CA2907455A1

CA2907455A1 - Alkyl 2-{[(2r,3s,5r)-5-(4-amino-2-oxo-2h-pyrimidin-1-yl)-3-hydroxy-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionates, nucleoside inhibitors of hcv rna-polymerase ns5b, methods for preparation and use thereof

Alkyl 2-{[(2r,3s,5r)-5-(4-amino-2-oxo-2h-pyrimidin-1-yl)-3-hydroxy-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionates, nucleoside inhibitors of hcv rna-polymerase ns5b, methods for preparation and use thereof

Info

Publication number: CA2907455A1
Authority: CA; Canada
Prior art keywords: furan; oxo; phenoxy; tetrahydro; pyrimidin
Prior art date: 2013-03-22
Legal status : Abandoned

Application number

CA2907455A

Other languages

English (en)

French (fr)

Inventor

Alexandre Vasilievich IVACHTCHENKO

Current Assignee

ASAVI LLC

Original Assignee

ASAVI LLC

Priority date

2013-03-22

Filing date

2014-02-19

Publication date

2014-09-25

2014-02-19 Application filed by ASAVI LLC filed Critical ASAVI LLC

2014-09-25 Publication of CA2907455A1 publication Critical patent/CA2907455A1/en

Status Abandoned legal-status Critical Current

Links

239000003112 inhibitor Substances 0.000 title claims description 82
-1 Alkyl 2-{[(2r,3s,5r)-5-(4-amino-2-oxo-2h-pyrimidin-1-yl)-3-hydroxy-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionates Chemical class 0.000 title claims description 59
239000002777 nucleoside Substances 0.000 title claims description 48
150000003833 nucleoside derivatives Chemical class 0.000 title claims description 41
108090000626 DNA-directed RNA polymerases Proteins 0.000 title claims description 37
102000004163 DNA-directed RNA polymerases Human genes 0.000 title claims description 37
238000000034 method Methods 0.000 title claims description 37
238000002360 preparation method Methods 0.000 title claims description 22
101710112514 Host translation inhibitor 5b Proteins 0.000 title 1
150000001875 compounds Chemical class 0.000 claims abstract description 96
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 52
150000003839 salts Chemical class 0.000 claims abstract description 45
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 33
239000001257 hydrogen Substances 0.000 claims abstract description 32
239000012453 solvate Substances 0.000 claims abstract description 29
150000004677 hydrates Chemical class 0.000 claims abstract description 23
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 15
229910052736 halogen Chemical group 0.000 claims abstract description 9
150000002367 halogens Chemical group 0.000 claims abstract description 9
125000001153 fluoro group Chemical group F* 0.000 claims abstract description 7
125000006823 (C1-C6) acyl group Chemical group 0.000 claims abstract description 6
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 3
150000002431 hydrogen Chemical class 0.000 claims abstract 15
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 177
238000011282 treatment Methods 0.000 claims description 37
101800001554 RNA-directed RNA polymerase Proteins 0.000 claims description 32
239000008194 pharmaceutical composition Substances 0.000 claims description 32
VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 28
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
239000003814 drug Substances 0.000 claims description 24
208000005176 Hepatitis C Diseases 0.000 claims description 22
201000010099 disease Diseases 0.000 claims description 13
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 13
230000003993 interaction Effects 0.000 claims description 12
108091005804 Peptidases Proteins 0.000 claims description 11
239000004365 Protease Substances 0.000 claims description 11
102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 claims description 11
PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 10
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 10
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 9
238000011321 prophylaxis Methods 0.000 claims description 9
229960002063 sofosbuvir Drugs 0.000 claims description 9
239000002253 acid Substances 0.000 claims description 8
208000036142 Viral infection Diseases 0.000 claims description 7
