodiments, a compound
of the invention serves to counter act the stimulation caused by
VEGF and other inflammatory agents that can be present in the
diseased retina. In some embodiments, administration of HPTP-.beta.
inhibitors to a subject can be used to maintain the level of
disease reversal after administration of anti-VEGF drugs to the
subject have been withdrawn.
[1311] Diabetic retinopathy, if left untreated, can lead ultimately
to blindness. Indeed, diabetic retinopathy is the leading cause of
blindness in working-age populations.
[1312] Therefore, the disclosed methods relate to preventing,
treating, controlling, abating, and/or otherwise minimizing ocular
neovascularization in a subject having diabetes or a subject
diagnosed with diabetes. In addition, subjects having or subjects
diagnosed with diabetes can be alerted to or can be made aware of
the risks of developing diabetes-related blindness, therefore the
present methods can be used to prevent or delay the onset of
non-proliferative retinopathy in subjects known to be at risk.
Likewise, the present methods can be used for treating subjects
having or being diagnosed with non-proliferative diabetic
retinopathy to prevent progression of the condition.
[1313] The disclosed methods relate to preventing or controlling
ocular neovascularization or treating a disease or condition that
is related to the onset of ocular neovascularization by
administering to a subject the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid s and one or more
anti-VEGF agents as disclosed herein.
[1314] Unlike previous ocular treatments which comprise
administration of an anti-VEGF agent, inter alia, ranibizumab
(Lucentis.TM.), bevacizumab (Avastin.TM.) and aflibercept
(Eylea.TM.), wherein these vascular leak inhibitors are injected
directly into the eye itself, the HPTP-.beta. inhibitor or a
pharmaceutically acceptable salt thereof can be administered
systemically or into the eye. The HPTP-.beta. inhibitor or a
pharmaceutically acceptable salt thereof can be used to increase or
enhance the effect of anti-VEGF agents, thereby improving the rate
and magnitude of the response and reducing the number of
treatments.
[1315] In one aspect, the HPTP-.beta. inhibitor or a
pharmaceutically acceptable salt thereof are administered in
combination with one or more pharmaceutical compounds or
compositions useful for treating ocular diseases. In one
embodiment, the present disclosure relates to a method for treating
an ocular disease, comprising administering: [1316] a) a
HPTP-.beta. inhibitor or a pharmaceutically acceptable salt
thereof; and [1317] b) ranibizumab.
[1318] In one aspect of the disclosure the methods comprise
administering: [1319] a) a HPTP-.beta. inhibitor or a
pharmaceutically acceptable salt thereof as disclosed herein; and
[1320] b) ranibizumab.
[1321] In another aspect the methods comprise administering: [1322]
a) a HPTP-.beta. inhibitor having the formula:
[1322] ##STR00343## [1323] wherein R.sup.2 and R.sup.4 are chosen
from: [1324] i) hydrogen; [1325] ii) substituted or unsubstituted
C.sub.1-C.sub.6 linear, C.sub.3-C.sub.6 branched, or
C.sub.3-C.sub.6 cyclic alkyl; [1326] iii) substituted or
unsubstituted phenyl; or [1327] iv) substituted or unsubstituted
thiophenyl; [1328] R.sup.1 is C.sub.1-C.sub.6 linear,
C.sub.3-C.sub.6 branched, or C.sub.3-C.sub.6 cyclic alkyl; [1329]
R.sup.5a is chosen from: [1330] i) hydrogen; [1331] ii)
C.sub.1-C.sub.6 linear, C.sub.3-C.sub.6 branched, or
C.sub.3-C.sub.6 cyclic alkyl; or [1332] iii) benzyl; or [1333] a
pharmaceutically acceptable salt thereof; and [1334] b)
ranibizumab.
[1335] A non-limiting embodiment of this aspect relates to methods
comprising administering: [1336] a) a HPTP-.beta. inhibitor having
the formula:
[1336] ##STR00344## [1337] wherein R.sup.2 and R.sup.4 are chosen
from: [1338] i) hydrogen; [1339] ii) substituted or unsubstituted
C.sub.1-C.sub.6 linear, C.sub.3-C.sub.6 branched, or
C.sub.3-C.sub.6 cyclic alkyl; [1340] iii) substituted or
unsubstituted phenyl; or [1341] iv) substituted or unsubstituted
thiophenyl; [1342] R.sup.1 is C.sub.1-C.sub.6 linear,
C.sub.3-C.sub.6 branched, or C.sub.3-C.sub.6 cyclic alkyl; or
[1343] a pharmaceutically acceptable salt; and [1344] b)
ranibizumab.
[1345] The compounds can be administered in any order convenient to
the user or to the subject receiving treatment. In one non-limiting
example of the disclosed methods, a compound herein or a
pharmaceutically acceptable salt thereof is administered first
followed by administration of ranibizumab. In another iteration of
this embodiment ranibizumab is administered first followed by
administration of the compound herein or a pharmaceutically
acceptable salt thereof. The time period between
dosing/administration of the first component of treatment can be
any time period convenient to the formulator or subject receiving
treatment. For example, the compound herein or a pharmaceutically
acceptable salt thereof can be administered minutes, hours, days or
weeks prior to the administration of ranibizumab or more than one
dosage of the compound herein or a pharmaceutically acceptable salt
thereof can be given to establish a therapeutic amount in the
subject being treated.
[1346] In another iteration, a compound herein or a
pharmaceutically acceptable salt thereof and ranibizumab can be
given in alternating administrations. For example, the compound
herein or a pharmaceutically acceptable salt thereof can be
administered then after a time desired by the administrator
ranibizumab is administered.
[1347] In a further iteration, the compound herein or a
pharmaceutically acceptable salt thereof are administered daily in
one or more doses and the ramibizumab is administered according to
a separate schedule. For example, in addition to daily dosing of
the compound herein, ranibizumab can be administered once a month,
once every 2 months, once every 3 months, once every 4 months, once
every 6 months, etc.
[1348] In another non-limiting example of the disclosed methods, a
compound herein or a pharmaceutically acceptable salt thereof is
administered first followed by administration of ranibizumab. In
another iteration of this embodiment, ranibizumab is administered
first followed by administration of the compound herein or a
pharmaceutically acceptable salt thereof. The time period between
dosing/administration of the first component of treatment can be
any time period convenient to the formulator or subject receiving
treatment. For example, the compound herein or a pharmaceutically
acceptable salt thereof can be administered minutes, hours, days or
weeks prior to the administration of ranibizumab or more than one
dosage of the compound herein or a pharmaceutically acceptable salt
thereof can be given to establish a therapeutic amount in the
subject being treated.
[1349] In another iteration, the compound herein or a
pharmaceutically acceptable salt thereof and ranibizumab can be
given in alternating administrations. For example, the compound
herein or a pharmaceutically acceptable salt thereof can be
administered then after a time desired by the administrator
ranibizumab is administered.
[1350] In a further iteration, the compound herein or a
pharmaceutically acceptable salt thereof are administered daily in
one or more doses and the ramibizumab is administered according to
a separate schedule. For example, in addition to daily dosing of
the compound herein, ranibizumab can be administered once a month,
once every 2 months, once every 3 months, once every 4 months, once
every 6 months, etc.
[1351] In a further non-limiting example of the disclosed methods,
a compound herein or a pharmaceutically acceptable salt thereof is
administered first followed by administration of ranibizumab. In
another iteration of this embodiment ranibizumab is administered
first followed by administration of the compound herein or a
pharmaceutically acceptable salt thereof. The time period between
dosing/administration of the first component of treatment can be
any time period convenient to the formulator or subject receiving
treatment. For example, the compound herein or a pharmaceutically
acceptable salt thereof can be administered minutes, hours, days or
weeks prior to the administration of ranibizumab or more than one
dosage of the compound herein or a pharmaceutically acceptable salt
thereof can be given to establish a therapeutic amount in the
subject being treated.
[1352] In another iteration, the compound herein or a
pharmaceutically acceptable salt thereof and ranibizumab can be
given in alternating administrations. For example, the compound
herein or a pharmaceutically acceptable salt thereof can be
administered then after a time desired by the administrator
ranibizumab is administered.
[1353] In a further iteration, the compound herein or a
pharmaceutically acceptable salt thereof are administered daily in
one or more doses and the ramibizumab is administered according to
a separate schedule. For example, in addition to daily dosing of
the compound herein, ranibizumab can be administered once a month,
once every 2 months, once every 3 months, once every 4 months, once
every 6 months, etc.
[1354] The dosage for ranibizumab can be in any amount necessary.
In one embodiment, ranibizumab is administered in an amount from
about 0.05 mg to about 1.5 mg. In a further embodiment, ranibizumab
is administered in an amount from about 0.1 mg to about 1.5 mg. In
another embodiment, ranibizumab is administered in an amount from
about 0.05 mg to about 1 mg. In a still further embodiment,
ranibizumab is administered in an amount from about 0.1 mg to about
1 mg. In one non-limiting example, ranibizumab is administered in
an amount of approximately 0.5 mg. The amount of an antibody, such
as ranibizumab, administered per treatment can be in any amount,
for example, about 0.05 mg, about 0.06 mg, about 0.07 mg, about
0.08 mg, about 0.09 mg, about 0.1 mg, about 0.11 mg, about 0.12 mg,
about 0.13 mg, about 0.14 mg, about 0.15 mg, about 0.16 mg, about
0.17, mg, about 0.18 mg, about 0.19 mg, about 0.2 mg, about 0.21
mg, about 0.22 mg, about 0.23 mg, about 0.24 mg, about 0.25 mg,
about 0.26 mg, about 0.27, mg, about 0.28 mg, about 0.29 mg, about
0.3 mg, about 0.31 mg, about 0.32 mg, about 0.33 mg, about 0.34 mg,
about 0.35 mg, about 0.36 mg, about 0.37, mg, about 0.38 mg, about
0.39 mg, about 0.4 mg, about 0.41 mg, about 0.42 mg, about 0.43 mg,
about 0.44 mg, about 0.45 mg, about 0.46 mg, about 0.47, mg, about
0.48 mg, about 0.49 mg, about 0.5 mg, about 0.51 mg, about 0.52 mg,
about 0.53 mg, about 0.54 mg, about 0.55 mg, about 0.56 mg, about
0.57, mg, about 0.58 mg, about 0.59 mg, about 0.6 mg, about 0.61
mg, about 0.62 mg, about 0.63 mg, about 0.64 mg, about 0.65 mg,
about 0.66 mg, about 0.67, mg, about 0.68 mg, about 0.69 mg, about
0.7 mg, about 0.71 mg, about 0.72 mg, about 0.73 mg, about 0.74 mg,
about 0.75 mg, about 0.76 mg, about 0.77, mg, about 0.78 mg, about
0.79 mg, about 0.8 mg, about 0.81 mg, about 0.82 mg, about 0.83 mg,
about 0.84 mg, about 0.85 mg, about 0.86 mg, about 0.87, mg, about
0.88 mg, about 0.89 mg, about 0.9 mg, about 0.91 mg, about 0.92 mg,
about 0.93 mg, about 0.94 mg, about 0.95 mg, about 0.96 mg, about
0.97, mg, about 0.98 mg, about 0.99 mg, about 1 mg, about 1.5 mg,
about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg,
about 4.5 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about
9 mg, or about 10 mg.
[1355] If the antibody is not administered simultaneously with the
other compound herein, then the time between administration of the
compound and the antibody can range, for example, from about 1
minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5
minutes, about 10 minutes, about 15 minutes, about 20 minutes,
about 25 minutes, about 30 minutes, about 40 minutes, about 50
minutes, about 60 minutes, about 2 hours, about 3 hours, about 4
hours, about 5 hours, about 10 hours, about 20 hours, about 1 day,
about 2 days, about 3 days, about 4 days, about 5 days, about 6
days, about 1 week, about 2 weeks, about 3 weeks, to about 4
weeks.
[1356] In another embodiment, the present disclosure relates to a
method for treating an ocular disease, comprising administering:
[1357] a) a HPTP-.beta. inhibitor or a pharmaceutically acceptable
salt thereof; and [1358] b) bevacizumab.
[1359] In one aspect of the disclosure the methods comprise
administering: [1360] a) a HPTP-.beta. inhibitor or a
pharmaceutically acceptable salt thereof as disclosed herein; and
[1361] b) bevacizumab.
[1362] In another aspect the methods comprise administering: [1363]
a) a HPTP-.beta. inhibitor having the formula:
[1363] ##STR00345## [1364] wherein R.sup.2 and R.sup.4 are chosen
from: [1365] i) hydrogen; [1366] ii) substituted or unsubstituted
C.sub.1-C.sub.6 linear, C.sub.3-C.sub.6 branched, or
C.sub.3-C.sub.6 cyclic alkyl; [1367] iii) substituted or
unsubstituted phenyl; or [1368] iv) substituted or unsubstituted
thiophenyl; [1369] R.sup.1 is C.sub.1-C.sub.6 linear,
C.sub.3-C.sub.6 branched, or C.sub.3-C.sub.6 cyclic alkyl; [1370]
R.sup.5a is chosen from: [1371] i) hydrogen; [1372] ii)
C.sub.1-C.sub.6 linear, C.sub.3-C.sub.6 branched, or
C.sub.3-C.sub.6 cyclic alkyl; or [1373] iii) benzyl; or [1374] a
pharmaceutically acceptable salt thereof; and [1375] b)
bevacizumab.
[1376] A non-limiting embodiment of this aspect relates to methods
comprising administering: [1377] a) a HPTP-.beta. inhibitor having
the formula:
[1377] ##STR00346## [1378] wherein R.sup.2 and R.sup.4 are chosen
from: [1379] i) hydrogen; [1380] ii) substituted or unsubstituted
C.sub.1-C.sub.6 linear, C.sub.3-C.sub.6 branched, or
C.sub.3-C.sub.6 cyclic alkyl; [1381] iii) substituted or
unsubstituted phenyl; or [1382] iv) substituted or unsubstituted
thiophenyl; [1383] R.sup.1 is C.sub.1-C.sub.6 linear,
C.sub.3-C.sub.6 branched, or C.sub.3-C.sub.6 cyclic alkyl; or
[1384] a pharmaceutically acceptable salt; and [1385] b)
bevacizumab.
[1386] The compounds can be administered in any order convenient to
the user or to the subject receiving treatment. In one non-limiting
example of the disclosed methods
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof is administered first followed by
administration of bevacizumab. In another iteration of this
embodiment bevacizumab is administered first followed by
administration of the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof. The time period between
dosing/administration of the first component of treatment can be
any time period convenient to the formulator or subject receiving
treatment. For example, the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof can be administered minutes, hours, days or
weeks prior to the administration of bevacizumab or more than one
dosage of the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof can be given to establish a therapeutic
amount in the subject being treated.
[1387] In another iteration, the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof and bevacizumab can be given in alternating
administrations. For example, the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof can be administered then after a time
desired by the administrator bevacizumab is administered.
[1388] In a further iteration, the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof are administered daily in one or more doses
and the ramibizumab is administered according to a separate
schedule. For example, in addition to daily dosing of the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid s, bevacizumab can be
administered once a month, once every 2 months, once every 3
months, once every 4 months, once every 6 months, etc.
[1389] In another non-limiting example of the disclosed methods
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthia-
zol-4-yl)ethyl}phenylsulfamic acid or a pharmaceutically acceptable
salt thereof is administered first followed by administration of
bevacizumab. In another iteration of this embodiment bevacizumab is
administered first followed by administration of the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthia-
zol-4-yl)ethyl}phenylsulfamic acid or a pharmaceutically acceptable
salt thereof. The time period between dosing/administration of the
first component of treatment can be any time period convenient to
the formulator or subject receiving treatment. For example, the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthia-
zol-4-yl)ethyl}phenylsulfamic acid or a pharmaceutically acceptable
salt thereof can be administered minutes, hours, days or weeks
prior to the administration of bevacizumab or more than one dosage
of the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthia-
zol-4-yl)ethyl}phenylsulfamic acid or a pharmaceutically acceptable
salt thereof can be given to establish a therapeutic amount in the
subject being treated.
[1390] In another iteration, the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthia-
zol-4-yl)ethyl}phenylsulfamic acid or a pharmaceutically acceptable
salt thereof and bevacizumab can be given in alternating
administrations. For example, the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthia-
zol-4-yl)ethyl}phenylsulfamic acid or a pharmaceutically acceptable
salt thereof can be administered then after a time desired by the
administrator bevacizumab is administered.
[1391] In a further iteration, the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthia-
zol-4-yl)ethyl}phenylsulfamic acid or a pharmaceutically acceptable
salt thereof are administered daily in one or more doses and the
ramibizumab is administered according to a separate schedule. For
example, in addition to daily dosing of the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthia-
zol-4-yl)ethyl}phenylsulfamic acid s, bevacizumab can be
administered once a month, once every 2 months, once every 3
months, once every 4 months, once every 6 months, etc.
[1392] In a further non-limiting example of the disclosed methods
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthia-
zol-2-yl)ethyl}phenylsulfamic acid or a pharmaceutically acceptable
salt thereof is administered first followed by administration of
bevacizumab. In another iteration of this embodiment bevacizumab is
administered first followed by administration of the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthia-
zol-2-yl)ethyl}phenylsulfamic acid or a pharmaceutically acceptable
salt thereof. The time period between dosing/administration of the
first component of treatment can be any time period convenient to
the formulator or subject receiving treatment. For example, the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthia-
zol-2-yl)ethyl}phenylsulfamic acid or a pharmaceutically acceptable
salt thereof can be administered minutes, hours, days or weeks
prior to the administration of bevacizumab or more than one dosage
of the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthia-
zol-2-yl)ethyl}phenylsulfamic acid or a pharmaceutically acceptable
salt thereof can be given to establish a therapeutic amount in the
subject being treated.
