JP2010502667A - Snac(サルカプロザートナトリウム)の製造法 - Google Patents
Snac(サルカプロザートナトリウム)の製造法 Download PDFInfo
- Publication number
- JP2010502667A JP2010502667A JP2009527117A JP2009527117A JP2010502667A JP 2010502667 A JP2010502667 A JP 2010502667A JP 2009527117 A JP2009527117 A JP 2009527117A JP 2009527117 A JP2009527117 A JP 2009527117A JP 2010502667 A JP2010502667 A JP 2010502667A
- Authority
- JP
- Japan
- Prior art keywords
- acid
- hydroxybenzoyl
- amino
- snac
- ethyl ester
- 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.)
- Granted
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- UOENJXXSKABLJL-UHFFFAOYSA-M sodium;8-[(2-hydroxybenzoyl)amino]octanoate Chemical compound [Na+].OC1=CC=CC=C1C(=O)NCCCCCCCC([O-])=O UOENJXXSKABLJL-UHFFFAOYSA-M 0.000 title description 40
- 238000004519 manufacturing process Methods 0.000 title description 4
- 238000000034 method Methods 0.000 claims abstract description 38
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 48
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 11
- RQSYZQMFSKGZTL-UHFFFAOYSA-N ethyl 2-(2,4-dioxo-1,3-benzoxazin-5-yl)octanoate Chemical compound O1C(=O)NC(=O)C2=C1C=CC=C2C(C(=O)OCC)CCCCCC RQSYZQMFSKGZTL-UHFFFAOYSA-N 0.000 claims description 11
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 10
- 238000002156 mixing Methods 0.000 claims description 10
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 8
- 235000010323 ascorbic acid Nutrition 0.000 claims description 6
- 229960005070 ascorbic acid Drugs 0.000 claims description 6
- 239000011668 ascorbic acid Substances 0.000 claims description 6
- 125000004494 ethyl ester group Chemical group 0.000 claims 2
- 230000003301 hydrolyzing effect Effects 0.000 claims 2
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 claims 1
- WERFEMAVNAGTHG-UHFFFAOYSA-N CCCCCCC(C1=C2C(=CC=C1)OC(=O)NC2=O)C(=O)O Chemical compound CCCCCCC(C1=C2C(=CC=C1)OC(=O)NC2=O)C(=O)O WERFEMAVNAGTHG-UHFFFAOYSA-N 0.000 claims 1
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 claims 1
- 238000010899 nucleation Methods 0.000 claims 1
- 150000003003 phosphines Chemical class 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 14
- 230000015572 biosynthetic process Effects 0.000 abstract description 8
- 239000012535 impurity Substances 0.000 abstract description 8
- 238000006243 chemical reaction Methods 0.000 abstract description 6
- 159000000000 sodium salts Chemical class 0.000 abstract description 4
- 238000010931 ester hydrolysis Methods 0.000 abstract 2
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- 229940122361 Bisphosphonate Drugs 0.000 description 53
- 150000004663 bisphosphonates Chemical class 0.000 description 53
- 239000002552 dosage form Substances 0.000 description 21
- 150000003839 salts Chemical class 0.000 description 20
- MPBVHIBUJCELCL-UHFFFAOYSA-N Ibandronate Chemical compound CCCCCN(C)CCC(O)(P(O)(O)=O)P(O)(O)=O MPBVHIBUJCELCL-UHFFFAOYSA-N 0.000 description 19
- 239000000243 solution Substances 0.000 description 17
- 229940015872 ibandronate Drugs 0.000 description 16
- 239000002253 acid Substances 0.000 description 15
- 239000007787 solid Substances 0.000 description 14
