ES2611077T3 - Forma solida de ácido 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-il) ciclopropanocarboxamida)-3-metilpiridin-2-il) benzoico - Google Patents
Forma solida de ácido 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-il) ciclopropanocarboxamida)-3-metilpiridin-2-il) benzoico Download PDFInfo
- Publication number
- ES2611077T3 ES2611077T3 ES08855812.7T ES08855812T ES2611077T3 ES 2611077 T3 ES2611077 T3 ES 2611077T3 ES 08855812 T ES08855812 T ES 08855812T ES 2611077 T3 ES2611077 T3 ES 2611077T3
- Authority
- ES
- Spain
- Prior art keywords
- difluorobenzo
- cyclopropanecarboxamide
- dioxol
- methylpyridin
- benzoic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- VCNWUOJJDJYPBK-UHFFFAOYSA-N 1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropane-1-carboxamide Chemical compound C=1C=C2OC(F)(F)OC2=CC=1C1(C(=O)N)CC1 VCNWUOJJDJYPBK-UHFFFAOYSA-N 0.000 title abstract description 8
- 239000007787 solid Substances 0.000 title description 8
- 238000000034 method Methods 0.000 abstract description 4
- 239000000843 powder Substances 0.000 abstract description 3
- 238000002441 X-ray diffraction Methods 0.000 abstract 1
- 230000005855 radiation Effects 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 239000002904 solvent Substances 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 238000000576 coating method Methods 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 239000006187 pill Substances 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000000945 filler Substances 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 150000003840 hydrochlorides Chemical group 0.000 description 3
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- 239000008247 solid mixture Substances 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 2
- -1 Difluorobenzo [d] [1,3] dioxol-5-yl Chemical group 0.000 description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 2
- 239000004705 High-molecular-weight polyethylene Substances 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- LGRFSURHDFAFJT-UHFFFAOYSA-N Phthalic anhydride Natural products C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 description 2
- 229910006124 SOCl2 Inorganic materials 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 description 2
- AIMMVWOEOZMVMS-UHFFFAOYSA-N cyclopropanecarboxamide Chemical compound NC(=O)C1CC1 AIMMVWOEOZMVMS-UHFFFAOYSA-N 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
- 238000009505 enteric coating Methods 0.000 description 2
- 239000002702 enteric coating Substances 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 235000010265 sodium sulphite Nutrition 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- GABVOLXSMGHLPI-UHFFFAOYSA-N tert-butyl 3-(3-methyl-1-oxidopyridin-1-ium-2-yl)benzoate Chemical compound CC1=CC=C[N+]([O-])=C1C1=CC=CC(C(=O)OC(C)(C)C)=C1 GABVOLXSMGHLPI-UHFFFAOYSA-N 0.000 description 2
- VNFCTMXMAKNWDJ-UHFFFAOYSA-N tert-butyl 3-(3-methylpyridin-2-yl)benzoate Chemical compound CC1=CC=CN=C1C1=CC=CC(C(=O)OC(C)(C)C)=C1 VNFCTMXMAKNWDJ-UHFFFAOYSA-N 0.000 description 2
- 239000001993 wax Substances 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- RGKFSYDEMAFDQP-UHFFFAOYSA-N 1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropane-1-carbonitrile Chemical compound C1=C2OC(F)(F)OC2=CC=C1C1(C#N)CC1 RGKFSYDEMAFDQP-UHFFFAOYSA-N 0.000 description 1
- FVNYSBKXILOVTD-UHFFFAOYSA-N 1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropane-1-carbonyl chloride Chemical compound C1=C2OC(F)(F)OC2=CC=C1C1(C(Cl)=O)CC1 FVNYSBKXILOVTD-UHFFFAOYSA-N 0.000 description 1
- IELWGOUPQRHXLS-UHFFFAOYSA-N 1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropane-1-carboxylic acid Chemical compound C=1C=C2OC(F)(F)OC2=CC=1C1(C(=O)O)CC1 IELWGOUPQRHXLS-UHFFFAOYSA-N 0.000 description 1
- DGCOGZQDAXUUBY-UHFFFAOYSA-N 2,2-difluoro-1,3-benzodioxole Chemical compound C1=CC=C2OC(F)(F)OC2=C1 DGCOGZQDAXUUBY-UHFFFAOYSA-N 0.000 description 1
- PZSISEFPCYMBDL-UHFFFAOYSA-N 2-bromo-3-methylpyridine Chemical compound CC1=CC=CN=C1Br PZSISEFPCYMBDL-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
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- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
