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US 6,486,196 B2Granted
Anticancer compounds: process for their preparation and pharmaceutical compositions containing them
AssigneeDr. Reddy's Research Foundation
InventorsSrinivas Nanduri, Sairam Pothukuchi, Sriram Rajagopal, Venkateswarlu Akella, Sunilkumar Bhadramma Kochunarayana Pillai, Ranjan Chakrabarti
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Abstract
The present invention relates to novel anticancer agents, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, and their pharmaceutically acceptable solvates. The present invention more particularly relates to novel derivatives of andrographolide, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, and their pharmaceutically acceptable solvates. The novel derivatives of andrographolide have the general formula (I).
Claims53
A compound of the formula (I),
- where R1, R2 and R3 may be same or different and independently represent hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, aralkenoyl, heteroaralkanoyl, heteroaralkenoyl, sulfonyl group or a group —(CO)—W—R5 where W represents O, S or NR6, wherein R6 represents hydrogen or substituted or unsubstituted (C1-C6)alkyl group, R5 represents substituted or unsubstituted groups selected from alkyl, aryl, aralkyl or aroyl or OR2 and OR3 together form a substituted or unsubstituted 6 or 7 membered cyclic structure containing carbon and oxygen atoms;
- R4 represents hydrogen, halogen or XR7 where X represents O, S, or NH and R7 represents hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, aralkyl, alkenoyl, alkanoyl, aroyl, heteroaroyl, aralkenoyl, aralkanoyl, sulfonyl groups or a group —(CO)—NH—R8 where R8 represents substituted or unsubstituted groups selected from alkyl, aryl, aralkyl;
- with provisos that (i) R1, R2 and R3 may be same except when they represent hydrogen or alkanoyl group and (ii) when R2 and R3 represent hydrogen, R1 does not represent unsubstituted alkanoyl;
- its stereoisomers, its polymorphs, its salts and its solvates.
1 more element
A compound selected from:
- 3,19-Isopropylidene andrographolide;
- 3,19-Benzylidene andrographolide;
- 3,19-(1-Phenylethylidene)andrographolide;
- 3,19-Isopropylidene-14-(N-Boc methionyl)andrographolide;
- 14-Acetyl 3,19-methylenedioxy andrographolide;
- 14-Acetyl 3,19—O—cyclic carbonyl andrographolide;
- 14-Acetyl andrographolide;
- 14-Chloroacetyl andrographolide;
- 14-(Phenylcarbamoyl)andrographolide;
- 14-(N-Isopropyl carbamoyl)andrographolide;
- 14-Cinnamoyl andrographolide;
- 14-Isopropanoyl andrographolide;
- 14-Pivaloyl andrographolide;
- 14-Benzoyl andrographolide;
- 14-Benzyl andrographolide;
- 3,19-Diacetyl-14-(2′-acetyl-3′-acetamido 3′-phenyl)propionyl andrographolide;
- 3,19-Diacetyl-14-[4′S,5 ′R-(N-t-Butoxycarbonyl)-2′,2′-dimethyl-4′-phenyl-5′-oxazolidine]carbonyl andrographolide;
- 3,19-Diacetyl-14-(2′hydroxy-3′-benzoylamino 3′-phenyl) propionyl andrographolide;
- 3,19-Diacetyl-14-(2′hydroxy-3-N-Boc amino-3′-phenyl)propionyl andrographolide;
- 14-(N-Boc-glycinyl)-3,19-dipropionyl andrographolide;
- 14-(N-Boc-glycinyl)-3,19-diacetyl andrographolide;
- 14-(N-Acetylglycinyl)-3,19-diacetyl andrographolide;
- 14-(N-Benzoylglycinyl)-3,19-diacetyl andrographolide;
- 3,19-Diacetyl-14—O—ethyl andrographolide;
- 3,19-Diacetyl-14—O—methyl andrographolide;
- 3,19-Diacetyl-14-(3,4-dimethoxycinnamoyl)andrographolide;
- 14-(3,4-dimethoxy)cinnamoyl-3,19-dipropionyl-andrographolide;
- 3-Acetyl andrographolide;
- 3,14-Diacetyl andrographolide;
- 3,14,19,7-Tetra acetyl andrographolide;
- 3,19-Isopropylidene-14-acetyl andrographolide;
- 14-Chloroacetyl-3,19-isopropylidene andrographolide;
- 14-Carbamoyl-3,19-isopropylidene andrographolide;
- 3,19-Isopropylidene-14-(N-isopropyl)carbamoyl andrographolide;
