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1. (WO2018160088) NUCLEOTIDES CONTAINING AN N-[(S)-1-CYCLOBUTOXYCARBONYL]PHOSPHORAMIDATE FRAGMENT, ANALOGS THEREOF, AND USE THEREOF
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Pub. No.: WO/2018/160088 International Application No.: PCT/RU2017/000209
Publication Date: 07.09.2018 International Filing Date: 07.04.2017
IPC:
C07H 19/10 (2006.01) ,C07H 19/20 (2006.01) ,C07F 9/36 (2006.01) ,C07F 9/44 (2006.01) ,C07F 9/6561 (2006.01) ,A61K 31/7076 (2006.01) ,A61K 31/7072 (2006.01) ,A61K 31/708 (2006.01) ,A61K 31/664 (2006.01) ,A61K 31/675 (2006.01) ,A61P 31/20 (2006.01) ,A61P 31/18 (2006.01)
C CHEMISTRY; METALLURGY
07
ORGANIC CHEMISTRY
H
SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
19
Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro derivatives thereof
02
sharing nitrogen
04
Heterocyclic radicals containing only nitrogen as ring hetero atom
06
Pyrimidine radicals
10
with the saccharide radical being esterified by phosphoric or polyphosphoric acids
C CHEMISTRY; METALLURGY
07
ORGANIC CHEMISTRY
H
SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
19
Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro derivatives thereof
02
sharing nitrogen
04
Heterocyclic radicals containing only nitrogen as ring hetero atom
16
Purine radicals
20
with the saccharide radical being esterified by phosphoric or polyphosphoric acids
C CHEMISTRY; METALLURGY
07
ORGANIC CHEMISTRY
F
ACYCLIC, CARBOCYCLIC, OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
9
Compounds containing elements of the 5th Group of the Periodic System
02
Phosphorus compounds
28
with one or more P-C bonds
30
Phosphinic acids (R2P(:O)OH); Thiophosphinic acids
36
Amides thereof
C CHEMISTRY; METALLURGY
07
ORGANIC CHEMISTRY
F
ACYCLIC, CARBOCYCLIC, OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
9
Compounds containing elements of the 5th Group of the Periodic System
02
Phosphorus compounds
28
with one or more P-C bonds
38
Phosphonic acids (R-P(:O)(OH)2); Thiophosphonic acids
44
Amides thereof
C CHEMISTRY; METALLURGY
07
ORGANIC CHEMISTRY
F
ACYCLIC, CARBOCYCLIC, OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
9
Compounds containing elements of the 5th Group of the Periodic System
02
Phosphorus compounds
547
Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
6561
containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
A HUMAN NECESSITIES
61
MEDICAL OR VETERINARY SCIENCE; HYGIENE
K
PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31
Medicinal preparations containing organic active ingredients
70
Carbohydrates; Sugars; Derivatives thereof
7042
Compounds having saccharide radicals and heterocyclic rings
7052
having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
706
containing six-membered rings with nitrogen as a ring hetero atom
7064
containing condensed or non-condensed pyrimidines
7076
containing purines, e.g. adenosine, adenylic acid
A HUMAN NECESSITIES
61
MEDICAL OR VETERINARY SCIENCE; HYGIENE
K
PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31
Medicinal preparations containing organic active ingredients
70
Carbohydrates; Sugars; Derivatives thereof
7042
Compounds having saccharide radicals and heterocyclic rings
7052
having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
706
containing six-membered rings with nitrogen as a ring hetero atom
7064
containing condensed or non-condensed pyrimidines
7068
having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
7072
having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
A HUMAN NECESSITIES
61
MEDICAL OR VETERINARY SCIENCE; HYGIENE
K
PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31
Medicinal preparations containing organic active ingredients