[1393] In another iteration, the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthia-
zol-2-yl)ethyl}phenylsulfamic acid or a pharmaceutically acceptable
salt thereof and bevacizumab can be given in alternating
administrations. For example, the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthia-
zol-2-yl)ethyl}phenylsulfamic acid or a pharmaceutically acceptable
salt thereof can be administered then after a time desired by the
administrator bevacizumab is administered.
[1394] In a further iteration, the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthia-
zol-2-yl)ethyl}phenylsulfamic acid or a pharmaceutically acceptable
salt thereof are administered daily in one or more doses and the
ramibizumab is administered according to a separate schedule. For
example, in addition to daily dosing of
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthia-
zol-2-yl)ethyl}phenylsulfamic acid or a pharmaceutically acceptable
salt thereof, bevacizumab can be administered once a month, once
every 2 months, once every 3 months, once every 4 months, once
every 6 months, etc.
[1395] The dosage for bevacizumab can be in any amount necessary.
In one embodiment, bevacizumab is administered in an amount from
about 0.1 mg to about 5 mg. In a further embodiment, bevacizumab is
administered in an amount from about 0.1 mg to about 3 mg. In
another embodiment, bevacizumab is administered in an amount from
about 0.5 mg to about 3 mg. In a still further embodiment,
bevacizumab is administered in an amount from about 0.5 mg to about
2 mg. In one non-limiting example, bevacizumab is administered in
an amount of 1.2 mg. The amount of bevacizumab administered per
treatment can be in any amount, for example, about 0.5 mg, about
0.51 mg, about 0.52 mg, about 0.53 mg, about 0.54 mg, about 0.55
mg, about 0.56 mg, about 0.57, mg, about 0.58 mg, about 0.59 mg,
about 0.6 mg, about 0.61 mg, about 0.62 mg, about 0.63 mg, about
0.64 mg, about 0.65 mg, about 0.66 mg, about 0.67, mg, about 0.68
mg, about 0.69 mg, about 0.7 mg, about 0.71 mg, about 0.72 mg,
about 0.73 mg, about 0.74 mg, about 0.75 mg, about 0.76 mg, about
0.77, mg, about 0.78 mg, about 0.79 mg, about 0.8 mg, about 0.81
mg, about 0.82 mg, about 0.83 mg, about 0.84 mg, about 0.85 mg,
about 0.86 mg, about 0.87, mg, about 0.88 mg, about 0.89 mg, about
0.9 mg, about 0.91 mg, about 0.92 mg, about 0.93 mg, about 0.94 mg,
about 0.95 mg, about 0.96 mg, about 0.97, mg, about 0.98 mg, about
0.99 mg, about 1 mg, about 1.01 mg, about 1.02 mg, about 1.03 mg,
about 1.04 mg, about 1.05 mg, about 1.06 mg, about 1.07, mg, about
1.08 mg, about 1.09 mg, 1.1 mg, about 1.11 mg, about 1.12 mg, about
1.13 mg, about 1.14 mg, about 1.15 mg, about 1.16 mg, about 1.17,
mg, about 1.18 mg, about 1.19 mg, about 1.2 mg, about 1.21 mg,
about 1.22 mg, about 1.23 mg, about 1.24 mg, about 1.25 mg, about
1.26 mg, about 1.27, mg, about 1.28 mg, about 1.29 mg, about 1.3
mg, about 1.31 mg, about 1.32 mg, about 1.33 mg, about 1.34 mg,
about 1.35 mg, about 1.36 mg, about 1.37, mg, about 1.38 mg, about
1.39 mg, about 1.4 mg, about 1.41 mg, about 1.42 mg, about 1.43 mg,
about 1.44 mg, about 1.45 mg, about 1.46 mg, about 1.47, mg, about
1.48 mg, about 1.49 mg, about 1.5 mg, about 1.51 mg, about 1.52 mg,
about 1.53 mg, about 1.54 mg, about 1.55 mg, about 1.56 mg, about
1.57, mg, about 1.58 mg, about 1.59 mg, or about 1.6 mg.
[1396] In another embodiment, the present disclosure relates to a
method for treating an ocular disease, comprising administering:
[1397] a) a HPTP-.beta. inhibitor or a pharmaceutically acceptable
salt thereof; and [1398] b) aflibercept.
[1399] In one aspect of the disclosure the methods comprise
administering: [1400] a) a HPTP-.beta. inhibitor or a
pharmaceutically acceptable salt thereof as disclosed herein; and
[1401] b) aflibercept.
[1402] In another aspect the methods comprise administering: [1403]
a) a HPTP-.beta. inhibitor having the formula:
[1403] ##STR00347## [1404] wherein R.sup.2 and R.sup.4 are chosen
from: [1405] i) hydrogen; [1406] ii) substituted or unsubstituted
C.sub.1-C.sub.6 linear, C.sub.3-C.sub.6 branched, or
C.sub.3-C.sub.6 cyclic alkyl; [1407] iii) substituted or
unsubstituted phenyl; or [1408] iv) substituted or unsubstituted
thiophenyl; [1409] R.sup.1 is C.sub.1-C.sub.6 linear,
C.sub.3-C.sub.6 branched, or C.sub.3-C.sub.6 cyclic alkyl; [1410]
R.sup.5a is chosen from: [1411] i) hydrogen; [1412] ii)
C.sub.1-C.sub.6 linear, C.sub.3-C.sub.6 branched, or
C.sub.3-C.sub.6 cyclic alkyl; or [1413] iii) benzyl; or [1414] a
pharmaceutically acceptable salt thereof; and [1415] b)
aflibercept.
[1416] A non-limiting embodiment of this aspect relates to methods
comprising administering: [1417] a) a HPTP-.beta. inhibitor having
the formula:
[1417] ##STR00348## [1418] wherein R.sup.2 and R.sup.4 are chosen
from: [1419] i) hydrogen; [1420] ii) substituted or unsubstituted
C.sub.1-C.sub.6 linear, C.sub.3-C.sub.6 branched, or
C.sub.3-C.sub.6 cyclic alkyl; [1421] iii) substituted or
unsubstituted phenyl; or [1422] iv) substituted or unsubstituted
thiophenyl; [1423] R.sup.1 is C.sub.1-C.sub.6 linear,
C.sub.3-C.sub.6 branched, or C.sub.3-C.sub.6 cyclic alkyl; or
[1424] a pharmaceutically acceptable salt; and [1425] b)
aflibercept.
[1426] The compounds can be administered in any order convenient to
the user or to the subject receiving treatment. In one non-limiting
example of the disclosed methods
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof is administered first followed by
administration of aflibercept. In another iteration of this
embodiment aflibercept is administered first followed by
administration of the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof. The time period between
dosing/administration of the first component of treatment can be
any time period convenient to the formulator or subject receiving
treatment. For example, the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof can be administered minutes, hours, days or
weeks prior to the administration of aflibercept or more than one
dosage of the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof can be given to establish a therapeutic
amount in the subject being treated.
[1427] In another iteration, the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof and aflibercept can be given in alternating
administrations. For example, the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof can be administered then after a time
desired by the administrator aflibercept is administered.
[1428] In a further iteration, the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid or a pharmaceutically
acceptable salt thereof are administered daily in one or more doses
and the ramibizumab is administered according to a separate
schedule. For example, in addition to daily dosing of the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid s, aflibercept can be
administered once a month, once every 2 months, once every 3
months, once every 4 months, once every 6 months, etc.
[1429] In another non-limiting example of the disclosed methods
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthia-
zol-4-yl)ethyl}phenylsulfamic acid or a pharmaceutically acceptable
salt thereof is administered first followed by administration of
aflibercept. In another iteration of this embodiment aflibercept is
administered first followed by administration of the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthia-
zol-4-yl)ethyl}phenylsulfamic acid or a pharmaceutically acceptable
salt thereof. The time period between dosing/administration of the
first component of treatment can be any time period convenient to
the formulator or subject receiving treatment. For example, the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthia-
zol-4-yl)ethyl}phenylsulfamic acid or a pharmaceutically acceptable
salt thereof can be administered minutes, hours, days or weeks
prior to the administration of aflibercept or more than one dosage
of the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthia-
zol-4-yl)ethyl}phenylsulfamic acid or a pharmaceutically acceptable
salt thereof can be given to establish a therapeutic amount in the
subject being treated.
[1430] In another iteration, the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthia-
zol-4-yl)ethyl}phenylsulfamic acid or a pharmaceutically acceptable
salt thereof and aflibercept can be given in alternating
administrations. For example, the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthia-
zol-4-yl)ethyl}phenylsulfamic acid or a pharmaceutically acceptable
salt thereof can be administered then after a time desired by the
administrator aflibercept is administered.
[1431] In a further iteration, the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthia-
zol-4-yl)ethyl}phenylsulfamic acid or a pharmaceutically acceptable
salt thereof are administered daily in one or more doses and the
ramibizumab is administered according to a separate schedule. For
example, in addition to daily dosing of the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthia-
zol-4-yl)ethyl}phenylsulfamic acid s, aflibercept can be
administered once a month, once every 2 months, once every 3
months, once every 4 months, once every 6 months, etc.
[1432] In a further non-limiting example of the disclosed methods
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthia-
zol-2-yl)ethyl}phenylsulfamic acid or a pharmaceutically acceptable
salt thereof is administered first followed by administration of
aflibercept. In another iteration of this embodiment aflibercept is
administered first followed by administration of the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthia-
zol-2-yl)ethyl}phenylsulfamic acid or a pharmaceutically acceptable
salt thereof. The time period between dosing/administration of the
first component of treatment can be any time period convenient to
the formulator or subject receiving treatment. For example, the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthia-
zol-2-yl)ethyl}phenylsulfamic acid or a pharmaceutically acceptable
salt thereof can be administered minutes, hours, days or weeks
prior to the administration of aflibercept or more than one dosage
of the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthia-
zol-2-yl)ethyl}phenylsulfamic acid or a pharmaceutically acceptable
salt thereof can be given to establish a therapeutic amount in the
subject being treated.
[1433] In another iteration, the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthia-
zol-2-yl)ethyl}phenylsulfamic acid or a pharmaceutically acceptable
salt thereof and aflibercept can be given in alternating
administrations. For example, the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthia-
zol-2-yl)ethyl}phenylsulfamic acid or a pharmaceutically acceptable
salt thereof can be administered then after a time desired by the
administrator aflibercept is administered.
[1434] In a further iteration, the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthia-
zol-2-yl)ethyl}phenylsulfamic acid or a pharmaceutically acceptable
salt thereof are administered daily in one or more doses and the
ramibizumab is administered according to a separate schedule. For
example, in addition to daily dosing of the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-(4-ethylthia-
zol-2-yl)ethyl}phenylsulfamic acid s, aflibercept can be
administered once a month, once every 2 months, once every 3
months, once every 4 months, once every 6 months, etc.
[1435] The dosage for aflibercept can be in any amount necessary.
In one embodiment, aflibercept is administered in an amount from
about 0.05 mg to about 5 mg. In a further embodiment, aflibercept
is administered in an amount from about 0.1 mg to about 3 mg. In
another embodiment, aflibercept is administered in an amount from
about 0.5 mg to about 2.5 mg. In a still further embodiment,
aflibercept is administered in an amount from about 0.5 mg to about
2 mg. The amount of aflibercept administered per treatment can be
in any amount, for example, about 0.5 mg, about 0.51 mg, about 0.52
mg, about 0.53 mg, about 0.54 mg, about 0.55 mg, about 0.56 mg,
about 0.57, mg, about 0.58 mg, about 0.59 mg, about 0.6 mg, about
0.61 mg, about 0.62 mg, about 0.63 mg, about 0.64 mg, about 0.65
mg, about 0.66 mg, about 0.67, mg, about 0.68 mg, about 0.69 mg,
about 0.7 mg, about 0.71 mg, about 0.72 mg, about 0.73 mg, about
0.74 mg, about 0.75 mg, about 0.76 mg, about 0.77, mg, about 0.78
mg, about 0.79 mg, about 0.8 mg, about 0.81 mg, about 0.82 mg,
about 0.83 mg, about 0.84 mg, about 0.85 mg, about 0.86 mg, about
0.87, mg, about 0.88 mg, about 0.89 mg, about 0.9 mg, about 0.91
mg, about 0.92 mg, about 0.93 mg, about 0.94 mg, about 0.95 mg,
about 0.96 mg, about 0.97, mg, about 0.98 mg, about 0.99 mg, about
1 mg, about 1.01 mg, about 1.02 mg, about 1.03 mg, about 1.04 mg,
about 1.05 mg, about 1.06 mg, about 1.07, mg, about 1.08 mg, about
1.09 mg, 1.1 mg, about 1.11 mg, about 1.12 mg, about 1.13 mg, about
1.14 mg, about 1.15 mg, about 1.16 mg, about 1.17, mg, about 1.18
mg, about 1.19 mg, about 1.2 mg, about 1.21 mg, about 1.22 mg,
about 1.23 mg, about 1.24 mg, about 1.25 mg, about 1.26 mg, about
1.27, mg, about 1.28 mg, about 1.29 mg, about 1.3 mg, about 1.31
mg, about 1.32 mg, about 1.33 mg, about 1.34 mg, about 1.35 mg,
about 1.36 mg, about 1.37, mg, about 1.38 mg, about 1.39 mg, about
1.4 mg, about 1.41 mg, about 1.42 mg, about 1.43 mg, about 1.44 mg,
about 1.45 mg, about 1.46 mg, about 1.47, mg, about 1.48 mg, about
1.49 mg, about 1.5 mg, about 1.51 mg, about 1.52 mg, about 1.53 mg,
about 1.54 mg, about 1.55 mg, about 1.56 mg, about 1.57, mg, about
1.58 mg, about 1.59 mg, about 1.6 mg, about 1.61 mg, about 1.62 mg,
about 1.63 mg, about 1.64 mg, about 1.65 mg, about 1.66 mg, about
1.67, mg, about 1.68 mg, about 1.69 mg, about 1.7 mg, about 1.71
mg, about 1.72 mg, about 1.73 mg, about 1.74 mg, about 1.75 mg,
about 1.76 mg, about 1.77, mg, about 1.78 mg, about 1.79 mg, about
1.8 mg, about 1.81 mg, about 1.82 mg, about 1.83 mg, about 1.84 mg,
about 1.85 mg, about 1.86 mg, about 1.87, mg, about 1.88 mg, about
1.89 mg, about 1.9 mg, about 1.91 mg, about 1.92 mg, about 1.93 mg,
about 1.94 mg, about 1.95 mg, about 1.96 mg, about 1.97, mg, about
1.98 mg, about 1.99 mg, or about 2 mg.
[1436] The HPTP-.beta. inhibitors or a pharmaceutically acceptable
salt thereof can be administered in any amount necessary or
convenient. For example, the compound can be administered in an
amount from about 0.1 mg to about 100 mg per dose as described
herein above in the disclosure relating to the compositions.
[1437] The HPTP-.beta. inhibitors or a pharmaceutically acceptable
salt thereof can be administered at any interval desired. For
example, the compound can be administered once a week, 2 times a
week, 3 times a week, 4 times a week, 6 times a week, 6 times a
week, 7 times a week, 8 times a week, 9 times a week or 10 times a
week. The interval between daily dosing can be any hourly interval,
for example, every hour, every 2 hours, every 3 hours, every 4
hours, every 5 hours, every 6 hours, every 7 hours, every 8 hours,
every 9 hours, every 10 hours, every 11 hours, and every 12 hours.
The administration of the compound can have irregular dosing
schedules to accommodate either the person administering the
compound or the subject receiving the compound. As such, the
compound can be administered once a day, twice a day, three times a
day, and the like.
[1438] In addition, the amount administered can be of the same
amount in each dose or the dosage can vary. For example, a first
amount dosed in the morning and a second amount administered in the
evening. The dosage for administration can be varied depending upon
the schedule of the anti-VEGF administration.
[1439] The HPTP-.beta. inhibitors or a pharmaceutically acceptable
salt thereof can be administered in combination with any anti-VEGF
agent in any combination, for example, at the beginning of the
treatment, at any time during the treatment or at any time after
treatment with the anti-VEGF agent has concluded. In addition, the
dosage of the HPTP-.beta. inhibitors or a pharmaceutically
acceptable salt thereof can be adjusted during treatment. Also, the
amount of anti-VEGF agent can be adjusted during treatment.
[1440] Further non-limiting examples of anti-VEGF agents includes
dexamethasone, fluocinolone and triamcinolone. In addition, the
disclosed methods can include implants which deliver an anti-VEGF
agent. For example, HPTP-.beta. inhibitors or a pharmaceutically
acceptable salt thereof can be co-administered either before,
during or after an implant is provided to a subject suffering from
a disease or condition described herein. For example, Ozurdex.TM.
is an intraviteal implant which provides a supply of dexamethasone
to a subject, Retisert.TM. and Iluvien.TM. are intraviteal implants
which provides a supply of fluocinolone.
[1441] In one aspect, anti-VEGF treatments if typically given
monthly, can have the frequency of treatment extended, for example,
to once every 3 months, once every 6 months or yearly wherein the
HPTP-.beta. inhibitor or a pharmaceutically acceptable salt thereof
is administered at any frequency between treatments.
[1442] Also disclosed herein are methods for decreasing the Central
Foveal Thickness (CFT) in a patient having a disease or condition
as disclosed herein. The method comprises administering to an eye:
[1443] a) a HPTP-.beta. inhibitor or a pharmaceutically acceptable
salt thereof; and [1444] b) one or more anti-VEGF agents; wherein
the administration of the HPTP-.beta. inhibitor or a
pharmaceutically acceptable salt thereof and the anti-VEGF agent
can be conducted in any manner desired by the administrator, for
example, as further described herein.
