US20030100537A1 - Calcium (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phos-phonooxy)propylcarbamate - Google Patents
Calcium (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phos-phonooxy)propylcarbamate Download PDFInfo
- Publication number
- US20030100537A1 US20030100537A1 US10/303,213 US30321302A US2003100537A1 US 20030100537 A1 US20030100537 A1 US 20030100537A1 US 30321302 A US30321302 A US 30321302A US 2003100537 A1 US2003100537 A1 US 2003100537A1
- Authority
- US
- United States
- Prior art keywords
- ppm
- compound
- formula
- calcium
- amino
- 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.)
- Abandoned
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- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 title abstract description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 title abstract description 8
- UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 title abstract description 7
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 title abstract description 6
- YNTOKMNHRPSGFU-UHFFFAOYSA-N n-Propyl carbamate Chemical compound CCCOC(N)=O YNTOKMNHRPSGFU-UHFFFAOYSA-N 0.000 title abstract description 6
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 title abstract description 6
- 239000011575 calcium Substances 0.000 title abstract description 5
- 229910052791 calcium Inorganic materials 0.000 title abstract description 5
- 238000000034 method Methods 0.000 claims abstract description 16
- 238000002360 preparation method Methods 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims description 57
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 35
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 32
- 239000000203 mixture Substances 0.000 claims description 28
- 239000002904 solvent Substances 0.000 claims description 23
- 239000011928 denatured alcohol Substances 0.000 claims description 22
- 239000007787 solid Substances 0.000 claims description 9
- 239000001639 calcium acetate Substances 0.000 claims description 6
- 229960005147 calcium acetate Drugs 0.000 claims description 6
- 235000011092 calcium acetate Nutrition 0.000 claims description 6
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 claims description 5
- 229910001424 calcium ion Inorganic materials 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 2
- 238000003306 harvesting Methods 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical group [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 claims 1
- 201000010099 disease Diseases 0.000 abstract description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 5
- 241001430294 unidentified retrovirus Species 0.000 abstract description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000004480 active ingredient Substances 0.000 description 15
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- ZMNCIAGFQBUWTJ-OEMFJLHTSA-N [(3s)-oxolan-3-yl] n-[(2s,3r)-3-hydroxy-4-[2-methylpropyl-(4-nitrophenyl)sulfonylamino]-1-phenylbutan-2-yl]carbamate Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(=CC=1)[N+]([O-])=O)NC(=O)O[C@@H]1COCC1)C1=CC=CC=C1 ZMNCIAGFQBUWTJ-OEMFJLHTSA-N 0.000 description 12
- YMARZQAQMVYCKC-OEMFJLHTSA-N amprenavir Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1COCC1)C1=CC=CC=C1 YMARZQAQMVYCKC-OEMFJLHTSA-N 0.000 description 12
- 238000009472 formulation Methods 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 11
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 11
- 229940043265 methyl isobutyl ketone Drugs 0.000 description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- 229960001830 amprenavir Drugs 0.000 description 10
- 239000003054 catalyst Substances 0.000 description 10
- MLBVMOWEQCZNCC-OEMFJLHTSA-N fosamprenavir Chemical compound C([C@@H]([C@H](OP(O)(O)=O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1COCC1)C1=CC=CC=C1 MLBVMOWEQCZNCC-OEMFJLHTSA-N 0.000 description 10
- 239000003826 tablet Substances 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000000725 suspension Substances 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 7
- XQKKWWCELHKGKB-UHFFFAOYSA-L calcium acetate monohydrate Chemical compound O.[Ca+2].CC([O-])=O.CC([O-])=O XQKKWWCELHKGKB-UHFFFAOYSA-L 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- XOGQXKBFJZURRD-HQROKSDRSA-N calcium;[(3s)-oxolan-3-yl] n-[(2s,3r)-4-[(4-aminophenyl)sulfonyl-(2-methylpropyl)amino]-1-phenyl-3-phosphonooxybutan-2-yl]carbamate Chemical compound [Ca].C([C@@H]([C@H](OP(O)(O)=O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1COCC1)C1=CC=CC=C1 XOGQXKBFJZURRD-HQROKSDRSA-N 0.000 description 6
- 239000004030 hiv protease inhibitor Substances 0.000 description 6
- 239000004615 ingredient Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- HHEVDQQNXOSEBD-OEMFJLHTSA-N [(3s)-oxolan-3-yl] n-[(2s,3r)-4-[2-methylpropyl-(4-nitrophenyl)sulfonylamino]-1-phenyl-3-phosphonooxybutan-2-yl]carbamate Chemical compound C([C@@H]([C@H](OP(O)(O)=O)CN(CC(C)C)S(=O)(=O)C=1C=CC(=CC=1)[N+]([O-])=O)NC(=O)O[C@@H]1COCC1)C1=CC=CC=C1 HHEVDQQNXOSEBD-OEMFJLHTSA-N 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 208000030507 AIDS Diseases 0.000 description 4
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- 241000282472 Canis lupus familiaris Species 0.000 description 4
- -1 L-697-661 Chemical compound 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 239000003638 chemical reducing agent Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 description 4
- 229940042402 non-nucleoside reverse transcriptase inhibitor Drugs 0.000 description 4
- 239000002726 nonnucleoside reverse transcriptase inhibitor Substances 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 230000000865 phosphorylative effect Effects 0.000 description 4
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- MLBVMOWEQCZNCC-OEMFJLHTSA-L CC(C)CN(C[C@@H](OP(=O)([O-])[O-])[C@H](CC1=CC=CC=C1)NC(=O)O[C@H]1CCOC1)S(=O)(=O)C1=CC=C(N)C=C1.[Ca+2] Chemical compound CC(C)CN(C[C@@H](OP(=O)([O-])[O-])[C@H](CC1=CC=CC=C1)NC(=O)O[C@H]1CCOC1)S(=O)(=O)C1=CC=C(N)C=C1.[Ca+2] MLBVMOWEQCZNCC-OEMFJLHTSA-L 0.000 description 3
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 3
- 208000031886 HIV Infections Diseases 0.000 description 3
- 241000725303 Human immunodeficiency virus Species 0.000 description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
- 208000036142 Viral infection Diseases 0.000 description 3
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- 230000037396 body weight Effects 0.000 description 3
- 239000001110 calcium chloride Substances 0.000 description 3
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- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 3
- 239000000920 calcium hydroxide Substances 0.000 description 3
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 3
- XPOQHMRABVBWPR-ZDUSSCGKSA-N efavirenz Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)O1)C(F)(F)F)#CC1CC1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
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- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- 230000009385 viral infection Effects 0.000 description 3
