CN112294817B - 多韦替尼用于治疗高尿酸相关疾病的用途 - Google Patents
多韦替尼用于治疗高尿酸相关疾病的用途 Download PDFInfo
- Publication number
- CN112294817B CN112294817B CN201910710538.4A CN201910710538A CN112294817B CN 112294817 B CN112294817 B CN 112294817B CN 201910710538 A CN201910710538 A CN 201910710538A CN 112294817 B CN112294817 B CN 112294817B
- Authority
- CN
- China
- Prior art keywords
- uric acid
- hyperuricemia
- dormitotinib
- diseases related
- gout
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 title claims abstract description 48
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 title claims abstract description 48
- 229940116269 uric acid Drugs 0.000 title claims abstract description 48
- 201000010099 disease Diseases 0.000 title claims abstract description 19
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 19
- 201000001431 Hyperuricemia Diseases 0.000 claims abstract description 26
- 230000000694 effects Effects 0.000 claims abstract description 17
- 101710169336 5'-deoxyadenosine deaminase Proteins 0.000 claims abstract description 14
- 102000055025 Adenosine deaminases Human genes 0.000 claims abstract description 14
- 102100033220 Xanthine oxidase Human genes 0.000 claims abstract description 14
- 108010093894 Xanthine oxidase Proteins 0.000 claims abstract description 14
- 239000003814 drug Substances 0.000 claims abstract description 14
- 201000005569 Gout Diseases 0.000 claims abstract description 11
- 206010020772 Hypertension Diseases 0.000 claims abstract description 3
- 208000000913 Kidney Calculi Diseases 0.000 claims abstract description 3
- 206010029148 Nephrolithiasis Diseases 0.000 claims abstract description 3
- 208000019622 heart disease Diseases 0.000 claims abstract description 3
- 201000008383 nephritis Diseases 0.000 claims abstract description 3
- 230000005764 inhibitory process Effects 0.000 claims description 7
- 239000002775 capsule Substances 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 11
- 229940079593 drug Drugs 0.000 abstract description 7
- 230000004144 purine metabolism Effects 0.000 abstract description 7
- 230000002401 inhibitory effect Effects 0.000 abstract description 6
- 210000002966 serum Anatomy 0.000 description 17
- 102000004190 Enzymes Human genes 0.000 description 10
- 108090000790 Enzymes Proteins 0.000 description 10
- 241000699666 Mus <mouse, genus> Species 0.000 description 10
- 230000004060 metabolic process Effects 0.000 description 6
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 4
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- OFCNXPDARWKPPY-UHFFFAOYSA-N allopurinol Chemical group OC1=NC=NC2=C1C=NN2 OFCNXPDARWKPPY-UHFFFAOYSA-N 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- -1 c-KIT Proteins 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 235000003599 food sweetener Nutrition 0.000 description 3