[1445] A further aspect relates to a method comprising
administering to the eye: [1446] a) a disclosed HPTP-.beta.
inhibitor or a pharmaceutically acceptable salt thereof; and [1447]
b) one or more anti-VEGF agents; wherein the administration of the
HPTP-.beta. inhibitor or a pharmaceutically acceptable salt thereof
and the anti-VEGF agent can be conducted in any manner desired by
the administrator, for example, as further described herein.
[1448] In one aspect the decrease in Central Foveal Thickness is
from about 50 .mu.m to about 1000 .mu.m. In one embodiment, the
decrease in Central Foveal Thickness is from about 50 .mu.m to
about 750 .mu.m. In another embodiment, the decrease in Central
Foveal Thickness is from about 200 .mu.m to about 1000 .mu.m. In a
further embodiment, the decrease in Central Foveal Thickness is
from about 150 .mu.m to about 500 .mu.m. In a still further
embodiment, the decrease in Central Foveal Thickness is from about
50 .mu.m to about 500 .mu.m. In a yet another embodiment, the
decrease in Central Foveal Thickness is from about 250 .mu.m to
about 650 .mu.m. In a yet still further embodiment, the decrease in
Central Foveal Thickness is from about 200 .mu.m to about 500
.mu.m. In another still further embodiment, the decrease in Central
Foveal Thickness is from about 400 .mu.m to about 700 .mu.m.
[1449] Further disclosed herein are methods for increasing the
visual acuity of a subject having a disease or condition as
disclosed herein.
Visual Acuity
[1450] Visual acuity (VA) is acuteness or clearness of vision,
which is dependent on the sharpness of the retinal focus within the
eye and the sensitivity of the interpretative faculty of the brain.
Visual acuity is a measure of the spatial resolution of the visual
processing system. VA is tested by requiring the person whose
vision is being tested to identify characters typically numbers or
letters on a chart from a set distance. Chart characters are
represented as black symbols against a white background. The
distance between the person's eyes and the testing chart is set at
a sufficient distance to approximate infinity in the way the lens
attempts to focus. Twenty feet, or six meters, is essentially
infinity from an optical perspective. In the present disclosure, an
improvement in visual acuity was assessed by an increase in the
number of letters read from the chart.
[1451] Visual Acuity Testing.
[1452] One non-limiting test for measuring Visual Acuity is the use
of the ESV-3000 ETDRS testing device (see, U.S. Pat. No. 5,078,486)
self-calibrated test lighting. The ESV-3000 device incorporates
highly advanced LED light source technology. The auto-calibration
circuitry constantly monitors the LED light source and calibrates
the test luminance to 85 cd/m2 or 3 cd/m2.
[1453] Although designed for clinical trials where large-format
ETDRS testing (up to 20/200) is performed at 4 meters, the device
can be used in a non-research setting, i.e., hospital or clinic
where ocular disease monitoring is conducted. To properly evaluate
ETDRS, the test should be conducted under standardized lighting
conditions, for, example, photopic test level of 85 cd/m2. This
light level has been recommended by the National Academy of
Sciences and by the American National Standards Institute for ETDRS
and contrast sensitivity vision testing. Scoring of visual acuity
can be accomplished in any manner chosen by the monitor. After
providing a baseline evaluation, the increase or decrease in the
number of letters that can be identified by the test subject
provides a measure of sight increase or decrease during
treatment.
[1454] In one aspect, disclosed herein is a method for increasing
visual acuity in a subject having a disease or condition of the eye
as disclosed herein. This method comprises administering to a
patient having a disease or condition of the eye: [1455] a) a
HPTP-.beta. inhibitor or a pharmaceutically acceptable salt
thereof; and [1456] b) one or more anti-VEGF agents;
[1457] A further embodiment of this aspect relates to a method for
increasing visual acuity in a subject, comprising administering to
a patient having a disease or condition of the eye: [1458] a) a
disclosed HPTP-.beta. inhibitor or a pharmaceutically acceptable
salt thereof; and [1459] b) one or more anti-VEGF agents; wherein
the administration of the HPTP-.beta. inhibitor or a
pharmaceutically acceptable salt thereof and the anti-VEGF agent
can be conducted in any manner desired by the administrator, for
example, as further described herein.
[1460] In some embodiments, the disclosure provides a method for
increasing visual acuity, the method comprising administering to a
subject in need thereof a compound disclosed herein.
[1461] In one embodiment, the method provides a method for
increasing the number of letters recognizable by a treated eye form
about 1 to about 30 letters. In another embodiment, the number of
letters recognizable is increased from about 5 to about 25 letters.
In a further embodiment, the number of letters recognizable is
increased from about 5 to about 20 letters. In another further
embodiment, the number of letters recognizable is increased from
about 5 to about 15 letters. In a still further embodiment, the
number of letters recognizable is increased from about 5 to about
10 letters. In a yet another embodiment, the number of letters
recognizable is increased from about 10 to about 25 letters. In a
yet still further embodiment, the number of letters recognizable is
increased from about 15 to about 25 letters. In yet still another
embodiment, the number of letters recognizable is increased from
about 20 to about 25 letters. The increase in visual acuity can be
about 1 letter, about 5 letters, about 10 letters, about 15
letters, about 20 letters, or about 25 letters.
Example 35
Baseline Study for Determining the Effectiveness of the Disclosed
Methods for Treating Ocular Diseases.
[1462] Described herein below is a study of four human subjects
with visual acuity loss due to diabetic macular edema (central
retinal thickness [CRT] of more than 325 microns and best corrected
visual acuity less than 70 letters) that were treated with
subcutaneous injections of 5 mg of the
4-{(S)-2-[(S)-2-methoxycarbonyl-amino)-3-phenylpropanamido]-2-[-
2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid twice a day
for 28 days. Improvement of visual acuity in these subjects was
observed for a period of two months (days 28 through 84). At any
time during the course of the study, investigators could administer
additional therapy consisting of intravitreal injection of an
anti-VEGF agent, for example, ranibizumab, bevacizumab and/or
aflibercept, if considered by the investigator to be medically
necessary. Retinal thickness as measured by ocular coherence
tomography and best corrected visual acuity as measured by a
standard vision test (ETDRS) were assessed at regular intervals
during the 28 day active treatment phase and through the 2 month
post-treatment observation phase, (Screening, Day 1 [baseline], Day
7, Day 14, Day 21, Day 28, Day 42, Day 56 and Day 84). The main
efficacy outcomes for the study were change in CRT and visual
acuity over time with treatment.
[1463] FIG. 1 depicts the results of two phase three studies to
determine the effect of intravitreal injections of ranibizumab in
patients with diabetic macular edema. In this study patients
received intravitreal injections with either 0.3 mg
(.diamond-solid.) or 0.5 mg (.box-solid.) ranibizumab monthly,
whereas the control group (.tangle-solidup.) received placebo. As
depicted in FIG. 1 the reduction in Central Foveal Thickness (CFT)
for both the 0.3 mg and 0.5 mg cohorts were essentially identical.
As shown in FIG. 1, the two groups receiving ranibizumab had a
reduction in Central Foveal Thickness of approximately 120 to 160
.mu.m from day 7 to 1 month after the first injection of
ranibizumab.
[1464] FIG. 2 depicts the results of a study wherein 4 patients
received 5 mg of the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-
-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid
subcutaneously twice daily for 28 days and subsequently were
treated in one or both eyes (7 eyes total) with either ranibizumab
(0.3 or 0.5 mg) or aflibercept (2 mg) by intravitreal injection at
the discretion of the study investigator. FIG. 2 is read in this
manner: 1 patient eye had a Central Foveal Reduction of between
50-100 .mu.m, 1 patient eye had a Central Foveal Reduction of
between 150-200 .mu.m, 1 patient eye had a Central Foveal Reduction
of between 200-250 .mu.m, 1 patient eye had a Central Foveal
Reduction of between 300-350 .mu.m, 2 patient eyes had a Central
Foveal Reduction of between 350-400 .mu.m, and 1 patient eye had a
Central Foveal Reduction of between 450-500 .mu.m at 14-28 days
post ranibizumab or aflibercept. The mean change in Central Foveal
Thickness was -289 .mu.m, approximately double the reduction seen
after ranibizumab injection in the study in FIG. 1.
[1465] FIG. 3 depicts the results of two phase three studies
performed to determine the effect of intravitreal injections of
ranibizumab in patients with diabetic macular edema. Results of
these studies were used to determining the effectiveness of the
disclosed methods for treating ocular diseases. The control group
is represented by (.diamond-solid.). Patients receiving 0.5 mg of
ranibizumab monthly via ocular injection are represented by
(.box-solid.). As shown in FIG. 3, the group receiving ranibizumab
had an increase in visual acuity of between approximately 4 to 6
letters from day 7 to 1 month after the first injection of
ranibizumab.
[1466] FIG. 4 depicts the increased visual acuity of a study
wherein 4 patients received 5 mg of the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid subcutaneously twice
daily for 28 days and subsequently were treated with either
ranibizumab (0.3 or 0.5 mg) or aflibercept (2 mg) by intravitreal
injection at the discretion of the study investigator. FIG. 4 is
read in this manner: 1 patient eye had an increase of from 16 to 18
letters improvement, 2 patient eyes had an increase of from 14 to
16 letters improvement, 1 patient eye had an increase of from 10 to
12 letters improvement, 1 patient eye had an increase of from 6 to
8 letters improvement, 1 patient eye had an increase of from 2 to 4
letters improvement, and 1 patient eye had a decrease of from 2 to
4 letters at 14-28 days post ranibizumab or aflibercept. The mean
change in Visual Acuity was 9 letters, approximately 3 to 5 letters
more improvement than seen in the benchmark study of ranibizumab
alone depicted in FIG. 3.
[1467] FIG. 5 represents the results of a single patient. The eye
having the greater Central Foveal Thickness was chosen as the Study
Eye. The patient from day one was given 5 mg of the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid subcutaneously twice
daily. At week 3 (21 days, indicated by arrow) the fellow eye was
treated with 0.5 mg of ranibizumab by injection. At week 6 (42
days, indicated by arrow) the treated eye was treated with 0.5 mg
of ranibizumab. As seen in FIG. 5, the Central Foveal Thickness of
the fellow eye fell significantly (350 .mu.m) by week 4 (28 days).
As a result, there was a pronounced reduction in CFT in the study
eye from day 21 to day 28 (approximately 250 .quadrature.m). As
seen in FIG. 5, by the next monitoring point, week 6, the effects
of the systemically received ranibizumab were no longer present and
the CFT returned to approximately 775 .mu.m. At week 6, the study
eye was treated with an intravitreal injection of 0.5 mg of
ranibizumab. As depicted in FIG. 5, by week 8, there was an overall
reduction in CFT of approximately 500 .mu.m, wherein the CFT of the
subject eye was approximately 225 .mu.m. Compared to the study
depicted in FIG. 1 wherein the average change in CFT at one month
after ranibizumab injection was approximately 160 mm, the
combination disclosed method provided substantially greater
reductions at 2-4 weeks following ranibizumab injection.
[1468] FIG. 6 represents the results of a single patient. The eye
having the greater Central Foveal Thickness was chosen as the Study
Eye. The patient from day one was given 5 mg of the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid subcutaneously twice
daily. At week 4 (28 days, indicated by arrow) the fellow eye was
rescued with 2 mg of aflibercept. After rescue, the Fellow eye had
a CFT reduction of approximately 400 .mu.m. At week 6 (42 days,
indicated by arrow) the study eye was rescued with 2 mg of
aflibercept. After rescue, the Study eye had a CFT reduction of
approximately 300 .mu.m. Unlike the results depicted for the
ranibizumab protocol, there was no evidence of systemically
delivered aflibercept to the Fellow Eye. From onset of the study,
there was a reduction of CFT in the study eye and non-treated eye
of approximately 300 .mu.m and 280 .mu.m respectively.
[1469] FIG. 7 graphically represents the results of a choroidal
neovascularization murine test involving an active control,
aflibercept (Eylea.TM.), the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid and a combination of
aflibercept and the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid. Rupture of Burch's
membrane in three locations of the eye was induced by standard
laser methods (see, Tobe T et al., "Targeted Disruption of the FGF2
Gene Does Not Prevent Choroidal Neovascularization in a Murine
Model," Am. J. Pathology, Vol. 153, No. 5, (1998)). Control animals
were given intraocular injections of phosphate buffered saline
(PBS), animals treated with aflibercept received one intraocular 40
lag of the drug on the day of laser treatment. The mice were then
treated with either the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid at 20 mg/kg by
subcutaneous injections twice daily or PBS injections twice daily.
This yielded four groups of mice; a negative control group treated
with intraocular and subcutaneous PBS, a monotherapy group treated
with intraocular aflibercept and subcutaneous PBS, a monotherapy
group treated with intraocular PBS and subcutaneous injections of
the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid and a combination
therapy group receiving one intraocular injection of 40 .mu.g of
the drug on the day of laser treatment and 20 mg/kg subcutaneous
injections twice daily.
[1470] FIG. 8A-D depicts the flat mounts of excised choroidal
tissue stained with FITC-labeled Griffonia simplicifolia (GSA). The
extent of choroidal neovascular is evident in the control sample
FIG. 8A. FIG. 8B represents the extent of neovascularization in the
choroidal tissue of animals treated with aflibercept, FIG. 8C
represents animals treated with the disclosed Tie-2 signaling
enhancer and FIG. 8D represents the extent of neovascularization
present in animals having a combined therapy of aflibercept and the
4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophen-
-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid.
Example 36
Solubility of Compounds of the Disclosure.
[1471] The room temperature aqueous solubility (mg/mL) of the a
compound
(4-{(S)-2-[(S)-2-methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid) in water,
HP.beta.CD, Poloxamer 407, and sulfobutylether-.beta.-cyclodextrin,
is provided in TABLE XXVII. Solubility in saline for the test
compound is reduced presumably due to the common ion effect. All
the solubilizing agents tested provided good improvements in
aqueous solubility of the test compound.
TABLE-US-00029 TABLE XXVII Solubility % HP.beta.CD 0 27 10 45 20 57
30 72 % SBE-.beta.-CD 15 44 % Poloxamer 407 20 44
[1472] The solubility (mg/mL) of the test compound in mixtures of
HP.beta.CD and PEG400 is illustrated in TABLE XXVIII. Use of either
HP.beta.CD or PEG400 individually provided an increase in
solubility. However, addition of PEG400 to a mixture of the test
compound and HP.beta.CD caused an erosion of solubility, with
solubility being inversely proportional to the amount of
PEG400.
TABLE-US-00030 TABLE XXVIII % HP.beta.CD % PEG400 Solubility 0 15
30 0 30 68 15 0 59 15 5 57 15 10 34 15 15 6
[1473] TABLE XXIX contains aqueous solution formulations of the
test compound above with the denoted solvents that have been
prepared and shown to be chemically stable through 1 month at
50.degree. C., and physically stable at 5.degree. C., at ambient
temperature, and at 50.degree. C. The formulations are more stable
at pH values above pH 4. The target pH range for the formulations
is pH 7+/-0.5 pH units.
TABLE-US-00031 TABLE XXIX Formulation Concentration of test
compound 10% HP.beta.CD 15 mg/mL 25% HP.beta.CD 50 mg/mL 30%
HP.beta.CD 50 mg/mL 15% HP.beta.CD/0.25% saline 40 mg/mL.sup.a 4.5%
mannitol 5 mg/mL.sup.b .sup.aEvaluated for short-term physical
stability at 5.degree. C. and ambient temperature. .sup.bPhysically
and chemically stable through one week at room temperature and one
week at 50.degree. C.
[1474] TABLE XXX shows the solubility (mg/mL) of two compounds with
varying concentrations of HP.beta.CD. TABLE XXX shows that 25%
HP.beta.CD almost doubles the solubility of the test compounds when
compared to their solubility in pure water.
TABLE-US-00032 TABLE XXX % HP.beta.CD ##STR00349## ##STR00350## 0
38 45 5 42 60 15 60 NT 25 74 89
Pharmacokinetic and Pharmacodynamic Measurements
Example 37
Plasma Concentration in Human Test Subjects.
[1475] FIG. 9 depicts the mean plasma concentration over time after
a single dose of a 5 mg, a 15 mg, a 22.5 mg, or a 30 mg of a test
compound on day 14, respectively, in a multiple ascending dose
study in patients with diabetic macular edema. The concentration
time curves are consistent with rapid absorption and elimination of
test compound with rapid Tmax (range 0.2 to 1.0 hours) and short
elimination half-life (range 0.6 to 1.5 hours). The overall
exposures were approximately dose proportional with Cmax ranging
from approximately 40-430 ng/ml and AUC ranging from approximately
70-920 nghr/ml at 5-30 mg dose.
Example 38
Phase 1B/2A Clinical Trial.
[1476] A phase 1B/2A open-label, Multiple-ascending dose cohort
study to assess the pharmacokinetics and pharmacodynamics effect of
28-day repeat subcutaneous dose of
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid (drug) in subjects
with diffuse diabetic macular edema (DME).
[1477] The aim of this study was to evaluate tolerability, safety,
efficacy and pharmacokinetics and pharmacodynamics in patients with
DME involving the center of the fovea with central subfield mean
thickness .gtoreq.325 .mu.m measured by spectral domain-optical
coherence tomography (SD-OCT).
