Quinoline derivatives as caspase-3 inhibitor, preparation for producing the same and pharmaceutical composition comprising the same

A method for preparing the compound of formula 1a

• Formula 1a
• wherein
• Y is O;
• or N;
• A is H;
• C3-6 alkenyl;
• C3-6 cycloalkyl;
• C6-14 aryl unsubstituted or substituted by halogen, C1-6 alkyl or C1-6 alkoxy;
• C1-6 alkoxyalkyl;
• or C1-6 alkyl unsubstituted or substituted by C6-14 aryl or 5–15 membered heteroaryl wherein the aryl group can be unsubstituted or substituted by halogen, C1-6 alkyl, C1-6 halogenoalkyl, C1-6 alkoxy or amino group;
• R is H;
• C6-14 aryl substituted by C1-6 alkyl;
• 5–15 membered heterocyclic group substituted by C1-6 alkyl;
• or —(CH2)n—CHR4R5
• wherein n is 0, 1, 2, 3 or 4;
• R4 is H;
• C1-6 alkyl;
• C1-6 alkoxy;
• C6-14 aryl unsubstituted or substituted by halogen, C1-6 alkyl, C1-6 halogenoalkyl, C1-6 alkoxy or amino;
• 5–15 membered heteroaryl;
• C3-6 cycloalkyl;
• 5–15 membered heterocyclic group;
• or C6-14 aryl fused to 5–15 membered heterocyclic group;
• R5 is H;
• C1-6 alkyl;
• C1-6 alkoxy;
• or C1-6 alkoxyalkyl;
• and
• R2 is H;
• halogen;
• C1-6 alkyl;
• C1-6 alkoxy;
• C1-6 alkoxyalkyl;
• or C3-6 cycloalkyl;
• or its pharmaceutically acceptable salt which is characterized by comprising the steps of:
• 1) reacting the compound of formula 2
• with the compound of formula 3
• without solvent at 100 to 150° C. with heating or with organic solvent at its boiling point to obtain the compound of formula 4
• 2) cyclizing the compound of formula 4 in organic solvent at 200° C. to the boiling point of the solvent with heating to obtain the compound of formula 5
• 3) reacting the compound of formula 5 with phosphorous oxychloride, phosphorous trichloride or phosphorous pentachloride to obtain the compound of formula 6
• wherein X is halogen, or reacting the compound of formula 5 with sulphonylchloride or phosphorylchloride in organic solvent with the addition of base at −10 C° to ambient temperature to obtain the compound of formula 6 wherein X is sulphonate or phosphonate;
• 4) reacting the compound of formula 6 with the amine of formula 7
• RNH2 Formula 7
• in organic solvent at ambient temperature to the boiling point of the solvent to obtain the compound of formula 8
• 5) hydrolyzing the compound of formula 8 with base in the solvent mixture of organic solvent and water to obtain the compound of formula 9
• 6) reacting the compound of formula 9 with thionylchloride, sulphonylchloride or phosphorylchloride in organic solvent with the addition of base at −10- to ambient temperature to obtain the compound of formula 10
• 7) reacting the compound of formula 10 with a compound of formulas 11a–c
• HOA Formula 11a
• H2NA Formula 11b
• HAS Formula 11c
• wherein A is H;
• C3-6 alkenyl;
• or C1-6 alkyl;
• in organic solvent at ambient temperature to the boiling point of the solvent to obtain the compound of formula 12
• and
• 8) reducing the compound of formula 12 with the metal catalyst and hydrogen gas in organic solvent at ambient temperature to obtain the compound of formula 1a.

A method for preparing the compound of formula 1b

• wherein
• n is 0, 1, 2, or 3;
• R2 is H;
• halogen;
• C1-6 alkyl;
• C1-6 alkoxy;
• C1-6 alkoxyalkyl;
• or C3-6 cycloalkyl;
• R3 is H;
• halogen;
• unsubstituted or substituted amino;
• C1-6 alkyl;
• C1-6 alkoxy;
• C1-6 alkoxyalkyl;
• or C3-6 cycloalkyl;
• R is H;
• C6-14 aryl unsubstitued or substituted by halogen, C1-6 alkyl, C1-6 alkoxy or amino;
• 5‥15 membered heterocyclic group unsubstituted or substituted by halogen, C1-6 alkyl, C1-6 alkoxy or amino;
• or —(CH2)n—CHR4R5
• wherein is 0, 1, 2, 3 or 4;
• R4 is H;
• C1-6 alkyl;
• C1-6 alkoxy;
• C6-14 aryl unsubstitued or substituted by halogen, C1-6 alkyl, C1-6 halogenoalkyl, C1-6 alkoxy or amino;
• 5–5 membered heteroaryl;
• C3-6 cycloalkyl;
• 5–5 membered heterocyclic group unsubstituted or substituted by C1-6 alkyl;
• or 5–15 membered C6-14 aryl fused to heterocyclic group;
• R5 is H;
• C1-6 alkyl;
• C1-6 alkoxy;
• or C1-6 alkoxyalkyl,
• or its pharmaceutically acceptable salt which is characterized by comprising the steps of:
• 1) reacting the compound of formula 2
• with the compound of formula 3
• without solvent at 100 to 150 C° with heating or with organic solvent at its boiling point to obtain the compound of formula 4
• 2) cyclizing the compound of formula 4 in organic solvent at 200 C° to the boiling point of the solvent with heating to obtain the compound of formula 5
• 3) reacting the compound of formula 5 with phosphorous oxychloride, phosphorous trichloride, or phosphorous pentachloride to obtain the compound of formula 6
• wherein X is halogen, or reacting the compound of formula 5 with sulphonylchloride or phosphorylchloride in organic solvent with the addition of base at −10 C° to ambient temperature to obtain the compound of formula 6 wherein X is sulphonate or phosphonate;
• 4) reacting the compound of formula 6 with the amine of formula 7
• RNH2 Formula 7
• in organic solvent at ambient temperature to the boiling poing of the solvent to obtain the compound of formula 8
• 5) hydrolyzing the compound of formula 8 with base in the solvent mixture of organic solvent and water to obtain the compound of formula 9
• 6) reacting the compound of formula 9 for Curtius rearrangement with sodium azide or diphenylphosphorylazide and amine in organic solvent at the boiling point of the solvent to obtain the compound of formula 13
• 7) reacting the compound of formula 13 with the substituted sulphonylchloride compound of formula 14
• in organic solvent at ambient temperature to the boiling point of the solvent to obtain the compound of formula 15
• 8) reducing the compound of formula 15 with the metal catalyst and hydrogen gas in organic solvent at ambient temperature to obtain the compound of formula 1b.

A method for preparing the compound of formula 1c

• R is H;
• C6-14 aryl substituted by C1-6 alkyl;
• 5–5 membered heterocyclic group substituted by C1-6 alkyl;
• or —(CH2)n—CHR4R5
• wherein n is 0, 1, 2, 3 or 4;
• R4 is H;
• C1-6 alkyl;
• C1-6 alkoxy;
• C6-14 aryl unsubstituted or substituted by halogen, C1-6 alkyl, C1-6 halogenoalkyl, C1-6 alkoxy or amino;
• 5–15 membered heteroaryl;
• C3-6 cycloalkyl;
• 5–15 membered heterocyclic group;
• or C6-14 aryl fused to 5–15 membered heterocyclic group;
• R5 is H;
• C1-6 alkyl;
• C1-6 alkoxy;
• or C1-6 alkoxyalkyl;
• and
• R2 is H;
• halogen;
• C1-6 alkyl;
• C1-6 alkoxy;
• C1-6 alkoxyalkyl;
• or C3-6 cycloalkyl;
• or its pharmaceutically acceptable salt which is characterized by comprising the steps of:
• 1) reacting the compound of formula 16
• with the compound of formula 17
• without solvent at 100 to 150 C° with heating or with organic solvent at its boiling point to obtain the compound of formula18
• 2) cyclizing the compound of formula 18 in organic solvent at 200 C° to the boiling point of the solvent with healing to obtain the compound of formula 19
• 3) reacting the compound of formula 19 with phosphorous oxychloride, phosphorous trichloride or phosphorous pentachloride to obtain the compound of formula 20
• wherein X is halogen, or reacting the compound of formula 19 with sulphonylchloride or phosphorylchloride in organic solvent with the addition of base at −10 C° to ambient temperature to obtain the compound of formula 20 wherein X is sulphonate or phosphonate;
• 4) reacting the compound of formula 20 with the amine of formula 7
• RNH2 Formula 7
• in organic solvent at ambient temperature to the boiling poing of the solvent to obtain the compound of formula 21
• 5) reducing the compound of formula 21 with the metal catalyst and hydrogen gas in organic solvent at ambient temperature to obtain the compound of formula 1c.