Substituted indolealkanoic acids

Details Substituted indolealkanoic acids Substituted indolealkanoic acids

2002-06-28

2004-05-04

Lambkin, Deborah C (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S494000

Reexamination Certificate

active

06730794

ABSTRACT:

BACKGROUND OF INVENTION:
The use of aldose reductase inhibitors (ARIs) for the treatment of diabetic complications is well known. The complications arise from elevated levels of glucose in tissues such as the nerve, kidney, retina and lens that enters the polyol pathway and is converted to sorbitol via aldose reductase. Because sorbitol does not easily cross cell membranes, it accumulates inside certain cells resulting in changes in osmotic pressure, alterations in the redox state of pyridine nucleotides (i.e. increased NADH/NAD
+
ratio) and depleted intracellular levels of myoinositol. These biochemical changes, which have been linked to diabetic complications, can be controlled by inhibitors of aldose reductase.
The use of aldose reductase inhibitors for the treatment of diabetic complications has been extensively reviewed, see: (a)
Textbook of Diabetes
, 2nd ed.; Pickup, J. C. and Williams, G. (Eds.); Blackwell Science, Boston, Mass. 1997.; (b) Larson, E. R.; Lipinski, C. A. and Sarges, R.,
Medicinal Research Reviews
, 1988, 8 (2), 159-198; (c) Dvornik, D.
Aldose Reductase Inhibition
. Porte, D. (ed), Biomedical Information Corp., New York, N.Y. Mc Graw Hill 1987; (d) Petrash, J. M., Tarle, I., Wilson, D. K. Quiocho. F. A. Perspectives in Diabetes,
Aldose Reductase Catalysis and Crystalography: Insights From Recent Advances in Enzyme Structure and Function
, Diabetes, 1994, 43, 955; (e) Aotsuka, T.; Abe, N.; Fukushima, K.; Ashizawa, N.and Yoshida, M.,
Bioorg
. &
Med. Chem. Letters
, 1997, 7, 1677, (f) T., Nagaki, Y.; Ishii, A.; Konishi, Y.; Yago, H; Seishi, S.; Okukado, N.; Okamoto, K.,
J. Med. Chem
., 1997, 40, 684; (g) Ashizawa, N.; Yoshida, M.; Sugiyama, Y.; Akaike, N.; Ohbayashi, S.; Aotsuka, T.; Abe, N.; Fukushima, K.; Matsuura, A,
Jpn. J. Pharmacol
. 1997, 73, 133; (h) Kador, P. F.; Sharpless, N. E.,
Molecular Pharmacology
, 1983, 24, 521; (I) Kador, P. F.; Kinoshita, J. H.; Sharpless, N. E.,
J. Med. Chem
. 1985, 28 (7), 841; (j) Hotta, N.,
Biomed
. &
Pharmacother
, 1995, 5, 232; (k) Mylar, B.; Larson, E. R.; Beyer, T. A.; Zembrowski, W. J.; Aldinger, C. E.; Dee, F. D.; Siegel, T. W.; Singleton, D. H.,
J. Med. Chem
. 1991, 34, 108; (1) Dvornik, D.
Croatica Chemica Acta
1996, 69 (2), 613.
Previously described aldose reductase inhibitors most closely related to the present invention include those sighted in: (a) U.S. Pat. No. 5,700,819: 2-Substituted benzothiazole derivatives useful in the treatment of diabetic complications, (b) U.S. Pat. No. 4,868,301: Processes and intermediates for the preparation of oxophthalazinyl acetic acids having benzothiazole or other heterocyclic side chains, (c) U.S. Pat. No. 5,330,997: 1H-indazole-3-acetic acids as aldose reductase inhibitors, and (d) U.S. Pat. No. 5,236,945: 1H-indazole-3-acetic acids as aldose reductase inhibitors. Although many aldose reductase inhibitors have been extensively developed, none have demonstrated sufficient efficacy in human clinical trials without significant undesirable side effects. Thus no aldose reductase inhibitors are currently available as approved therapeutic agents in the United States; and consequently, there is still a significant need for new, efficacious and safe medications for the treatment of diabetic complications.
SUMMARY OF THE INVENTION
This invention provides compounds that interact with and inhibit aldose reductase. Thus, in a broad aspect, the invention provides compounds of Formula I:
or pharmaceutically acceptable salts thereof wherein
A is a C
1
-C
4
alkylene group optionally substituted with C
1
-C
2
alkyl or mono- or disubstituted with halogen, preferably fluoro or chloro;
Z is a bond, O, S, C(O)NH, or C
1
-C
3
alkylene optionally substituted with C
1
-C
2
alkyl;
R
1
is hydrogen, alkyl having 1-6 carbon atoms, halogen, 2-, 3-, or 4-pyridyl, or phenyl, where the phenyl or pyridyl is optionally substituted with up to three groups selected from halogen, hydroxy, C
1
-C
6
alkoxy, C
1
-C
6
alkyl, nitro, amino, or mono- or di(C
1
-C
6
)alkylamino;
R
2
, R
3
, R
4
and R
5
are each independently
hydrogen, halogen, nitro, or an alkyl group of 1-6 carbon atoms (which may be substituted with one or more halogens);
OR
7
, SR
7
, S(O)R
7
, S(O)
2
(R
7
)
2
, C(O)N(R
7
)
2
, or N(R
7
)
2
, wherein each R
7
is independently hydrogen, an alkyl group of 1-6 carbon atoms (which may be substituted with one or more halogens) or benzyl, where the phenyl portion is optionally substituted with up to three groups independently selected from halogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, amino, and mono- or di(C
1
-C
6
)alkylamino; phenyl or heteroaryl such as 2-, 3- or 4-imidazolyl or 2-, 3- or 4-pyridyl, each of which phenyl or heteroaryl is optionally substituted with up to three groups independently selected from halogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, amino, and mono- or di(C
1
-C
6
)alkylamino;
phenoxy where the phenyl portion is optionally substituted with up to three groups independently selected from halogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, amino, and mono- or di(C
1
-C
6
)alkylamino; or
a group of the formula
 where
J is a bond, CH
2
, oxygen, or nitrogen; and
each r is independently 2 or 3;
R
6
is hydroxy or a prodrug group;
R
a
is hydrogen, C
1
-C
6
alkyl, fluoro, or trifluoromethyl; and
Ar represents aryl or heteroaryl, each of which is optionally substituted with up to five groups.
In another aspect, the invention provides methods for preparing such compounds.
The compounds of the invention inhibit aldose reductase. Since aldose reductase is critical to the production of high levels of sorbitol in individuals with diabetes, inhibitors of aldose reductase are useful in preventing and/or treating various complications associated with diabetes. The compounds of the invention are therefore effective for the treatment of diabetic complications as a result of their ability to inhibit aldose reductase.
Thus, in another aspect, the invention provides methods for treating and/or preventing chronic complications associated with diabetes mellitus, including, for example, diabetic cataracts, retinopathy, nephropathy, and neuropathy.
In still another aspect, the invention provides pharmaceutical compositions containing compounds of Formula I.
DETAILED DESCRIPTION OF THE INVENTION
The numbering system for the compounds of Formula I is as follows:
As noted above, the invention provides novel substituted indole alkanoic acids useful in treating and/or preventing complications associated with or arising from elevated levels of glucose in individuals suffering from diabetes mellitus. These compounds are represented by Formula I above.
In compounds of Formula I, the aryl and heteroaryl groups represented by Ar include:
a phenyl group optionally substituted with up to 5 groups independently selected from halogen, an alkyl group of 1-6 carbon atoms (which may be substituted with one or more halogens), nitro, OR
7
, SR
7
, S(O)R
7
, S(O)
2
R
7
or N(R
7
)
2
wherein R
7
is hydrogen, an alkyl group of 1-6 carbon atoms (which may be substituted with one or more halogens) or benzyl, where the phenyl portion is optionally substituted with up to three groups independently selected from halogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, amino, and mono- or di(C
1-C
6
)alkylamino, or the phenyl group may be condensed with benzo where the benzo is optionally substituted with one or two of halogen, cyano, nitro, trifluoromethyl, perfluoroethyl, trifluoroacetyl, or (C
1
-C
6
)alkanoyl, hydroxy, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, (C
1
-C
6
)alkylthio, trifluoromethoxy, trifluoromethylthio, (C
1-C
6
)alkylsulfinyl, (C
1
-C
6
)alkylsulfonyl;
a heterocyclic 5-membered ring having one nitrogen, oxygen or sulfur, two nitrogens one of which may be replaced by oxygen or sulfur, or three nitrogens one of which may be replaced by oxygen or sulfur, said heterocyclic 5-membered ring substituted by one or two fluoro, chloro, (C
1-C
6
)alkyl or phenyl, or condensed with benzo, or substituted by one of pyridyl, furyl or thienyl, said phenyl or benzo optionally substituted by one of iodo, cyano

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