Specification
Field of the Invention
The present invention relates to monosaccharide derivatives as anti-inflammatory agents.
The compounds disclosed herein can be useful for inhibition and prevention of inflammation and
associated pathologies, including inflammatory and autoimmune diseases such as bronchial asthma,
rheumatoid arthritis, type I diabetes, multiple sclerosis, allograft rejection psoriasis, inflammatory
bowel disease, ulcerative colitis, acne, atherosclerosis, cancer, pruritis or allergic rhinitis.
Pharmacological compositions containing the compounds disclosed herein and methods of treating
bronchial asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, multiple sclerosis,
type I diabetes, psoriasis, allograft rejection, inflamm-atory bowel disease, ulcerative colitis, acne,
atherosclerosis, cancer, pruritis, allergic rhinitis and other inflammatory and/or autoimmune
disorders, using the compounds are also provided.
Background of the Invention
Inflammation is a key defense mechanism of the body that is activated as a result of tissue
injury. The inflammatory process is self-containing, however, under certain pathophysiological
conditions, the inflammatory process tends to perpetuate itself, giving rise to chronic
inflammatory diseases like bronchial asthma, rheumatoid arthritis etc.
Although the exact cellular and molecular bases of most chronic inflammatory disease remain
unclear, it has become apparent that several inflammatory cells act in concert towards initiation and
perpetuation of an inflammatory response by releasing a wide range of chemo- kine, cytokine,
proteolytic enzymes and other bioactive molecules. A case in point is mast cells primed by lymphocytes
interact with environmental allergens and release mediators like histamine, prostaglandin,
leukotrienes, etc. (din. Exp. Allergy, 32, 1682, 2002) to initiate an early inflammatory response.
This is followed by a delayed inflammatory response due to release of cytokines (IL-4, IL-5, IL-6, IL-8,
IL-13, GM-CSF and TNFalpha), chemo-kines and proteolytic enzymes (chymase, tryptase) (Chest
112, 523, 1997; Lancet 350. 59, 1997) that not only bring about tissue damage, but attract other
inflammatory cells and initiate tissue fibrosis, and the cycle continues. Eosinophils infiltrate inflamed
tissue following allergen- mast cell interaction in bronchial asthma and allergic rhinitis. Evidence is
emerging that mast cells also interact with bacterial endotoxins leading to generation of cytokines like
TNF alpha, that encourage neutrophil influx into the site of inflammation (Br. J. Pharmacol 123. 31
(1998); Br. J. Pharmacol 128. 700, (1999); Br. J. Pharmacol 136. I l l , (2002); J. Clin. Invest., 109.
1351, 2002). Involvement of mast cells in the inflammatory response of chronic obstructive
pulmonary disease (New Eng. J. Med, 347. 1040, 2002; Thorax 57, 649, 2002), inflammatory bowel
disease (Gut, 45 Suppl 116, 1999) as well as rheumatoid arthritis (Science, 297. 1626, 2002),
pathologies with prominent neutrophilic inflammation, has been proposed.
U.S. Patent No. 6,329,34481 discloses several monosaccharide derivatives described as cell
adhesion inhibitors. It generally relates to substituted pentose and hexose monosaccharide
derivatives, which are said to exhibit cell adhesion inhibitory and anti-inflammatory activities. U.S.
Patent No. 6,590,08561 discloses several monosaccharide derivatives described as inhibitors of cell
adhesion and cell adhesion mediated pathologies, including inflammatory and autoimmune diseases.
