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CN116217621B - Nucleoside double-prodrug, synthesis method and application - Google Patents

Nucleoside double-prodrug, synthesis method and application Download PDF

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CN116217621B
CN116217621B CN202310462437.6A CN202310462437A CN116217621B CN 116217621 B CN116217621 B CN 116217621B CN 202310462437 A CN202310462437 A CN 202310462437A CN 116217621 B CN116217621 B CN 116217621B
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coronavirus
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prodrug
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CN116217621A (en
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李小林
齐龙武
许树森
路培超
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Beijing Muhua Biotechnology Co ltd
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom 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
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    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
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Abstract

The present invention provides a nucleoside dual prodrug having significant anti-coronavirus (e.g., human coronavirus OC43, human coronavirus 229E, feline coronavirus FIPV) activity. Wherein the half-effective concentration and 90% effective concentration of the nucleoside dual prodrug for human coronavirus OC43 can be as low as 0.05 μM and 0.38 μM, and the half-effective concentration and 90% effective concentration for human coronavirus 229E can be as low as 0.15 μM and 0.69 μM. Meanwhile, the nucleoside double-prodrug has good oral bioavailability and has therapeutic effect on target tissues (lung).

Description

Nucleoside double-prodrug, synthesis method and application
Technical Field
The invention relates to the field of medicines, in particular to a nucleoside double-prodrug, a synthesis method and application.
Background
Coronaviruses belong to the order of the family Coronaviridae, genus Coronavirales, and are a large class of single-stranded positive-strand RNA viruses that are widely available in nature.
Coronaviruses can also infect a variety of mammals, such as bats, pigs, dogs, cats, mice, cattle, horses, camels, etc., and can cause multiple system diseases including the respiratory tract, digestive tract, and nervous system.
The novel coronavirus (SARS-CoV-2) or the novel coronavirus (SARS-COV-2) with different degrees of symptoms appears in patients with the novel coronavirus (SARS-CoV-2) has the characteristics of long incubation period, strong infectivity and higher serious disease rate. Thus, there is an urgent need in the art to develop inhibitors of viral replication for the treatment of related diseases caused by viral infections.
Disclosure of Invention
In order to solve the technical problems, the invention provides a nucleoside double prodrug, a synthesis method thereof and application thereof in resisting novel coronaviruses.
In a first aspect, the present invention provides a compound of formula (I), stereoisomers, tautomers, isotopic labels, nitroxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs thereof:
wherein each R 1 Identical or different, independently of one another, from unsubstituted or optionally substituted by one, two or more R' s 1a substituted-C 1-20 alkyl-X-CO-X-C 1-20 Alkyl, X is selected from CH 2 O, S or Se; each R 2 Identical or different, independently of one another, from H, unsubstituted or optionally substituted by one, two or more R 1a Substituted with the following groups: -CO-C 1-20 Alkyl, -CO-C 3-20 Cycloalkyl, -CO-C 3-20 Heterocyclylalkyl, -CO-C 6-20 Aryl, -CO-C 5-20 Heteroaryl, -CO-C 6-20 aryl-SO 2 -N-(C 1-20 Alkyl group 2 ；R 1a Independently selected from C 1-10 Alkyl, halogen, hydroxy, cyano, nitro, amino; with the proviso that when R 1 Are all selected fromWhen R is 2 The non-uniformity is H;Representing the attachment site of the group.
According to an embodiment of the invention, each R 1 Identical or different, independently of one another, from unsubstituted or optionally substituted by one, two or more R' s 1a substituted-C 1-10 alkyl-X-CO-X-C 1-10 Alkyl, X is selected from CH 2 O, S or Se.
According to an embodiment of the invention, each R 2 Identical or different, independently of one another, from H, unsubstituted or optionally substituted by one, two or more R 1a Substituted with the following groups: -CO-C 1-10 Alkyl, -CO-C 3-10 Cycloalkyl, -CO-C 3-10 Heterocyclylalkyl, -CO-C 6-10 Aryl, -CO-C 5-10 Heteroaryl, -CO-C 6-10 aryl-SO 2 -N-(C 1-10 Alkyl group 2 ；R 1a Independently selected from C 1-6 Alkyl, halogen, hydroxy, cyano, nitro, amino.
According to an embodiment of the invention, each R 1 Identical or different, independently of one another, from unsubstituted or optionally substituted by one, two or more R' s 1a substituted-C 1-6 alkyl-X-CO-X-C 1-6 Alkyl, X is selected from CH 2 O, S or Se.
According to an embodiment of the invention, each R 2 Identical or different, independently of one another, from H, unsubstituted or optionally substituted by one, two or more R 1a Substituted with the following groups: -CO-C 1-8 Alkyl, -CO-C 3-6 Cycloalkyl, -CO-C 3-6 Heterocyclylalkyl, -CO-C 6-8 Aryl, -CO-C 5-8 Heteroaryl, -CO-C 6-8 aryl-SO 2 -N-(C 1-6 Alkyl group 2 ；R 1a Independently selected from C 1-6 Alkyl, halogen, hydroxy, cyano, nitro, amino.
According to an embodiment of the invention, R 1 Is that、Or->，Representing the attachment site of the group.
According to the implementation of the inventionScheme, each R 2 Identical or different, independently of one another, from H, unsubstituted or optionally substituted by one, two or more R 1a Substituted with the following groups: -CO-methyl, -CO-isopropyl, -CO-tert-butyl, -CO-CH- (CH) 2 CH 2 CH 3 ) 2 -CO-cyclopentylalkyl, -CO-tetrahydropyrrolyl, -CO-pyridinyl, -CO-phenyl-SO 2 -N-(CH 2 CH 2 CH 3 ) 2 ；R 1a Independently selected from C 1-3 Alkyl, halogen, hydroxy, cyano, nitro, amino.
According to an embodiment of the invention, two R in the compound of formula (I) 1 Identical and is。
According to an embodiment of the invention, two R in the compound of formula (I) 2 The same applies.
