Derivatives of flavones, xanthones and coumarins

Details Derivatives of flavones, xanthones and coumarins Derivatives of flavones, xanthones and coumarins

2002-02-15

2003-08-19

Owens, Amelia A. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S233500, C514S254110, C514S422000, C514S455000, C514S456000, C549S388000, C549S401000, C548S525000, C546S206000, C544S151000, C544S376000

Reexamination Certificate

active

06608089

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to a class of compounds which have a structure related to naturally and synthetically occurring flavanoids and to pharmaceutical uses of the compounds.
TECHNICAL FIELD
The development of multiple drug resistance represents an increasing problem in cancer treatment. Within the past decade several mechanisms of drug resistance of tumor cells have been identified. One type of multiple resistance (MDR) has been shown to be mediated by an energy dependent, membrane-bound efflux pump termed P-glycoprotein (PGP) (Biochem. Biophys. Acta, 455, 152, 1976). PGP represents a member of the ATP-binding cassette with low substrate specificity (Nature, 323, 448, 1986). A broad range of cytostatic drugs such as anthracyclines, epipodyphyllotoxins, actinomycin D, vinca alkaloids, colchicines and taxol are eliminated via PGP-mediate efflux. Within the past few years a variety of substances have been shown to inhibit PGP-mediated drug efflux and thereby re-establish sensitivity toward chemotherapeutic agents (Pharmacol, Rev. 42, 155, 1990). These include ion channel blockers such as verapamil (Cancer Res. 41, 1967, 1981), amiodarone (Cancer Res 46, 825, 1986), propafenone (Proc. Am. Assoc. Cancer Res. 34, 321, 1993), dihydropyridines (Cancer Res. 43, 2267, 1983) phenothiazines (Mol. Pharmacol. 35, 105, 1989). Preliminary results obtained in clinical studies clearly demonstrate that modulation of MDR might be a successful approach in haematological malignancies, but serious side effects (cardiac effects, immuno-suppression and nephrotoxicity) often preclude optimal dosage of modulators (Cancer 72, 3553, 1993). Therefore, specifically designed highly active modulators with limited side effects are urgently required.
The present invention relates to a novel class of compounds which have structures related to certain naturally occurring and synthetic flavonoids and to pharmaceutical uses thereof.
SUMMARY OF THE INVENTION
Thus according to one aspect of the present invention, there is provided a compound of Formula (I):
Z—OCH
2
—C≡CCH
2
—NRR
1
  (I)
or a pharmaceutically acceptable salt or solvate thereof wherein:
R and R
1
are the same or different and each represents
lower C
1-6
alkyl, or a carbocyclic group containing from 5 to 10 ring atoms, said ring atoms forming one or two rings wherein the or each ring contains 5 or 6 ring atoms, or
R and R
1
taken together with the nitrogen atom to which they are attached, form a four- to eight-membered heterocyclic ring which may contain one or more additional heteroatoms selected from N, O or S, said heterocyclic ring being optionally substituted with a lower C
1-4
alkyl group or a benzyl group;
Z represents:
wherein
R
2
and R
3
are each independently selected from:
(i) hydrogen, (ii) a substituted or unsubstituted, preferably aromatic, carbocydic or heterocyclic group containing from 5 to 10 ring atoms, said ring atoms forming one or two rings wherein the or each ring contains 5 or 6 ring atoms, any heteroatoms being selected from N, O and S, any substituents being independently selected from the group consisting of
(a) Cl, (b) Br, (c) F, (d) OH, (e) NO
2
, (f) CF
3
, (g) C
1-4
lower alkyl (in particular CH
3
), (h) SCH
3
, (i) NHCOCH
3
, (j) N(R
6
)(R
8
) wherein R
6
and R
8
, are the same or different and each represents H or lower C
1-4
alkyl, (k) OR
10
wherein R
10
represents H or lower C
1-6
alkyl which may be saturated or unsaturated and being unsubstituted or substituted with the group NRR
1
wherein R and R
1
is as defined above, and (I) OCOR
11
wherein R
11
represents H or lower C
1-4
alkyl,
(iii) Cl, (iv) Br, (v) F, (vi) OH, (vii) NO
2
, (viii) a saturated or unsaturated lower C
1-6
straight or branched hydrocarbyl group which may be unsubstituted or substituted by 1, 2 or 3 substituents selected from Cl, Br, F, OMe, NO