- GWKIPRVERALPRD-ZDUSSCGKSA-N (s)-4-isopropoxycarbonyl-6-methoxy-3-methylthiomethyl-3,4-dihydroquinoxalin-2(1h)-thione Chemical compound N1C(=S)[C@H](CSC)N(C(=O)OC(C)C)C2=CC(OC)=CC=C21 GWKIPRVERALPRD-ZDUSSCGKSA-N 0.000 description 2
- 229920002785 Croscarmellose sodium Polymers 0.000 description 2
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- SYZIUAAQNFJPJY-UHFFFAOYSA-N 1,4-dihydro-3,1-benzoxazin-2-one Chemical class C1=CC=C2COC(=O)NC2=C1 SYZIUAAQNFJPJY-UHFFFAOYSA-N 0.000 description 1
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- ASOMNDIOOKDVDC-UHFFFAOYSA-N 1h-indol-2-yl-[4-[3-(propan-2-ylamino)pyridin-2-yl]piperazin-1-yl]methanone Chemical compound CC(C)NC1=CC=CN=C1N1CCN(C(=O)C=2NC3=CC=CC=C3C=2)CC1 ASOMNDIOOKDVDC-UHFFFAOYSA-N 0.000 description 1
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- JARNKPQDFXUJTE-UHFFFAOYSA-N [3-hydroxy-5-[[3-methyl-2-[[methyl-[(2-propan-2-yl-1,3-thiazol-4-yl)methyl]carbamoyl]amino]butanoyl]amino]-1,6-diphenylhexan-2-yl]carbamic acid Chemical compound C=1C=CC=CC=1CC(NC(O)=O)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 JARNKPQDFXUJTE-UHFFFAOYSA-N 0.000 description 1
- UCPOMLWZWRTIAA-UHFFFAOYSA-N [4-[3-(ethylamino)pyridin-2-yl]piperazin-1-yl]-(5-methoxy-1h-indol-2-yl)methanone Chemical compound CCNC1=CC=CN=C1N1CCN(C(=O)C=2NC3=CC=C(OC)C=C3C=2)CC1 UCPOMLWZWRTIAA-UHFFFAOYSA-N 0.000 description 1
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- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 159000000007 calcium salts Chemical class 0.000 description 1
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- 229940068682 chewable tablet Drugs 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
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- 239000002270 dispersing agent Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 229960005102 foscarnet Drugs 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 150000005233 imidazopyridazines Chemical class 0.000 description 1
- 238000010965 in-process control Methods 0.000 description 1
- 229960001936 indinavir Drugs 0.000 description 1
- CBVCZFGXHXORBI-PXQQMZJSSA-N indinavir Chemical compound C([C@H](N(CC1)C[C@@H](O)C[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H]2C3=CC=CC=C3C[C@H]2O)C(=O)NC(C)(C)C)N1CC1=CC=CN=C1 CBVCZFGXHXORBI-PXQQMZJSSA-N 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- KELNNWMENBUHNS-NSHDSACASA-N isopropyl (2s)-2-ethyl-7-fluoro-3-oxo-3,4-dihydroquinoxaline-1(2h)-carboxylate Chemical compound FC1=CC=C2NC(=O)[C@H](CC)N(C(=O)OC(C)C)C2=C1 KELNNWMENBUHNS-NSHDSACASA-N 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 229950006243 loviride Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 229960000884 nelfinavir Drugs 0.000 description 1
- QAGYKUNXZHXKMR-HKWSIXNMSA-N nelfinavir Chemical compound CC1=C(O)C=CC=C1C(=O)N[C@H]([C@H](O)CN1[C@@H](C[C@@H]2CCCC[C@@H]2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 QAGYKUNXZHXKMR-HKWSIXNMSA-N 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 229960000689 nevirapine Drugs 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 238000003305 oral gavage Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical class OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- 150000003252 quinoxalines Chemical class 0.000 description 1
- WTTIBCHOELPGFK-LBPRGKRZSA-N r82150 Chemical class C1N(CC=C(C)C)[C@@H](C)CN2C(=S)NC3=CC=CC1=C32 WTTIBCHOELPGFK-LBPRGKRZSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 229960000311 ritonavir Drugs 0.000 description 1
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 description 1
- 229960001852 saquinavir Drugs 0.000 description 1
- QWAXKHKRTORLEM-UGJKXSETSA-N saquinavir Chemical compound C([C@@H]([C@H](O)CN1C[C@H]2CCCC[C@H]2C[C@H]1C(=O)NC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)C=1N=C2C=CC=CC2=CC=1)C1=CC=CC=C1 QWAXKHKRTORLEM-UGJKXSETSA-N 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 235000015096 spirit Nutrition 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
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- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 230000006514 viral protein processing Effects 0.000 description 1
- 210000002845 virion Anatomy 0.000 description 1
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- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Images
Classifications
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/665—Phosphorus compounds having oxygen as a ring hetero atom, e.g. fosfomycin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
Definitions
- the present invention relates to the antiviral compound calcium (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phos-phonooxy)propylcarbamate, pharmaceutical compositions comprising it, its use in the treatment of retroviral infections, and processes for its preparation.
- Virus-encoded proteases which are essential for viral replication, are required for the processing of viral protein precursors. Interference with the processing of protein precursors inhibits the formation of infectious virions. Accordingly, inhibitors of viral proteases may be used to prevent or treat chronic and acute viral infections.
- (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy) propylcarbamate has increased solubility in the pH range of the gastrointestinal tract compared to the HIV protease inhibitor [3S-[3R*(1R*,2S)]]-[3-[[(4-aminophenyl)sulfony](2-methyl-propyl)amino]-2-hydroxy-1-phenylmethyl)propyl]-tetrahydro-3-furanyl ester (amprenavir, 141W94).
- Amprenavir which has poor solubility and is thus available as a solution in gel capsules and has a high pill burden.
- This new HIV protease inhibitor with its increased solubility thus has the potential to reduce the perceived pill burden and may be formulated as a tablet.
- the calcium salt calcium (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-aminophenyl) sulfonyl](isobutyl)amino]-1-benzyl-2-phosphonooxy)propylcarbamate, has a stable crystalline form.
- this salt has advantageous properties making it suitable for formulation into tablets.
- the compound of the present invention provides an opportunity to reduce the pill burden associated with some HIV protease inhibitors.
- Form (I) the compound of formula (I) in crystalline form, hereinafter referred to as Form (I).
- the invention relates to Form (I) of the compound of formula (I) in crystalline form.
- Form (I) contains about 4 to 5 moles of water.
- any batch containing Form (I) of the compound of formula (I) there may also be other solvated crystalline forms of the compound of formula (I).
- Solid State Form (I) of the compound of formula (I) can be characterised by it's X-ray powder diffraction pattern, shown in FIG. 1. Diffraction traces were obtained using a Phillips PW1800 diffractometer (serial DY701) and Cu K ⁇ radiation. X-ray intensities were measured at 0.02° increments for 4 second intervals using a scintillation counter, between values of 2 and 45° 2 ⁇ .
- Intense diffraction peaks characteristic of Form (I) may occur at the following approximate 2theta angles (using copper K ⁇ X-radiation): 5.735, 9.945, 11.500, 13.780, 14.930, 15.225, 17.980, 19.745, 21.575, 22.170, 24.505, and 27.020. Further details are presented in Table 1.
- the compound of formula (I) may be in the form of a solvate, for example a hydrate.