- 230000002503 metabolic effect Effects 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 239000003765 sweetening agent Substances 0.000 description 3
- MPDGHEJMBKOTSU-YKLVYJNSSA-N 18beta-glycyrrhetic acid Chemical compound C([C@H]1C2=CC(=O)[C@H]34)[C@@](C)(C(O)=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@H](O)C1(C)C MPDGHEJMBKOTSU-YKLVYJNSSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229920000881 Modified starch Polymers 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 210000005252 bulbus oculi Anatomy 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229960001338 colchicine Drugs 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000000877 morphologic effect Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 description 1
- KCOYQXZDFIIGCY-CZIZESTLSA-N (3e)-4-amino-5-fluoro-3-[5-(4-methylpiperazin-1-yl)-1,3-dihydrobenzimidazol-2-ylidene]quinolin-2-one Chemical compound C1CN(C)CCN1C1=CC=C(N\C(N2)=C/3C(=C4C(F)=CC=CC4=NC\3=O)N)C2=C1 KCOYQXZDFIIGCY-CZIZESTLSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 208000037157 Azotemia Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 229920002101 Chitin Polymers 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- UDIPTWFVPPPURJ-UHFFFAOYSA-M Cyclamate Chemical compound [Na+].[O-]S(=O)(=O)NC1CCCCC1 UDIPTWFVPPPURJ-UHFFFAOYSA-M 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- MPDGHEJMBKOTSU-UHFFFAOYSA-N Glycyrrhetinsaeure Natural products C12C(=O)C=C3C4CC(C)(C(O)=O)CCC4(C)CCC3(C)C1(C)CCC1C2(C)CCC(O)C1(C)C MPDGHEJMBKOTSU-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- 238000012449 Kunming mouse Methods 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 102000018967 Platelet-Derived Growth Factor beta Receptor Human genes 0.000 description 1
- 108010051742 Platelet-Derived Growth Factor beta Receptor Proteins 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 229960003459 allopurinol Drugs 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 229960002233 benzalkonium bromide Drugs 0.000 description 1
- 229960002529 benzbromarone Drugs 0.000 description 1
- WHQCHUCQKNIQEC-UHFFFAOYSA-N benzbromarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC(Br)=C(O)C(Br)=C1 WHQCHUCQKNIQEC-UHFFFAOYSA-N 0.000 description 1
- KHSLHYAUZSPBIU-UHFFFAOYSA-M benzododecinium bromide Chemical compound [Br-].CCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 KHSLHYAUZSPBIU-UHFFFAOYSA-M 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000000625 cyclamic acid and its Na and Ca salt Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 229950005778 dovitinib Drugs 0.000 description 1
