US2014221439A1PendingUtilityA1
Polyunsaturated fatty acids for the treatment of diseases related to cardiovascular, metabolic and inflammatory disease areas
Est. expiryMay 8, 2029(~2.8 yrs left)· nominal 20-yr term from priority
A61P 3/06A61P 3/10A61P 7/00A61P 9/10A61P 3/04A61P 29/00A61P 1/04A61P 1/16A61P 19/02A61P 1/00C07C 69/675A61K 31/195C07C 59/60C07C 69/708A61K 31/22C07C 51/367C07D 263/26C07C 69/68C07C 67/31A61K 45/06C07B 2200/07A61K 31/19A61K 31/421C07C 57/03
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Claims
Abstract
The present disclosure relates to lipid compounds of the general formula (I): R 1 —O—C(R 2 )(R 3 )—X (I) wherein R 1 is a C 10 -C 22 alkyl group, a C 10 -C 22 alkenyl group having 1-6 double bonds, or a C 10 -C 22 alkynyl group having 1-6 triple bonds; R 2 and R 3 are the same or different and may be chosen from different substituents; and X is a carboxylic acid or a derivative thereof, such as a carboxylic ester, a carboxylic anhydride, a phospholipid, triglyceride, or a carboxamide; or a pharmaceutically acceptable salt, solvate, solvate of such salt, or a prodrug thereof. The present disclosure also relates to pharmaceutical compositions and lipid compositions comprising at least one compound according to the present disclosure, and to such compounds for use as medicaments or for use in therapy, in particular for the treatment of diseases related to the cardiovascular, metabolic, and inflammatory disease area.
Claims
exact text as granted — not AI-modified1 - 93 . (canceled)
94 . A lipid compound of formula (I):
wherein R 1 is a C 10 -C 22 alkenyl group having 3-6 double bonds or a C 10 -C 22 alkynyl group having 1-6 triple bonds;
R 2 and R 3 are the same or different and are chosen from a hydrogen atom, a hydroxy group, an alkyl group, a halogen atom, an alkoxy group, an acyloxy group, an acyl group, an alkenyl group, an alkynyl group, an aryl group, an alkylthio group, an alkoxycarbonyl group, a carboxy group, an alkylsulfinyl group, an alkylsulfonyl group, an amino group, and an alkylamino group, with the proviso that R 2 and R 3 are not both a hydrogen atom; or
R 2 and R 3 together form a cycloalkyl group; and
X is a carboxylic acid or a derivative thereof,
or a pharmaceutically acceptable salt thereof.
95 . The lipid compound according to claim 94 , wherein R 1 is a C 10 -C 22 alkenyl group having 3, 4, 5, or 6 double bonds.
96 . The lipid compound according to claim 94 , wherein the double bonds are methylene interrupted double bonds in Z configuration.
97 . The lipid compound according to claim 94 , wherein R 1 is a C 14 -C 22 alkenyl group having at least one double bond having Z configuration and having the first double bond at the third carbon-carbon bond from the omega (ω) end of the carbon chain.
98 . The lipid compound according to claim 94 , wherein R 1 is chosen from a C 18 , C 20 , or C 22 alkenyl group having 3, 4, 5, or 6 double bonds.
99 . The lipid compound according to claim 94 , of formula:
100 . The lipid compound according to claim 94 , of formula:
101 . The lipid compound according to claim 94 , wherein R 2 is hydrogen, R 3 is an alkyl group, and X is a carboxylic acid.
102 . The lipid compound according to claim 94 , wherein R 1 is a C 10 -C 22 alkynyl group having 1-6 triple bonds.
103 . The lipid compound according to claim 102 , wherein the compound is an omega-3 fatty acid.
104 . The lipid compound according to claim 94 , wherein the salt of the compound of formula (I) is chosen from
wherein X is COO − , and Z + is chosen from Li + , Na + , K + , NH 4 + , a protonated primary amine, a protonated aminopyridine, a protonated secondary amine, a protonated tertiary amine, a protonated guanidine, or a protonated heterocycle;
wherein X is COO − , and Z 2+ is chosen from Mg 2+ , Ca 2+ , or a diprotonated diamine; or
wherein X is COO − and Z n+ is protonated Chitosan:
wherein n and m are integers.