- the present invention provides a process for the production of the compound of formula (I) in a crystalline form, said process comprising the reaction of a compound of formula (II)
- a phosphorylating agent for example phosphorus oxychloride, phosphorus pentachloride, or dibenzylchlorophosphate
- a base for example pyridine, triethylamine or diisopropylethylamine
- a solvent for example methylisobutylketone or dichloromethane
- reduction typically of the sodium salt formed in aqueous solution by addition of sodium bicarbonate, sodium carbonate or sodium hydroxide
- a reducing agent for example formic acid or hydrogen with palladium/ or platinum/carbon catalyst
- a suitable solvent for example water, ethyl acetate, isopropanol, acetone, methanol, industrial methylated spirit or a mixture of two or more of the above solvents
- a source of calcium ions for example calcium acetate, calcium chloride or calcium hydroxide, optionally in the presence
- the present invention also provides a process for the production of the compound of formula (I), comprising dissolving a compound of formula (III)
- a suitable solvent for example isopropanol, methanol or industrial methylated spirit
- a source of calcium ions for example calcium acetate, calcium chloride or calcium hydroxide.
- the present invention also provides a process for the production of the compound of formula (I), comprising the reduction of a compound of formula (IV), typically of the sodium salt formed in aqueous solution by addition of sodium bicarbonate, sodium carbonate or sodium hydroxide
- a suitable reducing agent for example formic acid or hydrogen with palladium/ or platinum/carbon catalyst
- a suitable solvent for example water, ethyl acetate, isopropanol, acetone, methanol industrial methylated spirit or a mixture of two or more of the above solvents; followed by the addition of water and a source of calcium ions, for example calcium acetate, calcium chloride or calcium hydroxide, optionally in the presence of an additional solvent selected from the above-mentioned list.
- each step may be followed by a standard isolation and purification procedure such as those detailed in the examples hereinafter.
- the compound of formula (I) thus obtained may optionally be further purified by recrystallisation from an appropriate solvent, for example industrial methylated spirit, acetone, methanol or isopropanol and mixtures thereof with water, preferably a mixture of industrial methylated spirit and water.
- an appropriate solvent for example industrial methylated spirit, acetone, methanol or isopropanol and mixtures thereof with water, preferably a mixture of industrial methylated spirit and water.
- a further optional purification step may be carried out by heating a slurry of the product in water to a temperature in the range 70-99° C., preferably 85-97° C., most preferably 90-95° C., for about 2.5-6 hours, preferably 3-5 hours, most preferably 4 hours, followed by cooling to ambient temperature and harvesting the solid.
- the compound of formula (II) may be prepared by any method known in the art, but preferably by the methods described in WO94/05639, incorporated herein by reference hereto.
- the compound of formula (III) may be prepared by reaction of a compound of formula (II) with a phosphorylating agent, for example phosphorus oxychloride, phosphorus pentacloride or dibenzylchlorophosphate, in the presence of a base, for example pyridine, triethylamine or diisopropylethylamine, and optionally in the presence of a solvent, for example methylisobutylketone or dichloromethane; followed by reduction, typically of the sodium salt formed in aqueous solution by addition of sodium bicarbonate, sodium carbonate or sodium hydroxide, with a reducing agent, for example formic acid or hydrogen with a palladium/ or platinum/carbon catalyst; in the presence of a suitable solvent, for example water, ethyl acetate, isopropanol, methanol, acetone, industrial methylated spirit or a mixture of two or more of the above solvents.
- a phosphorylating agent for example phosphorus
- the compound of formula (IV) may be prepared by the reaction of a compound of formula (II) with a phosphorylating agent, for example phosphorus oxychloride or phosphorus pentachloride, in the presence of a base, for example pyridine, triethylamine or diisopropylethylamine and optionally in the presence of a solvent, for example methylisobutylketone or dichloromethane.
- a phosphorylating agent for example phosphorus oxychloride or phosphorus pentachloride
- the phosphorylating agent is phosphorus oxychloride.
- the base is pyridine.
- the solvent is methyl isobutylketone.
- the reducing agent is hydrogen with a palladium on carbon catalyst with a 5-10% loading of palladium.
- the solvent is a mixture of industrial methylated spirit and water
- the present invention also provides the compound of formula (I) for use in medical therapy, for example in the treatment of a viral disease in an animal, for example, a human.
- the compound is especially useful for the treatment of diseases caused by retroviruses, such as HIV infections, for example, Acquired Immune Deficiency Syndrome (AIDS) and AIDS-related complex (ARC) as well as diseases caused by hepatitis B and hepatitis C.
- retroviruses such as HIV infections, for example, Acquired Immune Deficiency Syndrome (AIDS) and AIDS-related complex (ARC)
- HIV infections for example, Acquired Immune Deficiency Syndrome (AIDS) and AIDS-related complex (ARC)
- ARC AIDS-related complex
- the compound of formula (I) can be administered to other animals for treatment of viral diseases, for example to other mammals.
- the present invention also provides a method for the treatment of a viral infection, particularly a retrovirus infection such as an HIV infection, in an animal, for example, a mammal such as a human, which comprises administering to the animal an effective antiviral amount of the compound of formula (I).
- the present invention also provides the use of the compound of formula (I) in the preparation of a medicament for the treatment of a viral infection, particularly a retrovirus infection such as an HIV infection.
- the compound of formula (I), also referred to herein as the active ingredient, may be administered by any route appropriate to the condition to be treated, but the preferred route of administration is oral. It will be appreciated however, that the preferred route may vary with, for example, the condition of the recipient.
- a suitable effective dose will be in the range of 0.1 to 150 mg per kilogram body weight of recipient per day, advantageously in the range of 0.5 to 70 mg per kilogram body weight per day, preferably in the range of 0.5 to 50 mg per kilogram body weight per day (unless otherwise indicated, all weights of the active ingredient are calculated with respect to the free base of the compound of formula (I)).
- the desired dose is preferably presented as one, two, three or four or more subdoses administered at appropriate intervals throughout the day.
- These sub-doses may be administered in unit dosage forms, for example, containing about 25 to 2000 mg, preferably about 50, 100, 150, 200, 250, 300, 450, 500, 570, 750 or 1000 mg of active ingredient per unit dose form.
- the active ingredient While it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical formulation.
- the formulation comprises the active ingredient as above defined, together with one or more pharmaceutically acceptable excipients thereof and optionally other therapeutic ingredients.
- the excipient(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
- the formulations include those suitable for oral administration and may conveniently be presented in unit dosage form prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing in to association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
- Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, sachets of granules or tablets (such as a swallowable, dispersible or chewable tablet) each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
- the active ingredient may also be presented as a bolus, electuary or paste.
- a tablet may be made by compression or moulding optionally with one or more accessory ingredients.
- Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent.
- Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
- the tablets may optionally be coated or scored any may be formulated so as to provide slow or controlled release of the active ingredient therein.
- the active ingredient may also be presented in a formulation comprising micrometer- or nanometer-size particles of active ingredient, which formulation may contain other pharmaceutical agents and may optionally be converted to solid form.
- Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose (as herein above recited) or an appropriate fraction thereof, of the active ingredient.
- formulation of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents or taste masking agents.
- the compound of formula (I) may be combined with one or more other HIV anti-viral agents, for example Reverse Transcriptase Inhibitors (RTIs), Non Nucleoside Reverse Transcriptase Inhibitor (NNRTIs), and other HIV protease inhibitors.