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- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- SSZBUIDZHHWXNJ-UHFFFAOYSA-N Stearinsaeure-hexadecylester Natural products CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC SSZBUIDZHHWXNJ-UHFFFAOYSA-N 0.000 description 1
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- 150000004781 alginic acids Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- OGBUMNBNEWYMNJ-UHFFFAOYSA-N batilol Chemical class CCCCCCCCCCCCCCCCCCOCC(O)CO OGBUMNBNEWYMNJ-UHFFFAOYSA-N 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
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- 239000006172 buffering agent Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- SNRCKKQHDUIRIY-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloromethane;dichloropalladium;iron(2+) Chemical compound [Fe+2].ClCCl.Cl[Pd]Cl.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 SNRCKKQHDUIRIY-UHFFFAOYSA-L 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
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- 230000029142 excretion Effects 0.000 description 1
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- 235000011852 gelatine desserts Nutrition 0.000 description 1
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- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 229910052622 kaolinite Inorganic materials 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000000346 nonvolatile oil Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000000668 oral spray Substances 0.000 description 1
- 229940041678 oral spray Drugs 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 239000003340 retarding agent Substances 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000003206 sterilizing agent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- RZGNTHQZYZRDDB-UHFFFAOYSA-N tert-butyl 3-(6-amino-3-methylpyridin-2-yl)benzoate Chemical compound CC1=CC=C(N)N=C1C1=CC=CC(C(=O)OC(C)(C)C)=C1 RZGNTHQZYZRDDB-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- AQLJVWUFPCUVLO-UHFFFAOYSA-N urea hydrogen peroxide Chemical compound OO.NC(N)=O AQLJVWUFPCUVLO-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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Abstract
Ácido 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-il) ciclopropanocarboxamida)-3-metilpiridin-2-il) benzoico, denominado Forma I; de manera que la Forma I se caracteriza por mostrar uno o más picos a 15,2-15,6 grados, 16,1-16,5 grados y 14,3-14,7 grados en una difracción de rayos X por el método de polvo que se ha obtenido usando radiación alfa de Cu K a 40 kV, 35 mA.
Description
Esquema 2. Síntesis del segmento o fracción de amina.
Esquema 3. Formación de una sal ácida de ácido 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-il) ciclopropanocarboxamida)-3-metilpiridina-2-il) benzoico.
25 Usando, por ejemplo la forma salina de HCl del ácido 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-il) ciclopropanocarboxamida)-3-metilpiridina-2-il) benzoico como punto de inicio o punto de partida, la Forma I puede producirse en grandes cantidades dispersando o disolviendo la forma salina de HCl del ácido 3-(6-(1-(2,2difluorobenzo[d][1,3]dioxol-5-il) ciclopropanocarboxamida)-3-metilpiridina-2-il) benzoico en un disolvente adecuado durante un periodo de tiempo efectivo. Pueden usarse otras formas salinas de ácido 3-(6-(1-(2,2
30 difluorobenzo[d][1,3]dioxol-5-il) ciclopropanocarboxamida)-3-metilpiridina-2-il) benzoico como, por ejemplo, otras formas ácidas minerales u orgánicas. Las otras formas salinas son el resultado de la hidrólisis del t-butil éster con el correspondiente ácido. Otras formas ácidas o salinas incluyen nítrico, sulfúrico, fosfórico, bórico, acético, benzoico, malónico y similares. La forma salina del ácido 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-il) ciclopropanocarboxamida)-3-metilpiridina-2-il) benzoico puede ser soluble o no dependiendo del disolvente utilizado,
35 pero la falta de solubilidad no impide la formación de la Forma I. Por ejemplo, en una realización, el disolvente adecuado puede ser agua o una mezcla alcohol/agua como una mezcla al 50% de metanol/agua, a pesar de que la forma salina de HCl del ácido 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-il) ciclopropanocarboxamida)-3-metilpiridina2-il) benzoico sólo es ligeramente soluble en agua. En una realización, el disolvente adecuado es agua.
