US2003229136A1PendingUtilityA1
Novel flavanoids as chemotherapeutic, chemopreventive, and antiangiogenic agents
Priority: Apr 18, 2002Filed: Apr 18, 2002Published: Dec 11, 2003
Est. expiryApr 18, 2022(expired)· nominal 20-yr term from priority
C07C 45/71C07D 491/04C07C 49/835A61P 35/00C07D 311/32C07C 45/74C07D 311/94C07D 311/92C07C 45/30C07C 49/84C07C 45/46A61P 9/00
43
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
Novel compounds useful as chemotherapeutic, chemopreventive, and antiangiogenic agents are provided. The compounds are flavanoids, including flavanones, flavanols, and chalcones. The compounds have the structure of formula (I) wherein R 1 through R 3 and R 5 through R 11 are defined herein, and α, β and γ are optional bonds, providing that when α is absent, β is present, and when β is absent, α is present. When α is present, preferred R 4 moieties are selected from O, S, NH and CH 2 , and when α is absent, preferred R 4 groups are selected from OH, SH, NH 2 and CH 3 . When γ is present, the preferred R 5 substituent is O, while when γ is absent, the preferred R 5 substituent is OH. Pharmaceutical compositions are provided as well, as are methods of synthesis and use.
Claims
exact text as granted — not AI-modifiedWe claim:
1 . A compound having the structural formula (I)
wherein:
α, β and γ are optional bonds, providing that when α is absent, β is present, and when β is absent, α is present;
R 1 , R 2 and R 3 are independently selected from the group consisting of hydroxyl, halo, sulfhydryl, alkoxy, aryloxy, and aralkyloxy, and further wherein either R 1 and R 2 or R 2 and R 3 can be linked to form a cyclic group;
when α is present, R 4 is selected from O, S, NR x , and CR y R z , and when α is absent, R 4 is selected from OH, SH, NHR x , and CR y R z H, wherein R x , R y , and R z are hydrogen or alkyl;
when γ is present, then R 5 is O, S or NR x ;
when γ is absent, then R 5 is selected from the group consisting of OH, SH, acyloxy, and N(R x ) wherein the R x may be the same or different and are as defined previously;
R 6 , R 7 , R 8 and R 9 are independently selected from the group consisting of hydrogen, alkoxy, aryloxy, and aralkyloxy, providing that either R 6 and R 7 , or R 8 and R 9 , may be linked together to form a cyclic structure selected from five-membered rings, six-membered rings, and fused five-membered and/or six-membered rings, wherein the cyclic structure is aromatic, alicyclic, heteroaromatic, or heteroalicyclic, and has zero to 4 non-hydrogen substituents and zero to 3 heteroatoms; and
R 10 and R 11 are independently selected from the group consisting of hydrogen, hydroxyl, alkyl, alkoxy, and halo.
2 . The compound of claim 1 , wherein R 1 , R 2 and R 3 are independently selected from the group consisting of hydroxyl, halo, C 1 -C 6 alkoxy, C 5 -C 12 aryloxy, and C 5 -C 12 aralkyloxy, and further wherein either R 1 and R 2 or R 2 and R 3 can be joined to form a two-atom or three-atom linkage selected from alkylene, substituted alkylene, and heteroalkylene;
when α is present, R 4 is selected from O, S, NH and CH 2 , and when α is absent, R 4 is selected from OH, SH, NH 2 and CH 3 ; when γ is present, then R 5 is O or NH; when γ is absent, then R 5 is selected from the group consisting of OH, C 6 -C 32 acyloxy, and NH 2 ; R 6 , R 7 , R 8 and R 9 are independently selected from the group consisting of hydrogen, C 1 -C 6 alkoxy, C 5 -C 12 aryloxy, and C 5 -C 12 aralkyloxy, or R 6 and R 7 are linked together to form a cyclohexyl, cyclopentyl, or phenyl ring, and R 8 and R 9 are hydrogen, or R 8 and R 9 are linked together to form a cyclohexyl, cyclopentyl, or phenyl ring, and R 6 and R 7 are hydrogen; and R 10 and R 11 are independently selected from the group consisting of hydrogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and halo.
3 . The compound of claim 2 , wherein α and γ are present, β is absent, R 4 is O, and R 5 is O, such that the compound has the structure of formula (II)
4 . The compound of claim 3 , wherein R 10 and R 11 are hydrogen.
5 . The compound of claim 2 , wherein α is present, β and γ are absent, R 4 is O, and R 5 is OH, such that the compound has the structure of formula (III)
6 . The compound of claim 5 , in enantiomerically pure form in the 2β,4β-cis, 2α,4α-cis, 2α,4β-trans, or 2β,4α-trans configuration.
7 . The compound of claim 5 , comprising a racemic mixture of the 2α,4β-trans and 2β, 4α-trans enantiomers.
8 . The compound of claim 5 , comprising a racemic mixture of the 2α,4α-cis and 2β,4β-cis enantiomers.
9 . The compound of claim 5 , wherein R 10 and R 11 are hydrogen.
10 . The compound of claim 2 , wherein β and γ are present, α is absent, R 4 is OH, and R 5 is O, such that the compound has the structure of formula (IV)
11 . The compound of claim 2 , wherein:
R 1 , R 2 and R 3 are identical, and are selected from the group consisting of C 1 -C 6 alkoxy and C 5 -C 12 aralkyloxy; when α is present, R 4 is O, and when α is absent, R 4 is OH; when γ is present, R 5 is O, and when γ is absent, R 5 is selected from the group consisting of hydroxyl and acyloxy substituents having the structure in which R 12 , R 13 and R 14 are independently selected from the group consisting of hydroxyl, C 1 -C 6 alkoxy, and C 5 -C 12 aralkyloxy; and either (a) R 6 and R 7 are linked together to form a phenyl ring, and R 8 and R 9 are hydrogen, (b) R 8 and R 9 are linked together to form a phenyl ring, and R 6 and R 7 are hydrogen, or (c) R 6 and R 8 are C 1 -C 6 alkoxy or C 5 -C 12 aralkyloxy and R 7 and R 9 are hydrogen; and R 10 and R 11 are hydrogen.
12 . The compound of claim 11 , wherein:
R 1 , R 2 and R 3 are selected from the group consisting of methoxy and benzyloxy; when γ is absent, R 5 is selected from the group consisting of hydroxyl and acyloxy substituents having the structure in which R 12 , R 13 and R 14 are independently selected from the group consisting of methoxy and benzyloxy; and R 8 and R 9 are linked together to form a phenyl ring.
13 . The compound of claim 12 , having the structure of formula (V)
14 . The compound of claim 13 , comprising a racemic mixture of the 2α,4β-trans and 2β, 4α-trans enantiomers.
15 . The compound of claim 12 , wherein R 1 , R 2 and R 3 are methoxy.
16 . The compound of claim 13 , wherein R 1 , R 2 and R 3 are methoxy.
17 . The compound of claim 14 , wherein R 1 , R 2 and R 3 are methoxy.
18 . The compound of claim 12 , wherein R 1 , R 2 and R 3 are benzyloxy.
19 . The compound of claim 13 , wherein R 1 , R 2 and R 3 are benzyloxy.
20 . The compound of claim 14 , wherein R 1 , R 2 and R 3 are benzyloxy.
21 . The compound of claim 12 , having the structure of formula (VIII)
22 . The compound of claim 21 , wherein R 1 , R 2 and R 3 are methoxy.
23 . The compound of claim 21 , wherein R 1 , R 2 and R 3 are benzyloxy.
24 . The compound of claim 12 , having the structure of formula (IX)
25 . The compound of claim 24 , wherein R 1 , R 2 and R 3 are methoxy.
26 . The compound of claim 24 , wherein R 1 , R 2 and R 3 are benzyloxy.
27 . A method for synthesizing a flavanone having the structure of formula (II)
wherein
R 1 , R 2 and R 3 are independently selected from the group consisting of hydroxyl, halo, C 1 -C 6 alkoxy, C 5 -C 12 aryloxy, and C 5 -C 12 aralkyloxy, and further wherein either R 1 and R 2 or R 2 and R 3 can be joined to form a two-atom or three-atom linkage selected from alkylene, substituted alkylene, and heteroalkylene,
R 6 , R 7 , R 8 and R 9 are independently selected from the group consisting of hydrogen, C 1 -C 6 alkoxy, C 5 -C 12 aryloxy, and C 5 -C 12 aralkyloxy, or R 6 and R 7 are linked together to form a cyclohexyl, cyclopentyl, or phenyl ring, and R 8 and R 9 are hydrogen, or R 8 and R 9 are linked together to form a cyclohexyl, cyclopentyl, or phenyl ring, and R 6 and R 7 are hydrogen, and
R 10 and R 11 are independently selected from the group consisting of hydrogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and halo,
the method comprising condensing the ketone (X)
with the aromatic aldehyde (XI)
in the presence of a nitrogenous organic base.
28 . The method of claim 27 , wherein the condensation is carried out under reflux conditions.
29 . A method for synthesizing a flavanol having the structure of formula (III)
wherein
R 1 , R 2 and R 3 are independently selected from the group consisting of hydroxyl, halo, C 1 -C 6 alkoxy, C 5 -C 12 aryloxy, and C 5 -C 12 aralkyloxy, and further wherein either R 1 and R 2 or R 2 and R 3 can be joined to form a two-atom or three-atom linkage selected from alkylene, substituted alkylene, and heteroalkylene,
R 6 , R 7 , R 8 and R 9 are independently selected from the group consisting of hydrogen, C 1 -C 6 alkoxy, C 5 -C 12 aryloxy, and C 5 -C 12 aralkyloxy, or R 6 and R 7 are linked together to form a cyclohexyl, cyclopentyl, or phenyl ring, and R 8 and R 9 are hydrogen, or R 8 and R 9 are linked together to form a cyclohexyl, cyclopentyl, or phenyl ring, and R 6 and R 7 are hydrogen, and
R 10 and R 11 are independently selected from the group consisting of hydrogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and halo,
the method comprising contacting a flavanone having the structure (II)
with a reducing agent under reaction conditions effective to convert the 4-oxo moiety to a hydroxyl group.
