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US 6,864,282 B2Granted
9,11-cycloendoperoxide pro-drugs of prostaglandin analogues for treatment of ocular hypertension and glaucoma
AssigneeAllergan, Inc.
InventorsKah-Hiing John Ling, Wu Yang, Jinsong Ni, Haiqing Yuan, Diane D. S. Tang-Liu
Life of this patent
Estimating the term…
Abstract
9,11-Cycloendoperoxide derivatives of biologically active prostaglandin analogs, and particularly of the ocular hypotensive drugs Bimatoprost, Latanaprost, Unoprostone, Travoprost and prostaglandin H2 1-ethanolamide or of structurally closely related analogs, are pro-drugs which hydrolyze under physiological conditions to provide prostaglandin analogues that are capable of providing sustained ocular and other in vivo concentrations of the respective drugs. The compounds of the invention have the formula shown below where the variables have the meaning defined in the specification.
Claims37
A compound of the formula:
- wherein the dashed lines represent the presence of a bond, or absence of a bond, wavy lines represent either alpha or beta configuration, solid triangles represent beta configuration and hatched lines represent alpha configuration;
- n is an integer having the values of 1 to 6;
- m is an integer having the values of 1 to 8;
- X is NH2, N(R)2, NHR, or OR where R is hydrogen, R4 or a —(CO)R4 group;
- Y is ═S or OH, OR5 or —O(CO)R5 groups, said OH, OR5 or O(CO)R5 groups being attached to the adjacent carbon in alpha or beta configuration;
- R1 is H, CH3, R7, OR7 or SR7 where R7 is an aliphatic, aromatic or heteroaromatic ring, said heteroaromatic ring having 1 to 3 heteroatoms selected from O, S, and N, said aliphatic, aromatic or heteroaromatic ring being optionally substituted with 1 to 3 H8 groups where H8 is F, Cl, Br, I, NO2, C1-6alkyl, C1-6 fluoro substituted alkyl, COOH, or COOR9 where R9 is alkyl of 1 to 6 carbons or CH2OCH3;
- R2 and R3 together represent ═O, ═S, or independently are hydrogen or alkyl of 1 to 6 carbon atoms, with the proviso that when X is OR then R1 is not H nor methyl;
- R4 represents (CH2)rOH, (CH2)rOCOR9 or (CH2)rOR9 where r is an integer having the values 1 to 6, or R4 represents saturated or unsaturated acyclic hydrocarbons having from 1 to 20 carbon atoms, or —CH2)qR6 where q is 0-10 and R6 is an aliphatic, aromatic or heteroaromatic ring, said heteroaromatic ring having 1 to 3 heteroatoms selected from O, S, and N, said aliphatic, aromatic or heteroaromatic ring being optionally substituted with 1 to R8 groups where R8 is F, Cl, Br, I, NO2, C1-6alkyl, C1-6fluoro substituted alkyl, COOH, COOR9 where R9 is alkyl of 1 to 6 carbons or CH2OCH3 with the further proviso that when X is NHR, m is 4 and R1 is methyl then R4 is not (CH2)2OH;
- R5 represents saturated or unsaturated acyclic hydrocarbons having from 1 to 20 carbon atoms, or —(CH2)qR6, or a pharmaceutically acceptable salt of said compound.
6 more elements
A compound having the formula:
- where Z is O or NH;
- R10 is H, R11 or (CH2)2OH;
- R11 is alkyl of 1 to 3 carbons, and
- R12 is selected from the group consisting of n-butyl, n-hexyl, CH2-phenyl and O-(3-trifluoromethyl)phenyl with the proviso that when Z is O and R12 is n-butyl then R10 is not H nor R11, with the further proviso that when Z is NH and R12 is n-butyl then R10 is not (CH2)2OH.
