CN113024534B - 2-pyridylthiazole derivatives and use thereof - Google Patents
2-pyridylthiazole derivatives and use thereof Download PDFInfo
- Publication number
- CN113024534B CN113024534B CN201911347393.2A CN201911347393A CN113024534B CN 113024534 B CN113024534 B CN 113024534B CN 201911347393 A CN201911347393 A CN 201911347393A CN 113024534 B CN113024534 B CN 113024534B
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- China
- Prior art keywords
- carboxylic acid
- compound
- methylthiazole
- pharmaceutically acceptable
- pyridin
- Prior art date
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- FZSXKNJOKINZSF-UHFFFAOYSA-N 2-pyridin-2-yl-1,3-thiazole Chemical class C1=CSC(C=2N=CC=CC=2)=N1 FZSXKNJOKINZSF-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 54
- 150000003839 salts Chemical class 0.000 claims abstract description 24
- 201000005569 Gout Diseases 0.000 claims abstract description 12
- 201000001431 Hyperuricemia Diseases 0.000 claims abstract description 12
- 239000003814 drug Substances 0.000 claims abstract description 9
- -1 2- (2-cyanopyridin-4-yl) -4-methylthiazole-5-carboxylic acid Chemical compound 0.000 claims description 105
- 239000003064 xanthine oxidase inhibitor Substances 0.000 claims description 11
- 229940123769 Xanthine oxidase inhibitor Drugs 0.000 claims description 7
- 239000004480 active ingredient Substances 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 3
- 239000004215 Carbon black (E152) Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 229930195733 hydrocarbon Natural products 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 claims description 2
- 125000001188 haloalkyl group Chemical group 0.000 claims description 2
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- 108010093894 Xanthine oxidase Proteins 0.000 abstract description 22
- 102100033220 Xanthine oxidase Human genes 0.000 abstract description 19
- 229940079593 drug Drugs 0.000 abstract description 5
- 239000003112 inhibitor Substances 0.000 abstract 1
- 150000003222 pyridines Chemical class 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 description 26
- 238000003786 synthesis reaction Methods 0.000 description 25
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 24
- 238000000034 method Methods 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 17
- CZXDCTUSFIKLIJ-UHFFFAOYSA-N 4-bromopyridine-2-carbonitrile Chemical compound BrC1=CC=NC(C#N)=C1 CZXDCTUSFIKLIJ-UHFFFAOYSA-N 0.000 description 13
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 239000002904 solvent Substances 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 9
- 230000002401 inhibitory effect Effects 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 8
- 201000010099 disease Diseases 0.000 description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- WISQBJLUORKXNY-UHFFFAOYSA-N ethyl 4-methyl-1,3-thiazole-5-carboxylate Chemical compound CCOC(=O)C=1SC=NC=1C WISQBJLUORKXNY-UHFFFAOYSA-N 0.000 description 8
- 229940116269 uric acid Drugs 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 125000004093 cyano group Chemical group *C#N 0.000 description 6
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical compound O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 229940075420 xanthine Drugs 0.000 description 6
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
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- 125000003118 aryl group Chemical group 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 239000002953 phosphate buffered saline Substances 0.000 description 4
- 230000002441 reversible effect Effects 0.000 description 4
- 239000003643 water by type Substances 0.000 description 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 3
- BAQKUNMKVAPWGU-UHFFFAOYSA-N 4-bromopyridin-2-amine Chemical group NC1=CC(Br)=CC=N1 BAQKUNMKVAPWGU-UHFFFAOYSA-N 0.000 description 3
- 125000005915 C6-C14 aryl group Chemical group 0.000 description 3
- UGQMRVRMYYASKQ-UHFFFAOYSA-N Hypoxanthine nucleoside Natural products OC1C(O)C(CO)OC1N1C(NC=NC2=O)=C2N=C1 UGQMRVRMYYASKQ-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