[1478] Twenty-four patients were administered ascending doses of
test compound twice daily (BID) for 28 days in 4 separate cohorts
at 5, 15, 22.5 or 30 mg BID, respectively.
[1479] Drug was supplied as a lyophilized powder in a vial for
reconstitution. Each vial contained 100 mg drug and 250 mg
HP.beta.CD. Vials were reconstituted with sterile 5% dextrose for
cohort 1 (5 mg BID) and with sterile diluent containing 5%
HP.beta.CD/1% dextrose for cohorts 2, 3, and 4 (15 mg, 22.5 mg and
30 mg BID).
[1480] For cohorts 1 (5 mg BID) and 2 (15 mg BID) the volume
administered for each dose was 0.5 ml (10 and 30 mg/ml,
respectively) and for cohorts 3 and 4 the volume was 0.75 ml (30
and 40 mg/ml, respectively).
[1481] Blood samples for pharmacokinetic profiling were taken
pre-dose(0), 15 minutes, 1 hour, 2 hours, 3 hours and 4 hours after
administration of the first dose on day 14.
[1482] Plasma drug concentration was determined with a validated
LC/MS-MS method. The pharmacokinetic (PK) parameters were
determined using a standard non-compartmental method, and Cmax,
AUC.sub.last (with last being from time 0 to the last quantifiable
point), AUCinf, were analyzed statistically using log-transformed
data. The dose proportionality 90% confidence intervals were
calculated from the mean.
[1483] The PK/PD parameter data and statistical analyses are
provided in Tables XXXI to XXXV (Day 14). FIG. 9 shows the drug
plasma concentration over time for Day 14.
Day 14 PK/PD Parameters
TABLE-US-00033 [1484] TABLE XXXI 5 mg BID 15 mg BID 22.5 mg BID 30
mg BID (N = 6) (N = 6) (N = 5) (N = 7) Day 14 C.sub.max (ng/mL) N 6
6 4 6 Mean (SD) 77.75 156.57 237.40 320.48 (24.103) (51.767)
(122.075) (68.471) Median 73.44 138.05 203.20 320.85 Min-Max
44.7-108.1 102.5-226.3 142.7-400.5 220.9-426.1 % CV 31.0 33.1 51.4
21.4 Geometric Mean 74.48 149.86 215.72 314.24 Geometric % CV 33.6
32.9 53.3 22.2 Power Model of Dose Proportionality Slope 0.815
Standard Error 0.1009 90% CI (0.602, 0.950)
TABLE-US-00034 TABLE XXXII 5 mg BID 15 mg BID 22.5 mg BID 30 mg BID
t.sub.max (hr) (N = 6) (N = 6) (N = 5) (N = 7) N 6 6 4 6 Mean (SD)
0.31 0.27 0.45 0.63 (0.134) (0.039) (0.370) (0.391) Median 0.26
0.25 0.27 0.64 Min-Max 0.3-0.6 0.2-0.3 0.3-1.0 0.2-1.0 % CV 42.9
14.3 82.9 62.3
TABLE-US-00035 TABLE XXXIII 5 mg BID 15 mg BID 22.5 mg BID 30 mg
BID (N = 6) (N = 6) (N = 5) (N = 7) Day 14 AUC.sub.last (ng hr/mL)
N 6 6 4 6 Mean (SD) 101.56 239.08 437.51 669.37 (26.956) (71.302)
(235.327) (130.226) Median 97.03 213.32 328.84 700.90 Min-Max
67.9-142.6 170.4-353.3 302.7-789.6 444.1-796.1 % CV 26.5 29.8 53.8
19.5 Geometric Mean 98.63 230.97 400.80 657.33 Geometric % CV 27.0
28.8 47.9 21.9 Power Model of Dose Proportionality Slope 1.021
Standard Error 0.0966 90% CI (0.854, 1.187)
TABLE-US-00036 TABLE XXXIV 5 mg BID 15 mg BID 22.5 mg BID 30 mg BID
(N = 6) (N = 6) (N = 5) (N = 7) Day 14 AUC.sub.inf (ng hr/mL) N 6 6
3 3 Mean (SD) 106.46 255.08 498.12 828.62 (30.665) (78.518)
(273.956) (95.996) Median 100.55 232.89 358.19 834.70 Min-Max
70.1-155.1 176.8-387.4 322.4-813.8 729.7-921.4 % CV 28.8 30.8 55.0
11.6 Geometric Mean 102.92 245.89 454.63 824.87 Geometric % CV 29.0
29.8 54.1 11.7 Power Model of Dose Proportionality Slope 1.056
Standard Error 0.1174 90% CI (0.851, 1.261)
TABLE-US-00037 TABLE XXXV 5 mg BID 15 mg BID 22.5 mg BID 30 mg BID
(N = 6) (N = 6) (N = 5) (N = 7) Day 14 t.sub.1/2 (hr) N 6 6 3 3
Mean (SD) 0.85 0.96 0.84 1.07 (0.186) (0.282) (0.093) (0.338)
Median 0.83 0.89 0.87 0.93 Min-Max 0.6-1.1 0.6-1.4 0.7-0.9 0.8-1.5
% CV 21.9 29.5 11.0 31.4
[1485] In some embodiments, the invention provides a pharmaceutical
composition in unit dose form for subcutaneously delivery of a
composition comprising an HPTP-.beta. inhibitor and
2-hydroxypropyl-.beta.-cyclodextrin wherein the mean C.sub.max of
the HPTP-.beta. inhibitor is within 70% to 130% of a C.sub.max of
80 ng/ml, after administration of a single dose of the HPTP-.beta.
inhibitor to a human.
[1486] In some embodiments, the invention provides a pharmaceutical
composition in unit dose form for subcutaneously delivery of a
composition comprising an HPTP-.beta. inhibitor and
2-hydroxypropyl-.beta.-cyclodextrin wherein the mean AUC.sub.last
of the HPTP-.beta. inhibitor is within 70% to 130% of an
AUC.sub.last of 100 nghr/ml, after administration of a single dose
of the HPTP-.beta. inhibitor to a human.
[1487] In some embodiments, the invention provides a pharmaceutical
composition in unit dose form for subcutaneously delivery of a
composition comprising an HPTP-.beta. inhibitor and
2-hydroxypropyl-.beta.-cyclodextrin wherein the mean AUC.sub.last
of the HPTP-.beta. inhibitor is within 70% to 130% of an
AUC.sub.inf of 100 nghr/ml, after administration of a single dose
of the HPTP-.beta. inhibitor to a human.
[1488] In some embodiments, the invention provides a pharmaceutical
composition in unit dose form for subcutaneously delivery of a
composition comprising an HPTP-.beta. inhibitor and
2-hydroxypropyl-.beta.-cyclodextrin wherein the mean t.sub.1/2 of
the HPTP-.beta. inhibitor is within 70% to 130% of a t.sub.1/2 of 1
hour, after administration of a single dose of the HPTP-.beta.
inhibitor to a human.
[1489] In some embodiments, the invention provides a pharmaceutical
composition in unit dose form for subcutaneously delivery of a
composition comprising an HPTP-.beta. inhibitor and
2-hydroxypropyl-.beta.-cyclodextrin wherein the mean C.sub.max of
the HPTP-.beta. inhibitor is within 70% to 130% of a C.sub.max of
80 ng/ml, after administration of a single dose of the HPTP-.beta.
inhibitor to a human; and wherein the mean AUC.sub.last of the
HPTP-.beta. inhibitor is within 70% to 130% of an AUC.sub.last of
100 nghr/ml, after administration of a single dose of the
HPTP-.beta. inhibitor to a human.
[1490] In some embodiments, the invention provides a pharmaceutical
composition in unit dose form for subcutaneously delivery of a
composition comprising an HPTP-.beta. inhibitor and
2-hydroxypropyl-.beta.-cyclodextrin wherein the mean C.sub.max of
the HPTP-.beta. inhibitor is within 70% to 130% of a C.sub.max of
80 ng/ml, after administration of a single dose of the HPTP-.beta.
inhibitor to a human; and wherein the mean AUC.sub.last of the
HPTP-.beta. inhibitor is within 70% to 130% of an AUC.sub.inf of
100 nghr/ml, after administration of a single dose of the
HPTP-.beta. inhibitor to a human.
[1491] In some embodiments, the invention provides a pharmaceutical
composition in unit dose form for subcutaneously delivery of a
composition comprising an HPTP-.beta. inhibitor and
2-hydroxypropyl-.beta.-cyclodextrin wherein the mean C.sub.max of
the HPTP-.beta. inhibitor is within 70% to 130% of a C.sub.max of
80 ng/ml, after administration of a single dose of the HPTP-.beta.
inhibitor to a human; and wherein the mean t.sub.1/2 of the
HPTP-.beta. inhibitor is within 70% to 130% of a t.sub.1/2 of 1
hour, after administration of a single dose of the HPTP-.beta.
inhibitor to a human.
[1492] In some embodiments, the invention provides a pharmaceutical
composition in unit dose form for subcutaneously delivery of a
composition comprising an HPTP-.beta. inhibitor and
2-hydroxypropyl-.beta.-cyclodextrin wherein the mean C.sub.max of
the HPTP-.beta. inhibitor is within 70% to 130% of a C.sub.max of
150 ng/ml, after administration of a single dose of the HPTP-.beta.
inhibitor to a human.
[1493] In some embodiments, the invention provides a pharmaceutical
composition in unit dose form for subcutaneously delivery of a
composition comprising an HPTP-.beta. inhibitor and
2-hydroxypropyl-.beta.-cyclodextrin wherein the mean AUC.sub.last
of the HPTP-.beta. inhibitor is within 70% to 130% of an
AUC.sub.last of 217 nghr/ml, after administration of a single dose
of the HPTP-.beta. inhibitor to a human.
[1494] In some embodiments, the invention provides a pharmaceutical
composition in unit dose form for subcutaneously delivery of a
composition comprising an HPTP-.beta. inhibitor and
2-hydroxypropyl-.beta.-cyclodextrin wherein the mean AUC.sub.last
of the HPTP-.beta. inhibitor is within 70% to 130% of an
AUC.sub.inf of 255 nghr/ml, after administration of a single dose
of the HPTP-.beta. inhibitor to a human.
[1495] In some embodiments, the invention provides a pharmaceutical
composition in unit dose form for subcutaneously delivery of a
composition comprising an HPTP-.beta. inhibitor and
2-hydroxypropyl-.beta.-cyclodextrin wherein the mean C.sub.max of
the HPTP-.beta. inhibitor is within 70% to 130% of a C.sub.max of
150 ng/ml, after administration of a single dose of the HPTP-.beta.
inhibitor to a human; and wherein the mean AUC.sub.last of the
HPTP-.beta. inhibitor is within 70% to 130% of an AUC.sub.last of
217 nghr/ml, after administration of a single dose of the
HPTP-.beta. inhibitor to a human.
[1496] In some embodiments, the invention provides a pharmaceutical
composition in unit dose form for subcutaneously delivery of a
composition comprising an HPTP-.beta. inhibitor and
2-hydroxypropyl-.beta.-cyclodextrin wherein the mean C.sub.max of
the HPTP-.beta. inhibitor is within 70% to 130% of a C.sub.max of
150 ng/ml, after administration of a single dose of the HPTP-.beta.
inhibitor to a human; and wherein the mean AUC.sub.last of the
HPTP-.beta. inhibitor is within 70% to 130% of an AUC.sub.inf of
255 nghr/ml, after administration of a single dose of the
HPTP-.beta. inhibitor to a human.
[1497] In some embodiments, the invention provides a pharmaceutical
composition in unit dose form for subcutaneously delivery of a
composition comprising an HPTP-.beta. inhibitor and
2-hydroxypropyl-.beta.-cyclodextrin wherein the mean C.sub.max of
the HPTP-.beta. inhibitor is within 70% to 130% of a C.sub.max of
150 ng/ml, after administration of a single dose of the HPTP-.beta.
inhibitor to a human; and wherein the mean t.sub.1/2 of the
HPTP-.beta. inhibitor is within 70% to 130% of a t.sub.1/2 of 1
hour, after administration of a single dose of the HPTP-.beta.
inhibitor to a human.
[1498] In some embodiments, the invention provides a pharmaceutical
composition in unit dose form for subcutaneously delivery of a
composition comprising an HPTP-.beta. inhibitor and
2-hydroxypropyl-.beta.-cyclodextrin wherein the mean C.sub.max of
the HPTP-.beta. inhibitor is within 70% to 130% of a C.sub.max of
240 ng/ml, after administration of a single dose of the HPTP-.beta.
inhibitor to a human.
[1499] In some embodiments, the invention provides a pharmaceutical
composition in unit dose form for subcutaneously delivery of a
composition comprising an HPTP-.beta. inhibitor and
2-hydroxypropyl-.beta.-cyclodextrin wherein the mean AUC.sub.last
of the HPTP-.beta. inhibitor is within 70% to 130% of an
AUC.sub.last of 440 nghr/ml, after administration of a single dose
of the HPTP-.beta. inhibitor to a human.
[1500] In some embodiments, the invention provides a pharmaceutical
composition in unit dose form for subcutaneously delivery of a
composition comprising an HPTP-.beta. inhibitor and
2-hydroxypropyl-.beta.-cyclodextrin wherein the mean AUC.sub.last
of the HPTP-.beta. inhibitor is within 70% to 130% of an
AUC.sub.inf of 500 nghr/ml, after administration of a single dose
of the HPTP-.beta. inhibitor to a human.
[1501] In some embodiments, the invention provides a pharmaceutical
composition in unit dose form for subcutaneously delivery of a
composition comprising an HPTP-.beta. inhibitor and
2-hydroxypropyl-.beta.-cyclodextrin wherein the mean C.sub.max of
the HPTP-.beta. inhibitor is within 70% to 130% of a C.sub.max of
240 ng/ml, after administration of a single dose of the HPTP-.beta.
inhibitor to a human; and wherein the mean AUC.sub.last of the
HPTP-.beta. inhibitor is within 70% to 130% of an AUC.sub.last of
440 nghr/ml, after administration of a single dose of the
HPTP-.beta. inhibitor to a human.
[1502] In some embodiments, the invention provides a pharmaceutical
composition in unit dose form for subcutaneously delivery of a
composition comprising an HPTP-.beta. inhibitor and
2-hydroxypropyl-.beta.-cyclodextrin wherein the mean C.sub.max of
the HPTP-.beta. inhibitor is within 70% to 130% of a C.sub.max of
240 ng/ml, after administration of a single dose of the HPTP-.beta.
inhibitor to a human; and wherein the mean AUC.sub.last of the
HPTP-.beta. inhibitor is within 70% to 130% of an AUC.sub.inf of
500 nghr/ml, after administration of a single dose of the
HPTP-.beta. inhibitor to a human.
[1503] In some embodiments, the invention provides a pharmaceutical
composition in unit dose form for subcutaneously delivery of a
composition comprising an HPTP-.beta. inhibitor and
2-hydroxypropyl-.beta.-cyclodextrin wherein the mean C.sub.max of
the HPTP-.beta. inhibitor is within 70% to 130% of a C.sub.max of
240 ng/ml, after administration of a single dose of the HPTP-.beta.
inhibitor to a human; and wherein the mean t.sub.1/2 of the
HPTP-.beta. inhibitor is within 70% to 130% of a t.sub.1/2 of 1
hour, after administration of a single dose of the HPTP-.beta.
inhibitor to a human.
[1504] In some embodiments, the invention provides a pharmaceutical
composition in unit dose form for subcutaneously delivery of a
composition comprising an HPTP-.beta. inhibitor and
2-hydroxypropyl-.beta.-cyclodextrin wherein the mean C.sub.max of
the HPTP-.beta. inhibitor is within 70% to 130% of a C.sub.max of
300 ng/ml, after administration of a single dose of the HPTP-.beta.
inhibitor to a human.
[1505] In some embodiments, the invention provides a pharmaceutical
composition in unit dose form for subcutaneously delivery of a
composition comprising an HPTP-.beta. inhibitor and
2-hydroxypropyl-.beta.-cyclodextrin wherein the mean AUC.sub.last
of the HPTP-.beta. inhibitor is within 70% to 130% of an
AUC.sub.last of 640 nghr/ml, after administration of a single dose
of the HPTP-.beta. inhibitor to a human.
[1506] In some embodiments, the invention provides a pharmaceutical
composition in unit dose form for subcutaneously delivery of a
composition comprising an HPTP-.beta. inhibitor and
2-hydroxypropyl-.beta.-cyclodextrin wherein the mean AUC.sub.last
of the HPTP-.beta. inhibitor is within 70% to 130% of an
AUC.sub.inf of 830 nghr/ml, after administration of a single dose
of the HPTP-.beta. inhibitor to a human.
[1507] In some embodiments, the invention provides a pharmaceutical
composition in unit dose form for subcutaneously delivery of a
composition comprising an HPTP-.beta. inhibitor and
2-hydroxypropyl-.beta.-cyclodextrin wherein the mean C.sub.max of
the HPTP-.beta. inhibitor is within 70% to 130% of a C.sub.max of
300 ng/ml, after administration of a single dose of the HPTP-.beta.
inhibitor to a human; and wherein the mean AUC.sub.last of the
HPTP-.beta. inhibitor is within 70% to 130% of an AUC.sub.last of
640 nghr/ml, after administration of a single dose of the
HPTP-.beta. inhibitor to a human.
