CN117417327A - Salt of HCV inhibitor, crystalline form of salt, pharmaceutical composition thereof and use thereof - Google Patents
Salt of HCV inhibitor, crystalline form of salt, pharmaceutical composition thereof and use thereof Download PDFInfo
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- CN117417327A CN117417327A CN202310884448.3A CN202310884448A CN117417327A CN 117417327 A CN117417327 A CN 117417327A CN 202310884448 A CN202310884448 A CN 202310884448A CN 117417327 A CN117417327 A CN 117417327A
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- Prior art keywords
- phosphate
- formula
- salt
- ray powder
- compound
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- 150000003839 salts Chemical class 0.000 title claims abstract description 56
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 28
- 239000003112 inhibitor Substances 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 81
- 239000013078 crystal Substances 0.000 claims abstract description 59
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 15
- 239000003814 drug Substances 0.000 claims abstract description 15
- 201000010099 disease Diseases 0.000 claims abstract description 12
- 208000015181 infectious disease Diseases 0.000 claims abstract description 11
- 229940079593 drug Drugs 0.000 claims abstract description 8
- 229910019142 PO4 Inorganic materials 0.000 claims description 140
- 239000010452 phosphate Substances 0.000 claims description 136
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 128
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 98
- -1 dannopevir Chemical compound 0.000 claims description 44
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 31
- 150000003013 phosphoric acid derivatives Chemical class 0.000 claims description 29
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 23
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 claims description 20
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 12
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 102100040018 Interferon alpha-2 Human genes 0.000 claims description 9
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 9
- 108010050904 Interferons Proteins 0.000 claims description 7
- 102000014150 Interferons Human genes 0.000 claims description 7
- 229940079322 interferon Drugs 0.000 claims description 7
- OLROWHGDTNFZBH-XEMWPYQTSA-N Alisporivir Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)N(CC)C(=O)[C@@H](C)N(C)C1=O OLROWHGDTNFZBH-XEMWPYQTSA-N 0.000 claims description 6
- 108010078049 Interferon alpha-2 Proteins 0.000 claims description 6
- 229950004789 alisporivir Drugs 0.000 claims description 6
- 108010058359 alisporivir Proteins 0.000 claims description 6
- 208000006454 hepatitis Diseases 0.000 claims description 6
- 231100000283 hepatitis Toxicity 0.000 claims description 6
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 claims description 6
- 108010047761 Interferon-alpha Proteins 0.000 claims description 5
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- 239000002671 adjuvant Substances 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 5
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- YQUCBFIQSJVCOR-JOCHJYFZSA-N (7r)-14-cyclohexyl-7-{[2-(dimethylamino)ethyl](methyl)amino}-7,8-dihydro-6h-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic acid Chemical compound C([C@@H](CN1C2=CC(=CC=C22)C(O)=O)N(C)CCN(C)C)OC3=CC=CC=C3C1=C2C1CCCCC1 YQUCBFIQSJVCOR-JOCHJYFZSA-N 0.000 claims description 3
- 108091032973 (ribonucleotides)n+m Proteins 0.000 claims description 3
- UBCHPRBFMUDMNC-UHFFFAOYSA-N 1-(1-adamantyl)ethanamine Chemical compound C1C(C2)CC3CC2CC1(C(N)C)C3 UBCHPRBFMUDMNC-UHFFFAOYSA-N 0.000 claims description 3
- YFXGICNMLCGLHJ-RSKRLRQZSA-N 2,2-dimethylpropyl (2s)-2-[[[(2r,3r,4r,5r)-5-(2-amino-6-methoxypurin-9-yl)-3,4-dihydroxy-4-methyloxolan-2-yl]methoxy-naphthalen-1-yloxyphosphoryl]amino]propanoate Chemical compound C1=CC=C2C(OP(=O)(N[C@@H](C)C(=O)OCC(C)(C)C)OC[C@H]3O[C@H]([C@]([C@@H]3O)(C)O)N3C=4N=C(N)N=C(C=4N=C3)OC)=CC=CC2=C1 YFXGICNMLCGLHJ-RSKRLRQZSA-N 0.000 claims description 3
- JXZYSNWHGBGZAI-GOSISDBHSA-N 2-[(1r)-5-cyano-8-methyl-1-propyl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl]acetic acid Chemical compound N1C2=C(C)C=CC(C#N)=C2C2=C1[C@@](CCC)(CC(O)=O)OCC2 JXZYSNWHGBGZAI-GOSISDBHSA-N 0.000 claims description 3
- BBGOSBDSLYHMRA-UHFFFAOYSA-N 4-[1-[4-cyclobutyl-2-methyl-5-(5-methyl-1h-1,2,4-triazol-3-yl)benzoyl]piperidin-4-yl]benzonitrile Chemical compound N1C(C)=NN=C1C1=CC(C(=O)N2CCC(CC2)C=2C=CC(=CC=2)C#N)=C(C)C=C1C1CCC1 BBGOSBDSLYHMRA-UHFFFAOYSA-N 0.000 claims description 3
- NYPIRLYMDJMKGW-VPCXQMTMSA-N 4-amino-1-[(2r,3r,4r,5r)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyloxolan-2-yl]pyrimidin-2-one Chemical compound C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N=C(N)C=C1 NYPIRLYMDJMKGW-VPCXQMTMSA-N 0.000 claims description 3
- XBEQSQDCBSKCHJ-UHFFFAOYSA-N 5-[[6-[2,4-bis(trifluoromethyl)phenyl]pyridazin-3-yl]methyl]-2-(2-fluorophenyl)imidazo[4,5-c]pyridine Chemical compound FC1=CC=CC=C1C1=NC2=CN(CC=3N=NC(=CC=3)C=3C(=CC(=CC=3)C(F)(F)F)C(F)(F)F)C=CC2=N1 XBEQSQDCBSKCHJ-UHFFFAOYSA-N 0.000 claims description 3
- WTDWVLJJJOTABN-UHFFFAOYSA-N 5-cyclopropyl-2-(4-fluorophenyl)-6-[(2-hydroxyethyl)(methylsulfonyl)amino]-n-methyl-1-benzofuran-3-carboxamide Chemical compound C1=C2C(C(=O)NC)=C(C=3C=CC(F)=CC=3)OC2=CC(N(CCO)S(C)(=O)=O)=C1C1CC1 WTDWVLJJJOTABN-UHFFFAOYSA-N 0.000 claims description 3
- ATSKNKMCQXHIRK-UHFFFAOYSA-N 6-[(7-chloro-1-hydroxy-3h-2,1-benzoxaborol-5-yl)-methylsulfonylamino]-5-cyclopropyl-2-(4-fluorophenyl)-n-methyl-1-benzofuran-3-carboxamide Chemical compound C1=C2C(C(=O)NC)=C(C=3C=CC(F)=CC=3)OC2=CC(N(C=2C=C(Cl)C=3B(O)OCC=3C=2)S(C)(=O)=O)=C1C1CC1 ATSKNKMCQXHIRK-UHFFFAOYSA-N 0.000 claims description 3
- RFGUWOCFYCYEDM-ZOMNBDOOSA-N 8v42y78hru Chemical compound OP([C@@]12C[C@H]1CCCCCCC[C@@H](C(=O)N1[C@H](C(N2)=O)C[C@H](C1)OC=1C2=CC=C(C(=C2N=C(C=1)C=1N=C(NC(C)C)SC=1)Cl)OC)NC(=O)OC1CCCC1)(=O)CC1=C(F)C=CC=C1F RFGUWOCFYCYEDM-ZOMNBDOOSA-N 0.000 claims description 3
- PVRFQJIRERYGTQ-DSQUMVBZSA-N 9-[(2s,4ar,6r,7r,7ar)-7-fluoro-7-methyl-2-oxo-2-propan-2-yloxy-4,4a,6,7a-tetrahydrofuro[3,2-d][1,3,2]dioxaphosphinin-6-yl]-6-ethoxypurin-2-amine Chemical compound C([C@H]1O2)O[P@@](=O)(OC(C)C)O[C@H]1[C@](F)(C)[C@@H]2N1C(N=C(N)N=C2OCC)=C2N=C1 PVRFQJIRERYGTQ-DSQUMVBZSA-N 0.000 claims description 3
- 108010019182 Alloferon Proteins 0.000 claims description 3
- 108020005544 Antisense RNA Proteins 0.000 claims description 3
- OTXAMWFYPMNDME-FQQWJMKMSA-N CC[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)O[C@@H]1C[C@@H]2C[C@@H]2C1)C(C)(C)C)Oc1cc(nc2c(Cl)c(OCCN3CCOCC3)ccc12)-c1csc(NC(C)C)n1)C(O)=O Chemical compound CC[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)O[C@@H]1C[C@@H]2C[C@@H]2C1)C(C)(C)C)Oc1cc(nc2c(Cl)c(OCCN3CCOCC3)ccc12)-c1csc(NC(C)C)n1)C(O)=O OTXAMWFYPMNDME-FQQWJMKMSA-N 0.000 claims description 3
- 108060003951 Immunoglobulin Proteins 0.000 claims description 3
- 108010079944 Interferon-alpha2b Proteins 0.000 claims description 3
- 108010074328 Interferon-gamma Proteins 0.000 claims description 3
- 102000008070 Interferon-gamma Human genes 0.000 claims description 3
- 102000013462 Interleukin-12 Human genes 0.000 claims description 3
- 108010065805 Interleukin-12 Proteins 0.000 claims description 3
- 102000000588 Interleukin-2 Human genes 0.000 claims description 3
- 108010002350 Interleukin-2 Proteins 0.000 claims description 3
- 102000004889 Interleukin-6 Human genes 0.000 claims description 3
- 108090001005 Interleukin-6 Proteins 0.000 claims description 3
- 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
- MHFMTUBUVQZIRE-WINRQGAFSA-N Sovaprevir Chemical compound C([C@H](C(=O)N1[C@@H](C[C@H](C1)OC=1C2=CC=C(C=C2N=C(C=1)C=1C=CC=CC=1)OC)C(=O)N[C@]1([C@@H](C1)C=C)C(=O)NS(=O)(=O)C1CC1)C(C)(C)C)C(=O)N1CCCCC1 MHFMTUBUVQZIRE-WINRQGAFSA-N 0.000 claims description 3
- 230000005867 T cell response Effects 0.000 claims description 3
- ZWELIJXAKMASLK-UGKPPGOTSA-N [(2r,3r,4r,5r)-4-acetyloxy-5-(5-amino-2-oxo-[1,3]thiazolo[4,5-d]pyrimidin-3-yl)-2-(hydroxymethyl)oxolan-3-yl] acetate Chemical compound CC(=O)O[C@@H]1[C@H](OC(=O)C)[C@@H](CO)O[C@H]1N1C(=O)SC2=CN=C(N)N=C21 ZWELIJXAKMASLK-UGKPPGOTSA-N 0.000 claims description 3
- XJBILYMRFVHPJB-XJQUKVTJSA-N [(2r,3s,4s,5r)-5-(4-amino-2-oxopyrimidin-1-yl)-2-azido-4-methyl-3-(2-methylpropanoyloxy)oxolan-2-yl]methyl 2-methylpropanoate Chemical compound C[C@H]1[C@H](OC(=O)C(C)C)[C@](COC(=O)C(C)C)(N=[N+]=[N-])O[C@H]1N1C(=O)N=C(N)C=C1 XJBILYMRFVHPJB-XJQUKVTJSA-N 0.000 claims description 3
- YQNQNVDNTFHQSW-UHFFFAOYSA-N acetic acid [2-[[(5-nitro-2-thiazolyl)amino]-oxomethyl]phenyl] ester Chemical compound CC(=O)OC1=CC=CC=C1C(=O)NC1=NC=C([N+]([O-])=O)S1 YQNQNVDNTFHQSW-UHFFFAOYSA-N 0.000 claims description 3
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 claims description 3
- 229960003805 amantadine Drugs 0.000 claims description 3
- WVROWPPEIMRGAB-UHFFFAOYSA-N bit225 Chemical compound C1=NN(C)C=C1C1=CC=CC2=CC(C(=O)NC(N)=N)=CC=C12 WVROWPPEIMRGAB-UHFFFAOYSA-N 0.000 claims description 3
