WO2014075618A1 - Dérivé de 5-hydroxyindole contenant un noyau hétérocyclique et son utilisation - Google Patents

Dérivé de 5-hydroxyindole contenant un noyau hétérocyclique et son utilisation Download PDF

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WO2014075618A1
WO2014075618A1 PCT/CN2013/087136 CN2013087136W WO2014075618A1 WO 2014075618 A1 WO2014075618 A1 WO 2014075618A1 CN 2013087136 W CN2013087136 W CN 2013087136W WO 2014075618 A1 WO2014075618 A1 WO 2014075618A1
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methyl
hydroxy
bromo
carboxylate
indole
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PCT/CN2013/087136
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English (en)
Chinese (zh)
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宫平
赵燕芳
刘亚婧
翟鑫
唐启东
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沈阳药科大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a series of 5-hydroxyindole derivatives containing a heterocyclic ring, and uses thereof, and pharmaceutical compositions containing the compound as an active ingredient, and in the preparation thereof for the treatment and/or prevention of viral infections, particularly Use in hepatitis B virus and influenza virus infection drugs.
  • Background technique :
  • Viral infections can cause a variety of diseases that seriously endanger human health and life. To date, more than 3,000 viruses have been discovered worldwide, and new viruses are still being discovered. According to statistics, 60-65% of epidemic infectious diseases are caused by viral infection. Due to the complexity of the interaction between the virus and the host, most antiviral drugs have a lower toxicity or antiviral effect on the human body when they exert therapeutic effects. This is also the reason for the slow development of antiviral drugs. As far as the current structure of antiviral drugs is concerned, the drugs available for clinical use are still scarce and far from meeting the needs of preventing and treating toxic diseases. It is of great significance to study antiviral drugs with novel antiviral mechanisms, strong antiviral activity and low toxicity.
  • the 5-hydroxyindole-3-carboxylate derivative was originally studied as a novel anti-influenza virus drug.
  • Grinev AH et al. Khim-Farm Zh, 1987, 21(1), 52; Parisheva EK et al. Khim Farm Zh, 1988, 22(5). 565; Mezentseva MV et al. Khim Farm Zh, 1990, 24 (10), 52; Otova SA, et al. Khim Farm Zh, 1992, 26(1), 52; Zotova SA et al. Khim Farm Zh, 1995, 29(1), 51 and other literature reports
  • 5-hydroxyindole-3-carboxylate compounds have shown that some of the compounds have anti-influenza activity and have pharmacological effects of inducing interferon production and enhancing human immunity.
  • CN1482118 discloses a novel 5-hydroxy-3-carboxylate steroid derivative and a process for the preparation thereof, which describe a 5-hydroxy-3-carboxylate steroid or a pharmaceutically acceptable salt thereof. It has a significant inhibitory effect on influenza virus and respiratory virus, and provides a new and highly effective anti-influenza virus drug.
  • CN1706827 discloses 5-hydroxyindole-3-carboxylate derivatives and uses thereof, and describes 5-hydroxyindole-3-carboxylate derivatives of another structure or a pharmaceutical thereof
  • the accepted salt can be used for the preparation of a medicament for the treatment and/or prevention of viral infections, in particular for the preparation of anti-hepatitis B virus and anti-human immunodeficiency virus drugs.
  • HBeAg is an important marker of HBV replication and infection.
  • HBeAg can synergize with human leukocyte antigen to regulate the host's immune response, inhibit the cytotoxic activity of host T cells, form immune tolerance to HBV infection, and make HBV escape immune clearance, enabling asymptomatic carriers. Long-term storage in the group.
  • the HBeAg seroconversion that occurs after antiviral therapy is more important than the reduction in HBV-DNA levels: patients receive a sustained response, improved prognosis, and improved immunity to HBV; indicating that HBV replication is continuously controlled.
  • the present invention relates to a 5-hydroxyindole derivative containing a heterocyclic ring of the formula I, or a racemate or an optical isomer thereof, or a pharmaceutically acceptable salt and/or hydrate thereof,
  • « is (dC 6 )alkyl, (C 3 -C 6 )cycloalkyl;
  • R 2 is (CC alkyl group
  • X is hydrogen, halogenated
  • Y is - R 3 R4 ;
  • R 3 and the same or different, each independently selected from (C Cs)alkyl, (C 3 -C 6 )cycloalkyl, optionally substituted by 1 to 3 identical or different;
  • Z is a CH 2 —(CH 2 ) n —Q ; m is 0, 1, 2;
  • n is an integer between 0 and 4;
  • R 5 is hydrogen, (dC 4 )alkyl, dC 4 alkoxy, hydroxy, optionally hydroxy, amino or halogenated (dC 4 )alkyl or (dc alkoxy, (dc alkylthio, free) , salt-forming, esterified and amidated carboxyl, halogenated,
  • R 5 is (C 6 -C 1Q )aryl or 5-10 membered heteroaryl, which are optionally substituted by 1 to 3 identical or different R 9 , wherein the heteroaryl and heterocyclic are Optionally containing from 1 to 3 heteroatoms selected from N, 0 or S;
  • R 9 is (dC alkyl, (dC alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethoxy, carboxy, amino, nitro, cyano, decyl, (CrC 4 ) alkenyl, (CrC 4 ) alkynyl, (CrC 4 )alkylthio, hydroxy(CrC 4 )alkyl, amino (dC alkyl, allyl, (2-methyl)allyl, (3-methyl)allyl , (2-methyl; )-2-enylbutyl, (Ci-C 4 )alkylamido, (CrC 4 )alkylsulfinyl, (CrC 4 )alkylsulfonyl, (CrC 4 ) alkane Oxymethyl group, (dC 4 ) Alkyl acyl, carbamoyl, N dc alkylcarbamoyl, N, N-di(dc alky
  • the invention preferably also relates to a compound of formula I, or a racemate or an optical isomer thereof, or a pharmaceutically acceptable salt and/or hydrate thereof,
  • « is (dC 6 )alkyl, (C 3 -C 6 )cycloalkyl;
  • R 2 is (CC alkyl group
  • X is hydrogen, halogenated
  • Y is - R 3 R4 ;
  • R 3 and the same or different, each independently selected from (C Cs)alkyl, (C 3 -C 6 )cycloalkyl, optionally substituted by 1 to 3 identical or different;
  • Z is a CH 2 —(CH 2 ) n -Q ;
  • n 0, 1, 2;
  • n is an integer between 0 and 4;
  • R 5 is hydrogen, (dC 4 )alkyl, (dC 4 )alkoxy, hydroxy, (dC 4 )alkyl or (CrC 4 )alkoxy optionally substituted by (hydroxy, amino or 3 ⁇ 4 ), (CrC 4 )alkylthio, (free, salt-forming, esterified or amidated) carboxyl, halogenated, (CrC 4 )alkyl acyl, nitro, cyano, amino, (CrC 4 ) alkane An amide group or an amino group substituted with a mono or di(CrC 6 )alkyl group; Or R 5 is phenyl or 5-6 membered heteroaryl, wherein said heteroaryl optionally contains 1-3 heteroatoms selected from N, 0 or S, and R 5 is optionally 1-3 The same or different R 9 substitutions;
  • R 9 is (dC alkyl, (dC alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethoxy, carboxy, amino, nitro, cyano, decyl, (dC 4 )alkenyl, (dC 4 ) alkynyl, (dC 4 )alkylthio, hydroxy(dC 4 )alkyl, amino (dC alkyl, allyl, (2-methyl)allyl, (3-methyl)allyl , (2-methyl; )-2-enylbutyl, (Ci-C 4 )alkylamido, (CrC 4 )alkylsulfinyl, (CrC 4 )alkylsulfonyl, (CrC 4 ) alkane Oxymethyl, (dC 4 ) alkyl acyl, carbamoyl, N dC alkylcarbamoyl, N,N-di (dC alkylcarbamo
  • the invention further relates to a compound of formula I, or a racemate or an optical isomer thereof, or a pharmaceutically acceptable salt and/or hydrate thereof,
  • « is (dC 6 )alkyl, (C 3 -C 6 )cycloalkyl;
  • R 2 is (C )alkyl
  • X is hydrogen, halogenated
  • Y is - R 3 R4 ;
  • R 3 and the same or different, each independently selected from (C Cs)alkyl, (C 3 -C 6 )cycloalkyl, optionally substituted by 1 to 3 identical or different;
  • Z is a CH 2 —(CH 2 ) n -Q ;
  • n 0, 1, 2;
  • n is an integer between 0 and 4;
  • R 5 is phenyl or a 5-6 membered heteroaryl group, wherein the heteroaryl group optionally contains 1-3 heteroatoms selected from N, 0 or S, and R 5 is optionally 1-3 identical Or a different R 9 substitution;
  • R 9 is (dC alkyl, (dC alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethoxy, carboxy, amino, nitro, cyano, decyl, (CrC 4 ) alkenyl, (CrC 4 ) alkynyl, (CrC 4 )alkylthio, hydroxy(CrC 4 )alkyl, amino (dC alkyl, allyl, (2-methyl)allyl, (3-methyl)allyl , (2-methyl; )-2-enylbutyl, (Ci-C 4 )alkylamido, (CrC 4 )alkylsulfinyl, (CrC 4 )alkylsulfonyl, (CrC 4 ) alkane Oxymethyl, (dC 4 ) alkyl acyl, carbamoyl, N dC alkylcarbamoyl, N,N-di (dC alkyl
  • the invention preferably also relates to a compound of formula I, or a racemate or an optical isomer thereof, or a pharmaceutically acceptable salt and/or hydrate thereof,
  • 1 ⁇ is methyl, ethyl, propyl, isopropyl, cyclopropyl;
  • R 2 is (C )alkyl
  • X is hydrogen, bromine or fluorine
  • Y is - R 3 R4 ;
  • R 3 and the same or different, respectively selected from (CC 4 ) alkyl, cyclopropyl;
  • Z is a CH 2 —(CH 2 ) n -Q ;
  • R 5 is hydrogen, (dC 4 )alkyl, (dC 4 )alkoxy, hydroxy, (dC 4 )alkyl or (CrC 4 )alkoxy optionally substituted by (hydroxy, amino or 3 ⁇ 4 ), (CrC 4 )alkylthio, (free, salt-forming, esterified and amidated) carboxyl, halogenated, (CrC 4 )alkyl acyl, nitro, cyano, amino, (CrC 4 ) alkane An amide group or an amino group substituted with a mono or di(CrC 6 )alkyl group;
  • R 5 is phenyl or 5-6 membered heteroaryl, wherein said heteroaryl optionally contains 1-3 heteroatoms selected from N, 0 or S, and R 5 is optionally 1-3 The same or different R 9 substitutions;
  • R 9 is (dC alkyl, (dC alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethoxy, carboxy, amino, nitro, cyano, decyl, (CrC 4 ) alkenyl, (CrC 4 ) alkynyl, (CrC 4 )alkylthio, hydroxy(CrC 4 )alkyl, amino (dC alkyl, allyl, (2-methyl)allyl, (3-methyl)allyl , (2-methyl; )-2-enylbutyl, (Ci-C 4 )alkylamido, (CrC 4 )alkylsulfinyl, (CrC 4 )alkylsulfonyl, (CrC 4 ) alkane Oxymethyl, (dC 4 ) alkyl acyl, carbamoyl, N dC alkylcarbamoyl, N,N-di (dC alkyl
  • the invention particularly preferably relates to a compound of formula I, or a racemate or an optical isomer thereof, or a pharmaceutically acceptable salt and/or hydrate thereof, as defined below,
  • 1 ⁇ is methyl, ethyl, propyl, isopropyl, cyclopropyl;
  • R 2 is (C )alkyl
  • X is hydrogen, bromine or fluorine
  • Y is - R 3 R4 ;
  • R 3 and the same or different, respectively selected from (CC 4 ) alkyl, cyclopropyl;
  • Z is a CH 2 —(CH 2 ) n -Q ;
  • n 0, 1, 2;
  • n is an integer between 0 and 4;
  • R 5 is hydrogen, (dC 4 )alkyl, phenyl optionally substituted by 1 to 3 identical or different R 9 ;
  • R 9 is (dC alkyl, (dC alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethoxy, carboxy, amino, nitro, cyano, decyl, (CrC 4 ) alkenyl, (CrC 4 ) alkynyl, (CrC 4 )alkylthio, hydroxy(CrC 4 )alkyl, amino (dC alkyl, allyl, (2-methyl)allyl, (3-methyl)allyl , (2-methyl; )-2-enylbutyl, (Ci-C 4 )alkylamido, (CrC 4 )alkylsulfinyl, (CrC 4 )alkylsulfonyl, (CrC 4 ) alkane Oxymethyl, (dC 4 ) alkyl acyl, carbamoyl, N dC alkylcarbamoyl, N,N-di (dC alkyl
  • the invention preferably also relates to a compound of formula I, or a racemate or an optical isomer thereof, or a pharmaceutically acceptable salt and/or hydrate thereof,
  • 1 ⁇ is methyl, ethyl, propyl, isopropyl, cyclopropyl;
  • R 2 is (C )alkyl
  • X is hydrogen, bromine
  • Y is - R 3 R4 ;
  • R 3 and the same or different, respectively selected from (CC 4 ) alkyl, cyclopropyl;
  • R 3 and together with the nitrogen atom to which they are attached form a mercapto group, 4-morpholinyl, 4-methyl-1-piperazinyl, 1-piperidinyl, 1-pyrrolidinyl, 1H-1, 2,4-triazol-1-yl, 1-imidazolyl, 2-methyl-1-imidazolyl and 1H-tetrazol-1-yl; Representative (CC 4 )alkyl, (dC 4 )alkoxy, halo, hydroxy, cyano, carboxy, ester, nitro; (0) m
  • Z is a CH 2 —(CH 2 ) n -Q ;
  • n 0, 1, 2;
  • n is an integer between 0 and 4;
  • R 5 is phenyl or a 5-6 membered heteroaryl group, wherein the heteroaryl group optionally contains 1-3 heteroatoms selected from N, 0 or S, and R 5 is optionally 1-3 identical Or a different R 9 substitution;
  • R 9 is (dC alkyl, (dC alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethoxy, carboxy, amino, nitro, cyano, decyl, (CrC 4 ) alkenyl, (CrC 4 ) alkynyl, (CrC 4 )alkylthio, hydroxy(CrC 4 )alkyl, amino (dC alkyl, allyl, (2-methyl)allyl, (3-methyl)allyl , (2-methyl; )-2-enylbutyl, (Ci-C 4 )alkylamido, (CrC 4 )alkylsulfinyl, (CrC 4 )alkylsulfonyl, (CrC 4 ) alkane Oxymethyl, (dC 4 ) alkyl acyl, carbamoyl, N dC alkylcarbamoyl, N, N-di (dC alkyl
  • the invention preferably also relates to a compound of formula I, or a racemate or an optical isomer thereof, or a pharmaceutically acceptable salt and/or hydrate thereof,
  • 1 ⁇ is methyl, ethyl, propyl, isopropyl, cyclopropyl;
  • R 2 is (C )alkyl
  • X is hydrogen, bromine
  • R 3 and the same or different, respectively selected from (CC 4 ) alkyl, cyclopropyl;
  • R 3 and together with the nitrogen atom to which they are attached form a mercapto group, 4-morpholinyl, 4-methyl-1-piperazinyl, 1-piperidinyl, 1-pyrrolidinyl, 1H-1, 2,4-triazol-1-yl, 1-imidazolyl, 2-methyl-1-imidazolyl and 1H-tetrazol-1-yl; Representative (CC 4 )alkyl, (dC 4 )alkoxy, halo, hydroxy, cyano, carboxy, ester, nitro; (0) m
  • Z is a CH 2 —(CH 2 ) n -Q ;
  • n 0, 1, 2;
  • n is an integer between 0 and 4;
  • R 5 is phenyl, furyl, pyrrolyl, thienyl, pyridyl, and R 5 is optionally substituted by 1 to 3 identical or different R 9 ;
  • R 9 is (dC alkyl, (dC alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethoxy, carboxy, amino, nitro, cyano, decyl, (CrC 4 ) alkenyl, (CrC 4 ) alkynyl, (CrC 4 )alkylthio, hydroxy(CrC 4 )alkyl, amino (dC alkyl, allyl, (2-methyl)allyl, (3-methyl)allyl , (2-methyl; )-2-enylbutyl, (Ci-C 4 )alkylamido, (CrC 4 )alkylsulfinyl, (CrC 4 )alkylsulfonyl, (CrC 4 ) alkane Oxymethyl, (dC 4 ) alkyl acyl, carbamoyl, N dC alkylcarbamoyl, N, N-di (dC alkyl
  • the invention preferably also relates to a compound of formula I, or a racemate or an optical isomer thereof, or a pharmaceutically acceptable salt and/or hydrate thereof,
  • 1 ⁇ is methyl, ethyl, propyl, isopropyl, cyclopropyl;
  • R 2 is (C )alkyl
  • X is hydrogen, bromine
  • R 3 and the same or different, respectively selected from (CC 4 ) alkyl, cyclopropyl;
  • R 3 and together with the nitrogen atom to which they are attached form a mercapto group, 4-morpholinyl, 4-methyl-1-piperazinyl, 1-piperidinyl, 1-pyrrolidinyl, 1H-1, 2,4-triazol-1-yl, 1-imidazolyl, 2-methyl-1-imidazolyl and 1H-tetrazol-1-yl; Representative (CC 4 )alkyl, (dC 4 )alkoxy, halo, hydroxy, cyano, carboxy, ester, nitro; (0) m
  • Z is a CH 2 —(CH 2 ) n -Q ;
  • n 0, 1, 2;
  • n is an integer between 0 and 4;
  • R 5 is furan-2-yl, pyridin-2-yl, thiophen-2-yl
  • R 9 is (dC alkyl, (dC alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethoxy, carboxy, amino, nitro, cyano, decyl, (CrC 4 ) alkenyl, (CrC 4 ) alkynyl, (CrC 4 )alkylthio, hydroxy(CrC 4 )alkyl, amino (dC alkyl, allyl, (2-methyl)allyl, (3-methyl)allyl , (2-methyl; )-2-enylbutyl, (Ci-C 4 )alkylamido, (CrC 4 )alkylsulfinyl, (CrC 4 )alkylsulfonyl, (CrC 4 ) alkane Oxymethyl, (dC 4 ) alkyl acyl, carbamoyl, N dC alkylcarbamoyl, N, N-di (dC alkyl
  • Very particularly preferred derivatives of the general formula I including racemates or optical isomers thereof, and pharmaceutically acceptable salts and/or hydrates thereof, are:
  • the heterocyclic 5-hydroxyindole derivative of the formula I of the present invention can form a pharmaceutically acceptable salt thereof with an acid according to some usual methods in the art to which the present invention pertains.
  • the acid may include an inorganic or organic acid, and a salt formed with the following acids is particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid , acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, tartaric acid, benzenesulfonic acid, benzoic acid or p-toluenesulfonic acid, and the like.
  • the compounds of the invention may exist in stereoisomeric forms which may be enantiomers or diastereomers.
  • the invention relates both to enantiomers or diastereomers, as well as to their respective mixtures, which, like diastereomers, can be separated into stereoisomeric single components in a manner known per se.
  • the invention also includes prodrugs of the compounds of the invention.
  • prodrugs are derivatives of the compounds of formula I which may themselves have weak or even no activity, but after administration, under physiological conditions (for example by metabolism, solvolysis or otherwise) It is converted to the corresponding biologically active form.
  • halo as used herein, unless otherwise indicated, means fluoro, chloro, bromo or iodo;
  • alkyl means a straight or branched alkyl;
  • cycloalkyl means a substituted Or an unsubstituted cycloalkyl group;
  • alkenyl means a straight or branched alkenyl group;
  • alkynyl means a straight or branched alkynyl group;
  • aryl means a hydrogen removed from an aromatic hydrocarbon.
  • An organic group derived from an atom such as a phenyl group or a naphthyl group; a 5-10 membered heteroaryl group includes a hetero atom containing one or more selected from N, 0 and S, wherein a cyclic system of each heteroaryl group may be used.
  • the cyclic system is aromatic, containing a total of 5-10 atoms, such as imidazolyl, pyridyl, pyrimidinyl, pyrazolyl, (1, 2, 3)- and (1, 2, 4)-triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, benzothienyl, a benzofuranyl group, a benzimidazolyl group, a benzothiazolyl group, a fluorenyl group, a quinolyl group or the like; a 5-10 membered heterocyclic group includes one or more hetero atoms selected from N, 0 and S, each of which Miscellaneous
  • the cyclic system of the radical may be monocyclic or polycyclic, but non-aromatic, the cyclic system isoxazolyl,
  • Particular compounds of the invention may have asymmetric centers and therefore exist in different enantiomers and diastereomers.
  • the present invention relates to all optical isomers, racemates and mixtures thereof of the compounds of the invention.
  • “Blancher” means a mixture containing equal amounts of a pair of enantiomers.
  • the 5-hydroxyindole compound of the above formula I according to the present invention has an antiviral action, particularly anti-HBV and anti-influenza activity, it can be used as a medicament for the preparation of a therapeutic and/or prophylactic viral infection.
  • infections caused by viruses such as HBV, influenza A virus, influenza B virus, respiratory syncytial virus, parainfluenza virus, rhinovirus, and adenovirus.
  • the compound according to the present invention can be used as an active ingredient for the preparation of a therapeutic and/or prophylactic agent for hepatitis B, influenza, acute viral respiratory infection and influenza, and the present invention also provides a method for treating or preventing the above-mentioned diseases, including giving or suffering from A patient having this condition has a therapeutically effective amount of a compound according to the invention.
  • the present invention includes a pharmaceutical composition
  • a pharmaceutical composition comprising a 5-hydroxyindole compound of the formula I or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable excipient refers to any diluent, adjuvant and/or carrier that can be used in the pharmaceutical field.
  • the compounds of the present invention can be used in combination with other active ingredients as long as they do not produce other adverse effects such as allergic reactions.
  • compositions of the present invention may be formulated in a number of dosage forms containing some of the excipients commonly used in the pharmaceutical arts; for example, oral preparations (e.g., tablets, capsules, solutions or suspensions); injectable preparations (e.g. Injectable solutions or suspensions, or injectable dry powders, ready to use by adding water for injection before injection; topical preparations (eg ointments or solutions).
  • oral preparations e.g., tablets, capsules, solutions or suspensions
  • injectable preparations e.g. Injectable solutions or suspensions, or injectable dry powders, ready to use by adding water for injection before injection
  • topical preparations eg ointments or solutions.
  • the carrier used in the pharmaceutical composition of the present invention is a common type available in the pharmaceutical field, and includes: a binder for an oral preparation, a lubricant, a disintegrant, a solubilizer, a diluent, a stabilizer, a suspending agent, and a non-pigment. , flavoring agents, etc.; preservatives, solubilizers, stabilizers, etc. for injectable preparations; bases, diluents, lubricants, preservatives, etc. for topical preparations.
  • the pharmaceutical preparations can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically), and if certain drugs are unstable under gastric conditions, they can be formulated into enteric coated tablets.
  • the clinical dose of the 5-hydroxy steroid of the formula I for use in a patient can be based on: the active ingredient is in the body
  • the therapeutic efficacy and bioavailability, their metabolic and excretion rates, and the age, sex, and disease period of the patient are appropriately adjusted, but the daily dose for adults should generally be 10-500 mg, preferably 50-300 mg.
  • each unit preparation should contain 10-500 mg of the 5-hydroxyindole compound of the above formula I, preferably 50-300 mg. These preparations may be administered several times at intervals (preferably one to six times; as directed by a physician or pharmacist).
  • Y is -NR 3 R4, wherein R 3 , the same or different, are respectively selected from hydrogen, amino, d-doalkyl, C 3 -C 7 a cycloalkyl group, a C 2 -C 1Q alkenyl group and a C 2 -C 1Q alkynyl group, which may be optionally substituted by 1 to 3; or R 3 , together with the nitrogen atom to which they are attached, form a 5-10 membered hetero a cyclo group, which may contain, in addition to R 3 and a bonded nitrogen atom, from 1 to 4 heteroatoms selected from N, 0 and S, except for R 3 and the attached nitrogen atom,
  • the ring group optionally includes 1 or 2 carbon-carbon double bonds or hydrazine
  • the heterocyclic group may be optionally substituted by 1 to 3;
  • Q is The substituents Ri, R 2 and R 5 are as defined in the Summary of the Invention.
  • Compound B1 can be prepared according to the synthesis method provided in Scheme A.
  • Compound B-1 is reacted with sodium perborate (NaB0 3 ) as an oxidant in glacial acetic acid at 40 ° C to 60 ° C by changing the ratio and reaction of the oxidizing agent.
  • NaB0 3 sodium perborate
  • monooxide B-2 and double oxide B-3 are obtained, and then the Mannich reaction is carried out to obtain compounds B-4 and B-5 of formula I or formula II.
  • Y is -NR 3 R4, -S(CH 2 ) r R 8 , r is an integer between 1-4, and Ri, R 2 and Z are as A compound of formula II as defined in the claims, R 3 , and together with the nitrogen atom to which they are attached form a fluorenyl group or a 5-10 membered heteroaryl group, which may be in addition to the nitrogen atom attached to R 3 and Containing from 1 to 4 heteroatoms selected from N, 0 and S, the heteroaryl group may be optionally substituted by from 1 to 3 identical or different R 8 ; other substituents are as defined in the formula ⁇ compound.
  • Compound C-1 can be obtained by the synthesis method provided in Schemes A and B, and compound C-1 is reacted with compound HNR 3 R4 or HS(CH 2 )mR 8 , and the organic solvent used for the reaction is ethanol-water (1 : 1) Solvent, reaction temperature is 60-80 °C, reaction time is 4-12 h, reaction is completed, concentrated reaction solution, dichloromethane extraction, combined, dried, evaporated to dryness, recrystallized from ethanol or methanol or column Analysis gave Compound C-2 of Formula I or Formula II. Detailed ways:
  • the nuclear magnetic resonance spectrum of the compound was determined by Bruker ARX-300, and the mass spectrum was determined by Agilent 1100 LC/MSD; the reagents used were either analytically pure or chemically pure.
  • Partial mercaptans or thiophenols are commercially available; other thiols or thiophenols are prepared as follows: Method 1 : Preparation of s"
  • a white solid 4-methylthiazole-2-thiol was obtained by using chloroacetone and ammonium dithiocarbamate as a raw material and ethanol as a solvent, and the yield was 87%.
  • the 3-hydrocarbylamino-2-butenoic acid ester can be directly used without a gas generating device.
  • the hydrocarbyl-substituted amine was dropped into acetoacetate and prepared according to the above method.
  • Step B Preparation of 1-hydrocarbyl-2-methyl-5-hydroxyindole-3-carboxylate (A-2)
  • Phenylhydrazine (0.096 mol) was dissolved in 100 mL of 1,2-dichloroethane, heated to 60 ° C, stirred until dissolved completely, and the compound Al was added dropwise, and the reaction was refluxed for 8 h. After cooling to room temperature, it was allowed to stand overnight, and the solid was precipitated, suction filtered, washed with cold acetone, dried, and then recrystallized from acetone to give compound A-2, yield: 40 60 %.
  • Step D Preparation of 1-hydrocarbyl-2-bromomethyl-5-acetoxy-6-bromo-1H-indole-3-carboxylate (A-4)
  • Compound A-3 (0.04 mol) was added In 50 mL of carbon tetrachloride, it was heated to reflux until the solid was completely dissolved.
  • Add a catalytic amount of benzoyl peroxide add 5.1 mL (0.1 mol) of dry bromine to the reaction droplets under reflux with heating, drop, reflux for 5 h, complete reaction, allow to stand, cool, suction filtration, water wash, methanol wash
  • the compound V was obtained in a yield of 65%-85%.
  • Step E Preparation of 1-hydrocarbyl-2-(substituted thiomethyl)-5-hydroxy-6-bromo-1H-indole-3-carboxylate (A-5) In 40 mL of methanol, hydrogen peroxide was added.
  • Step H 1-Hydroxy-4-[(fatty amino)methyl]-2-(substituted thiomethyl)-5-hydroxy-6-bromo-1H-indole-3-carboxylate (A- 6)
  • the obtained oil is dissolved in acetone 30 mL, and an appropriate amount of diethyl ether is added dropwise thereto, and the mixture is allowed to stand for crystallizing, filtered, washed with a small amount of acetone and washed with diethyl ether to obtain A-6 in a yield of 40 to 70%;
  • the oil is dissolved in acetone 30 mL, and the hydrochloric acid ethanol solution is added dropwise to pH 1-2, a small amount of diethyl ether is added dropwise to the turbidity, and left to stand overnight, and the crystallized to obtain A-6 hydrochloride, the yield is 40-70. %
  • Step A Preparation of 1-hydrocarbyl-2-substituted thiomethyl-5-hydroxy-6-substituted (hydrogen)-IH-indole-3-carboxylic acid ethyl ester (Bl)
  • Preparation of compound B-1 can be carried out according to The synthetic method for preparing the general methods 1 and 2 is prepared.
  • Step B Preparation of 1-hydrocarbyl-2-substituted sulfinylmethyl-5-hydroxy-6-substituted (hydrogen)-1H-indole-3-carboxylate (B-2)
  • Step C Preparation of 1-hydrocarbyl-2-substituted sulfonylmethyl-5-hydroxy-6-substituted (hydrogen)-1H-indole-3-carboxylic acid ethyl ester (B-3)
  • B-1 0.01 mol
  • NaB0 3 .43 ⁇ 40 sodium perborate tetrahydrate
  • Step D 1-hydrocarbyl-4-substituted aminemethyl-2-substituted sulfinylmethyl (substituted sulfonylmethyl)-5-hydroxy-6-substituted(hydro)-1H-indole-3 -Preparation of ethyl carboxylate (B4 or B-5)
  • the target product B-4 or B-5 is obtained by reacting Compound B-2 or B-3 with a suitable fatty amine, 37% formaldehyde solution according to the procedure of Preparation 1, Step 1.
  • Compound C-1 can be obtained according to the preparation of General Procedure 1 or 2.
  • the thiazole-5-hydroxyindole derivative of the above formula I or formula II according to the present invention is screened for anti-hepatitis B virus activity and anti-HIV-1 protease activity in vitro.
  • the ability of the sample to inhibit hepatitis B virus DNA replication and HBsAg, HBeAg was determined by using 2.2.15 cells as the hepatitis B virus vector.
  • sample processing The sample was dissolved in DMSO to prepare an appropriate concentration, and each sample was diluted 3 times with the culture solution for a total of 8 dilutions.
  • Test method 2.2.15 cell type 96-well culture plate, 36 hours later, add the sample and positive control drug according to the above dilution, and set the cell control well at the same time. After 96 hours, replace the sample culture solution with different dilution concentration. Cell supernatant and 2.2.15 cells were collected on the 8th day of the seed plate. The secretion of HBsAg and HBeAg in the supernatant was detected by RIA method. The degree of HBV DNA replication in the cells was detected by dot blot method, and IC 5Q and SI were calculated respectively.
  • Example 2 43.11 - - ⁇ 0. 23 2.37 1 1
  • Example 4 32.07 9.74 3.29 1. 49 21.52 1 1
  • Example 7 12.84 - - - - 1 1
  • Example 8 32.08 - - 3. 83 8.37 1 1
  • Example 10 32.08 - - 11. 97 2.68 1 1
  • Example 14 32.08 - - - - 1 1
  • Example 21 18.52 5.06 3.66 ⁇ 0. 23 1.54 1 1
  • Example 29 240.37 - - ⁇ 0. 23 3.84 1 1
  • Example 30 43.11 - - ⁇ 0. 23 2.73 1 1
  • Example 31 32.08 - - ⁇ 0.
  • Example 32 6.17 - - - - 1 1
  • Example 33 32.07 - - ⁇ 0. 69 6.98 1 1
  • Example 34 240.37 47.26 5.09 ⁇ 0. 69 7.58 1 1
  • Example 36 32.08 - - ⁇ 0. 69 24.29 1 1
  • Example 37 80.12 - - - - 1 1
  • Example 38 18.52 4.79 3.87 ⁇ 0.23 4.76 1 1
  • Example 39 55.56 - - - - 1 1
  • Example 40 32.08 - - ⁇ 0. 23 3.74 1 1
  • Example 41 96.23 18.47 5.21 ⁇ 2. 06 1,36 1 1
  • Example 42 55.56 - - - - 1 1
  • Example 43 80.12 - - ⁇ 0.
  • Example 44 43.11 3.88 11.11 ⁇ 0. 23 2.53 1 1
  • Example 45 43.11 3.26 13.22 ⁇ 0. 23 4.16 1 1
  • Example 48 166.67 33.41 4.99 ⁇ 2. 06 3.52 1 1
  • Example 49 80.12 - - ⁇ 0. 69 3.63 1 1
  • Example 50 43.11 - - ⁇ 0. 23 2.15 1 1
  • Example 51 32.07 - - ⁇ 0. 23 3.64 1 1
  • Example 53 26.71 4.74 5.64 ⁇ 0.23 6.83 1 1
  • Example 54 32.07 - - ⁇ 0. 69 2.56 1 1
  • Example 56 32.07 - - ⁇ 0.
  • Example 58 32.08 - - 10.21 3.14 1.62 4,31
  • Example 59 38.52 15.10 2.55 - - 34.42 9.75
  • Example 61 96.23 - - 7.65 12.58 4.28 6.46
  • Example 62 10.69 - - 3.21 3.34 3.64 2.94
  • 3TC 288.68 - - - 12.56 22.98 "/" means untested activity II, anti-influenza virus activity screening
  • MDCK (hamster kidney) cells were used as viral hosts to determine the extent to which MDCK cells were induced by inhibition of influenza A virus.
  • Virus strain A type 3 virus 90-15 strains.
  • Sample processing The sample is dissolved in DMSO to a suitable concentration before use, and the culture medium is diluted twice with a total of 8 dilutions.
  • ribavirin (RBV;), produced by Hubei Keyi Pharmaceutical Factory.
  • Test Method MDCK cells in 96-well culture plate, 24 hours after infection A / anti Ji / 90-15 strain 10_ 3, 3 hours adsorption, the virus solution was discarded, according to the above dilution and positive control samples were added, at the same time provided Cell control wells and virus control wells were observed for 30 hours for cytopathic effect (CPE), and the half-inhibitory concentration (IC 5 o) of the influenza virus A was determined by Reed-Muench method.
  • CPE cytopathic effect
  • Example 1 96.23 2.43 3.36
  • Example 9 32.08 10.23 2.5
  • Example 11 32.08 5.52 12.36
  • Example 13 80.12 4.28 5.85
  • Example 15 18.52 2.53 1.52
  • Example 18 32.08 11.02 5.83
  • Example 57 23.86 4.62 6.0
  • Example 60 10.69 8.46 5.27 Abby Dole 62.5 23.2 2.69 Ribavirin>1000 >33.81 >29.57

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Abstract

La présente invention porte sur un dérivé de 5-hydroxyindole contenant un noyau hétérocyclique représenté par la formule I, y compris un racémate du dérivé, un isomère optique de celui-ci et un sel pharmaceutiquement acceptable et/ou hydrate de celui-ci, dans laquelle formule les substituants R1, R2, X, Y et Z ont les significations fournies dans la description. Le composé de formule I est applicable en préparation d'un médicament pour le traitement et/ou la prévention d'infections virales et en particulier pour la préparation d'un médicament contre le virus de l'hépatite B et d'un médicament contre le virus de la grippe.
PCT/CN2013/087136 2012-11-15 2013-11-14 Dérivé de 5-hydroxyindole contenant un noyau hétérocyclique et son utilisation WO2014075618A1 (fr)

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CN102924443B (zh) * 2012-11-15 2015-03-25 沈阳药科大学 含有杂环的5-羟基吲哚类衍生物及其用途
CN106608874B (zh) * 2015-10-22 2019-04-12 湖南大学 2-[5-(氮唑-1-基)噻唑-2-亚氨基]噻唑啉酮及其制备方法与应用
CN112972466B (zh) * 2019-12-16 2022-09-09 沈阳药科大学 5-羟基吲哚-3-羧酸酯类化合物在抑制外周炎症及中枢神经系统炎症方面的用途
CN111529525A (zh) * 2020-05-15 2020-08-14 淮安市厚沐医疗技术咨询中心 一种Gab1抑制剂用于治疗胆管癌的用途
CN111358786A (zh) * 2020-05-15 2020-07-03 淮安市厚沐医疗技术咨询中心 一种Gab1抑制剂在治疗胆管癌方面的应用
CN114380770B (zh) * 2021-12-24 2022-12-09 山东艾孚特科技有限公司 利用固体超强酸催化的甲基巯基噻二唑的合成工艺

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