Method of treating dry eye disorders using 13(S)-HODE and its analogs
First Claim
Patent Images
1. A method for the treatment of dry eye in a mammal, which comprises topically administering to the eye of the mammal a composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of formula I:
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R1 is CO2R, CH2OR2, CONR3R4, or CO2−
R+;
R is H, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, or phenyl;
R+ is Li+, Na+, K+, or an ammonium moiety of formula +NR5R6R7R8, where R5, R6, R7, and R8 are independently H or C1-C6 alkyl, each alkyl group optionally bearing an OH or OCH3 substituent;
R2 is H, C(O)R9, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, benzyl, or phenyl, where R9 is H, C1-6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, benzyl, or phenyl;
R3 and R4 are independently H, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, H, benzyl, phenyl, OH, OCH3, or OC2H5, provided that at most only one of R3 and R4 is OH, OCH3, or OC2H5;
G is CH2, O, or S;
Z is CH2CH═
CH, CH═
CHCH2, CH2C≡
C, C≡
CCH2, (CH2)3, or CH═
C═
CH when G is CH2, and is CH═
CHCH2, C≡
CCH2, or (CH2)3 when G is O or S;
A and D are independently CH2CH2, CH═
CH, or C≡
C, provided that if A is CH2CH2, then D is not CH2CH2;
X is C═
O or CR10R11;
R10 is H or CH3;
R11 is H, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, phenyl, benzyl, or C(O)R12, where R12 is H, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, phenyl, or benzyl;
Y is n-C5H11, C(CH3)H-n-C4H9, C(CH3)2-n-C4H9, (CH2)pPh, or (CH2)pOPh;
p is 1-3;
Ph is a phenyl ring, optionally substituted with halogen, trihalogenated methyl, methyl, OR13, or C(O)CH3, where R13 is H, CH3, C2H5, C(O)CH3, or phenyl; and
Halogen is Cl, I, Br, or F.
1 Assignment
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Accused Products
Abstract
The topical use of 13(S)-HODE and analogs are disclosed for the treatment of dry eye disorders.
97 Citations
15 Claims
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1. A method for the treatment of dry eye in a mammal, which comprises topically administering to the eye of the mammal a composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of formula I:
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R1 is CO2R, CH2OR2, CONR3R4, or CO2−
R+;
R is H, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, or phenyl;
R+ is Li+, Na+, K+, or an ammonium moiety of formula +NR5R6R7R8, where R5, R6, R7, and R8 are independently H or C1-C6 alkyl, each alkyl group optionally bearing an OH or OCH3 substituent;
R2 is H, C(O)R9, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, benzyl, or phenyl, where R9 is H, C1-6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, benzyl, or phenyl;
R3 and R4 are independently H, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, H, benzyl, phenyl, OH, OCH3, or OC2H5, provided that at most only one of R3 and R4 is OH, OCH3, or OC2H5;
G is CH2, O, or S;
Z is CH2CH═
CH, CH═
CHCH2, CH2C≡
C, C≡
CCH2, (CH2)3, or CH═
C═
CH when G is CH2, and is CH═
CHCH2, C≡
CCH2, or (CH2)3 when G is O or S;
A and D are independently CH2CH2, CH═
CH, or C≡
C, provided that if A is CH2CH2, then D is not CH2CH2;
X is C═
O or CR10R11;
R10 is H or CH3;
R11 is H, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, phenyl, benzyl, or C(O)R12, where R12 is H, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, phenyl, or benzyl;
Y is n-C5H11, C(CH3)H-n-C4H9, C(CH3)2-n-C4H9, (CH2)pPh, or (CH2)pOPh;
p is 1-3;
Ph is a phenyl ring, optionally substituted with halogen, trihalogenated methyl, methyl, OR13, or C(O)CH3, where R13 is H, CH3, C2H5, C(O)CH3, or phenyl; and
Halogen is Cl, I, Br, or F. - View Dependent Claims (2, 3, 4, 5, 6)
where for all compounds, R=H, CH3, or C2H5.
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4. The method of claim 1 wherein the pharmaceutically acceptable amount is from 0.000001% to 0.01% (w/w).
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5. The method of claim 4 wherein the pharmaceutically acceptable amount is from 0.00001 % to 0.001% (w/v).
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6. The method of claim 1 wherein the pharmaceutically acceptable carrier comprises one or more ingredients selected from the group consisting of surfactants;
- tonicity agents;
buffers;
preservatives;
co-solvents; and
viscosity building agents.
