WO2012016510A1 - 哒嗪衍生物及其作为抗小rna病毒感染的药物的用途 - Google Patents

哒嗪衍生物及其作为抗小rna病毒感染的药物的用途 Download PDF

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WO2012016510A1
WO2012016510A1 PCT/CN2011/077896 CN2011077896W WO2012016510A1 WO 2012016510 A1 WO2012016510 A1 WO 2012016510A1 CN 2011077896 W CN2011077896 W CN 2011077896W WO 2012016510 A1 WO2012016510 A1 WO 2012016510A1
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group
compound
virus
pharmaceutically acceptable
acceptable salt
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PCT/CN2011/077896
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English (en)
French (fr)
Inventor
李松
王宏亮
肖军海
张献
王莉莉
郑志兵
钟武
谢云德
李行舟
周辛波
赵国明
王晓奎
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中国人民解放军军事医学科学院毒物药物研究所
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Priority to US13/813,806 priority Critical patent/US8846678B2/en
Priority to JP2013522088A priority patent/JP5886853B2/ja
Priority to EP11814093.8A priority patent/EP2602252B1/en
Publication of WO2012016510A1 publication Critical patent/WO2012016510A1/zh
Priority to US14/494,285 priority patent/US9522891B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/20—Nitrogen atoms
    • 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
    • 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
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • 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
    • 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
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/04—Drugs for disorders of the respiratory system for throat disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to a substituted pyridazine derivative or a pharmaceutically acceptable salt or hydrate thereof, a pharmaceutical composition containing the same, and a virus which is caused by a small RNA virus as a drug against infection by a small RNA virus in preventing and/or treating a small RNA virus Use in disease. Background technique
  • the picornavirus family is the smallest known animal RNA virus, which has seven genera, namely Rhinovirus, Enterovirus, Oral Disease, Genovirus, Hepatic, and Escherichia. There are also some unclassified picornaviruses. Small RNA viruses can cause diseases such as respiratory diseases, hand and foot diseases, meningitis/encephalitis, acute poliovirus, cardiovascular diseases, hemorrhagic conjunctivitis, and hepatitis.
  • Virology has made great progress in the late 1980s. Several important events in the life cycle of the virus have been well characterized, and many molecular targets have also been validated. In recent years, the emergence of many new antiviral drugs has also spurred the development of virology. Small RNA virus inhibitors are undergoing activity studies. Targets for the action of these inhibitors include viral capsid protein 1 (VP1), a relatively conserved capsid structure that mediates viral adsorption/decapitation.
  • VP1 viral capsid protein 1
  • the VP1 of different serotypes is highly conserved, but is essential for viral replication, inhibitors of this target and may be anti-picof RNA viruses, of which Pirodavir is a typical representative (ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 36(4) , 727-732), the compound exhibits significant anti-rhinovirus (HRV) activity both in vitro and in vivo.
  • Pirodavir is a typical representative (ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 36(4) , 727-732)
  • HRV anti-rhinovirus
  • V7: 621-624 discloses a series of compounds with good inhibitory activity against HRV, wherein the compound 4- ⁇ 2-[N-(3-chloropyridazin-4-yl)piperidine- Ethyl 4-yl]ethoxy ⁇ benzoate (5f) and 3,6-dichloro-4- ⁇ 4-[2-(4-ethoxyphenoxy)ethyl]piperazin-1-yl ⁇
  • the activity of pyridazine (5c) is comparable to that of Pirodavir, but the toxicity is relatively low and the selectivity index is higher.
  • an antiviral agent that is structurally novel, effective, and optionally has one or more advantages in terms of both physiological and/or physicochemical properties. Summary of the invention
  • the object of the present invention is to find and develop a novel class of small molecule compounds of VP1 which act on small RNA viruses, which can prevent adhesion and uncoating of viruses, and have small RNA virus inhibitory activity, thereby preventing and/or treating small RNAs.
  • the purpose of the disease caused by the virus is to find and develop a novel class of small molecule compounds of VP1 which act on small RNA viruses, which can prevent adhesion and uncoating of viruses, and have small RNA virus inhibitory activity, thereby preventing and/or treating small RNAs.
  • the present inventors have found through research that a compound of the following formula I can act on VP1 of a small RNA virus to prevent adhesion and husking of the virus, and thus can be used for the prevention and/or treatment of diseases caused by small RNA viruses.
  • the present invention has been completed based on the above findings.
  • the first aspect of the invention provides a compound I:
  • R1, R2 and R3 are each independently selected from the group consisting of hydrogen and halogen (e.g., fluorine, chlorine, bromine or hydrazine, preferably fluorine or chlorine);
  • halogen e.g., fluorine, chlorine, bromine or hydrazine, preferably fluorine or chlorine
  • n is an integer of 2-5 (for example, an integer of 3-5, an integer of 3-4, 2, 3, 4 or 5, preferably an integer of 3-5, an integer of 3-4, 2, 3 or 4);
  • R4, R5 and R6 are each independently selected from hydrogen, halogen (e.g., fluoro, chloro, bromo or iodo), C1-C8 straight or branched alkyl (e.g., C1-C8 straight or branched alkyl, C1-C6 a linear or branched alkyl group, a C1-C4 linear or branched alkyl group, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, an n-butyl group or a t-butyl group), -COOR7 and -OR8;
  • halogen e.g., fluoro, chloro, bromo or iodo
  • C1-C8 straight or branched alkyl e.g., C1-C8 straight or branched alkyl, C1-C6 a linear or branched alkyl group, a C1-C
  • R7 and R8 are each independently selected from hydrogen, C1-C6 straight or branched alkyl (e.g., C1-C4 straight or branched alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl Or tert-butyl).
  • C1-C6 straight or branched alkyl e.g., C1-C4 straight or branched alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl Or tert-butyl).
  • a compound according to the first aspect of the invention which is a compound of the formula la:
  • R1 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine and iodine (preferably fluorine and chlorine);
  • n is an integer of 2-5 (for example, an integer of 3-5, an integer of 3-4, 2, 3, 4 or 5, preferably an integer of 3-5, an integer of 3-4, 2, 3 or 4);
  • R4 is selected from the group consisting of hydrogen, halogen (e.g., fluorine, chlorine, bromine, iodine), C1-C8 linear or branched alkyl (e.g., C1-C8 straight or branched alkyl, C1-C6 straight or branched alkyl) , C1-C4 linear or branched alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl or t-butyl), -COOR7 and -OR8;
  • halogen e.g., fluorine, chlorine, bromine, iodine
  • C1-C8 linear or branched alkyl e.g., C1-C8 straight or branched alkyl, C1-C6 straight or branched alkyl
  • C1-C4 linear or branched alkyl methyl, ethyl, n-propyl, isopropy
  • R7 and R8 are each independently selected from hydrogen, C1-C6 straight or branched alkyl (e.g., C1-C4 straight or branched alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl Or tert-butyl).
  • C1-C6 straight or branched alkyl e.g., C1-C4 straight or branched alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl Or tert-butyl).
  • R1 is selected from the group consisting of fluorine and chlorine
  • n is an integer of 3-5 (preferably an integer of 3-4, 3 or 4);
  • R4 is selected from halogen (e.g., fluorine, chlorine), C1-C6 straight or branched alkyl (e.g., C1-C4 linear or branched alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl) Base or tert-butyl), -COOR7 and -OR8;
  • halogen e.g., fluorine, chlorine
  • C1-C6 straight or branched alkyl e.g., C1-C4 linear or branched alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl
  • Base or tert-butyl tert-butyl
  • R7 and R8 are each independently selected from hydrogen, a C1-C4 straight or branched alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl or t-butyl).
