US 6,608,089 B2Granted

Derivatives of flavones, xanthones and coumarins

AssigneeIndena S.p.A.

InventorsEzio Bombardelli, Piero Valenti

Life of this patent

Estimating the term…

Abstract

Compounds having the formula (I) Z—OCH2—C≡CCH2—NRR1 (I) or a pharmaceutically acceptable salt or solvate thereof wherein Z can represent the formula (1A) or (1B). The compounds possess antiproliferative activity and are useful as modulators of multiple drug resistance in cancer chemotherapy. The compounds may also be useful for the manufacture of a medicament for the treatment or prevention of neoplasms, menopausal disorders and osteoporosis.

Claims48

Dependent claims

A compound of Formula (I):

Z—OCH2—C≡CCH2—NRR1 (I)
or a pharmaceutically acceptable salt or solvate thereof wherein
R and R1 are the same or different and each represents a C1-6 alkyl, a carbocyclic group containing from 5 to 10 ring atoms or two rings with each ring containing 5 or 6 ring atoms, or R and R1 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 C1-4 alkyl group or a benzyl group;
Z represents:
wherein
R2 and R3 are each independently selected from:
(i) hydrogen;
(ii) a substituted or unsubstituted, aromatic or non-aromatic carbocyclic or heterocyclic group containing from 5 to 10 ring atoms or two rings with each ring containing 5 or 6 ring atoms, wherein the heterocyclic group comprises a heteroatom selected from N, O and S, and wherein the carbocyclic or heterocyclic group can be substituted with one or more substituents being independently selected from the group consisting of:
(a) Cl, (b) Br, (c) F, (d) OH, (e) NO2, (f) CF3, (g) C1-4 alkyl, (h) SCH3, (i) NHCOCH3, (j) N(R6)(R8) wherein R6 and R8, are the same or different and each represents H or a C1-4 alkyl, (k) OR10 wherein R10 represents H or C1-6 alkyl which may be saturated or unsaturated and may be unsubstituted or substituted with the group NRR1 wherein R and R1 is as defined above, and (1) OCOR11 wherein R11 represents H or C1-4 alkyl,
(iii) Cl;
(iv) Br;
(v) F;
(vi) OH;
(vii) NO2;
(viii) a saturated or unsaturated C1-6 straight or branched hydrocarbyl group which may be unsubstituted or substituted with from 1 to 3 substituents selected from Cl, Br, F, OMe, NO2 and CF3;
(ix) NHCOCH3;
(x) N(R6)(R8), wherein R6 and R8 are defined above;
(xi) SR10, wherein R10 is defined above;
(xii) OR10 wherein R10 is defined above;
and
(xiii) OCOR11 wherein R11 is defined above;
or
R2 and R3 taken together with the carbon atoms to which they are attached form a saturated or unsaturated carbocyclic or heterocyclic ring having 5 or 6 ring atoms, wherein the heterocyclic group comprises a heteroatom selected from N, O and S, and wherein the carbocyclic or heterocyclic group can be substituted with one or more substituents being independently selected from the group consisting of Cl, Br, F, OH, NO2, CF3, C1-4 alkyl, SCH3, NHCOCH3, N(R6)(R8), OR10 and OCOR11 wherein R6, R8, R10 and R11 are as defined above;
and
R4 represents hydrogen, or OR10 wherein R10 is as defined above;
or
wherein
R5 hydrogen or a C1-6 straight or branched hydrocarbyl group which may be unsubstituted or substituted with from 1 to 3 substituents selected from Cl, Br, F, OMe, NO2 and CF3;
with the proviso that when Z represents
and R5 is hydrogen or an alkyl group containing up to 4 carbon atoms then R and R1 cannot be an alkyl groups that contains from 1 to 4 carbon atoms or R and R1 when taken together with the nitrogen atom to which they are attached cannot form a saturated heterocyclic amino radical containing 5 to 7 ring members.