2
and CF
3
, (ix) NHCOCH
3
, (x) N(R
6
)(R
8
), (xi) SR
10
, (xii) OR
10
, and (xiii) OCOR
11
wherein R
6
, R
8
, R
10
and R
11
are as defined above;
or
R
2
and R
3
taken together with the carbon atoms to which they are attached form a carbocyclic or heterocyclic ring having 5 or 6 ring atoms, any heteroatom being selected from N, O or S, said carbocyclic or heterocyclic ring being saturated or unsaturated, and being unsubstituted or substituted with one or more substituents selected from Cl, Br, F, OH, NO
2
, CF
3
, C
1-4
lower alky, SCH
3
, NHCOCH
3
, N(R
6
)(R
8
), OR
10
and OCOR
11
wherein R
6
, R
8
, R
10
and R
11
are as defined above; and
R
4
represents hydrogen, or OR
10
wherein R
10
is as defined above
or
wherein R
5
represents hydrogen or a lower C
1-6
straight or branched hydrocarbyl group which may be unsubstituted or substituted by 1, 2 or 3 substituents selected from Cl, Br, F, OMe, NO
2
and CF
3
.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Thus in one aspect the invention provides compounds having the structure (1A′):
wherein
R
2
and R
3
are each independently selected from:
(i) hydrogen, (ii) a substituted or unsubstituted, preferably aromatic, carbocyclic or heterocyclic group containing from 5 to 10 ring atoms, said ring atoms forming one or two rings, wherein the or each ring contains 5 or 6 ring atoms, any heteroatoms being selected from N, O and S, any substituents being independently selected from the group consisting of:
Cl, Br, F, OH, NO
2
, CF
3
, C
1-4
lower alkyl (in particular CH
3
), SCH
3
, NHCOCH
3
, N(R
6
)(R
8
), OR
10
and OCOR
11
, wherein R
6
, R
8
, R
10
and R
11
are the same or different and each represents H or lower C
1-4
alkyl,
(iii) Cl, (iv) Br, (v) F, (vi) OH, (vii) NO
2
, (viii) a saturated or unsaturated lower C
1-6
straight or branched hydrocarbyl group which may be unsubstituted or substituted by 1, 2 or 3 substituents selected from Cl, Br, F, OMe, NO
2
and CF
3
, (ix) NHCOCH
3
, (x) N(R
6
)(R
8
), (xi) SR
10
, (xii) OR
10
, and (xiii) OCOR
11
wherein R
6
, R
8
, R
10
and R
11
are as defined above;
or
R
2
and R
3
taken together with the carbon atoms to which they are attached form a carbocyclic or heterocyclic ring having 5 or 6 ring atoms, any heteroatom being selected from N, O or S, said carbocyclic or heterocyclic ring being saturated or unsaturated, and being unsubstituted or substituted with one or more substituents selected from Cl, Br, F, OH, NO
2
, CF
3
, C
1-4
lower alkyl, SCH
3
, NHCOCH
3
, N(R
6
)(R
8
), OR
10
and OCOR
11
, wherein R
6
, R
8
, R
10
and R
11
are as defined above; and
R
4
represents hydrogen, or OR
10
wherein R
10
is as defined above.
A preferred group of compounds are those wherein R, R
1
and R
4
are as defined for Formula (IA′) above, and
R
2
and R
3
are each independently selected from:
(i) hydrogen, (ii) a substituted or unsubstituted, preferably aromatic, carbocyclic or heterocyclic group containing from 5 to 10 ring atoms, said ring atoms forming one or two rings, wherein the or each ring contains 5 or 6 ring atoms, any heteroatoms being selected from N, O and S, any substituents being independently selected from the group consisting of:
(a) Cl, (b) Br, (c) F, (d) OH, (e) NO
2
, (f) CF
3
, (g) C
1-4
lower alkyl (in particular CH
3
), (h) SCH
3
, (i) NHCOCH
3
, (j) N(R
6
)(R
8
) wherein R
6
and R
8
, are the same or different and each represents H or lower C
1-4
alkyl, (k) OR
10
wherein R
10
represents H or lower C
1-6
alkyl which may be saturated or unsaturated and being unsubstituted or substituted with the group NRR
1
wherein R and R
1
is as defined above, and (I) OCOR
11
wherein R
11
represents H or lower C
1-4
alkyl,
(iii) Cl, (iv) Br, (v) F, (vi) OH, (vii) NO
2
, (viii) a saturated or unsaturated lower C
1-6
straight or branched hydrocarbyl group which may be unsubstituted or substituted by 1, 2 or 3 substituents selected from Cl, Br, F, OMe, NO
2
and CF
3
, (ix) NHCOCH
3
, (x) N(R
6
)(R
8
), (xi) SR
10
, (xii) OR
10
, and (xiii) OCOR
11
wherein R
6
, R
8
, R
10
and R
11
are as defined for Formula (I).
Within this group, R
2
and R
3
can both represent hydrogen. A further preferred group of

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