  • a compound according to the first aspect of the invention which is a compound of the formula la:
  • R1 is chlorine
  • n 3 or 4;
  • R4 is selected from a C1-C6 straight or branched alkyl group (for example, a C1-C4 straight or branched alkyl group, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, and a n-butyl group), -COOR7, and -OR8; among them
  • R7 and R8 are each independently selected from the group consisting of hydrogen and a C1-C4 linear or branched alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, and n-butyl).
  • a C1-C4 linear or branched alkyl group e.g., methyl, ethyl, n-propyl, isopropyl, and n-butyl.
  • a compound according to the first aspect of the invention which is selected from the group consisting of
  • a second aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of a compound of the first aspect of the invention, or a pharmaceutically acceptable salt or hydrate thereof, and optionally one or A wide variety of pharmaceutically acceptable carriers or excipients.
  • a third aspect of the invention provides the compound of the first aspect of the invention, or a pharmaceutically acceptable salt or hydrate thereof, or the pharmaceutical composition of the second aspect of the invention, for use in the treatment and/or prevention of a viral infection
  • the virus is a small RNA virus.
  • the picornavirus is selected from the group consisting of: a rhinovirus, an enterovirus, an aphthous virus, a heart virus, a hepatic virus, a double echo virus.
  • the disease or condition associated with the viral infection is selected from the group consisting of: respiratory diseases (including but not limited to: common cold (eg, summer cold), pharyngitis, tonsillitis, and membranous Laryngitis), hand and foot disease, meningitis/encephalitis, acute poliomyelitis, cardiovascular disease, hemorrhagic conjunctivitis, hepatitis, etc.
  • respiratory diseases including but not limited to: common cold (eg, summer cold), pharyngitis, tonsillitis, and membranous Laryngitis
  • hand and foot disease meningitis/encephalitis, acute poliomyelitis, cardiovascular disease, hemorrhagic conjunctivitis, hepatitis, etc.
  • a fourth aspect of the invention provides the compound of the first aspect of the invention, or a pharmaceutically acceptable salt or hydrate thereof, or the pharmaceutical composition of the second aspect of the invention as a medicament against a disease or condition associated with a viral infection use.
  • the virus is a small RNA virus.
  • the picornavirus is selected from the group consisting of: a rhinovirus, an enterovirus, an aphthous virus, a heart virus, a hepatic virus, a double echo virus.
  • the disease or condition associated with the viral infection is selected from the group consisting of: respiratory diseases (including but not limited to: common cold (eg, summer cold), pharyngitis, tonsillitis, and membranous Laryngitis), hand and foot disease, meningitis/encephalitis, acute poliomyelitis, cardiovascular disease, hemorrhagic conjunctivitis, hepatitis, etc.
  • respiratory diseases including but not limited to: common cold (eg, summer cold), pharyngitis, tonsillitis, and membranous Laryngitis
  • hand and foot disease meningitis/encephalitis
  • acute poliomyelitis acute poliomyelitis
  • cardiovascular disease hemorrhagic conjunctivitis
  • hepatitis hepatitis
  • a fifth aspect of the invention provides a method of treating and/or preventing a disease or condition associated with a viral infection in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutic and/or prophylactically effective
  • the virus is a small RNA virus.
  • the small RNA virus is selected from the group consisting of: rhinovirus, enterovirus, aphthous virus, heart virus, hepatic virus, double echo virus.
  • the disease or condition associated with the viral infection is selected from the group consisting of: respiratory diseases (including but not limited to: common cold (eg, summer cold), pharyngitis, tonsillitis, and membranous Laryngitis), hand and foot disease, meningitis/encephalitis, acute poliomyelitis, cardiovascular disease, hemorrhagic conjunctivitis, hepatitis, etc.
  • respiratory diseases including but not limited to: common cold (eg, summer cold), pharyngitis, tonsillitis, and membranous Laryngitis
  • hand and foot disease meningitis/encephalitis
  • acute poliomyelitis acute poliomyelitis
  • cardiovascular disease hemorrhagic conjunctivitis
  • hepatitis hepatitis
  • a sixth aspect of the invention provides a compound of the first aspect of the invention, or a pharmaceutically acceptable salt or hydrate thereof, for use in the treatment and/or prevention of a disease or condition associated with a viral infection.
  • the virus is a small RNA virus.
  • the picornavirus is selected from the group consisting of: rhinovirus, enterovirus, oral disease virus, heart virus, liver virus, double echo virus.
  • the disease or condition associated with the viral infection is selected from the group consisting of: respiratory diseases (including but not limited to: common cold (eg, summer cold), pharyngitis, Tonsillitis and croup,) Foot and mouth disease, meningitis/encephalitis, acute leukoaraiosis, cardiovascular disease, hemorrhagic conjunctivitis, hepatitis, etc.
  • respiratory diseases including but not limited to: common cold (eg, summer cold), pharyngitis, Tonsillitis and croup,) Foot and mouth disease, meningitis/encephalitis, acute leukoaraiosis, cardiovascular disease, hemorrhagic conjunctivitis, hepatitis, etc.
  • the term "pharmaceutically acceptable”, for example when describing a “pharmaceutically acceptable salt,” means that the salt is not only physiologically acceptable to the subject, but may also be used pharmaceutically. The substance of value.
  • alkyl as used herein, includes both straight and branched chain saturated hydrocarbon groups containing the specified number of carbon atoms.
  • d- 6 alkyl or "C1-C6 straight or branched alkyl” or “C1-C6 alkyl” refers to an alkyl group having the specified number of carbon atoms, which is a straight chain.
  • branched alkyl group and which may include a subgroup thereof, for example, d- 4 alkyl, d- 3 alkyl, d- 2 alkyl, C 2 -6 alkyl, C 2 -4- alkyl, etc., such as methyl , ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl and the like.
  • halogen means fluoro, chloro, bromo or iodo, especially fluoro, chloro or bromo.
  • the term "effective amount” refers to a dose that can achieve treatment and/or prevent a disease or condition of the invention in a subject.
  • composition may also refer to a “composition” which is useful for achieving a treatment and/or prevention of a disease or condition of the invention in a subject, particularly a mammal.
  • the term "subject" can refer to a patient or other recipient of the present invention.
  • % refers to a percentage by weight/weight, unless otherwise specified, particularly in the context of describing a solid material.
  • the "%” may mean a weight/volume percentage (in the case where the solid is dissolved in a liquid), or may refer to a volume/volume percentage (in the case where the liquid is dissolved in a liquid).
  • a method of preventing and/or treating a disease associated with a picornavirus infection comprising administering a prophylactically and/or therapeutically effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt thereof, or hydrated thereof
  • the patient is administered a disease in need of prevention and/or treatment of a disease associated with a small RNA virus infection.
  • the compound of the formula (I) of the present invention or a pharmaceutically acceptable salt or hydrate thereof is preferably the following compound:
  • the compound of the present invention can be exemplarily prepared by the following reaction route.
  • an ethyl quinonecarboxylate is reacted with a compound of the formula II in the presence of potassium carbonate at room temperature in the presence of acetonitrile as a solvent to form a hydrazine compound, in the presence of a 10% aqueous sodium hydroxide solution.