- 238000010521 absorption reaction Methods 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 210000001035 gastrointestinal tract Anatomy 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- -1 SNAC trihydrate Chemical class 0.000 description 8
- 229940079593 drug Drugs 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 208000037147 Hypercalcaemia Diseases 0.000 description 6
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 6
- 208000001132 Osteoporosis Diseases 0.000 description 6
- 230000000148 hypercalcaemia Effects 0.000 description 6
- 208000030915 hypercalcemia disease Diseases 0.000 description 6
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 6
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 6
- 229940069328 povidone Drugs 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 208000036631 Metastatic pain Diseases 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 239000002002 slurry Substances 0.000 description 5
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 238000009826 distribution Methods 0.000 description 4
- 239000004005 microsphere Substances 0.000 description 4
- 239000000651 prodrug Substances 0.000 description 4
- 229940002612 prodrug Drugs 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 description 3
- 206010058019 Cancer Pain Diseases 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 238000007385 chemical modification Methods 0.000 description 3
- 239000003795 chemical substances by application Substances 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
- 238000007872 degassing Methods 0.000 description 3
- 230000002255 enzymatic effect Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 230000008929 regeneration Effects 0.000 description 3
- 238000011069 regeneration method Methods 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.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 WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 2
- 229920002785 Croscarmellose sodium Polymers 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- IIDJRNMFWXDHID-UHFFFAOYSA-N Risedronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CC1=CC=CN=C1 IIDJRNMFWXDHID-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DKJJVAGXPKPDRL-UHFFFAOYSA-N Tiludronic acid Chemical compound OP(O)(=O)C(P(O)(O)=O)SC1=CC=C(Cl)C=C1 DKJJVAGXPKPDRL-UHFFFAOYSA-N 0.000 description 2
- UGEPSJNLORCRBO-UHFFFAOYSA-N [3-(dimethylamino)-1-hydroxy-1-phosphonopropyl]phosphonic acid Chemical compound CN(C)CCC(O)(P(O)(O)=O)P(O)(O)=O UGEPSJNLORCRBO-UHFFFAOYSA-N 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 229940062527 alendronate Drugs 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000036983 biotransformation Effects 0.000 description 2
- 229940028101 boniva Drugs 0.000 description 2
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 229960001681 croscarmellose sodium Drugs 0.000 description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 2
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229960001021 lactose monohydrate Drugs 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- PUUSSSIBPPTKTP-UHFFFAOYSA-N neridronic acid Chemical compound NCCCCCC(O)(P(O)(O)=O)P(O)(O)=O PUUSSSIBPPTKTP-UHFFFAOYSA-N 0.000 description 2