- RTIs Reverse Transcriptase Inhibitors
- NRTIs Non Nucleoside Reverse Transcriptase Inhibitor
- HIV protease inhibitors for example Reverse Transcriptase Inhibitors (RTIs), Non Nucleoside Reverse Transcriptase Inhibitor (NNRTIs), and other HIV protease inhibitors.
- RTIs examples include zidovudine, didanosine (ddI), zalcitabine (ddC), stavudine (d4T), abacavir, lamivuidine (3TC) and FTC.
- NNRTIs include HEPT, TIBO derivatives, atevirdine, L-ofloxacin, L-697,639, L-697-661, nevirapine (BI-RG-587), loviride ( ⁇ -APA), delavuridine (BHAP), phosphonoformic acid, benzodiazepinones, dipyridodiazepinones, 2-pyridones, bis(heteroaryl)piperazines, 6-substituted pyrimidines, imidazopyridazines, 1,4-dihydro-2H-3,1-benzoxazin-2-ones, such as ( ⁇ )-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (L-743,726 or DMP-266), and quinoxalines, such as isopropyl (2S)-7-fluoro-3,4-
- HIV protease inhibitors include those disclosed in WO 94/05639, WO 95/24385, WO 94/13629, WO 92/16501, WO 95/16688, WO/US94/13085, WO/US94/12562, US 93/59038, EP 541168, WO 94/14436, WO 95/09843, WO 95/32185, WO 94/15906, WO 94/15608, WO 94/04492, WO 92/08701, WO 95/32185, and U.S. Pat. No.
- the compound of formula (I) and combinations thereof with RTIs, NNRTIs and/or HIV protease inhibitors are especially useful for the treatment of AIDS and related clinical conditions such as AIDS related complex (ARC), progressive generalized lymphadenopathy (PGL), Kaposi's sarcoma, thrombocytopenic purpura, AIDS-related neurological conditions such as AIDS dementia complex, multiple sclerosis or tropical paraperesis, and also anti-HIV antibody-positive and HIV-positive conditions, including such conditions in asymptomatic patients.
- Phosphorus oxychloride (69 ml) was added to a suspension of (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-nitrophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(hydroxy)propylcarbamate (300 g) in pyridine (450 ml) and methyl-isobutylketone (1500 ml). After stirring at 25-30° C. for 2.5 h, phosphorus oxychloride (7 ml) was added. After a further 1 h, the resulting suspension was added to 6M hydrochloric acid (500 ml).
- the mixture was then heated at 50-55° C. for 2 h, then cooled.
- the phases were separated and the aqueous phase was extracted with methyl-isobutylketone (600 ml).
- the combined organic solutions were washed with water (2 ⁇ 600 ml).
- the methyl-isobutylketone solution was concentrated to ca 600 ml in vacuo and then water (1500 ml) and sodium bicarbonate (94.g) were added. After stirring for 20 minutes, the phases were separated, and the aqueous solution was washed with ethyl acetate (3 ⁇ 200 ml). The aqueous solution was treated with 10% palladium on carbon catalyst (30 g), left under vacuum for 5 minutes, treated with industrial methylated spirit (1200 ml) then stirred under hydrogen at below 30° C. for 2.5 h. The catalyst was filtered off, washing with industrial methylated spirit (600 ml).
- Phosphorus oxychloride (24.1 kg) was added to a suspension of (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-nitrophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(hydroxy)propylcarbamate (37 kg) in pyridine (48.5 kg) and methyl-isobutylketone (170L). After stirring at 25-30° C. for 2.5 h, the resulting suspension was added to 2N hydrochloric acid (120L). The mixture was then heated at 65-70° C. for 3 h, then cooled. The phases were separated and the aqueous phase was extracted with methyl-isobutylketone (70L). The combined organic solutions were washed with water (2 ⁇ 70L).
- the methyl-isobutylketone solution was concentrated to ca 70L in vacuo and then water (150L) and 32% sodium hydroxide (14.3 kg) were added. After stirring for 15 minutes, the phases were separated, and the aqueous solution was washed with methyl-isobutylketone (3 ⁇ 34L). The aqueous solution was treated with 5% palladium on carbon catalyst (1.7 kg), treated with industrial methylated spirit (136L) then stirred under hydrogen at below 30° C. for 8 h. The catalyst was filtered off, washing with industrial methylated spirit (170L).
- Tablet Formulation Ingredient Actual mg/tablet Compound of formula (I) 576.1* Microcrystalline Cellulose, NF 102.2 Croscarmellose Sodium 38.0 Povidone, USP 34.2 Colloidal Silicon Dioxide, NF 1.9 Magnesium Stearate, NF 7.6 Total 760
- the components are weighed from bulk containers and then sieved using a Russell-SIV equipped with 14 mesh (1.4 mm opening) or an equivalent sieve and mesh, and deposited into a stainless-steel blending container.
- the compound of formula (I), microcrystalline cellulose NF, croscarmellose sodium, povidone USP and colloidal silicon dioxide NF are blended for 20 minutes using a suitable blender, such as a Matcon-Buls bin-type blender, a V-blender or equivalent.
- a suitable blender such as a Matcon-Buls bin-type blender, a V-blender or equivalent.
- the magnesium stearate is then added to the mixture and blending is continued for approximately 2 minutes.
- the blend is then compressed using a suitable rotary tablet press, typically a Courtoy R-190, R-200 or equivalent.
- a suitable rotary tablet press typically a Courtoy R-190, R-200 or equivalent.
- In-process controls for tablet weight and hardness are applied at appropriate intervals throughout the compression run and adjustments to the tablet press are made as necessary.
- the aqueous solubility of amprenavir is 0.095 mg/ml at pH 6.3, and the solubility in 0.1N Hcl ( ⁇ pH 1) is 0.29 mg/ml.
- the aqueous solubility profile of the compound of formula (I) is pH 6.27 0.531 mg/ml pH 5.02 3.20 mg/ml pH 4.11 9.41 mg/ml pH 3.27 61.1 mg/ml pH 1.47 3.20 mg/ml
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Abstract
Description
- The present invention relates to the antiviral compound calcium (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phos-phonooxy)propylcarbamate, pharmaceutical compositions comprising it, its use in the treatment of retroviral infections, and processes for its preparation.
- Virus-encoded proteases, which are essential for viral replication, are required for the processing of viral protein precursors. Interference with the processing of protein precursors inhibits the formation of infectious virions. Accordingly, inhibitors of viral proteases may be used to prevent or treat chronic and acute viral infections.
- A new antiviral compound, (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-aminophenyl) sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propylcarbamate, described in PCT/US98/04595, has HIV aspartyl protease inhibitory activity and is particularly well suited for inhibiting HIV-1 and HIV-2 viruses. Moreover, (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy) propylcarbamate has increased solubility in the pH range of the gastrointestinal tract compared to the HIV protease inhibitor [3S-[3R*(1R*,2S)]]-[3-[[(4-aminophenyl)sulfony](2-methyl-propyl)amino]-2-hydroxy-1-phenylmethyl)propyl]-tetrahydro-3-furanyl ester (amprenavir, 141W94). Amprenavir, which has poor solubility and is thus available as a solution in gel capsules and has a high pill burden. This new HIV protease inhibitor with its increased solubility thus has the potential to reduce the perceived pill burden and may be formulated as a tablet.
