Compositions comprising eicosapentaenoic acid and a hydroxyl compound and methods of use thereof
View Patent ↗The present invention relates to, inter alia, pharmaceutical compositions comprising a polyunsaturated fatty acid and to methods of using the same to treat or prevent cardiovascular-related diseases.
1. A composition comprising a hydroxyl compound and ethyl eicosapentaenoate, wherein the hydroxyl compound is a compound of Formula I;
wherein
(a) each occurrence of m is independently an integer ranging from 0 to 5;
(b) each occurrence of n is independently an integer ranging from 3 to 7;
(c) X is (CH2)z or Ph, wherein z is an integer from 0 to 4 and Ph is a 1,2-, 1,3-, or 1,4 substituted phenyl group;
(d) each occurrence of R 1 , R 2 , R 11 , and R 12 is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, or benzyl, wherein R 1 , R 2 , R 11 and R 12 are not each simultaneously H; and
(e) each occurrence of Y 1 and Y 2 is independently (C1-C6)alkyl, OH, COOH, COOR 5 , SO 3 H,
wherein
(i) Y 1 and Y 2 are not each simultaneously (C1-C6)alkyl;
(ii) R 3 is (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, or benzyl and is unsubstituted or substituted with one or more halo, OH, (C1-C6)alkoxy, or phenyl groups;
(iii) each occurrence of R 4 is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl and is unsubstituted or substituted with one or two halo, OH, (C1-C6)alkoxy, or phenyl groups; and
(iv) each occurrence of R 5 is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl,
a compound of Formula II;
(a) each occurrence of m is independently an integer ranging from 3 to 7;
(b) each occurrence of n is independently an integer ranging from 0 to 5;
(c) X is (CH2), or Ph, wherein z is an integer from 0 to 4 and Ph is a 1,2-, 1,3-, or 1,4 substituted phenyl group;
(d) each occurrence of Y 1 and Y 2 independently OH, COOH, COOR 7 , SO 3 H,
wherein
(i) R 7 is (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, or benzyl and is unsubstituted or substituted with one or more halo, OH, (C1-C6)alkoxy, or phenyl groups;
(ii) each occurrence of R 8 is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl and is unsubstituted or substituted with one or two halo, OH, (C1-C6)alkoxy, or phenyl groups;
(iii) each occurrence of R 9 is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl;
(e) R 3 and R 4 are (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, or benzyl;
(f) R 5 and R 6 are H, halogen, (C1-C4)alkyl, (C1-C4)alkoxy, (C6)aryloxy, CN, or NO2, N(R 5 )2 where R 5 is H, (C1-C4)alkyl, phenyl, or benzyl;
(g) C* 1 and C* 2 represent independent chiral-carbon centers wherein each center may independently be R or S,
a compound of Formula III;
(a) each occurrence of R 1 , R 2 , R 6 , R 7 , R 11 , or R 12 is independently hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, or benzyl;
(b) each occurrence of n is independently an integer ranging from 1 to 7;
(c) X is (CH2)z or Ph, wherein z is an integer from 0 to 4 and Ph is a 1,2-, 1,3-, or 1,4 substituted phenyl group;
(d) each occurrence of m is independently an integer ranging from 0 to 4;
(e) each occurrence of Y 1 and Y 2 is independently (C1-C6)alkyl, CH2OH, C(O)OH, OC(O)R 3 , C(O)OR 3 , SO 3 H,
(i) R 3 is (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, or benzyl and is unsubstituted or substituted with one or more halo, OH, (C1-C6)alkoxy, or phenyl groups;
(ii) each occurrence of R 4 is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl and is unsubstituted or substituted with one or two halo, OH, (C1-C6)alkoxy, or phenyl groups;
(iii) each occurrence of R 5 is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl; and
(f) b is 0 or 1 and optionally the ring contains the presence of one or more additional carbon-carbon bonds that when present complete one or more carbon-carbon double bonds such that when b is 0 the maximum number of carbon-carbon bonds is two or when b is 1 the maximum number of carbon-carbon bonds is three,
a compound of Formula IV;
(a) each occurrence of R 1 , R 2 , R 6 , R 7 , R 11 , or R 12 is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, or benzyl;
(b) each occurrence of n is independently an integer ranging from 1 to 7;
