WO2022222994A1 - 一种核苷类化合物及其在治疗猫传染性腹膜炎中的应用 - Google Patents
一种核苷类化合物及其在治疗猫传染性腹膜炎中的应用 Download PDFInfo
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- WO2022222994A1 WO2022222994A1 PCT/CN2022/088179 CN2022088179W WO2022222994A1 WO 2022222994 A1 WO2022222994 A1 WO 2022222994A1 CN 2022088179 W CN2022088179 W CN 2022088179W WO 2022222994 A1 WO2022222994 A1 WO 2022222994A1
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- Prior art keywords
- nhch
- compound
- alkylamino
- alkyl
- pharmaceutically acceptable
- Prior art date
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- 102000020233 phosphotransferase Human genes 0.000 description 1
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- 239000002562 thickening agent Substances 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
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- 235000013311 vegetables Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
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- 230000007444 viral RNA synthesis Effects 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Definitions
- the invention relates to a nucleoside compound and its application in the treatment of feline infectious peritonitis.
- Feline infectious peritonitis is a disease caused by infection with feline coronavirus. It is a chronic, progressive and fatal infectious disease. The disease is commonly found in two clinical forms, one is peritonitis. , Exudative type characterized by a large amount of ascites, that is, wet infectious peritonitis. One is dry infectious peritonitis characterized by uveitis such as obvious fibrin blood clots and retinal hemorrhages in the eyes without obvious symptom changes in the whole body.
- Feline coronavirus is an RNA virus, an infectious virus commonly found in felines. Cats infected with feline coronavirus have a 5-10% probability of mutating into feline infectious peritonitis (FIP). At present, GS-441524 is a drug molecule with good effect in the treatment of feline infectious peritonitis (FIP).
- GS-441524 is a 1'-cyano-substituted adenine C-nucleoside ribose analog, which exhibits strong antiviral activity against a variety of RNA viruses including SARS coronavirus. Inhibitory effect. Among them, GS-441524 is phosphorylated into active triphosphate metabolites (NTP structural analogs) by cellular kinases in cells. In viral RNA synthesis, active NTP structural analogs act as a competitor of natural nucleoside triphosphates with natural nuclear The glycoside (NTP) competes to participate in the transcription/replication of RNA.
- NTP structural analogs active triphosphate metabolites
- the transcription/replication product When the GS-441524 molecule is inserted into the transcription/replication product, the transcription/replication will be terminated prematurely, thereby inhibiting the viral RNA transcription/replication process. It has been found that it has certain inhibitory activity against Ebola, SARS, Junin virus, respiratory syncytial virus, etc.
- the GS441524 molecule has poor water solubility and limited membrane permeability and bioavailability. Therefore, the novel nucleoside compounds reported in the present invention have strong water solubility, and the compounds have antiviral effects, especially feline coronavirus.
- the present invention aims to provide a class of compounds whose structure is shown in formula (I) or a pharmaceutically acceptable salt thereof:
- R 1 is selected from C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 3-7 heterocyclyl, hydroxy substituted C 1-6 alkyl, amino-substituted C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkylamino C 1-6 alkyl, C 3-7 cycloalkane base C 1-6 alkyl, C 3-7 heterocyclyl C 1-6 alkyl, C 1-6 alkylamino, hydroxyl substituted C 1-6 alkylamino, amino substituted C 1-6 alkylamino, C 1-6 alkoxy C 1-6 alkylamino, C 1-6 alkylamino C 1-6 alkylamino, C 3-7 cycloalkyl C 1-6 alkylamino, C 3-7 hetero Cyclic C 1-6 alkylamino group.
- R 1 is selected from -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -CF 3 , -CH 2 CF 3 , -CH 2 OH, -CH 2 NH 2 , -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 , -CH 2 CH 2 NHCH 3 , - CH 2 CH 2 N(CH 3 ) 2 , -NHCH 3 , -NHCH 2 CH 3 , -NHCH 2 CH 2 CH 3 , -NHCH(CH 3 ) 2 , -N(CH 3 ) 2 , -N(CH 3 )CH 2 CH 3 , -N(CH 2 CH 3 ) 2 , -NHCH 2 CH 2 OH, -NHCH 2 CH 2 OH, -NHCH
- the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from:
- One object of the present invention provides the compound of the present invention or a pharmaceutically acceptable salt thereof, including each optical isomer, each crystal form, hydrate or solvate.
- Another object of the present invention is to provide a pharmaceutical composition, which contains a pharmaceutically acceptable excipient or carrier and the compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof, including each optical Isomers, crystalline forms, hydrates or solvates as active ingredients.
- Another object of the present invention provides that the compounds of the present invention, or their respective optical isomers, pharmaceutically acceptable inorganic or organic salts are used to prepare medicines for treating feline infectious peritonitis, a disease caused by feline coronavirus infection applications in .
- Fig. 1 is the body weight change diagram of cat adopting the compound water injection of the present invention in two weeks before and after treatment;
- Fig. 2 is a graph of changes in the number of leukocytes in two weeks before and after treatment with the compound water injection of the present invention in a cat;
- Fig. 3 is a graph showing the change of the leukocyte ratio in two weeks before and after the treatment of the cat with the compound water injection of the present invention.
- compositions of the present invention refer to organic and inorganic salts of the compounds of the present invention.
- Pharmaceutically acceptable salts are well known in the art as described in the literature: SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19, 1977.
- Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups, such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate ; organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate; or by other methods such as ion exchange as described in books and literature get these salts.
- salts include adipate, malate, 2-hydroxypropionate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate Salt, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate Diacid salt, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, caproate, hydroiodate, 2-hydroxy-ethanesulfonate, lactobionate, lactobionate acid salt, laurate, lauryl sulfate, malate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoic acid Salt, pectate, persulfate,
- Salts obtained with suitable bases include alkali metal, alkaline earth metal, ammonium and N + (C1-4alkyl) 4 salts.
- the present invention also contemplates quaternary ammonium salts formed from any compound containing an N-group. Water- or oil-soluble or dispersible products can be obtained by quaternization.
- Alkali or alkaline earth metals that can form salts include sodium, lithium, potassium, calcium, magnesium, and the like.
- Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations that resist counterion formation, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1- S sulfonates and aromatic sulfonates.
- a “solvate” of the present invention refers to an association of one or more solvent molecules with a compound of the present invention.
- Solvate-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, and aminoethanol.
- hydrate refers to an association in which the solvent molecule is water.
- the compounds disclosed herein, including their salts may also be obtained in their hydrate form or in a form containing a solvent (eg, ethanol, DMSO, etc.) for their crystallization.
- a solvent eg, ethanol, DMSO, etc.