- However, attempts to find a stable crystalline form of (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-aminophenyl) sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propylcarbamate suitable for formulation proved problematic. A range of salts of the phosphoric acid were made (for example, di-sodium, di-potassium, magnesium, zinc, ethylene diamine, piperazine). Of these, the piperazine salt was a crystalline solid, but had the practical disadvantage of likely toxicity at the anticipated dose. Surprisingly, we have found that the calcium salt, calcium (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-aminophenyl) sulfonyl](isobutyl)amino]-1-benzyl-2-phosphonooxy)propylcarbamate, has a stable crystalline form. Detailed further examination revealed that this salt has advantageous properties making it suitable for formulation into tablets. Thus the compound of the present invention provides an opportunity to reduce the pill burden associated with some HIV protease inhibitors.
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- We have now found that the compound of formula (I) can be prepared in crystalline form, exhibiting particularly good pharmaceutical properties.
- According to a first aspect of the invention there is provided the compound of formula (I) in crystalline form, hereinafter referred to as Form (I).
- The invention relates to Form (I) of the compound of formula (I) in crystalline form. Typically, Form (I) contains about 4 to 5 moles of water. However, in any batch containing Form (I) of the compound of formula (I) there may also be other solvated crystalline forms of the compound of formula (I).
- Solid State Form (I) of the compound of formula (I) can be characterised by it's X-ray powder diffraction pattern, shown in FIG. 1. Diffraction traces were obtained using a Phillips PW1800 diffractometer (serial DY701) and Cu K α radiation. X-ray intensities were measured at 0.02° increments for 4 second intervals using a scintillation counter, between values of 2 and 45° 2θ. Intense diffraction peaks characteristic of Form (I) may occur at the following approximate 2theta angles (using copper K α X-radiation): 5.735, 9.945, 11.500, 13.780, 14.930, 15.225, 17.980, 19.745, 21.575, 22.170, 24.505, and 27.020. Further details are presented in Table 1.
- It will be appreciated by those skilled in the art that the compound of formula (I) may be in the form of a solvate, for example a hydrate.
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- with a phosphorylating agent, for example phosphorus oxychloride, phosphorus pentachloride, or dibenzylchlorophosphate, in the presence of a base, for example pyridine, triethylamine or diisopropylethylamine, and optionally in the presence of a solvent, for example methylisobutylketone or dichloromethane; followed by reduction, typically of the sodium salt formed in aqueous solution by addition of sodium bicarbonate, sodium carbonate or sodium hydroxide, with a reducing agent, for example formic acid or hydrogen with palladium/ or platinum/carbon catalyst, in the presence of a suitable solvent, for example water, ethyl acetate, isopropanol, acetone, methanol, industrial methylated spirit or a mixture of two or more of the above solvents; followed by the addition of water and a source of calcium ions, for example calcium acetate, calcium chloride or calcium hydroxide, optionally in the presence of an additional solvent selected from the above-mentioned list.
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- in a suitable solvent, for example isopropanol, methanol or industrial methylated spirit, and adding to the solution water and a source of calcium ions, for example calcium acetate, calcium chloride or calcium hydroxide.
- In a further aspect, the present invention also provides a process for the production of the compound of formula (I), comprising the reduction of a compound of formula (IV), typically of the sodium salt formed in aqueous solution by addition of sodium bicarbonate, sodium carbonate or sodium hydroxide
- in the presence of a suitable reducing agent, for example formic acid or hydrogen with palladium/ or platinum/carbon catalyst, in the presence of a suitable solvent, for example water, ethyl acetate, isopropanol, acetone, methanol industrial methylated spirit or a mixture of two or more of the above solvents; followed by the addition of water and a source of calcium ions, for example calcium acetate, calcium chloride or calcium hydroxide, optionally in the presence of an additional solvent selected from the above-mentioned list.
- It will be appreciated by those skilled in the art that each step may be followed by a standard isolation and purification procedure such as those detailed in the examples hereinafter.
- The compound of formula (I) thus obtained may optionally be further purified by recrystallisation from an appropriate solvent, for example industrial methylated spirit, acetone, methanol or isopropanol and mixtures thereof with water, preferably a mixture of industrial methylated spirit and water.
- A further optional purification step may be carried out by heating a slurry of the product in water to a temperature in the range 70-99° C., preferably 85-97° C., most preferably 90-95° C., for about 2.5-6 hours, preferably 3-5 hours, most preferably 4 hours, followed by cooling to ambient temperature and harvesting the solid.
- The compound of formula (II) may be prepared by any method known in the art, but preferably by the methods described in WO94/05639, incorporated herein by reference hereto.
- The compound of formula (III) may be prepared by reaction of a compound of formula (II) with a phosphorylating agent, for example phosphorus oxychloride, phosphorus pentacloride or dibenzylchlorophosphate, in the presence of a base, for example pyridine, triethylamine or diisopropylethylamine, and optionally in the presence of a solvent, for example methylisobutylketone or dichloromethane; followed by reduction, typically of the sodium salt formed in aqueous solution by addition of sodium bicarbonate, sodium carbonate or sodium hydroxide, with a reducing agent, for example formic acid or hydrogen with a palladium/ or platinum/carbon catalyst; in the presence of a suitable solvent, for example water, ethyl acetate, isopropanol, methanol, acetone, industrial methylated spirit or a mixture of two or more of the above solvents.
- The compound of formula (IV) may be prepared by the reaction of a compound of formula (II) with a phosphorylating agent, for example phosphorus oxychloride or phosphorus pentachloride, in the presence of a base, for example pyridine, triethylamine or diisopropylethylamine and optionally in the presence of a solvent, for example methylisobutylketone or dichloromethane.
- Preferably the phosphorylating agent is phosphorus oxychloride. Preferably the base is pyridine. Preferably the solvent is methyl isobutylketone.
- Preferably the reducing agent is hydrogen with a palladium on carbon catalyst with a 5-10% loading of palladium. Preferably the solvent is a mixture of industrial methylated spirit and water
- The present invention also provides the compound of formula (I) for use in medical therapy, for example in the treatment of a viral disease in an animal, for example, a human. The compound is especially useful for the treatment of diseases caused by retroviruses, such as HIV infections, for example, Acquired Immune Deficiency Syndrome (AIDS) and AIDS-related complex (ARC) as well as diseases caused by hepatitis B and hepatitis C.
- In addition to its use in human medical therapy, the compound of formula (I) can be administered to other animals for treatment of viral diseases, for example to other mammals.
- The present invention also provides a method for the treatment of a viral infection, particularly a retrovirus infection such as an HIV infection, in an animal, for example, a mammal such as a human, which comprises administering to the animal an effective antiviral amount of the compound of formula (I).
- The present invention also provides the use of the compound of formula (I) in the preparation of a medicament for the treatment of a viral infection, particularly a retrovirus infection such as an HIV infection.
- The compound of formula (I), also referred to herein as the active ingredient, may be administered by any route appropriate to the condition to be treated, but the preferred route of administration is oral. It will be appreciated however, that the preferred route may vary with, for example, the condition of the recipient.