30 . The method of claim 29 , wherein the reducing agent is sodium borohydride.
31 . A method for synthesizing a chalcone having the structure of formula (IV)
wherein
R 1 , R 2 and R 3 are independently selected from the group consisting of hydroxyl, halo, C 1 -C 6 alkoxy, C 5 -C 12 aryloxy, and C 5 -C 12 aralkyloxy, and further wherein either R 1 and R 2 or R 2 and R 3 can be joined to form a two-atom or three-atom linkage selected from alkylene, substituted alkylene, and heteroalkylene,
R 6 , R 7 , R 8 and R 9 are independently selected from the group consisting of hydrogen, C 1 -C 6 alkoxy, C 5 -C 12 aryloxy, and C 5 -C 12 aralkyloxy, or R 6 and R 7 are linked together to form a cyclohexyl, cyclopentyl, or phenyl ring, and R 8 and R 9 are hydrogen, or R 8 and R 9 are linked together to form a cyclohexyl, cyclopentyl, or phenyl ring, and R 6 and R 7 are hydrogen, and
R 10 and R 11 are independently selected from the group consisting of hydrogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and halo,
the method comprising reacting the ketone (X)
with the aromatic aldehyde (XI)
in the presence of an aqueous inorganic base.
32 . The method of claim 31 , wherein the inorganic base is an alkali metal hydroxide.
33 . The method of claim 32 , wherein the alkali metal hydroxide is potassium hydroxide.
34 . A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 in combination with a pharmaceutically acceptable carrier.
35 . A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 3 in combination with a pharmaceutically acceptable carrier.
36 . A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 5 in combination with a pharmnaceutically acceptable carrier.
37 . A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 7 in combination with a pharmaceutically acceptable carrier.
38 . A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 10 in combination with a pharmaceutically acceptable carrier.
39 . The composition of any one of claims 34 through 38 , wherein the pharmaceutically acceptable carrier is suitable for oral administration and the composition comprises an oral dosage form.
40 . The composition of claim 39 , wherein the oral dosage form is a tablet.
41 . The composition of claim 39 , wherein the oral dosage form is a capsule.
42 . The composition of any one of claims 34 through 38 , wherein the pharmaceutically acceptable carrier is suitable for parenteral administration and the composition comprises a parenterally administrable formulation.
43 . A method for treating a patient suffering from cancer, comprising administering to the individual a therapeutically effective amount of the compound of claim 1 .
44 . A method for treating a patient suffering from cancer, comprising administering to the individual a therapeutically effective amount of the compound of claim 3 .
45 . A method for treating a patient suffering from cancer, comprising administering to the individual a therapeutically effective amount of the compound of claim 5 .
46 . A method for treating a patient suffering from cancer, comprising administering to the individual a therapeutically effective amount of the compound of claim 7 .
47 . A method for treating a patient suffering from cancer, comprising administering to the individual a therapeutically effective amount of the compound of claim 10 .
48 . The method of any one of claims 43 through 47 , wherein the cancer is prostate cancer, uterine cancer, or breast cancer.
49 . The method of claim 48 , wherein the cancer is breast cancer.
50 . A method for treating an individual suffering from a condition, disease or disorder associated with angiogenesis, comprising administering to the individual an effective anti-angiogenic amount of the compound of claim 1 .
51 . A method for treating an individual suffering from a condition, disease or disorder associated with angiogenesis, comprising administering to the individual an effective anti-angiogenic amount of the compound of claim 3 .
52 . A method for treating an individual suffering from a condition, disease or disorder associated with angiogenesis, comprising administering to the individual an effective anti-angiogenic amount of the compound of claim 5 .
53 . A method for treating an individual suffering from a condition, disease or disorder associated with angiogenesis, comprising administering to the individual an effective anti-angiogenic amount of the compound of claim 7 .
54 . A method for treating an individual suffering from a condition, disease or disorder associated with angiogenesis, comprising administering to the individual an effective anti-angiogenic amount of the compound of claim 10 .
55 . A method for treating an individual suffering from a condition, disease or disorder associated with angiogenesis, comprising administering to the individual an effective anti-angiogenic amount of the compound of claim 11 .
56 . A chemopreventive method comprising administering a prophylactically effective amount of the compound of claim 1 to a patient susceptible to developing cancer.
57 . A chemopreventive method comprising administering a prophylactically effective amount of the compound of claim 3 to a patient susceptible to developing cancer.
58 . A chemopreventive method comprising administering a prophylactically effective amount of the compound of claim 5 to a patient susceptible to developing cancer.
59 . A chemopreventive method comprising administering a prophylactically effective amount of the compound of claim 7 to a patient susceptible to developing cancer.
60 . A chemopreventive method comprising administering a prophylactically effective amount of the compound of claim 10 to a patient susceptible to developing cancer.Join the waitlist — get patent alerts
Track US2003229136A1 — get alerts on status changes and closely related new filings.
We store only your email — no account needed. See our privacy policy.