- Compounds of the present disclosure may form solvates, inherently or by design, with pharmaceutically acceptable solvents, including water; thus, the present invention is intended to include both solvated and unsolvated forms.
- the compounds disclosed herein, including their salts, can be prepared in various forms including, but not limited to, amorphous, comminuted and nano-particle size forms.
- the compounds of the present invention include crystalline forms, as well as polymorphic forms.
- Polymorphs include different lattice arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal form, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvent, crystallization rate and storage temperature may cause a single crystal form to dominate.
- pharmaceutically acceptable excipient or carrier includes any solvent, diluent, or other liquid excipient, dispersing or suspending agent, surfactant, isotonic agent, thickening agent Agents, emulsifiers, preservatives, solid binders or lubricants, etc., are suitable for the particular target dosage form.
- Substances that can be used as pharmaceutically acceptable excipients or carriers include, but are not limited to: ion exchangers, aluminum, aluminum oxide, aluminum stearate, lecithin, serum albumin, such as human serum albumin, buffer substances such as phosphoric acid Salt, glycine, sorbic acid, potassium sorbate, partial glyceride mixture of saturated vegetable fatty acids, water, electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, salts such as sodium chloride, zinc salts, colloids Silicon, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as cornstarch and potato starch; fibers Vegan and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; tal
- alkyl as used herein is a saturated straight or branched monovalent hydrocarbon group of 1-20 carbon atoms, wherein the alkyl group may be independently optionally substituted with one or more substituents described herein.
- the alkyl group contains 1-10 carbon atoms, in other embodiments, the alkyl group contains 1-8 carbon atoms, and in still other embodiments, the alkyl group contains 1-6 carbon atoms. carbon atoms, in other embodiments, the alkyl group contains 1-4 carbon atoms, and in other embodiments, the alkyl group contains 1-3 carbon atoms.
- alkyl groups include, but are not limited to, methyl (Me, -CH3 ), ethyl (Et, -CH2CH3), n - propyl (n - Pr, -CH2CH2 ) CH3 ), isopropyl (i-Pr, -CH( CH3 ) 2 ), n - butyl (-Bu, -CH2CH2CH2CH3 ), 2 - methylpropyl or isobutyl ( i-Bu, -CH 2 CH(CH 3 ) 2 ), 1-methylpropyl or sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C( CH3 ) 3 ), n-pentyl ( -CH2CH2CH2CH3 ), 2 - pentyl (-CH( CH3 ) CH2CH2CH3 ) , 3 - pentyl (
- alkenyl refers to unsaturated aliphatic hydrocarbon groups containing carbon-carbon double bonds, including straight and branched chain groups of 1 to 6 carbon atoms. Preference is given to lower alkenyl groups containing 1 to 4 carbon atoms, such as vinyl, 1-propenyl, 1-butenyl or 2-methpropenyl.
- alkynyl refers to a linear or branched monovalent hydrocarbon group of 2-12 carbon atoms, wherein at least one position is unsaturated, that is, one CC is a sp triple bond, wherein the alkynyl group Can be independently optionally substituted by one or more substituents described herein, specific examples include, but are not limited to, ethynyl propargyl and many more.
- alkoxy relates to an alkyl group, as defined herein, attached to the primary carbon chain through an oxygen atom. Unless otherwise specified, the alkoxy groups contain 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms; in another embodiment, the alkoxy group contains 1-4 carbon atoms; in yet another embodiment, the alkoxy group The group contains 1-3 carbon atoms. Such examples include, but are not limited to, methoxy, ethoxy, propoxy, and the like.
- haloalkyl or "haloalkoxy” as used in the present invention refers to the case where the alkyl or alkoxy group may be substituted with one or more same or different halogen atoms.
- alkyl and alkoxy groups have the meanings as described herein, such examples include, but are not limited to, 1,1,1-trifluoro-2-methylprop-2-yl (-C(CH 3 ) 2 CF 3 ), 1,1-difluoro-2-methylprop-2-yl (-C(CH 3 ) 2 CHF 2 ), 1-fluoro-2-methylprop-2-yl (- C(CH 3 ) 2 CH 2 F), difluoromethyl (-CHF 2 ), trifluoromethyl (-CF 3 ), trifluoromethoxy (-OCF 3 ), 2,2,2-trifluoro Ethoxy (-OCH 2 CF 3 ), 2,2,3,3-tetrafluoropropoxy (-OCH 2 CF 2 CHF 2 ), and the like
- Carbocyclyl or “cycloaliphatic”, “carbocycle”, “cycloalkyl” as used herein refer to a monovalent or polyvalent, non-aromatic, saturated or partially unsaturated ring, and No heteroatoms are included, including monocyclic rings of 3-12 carbon atoms or bicyclic or tricyclic rings of 7-12 carbon atoms.
- Bicarbocycles with 7-12 atoms can be bicyclic [4,5], [5,5], [5,6] or [6,6] systems, while bicarbocycles with 9 or 10 atoms Can be a bicyclic [5,6] or [6,6] system.
- Carbocyclyl or “cycloaliphatic”, “carbocycle”, “cycloalkyl” can be monoradical or diradical, i.e. in certain embodiments of the invention, Can be used in place of or as carbocyclylene, cycloalkylene.
- Suitable cycloaliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl.
- cyclic aliphatic groups further include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-Cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, Cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, adamantyl and the like.
- heterocyclyl refers to a saturated or partially unsaturated ring system radical containing one or more heteroatoms (O, S or N) wherein the nitrogen and sulfur atoms are optionally oxidized, the nitrogen Atoms are optionally quaternized as ring atoms.
- a “heterocycloalkyl” ring system can be a monocyclic, bicyclic, spirocyclic or polycyclic ring system.
- a “heterocycloalkyl” can be attached to the remainder of the molecule through more than one ring carbon or heteroatom.
- heterocycloalkyl examples include, but are not limited to, pyrrolidine, piperidine, N-methylpiperidine, tetrahydroimidazole, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, Dioxolane, phthalimide, piperidine, pyrimidine-2,4(1H,3H)-dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine Line-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyranone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, 2-azaspiro[3.3]heptane, etc.
- alkylamino refers to "N-alkylamino" in which the amino group is independently substituted with one or two alkyl groups, wherein the alkyl groups have as described herein meaning.
- the alkylamino group is a lower alkylamino group with a C1-6 alkyl group attached to a nitrogen atom.
- the alkylamino group is a C1-3 lower alkylamino group.
- Such examples include, but are not limited to, N-methylamino, N-ethylamino, and the like.
- the compounds of formula (I) described above can be synthesized using standard synthetic techniques or well-known techniques and methods incorporated herein.
- the solvents, temperatures and other reaction conditions mentioned herein may vary.