[1508] In some embodiments, the invention provides a pharmaceutical
composition in unit dose form for subcutaneously delivery of a
composition comprising an HPTP-.beta. inhibitor and
2-hydroxypropyl-.beta.-cyclodextrin wherein the mean C.sub.max of
the HPTP-.beta. inhibitor is within 70% to 130% of a C.sub.max of
300 ng/ml, after administration of a single dose of the HPTP-.beta.
inhibitor to a human; and wherein the mean AUC.sub.last of the
HPTP-.beta. inhibitor is within 70% to 130% of an AUC.sub.inf of
830 nghr/ml, after administration of a single dose of the
HPTP-.beta. inhibitor to a human.
[1509] In some embodiments, the invention provides a pharmaceutical
composition in unit dose form for subcutaneously delivery of a
composition comprising an HPTP-.beta. inhibitor and
2-hydroxypropyl-.beta.-cyclodextrin wherein the mean C.sub.max of
the HPTP-.beta. inhibitor is within 70% to 130% of a C.sub.max of
300 ng/ml, after administration of a single dose of the HPTP-.beta.
inhibitor to a human; and wherein the mean t.sub.1/2 of the
HPTP-.beta. inhibitor is within 70% to 130% of a t.sub.1/2 of 1
hour, after administration of a single dose of the HPTP-.beta.
inhibitor to a human.
[1510] In some embodiments, the HPTP-.beta. inhibitor is
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[2-(thiophe-
n-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid.
[1511] In some embodiments, the HPTP-.beta. inhibitor is
(4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-[4-ethylth-
iazol-2-yl]ethyl}phenyl)sulfamic acid.
[1512] In some embodiments, the HPTP-.beta. inhibitor is
4-{(S)-2-[(S)-2-(methoxycarbonylamino)-3-phenylpropanamido]-2-(2-ethylthi-
azol-4-yl)ethyl}phenylsulfamic acid.
[1513] In some embodiments, the HPTP-.beta. inhibitor is
(4-((S)-2-((S)-2-((methoxycarbonyl)amino)-3-phenylpropanamido)-2-(4-(thio-
phen-2-yl)thiazol-2-yl)ethyl)phenyl)sulfamic acid.
[1514] A dose can be modulated to achieve a desired pharmacokinetic
or pharmacodynamics profile, such as a desired or effective blood
profile, as described herein.
[1515] Pharmacokinetic and pharmacodynamic data can be obtained by
various experimental techniques. Appropriate pharmacokinetic and
pharmacodynamic profile components describing a particular
composition can vary due to variations in drug metabolism in human
subjects. Pharmacokinetic and pharmacodynamic profiles can be based
on the determination of the mean parameters of a group of subjects.
The group of subjects includes any reasonable number of subjects
suitable for determining a representative mean, for example, 5
subjects, 10 subjects, 15 subjects, 20 subjects, 25 subjects, 30
subjects, 35 subjects, or more. The mean is determined, for
example, by calculating the average of all subject's measurements
for each parameter measured. A dose can be modulated to achieve a
desired pharmacokinetic or pharmacodynamics profile, such as a
desired or effective blood profile, as described herein.
[1516] The pharmacodynamic parameters can be any parameters
suitable for describing compositions of the invention. For example,
the pharmacodynamic profile can be obtained at a time after dosing
of, for example, about zero minutes, about 1 minute, about 2
minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6
minutes, about 7 minutes, about 8 minutes, about 9 minutes, about
10 minutes, about 11 minutes, about 12 minutes, about 13 minutes,
about 14 minutes, about 15 minutes, about 16 minutes, about 17
minutes, about 18 minutes, about 19 minutes, about 20 minutes,
about 21 minutes, about 22 minutes, about 23 minutes, about 24
minutes, about 25 minutes, about 26 minutes, about 27 minutes,
about 28 minutes, about 29 minutes, about 30 minutes, about 31
minutes, about 32 minutes, about 33 minutes, about 34 minutes,
about 35 minutes, about 36 minutes, about 37 minutes, about 38
minutes, about 39 minutes, about 40 minutes, about 41 minutes,
about 42 minutes, about 43 minutes, about 44 minutes, about 45
minutes, about 46 minutes, about 47 minutes, about 48 minutes,
about 49 minutes, about 50 minutes, about 51 minutes, about 52
minutes, about 53 minutes, about 54 minutes, about 55 minutes,
about 56 minutes, about 57 minutes, about 58 minutes, about 59
minutes, about 60 minutes, about zero hours, about 0.5 hours, about
1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3
hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5
hours, about 5.5 hours, about 6 hours, about 6.5 hours, about 7
hours, about 7.5 hours, about 8 hours, about 8.5 hours, about 9
hours, about 9.5 hours, about 10 hours, about 10.5 hours, about 11
hours, about 11.5 hours, about 12 hours, about 12.5 hours, about 13
hours, about 13.5 hours, about 14 hours, about 14.5 hours, about 15
hours, about 15.5 hours, about 16 hours, about 16.5 hours, about 17
hours, about 17.5 hours, about 18 hours, about 18.5 hours, about 19
hours, about 19.5 hours, about 20 hours, about 20.5 hours, about 21
hours, about 21.5 hours, about 22 hours, about 22.5 hours, about 23
hours, about 23.5 hours, or about 24 hours.
[1517] The pharmacokinetic parameters can be any parameters
suitable for describing a compound. The C.sub.max can be, for
example, not less than about 1 ng/mL; not less than about 5 ng/mL;
not less than about 10 ng/mL; not less than about 15 ng/mL; not
less than about 20 ng/mL; not less than about 25 ng/mL; not less
than about 50 ng/mL; not less than about 75 ng/mL; not less than
about 100 ng/mL; not less than about 200 ng/mL; not less than about
300 ng/mL; not less than about 400 ng/mL; not less than about 500
ng/mL; not less than about 600 ng/mL; not less than about 700
ng/mL; not less than about 800 ng/mL; not less than about 900
ng/mL; not less than about 1000 ng/mL; not less than about 1250
ng/mL; not less than about 1500 ng/mL; not less than about 1750
ng/mL; not less than about 2000 ng/mL; or any other C.sub.max
appropriate for describing a pharmacokinetic profile of a compound
described herein. The C.sub.max can be, for example, about 1 ng/mL
to about 5,000 ng/mL; about 1 ng/mL to about 4,500 ng/mL; about 1
ng/mL to about 4,000 ng/mL; about 1 ng/mL to about 3,500 ng/mL;
about 1 ng/mL to about 3,000 ng/mL; about 1 ng/mL to about 2,500
ng/mL; about 1 ng/mL to about 2,000 ng/mL; about 1 ng/mL to about
1,500 ng/mL; about 1 ng/mL to about 1,000 ng/mL; about 1 ng/mL to
about 900 ng/mL; about 1 ng/mL to about 800 ng/mL; about 1 ng/mL to
about 700 ng/mL; about 1 ng/mL to about 600 ng/mL; about 1 ng/mL to
about 500 ng/mL; about 1 ng/mL to about 450 ng/mL; about 1 ng/mL to
about 400 ng/mL; about 1 ng/mL to about 350 ng/mL; about 1 ng/mL to
about 300 ng/mL; about 1 ng/mL to about 250 ng/mL; about 1 ng/mL to
about 200 ng/mL; about 1 ng/mL to about 150 ng/mL; about 1 ng/mL to
about 125 ng/mL; about 1 ng/mL to about 100 ng/mL; about 1 ng/mL to
about 90 ng/mL; about 1 ng/mL to about 80 ng/mL; about 1 ng/mL to
about 70 ng/mL; about 1 ng/mL to about 60 ng/mL; about 1 ng/mL to
about 50 ng/mL; about 1 ng/mL to about 40 ng/mL; about 1 ng/mL to
about 30 ng/mL; about 1 ng/mL to about 20 ng/mL; about 1 ng/mL to
about 10 ng/mL; about 1 ng/mL to about 5 ng/mL; about 10 ng/mL to
about 4,000 ng/mL; about 10 ng/mL to about 3,000 ng/mL; about 10
ng/mL to about 2,000 ng/mL; about 10 ng/mL to about 1,500 ng/mL;
about 10 ng/mL to about 1,000 ng/mL; about 10 ng/mL to about 900
ng/mL; about 10 ng/mL to about 800 ng/mL; about 10 ng/mL to about
700 ng/mL; about 10 ng/mL to about 600 ng/mL; about 10 ng/mL to
about 500 ng/mL; about 10 ng/mL to about 400 ng/mL; about 10 ng/mL
to about 300 ng/mL; about 10 ng/mL to about 200 ng/mL; about 10
ng/mL to about 100 ng/mL; about 10 ng/mL to about 50 ng/mL; about
25 ng/mL to about 500 ng/mL; about 25 ng/mL to about 100 ng/mL;
about 50 ng/mL to about 500 ng/mL; about 50 ng/mL to about 100
ng/mL; about 100 ng/mL to about 500 ng/mL; about 100 ng/mL to about
400 ng/mL; about 100 ng/mL to about 300 ng/mL; or about 100 ng/mL
to about 200 ng/mL.
[1518] The T.sub.max of a compound described herein can be, for
example, not greater than about 0.5 hours, not greater than about 1
hours, not greater than about 1.5 hours, not greater than about 2
hours, not greater than about 2.5 hours, not greater than about 3
hours, not greater than about 3.5 hours, not greater than about 4
hours, not greater than about 4.5 hours, not greater than about 5
hours, or any other T.sub.max appropriate for describing a
pharmacokinetic profile of a compound described herein. The
T.sub.max can be, for example, about 0.1 hours to about 24 hours;
about 0.1 hours to about 0.5 hours; about 0.5 hours to about 1
hour; about 1 hour to about 1.5 hours; about 1.5 hours to about 2
hour; about 2 hours to about 2.5 hours; about 2.5 hours to about 3
hours; about 3 hours to about 3.5 hours; about 3.5 hours to about 4
hours; about 4 hours to about 4.5 hours; about 4.5 hours to about 5
hours; about 5 hours to about 5.5 hours; about 5.5 hours to about 6
hours; about 6 hours to about 6.5 hours; about 6.5 hours to about 7
hours; about 7 hours to about 7.5 hours; about 7.5 hours to about 8
hours; about 8 hours to about 8.5 hours; about 8.5 hours to about 9
hours; about 9 hours to about 9.5 hours; about 9.5 hours to about
10 hours; about 10 hours to about 10.5 hours; about 10.5 hours to
about 11 hours; about 11 hours to about 11.5 hours; about 11.5
hours to about 12 hours; about 12 hours to about 12.5 hours; about
12.5 hours to about 13 hours; about 13 hours to about 13.5 hours;
about 13.5 hours to about 14 hours; about 14 hours to about 14.5
hours; about 14.5 hours to about 15 hours; about 15 hours to about
15.5 hours; about 15.5 hours to about 16 hours; about 16 hours to
about 16.5 hours; about 16.5 hours to about 17 hours; about 17
hours to about 17.5 hours; about 17.5 hours to about 18 hours;
about 18 hours to about 18.5 hours; about 18.5 hours to about 19
hours; about 19 hours to about 19.5 hours; about 19.5 hours to
about 20 hours; about 20 hours to about 20.5 hours; about 20.5
hours to about 21 hours; about 21 hours to about 21.5 hours; about
21.5 hours to about 22 hours; about 22 hours to about 22.5 hours;
about 22.5 hours to about 23 hours; about 23 hours to about 23.5
hours; or about 23.5 hours to about 24 hours.
[1519] The AUC.sub.(0-inf) or AUC.sub.(last) of a compound
described herein can be, for example, not less than about 1
nghr/mL, not less than about 5 nghr/mL, not less than about 10
nghr/mL, not less than about 20 nghr/mL, not less than about 30
nghr/mL, not less than about 40 nghr/mL, not less than about 50
nghr/mL, not less than about 100 nghr/mL, not less than about 150
nghr/mL, not less than about 200 nghr/mL, not less than about 250
nghr/mL, not less than about 300 nghr/mL, not less than about 350
nghr/mL, not less than about 400 nghr/mL, not less than about 450
nghr/mL, not less than about 500 nghr/mL, not less than about 600
nghr/mL, not less than about 700 nghr/mL, not less than about 800
nghr/mL, not less than about 900 nghr/mL, not less than about 1000
nghr/mL, not less than about 1250 nghr/mL, not less than about 1500
nghr/mL, not less than about 1750 nghr/mL, not less than about 2000
nghr/mL, not less than about 2500 nghr/mL, not less than about 3000
nghr/mL, not less than about 3500 nghr/mL, not less than about 4000
nghr/mL, not less than about 5000 nghr/mL, not less than about 6000
nghr/mL, not less than about 7000 nghr/mL, not less than about 8000
nghr/mL, not less than about 9000 nghr/mL, not less than about
10,000 nghr/mL, or any other AUC.sub.(0-inf) appropriate for
describing a pharmacokinetic profile of a compound described
herein. The AUC.sub.(0-inf) of a compound can be, for example,
about 1 nghr/mL to about 10,000 nghr/mL; about 1 nghr/mL to about
10 nghr/mL; about 10 nghr/mL to about 25 nghr/mL; about 25 nghr/mL
to about 50 nghr/mL; about 50 nghr/mL to about 100 nghr/mL; about
100 nghr/mL to about 200 nghr/mL; about 200 nghr/mL to about 300
nghr/mL; about 300 nghr/mL to about 400 nghr/mL; about 400 nghr/mL
to about 500 nghr/mL; about 500 nghr/mL to about 600 nghr/mL; about
600 nghr/mL to about 700 nghr/mL; about 700 nghr/mL to about 800
nghr/mL; about 800 nghr/mL to about 900 nghr/mL; about 900 nghr/mL
to about 1,000 nghr/mL; about 1,000 nghr/mL to about 1,250 nghr/mL;
about 1,250 nghr/mL to about 1,500 nghr/mL; about 1,500 nghr/mL to
about 1,750 nghr/mL; about 1,750 nghr/mL to about 2,000 nghr/mL;
about 2,000 nghr/mL to about 2,500 nghr/mL; about 2,500 nghr/mL to
about 3,000 nghr/mL; about 3,000 nghr/mL to about 3,500 nghr/mL;
about 3,500 nghr/mL to about 4,000 nghr/mL; about 4,000 nghr/mL to
about 4,500 nghr/mL; about 4,500 nghr/mL to about 5,000 nghr/mL;
about 5,000 nghr/mL to about 5,500 nghr/mL; about 5,500 nghr/mL to
about 6,000 nghr/mL; about 6,000 nghr/mL to about 6,500 nghr/mL;
about 6,500 nghr/mL to about 7,000 nghr/mL; about 7,000 nghr/mL to
about 7,500 nghr/mL; about 7,500 nghr/mL to about 8,000 nghr/mL;
about 8,000 nghr/mL to about 8,500 nghr/mL; about 8,500 nghr/mL to
about 9,000 nghr/mL; about 9,000 nghr/mL to about 9,500 nghr/mL; or
about 9,500 nghr/mL to about 10,000 nghr/mL.
[1520] The plasma concentration of a compound described herein can
be, for example, not less than about 1 ng/mL, not less than about 5
ng/mL, not less than about 10 ng/mL, not less than about 15 ng/mL,
not less than about 20 ng/mL, not less than about 25 ng/mL, not
less than about 50 ng/mL, not less than about 75 ng/mL, not less
than about 100 ng/mL, not less than about 150 ng/mL, not less than
about 200 ng/mL, not less than about 300 ng/mL, not less than about
400 ng/mL, not less than about 500 ng/mL, not less than about 600
ng/mL, not less than about 700 ng/mL, not less than about 800
ng/mL, not less than about 900 ng/mL, not less than about 1000
ng/mL, not less than about 1200 ng/mL, or any other plasma
concentration of a compound described herein. The plasma
concentration can be, for example, about 1 ng/mL to about 2,000
ng/mL; about 1 ng/mL to about 5 ng/mL; about 5 ng/mL to about 10
ng/mL; about 10 ng/mL to about 25 ng/mL; about 25 ng/mL to about 50
ng/mL; about 50 ng/mL to about 75 ng/mL; about 75 ng/mL to about
100 ng/mL; about 100 ng/mL to about 150 ng/mL; about 150 ng/mL to
about 200 ng/mL; about 200 ng/mL to about 250 ng/mL; about 250
ng/mL to about 300 ng/mL; about 300 ng/mL to about 350 ng/mL; about
350 ng/mL to about 400 ng/mL; about 400 ng/mL to about 450 ng/mL;
about 450 ng/mL to about 500 ng/mL; about 500 ng/mL to about 600
ng/mL; about 600 ng/mL to about 700 ng/mL; about 700 ng/mL to about
800 ng/mL; about 800 ng/mL to about 900 ng/mL; about 900 ng/mL to
about 1,000 ng/mL; about 1,000 ng/mL to about 1,100 ng/mL; about
1,100 ng/mL to about 1,200 ng/mL; about 1,200 ng/mL to about 1,300
ng/mL; about 1,300 ng/mL to about 1,400 ng/mL; about 1,400 ng/mL to
about 1,500 ng/mL; about 1,500 ng/mL to about 1,600 ng/mL; about
1,600 ng/mL to about 1,700 ng/mL; about 1,700 ng/mL to about 1,800
ng/mL; about 1,800 ng/mL to about 1,900 ng/mL; or about 1,900 ng/mL
to about 2,000 ng/mL.
[1521] The pharmacodynamic parameters can be any parameters
suitable for describing compositions of the disclosure. For
example, the pharmacodynamic profile can exhibit decreases in
viability phenotype for the tumor cells or tumor size reduction in
tumor cell lines or xenograft studies, for example, about 24 hours,
about 48 hours, about 72 hours, or 1 week.