- For each of the above-indicated utilities and indications the amounts required of the active ingredient (as above defined) will depend upon a number of factors including the severity of the condition to be treated and the identity of the recipient and will ultimately be at the discretion of the attendant physician or veterinarian. In general however, for each of these utilities and indications, a suitable effective dose will be in the range of 0.1 to 150 mg per kilogram body weight of recipient per day, advantageously in the range of 0.5 to 70 mg per kilogram body weight per day, preferably in the range of 0.5 to 50 mg per kilogram body weight per day (unless otherwise indicated, all weights of the active ingredient are calculated with respect to the free base of the compound of formula (I)). The desired dose is preferably presented as one, two, three or four or more subdoses administered at appropriate intervals throughout the day. These sub-doses may be administered in unit dosage forms, for example, containing about 25 to 2000 mg, preferably about 50, 100, 150, 200, 250, 300, 450, 500, 570, 750 or 1000 mg of active ingredient per unit dose form.
- While it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical formulation. The formulation comprises the active ingredient as above defined, together with one or more pharmaceutically acceptable excipients thereof and optionally other therapeutic ingredients. The excipient(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
- The formulations include those suitable for oral administration and may conveniently be presented in unit dosage form prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing in to association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
- Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, sachets of granules or tablets (such as a swallowable, dispersible or chewable tablet) each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
- A tablet may be made by compression or moulding optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored any may be formulated so as to provide slow or controlled release of the active ingredient therein.
- The active ingredient may also be presented in a formulation comprising micrometer- or nanometer-size particles of active ingredient, which formulation may contain other pharmaceutical agents and may optionally be converted to solid form.
- Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose (as herein above recited) or an appropriate fraction thereof, of the active ingredient.
- It should be understood that in addition to the ingredients particularly mentioned above the formulation of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents or taste masking agents.
- It will be further understood that the compound of formula (I) may be combined with one or more other HIV anti-viral agents, for example Reverse Transcriptase Inhibitors (RTIs), Non Nucleoside Reverse Transcriptase Inhibitor (NNRTIs), and other HIV protease inhibitors.
- Examples of suitable RTIs include zidovudine, didanosine (ddI), zalcitabine (ddC), stavudine (d4T), abacavir, lamivuidine (3TC) and FTC.
- Examples of suitable NNRTIs include HEPT, TIBO derivatives, atevirdine, L-ofloxacin, L-697,639, L-697-661, nevirapine (BI-RG-587), loviride (α-APA), delavuridine (BHAP), phosphonoformic acid, benzodiazepinones, dipyridodiazepinones, 2-pyridones, bis(heteroaryl)piperazines, 6-substituted pyrimidines, imidazopyridazines, 1,4-dihydro-2H-3,1-benzoxazin-2-ones, such as (−)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (L-743,726 or DMP-266), and quinoxalines, such as isopropyl (2S)-7-fluoro-3,4-dihydro-2-ethyl-3-oxo-1-(2H)-quinoxalinecarboxylate (HBY 1293) or HBY 097.
- Examples of suitable HIV protease inhibitors include those disclosed in WO 94/05639, WO 95/24385, WO 94/13629, WO 92/16501, WO 95/16688, WO/US94/13085, WO/US94/12562, US 93/59038, EP 541168, WO 94/14436, WO 95/09843, WO 95/32185, WO 94/15906, WO 94/15608, WO 94/04492, WO 92/08701, WO 95/32185, and U.S. Pat. No. 5,256,783, in particular (S)-N-((.alpha.S)-((1R)-2-((3S, 4αS,8αS)-3-(tert-Butylcarbamoyl)octahydro-2-(1H)-isoquinolyl)-1-hydroxyethyl)phenethyl)-2-quinaldaminosuccinamide monomethanesulfonate (saquinavir), N-(2(R)-Hydroxy-1(S)indanyl)-2(R)-(phenylmethyl)-4(S)-hydroxy-5-[1-[4-(3-pyridylmethyl)-2(S)-(N-tert-butylcarbamoyl)piperazinyl]]pentaneamide (indinavir), 10-hydroxy-2-methyl-5-(1-methylethyl)-1-[2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester (ritonavir), (N-(1,1-dimethyl)decahydro-2-[2-hydroxy-3-[(3-hydroxy-2-methylbenzoyl)amino]-4-(phenylthio)butyl]-3-isoquinolinecarboxamide monomethanesulfonate (nelfinavir), and related compounds.
- The compound of formula (I) and combinations thereof with RTIs, NNRTIs and/or HIV protease inhibitors are especially useful for the treatment of AIDS and related clinical conditions such as AIDS related complex (ARC), progressive generalized lymphadenopathy (PGL), Kaposi's sarcoma, thrombocytopenic purpura, AIDS-related neurological conditions such as AIDS dementia complex, multiple sclerosis or tropical paraperesis, and also anti-HIV antibody-positive and HIV-positive conditions, including such conditions in asymptomatic patients.
- The following examples are intended for illustration only and are not intended to limit the scope of the invention in any way.
- Preparation of Calcium (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-amino-phenyl)-sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propyl-carbamate (I) from (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-aminophenyl)-sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propylcarbamate (III)
- (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propylcarbamate (10 g) was dissolved in industrial methylated spirit (60 ml) and heated to 50° C. A solution of calcium acetate (2.43 g) in water (60 ml) was added slowly, causing a white crystalline precipitate to form. The mixture was allowed to cool slowly to 20° C. The solid was filtered off, washed with industrial methylated spirit/water (1:1, 2×25 ml) and water (25 ml), then dried in vacuo at 20° C. to give the title compound as white microcrystalline needles (7.52 g).
- NMR (Solvent 0.1N DCl in D2O) 0.8-0.9 ppm (m 6H), 1.2-1.3 ppm (m, 0.5H), 1.85-2.2 ppm (m, 2.5H), 2.6-2.75 ppm (m, 1H, J=13.0 Hz), 2.9-3.2 ppm (m, 3H), 3.34 (m 1H) 3.42 ppm (d, 1H, J=10.8 Hz), 3.55-3.9 ppm (m, 4H), 4.2-4.3 ppm (m, 1H, J=10.3 Hz), 4.55 ppm (m 1H), 4.8-5.0 ppm (m, 1H masked by HOD signal), 7.3-7.4 ppm (m, 5H), 7.6-7.7 ppm (m, 2H, J=8.3 Hz), 8.0-8.1 ppm (d, 2H, J=8.8 Hz). Ethanol content by NMR 2.7% w/w.
- Melting Point 282-284° C. (dec)
- Preparation of Calcium (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-aminophenyl)-sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propyl-carbamate (I) from (3S) tetrahydro-3-furanyl (1 S,2R)-3-[[(4-nitrophenyl)-sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propylcarbamate (IV)
- A solution of (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-nitrophenyl)sulfonyl]-(isobutyl)amino]-1-benzyl-2-(phosphonooxy)propylcarbamate (17.34 g) in industrial methylated spirit (68 ml) and water (17 ml) was treated with 10% palladium on carbon catalyst (3.4 g). The mixture was stirred under hydrogen at ambient temperature for 3 h. The catalyst was filtered off, washing with industrial methylated spirit (34 ml). The filtrate was warmed to 50° C. and a solution of calcium acetate (4.45 g) in water (85 ml) was added slowly, causing a white crystalline precipitate to form. The mixture was allowed to cool slowly to 20° C. The solid was filtered off, washed with industrial methylated spirit/water (1:2, 2×25 ml), then dried in vacuo at 20° C. to give the title compound as white microcrystalline needles (14.04 g).
