Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1994-06-20
1996-02-06
Berch, Mark L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
544237, A61K 3150, C07D23732, C07D40906
Patent
active
054895928
DESCRIPTION:
BRIEF SUMMARY
This Application is a 371 of PCT/FR92/00920, filed 20 Oct. 1992.
The present invention relates to new 3,4-dihydro-4-oxo-3-(2-propenyl)-1-phthalazineacetic acids, to processes which make it possible to prepare them and to their application in the therapeutic field and more particularly in the treatment of complications of diabetes such as cataracts, retinopathy, neuropathy and nephropathy.
Diabetes is characterized by a high glucose concentration in the blood. This glucose is normally metabolized by the enzyme hexokinase during the first stage of glycolysis, ending in degradation to pyruvate. When the glucose concentration is excessively high, the hexokinase is saturated and a second metabolic route comes into operation: the polyols route which involves two enzymes: aldose reductase, which converts glucose to sorbitol, and sorbitol dehydrogenase, which converts sorbitol to fructose. However, sorbitol is formed more rapidly than it is metabolized to fructose and therefore has a tendency to accumulate. This accumulation of sorbitol produces an intracellular osmotic pressure which can be sufficient to interfere with or destroy cell functions. Aldose reductase inhibitors are therefore useful in alleviating or preventing these effects of diabetes.
Numerous classes of products are described in the literature as in vitro aldose reductase inhibitors: the main ones are hydantoins, substituted acetic acids, flavonoids and anti-allergic compounds.
Only the first two classes have given clinically active products. In particular, in the class of acetic acids, Patent EP 2895 describes 3-benzyl-3,4-dihydro-4-oxo-1-phthalazineacetic acids having aldose reductase inhibiting properties. in which hydrogen atom, a halogen atom or a C.sub.1 -C.sub.4 alkyl group; atom, a halogen atom, a C.sub.1 -C.sub.4 alkyl group, a phenyl group, a phenyl group substituted by 1 to 5 substituents chosen from a halogen atom, a C.sub.1 -C.sub.4 alkyl group and the trifluoromethyl group, or a heterocyclic group having from 3 to 10 carbon atoms including 1 to 4 heteroatoms chosen from N, S and O, optionally substituted by 1 to 5 substituents chosen from a halogen atom, a C.sub.1 -C.sub.4 alkyl group and the trifluoromethyl group; or C.sub.1 -C.sub.4 alkoxy group,
More recently, Patents EP 222,576, 295,051 and 322,153 describe oxophthalazineacetic acids having side chains of benzothiazole or heterocyclic type and having the property of inhibiting aldose reductase.
The present invention relates to new 3,4-dihydro-4-oxo-3-(2-propenyl)-1-phthalazineacetic acids and derivatives of formula I. ##STR2##
C.sub.1 -C.sub.4 alkyl group is understood to mean groups containing a linear or branched chain, especially methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl groups.
C.sub.1 -C.sub.4 alkoxy group is understood to mean groups containing a linear or branched chain, especially methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and tert-butoxy groups.
Halogen atom is understood to mean fluorine, chlorine, bromine or iodine atoms.
Heterocycle having from 3 to 10 atoms including 1 to 4 heteroatoms chosen from N, S and O is understood to mean mono- or bicyclic heterocycles, especially thienyl, benzothienyl, furyl, pyranyl, isobenzofuranyl, chromenyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, indolyl, 3H-indolyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, isothiazolyl, isoxazolyl, furazanyl, isochromanyl, chromanyl, pyrrolidinyl, .DELTA..sup.2 -pyrrolinyl, imidazolidinyl, .DELTA..sup.2 -imidazolinyl, pyrazolidinyl, .DELTA..sup.3 -pyrazolinyl, piperidyl, piperazinyl, indolinyl, isoindolinyl and morpholinyl groups.
Advantageously, the R.sub.1, R.sub.2 and R.sup.3 groups represent H, F or CF.sub.3, the R.sub.6 group represents OH or OC.sub.2 H.sub.5 and the R.sub.7 group represents H.
Mention may especially be made, among the preferred compounds, of those in which one of R.sub.4 an
REFERENCES:
Shatalov, Chem Abs 98, 89286 (1982).
Malamas, J Med Chem 34, 1492 (1991).
Drug Evaulations Annual 1993 p. 149.
Dialog Abstract 08497366-93207366 For Narayanan, S, J. Ann. Clin Lab Sci 23 (2), 148 (1993).
Collonges Francois
Dumas Herve
Durbin Philippe
Guerrier Daniel
Berch Mark L.
Lipha Lyonnaise Industrielle Pharmaceutique
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