- 229950010733 neridronic acid Drugs 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- WRUUGTRCQOWXEG-UHFFFAOYSA-N pamidronate Chemical compound NCCC(O)(P(O)(O)=O)P(O)(O)=O WRUUGTRCQOWXEG-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- WGTYBPLFGIVFAS-UHFFFAOYSA-M tetramethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)C WGTYBPLFGIVFAS-UHFFFAOYSA-M 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 230000003442 weekly effect Effects 0.000 description 2
- XRASPMIURGNCCH-UHFFFAOYSA-N zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- 125000003816 2-hydroxybenzoyl group Chemical group OC1=C(C(=O)*)C=CC=C1 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 208000006386 Bone Resorption Diseases 0.000 description 1
- 208000020084 Bone disease Diseases 0.000 description 1
- WPJRISAWUPIQNF-UHFFFAOYSA-N C(C)OC(C(CCCCCC)C1ON=CC2=C1C=CC=C2)=O Chemical compound C(C)OC(C(CCCCCC)C1ON=CC2=C1C=CC=C2)=O WPJRISAWUPIQNF-UHFFFAOYSA-N 0.000 description 1
- 239000005635 Caprylic acid (CAS 124-07-2) Substances 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- DBVJJBKOTRCVKF-UHFFFAOYSA-N Etidronic acid Chemical compound OP(=O)(O)C(O)(C)P(O)(O)=O DBVJJBKOTRCVKF-UHFFFAOYSA-N 0.000 description 1
- 238000003109 Karl Fischer titration Methods 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 229940037127 actonel Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000024279 bone resorption Effects 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- ACSIXWWBWUQEHA-UHFFFAOYSA-N clodronic acid Chemical compound OP(O)(=O)C(Cl)(Cl)P(O)(O)=O ACSIXWWBWUQEHA-UHFFFAOYSA-N 0.000 description 1
- 229960002286 clodronic acid Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- ZZFKAZHZSSJSSE-UHFFFAOYSA-L disodium;[(cycloheptylamino)-[hydroxy(oxido)phosphoryl]methyl]-hydroxyphosphinate;hydrate Chemical compound O.[Na+].[Na+].OP(O)(=O)C(P([O-])([O-])=O)NC1CCCCCC1 ZZFKAZHZSSJSSE-UHFFFAOYSA-L 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000003118 drug derivative Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- SUSNCCGSNPFNOS-UHFFFAOYSA-N ethyl 2-(2H-1,3-benzoxazin-2-yl)-3,4-dioxooctanoate Chemical compound C(C)OC(C(C(C(CCCC)=O)=O)C1OC2=C(C=N1)C=CC=C2)=O SUSNCCGSNPFNOS-UHFFFAOYSA-N 0.000 description 1
- 229940009626 etidronate Drugs 0.000 description 1
- 229940001490 fosamax Drugs 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 229960005236 ibandronic acid Drugs 0.000 description 1
- 229950006971 incadronic acid Drugs 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 229940058213 medronate Drugs 0.000 description 1
- MBKDYNNUVRNNRF-UHFFFAOYSA-N medronic acid Chemical compound OP(O)(=O)CP(O)(O)=O MBKDYNNUVRNNRF-UHFFFAOYSA-N 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229960002446 octanoic acid Drugs 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229940046231 pamidronate Drugs 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229940089617 risedronate Drugs 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229940112726 skelid Drugs 0.000 description 1
- BYKRNSHANADUFY-UHFFFAOYSA-M sodium octanoate Chemical compound [Na+].CCCCCCCC([O-])=O BYKRNSHANADUFY-UHFFFAOYSA-M 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229940019375 tiludronate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 150000004684 trihydrates Chemical group 0.000 description 1