27 more elements

A method of treating cancer in a patient or modulating multiple drug resistance in a patient receiving cancer chemotherapy comprising administering to the patient a compound of Formula I:

Z—OCH2—C≡CCH2—NRR1 (I)
or a pharmaceutically acceptable salt or solvate thereof wherein
R and R1 are the same or different and each represents a C1-6 alkyl, a carbocyclic group containing from 5 to 10 ring atoms or two rings with each ring containing 5 or 6 ring atoms, or R and R1 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 C1-4 alkyl group or a benzyl group;
Z represents:
wherein
R2 and R3 are each independently selected from:
(i) hydrogen;
(ii) a substituted or unsubstituted, aromatic or non-aromatic carbocyclic or heterocyclic group containing from 5 to 10 ring atoms or two rings with each ring containing 5 or 6 ring atoms, wherein the heterocyclic group comprises a heteroatom selected from N, O and S, and wherein the carbocyclic or heterocyclic group can be substituted with one or more substituents being independently selected from the group consisting of:
(a) Cl, (b) Br, (c) F, (d) OH, (e) NO2, (f) CF3, (g) C1-4 alkyl, (h) SCH3, (i) NHCOCH3, (j) N(R6)(R8) wherein R6 and R8, are the same or different and each represents H or a C1-4 alkyl, (k) OR10 wherein R represents H or C1-6 alkyl which may be saturated or unsaturated and may be unsubstituted or substituted with the group NRR1 wherein R and R1 is as defined above, and (1) OCOR11 wherein R11 represents H or C1-4 alkyl,
(iii) Cl;
(iv) Br;
(v) F;
(vi) OH;
(vii) NO2;
(viii) a saturated or unsaturated C1-6 straight or branched hydrocarbyl group which may be unsubstituted or substituted with from 1 to 3 substituents selected from Cl, Br, F, OMe, NO2 and CF3;
(ix) NHCOCH3;
(x) N(R6)(R8), wherein R6 and R8 are defined above;
(xi) SR10, wherein R10 is defined above;
(xii) OR10 wherein R10 is defined above;
and
(xiii) OCOR11 wherein R11 is defined above;
or
R2 and R3 taken together with the carbon atoms to which they are attached form a saturated or unsaturated carbocyclic or heterocyclic ring having 5 or 6 ring atoms, wherein the heterocyclic group comprises a heteroatom selected from N, O and S, and wherein the carbocyclic or heterocyclic group can be substituted with one or more substituents being independently selected from the group consisting of Cl, Br, F, OH, NO2, CF3, C1-4 alkyl, SCH3, NHCOCH3, N(R6)(R8), OR10 and OCOR11 wherein R6, R8, R10 and R11 are as defined above;
and
R4 hydrogen, or OR10 wherein R10 is as defined above;
or
wherein
R5 hydrogen or a C1-6 straight or branched hydrocarbyl group which may be unsubstituted or substituted with from 1 to 3 substituents selected from Cl, Br, F, OMe, NO2 and CF3.

25 more elements

A method of treating neoplasms in a patient comprising administering to the patient a compound of Formula (I):

Z—OCH2—C≡CCH2—NRR1 (I)
or a pharmaceutically acceptable salt or solvate thereof wherein
R and R1 are the same or different and each represents a C1-6 alkyl, a carbocyclic group containing from 5 to 10 ring atoms or two rings with each ring containing 5 or 6 ring atoms, or R and R1 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 C1-4 alkyl group or a benzyl group;
Z represents:
wherein
R2 and R3 are each independently selected from:
(i) hydrogen;
(ii) a substituted or unsubstituted, aromatic or non-aromatic carbocyclic or heterocyclic group containing from 5 to 10 ring atoms or two rings with each ring containing 5 or 6 ring atoms, wherein the heterocyclic group comprises a heteroatom selected from N, O and S, and wherein the carbocyclic or heterocyclic group can be substituted with one or more substituents being independently selected from the group consisting of:
(a) Cl, (b) Br, (c) F, (d) OH, (e) NO2, (f) CF3, (g) C1-4 alkyl, (h) SCH3, (i) NHCOCH3, (j) N(R6)(R8) wherein R6 and R8, are the same or different and each represents H or a C1-4 alkyl, (k) OR10 wherein R represents H or C1-6 alkyl which may be saturated or unsaturated and may be unsubstituted or substituted with the group NRR1 wherein R and R1 is as defined above, and (1) OCOR11 wherein R11 represents H or C1-4 alkyl,
(iii) Cl;
(iv) Br;
(v) F;
(vi) OH;
(vii) NO2;
(viii) a saturated or unsaturated C1-6 straight or branched hydrocarbyl group which may be unsubstituted or substituted with from 1 to 3 substituents selected from Cl, Br, F, OMe, NO2 and CF3;
(ix) NHCOCH3;
(x) N(R6)(R8), wherein R6 and R8 are defined above;
(xi) SR10, wherein R10 is defined above;
(xii) OR10 wherein R10 is defined above;
and
(xiii) OCOR11 wherein R11 is defined above;
or
R2 and R3 taken together with the carbon atoms to which they are attached form a saturated or unsaturated carbocyclic or heterocyclic ring having 5 or 6 ring atoms, wherein the heterocyclic group comprises a heteroatom selected from N, O and S, and wherein the carbocyclic or heterocyclic group can be substituted with one or more substituents being independently selected from the group consisting of Cl, Br, F, OH, NO2, CF3, C1-4 alkyl, SCH3, NHCOCH3, N(R6)(R8), OR10 and OCOR11 wherein R6, R8, R10 and R11 are as defined above;
and
R4 represents hydrogen, or OR10 wherein R10 is as defined above;
or
wherein
R5 hydrogen or a C1-6 straight or branched hydrocarbyl group which may be unsubstituted or substituted with from 1 to 3 substituents selected from Cl, Br, F, OMe, NO2 and CF3.

25 more elements

A method of treating menopausal disorders or osteoporosis in a patient comprising administering to the patient a compound of Formula I:

Z—OCH2—C≡CCH2—NRR1 (I)
or a pharmaceutically acceptable salt or solvate thereof wherein
R and R1 are the same or different and each represents a C1-6 alkyl, a carbocyclic group containing from 5 to 10 ring atoms or two rings with each ring containing 5 or 6 ring atoms, or R and R1 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 C1-4 alkyl group or a benzyl group;
Z represents:
wherein
R2 and R3 are each independently selected from:
(i) hydrogen;
(ii) a substituted or unsubstituted, aromatic or non-aromatic carbocyclic or heterocyclic group containing from 5 to 10 ring atoms or two rings with each ring containing 5 or 6 ring atoms, wherein the heterocyclic group comprises a heteroatom selected from N, O and S, and wherein the carbocyclic or heterocyclic group can be substituted with one or more substituents being independently selected from the group consisting of:
(a) Cl, (b) Br, (c) F, (d) OH, (e) NO2, (f) CF3, (g) C1-4 alkyl, (h) SCH3, (i) NHCOCH3, (j) N(R6)(R8) wherein R6 and R8, are the same or different and each represents H or a C1-4 alkyl, (k) OR10 wherein R10 represents H or C1-6 alkyl which may be saturated or unsaturated and may be unsubstituted or substituted with the group NRR1 wherein R and R1 is as defined above, and (1) OCOR11 wherein R11 represents H or C1-4 alkyl,
(iii) Cl;
(iv) Br;
(v) F;
(vi) OH;
(vii) NO2;
(viii) a saturated or unsaturated C1-6 straight or branched hydrocarbyl group which may be unsubstituted or substituted with from 1 to 3 substituents selected from Cl, Br, F, OMe, NO2 and CF3;
(ix) NHCOCH3;
(x) N(R6)(R8), wherein R6 and R8 are defined above;
(xi) SR10 wherein R10 is defined above;
(xii) OR10 wherein R10 is defined above;
and
(xiii) OCOR11 wherein R11 is defined above;
or
R2 and R3 taken together with the carbon atoms to which they are attached form a saturated or unsaturated carbocyclic or heterocyclic ring having 5 or 6 ring atoms, wherein the heterocyclic group comprises a heteroatom selected from N, O and S, and wherein the carbocyclic or heterocyclic group can be substituted with one or more substituents being independently selected from the group consisting of Cl, Br, F, OH, NO2, CF3, C1-4 alkyl, SCH3, NHCOCH3, N(R6)(R8), OR10 and OCOR11 wherein R6, R8, R10 and R11 are as defined above;
and
R4 hydrogen, or OR10 wherein R10 as defined above;
or
wherein
R5 hydrogen or a C1-6 straight or branched hydrocarbyl group which may be unsubstituted or substituted with from 1 to 3 substituents selected from Cl, Br, F, OMe, NO2 and CF3.

25 more elements

A pharmaceutical composition comprising a compound of Formula I:

Z—OCH2—C≡CCH2—NRR1 (I)
or a pharmaceutically acceptable salt or solvate thereof wherein
R and R1 are the same or different and each represents a C1-6 alkyl, a carbocyclic group containing from 5 to 10 ring atoms or two rings with each ring containing 5 or 6 ring atoms, or R and R1 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 C1-4 alkyl group or a benzyl group;
Z represents:
wherein
R2 and R3 are each independently selected from:
(i) hydrogen;
(ii) a substituted or unsubstituted, aromatic or non-aromatic carbocyclic or heterocyclic group containing from 5 to 10 ring atoms or two rings with each ring containing 5 or 6 ring atoms, wherein the heterocyclic group comprises a heteroatom selected from N, O and S, and wherein the carbocyclic or heterocyclic group can be substituted with one or more substituents being independently selected from the group consisting of:
(a) Cl, (b) Br, (c) F, (d) OH, (e) NO2, (f) CF3, (g) C1-4 alkyl, (h) SCH3, (i) NHCOCH3, (j) N(R6)(R8) wherein R6 and R8, are the same or different and each represents H or a C1-4 alkyl, (k) OR10 wherein R represents H or C1-6 alkyl which may be saturated or unsaturated and may be unsubstituted or substituted with the group NRR1 wherein R and R1 is as defined above, and (1) OCOR11 wherein R11 represents H or C1-4 alkyl,
(iii) Cl;
(iv) Br;
(v) F;
(vi) OH;
(vii) NO2;
(viii) a saturated or unsaturated C1-6 straight or branched hydrocarbyl group which may be unsubstituted or substituted with from 1 to 3 substituents selected from Cl, Br, F, OMe, NO2 and CF3;
(ix) NHCOCH3;
(x) N(R6)(R8), wherein R6 and R8 are defined above;
(xi) SR10, wherein R10 is defined above;
(xii) OR10 wherein R10 is defined above;
and
(xiii) OCOR11 wherein R11 is defined above;
or
R2 and R3 taken together with the carbon atoms to which they are attached form a saturated or unsaturated carbocyclic or heterocyclic ring having 5 or 6 ring atoms, wherein the heterocyclic group comprises a heteroatom selected from N, O and S, and wherein the carbocyclic or heterocyclic group can be substituted with one or more substituents being independently selected from the group consisting of Cl, Br, F, OH, NO2, CF3, C1-4 alkyl, SCH3, NHCOCH3, N(R6)(R8), OR10 and OCOR11 wherein R6, R8, R10 and R11 are as defined above;
and
R4 represents hydrogen, or OR10 wherein R10 is as defined above;
or
wherein
R5 represents hydrogen or a C1-6 straight or branched hydrocarbyl group which may be unsubstituted or substituted with from 1 to 3 substituents selected from Cl, Br, F, OMe, NO2 and CF3;
with the proviso that when Z represents
and R5 is hydrogen or an alkyl group containing up to 4 carbon atoms then R and R1 cannot be an alkyl groups that contains from 1 to 4 carbon atoms or R and R1 when taken together with the nitrogen atom to which they are attached cannot form a saturated heterocyclic amino radical containing 5 to 7 ring members;
and a pharmaceutically acceptable excipient.

28 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/075,628Filed 15 Feb 2002 · continuation
Priority: EP 99209123 Sep 1999
Published: US 2002/0183318 A15 Dec 2002
Granted: 19 Aug 2003
Term ends: Not estimatedThe source records don’t support an estimate.

Classification17 codes

C07D 311/86
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…
A61K 31/35
Having oxygen as the only ring hetero atom, e.g. fungichromin: having six-membered rings with one oxygen as the only ring hetero atom
A61K 31/37
Having six-membered rings, e.g. delta-lactones: coumarins, e.g. psoralen
A61K 31/44
Having six-membered rings with one nitrogen as the only ring hetero atom: non condensed pyridines; Hydrogenated derivatives thereof

Family

PCT/EP00/08365Parent of this continuation · filed 28 Aug 2000
US 2002/0183318 A1Pre-grant publication · published 5 Dec 2002
US 6,608,089 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of Formula (I):

Z—OCH2—C≡CCH2—NRR1 (I)
or a pharmaceutically acceptable salt or solvate thereof wherein
R and R1 are the same or different and each represents a C1-6 alkyl, a carbocyclic group containing from 5 to 10 ring atoms or two rings with each ring containing 5 or 6 ring atoms, or R and R1 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 C1-4 alkyl group or a benzyl group;
Z represents:
wherein
R2 and R3 are each independently selected from:
(i) hydrogen;
(ii) a substituted or unsubstituted, aromatic or non-aromatic carbocyclic or heterocyclic group containing from 5 to 10 ring atoms or two rings with each ring containing 5 or 6 ring atoms, wherein the heterocyclic group comprises a heteroatom selected from N, O and S, and wherein the carbocyclic or heterocyclic group can be substituted with one or more substituents being independently selected from the group consisting of:
(a) Cl, (b) Br, (c) F, (d) OH, (e) NO2, (f) CF3, (g) C1-4 alkyl, (h) SCH3, (i) NHCOCH3, (j) N(R6)(R8) wherein R6 and R8, are the same or different and each represents H or a C1-4 alkyl, (k) OR10 wherein R10 represents H or C1-6 alkyl which may be saturated or unsaturated and may be unsubstituted or substituted with the group NRR1 wherein R and R1 is as defined above, and (1) OCOR11 wherein R11 represents H or C1-4 alkyl,
(iii) Cl;
(iv) Br;
(v) F;
(vi) OH;
(vii) NO2;
(viii) a saturated or unsaturated C1-6 straight or branched hydrocarbyl group which may be unsubstituted or substituted with from 1 to 3 substituents selected from Cl, Br, F, OMe, NO2 and CF3;
(ix) NHCOCH3;
(x) N(R6)(R8), wherein R6 and R8 are defined above;
(xi) SR10, wherein R10 is defined above;
(xii) OR10 wherein R10 is defined above;
and
(xiii) OCOR11 wherein R11 is defined above;
or
R2 and R3 taken together with the carbon atoms to which they are attached form a saturated or unsaturated carbocyclic or heterocyclic ring having 5 or 6 ring atoms, wherein the heterocyclic group comprises a heteroatom selected from N, O and S, and wherein the carbocyclic or heterocyclic group can be substituted with one or more substituents being independently selected from the group consisting of Cl, Br, F, OH, NO2, CF3, C1-4 alkyl, SCH3, NHCOCH3, N(R6)(R8), OR10 and OCOR11 wherein R6, R8, R10 and R11 are as defined above;
and
R4 represents hydrogen, or OR10 wherein R10 is as defined above;
or
wherein
R5 hydrogen or a C1-6 straight or branched hydrocarbyl group which may be unsubstituted or substituted with from 1 to 3 substituents selected from Cl, Br, F, OMe, NO2 and CF3;
with the proviso that when Z represents
and R5 is hydrogen or an alkyl group containing up to 4 carbon atoms then R and R1 cannot be an alkyl groups that contains from 1 to 4 carbon atoms or R and R1 when taken together with the nitrogen atom to which they are attached cannot form a saturated heterocyclic amino radical containing 5 to 7 ring members.

27 more elements

Facts

Application

10/075,628Filed 15 Feb 2002 · continuation

Priority

EP 99209123 Sep 1999

Published

US 2002/0183318 A15 Dec 2002

Granted

19 Aug 2003

Term ends

Not estimatedThe source records don’t support an estimate.

Classification17 codes

C07D 311/86
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…
A61K 31/35
Having oxygen as the only ring hetero atom, e.g. fungichromin: having six-membered rings with one oxygen as the only ring hetero atom
A61K 31/37
Having six-membered rings, e.g. delta-lactones: coumarins, e.g. psoralen
A61K 31/44
Having six-membered rings with one nitrogen as the only ring hetero atom: non condensed pyridines; Hydrogenated derivatives thereof