According to an embodiment of the invention, the compound of formula (I) is selected from the following compounds:
、、、、、、or->。
In a second aspect, the present invention provides a process for the preparation of a compound of formula (I), stereoisomers, tautomers, isotopic labels, nitroxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs thereof, comprising at least the steps of:
(S1) Compound 3 in POCl 3 、PO(OMe) 3 And buffer solution, reacting to obtain a compound 4;
(S2) Compound 4 in Ag in solvent 2 CO 3 Reacting in the presence of a catalyst to obtain a compound 5;
(S3) Compound 5 in solvent with R 1 -Y、R 2 -OH to give a compound of formula (I);
y is a leaving group, such as halogen;
the reaction formula is:
；
wherein R is 1 、R 2 Is defined herein for compounds of formula (I).
According to an embodiment of the present invention, in step (S1), the buffer is TEAB buffer; and/or, in step (S2), the solvent is water/acetonitrile; and/or, in step (S3), the solvent is NMP.
The preparation process of the present invention may select appropriate reaction conditions and starting materials according to each case, may, for example, replace only one substituent with another substituent according to the present invention in one reaction step, or may replace a plurality of substituents with other substituents according to the present invention in the same reaction step.
According to an embodiment of the present invention, after the reaction is completed, the reaction product may be isolated and purified by conventional technical means such as preparative HPLC, preparative TLC or recrystallization by treating the reaction product with a conventional post-treatment method.
In a third aspect, the present invention provides a pharmaceutical composition comprising one, two or more of a compound represented by the above formula (I), a stereoisomer, a tautomer, an isotopic label, a nitroxide, a solvate, a polymorph, a metabolite, an ester, a pharmaceutically acceptable salt, a prodrug thereof.
According to an embodiment of the invention, the pharmaceutical composition may optionally further comprise at least one pharmaceutically acceptable excipient.
According to an embodiment of the invention, the pharmaceutical composition may optionally further comprise at least one additional active ingredient; specifically, the pharmaceutical composition may further comprise one or more active ingredients other than the compound represented by formula (I), stereoisomers, tautomers, isotopic labels, nitroxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts, prodrugs thereof.
Active ingredients, such as other antiviral drugs: remdesivir (Rehdesivir or GS-5734), fadipiravir (favipiravir), galidesivir, GS-441524, NHC, EIDD-2801, lopinavir (Lopinavir), ritonavir (Ritonavir), fadipiravir, chloroquine (Chloroquine), hydroxychloroquine (hydroxychloroquine), chloroquine phosphate, nelfinavir (Nelfinavir).
In the pharmaceutical composition, the dosage of the compound shown as the formula (I), pharmaceutically acceptable salts, solvates, polymorphs, metabolites, stereoisomers, tautomers, isotopic labels, nitrogen oxides, esters and prodrugs thereof can be a therapeutically effective amount.
According to an embodiment of the invention, the pharmaceutical composition is used for the prevention and/or treatment of diseases associated with infection by RNA viruses, e.g. orthomyxoviruses or paramyxoviruses, such as coronaviruses, respiratory syncytial virus, RSV. The coronavirus is selected from the group consisting of:
(1) Coronavirus infecting humans: severe acute respiratory syndrome coronavirus SARS-CoV (Severe acuterespiratory syndrome coronavirus, SARS-CoV), 2019 novel coronavirus (2019-nCoV or SARS-CoV-2), middle east respiratory syndrome coronavirus MERS-CoV (Middle East respiratory syndromecoronavirus, MERS-CoV);
(2) Coronaviruses that cause common cold: the common cold causing coronavirus is preferably selected from the group consisting of: human coronavirus OC43 (Human coronavirus OC 43), human coronavirus 229E (Human coronavirus 229E), human coronavirus NL63 (Human coronavirus NL 63), human coronavirus HKUl (Human coronavirus HKUl);
(3) Coronavirus infecting animals: such as porcine epidemic diarrhea virus PEDV and feline infectious peritonitis virus FIPV.
The associated disease caused by the coronavirus is selected from the group consisting of:
(1) Common cold, high risk symptom infection, respiratory tract infection and complications thereof caused by human coronavirus infection;
(2) SARS-CoV-2-caused disease (Corona Virus Disease 2019, COVID-19);
(3) Porcine epidemic diarrhea caused by porcine epidemic diarrhea virus, and feline infectious peritonitis FIP caused by feline coronavirus.
The related diseases caused by the respiratory syncytial virus RSV infection are selected from the group consisting of:
common cold, high risk symptom infection, respiratory tract infection and complications thereof caused by human respiratory syncytial virus infection. According to embodiments of the present invention, the pharmaceutical compositions of the present invention may be formulated into dosage forms suitable for administration by methods known in the art.
According to an embodiment of the invention, the formulation (or pharmaceutical composition) comprises: oral and non-oral formulations.
According to an embodiment of the invention, the formulation comprises: powder, granule, capsule, injection, inhalant, tincture, oral liquid, tablet, buccal tablet, or dripping pill.
In a fourth aspect, the present invention also provides the use of a compound of formula (I), a pharmaceutically acceptable salt, solvate, polymorph, metabolite, ester, stereoisomer, tautomer, isotopic label, nitroxide, prodrug, or one, two or more thereof, as described above, in the manufacture of a medicament against RNA viruses, e.g. orthomyxoviruses or paramyxoviruses, such as coronaviruses, respiratory syncytial viruses, RSV.
In some embodiments, the medicament may be used for the prevention and/or treatment of diseases associated with RNA virus, e.g. orthomyxovirus or paramyxovirus, such as coronavirus, respiratory syncytial virus, RSV infection.
The coronavirus is selected from the group consisting of:
(1) Coronavirus infecting humans: severe acute respiratory syndrome coronavirus SARS-CoV (Severe acuterespiratory syndrome coronavirus, SARS-CoV), 2019 novel coronavirus (2019-nCoV or SARS-CoV-2), middle east respiratory syndrome coronavirus MERS-CoV (Middle East respiratory syndromecoronavirus, MERS-CoV);
(2) Coronaviruses that cause common cold: the common cold causing coronavirus is preferably selected from the group consisting of: human coronavirus OC43 (Human coronavirus OC 43), human coronavirus 229E (Human coronavirus 229E), human coronavirus NL63 (Human coronavirus NL 63), human coronavirus HKUl (Human coronavirus HKUl);
(3) Coronavirus infecting animals: such as porcine epidemic diarrhea virus PEDV and feline infectious peritonitis virus FIPV.