105 . The lipid compound according to claim 94 , wherein R 2 and R 3 are independently chosen from a hydrogen atom, an alkyl group, or an alkoxy group.
106 . The lipid compound according to claim 105 , wherein the alkyl group is a methyl group, an ethyl group, or a propyl group.
107 . The lipid compound according to claim 105 , wherein the alkoxy group is a methoxy group or an ethoxy group.
108 . The lipid compound according to claim 94 , wherein one of R 2 and R 3 is a hydrogen atom, and the other one of R 2 and R 3 is chosen from a hydroxy group, an alkyl group, a halogen atom, an alkoxy group, an acyloxy group, an acyl group, an alkenyl group, an alkynyl group, an aryl group, an alkylthio group, an alkoxycarbonyl group, a carboxy group, an alkylsulfinyl group, an alkylsulfonyl group, an amino group, and an alkylamino group.
109 . The lipid compound according to claim 94 , wherein R 2 and R 3 are the same or different and are chosen from a hydroxy group, an alkyl group, a halogen atom, an alkoxy group, an acyloxy group, an acyl group, an alkenyl group, an alkynyl group, an aryl group, an alkylthio group, an alkoxycarbonyl group, a carboxy group, an alkylsulfinyl group, an alkylsulfonyl group, and an amino group.
110 . The lipid compound according to claim 109 , wherein R 2 is a methyl group and R 3 is an ethyl group.
111 . The lipid compound according to claim 109 , wherein R 2 and R 3 are the same and are chosen from a methyl group or an ethyl group.
112 . The lipid compound according to claim 108 , wherein R 1 is a C 14 -C 22 alkenyl group with at least one double bond having Z configuration and having the first double bond at the third carbon-carbon bond from the omega (ω) end of the carbon chain.
113 . The lipid compound according to claim 94 , wherein X is a carboxylic acid or a derivative thereof in the form of an ester, a 1-mono-glyceride, a 2-mono-glyceride, a diglyceride, a triglyceride, or a phospholipid.
114 . The lipid compound according to claim 113 , wherein X is a carboxylic acid derivative in the form of an ethyl ester.
115 . The lipid compound according to claim 113 , wherein R 2 and R 3 are an ethyl group and a hydrogen, and X is a carboxylic acid derivative in the form of a 2-mono-glyceride.
116 . The lipid compound according to claim 113 , wherein X is a carboxylic acid.
117 . The lipid compound according to claim 94 , wherein the carboxylic acid derivative is a carboxamide.
118 . The lipid compound of claim 117 , wherein the carboxamide is chosen from N-methyl carboxamide, N,N-dimethyl carboxamide, N-ethyl carboxamide, and N,N-diethyl carboxamide.
119 . The lipid compound according to claim 94 , wherein the compound is:
wherein X is a carboxylic acid derivative, which is a carboxamide.
120 . The lipid compound of claim 119 , wherein the carboxamide is chosen from N-methyl carboxamide, N,N-dimethyl carboxamide, N-ethyl carboxamide, and N,N-diethyl carboxamide.
121 . The lipid compound according to claim 94 , in a mixture of diastereomers, enantiomers, or in racemic form.
122 . The lipid compound according to claim 94 , wherein the compound is chosen from:
(A) a lipid compound derived from polyunsaturated fatty acids, wherein R 1 is a C 20 alkenyl having 5 double bonds; (B) a lipid compound derived from polyunsaturated fatty acids, wherein R 1 is a C 22 alkenyl having 6 double bonds; (C) a lipid compound derived from polyunsaturated fatty acids, wherein R 1 is a C 18 alkenyl having 3 double bonds; (D) a lipid compound derived from polyunsaturated fatty acids, wherein R 1 is a C 15 alkenyl having 4 double bonds; (E) a lipid compound derived from polyunsaturated fatty acids, wherein R 1 is a C 18 alkenyl having 5 double bonds; (F) a lipid compound wherein X is a carboxylic acid derivative in the form of a triglyceride; or (G) a lipid compound wherein X is a carboxylate salt.
123 . The lipid compound according to claim 94 , wherein the compound is present as its R enantiomer at the carbon attached to —OR 1 , R 2 , R 3 , and X.
124 . The lipid compound according to claim 94 , wherein the compound is present as its S enantiomer at the carbon attached to —OR 1 , R 2 , R 3 , and X.
125 . The lipid compound according to claim 94 , wherein the compound is:
2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaen-1-yloxy)butanoic acid;
2-((3Z,6Z,9Z,12Z,15Z)-octadeca-3,6,9,12,15-pentaen-1-yloxy)butanoic acid;
2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenyloxy)-2-methylpropanoic acid;
2-((3Z,6Z,9Z,12Z)-pentadeca-3,6,9,12-tetraenyloxy)butanoic acid;
2-((9Z,12Z,15Z)-octadeca-9,12,15-trienyloxy)butanoic acid;
2-ethyl-2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenyloxy)butanoic acid; or
2-ethyl-2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenyloxy)butanoic acid.
126 . A pharmaceutical composition comprising a lipid compound of formula (I):
wherein R 1 is a C 10 -C 22 alkenyl group having 3-6 double bonds or a C 10 -C 22 alkynyl group having 1-6 triple bonds;
R 2 and R 3 are the same or different and are chosen from a hydrogen atom, a hydroxy group, an alkyl group, a halogen atom, an alkoxy group, an acyloxy group, an acyl group, an alkenyl group, an alkynyl group, an aryl group, an alkylthio group, an alkoxycarbonyl group, a carboxy group, an alkylsulfinyl group, an alkylsulfonyl group, an amino group, and an alkylamino group, with the proviso that R 2 and R 3 are not both a hydrogen atom; or
R 2 and R 3 together form a cycloalkyl group; and
X is a carboxylic acid or a derivative thereof,
or a pharmaceutically acceptable salt thereof;
and a pharmaceutically acceptable carrier, excipient, or diluent, or any combination thereof.
127 . The pharmaceutical composition according to claim 126 , further comprising a pharmaceutically acceptable antioxidant.
128 . The pharmaceutical composition according to claim 127 , wherein the antioxidant is tocopherol or 3-tert-butyl-4-hydroxyanisole (3-BHA).
129 . The pharmaceutical composition according to claim 126 , formulated for oral administration.
130 . The pharmaceutical composition according to claim 126 , wherein the at least one lipid compound is administered in a daily dose ranging from 1 mg to 3 g.
131 . The pharmaceutical composition according to claim 130 , wherein the daily dose ranges from 50 mg to 1 g.
132 . The pharmaceutical composition according to claim 130 , wherein the daily dose ranges from 50 mg to 500 mg.
133 . The pharmaceutical composition according to claim 130 , wherein the daily dose ranges from 10 mg to 2 g.
134 . The pharmaceutical composition according to claim 130 , wherein the daily dose ranges from 100 mg to 1 g.
135 . The pharmaceutical composition according to claim 130 , wherein the daily dose ranges from 100 mg to 500 mg.
136 . The pharmaceutical composition according to claim 130 , wherein the daily dose ranges from 100 mg to 250 mg.
137 . The pharmaceutical composition according to claim 126 , in the form of a gelatin capsule, a tablet, or a sachet.
138 . A pharmaceutical formulation comprising a lipid compound of formula (I):
wherein R 1 is a C 10 -C 22 alkenyl group having 3-6 double bonds or a C 10 -C 22 alkynyl group having 1-6 triple bonds;
R 2 and R 3 are the same or different and are chosen from a hydrogen atom, a hydroxy group, an alkyl group, a halogen atom, an alkoxy group, an acyloxy group, an acyl group, an alkenyl group, an alkynyl group, an aryl group, an alkylthio group, an alkoxycarbonyl group, a carboxy group, an alkylsulfinyl group, an alkylsulfonyl group, an amino group, and an alkylamino group, with the proviso that R 2 and R 3 are not both a hydrogen atom; or
R 2 and R 3 together form a cycloalkyl group; and
X is a carboxylic acid or a derivative thereof,
or a pharmaceutically acceptable salt thereof;
an emulsifier,
a viscosity modifier,
an antioxidant,
and a fatty substance.
139 . The pharmaceutical formulation of claim 138 , wherein the antioxidant is 3-tert-butyl-4-hydroxyanisole (3-BHA).
140 . The pharmaceutical formulation of claim 138 , wherein the formulation is in the form of an emulsion.
141 . The pharmaceutical formulation of claim 138 , further comprising gelatin.
142 . The pharmaceutical formulation of claim 138 , comprising a lipid chosen from
2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenyloxy)-2-methylpropanoic acid;
2-ethyl-2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenyloxy)butanoic acid;
2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenyloxy)propanoic acid;
methyl 2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yloxy)propanoate;
methyl 2-ethyl-2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yloxy)butanoate;
methyl 2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yloxy)-2-methylpropanoate;
ethyl 2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yloxy)propanoate;
ethyl 2-ethyl-2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yloxy)butanoate; or
ethyl 2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yloxy)-2-methylpropanoate.
143 . A method of treating inflammation comprising administering to a subject in need thereof at least one compound according to claim 94 .
144 . A method of treating rheumatoid arthritis comprising administering to a subject in need thereof at least one compound according to claim 94 .
145 . A method of treating inflammatory bowel disease (IBD) comprising administering to a subject in need thereof at least one compound according to claim 94 .
146 . A method of treating atherosclerosis comprising administering to a subject in need thereof at least one compound according to claim 94 .
147 . A method of treating diabetes comprising administering to a subject in need thereof at least one compound according to claim 94 .
148 . The method according to claim 147 , wherein the diabetes is type II diabetes.
149 . A method of treating peripheral insulin resistance comprising administering to a subject in need thereof at least one compound according to claim 94 .
150 . A method of treating dyslipidemia or mixed dyslipidemia comprising administering to a subject in need thereof at least one compound according to claim 94 .
151 . The method of claim 150 , wherein the dyslipidemia is hypertriglyceridemia.
152 . A method of treating metabolic syndrome comprising administering to a subject in need thereof at least one compound according to claim 94 .
153 . A method of lowering cholesterol comprising administering to a subject in need thereof at least one compound according to claim 94 .
154 . The method of claim 153 , wherein the cholesterol is non-HDL cholesterol.
155 . The method of claim 153 , wherein the cholesterol is LDL and/or VLDL cholesterol.
156 . A method of raising HDL cholesterol comprising administering to a subject in need thereof at least one compound according to claim 94 .
157 . A method for reduction of body weight and/or for preventing body weight gain, comprising administering to a mammal in need thereof a pharmaceutically active amount of a lipid compound according to claim 94 .
158 . A method of treating a fatty liver disease comprising administering to a subject in need thereof at least one compound according to claim 94 .
159 . The method according to claim 158 , wherein said fatty liver disease is non-alcoholic fatty liver disease (NAFLD).
160 . A method of treating a fatty liver disease comprising administering to a subject in need thereof at least one compound according to claim 94 wherein said at least one compound is of formula:
161 . The method according to claim 160 , wherein said fatty liver disease is non-alcoholic fatty liver disease (NAFLD).
162 . A method for the production of a lipid compound according to claim 94 comprising
a) reacting R 1 —OH with
wherein LG is a leaving group; and
b) isolating the lipid compound.
163 . The method according to claim 162 , wherein the leaving group is chosen from a mesylate group, a toslyate group, a hydroxy group, or a halogen atom.
164 . The method according to claim 162 , further comprising protection and de-protection steps.
165 . The method according to claim 162 , where step a) is conducted in the presence of a base.
166 . The method according to claim 165 , wherein the base is sodium hydroxide.
167 . The method according to claim 162 , wherein step a) is run under Mitsonubo conditions.
168 . The method according to claim 162 , wherein R 1 —OH is first converted to R-LG, wherein LG is a leaving group.Join the waitlist — get patent alerts
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