  • Heating under reflux with ethanol to give a compound of formula IV, a compound of formula V and a compound of formula IV in the presence of sodium carbonate at room temperature with chloroform, acetone, dichloromethane, N, N-dimethylformamide N,N-dimethylacetamide (preferably N,N-dimethylacetamide) is reacted as a solvent to give a compound of formula VI.
  • the compound of the formula VI is reacted with a compound of the formula W in the presence of triphenylphosphine and diethyl azodicarboxylate at room temperature in tetrahydrofuran to give the compound of the formula I.
  • the term "pharmaceutically acceptable salt" of a compound of the invention includes an acid salt of a compound of the invention with a pharmaceutically acceptable inorganic or organic acid or a base salt formed with a pharmaceutically acceptable base.
  • the acid salt thereof includes but is not limited to: hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, acetate, propionate, butyrate , oxalate, trimethylacetate, adipate, alginate, lactate, citrate, tartrate, succinate, maleate, fumarate, bitter Salts, aspartates, gluconates, benzoates, methanesulfonates, ethanesulfonates, besylate, p-toluenesulfonate and pamoate; alkali salts include However, it is not limited to: ammonium salts, alkali metal salts such as sodium and
  • the pharmaceutical composition of the present invention comprises an effective amount of a compound of the formula (I) of the present invention, or a pharmaceutically acceptable salt or hydrate thereof, and one or more suitable pharmaceutically acceptable carriers.
  • Pharmaceutically acceptable carriers herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphate, glycerol, sorbic acid, potassium sorbate, Partial glyceride mixture of saturated vegetable fatty acids, water, salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone , Cellulosic material, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, beeswax, polyethylene-polyoxypropylene block polymer and lanolin.
  • the compounds of the present invention are a class of potent small RNA viral inhibitors which are distinguished by the prevention and treatment of diseases caused by small RNA viruses.
  • the diseases caused by the small RNA virus include, but are not limited to, respiratory diseases, hand and foot diseases, meningitis/encephalitis, acute polio leukoencephalitis, cardiovascular diseases, hemorrhagic conjunctivitis, hepatitis, and the like.
  • the respiratory conditions include, but are not limited to, the common cold (summer cold), pharyngitis, tonsillitis, and croup. Such lesions are generally caused by rhinoviruses in the small RNA virus family.
  • the pharmaceutical composition of the compound of the present invention can be administered in any of the following ways: oral, spray inhalation, rectal administration, nasal administration, buccal administration, vaginal administration, topical administration, parenteral administration such as subcutaneous, intravenous, Intramuscular, internal, intrathecal, intraventricular, intrasternal, and intracranial injection or input or administration by means of an explant reservoir.
  • oral administration, intraperitoneal or intravenous administration is preferred.
  • intraventricular routes may be preferred to overcome the potentially low blood-brain barrier permeability of the compounds.
  • the compounds of the invention may be formulated into any orally acceptable form.
  • Formula including but not limited to tablets, capsules, aqueous solutions or aqueous suspensions.
  • carriers which are generally used for tablets include lactose and corn starch, and a lubricant such as magnesium stearate may also be added.
  • Diluents commonly used in capsule preparations include lactose and dried corn starch.
  • Aqueous suspension formulations are usually prepared by admixing the active ingredient with a suitable emulsifier and suspension. If desired, some of the above oral preparation forms may also contain some sweeteners, fragrances or colorants.
  • the compounds of the invention When administered rectally, the compounds of the invention will generally be in the form of a suppository which may be prepared by admixing the drug with a suitable non-irritating excipient.
  • the excipient appears solid at room temperature and melts at the rectal temperature to release the drug.
  • excipients include cocoa butter, beeswax and polyethylene glycol.
  • the compounds of the present invention can be formulated into different topical preparations according to different affected faces or organs.
  • the specific instructions are as follows:
  • the compound of the present invention When applied topically to the eye, the compound of the present invention can be formulated into a micronized suspension or solution in the form of a isotonic, sterile pH saline solution with or without a preservative such as benzyl chloride. Alkoxide.
  • the compound can also be formulated into a bone form such as Vaseline.
  • the compounds of the invention When applied topically to the skin, the compounds of the invention may be formulated in a suitable cartilage, lotion or cream formulation wherein the active ingredient is suspended or dissolved in one or more carriers.
  • Carriers which can be used herein for cartilage preparations include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; and lotions which can be used for lotions or creams include, but are not limited to: Mineral oil, sorbitan monostearate, Tween 60, cetyl esters wax, hexadecene aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the compound of the present invention When administered topically to the lower intestinal tract, the compound of the present invention can be formulated into a rectal suppository preparation as described above or a suitable enteral preparation, and a topical transdermal patch can also be used.
  • the compounds of the present invention can also be administered in the form of a sterile injectable preparation, including sterile injectable aqueous or oily suspensions, or sterile injectable solutions.
  • carriers and solvents which can be used include water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils may also be employed as a solvent or suspension medium such as a monoglyceride or a diglyceride.
  • the specific dosage and method of use of the compounds of the present invention for different patients depends on a number of factors, including the age, weight, sex, natural health status, nutritional status of the compound, the strength of the compound, the time of administration, the rate of metabolism, the condition. The severity of the diagnosis and the subjective judgment of the doctor. The preferred dose here is between
  • Example 2 Synthesis of 3- ⁇ 4-"3-(4-methylphenoxy)propylpiperazin-1-yl-6-chloropyridazine °+ [H PM] 'HI 'PHZ'L
  • HeLa cell self-existing in this laboratory
  • Virus Rhinovirus 3 (HRV-3) (ATCC: VR-1113)
  • Positive compound Reference i wrg M ⁇ id 2009, 17: 621-624, among which the preferred compound 4- ⁇ 2-[N-(3-chloropyridazin-4-yl)piperidin-4-yl]ethoxy Ethyl benzoate (5f) and 3,6-dichloro-4- ⁇ 4-[2-(4-ethoxyphenoxy)ethyl]piperazin-1-yl ⁇ pyridazine (5c)
  • Control 1 positive control drug 1
  • Control 2 positive control drug 2
  • the drug was dissolved in DMSO, it was diluted 20-fold with the cell maintenance solution, and then diluted 2 times to prepare different working solutions.
  • HeLa cells were seeded in 96-well plates in an amount of 10,000 (O.lmL) per well, and O.lmL maintenance solution was added. The cells were incubated at 37 ° C, and the maintenance solution was aspirated. Instead, 0.2 mL of the working solution of the compound was used as a control solution. The cell growth state was observed every 24 hours and observed for three days. The non-toxic limit (maximum non-toxic dilution) of the drug was determined as the minimum dilution factor of the lesion.
  • the drug is pre-mixed with the virus to prevent the virus from shelling and invading the cell.
  • METHODS The drug was added to a 12-well plate at a concentration of 100 ng/ml, and then a virus dose of TCID 50 of about 100 was added. After 0.5 h, 500,000 cells were added to each well and incubated at 33 ° C. Three days later, When the virus control group showed 100% cytopathic effect (CPE), the effect of the drug-protecting cells against phagocytosis was examined, and the cell protection rate (%) was expressed.
  • CPE cytopathic effect
  • the results of prophylactic administration showed that different compounds have different degrees of protection against cell phagocytosis; among them, Control 1, Control 2 and the compounds prepared in the respective examples all have a good protective effect on cells.
  • a concentration of 100 ng/mL was added to a 12-well plate at a total volume of 2 mL. After 48 h, when the virus control group showed 100% phagocytosis (CPE), the effect of the drug-protecting cells against phagocytosis was examined. %) indicates.
