Analogues or derivatives of quercetin (prodrugs)

Details Analogues or derivatives of quercetin (prodrugs) Analogues or derivatives of quercetin (prodrugs)

1999-07-20

2001-07-10

Rotman, Alan L. (Department: 1612)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C549S403000

Reexamination Certificate

active

06258840

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to the field of biochemistry and medicine. More particularly it relates to Quercetin analogues or derivatives and preparations thereof. These compounds are potentially useful in tumour chemotherapy, treatment of inflammation and allergy.
BACKGROUND
The flavonoid Quercetin (3,3′,4′,5,7-pentahydroxyflavone) has been shown to inhibit the activity of a variety of enzymes including the calcium- and phospholipid dependent protein kinase (protein kinase C) in vivo and in vitro. Furthermore, it synergistically enhances the antiproliferative activity of cis-diaminedichloroplatinum II (cis-DDP) both in vitro and in vivo and therefore is of interest as a promising therapeutic agent for use in the chemotherapy of human tumours. However, Phase I clinical trials have proved problematic owing to the limited solubility of Quercetin in pharmaceutically acceptable solvents, and this characteristic has prevented its further clinical development.
SUMMARY OF THE INVENTION
The present invention has developed from efforts to produce analogues or derivatives of Quercetin having greater aqueous solubility, more suitable for use in pharmaceutical formulations and capable of acting as prodrugs which can be biologically degraded or broken down to release Quercetin within the body after being administered to a patient in need of treatment.
More specifically, from one aspect, the present invention provides compounds of the structural formula I below:
and pharmaceutically acceptable salts thereof
wherein
one of R
1
, R
2
, R
3
, R
4
and R
5
is an amino acid carbamate group CONHCH(R
6
)CO
2
H and the remainder are each hydrogen,
and wherein
R
6
is hydrogen or C
1-4
lower alkyl, e.g. methyl.
Preferred compounds of this invention comprise those compounds wherein R
1
, R
2
, R
3
and R
5
are each hydrogen and R
4
is CONHCH
2
CO
2
H, and those compounds wherein R
1
, R
2
, R
4
and R
5
are each hydrogen and R
3
is CONHCH
2
CO
2
H. The invention also provides salts of these acid Quercetin analogues. Apart from alkali metal and ammonium salts, amine salts, for example amine salts formed with amino sugars, especially N-alkyl amino sugars such as N-methylglucamine, are of particular interest.
In general, the compounds of the invention as defined above are novel analogues or derivatives of Quercetin which have enhanced aqueous solubility and which are especially suitable for use as biodegradable prodrugs in pharmaceutical compositions formulated for clinical use.
Thus, the invention also includes pharmaceutical compositions comprising or containing such novel analogues or derivatives providing prodrugs made up or formulated for administration in any suitable manner in the course of medical or veterinary treatment, for example parentally (including intravenously, intramuscularly and subcutaneously) or orally. Such compositions containing or incorporating, conveniently in unit dosage form, therapeutically effective non-toxic amounts of the prodrug compound, or the equivalent of therapeutically effective non-toxic amounts of the active drug compound, together possibly with at least one other ingredient providing a compatible pharmaceutically acceptable additive, carrier, diluent or excipient, may be prepared by any of the methods well known in the art of pharmacy.
The invention also provides new processes for preparing at least some of the compounds referred to above involving in some cases certain novel intermediate compounds.
MORE DETAILED DESCRIPTION
The invention will be further described and exemplified with specific reference to the preparation and properties of Quercetin carbamate ester derivatives or analogues, particularly N-methylglucamine salts, referred to as meglumine salts, of 3′-[(N-carboxymethyl)carbamoyloxy]-3,4′,5,7-tetrahydroxyflavone and the corresponding 4′ isomer.
It has been found that these carbamate esters of Quercetin are reasonably stable in aqueous solution but they will degrade to Quercetin under physiological conditions.
First, there is presented below the analytical conditions that were used to demonstrate that the meglumine salts of 3′ and 4′-[(N-carboxymethyl) carbamoyloxy]-3,4′(3′),5,7-tetrahydroxyflavone have the desired properties for formulation for clinical trial. Then, there are presented details of a process for synthesising these analogues or derivatives of Quercetin.
Analytical Methodology-Non Biological samples
The following conditions were used to analyse the meglumine salts of 3′ and 4′-((N-carboxymethyl)carbamoyloxy)-3,4′(3′),5,7-tetrahydroxyflavone.
HPLC
Column:
Primesphere HC C-18, 5 &mgr;m, 250 × 3.2 mm.
Mobile phase:
45% Methanol in 3mM ammonium acetate pH
3.4
Flow rate:
0.5 ml/min
Temperature:
Ambient
Detection:
UV at 368 nm
Injection volume:
60 &mgr;l of a 100 mg/ml solution in water (6 &mgr;g of
sample was injected onto the column; 6 &mgr;g was
passed through the detector and using a 1:1
splitter, 3 &mgr;g was passed, in series, to the mass
spectrometer.
Retention times:
Component 1-15.8 minutes
Component 2-16.7 minutes
Mass Spectrometry
Cone voltage: 30V
Ionisation mode: Electrospray positive
Flow rate: ≅0.25 ml/min (The flow was split 1:1)
Aqueous Solubility
The solubility of the meglumine salts of 3′ and 4′-[(N-carboxymethyl)carbamoyloxy]-3,4′(3′),5,7-tetrahydroxyflavone has been determined by HPLC and shown to be in excess of 10 mg/ml.
Aqueous Stability
3′/4′-((N-Carboxymethyl)carbamoyloxy)-3,4′(3′),5,7-tetrahydroxyflavone shows greater stability at acidic pH than under basic conditions. A 10 mg/ml solution in water has a pH of approximately 7 and, whilst stable at −20° C. for a period of at least 12 weeks, up to 25% degradation occurs at 4° C. over the same period of time. Dilution into dextrose to a final prodrug concentration of 1 mg/ml affords a solution with a pH of approximately 6 which undergoes less than 5% degradation over a 4 h period at ambient temperature.
Stability to Human Plasma
The stability of the meglumine salts of 3′/4′-((N-carboxymethyl) carbamoyloxy)-3,4′(3′),5,7-tetrahydroxyflavone has been assessed in human plasma by HPLC. Freshly prepared plasma (2.5 ml) was incubated at 37° C. and 0.02 ml of a 6.3 mg/ml solution of the prodrug compound in water was added. Aliquots of plasma were taken for HPLC analysis at zero time and at intervals thereafter. Samples were quenched with chilled methanol, the resulting precipitate was centrifuged at 4° C. at 800 rpm for 5 minutes, and the supernatant was analysed by HPLC.
Both isomers, i.e. both the 3′ and 4′ carbamate esters, were found to be converted into Quercetin. The half life of each isomer in human plasma was approximately 1 hour.


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