40 El periodo de tiempo efectivo para la formación de la Forma I a partir de la forma salina del ácido 3-(6-(1-(2,2difluorobenzo[d][1,3]dioxol-5-il) ciclopropanocarboxamida)-3-metilpiridina-2-il) benzoico puede ser de entre 2 y 24 horas o mayor. Normalmente, no se necesitan más de 24 horas para obtener un alto rendimiento (~98%), pero algunos disolventes pueden requerir periodos de tiempo más largos. También se sabe que el periodo de tiempo que se necesita es inversamente proporcional a la temperatura. Es decir, cuanto mayor es la temperatura menor es el
45 tiempo necesario para provocar la disociación del ácido y formar la Forma I. Cuando el disolvente es agua, removiendo la dispersión durante aproximadamente 24 horas a temperatura ambiente se obtiene la Forma I con un rendimiento del 98% aproximadamente. Si se requiere una solución de la forma salina del ácido 3-(6-(1-(2,2difluorobenzo[d][1,3]dioxol-5-il) ciclopropanocarboxamida)-3-metilpiridina-2-il) benzoico por necesidades del proceso, puede utilizarse una temperatura elevada. Después de remover la solución durante un periodo de tiempo efectivo a
50 una temperatura elevada, la recristalización por enfriamiento produce formas básicamente puras de la Forma I. En una realización, 'básicamente puro(a)' hace referencia a mayor que alrededor del 90% de pureza. En otra realización, 'básicamente puro(a)' hace referencia a mayor que alrededor del 95% de pureza. En otra realización,
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del paciente; el tiempo de administración, la vía de administración y el ritmo de excreción del compuesto específico utilizado; la duración del tratamiento; los fármacos utilizados en combinación o de manera simlutánea con el compuesto específico empleado, y factores similares que son bien conocidos en el ámbito médico. Tal y como se utiliza en el presente texto, el término 'paciente' significa animal, preferiblemente un mamífero, y más preferiblemente un humano.
Las composiciones farmacéuticamente aceptables de la presente invención pueden administrarse a los humanos y a otros animales de forma oral, rectal, parenteral, intracisternal, intravaginal, intraperitoneal, tópica (como mediante polvos, ungüentos o gotas) o bucal; mediante un espray oral o nasal; y de otras formas similares, dependiendo de la gravedad de la infección que se está tratando. En algunas realizaciones, los compuestos de la invención pueden administrarse de forma oral o parenteral con unos niveles de dosis de entre alrededor de 0,01 mg/kg y alrededor de 50 mg/kg, y preferiblemente de entre alrededor de 1 mg/kg y alrededor de 25 mg/kg, en relación con el peso corporal del sujeto y por cada día, una o más veces al día, para obtener el efecto terapéutico deseado.
En algunas realizaciones, la cantidad de la dosis de la Forma I en la forma de dosificación unitaria va de 100 mg a 1000 mg. En otra realización, la cantidad de la dosis de la Forma I va de 200 mg a 900 mg. En otra realización, la cantidad de la dosis de la Forma I va de 300 mg a 800 mg. En otra realización, la cantidad de la dosis de la Forma I va de 400 mg a 700 mg. En otra realización, la cantidad de la dosis de la Forma I va de 500 mg a 600 mg.
Las preparaciones inyectables, por ejemplo, las suspensiones acuosas u oleaginosas inyectables y esterilizadas, pueden prepararse de acuerdo con las técnicas y métodos conocidos utilizando agentes humectantes o de dispersión adecuados y agentes de suspensión adecuados. La preparación inyectable estéril también puede ser una solución, suspensión o emulsión estéril inyectable en un disolvente o diluyente no tóxico y parenteralmente aceptable, por ejemplo, como solución en 1,3-butanediol. Entre los vehículos aceptables y los disolventes que pueden emplearse están el agua, la solución de Ringer, una solución U.S.P. y una solución isotónica de cloruro de sodio. Además, los aceites fijos y estériles se utilizan habitualmente como disolventes o como medio de suspensión. Para este propósito se puede utilizar cualquier aceite fijo suave, incluyendo monoglicéridos o diglicéridos sintéticos. Además, los ácidos grasos como el ácido oleico se utilizan en la preparación de inyectables.
Las preparaciones inyectables pueden esterilizarse, por ejemplo, mediante filtrado a través de un filtro de retención bacteriana, o añadiendo agentes esterilizadores en forma de composiciones sólidas estériles que pueden disolverse
o dispersarse en agua esterilizada o en otro medio esterilizado inyectable antes de su uso.
Preferiblemente, las composiciones para una administración rectal o vaginal son supositorios que pueden prepararse mezclando los compuestos de la presente invención o excipientes o portadores adecuados y no irritantes como mantequilla de cacao, polietilenglicol o cera para supositorios, que son sólidos a temperatura ambiente pero líquidos a temperatura corporal y, por lo tanto, se derriten en el recto o en la cavidad vaginal y liberan el compuesto activo.
Las dosis en forma sólida usadas para la administración oral incluyen cápsulas, comprimidos, pastillas, polvos y gránulos. En estas dosis en forma sólida, el compuesto activo se mezcla con al menos un excipiente o portador inerte y farmacéuticamente aceptable, como el citrato de sodio o el fosfato de dicalcio; y/o a) rellenos o expansores como almidones, lactosa, sucrosa, glucosa, manitol y ácido silícico; b) aglutinantes como, por ejemplo, carboximetilcelulosa, alginatos, gelatina, polivinilpirrolidinona, sucrosa y acacia; c) humectantes como glicerol; d) agentes desintegrantes como agar-agar, carbonato de calcio, almidón de patata o tapioca, ácido algínico, algunos silicatos y carbonato de sodio; e) agentes retardantes como parafina; f) acelerantes de la absorción como los compuestos de amonios cuaternarios; g) agentes para humedecer como, por ejemplo, alcohol cetílico y monoestearato de glicerol; h) absorbentes como caolinita y arcilla de bentonita; e i) lubricantes como talco, estearato de calcio, estearato de magnesio, polietilenglicoles sólidos, lauril sulfato de sodio, y mezclas de estos compuestos. En el caso de las cápsulas, comprimidos y pastillas, la dosis también puede incluir agentes amortiguadores.
Las composiciones sólidas similares también se pueden usar como relleno para cápsulas de gelatina blandas o duras utilizando excipientes como lactosa o azúcar lácteo, así como polietilenglicoles con un alto peso molecular y similares. Las dósis en forma -sólida-de comprimidos, grageas, cápsulas, pastillas y gránulos pueden prepararse utilizando revestimientos y carcasas como revestimientos entéricos y otros revestimientos bien conocidos en el campo de las preparaciones farmacéuticas. Opcionalmente, pueden contener agentes opacantes y también pueden tener una composición que hace que liberen los ingredientes activos sólo, o preferentemente, en ciertas partes del tracto intestinal y, opcionalmente, de manera retardada. Los ejemplos de composiciones aislantes que pueden utilizarse incluyen sustancias poliméricas y ceras. Las composiciones sólidas similares también pueden utilizarse como relleno en cápsulas de gelatina duras y blandas usando excipientes como lactosa o azúcar lácteo, así como polietilenglicoles con un elevado peso molecular y similares.
Los componentes activos también pueden estar en forma de microcápsulas, con uno o más excipientes, tal y como se ha explicado previamente. Las dósis en forma -sólida-de comprimidos, grageas, cápsulas, pastillas y gránulos pueden prepararse utilizando revestimientos y carcasas como revestimientos entéricos, revestimientos que controlan la liberación y otros revestimientos bien conocidos en el campo de las preparaciones farmacéuticas. En estas dosis en forma sólida, el compuesto activo puede mezclarse con al menos un diluyente inerte como sucrosa, lactosa o
10
El (2,2-difluoro-1,3-benzodioxol-5-il)-ciclopropanocarbonitrilo se hidroliza usando 6 M de NaOH (8 equiv.) en etanol (5 vol) a 80ºC durante la noche. La mezcla se enfría hasta alcanzar la temperatura ambiente y se evapora el etanol al vacío. El residuo o sobrante se pone en agua y MTBE, se añade 1 M de HCl y las capas se separan. Después se trata la capa de MTBE con diciclohexilamina (0,97 equiv). La lechada se enfría hasta 0ºC, se filtra y se lava con heptano para obtener la correspondiente sal de DCHA. La sal se pone en MTBE y 10% de ácido cítrico, y se remueve hasta que se disuelvan todos los sólidos. Se separan las capas y la capa de MTBE se lava con agua y salmuera. Si se intercambia el solvente al heptano y después se filtra, se obtiene ácido 1-(2,2-difluoro-1,3benzodioxol-5-il)-ciclopropanocarboxílico después de secar en una estufa u horno de vacío a 50ºC durante la noche.
Síntesis de 1-(2,2-difluoro-1,3-benzodioxol-5-il)-ciclopropanocarbonil cloruro.
mezcla se calienta hasta 60ºC. Se añade SOCl2 (1,4 eq) con un embudo de adición. El tolueno y el SOCl2 se destilan de la mezcla de reacción después de 30 minutos. Se añade tolueno adicional (2,5 vol) y se destila de nuevo.
El segmento o fracción de amina Síntesis de tert-butil-3-(3-metilpiridin-2-il)benzoato.
Se disuelve 2-Bromo-3-metilpiridina (1,0 eq) en tolueno (12 vol). Se añade K2CO3 (4,8 eq) seguido de agua (3,5 vol), y la mezcla se calienta hasta 65ºC bajo un chorro de N2 durante 1 hora. Después, se añaden ácido 3-(tButoxicarbonil)fenilborónico (1,05 eq) y Pd(dppf)Cl2-CH2Cl2 (0,015 eq), y la mezcla se calienta hasta 80ºC. Después de 2 horas, se detiene el calor, se añade agua (3,5 vol) y se deja que las capas se separen. Después se lava la fase orgánica con agua (3,5 vol) y se extrae con una solución acuosa (10%) de ácido metanosulfónico (2 eq de MsOH; 7,7 vol). Se hace que la fase acuosa sea básica con una solución acuosa (50%) de NaOH (2 eq) y se extrae con EtOAc (8 vol). Después se concentra la capa orgánica para obtener tert-butil-3-(3-metilpiridin-2-il)benzoato crudo (82%), que se usa directamente en el siguiente paso.
Síntesis de 2-(3-(tert-butoxicarbonil)fenil)-3-metilpiridina-1-óxido.
peróxido de hidrógeno de urea (3 eq). Se añade anhídrido ftálico (3 eq) en partes como sólido para mantener la temperatura en el reactor por debajo de 45ºC. Después de completar la adición de anhídrido ftálico, la mezcla se calienta hasta 45ºC. Después de remover durante 4 horas más, se detiene el calor. Se añade una solución acuosa (10% de porcentaje en peso) de Na2SO3 (1,5 eq) con un embudo de adición. Después de completar la adición de Na2SO3, se remueve la mezcla durante 30 minutos más y las capas se separan. Se remueve la capa orgánica y se añade una disolución acuosa (10% de porcentaje en peso) de Na2CO3 (2 eq). Después de remover durante 30 minutos, se deja que las capas se separen. La fase orgánica se lava con una solución acuosa (13% de peso en volumen [p/v]) de NaCl. Después, se filtra la fase orgánica y se concentra para obtener 2-(3-(tertbutoxicarbonil)fenil)-3-metilpiridina-1-óxido crudo (95%), que se usa directamente en el siguiente paso.
Síntesis de tert-butil-3-(6-amino-3-metilpiridin-2-il)benzoato.
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