- Starting materials for the synthesis of compounds can be synthesized or obtained from commercial sources such as, but not limited to, Aldrich Chemical Co. (Milwaukee, Wis.) or Sigma Chemical Co. (St. Louis, Mo.).
- the general methods of compound preparation can be varied by the use of appropriate reagents and conditions for the introduction of various groups into the formulae provided herein.
- the compounds described herein are according to methods well known in the art.
- the conditions of the method such as reactants, solvent, base, amount of the compound used, reaction temperature, time required for the reaction and the like are not limited to the following explanations.
- the compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily performed by those skilled in the art to which the present invention pertains.
- the present invention also provides a kind of preparation method of the compound shown in the described general formula (I), it adopts following general reaction scheme to prepare:
- R 1 and R 2 are as defined above.
- 1 H-NMR was recorded with a Vian Mercury 400 nuclear magnetic resonance apparatus, and chemical shifts were expressed in ⁇ (ppm); silica gel for separation was 200-300 mesh not specified, and the proportions of eluents were all volume ratios.
- RT room temperature
- rt aqueous solution
- PE petroleum ether
- EA ethyl acetate
- DCM dichloromethane
- MeOH methanol
- MTBE methyl tertiary Butyl ether
- EtOH trifluoroacetic acid
- equivalents eq
- grams per milligram g/mg
- moles per millimoles mol/mmol
- N 2 nuclear magnetic resonance
- NMR nuclear magnetic resonance
- LC-MS liquid-mass spectrometry
- TLC thin layer chromatography
- pre-HPLC Liquid Chromatograph
- Step 2 Dissolve 500 mg of the starting compound B1 in 10 mL of DCM, add 3 mL of TFA dropwise under an ice bath, and react at room temperature for 1 hour after the addition, and LCMS shows that the reaction is complete. product is generated. The reaction was stopped, the solvent was removed by concentration at low temperature, and the colorless oil was obtained by steaming twice with DCM, which was slurried with 10 mL of MTBE to obtain a white solid, which was then slurried twice with 5 mL of DCM. The white solid obtained by concentrating and draining was Compound 32 trifluoroacetic acid salt 600 mg.
- Experimental method refer to high performance liquid chromatography (Chinese Pharmacopoeia 2020 edition of the four general rules 0512).
- the compounds of the present invention Compared to GS-441524, the compounds of the present invention have higher solubility in water. The compounds of the present invention are thus more readily absorbed by the body.
- Example 3 Efficacy test of compounds 1, 32 and 85 on feline infectious peritonitis
- Figure 1 shows the changes in body weight of 15 cats in each group of 3 groups with feline infectious peritonitis before and after treatment with water injections prepared with compounds 1, 32 and 85 respectively (vertical axis unit: kg, white bars represent before treatment , the black bars represent after treatment, the first, second, and second data in each group are compound 1, the third and fourth are compound 32, and the fifth and sixth are compound 85).
- Figure 2 shows the changes in the number of leukocytes in 15 experimental cats before and after the treatment with the aqueous injection of compounds 1, 32 and 85 respectively (vertical axis unit: 1 ⁇ 10 9 cells/liter, white bars represent before treatment, black bars After the representative treatment, the first, second and second data in each group are compound 1, the third and fourth data are compound 32, and the fifth and sixth data are compound 85).
