Title of Invention

" A BAICALEIN DERIVATIVE"

Abstract The present invention relates to novel baicalein derivatives, and pharmaceutical formulations containing the same and methods of use thereof. Uses of the present invention include, but are not limited to, use for the prevention and treatment of septic shock, organ injury and other disorders. The compounds described herein can be salt forms and also water-soluble compounds.
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1/We claim:
1. A baicalein derivative of formula I:
(Formula Removed)
wherein:
R1, R2. and R3 are each independently H, alkyl, alkenyl, alkynyl, benzyl, -SO3H, or -PO3H2, or
R1 and R2 are each independently (CH2)nY and [CH2CH (OH) CH2]Y, wherein Y is H, OR4,
NR5R6,COOR4, or CONR5R6 ;wherein R4, R5, and R6 are each independently H, alkyl, alkenyl,
benzyl or alkynyl, and R5 and R6 together may form a 5 to 7-membered ring;
or R1 and R2 together are heterocycles;
or R2 and R3 together are heterocycles; and
X1 and X2 are each independently of the formula:
(Formula Removed)
Ar is optional when atleast X1 or X2 is present; and when both X1 and X2 are present, Ar is
phenyl, furanyl, thienyl, pyridyl, cyclohexyl or benzyl; wherein X3 is H, C, N, NR', NR'R",
NR'SO2 R", or O , wherein R' and R" are each independently H, alkyl, alkenyl, alkynyl,; wherein
T is (CH2)nY or [CH2CH (OH) CH2]Y, wherein n is 0 or 3, Y is H, OR4, NR5R6, COOR4, or
CONR5R6 wherein R4, R5, and R6 are each independently H, alkyl, or alkenyl, alkynyl,. and R
and R6 together may form a 5 to 7-membered ring; or pharmaceutically acceptable salts thereof;
when either of X or X is present, Ar is a substituted phenyl:
wherein X3 is C, N, NR, NR'R", NR'SO2 R", ORl;
or when either of X1 or X2 is present, Ar is furanyl, thienyl, pyridyl, cyclohexyl or benzyl and
X1 is H, C, N, NR', NR'R", NR'SO2 R",O, wherein R' and R" are each independently H, alkyl,
alkenyl, or alkynyl; and OR1 is O(CH2)nY, wherein n is 1 to 2, Y is OR4, NR5R6, COOR4, or
CONR5R6; or O[CH2CH (OH) CH2]Y, wherein Y is H, OR4, NR5R6, COOR4, or CONR5R6;
wherein T is (CH2)nY or [CH2CH (OH) CH2]Y, wherein n is 0-3, Y is H, OR4, NR5R6, COOR4, or CONR5R6, X1 and X2 represent Ar-X3-T whereinX3-T is OH or NH2 with an electrophile such as W (CH2)nY, W CH2CH(O) CH2, or HOCH2 CH(O)CH2 wherein W is a leaving group and Y is H. wherein R4, R5, and R6 are each independently H, alkyl, alkenyl, or alkynyl, and R5 and R6 together may form a 5 to 7-membered ring; or pharmaceutically acceptable salts thereof.
2. A compound as claimed in claim 1, wherein the alkyl is a lower alkyl.
3. A compound as claimed in claim 1, wherein R1, R2 and R3 are each independently-SO3H or-PO3H2.
4. A compound as claimed in claim 1, wherein R1 and R2 together is a five-membered or six-mem bered ring structure.
5. A compound as claimed in claim 1, wherein R and R3 together is a five-membered or six-membered heterocycle.
6. A compound as claimed in claim 1, wherein the salt form of the compound is a sodium or potassium salt of the compound.
7. A compound as claimed in claim 1, wherein the compound is selected from 4'- (amino)-5.7- dihydroxy-6-methoxy flavone, 4'- (amino)- 5,6,7-trimethoxy flavone, 4'- (N,N-dimethylamino)-5, 6,7-trimethoxyflavone, 4'- (methylamino)-5, 6,7- trimethoxyflavone, 4'-[N-methyl-N-(3-methoxypropyl)amino)-5,6,7-trimethoxyflavone, 4'-[N,N-di-(2-hydroxyethyl)-amino)-5,7-dihydroxy-6-methoxyflavone, 4,-(2-hydroxyethylamino)-5,7-dihydroxy-6-methoxyflavone, 4'-(2-methanesulfonatoethylamino)-5,7-dihydroxy-6-methoxyflavone, 4'-[2-(N,N-diethylamino)ethylamino]-5,7-dihydroxy-6-methoxyflavone, 2,3-diphenyl-5,6,7-trimethoxychromone, 2,3-diphenyl-5,6,7-trihydroxychromone, 4'-(methylsulfonamido)-5,6,7-trimethoxyflavone, 4'-[2-(N,N-diethylamino)ethoxy]-6,7-methylenedioxy-5-hydroxy-flavone, 4'-(2,3-dihydroxy-propyloxy)-5,6,7-trimethoxyflavone, or 4'-(Carbmethoxymethoxy)-5,6,7-trimethoxyflavone.
8. A compound as claimed in any of the preceding claims is in the form of a pharmaceutical
formulation for treating diseases associated with overproduction of TNF-a selected from the
group consisting of arthritis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, insulin
resistance, multiple sclerosis, organ failure, pulmonary fibrosis, and atherosclerosis
9. A compound as claimed in claim 1:
(Formula Removed)
wherein:
R',R2, and R3 are each independently H, alkyl,-SO3H,-PO3H2, or benzyl; or R1 and R2
together are heterocycles;
or R2 and R3 together are heterocycles; X1 is H, C, NH2, NHCOCH3, or OR4, wherein R4 is 11,
alkyl or benzyl, or pharmaceutically acceptable salts thereof.
10. A compound as claimed in claim 9, wherein the alkyl is a lower alkyl.
11. A compound as claimed in claim 9, wherein R1 and R2 together are heterocycles.
12. A compound as claimed in claim 9, wherein R1 and R2 together is a five-membered ring
structure or a six-membered ring structure.
13. A compound as claimed in claim 9, wherein R2 and R3 together is a five-membered or six-membered ring structure.
14. A compound as claimed in claim 9, wherein X1 is substituted on the ortho, meta, or para position of the phenyl ring.
15. A compound as claimed in claim 9, wherein the compound is 5, 6, 7- trihydroxyisoflavone.
16. A compound as claimed in claim 1, wherein the compound is selected from the group consisting of baicalein-6-sulfate, baicalein-6,7-disulfate, bacalein-6-phosphate, bacalein-6,7-diphosphate, baicalein- 5,6, 7-triphosphate, sodium and potassium salt derivatives thereof, and pharmaceutically acceptable salts thereof for treating conditions selected from the group consisting of diseases associated with the overproduction of TNF-α overproduction of superoxide anion radical, organ damage,- and combinations thereof.
17. A method of synthesizing a compound of formula I as defined in claim 1, or
pharmaceutically acceptable salts thereof, comprising a reacting compound of formula (VI):
(Formula Removed)
whereimR1, R2, and R3 are each independently H, alkyl, alkenyl, alkynyl, -SO3H, or -PO3H2; or R1 and R2 are each independently (CH2)nY and [CH2CH (OH) CH2]Y, wherein Y is H, OR4. NR5R6,COOR4, or OONR5R6 wherein R4,R5, andR6 are each independently H, alkyl, alkenyl, or alkynyl, and R5 and R6 together may form a 5 to 7-membered ring; or R1 and R2 together are heterocycles; with (ArCO)2O, ArCO2Na and an acid sodium salt wherein Ar is as defined above.
18. A method of synthesizing a compound of formula I as defined in claim 1 wherein X1 and X2
represent Ar-X3-T wherein X3 is H, R1, R2, and R3 are H or one ofR1 and R2 is CH3, or
pharmaceutically acceptable salts thereof, comprising reacting a compound of formula VII:
(Formula Removed)
wherein; X1 and X2 represent Ar-X3-T wherein X3 is H, with aqueous hydrobromic acid (HBr) or boron tribromide (BBr3).
19. A method of synthesizing a compound of formula I as defined in claim 1, or pharmaceutically
I "*
acceptable salts thereof, comprising reacting a compound of formula I wherein X1 and X2 represent Ar-X3-T whereinX3-T is OH or NH2 with an electrophile such as W (CH2)nY, W CH2CH(O) CH2, or HOCH2 CH(O)CH2 wherein W is a leaving group and Y is H, OR4, NR5R6, COOR4, orOONR5R6 wherein R4, R5, and R6 are each independently H, alkyl, alkenyl, or alkynyl, and R5 and R6 together may form a 5 to 7-membered ring.
20. The method according to claim 17, wherein the compound is 4', 5, 6, 7- tetrahydroxyflavone.
21. The method according to claim 17, wherein the compound is 4'-amino -5, 7- dihydroxy-6-methoxy flavone.
22. A baicalein derivative of formula I and a method of synthesizing a baicalein compound substantially as herein before described in any of the examples.

