Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Reexamination Certificate
2002-01-07
2003-08-26
Richter, Johann (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
C568S637000, C568S638000, C568S639000, C568S723000, C568S726000, C585S025000, C514S686000, C514S717000, C514S765000, C514S730000, C514S738000
Reexamination Certificate
active
06610890
ABSTRACT:
The present invention provides the use, as Aldose Reductase Inhibitors (ARIs), for the manufacture of a medicament for the treatment and/or prevention of diabetic complications, of a compound represented by the following general formula (A)
wherein at least one of Y or Y′ is OH and the others Y and Y′ are independently selected from the group consisting of hydrogen, halogen, hydroxy, methoxy, and nitro; X is selected from the group consisting of O, S, and ketone, or both substituted benzyl groups are directly linked as a substituted biphenyl compound.
In addition, these aldose reductase inhibitors can form salts with a pharmaceutically acceptable cation, all such salts are within the scope of this invention.
In addition, some of the compounds of this invention can form hydrates or solvates and they are also within the scope of the invention.
The present invention also provides six novel synthetic compounds having the following formula:
FIELD OF THE INVENTION
The present invention is directed to novel pharmaceutical compositions, which possess Aldose Reductase inhibitory activity, and are useful for the treatment and/or prevention of diabetic complications; the present invention is also directed to novel compounds which possess Aldose Reductase inhibitory activity.
BACKGROUND OF THE INVENTION
Diabetic neuropathy, diabetic cataract and retinopathy, diabetic corneal keratopathy, diabetic nephropathy, diabetic dermopathy and other diabetic microangiopathy have been known as chronic diseases as a result of diabetes which are difficult to treat. Accumulation of intracellular sorbitol, the reduced product of glucose, catalyzed by Aldose Reductase (AR) (EC 1.1.1.21), is thought to be the cause of the development of these diabetic complications
1-3
. Accordingly, agents for inhibiting this Aldose Reductase have been thought to be effective for the therapy and the prevention of diabetic complications and have been studied
4-6
. However, despite numerous attempts over 16 years, the results of aldose reductase inhibitor (ARI) trials, with the known aldose reductase inhibitors, for the treatment of diabetic complications have not proven efficacy
7
; also, despite the apparent structural diversity of aldose reductase inhibitors (ARIs), certain common electronic and steric features have become apparent through computer modeling, molecular orbital calculations, and known structure-activity relationships, and from competition studies using different aldose reductase inhibitors (ARIs) also suggest that ARIs interact at a single common site on the enzymes
8-10
.
Under these circumstances, the inventors have conducted a study looking for new compounds structurally different of the known aldose reductase inhibitors (ARIs). As a result, the present invention provides a novel class of aldose reductase inhibitors (ARIs) having the general formula (A). These compounds exhibit an excellent inhibitory activity to Aldose Reductase.
Compounds having the general formula (A) have long been known as antiseptic and antimicrobial agents
11
, as cardiac agents
12
, as antiinflammatory agents
13
, and as inhibitors of the enzymes: protein kinase C (PKC), protein tyrosine kinase (PTK), inosine monophosphate dehydrogenase (IMPDH), guanosine monophosphate synthetase (GMPS), and 15-lipoxygenase (15-LO)
14
.
Compounds having the general formula (A) have long been reported from marine sources
14-18
.
SUMMARY OF THE INVENTION
The present invention provides the use, as inhibitors of Aldose Reductase, for the manufacture of a medicament for the treatment and prevention of diabetic complications, of a compound represented by the following general formula (A)
wherein at least one of Y or Y′ is OH and the other Y and Y′ are independently selected from the group consisting of hydrogen, halogen, hydroxy, methoxy, and nitro; X is selected from the group consisting of O, S, and ketone, or both subtituted benzyl groups are directly linked as a subtituted biphenyl compound.
In addition, these aldose reductase inhibitors can form salts with a pharmaceutically acceptable cation, all such salts are within the scope of this invention.
In addition, some of the compounds of this invention can form hydrates or solvates and they are also within the scope of the invention.
The present invention further provides pharmaceutical compositions which contain as active ingredient a compound with the formula (A). Examples of pharmaceutical compositions include any solid (tablets, pills, capsules, granules, etc.) or liquid (solutions, suspensions or emulsions) with suitable formulation of oral, topical or parenteral administration, and they may contain the pure compound or in combination with any carrier or other pharmacologically active compounds. These compositions may need to be sterile when administered parenterally.
The correct dosage of a pharmaceutical composition comprising compounds with the formula (A), will vary according to the pharmaceutical formulation, the mode of application, and the particular situs, host and diabetic complication being treated. Other factors like age, body weight, sex, diet, time of administration, rate of excretion, condition of the host, drug combinations, reaction sensitivities and severity of the disease shall be taken into account. Administration can be carried out continuously or periodically within the maximum tolerated dose.
The present invention also provides six novel synthetic compounds having the following formula:
as well as a process for their preparation.
REFERENCES:
patent: 3786022 (1974-01-01), Hata et al.
patent: 3912782 (1975-10-01), Kiel et al.
patent: 5202355 (1993-04-01), Nakatsu
patent: 0 470 832 (1992-12-01), None
Chemical Abstracts, vol. 97, No. 5, (Aug. 2, 1982) Columbus, Ohio, US; abstract No. 33363b, H. Ono: “2,2′,4,4′—Tetrahydroxybenzophenone as a New Aldose Reductase Inhibitor”, p. 44; col. 2; XP002131322 abstract &Nippon Ganka Gakkai Zasshi,vol. 86, No. 4, (1982), pp. 353-357.
Hawkins, “Degradation of Novolak Resins”,J. Appl. Chem.,vol. 6, (1956), pp. 131-139.
Ono et al., “2,2′,4,4′—Tetrahydroxybenzophenone as a New Aldose Reductase Inhibitor”,Nippon Ganka Gakkai Zasshi,vol. 86, No. 4, (1982), pp. 353-357.
De La Fuente Blanco Jesús A
Garcia de Quesada Fort Teresa
Martin Lopez Ma Jesús
Reymundo Cuesta Isabel
O.N.C.E.-(Organizacion Nacional De Cicgos)
Richter Johann
Witherspoon Sikarl A.
LandOfFree
Aldose reductase inhibitors and pharmaceutical compositions does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Aldose reductase inhibitors and pharmaceutical compositions, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Aldose reductase inhibitors and pharmaceutical compositions will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3123765