U.S. Patent Application US 2002/ 0173632 Al discloses furanose and amino furanose compounds
said to be useful for rheumatoid, arthritis, immunomodulatory diseases inflammatory and
proliferative diseases. U.S. Patent No. 5,298,494 discloses derivatives of monosaccharides, which
exhibit anti-proliferative and/or anti-inflammatory activity and are described as useful for treating
mammals having inflammatory disorders and/or autoimmune disorders. U.S. Patent No. 5,367,062
discloses derivatives of disubstituted and deoxydisubstituted a,D-lyxofuranosides which reportedly
exhibit significant anti-inflammatory and antiproliferative activity and are said to be useful for
treating inflammatory and/or autoimmune disorders. U.S. Patent No. 5,360,794 discloses
deoxydisubstituted or dideoxy disubstituted derivatives of a-D-mannofuranoside and p-Lgulofuranosides,
which are said to exhibit anti-inflammatory and antiproliferative activity. U.S
Patent 4,996,195 discloses derivatives of a,D-glucofuranose and a,D-allofuranose described as
useful for treating animals and mammals with inflammatory and/or autoimmune disorders. U.S.
Patent No. 5,010,058 discloses derivatives of 1,2-O-iso-propylidene-a-D-glucofuranose described
as useful for treating animals and mammals with inflammatory and/or autoimmune disorders.
WO 93/13117 and U.S. Patent No. 5,360,792 discloses 5- or 6-deoxy hexose
monosaccharides having a saturated nitrogen containing heterocycle described as useful as antiproliferative
and anti-inflammatory compounds. WO 94/28910 discloses 5,6-dideoxy-5-amino
derivatives of idose and 6-deoxy-6-amino derivatives of glucose, which are said to exhibit
immunomodulatory, anti-inflammatory and anti-proliferative activity. WO 94/11381 discloses
derivatives of pentose monosaccharides described as anti-proliferative and anti-inflammatory
compounds.
Summary of the Invention
Monosaccharide derivatives, which can be used for the inhibition and prevention of cell
adhesion and cell adhesion-mediated pathologies including inflammatory and autoimmune
diseases such as bronchial asthma, rheumatoid arthritis, type I diabetes, multiple sclerosis,
allograft rejection or psoriasis are provided.
Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers,
diastereomers or N-oxides of these compounds having the same type of activity are also provided.
Pharmaceutical compositions containing the compounds, and which may also contain
pharmaceutically acceptable carriers or diluents, which may be used for the treatment of inflammatory
and autoimmune diseases such as bronchial asthma, rheumatoid arthritis, type I diabetes, multiple
sclerosis, allograft rejection, psoriasis inflammatory bowel disease, ulcerative colitis, acne,
atherosclerosis, cancer, pruritis and allergic rhinitis are also provided.
Other aspects will be set forth in accompanying description, which follows, and in part
will be apparent from the description or may be learnt by the practice of the invention.
In accordance with one aspect, there are provided compounds having a structure of
Formula I
wherein
X can be O, or NH.
RI can be hydrogen or methyl.
R: and Ra can together form a five-membered acetal, wherein the carbon joining the oxygens is
substituted with RI and Rm [wherein RI and Rm are independently selected from hydrogen, alkyl,
alkenyl, alkynyl, cycloalkyl, aryl, or aralkyl; or RI and Rm can together join to form a 3- to 8-
membered ring, wherein the ring may optionally contain one or more heteroatoms selected from
O, N or S, and the ring may be optionally substituted with one or more of alkyl, alkenyl, alkynyl,
acyl, substituted amino, cycloalkyl, or -C(=O)QR7 (wherein Q can be O or NH, and Ry can be
selected from alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, heteroaryl, and when Q is NH only
then can Ry also be selected from heteroarylalkyl, heterocyclyl, heterocyclylalkyl, carboxy, oxo,
hydroxyl, alkoxy, aryloxy, halogen (F,C1, Br, I), aryl, aralkyl, heteroaryl, heterocyclyl,
heteroarylalkyl, or heterocyclylalkyl), or RI and Rm can together join to form an oxo].