Documents:

1515-delnp-2005-abstract.pdf

1515-delnp-2005-assignment.pdf

1515-delnp-2005-claims.pdf

1515-delnp-2005-correspondence-others.pdf

1515-delnp-2005-correspondence-po.pdf

1515-delnp-2005-description (complete).pdf

1515-delnp-2005-drawings.pdf

1515-delnp-2005-form-1.pdf

1515-delnp-2005-form-13.pdf

1515-delnp-2005-form-18.pdf

1515-delnp-2005-form-2.pdf

1515-delnp-2005-form-26.pdf

1515-delnp-2005-form-3.pdf

1515-delnp-2005-form-5.pdf

1515-delnp-2005-petition-137.pdf


Patent Number 246467
Indian Patent Application Number 1515/DELNP/2005
PG Journal Number 09/2011
Publication Date 04-Mar-2011
Grant Date 01-Mar-2011
Date of Filing 15-Apr-2005
Name of Patentee JENKEN BIOSCIENCES,INC.
Applicant Address 102 TIMBER HITCH ROAD, CARY, NC 27513, U.S.A.
Inventors:
# Inventor's Name Inventor's Address
1 YEN,MAO-HSIUNG 8F, #14, LANE 147, SEC. 1, ZHONG-CHENG RD., SHILIN DISTRICT,TAIPEI, TAIWAN.
2 WU, EDWIN S.C 102 TIMBER HITCH ROAD, CARY,NC 27513,U.S.A.
PCT International Classification Number C07D 311/02
PCT International Application Number PCT/US2003/033578
PCT International Filing date 2003-10-22
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/420,360 2002-10-22 U.S.A.
2 60/453,771 2003-03-11 U.S.A.