- ZTRJLSWOQIDJIS-XMMPIXPASA-N chembl469738 Chemical compound CS(=O)(=O)NC1=CC=C2NC(C=3C(=O)[C@](C4=CC=CC=C4C=3O)(C)CCC(C)C)=NS(=O)(=O)C2=C1 ZTRJLSWOQIDJIS-XMMPIXPASA-N 0.000 claims description 3
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- 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
- 229960001418 dasabuvir Drugs 0.000 claims description 3
- BMAIGAHXAJEULY-UKTHLTGXSA-N deleobuvir Chemical compound C12=CC=C(C(=O)NC3(CCC3)C=3N(C4=CC(\C=C\C(O)=O)=CC=C4N=3)C)C=C2N(C)C(C=2N=CC(Br)=CN=2)=C1C1CCCC1 BMAIGAHXAJEULY-UKTHLTGXSA-N 0.000 claims description 3
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- LLGDPTDZOVKFDU-XUHJSTDZSA-N faldaprevir Chemical compound N([C@H](C(=O)N1[C@@H](C[C@H](C1)OC=1C2=CC=C(C(=C2N=C(C=1)C=1N=C(NC(=O)C(C)C)SC=1)Br)OC)C(=O)N[C@]1([C@@H](C1)C=C)C(O)=O)C(C)(C)C)C(=O)OC1CCCC1 LLGDPTDZOVKFDU-XUHJSTDZSA-N 0.000 claims description 3
- 229960003777 faldaprevir Drugs 0.000 claims description 3
- SLVAPEZTBDBAPI-GDLZYMKVSA-N filibuvir Chemical compound CCC1=NC(CC)=CC(CC[C@]2(OC(=O)C(CC3=NN4C(C)=CC(C)=NC4=N3)=C(O)C2)C2CCCC2)=C1 SLVAPEZTBDBAPI-GDLZYMKVSA-N 0.000 claims description 3
- 229950011045 filibuvir Drugs 0.000 claims description 3
- 210000002443 helper t lymphocyte Anatomy 0.000 claims description 3
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- 239000002348 inosinate dehydrogenase inhibitor Substances 0.000 claims description 3
- 230000002452 interceptive effect Effects 0.000 claims description 3
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- 229940117681 interleukin-12 Drugs 0.000 claims description 3
- 229940100601 interleukin-6 Drugs 0.000 claims description 3
- YMCAVGXTSCNFDE-BBACVFHCSA-N methyl n-[(2s)-1-[(2s)-2-[5-[4-[4-[2-[(8s)-7-[(2s)-2-(methoxycarbonylamino)-3-methylbutanoyl]-1,4-dioxa-7-azaspiro[4.4]nonan-8-yl]-1h-imidazol-5-yl]phenyl]phenyl]-1h-imidazol-2-yl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C1=NC=C(C=2C=CC(=CC=2)C=2C=CC(=CC=2)C=2NC(=NC=2)[C@H]2N(CC3(C2)OCCO3)C(=O)[C@@H](NC(=O)OC)C(C)C)N1 YMCAVGXTSCNFDE-BBACVFHCSA-N 0.000 claims description 3
- OSOOBMBDIGGTCP-UHFFFAOYSA-N miravirsen Chemical compound O=C1NC(=O)C(C)=CN1C1OC(COP(O)(=S)OC2C3(COP(O)(=S)OC4C(OC(C4)N4C(N=C(N)C=C4)=O)COP(O)(=S)OC4C5(CO)COC4C(O5)N4C(N=C(N)C=C4)=O)COC2C(O3)N2C3=NC=NC(N)=C3N=C2)C(OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC23OC(C(OC2)C3OP(O)(=S)OCC23OC(C(OC2)C3OP(O)(=S)OCC2C(CC(O2)N2C(N=C(N)C=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C3=NC=NC(N)=C3N=C2)OP(O)(=S)OCC23OC(C(OC2)C3OP(O)(=S)OCC2C(CC(O2)N2C3=NC=NC(N)=C3N=C2)OP(O)(=S)OCC23OC(C(OC2)C3OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC23OC(C(OC2)C3OP(O)(=S)OCC23C(C(OC2)C(O3)N2C(N=C(N)C=C2)=O)O)N2C(N=C(N)C=C2)=O)N2C(N=C(N)C=C2)=O)N2C(N=C(N)C=C2)=O)N2C(NC(=O)C(C)=C2)=O)N2C3=C(C(NC(N)=N3)=O)N=C2)C1 OSOOBMBDIGGTCP-UHFFFAOYSA-N 0.000 claims description 3
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicines, and relates to a salt of a hepatitis C inhibitor compound, a crystal form of the salt, a pharmaceutical composition of the salt and application of the salt and the pharmaceutical composition in preparation of medicines for preventing, treating or relieving HCV infection or diseases related to hepatitis C diseases. The salt and the crystal form of the salt of the compound can obviously improve the properties of pharmacokinetics and the like of the compound, and have better patentability.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to a salt of a hepatitis C inhibitor compound, a crystal form of the salt, a pharmaceutical composition of the salt and application of the salt and the pharmaceutical composition in preparation of medicines for preventing, treating or relieving HCV infection or diseases related to hepatitis C diseases.
Background
HCV is a major human pathogen, estimated to infect about 1.7 million people worldwide, 5 times the number of human immunodeficiency virus type 1 infections. While most of these HCV-infected individuals develop severe progressive liver disease, including cirrhosis and hepatocellular carcinoma. Thus, chronic HCV infection will be a major cause of premature death in patients worldwide due to liver disease.
Example 5 of chinese patent CN105968101a discloses a compound of the following formula (I) as a drug-resistant full genotype HCV inhibitor, which has a remarkable effect on the treatment of Hepatitis C Virus (HCV) infection or hepatitis c disease.
However, subsequent researches find that the compound shown in the formula (I) prepared in the patent CN105968101A is amorphous, has poor solid morphology and affects post-treatment operation and preparation process; in addition, the solubility and the pharmacokinetics data of the compound are poor, and the effectiveness of the medicament is influenced. These present a number of inconveniences for subsequent drug development.
Disclosure of Invention
The invention provides salts of compounds of formula (I) with acids, including phosphates, hydrochlorides, sulphates, methanesulfonates, p-toluenesulfonates, maleates and benzenesulfonates. In particular, the present invention provides phosphates of compounds of formula (I) having better pharmacokinetic properties than other salts. Especially, the crystal form B of the phosphate shown in the formula (IA) can obviously improve the stability, pharmacokinetics and other properties of the compound, thereby having better patentability.
In particular, the invention relates to salts of compounds of formula (I), crystalline form B of phosphates of formula (IA), pharmaceutical compositions comprising the salts or crystalline forms thereof, and their use in the manufacture of a medicament for the prevention, treatment or alleviation of HCV infection or a disease associated with hepatitis C disease.
In one aspect, the present invention provides a salt of a compound of formula (I),
wherein the salt is phosphate, hydrochloride, sulfate, mesylate, p-toluenesulfonate, maleate and benzenesulfonate.
In some embodiments, the salt of the compound of formula (I) described herein is a phosphate salt.
In some embodiments, the phosphate salts described herein have a molar ratio of the compound of formula (I) to phosphoric acid of from 1:2 to 1:4.
In other embodiments, the phosphate salts described herein have a molar ratio of the compound of formula (I) to phosphoric acid of 1:2 or 1 (8/3).
In other embodiments, the phosphate salts described herein have a molar ratio of the compound of formula (I) to phosphoric acid of 1:2.
In other embodiments, the phosphate salts described herein have a molar ratio of the compound of formula (I) to phosphoric acid of 1 (8/3).
In another aspect, the present invention provides a crystalline form B of a phosphate of formula (IA),
wherein the X-ray powder diffraction pattern of form B comprises diffraction peaks at the following 2θ angles: 3.49 ° ± 0.2 °,6.89 ° ± 0.2 °,9.15 ° ± 0.2 °,10.24 ° ± 0.2 ° and 12.16 ° ± 0.2 °.
In some embodiments, the X-ray powder diffraction pattern of form B of the phosphate of formula (IA) comprises diffraction peaks at the following 2θ angles: 3.49 ° ± 0.2 °,6.89 ° ± 0.2 °,7.33 ° ± 0.2 °,9.15 ° ± 0.2 °,10.24 ° ± 0.2 °,10.77 ° ± 0.2 °,12.16 ° ± 0.2 °,13.44 ° ± 0.2 °,14.65 ° ± 0.2 °,15.20 ° ± 0.2 °,16.22 ° ± 0.2 °,17.21 ° ± 0.2 °,17.58 ° ± 0.2 °,17.94 ° ± 0.2 °,18.64 ° ± 0.2 ° and 19.58 ° ± 0.2 °.
In some embodiments, the X-ray powder diffraction pattern of form B of the phosphate of formula (IA) comprises diffraction peaks at the following 2θ angles: 3.49 ° ± 0.2 °,6.40 ° ± 0.2 °,6.89 ° ± 0.2 °,7.33 ° ± 0.2 °,9.15 ° ± 0.2 °,9.87 ° ± 0.2 °,10.24 ° ± 0.2 °,10.77 ° ± 0.2 °,12.16 ° ± 0.2 °,12.72 ° ± 0.2 °,13.44 ° ± 0.2 °,14.65 ° ± 0.2 °,15.20 ° ± 0.2 °,15.40 ° ± 0.2 °,16.22 ° ± 0.2 °,16.83 ° ± 0.2 °,17.21 ° ± 0.2 °,17.58 ° ± 0.2 °,17.94 ° ± 0.2 °,18.64 ° ± 0.2 °,19.58 ° ± 0.2 °,21.11 ° ± 0.2 °,21.91 ° ± 0.24.24 ° ± 0.2 °,24.35 ° ± 0.2 °,25.65 ° ± 0.2 °, and 25.05 ° ± 0.27 °.
In some embodiments, form B of the phosphate of formula (IA) has an X-ray powder diffraction pattern substantially as shown in figure 3.
In some embodiments, the differential scanning calorimetry pattern of form B of the phosphate of formula (IA) comprises an endothermic peak at 227.22 ℃ ± 3 ℃.
In some embodiments, form B of the phosphate of formula (IA) has a differential scanning calorimetric diagram substantially as shown in fig. 4.
In some embodiments, the thermogravimetric analysis of form B of the phosphate of formula (IA) loses 1.83% ± 0.5% weight over the range of 30-150 ℃.
In some embodiments, form B of the phosphate of formula (IA) has a thermogravimetric analysis substantially as shown in figure 5.
In another aspect, the present invention provides an amorphous form of a phosphate of formula (IA),
in another aspect, the present invention provides a crystalline form A of a phosphate of formula (IA),
wherein the X-ray powder diffraction pattern of form a comprises diffraction peaks at the following 2θ angles: 3.41 ° ± 0.2 °,6.76 ° ± 0.2 °,8.74 ° ± 0.2 °,10.10 ° ± 0.2 ° and 16.82 ° ± 0.2 °.