[1522] Non-limiting examples of pharmacodynamic and pharmacokinetic
parameters that can be calculated for a compound that is
administered with the methods of the invention include: a) the
amount of drug administered, which can be represented as a dose D;
b) the dosing interval, which can be represented as .tau.; c) the
apparent volume in which a drug is distributed, which can be
represented as a volume of distribution V.sub.d, where
V.sub.d=D/C.sub.0; d) the amount of drug in a given volume of
plasma, which can be represented as concentration C.sub.0 or
C.sub.ss, where C.sub.0 or C.sub.ss, =D/Vd and can be represented
as a mean plasma concentration over a plurality of samples; e) the
half-life of a drug t.sub.1/2, where t.sub.1/2=ln(2)/k.sub.e; f)
the rate at which a drug is removed from the body k.sub.e, where
k.sub.e=ln(2)/t.sub.1/2=CL/V.sub.d; g) the rate of infusion
required to balance the equation K.sub.in, where
K.sub.in=C.sub.ssCL; h) the integral of the concentration-time
curve after administration of a single dose, which can be
represented as AUC.sub.0-.infin., wherein .intg..sub.0.sup..infin.
C dt, or in steady-state, which can be represented as
AUC.tau.,.sub.ss, wherein .intg..sub.t.sup.t+.pi. C dt; i) the
volume of plasma cleared of the drug per unit time, which can be
represented as CL (clearance), wherein CL=V.sub.dk.sub.e=D/AUC; j)
the systemically available fraction of a drug, which can be
represented as f, where
f = AUCpo . Div AUCiv . Dpo ; k ) ##EQU00001##
the peak plasma concentration of a drug after administration
C.sub.max; 1) the time taken by a drug to reach C.sub.max,
t.sub.max; m) the lowest concentration that a drug reaches before
the next dose is administered C.sub.min; and n) the peak trough
fluctuation within one dosing interval at steady state, which can
be represented as
% PTF = 100 ( Cmax , ss - Cmin , ss ) Cav , ss where C av , ss =
AUC .tau. , ss .tau. . ##EQU00002##
EMBODIMENTS
[1523] The following are illustrative embodiments.
Embodiment A1
[1524] A method of treating a condition in a subject in need
thereof, the method comprising administering to the subject a
therapeutically-effective amount of a compound that activates
Tie-2, or a pharmaceutically-acceptable salt thereof, and an agent
that increases solubility of the compound that activates Tie-2, or
the pharmaceutically-acceptable salt thereof as compared to
solubility in absence of the agent.
Embodiment A2
[1525] The method of embodiment A1, wherein the compound that
activates Tie-2 or the pharmaceutically-acceptable salt thereof
binds HPTP-beta.
Embodiment A3
[1526] The method of embodiment A1, wherein the compound that
activates Tie-2 or the pharmaceutically-acceptable salt thereof
inhibits HPTP-beta.
Embodiment A4
[1527] The method of embodiment A1, wherein the compound that
activates Tie-2 or the pharmaceutically-acceptable salt thereof is
a phosphate mimetic.
Embodiment A5
[1528] The method of embodiment A1, wherein the compound that
activates Tie-2 comprises an amino acid backbone.
Embodiment A6
[1529] The method of embodiment A1, wherein the compound that
activates Tie-2 comprises a sulfamic acid.
Embodiment A7
[1530] The method of embodiment A1, wherein the agent that improves
the aqueous solubility of the compound that activates Tie-2 or the
pharmaceutically-acceptable salt thereof comprises a polymer.
Embodiment A8
[1531] The method of embodiment A1, wherein the agent that improves
the aqueous solubility of the compound that activates Tie-2 or the
pharmaceutically-acceptable salt thereof comprises a poly-ethylene
glycol moiety.
Embodiment A9
[1532] The method of embodiment A1, wherein the agent that improves
the aqueous solubility of the compound that activates Tie-2 or the
pharmaceutically-acceptable salt thereof comprises a cyclodextrin
moiety.
Embodiment A10
[1533] The method of embodiment A1, wherein the agent that improves
the aqueous solubility of the compound that activates Tie-2 or the
pharmaceutically-acceptable salt thereof comprises a
2-hydroxypropyl-.beta.-cyclodextrin moiety.
Embodiment A1
[1534] The method of embodiment A1, wherein the agent that improves
the aqueous solubility of the compound that activates Tie-2 or the
pharmaceutically-acceptable salt thereof comprises a
sulfobutylether-.beta.-cyclodextrin moiety.
Embodiment A12
[1535] The method of embodiment A1, wherein the compound that
activates Tie-2, or the pharmaceutically-acceptable salt thereof,
and the agent that improves the aqueous solubility of the compound
that activates Tie-2 or the pharmaceutically-acceptable salt
thereof are held in a complex by non-covalent interactions.
Embodiment A13
[1536] The method of embodiment A1, wherein the agent that improves
the aqueous solubility of the compound that activates Tie-2 or the
pharmaceutically-acceptable salt thereof comprises a surfactant
moiety.
Embodiment A14
[1537] The method of embodiment A1, wherein the agent that
increases solubility of the compound that activates Tie-2 or the
pharmaceutically-acceptable salt thereof increases aqueous
solubility by at least 10% at each of 5.degree. C., ambient
temperature, and 50.degree. C.
Embodiment A15
[1538] The method of embodiment A1, wherein the agent that
increases solubility of the compound that activates Tie-2 or the
pharmaceutically-acceptable salt thereof increases aqueous
solubility by at least 25%.
Embodiment A16
[1539] The method of embodiment A1, wherein the agent that
increases solubility of the compound that activates Tie-2 or the
pharmaceutically-acceptable salt thereof increases aqueous
solubility by at least 50%.
Embodiment A17
[1540] The method of embodiment A1, wherein the
therapeutically-effective amount is from about 0.1 mg to about 100
mg.
Embodiment A18
[1541] The method of embodiment A1, wherein the
therapeutically-effective amount is from about 0.5 mg to about 30
mg.
Embodiment A19
[1542] The method of embodiment A1, wherein the compound that
activates Tie-2, or the pharmaceutically-acceptable salt thereof,
and the agent that improves the aqueous solubility of the compound
that activates Tie-2 or the pharmaceutically-acceptable salt
thereof are coadministered in a unit dosage form.
Embodiment A20
[1543] The method of embodiment A19, wherein the unit dosage form
is administered subcutaneously.
Embodiment A21
[1544] The method of embodiment A19, wherein the unit dosage form
is administered to an eye.
Embodiment A22
[1545] The method of embodiment A1, wherein the condition is an
ocular condition.
Embodiment A23
[1546] The method of embodiment A1, wherein the condition is
diabetic macular edema.
Embodiment A24
[1547] The method of embodiment A1, wherein the condition is
diabetic retinopathy.
Embodiment A25
[1548] The method of embodiment A1, wherein the condition is
macular degeneration.
Embodiment A26
[1549] The method of embodiment A1, wherein the condition is
vascular leak.
Embodiment A27
[1550] The method of embodiment A1, wherein the condition is a
cancer.
Embodiment A28
[1551] The method of embodiment A1, wherein the subject is a
human.
Embodiment A29
[1552] The method of embodiment A1, wherein the subject's visual
acuity improves by at least 5 letters.
Embodiment A30
[1553] The method of embodiment A1, wherein the compound that
activates Tie-2 is a compound of the formula:
##STR00351##
wherein aryl.sup.1 is an aryl group which is substituted or
unsubstituted, aryl.sup.2 is an aryl group which is substituted or
unsubstituted, X is alkylene, alkenylene, alkynylene, an ether
linkage, an amine linkage, an amide linkage, an ester linkage, a
thioether linkage, a carbamate linkage, a carbonate linkage, a
urethane linkage, a sulfone linkage, any of which is substituted or
unsubstituted, or a chemical bond, and Y is H, aryl, heteroaryl,
NH(aryl), NH(heteroaryl), NHSO.sub.2R.sup.g, or NHCOR.sup.g, any of
which is substituted or unsubstituted, or
##STR00352##
wherein L.sup.2 is alkylene, alkenylene, or alkynylene, any of
which is substituted or unsubstituted, or together with the
nitrogen atom to which L is bound forms an amide linkage, a
carbamate linkage, a urethane linkage, or a sulfonamide linkage, or
a chemical bond, or together with any of R.sup.a, R.sup.b, R.sup.c,
and R.sup.d forms a ring that is substituted or unsubstituted.
R.sup.a is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl,
heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl,
any of which is substituted or unsubstituted, or together with any
of L.sup.2, R.sup.b, R.sup.c, and R.sup.d forms a ring that is
substituted or unsubstituted. R.sup.b is H, alkyl, alkenyl,
alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,
heteroaryl, or heteroarylalkyl, any of which is substituted or
unsubstituted, or together with any of L.sup.2, R.sup.a, R.sup.c,
and R.sup.d forms a ring that is substituted or unsubstituted.
R.sup.c is H or alkyl which is substituted or unsubstituted, or
together with any of L.sup.2, R.sup.a, R.sup.b, and R.sup.d forms a
ring that is substituted or unsubstituted. R.sup.d is H or alkyl
which is substituted or unsubstituted, or together with any of
L.sup.2, R.sup.a, R.sup.b, and R.sup.c forms a ring that is
substituted or unsubstituted, and R.sup.g is H, alkyl, alkenyl,
alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,
heteroaryl, or heteroarylalkyl, any of which is substituted or
unsubstituted, or a pharmaceutically-acceptable salt, tautomer, or
zwitterion thereof.
Embodiment A31
[1554] The method of embodiment A30, wherein aryl.sup.1 is
substituted or unsubstituted phenyl, aryl.sup.2 is substituted or
unsubstituted heteroaryl, and X is alkylene.
Embodiment A32
[1555] The method of embodiment A31, wherein aryl.sup.1 is
substituted phenyl, aryl.sup.2 is substituted heteroaryl, and X is
methylene.
Embodiment A33
[1556] The method of embodiment A32, wherein the compound that
activates Tie-2 is a compound of the formula:
##STR00353##
wherein aryl.sup.1 is para-substituted phenyl, aryl.sup.2 is
substituted heteroaryl, X is methylene. L.sup.2 is alkylene,
alkenylene, or alkynylene, any of which is substituted or
unsubstituted, or together with the nitrogen atom to which L is
bound forms an amide linkage, a carbamate linkage, a urethane
linkage, or a sulfonamide linkage, or a chemical bond. R.sup.a is
H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is
substituted or unsubstituted. R.sup.b is H, alkyl, alkenyl,
alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,
heteroaryl, or heteroarylalkyl, any of which is substituted or
unsubstituted. R.sup.c is H or alkyl which is substituted or
unsubstituted, and R.sup.d is H or alkyl which is substituted or
unsubstituted.
Embodiment A34
[1557] The method of embodiment A33, wherein aryl.sup.1 is
para-substituted phenyl, aryl.sup.2 is a substituted thiazole
moiety. X is methylene, L.sup.2 together with the nitrogen atom to
which L is bound forms a carbamate linkage, R.sup.a is alkyl, which
is substituted or unsubstituted, R.sup.b is arylalkyl, which is
substituted or unsubstituted, R.sup.c is H, and R.sup.d is H.
Embodiment A35
[1558] The method of embodiment A34, wherein Aryl.sup.2 is:
##STR00354##
wherein R.sup.e is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl,
alkynyl, an alkoxy group, an ether group, a carboxylic acid group,
a carboxaldehyde group, an ester group, an amine group, an amide
group, a carbonate group, a carbamate group, a urethane group, a
thioether group, a thioester group, a thioacid group, aryl,
arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or
heteroarylalkyl, any of which is substituted or unsubstituted, and
R.sup.f is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an
alkoxy group, an ether group, a carboxylic acid group, a
carboxaldehyde group, an ester group, an amine group, an amide
group, a carbonate group, a carbamate group, a urethane group, a
thioether group, a thioester group, a thioacid group, aryl,
arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or
heteroarylalkyl, any of which is substituted or unsubstituted.
Embodiment A36
[1559] The method of embodiment A35, wherein R.sup.e is H, OH, F,
Cl, Br, I, alkyl, an alkoxy group, aryl, arylalkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is
substituted or unsubstituted, and R.sup.f is H, OH, F, Cl, Br, I,
alkyl, an alkoxy group, aryl, arylalkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is
substituted or unsubstituted.
Embodiment A37
[1560] The method of embodiment A35, wherein R.sup.e is H, OH, F,
Cl, Br, I, alkyl, or an alkoxy group, any of which is substituted
or unsubstituted and R.sup.f is alkyl, aryl, heterocyclyl, or
heteroaryl, any of which is substituted or unsubstituted.
Embodiment A38
[1561] The method of embodiment A35, wherein aryl.sup.1 is
4-phenylsulfamic acid, R.sup.a is alkyl, which is substituted or
unsubstituted, R.sup.b is arylalkyl, which is substituted or
unsubstituted, R.sup.e is H; and R.sup.f is heteroaryl.
Embodiment A39
[1562] The method of embodiment A30, wherein the compound is:
##STR00355##
Embodiment A40
[1563] The method of embodiment A30, wherein the compound is:
##STR00356##
Embodiment A41
[1564] The method of embodiment A35, wherein aryl.sup.1 is
4-phenylsulfamic acid, R.sup.a is alkyl, which is substituted or
unsubstituted, R.sup.b is arylalkyl, which is substituted or
unsubstituted, R.sup.e is H; and R.sup.f is alkyl.
Embodiment A42
[1565] The method of embodiment A30, wherein the compound is:
##STR00357##
Embodiment A43
[1566] The method of embodiment A32, wherein the compound is:
##STR00358##
Embodiment A44
[1567] The method of embodiment A34, wherein Aryl.sup.2 is:
##STR00359##
wherein R.sup.e is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl,
alkynyl, an alkoxy group, an ether group, a carboxylic acid group,
a carboxaldehyde group, an ester group, an amine group, an amide
group, a carbonate group, a carbamate group, a urethane group, a
thioether group, a thioester group, a thioacid group, aryl,
arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or
heteroarylalkyl, any of which is substituted or unsubstituted,
R.sup.f is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an
alkoxy group, an ether group, a carboxylic acid group, a
carboxaldehyde group, an ester group, an amine group, an amide
group, a carbonate group, a carbamate group, a urethane group, a
thioether group, a thioester group, a thioacid group, aryl,
arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or
heteroarylalkyl, any of which is substituted or unsubstituted.
Embodiment A45
[1568] The method of embodiment A44, wherein R.sup.e is H, OH, F,
Cl, Br, I, alkyl, an alkoxy group, aryl, arylalkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is
substituted or unsubstituted and R.sup.f is H, OH, F, Cl, Br, I,
alkyl, an alkoxy group, aryl, arylalkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is
substituted or unsubstituted.
Embodiment A46
[1569] The method of embodiment A44, wherein R.sup.e is H, OH, F,
Cl, Br, I, alkyl, or an alkoxy group, any of which is substituted
or unsubstituted and R.sup.f is alkyl, aryl, heterocyclyl, or
heteroaryl, any of which is substituted or unsubstituted.
Embodiment A47
[1570] The method of embodiment A44, wherein aryl.sup.1 is
4-phenylsulfamic acid, R.sup.a is alkyl, which is substituted or
unsubstituted, R.sup.b is arylalkyl, which is substituted or
unsubstituted, R.sup.e is H; and R.sup.f is heteroaryl.
Embodiment A48
[1571] The method of embodiment A30, wherein the compound is:
##STR00360##
Embodiment A49
[1572] The method of embodiment A30, wherein the compound is:
##STR00361##
Embodiment A50
[1573] The method of embodiment A40, wherein the agent that
improves the aqueous solubility of the compound that activates
Tie-2 or the pharmaceutically-acceptable salt thereof comprises a
2-hydroxypropyl-.beta.-cyclodextrin moiety.
Embodiment A51
[1574] The method of embodiment A50, wherein the condition is
diabetic macular edema.
Embodiment A52
[1575] The method of embodiment A51, wherein a plasma concentration
in the subject of the compound that activates Tie-2 or the
pharmaceutically-acceptable salt thereof is no greater than 500
ng/mL at about 0.25 hours after the administration.
Embodiment A53
[1576] The method of embodiment A51, wherein a plasma concentration
in the subject of the compound that activates Tie-2 or the
pharmaceutically-acceptable salt thereof is about 50 ng/mL to about
350 ng/mL at about 0.25 hours after the administration; about 30
ng/mL to about 350 ng/mL at about 1 hour after the administration;
about 10 ng/mL to about 200 ng/mL at about 2 hours after the
administration; and about 0 ng/mL to about 50 ng/mL at about 4
hours after the administration.
Embodiment A54
[1577] The method of embodiment A51, wherein a plasma concentration
in the subject of the compound that activates Tie-2 or the
pharmaceutically-acceptable salt thereof is for administration of a
dose of about 5 mg, about 50 ng/mL to about 100 ng/mL at about 0.25
hours after the administration; about 30 ng/mL to about 80 ng/mL at
about 1 hour after the administration; about 10 ng/mL to about 50
ng/mL at about 2 hours after the administration; and about 0 ng/mL
to about 30 ng/mL at about 4 hours after the administration; for
administration of a dose of about 15 mg, about 120 ng/mL to about
180 ng/mL at about 0.25 hours after the administration; about 70
ng/mL to about 130 ng/mL at about 1 hour after the administration;
about 20 ng/mL to about 70 ng/mL at about 2 hours after the
administration; and about 0 ng/mL to about 40 ng/mL at about 4
hours after the administration; for administration of a dose of
about 22.5 mg, about 190 ng/mL to about 250 ng/mL at about 0.25
hours after the administration; about 170 ng/mL to about 240 ng/mL
at about 1 hour after the administration; about 70 ng/mL to about
120 ng/mL at about 2 hours after the administration; and about 10
ng/mL to about 60 ng/mL at about 4 hours after the administration;
and for administration of a dose of about 30 mg, about 250 ng/mL to
about 330 ng/mL at about 0.25 hours after the administration; about
270 ng/mL to about 330 ng/mL at about 1 hour after the
administration; about 130 ng/mL to about 180 ng/mL at about 2 hours
after the administration; and about 25 ng/mL to about 75 ng/mL at
about 4 hours after the administration.