(c) X is (CH2)z or Ph, wherein z is an integer from 0 to 4 and Ph is a 1,2-, 1,3-, or 1,4 substituted phenyl group;
(d) each occurrence of m is independently an integer ranging from 0 to 4;
(e) each occurrence of Y 1 and Y 2 is independently (C1-C6)alkyl, CH2OH, C(O)OH, OC(O)R 3 , C(O)OR 3 , SO 3 H,
wherein
(i) R 3 is (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, or benzyl and is unsubstituted or substituted with one or more halo, OH, (C1-C6)alkoxy, or phenyl groups;
(ii) each occurrence of R 4 is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl and is unsubstituted or substituted with one or two halo, OH, (C1-C6)alkoxy, or phenyl groups;
(iii) each occurrence of R 5 is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl; and
(f) each occurrence of b is independently 0 or 1 and optionally each of the rings independently contains the presence of one or more additional carbon-carbon bonds that when present complete one or more carbon-carbon double bonds such that when b is 0 the maximum number of carbon-carbon bonds is two or when b is 1 the maximum number of carbon-carbon bonds is three,
a compound of Formula V;
(a) each occurrence of R 1 , R 2 , R 6 , R 7 , R 11 , or R 12 is independently hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, or benzyl;
(b) each occurrence of n is independently an integer ranging from 1 to 7;
(c) X is (CH2)z or Ph, wherein z is an integer from 0 to 4 and Ph is a 1,2-, 1,3-, or 1,4 substituted phenyl group;
(d) each occurrence of m is independently an integer ranging from 0 to 4;
(e) each occurrence of Y 1 and Y 2 is independently (C1-C6)alkyl, CH2OH, C(O)OH, OC(O)R 3 , C(O)OR 3 , SO 3 H,
wherein
(i) R 3 is (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, or benzyl and is unsubstituted or substituted with one or more halo, OH, (C1-C6)alkoxy, or phenyl groups;
(ii) each occurrence of R 4 is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl and is unsubstituted or substituted with one or two halo, OH, (C1-C6)alkoxy, or phenyl groups;
(iii) each occurrence of R 5 is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl; and
(f) b is 0 or 1 and optionally the ring contains one or more carbon-carbon bonds that when present complete one or more carbon-carbon double bonds;
a compound of Formula VI;
(a) each occurrence of R 1 , R 2 , R 6 , R 7 , R 11 , or R 12 is independently hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, or benzyl;
(b) each occurrence of n is independently an integer ranging from 1 to 7;
(c) X is (CH2)z or Ph, wherein z is an integer from 0 to 4 and Ph is a 1,2-, 1,3-, or 1,4 substituted phenyl group;
(d) each occurrence of m is independently an integer ranging from 0 to 4;
(e) each occurrence of Y 1 and Y 2 is independently (C1-C6)alkyl, CH2OH, C(O)OH, OC(O)R 3 , C(O)OR 3 , SO 3 H,
wherein
(i) R 3 is (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, or benzyl and is unsubstituted or substituted with one or more halo, OH, (C1-C6)alkoxy, or phenyl groups;
(ii) each occurrence of R 4 is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl and is unsubstituted or substituted with one or two halo, OH, (C1-C6)alkoxy, or phenyl groups;
(iii) each occurrence of R 5 is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl; and
(f) b is 0 or 1 and optionally the ring contains one or more carbon-carbon bonds that when present complete one or more carbon-carbon double bonds,
a compound of Formula VII;
(a) Z is CH2, CH═CH, or phenyl, where each occurrence of m is independently an integer ranging from 1 to 9, but when Z is phenyl then its associated m is 1;
(b) G is (CH2)x, where x is 1, 2, 3, or 4, CH2CH═CHCH2, CH═CH, CH2-phenyl-CH2, or phenyl;
(c) each occurrence of Y 1 and Y 2 is independently L, V, C(R 1 )(R 2 )—(CH2)c-C(R 3 )(R 4 )—(CH2)n-Y, or C(R 1 )(R 2 )—(CH2)c-V where c is 1 or 2 and n is an integer ranging from 0 to 4; when G is (CH2)x, where x is 1, 2, 3, or 4, W2 is CH3;
(d) each occurrence of R 1 or R 2 is independently (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, or benzyl or when one or both of Y 1 and Y 2 is C(R 1 )(R 2 )—(CH2)c-C(R 3 )(R 4 )—(CH2)n-W, then R 1 and R 2 can both be H to form a methylene group;