- 14-[4′S,5R-(N-t-butoxycarbonyl-2′,2′-dimethyl-4′-phenyl-5′-oxazolidine]carbonyl 3,19-isopropylidene andrographolide;
- 14-[4′S,5′R-(N-t-butoxycarbonyl-2′,2′-dimethyl-4′-phenyl-5′-oxazolidine]carbonyl andrographolide;
- 3,19-Isopropylidene-14-(N-Boc-glycinyl)andrographolide;
- 14-(N-Boc-glycinyl)andrographolide;
- 14-O-Ethyl-3,19-isopropylidene andrographolide;
- 14-O-Ethyl andrographolide;
- 14-O-Methyl-3,19-isopropylidene andrographolide;
- 14-O-Methyl andrographolide;
- 14-(3,4-Dimethoxy)cinnamoyl andrographolide;
- 19-Trityl andrographolide;
- 3-Acetyl-19-trityl andrographolide;
- 3,14-Diacetyl-19-trityl andrographolide and
- 7-Hydroxy-3,14,19-triacetyl andrographolide.
44 more elements
A process for the preparation of the compound of the formula (I)
- where R1, R2 and R3 may be same or different and independently represent hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, aralkenoyl, heteroaralkanoyl, heteroalkenoyl, sulfonyl group or a group —(CO)—W—R5 where W represents O, S or NR6, wherein R6 represents hydrogen or substituted or unsubstituted (C1-C6)alkyl group, R5 represents substituted or unsubstituted groups selected from alkyl, aryl, aralkyl or aroyl or OR2 and OR3 together form a substituted or unsubstituted 6 or 7 membered cyclic structure containing carbon and oxygen atoms and R4 represents hydrogen;
- with provisos that (i) R1, R2 and R3 may be same except when they represent hydrogen or alkanoyl group, (ii) when R2 and R3 represent hydrogen, R1 does not represent unsubstituted alkanoyl;
- its stereoisomers, its polymorphs, its salts and its solvates, which the steps of comprises:
- (a) reacting the compound of formula (VII)
- with R1-L, R2-L and R3-L, where R1, R2 and R3 are as defined above and L is hydroxy, halogen, p-toluenesulfonate, methanesulfonate or trifluoromethanesulfonate;
- or alkanoate group to produce a compound of formula (I), where all symbols are as defined above and R4 represents hydrogen or
- (b)(i) protecting the hydroxy groups present on carbons 3 or 19 or 3 and 19 together in the compound of formula (VII) with suitable protecting groups to produce a compound of formula (VIII),
- where R4 represents hydrogen;
- P1 and P2 are same or different and represent hydrogen, trityl, t-butyl dimethyl silyl or pivaloyl;
- or esters;
- or P1 and P together form methylene dioxy, isopropylidene, benzylidene, 1-phenyl ethylidene or carbonate,
- (ii) reacting the compound of formula (VIII) defined above with a compound of formula (IX)
- R1—L (IX)
- where R1 and L are as defined above to produce a compound of formula (X),
- where R1, R4, P1 and P2 are as defined above,
- (iii) deprotecting the compound of formula (X) to produce a compound of formula (XI),
- where R1 and R4 are as defined above,
- (iv) reacting the compound of formula (XI) where R1 has the meaning given above with R2—L and/or R3—L, where R2 and R3 are as defined above to produce a compound of formula (I), and if desired,
- (v) converting the compound of formula (I) into its stereoisomers, or pharmaceutical salts.
16 more elements
A compound of formula (X)
- where R1 represents hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkanoyl, alkenoyl, aroyl, aralkanoyl, aralkenoyl, heteroaroyl, heteroaralkanoyl, heteroaralkenoyl, sulfonyl groups or a group —(CO)—W—R5 where W represents O, S or NR6, wherein R6 represents hydrogen or substituted or unsubstituted (C1-C6)alkyl group, R5 represents substituted or unsubstituted groups selected from alkyl, aryl, aralkyl or aroyl;
- R4 represents hydrogen;
- P1 and P2 are same or different and independently represent trityl, t-butyldimethylsilyl or pivaloyl;
- or esters;
- or P1 and P2 together represent methylene dioxy, isopropylidene, benzylidene, 1-phenyl ethylidene or carbonate, its stereoisomers, its polymorphs, its salts and its solvates.
2 more elements
A compound of formula (XI),
- where R1 represents hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkanoyl, alkenoyl, aroyl, aralkanoyl, aralkenoyl, heteroaroyl, heteroaralkanoyl, heteroaralkenoyl, sulfonyl groups or a group —(CO)—W—R5 where W represents O, S or NR6, wherein R6 represents hydrogen or substituted or unsubstituted (C1-C6)alkyl group, R5 represents substituted or unsubstituted groups selected from alkyl, aryl, aralkyl or aroyl and R4 represents hydrogen, its stereoisomers, its polymorphs, its salts and its acceptable solvates.
A process for the preparation of the compound of formula (I),
- where R1, R2 and R3 may be same or different and independently represent hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, aralkenoyl, heteroaralkanoyl, heteroaralkenoyl, sulfonyl group or a group —(CO)—W—R5 where W represents O, S or NR6, wherein R6 represents hydrogen or substituted or unsubstituted (C1-C6)alkyl group, R5 represents substituted or unsubstituted groups selected from alkyl, aryl, aralkyl or aroyl or OR2 and OR3 together form a substituted or unsubstituted 6 or 7 membered cyclic structure containing carbon and oxygen atoms;
- R4 represents hydrogen, halogen or XR7 where X represents O, S, or NH and R7 represents hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, aralkyl, alkenoyl, alkanoyl, aroyl, heteroaroyl, aralkenoyl, aralkanoyl, sulfonyl groups or a group —(CO)—NH—R8 where R8 represents substituted or unsubstituted groups selected from alkyl, aryl, aralkyl;
- with provisos that (i) R1, R2 and R3 may be same except when they represent hydrogen or alkanoyl group and (ii) when R2 and R3 represent hydrogen, R1 does not represent unsubstituted alkanoyl;
- its stereoisomers, its polymorphs, its salts and its pharmaceutically acceptable solvates, which comprises the steps of:
- (i) converting the compound of formula (I) where R4 represents hydrogen and all other symbols are as defined earlier to produce a compound of formula (XII),
- where all the symbols are as defined above, the compound of formula (XII) represents a compound of formula (I) when X represents 0, and
- (ii) reacting the compound of formula (XII) with R7—L where R7 is as defined above, and L is hydroxy, halogen, p-toluenesulfonate, methanesulfonate or trifluoromethanesulfonate;
- or alkanoate group to produce a compound of formula (I).
5 more elements
A process for the preparation of the compound of formula (I),
- where R4 represents halogen and R1, R2 and R3 may be same or different and independently represent hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, aralkenoyl, heteroaralkanoyl, heteroaralkenoyl, sulfonyl group or a group —(CO)—W—R5 where W represents O, S or NR6, wherein R6 represents hydrogen or substituted or unsubstituted (C1-C6)alkyl group, R5 represents substituted or unsubstituted groups selected from alkyl, aryl, aralkyl or aroyl or OR2 and OR3 together form a substituted or unsubstituted 6 or 7 membered cyclic structure containing carbon and oxygen atoms;
- R4 represents halogen, with provisos that (i) R1, R2 and R3 may be same except when they represent hydrogen or alkanoyl group and (ii) when R2 and R3 represent hydrogen, R1 does not represent unsubstituted alkanoyl;
- its stereoisomers, its polymorphs, its pharmaceutically acceptable salts and its pharmaceutically acceptable solvates, which comprises the steps of:
- (a)(i) converting the compound of formula (I) where R4 represents hydrogen and all other symbols are as defined above to produce a compound of formula (XII),
- where all the symbols are as defined above, the compound of formula (XII) represents a compound of formula (I) when X represents O,
- (ii) converting the compound of formula (XII) to a compound of formula (I), where R4 represents halogen atom or
- (b) reacting the compound of formula (I) where R4 represents hydrogen and all other symbols are as defined earlier with a halogenating agent to produce a compound of formula (I), where R4 represents halogen atom.
4 more elements
Dependencies are inferred from the claim text.