- Figure 3 shows the changes in the white ball ratio of 15 experimental cats before and after treatment with the water injections prepared with Compounds 1, 32, and 85 respectively (white bars represent before treatment, black bars represent after treatment, each group of data at No. One, two, two are compound 1, the third and fourth are compound 32, and the fifth and sixth are compound 85).
- Example 4 Compound in vitro anti-feline infectious peritonitis virus (FIPV) activity
- Table 3 the inhibitory activity of the compounds of the present invention to feline infectious peritonitis virus (FIPV) in vitro
- the compounds 4, 14, 16, 18 and 32 of the present invention can all inhibit the replication of Feline Infectious Peritonitis Virus (FIPV) in vitro, wherein the compounds 4, 16 and 18 have significant antiviral activities with EC 50 0.65 ⁇ M, 0.81 ⁇ M and 0.35 ⁇ M, respectively.
- FIPV Feline Infectious Peritonitis Virus
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Abstract
本发明涉及一种核苷类化合物及其在治疗猫传染性腹膜炎中的应用，所述化合物属于GS-441524类似物。所述化合物对猫正常细胞的毒性作用很小，而对猫冠状病毒具有明显的抑制作用。所述化合物可用于制备猫冠状病毒抑制剂，用于治疗猫传染性腹膜炎，其具有疗效好，安全性高等优点，并且其水溶性非常好，更加易于吸收。
Description
相关申请
本申请要求2021年04月23日申请的，申请号为CN202110442975.X，名称为“一种核苷类化合物及其在治疗猫传染性腹膜炎中的应用”的中国专利申请的优先权，在此将其全文引入作为参考。
本发明涉及一种核苷类化合物及其在治疗猫传染性腹膜炎中的应用。
猫传染性腹膜炎(Feline infectious peritonitis,FIP)是感染猫冠状病毒而引起的疾病，是一种慢性、渐进性、致死性传染病，该病在临床上常见于两种形式，一种是以腹膜炎、大量腹水为特征的渗出型，也就是湿型传染性腹膜炎。一种是全身没有出现明显的症状变化，但是眼部出现明显的纤维蛋白血块、视网膜出血等葡萄膜炎为特征的干性传染性腹膜炎。
目前对于猫传染性腹膜炎的治疗主要采用免疫调节剂、免疫抑制剂及抗病毒等药物进行对症治疗，这些药物副作用较大，且不能降低该病的高致死率。因此亟待开发高效且安全性高的药物。
猫冠状病毒(FCoV)是一种RNA病毒，是在猫科动物中常见的一种传染性病毒。猫冠状病毒的感染猫会有5-10％的概率突变成猫传染性腹膜炎(FIP)，其主要症状是腹膜炎、胸腔大量积水，病猫致死率极高。目前GS-441524是治疗猫传染性腹膜炎(FIP)效果较好的一种药物分子。
GS-441524是一种1'-氰基取代的腺嘌呤C-核苷核糖类似物，对包括SARS冠状病毒在内的多种RNA病毒表现出较强的抗病毒活性，针对多种RNA病毒有抑制效果。其中GS-441524在细胞内通过细胞激酶磷酸化为具有活性的三磷酸代谢物(NTP结构类似物)，在病毒RNA合成中，活性 NTP结构类似物充当天然三磷酸核苷的竞争物与天然核苷(NTP)竞争参与RNA的转录/复制，当转录/复制产物中***GS-441524分子，转录/复制将提前终止，进而抑制病毒RNA转录/复制过程。目前已发现其对埃博拉、SARS、胡宁病毒、呼吸道合胞病毒等均表现出一定的抑制活性。
发明内容
GS441524分子的水溶性很差，其透膜率和生物利用度也比较有限。因此，本发明中所报道的这类新型核苷类化合物具有很强的水溶性，并且该类化合物具有抗病毒的作用，特别是猫冠状病毒。
本发明旨在提供一类结构如式(I)所示的化合物或其药学上可接受的盐：
式(I)中：
R
1选自C
1-6烷基、C
1-6烯基、C
1-6炔基、C
1-6卤代烷基、C
3-7环烷基、C
3-7杂环基、羟基取代C
1-6烷基、氨基取代C
1-6烷基、C
1-6烷氧基C
1-6烷基、C
1-6烷胺基C
1-6烷基、C
3-7环烷基C
1-6烷基、C
3-7杂环基C
1-6烷基、C
1-6烷胺基、羟基取代C
1-6烷胺基、氨基取代C
1-6烷胺基、C
1-6烷氧基C
1-6烷胺基、C
1-6烷胺基C
1-6烷胺基、C
3-7环烷基C
1-6烷胺基、C
3-7杂环基C
1-6烷胺基。
在另一优选例中，其中所述式(I)中，R
1选自-CH
3、-CH
2CH
3、-CH
2CH
2CH
3、-CH(CH
3)
2、-CH
2CH
2CH
2CH
3、
-CF
3、-CH
2CF
3、
-CH
2OH、-CH
2NH
2、-CH
2OCH
3、-CH
2CH
2OCH
3、-CH
2NHCH
3、-CH
2N(CH
3)
2、-CH
2CH
2NHCH
3、-CH
2CH
2N(CH
3)
2、
-NHCH
3、-NHCH
2CH
3、-NHCH
2CH
2CH
3、-NHCH(CH
3)
2、-N(CH
3)
2、-N(CH
3)CH
2CH
3、-N(CH
2CH
3)
2、
-NHCH
2CH
2OH、-NHCH
2CH
2NH
2、-N(CH
2CH
2OH)
2、-NHCH
2CH
2OCH
3、-N(CH
2CH
2OCH
3)
2、-NHCH
2CH
2NHCH
3、-NHCH
2CH
2N(CH
3)
2、-N(CH
3)CH
2CH
2NHCH
3、-N(CH
3)CH
2CH
2N(CH
3)
2、
本发明的一些方案中，如式(I)所述化合物或其药学上可接受的盐，其化合物选自：
本发明的一个目的提供了本发明的所述的化合物或其药学上可接受的盐、包括各光学异构体、各晶型、水合物或溶剂合物。
本发明的另一个目的是提供了一种药物组合物，它含有药学上可接受的赋形剂或载体以及本发明式(I)所述的化合物或其药学上可接受的盐、包括各光学异构体、各晶型、水合物或溶剂合物作为活性成分。
本发明的再一个目的提供了本发明的所述化合物、或其各光学异构体、药学上可接受的无机或有机盐用于制备治疗猫冠状病毒感染所引起的疾病即猫传染性腹膜炎药物中的应用。
应理解，本发明的前述一般性描述和以下详细描述都是示例性和说明性的，旨在提供对所要求保护的本发明的进一步说明。
下面结合附图和实施例对本发明进一步说明。
图1是患猫采用本发明化合物水针剂治疗前后两周的体重变化图；
图2是患猫采用本发明化合物水针剂治疗前后两周白细胞数目变化图；
图3是患猫采用本发明化合物水针剂治疗前后两周白球比变化图。