- NMR (Solvent 0.1N DCl in D2O) 0.65-0.75 ppm (m 6H), 1.1-1.2 ppm (m, 0.5H), 1.7-2.05 ppm (m, 2.5H), 2.45-2.55 ppm (m, 1H, J=13.0 Hz), 2.8-3.05 ppm (m, 3H), 3.15 (m, 1H) 3.3 ppm (d, 1H, J=10.8 Hz), 3.4-3.8 ppm (m, 4H), 4.05-4.15 ppm (m, 1H, J=10.3 Hz), 4.35 ppm (m 1H), 4.6-4.8 ppm (m, 1H masked by HOD signal), 7.3-7.4 ppm (m, 5H), 7.6 ppm (m, 2H, J=8.3 Hz), 7.9 ppm (d, 2H, J=8.3 Hz). Signals shifted upfield due to lost lock. Ethanol content by NMR 3.4% w/w.
- Water content by Karl Fisher analysis is 11.1% w/w.
- Preparation of Calcium (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-aminophenyl)-sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propyl-carbamate (I) from (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-nitrophenyl)-sulfonyl](isobutyl)amino]-1-benzyl-2-(hydroxy)propylcarbamate (II)
- Phosphorus oxychloride (69 ml) was added to a suspension of (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-nitrophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(hydroxy)propylcarbamate (300 g) in pyridine (450 ml) and methyl-isobutylketone (1500 ml). After stirring at 25-30° C. for 2.5 h, phosphorus oxychloride (7 ml) was added. After a further 1 h, the resulting suspension was added to 6M hydrochloric acid (500 ml). The mixture was then heated at 50-55° C. for 2 h, then cooled. The phases were separated and the aqueous phase was extracted with methyl-isobutylketone (600 ml). The combined organic solutions were washed with water (2×600 ml).
- The methyl-isobutylketone solution was concentrated to ca 600 ml in vacuo and then water (1500 ml) and sodium bicarbonate (94.g) were added. After stirring for 20 minutes, the phases were separated, and the aqueous solution was washed with ethyl acetate (3×200 ml). The aqueous solution was treated with 10% palladium on carbon catalyst (30 g), left under vacuum for 5 minutes, treated with industrial methylated spirit (1200 ml) then stirred under hydrogen at below 30° C. for 2.5 h. The catalyst was filtered off, washing with industrial methylated spirit (600 ml).
- The filtrate was warmed to 40-50° C. and a solution of calcium acetate monohydrate (99.5 g) in water (300 ml) was added over 20 minutes, then the resulting suspension was stirred at 40-50° C. for 30 minutes, then cooled to ambient temperature over 30 minutes. The product was filtered and washed with industrial methylated spirit/water (1:1, 2×600 ml), then dried in vacuo at 35-40° C. to give the title compound as white microcrystalline needles (293.28 g).
- NMR (Solvent 0.1N DCl in D2O) 0.8-0.9 ppm (m 6H), 1.2-1.3 ppm (m, 0.5H), 1.85-2.2 ppm (m, 2.5H), 2.6-2.75 ppm (m, 1H, J=13.0 Hz), 2.9-3.2 ppm (m, 3H), 3.34 (m 1H) 3.42 ppm (d, 1H, J=10.8 Hz), 3.55-3.9 ppm (m, 4H), 4.2-4.3 ppm (m, 1H, J=10.3 Hz), 4.55 ppm (m 1H), 4.8-5.0 ppm (m, 1H masked by HOD signal), 7.3-7.4 ppm (m, 5H), 7.6-7.7 ppm (m, 2H, J=8.3 Hz), 8.0-8.1 ppm (d, 2H, J=8.8 Hz). Ethanol content by NMR 1.7% w/w.
- Recrystallisation of Calcium (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-amino-phenyl)sulfonyl(isobutyl)amino]-1-benzyl-2-(phosphonooxy)propyl-carbamate (I)
- Calcium (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-aminophenyl)sulfonyl]-(isobutyl)amino]-1-benzyl-2-(phosphonooxy)propylcarbamate (5 g; prepared in a similar manner to that described in any of examples 1,2 or 3) was suspended in industrial methylated spirit (75 ml) and heated to 70° C. The mixture was clarified through a bed of filter-aid, washing through with industrial methylated spirit (25 ml). The filtrate was reheated to 70° C., then water (15 ml) was added. The resulting suspension was slowly cooled to 20° C., then the product was filtered off, washed with industrial methylated spirit/water (1:1, 2×10 ml), then dried in vacuo at 20° C. to give the title compound as white microcrystalline needles (4.58 g).
- NMR (Solvent 0.1N DCl in D2O) 0.8-0.9 ppm (m 6H), 1.2-1.3 ppm (m, 0.5H), 1.85-2.2 ppm (m, 2.5H), 2.6-2.75 ppm (m, 1H, J=13.0 Hz), 2.9-3.2 ppm (m, 3H), 3.34 (m 1H) 3.42 ppm (d, 1H, J=10.8 Hz), 3.55-3.9 ppm (m, 4H), 4.2-4.3 ppm (m, 1H, J=10.3 Hz), 4.51 ppm (m 1H), 4.8-5.0 ppm (m, 1H masked by HOD signal), 7.3-7.4 ppm (m, 5H), 7.6-7.7 ppm (m, 2H, J=8.3 Hz), 8.0-8.1 ppm (d, 2H, J=8.8 Hz). Ethanol content by NMR 3.1% w/w.
- Melting Point 282-284° C. (dec)
- Preparation of Calcium (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-aminophenyl)-sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propyl-carbamate (I) from (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-nitrophenyl)-sulfonyl](isobutyl)amino]-1-benzyl-2-(hydroxy)propylcarbamate (II)
- Phosphorus oxychloride (24.1 kg) was added to a suspension of (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-nitrophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(hydroxy)propylcarbamate (37 kg) in pyridine (48.5 kg) and methyl-isobutylketone (170L). After stirring at 25-30° C. for 2.5 h, the resulting suspension was added to 2N hydrochloric acid (120L). The mixture was then heated at 65-70° C. for 3 h, then cooled. The phases were separated and the aqueous phase was extracted with methyl-isobutylketone (70L). The combined organic solutions were washed with water (2×70L).
- The methyl-isobutylketone solution was concentrated to ca 70L in vacuo and then water (150L) and 32% sodium hydroxide (14.3 kg) were added. After stirring for 15 minutes, the phases were separated, and the aqueous solution was washed with methyl-isobutylketone (3×34L). The aqueous solution was treated with 5% palladium on carbon catalyst (1.7 kg), treated with industrial methylated spirit (136L) then stirred under hydrogen at below 30° C. for 8 h. The catalyst was filtered off, washing with industrial methylated spirit (170L).
