WO2019021319A1 - Pharmaceutical compositions - Google Patents
Pharmaceutical compositions Download PDFInfo
- Publication number
- WO2019021319A1 WO2019021319A1 PCT/IN2018/050495 IN2018050495W WO2019021319A1 WO 2019021319 A1 WO2019021319 A1 WO 2019021319A1 IN 2018050495 W IN2018050495 W IN 2018050495W WO 2019021319 A1 WO2019021319 A1 WO 2019021319A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- oxy
- methyl
- compound
- formula
- purin
- Prior art date
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- 239000008194 pharmaceutical composition Substances 0.000 title claims description 27
- 150000001875 compounds Chemical class 0.000 claims abstract description 116
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 67
- VUAXHMVRKOTJKP-UHFFFAOYSA-M 2,2-dimethylbutanoate Chemical compound CCC(C)(C)C([O-])=O VUAXHMVRKOTJKP-UHFFFAOYSA-M 0.000 claims abstract description 57
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims abstract description 53
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 claims abstract description 53
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims abstract description 49
- 239000002207 metabolite Substances 0.000 claims abstract description 44
- 208000036142 Viral infection Diseases 0.000 claims abstract description 9
- 230000009385 viral infection Effects 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims description 42
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 claims description 38
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 32
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 32
- 230000000694 effects Effects 0.000 claims description 28
- -1 (phenoxy) phosphoryl Chemical group 0.000 claims description 27
- 238000011282 treatment Methods 0.000 claims description 25
- 241000282414 Homo sapiens Species 0.000 claims description 23
- 239000003814 drug Substances 0.000 claims description 22
- 229960004556 tenofovir Drugs 0.000 claims description 22
- 229940002612 prodrug Drugs 0.000 claims description 15
- 239000000651 prodrug Substances 0.000 claims description 15
- 239000003112 inhibitor Substances 0.000 claims description 14
- 229940124597 therapeutic agent Drugs 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 11
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
- IACQCQDWSIQSRP-ZCFIWIBFSA-N [(2r)-1-(6-aminopurin-9-yl)propan-2-yl]oxymethyl-[hydroxy(phosphonooxy)phosphoryl]oxyphosphinic acid Chemical compound N1=CN=C2N(C[C@@H](C)OCP(O)(=O)OP(O)(=O)OP(O)(O)=O)C=NC2=C1N IACQCQDWSIQSRP-ZCFIWIBFSA-N 0.000 claims description 8
- 239000000725 suspension Substances 0.000 claims description 8
- 230000001225 therapeutic effect Effects 0.000 claims description 8
- 230000036436 anti-hiv Effects 0.000 claims description 7
- 239000003826 tablet Substances 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 6
- 239000000243 solution Substances 0.000 claims description 6
- 231100001274 therapeutic index Toxicity 0.000 claims description 6
- 229960005449 daclatasvir Drugs 0.000 claims description 5
- FKRSSPOQAMALKA-CUPIEXAXSA-N daclatasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C1=NC(C=2C=CC(=CC=2)C=2C=CC(=CC=2)C=2N=C(NC=2)[C@H]2N(CCC2)C(=O)[C@@H](NC(=O)OC)C(C)C)=CN1 FKRSSPOQAMALKA-CUPIEXAXSA-N 0.000 claims description 5
- 239000002777 nucleoside Substances 0.000 claims description 5
- 150000003833 nucleoside derivatives Chemical class 0.000 claims description 5
- 241001430294 unidentified retrovirus Species 0.000 claims description 5
- WHBIGIKBNXZKFE-UHFFFAOYSA-N delavirdine Chemical compound CC(C)NC1=CC=CN=C1N1CCN(C(=O)C=2NC3=CC=C(NS(C)(=O)=O)C=C3C=2)CC1 WHBIGIKBNXZKFE-UHFFFAOYSA-N 0.000 claims description 4
- 238000012377 drug delivery Methods 0.000 claims description 4
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 claims description 4
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 claims description 4
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 claims description 3
- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 claims description 3
- 229960000517 boceprevir Drugs 0.000 claims description 3
- LHHCSNFAOIFYRV-DOVBMPENSA-N boceprevir Chemical compound O=C([C@@H]1[C@@H]2[C@@H](C2(C)C)CN1C(=O)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C)NC(C(=O)C(N)=O)CC1CCC1 LHHCSNFAOIFYRV-DOVBMPENSA-N 0.000 claims description 3
- 239000002775 capsule Substances 0.000 claims description 3
- 229960001418 dasabuvir Drugs 0.000 claims description 3
- NBRBXGKOEOGLOI-UHFFFAOYSA-N dasabuvir Chemical compound C1=C(C(C)(C)C)C(OC)=C(C=2C=C3C=CC(NS(C)(=O)=O)=CC3=CC=2)C=C1N1C=CC(=O)NC1=O NBRBXGKOEOGLOI-UHFFFAOYSA-N 0.000 claims description 3
- 230000007423 decrease Effects 0.000 claims description 3
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 claims description 3
- 239000007884 disintegrant Substances 0.000 claims description 3
- 229960000366 emtricitabine Drugs 0.000 claims description 3
- 229960001627 lamivudine Drugs 0.000 claims description 3
- 239000000137 peptide hydrolase inhibitor Substances 0.000 claims description 3
- 238000010839 reverse transcription Methods 0.000 claims description 3
- 229960000329 ribavirin Drugs 0.000 claims description 3
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 claims description 3
- 229960000311 ritonavir Drugs 0.000 claims description 3
- 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 claims description 3
- 229960002091 simeprevir Drugs 0.000 claims description 3
- JTZZSQYMACOLNN-VDWJNHBNSA-N simeprevir Chemical compound O=C([C@@]12C[C@H]1\C=C/CCCCN(C)C(=O)[C@H]1[C@H](C(N2)=O)C[C@H](C1)OC=1C2=CC=C(C(=C2N=C(C=1)C=1SC=C(N=1)C(C)C)C)OC)NS(=O)(=O)C1CC1 JTZZSQYMACOLNN-VDWJNHBNSA-N 0.000 claims description 3
- 229960002063 sofosbuvir Drugs 0.000 claims description 3
- TTZHDVOVKQGIBA-IQWMDFIBSA-N sofosbuvir Chemical compound N1([C@@H]2O[C@@H]([C@H]([C@]2(F)C)O)CO[P@@](=O)(N[C@@H](C)C(=O)OC(C)C)OC=2C=CC=CC=2)C=CC(=O)NC1=O TTZHDVOVKQGIBA-IQWMDFIBSA-N 0.000 claims description 3
- AXRYRYVKAWYZBR-UHFFFAOYSA-N Atazanavir Natural products C=1C=C(C=2N=CC=CC=2)C=CC=1CN(NC(=O)C(NC(=O)OC)C(C)(C)C)CC(O)C(NC(=O)C(NC(=O)OC)C(C)(C)C)CC1=CC=CC=C1 AXRYRYVKAWYZBR-UHFFFAOYSA-N 0.000 claims description 2
- 108010019625 Atazanavir Sulfate Proteins 0.000 claims description 2
- 102100035875 C-C chemokine receptor type 5 Human genes 0.000 claims description 2
- 101710149870 C-C chemokine receptor type 5 Proteins 0.000 claims description 2
- QAGYKUNXZHXKMR-UHFFFAOYSA-N CPD000469186 Natural products CC1=C(O)C=CC=C1C(=O)NC(C(O)CN1C(CC2CCCCC2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 QAGYKUNXZHXKMR-UHFFFAOYSA-N 0.000 claims description 2
- BXZVVICBKDXVGW-NKWVEPMBSA-N Didanosine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(NC=NC2=O)=C2N=C1 BXZVVICBKDXVGW-NKWVEPMBSA-N 0.000 claims description 2
- XPOQHMRABVBWPR-UHFFFAOYSA-N Efavirenz Natural products O1C(=O)NC2=CC=C(Cl)C=C2C1(C(F)(F)F)C#CC1CC1 XPOQHMRABVBWPR-UHFFFAOYSA-N 0.000 claims description 2
- XQSPYNMVSIKCOC-NTSWFWBYSA-N Emtricitabine Chemical group C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)SC1 XQSPYNMVSIKCOC-NTSWFWBYSA-N 0.000 claims description 2
- 108010032976 Enfuvirtide Proteins 0.000 claims description 2
- 108010047761 Interferon-alpha Proteins 0.000 claims description 2
- 102000006992 Interferon-alpha Human genes 0.000 claims description 2
- KJHKTHWMRKYKJE-SUGCFTRWSA-N Kaletra Chemical compound N1([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=2C=CC=CC=2)NC(=O)COC=2C(=CC=CC=2C)C)CC=2C=CC=CC=2)CCCNC1=O KJHKTHWMRKYKJE-SUGCFTRWSA-N 0.000 claims description 2
- XNKLLVCARDGLGL-JGVFFNPUSA-N Stavudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1C=C[C@@H](CO)O1 XNKLLVCARDGLGL-JGVFFNPUSA-N 0.000 claims description 2
- WREGKURFCTUGRC-POYBYMJQSA-N Zalcitabine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)CC1 WREGKURFCTUGRC-POYBYMJQSA-N 0.000 claims description 2
- WMHSRBZIJNQHKT-FFKFEZPRSA-N abacavir sulfate Chemical compound OS(O)(=O)=O.C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1.C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 WMHSRBZIJNQHKT-FFKFEZPRSA-N 0.000 claims description 2
- 229960001830 amprenavir Drugs 0.000 claims description 2
- 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 claims description 2
- 229960003277 atazanavir Drugs 0.000 claims description 2
- AXRYRYVKAWYZBR-GASGPIRDSA-N atazanavir Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)[C@@H](O)CN(CC=1C=CC(=CC=1)C=1N=CC=CC=1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C1=CC=CC=C1 AXRYRYVKAWYZBR-GASGPIRDSA-N 0.000 claims description 2
- 239000011230 binding agent Substances 0.000 claims description 2
- 239000006189 buccal tablet Substances 0.000 claims description 2
- 239000000969 carrier Substances 0.000 claims description 2
- 229960002402 cobicistat Drugs 0.000 claims description 2
- ZCIGNRJZKPOIKD-CQXVEOKZSA-N cobicistat Chemical compound S1C(C(C)C)=NC(CN(C)C(=O)N[C@@H](CCN2CCOCC2)C(=O)N[C@H](CC[C@H](CC=2C=CC=CC=2)NC(=O)OCC=2SC=NC=2)CC=2C=CC=CC=2)=C1 ZCIGNRJZKPOIKD-CQXVEOKZSA-N 0.000 claims description 2
- 229960005107 darunavir Drugs 0.000 claims description 2
- CJBJHOAVZSMMDJ-HEXNFIEUSA-N darunavir 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]1[C@@H]2CCO[C@@H]2OC1)C1=CC=CC=C1 CJBJHOAVZSMMDJ-HEXNFIEUSA-N 0.000 claims description 2
- 229960005319 delavirdine Drugs 0.000 claims description 2
- 229960002656 didanosine Drugs 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000007919 dispersible tablet Substances 0.000 claims description 2
- 229960002542 dolutegravir Drugs 0.000 claims description 2
- RHWKPHLQXYSBKR-BMIGLBTASA-N dolutegravir Chemical compound C([C@@H]1OCC[C@H](N1C(=O)C1=C(O)C2=O)C)N1C=C2C(=O)NCC1=CC=C(F)C=C1F RHWKPHLQXYSBKR-BMIGLBTASA-N 0.000 claims description 2
- 229960003804 efavirenz Drugs 0.000 claims description 2
- 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 claims description 2
- 229960003586 elvitegravir Drugs 0.000 claims description 2
- JUZYLCPPVHEVSV-LJQANCHMSA-N elvitegravir Chemical compound COC1=CC=2N([C@H](CO)C(C)C)C=C(C(O)=O)C(=O)C=2C=C1CC1=CC=CC(Cl)=C1F JUZYLCPPVHEVSV-LJQANCHMSA-N 0.000 claims description 2
- 229960002062 enfuvirtide Drugs 0.000 claims description 2
- PEASPLKKXBYDKL-FXEVSJAOSA-N enfuvirtide Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(C)=O)[C@@H](C)O)[C@@H](C)CC)C1=CN=CN1 PEASPLKKXBYDKL-FXEVSJAOSA-N 0.000 claims description 2
- 239000000945 filler Substances 0.000 claims description 2
- 239000000796 flavoring agent Substances 0.000 claims description 2
- 230000004927 fusion Effects 0.000 claims description 2
- 229960001936 indinavir Drugs 0.000 claims description 2
- 229940124524 integrase inhibitor Drugs 0.000 claims description 2
- 239000002850 integrase inhibitor Substances 0.000 claims description 2
- 229950000038 interferon alfa Drugs 0.000 claims description 2
- 229960004525 lopinavir Drugs 0.000 claims description 2
- 239000000314 lubricant Substances 0.000 claims description 2
- 230000035800 maturation Effects 0.000 claims description 2
- 229960000884 nelfinavir Drugs 0.000 claims description 2
- 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 claims description 2
- 229960000689 nevirapine Drugs 0.000 claims description 2
- 229940042402 non-nucleoside reverse transcriptase inhibitor Drugs 0.000 claims description 2
- 239000002726 nonnucleoside reverse transcriptase inhibitor Substances 0.000 claims description 2
- 108010092853 peginterferon alfa-2a Proteins 0.000 claims description 2
- 108010092851 peginterferon alfa-2b Proteins 0.000 claims description 2
- 229960004742 raltegravir Drugs 0.000 claims description 2
- CZFFBEXEKNGXKS-UHFFFAOYSA-N raltegravir Chemical compound O1C(C)=NN=C1C(=O)NC(C)(C)C1=NC(C(=O)NCC=2C=CC(F)=CC=2)=C(O)C(=O)N1C CZFFBEXEKNGXKS-UHFFFAOYSA-N 0.000 claims description 2
- 229960002814 rilpivirine Drugs 0.000 claims description 2
- YIBOMRUWOWDFLG-ONEGZZNKSA-N rilpivirine Chemical compound CC1=CC(\C=C\C#N)=CC(C)=C1NC1=CC=NC(NC=2C=CC(=CC=2)C#N)=N1 YIBOMRUWOWDFLG-ONEGZZNKSA-N 0.000 claims description 2
- 229960001852 saquinavir Drugs 0.000 claims description 2
- 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 claims description 2
- 229960001203 stavudine Drugs 0.000 claims description 2
- 239000006188 syrup Substances 0.000 claims description 2
- 235000020357 syrup Nutrition 0.000 claims description 2
- 230000000699 topical effect Effects 0.000 claims description 2
- 235000012431 wafers Nutrition 0.000 claims description 2
- 229960000523 zalcitabine Drugs 0.000 claims description 2
- 229960002555 zidovudine Drugs 0.000 claims description 2
- 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 claims description 2
- 241000711549 Hepacivirus C Species 0.000 claims 1
- 241000700721 Hepatitis B virus Species 0.000 claims 1
- 229960002118 asunaprevir Drugs 0.000 claims 1
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 claims 1
- 229950010541 beclabuvir Drugs 0.000 claims 1
- ZTTKEBYSXUCBSE-QDFUAKMASA-N beclabuvir Chemical compound C1([C@@H]2C[C@@]2(CN2C3=CC(=CC=C33)C(=O)NS(=O)(=O)N(C)C)C(=O)N4[C@@H]5CC[C@H]4CN(C)C5)=CC(OC)=CC=C1C2=C3C1CCCCC1 ZTTKEBYSXUCBSE-QDFUAKMASA-N 0.000 claims 1
- 239000004067 bulking agent Substances 0.000 claims 1
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- BVAZQCUMNICBAQ-PZHYSIFUSA-N elbasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C1=NC(C=2C=C3O[C@H](N4C5=CC=C(C=C5C=C4C3=CC=2)C=2N=C(NC=2)[C@H]2N(CCC2)C(=O)[C@@H](NC(=O)OC)C(C)C)C=2C=CC=CC=2)=CN1 BVAZQCUMNICBAQ-PZHYSIFUSA-N 0.000 claims 1
- 229960002007 elbasvir Drugs 0.000 claims 1
- 235000019634 flavors Nutrition 0.000 claims 1
- 239000000499 gel Substances 0.000 claims 1
- 229960002914 grazoprevir Drugs 0.000 claims 1
- OBMNJSNZOWALQB-NCQNOWPTSA-N grazoprevir Chemical compound O=C([C@@H]1C[C@@H]2CN1C(=O)[C@@H](NC(=O)O[C@@H]1C[C@H]1CCCCCC1=NC3=CC=C(C=C3N=C1O2)OC)C(C)(C)C)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C OBMNJSNZOWALQB-NCQNOWPTSA-N 0.000 claims 1
- 239000007943 implant Substances 0.000 claims 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 claims 1
- VRTWBAAJJOHBQU-KMWAZVGDSA-N ledipasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N([C@@H](C1)C=2NC(=CN=2)C=2C=C3C(F)(F)C4=CC(=CC=C4C3=CC=2)C=2C=C3NC(=NC3=CC=2)[C@H]2N([C@@H]3CC[C@H]2C3)C(=O)[C@@H](NC(=O)OC)C(C)C)CC21CC2 VRTWBAAJJOHBQU-KMWAZVGDSA-N 0.000 claims 1
- 229960002461 ledipasvir Drugs 0.000 claims 1
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Definitions
- the present invention relates to metabolites and derivatives of ((((((R)-l-(6-amino- 9H-purin-9-yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl)oxy)methyl pivalate, including compound of (Formula I)
- the present invention also provides process for preparing the said metabolites and derivatives and their use for the prevention, treatment or prophylaxis of diseases caused by viruses, specifically acquired immune deficiency syndrome or an HIV infection, Hepatitis B infection, or Hepatitis C infection.
- HIV-1 infection Human immunodeficiency virus, type 1 (HIV-1) infection is a life-threatening and serious disease of major public health significance, with approximately 36.7 million people infected worldwide (Joint United Nations Programme on HIV/AIDS (UNAIDS). Global report: UNAIDS report on the global AIDS epidemic, 2016). Acquired Immune Deficiency Syndrome (AIDS) causes a gradual breakdown of the body's immune system as well as progressive deterioration of the central and peripheral nervous systems. Since its initial recognition in the early 1980s, AIDS has spread rapidly and has now reached epidemic proportions within a relatively limited segment of the population. Intensive research has led to the discovery of the responsible agent, human T-lymphotropic retrovirus 111 (HTLV-11 1) commonly referred to as the Human Immunodeficiency Virus or HIV.
- HTLV-11 1 human T-lymphotropic retrovirus 111
- Tenofovir is a highly potent nucleotide analog reverse-transcriptase inhibitor which is widely used in the treatment of diseases caused by retroviruses, especially Acquired Immune Deficiency Syndrome or an HIV infection.
- Tenofovir ⁇ 9-R-[(2- phosphonomethoxy)propyl]adenine ⁇ , an acyclic nucleotide analog of dAMP, is a potent in vitro and in vivo inhibitor of human immunodeficiency virus type 1 (HIV- 1) replication.
- Tenofovir is sequentially phosphorylated in the cell by AMP kinase and nucleoside diphosphate kinase to the active species, tenofovir diphosphate, which acts as a competitive inhibitor of HIV- 1 reverse transcriptase that terminates the growing viral DNA chain.
- the presence of a nonhydrolyzable phosphonic acid moiety in tenofovir circumvents an initial phosphorylation step that can be rate limiting for the activation of nucleoside analog inhibitors of HIV reverse transcriptase. Due to the presence of a phosphonate group, tenofovir is negatively charged at neutral pH, thus limiting its oral bioavailability.
- Tenofovir disoproxil fumarate (TDF; VIREAD ® ), the first-generation oral prodrug of tenofovir, has been extensively studied in clinical trials and has received marketing authorization in many countries as a once-daily tablet (300 mg) in combination with other antiretroviral agents for the treatment of HIV- 1 infection.
- Tenofovir D soproxil Fumarate is a water soluble ant -HIV and anti-HBV oral drug, stable in the stomach, enters the body with the blood after the intestinal absorption, and uniformly distributed within human tissues.
- TDF Tenofovir D soproxil Fumarate
- less than 20% of TDF is metabolized and activated into the Tenofovir parent drug under the action of esterase, and then diphosphorylated into Tenofovir diphosphate to take effect, and about the remaining 80% is excreted out of the body in original orm.
- the strategy of introducing the masking group onto the phosphate group of the Tenofovir to form the lipid soluble prodrug is usually adopted.
- Such prodrugs are proven to have the lymph and liver tissue targeting effect.
- the masking group of o-methyl benzyl of the compound structure disclosed in CN201380030061.6 has a high group-leaving activity and low stability during the blood esterase metabolism, therefore leading to the relative increase of the active parent drug in the blood and relative decrease of the active parent drug in the liver, and affecting the activity and systemic toxicity.
- U.S. Patent No. 7,390,791 describes certain prodrugs of phosphonate nucleotide analogs that are useful in therapy.
- One such prodrug is Tenofovir alafenamide hemifumarate (TAF; Vemlidy ® ) which is an isopropylalaninyl phenyl ester prodrug of tenofovir.
- U. S. Patent No. 9,227,990 (the content of which is incorporated by reference herein in its entirety) describe certain prodrugs of phosphonate nucleotide analogs that are useful in therapy.
- One such prodrug is ((((((R)-l-(6-amino-9H-purin-9-yl)propan- 2-yl)oxy)methyl)(phenoxy)phosphoryl)oxy)methyl pivalate.
- the inventors of present invention after rigorous experiments, have found a class of metabolite and derivatives of ((((((R)-l-(6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl) (phenoxy)phosphoryl)oxy)methyl pivalate which are stable for a reasonable time period , have enhanced bio-activity, limited conversion to parent compound having less bioactivity and upgrade its anti-virus activity.
- the inventors of the present invention have provided a method of determining the stability and bioactivity of the said metabolites and derivatives.
- the present invention concerns metabolites and derivatives of (((((((R)-l-(6- amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl)oxy)methyl pivalate, method of determining the stability and bioactivity of said metabolites and derivatives , process for preparing the said metabolites and derivatives and their use for the prevention, treatment or prophylaxis of diseases caused by viruses, specifically acquired immune deficiency syndrome or an HIV infection, Hepatitis B infection, or Hepatitis C infection.
- An object of the present invention is to provide a method of determining the stability of metabolites and derivatives of ((((((R)-l-(6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl)(phenoxy)phosphoryl)oxy)methyl pivalate represented as compound of formula I.
- Another object of the present invention is to provide a method of determining bioactivity of a compound of formula I.
- Another object of the present invention is to provide a compound of formula I
- Yet another object of the present invention is to provide a process for preparing a compound of formula I.
- Another object of the present invention is to provide a pharmaceutical composition
- a pharmaceutical composition comprising, as active principle, the compound of formula I or a pharmaceutically acceptable derivative thereof, and at least one pharmaceutically acceptable excipient.
- Yet another object of the present invention is to provide a use of compound of formula I or a pharmaceutically acceptable derivative thereof for the prophylactic or therapeutic treatment of a viral infection in a human, wherein the viral infection is human immunodeficiency virus (HIV) or Hepatitis B infection (HBV) or Hepatitis C infection (HCV).
- HIV human immunodeficiency virus
- HBV Hepatitis B infection
- HCV Hepatitis C infection
- Yet another object of the present invention is to provide a method of prevention, treatment or prophylaxis of diseases caused by viruses, specifically Acquired Immune Deficiency Syndrome or an HIV infection or Hepatitis B infection or Hepatitis C infection, which method comprises administering a pharmaceutical composition comprising compound of formula I or a pharmaceutically acceptable derivative thereof.
- Yet another object of the present invention is to provide a method of prevention, treatment or prophylaxis of diseases caused by viruses, specifically Acquired Immune Deficiency Syndrome or an HIV infection or Hepatitis B infection or Hepatitis C infection, which method comprises administering a pharmaceutical composition comprising compound of formula I or a pharmaceutically acceptable derivative thereof and at least one additional therapeutic agent.
- a pharmaceutical composition comprising, as active principle, the compound of formula I or a pharmaceutically acceptable derivative thereof, and at least one pharmaceutically acceptable excipient.
- a use of compound of formula I or a pharmaceutically acceptable derivative thereof for the prophylactic or therapeutic treatment of a viral infection in a human wherein the viral infection is human immunodeficiency virus (HIV) or Hepatitis B infection (HBV) or Hepatitis C infection (HCV).
- HIV human immunodeficiency virus
- HBV Hepatitis B infection
- HCV Hepatitis C infection
- a method of prevention, treatment or prophylaxis of diseases caused by viruses which method comprises administering a pharmaceutical composition comprising compound of formula I or a pharmaceutically acceptable derivative thereof.
- a method of prevention, treatment or prophylaxis of diseases caused by viruses comprising administering a pharmaceutical composition comprising compound of formula I or a pharmaceutically acceptable derivative thereof and at least one additional therapeutic agent.
- Figure 1 represents percentage of (((((((R)-l-(6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl)(phenoxy)phosphoryl) oxy)methyl pivalate fumarate remaining in dog and human plasma
- Figure 2 represents time dependent increase in percentage of compound of formula I in dog and human
- Figure 3 represents percentage of tenofovir in dog and human plasma DETAILED DESCRIPTION OF THE INVENTION:
- the inventors of the present invention invented compounds which are a class of metabolite and derivatives of ((((((R)-l-(6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl) (phenoxy)phosphoryl)oxy)methyl pivalate, and found that the compounds of the present invention are stable in plasma for a reasonable period of time, does not convert back to parent compound and have antiviais activities, in the in vivo animal test, the compounds can be enriched in the liver, where they are present in high amount and show antiviral activity also. Compared with Tenofovir, the compounds of the present invention have a higher anti-HBV activity, or are more stable in the plasma, are safer, and therefore the systemic toxic and side effects caused by the plasma metabolism are reduced.
- the present invention relates to metabolites and derivatives of ((((((R)-l-(6-amino- 9H-purin-9-yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl)oxy)methyl pivalate (Formula II), method of determining stability and bioactivity of said metabolites and derivatives,process for preparing the said metabolites and derivatives and their use for the prevention, treatment or prophylaxis of diseases caused by viruses, specifically acquired immune deficiency syndrome or an HIV infection, Hepatitis B infection, or Hepatitis C infection.
- Suitable pharmaceutically acceptable derivatives include pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable anhydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable esters, pharmaceutically acceptable isomers, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, pharmaceutically acceptable tautomers, pharmaceutically acceptable complexes etc.
- metabolites of ((((((R)-l-(6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl)(phenoxy)phosphoryl)oxy)methyl pivalate have been identified in and determined in the dog, human, and rat.
- the metabolites are compounds having Formula (I) as:
- the metabolites are provided in isolated form, having been identified in and isolated or separated from body tissues or fluids of a test animal and/or prepared synthetically.
- the compounds are provided in substantially pure form.
- substantially pure means that the compounds are pure enough for FDA approval and contain essentially no contaminants or other materials, or alternatively a level of impurity that does not adversely or unacceptably affect the properties of the compounds as regards safety, effectiveness, stability, and other desirable properties.
- the invention provides compound of Formula (I) in isolated form or pharmaceutically acceptable salts, hydrates, solvates, racemates, or optical isomers thereof.
- the metabolite and derivatives of ((((((R)-l-(6-amino-9H-purin- 9-yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl)oxy)methyl pivalate and compound I are stable for a reasonable time period.
- the reasonable time period includes time period from about 0 minutes till 360 minutes of administration, preferably till 240minutes.
- the amount of compound of formula I present in plasma after reasonable amount of time is 80% or greater, 90% or greater, 95% or greater, and 99% or greater and the amount of ((((((R)-l-(6-amino-9H-purin-9-yl)propan- 2-yl)oxy)methyl)(phenoxy)phosphoryl)oxy)methyl pivalate fumarate present in plasma after reasonable amount of time is lesser than 99%, lesser than 90%, lesser than 95% and lesser than 80%.
- liver microsomes a subcellular fraction containing major drug-metabolizing enzymes, including the cytochrome P450 (CYP) family and flavin monooxygenase (FMO).
- CYP cytochrome P450
- FMO flavin monooxygenase
- the present invention provides metabolites and derivatives of ((((((R)-l-(6-amino-9H-purin-9-yl)propan- 2-yl)oxy)methyl)(phenoxy)phosphoryl)oxy)methyl pivalate fumarate which are not metabolized by liver microsomes and are present in an amount of more than 80% or greater, 90% or greater, 95% or greater, and 99% or greater.
- the present invention provides compound of formula I which is not metabolized by liver microsomes and is present in an amount of more than 80% or greater, 90% or greater, 95% or greater, and 99% or greater.
- the inventors of present invention have found intermediate derivatives of (((((((R)- l-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl) (phenoxy)phosphoryl)oxy)methyl pivalate termed as compound of formula I, stabilize it for reasonable period of time and show combined activity with PMPA and tenofovir diphosphate and thus enhanced anti-viral activity.
- SI Selectivity Index numbers greater than 5 are moderately active, greater than 10 are highly active and greater than 100 are extraordinarily highly active.
- the Selectivity Index (SI) scale is the ratio of cytotoxicity of the agent (CC aka IC) to the selective antiviral activity (EC) (EC50 for cell-based assays; IC50 for biochemical or subcellular assays) such that a SI >10 indicates extraordinarily strong activity.
- the present invention provides anti-HIV and anti-HBV activity of ((((((R)- 1 -(6-amino-9H-purin-9-yl)propan-2-yl)oxy) methyl) (phenoxy) phosphoryl) oxy) methyl pivalate fumarate, compound of formula I, PMPA and tenofovir diphosphate and thus enhanced ami -viral activity.
- the present invention also provides metabolites and derivatives of (((((((R)-l-(6- amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl)oxy)methyl pivalate fumarate showing anti-HIV and anti-HBV activity independently from ((((((R)- 1 -(6-amino-9H-purin-9-yl)propan-2-yl)oxy) methyl) (phenoxy) phosphoryl) oxy) methyl pivalate fumarate, PMPA and tenofovir diphosphate.
- the metabolites and derivatives of present invention and compound of formula I have therapeutic index of greater than 5, 10, 20, 40, 60 when showing anti-HIV activity.
- the compound of formula I has therapeutic index of greater than 40% when showing anti-HIV activity.
- compositions comprising a pharmaceutically acceptable carrier and 0.1% to 90% by weight of an active material, wherein the active material comprises compound of Formula (I) and pharmaceutically acceptable salts, hydrates, solvates, optical isomers, and racemates thereof, and wherein the compound is not ((((((R)-l-(6-amino-9H-purin- 9-yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl)oxy) methyl pivalate.
- the compound of formula I is present in an amount from about 2% to about 80% of the composition.
- the invention provides pre-clinical ADME metabolites of ((((((R)- 1 -(6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl)(phenoxy)phosphoryl)oxy)methyl pivalate.
- Pre-clinical ADME metabolites means those metabolites of (((((R)-l-(6-amino-9H-purin-9- yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl)oxy)methyl pivalate formed in vivo or in vitro during pre-clinical testing on non-human subjects.
- Such testing is carried out to characterize the absorption, distribution, metabolism, and excretion (ADME) of a proposed drug product prior to clinical testing on humans. Non- limiting description of such testing is provided in Examples 1-4 below.
- compound of Formulas (I) is derived from (((((((R)- 1 -(6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl)(phenoxy)phosphoryl)oxy)m ethyl pivalate in mammals as the result of metabolism of the drug by so-called phase I and/ or phase II metabolic pathways.
- the invention includes administering (((((((R)-l-(6-amino- 9H-purin-9-yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl)oxy)methyl pivalate or its metabolite to a mammal and detecting metabolites by measuring the level or concentration of one of the metabolites in the tissues or bodily fluids of the mammal.
- Bodily fluids include without limitation blood plasma, bile, urine, and feces
- tissues include without limitation liver microsomes, hepatocytes, and perfused livers.
- compounds of the invention are formulated into suitable dosage forms for administration to humans or other mammals.
- the compounds of the invention may exhibit favorable toxicological profiles.
- the pharmaceutical composition further comprising an additional therapeutic agent.
- the additional therapeutic agent is selected from the group consisting of nucleoside reverse transcription inhibitors ( RTIs), non-nucleoside reverse transcriptase inhibitors (N RTIs), protease inhibitors (Pis), integrase inhibitors, CCR5 inhibitors, fusion inhibitors and maturation inhibitors (Mis) and any combination thereof.
- RTIs nucleoside reverse transcription inhibitors
- N RTIs non-nucleoside reverse transcriptase inhibitors
- Pro protease inhibitors
- integrase inhibitors CCR5 inhibitors
- fusion inhibitors and maturation inhibitors Mis
- Adjunctive therapy i.e. where one active ingredient is used as the primary treatment and the other active ingredient(s) is/are used to assist that primary treatment is also an embodiment of the present invention.
- the pharmaceutical composition is a combination of ((((((R)- 1 -(6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl)(phenoxy)phosphoryl)oxy)methyl pivalate or compound of formula I and one or more of additional therapeutic agent selected from, but not limiting to, emtricitabine, efavirenz, nevirapine, darunavir, atazanavir, zidovudine, didanosine, stavudine, lamivudine, zalcitabine, abacavir sulphate, delavirdine, saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, cobicistat, lopinavir, enfuvirtide, dolutegravir, elvitegravir, raltegravir, rilpivirine.
- additional therapeutic agent selected from, but not limiting to,
- the pharmaceutical composition is a combination of ((((((R)- 1 -(6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl)(phenoxy)phosphoryl)oxy)methyl pivalate or compound of formula I and one or more of additional therapeutic agent selected from, but not limiting to, recombinant Human Interferon Alfa such as pegylated interferon alfa-2a or pegylated interferon alfa-2b (collectively "peginterferon” or "PEG”), nucleoside analogs for example ribavirin, direct acting antivirals (for example daclatasvir, boceprevir and telapravir), NS3/4A protease inhibitors (Pis) (for example simeprevir), nucleotide NS5B polymerase inhibitors (for example sofosbuvir), NS5A Inhibitors (for example daclatasvir), non-nucleoside
- Compound of formula I is useful in the treatment and/or prophylaxis of one or more viral infections in man or animals, including infections caused by DNA viruses.
- RNA viruses herpesviruses (e.g., CMV, HSV 1, HSV 2, VZV), retroviruses, hepadnaviruses (e.g., HBV), papillomavirus, hantavirus, adenoviruses and HIV.
- a method for treating a human immunodeficiency virus (HIV) infection comprising administering to a subject in need thereof a therapeutically effective amount of compound of formula I or a pharmaceutically acceptable derivative thereof.
- HIV human immunodeficiency virus
- the methods of prophylactic or therapeutic treatment comprise administration of multiple daily doses. In other embodiments, the methods of prophylactic or therapeutic treatment comprise administration of a single daily dose.
- the term 'therapeutically effective compound of formula I as anti- HIV at a dose thai can be administered once daily' means that the compounds are suitable for dosing every 24 hours.
- the -term suitable for dosing every 24 hours' means that the compounds are such that they can be administered every 24 hours and give effective blood plasma concentrations of the active ingredients such thai they are effective to suppress HIV infection over a period of 24 hours.
- the compounds for use in the invention can be dosed ever*, ' ' 24 hours
- Compound of formula I can be administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including ocular, buccal, and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural).
- Suitable routes include oral, rectal, nasal, topical (including ocular, buccal, and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural).
- the formulations are in unit dosage form and are prepared by any of the methods well known in the art of pharmacy.
- compound of formula I may be combined with one or more excipients and used in the form of ingestible tablets, dispersible tablets, buccal tablets, troches, capsules, elixirs, solutions, suspensions, syrups, wafers, Self-emulsifying drug delivery system (SEDDS), Self-microemulsifying drug delivery system (SMEDDS) and the like.
- SEDDS Self-emulsifying drug delivery system
- SMEDDS Self-microemulsifying drug delivery system
- compositions suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets, each containing a predetermined amount of compound of formula I; as a powder or granules; as a solution or a suspension in an aqueous liquid or a nonaqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
- Compound of formula I may also be presented as a bolus, electuary, or paste.
- Suitable excipients may be used for formulating the dosage forms according to the present invention such as, but not limited to, surface stabilizers or surfactants, viscosity modifying agents, polymers including extended release polymers, stabilizers, disintegrants or super disintegrants, diluents, plasticizers, binders, glidants, lubricants, sweeteners, flavoring agents, anti-caking agents, opacifiers, anti-microbial agents, antifoaming agents, emulsifiers, buffering agents, coloring agents, carriers, fillers, anti-adherents, solvents, taste-masking agents, preservatives, antioxidants, texture enhancers, channeling agents, coating agents or combinations thereof.
- compositions suitable for parenteral administration are sterile and include aqueous and nonaqueous injection solutions that may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and nonaqueous sterile suspensions that may include suspending agents and thickening agents.
- the formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials with elastomeric stoppers, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier (e.g., water for injections) immediately prior to use.
- Injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the kind previously described.
- compositions/formulations may include other ingredients conventional in the art, having regard to the type of formulation in question.
- Useful dosages of compound of formula I can be determined by comparing in vitro activities, and the in vivo activities in animal models. Methods for the extrapolation of effective amounts/dosages in mice and other animals to therapeutically effective amounts/dosages in humans are known in the art.
- the amount of compound of formula I required for use in treatment will vary with several factors, including but not limited to the route of administration, the nature of the condition being treated, and the age and condition of the patient; ultimately, the amount administered will be at the discretion of the attendant physician or clinician.
- the therapeutically effective amount/dose of compound of formula I depends, at least, on the nature of the condition being treated, any toxicity or drug interaction issues, whether the compound is being used prophylactically (e.g., sometimes requiring lower doses) or against an active disease or condition, the method of delivery, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies.
- the oral dose of compound of formula I may be in the range from about 0.0001 to about 100 mg/kg body weight per day, for example, from about 0.01 to about 10 mg/kg body weight per day, from about 0.01 to about 5 mg/kg body weight per day, from about 0.5 to about 50 mg/kg body weight per day, from about 1 to about 30 mg/kg body weight per day, from about 1.5 to about 10 mg/kg body weight per day, or from about 0.05 to about 0.5 mg/kg body weight per day.
- the daily candidate dose for an adult human of about 70 kg body weight will range from about 0.1 mg to about 500 mg, or from about 1 mg to about 500 mg, or from about 5 mg to about 300 mg, or from about 10 mg to about 150 mg, or from about 25 mg to about 150 mg, or from about 5 mg to about 100 mg, and may take the form of single or multiple doses.
- the administration of compound of formula I or pharmaceutically acceptable derivative thereof, either alone or in combination with one or more additional therapeutic agent can lower detectable viral RNA/ DNA levels in a patient.
- methods disclosed herein can lower viral RNA/ DNA levels by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% relative to viral RNA/ DNA levels prior to initiating treatment.
- compound of formula I or pharmaceutically acceptable derivative thereof can be administered to a patient such that no viral RNA/ DNA levels is detectable in the patient after the treatment course is complete.
- Viral RNA/ DNA levels can be determined by quantitative, multi-cycle reverse transcriptase PCR.
- Therapeutic methods include administering compound of formula I to a subject/patient in need of the same as a therapeutic or prophylactic treatment.
- compound of formula I may be administered to a subject/patient having a medical disorder or to a subject who may acquire the disorder.
- a medical disorder or to a subject who may acquire the disorder.
- Such treatment is given in order to ameliorate, prevent, delay, cure, and/or reduce the severity of a symptom or set of symptoms of a disorder (including a recurring disorder).
- the treatment may also be given to prolong the survival of a subject, e.g., beyond the survival time expected in the absence of such treatment.
- the medical disorders that may be treated with compound of formula I include those discussed herein, including without limitation, HIV infection, HBV infection and HCV infection.
- Dog and human plasma (0. 396 mL) was added to 96 well plates in triplicates. The plate was pre-incubated for 10 min at 37 °C followed by addition of ((((((R)-l-(6- amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl) oxy)methyl pivalate fumarate at final concentration of 100 ⁇ . At 0, 7.5, 15, 30, 60 and 120 min, 50 ⁇ ⁇ of sample was removed and quenched with 250 ⁇ ⁇ of acetonitrile followed by analysing the samples by LCMS-MS for the presence of parent compound, compound of formula I and tenofovir.
- the objective of the study was to identify and quantify the metabolites of (((((((R)- l-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl) oxy)methyl pivalate fumarate in dog and human liver microsomes based on peak area.
- the active microsomes were removed from the deep freezer (-80°C), thawed at 37 °C and then kept on ice until use.
- the microsomes were diluted to the working concentrations using phosphate buffer.
- test item (((((((((R)-l-(6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl)(phenoxy)phosphoryl) oxy)methyl pivalate fumarate) and NADPH were mixed as per the following scheme.
- Test item cone 10.0 ⁇
- Time points (for incubation) 0, 5, 10, 15, 30, 60, 120 and 240 min.
- Microsomal suspension (1780 ⁇ .) was taken into micro centrifuge tubes, and 200 ⁇ . of NADPH (lOmM) was mixed with these microsomal suspensions. Pre-incubated at 37 °C and 120 rpm in an incubator shaker for 10 min and the reactions were initiated with the addition of 20 ⁇ of ((((((R)-l-(6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl)(phenoxy)phosphoryl) oxy)m ethyl pivalate fumarate (lmM) to all incubation mixtures except to the blank.
- Example 3 In vivo pharmacokinetics of ((((((R)-l-(6-amino-9H-purin-9- yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl) oxy)methyl pivalate fumarate in rats and dogs
- the aim of the study was to evaluate the comparative pharmacokinetic parameters of ((((((R)- 1 -(6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl)(phenoxy)phosphoryl) oxy)methyl pivalate fumarate in male Wistar rats after a single oral administration at 2.6 mg/kg and 31 mg/kg.
- Blood samples were collected through jugular vein cannulation at 0 (pre-dose), 0.25, 0.50, 1, 2, 4, 8 and 24 hr post-dose (Total 8 bleedings/rat).
- the aim of the study was to evaluate the comparative pharmacokinetic parameters of ((((((R)- 1 -(6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl)(phenoxy)phosphoryl)oxy) methyl pivalate fumarate in dogs after a single oral administration at 0.78 mg/kg and 9.25 mg/kg.
- Blood samples were collected through jugular vein cannulation at 0 (pre-dose), 0.25, 0.50, 1, 2, 4, 8 and 24 hr post-dose (Total 8 bleedings/dog).
- Table 3 Dog plasma concentration of Tenofovir on administration of (((((((R)- l-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl) oxy)methyl pivalate fumarate
- Table 4 Dog plasma concentration of compound of formula I on administration of ((((((R)-l-(6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl)(phenoxy)phosphoryl) oxy)methyl pivalate fumarate
- PBMCs Banded PBMCs were gently aspirated from the resulting interface and subsequently washed 2X with PBS by low speed centrifugation. After the final wash, cells were enumerated by trypan blue exclusion and re-suspended at 1 x 10 6 cells/mL in RPMI 1640 supplemented with 15 % Fetal Bovine Serum (FB S), and 2 mM L-glutamine, 4 ⁇ g/mL Phytohemagglutinin (PHA, Sigma). The cells were allowed to incubate for 48-72 hours at 37°C.
- FB S Fetal Bovine Serum
- PHA Phytohemagglutinin
- PBMCs were centrifuged and re-suspended in RPMI 1640 with 15% FBS, 2 mM L-glutamine, 100 U/mL penicillin, 100 ⁇ g/mL streptomycin, and approximately 100-150 U/mL recombinant human IL-2 (R&D Systems, Inc). IL-2 was included in the culture medium to maintain the cell division initiated by the PHA mitogenic stimulation. PBMCs were maintained in this medium at a concentration of 1-2 x 10 6 cells/mL with biweekly medium changes until used in the assay protocol. Cells were kept in culture for a maximum of two weeks before being deemed too old for use in assays and discarded.
- MDMs were depleted from the culture as the result of adherence to the tissue culture flask.
- PHA stimulated cells from at least two normal donors were pooled (mixed together), diluted in fresh medium to a final concentration of 1 x 106 cells/mL, and plated in the interior wells of a 96 well round bottom microplate at 50 [iL/well (5 x 10 4 cells/well) in a standard format developed by the Infectious Disease Research department of Southern Research Institute. Pooling (mixing) of mononuclear cells from more than one donor was used to minimize the variability observed between individual donors, which results from quantitative and qualitative differences in HIV infection and overall response to the PHA and IL-2 of primary lymphocyte populations.
- Each plate contained virus/cell control wells (cells plus virus), experimental wells (drug plus cells plus virus) and compound control wells (drug plus media without cells, necessary for MTS monitoring of cytotoxicity).
- PBMC viability remained high throughout the duration of the incubation period. Therefore, infected wells were used in the assessment of both antiviral activity and cytotoxicity.
- Test drug dilutions were prepared at a 2X concentration in microtiter tubes and 100 uL of each concentration (nine total concentrations) were placed in appropriate wells using the standard format. 50 ⁇ ⁇ of a predetermined dilution of virus stock was placed in each test well (final MOI approximately 0.1).
- the PBMC cultures were maintained for six-seven days following infection at 37°C, 5% C02. After this period, cell-free supernatant samples were collected for analysis of reverse transcriptase activity and/or p24 antigen content.
- RT reverse transcriptase
- the RT reaction buffer was prepared fresh on a daily basis and consisted of 125 1.0 M EGTA, 125 uL dH20, 125 ⁇ . 20% Triton X100, 50 1.0 M Tris (pH 7.4), 50 ⁇ , 1.0 M DTT, and 40 ⁇ , 1.0 M MgC12.
- the final reaction mixture was prepared by combining lpart 3 H-TTP, 4 parts dH20, 2.5 parts poly rA:oligo dT stock and 2.5 parts reaction buffer. Ten microliters of this reaction mixture was placed in a round bottom microtiter plate and 15 ⁇ . of virus containing supernatant was added and mixed. The plate was incubated at 37°C for 60 minutes.
- reaction volume was spotted onto DE81 filter-mats (Wallac), washed 5 times for 5 minutes each in a 5% sodium phosphate buffer or 2X SSC (Life Technologies). Next they were washed 2 times for 1 minute each in distilled water, 2 times for 1 minute each in 70% ethanol, and then dried. Incorporated radioactivity (counts per minute, CPM) was quantified using standard liquid scintillation techniques.
- assay plates were stained with the soluble tetrazolium-based dye MTS (CellTiter 96 Reagent, Promega) to determine cell viability and quantify compound toxicity.
- MTS CellTiter 96 Reagent, Promega
- the MTS is a stable solution that does not require preparation before use.
- 20 ⁇ _ of MTS reagent was added per well.
- the microtiter plates were then incubated 4-6 hrs at 37°C. The incubation intervals were chosen based on empirically determined times for optimal dye reduction.
- Adhesive plate sealers were used in place of the lids, the sealed plate was inverted several times to mix the soluble formazan product and the plate was read spectrophotometrically at 490/650 nm with a Molecular Devices SpectraMaxPlus i3 reader.
- the primary anti-HBV assay was performed as previously described (1, 2) with modifications to use real-time qPCR (TaqMan) to measure extracellular HBV DNA copy number associated with virions released from HepG2 2.2.15 cells.
- the HepG2 2.2.15 cell line is a stable human hepatoblastoma cell line that contains two copies of the HBV wild-type strain aywl genome and constitutively produces high levels of HBV.
- Antiviral compounds blocking any late step of viral replication such as transcription, translation, pregenome encapsidation, reverse transcription, particle assembly and release can be identified and characterized using this cell line.
- HepG2 2.2.15 cells were plated in 96-well microtiter plates at 1.5x104 cells/well in Dulbecco's Modified Eagle's Medium supplemented with 2% FBS, 380 ⁇ g/mL G418, 2.0 mM L-Glutamine, 100 units/mL Penicillin, 100 ⁇ g/mL Streptomycin, and 0.1 mM non-essential amino acids. Only the interior wells were utilized to reduce "edge effects" observed during cell culture; the exterior wells were filled with complete medium to help minimize sample evaporation. After 16-24 hours the confluent monolayer of HepG2 2.2.15 cells was washed and the medium was replaced with complete medium containing various concentrations of a test compound in triplicate.
- Lamivudine (3TC) was used as the positive control, while media alone was added to cells as a negative control (virus control, VC). Three days later the culture medium was replaced with fresh medium containing the appropriately diluted test compounds. Six days following the initial administration of the test compound, the cell culture supernatant was collected, treated with pronase and then used in a real-time quantitative TaqMan qPCR assay. The PCR- amplified HBV DNA was detected in real-time by monitoring increases in fluorescent signal that result from the exonucleolytic degradation of a quenched fluorescent probe molecule that hybridizes to the amplified HBV DNA. For each PCR amplification, a standard curve was simultaneously generated using dilutions of purified FIB V DNA.
- Antiviral activity was calculated from the reduction in FIB V DNA levels (EC50 & EC90 values determined).
- a tetrazolium dye MMS; 3-(4,5- dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H- tetrazolium; CellTiter®96 Reagent, Promega
- uptake assay was then employed to measure cell viability using the same assay plate, and the viability data was used to calculate compound cytotoxicity (CC50).
- the 50% cytotoxic concentration (CC50 in M) was defined as the concentration of compound that reduced the absorbance of the mock-infected control sample by 50%..
- Compound of formula I shows anti-HIV and anti-HBV activity.
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Abstract
The present invention provides metabolites and derivatives of ((((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl)oxy)methyl pivalate, including compound of (Formula I) The present invention also provides a process for preparing a compound of formula (Ia) and a compound of formula (I) for use in treating a viral infection.
Description
PHARMACEUTICAL COMPOSITIONS
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims priority to co-pending Indian Provisional Patent Application Serial Number 201721026781 filed on July 27, 2017. This application is incorporated herein by reference, in its entirety.
FIELD OF INVENTION:
The present invention relates to metabolites and derivatives of ((((((R)-l-(6-amino- 9H-purin-9-yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl)oxy)methyl pivalate, including compound of (Formula I)
(Formula I)
or salts, hydrates, solvates, racemates, or optical isomers thereof. The present invention also provides process for preparing the said metabolites and derivatives and their use for the prevention, treatment or prophylaxis of diseases caused by viruses, specifically acquired immune deficiency syndrome or an HIV infection, Hepatitis B infection, or Hepatitis C infection.
BACKGROUND OF INVENTION:
Human immunodeficiency virus, type 1 (HIV-1) infection is a life-threatening and serious disease of major public health significance, with approximately 36.7 million people infected worldwide (Joint United Nations Programme on HIV/AIDS (UNAIDS). Global report: UNAIDS report on the global AIDS epidemic, 2016).
Acquired Immune Deficiency Syndrome (AIDS) causes a gradual breakdown of the body's immune system as well as progressive deterioration of the central and peripheral nervous systems. Since its initial recognition in the early 1980s, AIDS has spread rapidly and has now reached epidemic proportions within a relatively limited segment of the population. Intensive research has led to the discovery of the responsible agent, human T-lymphotropic retrovirus 111 (HTLV-11 1) commonly referred to as the Human Immunodeficiency Virus or HIV.
Tenofovir is a highly potent nucleotide analog reverse-transcriptase inhibitor which is widely used in the treatment of diseases caused by retroviruses, especially Acquired Immune Deficiency Syndrome or an HIV infection. Tenofovir {9-R-[(2- phosphonomethoxy)propyl]adenine}, an acyclic nucleotide analog of dAMP, is a potent in vitro and in vivo inhibitor of human immunodeficiency virus type 1 (HIV- 1) replication. Tenofovir is sequentially phosphorylated in the cell by AMP kinase and nucleoside diphosphate kinase to the active species, tenofovir diphosphate, which acts as a competitive inhibitor of HIV- 1 reverse transcriptase that terminates the growing viral DNA chain. The presence of a nonhydrolyzable phosphonic acid moiety in tenofovir circumvents an initial phosphorylation step that can be rate limiting for the activation of nucleoside analog inhibitors of HIV reverse transcriptase. Due to the presence of a phosphonate group, tenofovir is negatively charged at neutral pH, thus limiting its oral bioavailability.
Tenofovir disoproxil fumarate (TDF; VIREAD®), the first-generation oral prodrug of tenofovir, has been extensively studied in clinical trials and has received marketing authorization in many countries as a once-daily tablet (300 mg) in combination with other antiretroviral agents for the treatment of HIV- 1 infection.
Tenofovir D soproxil Fumarate (TDF) is a water soluble ant -HIV and anti-HBV oral drug, stable in the stomach, enters the body with the blood after the intestinal absorption, and uniformly distributed within human tissues. However, less than 20% of TDF is metabolized and activated into the Tenofovir parent drug under the
action of esterase, and then diphosphorylated into Tenofovir diphosphate to take effect, and about the remaining 80% is excreted out of the body in original orm. To improve the bio-availability, currently, the strategy of introducing the masking group onto the phosphate group of the Tenofovir to form the lipid soluble prodrug is usually adopted. Such prodrugs are proven to have the lymph and liver tissue targeting effect. However, due to the unstability of the such masking group, metabolism may still occur in the blood to produce the active parent drug Tenofovir, and therefore brings certain systemic toxicity. The masking group of o-methyl benzyl of the compound structure disclosed in CN201380030061.6 has a high group-leaving activity and low stability during the blood esterase metabolism, therefore leading to the relative increase of the active parent drug in the blood and relative decrease of the active parent drug in the liver, and affecting the activity and systemic toxicity.
U.S. Patent No. 7,390,791 describes certain prodrugs of phosphonate nucleotide analogs that are useful in therapy. One such prodrug is Tenofovir alafenamide hemifumarate (TAF; Vemlidy®) which is an isopropylalaninyl phenyl ester prodrug of tenofovir.
U. S. Patent No. 9,227,990 (the content of which is incorporated by reference herein in its entirety) describe certain prodrugs of phosphonate nucleotide analogs that are useful in therapy. One such prodrug is ((((((R)-l-(6-amino-9H-purin-9-yl)propan- 2-yl)oxy)methyl)(phenoxy)phosphoryl)oxy)methyl pivalate.
Thus, there are many prodrugs and metabolites disclosed in prior literature which are either unstable or produce systemic toxicity or may convert back to parent compound or tenofovir in reasonable time.
The inventors of present invention after rigorous experiments, have found a class of metabolite and derivatives of ((((((R)-l-(6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl) (phenoxy)phosphoryl)oxy)methyl pivalate which are stable for a
reasonable time period , have enhanced bio-activity, limited conversion to parent compound having less bioactivity and upgrade its anti-virus activity. The inventors of the present invention have provided a method of determining the stability and bioactivity of the said metabolites and derivatives.
Thus, the present invention concerns metabolites and derivatives of ((((((R)-l-(6- amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl)oxy)methyl pivalate, method of determining the stability and bioactivity of said metabolites and derivatives , process for preparing the said metabolites and derivatives and their use for the prevention, treatment or prophylaxis of diseases caused by viruses, specifically acquired immune deficiency syndrome or an HIV infection, Hepatitis B infection, or Hepatitis C infection.
OBJECT OF THE INVENTION:
An object of the present invention is to provide a method of determining the stability of metabolites and derivatives of ((((((R)-l-(6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl)(phenoxy)phosphoryl)oxy)methyl pivalate represented as compound of formula I.
Formula (I)
Another object of the present invention is to provide a method of determining bioactivity of a compound of formula I.
Formula (I)
Another object of the present invention is to provide a compound of formula I
Formula (I)
Yet another object of the present invention is to provide a process for preparing a compound of formula I.
Another object of the present invention is to provide a pharmaceutical composition comprising, as active principle, the compound of formula I or a pharmaceutically acceptable derivative thereof, and at least one pharmaceutically acceptable excipient.
Yet another object of the present invention is to provide a use of compound of formula I or a pharmaceutically acceptable derivative thereof for the prophylactic or therapeutic treatment of a viral infection in a human, wherein the viral infection is human immunodeficiency virus (HIV) or Hepatitis B infection (HBV) or Hepatitis C infection (HCV).
Yet another object of the present invention is to provide a method of prevention, treatment or prophylaxis of diseases caused by viruses, specifically Acquired Immune Deficiency Syndrome or an HIV infection or Hepatitis B infection or Hepatitis C infection, which method comprises administering a pharmaceutical composition comprising compound of formula I or a pharmaceutically acceptable derivative thereof.
Yet another object of the present invention is to provide a method of prevention, treatment or prophylaxis of diseases caused by viruses, specifically Acquired
Immune Deficiency Syndrome or an HIV infection or Hepatitis B infection or Hepatitis C infection, which method comprises administering a pharmaceutical composition comprising compound of formula I or a pharmaceutically acceptable derivative thereof and at least one additional therapeutic agent.
SUMMARY OF THE INVENTION:
According to an aspect of the present invention, there is provided a method of determining the stability of metabolites and derivatives of ((((((R)-l-(6-amino-9H- purin-9-yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl)oxy)methyl pivalate represented as compound of formula I.
Formula (I)
According to another aspect of present invention , there is provided a method of determining the bioactivity of a compound of formula I.
Formula (I)
Formula (I)
According to yet another aspect of the present invention, there is provided a process for preparing a compound of formula I.
According to another aspect of the present invention, there is provided a pharmaceutical composition comprising, as active principle, the compound of formula I or a pharmaceutically acceptable derivative thereof, and at least one pharmaceutically acceptable excipient.
According to yet another aspect of the present invention, there is provided a use of compound of formula I or a pharmaceutically acceptable derivative thereof for the prophylactic or therapeutic treatment of a viral infection in a human, wherein the viral infection is human immunodeficiency virus (HIV) or Hepatitis B infection (HBV) or Hepatitis C infection (HCV).
According to yet another aspect of the present invention, there is provided a method of prevention, treatment or prophylaxis of diseases caused by viruses, specifically Acquired Immune Deficiency Syndrome or an HIV infection or Hepatitis B infection or Hepatitis C infection, which method comprises administering a pharmaceutical composition comprising compound of formula I or a pharmaceutically acceptable derivative thereof.
According to yet another aspect of the present invention, there is provided a method of prevention, treatment or prophylaxis of diseases caused by viruses, specifically Acquired Immune Deficiency Syndrome or an HIV infection or Hepatitis B
infection or Hepatitis C infection, which method comprises administering a pharmaceutical composition comprising compound of formula I or a pharmaceutically acceptable derivative thereof and at least one additional therapeutic agent.
BRIEF DESCRIPTION OF FIGURES:
Figure 1 represents percentage of ((((((R)-l-(6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl)(phenoxy)phosphoryl) oxy)methyl pivalate fumarate remaining in dog and human plasma
Figure 2 represents time dependent increase in percentage of compound of formula I in dog and human
Figure 3 represents percentage of tenofovir in dog and human plasma DETAILED DESCRIPTION OF THE INVENTION:
The inventors of the present invention invented compounds which are a class of metabolite and derivatives of ((((((R)-l-(6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl) (phenoxy)phosphoryl)oxy)methyl pivalate, and found that the compounds of the present invention are stable in plasma for a reasonable period of time, does not convert back to parent compound and have antiviais activities, in the in vivo animal test, the compounds can be enriched in the liver, where they are present in high amount and show antiviral activity also. Compared with Tenofovir, the compounds of the present invention have a higher anti-HBV activity, or are more stable in the plasma, are safer, and therefore the systemic toxic and side effects caused by the plasma metabolism are reduced.
U. S. Patent No. 9,227,990 (the content of which is incorporated by reference herein in its entirety) describe certain prodrugs of phosphonate nucleotide analogs that are useful in therapy. One such prodrug is ((((((R)-l-(6-amino-9H-purin-9-yl)propan- 2-yl)oxy)methyl)(phenoxy)phosphoryl)oxy)methyl pivalate (Formula II).
(Formula II)
The present invention relates to metabolites and derivatives of ((((((R)-l-(6-amino- 9H-purin-9-yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl)oxy)methyl pivalate (Formula II), method of determining stability and bioactivity of said metabolites and derivatives,process for preparing the said metabolites and derivatives and their use for the prevention, treatment or prophylaxis of diseases caused by viruses, specifically acquired immune deficiency syndrome or an HIV infection, Hepatitis B infection, or Hepatitis C infection.
The term "((((((R)-l-(6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl)(phenoxy)phosphoryl)oxy)methyl pivalate" and "compound of formula I" is used in broad sense to include not only "((((((R)-l-(6-amino-9H- purin-9-yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl)oxy)methyl pivalate" per se and "compound of formula I" per se but also its pharmaceutically acceptable derivatives thereof. Suitable pharmaceutically acceptable derivatives include pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable anhydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable esters, pharmaceutically acceptable isomers, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, pharmaceutically acceptable tautomers, pharmaceutically acceptable complexes etc.
In one embodiment, metabolites of ((((((R)-l-(6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl)(phenoxy)phosphoryl)oxy)methyl pivalate have been identified in and determined in the dog, human, and rat. In one aspect, the metabolites are compounds having Formula (I) as:
Formula I
In various embodiments, the metabolites are provided in isolated form, having been identified in and isolated or separated from body tissues or fluids of a test animal and/or prepared synthetically.
Organic synthetic routes are available for preparing the compounds in relative pure form, for example in purities of 80% or greater, 90% or greater, 95% or greater, and 99% or greater. Recrystallization and other purification methods can be carried out to provide compounds that are essentially 100% pure. Such synthetic methods and purification techniques are known in the art and are illustrated in non-limiting fashion in the Examples that follow.
In various embodiments, the compounds are provided in substantially pure form. Substantially pure means that the compounds are pure enough for FDA approval and contain essentially no contaminants or other materials, or alternatively a level of impurity that does not adversely or unacceptably affect the properties of the compounds as regards safety, effectiveness, stability, and other desirable properties.
In various embodiments, the invention provides compound of Formula (I) in isolated form or pharmaceutically acceptable salts, hydrates, solvates, racemates, or optical isomers thereof.
In an embodiment, the metabolite and derivatives of ((((((R)-l-(6-amino-9H-purin- 9-yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl)oxy)methyl pivalate and compound I are stable for a reasonable time period. The reasonable time period
includes time period from about 0 minutes till 360 minutes of administration, preferably till 240minutes. The amount of compound of formula I present in plasma after reasonable amount of time is 80% or greater, 90% or greater, 95% or greater, and 99% or greater and the amount of ((((((R)-l-(6-amino-9H-purin-9-yl)propan- 2-yl)oxy)methyl)(phenoxy)phosphoryl)oxy)methyl pivalate fumarate present in plasma after reasonable amount of time is lesser than 99%, lesser than 90%, lesser than 95% and lesser than 80%.
Further, metabolism of a drug can decrease its half-life and often determines whether it will be effective and safe. For this reason, candidate drug compounds are often screened early in the discovery process for metabolic stability. A common system for measuring hepatic metabolism uses liver microsomes, a subcellular fraction containing major drug-metabolizing enzymes, including the cytochrome P450 (CYP) family and flavin monooxygenase (FMO). The present invention provides metabolites and derivatives of ((((((R)-l-(6-amino-9H-purin-9-yl)propan- 2-yl)oxy)methyl)(phenoxy)phosphoryl)oxy)methyl pivalate fumarate which are not metabolized by liver microsomes and are present in an amount of more than 80% or greater, 90% or greater, 95% or greater, and 99% or greater. In a preferred embodiment, the present invention provides compound of formula I which is not metabolized by liver microsomes and is present in an amount of more than 80% or greater, 90% or greater, 95% or greater, and 99% or greater.
Without being bound to any theory, it is known that ((((((R)-l-(6-amino-9H-purin- 9-yl)propan-2-yl)oxy)methyl) (phenoxy)phosphoryl)oxy)methyl pivalate converts to PMPA ((R)-9~ 2-(phosphonomethoxy)propyl ! adenine and its protected intermediates) and to tenofovir diphosphate and show combined anti-viral activity. Al so, tenofovir disoproxil fumarate converts to PMPA. and to tenofovir diphosphate and show combined anti-viral activity.
The inventors of present invention have found intermediate derivatives of ((((((R)- l-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)
(phenoxy)phosphoryl)oxy)methyl pivalate termed as compound of formula I, stabilize it for reasonable period of time and show combined activity with PMPA and tenofovir diphosphate and thus enhanced anti-viral activity.
Selectivity Index (SI) numbers greater than 5 are moderately active, greater than 10 are highly active and greater than 100 are extraordinarily highly active. The Selectivity Index (SI) scale is the ratio of cytotoxicity of the agent (CC aka IC) to the selective antiviral activity (EC) (EC50 for cell-based assays; IC50 for biochemical or subcellular assays) such that a SI >10 indicates extraordinarily strong activity. The present invention provides anti-HIV and anti-HBV activity of ((((((R)- 1 -(6-amino-9H-purin-9-yl)propan-2-yl)oxy) methyl) (phenoxy) phosphoryl) oxy) methyl pivalate fumarate, compound of formula I, PMPA and tenofovir diphosphate and thus enhanced ami -viral activity.
The present invention also provides metabolites and derivatives of ((((((R)-l-(6- amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl)oxy)methyl pivalate fumarate showing anti-HIV and anti-HBV activity independently from ((((((R)- 1 -(6-amino-9H-purin-9-yl)propan-2-yl)oxy) methyl) (phenoxy) phosphoryl) oxy) methyl pivalate fumarate, PMPA and tenofovir diphosphate.
The metabolites and derivatives of present invention and compound of formula I have therapeutic index of greater than 5, 10, 20, 40, 60 when showing anti-HIV activity. Preferably, the compound of formula I has therapeutic index of greater than 40% when showing anti-HIV activity.
The metabolites and derivatives of present invention and compound of formula I have therapeutic index of greater than 5, 10, 20, 30, 40, 50 when showing anti-HBV activity. Preferably, the compound of formula I has therapeutic index of greater than 30 when showing anti-HBV activity.
In another embodiment, pharmaceutical dosage forms are provided that comprise a pharmaceutically acceptable carrier and 0.1% to 90% by weight of an active material, wherein the active material comprises compound of Formula (I) and pharmaceutically acceptable salts, hydrates, solvates, optical isomers, and racemates thereof, and wherein the compound is not ((((((R)-l-(6-amino-9H-purin- 9-yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl)oxy) methyl pivalate. In a preferred embodiment, the compound of formula I is present in an amount from about 2% to about 80% of the composition.
In another embodiment, the invention provides pre-clinical ADME metabolites of ((((((R)- 1 -(6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl)(phenoxy)phosphoryl)oxy)methyl pivalate. "Pre-clinical ADME metabolites" means those metabolites of ((((((R)-l-(6-amino-9H-purin-9- yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl)oxy)methyl pivalate formed in vivo or in vitro during pre-clinical testing on non-human subjects. Such testing is carried out to characterize the absorption, distribution, metabolism, and excretion (ADME) of a proposed drug product prior to clinical testing on humans. Non- limiting description of such testing is provided in Examples 1-4 below.
Surprisingly, the inventors have found that compound of Formulas (I) is derived from ((((((R)- 1 -(6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl)(phenoxy)phosphoryl)oxy)m ethyl pivalate in mammals as the result of metabolism of the drug by so-called phase I and/ or phase II metabolic pathways.
In another embodiment, the invention includes administering ((((((R)-l-(6-amino- 9H-purin-9-yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl)oxy)methyl pivalate or its metabolite to a mammal and detecting metabolites by measuring the level or concentration of one of the metabolites in the tissues or bodily fluids of the mammal. Bodily fluids include without limitation blood plasma, bile, urine, and feces, while tissues include without limitation liver microsomes, hepatocytes, and perfused livers.
In one embodiment, compounds of the invention, as well as their salts, optical isomers, racemates, and tautomers, are formulated into suitable dosage forms for administration to humans or other mammals. In some embodiments, for example, the compounds of the invention may exhibit favorable toxicological profiles.
In another embodiment, there is provided the pharmaceutical composition, further comprising an additional therapeutic agent. In a further embodiment, the additional therapeutic agent is selected from the group consisting of nucleoside reverse transcription inhibitors ( RTIs), non-nucleoside reverse transcriptase inhibitors (N RTIs), protease inhibitors (Pis), integrase inhibitors, CCR5 inhibitors, fusion inhibitors and maturation inhibitors (Mis) and any combination thereof. These active ingredients are formulated for simultaneous, separate or sequential administration. When the active ingredients are administered sequentially, either compound of formula I or additional therapeutic agent, may be administered first. When administration is simultaneous, the active ingredients may be administered either in the same or different pharmaceutical compositions. Adjunctive therapy, i.e. where one active ingredient is used as the primary treatment and the other active ingredient(s) is/are used to assist that primary treatment is also an embodiment of the present invention.
In yet another embodiment, the pharmaceutical composition is a combination of ((((((R)- 1 -(6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl)(phenoxy)phosphoryl)oxy)methyl pivalate or compound of formula I and one or more of additional therapeutic agent selected from, but not limiting to, emtricitabine, efavirenz, nevirapine, darunavir, atazanavir, zidovudine, didanosine, stavudine, lamivudine, zalcitabine, abacavir sulphate, delavirdine, saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, cobicistat, lopinavir, enfuvirtide, dolutegravir, elvitegravir, raltegravir, rilpivirine.
In yet another embodiment, the pharmaceutical composition is a combination of ((((((R)- 1 -(6-amino-9H-purin-9-yl)propan-2-
yl)oxy)methyl)(phenoxy)phosphoryl)oxy)methyl pivalate or compound of formula I and one or more of additional therapeutic agent selected from, but not limiting to, recombinant Human Interferon Alfa such as pegylated interferon alfa-2a or pegylated interferon alfa-2b (collectively "peginterferon" or "PEG"), nucleoside analogs for example ribavirin, direct acting antivirals (for example daclatasvir, boceprevir and telapravir), NS3/4A protease inhibitors (Pis) (for example simeprevir), nucleotide NS5B polymerase inhibitors (for example sofosbuvir), NS5A Inhibitors (for example daclatasvir), non-nucleoside NS5B Polymerase Inhibitors (for example dasabuvir).
The term "combination" as used herein, defines either a fixed combination in one dosage unit form, a non- fixed combination or a kit containing individual parts for combined administration.
Compound of formula I is useful in the treatment and/or prophylaxis of one or more viral infections in man or animals, including infections caused by DNA viruses. RNA viruses, herpesviruses (e.g., CMV, HSV 1, HSV 2, VZV), retroviruses, hepadnaviruses (e.g., HBV), papillomavirus, hantavirus, adenoviruses and HIV.
In one embodiment, there is provided a method for treating a human immunodeficiency virus (HIV) infection comprising administering to a subject in need thereof a therapeutically effective amount of compound of formula I or a pharmaceutically acceptable derivative thereof.
In some embodiments of the invention, the methods of prophylactic or therapeutic treatment comprise administration of multiple daily doses. In other embodiments, the methods of prophylactic or therapeutic treatment comprise administration of a single daily dose.
As used herein the term 'therapeutically effective compound of formula I as anti- HIV at a dose thai can be administered once daily' means that the compounds are
suitable for dosing every 24 hours. The -term suitable for dosing every 24 hours' means that the compounds are such that they can be administered every 24 hours and give effective blood plasma concentrations of the active ingredients such thai they are effective to suppress HIV infection over a period of 24 hours. The compounds for use in the invention can be dosed ever*,'' 24 hours
Compound of formula I can be administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including ocular, buccal, and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). The formulations are in unit dosage form and are prepared by any of the methods well known in the art of pharmacy.
For oral therapeutic administration, compound of formula I may be combined with one or more excipients and used in the form of ingestible tablets, dispersible tablets, buccal tablets, troches, capsules, elixirs, solutions, suspensions, syrups, wafers, Self-emulsifying drug delivery system (SEDDS), Self-microemulsifying drug delivery system (SMEDDS) and the like. Pharmaceutical compositions suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets, each containing a predetermined amount of compound of formula I; as a powder or granules; as a solution or a suspension in an aqueous liquid or a nonaqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. Compound of formula I may also be presented as a bolus, electuary, or paste.
Suitable excipients may be used for formulating the dosage forms according to the present invention such as, but not limited to, surface stabilizers or surfactants, viscosity modifying agents, polymers including extended release polymers, stabilizers, disintegrants or super disintegrants, diluents, plasticizers, binders, glidants, lubricants, sweeteners, flavoring agents, anti-caking agents, opacifiers, anti-microbial agents, antifoaming agents, emulsifiers, buffering agents, coloring
agents, carriers, fillers, anti-adherents, solvents, taste-masking agents, preservatives, antioxidants, texture enhancers, channeling agents, coating agents or combinations thereof.
Pharmaceutical formulations suitable for parenteral administration are sterile and include aqueous and nonaqueous injection solutions that may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and nonaqueous sterile suspensions that may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials with elastomeric stoppers, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier (e.g., water for injections) immediately prior to use. Injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the kind previously described.
In addition to the ingredients particularly mentioned above, the pharmaceutical compositions/formulations may include other ingredients conventional in the art, having regard to the type of formulation in question.
Useful dosages of compound of formula I can be determined by comparing in vitro activities, and the in vivo activities in animal models. Methods for the extrapolation of effective amounts/dosages in mice and other animals to therapeutically effective amounts/dosages in humans are known in the art.
The amount of compound of formula I required for use in treatment will vary with several factors, including but not limited to the route of administration, the nature of the condition being treated, and the age and condition of the patient; ultimately, the amount administered will be at the discretion of the attendant physician or clinician. The therapeutically effective amount/dose of compound of formula I depends, at least, on the nature of the condition being treated, any toxicity or drug
interaction issues, whether the compound is being used prophylactically (e.g., sometimes requiring lower doses) or against an active disease or condition, the method of delivery, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies.
In one embodiment, the oral dose of compound of formula I may be in the range from about 0.0001 to about 100 mg/kg body weight per day, for example, from about 0.01 to about 10 mg/kg body weight per day, from about 0.01 to about 5 mg/kg body weight per day, from about 0.5 to about 50 mg/kg body weight per day, from about 1 to about 30 mg/kg body weight per day, from about 1.5 to about 10 mg/kg body weight per day, or from about 0.05 to about 0.5 mg/kg body weight per day. As a nonlimiting example, the daily candidate dose for an adult human of about 70 kg body weight will range from about 0.1 mg to about 500 mg, or from about 1 mg to about 500 mg, or from about 5 mg to about 300 mg, or from about 10 mg to about 150 mg, or from about 25 mg to about 150 mg, or from about 5 mg to about 100 mg, and may take the form of single or multiple doses.
In certain embodiments, the administration of compound of formula I or pharmaceutically acceptable derivative thereof, either alone or in combination with one or more additional therapeutic agent, can lower detectable viral RNA/ DNA levels in a patient. For instance, methods disclosed herein can lower viral RNA/ DNA levels by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% relative to viral RNA/ DNA levels prior to initiating treatment. In some instances, compound of formula I or pharmaceutically acceptable derivative thereof can be administered to a patient such that no viral RNA/ DNA levels is detectable in the patient after the treatment course is complete. Viral RNA/ DNA levels can be determined by quantitative, multi-cycle reverse transcriptase PCR. Such techniques are known, for instance in U.S. 6, 172,046, col. 4, line 50 - col. 6, line 5, which is hereby incorporated by reference. As used herein, no detectable viral RNA/ DNA levels
describes a condition in which there are less than 100 copies per ml serum of the patient.
Therapeutic methods include administering compound of formula I to a subject/patient in need of the same as a therapeutic or prophylactic treatment. Thus, compound of formula I may be administered to a subject/patient having a medical disorder or to a subject who may acquire the disorder. One of ordinary skill will appreciate that such treatment is given in order to ameliorate, prevent, delay, cure, and/or reduce the severity of a symptom or set of symptoms of a disorder (including a recurring disorder). The treatment may also be given to prolong the survival of a subject, e.g., beyond the survival time expected in the absence of such treatment. The medical disorders that may be treated with compound of formula I include those discussed herein, including without limitation, HIV infection, HBV infection and HCV infection.
In order that this invention be more fully understood, the following examples are set forth. These examples are for the purpose of illustration only and are not to be construed as limiting the scope of the invention in any way.
Example I - In vitro plasma (dog and human) stability study
Experimental procedure:
Dog and human plasma (0. 396 mL) was added to 96 well plates in triplicates. The plate was pre-incubated for 10 min at 37 °C followed by addition of ((((((R)-l-(6- amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl) oxy)methyl pivalate fumarate at final concentration of 100 μΜ. At 0, 7.5, 15, 30, 60 and 120 min, 50 μΐ^ of sample was removed and quenched with 250 μΐ^ of acetonitrile followed by analysing the samples by LCMS-MS for the presence of parent compound, compound of formula I and tenofovir. The percentage of ((((((R)-l-(6- amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl) oxy)methyl pivalate fumarate remaining in dog and human plasma , Time dependent increase in percentage of compound of formula I (Tenphenol) in dog and human plasma and
Percentage of Tenofovir in dog and human plasma are illustrated in figure 1, figure 2 and figure 3 respectively.
Conclusion: The study indicates that compound of formula I is the major metabolite of ((((((R)- 1 -(6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl)(phenoxy)phosphoryl) oxy)methyl pivalate fumarate.
Example 2 - In vitro dog and human liver microsome stability study
The objective of the study was to identify and quantify the metabolites of ((((((R)- l-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl) oxy)methyl pivalate fumarate in dog and human liver microsomes based on peak area.
Experimental procedure:
The active microsomes were removed from the deep freezer (-80°C), thawed at 37 °C and then kept on ice until use. The microsomes were diluted to the working concentrations using phosphate buffer.
In the samples, test item (((((((R)-l-(6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl)(phenoxy)phosphoryl) oxy)methyl pivalate fumarate) and NADPH were mixed as per the following scheme.
Reaction composition for the test item,
Liver microsomes 0.5 mg/mL
NADPH (cofactor) 1.0 mM
Test item cone. 10.0 μΜ
Time points (for incubation) 0, 5, 10, 15, 30, 60, 120 and 240 min.
Microsomal suspension (1780μΙ.) was taken into micro centrifuge tubes, and 200μΙ. of NADPH (lOmM) was mixed with these microsomal suspensions. Pre-incubated at 37 °C and 120 rpm in an incubator shaker for 10 min and the reactions were initiated with the addition of 20μί of ((((((R)-l-(6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl)(phenoxy)phosphoryl) oxy)m ethyl pivalate fumarate (lmM) to all
incubation mixtures except to the blank. The final concentration of ((((((R)-l-(6- amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl) oxy)methyl pivalate fumarate in the assay was ΙΟμΜ. At each time point (0, 5, 10, 15, 30, 60, 120 and 240 min) an aliquot (200 μΐ.) of sample was withdrawn and immediately precipitated with 600 μΐ. of cold acetonitrile. 'Zero' sample was prepared by adding ((((((R)-l-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl) oxy)m ethyl pivalate fumarate (ImM) to the blank matrix containing NADPH which was already pre-quenched with acetonitrile (The final concentration of ((((((R)-l- (6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl) oxy)m ethyl pivalate fumarate in the assay was 10μΜ). All samples were mixed well by vortexing for 5 min. Centrifuged for 10 min at 10,000 rpm and 4°C and the supernatant was transferred into eppendorf tubes and stored at temperature below - 80 °C until analysis. Similarly blank samples were prepared in absence of ((((((R)- l-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl) oxy)methyl pivalate fumarate. Before analysis in-vitro samples were thawed and centrifuged at 10000 rpm for 10 min at 4°C. The supernatant was transferred to 96- well plate and injected into LC-MS/MS.
The concentrations of parent and its metabolites in both HLM and DLM were listed below. ((((((R)- 1 -(6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl)(phenoxy)phosphoryl) oxy)methyl pivalate fumarate was found to be metabolized completely within 5-10 mins, and the concentrations remaining at the end of 5 mins were 8.1 nM and 48.1 nM in HLM and BDLM respectively. At the end of 5 min the observed concentrations of PMPA and compound of formula I were 2.9 nM and 6.0 μΜ respectively in HLM and those are 2.7 nM and 5.2 μΜ respectively in DLM. By the end of 240 mins compound of formula I was formed as major metabolite (5 μΜ - 6.5 μΜ) accounting up to 68.0 % in HLM and 67.1 % in DLM samples. PMPA was quantified as below 30 nM by the end of 240 mins incubation and is accounting up to 0.22 % and 0.28 % of ((((((R)-l-(6-amino-9H- purin-9-yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl) oxy)methyl pivalate fumarate in HLM and DLM samples respectively.
Table 1: Metabolite concentration in HLM and BDLM after incubation of ((((((R)-l-(6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl)(phenoxy)phosphoryl) oxy)methyl pivalate fumarate up to 240min
% of
Concentration (nM) metabolites
((((((R)-l-(6- amino-9H-purin-
Matrix 9-yl)propan-2-
Sample
/ yl)oxy) Compound
ID Tenofovir
species methyl)(phenoxy) of formula PMPA TPH
(PMPA)
phosphoryl) I (TPH) oxy)methyl
pivalate fumarate
(Parent)
Blank 0 0 0 - -
Zero* 9635.433 0 92.968 - -
Omin 7221.962 0 916.717 0.0 9.5
5min 8.112 2.933 6048.908 0.03 62.8 lOmin 0 3.439 5745.622 0.04 59.6
HLM
15min 0 3.928 5437.910 0.04 56.4
3 Omin 0 5.185 5749.164 0.05 59.7
60min 0 7.972 6192.502 0.08 64.3
120min 0 13.925 6337.008 0.14 65.8
240min 0 21.544 6554.460 0.22 68.0
Blank 0 0 0 - -
Zero* 9773.266 0 97.052 - -
BDLM Omin 9872.826 0 704.649 0.0 7.2
5min 48.094 2.693 5179.609 0.03 53.0 lOmin 0 3.793 6051.597 0.04 61.9
15min 0 4.527 5785.997 0.05 59.2
30min 0 6.433 5760.799 0.07 58.9
60min 0 10.635 6099.434 0.11 62.4
120min 0 16.380 5876.590 0.17 60.1
240min 0 27.478 6559.415 0.28 67.1
Conclusion: The study indicates that compound of formula I is the major metabolite of ((((((R)- 1 -(6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl)(phenoxy)phosphoryl) oxy)methyl pivalate fumarate. To further confirm this, in vivo studies were performed
Example 3 - In vivo pharmacokinetics of ((((((R)-l-(6-amino-9H-purin-9- yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl) oxy)methyl pivalate fumarate in rats and dogs
Experimental procedure for rat PK study:
The aim of the study was to evaluate the comparative pharmacokinetic parameters of ((((((R)- 1 -(6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl)(phenoxy)phosphoryl) oxy)methyl pivalate fumarate in male Wistar rats after a single oral administration at 2.6 mg/kg and 31 mg/kg. Blood samples were collected through jugular vein cannulation at 0 (pre-dose), 0.25, 0.50, 1, 2, 4, 8 and 24 hr post-dose (Total 8 bleedings/rat). At each time point, approximately 0.300 mL of blood was withdrawn and transferred in to a pre-labeled 0.5 mL microcentrifuge tubes containing 10 μL of 1000 IU/mL sodium heparin as anticoagulant and mixed gently to facilitate mixing of anticoagulant with the blood. A pre-dose sample was collected 1.0 hour prior to dose administration from all rats. Blood samples were kept on ice bath until centrifugation. Centrifugation was done within 30 minutes of collection. The blood samples were centrifuged at 4000 rpm for 10 min at 4 °C. Plasma was separated and transferred in to two aliquots (each aliquot contains -0.075 mL) of pre-labeled tubes. Plasma samples were stored at below - 70 °C until analysis.
Table 1: Rat plasma concentration of Tenofovir on administration of ((((((R)-l-(6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl)(phenoxy)phosphoryl) oxy)methyl pivalate fumarate
Table 2: Rat plasma concentration of compound of formula I on administration of ((((((R)-l-(6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl)(phenoxy)phosphoryl) oxy)methyl pivalate fumarate
Experimental procedure for dog PK study:
The aim of the study was to evaluate the comparative pharmacokinetic parameters of ((((((R)- 1 -(6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl)(phenoxy)phosphoryl)oxy) methyl pivalate fumarate in dogs after a single oral administration at 0.78 mg/kg and 9.25 mg/kg. Blood samples were collected through jugular vein cannulation at 0 (pre-dose), 0.25, 0.50, 1, 2, 4, 8 and 24 hr post-dose (Total 8 bleedings/dog). At each time point, approximately 0.300 mL of blood was withdrawn and transferred in to a pre-labeled 0.5 mL microcentrifuge tubes containing 10 μΙ_, of 1000 IU/mL sodium heparin as anticoagulant and mixed gently to facilitate mixing of anticoagulant with the blood. A pre-dose sample was collected 1.0 hour prior to dose administration from all
dogs. Blood samples were kept on ice bath until centrifugation. Centrifugation was done within 30 minutes of collection. The blood samples were centrifuged at 5000 rpm for 5 min at 4 °C; plasma was separated and transferred into two aliquots (each aliquot contains 0.300mL) of pre-labeled microcentifuge tubes. Plasma samples were stored at below - 70 °C until analysis.
Table 3: Dog plasma concentration of Tenofovir on administration of ((((((R)- l-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl) oxy)methyl pivalate fumarate
Table 4: Dog plasma concentration of compound of formula I on administration of ((((((R)-l-(6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl)(phenoxy)phosphoryl) oxy)methyl pivalate fumarate
Conclusion: The study confirmed that compound of formula I is the major metabolite of ((((((R)-l-(6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl)(phenoxy)phosphoryl) oxy)methyl pivalate fumarate.
Example 4 - In vitro efficacy of compound of formula I against HIV and HBV
1. Experimental procedure - In vitro efficacy of compound of formula I against HIV Fresh human PBMCs, seronegative for HIV and HBV, were isolated from screened donors (Biological Specialty Corporation, Colmar, PA). Cells were pelleted/washed 2-3 times by low speed centrifugation and re-suspension in PBS to remove contaminating platelets. The Leukophoresed blood was then diluted 1 : 1
with Dulbecco's Phosphate Buffered Saline (DPBS) and layered over 15 mL of Ficoll (GE Healthcare #17-1440-02) in 50 mL centrifuge tube and then centrifuged for 30 minutes at 600 X g. Banded PBMCs were gently aspirated from the resulting interface and subsequently washed 2X with PBS by low speed centrifugation. After the final wash, cells were enumerated by trypan blue exclusion and re-suspended at 1 x 106 cells/mL in RPMI 1640 supplemented with 15 % Fetal Bovine Serum (FB S), and 2 mM L-glutamine, 4 μg/mL Phytohemagglutinin (PHA, Sigma). The cells were allowed to incubate for 48-72 hours at 37°C. After incubation, PBMCs were centrifuged and re-suspended in RPMI 1640 with 15% FBS, 2 mM L-glutamine, 100 U/mL penicillin, 100 μg/mL streptomycin, and approximately 100-150 U/mL recombinant human IL-2 (R&D Systems, Inc). IL-2 was included in the culture medium to maintain the cell division initiated by the PHA mitogenic stimulation. PBMCs were maintained in this medium at a concentration of 1-2 x 106 cells/mL with biweekly medium changes until used in the assay protocol. Cells were kept in culture for a maximum of two weeks before being deemed too old for use in assays and discarded. MDMs were depleted from the culture as the result of adherence to the tissue culture flask. For the standard PBMC assay, PHA stimulated cells from at least two normal donors were pooled (mixed together), diluted in fresh medium to a final concentration of 1 x 106 cells/mL, and plated in the interior wells of a 96 well round bottom microplate at 50 [iL/well (5 x 104 cells/well) in a standard format developed by the Infectious Disease Research department of Southern Research Institute. Pooling (mixing) of mononuclear cells from more than one donor was used to minimize the variability observed between individual donors, which results from quantitative and qualitative differences in HIV infection and overall response to the PHA and IL-2 of primary lymphocyte populations. Each plate contained virus/cell control wells (cells plus virus), experimental wells (drug plus cells plus virus) and compound control wells (drug plus media without cells, necessary for MTS monitoring of cytotoxicity). In this in vitro assay, PBMC viability remained high throughout the duration of the incubation period. Therefore, infected wells were used in the assessment of both antiviral activity and cytotoxicity. Test drug dilutions were prepared at a 2X concentration in microtiter tubes and 100 uL of
each concentration (nine total concentrations) were placed in appropriate wells using the standard format. 50 μΐ^ of a predetermined dilution of virus stock was placed in each test well (final MOI approximately 0.1). The PBMC cultures were maintained for six-seven days following infection at 37°C, 5% C02. After this period, cell-free supernatant samples were collected for analysis of reverse transcriptase activity and/or p24 antigen content.
Following removal of supernatant samples, compound cytotoxicity was measured by addition of MTS to the plates for determination of cell viability. Wells were also examined microscopically and any abnormalities were noted.
A microtiter plate-based reverse transcriptase (RT) reaction was utilized (Buckheit et al., AIDS Research and Human Retroviruses 7:295-302, 1991). Tritiated thymidine triphosphate (3H-TTP, 80 Ci/mmol, NEN) was received in 1 : 1 dH20:Ethanol at 1 mCi/mL. Poly rA:oligo dT template:primer (GE Healthcare) was prepared as a stock solution by combining 150 μΐ. poly rA (20 mg/mL) with 0.5 mL oligo dT (20 units/mL) and 5.35 mL sterile dH20 followed by aliquoting (1.0 mL) and storage at -20°C. The RT reaction buffer was prepared fresh on a daily basis and consisted of 125 1.0 M EGTA, 125 uL dH20, 125 μΐ. 20% Triton X100, 50 1.0 M Tris (pH 7.4), 50 μΐ, 1.0 M DTT, and 40 μΐ, 1.0 M MgC12. The final reaction mixture was prepared by combining lpart 3H-TTP, 4 parts dH20, 2.5 parts poly rA:oligo dT stock and 2.5 parts reaction buffer. Ten microliters of this reaction mixture was placed in a round bottom microtiter plate and 15 μΐ. of virus containing supernatant was added and mixed. The plate was incubated at 37°C for 60 minutes. Following incubation, the reaction volume was spotted onto DE81 filter-mats (Wallac), washed 5 times for 5 minutes each in a 5% sodium phosphate buffer or 2X SSC (Life Technologies). Next they were washed 2 times for 1 minute each in distilled water, 2 times for 1 minute each in 70% ethanol, and then dried. Incorporated radioactivity (counts per minute, CPM) was quantified using standard liquid scintillation techniques.
At assay termination, assay plates were stained with the soluble tetrazolium-based dye MTS (CellTiter 96 Reagent, Promega) to determine cell viability and quantify compound toxicity. The mitochondrial enzymes of metabolically active cells metabolize MTS to yield a soluble formazan product. This allows the rapid quantitative analysis of cell viability and compound cytotoxicity. The MTS is a stable solution that does not require preparation before use. At termination of the assay, 20 μΙ_, of MTS reagent was added per well. The microtiter plates were then incubated 4-6 hrs at 37°C. The incubation intervals were chosen based on empirically determined times for optimal dye reduction. Adhesive plate sealers were used in place of the lids, the sealed plate was inverted several times to mix the soluble formazan product and the plate was read spectrophotometrically at 490/650 nm with a Molecular Devices SpectraMaxPlus i3 reader.
Table 5: In vitro efficacy of compound of formula I against HIV
2. Experimental procedure - In vitro efficacy of compound of formula I against HBV
The primary anti-HBV assay was performed as previously described (1, 2) with modifications to use real-time qPCR (TaqMan) to measure extracellular HBV DNA copy number associated with virions released from HepG2 2.2.15 cells. The HepG2 2.2.15 cell line is a stable human hepatoblastoma cell line that contains two copies of the HBV wild-type strain aywl genome and constitutively produces high levels of HBV. Antiviral compounds blocking any late step of viral replication such as
transcription, translation, pregenome encapsidation, reverse transcription, particle assembly and release can be identified and characterized using this cell line. Briefly, HepG2 2.2.15 cells were plated in 96-well microtiter plates at 1.5x104 cells/well in Dulbecco's Modified Eagle's Medium supplemented with 2% FBS, 380 μg/mL G418, 2.0 mM L-Glutamine, 100 units/mL Penicillin, 100 μg/mL Streptomycin, and 0.1 mM non-essential amino acids. Only the interior wells were utilized to reduce "edge effects" observed during cell culture; the exterior wells were filled with complete medium to help minimize sample evaporation. After 16-24 hours the confluent monolayer of HepG2 2.2.15 cells was washed and the medium was replaced with complete medium containing various concentrations of a test compound in triplicate. Lamivudine (3TC) was used as the positive control, while media alone was added to cells as a negative control (virus control, VC). Three days later the culture medium was replaced with fresh medium containing the appropriately diluted test compounds. Six days following the initial administration of the test compound, the cell culture supernatant was collected, treated with pronase and then used in a real-time quantitative TaqMan qPCR assay. The PCR- amplified HBV DNA was detected in real-time by monitoring increases in fluorescent signal that result from the exonucleolytic degradation of a quenched fluorescent probe molecule that hybridizes to the amplified HBV DNA. For each PCR amplification, a standard curve was simultaneously generated using dilutions of purified FIB V DNA. Antiviral activity was calculated from the reduction in FIB V DNA levels (EC50 & EC90 values determined). A tetrazolium dye (MTS; 3-(4,5- dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H- tetrazolium; CellTiter®96 Reagent, Promega) uptake assay was then employed to measure cell viability using the same assay plate, and the viability data was used to calculate compound cytotoxicity (CC50). The 50% cytotoxic concentration (CC50 in M) was defined as the concentration of compound that reduced the absorbance of the mock-infected control sample by 50%.. The dose achieving 50% protection was defined as the 50% inhibitory concentration (IC50 in M). The ratio of CC50 to IC50 was defined as the selectivity index (SI). The Selectivity Index (SI50) was calculated as CC50/EC50.
Table 6: In vitro efficacy of compound of formula I against HBV
1. In vitro and in vivo studies indicated that compound of formula I and Tenofovir are the metabolites of ((((((R)-l-(6-amino-9H-purin-9-yl)propan- 2-yl)oxy)methyl)(phenoxy)phosphoryl) oxy)methyl pivalate fumarate.
2. Compound of formula I was identified as the major metabolite of ((((((R)- l-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl) oxy)methyl pivalate fumarate.
3. Compound of formula I shows anti-HIV and anti-HBV activity.
Example 5 - ((((((R)-l-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)i
(phenoxy) phosphoryl)oxy)methyl pivalate fumarate tablets
Ingredient Qty (% w/w)
Dry mix
((((((R)- 1 -(6-amino-9H-purin-9-yl)propan-2- 2% - 80% yl)oxy)methyl)(phenoxy)phosphoryl) oxy)methyl
pivalate fumarate
Microcrystalline Cellulose 10% - 40%
Lactose 10% - 70%
Croscarmellose sodium 2% - 10%
Blending & Lubrication
Colloidal silicon dioxide 1% - 10%
Magnesium Stearate 0.5% - 5%
Film Coating
Opadry 1% - 10%
Example 6 - Emtricitabine + ((((((R)-l-(6-amino-9H-purin-9-yl)propan-2- yl)oxy) methyl)(phenoxy)phosphoryl) oxy)methyl pivalate fumarate tablets
It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by the preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and such modifications and variations are considered to be falling within the scope of the invention.
It is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of "including," "comprising," or "having" and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.
It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "an excipient" includes a single excipient as well as two or more different excipients, and the like.
Claims
We claim:
1. A method for determining the stability of metabolites and derivatives of ((((((R)-l-(6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl)(phenoxy)phosphoryl)oxy)methyl pivalate.
The method according to claim 1, wherein the method comprises of : i. selecting at least one therapeutic target tissue,
ii. providing the prodrug compound,
iii. determining the amount of prodrug compound, compound of
formula I
and tenofovir at reasonable time points and for reasonable time period.
3. The method according to claim 2 , wherein the therapeutic target tissue is plasma.
4. The method according to claim 2 , wherein the prodrug compound is ((((((R)-l-(6-amino-9H-purin-9-yl)propan-2-yl) oxy) methyl) (phenoxy) phosphoryl)oxy)methyl pivalate fumarate.
5. The method according to claim 2, wherein the amount of ((((((R)-l-(6- amino-9H-purin-9-yl)propan-2-yl) oxy) methyl) (phenoxy) phosphoryl)oxy)methyl pivalate fumarate decreases from about 99.9% to about 0.1%), amount of compound of formula I increases from 0.1%> to
99.9%, and amount of tenofovir change substantially in a reasonable time points.
6. The method according to claim 2, wherein the amount of ((((((R)-l-(6- amino-9H-purin-9-yl)propan-2-yl) oxy) methyl) (phenoxy) phosphoryl)oxy)methyl pivalate fumarate present in plasma is lesser than 99%), amount of compound of formula I is 99% or greater after a reasonable time period.
7. The method, according to claim 2, wherein the reasonable time period is about 360minutes from initial dosing.
8. A method of determing bioactivity of metabolites and derivatives of ((((((R)- 1 -(6-amino-9H-purin-9-yl)propan-2-yl)oxy) methyl) (phenoxy) phosphoryl)oxy)methyl pivalate.
9. A compound of Formula I:
or a pharmaceutically acceptable salt thereof
10. A pharmaceutical composition comprising ((((((R)-l-(6-amino-9H-purin-9- yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl)oxy)methyl pivalate or a pharmaceutically acceptable metabolite or derivative thereof and one or more pharmaceutically acceptable excipients.
11. The pharmaceutical composition according to claim 10, wherein ((((((R)-l- (6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl)(phenoxy)phosphoryl)oxy)methyl pivalate or a pharmaceutically acceptable metabolite, derivative thereof is present in an amount from about 2% to about 80% of the composition.
12. The pharmaceutical composition according to claim 10, wherein the one or more pharmaceutically acceptable excipients are selected from carriers, diluents, fillers, binders, lubricants, glidants, disintegrants, bulking agents, flavorants or any combination thereof.
13. The pharmaceutical composition according to claim 10, wherein the composition is administered by oral route, topical route, rectal route, parenteral route or vaginal route.
14. The pharmaceutical composition according to claim 10, wherein the composition is in the form of an ingestible tablets, dispersible tablets, buccal tablets, troches, capsules, elixirs, solutions, suspensions, syrups, wafers, self-emulsifying drug delivery system (SEDDS), self-microemulsifying drug delivery system (SMEDDS), topical ointment, cream, gel, lozenges, ointment, suppository, vaginal ring, implant, spray foam, injectables, or in the form of a kit.
15. The pharmaceutical composition according to claim 10, further comprising an additional therapeutic agent selected from the group consisting of nucleoside reverse transcription inhibitors ( RTIs), non-nucleoside reverse transcriptase inhibitors (N RTIs), protease inhibitors (Pis), integrase inhibitors, CCR5 inhibitors, fusion inhibitors and maturation inhibitors (Mis) or any combination thereof.
16. The pharmaceutical composition according to claim 15, wherein the additional therapeutic agent is selected from emtricitabine, efavirenz, nevirapine, darunavir, atazanavir, zidovudine, didanosine, stavudine, lamivudine, zalcitabine, abacavir sulphate, delavirdine, saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, cobicistat, lopinavir, enfuvirtide, dolutegravir, elvitegravir, raltegravir, rilpivirine or any combination thereof.
17. The pharmaceutical composition according to claim 15, wherein the additional therapeutic agent is selected from, recombinant Human Interferon Alfa such as pegylated interferon alfa-2a or pegylated interferon alfa-2b , ribavirin, daclatasvir, boceprevir and telapravir, simeprevir), sofosbuvir, daclatasvir, dasabuvir or any combination thereof.
18. The pharmaceutical composition according to claim 15, wherein the additional therapeutic agent is selected from peginterferon, ribavirin, sofosbuvir, daclatasvir, velpatasvir, voxilapravir, boceprevir, telaprevir, simeprevir, dasabuvir, ledipasvir, ombitasvir, paritaprevir, ritonavir, elbasvir, grazoprevir, asunaprevir, beclabuvir or any combination thereof.
19. A method of treating viral infection in a patient in need of such treatment, the method comprising administering a pharmaceutical composition comprising a therapeutically effective amount of ((((((R)- l-(6-amino- 9H-purin-9-yl)propan-2-yl) oxy) methyl) (phenoxy) phosphoryl) oxy) methyl pivalate or a pharmaceutically acceptable metabolite , derivative thereof and one or more pharmaceutically acceptable excipients.
20. The method according to claim 19, wherein viral infection is caused by retroviruses and the activity is anti-HIV activity.
21. The method according to claim 19, wherein viral infection is hepatitis B viruses or hepatitis C virus and the activity is anti-HBV activity.
22. The method of treatment according to claim 20, wherein the therapeutic index of compound of formula I is greater than 40.
23. The method of treatment according to claim 21, wherein the therapeutic index of compound of formula I is greater than 30.
24. The method of treatment according to claim 19, wherein the treatment is combined activity of ((((((R)- 1 -(6-amino-9H-purin-9-yl)propan-2-yl) oxy) methyl) (phenoxy) phosphoryl) oxy) methyl pivalate , compound of formula I, PMPA and tenofovir diphosphate.
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