- 230000002888 effect on disease Effects 0.000 description 1
- 238000005485 electric heating Methods 0.000 description 1
- 229960003720 enoxolone Drugs 0.000 description 1
- 239000000686 essence Substances 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 229940044949 eucalyptus oil Drugs 0.000 description 1
- 239000010642 eucalyptus oil Substances 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 238000001422 normality test Methods 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 229960003081 probenecid Drugs 0.000 description 1
- DBABZHXKTCFAPX-UHFFFAOYSA-N probenecid Chemical compound CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 description 1
- 229940085605 saccharin sodium Drugs 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229960001462 sodium cyclamate Drugs 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 208000009852 uremia Diseases 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physical Education & Sports Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明涉及提供多韦替尼用于治疗高尿酸相关疾病的药物用途，即具有多韦替尼基本结构母核的化合物在降尿酸方面的用途。其中，由高尿酸相关疾病包括但不限于高尿酸血症、高尿酸血症肾炎、高尿酸血症高血压、高尿酸血症心脏病、痛风肾结石、痛风。本发明发现多韦替尼具有明显的抑制腺苷脱氨酶活性、抑制黄嘌呤氧化酶活性、降低尿酸等嘌呤代谢抑制作用，即具有多韦替尼基本结构母核的化合物能用于治疗高尿酸相关疾病。本发明的目的是提供了具有多韦替尼的降尿酸用途，还涉及具有多韦替尼基本结构母核的化合物降尿酸的用药方案。
Description
技术领域
本发明涉及药理毒理学领域，具体而言，本发明涉及多韦替尼用于治疗高尿酸相关疾病的药物用途，即具有多韦替尼基本结构母核的化合物在降尿酸方面的用途。
背景技术
临床上，对高尿酸相关疾病的防治主要通过抑制尿酸水平及相关代谢关键酶的表达来实现。尿酸是体内嘌呤代谢的最终产物，主要由肾脏排出；腺苷脱氨酶(ADA)、黄嘌呤氧化酶(XOD)是嘌呤代谢的关键酶，对尿酸的代谢降解有非常重要的作用。当嘌呤代谢紊乱导致尿酸值在血液里的浓度超过正常值，过量的尿酸易沉积在软组织或关节引发生急性发炎反应，导致高尿酸血症、痛风等。随着人们生活水平的提高以及饮食结构的变化，高嘌呤食品的过量摄入，使嘌呤代谢发生紊乱，血液中尿酸增多，导致了全球痛风及高尿酸血症的发生率呈现出增长的趋势。数据显示，我国痛风及高尿酸血症发病率每年以7.5％的速度大幅度上升，我国痛风及高尿酸血症发病人数已达1350万人，其中病人病程超过10年，绝大部分均发生难以治愈的尿毒症，其危害不可小视。痛风及高尿酸血症等高尿酸相关疾病的发病机制至今仍未完全明确，治疗上，目前西医也仅仅停留在利用药物改善症状和控制尿酸水平，如秋水仙碱、非甾体抗炎药、糖皮质激素等药物，尚未能够根治这类高尿酸相关疾病，且容易引起严重的胃肠道反应等不良事件，影响治疗开展。多韦替尼(Dovitinib)是一种口服有效的小分子多靶点酪氨酸激酶抑制剂，对多种生长因子有抑制作用，如VEGFR1-3，FGFR1-3，PDGFR-β，c-KIT，Ret，TraA和csf-1。在临床研究中，多韦替尼用于治疗乳腺癌、肾癌、多发性骨髓瘤、急性白血病、前列腺癌等。但其对尿酸排泄的影响尚未有人探讨。因此，本发明的目的是提供了多韦替尼用于高尿酸相关疾病的用途。
发明内容
本发明的目的之一是提供多韦替尼在治疗高尿酸相关疾病的用途。动物实验证实多韦替尼能显著抑制尿酸水平及相关代谢关键酶表达，表明具有多韦替尼基本结构母核的化合物对高尿酸相关疾病具有一定的预防和治疗作用。
所述的高尿酸相关疾病包括但不限于高尿酸血症、高尿酸血症肾炎、高尿酸血症高血压、高尿酸血症心脏病、痛风肾结石、痛风。
本发明目的之二是提供多韦替尼在降尿酸方面的应用，具体包括多韦替尼具有明显的抑制腺苷脱氨酶活性、抑制黄嘌呤氧化酶活性、降低尿酸等嘌呤代谢抑制作用，能用于预防或治疗高尿酸相关疾病。
本发明的目的之三是提供多韦替尼对尿酸的抑制作用，还涉及多韦替尼降低尿酸的用药方案，包括给予患者给药有效量的具有多韦替尼基本结构母核的化合物或其药学上可接受的盐。
本发明的目的之四是提供一种具有降尿酸作用的药物组合物。该组合物包含以治疗有效量存在的具有多韦替尼基本结构母核的化合物或其药学可接受的盐与至少一种药学可接受的赋形剂的混合物。
进一步，所述组合物还包含至少一种常规降尿酸药。
更进一步，所述降尿酸药选自别嘌呤醇、苯溴马隆、丙磺舒、普瑞凯西、拉布立酶、碳酸氢钠或秋水仙碱。本发明中涉及的具有多韦替尼通式结构的化合物或其药学上可接受的盐，