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- 108090000854 Oxidoreductases Proteins 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 102000005773 Xanthine dehydrogenase Human genes 0.000 description 3
- 108010091383 Xanthine dehydrogenase Proteins 0.000 description 3
- OFCNXPDARWKPPY-UHFFFAOYSA-N allopurinol Chemical compound OC1=NC=NC2=C1C=NN2 OFCNXPDARWKPPY-UHFFFAOYSA-N 0.000 description 3
- 229960003459 allopurinol Drugs 0.000 description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 229940125898 compound 5 Drugs 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- CIPMPQGRFNDLAP-UHFFFAOYSA-N ethyl 1,3-thiazole-5-carboxylate Chemical compound CCOC(=O)C1=CN=CS1 CIPMPQGRFNDLAP-UHFFFAOYSA-N 0.000 description 3
- YDVJUPSKFKJIQN-UHFFFAOYSA-N ethyl 4-ethyl-1,3-thiazole-5-carboxylate Chemical group CCOC(=O)C=1SC=NC=1CC YDVJUPSKFKJIQN-UHFFFAOYSA-N 0.000 description 3
- BQSJTQLCZDPROO-UHFFFAOYSA-N febuxostat Chemical compound C1=C(C#N)C(OCC(C)C)=CC=C1C1=NC(C)=C(C(O)=O)S1 BQSJTQLCZDPROO-UHFFFAOYSA-N 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
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- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
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- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
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- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- MLZQFBNVLJIBLJ-UHFFFAOYSA-N ethyl 4-(trifluoromethyl)-1,3-thiazole-5-carboxylate Chemical compound CCOC(=O)C=1SC=NC=1C(F)(F)F MLZQFBNVLJIBLJ-UHFFFAOYSA-N 0.000 description 1
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- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
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- ILUJQPXNXACGAN-UHFFFAOYSA-N ortho-methoxybenzoic acid Natural products COC1=CC=CC=C1C(O)=O ILUJQPXNXACGAN-UHFFFAOYSA-N 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
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- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
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- 125000004076 pyridyl group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
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- 235000002906 tartaric acid Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
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- SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (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)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention develops pyridine derivatives shown in a general formula (I), pharmaceutically acceptable salts thereof and application thereof as a Xanthine Oxidase (XO) inhibitor. The compounds can be applied to medicines for preventing and/or treating hyperuricemia and gout.
Description
Technical Field
The present invention relates to a novel compound having xanthine oxidase inhibitory activity and a process for producing the same, and more particularly, to a 2-pyridyl thiazole derivative which is useful as a therapeutic and/or prophylactic agent for diseases in which hyperuricemia and gout involve xanthine oxidase.
Background
Xanthine Oxidase (XO) is an enzyme with low specificity, which can catalyze hypoxanthine to generate Xanthine and further generate uric acid, and can directly catalyze Xanthine to generate uric acid.
Xanthine Oxidase Inhibitors (XOI) reduce the level of uric acid in the blood by inhibiting the synthesis of uric acid. Therefore, xanthine oxidase inhibitors are effective for the treatment of hyperuricemia and various diseases caused by the same. Such as: the urate caused by persistent hyperuricemia precipitates crystals in tissues, organs and joints, and causes gouty arthritis, gouty stones and the like. Research has shown that hyperuricemia is not only the most important biochemical basis for gout and the most dangerous factor inducing gout, but is also associated with various metabolic disorder syndromes such as hypertension, renal disease, metabolic syndrome, hyperlipidemia, diabetes, insulin resistance, and cardiovascular and cerebrovascular diseases (Zhu Y, pandya BJ, choi HK, comorbidities of gout and hyperuricemia in the US general publication: NHANES 2007-2008J ]. Am J Med,2012,125 (7): 679-687.)