(e) R 3 is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, phenyl, benzyl, Cl, Br, CN, NO2, or CF3;
(f) R 4 is OH, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, phenyl, benzyl, Cl, Br, CN, NO2, or CF3;
(g) L is C(R 1 )(R 2 )—(CH2)n-W;
(h) V is:
(i) each occurrence of W is independently OH, COOH, CHO, COOR 5 , SO3H,
wherein
(i) R 5 is (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, or benzyl and is unsubstituted or substituted with one or more halo, OH, (C1-C6)alkoxy, or phenyl groups;
(ii) each occurrence of R 6 is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl and is unsubstituted or substituted with one or two halo, OH, (C1-C6)alkoxy, or phenyl groups;
(iii) each occurrence of R 7 is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl; and
(j) X is (CH2)z or PH, wherein z is an integer from 0 to 4,
a compound of Formula VIII;
(a) Z is CH2, CH═CH, or phenyl, where each occurrence of m is independently an integer ranging from 1 to 9, but when Z is phenyl then its associated m is 1;
(b) G is (CH2)x, where x is 1, 2, 3, or 4, CH2CH═CHCH2, CH═CH, CH2-phenyl-CH2, or phenyl;
(c) each occurrence of Y 1 and Y 2 is independently L, V, C(R 1 )(R 2 )(CH2)c-C(R 3 )(R 4 )—(CH2)n-Y, or C(R 1 )(R 2 )—(CH2)c-V where c is 1 or 2 and n is an integer ranging from 0 to 4; when G is (CH2)x, where x is 1, 2, 3, or 4, W2 is CH3;
(d) each occurrence of R 1 or R 2 is independently (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, or benzyl or when one or both of Y 1 and Y 2 is C(R 1 )(R 2 )—(CH2)c-C(R 3 )(R 4 )—(CH2)n-W, then R 1 and R 2 can both be H to form a methylene group;
(e) R 3 is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, phenyl, benzyl, Cl, Br, CN, NO2, or CF3;
(f) R 4 is OH, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, phenyl, benzyl, Cl, Br, CN, NO2, or CF3;
(g) L is C(R 1 )(R 2 )—(CH2)n-W;
(h) V is:
(i) each occurrence of W is independently OH, COOH, CHO, COOR 5 , SO 3 H,
(i) R 5 is (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, or benzyl and is unsubstituted or substituted with one or more halo, OH, (C1-C6)alkoxy, or phenyl groups;
(ii) each occurrence of R 6 is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl and is unsubstituted or substituted with one or two halo, OH, (C1-C6)alkoxy, or phenyl groups; and
(iii) each occurrence of R 7 is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl,
a compound of Formula IX; or
(a) Z is CH2, CH═CH, or phenyl, where each occurrence of m is independently an integer ranging from 1 to 9, but when Z is phenyl then its associated m is 1;
(b) G is (CH2)x, where x is 1, 2, 3, or 4, CH2CH═CHCH2, CH═CH, CH2-phenyl-CH2, or phenyl;
(c) each occurrence of Y 1 and Y 2 is independently L, V, C(R 1 )(R 2 )—(CH2)c-C(R 3 )(R 4 )—(CH2)n-Y, or C(R 1 )(R 2 )—(CH2)c-V where c is 1 or 2 and n is an integer ranging from 0 to 4; when G is (CH2)x, where x is 1, 2, 3, or 4, W2 is CH3;
(d) each occurrence of R 1 or R 2 is independently (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, or benzyl or when one or both of Y 1 and Y 2 is C(R 1 )(R 2 )—(CH2)c-C(R 3 )(R 4 )—(CH2)n-W, then R 1 and R 2 can both be H to form a methylene group;
(e) R 3 is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, phenyl, benzyl, Cl, Br, CN, NO2, or CF3;
(f) R 4 is OH, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, phenyl, benzyl, Cl, Br, CN, NO2, or CF3;
(g) L is C(R 1 )(R 2 )—(CH2)n-W;
(h) V is:
(i) each occurrence of W is independently OH, COOH, CHO, COOR 5 , SO3H,
wherein
(i) R 5 is (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, or benzyl and is unsubstituted or substituted with one or more halo, OH, (C1-C6)alkoxy, or phenyl groups;
(ii) each occurrence of R 6 is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl and is unsubstituted or substituted with one or two halo, OH, (C1-C6)alkoxy, or phenyl groups; and
(iii) each occurrence of R 7 is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl, a pharmaceutically acceptable salt thereof, a hydrate thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a stereoisomer thereof, and mixtures thereof.
