Patent EA-004862-B1 (EA)
Title: Calcium diicarboxylate ethers, methods of making same, pharmaceutical compositions and method of treatment
Inventor: ANDO HOWARD YOSHIHISA
IPC: A61K31/194
Filed: 2001-01-11
Abstract: 1. The compound 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid monocalcium salt Crystal Form 1 that exhibits an x-ray powder diffraction pattern comprising a characteristic peak expressed in degrees 2theta at 6.760. 2. The compound 6-(5-carboxy-5-methyl-bexyloxy)-2,2-dimethylhexanoic acid monocalcium salt Crystal Form 1 according to claim 1 that exhibits an x-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 2theta at 6.760 and 17.420. 3. The compound 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid monocalcium salt Crystal Form 1 according to claim 2 that exhibits an x-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 2theta at 8.183. 4. The compound 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid monocalcium salt Crystal Form 1 according to claim 2 that exhibits an x-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 2theta at 8.560. 5. The compound 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid monocalcium salt Crystal Form 1 according to claim 2 that exhibits an x-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 2theta at 9.760. 6. The compound 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid monocalcium salt Crystal Form 1 according to claim 2 that exhibits an x-ray powder diffraction pattern comprising characteristic peaks expressed in degrees 2theta at 8.183, 8.560, 9.239, 9.760, 10.569, 11.141; 13.760; 15.599; 16.740; 20.639; 21.391; 22.139 or 31.559. 7. The compound 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid monocalcium salt Crystal Form 1 according to claim 6 having an x-ray powder diffraction pattern comprising (	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	9.5538	224	4.6	29	1.9	0.096 5	9.760	9.0546	972	19.0	220	14.7	0.181 6	10.569	8.3534	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	333	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 8. The crystalline compound of claim 7 having a <13>C NMR (solid state) in ppm<-1> of: 189.6; 186.2; 71.4; 43.4; 30.1; 28.4; 25.2; 23.1 externally referenced to the CH resonance of adamantane at 29.50 pmm<-1>. 9. The crystalline compound of claim 7 having a <13>C NMR peak at 25.2 ppm<-1> externally referenced to the CH resonance of adamantane at 29.50 pmm<-1>. 10. The compound of claim 7, wherein said crystalline structure contains from 0.1 to 1.0 water molecules per salt ion. 11. The crystalline compound 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid monocalcium salt ethanol solvate that exhibits an x-ray powder diffraction pattern comprising a characteristic peak expressed in degrees 2theta at 6.899. 12. The crystalline compound 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid monocalcium salt ethanol solvate that exhibits an x-ray powder diffraction pattern comprising a characteristic peak expressed in degrees 2theta at 8.261. 13. The crystalline compound 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid monocalcium salt ethanol solvate according to claim 11 or 12 that exhibits an x-ray powder diffraction pattern comprising a characteristic peak expressed in degrees 2theta at 6.899 and 8.261. 14. The crystalline compound 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid monocalcium salt ethanol solvate according to claim 13 that exhibits an x-ray powder diffraction pattern comprising a characteristic peak expressed in degrees 2theta at 8.838. 15. The crystalline compound 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid monocalcium salt ethanol solvate according to claim 13 that exhibits an x-ray powder diffraction pattern comprising a characteristic peak expressed in degrees 2theta at 18.180. 16. The crystalline compound 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid monocalcium salt ethanol solvate according to claim 13 that exhibits an x-ray powder diffraction pattern comprising a characteristic peak expressed in degrees 2theta at 8.838, 11.061, 12.100, 13.619, 17.677, 18.180, 20.840, or 21.334. #	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	735	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	13	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	13	0.072 10	21.334	4.1615	427	3.2	67	2.2	0.125 18. The crystalline compound of claim 17 having a <13>C NMR (solid state) in ppm<-1> of: 189.9; 186.7; 71.6; 58.5; 43.2; 29.9; 23.5 externally referenced to the CH resonance of adamantane at 29.50 pmm<-1>. 19. The crystalline compound of claim 7 having a <13>C NMR peak at 58.5 ppm<-1> externally referenced to the CH resonance of adamantane at 29.50 pmm<-1>. 20. The crystalline compound 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid monocalcium salt methanol solvate that exhibits an x-ray powder diffraction pattern comprising a characteristic peak expressed in degrees 2theta at 6.896. 21. The crystalline compound 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid monocalcium salt methanol solvate that exhibits an x-ray powder diffraction pattern comprising a characteristic peak expressed in degrees 2theta at 18.160. 22. The crystalline compound 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid monocalcium salt methanol solvate according to claim 20 or 21 that exhibits an x-ray powder diffraction pattern comprising a characteristic peak expressed in degrees 2theta at 6.896 and 18.160. 23. The crystalline compound 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid monocalcium salt methanol solvate according to claim 22 that exhibits an x-ray powder diffraction pattern comprising a characteristic peak expressed in degrees 2theta at 8.339. 24. The crystalline compound 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid monocalcium salt methanol solvate according to claim 22 that exhibits an x-ray powder diffraction pattern comprising a characteristic peak expressed in degrees 2theta at 9.219. 25. The crystalline compound 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid monocalcium salt methanol solvate according to claim 22 that exhibits an x-ray powder diffraction pattern comprising a characteristic peak expressed in degrees 2theta at 11.320. 26. The crystalline compound 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid monocalcium salt methanol solvate according to claim 22 that exhibits an x-ray powder diffraction pattern comprising a characteristic peak expressed in degrees 2theta at 8.339, 9.219, 10.280, 11.320, 15.800, 16.741, 18.702, 19.816 or 21.724. 27. The compound 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid monocalcium salt methanol solvate according to claim 26 having an x-ray powder diffraction pattern comprising (	2-Theta	d(A)	Peak	P%	Area	Area%	FWHM 1	6.896	12.8072	11991	100.0	2593	100.0	0.173 2	8.339	10.5940	2046	17.1	334	12.9	0.131 3	9.219	9.5853	1438	12.0	231	10.8	0.156 4	10.280	8.5979	632	5.3	180	6.9	0.227 5	11.320	7.8105	1079	9.0	322	12.4	0.238 6	15.300	5.6044	463	3.9	59	2.3	0.102 7	15.741	5.2513	432	3.6	38	1.4	0.069 8	18.160	4.8809	1260	10.5	599	23.1	0.380 9	18.702	4.7408	700	5.8	184	7.1	0.210 10	19.816	4.4766	5S9	4.9	94	3.6	0.127 11	21.724	4.0876	510	4.3	96	3.7	0.150 28. The crystalline compound of claim 27 having a <13>C NMR (solid state) in ppm<-1> of: 189.6; 186.2; 71.4; 43.2; 29.6; 23.5 externally referenced to the CH resonance of adamantane at 29.50 pmm<-1>. 29. The compound 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid monocalcium salt 1-propyl alcohol solvate that exhibits an x-ray powder diffraction pattern comprising a characteristic peak expressed in degrees 2theta at 6.899. 30. The compound 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid monocalcium salt 1-propyl alcohol solvate that exhibits an x-ray powder diffraction pattern comprising a characteristic peak expressed in degrees 2theta at 7.843. 31. The compound 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid monocalcium salt 1-propyl alcohol solvate according to claim 29 or 30 that exhibits an x-ray powder diffraction pattern comprising a characteristic peak expressed in degrees 2theta at 6.899 and 7.843. 32. The compound 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid monocalcium salt 1-propyl alcohol solvate according to claim 31 that exhibits an x-ray powder diffraction pattern comprising a characteristic peak expressed in degrees 2theta at 8.661. 33. The compound 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid monocalcium salt 1-propyl alcohol solvate according to claim 31 that exhibits an x-ray powder diffraction pattern comprising a characteristic peak expressed in degrees 2theta at 18.262. 34. The compound 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid monocalcium salt 1-propyl alcohol solvate according to claim 31 that exhibits an x-ray powder diffraction pattern comprising a characteristic peak expressed in degrees 2theta at 8.661, 11.359, 12.300, 13.100, 18.262, 20.721, or 21.740. 35. The crystalline compound 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid monocalcium salt 1-propyl alcohol solvate according to claim 31 having an x-ray powder diffraction pattern comprising #	2-Theta	d(A)	Peak	P%	Area	Area %	FWHM 1	6.899	12.8025	12371	100.0	3495	100.0	0.226 2	7.843	11.2637	4815	38.9	1119	32.0	0.186 3	8.661	10.2009	1709	13.8	357	10.2	0.167 4	11.359	7.7833	771	6.2	141	4.0	0.146 5	1