230000009385 viral infection Effects 0.000 claims description 7
241000700605 Viruses Species 0.000 claims description 6
108010087227 IMP Dehydrogenase Proteins 0.000 claims description 5
102000006674 IMP dehydrogenase Human genes 0.000 claims description 5
101800001014 Non-structural protein 5A Proteins 0.000 claims description 5
239000007924 injection Substances 0.000 claims description 5
238000002347 injection Methods 0.000 claims description 5
229960002118 asunaprevir Drugs 0.000 claims description 4
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 description 4
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 4
230000001747 exhibiting effect Effects 0.000 claims description 4
230000002401 inhibitory effect Effects 0.000 claims description 3
239000000725 suspension Substances 0.000 claims description 3
YGDVHHLCSRUOEQ-CRJAGRCWSA-N CN(CC(=O)NC1=NC(N(C=C1)[C@H]1[C@@]([C@@H]([C@H](O1)COC1=C(OP(=O)=N[C@@H](C(=O)OC(C)C)C)C=CC=C1)O)(F)C)=O)C Chemical compound CN(CC(=O)NC1=NC(N(C=C1)[C@H]1[C@@]([C@@H]([C@H](O1)COC1=C(OP(=O)=N[C@@H](C(=O)OC(C)C)C)C=CC=C1)O)(F)C)=O)C YGDVHHLCSRUOEQ-CRJAGRCWSA-N 0.000 claims description 2
150000008064 anhydrides Chemical class 0.000 claims description 2
239000002674 ointment Substances 0.000 claims description 2
238000004806 packaging method and process Methods 0.000 claims description 2
229960002091 simeprevir Drugs 0.000 claims description 2
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 2
YGDVHHLCSRUOEQ-PEFCGTTCSA-N CN(CC(=O)NC1=NC(N(C=C1)[C@H]1[C@@]([C@@H]([C@H](O1)COC1=C(OP(=O)=N[C@H](C(=O)OC(C)C)C)C=CC=C1)O)(F)C)=O)C Chemical compound CN(CC(=O)NC1=NC(N(C=C1)[C@H]1[C@@]([C@@H]([C@H](O1)COC1=C(OP(=O)=N[C@H](C(=O)OC(C)C)C)C=CC=C1)O)(F)C)=O)C YGDVHHLCSRUOEQ-PEFCGTTCSA-N 0.000 claims 1
LAVPGHVYQMUUGT-AOWSIMJJSA-N CN1[C@@H](CCC1)C(=O)O[C@H]1[C@H](O[C@H](C1(F)F)N1C(N=C(C=C1)N)=O)C(N=P(=O)OC1=CC=CC=C1)N[C@@H](C)C(=O)OC(C)C Chemical compound CN1[C@@H](CCC1)C(=O)O[C@H]1[C@H](O[C@H](C1(F)F)N1C(N=C(C=C1)N)=O)C(N=P(=O)OC1=CC=CC=C1)N[C@@H](C)C(=O)OC(C)C LAVPGHVYQMUUGT-AOWSIMJJSA-N 0.000 claims 1
239000000499 gel Substances 0.000 claims 1
125000000266 alpha-aminoacyl group Chemical group 0.000 abstract 2
229910052731 fluorine Inorganic materials 0.000 abstract 2
239000011737 fluorine Substances 0.000 abstract 2
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 abstract 1
241000711549 Hepacivirus C Species 0.000 description 78
125000000547 substituted alkyl group Chemical group 0.000 description 37
125000001424 substituent group Chemical group 0.000 description 30
210000004027 cell Anatomy 0.000 description 28
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
125000000623 heterocyclic group Chemical group 0.000 description 24
239000000243 solution Substances 0.000 description 22
125000003118 aryl group Chemical group 0.000 description 21
239000000203 mixture Substances 0.000 description 19
239000003826 tablet Substances 0.000 description 19
101100063435 Caenorhabditis elegans din-1 gene Proteins 0.000 description 18
125000001072 heteroaryl group Chemical group 0.000 description 18
125000004435 hydrogen atom Chemical class [H]* 0.000 description 17
239000008187 granular material Substances 0.000 description 16
238000004895 liquid chromatography mass spectrometry Methods 0.000 description 16
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical class CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 15
125000004122 cyclic group Chemical group 0.000 description 15
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
239000003795 chemical substances by application Substances 0.000 description 14
125000000217 alkyl group Chemical group 0.000 description 13
108010050904 Interferons Proteins 0.000 description 12
102000014150 Interferons Human genes 0.000 description 12
RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 12
230000000840 anti-viral effect Effects 0.000 description 12
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 11
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
239000011449 brick Substances 0.000 description 10
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 10
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 9
238000002648 combination therapy Methods 0.000 description 9
LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 9
229940079322 interferon Drugs 0.000 description 9
125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 9
239000002953 phosphate buffered saline Substances 0.000 description 9
UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
241000710781 Flaviviridae Species 0.000 description 8
125000004432 carbon atom Chemical group C* 0.000 description 8
229940079593 drug Drugs 0.000 description 8
125000003835 nucleoside group Chemical group 0.000 description 8
108091032973 (ribonucleotides)n+m Proteins 0.000 description 7
CWLQUGTUXBXTLF-YFKPBYRVSA-N N-methylproline Chemical compound CN1CCC[C@H]1C(O)=O CWLQUGTUXBXTLF-YFKPBYRVSA-N 0.000 description 7
230000003013 cytotoxicity Effects 0.000 description 7
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238000004128 high performance liquid chromatography Methods 0.000 description 7
208000015181 infectious disease Diseases 0.000 description 7
230000005764 inhibitory process Effects 0.000 description 7
239000008101 lactose Substances 0.000 description 7
IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
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SZXBQTSZISFIAO-ZETCQYMHSA-N (2s)-3-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoic acid Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)OC(C)(C)C SZXBQTSZISFIAO-ZETCQYMHSA-N 0.000 description 6
LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
229920002472 Starch Polymers 0.000 description 6
230000009471 action Effects 0.000 description 6
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238000005160 1H NMR spectroscopy Methods 0.000 description 5
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 description 5
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239000000377 silicon dioxide Substances 0.000 description 5
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LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
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239000007832 Na2SO4 Substances 0.000 description 4
GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
235000001014 amino acid Nutrition 0.000 description 4
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QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
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238000004020 luminiscence type Methods 0.000 description 4
CKFGINPQOCXMAZ-UHFFFAOYSA-N methanediol Chemical compound OCO CKFGINPQOCXMAZ-UHFFFAOYSA-N 0.000 description 4
125000001624 naphthyl group Chemical group 0.000 description 4
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229910052760 oxygen Chemical group 0.000 description 4
239000001301 oxygen Chemical group 0.000 description 4
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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 description 4
239000012047 saturated solution Substances 0.000 description 4
235000017557 sodium bicarbonate Nutrition 0.000 description 4
229910052938 sodium sulfate Inorganic materials 0.000 description 4
235000011152 sodium sulphate Nutrition 0.000 description 4
238000007920 subcutaneous administration Methods 0.000 description 4
125000005017 substituted alkenyl group Chemical group 0.000 description 4
238000003786 synthesis reaction Methods 0.000 description 4
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
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IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
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238000005481 NMR spectroscopy Methods 0.000 description 3
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
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TVRCRTJYMVTEFS-ICGCPXGVSA-N [(2r,3r,4r,5r)-5-(4-amino-2-oxopyrimidin-1-yl)-4-hydroxy-2-(hydroxymethyl)-4-methyloxolan-3-yl] (2s)-2-amino-3-methylbutanoate Chemical compound C[C@@]1(O)[C@H](OC(=O)[C@@H](N)C(C)C)[C@@H](CO)O[C@H]1N1C(=O)N=C(N)C=C1 TVRCRTJYMVTEFS-ICGCPXGVSA-N 0.000 description 3
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MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 2
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