Sesquiterpene derivatives and their use in inflammation or cancer treatment

A method of preparing the compound of Formula (I)

• or a pharmaceutically acceptable salt thereof,
• wherein R1 is selected from the group consisting of hydrogen, —CO—C(CH3)═CH2, —CO-(E)C(CH3)═CHCH2CH3, —CO-(E)CH═CH-phenyl, —CO-(E)CH═CH-(3,4,5-trimethoxy)phenyl, —CO—CH═C(CH3)2, —CO—CH(Cl)2, —CO—CH2—CH(CH3)2, —CO—CH2C(CH3)(CH2CH3)(OCOCH3), —CO-(E)CH═C(CH3)CH(CH3)2, —CO—CH(CH3)CH2CH3, —CO-(E)CH═C(CH3)CH2CH2CH═C(CH3)2, —CO—CH(CH2CH3)2, —CO—CH3, —CO—CH2C(CH3)CH2CH3, —CO—C(CH2CH3)═CH2, —CO—C(CH3)(CH2)2CH3, —CO—C(CH2CH3)(CH2)3CH3, —CO—CH(CH3)(CH2)3CH3, —CO—CH2C(OH)((CH(CH3)2)2, —CO-(E)CH═CHCH3, —CO-(E)CH═CHCH2CH3, —CO-(E)CH═CH-(4-methoxyphenyl), —CO-(E)CH═CH-(4-methylphenyl), —CO-(E)CH═CH-(4-chlorophenyl), —CO-(E)CH═CH(furan-2-yl), —CO-2-thiofuranyl, —CO-phenyl, —CO-(4-methoxyphenyl), —CO-(4-methylphenyl), —CO-(4-bromophenyl), —CO—CH2-naphthalene-1-yl, —CO-cyclopropyl, —CO-cyclopentyl, —CO-cyclohexyl, —CO-(E)CH═CH(3-methoxyphenyl), —CO-benzofuran-2-yl, —CO-benzothiofuran-2-yl, —CO-(E)CH═CH-(thiofuran-2-yl), —CO—CH2-phenyl, —CO—CH2-(4-methoxyphenyl), —CO—CH2-(6-methoxynaphthalene-1-yl), —CO—CH2-(6-methoxynaphthalene-2-yl), —CO-(E)CH═CH-(3-trifluromethoxyphenyl), —CO-(E)CH═CH-(3-trifluromethylphenyl), —CO-(E)CH═CH-(3,4-dimethoxyphenyl), —CO-(E)CH═CH-(3-ethoxyphenyl), —CO—(CH2)2-(naphthalene-1-yl), —CO—CH2-(quinolin-8-yl), —CO—CH(S—CH3)(6-methoxylnaphthalene-2-yl), —CO—CH(R—CH3)(6-methoxylnaphthalene-2-yl), —CO—C(CH3)(OCH3)-(naphthalene-2-yl), —CO—CH(S—OCH3)-(naphthalene-2-yl), —CO—CH(R—OCH3)-(naphthalene-2-yl), —CO—CH2-(benzothiofuran-3-yl), —CO—CH2-(benzofuran-3-yl), —CO-(E)CH═CH-(4-ethoxyphenyl), —CO-(E)CH═CH-(1,3-benzodioxane-5-yl), and —CO—CH2-(napthalene-1-yl), the method comprising the steps of:
• (5) reacting the compound of Formula (II)
• with aqueous sodium hydroxide to obtain the compound of Formula (I),
• wherein R1 is hydrogen;
• and
• (6) reacting the compound of Formula (I), wherein R1 is hydrogen, with 1-naphthylacetic acid, diethyl azodicarboxylate (DEAD) and triphenylphosphine (PPh3) to afford the compound of Formula (I), wherein R1 is —CO—CH2-(napthalene-1-yl);
• or
• (7) reacting the compound of Formula (I), wherein R, is hydrogen, with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) dimethylaminopyridine (DMAP), and a compound of Formula (III)
• R2COOH Formula (III),
• wherein R2 is selected from the group consisting of —CO—C(CH3)═CH2, —CO-(E)C(CH3)═CHCH2CH3, —CO-(E)CH═CH-phenyl, —CO-(E)CH═CH-(3,4,5-trimethoxy)phenyl, —CO—CH═C(CH3)2, —CO—CH(Cl)2, —CO—CH2—CH(CH3)2, —CO—CH2C(CH3)(CH2CH3)(OCOCH3), —CO-(E)CH═C(CH3)CH(CH3)2, —CO—C(CH3)CH2CH3, —CO-(E)CH═C(CH3)CH2CH2CH═C(CH3)2, —CO—CH(CH2CH3)2, —CO—CH3, —CO—CH2C(CH3)CH2CH3, —CO—C(CH2CH3)═CH2, —CO—C(CH3)(CH2)2CH3, —CO—C(CH2CH3)(CH2)3CH3, —CO—CH(CH3)(CH2)3CH3, —CO—CH2C(OH)((CH(CH3)2)2, —CO-(E)CH═CHCH3, —CO-(E)CH═CHCH2CH3, —CO-(E)CH═CH-(4-methoxyphenyl), —CO-(E)CH═CH-(4-methylphenyl), —CO-(E)CH═CH(4-chlorophenyl), —CO-(E)CH═CH(furan-2-yl), —CO-2-thiofuranyl, —CO-phenyl, —CO—CH2-naphthalene-1-yl, —CO-(E)CH═CH(3-methoxyphenyl), —CO-benzofuran-2-yl, —CO-benzothiofuran-2-yl, —CO-(E)CH═CH-(thiofuran-2-yl), —CO—CH2-phenyl, —CO—CH2-(4-methoxyphenyl), —CO—CH2-(6-methoxynaphthalene-1-yl), —CO—CH2-(6-methoxynaphthalene-2-yl), —CO-(E)CH═CH-(3-trifluromethoxyphenyl), —CO-(E)CH═CH-(3-trifluromethylphenyl), —CO-(E)CH═CH-(3,4-dimethoxyphenyl), —CO-(E)CH═CH-(3-ethoxyphenyl), —CO—(CH2)2-(naphthalene-1-yl), —CO—CH2-(quinolin-8-yl), —CO—CH(S—CH3)(6-methoxylnaphthalene-2-yl), —(CO—CH(R—CH3)(6-methoxylnaphthalene-2-yl), —CO—C(CH3)(OCH3)-(naphthalene-2-yl), —CO—CH(S—OCH3)-(naphthalene-2-yl), —CO—CH(R—OCH3)-(naphthalene-2-yl), —CO—CH2-(benzothiofuran-3-yl), —CO—CH2-(benzofuran-3-yl), —CO-(E)CH═CH-(4-ethoxyphenyl), or —CO-(E)CH═CH-(1,3-benzodioxane-5-yl), and —CO—CH2-(napthalene-1-yl),
• to obtain the compound of Formula (I),
• wherein R1 is selected from the group consisting of —CO—C(CH3)═CH2, —CO-(E)C(CH3)═CHCH2CH3, —CO-(E)CH═CH-phenyl, —CO-(E)CH═CH-(3,4,5-trimethoxy)phenyl, —CO—CH═C(CH3)2, —CO—CH(Cl2), —CO—CH2—CH(CH3)2, —CO—CH2C(CH3)(CH2CH3)(OCOCH3), —CO-(E)CH═C(CH3)CH(CH3)2, —CO—CH(CH3)CH2CH3, —CO-(E)CH═C(CH3)CH2CH2CH═C(CH3)2, —CO—CH—(CH2CH3)2, —CO—CH3, —CO—CH2C(CH3)CH2CH3, —CO—C(CH2CH3)═CH2, —CO—C(CH3)(CH2)2CH3, —CO—C(CH2CH3)(CH2)3CH3, —CO—CH(CH3)(CH2)CH3, —CO—CH2C(OH)((CH(CH3)2)2, —CO-(E)CH═CHCH3, —CO-(E)CH═CHCH2CH3, —CO-(E)CH═CH-(4-methoxyphenyl), —CO-(E)CH═CH-(4-methylphenyl), —CO-(E)CH═CH-(4-chlorophenyl), —CO-(E)CH═CH(furan-2-yl), —CO-2-thiofuranyl, —CO-phenyl, —CO—CH2-naphthalene-1-yl, —CO-(E)CH═CH(3-methoxyphenyl), —CO-benzofuran-2-yl, —CO-benzothiofuran-2-yl, —CO-(E)CH═CH-(thiofuran-2-yl), —CO—CH2-phenyl, —CO—CH2-(4-methoxyphenyl), —CO—CH2-(6-methoxynaphthalene-1-yl), —CO—CH2-(6-methoxynaphthalene-2-yl), —CO-(E)CH═CH-(3-trifluromethoxyphenyl), —CO-(E)CH═CH-(3-trifluromethylphenyl), —CO-(E)CH═CH-(3,4-dimethoxyphenyl), —CO-(E)CH═CH-(3-ethoxyphenyl), —CO—(CH2)2-(naphthalene-1-yl), —CO—CH2-(quinolin-8-yl), —CO—CH(S—CH3)(6-methoxylnaphthalene-2-yl), —CO—CH(R—CH3)(6-methoxylnaphthalene-2-yl), —CO—C(CH3)(OCH3)-(naphthalene-2-yl), —CO—CH(S—OCH3)-(naphthalene-2-yl), —CO—CH(R—OCH3)-(naphthalene-2-yl), —CO—CH2-(benzothiofuran-3-yl), —CO—CH2-(benzofuran-3-yl), —CO-(E)CH═CH-(4-ethoxyphenyl), —CO-(E)CH═CH-(1,3-benzodioxane-5-yl), and —CO—CH2-(napthalene-1-yl);
• or
• (8) reacting the compound of Formula (I), wherein R1 is hydrogen, with triethylamine and a compound of Formula (IV)
• R3COCl Formula (IV),
• wherein R3 is -(4-methoxyphenyl), -(4-methylphenyl), -(4-bromophenyl), -cyclopropyl, -cyclopentyl, or cyclohexyl to obtain the compound of Formula (I), wherein R1 is —CO-(4-methoxyphenyl), —CO-(4-methylphenyl), —CO-(4-bromophenyl), —CO-cyclopropyl, —CO-cyclopentyl, or —CO-cyclohexyl.