Substituted phenoxyacetic acids

Details Substituted phenoxyacetic acids Substituted phenoxyacetic acids

2000-06-23

2002-07-16

Higel, Floyd D. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Radical -xh acid, or anhydride, acid halide or salt thereof...

C562S405000, C562S450000, C562S455000, C544S111000, C544S359000, C546S187000, C546S192000

Reexamination Certificate

active

06420426

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to substituted phenoxy acetic acids and pharmaceutical compositions containing such compounds. It also relates to the use of such compounds in the treatment or prevention of chronic complications arising from diabetes mellitus.
2. Description of the Related Art
The use of aldose reductase inhibitors (ARIs) for the treatment of chronic 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 chronic diabetic complications has been extensively reviewed, see: (a)
Textbook of Diabetes
, 2
nd
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; (l) Dvornik, D.
Croatica Chemica Acta
1996, 69 (2), 613.
The following patents disclose compounds said to have activity as aldose reductase inhibitors: U.S. Pat. Nos. 5,700,819; 4,868,301; and 4,734,419. 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 covalent bond, C
1
-C
4
alkylene group optionally substituted with C
1
-C
2
alkyl or mono- or disubstituted with halogen, preferably fluoro or chloro;
X is oxygen, sulfur or NR
6
, wherein each R
6
is hydrogen, cyano or an alkyl group of 1-6 carbon atoms (which may be substituted with one or more halogens);
R
1
, R
2
, R
3
and R
4
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
, 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
5
is hydroxy or a prodrug group; 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 another aspect, the invention provides methods for treating and/or preventing chronic complications associated with diabetes mellitus, including, for example, diabetic cataracts, retinopathy, keratopathy, wound healing, diabetic uveitis, diabetic cardiomyopathy, nephropathy, and neuropathy.
The compounds of the invention promote healing of wounds in mammals. In preferred aspects, the compounds are useful in promoting wound healing in diabetic mammals. Thus, the compounds of the invention may be employed in the treatment of wounds in mammals, preferably humans, more preferably in diabetic humans.
In still another aspect, the invention provides for the use of a compound or compounds of Formula I for the preparation of a medicament for the treatment of any of the disorders or diseases (a) listed above or (b) connected with diabetic complications.
Prolonged administration of an ACE inhibitor at a therapeutically effective dose may be deleterious or give rise to side effects in certain patients, for example, it may lead to significant deterioration of renal function, induce hyperkalemia, neutropenia, angioneurotic oedema, rash or diarrhea or give rise to a dry cough. The present invention provides combination therapy comprising administration of a compound of Formula I together with a vasodilator, preferably an ACE inhibitor. Such administration decreases the likelihood of problems associated with administration of vasodilators such as ACE inhibitors that otherwise may result from administration of one of these agents alone. Furthermore, diabetic complications involve a complex mechanism or number of mechanisms, which initiate a cascade of biochemical alternations that in turn lead to structural changes. These may result in a diverse patient population. The present invention, therefore, provides the additional advantage that it allows tailoring of treatment to the needs of a particular patient population.
In this aspect, the present invention provides a pharmaceutical composition which comprises a compound of Formula I and vasodilator, preferably an ACE inhibitor, together with a pharmaceutically acceptable carrier and/or diluent. In addition, the invention contemplates methods of treating diseases or disorders associated with elevated plasma levels of glucose, including complications associated with

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