  • Maximum inhibitory virus concentration The compound concentration was set to 100% inhibition of virus titer (TCID 5 , value of approximately 100), and the virus was added stepwise in a multiplicative manner to determine the maximum virus concentration that can be inhibited at a given compound concentration.
  • the therapeutic activity screening data of the positive control drugs Control 1, Control 2 and the compounds prepared in the examples are shown in Table 1.
  • the results show that: under the therapeutic administration conditions, Control 1, Control 2 and the examples were prepared.
  • the compounds have a good protective effect on the cells, and some of the compounds of the present invention exhibit stronger activity than the control compounds under the same inhibition index.

Description

哒嗪衍生物及其作为抗小 RNA
病毒感染的药物的用途 技术领域
本发明涉及取代的哒嗪衍生物或其药学上可接受的盐或水合物， 含它们的药物组合物， 以及作为抗小 RNA病毒感染的药物在预防和 /或治疗小 RNA病毒引起的病毒性疾病中的用途。 背景技术
小 RNA病毒科是已知最小的动物 RNA病毒， 它共有 7个属， 即鼻病毒属、 肠道病毒属、 口疾病毒属、 心脏病毒属、 肝病毒属、 以 及双艾柯病毒属， 另外还有一些未分类的小 RNA病毒。 小 RNA病 毒可以引起诸如呼吸疾病、 手脚口疾病、 脑膜炎 /脑炎、 急性骨髓灰 白质炎、 心脏血管疾病、 出血性结膜炎、 肝炎等多个系统的疾病。
80 年代后期病毒学取得了很大进展。 病毒生命周期中的几个重 要事件已经被很好的描绘，许多分子靶标也已被验证，近年来随着许 多新型的抗病毒药物的出现也促使病毒学的发展达到高潮。 小 RNA 病毒抑制剂正在进行活性研究。这些抑制剂的作用靶标包括病毒衣壳 蛋白 1(VP1)， 一种相对保守的衣壳结构介导病毒的吸附 /脱壳过程。 不同血清型病毒的 VP1 高度保守结构， 但是对于病毒的复制非常必 要， 作用于这个靶标的抑制剂和可能成为抗细小 RNA病毒的药物， 其中 Pirodavir 是典型代表（ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 36(4), 727-732) ,该化合物在体内外均表现出显 著的抗鼻病毒 (HRV)活性。文献 Bioorg Med Chem. 2009, V7: 621-624 公开了一系列对 HRV 具有较好抑制活性的化合物， 其中化合物 4-{2-[N-(3-氯哒嗪 -4-基)哌啶 -4-基】乙氧基 }苯甲酸乙酯 (5f)和 3，6-二氯 -4-{4- [2-(4-乙氧基苯氧基）乙基】哌嗪 -1-基}哒嗪（5c)的活性与 Pirodavir相当， 但毒性相对较低， 选择性指数较高。 然而，本领域仍然需要有结构新颖的、有效的并且任选具有一种 或多种在生理学和 /或物理化学方面具有优点的抗病毒剂。 发明内容
本发明的目的是寻找并开发一类新型的作用于小 RNA 病毒的 VP1的小分子化合物， 其可阻止病毒的黏附和脱壳， 具有小 RNA病 毒抑制活性， 从而达到预防和 /或治疗小 RNA 病毒引起的疾病的目 的。
本发明人经过研究现已发现，具有下面通式 I的化合物可作用于 小 RNA病毒的 VP1来阻止病毒的黏附及脱壳， 因此可用于预防和 / 或治疗小 RNA病毒引起的疾病。 本发明基于上述发现而得以完成。
本发明第一方面提 I化合物：
Figure imgf000004_0001
I
或其药学上可接受的盐或水合物， 其中：
Rl、 R2和 R3各自独立地选自氢和卤素 (例如氟、 氯、 溴或砩， 优选氟或氯）；
n为 2-5的整数 (例如 3-5的整数、 3-4的整数、 2、 3、 4或 5， 优 选 3-5的整数、 3-4的整数、 2、 3或 4); 并且
R4、 R5和 R6各自独立地选自氢、 卤素 (例如氟、 氯、 溴或碘)、 C1-C8直链或支链烷基 (例如 C1-C8直链或支链烷基、 C1-C6直链或 支链烷基、 C1-C4直链或支链烷基、 甲基、 乙基、 正丙基、 异丙基、 正丁基或叔丁基)、 -COOR7和 -OR8; 其中
R7和 R8各自独立地选自氢、 C1-C6直链或支链烷基 (例如 C1-C4 直链或支链烷基、 甲基、 乙基、 正丙基、 异丙基、 正丁基或叔丁基)。
根据本发明第一方面的化合物， 其为以下式 la化合物：
Figure imgf000005_0001
或其药学上可接受的盐或水合物， 其中：
R1选自氢、 氟、 氯、 溴和碘 (优选氟和氯)；
n为 2-5的整数 (例如 3-5的整数、 3-4的整数、 2、 3、 4或 5， 优 选 3-5的整数、 3-4的整数、 2、 3或 4); 并且
R4选自氢、 卤素 (例如氟、 氯、 溴、 碘)、 C1-C8直链或支链烷 基 (例如 C1-C8直链或支链烷基、 C1-C6直链或支链烷基、 C1-C4直 链或支链烷基、 甲基、 乙基、 正丙基、 异丙基、 正丁基或叔丁基)、 -COOR7和 -OR8; 其中
R7和 R8各自独立地选自氢、 C1-C6直链或支链烷基 (例如 C1-C4 直链或支链烷基、 甲基、 乙基、 正丙基、 异丙基、 正丁基或叔丁基)。
根据本发明 物：
Figure imgf000005_0002
或其药学上可接受的盐或水合物， 其中：
R1选自氟和氯；
n为 3-5的整数 (优选 3-4的整数、 3或 4); 并且
R4选自卤素 (例如氟、 氯)、 C1-C6直链或支链烷基 (例如 C1-C4 直链或支链烷基、 甲基、 乙基、 正丙基、 异丙基、 正丁基或叔丁基)、 -COOR7和 -OR8; 其中