现在详细描述本发明的某些实施方案，其实例由随附的结构式和化学式说明。本发明意图涵盖所有的替代、修改和等同技术方案，它们均包括在如权利要求定义的本发明范围内。本领域技术人员应认识到，许多与本文所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本文所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术等等)，以本申请为准。
除非另外说明，应当应用本文所使用的下列定义。出于本发明的目的，化学元素根据化学元素周期表，CAS版和化学药品手册，第75版，1994 来定义。此外，有机化学一般原理可参考“Organic Chemistry”,Thomas Sorrell,University Science Books,Sausalito:1999,和“March's Advanced Organic Chemistry”,by Michael B.Smith and Jerry March,John Wiley&Sons,New York:2007中的描述，其全部内容通过引用并入本文。
本发明的“药学上可接受的盐”是指本发明化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：S.M.Berge et al.，describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,66:1-19,1977.所记载的。药学上可接受的无毒的酸形成的盐包括，但并不限于：与氨基基团反应形成的无机酸盐，如盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、高氯酸盐；有机酸盐，如乙酸盐、草酸盐、马来酸盐、酒石酸盐、柠檬酸盐、琥珀酸盐、丙二酸盐；或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括，己二酸盐、苹果酸盐、2-羟基丙酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、重硫酸盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、环戊基丙酸盐、二葡萄糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、反丁烯二酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖醛酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、棕榈酸盐、扑酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、特戊酸盐、丙酸盐、硬脂酸盐、硫氰酸盐、对甲苯磺酸盐、十一酸盐、戊酸盐等。通过适当的碱得到的盐包括，碱金属，碱土金属，铵和N
+(C1-4烷基)
4的盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。可以形成盐的碱金属或碱土金属包括钠、锂、钾、钙、镁等。药学上可接受的盐进一步包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物、氢氧化物、羧化物、硫酸化物、磷酸化物、硝酸化物、C1-S 磺酸化物和芳香磺酸化物。
本发明的“溶剂合物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于:水、异丙醇、乙醇、甲醇、二甲亚砜、乙酸乙酯、乙酸和氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。
另外，本发明公开的化合物，包括它们的盐，也可以以它们的水合物形式或包含其溶剂(例如乙醇、DMSO等等)的形式得到，用于它们的结晶。本发明公开化合物可以与药学上可接受的溶剂(包括水)固有地或通过设计形成溶剂化物；因此，本发明旨在包括溶剂化的和未溶剂化的形式。
本发明公开的化合物，包括它们的盐，可以被制备成不同的形式，包括但不限于，无定形，粉碎形和毫微-粒度形式。此外，本发明化合物包括结晶型，也可以作为多晶型。多晶型包括化合物的相同元素组成的不同晶格排列。多晶型通常有不同的X-射线衍射图，红外光谱，熔点，密度，硬度，晶型，光和电的性质，稳定性和溶解性。不同的因素如重结晶溶剂，结晶速率和贮存温度可能引起单一晶型为主导。
像本发明所描述的，“药学上可以接受的赋形剂或载体”，包括任何溶剂，稀释剂，或其他液体赋形剂，分散剂或悬浮剂，表面活性剂，等渗剂，增稠剂，乳化剂，防腐剂，固体粘合剂或润滑剂，等等，适合于特有的目标剂型。如以下文献所描述的：In Remington:The Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Dekker,New York，综合此处文献的内容，表明不同的载体可应用于药学上可接受的组合物的制剂和它们公知的制备方法。除了任何常规的载体媒介与本发明的化合物不相容的范围，例如所产生的任何不良的生物效应或与药学上可接受的组合物的任何其他组分以有害的方式产生的相互作用，它们的用途也是本发明所考虑 的范围。
可作为药学上可接受的赋形剂或载体的物质包括，但并不限于:离子交换剂，铝，氧化铝，硬脂酸铝，卵磷脂，血清蛋白，如人血清蛋白，缓冲物质如磷酸盐，甘氨酸，山梨酸，山梨酸钾，饱和植物脂肪酸的部分甘油酯混合物，水，电解质，如硫酸鱼精蛋白，磷酸氢二钠，磷酸氢钾，盐，如氯化钠，锌盐，胶体硅，三硅酸镁，聚乙烯吡咯烷酮，聚丙烯酸脂，蜡，聚乙烯-聚氧丙烯-阻断聚合体，羊毛脂，糖，如乳糖，葡萄糖和蔗糖；淀粉如玉米淀粉和土豆淀粉；纤维素和它的衍生物如羧甲基纤维素钠，乙基纤维素和乙酸纤维素；树胶粉；麦芽；明胶；滑石粉；辅料如可可豆脂和栓剂蜡状物；油如花生油，棉子油，红花油，麻油，橄榄油，玉米油和豆油；二醇类化合物，如丙二醇和聚乙二醇；酯类如乙基油酸酯和乙基月桂酸酯；琼脂；缓冲剂如氢氧化镁和氢氧化铝；海藻酸；无热原的水；等渗盐；林格(氏)溶液；乙醇；磷酸缓冲溶液；和其他无毒的合适的润滑剂如月桂硫酸钠和硬脂酸镁，着色剂，释放剂，包衣衣料，甜味剂，调味剂和香料，防腐剂和抗氧化剂。为方便起见，局部麻醉剂，防腐剂，缓冲剂等可直接溶于载体中。
本发明使用的术语“烷基”是1-20个碳原子饱和直链或支链的单价烃基，其中烷基可以独立任选地被一个或多个本发明所描述的取代基所取代。其中一些实施例是，烷基基团含有1-10个碳原子，另外一些实施例是，烷基基团含有1-8个碳原子，另外一些实施例是，烷基基团含有1-6个碳原子，另外一些实施例是，烷基基团含有1-4个碳原子，另外一些实施例是，烷基基团含有1-3个碳原子。烷基基团更进一步的实例包括，但并不限于，甲基(Me，-CH
3)，乙基(Et,-CH
2CH
3)，正丙基(n-Pr，-CH
2CH
2CH
3)，异丙基(i-Pr，-CH(CH
3)
2)，正丁基(-Bu，-CH
2CH
2CH
2CH
3)，2-甲基丙基或异丁基(i-Bu，-CH
2CH(CH
3)
2)，1-甲基丙基或仲丁基(s-Bu，-CH(CH
3)CH
2CH
3)，叔丁基(t-Bu，-C(CH
3)
3)，正戊基(-CH
2CH
2CH
2CH
2CH
3)，2-戊基 (-CH(CH
3)CH
2CH
2CH
3)，3-戊基(-CH(CH
2CH
3)
2)，2-甲基-2-丁基(-C(CH
3)
2CH
2CH
3)，3-甲基-2-丁基(-CH(CH
3)CH(CH
3)
2)，3-甲基-1-丁基(-CH
2CH
2CH(CH
3)
2)，2-甲基-1-丁基(-CH
2CH(CH
3)CH
2CH
3)，正己基(-CH
2CH
2CH
2CH
2CH
2CH
3)，2-己基(-CH(CH
3)CH
2CH
2CH
2CH
3)，3-己基(-CH(CH
2CH
3)(CH
2CH
2CH
3))，2-甲基-2-戊基(-C(CH
3)
2CH
2CH
2CH
3)，3-甲基-2-戊基(-CH(CH
3)CH(CH
3)CH
2CH
3)，4-甲基-2-戊基(-CH(CH
3)CH
2CH(CH
3)
2)，3-甲基-3-戊基(-C(CH
3)(CH
