Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Patent
1998-12-14
2000-06-06
Geist, Gary
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
560190, C07C 6940, A61K 31225
Patent
active
060719605
DESCRIPTION:
BRIEF SUMMARY
This invention relates to a hitherto unknown class of compounds which show effect in metabolic diseases including diabetes, acute starvation, endotoxemia, sepsis, systemic inflammatory response syndrome (SIRS) and multiple organ failure, to pharmaceutical preparations containing these compounds, to dosage units of such preparations, and to their use in the treatment and prophylaxis of said diseases and other diseases caused by or resulting in a disturbed metabolism and/or energy deprivation.
The compounds of the present invention are represented by the general formula I ##STR2## in which Y and Q are the same or different and are hydrogen atoms or C.sub.1-6 alkyl groups, optionally substituted by 1-4 hydroxy or 1-4 R.sup.3 O.sub.2 CCH.sub.2 CH.sub.2 CO.sub.2 -- groups, where R.sup.3 is a hydrogen atom or a C.sub.1-6 alkyl group which may be straight or branched and saturated or unsaturated, and groups, which may be straight or branched and saturated or unsaturated, which R.sup.3 is a hydrogen atom.
Examples of R.sup.1 and R.sup.2 include, but are not limited to, methyl, ethyl, n-propyl, butyl, allyl and isopropyl.
Examples of Q and Y, include, but-are not limited to, hydrogen, methyl, ethyl, hydroxymethyl, dihydroxyethyl, methyl butandioic acid esters of formula R.sup.3 O.sub.2 CCH.sub.2 CH.sub.2 CO.sub.2 CH.sub.2 --, and ethyl dibutandioic acid esters of formula ##STR3##
Preferably, Y and Q stand for C.sub.1 -C.sub.2 alkyl, optionally substituted with 1-2 hydroxy or 1-2 R.sup.3 O.sub.2 CCH.sub.2 CH.sub.2 CO.sub.2 --groups, or one of Y and Q is a hydrogen atom and the other is such a group. Particularly important compounds of the invention are 1,2,3,-trihydroxypropane-1,2,3-trimethyl-tributandioate and 1,2,-dihydroxypropane-1,2-dimethyl-dibutandioate.
The compounds of the invention can comprise more than one stereoisomeric form (e.g. R and S configurations at one or more stereochemical centres). The invention covers all these stereoisomers in pure form as well as mixtures thereof. In addition, prodrugs of I in which one or more of the hydroxy groups are masked as groups which can be reconverted to hydroxy groups in vivo are also envisaged.
The compounds of formula I may be obtained in crystalline form either directly by concentration from an organic solvent or by crystallisation or recrystallisation from an organic solvent or mixture of said solvent and a cosolvent which may be organic or inorganic, such as water. The crystals may be isolated in essentially solvent-free form or as a solvate, such as a hydrate. The invention covers all crystalline modifications and forms and also mixtures thereof.
Compounds in which R.sup.3 is a hydrogen atom are capable of salt formation with inorganic and organic bases, for example alkali metal, alkaline earth metal and organic amine salts.
It has recently been shown that esters of 1,4-butandioic acid exhibit an insulinotropic activity. The insulinotropic action is believed to be a result of the metabolism of the compound in the S-cell via the Krebs cycle to produce energy in form of adenosine triphosphate (ATP), which in turn causes release of insulin. The direct access of intermediates to the Krebs cycle is of particular importance where the normal glycolytic pathway is dysfunctional as has been indicated in type 2 diabetes. Glucose is a natural trigger for insulin release via its metabolism, however in diabetes its insulinotropic potency is weakened probably due to a metabolic defect early in the metabolic sequence.
A similar metabolic event may also take place in other cell types and any cells deprived of energy (ATP) may benefit from the treatment with particular Krebs cycle intermediates.
Our present findings suggest the beneficial use of the compounds of this invention in the treatment and prophylaxis of diseases characterized by a dysfunction in the metabolism and energy status e.g. diabetes, endotoxemia, severe starvation, sepsis, systemic inflammatory response syndrome (SIRS), and multiple organ dysfunction syndrome (MODS).
The compounds of the present invention
REFERENCES:
patent: 2379251 (1945-06-01), Muskat et al.
patent: 4325963 (1982-04-01), Hitzel et al.
patent: 5512549 (1996-04-01), Chen et al.
Fahien, L. A., et al J Biol Chem vol. 263 No. 27 pp 13610-4. See abstract, 1988.
Virkamaki, A. et al J Clin Endocrinol Metab vol. 74 No. 3 pp 673-9. See p. 673, 1992.
Bjorkling Fredrik
Malaisse Willy Jean
Geist Gary
Leo Pharmaceuticals Products Ltd. A/S (L.o slashed.vens kemiske
Maier Leigh C.
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