The associated disease caused by the coronavirus is selected from the group consisting of:
(1) Common cold, high risk symptom infection, respiratory tract infection and complications thereof caused by human coronavirus infection;
(2) SARS-CoV-2-caused disease (Corona Virus Disease 2019, COVID-19);
(3) Porcine epidemic diarrhea caused by porcine epidemic diarrhea virus, and feline infectious peritonitis FIP caused by feline coronavirus.
The related diseases caused by the respiratory syncytial virus RSV infection are selected from the group consisting of:
common cold, high risk symptom infection, respiratory tract infection and complications thereof caused by human respiratory syncytial virus infection.
In a fifth aspect, the present invention also provides a method of treating and/or preventing a condition or disease caused by an infection by an RNA virus, e.g., a orthomyxovirus or a paramyxovirus, such as coronavirus, respiratory syncytial virus, RSV, comprising administering to a subject a therapeutically effective amount of one, two or more of a compound of formula (I), a pharmaceutically acceptable salt, solvate, polymorph, metabolite, ester, stereoisomer, tautomer, isotopic label, oxynitride, prodrug thereof.
The coronavirus is selected from the group consisting of:
(1) Coronavirus infecting humans: severe acute respiratory syndrome coronavirus SARS-CoV (Severe acuterespiratory syndrome coronavirus, SARS-CoV), 2019 novel coronavirus (2019-nCoV or SARS-CoV-2), middle east respiratory syndrome coronavirus MERS-CoV (Middle East respiratory syndromecoronavirus, MERS-CoV);
(2) Coronaviruses that cause common cold: the common cold causing coronavirus may be selected from the group consisting of: human coronavirus OC43 (Human coronavirus OC 43), human coronavirus 229E (Human coronavirus 229E), human coronavirus NL63 (Human coronavirus NL 63), human coronavirus HKUl (Human coronavirus HKUl);
(3) And coronaviruses infecting animals: such as porcine epidemic diarrhea virus PEDV and feline infectious peritonitis virus FIPV.
The associated disease caused by the coronavirus is selected from the group consisting of:
(1) Common cold, high risk symptom infection, respiratory tract infection and complications thereof caused by human coronavirus infection;
(2) SARS-CoV-2-caused disease (Corona Virus Disease 2019, COVID-19);
(3) Porcine epidemic diarrhea caused by porcine epidemic diarrhea virus, and feline infectious peritonitis FIP caused by feline coronavirus.
The related diseases caused by the respiratory syncytial virus RSV infection are selected from the group consisting of:
common cold, high risk symptom infection, respiratory tract infection and complications thereof caused by human respiratory syncytial virus infection.
In a sixth aspect, the invention also provides a compound 154, a stereoisomer, tautomer, isotopic label, nitroxide, solvate, polymorph, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof for use in the preparation of an anti-cancer agent Use of coronavirus, respiratory syncytial virus RSV in medicine:；
the coronavirus is selected from the group consisting of:
(1) Coronavirus infecting humans: severe acute respiratory syndrome coronavirus SARS-CoV (Severe acuterespiratory syndrome coronavirus, SARS-CoV), 2019 novel coronavirus (2019-nCoV or SARS-CoV-2), middle east respiratory syndrome coronavirus MERS-CoV (Middle East respiratory syndromecoronavirus, MERS-CoV);
(2) Coronaviruses that cause common cold: the common cold causing coronavirus is preferably selected from the group consisting of: human coronavirus OC43 (Human coronavirus OC 43), human coronavirus 229E (Human coronavirus 229E), human coronavirus NL63 (Human coronavirus NL 63), human coronavirus HKUl (Human coronavirus HKUl);
(3) Coronavirus porcine epidemic diarrhea virus PEDV infecting animals.
In some embodiments, the medicament is useful for preventing and/or treating a disease associated with coronavirus, respiratory syncytial virus, RSV, infection;
the associated disease caused by the coronavirus is selected from the group consisting of:
(1) Common cold, high risk symptom infection, respiratory tract infection and complications thereof caused by human coronavirus infection;
(2) SARS-CoV-2-caused disease (Corona Virus Disease 2019, COVID-19);
(3) Porcine epidemic diarrhea caused by porcine epidemic diarrhea virus.
In some embodiments, the disease associated with respiratory syncytial virus RSV infection is selected from the group consisting of:
common cold, high risk symptom infection, respiratory tract infection and complications thereof caused by human respiratory syncytial virus infection.
Those skilled in the art will appreciate that features recited in the various aspects and embodiments of the invention can be freely combined in accordance with them as long as they do not conflict with each other or are incompatible therewith.
Advantageous effects
The present invention provides a nucleoside dual prodrug having significant anti-coronavirus (e.g., human coronavirus OC43, human coronavirus 229E, feline coronavirus FIPV) activity. Wherein the half-effective concentration and 90% effective concentration of the nucleoside dual prodrug for human coronavirus OC43 can be as low as 0.05 μM and 0.38 μM, and the half-effective concentration and 90% effective concentration for human coronavirus 229E can be as low as 0.15 μM and 0.69 μM. Meanwhile, the nucleoside double-prodrug has good oral bioavailability and has therapeutic effect on target tissues.
Definition and description of terms
Unless otherwise indicated, the radical and term definitions recited in the specification and claims of the present application, including as examples, exemplary definitions, preferred definitions, definitions recited in tables, definitions of specific compounds in the examples, and the like, may be arbitrarily combined and coupled with each other. Such combinations and combinations of radical definitions and structures should be understood to be within the scope of the present description and/or claims.
The numerical ranges recited in the specification and claims are equivalent to at least each specific integer number recited therein unless otherwise stated. For example, the numerical range "1 to 40" corresponds to each of the integer numbers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 in the numerical range "1 to 10", and each of the integer numbers 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 in the numerical range "11 to 40". It is to be understood that "more" in one, two or more as used herein in describing substituents shall mean an integer of ≡3, such as 3, 4, 5, 6, 7, 8, 9 or 10.
The term "halogen" or "halo" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a specific substituent. Further, when the group is substituted with 1 or more of the substituents, the substituents are independent of each other, that is, the 1 or more substituents may be different from each other or the same. Unless otherwise indicated, a substituent group may be substituted at each substitutable position of the substituted group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, then the substituents may be the same or different at each position. Wherein the substituents may be, but are not limited to, =o, hydrogen, deuterium, cyano, nitro, halogen, alkyl, haloalkyl, alkoxy, carboxyl, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, and the like.
In addition, unless explicitly indicated otherwise, the description that "… is independently selected" as used in the present invention is to be understood broadly as meaning that each individual described is independent of the other and may be independently selected from the same or different specific groups. In more detail, the description that "… is independently selected" may mean that specific options expressed between the same symbols in different groups do not affect each other; it may also be expressed that specific options expressed between the same symbols in the same group do not affect each other.
In the various parts of the present specification, substituents of the presently disclosed compounds are disclosed in terms of the type or scope of groups. It is specifically noted that the present invention includes each individual subcombination of the individual members of these group classes and ranges. For example, the term "C 1 - 6 Alkyl "means in particular independently disclosed C 1 Alkyl, C 2 Alkyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl or C 6 An alkyl group.
In the various parts of the invention, linking substituents are described. When the structure clearly requires a linking group, the markush variables recited for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for that variable enumerates an "alkyl" or "aryl" group, it will be understood that the "alkyl" or "aryl" represents a linked alkylene group or arylene group, respectively.
The term "C 1-20 The alkyl group "represents a straight-chain or branched saturated monovalent hydrocarbon group having 1 to 20 carbon atoms. For example, "C 1-6 Alkyl "means straight and branched alkyl groups having 1,2, 3, 4, 5 or 6 carbon atoms. Wherein the alkyl group may be optionally substituted with one or more substituents described herein. In some embodiments, the alkyl group contains 1 to 12 carbon atoms; in other embodiments, the alkyl group contains 1 to 6 carbon atoms; in still other embodiments, the alkyl group contains 1 to 4 carbon atoms. Examples of such alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 2, 3-dimethylbutyl, 1, 3-dimethylbutyl, or 1, 2-dimethylbutyl, and the like, or isomers thereof.
The term "C 3-20 Cycloalkyl "is understood to mean a saturated monovalent monocyclic, bicyclic hydrocarbon ring or bridged cycloalkane having 3 to 20 carbon atoms, preferably" C 3-10 Cycloalkyl groups). The term "C 3-10 Cycloalkyl "is understood to mean a saturated monovalent monocyclic, bicyclic hydrocarbon ring or bridged cycloalkane having 3,4, 5,6, 7, 8, 9 or 10 carbon atoms. The C is 3-10 Cycloalkyl may be a monocyclic hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as a decalin ring.
The term "3-20 membered heterocyclyl" is understood to mean a saturated monovalent monocyclic, bicyclic hydrocarbon ring or bridged cycloalkane comprising 1 to 5 non-aromatic cyclic groups of 3 to 20 (e.g. 3,4, 5,6, 7, 8, 9, 10, etc. atoms) total ring atoms independently selected from the group N, O and S heteroatoms, preferably a "3-10 membered heterocyclyl". The term "3-10 membered heterocyclyl" means a saturated monovalent monocyclic, bicyclic hydrocarbon ring or bridged cycloalkane comprising 1-5, preferably 1-3 heteroatoms independently selected from N, O and S, e.g. 1,2, 3 heteroatoms independently selected from N, O and S. The heterocyclic group may be attached to the remainder of the molecule through any of the carbon atoms or a nitrogen atom, if present. In particular, the heterocyclic groups may include, but are not limited to: 4-membered rings such as azetidinyl, oxetanyl; a 5-membered ring such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6 membered ring such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or a 7-membered ring such as diazepanyl. Optionally, the heterocyclyl may be benzo-fused. The heterocyclyl may be bicyclic, such as, but not limited to, a 5,5 membered ring, such as hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl ring, or a 5,6 membered bicyclic ring, such as hexahydropyrrolo [1,2-a ] pyrazin-2 (1H) -yl ring. The nitrogen atom-containing ring may be partially unsaturated, i.e., it may contain one or more double bonds, such as, but not limited to, 2, 5-dihydro-1H-pyrrolyl, 4H- [1,3,4] thiadiazinyl, 4, 5-dihydro-oxazolyl, or 4H- [1,4] thiazide, or it may be benzo-fused, such as, but not limited to, dihydroisoquinolinyl. According to the invention, the heterocyclic group is non-aromatic. When the 3-20 membered heterocyclic group is linked to other groups to form the compound of the present invention, the carbon atom on the 3-20 membered heterocyclic group may be linked to other groups, or the heterocyclic atom on the 3-20 membered heterocyclic ring may be linked to other groups. For example, when the 3-20 membered heterocyclic group is selected from piperazinyl, it may be that the nitrogen atom on the piperazinyl group is attached to other groups. Or when the 3-20 membered heterocyclic group is selected from piperidyl, it may be that the nitrogen atom on the piperidyl ring and the carbon atom at the para position thereof are attached to other groups.
The term "C 6-20 Aryl "is understood to mean a mono-, bi-or tricyclic hydrocarbon ring, preferably" C ", of monovalent aromatic or partly aromatic character having 6 to 20 carbon atoms 6-14 Aryl group). The term "C 6-14 Aryl "is understood to mean preferably a mono-, bi-or tricyclic hydrocarbon ring (" C ") having a monovalent aromatic or partially aromatic character of 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms 6-14 Aryl), in particular a ring having 6 carbon atoms ("C) 6 Aryl "), such as phenyl; or biphenyl, or a ring having 9 carbon atoms ("C 9 Aryl "), e.g. indanyl or indenyl, or a ring having 10 carbon atoms (" C 10 Aryl "), such as tetralin, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms (" C " 13 Aryl "), e.g. fluorenyl, or a ring having 14 carbon atoms (" C) 14 Aryl "), such as anthracenyl. When said C 6-20 When aryl is substituted, it may be mono-substituted or poly-substituted. The substitution site is not limited, and may be, for example, ortho, para or meta substitution.