Embodiment B1
[1578] A method of treating a condition in a subject in need
thereof, the method comprising administering to the subject a
therapeutically-effective amount of a compound that activates
Tie-2, or a pharmaceutically-acceptable salt thereof, wherein the
administration provides a plasma concentration in the subject of
the compound that activates Tie-2 or the
pharmaceutically-acceptable salt thereof of about 25 ng/mL to about
500 ng/mL.
Embodiment B2
[1579] The method of embodiment B1, wherein the plasma
concentration in the subject of the compound that activates Tie-2
or the pharmaceutically-acceptable salt thereof is no greater than
350 ng/mL at about 0.25 hours after the administration.
Embodiment B3
[1580] The method of embodiment B2, wherein the plasma
concentration in the subject of the compound that activates Tie-2
or the pharmaceutically-acceptable salt thereof is greater than 50
ng/mL.
Embodiment B4
[1581] The method of embodiment B1, wherein the plasma
concentration in the subject of the compound that activates Tie-2
or the pharmaceutically-acceptable salt thereof is about 50 ng/mL
to about 350 ng/mL at about 0.25 hours after the administration;
about 30 ng/mL to about 350 ng/mL at about 1 hour after the
administration; about 10 ng/mL to about 200 ng/mL at about 2 hours
after the administration; and about 0 ng/mL to about 50 ng/mL at
about 4 hours after the administration.
Embodiment B5
[1582] The method of embodiment B1, wherein the plasma
concentration in the subject of the compound that activates Tie-2
or the pharmaceutically-acceptable salt thereof is for
administration of a dose of about 5 mg, about 50 ng/mL to about 100
ng/mL at about 0.25 hours after the administration; about 30 ng/mL
to about 80 ng/mL at about 1 hour after the administration; about
10 ng/mL to about 50 ng/mL at about 2 hours after the
administration; and about 0 ng/mL to about 30 ng/mL at about 4
hours after the administration; for administration of a dose of
about 15 mg, about 120 ng/mL to about 180 ng/mL at about 0.25 hours
after the administration; about 70 ng/mL to about 130 ng/mL at
about 1 hour after the administration; about 20 ng/mL to about 70
ng/mL at about 2 hours after the administration; and about 0 ng/mL
to about 40 ng/mL at about 4 hours after the administration; for
administration of a dose of about 22.5 mg, about 190 ng/mL to about
250 ng/mL at about 0.25 hours after the administration; about 170
ng/mL to about 240 ng/mL at about 1 hour after the administration;
about 70 ng/mL to about 120 ng/mL at about 2 hours after the
administration; and about 10 ng/mL to about 60 ng/mL at about 4
hours after the administration; and for administration of a dose of
about 30 mg, about 250 ng/mL to about 330 ng/mL at about 0.25 hours
after the administration; about 270 ng/mL to about 330 ng/mL at
about 1 hour after the administration; about 130 ng/mL to about 180
ng/mL at about 2 hours after the administration; and about 25 ng/mL
to about 75 ng/mL at about 4 hours after the administration.
Embodiment B6
[1583] The method of embodiment BI, wherein the compound that
activates Tie-2, or the pharmaceutically-acceptable salt thereof,
is administered in a unit dosage form, wherein the unit dosage form
further comprises a pharmaceutically-acceptable excipient.
Embodiment B7
[1584] The method of embodiment B6, wherein the
pharmaceutically-acceptable excipient comprises a poly-ethylene
glycol moiety.
Embodiment B8
[1585] The method of embodiment B6, wherein the
pharmaceutically-acceptable excipient comprises a cyclodextrin
moiety.
Embodiment B9
[1586] The method of embodiment B6, wherein the
pharmaceutically-acceptable excipient comprises a
2-hydroxypropyl-.beta.-cyclodextrin moiety.
Embodiment B10
[1587] The method of embodiment B6, wherein the
pharmaceutically-acceptable excipient comprises a
sulfobutylether-.beta.-cyclodextrin moiety.
Embodiment B11
[1588] The method of embodiment B6, wherein the compound that
activates Tie-2, or the pharmaceutically-acceptable salt thereof,
and the pharmaceutically-acceptable excipient are held in a complex
by non-covalent interactions.
Embodiment B12
[1589] The method of embodiment B6, wherein the
pharmaceutically-acceptable excipient comprises a surfactant
moiety.
Embodiment B13
[1590] The method of embodiment B1, wherein the
therapeutically-effective amount is from about 0.1 mg to about 100
mg.
Embodiment B14
[1591] The method of embodiment B1, wherein the
therapeutically-effective amount is from about 0.5 mg to about 30
mg.
Embodiment B15
[1592] The method of embodiment B1, wherein the administration is
subcutaneous.
Embodiment B16
[1593] The method of embodiment B1, wherein the administration is
to an eye.
Embodiment B17
[1594] The method of embodiment B1, wherein the condition is an
ocular condition.
Embodiment B18
[1595] The method of embodiment B1, wherein the condition is
diabetic macular edema.
Embodiment B19
[1596] The method of embodiment B1, wherein the condition is
diabetic retinopathy.
Embodiment B20
[1597] The method of embodiment B1, wherein the condition is
macular degeneration.
Embodiment B21
[1598] The method of embodiment B1, wherein the condition is
vascular leak.
Embodiment B22
[1599] The method of embodiment B1, wherein the condition is a
cancer.
Embodiment B23
[1600] The method of embodiment B1, wherein the subject is a
human.
Embodiment B24
[1601] The method of embodiment B1, wherein the compound that
activates Tie-2 or the pharmaceutically-acceptable salt thereof
binds HPTP-beta.
Embodiment B25
[1602] The method of embodiment B1, wherein the compound that
activates Tie-2 or the pharmaceutically-acceptable salt thereof
inhibits HPTP-beta.
Embodiment B26
[1603] The method of embodiment B1, wherein the compound that
activates Tie-2 or the pharmaceutically-acceptable salt thereof is
a phosphate mimetic.
Embodiment B27
[1604] The method of embodiment B1, wherein the compound that
activates Tie-2 comprises an amino acid backbone.
Embodiment B28
[1605] The method of embodiment B1, wherein the compound that
activates Tie-2 comprises a sulfamic acid.
Embodiment B29
[1606] The method of embodiment B1, wherein the subject's visual
acuity improves by at least 5 letters.
Embodiment B30
[1607] The method of embodiment B9, wherein the compound that
activates Tie-2 is:
##STR00362##
or a pharmaceutically-acceptable salt or zwitterion thereof.
Embodiment B31
[1608] The method of embodiment B30, wherein a plasma concentration
in the subject of the compound that activates Tie-2 or the
pharmaceutically-acceptable salt thereof is no greater than 350
ng/mL at about 0.25 hours after the administration.
Embodiment B32
[1609] The method of embodiment B30, wherein the plasma
concentration in the subject of the compound that activates Tie-2
or the pharmaceutically-acceptable salt thereof is about 50 ng/mL
to about 350 ng/mL at about 0.25 hours after the administration;
about 30 ng/mL to about 350 ng/mL at about 1 hour after the
administration; about 10 ng/mL to about 200 ng/mL at about 2 hours
after the administration; and about 0 ng/mL to about 50 ng/mL at
about 4 hours after the administration.
Embodiment B33
[1610] The method of embodiment B30, wherein the plasma
concentration in the subject of the compound that activates Tie-2
or the pharmaceutically-acceptable salt thereof is for
administration of a dose of about 5 mg, about 50 ng/mL to about 100
ng/mL at about 0.25 hours after the administration; about 30 ng/mL
to about 80 ng/mL at about 1 hour after the administration; about
10 ng/mL to about 50 ng/mL at about 2 hours after the
administration; and about 0 ng/mL to about 30 ng/mL at about 4
hours after the administration; for administration of a dose of
about 15 mg, about 120 ng/mL to about 180 ng/mL at about 0.25 hours
after the administration; about 70 ng/mL to about 130 ng/mL at
about 1 hour after the administration; about 20 ng/mL to about 70
ng/mL at about 2 hours after the administration; and about 0 ng/mL
to about 40 ng/mL at about 4 hours after the administration; for
administration of a dose of about 22.5 mg, about 190 ng/mL to about
250 ng/mL at about 0.25 hours after the administration; about 170
ng/mL to about 240 ng/mL at about 1 hour after the administration;
about 70 ng/mL to about 120 ng/mL at about 2 hours after the
administration; and about 10 ng/mL to about 60 ng/mL at about 4
hours after the administration; and for administration of a dose of
about 30 mg, about 250 ng/mL to about 330 ng/mL at about 0.25 hours
after the administration; about 270 ng/mL to about 330 ng/mL at
about 1 hour after the administration; about 130 ng/mL to about 180
ng/mL at about 2 hours after the administration; and about 25 ng/mL
to about 75 ng/mL at about 4 hours after the administration.
Embodiment B34
[1611] The method of any above embodiment wherein the compound that
activates Tie-2 is any compound described herein.
Embodiment C1
[1612] A pharmaceutical composition comprising a compound that
activates Tie-2, or a pharmaceutically-acceptable salt thereof and
an agent that increases solubility of the compound that activates
Tie-2, or the pharmaceutically-acceptable salt thereof compared to
solubility in absence of the agent.
Embodiment C2
[1613] The pharmaceutical composition of embodiment C1, wherein the
agent that increases solubility of the compound that activates
Tie-2 or the pharmaceutically-acceptable salt thereof comprises a
polymer.
Embodiment C3
[1614] The pharmaceutical composition of embodiment C1, wherein the
agent that increases solubility of the compound that activates
Tie-2 or the pharmaceutically-acceptable salt thereof comprises a
poly-ethylene glycol moiety.
Embodiment C4
[1615] The pharmaceutical composition of embodiment C1, wherein the
agent that increases solubility of the compound that activates
Tie-2 or the pharmaceutically-acceptable salt thereof comprises a
cyclodextrin moiety.
Embodiment C5
[1616] The pharmaceutical composition of embodiment C1, wherein the
agent that increases solubility of the compound that activates
Tie-2 or the pharmaceutically-acceptable salt thereof comprises a
2-hydroxypropyl-.beta.-cyclodextrin moiety.
Embodiment C6
[1617] The pharmaceutical composition of embodiment C1, wherein the
agent that increases solubility of the compound that activates
Tie-2 or the pharmaceutically-acceptable salt thereof comprises a
sulfobutylether-.beta.-cyclodextrin moiety.
Embodiment C7
[1618] The pharmaceutical composition of embodiment C1, wherein the
agent that increases solubility of the compound that activates
Tie-2 or the pharmaceutically-acceptable salt thereof comprises a
surfactant moiety.
Embodiment C8
[1619] The pharmaceutical composition of embodiment C1, wherein the
agent that increases solubility of the compound that activates
Tie-2 or the pharmaceutically-acceptable salt thereof increases
aqueous solubility by at least 10% at each of 5.degree. C., ambient
temperature, and 50.degree. C.
Embodiment C9
[1620] The pharmaceutical composition of embodiment C1, wherein the
agent that increases solubility of the compound that activates
Tie-2 or the pharmaceutically-acceptable salt thereof improves
solubility by at least 25%.
Embodiment C10
[1621] The pharmaceutical composition of embodiment C1, wherein the
agent that increases solubility of the compound that activates
Tie-2 or the pharmaceutically-acceptable salt thereof improves
solubility by at least 50%.
Embodiment C11
[1622] The pharmaceutical composition of embodiment C1, wherein the
agent that increases solubility of the compound that activates
Tie-2 or the pharmaceutically-acceptable salt thereof is a
cyclodextrin, and the pharmaceutical composition has a solubility
of the compound that activates Tie-2, or the
pharmaceutically-acceptable salt thereof, that is greater than that
of an alternative formulation, wherein the alternative formulation
comprises the compound that activates Tie-2, or the
pharmaceutically-acceptable salt thereof; the cyclodexrin; and a
polyethylene glycol moiety.
Embodiment C12
[1623] The pharmaceutical composition of embodiment C1, wherein the
compound that activates Tie-2, or the pharmaceutically-acceptable
salt thereof, is present in an amount from about 0.1 mg to about
100 mg.
Embodiment C13
[1624] The pharmaceutical composition of embodiment C1, wherein the
compound that activates Tie-2, or the pharmaceutically-acceptable
salt thereof, is present in an amount from about 0.5 mg to about 30
mg.
Embodiment C14
[1625] The pharmaceutical composition of embodiment C1, wherein the
pharmaceutical composition is stable at about 5.degree. C. for at
least 30 days.
Embodiment C15
[1626] The pharmaceutical composition of embodiment C1, wherein the
pharmaceutical composition is stable at about 50.degree. C. for at
least 30 days.
Embodiment C16
[1627] The pharmaceutical composition of embodiment C1, wherein the
compound that activates Tie-2, or the pharmaceutically-acceptable
salt thereof, and the agent that increases solubility of the
compound that activates Tie-2 or the pharmaceutically-acceptable
salt thereof are in a unit dosage form.
Embodiment C17
[1628] The pharmaceutical composition of embodiment C16, wherein
the unit dosage for further comprises a pharmaceutically-acceptable
carrier.
Embodiment C18
[1629] The pharmaceutical composition of embodiment C16, wherein
the unit dosage form is formulated for subcutaneous
administration.
Embodiment C19
[1630] The pharmaceutical composition of embodiment C16, wherein
the unit dosage form is formulated for administration to an
eye.
Embodiment C20
[1631] The pharmaceutical composition of embodiment C1, wherein the
compound that activates Tie-2 or the pharmaceutically-acceptable
salt thereof binds HPTP-beta.
Embodiment C21
[1632] The pharmaceutical composition of embodiment C1, wherein the
compound that activates Tie-2 or the pharmaceutically-acceptable
salt thereof inhibits HPTP-beta.
Embodiment C22
[1633] The pharmaceutical composition of embodiment C1, wherein the
compound that activates Tie-2 or the pharmaceutically-acceptable
salt thereof is a phosphate mimetic.
Embodiment C23
[1634] The pharmaceutical composition of embodiment C1, wherein the
compound that activates Tie-2 comprises an amino acid backbone.
Embodiment C24
[1635] The pharmaceutical composition of embodiment C1, wherein the
compound that activates Tie-2 comprises a sulfamic acid.
Embodiment C25
[1636] The pharmaceutical composition of any above embodiment
wherein the compound that activates Tie-2 is any compound described
herein.
Embodiment D1
[1637] A pharmaceutical composition comprising a Tie-2 activator or
a pharmaceutically-acceptable salt thereof, and an antibody.
Embodiment D2
[1638] The pharmaceutical composition of embodiment D1, wherein the
Tie-2 activator or the pharmaceutically-acceptable salt thereof
binds HPTP-beta.
Embodiment D3
[1639] The pharmaceutical composition of embodiment D1, wherein the
Tie-2 activator or the pharmaceutically-acceptable salt thereof
inhibits HPTP-beta.
Embodiment D4
[1640] The pharmaceutical composition of embodiment D1, wherein the
Tie-2 activator or the pharmaceutically-acceptable salt thereof is
a phosphate mimetic.
Embodiment D5
[1641] The pharmaceutical composition of embodiment D1, wherein the
Tie-2 activator comprises an amino acid backbone.
Embodiment D6
[1642] The pharmaceutical composition of embodiment D1, wherein the
Tie-2 activator comprises a sulfamic acid.
Embodiment D7
[1643] The pharmaceutical composition of embodiment D1, wherein the
antibody binds HPTP-beta.
Embodiment D8
[1644] The pharmaceutical composition of embodiment D1, wherein the
antibody is an anti-VEGF agent.
Embodiment D9
[1645] The pharmaceutical composition of embodiment D1, wherein the
antibody is ranibizumab.
Embodiment D10
[1646] The pharmaceutical composition of embodiment D1, wherein the
antibody is bevacizumab.
Embodiment D11
[1647] The pharmaceutical composition of embodiment D1, wherein the
antibody is aflibercept.
Embodiment D12
[1648] The pharmaceutical composition of embodiment D1, wherein the
antibody comprises SEQ ID NO: 1.
Embodiment D13
[1649] The pharmaceutical composition of embodiment D1, wherein the
antibody comprises SEQ ID NO: 2.
Embodiment D14
[1650] The pharmaceutical composition of embodiment D1, wherein the
antibody comprises SEQ ID NO: 1 and SEQ ID NO: 2.
Embodiment D15
[1651] The pharmaceutical composition of embodiment D1, wherein the
Tie-2 activator or the pharmaceutically-acceptable salt thereof and
the antibody are in a unit dosage form, wherein the unit dosage
form further comprises a pharmaceutically-acceptable excipient.
Embodiment D16
[1652] The pharmaceutical composition of embodiment D15, wherein
the pharmaceutically-acceptable excipient comprises a poly-ethylene
glycol moiety.
Embodiment D17
[1653] The pharmaceutical composition of embodiment D15, wherein
the pharmaceutically-acceptable excipient comprises a cyclodextrin
moiety.
Embodiment D18
[1654] The pharmaceutical composition of embodiment D15, wherein
the pharmaceutically-acceptable excipient comprises a
2-hydroxypropyl-.beta.-cyclodextrin moiety.
Embodiment D19
[1655] The pharmaceutical composition of embodiment D15, wherein
the pharmaceutically-acceptable excipient comprises a
sulfobutylether-.beta.-cyclodextrin moiety.
Embodiment D20
[1656] The pharmaceutical composition of embodiment D15, wherein
the Tie-2 activator, or the pharmaceutically-acceptable salt
thereof, and the pharmaceutically-acceptable excipient are held in
a complex by non-covalent interactions.
Embodiment D21
[1657] The pharmaceutical composition of embodiment D15, wherein
the pharmaceutically-acceptable excipient comprises a surfactant
moiety.
Embodiment D22
[1658] The pharmaceutical composition of embodiment D15, wherein
the unit dosage form is formulated for subcutaneous
administration.
Embodiment D23
[1659] The pharmaceutical composition of embodiment D15, wherein
the unit dosage form is formulated for administration to an
eye.
Embodiment D24
[1660] The pharmaceutical composition of embodiment D1, wherein the
Tie-2 activator is present in an amount from about 0.1 mg to about
100 mg.
Embodiment D25
[1661] The pharmaceutical composition of embodiment D1, wherein the
Tie-2 activator is present in an amount from about 0.5 mg to about
30 mg.
Embodiment D26
[1662] The pharmaceutical composition of embodiment D1, wherein the
antibody is present in an amount from about 0.01 mg to about 5
mg.
Embodiment D27
[1663] The pharmaceutical composition of embodiment D1, wherein the
antibody is present in an amount from about 0.1 mg to about 5
mg.
Embodiment D28
[1664] The pharmaceutical composition of any above embodiment
wherein the compound that activates Tie-2 is any compound described
herein.
Embodiment D1
[1665] A kit comprising a Tie-2 activator or a
pharmaceutically-acceptable salt thereof, an antibody, and written
instructions on use of the kit in treatment of a condition.
Embodiment D2
[1666] The kit of embodiment D1, wherein the condition is an ocular
condition.
Embodiment D3
[1667] The kit of embodiment D1, wherein the condition is an ocular
condition.
Embodiment D4
[1668] The kit of embodiment D1, wherein the condition is diabetic
macular edema.
Embodiment D5
[1669] The kit of embodiment D1, wherein the condition is diabetic
retinopathy.
Embodiment D6
[1670] The kit of embodiment D1, wherein the condition is macular
degeneration.
Embodiment D7
[1671] The kit of embodiment D1, wherein the condition is vascular
leak.
Embodiment D8
[1672] The kit of embodiment D1, wherein the condition is a
cancer.
Embodiment D9
[1673] The kit of embodiment D1, wherein the instructions describe
administration by subcutaneous injection.
Embodiment D10
[1674] The kit of embodiment D1, wherein the instructions describe
administration to an eye.
Embodiment D11
[1675] The kit of any above embodiment wherein the Tie-2 activator
is any compound described herein.
Embodiment E1
[1676] A method of treating a condition, the method comprising
administering to a subject in need thereof a
therapeutically-effective amount of a Tie-2 activator or a
pharmaceutically-acceptable salt thereof and a
therapeutically-effective amount of an antibody.
Embodiment E2
[1677] The method of embodiment E1, wherein the Tie-2 activator or
the pharmaceutically-acceptable salt thereof binds HPTP-beta.
Embodiment E3
[1678] The method of embodiment E1, wherein the Tie-2 activator or
the pharmaceutically-acceptable salt thereof inhibits
HPTP-beta.
Embodiment E4
[1679] The method of embodiment E1, wherein the Tie-2 activator or
the pharmaceutically-acceptable salt thereof is a phosphate
mimetic.
Embodiment E5
[1680] The method of embodiment E1, wherein the Tie-2 activator
comprises an amino acid backbone.
Embodiment E6
[1681] The method of embodiment E1, wherein the Tie-2 activator
comprises a sulfamic acid.
Embodiment E7
[1682] The method of embodiment E1, wherein the antibody binds
HPTP-beta.
Embodiment E8
[1683] The method of embodiment E1, wherein the antibody is an
anti-VEGF agent.
Embodiment E9
[1684] The method of embodiment E1, wherein the antibody is
ranibizumab.
Embodiment E10
[1685] The method of embodiment E1, wherein the antibody is
bevacizumab.
Embodiment E11
[1686] The method of embodiment E1, wherein the antibody is
aflibercept.
Embodiment E12
[1687] The method of embodiment E1, wherein the antibody comprises
SEQ ID NO: 1.
Embodiment E13
[1688] The method of embodiment E1, wherein the antibody comprises
SEQ ID NO: 2.
Embodiment E14
[1689] The method of embodiment E1, wherein the antibody comprises
SEQ ID NO: 1 and SEQ ID NO: 2.
Embodiment E15
[1690] The method of embodiment E1, wherein the Tie-2 activator or
the pharmaceutically-acceptable salt thereof and the antibody are
in a unit dosage form, wherein the unit dosage form further
comprises a pharmaceutically-acceptable excipient.
Embodiment E16
[1691] The method of embodiment E15, wherein the
pharmaceutically-acceptable excipient comprises a poly-ethylene
glycol moiety.
Embodiment E17
[1692] The method of embodiment E15, wherein the
pharmaceutically-acceptable excipient comprises a cyclodextrin
moiety.
Embodiment E18
[1693] The method of embodiment E15, wherein the
pharmaceutically-acceptable excipient comprises a
2-hydroxypropyl-.beta.-cyclodextrin moiety.
Embodiment E19
[1694] The method of embodiment E15, wherein the
pharmaceutically-acceptable excipient comprises a
sulfobutylether-.beta.-cyclodextrin moiety.
Embodiment E20
[1695] The method of embodiment E15, wherein the Tie-2 activator,
or the pharmaceutically-acceptable salt thereof, and the
pharmaceutically-acceptable excipient are held in a complex by
non-covalent interactions.
Embodiment E21
[1696] The method of embodiment E15, wherein the
pharmaceutically-acceptable excipient comprises a surfactant
moiety.
Embodiment E22
[1697] The method of embodiment E1, wherein the
therapeutically-effective amount of the Tie-2 activator or the
pharmaceutically-acceptable salt thereof is from about 0.1 mg to
about 100 mg.
Embodiment E23
[1698] The method of embodiment E1, wherein the
therapeutically-effective amount of the Tie-2 activator or the
pharmaceutically-acceptable salt thereof is from about 0.5 mg to
about 30 mg.
Embodiment E24
[1699] The method of embodiment E1, wherein the
therapeutically-effective amount of the antibody is from about 0.01
mg to about 5 mg.
Embodiment E25
[1700] The method of embodiment E1, wherein the
therapeutically-effective amount of the antibody is from about 0.1
mg to about 5 mg.
Embodiment E26
[1701] The method of embodiment E1, wherein the administration of
the Tie-2 activator or the pharmaceutically-acceptable salt thereof
is subcutaneous administration.
Embodiment E27
[1702] The method of embodiment E1, wherein the administration of
the antibody is subcutaneous administration.
Embodiment E28
[1703] The method of embodiment E1, wherein the administration of
the Tie-2 activator or the pharmaceutically-acceptable salt thereof
is to an eye.
Embodiment E29
[1704] The method of embodiment E1, wherein the administration of
the antibody is to an eye.
Embodiment E30
[1705] The method of embodiment E1, wherein the Tie-2 activator or
the pharmaceutically-acceptable salt thereof and the antibody are
administered simultaneously.
Embodiment E31
[1706] The method of embodiment E1, wherein the Tie-2 activator or
the pharmaceutically-acceptable salt thereof and the antibody are
administered sequentially.
Embodiment E32
[1707] The method of embodiment E31, wherein the sequential
administration is administration of the Tie-2 activator or the
pharmaceutically-acceptable salt thereof and the antibody on the
same day.
Embodiment E33
[1708] The method of embodiment E31, wherein the sequential
administration is administration of the Tie-2 activator or the
pharmaceutically-acceptable salt thereof and the antibody within
one month.
Embodiment E34
[1709] The method of embodiment E1, wherein the condition is an
ocular condition.
Embodiment E35
[1710] The method of embodiment E1, wherein the condition is
diabetic macular edema.
Embodiment E36
[1711] The method of embodiment E1, wherein the condition is
diabetic retinopathy.
Embodiment E37
[1712] The method of embodiment E1, wherein the condition is
macular degeneration.
Embodiment E38
[1713] The method of embodiment E1, wherein the condition is
vascular leak.
Embodiment E39
[1714] The method of embodiment E1, wherein the condition is a
cancer.
Embodiment E40
[1715] The method of embodiment E1, wherein the subject is a
human.
Embodiment E41
[1716] The method of embodiment E1, wherein the subject's visual
acuity improves by at least 5 letters.
Embodiment E42
[1717] The method of any above embodiment wherein the Tie-2
activator is any compound described herein.
Embodiment F1
[1718] A complex comprising a Tie-2 activator, or a
pharmaceutically-acceptable salt thereof, and a molecule comprising
a channel, wherein the compound that activates Tie-2, or the
pharmaceutically-acceptable salt thereof is held in the channel of
the molecule by non-covalent interactions.
Embodiment F2
[1719] The complex of embodiment F1, wherein the Tie-2 activator or
the pharmaceutically-acceptable salt thereof binds HPTP-beta.
Embodiment F3
[1720] The complex of embodiment F1, wherein the Tie-2 activator or
the pharmaceutically-acceptable salt thereof inhibits
HPTP-beta.
Embodiment F4
[1721] The complex of embodiment F1, wherein the Tie-2 activator or
the pharmaceutically-acceptable salt thereof is a phosphate
mimetic.
Embodiment F5
[1722] The complex of embodiment F1, wherein the Tie-2 activator
comprises an amino acid backbone.
Embodiment F6
[1723] The complex of embodiment F1, wherein the Tie-2 activator
comprises a sulfamic acid.
Embodiment F7
[1724] The complex of embodiment F1, wherein the molecule
comprising the channel comprises a cyclodextrin moiety.
Embodiment F8
[1725] The complex of embodiment F1, wherein the molecule
comprising the channel comprises a
2-hydroxypropyl-.beta.-cyclodextrin moiety.
Embodiment F9
[1726] The complex of embodiment F1, wherein the molecule
comprising the channel comprises a
sulfobutylether-.beta.-cyclodextrin moiety.
Embodiment F10
[1727] The complex of embodiment F1, wherein the complex is more
soluble in water than is the Tie-2 activator in the absence of the
molecule comprising the channel.
Embodiment F11
[1728] The complex of any above embodiment wherein the Tie-2
activator is any compound described herein.
Embodiment G1
[1729] A method of treating a condition, the method comprising
administering to a subject in need thereof a
therapeutically-effective amount of complex comprising a Tie-2
activator, or a pharmaceutically-acceptable salt thereof and a
molecule comprising a channel, wherein the Tie-2 activator or the
pharmaceutically-acceptable salt thereof is held in the channel of
the molecule by non-covalent interactions.
Embodiment G2
[1730] The method of embodiment G1, wherein the Tie-2 activator or
the pharmaceutically-acceptable salt thereof binds HPTP-beta.
Embodiment G3
[1731] The method of embodiment G1, wherein the Tie-2 activator or
the pharmaceutically-acceptable salt thereof inhibits
HPTP-beta.
Embodiment G4
[1732] The method of embodiment G1, wherein the Tie-2 activator or
the pharmaceutically-acceptable salt thereof is a phosphate
mimetic.
Embodiment G5
[1733] The method of embodiment G1, wherein the Tie-2 activator
comprises an amino acid backbone.
Embodiment G6
[1734] The method of embodiment G1, wherein the Tie-2 activator
comprises a sulfamic acid.
Embodiment G7
[1735] The method of embodiment G1, wherein the molecule comprising
the channel comprises a cyclodextrin moiety.
Embodiment G8
[1736] The method of embodiment G1, wherein the molecule comprising
the channel comprises a 2-hydroxypropyl-.beta.-cyclodextrin
moiety.
Embodiment G9
[1737] The method of embodiment G1, wherein the molecule comprising
the channel comprises a sulfobutylether-.beta.-cyclodextrin
moiety.
Embodiment G10
[1738] The method of embodiment G1, wherein the complex is more
soluble in water than is the Tie-2 activator in the absence of the
molecule comprising the channel.
Embodiment G11
[1739] The method of embodiment G1, wherein the administration of
the complex is subcutaneous administration.
Embodiment G12
[1740] The method of embodiment G1, wherein the administration of
the complex is to an eye.
Embodiment G13
[1741] The method of embodiment G1, wherein the complex is in a
unit dosage form.
Embodiment G14
[1742] The method of embodiment G1, wherein the
therapeutically-effective amount of the complex is from about 0.1
mg to about 300 mg.
Embodiment G15
[1743] The method of embodiment G1, wherein the
therapeutically-effective amount of the Tie-2 activator or the
pharmaceutically-acceptable salt thereof is from about 0.5 mg to
about 100 mg.
Embodiment G16
[1744] The method of embodiment G1, wherein the condition is an
ocular condition.
Embodiment G17
[1745] The method of embodiment G1, wherein the condition is
diabetic macular edema.
Embodiment G18
[1746] The method of embodiment G1, wherein the condition is
diabetic retinopathy.
Embodiment G19
[1747] The method of embodiment G1, wherein the condition is
macular degeneration.
Embodiment G20
[1748] The method of embodiment G1, wherein the condition is
vascular leak.
Embodiment G21
[1749] The method of embodiment G1, wherein the condition is a
cancer.
Embodiment G22
[1750] The method of embodiment G1, further comprising
administering to the subject a therapeutically-effective amount of
an additional therapeutic agent.
Embodiment G23
[1751] The method of embodiment G22, wherein the additional
therapeutic agent is an antibody.
Embodiment G24
[1752] The method of embodiment G22, wherein the additional
therapeutic agent binds HPTP-beta.
Embodiment G25
[1753] The method of embodiment G22, wherein the additional
therapeutic agent is an anti-VEGF agent.
Embodiment G26
[1754] The method of embodiment G22, wherein the additional
therapeutic agent is ranibizumab.
Embodiment G27
[1755] The method of embodiment G22, wherein the additional
therapeutic agent is bevacizumab.
Embodiment G28
[1756] The method of embodiment G22, wherein the additional
therapeutic agent is aflibercept.
Embodiment G29
[1757] The method of embodiment G22, wherein the additional
therapeutic agent comprises SEQ ID NO: 1.
Embodiment G30
[1758] The method of embodiment G22, wherein the additional
therapeutic agent comprises SEQ ID NO: 2.
Embodiment G31
[1759] The method of embodiment G22, wherein the additional
therapeutic agent comprises SEQ ID NO: 1 and SEQ ID NO: 2.
Embodiment G32
[1760] The method of embodiment G22, wherein the
therapeutically-effective amount of the additional therapeutic
agent is from about 0.01 mg to about 5 mg.
Embodiment G33
[1761] The method of embodiment G22, wherein the
therapeutically-effective amount of the additional therapeutic
agent is from about 0.1 mg to about 5 mg.
Embodiment G34
[1762] The method of embodiment G22, wherein the administration of
the additional therapeutic agent is subcutaneous
administration.
Embodiment G35
[1763] The method of embodiment G22, wherein the administration of
the additional therapeutic agent is to an eye.
Embodiment G36
[1764] The method of embodiment G22, wherein the complex and the
additional therapeutic agent are administered simultaneously.
Embodiment G37
[1765] The method of embodiment G22, wherein the complex and the
additional therapeutic agent are administered sequentially.
Embodiment G38
[1766] The method of embodiment G37, wherein the sequential
administration is administration of the Tie-2 activator or the
pharmaceutically-acceptable salt thereof and the antibody on the
same day.
Embodiment G39
[1767] The method of embodiment G37, wherein the sequential
administration is administration of the Tie-2 activator or the
pharmaceutically-acceptable salt thereof and the antibody within
one month.
Embodiment G40
[1768] The method of embodiment G1, wherein the subject is a
human.
Embodiment G41
[1769] The method of embodiment G1, wherein the subject's visual
acuity improves by at least 5 letters.
Embodiment G42
[1770] The method of any above embodiment wherein the Tie-2
activator is any compound described herein.
Sequence CWU 1
1
21231PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 1Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Tyr Asp Phe Thr His Tyr 20 25 30 Gly Met Asn Trp Val Arg Gln
Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Trp Ile Asn Thr
Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe 50 55 60 Lys Arg Arg
Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr 65 70 75 80 Leu
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90
95 Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val
100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr
Lys Gly 115 120 125 Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser
Thr Ser Gly Gly 130 135 140 Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
Tyr Phe Pro Glu Pro Val 145 150 155 160 Thr Val Ser Trp Asn Ser Gly
Ala Leu Thr Ser Gly Val His Thr Phe 165 170 175 Pro Ala Val Leu Gln
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 180 185 190 Thr Val Pro
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val 195 200 205 Asn
His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys 210 215
220 Ser Cys Asp Lys Thr His Leu 225 230 2231PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
2Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1
5 10 15 Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn
Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
Val Leu Ile 35 40 45 Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro
Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu
Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr
Cys Gln Gln Tyr Ser Thr Val Pro Trp 85 90 95 Thr Phe Gly Gln Gly
Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val
Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135
140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr
Ser Leu Ser 165 170 175 Ser Thr Leu Thr Gln Ser Ser Gly Leu Tyr Ser
Leu Ser Ser Val Val 180 185 190 Thr Val Pro Ser Ser Ser Leu Gly Thr
Gln Thr Tyr Ile Cys Asn Val 195 200 205 Asn His Lys Pro Ser Asn Thr
Lys Val Asp Lys Lys Val Glu Pro Lys 210 215 220 Ser Cys Asp Lys Thr
His Leu 225 230
* * * * *