In some embodiments, the X-ray powder diffraction pattern of form a of the phosphate of formula (IA) comprises diffraction peaks at the following 2θ angles: 3.41 ° ± 0.2 °,6.76 ° ± 0.2 °,7.51 ° ± 0.2 °,8.74 ° ± 0.2 °,10.10 ° ± 0.2 °,10.39 ° ± 0.2 °,13.48 ° ± 0.2 °,14.71 ° ± 0.2 °,16.82 ° ± 0.2 °,17.68 ° ± 0.2 °,20.80 ° ± 0.2 °,23.62 ° ± 0.2 °,24.75 ° ± 0.2 ° and 27.09 ° ± 0.2 °.
In some embodiments, the X-ray powder diffraction pattern of form a of the phosphate of formula (IA) comprises diffraction peaks at the following 2θ angles: 3.41 ° ± 0.2 °,6.76 ° ± 0.2 °,7.51 ° ± 0.2 °,8.74 ° ± 0.2 °,9.27 ° ± 0.2 °,10.10 ° ± 0.2 °,10.39 ° ± 0.2 °,12.53 ° ± 0.2 °,13.48 ° ± 0.2 °,14.71 ° ± 0.2 °,15.02 ° ± 0.2 °,16.24 ° ± 0.2 °,16.82 ° ± 0.2 °,17.68 ° ± 0.2 °,18.84 ° ± 0.2 °,20.04 ° ± 0.2 °,20.52 ° ± 0.2 °,20.80 ° ± 0.2 °,21.39 ° ± 0.2 °,21.77 ° ± 0.2 °,22.90 ° ± 0.2 °,23.62 ° ± 0.2 °,23.89 ° ± 0.2 °,24.75 ° ± 0.2 °,26.74 ° ± 0.27 ° ± 0.2 °, and 2.81 ° ± 0.12 ° ± 0.27 ° ± 0.2.12 °.
In some embodiments, form a of the phosphate of formula (IA) has an X-ray powder diffraction pattern substantially as shown in figure 1.
In some embodiments, the differential scanning calorimetry pattern of form a of the phosphate of formula (IA) comprises an endothermic peak at 225.33 ℃ ± 3 ℃.
In some embodiments, form a of the phosphate of formula (IA) has a differential scanning calorimetric diagram substantially as shown in fig. 2.
In another aspect, the present invention provides a crystalline form D of a phosphate of formula (IA),
wherein the X-ray powder diffraction pattern of form D comprises diffraction peaks at the following 2θ angles: 3.37 ° ± 0.2 °,6.67 ° ± 0.2 °,16.62 ° ± 0.2 °,23.32 ° ± 0.2 ° and 33.53 ° ± 0.2 °.
In some embodiments, the X-ray powder diffraction pattern of form D of the phosphate of formula (IA) comprises diffraction peaks at the following 2θ angles: 3.37 ° ± 0.2 °,6.67 ° ± 0.2 °,16.62 ° ± 0.2 °,18.60 ° ± 0.2 °,19.97 ° ± 0.2 °,21.87 ° ± 0.2 °,23.32 ° ± 0.2 °,25.64 ° ± 0.2 °,26.71 ° ± 0.2 ° and 33.53 ° ± 0.2 °.
In some embodiments, the X-ray powder diffraction pattern of form D of the phosphate of formula (IA) comprises diffraction peaks at the following 2θ angles: 3.37 ° ± 0.2 °,6.04 ° ± 0.2 °,6.67 ° ± 0.2 °,9.18 ° ± 0.2 °,10.00 ° ± 0.2 °,13.30 ° ± 0.2 °,15.39 ° ± 0.2 °,16.62 ° ± 0.2 °,18.60 ° ± 0.2 °,19.97 ° ± 0.2 °,20.66 ° ± 0.2 °,21.87 ° ± 0.2 °,23.32 ° ± 0.2 °,23.82 ° ± 0.2 °,25.13 ° ± 0.2 °,25.64 ° ± 0.2 °,26.71 ° ± 0.2 °,27.74 ° ± 0.2 °,30.25 ° ± 0.2 ° and 33.53 ° ± 0.2 °.
In some embodiments, form D of the phosphate of formula (IA) has an X-ray powder diffraction pattern substantially as shown in figure 6.
In another aspect, the present invention provides a crystalline form E of a phosphate of formula (IA),
wherein the X-ray powder diffraction pattern of form E comprises diffraction peaks at the following 2θ angles: 3.35 ° ± 0.2 °,6.62 ° ± 0.2 °,22.89 ° ± 0.2 ° and 23.79 ° ± 0.2 °.
In some embodiments, the X-ray powder diffraction pattern of form E of the phosphate of formula (IA) comprises diffraction peaks at the following 2θ angles: 3.35 ° ± 0.2 °,6.62 ° ± 0.2 °,9.15 ° ± 0.2 °,12.11 ° ± 0.2 °,16.46 ° ± 0.2 °,18.07 ° ± 0.2 °,22.89 ° ± 0.2 °,23.28 ° ± 0.2 ° and 23.79 ° ± 0.2 °.
In some embodiments, the X-ray powder diffraction pattern of form E of the phosphate of formula (IA) comprises diffraction peaks at the following 2θ angles: 3.35 ° ± 0.2 °,6.62 ° ± 0.2 °,9.15 ° ± 0.2 °,12.11 ° ± 0.2 °,15.60 ° ± 0.2 °,16.46 ° ± 0.2 °,17.33 ° ± 0.2 °,18.07 ° ± 0.2 °,20.56 ° ± 0.2 °,22.06 ° ± 0.2 °,22.89 ° ± 0.2 °,23.28 ° ± 0.2 °,23.79 ° ± 0.2 °,25.04 ° ± 0.2 °,25.55 ° ± 0.2 °,30.29 ° ± 0.2 ° and 33.52 ° ± 0.2 °.
In some embodiments, form E of the phosphate of formula (IA) has an X-ray powder diffraction pattern substantially as shown in figure 7.
In another aspect, the present invention provides a crystalline form N1 of a phosphate of formula (IA),
wherein the X-ray powder diffraction pattern of crystalline form N1 comprises diffraction peaks at the following 2θ angles: 6.35 ° ± 0.2 °,7.67 ° ± 0.2 °,10.34 ° ± 0.2 °,16.31 ° ± 0.2 ° and 17.73 ° ± 0.2 °.
In some embodiments, the X-ray powder diffraction pattern of crystalline form N1 of the phosphate of formula (IA) comprises diffraction peaks at the following 2θ angles: 6.35 ° ± 0.2 °,7.67 ° ± 0.2 °,8.92 ° ± 0.2 °,10.34 ° ± 0.2 °,12.50 ° ± 0.2 °,13.40 ° ± 0.2 °,16.31 ° ± 0.2 °,17.73 ° ± 0.2 °,19.02 ° ± 0.2 °,20.55 ° ± 0.2 °,22.27 ° ± 0.2 °,23.79 ° ± 0.2 °,24.42 ° ± 0.2 ° and 25.88 ° ± 0.2 °.
In some embodiments, form N1 of the phosphate of formula (IA) has an X-ray powder diffraction pattern substantially as shown in figure 8.
In some embodiments, the differential scanning calorimetry pattern of crystalline form N1 of the phosphate of formula (IA) comprises an endothermic peak at 223.05 ℃ ± 3 ℃.
In some embodiments, form N1 of the phosphate of formula (IA) has a differential scanning calorimetric diagram substantially as shown in fig. 9.
In some embodiments, the thermogravimetric analysis of form N1 of the phosphate of formula (IA) loses 6.76% ± 0.5% weight over the range of 30-193 ℃.
In some embodiments, form N1 of the phosphate of formula (IA) has a thermogravimetric analysis substantially as shown in figure 10.
In another aspect, the present invention provides a crystalline form N2 of a phosphate of formula (IA),
wherein the X-ray powder diffraction pattern of crystalline form N2 comprises diffraction peaks at the following 2θ angles: 6.47 ° ± 0.2 °,10.22 ° ± 0.2 °,16.37 ° ± 0.2 °,17.59 ° ± 0.2 ° and 22.82 ° ± 0.2 °.
In some embodiments, the X-ray powder diffraction pattern of crystalline form N2 of the phosphate of formula (IA) comprises diffraction peaks at the following 2θ angles: 6.47 ° ± 0.2 °,7.42 ° ± 0.2 °,8.26 ° ± 0.2 °,8.92 ° ± 0.2 °,10.22 ° ± 0.2 °,12.69 ° ± 0.2 °,14.22 ° ± 0.2 °,14.82 ° ± 0.2 °,15.64 ° ± 0.2 °,16.37 ° ± 0.2 °,17.59 ° ± 0.2 °,19.42 ° ± 0.2 °,20.32 ° ± 0.2 °,20.92 ° ± 0.2 °,22.82 ° ± 0.2 °,23.79 ° ± 0.2 °,24.43 ° ± 0.2 ° and 25.15 ° ± 0.2 °.
In some embodiments, form N2 of the phosphate of formula (IA) has an X-ray powder diffraction pattern substantially as shown in figure 11.
In some embodiments, the differential scanning calorimetry pattern of crystalline form N2 of the phosphate of formula (IA) comprises an endothermic peak at 226.28 ℃ ± 3 ℃.
In some embodiments, form N2 of the phosphate of formula (IA) has a differential scanning calorimetric diagram substantially as shown in fig. 12.
In some embodiments, the thermogravimetric analysis of form N2 of the phosphate of formula (IA) loses 6.99% ± 0.5% weight over the range of 30-212 ℃.
In some embodiments, form N2 of the phosphate of formula (IA) has a thermogravimetric analysis substantially as shown in figure 13.
In another aspect, the present invention provides a crystalline form N5 of a phosphate of formula (IA),
wherein the X-ray powder diffraction pattern of crystalline form N5 comprises diffraction peaks at the following 2θ angles: 3.37 ° ± 0.2 °,6.57 ° ± 0.2 °,10.24 ° ± 0.2 °,17.86 ° ± 0.2 ° and 21.41 ° ± 0.2 °.
In some embodiments, the X-ray powder diffraction pattern of crystalline form N5 of the phosphate of formula (IA) comprises diffraction peaks at the following 2θ angles: 3.37 ° ± 0.2 °,6.57 ° ± 0.2 °,7.35 ° ± 0.2 °,8.49 ° ± 0.2 °,9.06 ° ± 0.2 °,10.24 ° ± 0.2 °,16.28 ° ± 0.2 °,17.86 ° ± 0.2 °,20.58 ° ± 0.2 °,21.41 ° ± 0.2 °,22.97 ° ± 0.2 ° and 24.55 ° ± 0.2 °.
In some embodiments, the X-ray powder diffraction pattern of crystalline form N5 of the phosphate of formula (IA) comprises diffraction peaks at the following 2θ angles: 3.37 ° ± 0.2 °,6.57 ° ± 0.2 °,7.35 ° ± 0.2 °,8.49 ° ± 0.2 °,9.06 ° ± 0.2 °,10.24 ° ± 0.2 °,12.18 ° ± 0.2 °,13.02 ° ± 0.2 °,14.67 ° ± 0.2 °,15.45 ° ± 0.2 °,16.28 ° ± 0.2 °,17.86 ° ± 0.2 °,19.61 ° ± 0.2 °,20.18 ° ± 0.2 °,20.58 ° ± 0.2 °,21.41 ° ± 0.2 °,22.97 ° ± 0.2 °,23.83 ° ± 0.2 °,24.55 ° ± 0.2 °,25.40 ° ± 0.2 ° and 25.88 ° ± 0.2 °.
