Aromatic di-keto derivatives, processes for their production...

Details Aromatic di-keto derivatives, processes for their production... Aromatic di-keto derivatives, processes for their production...

2000-10-24

2002-04-30

Lambkin, Deborah C. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S568000, C514S510000, C514S462000, C514S473000, C562S461000, C562S459000, C560S053000, C549S298000, C549S449000, C549S499000

Reexamination Certificate

active

06380257

ABSTRACT:

The present invention relates to new aromatic di-keto derivatives, and to their pharmaceutically acceptable salts, esters, ethers, and other chemical equivalents. The di-keto derivatives are glucose-6-phosphate translocase inhibitors, and can be used in the treatment of diabetes mellitus. The present invention further relates to a process for the production of the di-keto derivatives, to the use of the di-keto derivatives and their pharmaceutically acceptable salts, esters, ethers, and other chemical equivalents as pharmaceuticals, in particular to their use in the treatment of diabetes mellitus, and to pharmaceutical compositions comprising the di-keto derivatives, pharmaceutically acceptable salts, esters, ethers, or other chemical equivalents thereof.
Increased rate of hepatic glucose output is a general feature of diabetes mellitus. In particular, a strong correlation exists between fasting plasma glucose level in non-insulin dependent diabetes mellitus (NIDDM) and hepatic glucose output. The two pathways by which glucose is produced in the liver are gluconeogenesis and glycogenolysis. The terminal steps of both pathways are catalyzed by the microsomal glucose-6-phosphatase, a key enzyme in the homeostatic regulation of blood glucose levels. The level of this enzyme has also been known to be elevated in both experimental and pathological conditions of diabetes. Interference with this enzyme system should, therefore, result in a reduced hepatic glucose production.
Hepatic glucose-6-phosphatase is a multicomponent system comprised of at least three functional activities: a glucose-6-phosphate translocase (T1), a glucose-6-phosphate phosphohydrolase and a phosphate/pyrophosphate translocase (T2). The glucose-6-phosphate translocase facilitates transport of glucose-6-phosphate into the lumen of the endoplasmic reticulum (ER). The phosphohydrolase, with its active site situated on the lumenal surface of the ER, hydrolyzes glucose-6-phosphate and releases glucose and phosphate into the lumen. While the efflux of phosphate is facilitated by the phosphate/pyrophosphate translocase, the exact mechanism of glucose efflux is still not clear.
The high degree of substrate specificity of glucose-6-phosphate translocase makes this a potential target for pharmacological intervention in the treatment of diabetes mellitus. Thus, amongst physiologically occurring sugar phosphates, only glucose-6-phosphate is transported by the translocase. In contrast, the phosphatase is non-specific and is known to hydrolyse a variety of organic phosphate esters.
A series of non-specific inhibitors of glucose-6-phosphatase has been described in the literature, e.g. phlorrhizin (
J. Biol. Chem.
242, 1955-1960 (1967)), 5,5′-dithio-bis-2-nitrobenzoic acid (
Biochem. Biophys. Res. Commun.
48, 694-699 (1972)), 2,2′-diisothiocyanatostilbene and 2-isothiocyanato-2′-acetoxystilbene (
J. Biol. Chem.
255, 1113-1119 (1980)). The first therapeutically utilizable inhibitors of the glucose-6-phosphatase system are proposed in EP-A-587 087 and EP-A-587 088. Kodaistatins A, B, C, and D described in PCT/EP 98/02247 are the first glucose-6-phosphate translocase inhibitors from microbial sources.
The aromatic di-keto derivatives according to the present invention may be derived from a compound named mumbaistatin. Mumbaistatin is described in PCT/EP99/04127. It is a natural product obtainable by cultivation of the microorganism
Streptomyces litmocidini,
a sample of which was deposited on Jul. 4, 1997, with the German Collection of Microorganisms and Cell Cultures (DSMZ) under accession no. DSM 11641.The structural formula of mumbaistatin has now been determined and is given below:
It has been found that certain derivatives of mumbaistatin have improved activity and are better tolerated in the mammalian body than mumbaistatin itself. Also, the separated diastereomers of mumbaistatin have advantages over the mumbaistatin mixture of diastereomers.