1 more element
A pharmaceutical composition adapted for administration to a mammal, the composition comprising a pharmaceutically acceptable excipient and a compound of the formula:
- wherein the dashed lines represent the presence of a bond, or absence of a bond, wavy lines represent either alpha or beta configuration, solid triangles represent beta configuration and hatched lines represent alpha configuration;
- n is an integer having the values of 1 to 6;
- m is an integer having the values of 1 to 8;
- X is NH2, N(R)2, NHR, or OR where R is hydrogen, R4 or a —(CO)R4 group;
- Y is ═O, ═S or OH, OR5 or —O(CO)R5 groups, said OH, OR5 or O(CO)R5 groups being attached to the adjacent carbon in alpha or beta configuration;
- R1 is H, CH3, R7, OR7 or SR7 where R7 is an aliphatic, aromatic or heteroaromatic ring, said heteroaromatic ring having 1 to 3 heteroatoms selected from O, S, and N, said aliphatic, aromatic or heteroaromatic ring being optionally substituted with 1 to 3 R8 groups where R8 is F, C1, Br, I, NO2, C1-6alkyl, C1-6fluoro substituted alkyl, COOH, or COOR9 where R9 is alkyl of 1 to 6 carbons or CH2OCH3;
- R2 and R3 together represent ═O, ═S, or independently are hydrogen or alkyl of 1 to6 carbon atoms;
- R4 represents (CH2)rOH, (CH2)rOCOR9 or (CH2)rOR9 where r is an integer having the values 1 to 6, or R4 represents saturated or unsaturated acyclic hydrocarbons having from 1 to 20 carbon atoms, or —(CH2)qR6 where q is 0-10 and R6 is an aliphatic, aromatic or heteroaromatic ring, said heteroaromatic ring having 1 to 3 heteroatoms selected from O, S, and N, said aliphatic, aromatic or heteroaromatic ring being optionally substituted with 1 to R8 groups where R8 is F, C1, Br, I, NO2, C1-6alkyl, C1-6fluoro substituted alkyl, COOH, COOR9 where R9 is alkyl of 1 to 6 carbons or CH2OCH3;
- R5 represents saturated or unsaturated acyclic hydrocarbons having from 1 to 20 carbon atoms, or —(CH2)qR6, or a pharmaceutically acceptable salt of said compound.
6 more elements
A method of administering a drug to a mammal suffering from a condition selected from the group consisting of ocular hypertension, glaucoma, inflammation, gastric ulceration and blood clotting disorders comprising administering to said mammal a corresponding pro-drug compound comprising a compound of the formula
- wherein the dashed lines represent the presence of a bond, or absence of a bond, wavy lines represent either alpha or beta configuration, solid triangles represent beta configuration and hatched lines represent alpha configuration;
- n is an integer having the values of 1 to 6;
- m is an integer having the values of 1 to 8;
- X is NH2, N(R)2, NHR, or OR where R is hydrogen, R4 or a —(CO)R4 group;
- Y is ═O, ═S or OH, OR5 or —O(CO)R5 groups, said OH, OR5 or O(CO)R5 groups being attached to the adjacent carbon in alpha or beta configuration;
- R1 is H, CH3, R7, OR7 or SR7 where R7 is an aliphatic, aromatic or heteroaromatic ring, said heteroaromatic ring having 1 to 3 heteroatoms selected from O, S, and N, said aliphatic, aromatic or heteroaromatic ring being optionally substituted with 1 to 3 R8 groups where R8 is F, Cl, Br, I, NO2, C1-6alkyl, C1-6fluoro substituted alkyl, COOH, or COOR9 where R9 is alkyl of 1 to 6 carbons or CH2OCH3;
- R2 and R3 together represent ═O, ═S, or independently are hydrogen or alkyl of 1 to 6 carbon atoms;
- R4 represents (CH2)rOH, (CH2)rOCOR9 or (CH2)rOR9 where r is an integer having the values 1 to 6, or R4 represents saturated or unsaturated acyclic hydrocarbons having from 1 to 20 carbon atoms, or —(CH2)qR6 where q is 0-10 and R6 is an aliphatic, aromatic or heteroaromatic ring, said heteroaromatic ring having 1 to 3 heteroatoms selected from O, S, and N, said aliphatic, aromatic or heteroaromatic ring being optionally substituted with 1 to R8 groups where R8 is F, Cl, Br, I, NO2, C1-6alkyl, C1-6fluoro substituted alkyl, COOH, COOR9 where R9 is alkyl of 1 to 6 carbons or CH2OCH3;
- R5 represents saturated or unsaturated acyclic hydrocarbons having from 1 to 20 carbon atoms, or —(CH2)qR6, or a pharmaceutically acceptable salt of said compound.
6 more elements
Dependencies are inferred from the claim text.