- tonicity agents;
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7. A composition for the treatment of dry eye in humans comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of one or more compounds of formula I:
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wherein;
R1 is CO2R, CH2OR2, CONR3R4, or CO2−
R+;
R is H, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, or phenyl;
R+ is Li+, Na+, K+, or an ammonium moiety of formula +NR5R6R7R8, where R5, R6, R7, and R8 are independently H or C1-C6 alkyl, each alkyl group optionally bearing an OH or OCH3 substituent;
R2 is H, C(O)R9, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, benzyl, or phenyl, where R9 is H, C1-6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, benzyl, or phenyl;
R3 and R4 are independently H, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, H, benzyl, phenyl, OH, OCH3, or OC2H5, provided that at most only one of R3 and R4 is OH, OCH3, or OC2H5;
G is CH2, O, or S;
Z is CH2CH═
CH, CH═
CHCH2, CH2C≡
C, C≡
CCH2, (CH2)3, or CH═
C═
CH when G is CH2, and is CH═
CHCH2, C≡
CCH2, or (CH2)3 when G is O or S;
A and D are independently CH2CH2, CH═
CH, or C≡
C, provided that if A is CH2CH2, then D is not CH2CH2;
X is C═
O or CR10R11;
R10 is H or CH3;
R11 is H, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, phenyl, benzyl, or C(O)R12, where R12 is H, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, phenyl, or benzyl;
Y is n-C5H11, C(CH3)H-n-C4H9, C(CH3)2-n-C4H9, (CH2)pPh, or (CH2)pOPh;
p is 1-3;
Ph is a phenyl ring, optionally substituted with halogen, trihalogenated methyl, methyl, OR13, or C(O)CH3, where R13 is H, CH3, C2H5, C(O)CH3, or phenyl; and
Halogen is Cl, I, Br, or F. - View Dependent Claims (8, 9, 10, 11, 12)
where for all compounds, R=H, CH3, or C2H5.
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10. The composition of claim 7, wherein the composition is a topical ophthalmic formulation.
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11. The composition of claim 8, wherein the composition is a topical ophthalmic formulation.
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12. The composition of claim 9, wherein the composition is a topical ophthalmic formulation.
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13. A compound of formula I:
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wherein;
R1 is CO2R, CH2OR2, CONR3R4, or CO2−
R+;
R is H, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, or phenyl;
R+ is Li+, Na+, K+, or an ammonium moiety of formula +NR5R6R7R8, where R5, R6, R7, and R8 are independently H or C1-C6 alkyl, each alkyl group optionally bearing an OH or OCH3 substituent;
R2 is H, C(O)R9, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, benzyl, or phenyl, where R9 is H, C1-6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, benzyl, or phenyl;
R3 and R4 are independently H, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, H, benzyl, phenyl, OH, OCH3, or OC2H5, provided that at most only one of R3 and R4 is OH, OCH3, or OC2H5;
G is CH2, O, or S;
Z is CH2CH═
CH, CH═
CHCH2, CH2C≡
C, C≡
CCH2, (CH2)3, or CH═
C═
CH when G is CH2, and is CH═
CHCH2, C≡
CCH2, or (CH2)3 when G is O or S;
A and D are independently CH2CH2, CH═
CH, or C≡
C, provided that if A is CH2CH2, then D is not CH2CH2;
X is C═
O or CR10R11;
R10 is H or CH3;
R11 is H, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, phenyl, benzyl, or C(O)R12, where R12 is H, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, phenyl, or benzyl;
Y is n-C5H11, C(CH3)H-n-C4H9, C(CH3)2-n-C4H9, (CH2)pPh, or (CH2)pOPh;
p is 1-3;
Ph is a phenyl ring, optionally substituted with halogen, trihalogenated methyl, methyl, OR13, or C(O)CH3, where R13 is H, CH3, C2H5, C(O)CH3, or phenyl; and
Halogen is Cl, I, Br, or F;
with the proviso that the following compounds are excluded;
where R=H, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, or phenyl;
or R is a carboxylate salt of formula CO2−
R+, where R+ is Li+, Na+, K+, or an ammonium moiety of formula +NR5R6R7R8, where R5, R6, R7, and R8 are independently H or C1-C6 alkyl, each alkyl group optionally bearing an OH or OCH3 substituent; and
with the substituents at the hydroxyl-bearing carbon (*) being arranged to afford either the R or S absolute configuration.- View Dependent Claims (14, 15)
where R=H, CH3, or C2H5.
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Specification
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Current AssigneeAlcon Incorporated
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Original AssigneeAlcon Incorporated
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InventorsYanni, John M., Hellberg, Mark R., Klimko, Peter G., Gamache, Daniel A., Falck, John R., Graff, Gustav
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Application NumberUS11/302,836Publication NumberTime in Patent OfficeDaysField of SearchUS Class Current514/559CPC Class CodesA61K 31/201 having one or two double bo...A61K 31/202 having three or more double...A61P 27/04 Artificial tears; Irrigatio...