所述化合物可加入制剂领域常规辅料制成片剂、胶囊剂、颗粒剂、散剂、口服液、注射剂等常规剂型。为使上述剂型能够实现，需在制备这些剂型时加入药学可接受的赋形剂，例如填充剂、崩解剂、润滑剂、助悬剂、粘合剂、甜味剂、矫味剂、防腐剂等，填充剂包括：淀粉、预胶化淀粉、乳糖、甘露醇、甲壳素、微晶纤维素、蔗糖等，崩解剂包括：淀粉、预胶化淀粉、微晶纤维素、羧甲基淀粉钠、交联聚乙烯吡咯烷酮、低取代羟丙纤维素、交联羧甲基纤维素钠等，润滑剂包括：硬脂酸镁、十二烷基硫酸钠、滑石粉、二氧化硅等，助悬剂包括：聚乙烯吡咯烷酮、微晶纤维素、蔗糖、琼脂、羟丙基甲基纤维素等，粘合剂包括，淀粉浆、聚乙烯吡咯烷酮、羟丙基甲基纤维素等，甜味剂包括：糖精钠、阿斯帕坦、蔗糖、甜蜜素、甘草次酸等，矫味剂包括：甜味剂及各种香精，防腐剂包括：尼泊金类、苯甲酸、苯甲酸钠、山梨酸及其盐类、苯扎溴铵、醋酸氯乙定、桉叶油等。
本发明所述“药学可接受的”表示化合物或组合物必须在化学上和/或毒理学上与制剂中包含的其他成分相容。
所述“治疗有效量”表示本发明化合物治疗或预防特定疾病或症状；减弱、改善或消除特定疾病的一种或多种症状；或预防或延迟特定疾病或症状的发作的量。具体治疗剂量根据病情的严重程度、治疗时间而定，医生根据病情和被治疗患者的具体情况来确定适当的剂量。
附图说明
图1多韦替尼对小鼠血清尿酸水平的影响，该图以组别横轴，小鼠血清尿酸水平为纵轴；
图2为多韦替尼对血清尿酸代谢关键酶ADA表达的影响，该图以组别横轴，小鼠血清ADA水平为纵轴。
图3为多韦替尼对血清尿酸代谢关键酶XOD表达的影响，该图以组别横轴，小鼠血清XOD水平为纵轴。
具体实施方式
多韦替尼对小鼠尿酸水平的抑制作用通过以下方法在动物实验上得到证实。
一、材料与方法
1.试剂
UA试剂盒(微板法)、ADA试剂盒(微板法)、XOD试剂盒(比色法)购买于南京建成生物工程研究所。PBS,购买于中科迈晨(北京)科技有限公司(Lot:F31HU030)。无水乙醇、盐酸、二甲苯、中性树胶、氨水，以上试剂均购买于国药集团化学试剂有限公司。
2.实验设备
电子天平(梅特勒-托利多仪器(上海)有限公司)；电热恒温水浴锅(北京市长风仪器仪表公司)；4℃冰箱(青岛海尔股份有限公司)；-80℃冰箱(青岛海尔股份有限公司)；Synergy H1 Hybrid Reader(美国伯腾仪器有限公司)；高速冷冻离心机(Thermoscientific)。
3.动物分组
昆明小鼠30只，全部为雄性，体重18-20g，由斯贝福(北京)实验动物科技有限公司提供，许可证号SCXK(京)2019-0012，适应性喂养三天，使其自由饮食饮水，饲养与实验均在北京中医药大学动物房内进行。
4.给药
多韦替尼组：0.5ml/只取材前间隔两天灌胃三次；别嘌醇组：0.5ml/只连续灌胃三周；正常对照组(空白组)：灌胃等体积生理盐水。
药效学检测：在多韦替尼最后一次灌胃后2h摘眼球取血，装于1.5ml EP管中，做好标记，静置4h，3500rpm，4℃离心10分钟，取上清液至另一EP管中，重复上述离心操作，得到上清液血清标本，放入4℃冰箱待检测。
5.检测指标
5.1.血清尿酸UA水平检测，采用尿酸(UA)试剂盒进行尿酸水平检测。
5.2.血清尿酸代谢关键酶水平检测，按照腺苷脱氨酶(ADA)、抑制黄嘌呤氧化酶(XOD)试剂盒说明书进行血清ADA、XOD水平检测。
5.3.统计学分析，采用SPSS 19.0软件进行分析，数据进行正态性检验，若服从正态分布后再进行单因素方差分析，P<0.05表明差异显著，有统计学意义。
二、结果
1.多韦替尼对小鼠血清尿酸水平的影响
多韦替尼间隔给药三次后，小鼠无特殊形态表现，末次给药2小时后，血清尿酸显著(P<0.001)降低至37.52μM，与正常对照组(107.87μM)相比，抑制率高达65％。与连续给药3周阳性对照药别嘌醇组(42.21μM)相比，其尿酸降低效果更好。见图1、表1。
2.多韦替尼对血清尿酸代谢关键酶ADA、XOD表达的影响
小鼠血清尿酸代谢关键酶ADA、XOD水平是检测嘌呤代谢的重要指标，能再验证尿酸检测结果。多韦替尼间隔给药三次后，小鼠无特殊形态表现，末次给药2小时后，与正常对照组(10.43、20.73U/L)相比，血清尿酸代谢关键酶ADA、XOD表达显著(P<0.05)降低至6.81、14.72U/L。与连续给药3周阳性对照药别嘌醇组(6.63、13.41U/L)相比，效果相似。见图2-3、表1。
表1多韦替尼对小鼠血清尿酸及嘌呤代谢关键酶的抑制作用
*P<0.05，与正常对照组比，具有统计学差异；***P<0.001，与正常对照组比，差异极显著
Claims (3)
1.多韦替尼在制备治疗高尿酸相关疾病的药物中的用途，其中，高尿酸相关疾病包括高尿酸血症、高尿酸血症肾炎、高尿酸血症高血压、高尿酸血症心脏病、痛风肾结石及痛风。
2.如权利要求1所述的用途，其特征在于，所述药物制成片剂、胶囊剂、颗粒剂、散剂、口服液或注射剂。
3.如权利要求1所述的用途，所述药物具有降尿酸相关活性，所述降尿酸相关活性包括但不限于(1)抑制腺苷脱氨酶活性、(2)抑制黄嘌呤氧化酶活性、(3)降低尿酸。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910710538.4A CN112294817B (zh) | 2019-08-02 | 2019-08-02 | 多韦替尼用于治疗高尿酸相关疾病的用途 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910710538.4A CN112294817B (zh) | 2019-08-02 | 2019-08-02 | 多韦替尼用于治疗高尿酸相关疾病的用途 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112294817A CN112294817A (zh) | 2021-02-02 |
| CN112294817B true CN112294817B (zh) | 2022-08-16 |
Family
ID=74486003
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910710538.4A Active CN112294817B (zh) | 2019-08-02 | 2019-08-02 | 多韦替尼用于治疗高尿酸相关疾病的用途 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112294817B (zh) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016149668A1 (en) * | 2015-03-18 | 2016-09-22 | Arvinas, Inc. | Compounds and methods for the enhanced degradation of targeted proteins |
| WO2017011590A1 (en) * | 2015-07-13 | 2017-01-19 | Arvinas, Inc. | Alanine-based modulators of proteolysis and associated methods of use |
| CN109846869A (zh) * | 2019-01-28 | 2019-06-07 | 广东省微生物研究所（广东省微生物分析检测中心） | 2-羟基-4-甲氧基-5-磺酸二苯甲酮在制备治疗/预防高尿酸相关疾病药物中的应用 |
| CN109893654A (zh) * | 2017-12-11 | 2019-06-18 | 江苏恒瑞医药股份有限公司 | Vegfr抑制剂治疗肿瘤的方法 |
-
2019
- 2019-08-02 CN CN201910710538.4A patent/CN112294817B/zh active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016149668A1 (en) * | 2015-03-18 | 2016-09-22 | Arvinas, Inc. | Compounds and methods for the enhanced degradation of targeted proteins |
| WO2017011590A1 (en) * | 2015-07-13 | 2017-01-19 | Arvinas, Inc. | Alanine-based modulators of proteolysis and associated methods of use |
| CN109893654A (zh) * | 2017-12-11 | 2019-06-18 | 江苏恒瑞医药股份有限公司 | Vegfr抑制剂治疗肿瘤的方法 |
| CN109846869A (zh) * | 2019-01-28 | 2019-06-07 | 广东省微生物研究所（广东省微生物分析检测中心） | 2-羟基-4-甲氧基-5-磺酸二苯甲酮在制备治疗/预防高尿酸相关疾病药物中的应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN112294817A (zh) | 2021-02-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2013258566B2 (en) | Pyrazole derivative and use thereof for medical purposes | |
| ES2654093T3 (es) | Uso de levocetirizina y montelukast en el tratamiento de trastornos autoinmunes | |
| WO2019149156A1 (zh) | 一种白头翁提取物在制备治疗病毒性和/或细菌性疾病的药物中的用途 | |
| JP2016029116A (ja) | 炎症性腸疾患および／または過敏性腸管症候群に対する処置としてのｐｈｙ９０６の使用 | |
| CN114209810B (zh) | 枸杞糖肽在制备用于预防或治疗炎性肠病的药物中的用途 | |
| JP2011500853A5 (zh) | ||
| CN112294817B (zh) | 多韦替尼用于治疗高尿酸相关疾病的用途 | |
| CA3107624C (en) | Composition for eradicating helicobacter pylori | |
| CN103813792B (zh) | 用于治疗膀胱过度活动症的索利那新和唾液刺激剂的组合 | |
| CN112022966B (zh) | 一种预防、缓解和/或治疗高尿酸血症的中药组合物 | |
| WO2021036537A1 (zh) | 钩吻素子在制备用于治疗炎症性肠病的药物中的用途 | |
| CN102716128A (zh) | 一种治疗哮喘的药用组合物 | |
| US20220257727A1 (en) | Pharmaceutical composition containing lysozyme and use thereof | |
| CN102274428B (zh) | 一种具有治疗肠易激综合症作用的药物组合物及其制备方法和应用 | |
| CN111956751A (zh) | 一种治疗高尿酸血症的药物组合物及其制备方法 | |
| CN112826820B (zh) | Nlrp3抑制剂及其应用 | |
| TW202029961A (zh) | Ar拮抗劑聯合parp抑制劑在製備治療前列腺癌的藥物中的用途 | |
| CN111991387B (zh) | 去氢二异丁香酚在制备防治溃疡性结肠炎的药物中的应用 | |
| CN103690555B (zh) | 一种治疗乙酰胆碱性荨麻疹的药物组合物 | |
| CN109394753B (zh) | 香叶木素在制备预防和/或治疗高尿酸血症肾病的药物中的应用 | |
| CN112138011A (zh) | 防己诺林碱在制备防治溃疡性结肠炎的药物中的应用 | |
| CN113768989A (zh) | 芍药檗皮丸在制备治疗炎症性肠病或炎症相关性结直肠癌药物中的应用 | |
| CN115154447A (zh) | 一种2,6-二(2-(三氟甲基)苯亚甲基)环己酮在炎症性肠病药物制备中的应用 | |
| CN114272254A (zh) | 甘草次酸和芍药苷的组合在治疗肝损伤、肝纤维化中的应用 | |
| CN116036102A (zh) | 曼那斯汀降低xelox联合治疗方案导致的肠道损伤的应用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |