US 2003/0171339 A1Published application

Novel retinoid derivatives and methods for producing said compounds and anti-cancer pharmaceutical composition comprising said compounds

AssigneeChebigen, Inc.

InventorsHong-Sig Sin, Soo-Jong Um, Young-Soy Rho, Si-Ho Park, Youn-Ja Kwon, Myoung-Soon Park, Hye-Sook Han, So-Mi Kim, Dong-Myong Kim, Deon-Kun Oh, Jong-Sup Park, Tae-Sung Bae

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Abstract

The present invention relates to a novel retinoid derivative compound represented by the formula I: 1 wherein X, R1, R2 and R3 are as defined herein or pharmaceutically acceptalbe salts thereof. Also, the present invention relates to processes for producing the compound of the formula I and to an anti-cancer composition comprising the compound of the formula I. The compound of the formula I according to the present invention exerts high anti-cancer effects while not causing undesirable side effects.

Claims11

Dependent claims

A compound of the formula I:

25
wherein
(i) X is O, NH or S;
R1 and R2, which may be identical or different, are each independently —OH, —SH, —NH2, —COOH, —R(CH2)mCH3, —RCOCO(CH2)mCH3, —RCO(CH2)mCHCH3CH3, —RCO(CH2)mNR4CH3, —RCOCHOH(CH2)mCH3, —RCOCH2(CH2)mCH3, —RCOCH2CHOH(CH2)mCH3, —RCOCH2(CH2)mCOOH, —RSO2CH2(CH2)mCH3, —RPO2(OH)CH2(CH2)mCH3 or RCOCH(NHCOCH3)CH2CH2CONH2, in which each R is CH2, O, NH or S, R4 is H or C1-C6 alkyl, and each m is an integer of 0 to 5;
and R3 is H;
(ii) X is the same as defined above;
R1 and R3, which may be identical or different, are each independently —OH, —SH, —NH2, —COOH, —R(CH2)mCH3, —RCOCO(CH2)mCH3, —RCO(CH2)mCHCH3CH3, —RCO(CH2)mNR4CH3, —RCOCHOH(CH2)mCH3, —RCOCH2(CH2)mCH3, —RCOCH2CHOH(CH2)mCH3, —RCOCH2(CH2)mCOOH, —RSO2CH2(CH2)mCH3, —RPO2(OH)CH2(CH2)mCH3 or RCOCH(NHCOCH3)CH2CH2CONH2, in which each R is CH2, O, NH or S, R4 is H or C1-C6 alkyl, and each m is an integer of 0 to 5;
and R2 is H;
(iii) X is the same as defined above;
R1 is —OH, —SH, —NH2, —COOH, —R(CH2)mCH3, —RCOCO(CH2)mCH3, —RCO(CH2)mCHCH3CH3, —RCO(CH2)mNR4CH3, —RCOCHOH(CH2)mCH3, —RCOCH2(CH2)mCH3, —RCOCH2CHOH(CH2)mCH3, —RCOCH2(CH2)mCOOH, —RSO2CH2(CH2)mCH3, —RPO2(OH)CH2(CH2)mCH3 or RCOCH(NHCOCH3)CH2CH2CONH2, in which each R is CH2, O, NH or S, R4 is H or C1-C6 alkyl, and each m is an integer of 0 to 5;
R2 is H;
and R3 is H, OH or Cl;
(iv) X is the same as defined above;
R3 is —OH, —SH, —NH2, —COOH, —R(CH2)mCH3, —RCOCO(CH2)mCH3, —RCO(CH2)mCHCH3CH3, —RCO(CH2)mNR4CH3, —RCOCHOH(CH2)mCH3, —RCOCH2(CH2)mCH3, —RCOCH2CHOH(CH2)mCH3, —RCOCH2(CH2)mCOOH, —RSO2CH2(CH2)mCH3, —RPO2(OH)CH2(CH2)mCH3 or RCOCH(NHCOCH3)CH2CH2CONH2, in which each R is CH2, O, NH or S, R4 is H or C1-C6 alkyl, and each m is an integer of 0 to 5;
R2 is H;
and R1 is H, OH or Cl;
or
(v) X is the same as defined above;
R1, R2 and R3, which may be identical or different, are each independently —OH, —SH, —NH2, —COOH, —R(CH2)mCH3, —RCOCO(CH2)mCH3, —RCO(CH2)mCHCH3CH3, —RCO(CH2)mNR4CH3, —RCOCHOH(CH2)mCH3, —RCOCH2(CH2)mCH3, —RCOCH2CHOH(CH2)mCH3, —RCOCH2(CH2)mCOOH, —RSO2CH2(CH2)mCH3, —RPO2(OH)CH2(CH2)mCH3 or RCOCH(NHCOCH3)CH2CH2CONH2, in which each R is CH2, O, NH or S, R4 is H or C1-C6 alkyl, and each m is an integer of 0 to 5;
or pharmaceutically acceptable salts thereof.

17 more elements

A process for producing a compound of the formula I:

26
wherein
(i) X is O, NH or S;
R1 and R2, which may be identical or different, are each independently —OH, —SH, —NH2, —COOH, —R(CH2)mCH3, —RCOCO(CH2)mCH3, —RCO(CH2)mCHCH3CH3, —RCO(CH2)mNR4CH3, —RCOCHOH(CH2)mCH3, —RCOCH2(CH2)mCH3, —RCOCH2CHOH(CH2)mCH3, —RCOCH2(CH2)mCOOH, —RSO2CH2(CH2)mCH3, —RPO2(OH)CH2(CH2)mCH3 or RCOCH(NHCOCH3)CH2CH2CONH2, in which each R is CH2, O, NH or S, R4 is H or C1-C6 alkyl, and each m is an integer of 0 to 5;
and R3 is H;
(ii) X is the same as defined above;
R1 and R3, which may be identical or different, are each independently —OH, —SH, —NH2, —COOH, —R(CH2)mCH3, —RCOCO(CH2)mCH3, —RCO(CH2)mCHCH3CH3, —RCO(CH2)mNR4CH3, —RCOCHOH(CH2)mCH3, —RCOCH2(CH2)mCH3, —RCOCH2CHOH(CH2)mCH3, —RCOCH2(CH2)mCOOH, —RSO2CH2(CH2)mCH3, —RPO2(OH)CH2(CH2)mCH3 or RCOCH(NHCOCH3)CH2CH2CONH2, in which each R is CH2, O, NH or S, R4 is H or C1-C6 alkyl, and each m is an integer of 0 to 5;
and R2 is H;
(iii) X is the same as defined above;
R1 is —OH, —SH, —NH2, —COOH, —R(CH2)mCH3, —RCOCO(CH2)mCH3, —RCO(CH2)mCHCH3CH3, —RCO(CH2)mNR4CH3, —RCOCHOH(CH2)mCH3, —RCOCH2(CH2)mCH3, —RCOCH2CHOH(CH2)mCH3, —RCOCH2(CH2)mCOOH, —RSO2CH2(CH2)mCH3, —RPO2(OH)CH2(CH2)mCH3 or RCOCH(NHCOCH3)CH2CH2CONH2, in which each R is CH2, O, NH or S, R4 is H or C1-C6 alkyl, and each m is an integer of 0 to 5;
R2 is H;
and R3 is H, OH or Cl;
(iv) X is the same as defined above;
R3 is —OH, —SH, —NH2, —COOH, —R(CH2)mCH3, —RCOCO(CH2)mCH3, —RCO(CH2)mCHCH3CH3, —RCO(CH2)mNR4CH3, —RCOCHOH(CH2)mCH3, —RCOCH2(CH2)mCH3, —RCOCH2CHOH(CH2)mCH3, —RCOCH2(CH2)mCOOH, —RSO2CH2(CH2)mCH3, —RPO2(OH)CH2(CH2)mCH3 or RCOCH(NHCOCH3)CH2CH2CONH2, in which each R is CH2, O, NH or S, R4 is H or C1-C6 alkyl, and each m is an integer of 0 to 5;
R2 is H;
and R1 is H, OH or Cl;