In some embodiments, form N5 of the phosphate of formula (IA) has an X-ray powder diffraction pattern substantially as shown in figure 14.
In some embodiments, the differential scanning calorimetry pattern of crystalline form N5 of the phosphate of formula (IA) comprises an endothermic peak at 223.05 ℃ ± 3 ℃.
In some embodiments, form N5 of the phosphate of formula (IA) has a differential scanning calorimetric diagram substantially as shown in fig. 15.
In some embodiments, the thermogravimetric analysis of form N5 of the phosphate of formula (IA) loses 5.49% ± 0.5% weight over the range of 30-198 ℃.
In some embodiments, form N5 of the phosphate of formula (IA) has a thermogravimetric analysis substantially as shown in figure 16.
In another aspect, the present invention provides a crystalline form N6 of the phosphate of formula (IA),
wherein the X-ray powder diffraction pattern of crystalline form N6 comprises diffraction peaks at the following 2θ angles: 3.38 ° ± 0.2 °,6.60 ° ± 0.2 °,10.25 ° ± 0.2 °,16.49 ° ± 0.2 ° and 23.17 ° ± 0.2 °.
In some embodiments, the X-ray powder diffraction pattern of crystalline form N6 of the phosphate of formula (IA) comprises diffraction peaks at the following 2θ angles: 3.38 ° ± 0.2 °,6.60 ° ± 0.2 °,7.43 ° ± 0.2 °,8.52 ° ± 0.2 °,10.25 ° ± 0.2 °,16.49 ° ± 0.2 °,17.97 ° ± 0.2 °,22.75 ° ± 0.2 °,23.17 ° ± 0.2 °,24.48 ° ± 0.2 ° and 24.85 ° ± 0.2 °.
In some embodiments, the X-ray powder diffraction pattern of crystalline form N6 of the phosphate of formula (IA) comprises diffraction peaks at the following 2θ angles: 3.38 ° ± 0.2 °,6.60 ° ± 0.2 °,7.43 ° ± 0.2 °,8.52 ° ± 0.2 °,9.07 ° ± 0.2 °,10.25 ° ± 0.2 °,14.55 ° ± 0.2 °,14.89 ° ± 0.2 °,15.63 ° ± 0.2 °,16.49 ° ± 0.2 °,17.05 ° ± 0.2 °,17.63 ° ± 0.2 °,17.97 ° ± 0.2 °,18.58 ° ± 0.2 °,19.78 ° ± 0.2 °,20.44 ° ± 0.2 °,21.50 ° ± 0.2 °,22.75 ° ± 0.2 °,23.17 ° ± 0.2 °,24.48 ° ± 0.2 °,24.85 ° ± 0.2 °,25.57 ° ± 0.2 °,26.27 ° ± 0.39 ° ± 0.2 °,28.02 ° ± 0.2 °, 29.39.25 ° ± 0.2 °, and 30 ° ± 0.87 ° ± 0.2 °.
In some embodiments, form N6 of the phosphate of formula (IA) has an X-ray powder diffraction pattern substantially as shown in figure 17.
In some embodiments, the differential scanning calorimetry pattern of crystalline form N6 of the phosphate of formula (IA) comprises an endothermic peak at 223.74 ℃ ± 3 ℃.
In some embodiments, form N6 of the phosphate of formula (IA) has a differential scanning calorimetric diagram substantially as shown in fig. 18.
In some embodiments, the thermogravimetric analysis of form N6 of the phosphate of formula (IA) loses 4.69% ± 0.5% weight in the range of 30-196 ℃.
In some embodiments, form N6 of the phosphate of formula (IA) has a thermogravimetric analysis substantially as shown in figure 19.
In another aspect, the invention provides a pharmaceutical composition comprising a salt according to the invention or a crystalline form of a phosphate according to the invention or an amorphous form of a phosphate according to the invention.
In some embodiments, the present invention provides a pharmaceutical composition comprising a salt of the present invention or crystalline form B of a phosphate salt of the present invention or amorphous form of a phosphate salt of the present invention.
In some preferred embodiments, the present invention provides a pharmaceutical composition comprising form B of the phosphate salt of the present invention or the amorphous form of the phosphate salt of the present invention.
In still another aspect, the present invention provides a method for preparing a salt of a compound of formula (I) according to the present invention, which comprises reacting a compound of formula (I) with an acid in a suitable solvent.
In some embodiments, the pharmaceutical compositions of the present invention further comprise a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or combination thereof.
In other embodiments, the pharmaceutical compositions of the invention further comprise additional anti-HCV agents.
In some embodiments, other anti-HCV agents described herein are interferon, ribavirin, interleukin 2, interleukin 6, interleukin 12, compounds that promote the development of a type 1 helper T cell response, interfering RNA, antisense RNA, imiqimod, inosine 5' -monophosphate dehydrogenase inhibitor, amantadine, rimantadine, bavisimab, hepatitis C immunoglobulin, civacir TM Boprenvir, telarevir, english Jiang Buwei, semepivir, anapivir, vaniprevir, faldaprevir, dannopevir, sovaprevir, vedroprevir, BZF-961, GS-9256, narlaprevir, ANA975, SH229, GSK-2336805, western Lu Ruiwei, ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136, IDX-316, modithromycin, VBY-376, TMC-649128, mericitabine, sofebuvir, INX-189, IDX-184, IDX102, R-1479, UNX-08189, PSI-6130, PSI-938, PSI-879, nesbuvir, HCV-371, VCH-916, lomibuvir, MK-3281, dasabuvir, ABT-072, filibuvir, deleobuvir, tegobuvir, A-837093, JKT-109, gl-59728 GL-60667, TMC647055, ledipasvir, setrobuvir, alisporivir, BIT-225, ACH-3422, MK-2748, ABP-560, TVB-2640, ID-12, PPI-383, A-848837, RG-7795, BC-2125, alloferon, nivolumab, WF-10, nitazoxanide, multiferron, nevirapine, ACH-3422, alisporivir, MK-3682, GS-9857, CD-AdNS3, RG-101, MBL-HCV1, CIGB-230, TG-2349, procvax, CB-5300, miravirsen, chronvac-C, MK-1075, ACH-0143422, WS-007, MK-7680, MK-2248, IDX-21459, MK-8876, GSK-2878175, MBX-700, AL-335, AL-704, SB-9200, ITX-5061 or combinations thereof; the interferon is interferon alpha-2 b, pegylated interferon alpha, interferon alpha-2 a, pegylated interferon alpha-2 a, A complex alpha-interferon, interferon gamma, or a combination thereof.
In another aspect, the invention provides the use of a salt of the invention, or of form B of a phosphate salt of the invention, or of a pharmaceutical composition of the invention, in the manufacture of a medicament for the prevention, treatment or alleviation of a disease associated with HCV infection or hepatitis c disease.
The solvent used in the process for producing a salt and/or a crystal form thereof of the present invention is not particularly limited, and any solvent which dissolves the starting materials to a certain extent and does not affect the properties thereof is included in the present invention. In addition, many similar modifications, equivalent substitutions, or equivalent solvents, combinations of solvents, and different proportions of solvent combinations described herein are considered to be encompassed by the present invention. The present invention gives the preferred solvents to be used in each reaction step.
The preparation experiments of the salts or crystal forms thereof according to the present invention will be described in detail in the examples section. Meanwhile, the invention provides pharmacological test experiments (such as pharmacokinetic experiments) and the like of the salt or the crystal forms thereof. Experiments prove that the salt or the crystal form thereof has good stability and pharmaceutical properties.
Definitions and general terms
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are described herein.
"crystalline form" or "crystalline form" refers to a solid having a highly regular chemical structure, including, but not limited to, single or multicomponent crystals, and/or polymorphs, solvates, hydrates, clathrates, co-crystals, salts, solvates of salts, hydrates of salts of the compounds. The crystalline form of a substance may be obtained by a number of methods known in the art. Such methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in a defined space, e.g., in a nanopore or capillary, crystallization on a surface or template, e.g., on a polymer, crystallization in the presence of additives such as co-crystallizing anti-molecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, anti-solvent addition, milling, solvent drop milling, and the like.
"solvent" refers to a substance (typically a liquid) that is capable of completely or partially dissolving another substance (typically a solid). Solvents useful in the practice of the present invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, methylene chloride, dimethyl sulfoxide, 1, 4-dioxane, ethanol, ethyl acetate, butanol, tertiary butanol, N-dimethylacetamide, N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof, and the like.
"antisolvent" refers to a fluid that facilitates precipitation of a product (or product precursor) from a solvent. The antisolvent may comprise a cold gas, or a fluid that promotes precipitation by a chemical reaction, or a fluid that reduces the solubility of the product in the solvent; it may be the same liquid as the solvent but at a different temperature, or it may be a different liquid than the solvent.
The crystalline forms may be identified by a variety of techniques such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point, differential Scanning Calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance, raman spectroscopy, X-ray single crystal diffraction, dissolution calorimetry, scanning Electron Microscopy (SEM), quantitative analysis, solubility and dissolution rate, and the like.
The X-ray powder diffraction (XRPD) can detect the information of crystal form change, crystallinity, crystal structure state and the like, and is a common means for identifying the crystal form. The peak positions of the XRPD patterns are largely dependent on the structure of the crystalline form, relatively insensitive to experimental details, and their relative peak heights depend on many factors related to sample preparation and instrument geometry. Thus, in some embodiments, the crystalline forms of the invention are characterized by XRPD patterns having certain peak positions, substantially as shown in the XRPD patterns provided in the figures of the invention. Meanwhile, the measure of 2θ of the XRPD pattern may have experimental errors, and the measure of 2θ of the XRPD pattern may slightly differ from instrument to instrument and sample to sample, so the value of 2θ cannot be regarded as absolute. Depending on the instrument conditions used in this test, diffraction peaks have a margin of error of + -0.2 deg..
Differential Scanning Calorimeter (DSC) is a method for measuring the temperature of a sample and an inert reference substance (commonly used alpha-Al) by continuously heating or cooling under the control of a program 2 O 3 ) A technique in which the energy difference between them varies with temperature. The endothermic peak height of the DSC curve depends on many factors related to sample preparation and instrument geometry, while peak position is relatively insensitive to experimental details. Thus, in some embodiments, the crystalline forms of the invention are characterized by a DSC profile with characteristic peak positions substantially as shown in the DSC profile provided in the accompanying figures of the invention. Meanwhile, the DSC profile may have experimental errors, and the peak position and peak value of the DSC profile may slightly differ from instrument to instrument and from sample to sample, so that the peak position or the value of the DSC endothermic peak cannot be regarded as absolute. Depending on the instrument conditions used in this test, there is an error margin of + -3deg.C for the endothermic peak.
Thermogravimetric analysis (TGA) is a technique for measuring the mass of a substance as a function of temperature under program control, and is suitable for examining the loss of a solvent in a crystal or the sublimation and decomposition processes of a sample, and can be used to infer the presence of water of crystallization or a crystallization solvent in the crystal. The quality change exhibited by the TGA profile depends on many factors such as sample preparation and instrumentation; the quality of TGA detection varies slightly from instrument to instrument and sample to sample, with a margin of error of + -0.5%. Depending on the instrument conditions used in the test, the mass change introduced by the instrument has a margin of error of + -0.1%.
In the context of the present invention, the 2 theta values in the X-ray powder diffraction pattern are all in degrees (°).
The term "substantially as shown in the figures" means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks in the X-ray powder diffraction pattern or DSC pattern or raman spectrum or infrared spectrum are shown in its figure.
When referring to a spectrogram or/and data appearing in the graph, a "peak" refers to a feature that one skilled in the art can recognize that is not attributable to background noise.