The present invention accordingly provides compounds of the general formula I
wherein:
R
4
, R
5
, R
6
and R
7
are independently selected from H, OH, halogen, optionally substituted alkyl, aryl or acyl, X-alkyl, and X-aryl, where X is O, NH, N-alkyl or S,
K is a group of formula II or III:
L is a group of formula IV or V:
or K and L form, together with the respective carbon atoms to which they are bound, a group of formula VI, VII, or VIII:
 wherein:
R
1
and R
3
are independently selected from a cation, H, alkyl, and aryl,
R
2
is H, alkyl, aryl, or acyl,
X
1
, X
2
, X
3
, X
4
, X
5
, X
6
and X
7
are independently selected from O, NH, N-alkyl and S, and the Cyclus is, together with the C-atoms marked c′ and d′ an optionally substituted saturated, partly unsaturated or aromatic, carbocyclic or heterocyclic, simple or condensed ring system, and its pharmaceutically acceptable salts, esters and ethers and other chemical equivalents in all their stereoisomeric and tautomeric forms and mixtures thereof in any ratio with the exclusion of the compound where K is a group of formula II, and L is a group of formula IV in which X
1
, X
2
, X
3
, X
4
, X
5
, X6 and X
7
are O, R
1
, R
2
and R
3
are H, R
4
is OH, R
5
, R
6
and R
7
are H, and Cyclus is 3,8, di-hydroxy anthraquinone, and the compound where K and L form together a group of formula VI in which X
1
, X
2
, X
3
, X
4
, X
5
, X
6
and X
7
are O, R
1
is CH
3
, R
2
and R
3
are H, R
4
is OH, R
5
, R
6
and R
7
are H, and Cyclus is 3,8-dihydroxy anthraquinone.
The present invention furthermore includes compounds of the general formula IX
wherein:
M is a group of formula X
N is a group of formula XI
—X
5
R
3
  XI
or M and N form, together with the C atom to which they are bound, a residue of formula XII
 which is bonded through the C atom marked e
O is a group of formula XIII
 and
P is a group of formula XIV
—X
5
R
2
  XIV
or O and P form, together with the C atom to which they are bound, a residue of formula XV
 which is bonded through the C atom marked f
wherein R
1
to R
7
, X
1
to X
7
, Cyclus, c and d are as defined in claim 1, and its pharmaceutically acceptable salts, esters and ethers and other chemical equivalents in all their stereoisomeric and tautomeric forms and mixtures thereof in any ratio.
The term ‘alkyl’ as used herein represents a straight or branched, optionally substituted C
1
-C
6
-alkyl, preferably a C
1
-C
4
-alkyl such as: methyl, ethyl, n-propyl, i-propyl, n-butyl, or i-butyl, a straight or branched, optionally substituted, C
2
-C
6
-alkenyl, preferably C
2
-C
4
-alkenyl such as allyl, a straight or branched, optionally substituted C
2
-C
6
-alkynyl, preferably C
2
-C
4
-alkynyl such as allylene.
The term ‘aryl’ as used herein represents an optionally substituted benzyl or phenyl.
The term ‘acyl’ as used herein represents an optionally substituted aliphatic, aromatic, or heterocyclic acyl, for example C
1
-C
4
aliphatic acyl, such as acetyl or propionyl, aromatic acyl, such as benzoyl or toluyl, and heterocyclic acyl which is derived from 5- or 6-membered rings with 1-4 hetero atoms, such as, nicotinoyl, furyl, pyrrolyl, thienyl, thiazolyl and oxazolyl.
‘Optionally substituted’ as used herein means that the group in question is optionally substituted by one or more, preferably 1, 2, 3, or 4, identical or different substituents selected from: hydroxyl, C
1
-C
4
alkyl, C
1
-C
4
alkenyl, C
1
-C
4
alkoxy, C
1
-C
4
alkylthio, C
1
-C
4
alkoxycarbonyl, carbamoyl, carboxyl, trifluoromethyl, cyano, nitro, amino, C
1
-C
4
alkylamino, diC
1
-C
4
alkylamino, amidino, aryloxy, arylamino and halogen.
Halogen represents I, Br, Cl, or F, preferably Cl or Br.
The term ‘cation’ represents an inorganic metal ion or an organic ammonium ion. Examples are pharmacologically acceptable alkali metal ions or alkaline earth metal ions, preferably sodium, potassium, calcium, or magnesium ion, the ammonium ion and, from the organic ammonium ions, in particular, an optionally substituted alkylated ammonium ion, such as, for example, the triethyla

Affiliated with

Also associated with

Rating

Aromatic di-keto derivatives, processes for their production... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Aromatic di-keto derivatives, processes for their production..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Aromatic di-keto derivatives, processes for their production... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2818514