- The filtrate was warmed to 40-50° C. and a solution of calcium acetate hydrate (9.5 kg) in water (136L) was added over 2 h, then the resulting suspension was stirred at 40-50° C. for 30 minutes, then cooled to ambient temperature over 2 h. The product was filtered and washed with industrial methylated spirit/water (1:1, 2×68L), then water (2×68L). The product was then stirred and heated with water (340L) for 4 h at 90-95° C. then cooled to 20-25° C. The solid was filtered and washed with industrial methylated spirits (3×34L) then dried in vacuo at 35-40° C. to give the title compound as white microcrystalline needles (25.8 kg).
- NMR (Solvent 0.1N DCl in D2O) 0.8-0.9 ppm (m 6H), 1.2-1.3 ppm (m, 0.5H), 1.85-2.2 ppm (m, 2.5H), 2.6-2.7 ppm (m, 1H, J=13.0 Hz), 2.9-3.2 ppm (m, 3H), 3.3-3.4 ppm (m 1H) 3.42 ppm (d, 1H, J=10.8 Hz), 3.55-3.9 ppm (m, 4H), 4.2-4.3 ppm (m, 1H, J=10.3 Hz), 4.5 ppm (m 1H), 4.8-5.0 ppm (m, 1H masked by HOD signal), 7.3-7.4 ppm (m, 5H), 7.6-7.7 ppm (m, 2H, J=8.3 Hz), 8.0-8.1 ppm (d, 2H, J=8.8 Hz). Ethanol content by NMR 1.0% w/w.
- Water content by Karl Fisher analysis is 10.9% w/w.
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Tablet Formulation Ingredient Actual mg/tablet Compound of formula (I) 576.1* Microcrystalline Cellulose, NF 102.2 Croscarmellose Sodium 38.0 Povidone, USP 34.2 Colloidal Silicon Dioxide, NF 1.9 Magnesium Stearate, NF 7.6 Total 760 - Preparation Method
- First, the components are weighed from bulk containers and then sieved using a Russell-SIV equipped with 14 mesh (1.4 mm opening) or an equivalent sieve and mesh, and deposited into a stainless-steel blending container.
- The compound of formula (I), microcrystalline cellulose NF, croscarmellose sodium, povidone USP and colloidal silicon dioxide NF are blended for 20 minutes using a suitable blender, such as a Matcon-Buls bin-type blender, a V-blender or equivalent. The magnesium stearate is then added to the mixture and blending is continued for approximately 2 minutes.
- The blend is then compressed using a suitable rotary tablet press, typically a Courtoy R-190, R-200 or equivalent. In-process controls for tablet weight and hardness are applied at appropriate intervals throughout the compression run and adjustments to the tablet press are made as necessary.
- Relative Oral Bioavailability of the Compound of Formula (I) Compared to Amprenavir in Beagle Dogs.
- The relative oral bioavailability of the compound of formula (I) was measured in Beagle dogs, as compared to the bioavailability of amprenavir (141W94) in the same animals. This existing model had previously been used for testing the oral bioavailability of amprenavir and other compounds. The results were obtained from dosing in three animals.
- Oral dosing of the compound of formula (I) directly to the dogs resulted in a relative bioavailability of 23.8±23.8% as compared to amprenavir.
- Oral dosing of the compound of formula (I) to dogs given an oral gavage of 0.1N HCl before administration of the drug, resulted in a relative bioavailability of 58.4±11.5% as compared to amprenavir.
- These results suggested that the compound of formula (I) was less bioavailable than amprenavir itself. However, the pH in the stomach of dogs is typically much higher than in man.
- Aqueous Solubility
- The aqueous solubility of amprenavir is 0.095 mg/ml at pH 6.3, and the solubility in 0.1N Hcl (˜pH 1) is 0.29 mg/ml.
- The aqueous solubility profile of the compound of formula (I) is
pH 6.27 0.531 mg/ml pH 5.02 3.20 mg/ml pH 4.11 9.41 mg/ml pH 3.27 61.1 mg/ml pH 1.47 3.20 mg/ml - These data illustrate the surprisingly increased and pH dependent aqueous solubility of the compound of formula (I) as compared to amprenavir. The solubility is notably good between about pH 3 and 4.
TABLE 1 Angles 2θ and their relative intensities compared to the strongest peak for the X-ray powder diffraction pattern of the compound of formula (I) Angle 2θ rel. int. 5.7350 100 9.9450 38 11.1150 7 11.5000 10 13.7800 18 14.9300 10 15.2250 16 17.9800 35 19.7450 14 19.9600 5 20.8050 8 21.5750 12 22.1700 15 22.3550 7 22.9100 6 23.1350 5 24.5050 14 25.0350 2 25.2550 2 25.8600 7 26.5050 2 27.0200 10 27.7850 3 28.2150 4 28.3650 6 28.8250 2 28.9450 2 29.4150 4 30.1950 2 30.5750 3 31.1200 2 31.7950 2 32.2450 4 32.7750 3 32.8900 3 33.8150 2 34.9050 2 35.2950 3 35.8050 2 36.4600 3 36.8300 2 37.8400 2 38.6550 2 39.5350 2 39.6150 2 40.5850 3 41.3550 2 41.8100 2 42.2350 2 42.6900 3 43.2000 2 43.9200 1 44.4000 2
Claims (5)
2. A process for the preparation of a compound of formula (I) as claimed in claim 1 wherein the calcium ion source is calcium acetate.
3. A process for the preparation of a compound of formula (I) as claimed in claim 1 , additionally comprising recrystallising the compound from an appropriate solvent.
4. A process for the preparation of a compound of formula (I) as claimed in claim 3 , wherein the solvent is a mixture of industrial methylated spirit and water.
5. A process for the preparation of a compound of formula (I) as claimed in claim 1 , additionally comprising heating the product in water to a temperature in the range 70 to 99° C. for 2.5 to 6 hours, then cooling to ambient temperature and harvesting to solid.
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US10/303,213 US20030100537A1 (en) | 1998-07-18 | 2002-11-25 | Calcium (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phos-phonooxy)propylcarbamate |
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GB9815567.4 | 1998-07-18 | ||
GBGB9815567.4A GB9815567D0 (en) | 1998-07-18 | 1998-07-18 | Antiviral compound |
US09/744,051 US6514953B1 (en) | 1998-07-18 | 1999-07-15 | Calcium (3S) tetrahydro-3-furanyl(1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propylcarbamate |
US10/303,213 US20030100537A1 (en) | 1998-07-18 | 2002-11-25 | Calcium (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phos-phonooxy)propylcarbamate |
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US09/744,051 Division US6514953B1 (en) | 1998-07-18 | 1999-07-15 | Calcium (3S) tetrahydro-3-furanyl(1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propylcarbamate |
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US09/744,051 Expired - Lifetime US6514953B1 (en) | 1998-07-18 | 1999-07-15 | Calcium (3S) tetrahydro-3-furanyl(1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propylcarbamate |
US10/303,213 Abandoned US20030100537A1 (en) | 1998-07-18 | 2002-11-25 | Calcium (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phos-phonooxy)propylcarbamate |
US10/303,366 Abandoned US20030096795A1 (en) | 1998-07-18 | 2002-11-25 | Calcium (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phos-phonooxy)propylcarbamate |
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STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |