WO2021254265A1 - 一种化合物在预防和/或治疗动物的病原体感染中的应用 - Google Patents
一种化合物在预防和/或治疗动物的病原体感染中的应用 Download PDFInfo
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
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- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
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- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
Definitions
- the present invention relates to the technical field of chemical medicine, in particular to a compound (4-(3- ⁇ 2-amino-5-[2-(1-methyl-piperidin-4-yl)-thiazol-5-yl]- Pyridin-3-yloxymethyl ⁇ -phenyl)-2-methylbut-3-yn-2-ol) in the prevention and/or treatment of animal pathogens (especially viruses, such as coronavirus) infections application.
- animal pathogens especially viruses, such as coronavirus
- Viral diseases are one of the most serious diseases that harm animals in veterinary clinics, especially the prevalence of some highly pathogenic viral diseases, which often brings huge economic and spiritual losses to feeders. Viral diseases in animals usually spread quickly, with high morbidity and fatality rates, which seriously endanger the health and lives of animals. Moreover, some viruses can also be transmitted to humans through animals, posing a threat to human life.
- Viral diseases in animals can be caused by a wide range of viruses, for example, Herpesviridae, Rhabdoviridae, Reoviridae, Poxviridae, African swine fever virus, Adenoviridae, Parvoviridae, Circovirus Family, Orthomyxoviridae, Paramyxoviridae, Coronaviridae, etc.
- Coronavirus is a large virus family that exists widely in nature. It is named after its shape is similar to a crown when observed under an electron microscope. It mainly causes respiratory diseases and can infect pigs, cattle, cats, dogs, minks, camels and other mammals. And many kinds of birds.
- porcine delta coronavirus is a new type of porcine intestinal coronavirus, which can cause diarrhea and vomiting, rapid dehydration, exhaustion and death in 5-15-day-old suckling piglets.
- the morbidity and mortality rate are as high as 50%. %-100%;
- Avian infectious bronchitis is an acute high-contact respiratory infectious disease in chickens caused by infectious bronchitis virus.
- bovine coronavirus (BCV) is a pathogenicity of cattle Viruses are currently generally considered to be an important pathogen of diarrhea in newborn calves, and can also cause respiratory infections in cattle and blood dysentery in adult cattle in winter; epidemic diarrhea (coronavirus enteritis) in mink, fox, and raccoon is caused by mink parvovirus Epidemic diarrhea in mink caused by coronaviruses other than enteritis.
- Dogs, foxes, raccoon dogs, and mink will show symptoms of hemorrhagic gastroenteritis, which is prone to mass epidemic diarrhea, which spreads quickly and causes mortality. As much as 30%, the incidence of calving animals was higher than that of breeding animals.
- the present invention provides a compound: 4-(3- ⁇ 2-amino-5-[2-(1-methyl-piperidin-4-yl)-thiazol-5-yl]-pyridin-3-yloxy (Methyl)-phenyl)-2-methylbut-3-yn-2-ol (which has the structure of the following formula I) or its pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvents
- a compound 4-(3- ⁇ 2-amino-5-[2-(1-methyl-piperidin-4-yl)-thiazol-5-yl]-pyridin-3-yloxy (Methyl)-phenyl)-2-methylbut-3-yn-2-ol (which has the structure of the following formula I) or its pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvents
- medicaments or deuterated compounds for the prevention and/or treatment of diseases or disorders caused by or related to pathogen infection in animals
- the above-mentioned pathogens of the present invention may be microorganisms, parasites (protozoa, worms, etc.) or other media; specifically, the above-mentioned microorganisms may be selected from: viruses, chlamydia, rickettsia, mycoplasma, bacteria, spirochetes, fungi, etc. One or more of.
- the above-mentioned pathogen of the present invention is a virus.
- the above-mentioned virus may be the herpesvirus family (e.g., pseudorabies virus, bovine infectious rhinotracheitis virus, Marek’s virus, avian infectious laryngotracheitis virus, duck plague virus), iridoviridae (e.g. lymphatic cyst virus) , Baculoviridae (e.g. shrimp baculovirus), Rhabdoviridae (e.g. rabies virus, carp viremia virus), reoviridae (e.g. avian orthoreovirus, bluetongue virus, qualitative Polyhedrosis virus), BiRNAviridae (e.g. infectious bursal disease virus), poxvirus family (e.g.
- pseudorabies virus bovine infectious rhinotracheitis virus, Marek’s virus, avian infectious laryngotracheitis virus, duck plague virus
- iridoviridae e.g. lymphatic cyst virus
- Baculoviridae e.g. shrimp baculovirus
- Avian Leukemia Virus Goat Arthritis/Encephalomyelitis Virus, Equine Infectious Anemia Virus
- Orthomyxoviridae e.g. Avian Influenza
- Paramyxoviridae e.g. Newcastle Disease Virus, Canine Distemper Virus, Rinderpest Virus
- Coronaviridae e.g. Porcine Reproductive and Respiratory Syndrome Virus
- MicroRNA Virus e.g. Foot-and-Mouth Disease Virus
- Swine Vesicular Disease Virus Duck Hepatitis Virus
- Ingroviridae e.g. Rabbit Haemorrhagic Disease Virus
- Flaviviridae e.g.
- Swine Fever Virus Bovine Viral Diarrhea Virus, Japanese Encephalitis Virus
- Prion Filavirus Families (e.g. Marburg virus, Ebola virus), Polyomaviridae and Papillomaviridae, Threadnoviridae, Retroviridae, Hepatoviridae, Papovaviridae, Bonaviridae, Buni Viridae, Arenaviridae, Baculoviridae, Hepatitis E, Astroviridae, Togaviridae, Bicistronic Virus and Nodamura Virus, etc.
- the above-mentioned virus may be, for example, avian infectious bronchitis virus (IBV), porcine transmissible gastroenteritis virus (TGEV), porcine epidemic diarrhea virus (PEDV), porcine hemagglutinating encephalomyelitis virus (HEV) ), mouse hepatitis virus (MHV), turkey blue crown virus (TCDV), bovine coronavirus (BCV), canine coronavirus (CCV), feline infectious peritonitis virus (FIPV), rat coronavirus (RCV) , Rat sialorrhea coronavirus (SDAV), mink epidemic diarrhea coronavirus, sheep pox virus, goat pox virus, bovine pimple skin disease virus, fowlpox virus, cat pox virus, infectious impetigo virus, rabbit myxoma Disease virus, African swine fever virus, pseudorabies virus, porcine cytomegalovirus, avian infectious laryngotracheitis virus, duck plague virus, feline rhino
- the above-mentioned virus is a coronavirus, specifically, avian infectious bronchitis virus (IBV), porcine transmissible gastroenteritis virus (TGEV), porcine epidemic diarrhea virus (PEDV), porcine blood Coagulative encephalomyelitis virus (HEV), mouse hepatitis virus (MHV), turkey blue crown virus (TCDV), bovine coronavirus (BCV), canine coronavirus (CCV), feline infectious peritonitis virus (FIPV) , Rat coronavirus (RCV), rat sialorrhea coronavirus (SDAV), mink epidemic diarrhea coronavirus, etc.
- IBV infectious infectious bronchitis virus
- TGEV porcine transmissible gastroenteritis virus
- PEDV porcine epidemic diarrhea virus
- HEV porcine blood Coagulative encephalomyelitis virus
- MHV mouse hepatitis virus
- TCDV turkey blue crown virus
- BCV bovine coronavirus
- the above-mentioned virus is feline infectious peritonitis virus.
- the "animals” described herein are non-human animals, especially vertebrates, such as mammals (e.g., pigs, cows, sheep, horses, donkeys, dogs, cats, rabbits, Rats, foxes, raccoon dogs, minks, camels), fishes, birds (such as chickens, ducks, geese, pigeons, quails, parrots, etc.), amphibians, reptiles.
- the above-mentioned animals of the present invention are domestic animals, that is, animals that are raised and domesticated by humans and can be artificially controlled to reproduce. They are used for functions such as food, labor, fur, pets, experiments, etc., such as economic animals, pets, laboratory animals, etc. .
- the animal is an economic animal, such as domestic animals (such as pigs, cattle, sheep, horses, donkeys, foxes, raccoons, minks, camels, etc.), poultry (chickens, ducks, geese, etc.) , Pigeon, quail, etc.).
- domestic animals such as pigs, cattle, sheep, horses, donkeys, foxes, raccoons, minks, camels, etc.
- poultry chickens, ducks, geese, etc.
- Pigeon quail, etc.
- the animals are pets, such as dogs, cats, rabbits, rats (such as guinea pigs, hamsters, gerbils, chinchillas, squirrels, etc.), fish, pigeons, parrots, and the like.
- pets such as dogs, cats, rabbits, rats (such as guinea pigs, hamsters, gerbils, chinchillas, squirrels, etc.), fish, pigeons, parrots, and the like.
- the animals are experimental animals, such as monkeys, dogs, rabbits, cats, mice and the like.
- the aforementioned diseases or conditions may include infectious bronchitis in chickens, transmissible gastroenteritis in pigs, epidemic diarrhea in pigs, canine coronavirus disease, porcine hemagglutinating encephalomyelitis, hepatitis caused by mouse hepatitis virus, encephalitis And enteritis, turkey blue crown disease, newborn calf diarrhea, bovine blood dysentery, feline infectious peritonitis, rat salivary gland inflammation, mink epidemic diarrhea, sheep pox, goat pox, cow bump skin disease, fowlpox, cat pox , Infectious pustules, rabbit myxomatosis, African swine fever, pseudorabies, swine cytomegalovirus infection, chicken infectious laryngotracheitis, duck plague, cat viral rhinotracheitis, canine herpes virus infection, bovine infectious nose Tracheitis, equine infectious rhino pneumonia, Marek's disease, malignant catarrhal fever, porcine a
- the above-mentioned disease or condition is selected from: chicken infectious bronchitis, porcine transmissible gastroenteritis, porcine epidemic diarrhea, canine coronavirus disease, porcine hemagglutinative encephalomyelitis, mouse hepatitis Virus-induced hepatitis, encephalitis and enteritis, turkey blue crown disease, newborn calf diarrhea, bovine blood dysentery, cat infectious peritonitis, rat sialorrhea, and mink epidemic diarrhea.
- the above-mentioned disease is feline infectious peritonitis.
- the present invention also provides an application of the compound of the above formula I or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound in the preparation of an animal-use anti-pathogen infection product.
- pathogens and animals have the above-mentioned corresponding definitions of the present invention.
- the above-mentioned products can be used for therapeutic purposes as well as non-therapeutic purposes.
- the above-mentioned product is a pharmaceutical composition.
- the above-mentioned compound of formula I can be used as the sole active ingredient, or can be used in combination with one or more other active ingredients for the same indication or different indications, wherein the above-mentioned heterocyclic ring
- the compound and the other active ingredients can be formulated for simultaneous, separate or sequential administration (simultaneous, separate or sequential administration).
- the above-mentioned pharmaceutical composition also contains pharmaceutically acceptable excipients, especially those acceptable in the veterinary field.
- the above-mentioned pharmaceutical composition can adopt any dosage form or administration form, and those skilled in the art can choose according to the situation.
- the administration form can be, but not limited to, oral, sublingual, inhalation, subcutaneous, intramuscular, intravenous Intraperitoneal, intra-organ, intranasal, intrarectal, transdermal, ocular or rectal forms; its dosage form can be, but not limited to, tablets, pills, powders, granules, capsules, lozenges, syrups , Solutions, emulsions, suspensions, controlled release preparations, aerosols, films, injections, intravenous drips, transdermal absorption preparations, ointments, lotions, adhesive preparations, suppositories, nasal preparations, lung preparations , Eye drops, etc.
- the above-mentioned pharmaceutical composition is an injection.
- compositions can be prepared according to conventional production methods in the field of veterinary medicine.
- the above-mentioned product is a functional food composition.
- the compound of formula I can be used as the sole active ingredient, or can be used in combination with one or more other active ingredients.
- the above-mentioned functional food composition may also include animal food supplements.
- the form of the above-mentioned functional food composition can take any form, such as tablets, pills, capsules, candies (such as tableted candies, jelly candies, gum-based candies, etc.), solid beverages (such as powders, Granules, etc.), liquid beverages, etc.
- candies such as tableted candies, jelly candies, gum-based candies, etc.
- solid beverages such as powders, Granules, etc.
- liquid beverages etc.
- the various forms of the above-mentioned functional food composition can be prepared according to conventional production methods in the field of veterinary functional foods.
- the above-mentioned product is an additive, which can be added in small amounts during the production, processing, and use of animal food (such as livestock and poultry feed, pet diets, pet snacks, etc.).
- animal food such as livestock and poultry feed, pet diets, pet snacks, etc.
- the present invention also provides a method for preventing and/or treating diseases or disorders caused by or related to pathogen infection in animals, which comprises administering to the subject an effective amount of the compound of formula I of the present invention or its pharmaceutically acceptable Steps to accept salts, stereoisomers, esters, prodrugs, solvates, or deuterated compounds.
- the pathogen, animal, disease or condition has the corresponding definition of the present invention.
- the inventors of the present invention have found through experiments that the compound of formula I can effectively treat diseases caused by animal pathogens (especially viruses, such as coronavirus) infections (such as cat infectious peritonitis), improve animal survival, and have anti-pathogens (especially It is a virus (such as coronavirus) in the field of drugs that may have better commercial value and application prospects.
- animal pathogens especially viruses, such as coronavirus
- infections such as cat infectious peritonitis
- anti-pathogens especially It is a virus (such as coronavirus) in the field of drugs that may have better commercial value and application prospects.
- Figure 1 shows a chest X-ray image of a sick cat in Example 1 of the present invention.
- Figure 2 shows the clinical survival curve of Example 2 of the present invention, in which the day of administration is taken as the first day.
- pathogen refers to microorganisms (including viruses, chlamydia, rickettsia, mycoplasma, bacteria, spirochetes, fungi, etc.), parasites (protozoa, worms, etc.) or other vectors that can cause infections in humans or animals and plants.
- the bacteria may be, for example, Gram-positive cocci, Enterobacter, Vibrio, Pasteurella, Gram-negative aerobes, Gram-negative microaerobes and anaerobes, Gram-positive non-bacillus, Gram Blue-positive bacillus, mycobacterium, etc.
- the fungus may be, for example, Candida, Cryptococcus, Aspergillus, etc.
- pathogens generally refer to microorganisms, parasites, or other vectors that can cause infections in animals.
- the pathogen is a virus.
- viral infection refers to a process in which viruses invade the body through multiple channels and multiply in susceptible host cells. After the body is infected with the virus, it can show different clinical types. According to whether there are symptoms, it can be divided into dominant infection and recessive infection. Because the number of viruses that invade the body is small, the virulence is weak or the body's resistance is strong, the virus multiplies in the host cell, but the body does not show obvious clinical symptoms, which is called recessive infection. Although the recessive infection does not show clinical symptoms, the virus is still multiplying in the body and spreading the virus to the outside world, becoming an important source of infection. Therefore, for the host of recessive infection, it is also necessary to resist viral infection. Due to the large number of viruses that invade the body, the strong virulence or the weak resistance of the body, the virus proliferates in large numbers in the host cell, and obvious clinical symptoms appear, which is called a dominant infection.
- the "animals” described herein are non-human animals, especially vertebrates, such as mammals (e.g., pigs, cows, sheep, horses, donkeys, dogs, cats, rabbits, Rats, foxes, raccoon dogs, minks, camels), fishes, birds (such as chickens, ducks, geese, pigeons, quails, parrots, etc.), amphibians, reptiles.
- the above-mentioned animals of the present invention are domestic animals, that is, animals that are raised and domesticated by humans and can be artificially controlled to reproduce.
- economic animals refers to animals raised for meat, milk, fur, labor or other economic purposes, such as livestock, poultry, etc.
- livestock refers to animals raised by humans for reproduction and use, which is beneficial to Animals produced in agriculture
- pents refers to artificially raised bird animals, mainly for obtaining meat, eggs and feathers, but also for other purposes
- domestic animals are pointed out for spiritual purposes (such as entertainment and companion purposes) rather than economic Animals raised for purposes
- experimental animals refer to animals raised for scientific applications.
- salt must be understood as any form of the compound according to the present invention, wherein said compound is in ionic form or is charged and coupled with oppositely charged ions (cations or anions) or in solution.
- This definition also includes quaternary ammonium salts and complexes of the molecule with other molecules and ions, especially complexes formed by ionic interactions.
- solvate should be understood to refer to any form of the compound of the present invention, wherein the compound is connected to another molecule (usually a polar solvent) by a non-covalent bond, especially including hydrates and alcoholates, such as Methanolate.
- solvates are hydrates.
- prodrug uses its broad meaning and encompasses derivatives that can be converted into compounds of the invention in the body.
- examples of prodrugs include but are not limited to derivatives and metabolites of the compound, including biohydrolyzable moieties, such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable Carbonate, biohydrolyzable urea and biohydrolyzable phosphate analogues.
- the prodrug with a carboxyl functional group is a lower alkyl ester of a carboxylic acid. The carboxylic acid ester is easily obtained by esterification of any carboxylic acid moiety present in the molecule.
- Prodrugs are usually prepared by known methods, such as in Burger “Medicinal Chemistry and Drug Discovery Sixth Edition (Donald J. Abraham ed., 2001, Wiley) and “Design and Applications of Prodrugs” (H. Bundgaard ed., 1985). , The method described in Harwood Academic Publishers).
- any compounds referred to herein are intended to represent such specific compounds and certain variations or certain forms thereof.
- the compounds referred to herein may have asymmetric centers and therefore exist in different enantiomeric or diastereomeric forms.
- any given compound referred to herein represents any one of racemates, one or more enantiomeric forms, one or more diastereomeric forms, and mixtures thereof.
- each double bond will have its own stereoisomerism, which can be the same or different from the stereoisomerism of other double bonds of the molecule.
- the compounds referred to herein may exist atroisomers. All stereoisomers of the compounds referred to herein, including enantiomers, diastereomers, geometric isomers and atroisomers, and mixtures thereof, are within the scope of the present invention.
- the compounds of the present invention may also include isotopically labeled forms, that is, compounds that differ only in the presence of one or more isotopically-rich atoms.
- isotopically labeled forms that is, compounds that differ only in the presence of one or more isotopically-rich atoms.
- isotopically labeled forms that is, compounds that differ only in the presence of one or more isotopically-rich atoms.
- the compounds are all included in the scope of the present invention.
- the compounds described in the present invention or their salts, solvates, stereoisomers, ethers, and esters are preferably in a pharmaceutically acceptable form.
- pharmaceutically acceptable means that when the molecule body and the composition containing it are properly administered to a subject, they will not produce adverse, allergic or other adverse reactions.
- the above-mentioned pharmaceutically active compound of the present invention has the following structure, which is a pure powder, is mixed with 0.9% normal saline (50ml endotoxin-free water, 0.45g NaCl), and filtered until the solution is clear.
- 0.9% normal saline 50ml endotoxin-free water, 0.45g NaCl
- Store the diluted medicine in the form of a plastic-sealed sterile vial store it in a refrigerator at 4°C, cool to room temperature before injection, and use it with a disposable syringe.
- the scope of injection spans the back, starting from the back of the scapula 2cm to the middle of the lumbar spine, which is half the distance from the adjacent chest and flanks.
- Each group uses GS-441524 for 3 days first, then the control group D1-D14: the necessary supportive treatment is given, and the A group observes after 3 days D1-D14: the necessary supportive treatment is given, and the drug of the invention is given 2.0mg/kg , SC q 24h.
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Abstract
本发明公开了一种化合物在预防和/或治疗动物的病原体感染中的应用。该化合物为4-(3-{2-氨基-5-[2-(1-甲基-哌啶-4-基)-噻唑-5-基]-吡啶-3-基氧基甲基}-苯基)-2-甲基丁-3-炔-2-醇，其具有如下式Ⅰ的结构。该化合物可有效治疗动物病原体(特别是病毒，如冠状病毒)感染引起的疾病(如猫传染性腹膜炎)，改善动物生存情况，在兽用抗病原体(特别是病毒，如冠状病毒)药物领域可具有较佳的商业价值和应用前景。
Description
本发明涉及化学医药技术领域，具体涉及一种化合物(4-(3-{2-氨基-5-[2-(1-甲基-哌啶-4-基)-噻唑-5-基]-吡啶-3-基氧基甲基}-苯基)-2-甲基丁-3-炔-2-醇)在预防和/或治疗动物的病原体(特别是病毒，如冠状病毒)感染中的应用。
病毒性疾病是在兽医临床上对动物危害最为严重的疾病之一，特别是一些高致病性病毒性疾病的流行，往往给饲主带来巨大的经济和精神上的损失。动物的病毒病通常传染快，致病率和致死率高，严重危害动物的健康和生命。而且，一些病毒还能够通过动物传染给人类，给人类的生命安全带来威胁。
动物的病毒性疾病可由广泛种类的病毒引起，例如，疱疹病毒科、弹状病毒科、呼肠孤病毒科、痘病毒科、非洲猪瘟病毒科、腺病毒科、细小病毒科、圆环病毒科、正粘病毒科、副粘病毒科、冠状病毒科，等等。冠状病毒是在自然界广泛存在的一个大型病毒家族，因其形态在电镜下观察类似王冠而得名，主要引起呼吸系统疾病，可感染猪、牛、猫、犬、貂、骆驼等多种哺乳动物及多种鸟类等。例如，猪德尔塔冠状病毒(Porcine deltacoronavirus，PDCoV)是一种新型猪肠道冠状病毒,可引起5-15日龄哺乳仔猪腹泻和呕吐，迅速脱水，衰竭而亡，发病率和死亡率高达50％-100％；鸡传染性支气管炎是由传染性支气管炎病毒引起的鸡的一种急性高度接触性呼吸道传染病，其临诊特征是呼吸困难、发出罗音、咳嗽、张口呼吸、打喷嚏，如果病原不是 肾病变型毒株或不发生并发病，死亡率一般很低，产蛋鸡感染通常变现产蛋量降低，蛋的品质下降；牛冠状病毒(BCV)是牛的一种致病性病毒，目前普遍认为是新生犊牛腹泻的重要病原，还可引起牛的呼吸道感染和成年牛的冬季血痢；水貂、狐狸、貉子流行性腹泻(冠状病毒性肠炎)，是由水貂细小病毒性肠炎之外的冠状病毒引起的水貂流行性腹泻，犬、狐、貉、貂患病后，表现为出血性胃肠炎症状，易发升群体性的流行性腹泻，传播速度快，死亡率高达30％以上，当年产仔兽比种兽发病率高。
虽然随着医疗技术不断发展，很多病毒性疾病的相关疫苗被研制出来，但是病毒可能发生变异，疫苗对新出现的病毒的效用需要评估，且耗费较大，病毒性疾病的发病率和死亡率依然居高不下，因此兽医领域对抗病毒感染效果好的药物有较大需求。
发明内容
本发明提供一种化合物：4-(3-{2-氨基-5-[2-(1-甲基-哌啶-4-基)-噻唑-5-基]-吡啶-3-基氧基甲基}-苯基)-2-甲基丁-3-炔-2-醇(其具有如下式Ⅰ的结构)或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物或氘代化合物制备预防和/或治疗动物中由病原体感染引起或病原体感染相关的疾病或病症的药物中的应用
具体地，本发明上述病原体可以为微生物、寄生虫(原虫、蠕虫等)或其他媒介；具体地，上述微生物可选自：病毒、衣原体、立克次体、支原体、细菌、螺旋体、真菌等中的一种或多种。
在本发明的一个实施方式中，本发明上述病原体为病毒。
具体地，上述病毒可以为疱疹病毒科(例如伪狂犬病毒、牛传染性鼻气管炎病毒、马立克氏病毒、禽传染性喉气管炎病毒、鸭瘟病毒)、虹彩病毒科(例如淋巴囊肿病毒)、杆状病毒科(例如对虾杆状病毒)、弹状病毒科(例如狂犬病毒、鲤春病毒血症病毒)、呼肠孤病毒科(例如禽正呼肠孤病毒、蓝舌病毒、质型多角体病毒)、双RNA病毒科(例如传染性法氏囊病病毒)、痘病毒科(例如绵阳痘病毒、山羊痘病毒、粘液瘤病毒)、非洲猪瘟病毒科(例如非洲猪瘟病毒)、腺病毒科(例如犬传染性肝炎病毒、减蛋综合征病毒)、细小病毒科(例如猪细小病毒、犬细小病毒、鹅细小病毒、猫泛白细胞减少症病毒、貂肠炎病毒、貂阿留申病毒)、圆环病毒科(例如猪圆环病毒)、反转录病毒科(例如禽白血病病毒、山羊关节炎/脑脊髓炎病毒、马传染性贫血病毒)、正粘病毒科(例如禽流感病毒)、副粘病毒科(例如新城疫病毒、犬瘟热病毒、牛瘟病毒)、冠状病毒科、动脉炎病毒科(例如猪繁殖与呼吸综合征病毒)、微RNA病毒科(例如口蹄疫病毒、猪水疱病病毒、鸭肝炎病毒)、嵌杯病毒科(例如兔出血症病毒)、黄病毒科(例如猪瘟病毒、牛病毒性腹泻病毒、日本脑炎病毒)、朊病毒、丝状病毒科(例如马堡病毒、埃博拉病毒)、多瘤病毒科和乳头瘤病毒科、线头病毒科、反录病毒科、嗜肝病毒科、乳多空病毒科、波纳病毒科、布尼病毒科、砂粒病毒科、杆套病毒科、戊肝病毒科、星状病毒科、披膜病毒科、双顺反子病毒科和野田村病毒科等。
具体地，上述病毒可以为，例如，鸡传染性支气管炎病毒(IBV)、猪传染性胃肠炎病毒(TGEV)、猪流行性腹泻病毒(PEDV)、猪血凝性脑脊髓炎病毒(HEV)、小鼠肝炎病毒(MHV)、火鸡蓝冠病病毒(TCDV)、牛冠状病毒(BCV)、犬冠状病毒(CCV)、猫传染性腹膜炎病毒(FIPV)、大鼠冠状病毒(RCV)、大鼠涎泪腺炎冠状病毒(SDAV)、水貂流行性腹泻冠状病毒、绵羊痘病毒、山羊痘病毒、牛疙瘩皮肤病病毒、禽痘病毒、猫痘病毒、传染性脓疱病毒、兔黏液瘤病病毒、非洲猪瘟病毒、伪狂犬病病毒、 猪巨细胞病毒、鸡传染性喉气管炎病毒、鸭瘟病毒、猫病毒性鼻气管炎病毒、犬疱疹病毒、牛传染性鼻气管炎病毒、马传染性鼻肺炎病毒、马立克氏病病毒、恶性卡他热病毒、猪腺病毒、犬病毒性肝炎病毒、猫腺病毒、猪细小病毒、猫泛白细胞减少症(猫瘟、猫传染性肠炎)病毒、小鹅瘟病毒、犬细小病毒、番鸭细小病毒、猪圆环病毒、鸡传染性贫血病毒、禽白血病病毒、猫白血病病毒、牛白血病病毒、猫免疫缺陷病病毒、梅迪-维斯纳病病毒、山羊病毒性关节炎-脑炎病毒、马传染性贫血病毒、牛免疫缺陷病毒、猫合胞体形成病毒(泡沫病毒)、禽病毒性关节炎病毒、蓝舌病病毒、茨城病病毒、中山病病毒、非洲马瘟病毒、轮状病毒、传染性法氏囊病病毒、犬病毒性乳头状瘤病毒、猫病毒性乳状瘤病病毒、尼帕病病毒、亨德拉病病毒、猪蓝眼病病毒、犬副流感病毒、禽副黏病毒、鸡新城疫病毒、犬瘟热病毒、小反刍兽疫病毒、牛瘟病毒、禽肺病毒、禽腮腺炎病毒(麻疹病毒)、猫副黏病、狂犬病病毒、水疱性口炎病毒、牛流行热/三日热/暂时热病毒、博纳病病毒、流行性感冒病毒、裂谷热病毒、赤羽病病毒、汉坦病毒、猫肠道冠状病毒、猪血球凝集性脑脊髓炎病毒、猪繁殖与呼吸综合征病毒、马病毒性动脉炎病毒、口蹄疫病毒、猪水疱病病毒、猪肠病毒、鸭病毒性肝炎病毒、禽脑脊髓炎病毒、脑心肌炎病毒、猪水疱疹病毒、猫杯状病毒、兔病毒性出血症病毒、犬戊型病毒性肝炎病毒、盖他病毒、日本乙型脑炎/流行性乙型脑炎病毒、森林脑炎病毒、鸭黄病毒、猪瘟病毒、牛病毒性腹泻-粘膜病病毒、边界病病毒等。
在本发明的一个实施方式中，上述病毒为冠状病毒，具体如，鸡传染性支气管炎病毒(IBV)、猪传染性胃肠炎病毒(TGEV)、猪流行性腹泻病毒(PEDV)、猪血凝性脑脊髓炎病毒(HEV)、小鼠肝炎病毒(MHV)、火鸡蓝冠病病毒(TCDV)、牛冠状病毒(BCV)、犬冠状病毒(CCV)、猫传染性腹膜炎病毒(FIPV)、大鼠冠状病毒(RCV)、大鼠涎泪腺炎冠状病毒(SDAV)、水貂流行性腹泻冠状病毒等。
在本发明的一个实施例中，上述病毒为猫传染性腹膜炎病毒。
在本发明中，除非另外指出，否则本文中所述的“动物”为非人类动物，特别是脊椎动物，具体如哺乳动物(例如猪、牛、羊、马、驴、狗、猫、兔、鼠、狐、貉、貂、骆驼)、鱼类、鸟类(例如鸡、鸭、鹅、鸽子、鹌鹑、鹦鹉等)、两栖类动物、爬行类动物。特别是，本发明上述动物为家养动物，即由人类饲养驯化，且可以人为控制其繁殖的动物，用于例如食用、劳役、毛皮、宠物、实验等功能，例如经济动物、宠物、实验动物等。
在本发明的一个实施方式中，在上述应用中，动物为经济动物，如家畜(如猪、牛、羊、马、驴、狐、貉、貂、骆驼等)、家禽(鸡、鸭、鹅、鸽子、鹌鹑等)。
在本发明的一个实施方式中，在上述应用中，动物为宠物，如狗、猫、兔、鼠(如豚鼠、仓鼠、沙鼠、龙猫、松鼠等)、鱼、鸽子、鹦鹉等。
在本发明的一个实施方式中，在上述应用中，动物为实验动物，如猴、狗、兔、猫、鼠等。
具体地，上述疾病或病症可包括鸡传染性支气管炎、猪传染性胃肠炎、猪流行性腹泻、犬冠状病毒病、猪血凝性脑脊髓炎、小鼠肝炎病毒引起的肝炎、脑炎和肠炎、火鸡蓝冠病、新生犊牛腹泻、牛血痢、猫传染性腹膜炎、大鼠涎泪腺炎、水貂流行性腹泻、绵羊痘、山羊痘、牛疙瘩皮肤病、禽痘、猫痘、传染性脓疱、兔黏液瘤病、非洲猪瘟、伪狂犬病、猪巨细胞病毒感染、鸡传染性喉气管炎、鸭瘟、猫病毒性鼻气管炎、犬疱疹病毒感染、牛传染性鼻气管炎、马传染性鼻肺炎、马立克氏病、恶性卡他热、猪腺病毒感染、犬病毒性肝炎、猫腺病毒病、猪细小病毒病、猫泛白细胞减少症(猫瘟、猫传染性肠炎)、小鹅瘟、犬细小病毒病、番鸭细小病毒病、猪圆环病毒病、鸡传染性贫血、禽白血病、猫白血病、牛白血病、猫免疫缺陷病、梅迪-维斯纳病、山羊病毒性关节炎-脑炎、马传染性贫血、牛免疫缺陷病毒感染、猫合胞体形成病毒(泡沫病毒)感染、禽病毒性关节炎、蓝舌病、茨城病、中 山病、非洲马瘟、轮状病毒病、传染性法氏囊病、犬病毒性乳头状瘤、猫病毒性乳状瘤病、尼帕病、亨德拉病、猪蓝眼病、犬副流感病毒感染、禽副黏病毒感染、鸡新城疫、犬瘟热、小反刍兽疫、牛瘟、禽肺病毒感染、禽腮腺炎病毒感染(麻疹病毒感染)、猫副黏病毒病、狂犬病、水疱性口炎、牛流行热/三日热/暂时热、博纳病、流行性感冒、裂谷热、赤羽病、汉坦病毒病、猫肠道冠状病毒感染、猪血球凝集性脑脊髓炎、猪繁殖与呼吸综合征、马病毒性动脉炎、口蹄疫、猪水疱病、猪肠病毒感染、鸭病毒性肝炎、禽脑脊髓炎、脑心肌炎、猪水疱疹、猫杯状病毒病、兔病毒性出血症、犬戊型病毒性肝炎、盖他病毒病、日本乙型脑炎/流行性乙型脑炎、森林脑炎、鸭黄病毒感染、猪瘟、牛病毒性腹泻-粘膜病、边界病等。
在本发明的一个实施方式中，上述疾病或病症选自：鸡传染性支气管炎、猪传染性胃肠炎、猪流行性腹泻、犬冠状病毒病、猪血凝性脑脊髓炎、小鼠肝炎病毒引起的肝炎、脑炎和肠炎、火鸡蓝冠病、新生犊牛腹泻、牛血痢、猫传染性腹膜炎、大鼠涎泪腺炎、水貂流行性腹泻。
在本发明的一个实施例中，上述疾病为猫传染性腹膜炎。
本发明还提供一种上述式Ⅰ的化合物或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物或氘代化合物在制备动物用抗病原体感染的产品中的应用。
具体地，在上述应用中，病原体和动物具有本发明上述相应定义。
具体地，上述产品可用于治疗目的，也可用于非治疗目的。
在本发明的一个实施方式中，上述产品为药物组合物。
具体地，上述药物组合物中，上述式Ⅰ的化合物可以作为唯一的活性成分，也可与一种或多种其它用于相同适应症或不同适应症的活性成分联用，其中，上述杂环化合物与该其他活性成分可配制用于同时、单独或顺序施用(simultaneous,separate or sequential administration)。
具体地，上述药物组合物还包含药学上可接受的辅料，特别是兽医领域 可接受的辅料。
具体地，上述药物组合物可以采用任意的剂型或施用形式，本领域技术人员可以根据情况选用，例如，其施用形式可以为，但不限于，口服、舌下、吸入、皮下、肌肉内、静脉内、腹膜内、器官内、鼻内、直肠内、经皮、眼或直肠等形式；其剂型可以为，但不限于，片剂、丸剂、粉剂、颗粒剂、胶囊剂、锭剂、糖浆剂、溶液剂、乳剂、混悬剂、控制释放制剂、气雾剂、膜剂、注射剂、静脉滴注剂、透皮吸收制剂、软膏剂、洗剂、粘附制剂、栓剂、鼻制剂、肺制剂、眼睛滴剂等。
在本发明的一个实施方式中，上述药物组合物为注射剂。
上述药物组合物的各种形式可以按照兽用药物领域的常规生产方法制备。
在本发明的一个实施方式中，上述产品为功能性食品组合物。
具体地，上述功能性食品组合物中，式Ⅰ的化合物可以作为唯一的活性成分，也可与一种或多种其它活性成分联用。
具体地，上述功能性食品组合物还可包含动物食品辅料。
具体地，上述功能性食品组合物的形式可以采用任意的形式，如，片剂、丸剂、胶囊剂、糖果(如压片糖果、凝胶糖果、胶基糖果等)、固体饮料(如粉剂、颗粒剂等)、液体饮料等。
上述功能性食品组合物的各种形式可以按照兽用功能性食品领域的常规生产方法制备。
在本发明的一个实施方式中，上述产品为添加剂，其可以在动物的食物(如畜禽饲料、宠物日粮、宠物零食等)生产加工、使用过程中以少量为微量添加。
本发明还提供一种预防和/或治疗动物中由病原体感染引起或病原体感染相关的疾病或病症的方法，其包括对受试者给予有效量的本发明上述式Ⅰ的化合物或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物或氘代 化合物的步骤。
具体地，上述方法中，病原体、动物、疾病或病症具有本发明上述相应定义。
本发明发明人通过实验发现，式Ⅰ的化合物可有效治疗动物病原体(特别是病毒，如冠状病毒)感染引起的疾病(如猫传染性腹膜炎)，改善动物生存情况，在兽用抗病原体(特别是病毒，如冠状病毒)药物领域可具有较佳的商业价值和应用前景。
图1所示为本发明实施例1中患病猫的胸部X光图。
图2所示为本发明实施例2的临床生存曲线图，其中，以给药天作为第一天。
除非另有定义，本发明中所使用的所有科学和技术术语具有与本发明涉及技术领域的技术人员通常理解的相同的含义。
术语“病原体”是指可造成人或动植物感染疾病的微生物(包括病毒、衣原体、立克次体、支原体、细菌、螺旋体和真菌等)、寄生虫(原虫、蠕虫等)或其他媒介。其中，细菌可以为，例如，革兰阳性球菌，肠杆菌，弧菌，巴氏杆菌，革兰阴性需氧杆菌，革兰阴性微需氧菌和厌氧菌，革兰阳性无芽孢杆菌，革兰阳性产芽孢杆菌，分枝杆菌等；真菌可以为，例如，假丝酵母菌、隐球菌、曲霉菌等。在本发明中，病原体一般是指可造成动物感染疾病的微生物、寄生虫或其他媒介。在本发明的一个实施方式中，病原体为病毒。
术语“病毒感染”是指病毒通过多种途径侵入机体，并在易感的宿主细胞中增殖的过程。机体感染病毒后，可表现出不同的临床类型。依据有无症状， 可分为显性感染和隐性感染。由于侵入机体的病毒数量较少、毒力较弱或机体的抵抗力较强，病毒在宿主细胞内增殖，但机体不出现明显的临床症状，称为隐性感染。隐性感染虽不出现临床症状，但病毒仍在体内增殖并向外界传播病毒，成为重要的传染源，因此对于隐性感染的宿主，也有抗病毒感染的必要。由于侵入机体的病毒数量较多、毒力较强或是机体的抵抗力较弱，病毒在宿主细胞内大量增殖，出现明显的临床症状，称为显性感染。
在本发明中，除非另外指出，否则本文中所述的“动物”为非人类动物，特别是脊椎动物，具体如哺乳动物(例如猪、牛、羊、马、驴、狗、猫、兔、鼠、狐、貉、貂、骆驼)、鱼类、鸟类(例如鸡、鸭、鹅、鸽子、鹌鹑、鹦鹉等)、两栖类动物、爬行类动物。特别是，本发明上述动物为家养动物，即由人类饲养驯化，且可以人为控制其繁殖的动物，用于例如食用、劳役、毛皮、宠物、实验等功能，例如经济动物、宠物、实验动物等。其中，“经济动物”是指为肉用、乳用、皮毛、役用或其他经济目的而饲养的动物，如家畜、家禽等，“家畜”是指由人类饲养使之繁殖而利用，有利于农业生产的畜类；“家禽”是指人工豢养的鸟类动物，主要为了获取其肉、卵和羽毛，也有作为其他用处；“宠物”是指出于精神目的(例如玩赏和伴侣目的)而非经济目的而饲养的动物；“实验动物”是指为科学应用目的而饲养的动物。
术语“盐”须理解为根据本发明的化合物的任意形式，其中所述的化合物为离子形式或者为带电荷的且与带相反电荷的离子(阳离子或阴离子)耦合或在溶液中。该定义还包括季铵盐和该分子与其它分子和离子的复合物，特别是通过离子相互作用形成的复合物。
术语“溶剂化物”应理解为是指本发明的化合物的任意形式，其中所述化合物通过非共价键与另一个分子相连(通常为极性溶剂)，特别是包括水化物和醇化物，例如甲醇化物。特别是，溶剂化物为水化物。
术语“前药”使用其广义含义，并涵盖在体内可转化成本发明化合物的衍生物。前药的例子包括但不限于该化合物的衍生物和代谢物，包括可生物水 解的部分，如可生物水解的酰胺、可生物水解的酯、可生物水解的氨基甲酸酯、可生物水解的碳酸酯、可生物水解的酰脲和可生物水解的磷酸酯类似物。优选地，具有羧基官能团的前体药物为羧酸的低级烷基酯。所述的羧酸酯易由存在于分子中的任何羧酸部分进行酯化得到。前药通常可由已知方法来制备，如在Burger“Medicinal Chemistry and Drug Discovery第六版(Donald J.Abraham ed.，2001，Wiley)和“Design and Applications of Prodrugs”(H.Bundgaard ed.，1985，Harwood Academic Publishers)中描述的方法。
在这里所涉及的任何化合物均旨在代表这样的特定化合物及其某些变形或某些形式。特别地，在这里所涉及的化合物可能具有不对称中心，并因此存在不同的对映体或非对映体形式。由此，本文涉及的任何给定的化合物代表外消旋物的任意一种、一种或多种对映体形式、一种或多种非对映体形式、及其混合物。同样地，也可能存在双键的立体异构体或几何异构体，由此在一些情况中，分子可能存在为(E)-异构体或(Z)-异构体(反式和顺式异构体)。如果分子包含多个双键，那么每个双键将具有其自身的立体异构现象，其可以与所述分子的其它双键的立体异构现象相同或不同。此外，本文中涉及的化合物可存在阿托异构体。本文涉及的化合物的所有立体异构体，包括对映体、非对映异构体、几何异构体和阿托异构体、及其混合物，都在本发明的范围内。
除非另有说明，本发明的化合物还可包括同位素标记的形式，即区别仅在于存在一种或多种富含同位素的原子的化合物。例如，具有仅用氘或氚来替代至少一个氢原子、或者使用富含
13C或
14C的碳来替代至少一个碳、或者使用富含
15N的氮来替代至少一个氮的现有结构的化合物均包含在本发明范围内。
本发明中所述的化合物或其盐、溶剂化物、立体异构体、醚、酯优选为药学上可接受的形式。其中，“药学上可接受的”是指当分子本体及包含其的组合物适当地给予受试者时，它们不会产生不利的、过敏的或其它不良反应。
下面将结合本发明实施例，对本发明的技术方案进行清楚、完整地描述，显然，所描述的实施例仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例1
1、实验方法
8月龄英国短毛猫(乐乐)，雌性未绝育，2.5kg体重。2020年1月该猫出现体温升高、精神沉郁、食欲减退、腹围变大等症状。1周后入院问诊，1月18日确诊猫传染性腹膜炎(FIP)阳性，用GS-441524治疗3天后，继续使用速尿、速诺、泼尼松龙、伊曲康唑(口服，q 24h，10mg/kg)1个月，腹水消失后停药。4月初病情反复，食量减退、精神萎靡，X光检测出现胸水，PCR检测猫冠状病毒阳性(CT值25.11)。于4月8日入组，第1-14天(D1-14)：给与本发明药物2.0mg/kg，SC q 24h。同时给予恰当支持治疗，辅助治疗药物莫瑞加(保肝药)、丰兹赖(赖氨酸)、康健灵(乳铁蛋白类)。
2、药物制备及使用
本发明上述药物活性化合物具有如下结构，其为纯净粉末，加入0.9％生理盐水(50ml无内毒素水，0.45g NaCl)混匀、滤膜过滤至溶液澄清。以塑封无菌西林瓶的形式存储稀释药物，存放在4℃冰箱里，注射前缓至室温，配合一次性注射器使用。注射范围跨越背部，从肩胛骨后部2cm开始至腰椎中部，是距相邻的胸部和侧腹的距离的一半。
3、实验结果
每日上午注射药物后，下午15:00测一次体温、评估食欲、精神状态、呼吸状态，记录排尿和排便情况，结果如表1所示。
表1 实验结果
入组D0、D7、D14时操作如下：
冷冻保留1ml血清样本，用于多因子检测，结果如表2所示。
表2 血常规检测结果
3)胸部X光
如图1所示。
4)结果分析
根据如上结果可知，该病例检出湿性FIP(位于胸部)，临床症状胸水出现，精神萎靡、食欲减退，呈典型猫传腹症状。
因为在入组时病例没有发热症状，所以用药期间看不到退烧效果，体温始终维持在38℃～38.5℃正常范围。完成2周治疗后猫的临床反应是引人注目的，每日食欲、精神状态和体重增加。从治疗后7天左右，胸部积液完全消失。在治疗期间和治疗后体重增加9％。
实施例2
临床诊断入组患有FIP的猫共15只，有胸/腹水产生、PCR检测CT值呈阳性、无神经症状，其中8只为对照组，7只为实验组。
各组先使用3天GS-441524，之后对照组D1-D14：给与必要的支持治疗，A组观察3天后D1-D14：给与必要的支持治疗，并给与本发明药物2.0mg/kg，SC q 24h。
出现死亡或者神经症状则判定为临床性死亡，14天后计算其临床生存曲线，结果如图2所示。使用Log Rank(Mantel-Cox)和Breslow(Generalized Wilcoxon)方法进行有效性检验，两种方法检验结果皆有显著性差异(P<0.05)。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换等，均应包含在本发明的保护范围之内。
本发明中描述的前述实施例和方法可以基于本领域技术人员的能力、经验和偏好而有所不同。
本发明中仅按一定顺序列出方法的步骤并不构成对方法步骤顺序的任何限制。
Claims (10)
- 一种式Ⅰ的化合物或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物或氘代化合物在制备预防和/或治疗动物中由病原体感染引起或病原体感染相关的疾病或病症的药物中的应用
- 如权利要求1所述的应用，其特征在于，所述病原体为病毒；优选地，所述病毒选自：疱疹病毒科、虹彩病毒科、杆状病毒科、弹状病毒科、呼肠孤病毒科、双RNA病毒科、痘病毒科、非洲猪瘟病毒科、腺病毒科、细小病毒科、圆环病毒科、反转录病毒科、正粘病毒科、副粘病毒科、冠状病毒科、动脉炎病毒科、微RNA病毒科、嵌杯病毒科、黄病毒科、朊病毒、丝状病毒科、多瘤病毒科和乳头瘤病毒科、线头病毒科、反录病毒科、嗜肝病毒科、乳多空病毒科、波纳病毒科、布尼病毒科、砂粒病毒科、杆套病毒科、戊肝病毒科、星状病毒科、披膜病毒科、双顺反子病毒科和野田村病毒科；优选地，所述病毒为冠状病毒。
- 如权利要求1所述的应用，其特征在于，所述病毒选自：鸡传染性支气管炎病毒、猪传染性胃肠炎病毒、猪流行性腹泻病毒、猪血凝性脑脊髓炎病毒、小鼠肝炎病毒、火鸡蓝冠病病毒、牛冠状病毒、犬冠状病毒、猫传染性腹膜炎病毒、大鼠冠状病毒、大鼠涎泪腺炎冠状病毒、水貂流行性腹泻冠状病毒、绵羊痘病毒、山羊痘病毒、牛疙瘩皮肤病病毒、禽痘病毒、猫痘病毒、传染性脓疱病毒、兔黏液瘤病病毒、非洲猪瘟病毒、伪狂犬病病毒、猪巨细胞病毒、鸡传染性喉气管炎病毒、鸭瘟病毒、猫病毒性鼻气管炎病毒、 犬疱疹病毒、牛传染性鼻气管炎病毒、马传染性鼻肺炎病毒、马立克氏病病毒、恶性卡他热病毒、猪腺病毒、犬病毒性肝炎病毒、猫腺病毒、猪细小病毒、猫泛白细胞减少症病毒、小鹅瘟病毒、犬细小病毒、番鸭细小病毒、猪圆环病毒、鸡传染性贫血病毒、禽白血病病毒、猫白血病病毒、牛白血病病毒、猫免疫缺陷病病毒、梅迪-维斯纳病病毒、山羊病毒性关节炎-脑炎病毒、马传染性贫血病毒、牛免疫缺陷病毒、猫合胞体形成病毒、禽病毒性关节炎病毒、蓝舌病病毒、茨城病病毒、中山病病毒、非洲马瘟病毒、轮状病毒、传染性法氏囊病病毒、犬病毒性乳头状瘤病毒、猫病毒性乳状瘤病病毒、尼帕病病毒、亨德拉病病毒、猪蓝眼病病毒、犬副流感病毒、禽副黏病毒、鸡新城疫病毒、犬瘟热病毒、小反刍兽疫病毒、牛瘟病毒、禽肺病毒、禽腮腺炎病毒、猫副黏病、狂犬病病毒、水疱性口炎病毒、牛流行热/三日热/暂时热病毒、博纳病病毒、流行性感冒病毒、裂谷热病毒、赤羽病病毒、汉坦病毒、猫肠道冠状病毒、猪血球凝集性脑脊髓炎病毒、猪繁殖与呼吸综合征病毒、马病毒性动脉炎病毒、口蹄疫病毒、猪水疱病病毒、猪肠病毒、鸭病毒性肝炎病毒、禽脑脊髓炎病毒、脑心肌炎病毒、猪水疱疹病毒、猫杯状病毒、兔病毒性出血症病毒、犬戊型病毒性肝炎病毒、盖他病毒、日本乙型脑炎/流行性乙型脑炎病毒、森林脑炎病毒、鸭黄病毒、猪瘟病毒、牛病毒性腹泻-粘膜病病毒、边界病病毒；优选地，所述病毒为冠状病毒，其选自：鸡传染性支气管炎病毒、猪传染性胃肠炎病毒、猪流行性腹泻病毒、猪血凝性脑脊髓炎病毒、小鼠肝炎病毒、火鸡蓝冠病病毒、牛冠状病毒、犬冠状病毒、猫传染性腹膜炎病毒、大鼠冠状病毒、大鼠涎泪腺炎冠状病毒和水貂流行性腹泻冠状病毒；更优选地，所述病毒为猫传染性腹膜炎病毒。
- 如权利要求1所述的应用，其特征在于，所述动物为家养动物；优选地，所述动物为经济动物、宠物或实验动物。
- 如权利要求1所述的应用，其特征在于，所述疾病或病症包括鸡传 染性支气管炎、猪传染性胃肠炎、猪流行性腹泻、犬冠状病毒病、猪血凝性脑脊髓炎、小鼠肝炎病毒引起的肝炎、脑炎和肠炎、火鸡蓝冠病、新生犊牛腹泻、牛血痢、猫传染性腹膜炎、大鼠涎泪腺炎、水貂流行性腹泻、绵羊痘、山羊痘、牛疙瘩皮肤病、禽痘、猫痘、传染性脓疱、兔黏液瘤病、非洲猪瘟、伪狂犬病、猪巨细胞病毒感染、鸡传染性喉气管炎、鸭瘟、猫病毒性鼻气管炎、犬疱疹病毒感染、牛传染性鼻气管炎、马传染性鼻肺炎、马立克氏病、恶性卡他热、猪腺病毒感染、犬病毒性肝炎、猫腺病毒病、猪细小病毒病、猫泛白细胞减少症、小鹅瘟、犬细小病毒病、番鸭细小病毒病、猪圆环病毒病、鸡传染性贫血、禽白血病、猫白血病、牛白血病、猫免疫缺陷病、梅迪-维斯纳病、山羊病毒性关节炎-脑炎、马传染性贫血、牛免疫缺陷病毒感染、猫合胞体形成病毒感染、禽病毒性关节炎、蓝舌病、茨城病、中山病、非洲马瘟、轮状病毒病、传染性法氏囊病、犬病毒性乳头状瘤、猫病毒性乳状瘤病、尼帕病、亨德拉病、猪蓝眼病、犬副流感病毒感染、禽副黏病毒感染、鸡新城疫、犬瘟热、小反刍兽疫、牛瘟、禽肺病毒感染、禽腮腺炎病毒感染、猫副黏病毒病、狂犬病、水疱性口炎、牛流行热/三日热/暂时热、博纳病、流行性感冒、裂谷热、赤羽病、汉坦病毒病、猫肠道冠状病毒感染、猪血球凝集性脑脊髓炎、猪繁殖与呼吸综合征、马病毒性动脉炎、口蹄疫、猪水疱病、猪肠病毒感染、鸭病毒性肝炎、禽脑脊髓炎、脑心肌炎、猪水疱疹、猫杯状病毒病、兔病毒性出血症、犬戊型病毒性肝炎、盖他病毒病、日本乙型脑炎/流行性乙型脑炎、森林脑炎、鸭黄病毒感染、猪瘟、牛病毒性腹泻-粘膜病、边界病；优选地，所述疾病为猫传染性腹膜炎。
- 一种式Ⅰ的化合物或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物或氘代化合物在制备动物用抗病原体感染产品中的应用
- 如权利要求6所述的应用，其特征在于，所述病原体为病毒；优选地，所述病毒选自：疱疹病毒科、虹彩病毒科、杆状病毒科、弹状病毒科、呼肠孤病毒科、双RNA病毒科、痘病毒科、非洲猪瘟病毒科、腺病毒科、细小病毒科、圆环病毒科、反转录病毒科、正粘病毒科、副粘病毒科、冠状病毒科、动脉炎病毒科、微RNA病毒科、嵌杯病毒科、黄病毒科、朊病毒、丝状病毒科、多瘤病毒科和乳头瘤病毒科、线头病毒科、反录病毒科、嗜肝病毒科、乳多空病毒科、波纳病毒科、布尼病毒科、砂粒病毒科、杆套病毒科、戊肝病毒科、星状病毒科、披膜病毒科、双顺反子病毒科和野田村病毒科；优选地，所述病毒为冠状病毒。
- 如权利要求6所述的应用，其特征在于，所述冠状病毒选自：鸡传染性支气管炎病毒、猪传染性胃肠炎病毒、猪流行性腹泻病毒、猪血凝性脑脊髓炎病毒、小鼠肝炎病毒、火鸡蓝冠病病毒、牛冠状病毒、犬冠状病毒、猫传染性腹膜炎病毒、大鼠冠状病毒、大鼠涎泪腺炎冠状病毒、水貂流行性腹泻冠状病毒、绵羊痘病毒、山羊痘病毒、牛疙瘩皮肤病病毒、禽痘病毒、猫痘病毒、传染性脓疱病毒、兔黏液瘤病病毒、非洲猪瘟病毒、伪狂犬病病毒、猪巨细胞病毒、鸡传染性喉气管炎病毒、鸭瘟病毒、猫病毒性鼻气管炎病毒、犬疱疹病毒、牛传染性鼻气管炎病毒、马传染性鼻肺炎病毒、马立克氏病病毒、恶性卡他热病毒、猪腺病毒、犬病毒性肝炎病毒、猫腺病毒、猪细小病毒、猫泛白细胞减少症病毒、小鹅瘟病毒、犬细小病毒、番鸭细小病毒、猪圆环病毒、鸡传染性贫血病毒、禽白血病病毒、猫白血病病毒、牛白 血病病毒、猫免疫缺陷病病毒、梅迪-维斯纳病病毒、山羊病毒性关节炎-脑炎病毒、马传染性贫血病毒、牛免疫缺陷病毒、猫合胞体形成病毒、禽病毒性关节炎病毒、蓝舌病病毒、茨城病病毒、中山病病毒、非洲马瘟病毒、轮状病毒、传染性法氏囊病病毒、犬病毒性乳头状瘤病毒、猫病毒性乳状瘤病病毒、尼帕病病毒、亨德拉病病毒、猪蓝眼病病毒、犬副流感病毒、禽副黏病毒、鸡新城疫病毒、犬瘟热病毒、小反刍兽疫病毒、牛瘟病毒、禽肺病毒、禽腮腺炎病毒、猫副黏病、狂犬病病毒、水疱性口炎病毒、牛流行热/三日热/暂时热病毒、博纳病病毒、流行性感冒病毒、裂谷热病毒、赤羽病病毒、汉坦病毒、猫肠道冠状病毒、猪血球凝集性脑脊髓炎病毒、猪繁殖与呼吸综合征病毒、马病毒性动脉炎病毒、口蹄疫病毒、猪水疱病病毒、猪肠病毒、鸭病毒性肝炎病毒、禽脑脊髓炎病毒、脑心肌炎病毒、猪水疱疹病毒、猫杯状病毒、兔病毒性出血症病毒、犬戊型病毒性肝炎病毒、盖他病毒、日本乙型脑炎/流行性乙型脑炎病毒、森林脑炎病毒、鸭黄病毒、猪瘟病毒、牛病毒性腹泻-粘膜病病毒、边界病病毒；优选地，所述病毒为冠状病毒，其选自：鸡传染性支气管炎病毒、猪传染性胃肠炎病毒、猪流行性腹泻病毒、猪血凝性脑脊髓炎病毒、小鼠肝炎病毒、火鸡蓝冠病病毒、牛冠状病毒、犬冠状病毒、猫传染性腹膜炎病毒、大鼠冠状病毒、大鼠涎泪腺炎冠状病毒和水貂流行性腹泻冠状病毒；更优选地，所述病毒为猫传染性腹膜炎病毒。
- 如权利要求6所述的应用，其特征在于，所述动物为家养动物；优选地，所述动物为经济动物、宠物或实验动物。
- 如权利要求6-9任一项所述的应用，其特征在于，所述产品为药物组合物、功能性食品组合物或添加剂；优选地，所述药物组合物还包含药学上可接受的辅料；优选地，所述药物组合物为注射剂。
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| JP2022549814A JP7442662B2 (ja) | 2020-06-16 | 2021-06-11 | 動物の病原体感染症の予防及び／又は治療における化合物の使用 |
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| WO2019090198A1 (en) * | 2017-11-06 | 2019-05-09 | Bristol-Myers Squibb Company | Isofuranone compounds useful as hpk1 inhibitors |
| CN110063954A (zh) * | 2019-04-10 | 2019-07-30 | 华中农业大学 | Fhpi在制备治疗猫传染性腹膜炎药物中的应用 |
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| CN110396087A (zh) * | 2018-04-25 | 2019-11-01 | 珠海宇繁生物科技有限责任公司 | Hpk1激酶抑制剂、制备方法及其应用 |
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| WO2019090198A1 (en) * | 2017-11-06 | 2019-05-09 | Bristol-Myers Squibb Company | Isofuranone compounds useful as hpk1 inhibitors |
| CN110396087A (zh) * | 2018-04-25 | 2019-11-01 | 珠海宇繁生物科技有限责任公司 | Hpk1激酶抑制剂、制备方法及其应用 |
| CN110063954A (zh) * | 2019-04-10 | 2019-07-30 | 华中农业大学 | Fhpi在制备治疗猫传染性腹膜炎药物中的应用 |
| CN110215456A (zh) * | 2019-06-25 | 2019-09-10 | 华中农业大学 | 一种由gc376与gs-441524组成的猫冠状病毒抑制剂组合物 |
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| LI TING, ZHANG GUANGYI: "The Role of HPK1 in Ischemic Brain Injury", ACTA ACADEMIAE MEDICINAE XUZHOU, vol. 29, no. 3, 25 March 2009 (2009-03-25), pages 141 - 143, XP055881626, ISSN: 1000-2065 * |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114839378A (zh) * | 2022-07-04 | 2022-08-02 | 山东康华生物医疗科技股份有限公司 | 一种猫疱疹和猫杯状病毒联合检测试剂盒 |
| CN114839378B (zh) * | 2022-07-04 | 2022-09-06 | 山东康华生物医疗科技股份有限公司 | 一种猫疱疹和猫杯状病毒联合检测试剂盒 |
Also Published As
| Publication number | Publication date |
|---|---|
| US20230097009A1 (en) | 2023-03-30 |
| KR20220129592A (ko) | 2022-09-23 |
| EP4094763A4 (en) | 2023-04-26 |
| CO2022011666A2 (es) | 2022-08-30 |
| AU2021291983A1 (en) | 2022-09-08 |
| JP7442662B2 (ja) | 2024-03-04 |
| JP2023525430A (ja) | 2023-06-16 |
| CA3168377A1 (en) | 2021-12-23 |
| ZA202213500B (en) | 2023-07-26 |
| CN113797198B (zh) | 2023-11-28 |
| EP4094763A1 (en) | 2022-11-30 |
| CN117338775A (zh) | 2024-01-05 |
| EP4094763B1 (en) | 2024-09-18 |
| CN113797198A (zh) | 2021-12-17 |
| MX2022010020A (es) | 2022-10-10 |
| BR112022016727A2 (pt) | 2022-12-27 |
| AU2021291983B2 (en) | 2024-01-18 |
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