U.S. patent application number 16/149524 was filed with the patent office on 2019-09-05 for alkylamido compounds and uses thereof.
The applicant listed for this patent is Nogra Pharma Limited. Invention is credited to Sergio Baroni, Salvatore Bellinvia, Francesca Viti.
Application Number | 20190269637 16/149524 |
Document ID | / |
Family ID | 42562114 |
Filed Date | 2019-09-05 |
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United States Patent
Application |
20190269637 |
Kind Code |
A1 |
Baroni; Sergio ; et
al. |
September 5, 2019 |
Alkylamido Compounds and Uses Thereof
Abstract
Disclosed herein are compounds that may be specific to PPAR
and/or EGF receptors, and methods of making and using same.
Inventors: |
Baroni; Sergio; (Villa
D'adda, IT) ; Bellinvia; Salvatore; (Mendrisio,
CH) ; Viti; Francesca; (Salorino, CH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Nogra Pharma Limited |
Dublin |
|
IE |
|
|
Family ID: |
42562114 |
Appl. No.: |
16/149524 |
Filed: |
October 2, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15337707 |
Oct 28, 2016 |
10137101 |
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16149524 |
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14255255 |
Apr 17, 2014 |
9511041 |
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15337707 |
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13201786 |
Nov 17, 2011 |
8754127 |
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PCT/EP2010/000935 |
Feb 16, 2010 |
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14255255 |
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61287461 |
Dec 17, 2009 |
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61179062 |
May 18, 2009 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 8/44 20130101; A61Q
19/02 20130101; A61K 2800/78 20130101; C07D 307/79 20130101; A61Q
5/00 20130101; A61Q 19/08 20130101; C07D 319/08 20130101; A61P
17/10 20180101; A61K 8/42 20130101; A61Q 19/06 20130101; C07C
233/54 20130101; C07C 235/38 20130101; A61K 31/196 20130101; A61Q
19/008 20130101; A61Q 7/00 20130101 |
International
Class: |
A61K 31/196 20060101
A61K031/196; A61Q 7/00 20060101 A61Q007/00; A61Q 5/00 20060101
A61Q005/00; C07C 233/54 20060101 C07C233/54; C07C 235/38 20060101
C07C235/38; C07D 319/08 20060101 C07D319/08; A61K 8/42 20060101
A61K008/42; A61Q 19/08 20060101 A61Q019/08; A61Q 19/06 20060101
A61Q019/06; A61Q 19/02 20060101 A61Q019/02; C07D 307/79 20060101
C07D307/79 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 16, 2009 |
EP |
09425056.0 |
Claims
1-19. (canceled)
20. The compound N-acetyl-(S)-3-(4-aminophenyl)-2-methoxypropionic
acid, or a pharmaceutically acceptable salt or an N-oxide
thereof.
21. A pharmaceutical composition comprising the compound of claim
20, or a pharmaceutically acceptable salt or an N-oxide thereof;
and a pharmaceutically acceptable carrier.
22. The compound N-acetyl-(S)-3-(4-aminophenyl)-2-methoxypropionic
acid, or a pharmaceutically acceptable salt thereof.
23. A pharmaceutical composition comprising the compound of claim
22, or a pharmaceutically acceptable salt thereof; and a
pharmaceutically acceptable carrier.
24. The compound N-acetyl-(S)-3-(4-aminophenyl)-2-methoxypropionic
acid.
25. A pharmaceutical composition comprising the compound of claim
24; and a pharmaceutically acceptable carrier.
Description
[0001] This application is a continuation application of U.S.
patent application Ser. No. 15/337,707, filed on Oct. 28, 2016,
which is a continuation application of U.S. patent application Ser.
No. 14/255,255, filed on Apr. 17, 2014, which is a continuation
application of U.S. patent application Ser. No. 13/201,786, filed
on Nov. 17, 2011, which is a U.S. national stage application under
35 U.S.C. .sctn. 371 of International Application No.
PCT/EP2010/000935, filed on Feb. 16, 2010, which claims priority to
European Application No. 09425056.0, filed on Feb. 16, 2009, U.S.
Patent Application No. 61/179,062, filed on May 18, 2009 and U.S.
Patent Application No. 61/287,461, filed on Dec. 17, 2009, each of
which is incorporated by reference herein in its entirety.
BACKGROUND
[0002] Peroxisome Proliferator Activated Receptors (PPARs) are
members of the nuclear hormone receptor super family, which are
ligand-activated transcription factors regulating gene expression.
Certain PPARs play roles in the regulation of cell differentiation,
development and metabolism of higher organisms.
[0003] Three types of PPAR has been identified: alpha, expressed in
the liver, kidney, heart and other tissues and organs, beta/delta
expressed for example in the brain, and gamma, expressed in three
forms: gamma1, gamma2, and gamma3. PPAR.gamma. receptors have been
associated with a number of disease states including dyslipidemia,
hyperlipidemia, hypercholesteremia, atherosclerosis, atherogenesis,
hypertriglyceridemia, heart failure, myocardial infarction,
vascular diseases, cardiovascular diseases, hypertension, obesity,
inflammation, arthritis, cancer, Alzheimer's disease, skin
disorders, respiratory diseases, ophthalmic disorders, IBDs
(irritable bowel disease), ulcerative colitis and Crohn's
disease.
[0004] Further, treatment of tumor cells with ligands of
PPAR.gamma. receptors can induce a decrease in cellular
proliferation, cell differentiation and apoptosis, and therefore
may be useful in preventing carcinogenesis. Intestinal
anti-inflammatory activity may be dependent on binding and
subsequent activation of PPAR.gamma. receptors.
[0005] In addition, numerous studies have indicated that EGF
receptor inhibitors may control proliferation and spread of
tumors.
[0006] Accordingly, molecules that modulate the activity of PPARs
and/or EGF receptors are useful as therapeutic agents in the
treatment of such diseases.
SUMMARY
[0007] This disclosure is generally directed to compounds which may
be specific to PPAR receptors and/or EGF receptors, and their use
as, for example, medicinal agents. Also provided are pharmaceutical
compositions comprising at least one disclosed compound, or
pharmaceutically acceptable salt or N-oxide thereof, and a
pharmaceutically acceptable carrier.
[0008] One embodiment provides compounds represented by formula I,
and compositions comprising such compounds:
##STR00001## [0009] wherein X is C.sub.1-C.sub.3alkylene,
optionally substituted with one, two or three substituents selected
from halogen or hydroxyl; [0010] R.sub.1 is selected from the group
consisting of C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.6cycloalkyl,
C.sub.2-C.sub.6alkenyl, and C.sub.2-C.sub.6alkynyl; [0011] R.sub.2
is selected from the group consisting of hydrogen and
C.sub.1-C.sub.6alkyl; [0012] R.sub.3 is independently selected, for
each occurrence from the group consisting of hydrogen,
C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6alkyl, cyano,
C.sub.3-C.sub.6cycloalkyl, halogen, hydroxyl, and nitro; [0013]
R.sub.4 is selected from the group consisting of hydrogen and
C.sub.1-C.sub.6alkyl; [0014] R.sub.5 is hydrogen or
C.sub.1-C.sub.6alkyl; [0015] or pharmaceutically acceptable salts
or N-oxides thereof.
[0016] Another embodiment provides compounds represented by formula
II, and compositions comprising such compounds:
##STR00002## [0017] wherein R.sub.1 is selected from the group
consisting of C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.6cycloalkyl,
C.sub.2-C.sub.6alkenyl, and C.sub.2-C.sub.6alkynyl; [0018] R.sub.2
is selected from the group consisting of hydrogen and
C.sub.1-C.sub.6alkyl; [0019] R.sub.3 is independently selected, for
each occurrence from the group consisting of hydrogen,
C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6alkyl, cyano,
C.sub.3-C.sub.6cycloalkyl, halogen, hydroxyl, and nitro; [0020]
R.sub.5 is C.sub.1-C.sub.6alkyl; or pharmaceutically acceptable
salts or N-oxides thereof.
[0021] Also provided herein are methods of treating cancer (e.g.
colorectal cancer) such as tumors expressing PPAR receptors and/or
EGF receptors, comprising administering to a subject in need
thereof a therapeutically effective amount of a compound of formula
I or II, or a pharmaceutically acceptable salt or N-oxides thereof.
Also contemplated herein are compositions that include a compound
represented by formula I or II and e.g., a pharmaceutically
acceptable excipient.
[0022] Also provided are compounds represented by formulas I and II
for use in therapy and/or for the manufacture of a medicament for
the treatment of cancer such as colorectal cancer.
BRIEF DESCRIPTION OF THE FIGURES
[0023] FIG. 1 depicts the % mortality of mice receiving TNBS
(trinitrobenzene sulfonic acid) versus mice receiving TNBS and
N-acetyl E2 in a murine colitis model.
[0024] FIG. 2 depicts the observed level of colonic lesions in mice
receiving TNBS versus mice receiving TNBS and N-acetyl E2 in a
murine colitis model.
[0025] FIG. 3 depicts the observed level of MPO activity in mice
receiving TNBS versus mice receiving TNBS and N-acetyl E2 in a
murine colitis model.
[0026] FIG. 4 depicts the observed level of colonic inflammation in
mice receiving TNBS versus mice receiving TNBS and N-acetyl E2 in a
murine colitis model.
[0027] FIG. 5 depicts effects of a disclosed compound on human
keratinocytes.
[0028] FIG. 6 depicts inhibition of TNF alpha by H.sub.2O.sub.2 and
a disclosed compound.
[0029] FIG. 7 depicts inhibition on mRNA expression of IL-6 induced
by the presence of IFN-gamma.
[0030] FIG. 8 depicts inhibition of a disclosed compound on the
activation of NF-kB.
[0031] FIG. 9 depicts inhibition of a disclosed compound on protein
expression of IL-6 induced by presence of LPS.
[0032] FIG. 10 depicts effect of a disclosed compound on human
sebocytes.
[0033] FIG. 11 depicts inhibitory capacity of a disclosed compound
on sebogenesis induced by lipid type stimulus.
[0034] FIG. 12A and FIG. 12B depict the results of a fatty acid
assay and squalene analysis of sebogenesis inhibition,
respectively.
[0035] FIG. 13 depicts treatment with linoleic acid and
testosterone with lipidogenic stimulus.
DETAILED DESCRIPTION
[0036] The features and other details of the disclosure will now be
more particularly described. Before further description of the
present invention, certain terms employed in the specification,
examples and appended claims are collected here. These definitions
should be read in light of the remainder of the disclosure and
understood as by a person of skill in the art. Unless defined
otherwise, all technical and scientific terms used herein have the
same meaning as commonly understood by a person of ordinary skill
in the art.
Definitions
[0037] "Treating" includes any effect, e.g., lessening, reducing,
modulating, or eliminating, that results in the improvement of the
condition, disease, disorder and the like.
[0038] The term "alkenyl" as used herein refers to an unsaturated
straight or branched hydrocarbon having at least one carbon-carbon
double bond, such as a straight or branched group of 2-12, 2-10, or
2-6 carbon atoms, referred to herein as C.sub.2-C.sub.12alkenyl,
C.sub.2-C.sub.10alkenyl, and C.sub.2-C.sub.6alkenyl, respectively.
Exemplary alkenyl groups include, but are not limited to, vinyl,
allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl,
hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl,
4-(2-methyl-3-butene)-pentenyl, etc.
[0039] The term "alkoxy" as used herein refers to an alkyl group
attached to an oxygen (--O-alkyl-). Exemplary alkoxy groups
include, but are not limited to, groups with an alkyl, alkenyl or
alkynyl group of 1-12, 1-8, or 1-6 carbon atoms, referred to herein
as C.sub.1-C.sub.12alkoxy, C.sub.1-C.sub.8alkoxy, and
C.sub.1-C.sub.6alkoxy, respectively. Exemplary alkoxy groups
include, but are not limited to methoxy, ethoxy, etc. Similarly,
exemplary "alkenoxy" groups include, but are not limited to
vinyloxy, allyloxy, butenoxy, etc.
[0040] The term "alkyl" as used herein refers to a saturated
straight or branched hydrocarbon, such as a straight or branched
group of 1-12, 1-10, or 1-6 carbon atoms, referred to herein as
C.sub.1-C.sub.12alkyl, C.sub.1-C.sub.10alkyl, and
C.sub.1-C.sub.6alkyl, respectively. Exemplary alkyl groups include,
but are not limited to, methyl, ethyl, propyl, isopropyl,
2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl,
3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl,
2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,
2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,
2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl,
isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl,
octyl, etc. In certain embodiments, alkyl refers to C.sub.1-C.sub.6
alkyl. In certain embodiments, cycloalkyl refers to
C.sub.3-C.sub.6cycloalkyl.
[0041] Alkyl, alkenyl and alkynyl groups can, in some embodiments,
be optionally be substituted with or interrupted by at least one
group selected from alkanoyl, alkoxy, alkyl, alkenyl, alkynyl,
amido, amidino, amino, aryl, arylalkyl, azido, carbamate,
carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl,
halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino,
ketone, nitro, phosphate, phosphonato, phosphinato, sulfate,
sulfide, sulfonamido, sulfonyl and thiocarbonyl.
[0042] The term "alkynyl" as used herein refers to an unsaturated
straight or branched hydrocarbon having at least one carbon-carbon
triple bond, such as a straight or branched group of 2-12, 2-8, or
2-6 carbon atoms, referred to herein as C.sub.2-C.sub.8alkynyl,
C.sub.2-C.sub.8alkynyl, and C.sub.2-C.sub.6alkynyl, respectively.
Exemplary alkynyl groups include, but are not limited to, ethynyl,
propynyl, butynyl, pentynyl, hexynyl, methylpropynyl,
4-methyl-1-butynyl, 4-propyl-2-pentynyl, and 4-butyl-2-hexynyl,
etc.
[0043] The term "amide" or "amido" as used herein refers to a
radical of the form --R.sub.aC(O)N(R.sub.b)--,
--R.sub.aC(O)N(R.sub.b)R.sub.c--, or --C(O)NR.sub.bR.sub.c, wherein
R.sub.a, R.sub.b and R.sub.c are each independently selected from
alkoxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl,
carbamate, cycloalkyl, ester, ether, formyl, halogen, haloalkyl,
heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone, and nitro.
The amide can be attached to another group through the carbon, the
nitrogen, R.sub.b, R.sub.c, or R.sub.a. The amide also may be
cyclic, for example R.sub.b and R.sub.c, R.sub.a and R.sub.b, or
R.sub.a and R.sub.c may be joined to form a 3- to 12-membered ring,
such as a 3- to 10-membered ring or a 5- to 6-membered ring. The
term "carboxamido" refers to the structure
--C(O)NR.sub.bR.sub.c.
[0044] The term "amidino" as used herein refers to a radical of the
form --C(=NR)NR'R'' where R, R', and R'' can each independently be
selected from alkyl, alkenyl, alkynyl, amide, aryl, arylalkyl,
cyano, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, hydroxyl,
ketone and nitro.
[0045] The term "amine" or "amino" as used herein refers to a
radical of the form --NR.sub.dR.sub.e, --N(R.sub.d)R.sub.e--, or
--R.sub.eN(R.sub.d)R.sub.f-- where R.sub.d, R.sub.e, and R.sub.f
are independently selected from alkoxy, alkyl, alkenyl, alkynyl,
amide, amino, aryl, arylalkyl, carbamate, cycloalkyl, ester, ether,
formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen,
hydroxyl, ketone, and nitro. The amino can be attached to the
parent molecular group through the nitrogen, R.sub.d, R.sub.e or
R.sub.f. The amino also may be cyclic, for example any two of Rd,
Re or Rf may be joined together or with the N to form a 3- to
12-membered ring, e.g., morpholino or piperidinyl. The term amino
also includes the corresponding quaternary ammonium salt of any
amino group, e.g., --[N(Rd)(Re)(Rf)]+. Exemplary amino groups
include aminoalkyl groups, wherein at least one of R.sub.d,
R.sub.e, or R.sub.f is an alkyl group.
[0046] The term "aryl" as used herein refers to refers to a mono-,
bi-, or other multi-carbocyclic, aromatic ring system. In certain
embodiments, aryl refers to a monocyclic and/or bicyclic, 5 to 6
membered ring. The aromatic ring may be substituted at one or more
ring positions with substituents selected from alkanoyl, alkoxy,
alkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl,
azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester,
ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl,
hydroxyl, imino, ketone, nitro, phosphate, phosphonato,
phosphinato, sulfate, sulfide, sulfonamido, sulfonyl and
thiocarbonyl. The term "aryl" also includes polycyclic ring systems
having two or more cyclic rings in which two or more carbons are
common to two adjoining rings (the rings are "fused rings") wherein
at least one of the rings is aromatic, e.g., the other cyclic rings
may be cycloalkyls, cycloalkenyls, cycloalkynyls, and/or aryls.
Exemplary aryl groups include, but are not limited to, phenyl,
tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as
well as benzo-fused carbocyclic moieties such as
5,6,7,8-tetrahydronaphthyl.
[0047] The term "arylalkyl" as used herein refers to an aryl group
having at least one alkyl substituent, e.g. -aryl-alkyl-. Exemplary
arylalkyl groups include, but are not limited to, arylalkyls having
a monocyclic aromatic ring system, wherein the ring comprises 6
carbon atoms. For example, "phenylalkyl" includes
phenylC.sub.4alkyl, benzyl, 1-phenylethyl, 2-phenylethyl, etc.
[0048] The term "carbonyl" as used herein refers to the radical
--C(O)--.
[0049] The term "carboxamido" as used herein refers to the radical
--C(O)NRR', where R and R' may be the same or different. R and R'
may be selected from, for example, alkyl, aryl, arylalkyl,
cycloalkyl, formyl, haloalkyl, heteroaryl and heterocyclyl.
[0050] The term "carboxy" as used herein refers to the radical
--COOH or its corresponding salts, e.g. --COONa, etc.
[0051] The term "cyano" as used herein refers to the radical
--CN.
[0052] The term "cycloalkoxy" as used herein refers to a cycloalkyl
group attached to an oxygen.
[0053] The term "cycloalkyl" as used herein refers to a monovalent
saturated or unsaturated cyclic, bicyclic, or bridged bicyclic
hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons, referred to
herein, e.g., as "C.sub.4-8cycloalkyl," derived from a cycloalkane.
Exemplary cycloalkyl groups include, but are not limited to,
cyclohexanes, cyclohexenes, cyclopentanes, cyclopentenes,
cyclobutanes and cyclopropanes. Cycloalkyl groups may be
substituted with alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido,
amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate,
carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen,
haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone,
nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide,
sulfonamido, sulfonyl and thiocarbonyl. Cycloalkyl groups can be
fused to other cycloalkyl, aryl, or heterocyclyl groups. In certain
embodiments, cycloalkyl refers to C.sub.3-C.sub.6 alkyl.
[0054] The terms "halo" or "halogen" or "Hal" as used herein refer
to F, Cl, Br, or I.
[0055] The term "haloalkyl" as used herein refers to an alkyl group
substituted with one or more halogen atoms.
[0056] The term "nitro" as used herein refers to the radical
--NO.sub.2.
[0057] The term "phenyl" as used herein refers to a 6-membered
carbocyclic aromatic ring. The phenyl group can also be fused to a
cyclohexane or cyclopentane ring. Phenyl can be substituted with
one or more substituents including alkanoyl, alkoxy, alkyl,
alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido,
carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether,
formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl,
imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate,
sulfide, sulfonamido, sulfonyl and thiocarbonyl.
[0058] The term "phosphate" as used herein refers to the radical
--OP(O)(OR.sub.aa).sub.2 or its anions. The term "phosphanate"
refers to the radical --P(O)(OR.sub.aa).sub.2 or its anions. The
term "phosphinate" refers to the radical --PR.sub.aa(O)(OR.sub.aa)
or its anion, where each R.sub.aa can be selected from, for
example, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl,
hydrogen, haloalkyl, heteroaryl, and heterocyclyl.
[0059] The term "pharmaceutically acceptable carrier" or
"pharmaceutically acceptable excipient" as used herein refers to
any and all solvents, dispersion media, coatings, isotonic and
absorption delaying agents, and the like, that are compatible with
pharmaceutical administration. The use of such media and agents for
pharmaceutically active substances is well known in the art. The
compositions may also contain other active compounds providing
supplemental, additional, or enhanced therapeutic functions.
[0060] The term "pharmaceutical composition" as used herein refers
to a composition comprising at least one compound as disclosed
herein formulated together with one or more pharmaceutically
acceptable carriers.
[0061] "Individual," "patient," or "subject" are used
interchangeably and include to any animal, including mammals,
preferably mice, rats, other rodents, rabbits, dogs, cats, swine,
cattle, sheep, horses, or primates, and most preferably humans. The
compounds of the invention can be administered to a mammal, such as
a human, but can also be other mammals such as an animal in need of
veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and
the like), farm animals (e.g., cows, sheep, pigs, horses, and the
like) and laboratory animals (e.g., rats, mice, guinea pigs, and
the like). The mammal treated in the methods of the invention is
desirably a mammal in whom modulation of PPAR and/or EGF receptors
is desired. "Modulation" includes antagonism (e.g., inhibition),
agonism, partial antagonism and/or partial agonism.
[0062] In the present specification, the term "therapeutically
effective amount" means the amount of the subject compound that
will elicit the biological or medical response of a tissue, system,
animal or human that is being sought by the researcher,
veterinarian, medical doctor or other clinician. The compounds of
the invention are administered in therapeutically effective amounts
to treat a disease. Alternatively, a therapeutically effective
amount of a compound is the quantity required to achieve a desired
therapeutic and/or prophylactic effect, such as an amount which
results in the prevention of or a decrease in the symptoms
associated with a disease associated with PPAR and/or EGF
receptors.
[0063] The term "pharmaceutically acceptable salt(s)" as used
herein refers to salts of acidic or basic groups that may be
present in compounds used in the present compositions. Compounds
included in the present compositions that are basic in nature are
capable of forming a wide variety of salts with various inorganic
and organic acids. The acids that may be used to prepare
pharmaceutically acceptable acid addition salts of such basic
compounds are those that form non-toxic acid addition salts, i.e.,
salts containing pharmacologically acceptable anions, including but
not limited to malate, oxalate, chloride, bromide, iodide, nitrate,
sulfate, bisulfate, phosphate, acid phosphate, isonicotinate,
acetate, lactate, salicylate, citrate, tartrate, oleate, tannate,
pantothenate, bitartrate, ascorbate, succinate, maleate,
gentisinate, fumarate, gluconate, glucuronate, saccharate, formate,
benzoate, glutamate, methanesulfonate, ethanesulfonate,
benzenesulfonate, p-toluenesulfonate and pamoate (i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds
included in the present compositions that include an amino moiety
may form pharmaceutically acceptable salts with various amino
acids, in addition to the acids mentioned above. Compounds included
in the present compositions that are acidic in nature are capable
of forming base salts with various pharmacologically acceptable
cations. Examples of such salts include alkali metal or alkaline
earth metal salts and, particularly, calcium, magnesium, sodium,
lithium, zinc, potassium, and iron salts.
[0064] The compounds of the disclosure may contain one or more
chiral centers and/or double bonds and, therefore, exist as
stereoisomers, such as geometric isomers, enantiomers or
diastereomers. The term "stereoisomers" when used herein consist of
all geometric isomers, enantiomers or diastereomers. These
compounds may be designated by the symbols "R" or "S," depending on
the configuration of substituents around the stereogenic carbon
atom. The present invention encompasses various stereoisomers of
these compounds and mixtures thereof. Stereoisomers include
enantiomers and diastereomers. Mixtures of enantiomers or
diastereomers may be designated "(.+-.)" in nomenclature, but the
skilled artisan will recognize that a structure may denote a chiral
center implicitly.
[0065] Individual stereoisomers of compounds of the present
invention can be prepared synthetically from commercially available
starting materials that contain asymmetric or stereogenic centers,
or by preparation of racemic mixtures followed by resolution
methods well known to those of ordinary skill in the art. These
methods of resolution are exemplified by (1) attachment of a
mixture of enantiomers to a chiral auxiliary, separation of the
resulting mixture of diastereomers by recrystallization or
chromatography and liberation of the optically pure product from
the auxiliary, (2) salt formation employing an optically active
resolving agent, or (3) direct separation of the mixture of optical
enantiomers on chiral chromatographic columns. Stereoisomeric
mixtures can also be resolved into their component stereoisomers by
well known methods, such as chiral-phase gas chromatography,
chiral-phase high performance liquid chromatography, crystallizing
the compound as a chiral salt complex, or crystallizing the
compound in a chiral solvent. Stereoisomers can also be obtained
from stereomerically-pure intermediates, reagents, and catalysts by
well known asymmetric synthetic methods.
[0066] Geometric isomers can also exist in the compounds of the
present invention. The symbol denotes a bond that may be a single,
double or triple bond as described herein. The present invention
encompasses the various geometric isomers and mixtures thereof
resulting from the arrangement of substituents around a
carbon-carbon double bond or arrangement of substituents around a
carbocyclic ring. Substituents around a carbon-carbon double bond
are designated as being in the "Z" or "E" configuration wherein the
terms "Z" and "E" are used in accordance with IUPAC standards.
Unless otherwise specified, structures depicting double bonds
encompass both the "E" and "Z" isomers.
[0067] Substituents around a carbon-carbon double bond
alternatively can be referred to as "cis" or "trans," where "cis"
represents substituents on the same side of the double bond and
"trans" represents substituents on opposite sides of the double
bond. The arrangement of substituents around a carbocyclic ring are
designated as "cis" or "trans." The term "cis" represents
substituents on the same side of the plane of the ring and the term
"trans" represents substituents on opposite sides of the plane of
the ring. Mixtures of compounds wherein the substituents are
disposed on both the same and opposite sides of plane of the ring
are designated "cis/trans."
[0068] The compounds disclosed herein can exist in solvated as well
as unsolvated forms with pharmaceutically acceptable solvents such
as water, ethanol, and the like, and it is intended that the
invention embrace both solvated and unsolvated forms. In one
embodiment, the compound is amorphous. In one embodiment, the
compound is a polymorph. In another embodiment, the compound is in
a crystalline form.
[0069] The invention also embraces isotopically labeled compounds
of the invention which are identical to those recited herein,
except that one or more atoms are replaced by an atom having an
atomic mass or mass number different from the atomic mass or mass
number usually found in nature. Examples of isotopes that can be
incorporated into compounds of the invention include isotopes of
hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and
chlorine, such as .sup.2H, .sup.3H, .sup.13C, .sup.14C, .sup.15N,
.sup.18O, .sup.17O, .sup.31P, .sup.32P, .sup.35S, .sup.18F, and
.sup.36Cl, respectively.
[0070] Certain isotopically-labeled disclosed compounds (e.g.,
those labeled with .sup.3H and .sup.14C) are useful in compound
and/or substrate tissue distribution assays. Tritiated (i.e.,
.sup.3H) and carbon-14 (i.e., .sup.14C) isotopes are particularly
preferred for their ease of preparation and detectability. Further,
substitution with heavier isotopes such as deuterium (i.e.,
.sup.2H) may afford certain therapeutic advantages resulting from
greater metabolic stability (e.g., increased in vivo half-life or
reduced dosage requirements) and hence may be preferred in some
circumstances. Isotopically labeled compounds of the invention can
generally be prepared by following procedures analogous to those
disclosed in the e.g., Examples herein by substituting an
isotopically labeled reagent for a non-isotopically labeled
reagent.
[0071] The term "prodrug" refers to compounds that are transformed
in vivo to yield a disclosed compound or a pharmaceutically
acceptable salt, hydrate or solvate of the compound. The
transformation may occur by various mechanisms, such as through
hydrolysis in blood. For example, if a compound of the invention or
a pharmaceutically acceptable salt, hydrate or solvate of the
compound contains a carboxylic acid functional group, a prodrug can
comprise an ester formed by the replacement of the hydrogen atom of
the acid group with a group such as (C.sub.1-C.sub.8)alkyl,
(C.sub.2-C.sub.12)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having
from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having
from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to
6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7
carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to
8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9
carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10
carbon atoms, 3-phthalidyl, 4-crotonolactonyl,
gamma-butyrolacton-4-yl,
di-N,N-(C.sub.1-C.sub.2)alkylamino(C.sub.2-C.sub.3)alkyl (such as
.beta.-dimethylaminoethyl), carbamoyl-(C.sub.1-C.sub.2)alkyl,
N,N-di(C.sub.1-C.sub.2)alkylcarbamoyl-(C.sub.1-C.sub.2)alkyl and
piperidino-, pyrrolidino- or morpholino(C.sub.2-C.sub.3)alkyl.
[0072] Similarly, if a compound of the invention contains an
alcohol functional group, a prodrug can be formed by the
replacement of the hydrogen atom of the alcohol group with a group
such as (C.sub.1-C.sub.6)alkanoyloxymethyl,
1-((C.sub.1-C.sub.6)alkanoyloxy)ethyl, 1-methyl-1
-((C.sub.1-C.sub.6)alkanoyloxy)ethyl
(C.sub.1-C.sub.6)alkoxycarbonyloxymethyl,
N-(C.sub.1-C.sub.6)alkoxycarbonylaminomethyl, succinoyl,
(C.sub.1-C.sub.6)alkanoyl, .alpha.-amino(C.sub.1-C.sub.4)alkanoyl,
arylacyl and .alpha.-aminoacyl, or
.alpha.-aminoacyl-.alpha.-aminoacyl, where each .alpha.-aminoacyl
group is independently selected from the naturally occurring
L-amino acids, P(O)(OH).sub.2,
--P(O)(O(.sub.C1-C.sub.6)alkyl).sub.2 or glycosyl (the radical
resulting from the removal of a hydroxyl group of the hemiacetal
form of a carbohydrate).
[0073] If a compound of the invention incorporates an amine
functional group, a prodrug can be formed by the replacement of a
hydrogen atom in the amine group with a group such as R-carbonyl,
RO-carbonyl, NRR'-carbonyl where R and R' are each independently
(C.sub.1-C.sub.10)alkyl, (C.sub.3-C.sub.7)cycloalkyl, benzyl, or
R-carbonyl is a natural .alpha.-aminoacyl or natural
.alpha.-aminoacyl-natural .alpha.-aminoacyl, --C(OH)C(O)OY.sup.1
wherein Y.sup.1 is H, (C.sub.1-C.sub.6)alkyl or benzyl,
--C(OY.sup.2)Y.sup.3 wherein Y.sup.2 is (C.sub.1-C.sub.4) alkyl and
Y.sup.3 is (C.sub.1-C.sub.6)alkyl, carboxy(C.sub.1-C.sub.6)alkyl,
amino(C.sub.1-C.sub.4)alkyl or mono-N-- or
di-N,N--(C.sub.1-C.sub.6)alkylaminoalkyl, --C(Y.sup.4)Y.sup.5
wherein Y.sup.4 is H or methyl and Y.sup.5 is mono-N-- or
di-N,N--(C.sub.1-C.sub.6)alkylamino, morpholino, piperidin-1-yl or
pyrrolidin-1-yl.
[0074] The disclosure provides, at least in part, compounds
represented by formula I, as depicted below. Also contemplated
herein are compositions that include a compound represented by
formula I and e.g., a pharmaceutically acceptable carrier.
##STR00003## [0075] wherein X is C.sub.1-C.sub.3alkylene,
optionally substituted with one, two or three substituents selected
from halogen or hydroxyl; [0076] R.sub.1is selected from the group
consisting of C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.6cycloalkyl,
C.sub.2-C.sub.6alkenyl, and C.sub.2-C.sub.6alkynyl; [0077] R.sub.2
is selected from the group consisting of hydrogen and
C.sub.1-C.sub.6alkyl; [0078] R.sub.3 is independently selected, for
each occurrence from the group consisting of hydrogen,
C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6alkyl, cyano,
C.sub.3-C.sub.6cycloalkyl, halogen, hydroxyl, and nitro; [0079]
R.sub.4 is selected from the group consisting of hydrogen and
C.sub.1-C.sub.6alkyl; [0080] R.sub.5 is C.sub.1-C.sub.6alkyl; or
pharmaceutically acceptable salts or N-oxides thereof.
[0081] In one embodiment, R.sub.1 can be C.sub.1-C.sub.6alkyl, such
as methyl. In one embodiment, R.sub.2 can be hydrogen. In another
embodiment, R.sub.3 can be selected from the group consisting of
hydrogen, C.sub.1-C.sub.6alkyl, halogen, and hydroxyl. In a further
embodiment, R.sub.3 can be hydrogen. In one embodiment, R.sub.4 and
R.sub.5 can each be C.sub.1-C.sub.6alkyl. In another embodiment,
R.sub.4 may be hydrogen and R.sub.5 may be methyl. In one
embodiment, X may be (CH.sub.2).sub.n , wherein n is 1 or 2, such
as 1.
[0082] In another embodiment, --NR.sub.2--COR.sub.1 can be in the
meta position relative to X as shown in formula III.
##STR00004##
[0083] In another embodiment, --NR.sub.2--COR.sub.1 can be in the
para position relative to X as shown in formula IV.
##STR00005##
[0084] The disclosure provides, at least in part, compounds
represented by formula II, as depicted below. Also contemplated
herein are compositions that include a compound represented by
formula II and e.g., a pharmaceutically acceptable carrier.
##STR00006## [0085] wherein R.sub.1 is selected from the group
consisting of C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.6cycloalkyl,
C.sub.2-C.sub.6alkenyl, and C.sub.2-C.sub.6alkynyl; [0086] R.sub.2
is selected from the group consisting of hydrogen and
C.sub.1-C.sub.6alkyl; [0087] R.sub.3 is independently selected, for
each occurrence from the group consisting of hydrogen,
C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6alkyl, cyano,
C.sub.3-C.sub.6cycloalkyl, halogen, hydroxyl, and nitro; [0088]
R.sub.5 is hydrogen or C.sub.1-C.sub.6alkyl; or pharmaceutically
acceptable salts or N-oxides thereof.
[0089] Compounds of Formula V are also contemplated as shown below,
as well as compositions that include a compound represented by
formula V and e.g., a pharmaceutically acceptable carrier.
##STR00007## [0090] wherein R.sub.1 is selected from the group
consisting of C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.6cycloalkyl,
C.sub.2-C.sub.6alkenyl, and C.sub.2-C.sub.6alkynyl; [0091] R.sub.3
is independently selected, for each occurrence from the group
consisting of hydrogen, C.sub.1-C.sub.6alkoxy,
C.sub.1-C.sub.6alkyl, cyano, C.sub.3-C.sub.6cycloalkyl, halogen,
hydroxyl, and nitro; [0092] R.sub.4 is selected from the group
consisting of hydrogen and C.sub.1-C.sub.6alkyl; [0093] R.sub.5 is
hydrogen or C.sub.1-C.sub.6alkyl; and [0094] A is a fused five or
six membered heterocycle; or pharmaceutically acceptable salts or
N-oxides thereof.
[0095] In one embodiment, R.sub.1 can be C.sub.1-C.sub.6alkyl, such
as methyl. In another embodiment, R.sub.1 and R.sub.3 can each be
C.sub.1-C.sub.6alkyl, such as methyl. In one embodiment, R.sub.2
can be hydrogen.
[0096] In some embodiments, a compound can be represented by
##STR00008## [0097] wherein p is 1 or 2; [0098] R.sub.1 is selected
from the group consisting of C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.6cycloalkyl, C.sub.2-C.sub.6alkenyl, and
C.sub.2-C.sub.6alkynyl; [0099] R.sub.4 and R.sub.8 are each
independently selected from the group consisting of hydrogen and
C.sub.1-C.sub.6alkyl; or pharmaceutically acceptable salts or
N-oxides thereof.
[0100] Contemplated compounds, and pharmaceutical compositions,
comprising at least one compound, may be selected from the group
consisting of: N-acetyl-(R)-3-(4-aminophenyl)-2-methoxypropionic
acid (Compound A),
N-acetyl-(S)-3-(4-aminophenyl)-2-methoxypropionic acid (Compound
B), racemic N-acetyl-3-(4-aminophenyl)-2-methoxypropionic acid
(Compound AB);
##STR00009## ##STR00010##
4-acetamino-N-hydroxy-2-methoxybenzamide;
1-acetyl-6-methoxy-1,2,3,4-tetrahydroquinoline-5-carboxylic acid,
5-acetamido-2hydroxybenzoic acid (e.g., acetalyated
5-aminosalicyclic acid) or pharmaceutically acceptable salts or
N-oxides thereof.
[0101] The present disclosure also provides pharmaceutical
compositions comprising compounds as disclosed herein formulated
together with one or more pharmaceutically acceptable carriers.
These formulations include those suitable for oral, rectal,
topical, buccal and parenteral (e.g., subcutaneous, intramuscular,
intradermal, or intravenous) administration, although the most
suitable form of administration in any given case will depend on
the degree and severity of the condition being treated and on the
nature of the particular compound being used.
Therapeutic Applications
[0102] The disclosure further provides, in some embodiments,
methods of modulating activity of one or more PPAR and/or EGF
receptors comprising exposing said receptor to a compound of the
invention. For example, provided herein are methods of treating a
disease associated with expression or activity of one or more PPAR
and/or EGF receptors in a patient comprising administering to the
patient a therapeutically effective amount of a compound of the
invention.
[0103] One embodiment of the invention provides a method of
treating tumors of the esophagus, stomach, pancreas, colon,
prostate, breast, uterus, kidneys, and lungs comprising
administering to a subject in need thereof a therapeutically
effective amount of a compound of the invention. Also contemplated
herein is a method for delaying clinical manifestation of a
colorectal tumor, or a solid tumor (e.g., a breast, prostate, lung
or hepatocellular carcinoma) in a patient, for example, a patient
at risk of colorectal cancer, comprising administering to the
patient an effective amount of a compound disclosed herein.
Administering such a compound may be on e.g., at least a daily
basis. For example, the delay of clinical manifestation of a
colorectal tumor in a patient as a consequence of administering a
compound disclosed here may be at least e.g., 6 months, 1 year, 18
months or even 2 years or more as compared to a patient who is not
administered a compound such as one disclosed herein.
[0104] Another embodiment of the invention provides a method of
treating or ameliorating chronic inflammation, such as Crohn's
disease or ulcerative colitis, comprising administering to a
subject in need thereof a therapeutically effective amount of a
compound of the invention.
[0105] Methods of treating dermatological conditions are also
provided, such as the treatment of at least one of: acne vulgaris,
comedo-type acne, polymorphic acne, acne rosacea, nodulocystic
acne, acne conglobata, senile acne, secondary acne, solar acne,
acne medicamentosa or occupational acne, ichthyosis, Darrier's
disease, keratosis palmaris or plantaris, cutaneous, mucosal or
ungual psoriasis, skin disorders due to exposure to UV radiation,
of skin aging, photoinduced or chronological or actinic
pigmentations and keratoses, acne hyperseborrhoea, simple
seborrhoea or seborrhoeic dermatitis, cicatrization disorders or
stretch marks. Methods of treating atopic dermatitis is also
contemplated. The composition may be administered orally or
topically.
[0106] For example, continuous sebum production can increase in
acne patients; and application of a sebum inhibitor, such as
disclosed herein, may be useful in the treatment of acne, seborrhea
or alopecia. In another example, chronic inflammation of hair
follicles (keratinocytes) can be an indication of e.g., androgenic
alopecia. An inhibitor of such inflammation such as disclosed
herein can be useful in e.g., the treatment of hair loss.
[0107] Provided herein are methods of treating fine lines, wrinkles
or surface irregularities of the skin, or protecting from and/or
ameliorating free radical damage to the skin, comprising topically
administering an effective amount of a composition comprising a
compound of the invention.
[0108] In some embodiments, a method of treating hair loss in a
patient suffering from unwanted hair loss is provided, comprising
administering an effective amount of a composition comprising a
disclosed compound. Methods of treating alopecia areata,
androgenetic alopecia and/or telogenic defluvium are
contemplated.
[0109] Also provided herein are methods of treating an age-related
disorder selected from the group consisting of: diabetes,
cataracts, Alzheimer's disease, Parkinson's disease, macular
degeneration, retinal ulcers or retinal vasculitis, comprising
administering an effective amount of a composition comprising a
disclosed compound. Also provided herein are methods of treating a
vascular or cardiac disorder, comprising identifying a patient
suffering from or at risk of developing said disorder and
administering to said patient an effective amount of a disclosed
compound as defined above. For example, a cardiac disorder being
treated may be chosen from chronic coronary ischemia,
arteriosclerosis, congestive heart failure, ischemic or reperfusion
related injury, angina, atherosclerosis, myocardial infarction,
stroke and myocardial hypertrophy. In another embodiment, a method
of treating an autoimmune disorder is provided, wherein the
autoimmune disorder may be chosen from, for example, Addison's
disease, chronic thyroiditis, dermatomyositis, Grave's disease,
multiple sclerosis, systemic lupus erythematosis, psoriasis, or
rheumatoid arthritis.
[0110] The compounds of the invention may be administered to
patients (animals and humans) in need of such treatment in dosages
that will provide optimal pharmaceutical efficacy. It will be
appreciated that the dose required for use in any particular
application will vary from patient to patient, not only with the
particular compound or composition selected, but also with the
route of administration, the nature of the condition being treated,
the age and condition of the patient, concurrent medication or
special diets then being followed by the patient, and other factors
which those skilled in the art will recognize, with the appropriate
dosage ultimately being at the discretion of the attendant
physician. For treating clinical conditions and diseases noted
above, the compound of this invention may be administered orally,
topically, parenterally, by inhalation spray or rectally in dosage
unit formulations containing conventional non-toxic
pharmaceutically acceptable carriers, adjuvants and vehicles. The
term parenteral as used herein includes subcutaneous injections,
intravenous, intramuscular, intrasternal injection or infusion
techniques.
[0111] Generally, a therapeutically effective amount of active
component will be in the range of from about 0.1 mg/kg to about 100
mg/kg, optionally from about 1 mg/kg to about 100 mg/kg, optionally
from about 1 mg/kg to 10 mg/kg. The amount administered will depend
on variables such as the type and extent of disease or indication
to be treated, the overall health status of the particular patient,
the relative biological efficacy of the compounds, formulation of
compounds, the presence and types of excipients in the formulation,
and the route of administration. The initial dosage administered
may be increased beyond the upper level in order to rapidly achieve
the desired blood-level or tissue level, or the initial dosage may
be smaller than the optimum and the daily dosage may be
progressively increased during the course of treatment depending on
the particular situation. Human dosage can be optimized, e.g., in a
conventional Phase I dose escalation study designed to run from 0.5
mg/kg to 20 mg/kg. Dosing frequency can vary, depending on factors
such as route of administration, dosage amount and the disease
condition being treated. Exemplary dosing frequencies are once per
day, once per week and once every two weeks.
[0112] Contemplated formulations or compositions comprise a
disclosed compound and typically include a compound a
pharmaceutically acceptable carrier.
[0113] Contemplated compositions may be administered by various
means, depending on their intended use, as is well known in the
art. For example, if compositions of the present invention are to
be administered orally, they may be formulated as tablets,
capsules, granules, powders or syrups. Alternatively, formulations
of the present invention may be administered parenterally as
injections (intravenous, intramuscular or subcutaneous), drop
infusion preparations or enemas or suppositories. For application
by the ophthalmic mucous membrane route, compositions of the
present invention may be formulated as eyedrops or eye ointments.
These formulations may be prepared by conventional means, and, if
desired, the compositions may be mixed with any conventional
additive, such as an excipient, a binder, a disintegrating agent, a
lubricant, a corrigent, a solubilizing agent, a suspension aid, an
emulsifying agent or a coating agent.
[0114] In formulations of the subject invention, wetting agents,
emulsifiers and lubricants, such as sodium lauryl sulfate and
magnesium stearate, as well as coloring agents, release agents,
coating agents, sweetening, flavoring and perfuming agents,
preservatives and antioxidants may be present in the formulated
agents.
[0115] Subject compositions may be suitable for oral, nasal,
topical (including buccal and sublingual), rectal, vaginal, aerosol
and/or parenteral administration. The formulations may conveniently
be presented in unit dosage form and may be prepared by any methods
well known in the art of pharmacy. The amount of composition that
may be combined with a carrier material to produce a single dose
vary depending upon the subject being treated, and the particular
mode of administration.
[0116] Methods of preparing these formulations include the step of
bringing into association compositions of the present invention
with the carrier and, optionally, one or more accessory
ingredients. In general, the formulations are prepared by uniformly
and intimately bringing into association agents with liquid
carriers, or finely divided solid carriers, or both, and then, if
necessary, shaping the product.
[0117] Formulations suitable for oral administration may be in the
form of capsules, cachets, pills, tablets, lozenges (using a
flavored basis, usually sucrose and acacia or tragacanth), powders,
granules, or as a solution or a suspension in an aqueous or
non-aqueous liquid, or as an oil-in-water or water-in-oil liquid
emulsion, or as an elixir or syrup, or as pastilles (using an inert
base, such as gelatin and glycerin, or sucrose and acacia), each
containing a predetermined amount of a subject composition thereof
as an active ingredient. Compositions of the present invention may
also be administered as a bolus, electuary, or paste.
[0118] In solid dosage forms for oral administration (capsules,
tablets, pills, film-coated tablets, sugar-coated tablets, powders,
granules and the like), the subject composition is mixed with one
or more pharmaceutically acceptable carriers, such as sodium
citrate or dicalcium phosphate, and/or any of the following: (1)
fillers or extenders, such as starches, lactose, sucrose, glucose,
mannitol, and/or silicic acid; (2) binders, such as, for example,
carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone,
sucrose and/or acacia; (3) humectants, such as glycerol; (4)
disintegrating agents, such as agar-agar, calcium carbonate, potato
or tapioca starch, alginic acid, certain silicates, and sodium
carbonate; (5) solution retarding agents, such as paraffin; (6)
absorption accelerators, such as quaternary ammonium compounds; (7)
wetting agents, such as, for example, acetyl alcohol and glycerol
monostearate; (8) absorbents, such as kaolin and bentonite clay;
(9) lubricants, such a talc, calcium stearate, magnesium stearate,
solid polyethylene glycols, sodium lauryl sulfate, and mixtures
thereof; and (10) coloring agents. In the case of capsules, tablets
and pills, the compositions may also comprise buffering agents.
Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugars, as well as high molecular
weight polyethylene glycols and the like.
[0119] Formulations and compositions may include micronized
crystals of the disclosed compounds. Micronization may be performed
on crystals of the compounds alone, or on a mixture of crystals and
a part or whole of pharmaceutical excipients or carriers. Mean
particle size of micronized crystals of a disclosed compound may be
for example about 5 to about 200 microns, or about 10 to about 110
microns.
[0120] A tablet may be made by compression or molding, optionally
with one or more accessory ingredients. Compressed tablets may be
prepared using binder (for example, gelatin or hydroxypropylmethyl
cellulose), lubricant, inert diluent, preservative, disintegrant
(for example, sodium starch glycolate or cross-linked sodium
carboxymethyl cellulose), surface-active or dispersing agent.
Molded tablets may be made by molding in a suitable machine a
mixture of the subject composition moistened with an inert liquid
diluent. Tablets, and other solid dosage forms, such as film coated
tablets or sugar coated tablets, capsules, pills and granules, may
optionally be scored or prepared with coatings and shells, such as
enteric coatings and other coatings well known in the
pharmaceutical-formulating art.
[0121] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, microemulsions, solutions,
suspensions, syrups and elixirs. In addition to the subject
composition, the liquid dosage forms may contain inert diluents
commonly used in the art, such as, for example, water or other
solvents, solubilizing agents and emulsifiers, such as ethyl
alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl
alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,
oils (in particular, cottonseed, groundnut, corn, germ, olive,
castor and sesame oils), glycerol, tetrahydrofuryl alcohol,
polyethylene glycols and fatty acid esters of sorbitan,
cyclodextrins and mixtures thereof.
[0122] Suspensions, in addition to the subject composition, may
contain suspending agents as, for example, ethoxylated isostearyl
alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite,
agar-agar and tragacanth, and mixtures thereof.
[0123] Formulations for rectal or vaginal administration may be
presented as a suppository, which may be prepared by mixing a
subject composition with one or more suitable non-irritating
excipients or carriers comprising, for example, cocoa butter,
polyethylene glycol, a suppository wax or a salicylate, and which
is solid at room temperature, but liquid at body temperature and,
therefore, will melt in the body cavity and release the active
agent. Formulations which are suitable for vaginal administration
also include pessaries, tampons, creams, gels, pastes, foams or
spray formulations containing such carriers as are known in the art
to be appropriate.
[0124] Dosage forms for transdermal or topical administration of a
subject composition include powders, sprays, ointments, pastes,
creams, lotions, gels, solutions, patches and inhalants. The active
component may be mixed under sterile conditions with a
pharmaceutically acceptable carrier, and with any preservatives,
buffers, or propellants which may be required.
[0125] The ointments, pastes, creams and gels may contain, in
addition to a subject composition, excipients, such as animal and
vegetable fats, oils, waxes, paraffins, starch, tragacanth,
cellulose derivatives, polyethylene glycols, silicones, bentonites,
silicic acid, talc and zinc oxide, or mixtures thereof.
[0126] Powders and sprays may contain, in addition to a subject
composition, excipients such as lactose, talc, silicic acid,
aluminum hydroxide, calcium silicates and polyamide powder, or
mixtures of these substances. Sprays may additionally contain
customary propellants, such as chlorofluorohydrocarbons and
volatile unsubstituted hydrocarbons, such as butane and
propane.
[0127] Compositions and compounds of the present invention may
alternatively be administered by aerosol. This is accomplished by
preparing an aqueous aerosol, liposomal preparation or solid
particles containing the compound. A non-aqueous (e.g.,
fluorocarbon propellant) suspension could be used. Sonic nebulizers
may be used because they minimize exposing the agent to shear,
which may result in degradation of the compounds contained in the
subject compositions.
[0128] Ordinarily, an aqueous aerosol is made by formulating an
aqueous solution or suspension of a subject composition together
with conventional pharmaceutically acceptable carriers and
stabilizers. The carriers and stabilizers vary with the
requirements of the particular subject composition, but typically
include non-ionic surfactants (Tweens, Pluronics, or polyethylene
glycol), innocuous proteins like serum albumin, sorbitan esters,
oleic acid, lecithin, amino acids such as glycine, buffers, salts,
sugars or sugar alcohols. Aerosols generally are prepared from
isotonic solutions.
[0129] Pharmaceutical compositions of this invention suitable for
parenteral administration comprise a subject composition in
combination with one or more pharmaceutically-acceptable sterile
isotonic aqueous or non-aqueous solutions, dispersions, suspensions
or emulsions, or sterile powders which may be reconstituted into
sterile injectable solutions or dispersions just prior to use,
which may contain antioxidants, buffers, bacteriostats, solutes
which render the formulation isotonic with the blood of the
intended recipient or suspending or thickening agents.
[0130] Examples of suitable aqueous and non-aqueous carriers which
may be employed in the pharmaceutical compositions of the invention
include water, ethanol, polyols (such as glycerol, propylene
glycol, polyethylene glycol, and the like), and suitable mixtures
thereof, vegetable oils, such as olive oil, and injectable organic
esters, such as ethyl oleate and cyclodextrins. Proper fluidity may
be maintained, for example, by the use of coating materials, such
as lecithin, by the maintenance of the required particle size in
the case of dispersions, and by the use of surfactants. The
efficacy of treatment with the subject compositions may be
determined in a number of fashions known to those of skill in the
art.
[0131] Throughout the description, where compositions are described
as having, including, or comprising specific components, it is
contemplated that compositions also consist essentially of, or
consist of, the recited components. Similarly, where processes are
described as having, including, or comprising specific process
steps, the processes also consist essentially of, or consist of,
the recited processing steps. Except where indicated otherwise, the
order of steps or order for performing certain actions are
immaterial so long as the invention remains operable. Moreover,
unless otherwise noted, two or more steps or actions may be
conducted simultaneously.
EXAMPLES
[0132] The compounds of the present invention can be prepared in a
number of ways well known to one skilled in the art of organic
synthesis. More specifically, compounds of the invention may be
prepared using the reactions and techniques described herein. In
the description of the synthetic methods described below, it is to
be understood that all proposed reaction conditions, including
choice of solvent, reaction atmosphere, reaction temperature,
duration of the experiment and workup procedures, can be chosen to
be the conditions standard for that reaction, unless otherwise
indicated. It is understood by one skilled in the art of organic
synthesis that the functionality present on various portions of the
molecule should be compatible with the reagents and reactions
proposed. Substituents not compatible with the reaction conditions
will be apparent to one skilled in the art, and alternate methods
are therefore indicated. The starting materials for the examples
are either commercially available or are readily prepared by
standard methods from known materials.
Example 1 Preparation of
N-acetyl-(R)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid
(N-Acetyl E2), Compound A
[0133] To (R)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid (40 g)
in a 0.5 L glass reactor was added ethyl acetate (80 g) and acetic
anhydride (62.8 g). The mixture was stirred at 90.degree. C. for 1
hour. Upon cooling, the solvent was removed by vacuum distillation,
providing an oily residue. To this residue was added water (120 g)
and ethyl acetate (120 g). After stirring for 10 min at 35.degree.
C., the layers were separated and the aqueous layer discarded. The
organic layer solvent was removed by vacuum distillation. Acetone
(120 g) was then added and the resulting mixture was warmed until
dissolution was complete. The solution was cooled to 0.degree. C.,
and the product precipitated which was collected by filtration. The
solid was rinsed with acetone (20 g) and dried at 65.degree. C. to
afford 26g of the title compound.
Example 2 Docking Studies
[0134] The binding of compounds A, B, and their non-acetylated
derivatives, (as well as 5-aminosalicyclic acid (5-ASA) and
5-acetamido-hydroxybenzoic acid) to PPAR.gamma. and PPAR.alpha.
receptors is evaluated.
[0135] While 5-ASA shows good affinity for PPAR.gamma., the
N-acetylation of 5-ASA led to a rigid linear structure that did not
occupy the active site in a optimal way. A loss of the hydrogen
bond between H449 and the phenolic group of the compound occurred
which may explain the inactivity of NAc-5-ASA. The binding of
compound B and its non-acetylated counterpart into PPAR.gamma.
indicated that these compounds may activate the receptor based on
the receptor's binding structural prerequisites. Superposition of
the compounds indicated that they bind to different parts of the
active site.
[0136] The binding of compound A and its non acetylated counterpart
3-(4-aminophenyl)-2-methoxypropanoic acid) into PPAR.gamma.
indicated that these compounds may also activate the receptor. In
contrast to compound B, the superposition of compound A free amine
and N-acetyl derivative show that they occupy the same portion of
the active site, indicating a possible similarity in activity.
Example 3 Anti-Murine Colitis Model
[0137] Colitis in C57bI6 mice is induced by administering TNBS (150
mg/kg) by oral gavage on day -3. Stool samples were taken 8 hours
after administration. At day 0-5, N-acetylated E2 (30 mM) was
administrated by oral gavage. On day 5, mice were analyzed to
obtain a mortality macroscopic score (Wallace, Gastroenterology 96:
29-36, 1989).
[0138] As shown in FIG. 1, mortality was comparable between mice
given TNBS versus those given TNBS and N-acetyl E2. However, as
shown in FIG. 2, the level of colonic lesions was significantly
less in mice given TNBS and N-acetyl E2 compared to those given
TNBS alone. FIG. 3 demonstrates how MPO (myleoperoxidase) decreased
with administration of N-acetyl E2 with TNBS. In FIG. 4, the Ameho
score (Gut 41: 487-493, 1997) indicated that colonic inflammation
had decreased with administration of N-acetyl E2 with TNBS.
Example 4 Keratinocytes
[0139] To assess the possible toxic or cytostatic effect of the
substances under study, a spectrophotometric test (MTT) was carried
out. The human primary keratinocytes, isolated from skin biopsies,
were plated in wells of a 24-well plate in suitable medium with
addition of antibiotics, calcium, and specific growth factors. At
around 70% confluence, the cells were exposed to the presence of
Compound A, at various concentrations (0.1-1-2 mM), for 24 and 48 h
in suitable medium with addition of antibiotics, calcium, but no
growth factors. This culture condition was done for all the
subsequent experiments. At the end of the treatment, the MTT test
was done. The results are indicated in FIG. 5. Compound A in all
concentrations used did not show any effect on cellular
vitality.
Example 5 TNF Alpha
[0140] Analysis of the inhibition of compound A of the mRNA
induction of the proinflammatory cytokine TNF-alpha by
H.sub.2O.sub.2 was carried out by Real time RT-PCR. The
keratinocytes were plated in dishes of 6 cm/O. At 80% confluence,
the cells were treated with H.sub.2O.sub.2 (300 .mu.M) in presence
of Compound A at the three concentrations (0.01-0.1-0.5 mM) for 6
h. At the end of the treatment, the cells were lysed in a lysis
buffer and subjected to isolation and subsequent retrotranscription
of the RNA. Compound A proved able to inhibit the expression of the
mRNA of TNF-.alpha. induced by H.sub.2O.sub.2 at the two higher
doses (0.1 mM; 0.5 mM). The higher dose demonstrated a complete
inhibition of the proinflammatory cytokine with an effect similar
to troglitazone (Tg). (FIG. 6)
Example 6 Inhibition of mRNA Expression of IL-6 Induced by Presence
of IFN-.gamma.
[0141] Analysis of the inhibition by compound A of the mRNA
induction of the proinflammatory cytokine IL-6 by IFN-.gamma. was
done through Real time RT-PCR. The keratinocytes were plated in
dishes of 6 cm/O.
[0142] At 80% confluence, the cells were treated with IFN-.gamma.
(30 ng/ml) in presence of compound A (N-Acetylged) at the three
concentrations (0.01-0.1-0.5 mM) for 6 h. At the end of the
treatment, the cells were lysed in a lysis buffer and subjected to
isolation and subsequent retrotranscription of the RNA The results
(as shown in FIG. 7) reveal the ability of Compound A to inhibit
the expression of the inflammatory cytokine induced by presence of
IFN-.gamma. which does not appear to be dose-dependent.
Example 7 Inhibitory Capacity on the Activation of Nuclear Factor
NF-kB Induced by Presence of H.sub.2O.sub.2
[0143] Evaluation of the inhibition by compound A of the activation
of nuclear transcription factor NF-kB induced by the presence of
H.sub.2O.sub.2 was done by analysis in cytofluorimetry.
[0144] The keratinocytes were plated in wells of a 12-well plate.
At 80% confluence, the cells were treated with H.sub.2O.sub.2 (300
.mu.M) in presence of compound A at the three concentrations
(0.01-0.1-0.5 mM) for 1 h. At the end of the treatment, the cells
were fixed in paraformaldehyde, permeabilized in methanol and then
incubated in presence of the specific antibody of subunit p65.
Compound A revealed an inhibitory effect on the activation and
subsequent translocation of NF-kB in dose-dependent manner (FIG.
8).
Example 8 Inhibition of Protein Expression of IL-6 Induced by
Presence of LPS
[0145] Analysis of the inhibition by Compound A of the protein
induction of IL-6 by LPS (lipopolysaccharide) was done with the
ELISA kit. The keratinocytes were plated in wells of a 24-well
plate. At 80% confluence, the cells were treated with LPS (10
.mu.g/ml) in presence of compound A at the three concentrations
(0.01-0.1-0.5 mM) for 24 h. At the end of the treatment, the
supernatant was decanted, centrifuged so as to remove any cell
detritus, and kept at -80.degree. C. until the time of the
analysis. The quantity of IL-6 present in the supernatant was
normalized by the protein concentration of the sample itself. The
results (FIG. 9) revealed the ability of compound A to inhibit, in
dose-dependent manner, the protein expression of the inflammatory
cytokine under study.
Example 9--Human Sebocytes
[0146] To assess the possible toxic or cytostatic effect of the
substances under study, a spectrophotometric test (MTT) was carried
out. The sebocytes were plated in wells of a 24-well plate in
suitable medium with addition of antibiotics, calcium and EGF. At
roughly 70% confluence, the cells were exposed to the presence of
compound A, in various concentrations (0.1-0.5-1-2 mM), for 24 and
48 h. At the end of the treatment, the MTT test was performed.
Compound A in all concentrations used demonstrated no effects on
cell vitality. (FIG. 10)
Example 10 Evaluation of the Inhibitory Capacity of a Compound on
Sebogenesis Induced by Stimuli of Lipid Type (Linoleic Acid,
Testosterone)
[0147] Analysis of the inhibition by (compound A) of sebogenesis
induced by treatment with linoleic acid (LA) and with testosterone
(TST) was evaluated by spectrofluorimetry, using Nile Red as
selective marker of intracellular lipids (Nile Red Assay). The
sebocytes were plated in wells of a 24-well plate. Next day, they
were deprived of serum (2%) and after 24 h they were stimulated,
for another 24 h, with LA (10-4M), TST (20 nM) in presence or in
absence of A (1 mM). At the end of the treatment, the sebocytes
were stained with Nile Red. The quantitative analysis was done by
spectrofluorimetry, which made it possible to distinguish between
neutral lipids and polar lipids based on the different wavelength
of excitation and emission. The data obtained revealed that the
treatment with LA is able to induce lipid synthesis and that the
combined LA+TST treatment further increases this effect. The
presence of Compound A proved able to reduce the lipidogenic
stimulus. (FIG. 11).
Example 11 Evaluation of the Inhibitory Capacity on Sebogenesis
Induced by Stimuli of Lipid Type (Linoleic Acid, Testosterone):
Evaluation of Fatty Acids and Squalene
[0148] In order to evaluate in greater detail the inhibition by
Compound A of sebogenesis induced by LA and TST, assays were
performed on the lipid extract of the sebocytes using gas
chromatography coupled with mass spectrometry (GC-MS). The
sebocytes were treated by the scheme described for the Nile Red
assay. At the end of the treatment, the cells were removed and then
the lipid extraction was done by using organic solvents. One part
of the extract was used to analyze the fatty acid composition,
while the other part was used for the determination of the quantity
of squalene, a lipid characteristic of sebum. The fatty acid assay
showed that the lipidogenic stimulus induced by the treatment with
LA and LA+TST was reduced by the presence of A (FIG. 12A). These
results are confirmed by the squalene analysis. (FIG. 12B)
Example 12 Evaluation of the Inhibitory Capacity on Sebogenesis
Induced by Stimuli of Lipid Type (Linoleic Acid, Testosterone)
[0149] Analysis of the inhibition by compound A of sebogenesis
induced by treatment with linoleic acid (LA) and with testosterone
(TST) was evaluated by spectrofluorimetry, using Nile Red as
selective marker of intracellular lipids (Nile Red Assay). The
sebocytes were plated in wells of a 24-well plate. Next day, they
were deprived of serum (2%) and after 24 h they were stimulated,
for another 24 h, with LA (10-4M), TST (20 nM) in presence or in
absence of compound A (1 mM). At the end of the treatment, the
sebocytes were stained with Nile Red. The quantitative analysis was
done by spectrofluorimetry, which made it possible to distinguish
between neutral lipids and polar lipids based on the different
wavelength of excitation and emission. The data obtained (FIG. 13)
revealed that the treatment with LA is able to induce lipid
synthesis and that the combined LA+TST treatment further increases
this effect. The presence of A proved able to reduce the
lipidogenic stimulus. No differences were observed in regard to the
times of treatment with the A.
References
[0150] All publications and patents mentioned herein, including
those items listed below, are hereby incorporated by reference in
their entirety as if each individual publication or patent was
specifically and individually incorporated by reference. In case of
conflict, the present application, including any definitions
herein, will control.
Equivalents
[0151] While specific embodiments of the subject invention have
been discussed, the above specification is illustrative and not
restrictive. Many variations of the invention will become apparent
to those skilled in the art upon review of this specification. The
full scope of the invention should be determined by reference to
the claims, along with their full scope of equivalents, and the
specification, along with such variations.
[0152] Unless otherwise indicated, all numbers expressing
quantities of ingredients, reaction conditions, and so forth used
in the specification and claims are to be understood as being
modified in all instances by the term "about." Accordingly, unless
indicated to the contrary, the numerical parameters set forth in
this specification and attached claims are approximations that may
vary depending upon the desired properties sought to be obtained by
the present invention.
* * * * *