70
Carbohydrates; Sugars; Derivatives thereof
7042
Compounds having saccharide radicals and heterocyclic rings
7052
having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
706
containing six-membered rings with nitrogen as a ring hetero atom
7064
containing condensed or non-condensed pyrimidines
7076
containing purines, e.g. adenosine, adenylic acid
708
having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
A HUMAN NECESSITIES
61
MEDICAL OR VETERINARY SCIENCE; HYGIENE
K
PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31
Medicinal preparations containing organic active ingredients
66
Phosphorus compounds
664
Amides of phosphorus acids
A HUMAN NECESSITIES
61
MEDICAL OR VETERINARY SCIENCE; HYGIENE
K
PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31
Medicinal preparations containing organic active ingredients
66
Phosphorus compounds
675
having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
A HUMAN NECESSITIES
61
MEDICAL OR VETERINARY SCIENCE; HYGIENE
P
SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
31
Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
12
Antivirals
20
for DNA viruses
A HUMAN NECESSITIES
61
MEDICAL OR VETERINARY SCIENCE; HYGIENE
P
SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
31
Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
12
Antivirals
14
for RNA viruses
18
for HIV
Applicants:
ИВАЩЕНКО, Александр Васильевич IVACHTCHENKO, Alexandrе Vasilievich [US/US]; US
ИВАЩЕНКО, Андрей Александрович IVASHCHENKO, Andrey Alexandrovich [RU/RU]; RU
ИВАЩЕНКО, Алена Александровна IVACHTCHENKO, Alena Alexandrovna [US/US]; US
САВЧУК, Николай Филиппович SAVCHUK, Nikolay Filippovich [US/US]; US
АЛЛА ХЕМ, ЛЛС ALLA CHEM, LLC [US/US]; 1835 Е. Халландале Беач Блад 442, Халландале Беач Флорида, 1835 E. Hallandale Bch Blvd 442, Hallandale Beach Florida, 33009, US
Inventors:
ИВАЩЕНКО, Александр Васильевич IVACHTCHENKO, Alexandrе Vasilievich; US
МИТЬКИН, Олег Дмитриевич MITKIN, Oleg Dmitrievich; RU
Priority Data:
201710661128.02.2017RU
Title (EN) NUCLEOTIDES CONTAINING AN N-[(S)-1-CYCLOBUTOXYCARBONYL]PHOSPHORAMIDATE FRAGMENT, ANALOGS THEREOF, AND USE THEREOF
(FR) NUCLÉOTIDES CONTENANT UN FRAGMENT DE N-[(S)-1-CYCLOBUTOXYCARBONYL]PHOSPHORAMIDATE, ANALOGUES ET UTILISATION
(RU) НУКЛЕОТИДЫ, ВКЛЮЧАЮЩИЕ N-[(S)-1-ЦИКЛОБУТОКСИКАРБОНИЛ]ФОСФОРАМИДАТНЫЙ ФРАГМЕНТ, ИХ АНАЛОГИ И ИХ ПРИМЕНЕНИЕ
Abstract:
(EN) The present invention relates to a prodrug and the use thereof to treat patients suffering from viral and cancerous diseases. The present prodrug provides inhibition of NS5B HCV polymerase, HBV DNA polymerase and HIV-1 reverse transcriptase (RT), and also treatment of hepatitis B and C infections in mammals. Claimed are prodrugs of general formula 1 and their stereoisomers, as well as isotopically enriched analogs, and pharmaceutically acceptable salts, hydrates, solvates or crystalline or polycrystalline forms of prodrugs of general formula 1 and their stereoisomers, where: n is 1 or 0: Nuc is (II) or (III); R1 is hydrogen or methyl; R2, R3 are optionally identical substituents selected from Н, F, Cl, СН3, ОН on condition that the continuous line and the accompanying broken line (IV) together represent a single carbon-carbon bond (C-C), or R2 and R3 are hydrogen on condition that the continuous line and the accompanying broken line (IV) together represent a double carbon-carbon bond (C=C); X is О, СН2 or С=СН2, and Y is О, S, CH2 or an НО-СН group on condition that the continuous line and the accompanying broken line (IV) together represent a single carbon-carbon bond (C-C), or Y is a CH group on condition that the continuous line and the accompanying broken line (IV) together represent a double carbon-carbon bond (C=C).
(FR) La présente invention concerne un pro-médicament et son utilisation pour traiter des affections virales et cancéreuses chez des patients. Ce pro-médicament assure l'inhibition de NS5B HCV polymérase HBV, de polymérase ADN et de transcriptase inverse de VIH-1 (RT) ainsi que le traitement d'infections par hépatite B et C chez les mammifères. L'invention concerne un pro-médicament correspondant à la formule générale 1 ainsi que ses stéréoisomères, ainsi que des analogues enrichis en isotopes, leurs sels, hydrates, solvates ou formes cristallines ou polycristallines pharmaceutiquement acceptables de pro-médicaments de la formule générale 1 et leurs stéréoisomères (I) où: n a une velru de 1 ou 0; Nuc représente (II) ou (III) R1 représente hydrogène ou méthyle; R2, R3 représentent des substituants non obligatoirement identiques choisis parmi Н, F, Cl, СН3, ОН dans des conditions où la ligne pleine et la ligne en pointillé l'accompagnant (IV) représentent ensemble une liaison carbone-cabrone (C-C) simple, ou R2 et R3 représentent hydrogène dans des conditions où la ligne pleine et la ligne en pointillé l'accompagnant (IV) représentent ensemble une liaison carbone-cabrone (C=C) double; X reprlsente O, СН2 ou С=СН2, Y représente О, S, CH2 ou un groupe НО-СН dans des conditions où la ligne continue et la ligne en pointillé l'accompagnant (IV) représentent ensemble une liaison carbone-cabrone (C-C) , ou Y représente un groupe CH dans des conditions où la ligne pleine et la ligne en pointillé l'accompagnant (IV) représentent ensemble une liaison carbone-cabrone (C=C) double.
(RU) Настоящее изобретение относится к пролекарству и применению его для лечения у пациентов вирусных и раковых заболеваний. Это пролекарство обеспечивает ингибирование NS5B HCV полимеразы HBV, ДНК-полимеразы и ВИЧ-1 обратной транскриптазы (RT), а также лечение гепатита В и С-инфекции у млекопитающих. Пролекарства общей формулы 1 и их стереоизомеры, а также изотопно-обогащенные аналоги, их фармацевтически приемлемые соли, гидраты, сольваты или кристаллические или поликристаллические формы пролекарств общей формулы 1 и их стереоизомеров, (l) где: n имеет значение 1 или 0; Nuс представляет собой (ll) или (lll) R1 представляет собой водород или метил; R2, R3 представляют собой необязательно одинаковые заместители, выбранные из Н, F, Cl, СН3, ОН при условии, когда сплошная линия и сопровождающая ее пунктирная линия (IV) вместе представляют одинарную углерод-углеродную (С-С) связь, или R2 и R3 представляют собой водород при условии, когда сплошная линия и сопровождающая ее пунктирная линия (IV) вместе представляют собой двойную углерод-углеродную связь (С=С); Х представляет собой О, СН2 или С=СН2, Y представляет собой О, S, CH2 или НО-СН-группу при условии, когда непрерывная линия и сопровождающая ее пунктирная линия (IV) вместе представляют собой одинарную углерод-углеродную (С-С) связь, или Y представляет собой СН-группу при условии, когда сплошная линия и сопровождающая ее пунктирная линия (IV) вместе представляют собой двойную углерод-углеродную связь (С=С).
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African Regional Intellectual Property Organization (ARIPO) (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW)
Eurasian Patent Office (AM, AZ, BY, KG, KZ, RU, TJ, TM)
European Patent Office (EPO) (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR)
African Intellectual Property Organization (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG)
Publication Language: Russian (RU)
Filing Language: Russian (RU)