2. The composition of claim 1 , wherein the composition comprises at least about 80%, by weight of all fatty acids present, ethyl eicosapentaenoate.
3. The composition of claim 1 , wherein the hydroxyl compound is present in an amount less than, about equal to, or greater than an effective amount of the hydroxyl compound when administered as a monotherapy.
4. The composition of claim 1 , wherein the hydroxyl compound is present in an amount of about 5 mg to about 2000 mg.
5. The composition of claim 1 , wherein the ethyl eicosapentaenoate is present in an amount of about 400 mg to about 5000 mg.
6. The composition of claim 1 , wherein the hydroxyl compound is dispersed or suspended in the ethyl eicosapentaenoate.
7. The composition of claim 1 , wherein the hydroxyl compound is 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid.
8. A method of treating a cardiovascular-related disease or disorder in a subject comprising administering to the subject a composition comprising a hydroxyl compound and a composition comprising at least about 80%, by weight of all fatty acids present, ethyl eicosapentaenoate, wherein the hydroxyl compound is:
a compound of Formula I;
a compound of Formula II;
a compound of Formula III;
a compound of Formula IV;
a compound of Formula V;
a compound of Formula VI;
a compound of Formula VII;
a compound of Formula VIII;
a compound of Formula IX; or
a pharmaceutically acceptable salt thereof, a hydrate thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a stereoisomer thereof, and mixtures thereof.
9. The method of claim 8 , wherein the cardiovascular-related disease or disorder is hyperlipidemia or homozygous familial hypercholesterolemia (HoFH).
10. The method of claim 8 , wherein the subject has a baseline fasting triglyceride level of about 200 mg/dl to about 499 mg/dl.
11. The method of claim 10 , wherein the subject is on statin therapy.
12. The method of claim 8 , wherein the subject has a baseline fasting triglyceride level of at least about 500 mg/dl.
13. The method of claim 8 , wherein the subject is administered the composition for a period of time to effect a reduction in triglyceride levels of at least about 5%.
14. The method of claim 13 , wherein the reduction is in comparison to baseline, to placebo control or to a second subject or subject group who has received ethyl eicosapentaenoate but not the hydroxyl compound.
15. The method of claim 13 , wherein the reduction is in comparison to a second subject or subject group who has received the hydroxyl compound but not ethyl eicosapentaenoate.
16. The method of claim 8 , wherein the composition comprising the hydroxyl compound and the composition comprising ethyl eicosapentaenoate are present in a single dosage form.
17. The method of claim 8 , wherein the hydroxyl compound is in a dosage form separate from the ethyl eicosapentaenoate.
18. A method of treating a cardiovascular-related disease or disorder in a subject receiving therapy including a hydroxyl compound, the method comprising administering to the subject a composition comprising at least about 80%, by weight of all fatty acids present, ethyl eicosapentaenoate, wherein the hydroxyl compound is:
a compound of Formula I;
a compound of Formula II;
a compound of Formula III;
a compound of Formula IV;
a compound of Formula V;
a compound of Formula VI;
a compound of Formula VII;
a compound of Formula VIII;
a compound of Formula IX; or
a pharmaceutically acceptable salt thereof, a hydrate thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a stereoisomer thereof, and mixtures thereof.
19. The method of claim 18 , wherein the subject is administered the composition for a period of time to effect a reduction in triglyceride levels of at least about 5%.
20. The method of claim 19 , wherein the reduction is in comparison to baseline, to placebo control, to a second subject or subject group who has received ethyl eicosapentaenoate but not the hydroxyl compound, or to a second subject or subject group who has received the hydroxyl compound but not ethyl eicosapentaenoate.