R4 can be hydrogen, or ORC (wherein Rc is selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl, or heterocyclylalkyl). Also, when R4 is ORC, RS
and Rc may together form an acetal (wherein the acetal is as defined earlier) and then R2 can be
alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl, or
heterocyclylalkyl. Also, R2 and Ra, instead of forming an acetal as defined earlier, may optionally
and independently be selected from lower (C|-C4) alkyl, (CHi)k -aryl (wherein k is an integer
from 1-4), acyl, -C(=Ry)NHRx (wherein Ry is O or S and Rx is alkyl, alkenyl, alkynyl, cycloalkyl,
aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl, or heterocyclylalkyl), and the R4 is as
defined earlier. Also, Rj and Rc (when R4 is ORC) instead of forming an acetal as defined earlier,
may optionally and independently be selected from lower (Cj-C4) alkyl, (CH2)k -aryl (wherein k
is an integer from 1-4), -C(=Ry)NHRx (wherein Ry is O or S and Rx is the same as defined earlier)
or acyl, and then Ra is as defined earlier.
RS may be alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocylyl, heteroarylalkyl,
heterocyclylalkyl, or -(CH2)n (C=O)ORZ (wherein n is 1 -4, and Rz is hydrogen, alkyl, aralkyl, aryl,
or heteroarylalkyl), -(CH2)n (C=O)NRaRb [wherein n is same as defined earlier, and Ra and Rb are
independently selected from hydrogen or Rd, (wherein Rd is alkyl, alkenyl, alkynyl, cycloalkyl,
aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl, or heterocyclylalkyl)]. Also Ra and Rb,
together with the nitrogen atom carrying them, can be the N-terminus of an aminoacid or ditetrapeptide.
When X is O, then RS can be acyl or -C(=O)NRfRq [wherein Rf and Rq can be independently selected
from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl,
heteroarylalkyl, hetrocyclylalkyl, or S(O)2R6 (wherein R& can be selected from alkyl, alkenyl,
alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heterocyclyl- alkyl, heteroarylalkyl, or
substituted amino)]. Also Rf and Rq can together form a ring.
When X is NH, then RS can be -C(=O)ORS (wherein Rs can be selected from alkyl, alkenyl,
alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heteroarylalkyl), -YRd (wherein Y is -
C(=O), -C(=S) or SO2 and Rd is same as defined earlier), or -C(=T)NR,Rf (wherein Rt is OH or Rf,
and T is O, S, -N(CN), -N(NO2), or -CH(N02), and Rf is the same as defined earlier).
The following definitions apply to terms as used herein:
The term "alkyl" unless otherwise specified refers to a monoradical branched or unbranched
saturated hydrocarbon chain having from 1 to 20 carbon atoms. This term can be exemplified by
groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, n-decyl,
tetradecyl, and the like. Alkyl may further be substituted with one or more substituents selected
from alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy,
alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thio- carbonyl, carboxy, arylthio,
thiol, alkylthio, aryloxy, aminosulfonyl, aminocarbonylamino, -COORX (wherein Rx is the same
as defined earlier), -NHC(=O)Rd, -NRtRq, -(=O)NRfRq, -NHC(=O)NRtR,,, -N(OH)C(=O)NRxRt, -
C(=O)heteroaryl, C(=O)heterocyclyl, -O-C(=O)NRtRq wherein Rd, Rt, Rf and Rq are the same as
defined earlier, nitro, -S(O)mR6 wherein m is an integer from 0-2 and Rf, is the same as defined
earlier. Unless otherwise constrained by the definition, all such alkyl substituents may be further
substituted by 1-3 substituents chosen from alkyl, carboxy, -NRfRq, -C(=O)NRfRq, -OC(=
O)NRfRq, -NHC(=O)NRfRt (wherein Rf, Rq and Rt are the same as defined earlier), hydroxy,
alkoxy, halogen, CFs, cyano, and -S(0)mR6, (wherein Re and m are the same as defined earlier);
or an alkyl group as defined above may also be interrupted by 1-5 atoms of groups independently
chosen from oxygen, sulfur and -NRa-, (where Ra is chosen from hydrogen, alkyl, cycloalkyl,
alkenyl, cyclo-alkenyl, alkynyl, aryl, acyl, aralkyl,-C(=O)ORs wherein Rs is the same as defined
earlier, S(O)2R6 where Re is as defined earlier, or -C(=O)NRfRq wherein Rf and Rq are as defined
earlier). Unless otherwise constrained by the definition, all substituents may be further substituted
by 1-3 substituents chosen from alkyl, carboxy, -NRfRq, -C(=O)NRfRq, -O-C(=O)NRfRq (wherein
Rf and Rq are the same as defined earlier), hydroxy, alkoxy, halogen, CFs, cyano, and -S(O)mR6,
(wherein m and R& are the same as defined earlier); or an alkyl group as defined above that has
both substituents as defined above may also be interrupted by 1-5 atoms or groups as defined
above.
The term "alkenyl" unless otherwise specified refers to a monoradical of a branched or
unbranched unsaturated hydrocarbon group preferably having from 2 to 20 carbon atoms with cis
or trans geometry. In the event that alkenyl is attached to the heteroatom, the double bond cannot
be alpha to the heteroatom. Alkenyl may further be substituted with one or more substituents
selected from alkyl, alkynyl, alkoxy, cycloalkyl, cyclo-alkenyl, acyl, acylamino, acyloxy, -
COORX (wherein Rx is the same as defined earlier),
-NHC(O)Rd, -NRfRq, -C(=O)NRfRq, N(OH)C(=O)NRXR,, -NHC(=O)NRfR,, -O-C(=O)NR,Rq (wherein
Rt; Rq and Rt are the same as defined earlier), alkoxycarbonylamino, azido, cyano, halogen,
hydroxy, oxo, thiocarbonyl, carboxy, arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, heterocyclyl,
heteroaryl, heterocyclyl alkyl, heteroaryl alkyl, aminosulfonyl, amino- carbonylamino, alkoxyamino,
nitro, or S(O)mR6 (wherein Re and m are the same as defined earlier). Unless otherwise constrained by
the definition, all such alkyl substituents may optionally be further substituted by 1-3 substituents
chosen from alkyl, carboxy, hydroxy, alkoxy, halogen,-CF3, cyano, -NRfRq, -C(=O)NRfRq,
C(=O)NRfRq (wherein Rf and Rq are the same as defined earlier) and -S(O)mR6, (wherein R$ and m are
the same as defined earlier).
The term "alkynyl" unless and otherwise specified refers to a monoradical of an unsaturated
hydrocarbon, preferably having from 2 to 20 carbon atoms. In the event that alkynyl is attached to
the heteroatom, the triple bond cannot be alpha to the heteroatom. Alkynyl may further be
substituted with one or more substituents selected from alkyl, alkenyl, alkoxy, cycloalkyl,
cycloalkenyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo,
thiocarbonyl, carboxy, arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, aminosulfonyl,
aminocarbonylamino, nitro, heterocyclyl, heteroaryl, heterocyclyl alkyl, heteroarylalkyl, -COORX
(wherein Rx is the same as defined earlier), -NHC(=O)Rd, -NRfRq, -NHC(=O)NRfR, ,
N(OH)C(=O)NRXR,, -C(=O)NRfRq, -O-C(=O)NRfRq (wherein R
Documents
Application Documents
| # |
Name |
Date |
| 1 |
1634-delnp-2007-abstract.pdf |
2011-08-21 |
| 1 |
1634-delnp-2007-form-2.pdf |
2011-08-21 |
| 2 |
1634-delnp-2007-claims.pdf |
2011-08-21 |
| 2 |
1634-delnp-2007-form-1.pdf |
2011-08-21 |
| 3 |
1634-delnp-2007-correspondence-others.pdf |
2011-08-21 |
| 3 |
1634-delnp-2007-description (complete).pdf |
2011-08-21 |
| 4 |
1634-delnp-2007-correspondence-others.pdf |
2011-08-21 |
| 4 |
1634-delnp-2007-description (complete).pdf |
2011-08-21 |
| 5 |
1634-delnp-2007-claims.pdf |
2011-08-21 |
| 5 |
1634-delnp-2007-form-1.pdf |
2011-08-21 |
| 6 |
1634-delnp-2007-abstract.pdf |
2011-08-21 |
| 6 |
1634-delnp-2007-form-2.pdf |
2011-08-21 |