2CH
3)
2)，2-甲基-3-戊基(-CH(CH
2CH
3)CH(CH
3)
2)，2,3-二甲基-2-丁基(-C(CH
3)
2CH(CH
3)
2)，3,3-二甲基-2-丁基(-CH(CH
3)C(CH
3)
3)，正庚基，正辛基，等等。术语“烷基”和其前缀“烷”在此处使用，都包含直链和支链的饱和碳链。
本发明中所使用的术语“烯基”指含有碳-碳双键的不饱和脂肪烃基团，包括1至6个碳原子的直链和支链基团。优选含有1至4个碳原子的低级烯基，例如乙烯基、1-丙烯基、1-丁烯基或2-甲基丙烯基。
本发明中所使用的术语“炔基”表示2-12个碳原子直链或支链的一价烃基，其中至少一个位置为不饱和状态，即一个C-C为sp三键，其中炔基基团可以独立任选地被一个或多个本发明所描述的取代基所取代，具体的实例包括，但并不限于，乙炔基
炔丙基
等等。
本发明中所使用的术语“烷氧基”，涉及到烷基，像本发明所定义的，通过氧原子连接到主要的碳链上。除非另外详细说明，所述烷氧基基团含有1-12个碳原子。在一实施方案中，烷氧基基团含有1-6个碳原子；在另一实施方案中，烷氧基基团含有1-4个碳原子；在又一实施方案中，烷氧基基团含有1-3个碳原子。这样的实施例包括，但并不限于，甲氧基，乙氧基，丙氧基等等。
本发明中所使用的术语“卤代烷基”或“卤代烷氧基”表示烷基或烷氧基可以被一个或多个相同或不同卤素原子所取代的情况。其中烷基和烷氧基基团具有如本发明所述的含义，这样的实例包括，但并不限于1,1,1-三氟-2- 甲基丙-2-基(-C(CH
3)
2CF
3)，1,1-二氟-2-甲基丙-2-基(-C(CH
3)
2CHF
2)、1-氟-2-甲基丙-2-基(-C(CH
3)
2CH
2F)、二氟甲基(-CHF
2)、三氟甲基(-CF
3)、三氟甲氧基(-OCF
3)、2,2,2-三氟乙氧基(-OCH
2CF
3)、2,2,3,3-四氟丙氧基(-OCH
2CF
2CHF
2)，等。
本发明中所使用的术语“碳环基”或“环状脂肪族”，“碳环”，“环烷基”是指一价或多价，非芳香族，饱和或部分不饱和环，且不包含杂原子，其中包括3-12个碳原子的单环或7-12个碳原子的二环或三环。具有7-12个原子的双碳环可以是二环[4,5]，[5,5]，[5,6]或[6,6]体系，同时具有9或10个原子的双碳环可以是二环[5,6]或[6,6]体系。视结构而定，“碳环基”或“环状脂肪族”，“碳环”，“环烷基”可为单价基团或二价基团，即在本发明的某些实施例中，可以替代或做为亚碳环基，亚环烷基使用。合适的环状脂肪族基团包括，但并不限于，环烷基，环烯基和环炔基。环状脂肪族基团的实例进一步包括，但绝不限于，环丙基，环丁基，环戊基，1-环戊基-1-稀基，1-环戊基-2-稀基，1-环戊基-3-稀基，环己基，1-环己基-1-稀基，1-环己基-2-烯基，1-环己基-3-烯基，环己二烯基，环庚基，环辛基，环壬基，环癸基，环十一烷基，环十二烷基，金刚烷基等等。并且所述“碳环基”或“环状脂肪族”，“碳环”，“环烷基”可以是取代或非取代的，其中取代基可以是，但并不限于，氧代(＝O)，氟，氯，溴，碘，羟基，氨基，-C(＝O)-NH
2，羧基，-S(＝O)
tO-H，-OS(＝O)
t-H，-S(＝O)
tNH
2，***基，四唑基，-(CR
3bR
3c)
n-NH
2，烷基，烷基-S(＝O)
t-，卤代烷基，羟基烷基，烷氧基，烷氨基，烷硫基，卤代烷氧基，氨基，芳基，杂芳基，烯基，炔基，杂环基，疏基，硝基，芳氧基，羟基烷氧基，烷酰基，苄基，环丙基，苯基，烷基-C(＝O)-，烷基-C(＝O)-NH-，甲酰胺基或烷氧基烷基等。
本发明中所使用的术语“杂环基”指含有一个或多个杂原子(O、S或N)的饱和或部分不饱和环体系基团，其中氮和硫原子任选地被氧化，氮原子任选地被季铵化，作为环原子。除非另有说明，“杂环烷基”的环体系可以 是单环、双环、螺环或多环的环体系。“杂环烷基”可以通过一个以上环碳或杂原子连接于分子的其余部分。“杂环烷基”的例子包括但不限于吡咯烷、哌啶、N-甲基哌啶、四氢咪唑、吡唑烷、丁内酰胺、戊内酰胺、咪唑啉酮、乙内酰脲、二氧戊环、邻苯二甲酰亚胺、哌啶、嘧啶-2,4(1H,3H)-二酮、1,4-二氧六环、吗啉、硫代吗啉、硫代吗啉-S-氧化物、硫代吗啉-S,S-氧化物、哌嗪、吡喃、吡啶酮、3-吡咯啉、噻喃、吡喃酮、四氢呋喃、四氢噻吩、奎宁环、2-氮杂螺[3.3]庚烷等。
本发明中所使用的术语“烷氨基”指“N-烷基氨基”，其中氨基基团分别独立地被一个或者两个烷基基团所取代，其中烷基基团具有如本发明所述的含义。其中一些实施例是，烷氨基是C
1-6烷基连接到氮原子上的较低级的烷基氨基基团。另外一些实施例是，烷氨基是C
1-3的较低级的烷基氨基基团。这样的实例包括，但并不限于，N-甲氨基，N-乙氨基，等等。
化合物的合成：
下面具体地描述本发明式(I)化合物的制备方法，但这些具体方法不对本发明构成任何限制。
以上说明的式(I)化合物可使用标准的合成技术或公知的技术与文中结合的方法来合成。此外，在此提到的溶剂，温度和其他反应条件可以改变。用于化合物的合成的起始物料可以由合成或从商业来源上获得，如，但不限于Aldrich Chemical Co.(Milwaukee，Wis.)或Sigma Chemical Co.(St.Louis，Mo.)。化合物制备的一般方法可通过使用适当的试剂和在此提供的分子式中引入不同基团的条件来改变。
一方面，本文所述的化合物根据工艺中公知的方法。然而方法的条件，例如反应物、溶剂、碱、所用化合物的量、反应温度、反应所需时间等不限于下面的解释。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得，这样的组合可由本发明所 属领域的技术人员容易的进行。一方面，本发明还提供了一种所述的通式(I)所示化合物的制备方法，其采用下列一般反应流程制备：
其中R
1和R
2的定义如前所述。
以化合物A为起始原料，经过亲核取代反应得到通式(I)化合物。
本发明提到的上述特征，或实施例提到的特征可以任意组合。本案说明书所揭示的所有特征可与任何组合物形式并用，说明书中所揭示的各个特征，可以任何可提供相同、均等或相似目的的替代性特征取代。因此除有特别说明，所揭示的特征仅为均等或相似特征的一般性例子。
在下面的说明中将会详细阐述上述化合物、方法、药物组合物的各个具体方面、特性和优势，使本发明的内容变得十分明了。在此应理解，下述的详细说明及实例描述了具体的实施例，仅用于参考。在阅读了本发明的说明内容后，本领域的技术人员可对本发明作各种改动或修改，这些等价形势同样落于本申请所限定的范围。
所有实施例中，
1H-NMR用Vian Mercury 400核磁共振仪记录，化学位移以δ(ppm)表示；分离用硅胶未说明均为200-300目，洗脱液的配比均为体积比。
本发明采用下述缩略词：室温(RT，rt)；水溶液(aq.)；石油醚(PE)；乙酸乙酯(EA)；二氯甲烷(DCM)；甲醇(MeOH)；甲基叔丁基醚(MTBE)；乙醇(EtOH)；三氟乙酸(TFA)；当量(eq)；克/毫克(g/mg)；摩尔/毫摩尔(mol/mmol)；升/毫升(L/mL)；分钟(min(s))；小时(h,hr,hrs)；氮气(N
2)；核 磁共振(NMR)；液相-质谱仪(LC-MS)；薄层色谱(TLC)；制备液相色谱仪(pre-HPLC)。
实施例1：化合物32的制备：
步骤1：将叔丁氧基乙酸1.32g，碳酸氢钠0.84g加至DMSO 30mL中，室温搅拌20min至溶解。室温加入原料A1 2.0g，升温65℃反应过夜，原料消失，产物生成。停止反应，EA/水萃取至水层基本无产物，有机相饱和食盐水洗，干燥浓缩上柱，DCM/MeOH＝30/1洗脱得1.1g白色固体B1。
1H NMR(400MHz,DMSO-d
6)δ8.05–7.86(m,3H),6.92(d,J＝4.4Hz,1H),6.82(d,J＝4.4Hz,1H),6.36(d,J＝6.0Hz,1H),5.42(d,J＝5.8Hz,1H),4.68(t,J＝5.4Hz,1H),4.38(d,J＝9.8Hz,1H),4.28–4.14(m,2H),4.00(s,2H),3.96–3.89(m,1H),1.12(s,9H).
步骤2：将500mg原料化合物B1溶于DCM 10mL中，冰浴下滴加TFA 3mL，加完室温反应1小时，LCMS显示反应完全。产物生成。停止反应，低温浓缩除去溶剂，以DCM带蒸两次得无色油状物，以10mL MTBE打浆得白色固体，再以5mL DCM打浆两次。浓缩抽干得到的白色固体为 化合物32的三氟乙酸盐600mg。
类似化合物的合成，可以得到表1所列的化合物：
表1.化合物1-106：
代表性化合物
1H-NMR数据
1H NMR(500MHz,DMSO-d
6)δ7.93(s,3H),6.91(d,J＝4.5Hz,1H),6.81(d,J＝4.5Hz,1H),6.33(d,J＝6.0Hz,1H),5.39(d,J＝5.8Hz,1H),4.71–4.68(m,1H),4.31(dd,J＝12.0,2.9Hz,1H),4.26–4.21(m,1H),4.17(dd,J＝12.1,5.2Hz,1H),3.98–3.93(m,1H),2.56–2.52(m,1H),1.08– 1.03(m,6H).
1H NMR(500MHz,DMSO-d
6)δ8.05–7.80(m,3H),6.93(d,J＝4.6Hz,1H),6.82(d,J＝4.5Hz,1H),6.34(d,J＝6.1Hz,1H),5.42(d,J＝5.9Hz,1H),4.74–4.68(m,1H),4.48–4.41(m,1H),4.33–4.23(m,2H),4.01–3.93(m,1H),3.80–3.67(m,2H).
1H NMR(500MHz,DMSO-d
6)δ8.02–7.78(m,3H),6.91(d,J＝4.6Hz,1H),6.79(d,J＝4.5Hz,1H),6.34(d,J＝6.0Hz,1H),5.38(d,J＝6.0Hz,1H),4.67(t,J＝5.4Hz,1H),4.38–4.29(m,1H),4.26–4.12(m,2H),3.98–3.88(m,1H),3.21–3.09(m,1H),2.20–2.06(m,4H),1.98–1.86(m,1H),1.84–1.73(m,1H).
1H NMR(500MHz,DMSO-d
6)δ8.04–7.78(m,3H),6.92(d,J＝4.5Hz,1H),6.81(d,J＝4.6Hz,1H),6.34(d,J＝6.0Hz,1H),5.39(d,J＝5.9Hz,1H),4.74–4.65(m,1H),4.36–4.28(m,1H),4.27–4.21(m,1H),4.20–4.14(m,1H),4.00–3.91(m,1H),2.76–2.66(m,1H),1.85–1.71(m,2H), 1.69–1.45(m,6H).
1H NMR(500MHz,DMSO-d
6)δ8.06–7.79(m,3H),6.93(d,J＝4.5Hz,1H),6.82(d,J＝4.5Hz,1H),6.34(d,J＝6.0Hz,1H),5.38(d,J＝5.9Hz,1H),4.74–4.68(m,1H),4.31(dd,J＝12.2,2.9Hz,1H),4.26–4.21(m,1H),4.15(dd,J＝12.2,5.0Hz,1H),4.00–3.94(m,1H),2.30–2.22(m,1H),1.81–1.54(m,5H),1.34–1.11(m,5H).
1H NMR(400MHz,DMSO-d
6)δ8.05–7.77(m,3H),6.91(d,J＝3.4Hz,1H),6.81(d,J＝3.4Hz,1H),6.29(d,J＝5.9Hz,1H),5.44–5.31(m,2H),4.76–4.65(m,1H),4.44–4.33(m,1H),4.30–4.16(m,2H),4.06–3.88(m,3H).
1H NMR(500MHz,DMSO-d
6)δ8.02–7.78(s,3H),6.90(d,J＝4.5Hz,1H),6.78(d,J＝4.5Hz,1H),6.30–6.24(m,1H),5.39–5.31(m,1H),4.73–4.66(m,1H),4.36–4.18(m,2H),4.16–4.07(m,1H),4.00–3.94(m,1H),3.28–3.17(m,2H),2.85–2.74(m,3H),2.35–2.24(m,2H),2.14(s,3H),2.06(s,3H).
实施例2：溶解度测试
实验方法：参照高效液相色谱法(中国药典2020年版四部通则0512)测定。
a.取化合物约1-2mg，置10ml量瓶中，加水1ml，每隔5分钟强力振摇30秒钟，观察30分钟，样品未完全溶解，经0.45μm滤膜过滤，取续滤液，作为供试品溶液。
b.另取对照品适量，加溶剂(DMSO：甲醇＝10：90)溶解并定量稀释制成每1ml含0.1mg的溶液，作为对照品溶液。
c.精密量取对照品和供试品溶液各20μl，分别注入液相色谱仪，按外标法以峰面积计算，所得数据见表2。计算公式：
式中：A
供：供试品溶液主峰面积；A
对：对照品溶液主峰面积；W
对：对照品称样量，mg；V
对：对照品溶液稀释体积，ml；S：对照品含量，％。
d.色谱条件：用十八烷基硅烷键合硅胶为填充剂(Welch Ultimate XB-C18，4.6×150mm，5um柱适用)；以0.05％H
3PO
4溶液(取H
3PO
4 0.5ml，加水稀释至1000ml)为流动相A，以乙腈为流动相B，按下表进行线性梯度洗脱；柱温30℃，检测波长254nm。
表2.本发明化合物在水中的溶解度
| 编号 | 溶解度 | 编号 | 溶解度 | 编号 | 溶解度 | 编号 | 溶解度 |
| 1 | ++ | 2 | ++ | 4 | ++ | 6 | ++ |
| 11 | ++ | 13 | ++ | 15 | ++ | 26 | ++ |
| 30 | +++ | 32 | ++ | 33 | +++ | 35 | ++ |
| 39 | +++ | 40 | ++ | 55 | +++ | 61 | ++ |
| 79 | +++ | 81 | ++ | 85 | +++ | 88 | ++ |
| 97 | +++ | GS-441524 | 0.05mg/mL |
注：“+”代表1≤本发明化合物的溶解度/GS-441524的溶解度<10；“++”代表10≤本发明化合物的溶解度/GS-441524的溶解度<100；“+++”代表本发明化合物的溶解度/GS-441524的溶解度≥100。
与GS-441524相比，本发明化合物在水中具有更高的溶解度。因此本发明的化合物更易于被动物体吸收。
实施例3：化合物1、32、85的猫传染性腹膜炎的药效实验
实验方法：
将15mg化合物1、32、85分别溶解于5mL溶液(水：丙二醇：PEG＝2：1：1)中制成注射溶液，进行注射给药。注射液可以室温保存，用2mL的一次性兽用注射器吸取相应体积的注射溶液，向上排除空气。注射时选择皮肤较软，皮下组织疏松而且血管较少的部位，如颈部或股内侧皮下进行注射。给药剂量为2mg/Kg体重每天一次，每隔三天进行采血并进行血常规及相应生化指标测定，以猫的生化指标恢复正常为实验结束标志，实验测定的指标数据为体重数据、白细胞数据和白球比数据，每个化合物的实验对象分别是15只确诊患猫传染性腹膜炎的猫。
图1表示3组每组15只患猫传染性腹膜炎的猫在分别用化合物1、32、85配成的水针剂治疗前后两周的体重变化图(纵轴单位：公斤，白色柱代表治疗前，黑色柱代表治疗后，每组数据第一二两根为化合物1，第三四两根为化合物32，第五六两根为化合物85)。
从图1中可以看到分别经过注射化合物1、32和85的水针剂治疗的猫 体重在治疗前后两周的变化情况，治疗后猫的体重均大于治疗前。
图2表示在分别使用化合物1、32和85的水针剂治疗的前后两周15只实验猫白细胞数目的变化图(纵轴单位：1×10
9个/升，白色柱代表治疗前，黑色柱代表治疗后，每组数据第一二两根为化合物1，第三四两根为化合物32，第五六两根为化合物85)。
从图2中可以看到在分别经过注射化合物1、32和85配成的水针剂治疗的猫的白细胞数目均有显著提高。
图3表示在分别使用化合物1、32、85所配的水针剂治疗的前后两周各自对应的15只实验猫的白球比变化(白色柱代表治疗前，黑色柱代表治疗后，每组数据第一二两根为化合物1，第三四两根为化合物32，第五六两根为化合物85)。
从图3中可见化合物1、32、85所分别对应的15只患有猫传染性腹膜炎的猫分别经过化合物1、32、85所配制的水针剂各自治疗两周时间后的白球比均达到了正常的数值。
此次实验，三组各15只患有猫传染性腹膜炎的病猫均被治愈，且没有复发。本专利报道的系列化合物均具有非常好的水溶性，于传统的GS441524油性针剂有很大的不同。其吸收效率更高，更容易在体内分散，使用剂量也明显低于传统的针剂。
实施例4：化合物体外抗猫传染性腹膜炎病毒(FIPV)活性
实验方法：
取生长状态良好的CRFK细胞，接种于96孔板上，当细胞生长到80％-90％融合时，向每孔中加入0.1MOI猫冠状病毒(FIPV)以及不同浓度的测试化合物(0.3125μM,0.625μM,1.25μM,2.5μM,5μM,10μM,20μM and 40μM)，同时设置细胞对照和病毒对照，所有孔中含有1％的DMSO。37℃孵化72h后，细胞使用CellTiter-Glo发光法细胞活力检测试剂(Promega,Madison,WI,USA)处理，使用GraphPad prism 7软件计算 化合物对病毒抑制的半数有效浓度(EC
50)值。
表3，本发明化合物体外对猫传染性腹膜炎病毒(FIPV)的抑制活性
| 化合物 | 4 | 14 | 16 | 18 | 32 |
| EC 50(μM) | 0.65 | 2.95 | 0.81 | 0.35 | 6.21 |
从表3中可见，本发明的化合物4、14、16、18和32均能在体外抑制猫传染性腹膜炎病毒(FIPV)的复制，其中化合物4、16和18的抗病毒活性显著，EC
50分别为0.65μM、0.81μM和0.35μM。
Claims (7)
- 一种结构如式(I)所示的化合物或其药学上可接受的盐：
其中：R 1选自C 1-6烷基、C 1-6烯基、C 1-6炔基、C 1-6卤代烷基、C 3-7环烷基、C 3-7杂环基、羟基取代C 1-6烷基、氨基取代C 1-6烷基、C 1-6烷氧基C 1-6烷基、C 1-6烷胺基C 1-6烷基、C 3-7环烷基C 1-6烷基、C 3-7杂环基C 1-6烷基、C 1-6烷胺基、羟基取代C 1-6烷胺基、氨基取代C 1-6烷胺基、C 1-6烷氧基C 1-6烷胺基、C 1-6烷胺基C 1-6烷胺基、C 3-7环烷基C 1-6烷胺基、C 3-7杂环基C 1-6烷胺基。 - 根据权利要求1所述的化合物或其药学上可接受的盐，其特征在于，所述R 1选自-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、-CH(CH 3) 2、-CH 2CH 2CH 2CH 3、-CF 3、-CH 2CF 3、
-CH 2OH、-CH 2NH 2、-CH 2OCH 3、-CH 2CH 2OCH 3、-CH 2NHCH 3、-CH 2N(CH 3) 2、-CH 2CH 2NHCH 3、-CH 2CH 2N(CH 3) 2、
-NHCH 3、-NHCH 2CH 3、-NHCH 2CH 2CH 3、-NHCH(CH 3) 2、-N(CH 3) 2、-N(CH 3)CH 2CH 3、-N(CH 2CH 3) 2、
-NHCH 2CH 2OH、-NHCH 2CH 2NH 2、-N(CH 2CH 2OH) 2、-NHCH 2CH 2OCH 3、-N(CH 2CH 2OCH 3) 2、-NHCH 2CH 2NHCH 3、-NHCH 2CH 2N(CH 3) 2、、-N(CH 3)CH 2CH 2NHCH 3、-N(CH 3)CH 2CH 2N(CH 3) 2、
- 根据权利要求1所述的化合物或其药学上可接受的盐，其特征在于，所述化合物具有以下结构之一：
- 一种药物组合物，其特征在于，含有药学上可接受的赋形剂或载体以及作为活性成分的权利要求1-3中任意一项所述的化合物或其药学上可接受的盐，上述活性成分包括其各光学异构体、各晶型、水合物或溶剂合物。
- 如权利要求1-3中任意一项化合物或其药学上可接受的盐，在治疗猫冠状病毒感染所引起的疾病中的用途，或在制备治疗猫冠状病毒感染所引起的疾病的药物中的用途。
- 如权利要求4所述的药物组合物在治疗猫冠状病毒感染所引起的疾病药物中的用途，或在制备治疗猫冠状病毒感染所引起的疾病的药物中的用途。
- 如权利要求5或6所述的用途，其特征在于，所述猫冠状病毒感染所引起的疾病为猫传染性腹膜炎。
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