or
(v) X is the same as defined above;
R1, R2 and R3, which may be identical or different, are each independently —OH, —SH, —NH2, —COOH, —R(CH2)mCH3, —RCOCO(CH2)mCH3, —RCO(CH2)mCHCH3CH3, —RCO(CH2)mNR4 CH3, —RCOCHOH(CH2)mCH3, —RCOCH2(CH2)mCH3, —RCOCH2CHOH(CH2)mCH3, —RCOCH2(CH2)mCOOH, —RSO2CH2(CH2)mCH3, —RPO2(OH)CH2(CH2)mCH3 or RCOCH(NHCOCH3)CH2CH2CONH2, in which each R is CH2, O, NH or S, R4 is H or C1-C6 alkyl, and each m is an integer of 0 to 5;
or pharmaceutically acceptable salts thereof which comprises reacting retinoic acid with a compound of the formula II:
27
wherein X is the same as defined above;
and R5 and R6 are each independently OH, NH2 or SH and R7 is H or Cl for the preparation of the above class (i) of the compounds of the formual I;
R5 and R7 are each independently OH, NH2 or SH and R6 is H for the preparation of the above class (ii) of the compounds of the formual I;
R5 is OH, NH2 or SH, R6 is H and R7 is H, OH or Cl for the preparation of the above class (iii) of the compounds of the formual I;
R5 is H, OH or Cl, R6 is H and R7 is OH, NH2 or SH for the preparation of the above class (iv) of the compounds of the formual I;
or R5, R6 and R7 are each independently OH, NH2 or SH for the preparation of the above class (v) of the compounds of the formual I to form a compound of the formula III:
28
wherein X, R5, R6 and R7 are the same as defined above and reacting the compound of the formula III with a compound of the formula IV:
W—Y (IV)
wherein W is —OH, —SH, —NH2, —COOH, —R(CH2)mCH3, —RCOCO(CH2)mCH3, —RCO(CH2)mCHCH3CH3, —RCO(CH2)mNR4CH3, —RCOCHOH(CH2)mCH3, —RCOCH2(CH2)mCH3, —RCOCH2CHOH (CH2)mCH3, —RCOCH2(CH2)mCOOH, —RSO2CH2(CH2)mCH3, —RPO2(OH)CH2(CH2)mCH3 or —RCOCH(NCOCH3)CH2CH2 CONH2;
and Y is OH or Cl to form the above compound of the formula I.

29 more elements

A process for producing a compound of the formula I:

29
wherein
(i) X is O, NH or S;
R1 and R2, which may be identical or different, are each independently —OH, —SH, —NH2, —COOH, —R(CH2)mCH3, —RCOCO(CH2)mCH3, —RCO(CH2)mCHCH3CH3, —RCO(CH2)mNR4CH3, —RCOCHOH(CH2)mCH3, —RCOCH2(CH2)mCH3, —RCOCH2CHOH(CH2)mCH3, —RCOCH2(CH2)mCOOH, —RSO2CH2(CH2)mCH3, —RPO2(OH)CH2(CH2)mCH3 or RCOCH(NHCOCH3)CH2CH2CONH2, in which each R is CH2, O, NH or S, R4 is H or C1-C6 alkyl, and each m is an integer of 0 to 5;
and R3 is H;
(ii) X is the same as defined above;
R1 and R3, which may be identical or different, are each independently —OH, —SH, —NH2, —COOH, —R(CH2)mCH3, —RCOCO(CH2)mCH3, —RCO(CH2)mCHCH3CH3, —RCO(CH2)mNR4CH3, —RCOCHOH(CH2)mCH3, —RCOCH2(CH2)mCH3, —RCOCH2CHOH(CH2)mCH3, —RCOCH2(CH2)mCOOH, —RSO2CH2(CH2)mCH3, —RPO2(OH)CH2(CH2)mCH3 or RCOCH(NHCOCH3)CH2CH2CONH2, in which each R is CH2, O, NH or S, R4 is H or C1-C6 alkyl, and each m is an integer of 0 to 5;
and R2 is H;
(iii) X is the same as defined above;
R1 is —OH, —SH, —NH2, —COOH, —R(CH2)mCH3, —RCOCO(CH2)mCH3, —RCO(CH2)mCHCH3CH3, —RCO(CH2)mNR4CH3, —RCOCHOH(CH2)mCH3, —RCOCH2(CH2)mCH3, —RCOCH2CHOH(CH2)mCH3, —RCOCH2(CH2)mCOOH, —RSO2CH2(CH2)mCH3, —RPO2(OH)CH2(CH2)mCH3 or RCOCH(NHCOCH3)CH2CH2CONH2, in which each R is CH2, O, NH or S, R4 is H or C1-C6 alkyl, and each m is an integer of 0 to 5;
R2 is H;
and R3 is H, OH or Cl;
(iv) X is the same as defined above;
R3 is —OH, —SH, —NH2, —COOH, —R(CH2)mCH3, —RCOCO(CH2)mCH3, —RCO(CH2)mCHCH3CH3, —RCO(CH2)mNR4CH3, —RCOCHOH(CH2)mCH3, —RCOCH2(CH2)mCH3, —RCOCH2CHOH(CH2)mCH3, —RCOCH2(CH2)mCOOH, —RSO2CH2(CH2)mCH3, —RPO2(OH)CH2(CH2)mCH3 or RCOCH(NHCOCH3)CH2CH2CONH2, in which each R is CH2, O, NH or S, R4 is H or C1-C6 alkyl, and each m is an integer of 0 to 5;
R2 is H;
and R1 is H, OH or Cl;
or
(v) X is the same as defined above;
R1, R2 and R3, which may be identical or different, are each independently —OH, —SH, —NH2, —COOH, —R(CH2)mCH3, —RCOCO(CH2)mCH3, —RCO(CH2)mCHCH3CH3, —RCO(CH2)mNR4CH3, —RCOCHOH(CH2)mCH3, —RCOCH2(CH2)mCH3, —RCOCH2CHOH(CH2)mCH3, —RCOCH2(CH2)mCOOH, —RSO2CH2(CH2)mCH3, —RPO2(OH)CH2(CH2)mCH3 or RCOCH(NHCOCH3)CH2CH2CONH2, in which each R is CH2, O, NH or S, R4 is H or C1-C6 alkyl, and each m is an integer of 0 to 5;
or pharmaceutically acceptable salts thereof which comprises reacting a compound of the formula II:
30
wherein X are the same as defined above;
and R5 and R6 are each independently OH, NH2 or SH and R7 is H or Cl for the preparation of the above class (i) of the compounds of the formual I;
R5 and R7 are each independently OH, NH2 or SH and R6 is H for the preparation of the above class (ii) of the compounds of the formual I;
R5 is OH, NH2 or SH, R6 is H and R7 is H, OH or Cl for the preparation of the above class (iii) of the compounds of the formual I;
R5 is H, OH or Cl, R6 is H and R7 is OH, NH2 or SH for the preparation of the above class (iv) of the compounds of the formual I;
or R5, R6 and R7 are each independently OH, NH2 or SH for the preparation of the above class (v) of the compounds of the formual I with a compound of the formula IV:
W—Y (IV)
wherein W is —OH, —SH, —NH2, —COOH, —R(CH2)mCH3, —RCOCO(CH2)mCH3, —RCO(CH2)mCHCH3CH3, —RCO(CH2)mNR4CH3, —RCOCHOH(CH2)mCH3, —RCOCH2(CH2)mCH3, —RCOCH2CHOH (CH2)mCH3, —RCOCH2(CH2)mCOOH, —RSO2CH2(CH2)mCH3, —RPO2(OH)CH2(CH2)mCH3 or —RCOCH(NCOCH3)CH2CH2 CONH2;
and Y is OH or Cl to form a compound of the formula V:
31
wherein X, R1, R2 and R3 are the same as defined above and reacting the compound of the formula V with retinoic acid to form the above compound of the formula I.

29 more elements

A compound of the formula V:

37
wherein
(i) X is OH, NH2 or SH;
R1 and R2, which may be identical or different, are each independently —OH, —SH, —NH2, —COOH, —R(CH2)mCH3, —RCOCO(CH2)mCH3, —RCO(CH2)mCHCH3CH3, —RCO(CH2)mNR4CH3, —RCOCHOH(CH2)mCH3, —RCOCH2(CH2)mCH3, —RCOCH2CHOH(CH2)mCH3, —RCOCH2(CH2)mCOOH, —RSO2CH2(CH2)mCH3, —RPO2(OH)CH2(CH2)mCH3 or RCOCH(NHCOCH3)CH2CH2CONH2, in which each R is CH2, O, NH or S, R4 is H or C1-C6 alkyl, and each m is an integer of 0 to 5;
and R3 is H;
(ii) X is the same as defined above;
R1 and R3, which may be identical or different, are each independently —OH, —SH, —NH2, —COOH, —R(CH2)mCH3, —RCOCO(CH2)mCH3, —RCO(CH2)mCHCH3CH3, —RCO(CH2)mNR4CH3, —RCOCHOH(CH2)mCH3, —RCOCH2(CH2)mCH3, —RCOCH2CHOH(CH2)mCH3, —RCOCH2(CH2)mCOOH, —RSO2CH2(CH2)mCH3, —RPO2(OH)CH2(CH2)mCH3 or RCOCH(NHCOCH3)CH2CH2CONH2, in which each R is CH2, O, NH or S, R4 is H or C1-C6 alkyl, and each m is an integer of 0 to 5;
and R2 is H;
(iii) X is the same as defined above;
R1 is —OH, —SH, —NH2, —COOH, —R(CH2)mCH3, —RCOCO(CH2)mCH3, —RCO(CH2)mCHCH3CH3, —RCO(CH2)mNR4CH3, —RCOCHOH(CH2)mCH3, —RCOCH2(CH2)mCH3, —RCOCH2CHOH(CH2)mCH3, —RCOCH2(CH2)mCOOH, —RSO2CH2(CH2)mCH3, —RPO2(OH)CH2(CH2)mCH3 or RCOCH(NHCOCH3)CH2CH2CONH2, in which each R is CH2, O, NH or S, R4 is H or C1-C6 alkyl, and each m is an integer of 0 to 5;
R2 is H;
and R3 is H, OH or Cl;
(iv) X is the same as defined above;
R3 is —OH, —SH, —NH2, —COOH, —R(CH2)mCH3, —RCOCO(CH2)mCH3, —RCO(CH2)mCHCH3CH3, —RCO(CH2)mNR4CH3, —RCOCHOH(CH2)mCH3, —RCOCH2(CH2)mCH3, —RCOCH2CHOH(CH2)mCH3, —RCOCH2(CH2)mCOOH, —RSO2CH2(CH2)mCH3, —RPO2(OH)CH2(CH2)mCH3 or RCOCH(NHCOCH3)CH2CH2CONH2, in which each R is CH2, O, NH or S, R4 is H or —C1-C6 alkyl, and each m is an integer of 0 to 5;
R2 is H;
and R1 is H, OH or Cl;
or
(v) X is the same as defined above;
R1, R2 and R3, which may be identical or different, are each independently —OH, —SH, —NH2, —COOH, —R(CH2)mCH3, —RCOCO(CH2)mCH3, —RCO(CH2)mCHCH3CH3, —RCO(CH2)mNR4CH3, —RCOCHOH(CH2)mCH3, —RCOCH2(CH2)mCH3, —RCOCH2CHOH(CH2)mCH3, —RCOCH2(CH2)mCOOH, —RSO2CH2(CH2)mCH3, —RPO2(OH)CH2(CH2)mCH3 or RCOCH(NHCOCH3)CH2CH2CONH2, in which each R is CH2, O, NH or S, R4 is H or C1-C6 alkyl, and each m is an integer of 0 to 5.

16 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/239,001Filed 17 Sep 2002
Priority: KR 2001-002981329 May 2001
Published: 11 Sep 2003
Term ends: Not estimatedThe source records don’t support an estimate.

Classification15 codes

C07C 403/20
Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four…:…
A61P 35/00
Antineoplastic agents
C07C 205/43
Having nitro groups or esterified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton: to carbon atoms of…
C07C 233/10
Having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals: with carbon atoms of…