R7和 R8各自独立地选自氢、 C1-C4直链或支链烷基 (例如甲基、 乙基、 正丙基、 异丙基、 正丁基或叔丁基)。
根据本发明第一方面的化合物， 其为以下式 la化合物：
Figure imgf000005_0003
la 或其药学上可接受的盐或水合物， 其中：
R1为氯；
n为 3或 4; 并且
R4选自 C1-C6直链或支链烷基 (例如 C1-C4直链或支链烷基、 甲基、 乙基、 正丙基、 异丙基和正丁基)、 -COOR7和 -OR8; 其中
R7和 R8各自独立地选自氢和 C1-C4直链或支链烷基 (例如甲 基、 乙基、 正丙基、 异丙基和正丁基)。
根据本发明第一方面的化合物， 其选自：
3-{4-[3-(4-乙氧基苯氧基)丙基】哌嗪 -1-基}-6-氯哒嗪，
3-{4-[3-(4-甲基苯氧基)丙基】哌嗪 -1-基}-6-氯哒嗪，
3-{4-[3-(4-乙基苯氧基)丙基】哌嗪 -1-基}-6-氯-哒嗪，
3- {4-[3-(4-异丙基苯氧基)丙基】哌嗪 -1-基}-6-氯哒嗪，
4- {3-[4-(6-氯哒嗪 -3-基)哌嗪 -1-基】丙氧基 }苯甲酸甲酯， 以及
4-{3-[4-(6-氯哒嗪 -3-基)哌嗪 -1-基】丙氧基 }苯甲酸乙酯， 或其药学上可接受的盐或水合物。
本发明第二方面提供了一种药物组合物， 其包含治疗和 /或预防 有效量的本发明第一方面所述化合物或其药学上可接受的盐或水合 物， 以及任选的一种或多种药学上可接受的载体或赋形剂。
本发明第三方面提供了本发明第一方面所述化合物或其药学上 可接受的盐或水合物或者本发明第二方面所述药物组合物在制备用 于治疗和 /或预防与病毒感染有关的疾病或病症的药物中的用途。 在 本发明第三方面的一个实施方案中， 所述病毒是小 RNA病毒。 在本 发明第三方面的一个实施方案中， 所述小 RNA病毒选自： 鼻病毒、 肠道病毒、 口疮病毒、 心脏病毒、 肝病毒、 双艾柯病毒。 在本发明第 三方面的一个实施方案中， 所述与病毒感染有关的疾病或病症选自： 呼吸疾病（包括但不限于： 普通感冒 (例如夏季感冒）、咽炎、扁桃腺炎 和义膜性喉炎)、 手脚口疾病、 脑膜炎 /脑炎、 急性骨髓灰白质炎、 心 脏血管疾病、 出血性结膜炎、 肝炎等。 本发明第四方面提供了本发明第一方面所述化合物或其药学上 可接受的盐或水合物或者本发明第二方面所述药物组合物作为抗与 病毒感染有关的疾病或病症的药物的用途。在本发明第四方面的一个 实施方案中， 所述病毒是小 RNA病毒。 在本发明第四方面的一个实 施方案中， 所述小 RNA病毒选自： 鼻病毒、 肠道病毒、 口疮病毒、 心脏病毒、肝病毒、双艾柯病毒。在本发明第四方面的一个实施方案 中， 所述与病毒感染有关的疾病或病症选自： 呼吸疾病（包括但不限 于： 普通感冒 (例如夏季感冒)、 咽炎、 扁桃腺炎和义膜性喉炎)、 手脚 口疾病、 脑膜炎 /脑炎、 急性骨髓灰白质炎、 心脏血管疾病、 出血性 结膜炎、 肝炎等。
本发明第五方面提供了一种在有需要的受试者中治疗和 /或预防 与病毒感染有关的疾病或病症的方法，该方法包括给有需要的受试者 施用治疗和 /或预防有效量的至少一种本发明第一方面所述化合物或 其药学上可接受的盐或水合物或者本发明第二方面所述药物组合物。 在本发明第五方面的一个实施方案中， 所述病毒是小 RNA病毒。 在 本发明第五方面的一个实施方案中，所述小 RNA病毒选自：鼻病毒、 肠道病毒、 口疮病毒、 心脏病毒、 肝病毒、 双艾柯病毒。 在本发明第 五方面的一个实施方案中， 所述与病毒感染有关的疾病或病症选自： 呼吸疾病（包括但不限于： 普通感冒 (例如夏季感冒）、咽炎、扁桃腺炎 和义膜性喉炎)、 手脚口疾病、 脑膜炎 /脑炎、 急性骨髓灰白质炎、 心 脏血管疾病、 出血性结膜炎、 肝炎等。
本发明第六方面提供了用于治疗和 /或预防与病毒感染有关的疾 病或病症的本发明第一方面所述的化合物或其药学上可接受的盐或 水合物。 在本发明第六方面的一个实施方案中， 所述病毒是小 RNA 病毒。在本发明第六方面的一个实施方案中，所述小 RNA病毒选自： 鼻病毒、 肠道病毒、 口疾病毒、 心脏病毒、 肝病毒、 双艾柯病毒。 在 本发明第六方面的一个实施方案中，所述与病毒感染有关的疾病或病 症选自： 呼吸疾病（包括但不限于： 普通感冒 (例如夏季感冒）、 咽炎、 扁桃腺炎和义膜性喉炎)、 手脚口疾病、 脑膜炎 /脑炎、 急性骨髓灰白 质炎、 心脏血管疾病、 出血性结膜炎、 肝炎等。 下面对本发明的各个方面和特点作进一步的描述。
本发明所引述的所有文献， 它们的全部内容通过引用并入本文， 并且如果这些文献所表达的含义与本发明不一致时，以本发明的表述 为准。 此外， 如在本文中没有特别定义， 本发明中使用的各种术语和 短语具有本领域技术人员公知的一般含义，。 如果本文中所定义的术 语和短语与其公知含义不一致， 则以本文中所定义的含义为准。
如本文所述的， 术语"药学上可接受的"例如在描述"药学上可接 受的盐 "时， 表示该盐其不但是受试者生理学上可接受， 而且还可指 在药学上有使用价值的物质。
本文所用的术语 "烷基"包括含指定数目碳原子的直链和支链饱 和烃基。如本文所述的，术语" d_6烷基"或 "C1-C6直链或支链烷基" 或 "C1-C6烷基"是指具有指定数目碳原子数的烷基， 其为直链或支 链的烷基， 并且其可包括其子基团， 例如 d_4烷基、 d_3烷基、 d_2 烷基、 C2_6烷基、 C2_4烷基等， 例如甲基、 乙基、 正丙基、 异丙基、 正丁基、 异丁基、 叔丁基、 戊基、 己基等。
如本文所述的，术语"卤素"、 "卤素原子"、 "卤代 "等表示氟、氯、 溴或碘， 特别是表示氟、 氯或溴。
如本文所述的， 术语"有效量 "是指可在受试者中实现治疗和 /或 预防本发明所述疾病或病症的剂量。
如本文所述的， 术语"药物组合物"， 其还可以是指 "组合物"， 其 可用于在受试者特别是哺乳动物中实现治疗和 /或预防本发明所述疾 病或病症。
如本文所述的，术语 "受试者"可以指患者或者其它接受本发明式
I化合物或其药物组合物以治疗和 /或预防本发明所述疾病或病症的 动物， 特别是哺乳动物， 例如人、 狗、 猴、 牛、 马等。 如本文所述的， 如未特别指明， "％ "是指重量 /重量的百分比， 特别是在描述固体物质的情况下。 当然， 在描述液体物质时， 该"％" 可以指重量 /体积的百分比 (对于固体溶于液体的情形），或者可以指体 积 /体积百分比 (对于液体溶于液体的情形）。
在本发明的一个实施方案中，涉及预防和 /或治疗与小 RNA病毒 感染有关疾病的方法，其包括将预防和 /或治疗有效量的至少一种式 I 化合物或其药用盐或其水合物给予需要预防和 /或治疗小 RNA 病毒 感染有关的疾病的患者。
根据本发明， 本发明式 (I)的化合物或其药用盐或水合物优选下 面的化合物：
3-{4-[3-(4-乙氧基苯氧基)丙基】哌嗪 -1-基}-6-氯哒嗪，
3-{4-[3-(4-甲基苯氧基)丙基】哌嗪 -1-基}-6-氯哒嗪，
3-{4-[3-(4-乙基苯氧基)丙基】哌嗪 -1-基}-6-氯-哒嗪，
3- {4-[3-(4-异丙基苯氧基)丙基】哌嗪 -1-基}-6-氯哒嗪，
4- {3-[4-(6-氯哒嗪 -3-基)哌嗪 -1-基】丙氧基 }苯甲酸甲酯，
4-{3-[4-(6-氯哒嗪 -3-基)哌嗪 -1-基】丙氧基 }苯甲酸乙酯。
根据本发明， 本发明化合物可示例性地通过下面的反应路线制 备 ··
Figure imgf000010_0001
m IV
Figure imgf000010_0002
VI n
Figure imgf000010_0003
例如， 使 N-派喙甲酸乙酯与式 II化合物在碳酸钾的存在下， 于 室温下， 以乙腈作为溶剂进行反应， 反应生成式 ΠΙ化合物， 式 ΠΙ化合 物在 10%氢氧化钠水溶液的存在下， 以乙醇为溶剂加热回流， 生成 式 IV化合物，式 V化合物与式 IV化合物在碳酸钠的存在下，于室温下， 以氯仿、 丙酮、 二氯甲烷、 N， N-二甲基甲酰胺、 N， N-二甲基乙酰 胺 (优选 N， N-二甲基乙酰胺)作为溶剂进行反应， 得到式 VI化合物。 式 VI化合物与式 W化合物在三苯基膦和偶氮二甲酸二乙酯的存在下， 于室温下， 以四氢呋喃为溶剂进行反应， 得到式 I化合物。
根据本发明，本发明化合物的术语 "药学上可接受的盐 "包括本发 明化合物与制药学上可接受的无机或有机酸形成的酸盐或与制药学 上可接受的碱形成的碱盐。 其中酸盐包括但不限于： 盐酸盐、 氢溴酸 盐、 氢碘酸盐、 硝酸盐、 硫酸盐、 硫酸氢盐、 磷酸盐、 磷酸氢盐、 乙 酸盐、 丙酸盐、 丁酸盐、草酸盐、三甲基乙酸盐、 己二酸盐、 藻酸盐、 乳酸盐、 柠檬酸盐、 酒石酸盐、 琥珀酸盐、 马来酸盐、 富马酸盐、 苦 味酸盐、 天冬氨酸盐、 葡糖酸盐、 苯甲酸盐、 甲磺酸盐、 乙磺酸盐、 苯磺酸盐、 对甲苯磺酸盐和双羟萘酸盐； 碱盐包括但不限于： 铵盐、 碱金属盐如钠和钾盐、碱土金属盐如钙和镁盐、有机碱盐如二环己胺 和 N-甲基 -D-葡糖胺盐、 以及氨基酸盐如精氨酸和赖氨酸盐。
根据本发明， 本发明的药用组合物包括有效剂量的本发明式 (I) 化合物或其药学上可接受的盐或水合物和一种或多种适宜的药学上 可接受的载体。这里药学上可接受的载体包括但不限于：离子交换剂、 氧化铝、硬脂酸铝、 卵磷脂、血清蛋白如人血清蛋白、 緩冲物质如磷 酸盐、甘油、 山梨酸、 山梨酸钾、 饱和植物脂肪酸的部分甘油酯混合 物、 水、 盐或电解质、 如硫酸鱼精蛋白、 磷酸氢二钠、 磷酸氢钾、 氯 化钠、辞盐、胶态氧化硅、三硅酸镁、聚乙烯吡咯烷酮、纤维素物质、 聚乙二醇、 羧甲基纤维素钠、 聚丙烯酸酯、 蜂蜡、 聚乙烯-聚氧丙烯 嵌段聚合物和羊毛脂。
本发明化合物是一类强效的小 RNA病毒抑制剂， 该类化合物的 突出特点是既可预防又可治疗小 RNA病毒引起的疾病。所述小 RNA 病毒引起的疾病包括但不限于： 呼吸疾病、 手脚口疾病、 脑膜炎 /脑 炎、 急性骨髓灰白质炎、 心脏血管疾病、 出血性结膜炎、 肝炎等。
所述呼吸病症包括但不限于： 普通感冒 (夏季感冒）， 咽炎， 扁桃 腺炎和义膜性喉炎。 该类病变一般由小 RNA病毒家族中的鼻病毒所 致。
根据本发明，本发明化合物的药用组合物可以以下面的任意方式 施用： 口服、喷雾吸入、 直肠用药、鼻腔用药、颊部用药、 阴道用药、 局部用药、 非肠道用药如皮下、静脉、肌内、 内、鞘内、 心室内、 胸骨内和颅内注射或输入或借助一种外植储器用药。 其中优选口服、 腹膜内或静脉内用药方式。另外，为使本发明化合物有效治疗中枢神 经系统紊乱病症，可优选心室内途径用药以克服化合物可能低的血脑 屏障透过率。
当口服用药时， 本发明化合物可制成任意口服可接受的制剂形 式， 包括但不限于片剂、 胶嚢、 水溶液或水悬浮液。 其中， 片剂一 般使用的载体包括乳糖和玉米淀粉， 另外也可加入润滑剂如硬脂酸 镁。胶嚢制剂一般使用的稀释剂包括乳糖和干燥玉米淀粉。水悬浮液 制剂则通常是将活性成分与适宜的乳化剂和悬浮剂混合使用。如果需 要， 以上口服制剂形式中还可加入一些甜味剂、 芳香剂或着色剂。
当直肠用药时，本发明化合物一般可制成栓剂的形式，其通过将 药物与一种适宜的非刺激性赋形剂混合而制得。该赋形剂在室温下呈 现固体状态，而在直肠温度下熔化释出药物。这类赋形剂包括可可脂、 蜂蜡和聚乙二醇。
当局部用药时，特别是治疗局部外敷容易达到的患面或器官，如 眼睛、皮肤或下肠道神经性疾病时，本发明化合物可根据不同的患面 或器官制成不同的局部用药制剂形式， 具体说明如下：
当眼部局部施用时，本发明化合物可配制成一种微粉化悬浮液或 溶液的制剂形式， 所使用载体为等渗的一定 pH的无菌盐水， 其中可 加入也可不加防腐剂如氯化苄基烷醇盐。此外对于眼用，也可将化合 物制成骨剂形式如凡士林骨。
当皮肤局部施用时，本发明化合物可制成适当的软骨、洗剂或霜 剂制剂形式，其中活性成分悬浮或溶解于一种或多种载体中。这里软 骨制剂可使用的载体包括但不限于：矿物油、液体凡士林、白凡士林、 丙二醇、 聚氧化乙烯、 聚氧化丙烯、 乳化蜡和水； 洗剂或霜剂可使用 的载体包括但不限于： 矿物油、 脱水山梨糖醇单硬脂酸酯、 吐温 60、 十六烷酯蜡、 十六碳烯芳醇、 2-辛基十二烷醇、 苄醇和水。
当下肠道局部施用时，本发明化合物可制成如上所述的直肠栓剂 制剂或适宜的濯肠制剂形式， 另外也可使用局部透皮贴剂。
本发明化合物还可以无菌注射制剂形式用药，包括无菌注射水或 油悬浮液， 或无菌注射溶液。 其中， 可使用的载体和溶剂包括水， 林 格氏溶液和等渗氯化钠溶液。另外，灭菌的非挥发油也可用作溶剂或 悬浮介质， 如单甘油酯或二甘油酯。 另外需要指出，本发明化合物针对不同患者的特定使用剂量和使 用方法决定于诸多因素， 包括患者的年龄， 体重， 性别， 自然健康状 况， 营养状况， 化合物的活性强度， 服用时间， 代谢速率， 病症的严 重程度以及诊治医师的主观判断。 这里优选使用剂量介于
0.01~100mg/kg体重 /天。 具体实施方式
通过下面的实施例和试验例对本发明进行进一步的描述。 然而， 本发明的范围并不限于下述实施例或试验例。本领域的技术人员能够 理解，在不背离本发明的实质和范围的前提下， 可以对本发明进行各 种变化和修饰。如果在下文中没有特别说明，则所使用的材料和操作 方法是本领域公知的。
对于以下全部实施例，可以使用本领域技术人员已知的标准操作 和纯化方法。 除非另有说明， 所有温度以。 C (摄氏度)表示。 化合物 的结构是通过核磁共振 (NMR)或质谱 (MS)来确定的。化合物熔点 m.p. 由 RY-1型熔点仪测定，温度计未经较正， m.p.是以。 C给出。 iH NMR 由日本电子 JNM-ECA-400型核磁共振仪测定。 质谱由 Agilent 5875 (EI)仪测定。 所有反应用溶剂未注明都经标准化预处理。 实施例 1: 3-{4-『3-(4-乙氧基苯氧基)丙基〗哌嗪 -1-基}-6-氯哒嗪的 合成
1.1 4-(3-羟基丙基)哌嗪基甲酸乙酯的合成
将 N-派喙甲酸乙酯 (25.50g， 161.39mmol)、 3-溴 -1-丙醇 (22.43g， 161.39mmol)、碳酸钾 (55.68g， 403.48)和无水乙腈 (200mL)置于 500mL 圆底烧瓶中， 加热回流搅拌过夜， 反应降到室温， 过滤， 浓缩后柱层 析分离（洗脱剂： 二氯甲烷 /甲醇 /三乙胺系统， v/v/v l00: 1: 0.5)， 得淡 黄色油状物 26.60g， 收率 76.3%， 其直接投入下一步反应。
1.2 1-(3-羟基丙基)哌嗪的合成 将 4-(3-羟基丙基)哌嗪基甲酸乙酯 (14.06g， 65.09mmol)、 10%氢 氧化钠水溶液 (150mL)和乙醇 (150mL)置于 500mL圆底烧瓶中，加热 回流搅拌过夜， 反应降到室温， 减压蒸去溶剂得到淡黄色油状物， 加 入 200mL饱和食盐水， 用二氯甲烷 (5x200mL)萃取， 干燥 (Na2S04)， 过滤， 浓缩， 得到淡黄色油状物 7.56g， 收率 80.7%， 其直接投入下一 步反应。
1.3 3-『4-(6-氯哒嗪 -3-基)哌嗪 -1-基〗丙基 -1-醇的合成
将 3,6-二氯哒嗪 (14.90g， lOOmmol) , 碳酸钠 (10.60g， lOOmmol) 和 DMA(80mL)置于 250mL三颈瓶中， 冰浴条件下緩慢滴加 1-(3-羟 基丙基)派漆 (14.4g， lOOmmol)的 DMA(20mL)溶液， 30min内滴加完 毕， 在室温上搅拌过夜， 减压蒸去溶剂， 得到褐色固体， 柱层析分离 (梯度洗脱： 石油醚 /丙酮系统， vlv 2 1至丙酮）， 得到白色固体 13g， 收率 50.8%„
1.4 3-{4-『3-(4-乙氧基苯氧基)丙基〗哌嗪 -1-基 }-6-氯哒嗪的合成 将 3-[4-(6-氯哒嗪 -3-基)哌嗪 -1-基】丙基 -1-醇 (0.77g， 3mmol)、 对 乙氧基苯酚（0.41g， 3mmol)、 三苯基膦（0.79g， 3mmol)和无水 THF(20mL)置于 lOOmL 三颈瓶中， 冰浴条件下緩慢滴加 DEAD(0.52g, 3mmol) , lOmin内滴加完毕， 在室温下搅拌过夜， 柱 层析分离 剂：石油醚 /乙酸乙酯系统， v/v 3: 2)，得白色固体 0.27g， 收率 23.9%。 mp : 125-127°C ; 1H-NMR(400MHz, CDC13, ριη) ^1.39(t, 3H, =7.2 Hz), 2.00(m, 2H)， 2.61(br, 6H)， 3.67(br, 4H)， 3.98 (m， 4H)， 6.83(s, 4H)， 6.90(d, 1H， =9.6 Hz), 7.21(d, 1H， =9.6 Hz); EI-MS(m/z): 376·2[Μ+Η】+。
下述化合物可参考实施例 1步骤 1.4的方法制备，用不同的反应 物 (各种取代的苯酚)代替步骤 1.4中的对乙氧基苯酚进行制备。 实施例 2: 3-{4-『3-(4-甲基苯氧基)丙基〗哌嗪 -1-基 6-氯哒嗪的合 成 °+ [H PM]
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968..0/llOZN3/X3d 0IS9雕 ΪΟΖ OAV 基苯酚得标题化合物， 其为白色固体， 收率 23.9%。 mp: 128-130°C; ^ NMR (400MHz, CDC13, ^ppm) ^2.04(t, 2H， J=6A Hz), 2.60(br, 6H)， 3.66(br, 4H)， 3.89(s, 3H), 4.11 (t, 2H， =6.0 Hz), 6.91(m, 3H), 7.21(d, 1H, J=9.6 Hz), 7.99(d, 2H, =8.8 Hz); EI-MS(m/z): 390.2
[M-H】+。 实施例 6: 4-{3-『4-(6-氯哒嗪 -3-基)哌嗪 -1-基〗丙氧基 }苯甲酸乙酯 的合成
参考实施例 1步骤 1.4的方法， 以对羟基苯甲酸乙酯替代对乙氧 基苯酚得标题化合物， 其为白色固体， 收率 28.5%。 mp: 125-127°C; ^ NMR (400MHz, CDC13, ^ppm) ^1.38(t, 3H, J=7.2 Hz), 2.05(br, 2H)， 2.61(br, 6H)， 3.66(br, 4H)， 4.11(t, 2H， =6.0 Hz), 4.35(m, 2H)， 6.91(m, 3H), 7.20(d, 1H， J=9.6 Hz), 7.99(d, 2H， =8.8 Hz);
EI-MS(m/z): 404.2 [M-H】 +。 试验例 1 : 体外模型上的抗小 RNA病毒活性
实验材料：
宿主细胞： HeLa细胞 (本实验室自存）
病毒： 鼻病毒 3(HRV-3) (ATCC: VR-1113)
阳性化合物： 参考文献 i wrg M^ id 2009， 17: 621-624， 以其中优选化合物 4-{2-[N-(3-氯哒嗪 -4-基)哌啶 -4-基】乙氧基 }苯甲酸 乙酯 (5f)和 3，6-二氯 -4-{4-[2-(4-乙氧基苯氧基）乙基】哌嗪 -1-基}哒嗪 (5c) 分别作为阳性对照药 1(在本文可称为 Control 1)和阳性对照药 2(在本 文可称为 Control 2)。
1) 化合物最大无毒量的测定
药物以 DMSO溶解后， 以细胞维持液稀释 20倍， 而后 2倍逐级 稀释，配成不同浓度的工作液。 HeLa细胞以每孔 1万 (O.lmL)的数量 接种于 96孔板上， 加 O.lmL维持液， 37°C孵育贴壁， 吸去维持液， 代之以 0.2mL的化合物工作液， 以维持液作对照。 每 24h观察细胞 生长状态，观察三天。 以不出现病变最低稀释倍数确定为药物的无毒 限量 (最大无毒稀释度)。
2) 预防给药
原理： 药物与病毒预先混合温育， 以阻止病毒脱壳侵入细胞这一 过程。方法：药物以 100ng/ml浓度加入到 12孔板中，而后加入 TCID50 值约为 100的病毒剂量， 0.5h后，向每个孔中加入 50万细胞，于 33°C 孵育， 三天后在病毒对照组呈现 100%细胞病变效应 (CPE)时， 考察 药物保护细胞免遭吞噬的效果， 以细胞保护率(％)表示。 预防给药结 果表明，不同化合物对防止细胞吞噬均有不同程度的保护作用；其中 Control 1、 Control 2以及各实施例制备的化合物均对细胞有艮好的 保护作用。
3) 治疗给药
对预防给药中效果较好的化合物进行进一步治疗给药筛选，每个 孔中加入 50万细胞， 于 33°C孵育过夜以贴壁， 而后加入 ΙΟΟμΙ TCID5。值约为 100的病毒剂量， 30min后吸去培养液， 药物以
100ng/mL的浓度加入到 12孔板中， 反应总体积为 2mL， 48h后在 病毒对照组呈现 100%细胞吞噬作用（CPE)时， 考察药物保护细胞免 遭吞噬的效果， 以细胞保护率(％)表示。
4) 化合物的半有效浓度、化合物抑制指数及最大抑制病毒浓度 在初筛的基础上，确定化合物的半有效浓度、化合物抑制指数及 最大抑制病毒浓度。
半有效浓度测定 (治疗）： 向 24孔板每个孔中加入 10万细胞， 于 33°C孵育， 而后加入 5(^L TCID5Q值约为 100的病毒，化合物以五倍 稀释梯度逐级加入到 24孔板中， 48h后在病毒对照组呈现 100%细胞 吞噬作用（CPE)时，确定化合物保护 50%细胞免遭细胞吞噬作用时的 浓度 (以 ng/ml表示)。 同时确定化合物的最低有效剂量。
化合物的抑制指数的测定： 药物浓度从初筛时 100%抑制作用的 浓度开始， 2倍逐级稀释，记录不出现病毒病变的药物最高稀释倍数。 计算出药物的抑制指数：抑制指数=抑制病毒最高稀释倍数 /无毒限量 稀释倍数。
最大抑制病毒浓度： 化合物浓度设定为 100%抑制病毒滴度 (TCID5。值约为 100)， 而后病毒以倍增方式逐级加入， 确定在给定化 合物浓度下可抑制的最大病毒浓度。
5) 试验结杲
根据以上试验方法， 测定的阳性对照药 Control 1、 Control 2以 及实施例制备的化合物的治疗活性筛选数据见表 1， 结果表明： 在治 疗给药条件下， Control 1、 Control 2以及实施例制备的化合物对细 胞有很好的保护作用，在相同抑制指数条件下本发明部分化合物表现 出强于对照化合物的活性。
化合物治疗活性筛选数据
Figure imgf000018_0001

Claims

权利要求
1. 式 I的化合物:
Figure imgf000019_0001
I
或其药学上可接受的盐， 其中：
Rl、 R2和 R3各自独立地选自氢和卤素；
n为 2、 3、 4或 5; 并且
R4、 R5和 R6各自独立地选自氢、 卤素、 C1-C8直链或支链烷 基、 -COOR7和 -OR8; 其中
R7和 R8各自独立地选自氢和 C1-C6直链或支链烷基。
2. 权利要求 1的化合物， 其为下式 la化合物：
Figure imgf000019_0002
la
或其药学上可接受的盐， 其中：
R1选自氢、 氟、 氯、 溴和碘；
n为 2、 3、 4或 5; 并且
R4选自氢、 卤素、 C1-C8直链或支链烷基、 -COOR7和 -OR8; 其中
R7和 R8各自独立地选自氢和 C1-C6直链或支链烷基。
3. 权利要求 1的化合物， 其为下式 la化合物：
Figure imgf000019_0003
la
或其药学上可接受的盐， 其中： Rl选自氟和氯；
n为 3、 4或 5; 并且
R4选自卤素、 C1-C6直链或支链烷基、 -COOR7和 -OR8; 其中 R7和 R8各自独立地选自氢和 C1-C4直链或支链烷基。
4. 权利要求 1的化合物， 其为以下式 la化合物:
Figure imgf000020_0001
la
或其药学上可接受的盐， 其中：
R1为氯；
n为 3或 4; 并且
R4选自 C1-C6直链或支链烷基、 -COOR7和 -OR8; 其中
R7和 R8各自独立地选自氢和 C1-C4直链或支链烷基。
5. 权利要求 1的化合物， 其选自：
3-{4-[3-(4-乙氧基苯氧基)丙基】哌嗪 -1-基}-6-氯哒嗪，
3-{4-[3-(4-甲基苯氧基)丙基】哌嗪 -1-基}-6-氯哒嗪，
3-{4_[3-(4_乙基苯氧基)丙基】哌嗪 -1-基}-6_氯-哒嗪，
3- {4-[3-(4-异丙基苯氧基)丙基】哌嗪 -1-基}-6-氯哒嗪，
4- {3-[4-(6-氯哒嗪 -3-基)哌嗪 -1-基】丙氧基 }苯甲酸甲酯， 以及
4-{3-[4-(6-氯哒嗪 -3-基)哌嗪 -1-基】丙氧基 }苯甲酸乙酯， 或其药学上可接受的盐。
6. 一种药物组合物，其包含权利要求 1至 5任一项所述的化合物 或其药学上可接受的盐，以及一种或多种药学上可接受的载体或赋形 剂。
7. 权利要求 1至 5任一项所述的化合物或其药学上可接受的盐或 者权利要求 6所述的药物组合物在制备用于治疗和 /或预防与小 RNA 病毒感染有关的疾病或病症的药物中的用途。
8. 根据权利要求 7的用途，其中所述小 RNA病毒选自：鼻病毒、 肠道病毒、 口疾病毒、 心脏病毒、 肝病毒和双艾柯病毒。
9. 根据权利要求 7至 8任一项的用途， 其中所述与小 RNA病毒 感染有关的疾病或病症选自： 普通感冒、 咽炎、 扁桃腺炎、 义膜性喉 炎、 手脚口疾病、 脑膜炎 /脑炎、 急性骨髓灰白质炎、 心脏血管疾病、 出血性结膜炎和肝炎。
10. 权利要求 1至 5任一项所述的化合物或其药学上可接受的盐， 用于治疗和 /或预防与小 RNA病毒感染有关的疾病或病症。
11. 根据权利要求 10的化合物或其药学上可接受的盐， 其中所述 小 RNA病毒选自： 鼻病毒、 肠道病毒、 口疾病毒、 心脏病毒、 肝病 毒和双艾柯病毒。
12. 根据权利要求 10或 11的化合物或其药学上可接受的盐，其中 所述与小 RNA病毒感染有关的疾病或病症选自： 普通感冒、 咽炎、 扁桃腺炎、 义膜性喉炎、 手脚口疾病、 脑膜炎 /脑炎、 急性骨髓灰白 质炎、 心脏血管疾病、 出血性结膜炎和肝炎。
PCT/CN2011/077896 2010-08-02 2011-08-02 哒嗪衍生物及其作为抗小rna病毒感染的药物的用途 WO2012016510A1 (zh)

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