Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-12-31
2003-07-22
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S367000
Reexamination Certificate
active
06596744
ABSTRACT:
The present invention relates to methods for treating certain fibrotic diseases or other indications, and to compounds and compositions for use in such treating.
Glucose and other sugars react with proteins by a non-enzymatic, post-translational modification process called non-enzymatic glycosylation. At least a portion of the resulting sugar-derived adducts, called advanced glycosylation end products (AGEs), mature to a molecular species that is very reactive, and can readily bind to amino groups on adjacent proteins, resulting in the formation of AGE cross-links between proteins. Recently a number of classes of compounds have been identified whose members inhibit the formation of the cross-links, or in some cases break the cross-links. These compounds include, for example, the thiazolium compounds described in U.S. Pat. No. 5,853,703. As AGEs, and particularly the resulting cross-links, are linked to several degradations in body function linked with diabetes or age, these compounds have been used, with success, in animal models for such indications. These indications include loss of elasticity in blood vasculature, loss of kidney function and retinopathy. Now, as part of studies on these compounds, it has been identified that these compounds inhibit the formation of bioactive agents, such as growth factors and inflammatory mediators, that are associated with a number of indications. These agents include vascular endothelial growth factor (VEGF) and TGF [beta]. As a result, a number of new indications have been identified for treatment with agents that inhibit the formation of, or more preferably break, AGE-mediated cross-links. It is not unreasonable to infer that the effects seen are due to the removal of AGE-related molecules that provide a stimulus for the production or release of these growth factors. Removal of such molecules is believed to proceed in part due to the elimination of AGE-related cross-links that lock the AGE-modified proteins in place. Moreover, such compounds also reduce the expression of collagen in conditions associated with excess collagen production. Regardless of the mechanism, now provided are new methods of treating a number of indications.
SUMMARY OF THE INVENTION
In one embodiment, the invention relates to a method of treating or ameliorating or preventing an indication of the invention in an animal, including a human, comprising administering an effective amount of a compound of the formula I or IA,
wherein the substituent groups are as defined below.
DETAILED DESCRIPTION OF THE INVENTION
The agents used in the invention are compounds or formulas I or IA, wherein:
a. J is oxygen, sulfur, or N—R
d
;
b. the carbon 2 to nitrogen bond is a double bond except when R
c
is oxo;
c. the bond between carbons 4 and 5 is a single bond or a double bond (in one embodiment, a single bond);
d. R
a
and R
b
are
1. independently selected from hydrogen, acylamino, acyloxyalkyl, alkanoyl, alkanoylalkyl, alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylamino, (C
1
-C
3
)alkylenedioxy, allyl, amino, &ohgr;-alkylenesulfonic acid, carbamoyl, carboxy, carboxyalkyl (which alkyl can be substituted with alkyloxyimino), cycloalkyl, dialkylamino, halo, hydroxy, (C
2
-C
6
)hydroxyalkyl, mercapto, nitro, sulfamoyl, sulfonic acid, alkylsulfonyl, alkylsulfinyl, alkylthio, trifluoromethyl, morpholin-4-yl, thiomorpholin-4-yl, piperidin-1-yl, 4-[C
6
or C
10
]arylpiperidin-1-yl, 4-[C
6
or C
10
]arylpiperazin-1-yl, Ar {wherein, consistent with the rules of aromaticity, Ar is C
6
or C
10
aryl or a 5- or 6-membered heteroaryl ring, wherein the 6-membered heteroaryl ring contains one to three atoms of N, and the 5-membered heteroaryl ring contains from one to three atoms of N or one atom of O or S and zero to two atoms of N, each heteroaryl ring can be fused to a substituted benzene, pyridine, pyrimidine, pyrazine, pyridazine, or (1,2,3)triazine (wherein the ring fusion is at a carbon-carbon double bond of Ar) (or wherein Ar is as above but not heteroaryl fused to pyridine) (in one embodiment. Ar is C
6
or C
10
aryl)}, Ar-alkyl, ArO—, ArSO
2
—, ArSO—, ArS—, ArSO
2
NH—, ArNH, (N—Ar)(N-alkyl)N—, ArC(O)—, ArC(O)NH—, ArNH—C(O)—, and (N—Ar)(N-alkyl)N—C(O)—, or together R
a
and R
b
comprise methylenedioxy—(in one embodiment R
a
and R
b
are not acyloxyalkyl, alkenyl, (C
1
-C
3
)alkylenedioxy or allyl, or together do not comprise methylenedioxy); or
2. together with their ring carbons form a C
6
- or C
10
-aryl fused ring; or
3. together with their ring carbons form a C
5
-C
7
fused cycloalkyl ring having up to two double bonds including any fused double bond of the containing group, which cycloalkyl ring can be substituted by one or more of the group consisting of alkyl, alkoxycarbonyl, amino, aminocarbonyl, carboxy, fluoro, or oxo (in one embodiment, the ring having no double bonds except any fused double bond of the formula I or IA ring, which cycloalkyl ring can be substituted by one or more of the group consisting of alkyl, amino, aminocarbonyl, carboxy, fluoro, or oxo, where multiple substituents are located on different carbon atoms of the cycloalkyl ring, except in the case of alkyl and fluoro substituents, which can be located on the same or different carbon atoms); or
4. together with their ring carbons form a fused 5- or 6-membered heteroaryl ring, wherein the 6-membered heteroaryl ring contains one to three atoms of N, and the 5-membered heteroaryl ring contains from one to three atoms of N or one atom of O or S and zero to two atoms of N; or
5. together with their ring carbons form a fused five to eight membered second heterocycle (in one embodiment, a fused five to six membered second heterocycle), wherein the fused heterocycle consists of ring atoms selected from the group consisting of carbon, nitrogen, oxygen, sulfur, and S(O)
n
, wherein n is 1 or 2;
e. R
d
is alkyl, alkenyl, hydrogen, or Ar;
f. R
c
is
1. oxo (when &Dgr;
2,3
is not present), or (when &Dgr;
2,3
is present) hydrogen, alkyl, alkylthio, hydrogen, mercapto, amino, amino(C
1
-C
5
)alkyl, or amino(C
6
or C
10
)aryl, or wherein the amino of the last three groups can be substituted with
(a) Ar,
(b) Ar—Z—, Ar-alkyl-Z—, Ar—Z-alkyl, Ar-amino-Z—, Ar-aminoalkyl-Z—, or Ar-oxyalkyl-Z—, wherein Z is a carbonyl or —SO
2
—
(c) formyl or alkanoyl (in one embodiment, R
c
is according to one of these optionally substituted three groups; in another, J is S or O (in one embodiment S), and R
c
is hydrogen, oxo, alkyl, amino, amino(C
1
-C
5
)alkyl or aminophenyl, wherein the amino of the latter three groups can be substituted as outlined here),
2. —NHC(O)(CH
2
)
n
—D—R
e
R
f
wherein D is oxygen, sulfur or nitrogen, wherein where D is nitrogen n is 0,1 or 2, but when D is oxygen or sulfur n=1 or 2, and R
f
is present only when D is nitrogen,
wherein
(a) R
e
is
(1) Ar,
(2) a group of the formula
wherein E is sulfur, oxygen, or N—R
i
, and R
g
, R
h
and R
i
are independently the same as R
a
, R
b
and R
d
, respectively,
(3) a C
3
-C
8
cycloalkyl ring having up to one double bond with the proviso that the carbon linking the cyloalkyl ring to D is saturated, which cycloalkyl ring can be substituted by one or more alkyl-, alkoxycarbonyl-, amino-, aminocarbonyl-, carboxy-, fluoro-, or oxo-substituents,
(4) a 5- or 6-membered heteroaryl ring containing at least one and up to three atoms of N for the 6-membered heteroaryl rings and from one to three atoms of N or one atom of O or S and zero to two atoms of N for the 5-membered heteroaryl rings;
(5) hydrogen, (C
2
-C
6
)hydroxyalkyl, alkanoylalkyl, alkyl, alkoxycarbonylalkyl, alkenyl, carboxyalkyl (which alkyl can be substituted with alkoxyimino), alkoxycarbonyl, a group Ar
&phgr;
which is C
6
- or C
10
-aryl or a 5- or 6-membered, or 9- or 10-membered heteroaryl (wherein the heteroatom is one oxygen, one sulfur or one nitrogen) or Ar
&phgr;
-alkyl; and
(b) R
f
is independently hydrogen, (C
2
-C
6
)hydroxyalkyl, alkanoylalkyl, alkyl, alkoxycarbonylalkyl, alkenyl, carboxyalkyl (which alkyl
Bell Stanley C.
Gall Martin
LaVoie Edmond J.
Wagle Dilip
Alteon Inc.
Dechert
Henley III Raymond
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