The term "5-20 membered heteroaryl" is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems, including aromatic or partially aromatic, having 5 to 20 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O and S, e.g. "5-14 membered heteroaryl". The term "5-14 membered heteroaryl" is understood to include such monovalent monocyclic, bicyclic or tricyclic aromatic ring systems: it has 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and it contains 1 to 5, preferably 1 to 3 heteroatoms each independently selected from N, O and S and, in addition, can be benzo-fused in each case. In particular, the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl and the like and their benzo derivatives, such as benzofuryl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazole, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and their benzo derivatives, such as quinolinyl, quinazolinyl, isoquinolinyl, and the like; or an axcinyl group, an indolizinyl group, a purinyl group, etc., and their benzo derivatives; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and the like. When the 5-20 membered heteroaryl is attached to other groups to form the compounds of the invention, the carbon atom on the 5-20 membered heteroaryl ring may be attached to other groups, or the heteroatom on the 5-20 membered heteroaryl ring may be attached to other groups. When the 5-20 membered heteroaryl is substituted, it may be mono-substituted or poly-substituted. And, the substitution site thereof is not limited, and for example, hydrogen attached to a carbon atom on a heteroaryl ring may be substituted, or hydrogen attached to a heteroatom on a heteroaryl ring may be substituted.
Unless otherwise indicated, heterocyclyl, heteroaryl or heteroarylene include all possible isomeric forms thereof, e.g. positional isomers thereof. Thus, for some illustrative non-limiting examples, forms that may include substitution at one, two, or more of its 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-positions, etc. (if present) or bonding to other groups include pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, and pyridin-4-yl; thienyl or thienylene include thiophen-2-yl, thienylene-2-yl, thiophen-3-yl and thienylene-3-yl; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, and pyrazol-5-yl.
The stereochemical definitions and rules used in the present invention generally follow S.P. Parker, ed., mcGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, new York; and Eliel, e.and Wilen, s., "Stereo chemistry of Organic Compounds", john Wiley & Sons, inc., new York,1994.
"stereoisomers" refer to compounds having the same chemical structure but different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.
"enantiomer" refers to two isomers of a compound that do not overlap but are in mirror image relationship to each other.
"diastereoisomers" refers to stereoisomers which have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. The diastereomeric mixture may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.
Any asymmetric atom (e.g., carbon, etc.) of the disclosed compounds may exist in racemic or enantiomerically enriched form, such as in the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 0% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration.
The resulting mixture of any stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, e.g., by chromatography and/or fractional crystallization, depending on the differences in the physicochemical properties of the components.
In the case of racemic amines, diastereomers are prepared from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g.N-benzoylproline or N-benzenesulfonylproline) or various optically active camphorsulfonic acids in R and S form. The chromatographic resolution can also advantageously be carried out with the aid of optically active resolving agents, such as dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chiral derivatized methacrylate polymers, immobilized on silica. Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example hexane/isopropanol/acetonitrile.
The term "tautomer" refers to structural isomers having different energies that can be interconverted by a low energy barrier (low energy barrier). If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as proton tautomers) (prototro pictautomer) include interconversions by proton transfer, such as keto-enol isomerisation and imine-enamine isomerisation. Valence tautomers (valen customer) include interconversions by recombination of some of the bond-forming electrons. Specific examples of keto-enol tautomerism are tautomerism of pentane-2, 4-dione and 4-hydroxypent-3-en-2-one tautomer. Another example of tautomerism is phenol-ketone tautomerism. One specific example of phenol-ketone tautomerism is the interconversion of pyridin-4-ol and pyridin-4 (1H) -one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
"nitroxide" in the present invention means that when a compound contains several amine functions, 1 or more than 1 nitrogen atom can be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms of nitrogen-containing heterocycles. The corresponding amine may be treated with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) to form an N-oxide (see Advanced Organic Chemistry, wiley Interscience, 4 th edition, jerry March, pages). In particular, the N-oxides can be prepared by the method L.W.Deady (Syn.Comm.1977, 7, 509-514) in which an amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example in an inert solvent such as methylene chloride.
The term "isotopic label" includes, but is not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur, and chlorine (e.g. 2 H， 3 H， 13 C， 14 C， 15 N， 18 O， 17 O， 18 F， 35 S and 36 cl) labeled compound of the invention. Isotopically-labeled compounds of the present invention are useful in the determination of the tissue distribution of a compound, prodrug thereof, and metabolite thereof; preferred isotopes for use in such assays include 3 H and 14 C. in addition, in some cases, heavier isotopes are usedFor example deuterium (2H or D)) substitution may provide increased metabolic stability, which provides therapeutic advantages such as increased in vivo half-life or reduced dosage requirements. Isotopically-labeled compounds of the present invention can generally be prepared according to the methods described herein by substituting an isotopically-labeled reagent for a non-isotopically-labeled reagent.
The term "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable and do not generally produce allergies or similar inappropriate reactions, such as gastrointestinal discomfort, dizziness, etc., when administered to humans.
The term "carrier" refers to a diluent, adjuvant, excipient, or matrix with which the compound is administered. These pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water and aqueous solutions saline solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, particularly injectable solutions. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" of e.w. Martin.
The term "prodrug" as used herein means a compound that is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or enzymatic conversion to the parent structure in the blood or tissue. The prodrug of the invention can be ester, and in the prior invention, the ester can be phenyl ester, aliphatic (C 1 - 24 ) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, one compound of the invention may contain a hydroxyl group, i.e., it may be acylated to provide the compound in a prodrug form. Other prodrug forms include phosphates, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following documents: t, higuchiand V. Stilla, pro-drugsas Novel Delivery Systems, vol.14 of the A.C.S. Symposium Series, edward B, roche, ed., bioreversible Carriersin Drug Design, american Pharmaceutical Associationand Pergamon Press, 1987, J. Rautioetal., Prodrugs: Designand Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and S. J. Heckeretal., Prodrugs of Phosphatesand Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345。
The term "metabolite" as used herein refers to a product obtained by metabolizing a specific compound or salt thereof in vivo. The metabolites of a compound may be identified by techniques well known in the art and their activity may be characterized by employing the assay methods as described herein. Such products may be obtained by oxidation, reduction, hydrolysis, amidization, deamination, esterification, degreasing, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a period of time sufficient.
The pharmaceutically acceptable salts may be acid addition salts of compounds of the invention having a nitrogen atom in the chain or ring, for example, which are sufficiently basic, for example, with the following inorganic acids: such as hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid or nitric acid, or hydrogen sulfate, or acid addition salts with organic acids such as: for example formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2- (4-hydroxybenzoyl) benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectate acid, persulphuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptonic acid, glycerophosphate, aspartic acid, sulfosalicylic acid, hemisulfuric acid, or thiocyanic acid.
In addition, another suitable pharmaceutically acceptable salt of a compound of the invention having sufficient acidity is an alkali metal salt (e.g., sodium or potassium salt), alkaline earth metal salt (e.g., calcium or magnesium salt), ammonium salt, or a salt with an organic base that provides a physiologically acceptable cation, such as a salt with: sodium ion, potassium ion, N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, dicyclohexylamine, 1, 6-hexamethylenediamine, ethanolamine, glucamine, meglumine, sarcosine, serinol, tris-hydroxymethyl aminomethane, aminopropanediol, 1-amino-2, 3, 4-butanetriol. As an example, the pharmaceutically acceptable salts include salts of the group-COOH with: sodium ion, potassium ion, calcium ion, magnesium ion, N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, dicyclohexylamine, 1, 6-hexamethylenediamine, ethanolamine, glucamine, meglumine, sarcosine, serinol, tris-hydroxymethyl aminomethane, aminopropanediol, 1-amino-2, 3, 4-butanetriol.
Alternatively, the basic nitrogen-containing groups may be quaternized with the following agents: lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and dipentyl sulfate; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides such as benzyl and phenethyl bromides, and the like. As examples, pharmaceutically acceptable salts include hydrochloride, sulfate, nitrate, bisulfate, hydrobromide, acetate, oxalate, citrate, methanesulfonate, formate, or meglumine salts, and the like.
Since the compounds of the present invention may have multiple salt-forming sites, the pharmaceutically acceptable salts include not only salts formed at 1 of the salt-forming sites of the compounds of the present invention, but also salts formed at 2, 3 or all of the salt-forming sites. For this purpose, the molar ratio of the compound of formula (I) to the radical ion (anion) of the acid or the cation of the base required for salification in the pharmaceutically acceptable salts may vary within a wide range, for example 4:1 to 1:4, such as 3:1, 2:1, 1:1, 1:2, 1:3, etc.
"solvate" according to the present invention refers to an association of one or more solvent molecules with a compound according to the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association of solvent molecules that are water.
The term "ester" as used herein refers to an in vivo hydrolysable ester formed from a compound containing a hydroxyl or carboxyl group. Such esters are, for example, pharmaceutically acceptable esters which hydrolyze in the human or animal body to produce the parent alcohol or acid. The compounds of formula (I) of the present invention contain a carboxyl group which may form an in vivo hydrolysable ester with suitable groups including, but not limited to, alkyl, arylalkyl and the like.
The term "treating" as used herein refers in some embodiments to ameliorating a disease or disorder (i.e., slowing or preventing or alleviating the progression of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to modulating a disease or disorder physically (e.g., stabilizing a perceived symptom) or physiologically (e.g., stabilizing a parameter of the body) or both. In other embodiments, "treating" refers to preventing or delaying the onset, or exacerbation of a disease or disorder.
The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound of the present invention that is sufficient to achieve the intended use, including but not limited to the treatment of a disease as defined below. The therapeutically effective amount may vary depending on the following factors: the intended use (in vitro or in vivo), or the subject and disease condition being treated, such as the weight and age of the subject, the severity of the disease condition, the manner of administration, and the like, can be readily determined by one of ordinary skill in the art. The specific dosage will vary depending on the following factors: the particular compound selected, the regimen based on, whether to administer in combination with other compounds, the timing of administration, the organization of administration, and the physical delivery system carried.
Abbreviations for any protecting groups, amino acids and other compounds used in the present invention are, unless otherwise indicated, based on their commonly used, accepted abbreviations or with reference to IUPAC-IUB Commissionon Biochemical Nomen clature (see biochem.1972, 11:942-944).
The pharmaceutical excipients can be widely used in the field of pharmaceutical production. Adjuvants are used primarily to provide a safe, stable and functional pharmaceutical composition, and may also provide means for allowing the subject to dissolve at a desired rate after administration, or for promoting effective absorption of the active ingredient after administration of the composition. The pharmaceutical excipients may be inert fillers or provide a function such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition. The pharmaceutical excipients can comprise one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, sizing agents, disintegrants, lubricants, anti-adherents, glidants, wetting agents, gelling agents, absorption retarders, dissolution inhibitors, enhancing agents, adsorbents, buffering agents, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.
Substances that may be pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, aluminum stearate, lecithin, serum proteins, such as human serum proteins, buffer substances, such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures 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, polyacrylates, waxes, 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, and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, coloring agents, releasing agents, coating materials, sweetening, flavoring and perfuming agents, preserving and antioxidant agents.
The pharmaceutical compositions of the present invention may be prepared in accordance with the disclosure using any method known to those of skill in the art. For example, conventional mixing, dissolving, granulating, emulsifying, levigating, encapsulating, entrapping or lyophilizing processes.
The dosage form of the medicament of the invention can be selected according to specific conditions. Pharmaceutical dosage forms often consist of a drug, excipients and a container/sealing system. One or more excipients (also known as inactive ingredients) may be added to the compounds of the present invention to improve or promote the manufacture, stability, administration and safety of the drug, and may provide a means to achieve a desired drug release profile. Thus, the type of excipient added to a drug may depend on various factors, such as the physical and chemical characteristics of the drug, the route of administration, and the manufacturing steps. Pharmaceutically acceptable excipients are present in this field and include those listed in the various pharmacopoeias. (see U.S. Pharmacopeia, USP), japanese pharmacopoeia (Japanese Pharmacopoeia, JP), european pharmacopoeia (European Pharmacopoeia, EP) and British pharmacopoeia (British pharmacopoeia, BP); U.S. food and drug administration (the U.S. Food and Drug Administration, www.fda.gov) drug evaluation and research center (Centerfor Drug Evaluation and Research, CEDR) publications, such as Inactive ingredient guide (Inactive Ingredient Guide, 1996); drug additives handbook written by Ash (Hand book of Pharmaceutical Additives, 2002), joint information resources company (Synapse Information Resources, inc., endiott NY; etc.).
The pharmaceutical compositions of the present invention may include one or more physiologically acceptable inactive ingredients that facilitate processing of the active molecule into a formulation for pharmaceutical use.
Suitable formulations will depend upon the route of administration desired. The administration route includes intravenous injection, transmucosal or nasal administration, oral administration, etc. For oral administration, the compounds may be formulated in liquid or solid dosage forms and as immediate release or controlled release/sustained release formulations. Suitable dosage forms for oral ingestion by an individual include tablets, pills, dragees, hard and soft shell capsules, liquids, gels, syrups, slurries, suspensions and emulsions.
Solid oral dosage forms may be obtained using excipients including fillers, disintegrants, binders (dry and wet), dissolution retarders, lubricants, glidants, anti-sticking agents, cationic exchange resins, wetting agents, antioxidants, preservatives, colorants, and flavoring agents. These excipients may be of synthetic or natural origin. Examples of such excipients include cellulose derivatives, citric acid, dicalcium phosphate, gelatin, magnesium carbonate, magnesium/sodium lauryl sulfate, mannitol, polyethylene glycol, polyvinylpyrrolidone, silicates, silica, sodium benzoate, sorbitol, starch, stearic acid or salts thereof, sugars (i.e., dextrose, sucrose, lactose, etc.), talc, tragacanth, vegetable oils (hydrogenated), and waxes. Ethanol and water may be used as granulation aids. In some cases it may be desirable to coat the tablet with, for example, a taste masking film, a gastric acid resistant film, or a delayed release film. Natural and synthetic polymers are often used in combination with colorants, sugars and organic solvents or water to coat tablets, resulting in dragees. When the capsule is preferred over a tablet, the drug powder, suspension or solution thereof may be delivered in the form of a compatible hard shell or soft shell capsule.
The therapeutically effective dose may be estimated first using various methods well known in the art. The initial dose used for animal studies may be based on the established effective concentration in the cell culture assay. The dosage range suitable for the human body can be determined, for example, using data obtained from animal studies and cell culture assays. In certain embodiments, the compounds of the present invention may be prepared as medicaments for oral administration.
The correct formulation, route of administration, dosage and interval of administration may be selected in consideration of the particularities of the individual condition according to methods known in the art.
Drawings
FIG. 1 is a concentration-time curve of plasma GS441524 after single oral administration of compound 154 to golden mice;
figure 2 is a bar graph of mean drug concentration of GS-443902 in different tissues at different time points after single oral administration of compound 154 to golden mice.
Detailed Description
The technical scheme of the invention will be further described in detail below with reference to specific embodiments. It is to be understood that the following examples are illustrative only and are not to be construed as limiting the scope of the invention. All techniques implemented based on the above description of the invention are intended to be included within the scope of the invention.
Unless otherwise indicated, the starting materials and reagents used in the following examples were either commercially available or may be prepared by known methods.
Example 1: synthesis of Compound 154
The first step: synthesis of isopropyl iodomethyl carbonate (Compound 2)
NaI (19.7 g,131.426 mmol,4.01 eq) and TBAI (5 mg) were added to a stirred mixture of chloromethyl isopropyl carbonate (5 g,32.772 mmol,1 eq) in acetonitrile (70 mL) under argon at room temperature. The mixture was stirred at 40℃for 16 hours. The resulting mixture was diluted with dichloromethane (200 mL) and sequentially saturated NaHCO 3 Aqueous (50 ml) wash, saturated Na 2 S 2 O 3 Aqueous (50 mL) and aqueous NaCl (2X 50 mL) are washed twice, then with anhydrous MgSO 4 And (5) drying. After filtration, concentrating under reduced pressureThe filtrate was concentrated to give the title compound 2 (7.3 g,0.030 mol,91.28%) as a pale yellow oil.
1 H NMR (400 MHz, deuterated chloroform) delta 5.95 (s, 2H), 4.97-4.91 (m, 1H), 1.33 (d, j=8.0 Hz, 6H).
And a second step of: synthesis of dihydro-methyl (((2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) phosphate (Compound 4)
To a mixture of compound 3 (300 mg,0.716mmol,1.00 eq.) in trimethyl phosphate (5 mL) at 0deg.C was added POCl 3 (219.47 mg,1.432mmol,2 eq.). The resulting mixture was stirred at 0 ℃ for 4 hours. The reaction was quenched with TEAB buffer to ph=7 and the resulting mixture was stirred for an additional 30 minutes. The resulting mixture was treated with CHCl 3 (10 mL) and water (10 mL). The aqueous phase was treated with CHCl 3 (2X 10 mL) and then concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: XBridge Shield RP18 OBD column, 30 x 150 mm,5 μm; mobile phase a:10 mM aq. NH 4 HCO 3 Mobile phase B: acetonitrile; flow rate: 35 mL/min; gradient: 0 to 20% B, detector within 11 minutes: 254/210 nm; RT: compound 4 (200 mg,0.539mmol, 52.2%) was obtained as an off-white solid for 10.2 min.
1 H NMR (400 MHz, heavy water) delta 7.82 (s, 1H), 6.88 (d, j=4.0 Hz, 1H), 6.74 (d, j=8.0 Hz, 1H), 4.88 (d, j=4.0 Hz, 1H), 4.40-4.37 (m, 2H), 3.93-3.78 (m, 2H).
And a third step of: synthesis of Di-silver salt of (2R, 3S,4R, 5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) phosphate (Compound 5)
Compound 4 (100 mg, 0.269 mmol, 1 eq.) and Ag 2 CO 3 (148.49 mg, 0.538 mmol, 2 eq.) A mixture of acetonitrile (1 mL) and water (1 mL) was stirred at 25℃for 2 h. The solid was filtered off and the filtrate was concentrated under reduced pressure to give compound 5 (100 mg,0.171mmol, 63.46%) as a pale brown solid which was used directly in the next reaction without purification.
Fourth step: synthesis of Compound 154
A solution of compound 2 (500 mg, 0.855 mmol, 1 eq.) and molecular sieve in NMP (24 mL) was stirred at room temperature under an argon atmosphere for 15 minutes. To the mixture was added dropwise a solution of TEA (345.98 mg,3.420mmol,4 eq.) and compound 5 (1251.50 mg,5.130mmol,6 eq.) in NMP (1 mL) at 0℃and the resulting mixture was stirred at room temperature for an additional 3 hours. LC-MS showed that 12% of the desired product could be detected. The combined crude product was purified by reverse phase flash chromatography using acetonitrile and 5 mM NH 4 HCO 3 Gradient elution with water afforded 800 mg crude (40% purity). The crude product was further purified by preparative HPLC under the following conditions: column: YMC-actual Triart C8, 20 x 250 mm,5 μm; mobile phase a: water (10 mM formic acid, mobile phase B: acetonitrile; flow rate: 20 mL/min; gradient: from 20% B to 30% B in 8 min; wavelength: 254/210 nm; RT:6.67 min gave compound 154 (130 mg,6.2% yield) as a pale yellow solid.
1 H NMR: (400 MHz, deuterated methanol) delta 7.88 (s, 1H), 6.94-6.89 (m, 2H), 5.67-5.55 (m, 4H), 4.94-4.85 (m, 3H), 4.48-4.43 (m, 1H), 4.41-4.28 (m, 2H), 4.20-4.17 (m, 1H), 1.31-1.22 (m, 12H).
Example 2: synthesis of Compound 271
To a solution of compound 154 (130 mg, 0.216 mmol, 1 eq.) in DMF (2.5 mL) was added isobutyric acid (57.07 mg, 0.648 mmol, 3 eq.) and N, N' -diisopropylcarbodiimide (81.75 mg, 0.648 mmol, 3 eq.) under argon at 0 ℃. The resulting mixture was stirred at room temperature for 15 minutes, and DMAP (13.19 mg,0.108mmol,0.5 eq.) was added to the mixture. After stirring the mixture at room temperature for 15 hours, compound 271 was detected by LCMS. The mixture was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water, gradient 0% to 70%, 25 min; a detector: 254/210/nm.
Example 3: synthesis of compounds 272, 282, 283, 284, 285, 286, 287:
referring to example 2, compounds 272, 282, 283, 284, 285, 286, 287 were prepared by substituting a different starting compound for isobutyric acid in example 2.
Structural formula and structural characterization data for the compounds of Table 1
Biological example 1: cytopathic (CPE) assay
Cells were seeded at a density in microplates and at 5% CO 2 Culturing overnight in an incubator at 37 ℃. The next day, the compound and virus after dilution at the double ratio were added. Cell controls (cells, no compound treatment or virus infection), virus controls (cells infected with virus, no compound treatment) and broth controls (broth alone) were set. The final concentration of DMSO in the culture was 0.5%. Cells were cultured in an incubator for 3 (229E) or 7 (OC 43) days. The cytotoxicity test is the same as the antiviral test, but no virus infection. Cell viability was measured using Cell Titer Glo (Promega) kit.
The antiviral activity and cytotoxicity of the compounds are represented by the inhibition (%) of the virus-induced cytopathic effect of the compounds at different concentrations and the activity (%) of the cells, respectively. Nonlinear fitting analysis of inhibition and cell viability of compounds using GraphPad Prism, calculation of half-effectiveness of compoundsConcentration (EC) 50 ) 90% effective concentration (EC 90 ) The results are shown in Table 2.
Table 2: activity results of exemplary Compounds
Biological example 2:
Compounds Echo liquid treatment agents were used in 384 well plates. Each plate used adefovir as a reference compound. CRFK feline kidney cells (with or without feline infectious peritonitis virus) (passage 10) were accessed at a density of 3000 cells per well. The dishes were incubated at 37℃with 5% CO 2 Is incubated in a humid environment. After 4 days, CTG reagent (CellTiter-Glo) was added (10 μl) to each well and luminescence was measured using an Envision multi-tag plate reader. Analysis of data using Excel-fit software to evaluate detection quality control, draw dose response curves, and calculate EC 50 Or CC 50 The results are shown in Table 3.
Table 3: activity results of exemplary Compounds
Biological example 3: gold ground mouse prodrug active metabolite research
The active metabolite of the prodrug directly reflects the curative effect of the drug, and optimizing and affecting the pharmacokinetics and tissue distribution is a target of the design of the oral prodrug. Thus, the distribution of the active metabolites of compound 154 was studied in golden mice.
Golden mice were randomly grouped according to body weight, with 30% PEG300:70% Saline dissolved the target compound, and was prepared as a solution of 4 mg/mL, and the administration route was oral, the administration dose was 20 mg/kg, and the administration was single administration, and the administration was performed overnight fast, and 4 hours after administration. The fundus venous plexus was bled, and 0.083, 0.25, 0.5, 1, 2, 4, 8, 24 hours after the end of administration. Animal tissue was harvested at 4, 8, 24 hours.
200. And manually reversing the blood sample with the volume of mu L for 5-8 times after the blood sample is collected in a blood collection tube, shaking the blood sample uniformly, temporarily placing the blood sample on wet ice, centrifuging the blood sample in 1 h at 4000 rpm for 5 min (4 ℃) to separate blood plasma, subpackaging the blood plasma in an EP tube with a label, and placing the subpackaged sample in an ultralow temperature refrigerator or dry ice at-70+/-10 ℃ for 30 min for preservation.
After the collection, the lung, the liver and the small intestine are cleaned by using the physiological saline of an ice bath and are dried by absorbing water, the obtained mixture is filled into a sample tube with a label, and 4 times of homogenate is added after the mixture is weighed, and the homogenate is immediately carried out. After homogenization, protein precipitation treatment was performed on site by a bioanalyzer, LC-MS/MS analysis was performed immediately after vortexing, and all tissue samples were placed in one batch and quantified with lung standard curve.
Wherein the content of GS441524 in the blood plasma and the distribution of GS443902 in the tissue are shown in FIGS. 1-2.
Analysis of fig. 1 and 2 shows that:
compound 154 was orally administered, and GS441524 was detected in the plasma, a key intermediate for conversion to active ingredient GS443902, also demonstrating that compound 154 was orally absorbed;
the oral administration of compound 154, the active metabolite GS443902 was detected in the tissue, indicating therapeutic effects on the intended target tissue.
Regarding the design of dual prodrugs, with reference to the dual prodrug oral bioavailability variation, an oral bioavailability of better than 154 is expected.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (3)

1. The following compounds or pharmaceutically acceptable salts thereof:
。
2. a pharmaceutical composition comprising one, two or more of the compounds of claim 1 or pharmaceutically acceptable salts thereof, and optionally at least one pharmaceutically acceptable adjuvant, and/or optionally at least one additional active ingredient other than the compounds of claim 1 or pharmaceutically acceptable salts thereof.
3. Use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of an anti-RNA virus medicament;
the RNA virus is feline infectious peritonitis virus FIPV.
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