By "substantially pure" is meant that one form is substantially free of the other form or forms, i.e., the purity of the form is at least 80%, or at least 85%, or at least 90%, or at least 93%, or at least 95%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or at least 99.9%, or the form contains less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01% of the total volume or total weight of the forms.
By "substantially free" is meant that the percentage of one or more other crystalline forms in the total volume or weight of the crystalline forms is less than 20%, or less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.
"relative intensity" or "relative peak height" in an X-ray powder diffraction (XRPD) pattern refers to the ratio of the intensity of the first intensity peak to the intensity of the other peaks when the intensity of the first intensity peak is 100% of all diffraction peaks of the X-ray powder diffraction (XRPD) pattern.
In the context of the present invention, when used or whether or not the word "about" or "about" is used, means within 10%, suitably within 5%, particularly within 1% of a given value or range. Alternatively, the term "about" or "approximately" means within an acceptable standard error of the average value to one of ordinary skill in the art. Whenever a number is disclosed having a value of N, any number within the values of N+/-1%, N+/-2%, N+/-3%, N+/-5%, N+/-7%, N+/-8% or N+/-10% will be explicitly disclosed, where "+/-" means plus or minus.
"room temperature" in the present invention means a temperature from about 20℃to about 30 ℃.
Pharmaceutical compositions, formulations, administration and uses of salts and crystalline forms of the compounds of the invention
The pharmaceutical composition of the invention is characterized by comprising a salt of a compound shown in formula (I) or a crystal form of the phosphate of the invention, and a pharmaceutically acceptable carrier, adjuvant or excipient. The amount of the salt of the compound of the pharmaceutical composition of the invention or the crystalline form of the phosphate salt of the invention is effective to detectably treat or reduce a disease associated with HCV infection or hepatitis c disease in a patient.
As described herein, the pharmaceutically acceptable compositions of the present invention further comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, as used herein, including any solvents, diluents, or other liquid excipients, dispersing or suspending agents, surfactants, isotonic agents, thickening agents, emulsifying agents, preservatives, solid binders or lubricants, and the like, suitable for the particular target dosage form. As described in the following documents: in Remington, the Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Dekker,New York, in combination with the teachings of the present document, shows that different carriers can be used In the preparation of pharmaceutically acceptable compositions and their well-known methods of preparation. In addition to the extent to which any conventional carrier vehicle is incompatible with salts of the compounds of the invention or crystalline forms thereof, such as any adverse biological effects produced or interactions with any other component of the pharmaceutically acceptable composition in a deleterious manner, their use is also contemplated by the present invention.
Materials that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum proteins; buffer substances such as phosphates; glycine; sorbic acid; potassium sorbate; a partial glyceride mixture of saturated vegetable fatty acids; water; salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silicon; magnesium trisilicate; polyvinylpyrrolidone; polyacrylate; a wax; polyethylene-polyoxypropylene-block polymers; lanolin; sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; a gum powder; malt; gelatin; talc powder; adjuvants such as cocoa butter and suppository waxes; oils such as peanut oil, cotton seed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycol compounds such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salt; ringer's solution; ethanol; phosphate buffer solution; and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate; a colorant; a release agent; coating the clothing material; a sweetener; a flavoring agent; a perfume; preservatives and antioxidants.
The pharmaceutical compositions of the present invention may be in the form of capsules, tablets, pills, powders, granules and aqueous suspensions or solutions; the administration may be by the following route: oral administration, injection, spray inhalation, topical administration, rectal administration, nasal administration, buccal administration, vaginal administration or administration via an implantable drug cassette.
Oral administration may be in the form of: tablets, pills, capsules, dispersible powders, granules or suspensions, syrups and elixirs and the like; administration by topical means may be by the following forms: ointments, gels, medicated plasters, and the like.
The salts of the invention or crystalline forms thereof are preferably formulated in dosage unit form to reduce the amount and uniformity of dosage administered. The term "dosage unit form" as used herein refers to physically discrete units of medicament for the patient for the appropriate treatment. However, it will be appreciated that the daily total usage of the salts of the compounds of formula (I) of the present invention, or the crystalline forms thereof, or the pharmaceutical compositions of the present invention, will be determined by the attending physician according to the sound judgment of the medical scope. The particular effective dosage level for any particular patient or organism will depend upon a number of factors including the condition being treated and the severity of the condition, the particular composition used, the age, weight, health, sex and dietary habits of the patient, the time of administration, the route of administration and rate of excretion of the salt or crystal form of the particular compound being used, the duration of the treatment, the application of the drug to a combination or combination with a salt or crystal form of the particular compound, and other factors well known in the pharmaceutical arts.
The present invention provides the use of a salt of a compound of the invention or a crystalline form of a salt or a pharmaceutical composition thereof in the manufacture of a medicament useful for inhibiting HCV replication processes and/or inhibiting the function of HCV viral proteins; the HCV replication process includes HCV entry, HCV uncoating, HCV translation, HCV replication, HCV assembly, or HCV release; the HCV viral proteins are selected from the group consisting of metalloproteases, NS2, NS3, NS4A, NS4B, NS A or NS5B, and Internal Ribosome Entry Sites (IRES) and inosine monophosphate dehydrogenase (IMPDH) required for HCV viral replication. Any of the compounds or pharmaceutical compositions of the present invention may be used to treat Hepatitis C Virus (HCV) infection or hepatitis c disease.
The present invention provides a method of treatment comprising administering a salt or a crystalline form of a salt of a compound of the invention or a pharmaceutical composition thereof, further comprising administering to a patient an additional HCV agent whereby the compound of the invention may be treated in combination with the additional anti-HCV agent, wherein the anti-HCV agent is an interferon, ribavirin, interleukin 2, interleukin 6, interleukin 12, a compound that promotes the generation of a type 1 helper T cell response, interfering RNA, antisense RNA, imiqimod, an inosine 5' -monophosphate dehydrogenase inhibitor, amantadine, rimantadine, bavacizumab, hepatitis C immunoglobulin, civacir TM Boprenvir, telarevir, english Jiang Buwei, semaprevir, anapivir, vaniprevir, faldaprevir, danoprevir, sovaprevir, vedroprevir, BZF-961, GS-9256, narlaprevir, ANA975, SH229, GSK-2336805, western Lu Ruiwei, ACH-1095, VX-985, IDX-375, VX-500, VX-813. PHX-1766, PHX-2054, IDX-136, IDX-316, modithromycin, VBY-376, TMC-649128, mericititabine, sofebuvir, INX-189, IDX-184, IDX102, R-1479, UNX-08189, PSI-6130, PSI-938, PSI-879, nesbuvir, HCV-371, VCH-916, lomibrevir, MK-3281, dasabuvir, ABT-072, filibuvir, deleobuvir, tegobuvir, A-837093, JKT-109, gl-59728, GL-60667, TMC647055, ledipal, setrobuvir, alisporivir, BIT-225, ACH-3422, MK-2748, ABP-560, TVB-2640, ID-12 PPI-383, A-848837, RG-7795, BC-2125, alloferon, nivolumab, WF-10, nitazoxanide, multi-feron, nevirapine, ACH-3422, alisporivir, MK-3682, GS-9857, CD-AdNS3, RG-101, MBL-HCV1, CIGB-230, TG-2349, procvax, CB-5300, miravirsen, chronvac-3995-1075, ACH-0143422, WS-007, MK-7680, MK-2248, IDX-21459, MK-8876, GSK-2878175, MBX-700, AL-335, AL-704, SB-9200, ITX-5061 or combinations thereof. Wherein the interferon is interferon alpha-2 b, pegylated interferon alpha, interferon alpha-2 a, pegylated interferon alpha-2 a, consensus interferon alpha, interferon gamma, or a combination thereof.
And a crystalline form or pharmaceutical composition comprising a salt or salt of a compound of the invention, further comprising the administration of an additional anti-HCV agent, wherein the additional anti-HCV agent can be administered in combination with a compound of the invention or a pharmaceutical composition thereof, as a single dosage form, or as part of a multiple dosage form, as separate compounds or pharmaceutical compositions. Other anti-HCV agents can be administered simultaneously with the compounds of the present invention or at different times. In the latter case, the administration may be performed in a staggered manner, for example, for 6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month, or 2 months.
An "effective amount" or "effective dose" of a salt of a compound of the invention or a crystalline or pharmaceutically acceptable composition of the salt refers to an effective amount to treat or reduce the severity of one or more of the conditions mentioned herein. The compounds and compositions according to the methods of the invention can be in any amount and by any route effective for treating or lessening the severity of the disease. The exact amount necessary will vary depending on the patient's condition, the general condition of the patient, the severity of the infection, the particular factors, the mode of administration, and the like. The compound or composition may be administered in combination with one or more other therapeutic agents, as discussed herein.
Drawings
Fig. 1 is an X-ray powder diffraction (XRPD) pattern of form a of the phosphate of formula (IA).
Fig. 2 is a Differential Scanning Calorimetry (DSC) diagram of form a of the phosphate of formula (IA).
Fig. 3 is an X-ray powder diffraction (XRPD) pattern of form B of the phosphate of formula (IA).
Fig. 4 is a Differential Scanning Calorimeter (DSC) diagram of form B of the phosphate salt of formula (IA).
Fig. 5 is a thermal weight loss (TGA) analysis of form B of the phosphate of formula (IA).
Fig. 6 is an X-ray powder diffraction (XRPD) pattern of form D of the phosphate of formula (IA).
Fig. 7 is an X-ray powder diffraction (XRPD) pattern of form E of the phosphate of formula (IA).
Fig. 8 is an X-ray powder diffraction (XRPD) pattern of crystalline form N1 of the phosphate of formula (IA).
Fig. 9 is a Differential Scanning Calorimeter (DSC) diagram of crystal form N1 of the phosphate of formula (IA).
Fig. 10 is a thermal weight loss (TGA) analysis of form N1 of the phosphate of formula (IA).
Fig. 11 is an X-ray powder diffraction (XRPD) pattern of crystalline form N2 of the phosphate of formula (IA).
Fig. 12 is a Differential Scanning Calorimeter (DSC) diagram of crystal form N2 of the phosphate of formula (IA).
FIG. 13 is a graph of thermal weight loss (TGA) analysis of crystalline form N2 of the phosphate salt of formula (IA).
Fig. 14 is an X-ray powder diffraction (XRPD) pattern of crystalline form N5 of the phosphate of formula (IA).
Fig. 15 is a Differential Scanning Calorimeter (DSC) diagram of crystalline form N5 of the phosphate salt of formula (IA).
FIG. 16 is a graph of thermogravimetric analysis (TGA) of crystalline form N5 of the phosphate salt of formula (IA).
Fig. 17 is an X-ray powder diffraction (XRPD) pattern of crystalline form N6 of the phosphate of formula (IA).
Fig. 18 is a Differential Scanning Calorimeter (DSC) diagram of crystalline form N6 of the phosphate salt of formula (IA).
Fig. 19 is a thermal weight loss (TGA) analysis of form N6 of the phosphate of formula (IA).
FIG. 20 is an XRPD pattern for the influencing factors of phosphate form B of formula (IA) of example 18, with the corresponding XRPD patterns at light for 30 days, high humidity for 30 days, high temperature for 30 days and 0 day in order from top to bottom.
FIG. 21 is an XRPD pattern for the phosphate amorphous influence factor of formula (IA) of example 18, with corresponding XRPD patterns at 15 days of light, 15 days of high humidity, 15 days of high temperature, 10 days of light, 10 days of high humidity, 10 days of high temperature, 5 days of light, 5 days of high humidity, 5 days of high temperature and 0 days in that order from top to bottom.