- 229960004276 zoledronic acid Drugs 0.000 description 1
- 229940002005 zometa Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/60—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/84—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
- C07F1/04—Sodium compounds
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
Description
(a)単独で経口投与したときに治療上有効でない量で存在するビスホスホネート、または薬学的に許容され得るその塩と;
(b)胃腸管内でのビスホスホネートの吸収を、ビスホスホネートが治療上有効になるように促進するのに有効な量で存在する、本発明の方法に従って製造されたSNACと
を混合する工程を含んで、ビスホスホネート対SNACの比率が、それぞれ、約1:30〜約1:1である方法を提供する。
実施例1:SNAC遊離酸の生成
スキーム1:
スキーム2:
Claims (9)
- N−(8−[2−ヒドロキシベンゾイル]アミノ)カプリル酸を合成する方法であって、
2,4−ジオキソ−1,3−ベンゾオキサジニルオクタン酸エチルエステルを水酸化ナトリウム、水、およびエチレンジアミンテトラ酢酸、アスコルビン酸、NaHSO3およびトリフェニルホスフィンからなる群から選ばれる一員と混合することによって、2,4−ジオキソ−1,3−ベンゾオキサジニルオクタン酸エチルエステルを加水分解する工程を含む方法。 - N−(8−[2−ヒドロキシベンゾイル]アミノ)カプリル酸を合成する方法であって、
2,4−ジオキソ−1,3−ベンゾオキサジニルオクタン酸エチルエステルを水酸化ナトリウムおよび予め沸騰させた水と混合することによって、2,4−ジオキソ−1,3−ベンゾオキサジニルオクタン酸エチルエステルを加水分解する工程を含む方法。 - アセトンおよび塩酸を、水酸化ナトリウム、水、およびエチレンジアミンテトラ酢酸、アスコルビン酸、NaHSO3およびトリフェニルホスフィンからなる群から選ばれる一員とともに該2,4−ジオキソ−1,3−ベンゾオキサジニルオクタン酸エチルエステルと混合する工程を更に含む、請求項1記載の方法。
- アセトンおよび塩酸を、水酸化ナトリウムおよび予め沸騰させた水とともに該2,4−ジオキソ−1,3−ベンゾオキサジニルオクタン酸エチルエステルに加える工程を更に含む、請求項2記載の方法。
- N−(8−[2−ヒドロキシベンゾイル]アミノ)カプリル酸ナトリウム塩を合成する方法であって、
2−プロパノールに懸濁させたN−(8−[2−ヒドロキシベンゾイル]アミノ)カプリル酸を水性水酸化ナトリウムと混合して、N−(8−[2−ヒドロキシベンゾイル]アミノ)カプリル酸ナトリウム塩の溶液を形成する工程を含む方法。 - 該溶液に2−プロパノールを更に加え、該N−(8−[2−ヒドロキシベンゾイル]アミノ)カプリル酸ナトリウム塩の溶液に結晶N−(8−[2−ヒドロキシベンゾイル]アミノ)カプリル酸ナトリウム塩を種晶添加して、該N−(8−[2−ヒドロキシベンゾイル]アミノ)カプリル酸ナトリウム塩を該溶液から沈澱させ、次いで、より多くの2−プロパノールを該溶液に加える工程を更に含む、請求項5記載の方法。
- 該結晶N−(8−[2−ヒドロキシベンゾイル]アミノ)カプリル酸ナトリウム塩が無水N−(8−[2−ヒドロキシベンゾイル]アミノ)カプリル酸ナトリウム塩である、請求項5記載の方法。
- 該N−(8−[2−ヒドロキシベンゾイル]アミノ)カプリル酸が、該2,4−ジオキソ−1,3−ベンゾオキサジニルオクタン酸エチルエステルをエチレンジアミンテトラ酢酸、アスコルビン酸、NaHSO3およびトリフェニルホスフィンのうち少なくとも一つの不在下で加水分解した場合より少ない桃色の着色体を含有する、請求項1記載の方法。
- 該N−(8−[2−ヒドロキシベンゾイル]アミノ)カプリル酸が、該2,4−ジオキソ−1,3−ベンゾオキサジニルオクタン酸エチルエステルを予め沸騰させなかった水中で加水分解した場合より少ない桃色の着色体を含有する、請求項1記載の方法。
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PCT/EP2007/059037 WO2008028859A1 (en) | 2006-09-07 | 2007-08-30 | A process for the manufacture of snac (salcaprozate sodium) |
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JPH09188661A (ja) * | 1996-01-10 | 1997-07-22 | Kao Corp | ポリオキシアルキレン脂肪酸アミド硫酸エステル塩の製造方法 |
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WO2022080294A1 (ja) | 2020-10-16 | 2022-04-21 | 学校法人常翔学園 | 組成物 |
KR20230090333A (ko) | 2020-10-16 | 2023-06-21 | 각코호우징 조쇼 가쿠엔 | 조성물 |
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KR101081149B1 (ko) | 2011-11-07 |
BRPI0716539A2 (pt) | 2016-11-01 |
EP2064175A1 (en) | 2009-06-03 |
US7544833B2 (en) | 2009-06-09 |
MX2009002121A (es) | 2009-05-20 |
US10875826B2 (en) | 2020-12-29 |
CA2662080C (en) | 2012-07-17 |
AU2007293916A1 (en) | 2008-03-13 |
KR20090060997A (ko) | 2009-06-15 |
CA2662080A1 (en) | 2008-03-13 |
CN101506147A (zh) | 2009-08-12 |
ES2498519T3 (es) | 2014-09-24 |
US20210070691A1 (en) | 2021-03-11 |
WO2008028859A1 (en) | 2008-03-13 |
EP2064175B1 (en) | 2014-08-06 |
IL197014A0 (en) | 2009-11-18 |
US20200071263A1 (en) | 2020-03-05 |
US20080064890A1 (en) | 2008-03-13 |
CN101506147B (zh) | 2012-03-21 |
JP5021033B2 (ja) | 2012-09-05 |
AU2007293916B2 (en) | 2011-02-03 |
IL197014A (en) | 2013-01-31 |
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