Calcium dicarboxylate ethers, methods of making same, and treatment of vascular disease and diabetes therewith
AssigneeWarner-Lambert Company
InventorsHoward Yoshihisa Ando, Donald Eugene Butler, Gary Jay Dozeman
Life of this patent
Estimating the term…
Abstract
Alcohol and water solvates of 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexonoic acid monocalcium salt are crystalline and have the formula (I), wherein R1 is H or lower alkyl, and x is a number from 0 to 10, and are useful for treating dyslipidemia.
Claims51
A compound that is 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid monocalcium salt of Formula II:
- 11
- wherein R1 is H or lower alkyl and x is a number from 0 to 10.
The compound 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid monocalcium salt.
The compound 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid monocalcium salt hydrate.
The compound 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid monocalcium salt Crystal Form 1 having an x-ray powder diffraction pattern substantially comprising:
- 9 # 2-Theta d(A) Peak P % Area Area % FWHM 1 6.760 13.0648 5106 100.0 1497 100.0 0.234 2 8.183 10.7953 1743 34.1 435 29.1 0.200 3 8.560 10.3207 1866 36.5 543 36.3 0.233 4 9.239 9.5638 234 4.6 29 1.9 0.096 5 9.760 9.0546 972 19.0 220 14.7 0.181 6 10.569 8.3634 156 3.1 12 0.8 0.061 7 11.141 7.9353 178 3.5 29 1.9 0.130 8 13.760 6.4304 266 5.2 46 3.1 0.138 9 15.599 5.6761 338 6.6 63 4.2 0.148 10 16.740 5.2917 433 8.5 64 4.3 0.118 11 17.420 5.0866 1890 37.0 689 46.0 0.291 12 20.639 4.3000 523 10.2 128 8.5 0.196 13 21.391 4.1505 188 3.7 20 1.3 0.085 14 22.139 4.0119 445 8.7 74 4.9 0.132 15 31.559 2.8326 270 5.3 24 1.6 0.070
The compound 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid monocalcium salt having a 13C NMR (solid state) in ppm of:
- 189.6;
- 186.2;
- 71.4;
- 43.14;
- 30.1;
- 28.4;
- 25.2;
- 23.1.
The compound 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid monocalcium salt having a 13C NMR peak at 25.2 ppm.
The crystalline compound 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid monocalcium salt ethanol solvate having an x-ray powder diffraction pattern substantially comprising:
- 10 # 2-Theta d(A) Peak P % Area Area % FWHM 1 6.899 12.8028 13186 100.0 3025 100.0 0.184 2 8.261 10.6945 5221 39.6 931 30.8 0.143 3 8.838 9.9969 2057 15.6 482 15.9 0.187 4 11.061 7.9927 785 6.0 160 5.3 0.163 5 12.100 7.3086 1355 10.3 150 4.9 0.088 6 13.619 6.4964 450 3.4 89 2.9 0.157 7 17.677 5.0132 753 5.7 126 4.2 0.134 8 18.180 4.8755 2011 15.3 588 19.4 0.234 9 20.840 4.2588 439 3.3 40 1.3 0.072 10 21.334 4.1615 427 3.2 67 2.2 0.125
The compound 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid monocalcium salt, ethyl alcohol solvate, having a 13C NMR peak at 58.5 ppm.
The crystalline compound 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid mono-calcium salt methanol solvate.
The compound which is 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid monocalcium salt 1-propyl alcohol solvate.
The compound which is 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid mono-calcium salt 2-propyl alcohol solvate.
The compound 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid monocalcium salt 2-propyl alcohol solvate having a 13C NMR peak at 63.8, 18.7. or 14.3 ppm.
The compound which is 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid monocalcium salt 1-butyl alcohol solvate.
The compound 6-(5-carboxy-5-mentyl-hexyloxy)-2,2-dimethylhexanoic acid monocalcium salt Crystal Form 2 having an x-ray powder diffraction pattern substantially comprising:
- 15 # 2-Theta d(A) Peak P % Area Area % FWHM 1 7.259 12.1686 9283 100.0 2482 100.0 0.214 2 8.739 10.1100 4191 45.1 603 24.3 0.115 3 9.386 8.9628 967 10.4 161 6.5 0.133 4 11.659 7.5838 430 4.6 49 1.9 0.089 5 13.955 6.3408 305 3.3 58 2.3 0.151 6 14.220 6.2233 326 3.5 73 2.9 0.178 7 15.387 5.7537 278 3.0 19 0.7 0.053 8 16.461 5.3806 986 10.6 187 7.5 0.152 9 17.361 5.1039 1490 16.1 348 14.0 0.187 10 18.063 4.9069 1284 13.8 323 13.0 0.201 11 19.302 4.5947 871 9.4 166 6.7 0.152 12 19.862 4.4664 686 7.4 142 5.7 0.166 13 20.200 4.3923 457 4.9 103 4.1 0.179 14 21.178 4.1918 656 7.1 97 3.9 0.117 15 21.641 4.1031 167 1.8 6 0.2 0.029 16 22.300 3.9833 794 8.6 192 7.7 0.193 17 23.218 3.8278 247 2.7 23 0.9 0.071 18 24.100 3.6897 183 2.0 34 1.3 0.145 19 25.481 3.4928 487 5.2 141 5.7 0.231 20 28.800 3.0974 134 1.4 14 0.6 0.083 21 29.297 3.0459 259 2.8 28 1.1 0.084 22 30.700 2.9099 287 3.1 20 0.8 0.055
The compound 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid monocalcium salt Crystal Form 2 having a 13CNMR peak at 72.7, 44.7, or 26.2 ppm.
A method for preparing a stable crystalline compound of Formula II:
- 12
- wherein R1 is lower alkyl and x is a number from 0 to 10, comprising reacting a compound of Formula I
- 13
- with calcium oxide in an alkanol organic solvent of the formula R1OH to yield a solid product:
- and drying the solid product to obtain the monocalcium dicarboxylate ether salt of the compound of Formula II having a stoichiometric ratio of calcium to dicarboxylate of approximately 1:1.
A method for preparing a crystalline hydrate of the Formula II
- 14
- wherein R1 is H and x is a number from 0 to 10. comprising reacting an alcohol solvate of Formula II where R1 is lower alkyl with water.
A method of converting the compound 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid monocalcium salt hydrate Crystal Form 1 into the compound 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid monocalcium salt hydrate Crystal Form 2, said method comprising the steps of:
- exposing the Crystal Form 1 to water:
- agitating the Crystal Form 1 and water:
- heating the Crystal Form 1 and water for sufficient time for a conversion to occur so as to yield Crystal Form 2:
- and drying the solid product to obtain the 6-(5-carboxy-5-methylhexyloxy)-2,2-dimethylhexanoic acid monocalcium salt hydrate Crystal Form 2, wherein the Crystal Form 2 has a stoichiometric ratio of calcium to dicarboxylate form of the compound of 1:1.
A pharmaceutical composition comprising the compound 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid monocalcium salt together with one or more pharmaceutically acceptable diluents, carriers or excipients.
A pharmaceutical composition comprising a crystalline form 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid monocalcium salt together with one or more pharmaceutically acceptable diluents, carriers or excipients.
A pharmaceutical composition comprising 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid monocalcium salt hydrate Crystal Form 1 together with one or more pharmaceutically acceptable diluents. carriers or excipients.
A pharmaceutical composition comprising 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid monocalcium salt hydrate Crystal Form 2 together with one or more pharmaceutically acceptable diluents, carriers or excipients.
A method of treating a vascular disease in a patient in need thereof, said method comprising administering to the patient a therapeutically effective amount of 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid monocalcium salt.
Dependencies are inferred from the claim text.