Detailed Description
The invention is further illustrated by way of examples which are not intended to limit the scope of the invention.
The X-ray powder diffraction analysis method used in the invention comprises the following steps: x-ray powder diffraction (XRPD) patterns were collected on a netherlands PANalytical Empyrean X-ray diffractometer equipped with a transmission-reflection sample stage with an automated 3X 15 zero background sample holder. The radiation sources used are (Cu, ka, 1.540598;/>1.544426; kα2/kα1 intensity ratio: 0.50 The voltage is set at 45KV, the current is set at 40 mA.X-ray beam divergence, namely the effective size of X-ray constraint on a sample is 10mm, and a theta-theta continuous scanning mode is adopted, so that an effective 2 theta range of 3-40 DEG is obtained. And taking a proper amount of sample, lightly pressing the sample at the circular groove of the zero background sample frame under the environmental condition (about 18-32 ℃), obtaining a flat plane by using a clean glass slide, and fixing the zero background sample frame. The sample was scanned in 0.0167 ° steps to produce a conventional XRPD pattern with 2θ in the range of (3-40 °) ±0.2°.The software used for Data collection was the Data Collector, and the Data was analyzed and presented with Data Viewer and HighScore Plus. In the X-ray powder diffraction pattern, the ordinate represents the diffraction intensity expressed in terms of a number (counts), and the abscissa represents the diffraction angle 2θ expressed in terms of degrees (°).
The Differential Scanning Calorimeter (DSC) analysis method used in the invention comprises the following steps: differential Scanning Calorimetry (DSC) was performed using a TA Instruments differential scanning calorimeter Q2000. Samples (about 1mg to 3 mg) were placed in an aluminum pan and the weight was accurately recorded. The tray is covered with a cap, then crimped, and the sample is transferred to an instrument for measurement. The cell was equilibrated at 30 ℃ and heated to a final temperature of 300 ℃ at a rate of 10 ℃/min under a nitrogen sweep. In the DSC chart, the abscissa indicates Temperature (DEG C), and the ordinate indicates Heat Flow (Heat Flow, W/g) emitted per unit mass of the substance.
The thermal weight loss (TGA) analysis method used in the invention comprises the following steps: thermogravimetric analysis was performed using a TA Instruments thermogravimetric analyzer Q500, placing an appropriate amount of sample in a platinum sample pan, and heating at a rate of 10 ℃/min under nitrogen at a temperature ranging from 30 to 300 ℃. In the TGA graph, the abscissa represents Temperature (DEG C) and the ordinate represents Weight percent (Weight).
The dynamic vapor adsorption analysis (DVS) analysis method used in the invention comprises the following steps: the method and instrument for testing the isothermal adsorption balance curve of the DVS test: DVS-INTRINSIC, starting from 0% relative humidity, with a change in relative humidity (0% -95.0% -0%) at 25.0 ℃, reaches 95% relative humidity with a 10% step change in relative humidity, and then reaches 0% relative humidity with a 10% step change in relative humidity. Equilibrium is considered to be reached when the absolute value of the change in sample weight per unit time dm/dt is less than 0.1% at a particular relative humidity, and the next relative humidity is entered. And detecting the moisture permeability change condition of the product under the (0% -95.0% -0%) relative humidity circulation condition.
The usage of shorthand words in this specification is as follows:
HCl hydrochloric acid; h 2 SO 4 Sulfuric acid; h 3 PO 4 Phosphoric acid; msOH methane sulfonic acid; PTSA p-toluenesulfonic acid; MA maleic acid; BSA benzenesulfonic acid The method comprises the steps of carrying out a first treatment on the surface of the min; m mol/liter; mmol millimoles; mL of water; h, the time is h; g.
Examples
The compound shown in the formula (I) is obtained by referring to the synthetic method of example 5 in Chinese patent CN 105968101A.
Unless otherwise indicated, each crystal form or amorphous form of the phosphate of the compound represented by formula (I) in the present specification is each crystal form or amorphous form of the phosphate represented by formula (IA) formed by the compound represented by formula (I) and 8/3 molecule phosphoric acid.
The room temperature in this specification is 20℃to 30℃unless otherwise specified.
EXAMPLE 1 Compound of formula (I) & 2H 3 PO 4 Is prepared from
0.50g of the compound of formula (I) (0.559 mmol,1.0 eq) is dissolved in 5mL of ethanol, a mixture of 0.14g of phosphoric acid (1.42 mmol,2.56 eq) and 5mL of ethanol is added dropwise at room temperature, a white solid is precipitated after the dripping, the mixture is stirred at room temperature for 12h and then filtered off with suction, the wet product is dried to obtain 0.60g of a yellowish white solid, and the content of phosphate radical is 18.4% by ion chromatography, which indicates that the compound of formula (I) and two molecules of phosphoric acid form phosphate.
EXAMPLE 2 preparation of Compound of formula (I). 2MsOH
0.50g of the compound of formula (I) (0.559 mmol,1.0 eq) is dissolved in 10mL of ethyl acetate, a mixture of 0.12g of methanesulfonic acid (1.25 mmol,2.24 eq) and 5mL of ethyl acetate is added dropwise at room temperature, a pink solid is precipitated after the dripping, the mixture is stirred at room temperature for 4h and then filtered off with suction, the wet product is dried to obtain 0.60g of pink solid, 1 HNMR shows that it is a mesylate salt of a compound of formula (I) with two molecules of methanesulfonic acid.
1 H NMR(400MHz,CDCl 3 ):δ(ppm)15.00(s,1H),14.80–13.92(m,3H),8.77–8.55(m,1H),7.91(dd,J=40.0,11.9Hz,2H),7.80–7.59(m,2H),7.57–7.33(m,6H),7.21(s,1H),6.13(s,1H),5.62(dd,J=54.2,35.0Hz,1H),5.43(dd,J=13.5,7.0Hz,2H),5.30(d,J=10.5Hz,1H),4.83–4.19(m,2H),3.75(d,J=38.8Hz,2H),3.64(s,3H),3.62–3.38(m,3H),3.30(s,3H),3.23–3.03(m,4H),2.55–2.27(m,9H),2.24–1.90(m,8H),1.71(d,J=59.4Hz,2H),1.42–1.30(m,3H),1.16–0.78(m,6H).
EXAMPLE 3 Compound of formula (I) & 2H 2 SO 4 Is prepared from
0.50g of the compound of formula (I) (0.559 mmol,1.0 eq) was dissolved in 10mL of ethyl acetate, and a mixture of 0.12g of concentrated sulfuric acid (1.22 mmol,2.19 eq) and 10mL of ethyl acetate was added dropwise at room temperature, after the addition, a pink solid was precipitated, stirred at room temperature for 2 hours, and then suction-filtered, and the wet product was dried to give 0.54g of pink solid, and the sulfate content by ion chromatography test was 18%, indicating that it was a sulfate formed by the compound of formula (I) and two molecules of sulfuric acid.
EXAMPLE 4 preparation of Compound 2HCl of formula (I)
0.50g of the compound of formula (I) (0.559 mmol,1.0 eq) was dissolved in 10mL of ethyl acetate, and a mixture of 0.6mL of 2M hydrochloric acid (1.20 mmol,2.14 eq) and 10mL of ethyl acetate was added dropwise at room temperature, after the addition was completed, a pink solid was precipitated, stirred at room temperature for 2 hours, and then suction-filtered, and the wet product was dried to obtain 0.54g of pink solid, and the chlorine content was 8.11% by ion chromatography, indicating that it was hydrochloride formed by the compound of formula (I) and two molecules of hydrochloric acid.
EXAMPLE 5 preparation of Compound 2MA of formula (I)
0.50g of the compound of formula (I) (0.559 mmol,1.0 eq) is dissolved in 10mL of ethyl acetate, a mixture of 142mg of maleic acid (1.22 mmol,2.19 eq) and 5mL of ethyl acetate is added dropwise at-4℃and stirred at room temperature for 20h, and then filtered off with suction, and the wet product is dried to give 0.59g of a pale yellow solid. 1 HNMR indicates that it is the maleate salt of a compound of formula (I) with two molecules of maleic acid.
1 H NMR(400MHz,CDCl 3 ):δ(ppm)8.65(s,1H),7.70(s,1H),7.55–7.28(m,7H),7.02(s,1H),6.79(s,1H),6.39–6.33(m,5H),5.46(dt,J=29.2,25.7Hz,4H),4.76–4.68(m,2H),4.40–4.24(m,1H),4.03–3.81(m,2H),3.73(s,1H),3.69(s,3H),3.50(dd,J=33.7,5.6Hz,4H),3.30(s,3H),3.26(s,1H),3.19(s,2H),3.10(s,2H),2.84–2.73(m,2H),2.39(s,3H),2.28–2.010(m,4H),1.29(d,J=9.0Hz,4H),1.01(d,J=4.2Hz,6H).
EXAMPLE 6 preparation of Compound 2BSA of formula (I)
0.50g of the compound of formula (I) (0.559 mmol,1.0 eq) is dissolved in 10mL of ethyl acetate, a mixture of 194mg of benzenesulfonic acid (1.23 mmol,2.20 eq) and 5mL of ethyl acetate is added dropwise at-4℃and stirred at room temperature for 18h, and then filtered off with suction, and the wet product is dried to give 0.61g of a white solid. 1 HNMR shows that it is a benzenesulfonate salt of a compound of formula (I) with two molecules of benzenesulfonic acid.
1 H NMR(400MHz,CDCl 3 ):δ(ppm)15.03(s,1H),14.80–13.92(m,3H),8.66(s,1H),7.92–7.80(m,6H),7.71(s,1H),7.58–7.29(m,11H),7.02(s,1H),6.79(s,1H),6.35(s,1H),5.43(dt,J=29.2,25.7Hz,4H),4.78–4.70(m,2H),4.46–4.26(m,1H),4.05–3.80(m,2H),3.74(s,1H),3.67(s,3H),3.49(dd,J=33.7,5.6Hz,4H),3.30(s,3H),3.26(s,1H),3.19(s,2H),3.10(s,2H),2.84–2.73(m,2H),2.39(s,3H),2.27–2.08(m,4H),1.27(d,J=9.0Hz,4H),1.02(d,J=4.2Hz,6H).
EXAMPLE 7 preparation of Compound of formula (I) & 2PTSA
0.46g of the compound of formula (I) (0.514 mmol,1.0 eq) is dissolved in 10mL of ethyl acetate, a mixture of 194mg of p-toluenesulfonic acid (1.13 mmol,2.19 eq) and 5mL of ethyl acetate is added dropwise at room temperature, and after the addition, the mixture is directly filtered off with suction, and the wet product is dried to give 0.60g of white solid. 1 HNMR shows that it is a p-toluenesulfonate salt formed by a compound of formula (I) with two molecules of p-toluenesulfonic acid.
1 H NMR(400MHz,CDCl 3 ):δ(ppm)15.08(s,1H),14.81–13.94(m,3H),8.66(s,1H),7.90(d,J=7.8Hz,4H),7.71(s,1H),7.58–7.29(m,7H),7.21(d,J=7.7Hz,4H),7.02(s,1H),6.79(s,1H),6.35(s,1H),5.44(dt,J=29.2,25.7Hz,4H),4.78–4.70(m,2H),4.45–4.24(m,1H),4.04–3.81(m,2H),3.74(s,1H),3.68(s,3H),3.49(dd,J=33.7,5.6Hz,4H),3.30(s,3H),3.26(s,1H),3.19(s,2H),3.10(s,2H),2.84–2.73(m,2H),2.39(s,3H),2.37(s,6H),2.27–2.07(m,4H),1.29(d,J=9.0Hz,4H),1.01(d,J=4.2Hz,6H).
EXAMPLE 8 phosphate salt of formula (IA) (Compound of formula (I). Cndot.8/3H 3 PO 4 ) Is prepared from
3.00g of the compound of formula (I) (3.35 mmol,1.0 eq) are dissolved in 26.7mL of acetone, a mixture of 1.16g of phosphoric acid (10.05 mmol,3.0 eq) and 3.3mL of acetone is added dropwise at room temperature, a white solid is precipitated after the addition, after stirring for 0.5h, 1mL of water is added, and stirring is carried out by heating to 60℃for 24h. After the reaction was cooled to room temperature, it was filtered and dried to obtain 3.50g of a white solid powder. Ion chromatography tests show that the phosphate content is 23.05%, which shows that the phosphate is formed by the compound of the formula (I) and 8/3 molecule phosphoric acid, namely the phosphate shown in the formula (IA).
Example 9 phosphate form B of formula (IA)
1. Preparation of phosphate Crystal form B of formula (IA)
A400 mL glass kettle was charged with 10.01g of a phosphate solid (phosphate represented by formula (IA)), 60mL of acetone and 10mL of water, and the solution was stirred at a stirring speed of 150rpm and a temperature of 55 ℃.40 mL of acetone is added dropwise in 1h, after stirring is carried out for 11h, 200mL of acetone is added dropwise in 12h, after the dropwise addition is finished, the temperature is reduced to 25 ℃ linearly in 4h, all the materials are filtered, and the wet product is dried in vacuum at 60 ℃ for 21h to obtain 9.10g of quasi-white flaky crystal type B solid product.
2. Identification of phosphate form B of formula (IA)
(1) Analysis by Empyrean X-ray powder diffraction (XRPD): using Cu-ka radiation, there are the following characteristic peaks expressed in degrees 2θ:3.49 °,6.40 °,6.89 °,7.33 °,9.15 °,9.87 °,10.24 °,10.77 °,12.16 °,12.72 °,13.44 °,14.65 °,15.20 °,15.40 °,16.22 °,16.83 °,17.21 °,17.58 °,17.94 °,18.64 °,19.58 °,21.11 °,21.91 °,23.24 °,24.35 °,25.65 °,27.05 °, with a margin of error of ±0.2°, the resulting X-ray powder diffraction pattern is substantially as shown in fig. 3.
(2) Analysis by TA Q2000 Differential Scanning Calorimeter (DSC): the ramp rate was 10 c/min and the DSC curve was substantially as shown in figure 4, containing an endothermic peak at 227.22 c with a margin of error of ± 3 c.
(3) Thermogravimetric analysis (TGA) was performed by TA Q500: the temperature ramp rate was 10 c/min and the resulting TGA profile was substantially as shown in fig. 5 with about 1.83% weight loss in the range of 30-150 c with a margin of error of + 0.5%.
EXAMPLE 10 phosphate Crystal form A of formula (IA)
1. Preparation of phosphate Crystal form A of formula (IA)
A100 mL glass bottle was charged with 1.00g of a phosphate solid (phosphate represented by formula (IA)), 3mL of acetone and 1mL of water, heated to 65℃to dissolve it completely, 12mL of acetone was added dropwise, stirred at 65℃for 39 hours, 5mL of acetone was added dropwise, stirred at 65℃for 7 hours, 10mL of acetone was added dropwise, stirred at 65℃for 15 hours, and cooled to room temperature and filtered. The filter cake was rinsed with 5mL of acetone/water (V/v=30/1) solution and dried to give 0.99g of an off-white solid powder having a phosphate content of 22.32% as measured by ion chromatography, indicating that it was crystalline form a of the phosphate of formula (IA).
2. Identification of phosphate form A of formula (IA)
(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, there are the following characteristic peaks expressed in degrees 2θ:3.41 °,6.76 °,7.51 °,8.74 °,9.27 °,10.10 °,10.39 °,12.53 °,13.48 °,14.71 °,15.02 °,16.24 °,16.82 °,17.68 °,18.84 °,20.04 °,20.52 °,20.80 °,21.39 °,21.77 °,22.90 °,23.62 °,23.89 °,24.55 °,24.75 °,26.74 °,27.09 °,27.81 °,28.18 °,30.12 °, there is an error margin of ±0.2°, and the obtained X-ray powder diffraction pattern is substantially as shown in fig. 1.
(2) Identification by TA Q2000 Differential Scanning Calorimeter (DSC) analysis: the heating rate was 10 c/min and the DSC profile was substantially as shown in figure 2, containing an endothermic peak at 225.33 c with a margin of error of ± 3 c.
EXAMPLE 11 phosphate form D of formula (IA)
1. Preparation of phosphate form D of formula (IA)
52mg of the solid of the phosphate crystal form B shown in the formula (IA) is added with 5mL of tetrahydrofuran, stirred for 2 days at 25 ℃, and filtered to obtain 20mg of off-white solid powder of the phosphate crystal form D shown in the formula (IA).
2. Identification of phosphate form D of formula (IA)
Analysis by Empyrean X-ray powder diffraction (XRPD): using Cu-ka radiation, there are the following characteristic peaks expressed in degrees 2θ:3.37 °,6.04 °,6.67 °,9.18 °,10.00 °,13.30 °,15.39 °,16.62 °,18.60 °,19.97 °,20.66 °,21.87 °,23.32 °,23.82 °,25.13 °,25.64 °,26.71 °,27.74 °,30.25 °,33.53 °, with a margin of error of ± 0.2 °, the resulting X-ray powder diffraction pattern is substantially as shown in fig. 6.
EXAMPLE 12 phosphate Crystal form E of formula (IA)
1. Preparation of phosphate Crystal form E of formula (IA)
25mg of phosphate solid (phosphate represented by formula (IA)) was added with 2mL of tetrahydrofuran, stirred at 50℃for 3 days, and filtered to obtain 20mg of an off-white solid powder of phosphate form E represented by formula (IA).
2. Identification of phosphate form E of formula (IA)
Analysis by Empyrean X-ray powder diffraction (XRPD): using Cu-ka radiation, there are the following characteristic peaks expressed in degrees 2θ:3.35 °,6.62 °,9.15 °,12.11 °,15.60 °,16.46 °,17.33 °,18.07 °,20.56 °,22.06 °,22.89 °,23.28 °,23.79 °,25.04 °,25.55 °,30.29 °,33.52 °, there is a margin of error of ±0.2°, the resulting X-ray powder diffraction pattern is substantially as shown in fig. 7.
Example 13 amorphous phosphate salt of formula (IA)
2g of phosphate solid (phosphate crystal form B shown in formula (IA)) and 30mL of methanol are added into a 250mL eggplant-shaped bottle, and after the phosphate solid is dissolved and cleaned at room temperature, amorphous solid of the phosphate shown in formula (IA) is obtained by rotary evaporation at 50 ℃.
EXAMPLE 14 phosphate Crystal form N1 of formula (IA)
1. Preparation of phosphate Crystal form N1 of formula (IA)
1.20g of amorphous solid of phosphate of formula (IA) is added into a 50mL glass bottle, 30mL of 1, 4-dioxane is added, stirring is carried out for 2 days at 50 ℃, all the materials are filtered, and the wet product is dried at room temperature for 1 day to obtain 0.65g of yellow solid powder of phosphate crystal form N1 of formula (IA).
2. Identification of phosphate Crystal form N1 of formula (IA)
(1) Analysis by Empyrean X-ray powder diffraction (XRPD): using Cu-ka radiation, there are the following characteristic peaks expressed in degrees 2θ:6.35 °,7.67 °,8.92 °,10.34 °,12.50 °,13.40 °,16.31 °,17.73 °,19.02 °,20.55 °,22.27 °,23.79 °,24.42 °,25.88 °, there is a margin of error of ±0.2°, and the resulting X-ray powder diffraction pattern is substantially as shown in fig. 8.
(2) Analysis by TA Q2000 Differential Scanning Calorimeter (DSC): the ramp rate was 10 c/min and the DSC curve was substantially as shown in figure 9, containing an endothermic peak at 223.05 c with a margin of error of ± 3 c.
(3) Thermogravimetric analysis (TGA) was performed by TA Q500: the temperature ramp rate was 10 c/min and the resulting TGA profile was substantially as shown in figure 10 with a weight loss of about 6.76% over the 30-193 c range, with a margin of error of + 0.5%.
EXAMPLE 15 preparation of phosphate form N2 of formula (IA)
1. Preparation of phosphate Crystal form N2 of formula (IA)
A100 mL glass bottle was charged with 500mg of a phosphate solid (phosphate form B of formula (IA)), 15mL of 1, 4-dioxane and 1mL of purified water, and the solution was stirred at room temperature. 20mL of 1, 4-dioxane is added dropwise, an oily substance is formed at the bottom, the mixture is stirred at 60 ℃ for 10 hours, then the mixture is stirred in an open way until the solvent volatilizes to half the volume, all the mixture is filtered, and the wet product is dried at room temperature for 1 day to obtain yellowish green solid powder of the phosphate crystal form N2 shown in the formula (IA).
2. Identification of phosphate Crystal form N2 of formula (IA)
(1) Analysis by Empyrean X-ray powder diffraction (XRPD): using Cu-ka radiation, there are the following characteristic peaks expressed in degrees 2θ:6.47 °,7.42 °,8.26 °,8.92 °,10.22 °,12.69 °,14.22 °,14.82 °,15.64 °,16.37 °,17.59 °,19.42 °,20.32 °,20.92 °,22.82 °,23.79 °,24.43 °,25.15 °, there is a margin of error of ±0.2°, the resulting X-ray powder diffraction pattern is substantially as shown in fig. 11.
(2) Analysis by TA Q2000 Differential Scanning Calorimeter (DSC): the ramp rate was 10 c/min and the DSC curve was substantially as shown in figure 12, containing an endothermic peak at 226.28 c with a margin of error of ± 3 c.
(3) Thermogravimetric analysis (TGA) was performed by TA Q500: the temperature rise rate was 10 c/min and the resulting TGA profile was substantially as shown in figure 13 with a weight loss of about 6.99% at 30-212 c with a margin of error of + 0.5%.
EXAMPLE 16 phosphate form N5 of formula (IA)
1. Preparation of phosphate Crystal form N5 of formula (IA)
50mg of a phosphate solid (a phosphate crystal form B shown in a formula (IA)) and 0.1mL of DMF are added into a 5mLEP tube, the mixture is stirred at room temperature to dissolve, 2mL of butanone is added dropwise to precipitate a solid, the mixture is stirred at 60 ℃ for 2 days and filtered, and the wet product is dried at room temperature for 1 day to obtain white solid powder of the phosphate crystal form N5 shown in the formula (IA).
2. Identification of phosphate form N5 of formula (IA)
(1) Analysis by Empyrean X-ray powder diffraction (XRPD): using Cu-ka radiation, there are the following characteristic peaks expressed in degrees 2θ:3.37 °,6.57 °,7.35 °,8.49 °,9.06 °,10.24 °,12.18 °,13.02 °,14.67 °,15.45 °,16.28 °,17.86 °,19.61 °,20.18 °,20.58 °,21.41 °,22.97 °,23.83 °,24.55 °,25.40 °,25.88 °, there is a margin of error of ±0.2°, and the resulting X-ray powder diffraction pattern is substantially as shown in fig. 14.
(2) Analysis by TA Q2000 Differential Scanning Calorimeter (DSC): the ramp rate was 10 c/min and the DSC curve was substantially as shown in figure 15, containing an endothermic peak at 223.05 c with a margin of error of ± 3 c.
(3) Thermogravimetric analysis (TGA) was performed by TA Q500: the temperature ramp rate was 10 c/min and the resulting TGA profile was substantially as shown in figure 16 with a weight loss of about 5.49% over the 30-198 c range, with a margin of error of + 0.5%.
EXAMPLE 17 phosphate form N6 of formula (IA)
1. Preparation of phosphate Crystal form N6 of formula (IA)
A50 mL glass bottle was charged with 400mg of amorphous solid of the phosphate of formula (IA) and 10mL of sec-butanol, and after stirring at 50℃for 2 days, all the solid was filtered to obtain 300mg of white crystalline form N6 of the phosphate of formula (IA).
2. Identification of phosphate Crystal form N6 of formula (IA)
(1) Analysis by Empyrean X-ray powder diffraction (XRPD): using Cu-ka radiation, there are the following characteristic peaks expressed in degrees 2θ:3.38 °,6.60 °,7.43 °,8.52 °,9.07 °,10.25 °,14.55 °,14.89 °,15.63 °,16.49 °,17.05 °,17.63 °,17.97 °,18.58 °,19.78 °,20.44 °,21.50 °,22.75 °,23.17 °,24.48 °,24.85 °,25.57 °,26.27 °,27.39 °,28.02 °,29.39 °,30.87 °, with a margin of error of ±0.2°, the resulting X-ray powder diffraction pattern is substantially as shown in fig. 17.
(2) Analysis by TA Q2000 Differential Scanning Calorimeter (DSC): the ramp rate was 10 c/min and the DSC curve was substantially as shown in figure 18, containing an endothermic peak at 223.74 c with a margin of error of ± 3 c.
(3) Thermogravimetric analysis (TGA) was performed by TA Q500: the temperature ramp rate was 10 c/min and the resulting TGA profile was substantially as shown in figure 19 with a weight loss of about 4.69% over the 30-196 c range, with a margin of error of + 0.5%.
Example 18 influence factor test of phosphate form B and amorphous form of formula (IA)
According to the guiding principle of the stability test of the pharmaceutical preparation, carrying out an influence factor experiment on the crystal form B and the amorphous form of the phosphate shown in the formula (IA), including a high-temperature experiment, a high-humidity experiment and a strong light irradiation experiment, and examining the stability condition affecting the crystal form.
High temperature test: taking appropriate amounts of samples of different crystal forms respectively, spreading the samples in a weighing bottle, placing the weighing bottle in a constant temperature and humidity box with the temperature of 60+/-5 ℃ and the RH of 75+/-5%, and then taking about 10mg of the samples respectively at 5, 10 and/or 15 (or 30) days to test the crystal form condition of the samples.
High humidity test: taking appropriate amounts of samples of different crystal forms respectively, spreading the samples in a weighing bottle, placing the weighing bottle in a constant temperature and humidity box with the RH of 92.5+/-5%, and then taking about 10mg of the samples respectively at 5, 10 and/or 15 (or 30) days to test the crystal form condition of the samples.
Illumination test: respectively taking appropriate amounts of samples with different crystal forms, spreading into a weighing bottle, and collecting visible light 4500 Lux+ -500 Lux and ultraviolet light 1.7w.h/m 2 Is placed under the conditions of constant temperature and humidity (25 ℃ C., RH 60+/-5%) and then the samples are taken for 5, 10 and/or 15 (or 30) days to obtain about 10mg of the samples, and the crystal forms are tested. The experimental results are shown in table 1:
TABLE 1 results of influence factor test of phosphate form B shown by formula (IA) and amorphous phosphate shown by formula (IA)
The results of the phosphate form B and amorphous influencing factor tests of formula (IA) are shown in fig. 20 and 21, respectively. Wherein the crystal form B is kept as the original crystal form under the conditions of high temperature, high humidity and illumination; amorphous forms are also stable and no seeding occurs.
EXAMPLE 19 evaluation of Compounds of formula (I), crystal form B of phosphate of formula (IA) and amorphous pharmacokinetics of phosphate of formula (IA)
Testing amorphous pharmacokinetic data of a compound of formula (I), a crystalline form B of a phosphate of formula (IA) and a phosphate of formula (IA), test methods: the male beagle dogs were orally administered 5mg/kg (calculated as the amount of compound of formula (I)) of test compound via capsules, 5 beagle dogs of each group species were tested, and the test compound was directly filled into capsules for oral administration; blood was collected from the anterior extremity vein at time points (0.25,0.5,1,2.4,6.8 and 24 hours) after administration and collected at EDTA-K addition 2 Is arranged in the anticoagulation tube. Plasma samples were subjected to protein precipitation and centrifugation to obtain supernatants, and then quantitatively analyzed by multiplex reaction ion monitoring (MRM) on a high performance liquid tandem mass spectrometer. Pharmacokinetic parameters were calculated using non-compartmental modeling using WinNonlin 6.3 software. The experimental results are shown in table 2:
TABLE 2 pharmacokinetic parameters of Compounds of formula (I), phosphate Crystal form B of formula (IA) and phosphate amorphous form of formula (IA) in beagle dogs
Compounds of formula (I) | AUC last (h*ng/mL) | C max (ng/mL) | T max (h) |
Phosphate crystal form B of formula (IA) | 3770 | 392 | 2 |
Amorphous phosphate represented by formula (IA) | 1070 | 134 | 2.2 |
A compound of formula (I) | 564 | 75.6 | 2.4 |
Experimental results show that the phosphate crystal form B shown in the formula (IA) and the amorphous phosphate shown in the formula (IA) have higher exposure (AUC) and peak blood concentration (C) in beagle dogs compared with the compound shown in the formula (I) max ) It is illustrated that the phosphate form B of formula (IA) and the phosphate amorphous form of formula (IA) are better absorbed orally than the compound of formula (I).
The above description is merely a basic description of the inventive concept, and any equivalent transformation according to the technical solution of the present invention shall fall within the protection scope of the present invention.
In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.
Claims (13)
1. Salts of the compounds of formula (I),
the salt is phosphate, hydrochloride, sulfate, mesylate, p-toluenesulfonate, maleate and benzenesulfonate.
2. The salt according to claim 1, wherein the molar ratio of the compound of formula (I) to phosphoric acid in the phosphate salt is 1:2 to 1:4.
3. The salt according to claim 2, wherein the molar ratio of the compound of formula (I) to phosphoric acid in the phosphate salt is 1:2 or 1 (8/3).
4. A crystal form B of a phosphate of formula (IA),
characterized in that the X-ray powder diffraction pattern of form B comprises diffraction peaks at the following 2θ angles: 3.49 ° ± 0.2 °,6.89 ° ± 0.2 °,9.15 ° ± 0.2 °,10.24 ° ± 0.2 ° and 12.16 ° ± 0.2 °.
5. Form B according to claim 4, characterized in that the X-ray powder diffraction pattern of form B comprises diffraction peaks at the following 2Θ angles: 3.49 ° ± 0.2 °,6.89 ° ± 0.2 °,7.33 ° ± 0.2 °,9.15 ° ± 0.2 °,10.24 ° ± 0.2 °,10.77 ° ± 0.2 °,12.16 ° ± 0.2 °,13.44 ° ± 0.2 °,14.65 ° ± 0.2 °,15.20 ° ± 0.2 °,16.22 ° ± 0.2 °,17.21 ° ± 0.2 °,17.58 ° ± 0.2 °,17.94 ° ± 0.2 °,18.64 ° ± 0.2 ° and 19.58 ° ± 0.2 °.
6. Form B according to claim 4, characterized in that the X-ray powder diffraction pattern of form B comprises diffraction peaks at the following 2Θ angles: 3.49 ° ± 0.2 °,6.40 ° ± 0.2 °,6.89 ° ± 0.2 °,7.33 ° ± 0.2 °,9.15 ° ± 0.2 °,9.87 ° ± 0.2 °,10.24 ° ± 0.2 °,10.77 ° ± 0.2 °,12.16 ° ± 0.2 °,12.72 ° ± 0.2 °,13.44 ° ± 0.2 °,14.65 ° ± 0.2 °,15.20 ° ± 0.2 °,15.40 ° ± 0.2 °,16.22 ° ± 0.2 °,16.83 ° ± 0.2 °,17.21 ° ± 0.2 °,17.58 ° ± 0.2 °,17.94 ° ± 0.2 °,18.64 ° ± 0.2 °,19.58 ° ± 0.2 °,21.11 ° ± 0.2 °,21.91 ° ± 0.24.24 ° ± 0.2 °,24.35 ° ± 0.2 °,25.65 ° ± 0.2 °, and 25.05 ° ± 0.27 °.
7. Form B according to claim 4, characterized in that it has an X-ray powder diffraction pattern substantially as shown in figure 3.
8. Form B according to claim 4, characterized in that the differential scanning calorimetry pattern of form B comprises an endothermic peak at 227.22 ℃ ± 3 ℃.
9. Form B of claim 4, wherein the form B has a differential scanning calorimeter substantially as shown in fig. 4.
10. An amorphous form of a phosphate of formula (IA),
11. a pharmaceutical composition comprising a salt according to any one of claims 1-3 or crystalline form B of the phosphate according to any one of claims 4-9 or an amorphous form of the phosphate according to claim 10; optionally, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or combination thereof.
12. The pharmaceutical composition of claim 11, further comprising an additional anti-HCV drug; optionally, the additional anti-HCV agent is an interferon, ribavirin, interleukin 2, interleukin 6, interleukin 12, a compound that promotes the generation of a type 1 helper T cell response, interfering RNA, antisense RNA, imiqimod, inosine 5' -monophosphate dehydrogenase inhibitor, amantadine, rimantadine, bavisximab, hepatitis c immunoglobulin, cisacir TM Boprenvir, telarevir, english Jiang Buwei, semepivir, anapivir, vaniprevir, faldaprevir, dannopevir, sovaprevir, vedroprevir, BZF-961, GS-9256, narlaprevir, ANA975, SH229, GSK-2336805, western Lu Ruiwei, ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136, IDX-316, modithromycin, VBY-376, TMC-649128, mericitabine, sofebuvir, INX-189, IDX-184, IDX102, R-1479, UNX-08189, PSI-6130, PSI-938, PSI-879, nesbuvir, HCV-371, VCH-916, lomibuvir, MK-3281, dasabuvir, ABT-072, filibuvir, deleobuvir, tegobuvir, A-837093, JKT-109, gl-59728 GL-60667, TMC647055, ledipasvir, setrobuvir, alisporivir, BIT-225, ACH-3422, MK-2748, ABP-560, TVB-2640, ID-12, PPI-383, A-848837, RG-7795, BC-2125, alloferon, nivolumab, WF-10, nitazoxanide, multiferron, nevirapine, ACH-3422, alisporivir, MK-3682, GS-9857, CD-AdNS3, RG-101, MBL-HCV1, CIGB-230, TG-2349, procvax, CB-5300, miravirsen, chronvac-C, MK-1075, ACH-0143422, WS-007, MK-7680, MK-2248, IDX-21459, MK-8876, GSK-2878175, MBX-700, AL-335, AL-704, SB-9200, ITX-5061 or combinations thereof; the interferon is interferon alpha-2 b, pegylated interferon alpha, interferon alpha-2 a, pegylated interferon alpha-2 a, consensus interferon, interferon gamma, or a combination thereof.
13. Use of a salt according to any one of claims 1-3, or form B of a phosphate according to any one of claims 4-9, or an amorphous form of a phosphate according to claim 10, or a pharmaceutical composition according to any one of claims 11-12, for the manufacture of a medicament for the prevention, treatment or alleviation of a disease associated with HCV infection or a hepatitis c disease.
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