Clinical uric acid lowering drugs, namely: the xanthine oxidase inhibitor is represented by allopurinol and febuxostat, and research shows that although allopurinol is a first-line medicine for hyperuricemia and gout, the allopurinol can cause skin anaphylaxis and liver and kidney function damage, severe patients can generate hypersensitivity syndromes such as lethal exfoliative dermatitis and the like, and febuxostat has a remarkable curative effect, but still shows some obvious adverse reactions such as liver dysfunction, diarrhea, headache, rash, cardiotoxicity and the like. As an initial drug with clear drug target and clear action mechanism, the febuxostat structure is not fully optimized, so that the deep optimization research on the target and the structure has great clinical significance and market value.
Disclosure of Invention
Problems to be solved by the invention
The object of the present invention is to provide a novel compound having xanthine oxidase inhibitory activity. Further, an object of the present invention is to provide a compound having an excellent uric acid lowering effect. It is another object of the present invention to provide compounds effective as therapeutic and/or prophylactic agents for diseases in which hyperuricemia, gout, and xanthine oxidase are involved.
Means for solving the problems
The technical means of the invention comprises the following scheme:
the present invention provides a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof:
wherein the content of the first and second substances,
R 1 selected from-OH, -NH 2 C1-C5 alkoxy, C1-C5 haloalkoxy;
R 2 selected from H, C1-C5 alkyl, C1-C5 haloalkyl;
R 3 and R 4 Selected from H, -NH 2 -CN, halogen, -C (O) NH 2 C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C6-C14 aryl, 5-6 membered cycloarenyl, wherein each of the C1-C5 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, aryl, 5-6 membered cycloarenyl may optionally be substituted one or more times independently of each other by the following optional groups: halogen, -OH, -NH 2 ，-CONH 2 ，-COOH，-CN，-OCH 3 C3-C6 heterocycloalkyl, 5-to 6-membered heterocyclic aromatic hydrocarbon groups.
In the above compound or a pharmaceutically acceptable salt thereof, R 1 Selected from-OH and-OCH 3 、-OEt。
In the above compound or a pharmaceutically acceptable salt thereof, R 2 Selected from H, methyl, ethyl, trifluoromethyl.
In the above compound or a pharmaceutically acceptable salt thereof, R 3 And R 4 Selected from H, -NH 2 、-CN、-CONH 2 C3-C6 cycloalkyl, C6-C14 aryl, 5-6 membered heterocyclic aromatic hydrocarbon, wherein each of the C3-C6 cycloalkyl, C6-C14 aryl, 5-6 membered heterocyclic aromatic hydrocarbon may optionally be substituted one or more times independently of each other by the following optional groups: halogen, -OH, -NH 2 ，-CONH 2 ，-COOH，-CN，-CH 3 ，-OCH 3 ，-CF 3 。
In the above compound or a pharmaceutically acceptable salt thereof, when R is 3 And R 4 When the aromatic hydrocarbon is C6-C14 aromatic hydrocarbon or 5-6 membered heterocyclic aromatic hydrocarbon, the C6-C14 aromatic hydrocarbon or 5-6 membered heterocyclic aromatic hydrocarbon is selected from
In the above compound or a pharmaceutically acceptable salt thereof, R 3 And R 4 Is selected from-CN, -CONH 2 ，
The present invention provides the following compounds:
2- (2-cyanopyridin-4-yl) -4-methylthiazole-5-carboxylic acid,
2- (2-cyanopyridin-4-yl) thiazole-5-carboxylic acid,
2- (2-cyanopyridin-4-yl) -4-ethylthiazole-5-carboxylic acid,
2- (2-cyanopyridin-4-yl) -4- (trifluoromethyl) thiazole-5-carboxylic acid,
2- (2- (1H-imidazol-4-yl) pyridin-4-yl) -4-methylthiazole-5-carboxylic acid,
2- (2- (1H-imidazol-4-yl) pyridin-4-yl) thiazole-5-carboxylic acid,
2- (2- (1H-imidazol-4-yl) pyridin-4-yl) -4-ethylthiazole-5-carboxylic acid,
2- (2-aminopyridin-4-yl) -4-methylthiazole-5-carboxylic acid,
2- (2-aminopyridin-4-yl) thiazole-5-carboxylic acid,
2- (2-aminopyridin-4-yl) -4-ethylthiazole-5-carboxylic acid,
2- (2-cyano-6- (2H-tetrazol-5-yl) pyridin-4-yl) -4-methylthiazole-5-carboxylic acid,
4- (4- (5-carboxy-4-methylthiazol-2-yl) -6-cyanopyridin-2-yl) thiazole-2-carboxylic acid,
2- (2-cyano-6- (2- (tetrahydrofuran-2-yl) -1H-imidazol-4-yl) pyridin-4-yl) -4-methylthiazole-5-carboxylic acid,
2- (5 '-chloro-6-cyano- [2,2' -bipyridine ] -4-yl) -4-methylthiazole-5-carboxylic acid,
2- (2-cyano-6- (furan-2-yl) pyridin-4-yl) -4-methylthiazole-5-carboxylic acid,
2- (2-cyano-6- (6-oxo-1, 6-dihydropyridazin-3-yl) pyridin-4-yl) -4-methylthiazole-5-carboxylic acid,
2- (2-cyano-6-phenylpyridin-4-yl) -4-methylthiazole-5-carboxylic acid,
2- (2-carbamoylpyridin-4-yl) -4-methylthiazole-5-carboxylic acid,
2- (2- (2H-tetrazol-5-yl) pyridin-4-yl) -4-methylthiazole-5-carboxylic acid,
2- (2- (2H-tetrazol-5-yl) pyridin-4-yl) thiazole-5-carboxylic acid,
2- (2- (2H-tetrazol-5-yl) pyridin-4-yl) -4-ethylthiazole-5-carboxylic acid,
2- (2- (1H-tetrazol-1-yl) pyridin-4-yl) -4-methylthiazole-5-carboxylic acid,
2- (2- (1H-tetrazol-1-yl) pyridin-4-yl) thiazole-5-carboxylic acid,
2- (2- (1H-tetrazol-1-yl) pyridin-4-yl) -4-ethylthiazole-5-carboxylic acid.
The present invention provides a pharmaceutical composition comprising a compound of any one of the above or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier.
The invention provides the use of a compound as described in any one of the above or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a xanthine oxidase inhibitor.
The present invention provides a xanthine oxidase inhibitor containing the compound according to any one of the above or a pharmaceutically acceptable salt thereof as an active ingredient.
The invention provides application of the compound or the pharmaceutically acceptable salt thereof in preparing medicines for preventing and/or treating hyperuricemia and gout.
The invention provides application of the 2-pyridyl thiazole compound in preparing xanthine oxidase inhibitors or medicines for preventing and/or treating cardiovascular diseases such as hyperuricemia, gout and the like.
Unless otherwise indicated, the following terms used in the claims and specification have the following meanings:
the term "halogen atom", "halo- (halo)" is to be understood as meaning a fluorine, chlorine, bromine or iodine atom.
<xnotran> "C1-C5 " 1,2,3, 4, 5 , "C1-C6 " 1,2,3, 4, 5, 6 , , , , , , , , , , ,1- - ,2- - ,3- - ,1,1- - ,1,2- - ,2,2- - ,1- - , ,1- - ,2- - ,3- - ,4- - ,1,1- - ,1,2- - ,1,3- - ,2,2- - ,2,3- - ,3,3- - ,1- - ,2- - ,1,1,2- - ,1,2,2- - ,1- -1- - ,1- -2- - . </xnotran>
The term "C1-C6 alkoxy" is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical of the formula-O-alkyl. <xnotran> , , , , , , , , , ,1- - ,2- - ,3- - ,1,1- - ,1,2- - ,2,2- - ,1- - , ,1- - ,2- - ,3- - ,4- - ,1,1- - ,1,2- - ,1,3- - ,2,2- - ,2,3- - ,3,3- - ,1- - ,2- - ,1,1,2- - ,1,2,2- - ,1- -1- - ,1- -2- - . </xnotran>
The term "C3-C6 cycloalkyl" is to be understood as meaning a cyclic saturated monovalent hydrocarbon radical having 3, 4, 5, 6 carbon atoms, which may in particular be, <xnotran> , ,1- - ,2- - , ,1- - ,2- - ,3- - ,1,2- - ,2,3- - ,1- - ,2- - , ,1- - ,2- - ,3- - ,1- - ,2- - ,3- - ,1,2- - ,1,3- - ,2,2- - ,2,3- - ,2,4- - ,3,3- - ,1- - ,2- - ,1- - ,2- - ,1,2,2- - ,1,2,3- - ,2,2,3- - ,1- -2- - ,2- -1- - ,2- -2- - ,2- -3- - . </xnotran>
The term "substituted" means that one or more hydrogens on the designated atom is replaced with a group selected from the group indicated, with the proviso that: not exceeding the existing normal valency of the designated atom, and which substitution results in a stable compound. Substituents and/or variables can be combined as long as such combination can result in a stable compound.
The term "heteroaryl" denotes a monocyclic or fused ring group of 5 to 12 ring atoms, containing one, two, three or four ring heteroatoms selected from N, O or S, the remaining ring atoms being C, and additionally having a completely conjugated pi-electron system. Non-limiting examples of unsubstituted heteroaryl groups are tetrazolyl, triazolyl, imidazolyl, pyridyl, thiazolyl, isoxazolyl, thienyl, furyl.
The term "aryl" denotes an all-carbon monocyclic or fused polycyclic group of 6 to 12 carbon atoms with a completely conjugated pi-electron system. A non-limiting example of an aryl group is phenyl. The aromatic group may be substituted or unsubstituted. The substituents for the aromatic groups may be halogen, -OH, -NH 2 ，-CONH 2 ，-COOH，-CN，-CH 3 ，-OCH 3 ，-CF 3 And the like.
The term "pharmaceutically acceptable salts" refers to salts of the compounds of formula (I) with organic or inorganic acids, and refers to those salts that retain the biological effectiveness and properties of the parent compound. Such salts include:
(1) Salt formation with an acid is achieved by reaction of the pyridine group of the parent compound with an inorganic acid such as (but not limited to) hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid, perchloric acid, and the like, or an organic acid such as (but not limited to) acetic acid, propionic acid, acrylic acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid, hydroxybenzoic acid, γ -hydroxybutyric acid, methoxybenzoic acid, phthalic acid, methanesulfonic acid, ethanesulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, mandelic acid, succinic acid, malonic acid, and the like.
(2) The acidic proton present in the parent compound is replaced by a metal ion such as an alkali metal ion, an alkaline earth metal ion or an aluminum ion, or is complexed with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, or the like.
The term "pharmaceutical composition" refers to a mixture of one or more compounds described herein or their pharmaceutically acceptable salts and prodrugs with other chemical ingredients, such as pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to an organism.
The term "preventing" refers to preventing a disease or illness from occurring in the future for an individual who has not yet suffered from a disease or illness, "treating" refers to curing, inhibiting, or ameliorating the disease or condition for an individual who has suffered from a disease or illness.
The term "xanthine oxidase" is generally classified into a broad sense which is an enzyme that catalyzes an oxidation reaction in which hypoxanthine is converted into xanthine and then converted into uric acid, and a narrow sense which is an oxidase type xanthine oxidoreductase which is one of enzymes catalyzing the same reaction. In the present invention, unless otherwise specified, "xanthine oxidase" is a generic term for enzymes that catalyze an oxidation reaction in which hypoxanthine is converted to xanthine and then converted to uric acid. In the xanthine oxidoreductase responsible for this reaction, there are two types, an oxidase type and a dehydrogenase type, both of which are included in the xanthine oxidase of the present invention. Similarly, unless otherwise specified, "xanthine oxidase" in terms of "xanthine oxidase inhibitory activity", "xanthine oxidase inhibitor" and the like is also synonymous with the above.
Advantageous effects
The compound of the invention has xanthine oxidase inhibitory activity, and part of the compounds have very excellent xanthine oxidase inhibitory activity, the enzyme activity and the cell activity of the compounds exceed the prior art (positive control), and the compounds have significant difference, which is beyond the expectation of the technical personnel in the field. Therefore, the compounds of the present invention are expected to have excellent effects of treating and/or preventing hyperuricemia, gout, and related diseases in which xanthine oxidase is involved.
Detailed Description
The present invention is described in detail below by way of examples, but is not meant to be limiting in any way, and is only illustrative and representative thereof. Having described the invention in detail and having disclosed specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.
Synthetic examples
Example 1
Compound 1: synthesis of 2- (2-cyanopyridin-4-yl) -4-methylthiazole-5-carboxylic acid
The method comprises the following steps: to a reaction flask were added ethyl 4-methylthiazole-5-carboxylate (3.2g, 21.1 mmol), 4-bromopyridine-2-carbonitrile (3.0g, 16.3 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (0.27g, 0.33mmol), sodium hydrogencarbonate (3.4g, 34mmol), cuprous bromide (0.23g, 1.6 mmol) and a solution of isobutyric acid (0.04 g) in this order, followed by addition of toluene (100 ml), nitrogen protection, heating to 110 ℃ with stirring for 6 hours, cooling to room temperature, filtering and spin-drying the reaction solution, and purifying the crude product with a petroleum ether, ethyl acetate (10) column to obtain ethyl 2- (2-cyanopyridin-4-yl) -4-methylthiazole-5-carboxylate (A1-3) (3g, 67.1%) as a white solid.
Step two: to a reaction flask was added ethyl 2- (2-cyanopyridin-4-yl) -4-methylthiazole-5-carboxylate (A1-3) (0.20g, 0.73mmol), followed by cesium carbonate (0.24g, 0.73mmol) and dimethyl sulfoxide (5.0 ml), and the reaction was stirred at 90 ℃ for 2 hours, cooled to room temperature, filtered, the filtrate was adjusted to pH 4.0 with 1N hydrochloric acid, and the reaction solution was subjected to reverse phase preparative liquid phase HPLC [ column: waters Sunfire C18,10 μm,
gradient elution: 5-95% of B (solvent A, water; solvent B, CH) 3 CN)]Purification gave 2- (2-cyanopyridin-4-yl) -4-methylthiazole-5-carboxylic acid (1) (0.11g, 53.6%) as a white solid.
LCMS(MS-ESI,m/z):(M+1)＝246.0
1 H NMR(400MHz,DMSO-d 6 ,ppm)：δ8.36(d,J＝5.7Hz,1H),7.95(d,J＝2.3Hz,1H),7.81(dd,J＝5.7,2.2Hz,1H),7.46(s,1H),2.59(s,3H)
Compounds 2 to 17 were synthesized in the same manner as in example 1.
Example 2:
compound 2: synthesis of 2- (2-cyanopyridin-4-yl) thiazole-5-carboxylic acid
(Compound 2)
Except that A1-1 (4-methylthiazole-5-carboxylic acid ethyl ester) in the first step
LCMS(MS-ESI,m/z):(M+1)＝232.0
1 H NMR(400MHz,DMSO-d 6 ,ppm)：δ8.36(d,J＝5.7Hz,1H),7.95(d,J＝2.3Hz,1H),7.81(dd,J＝5.7,2.2Hz,1H),7.46(s,1H),2.59(s,3H)
Example 3
Compound 3: synthesis of 2- (2-cyanopyridin-4-yl) -4-ethylthiazole-5-carboxylic acid
Except that A1-1: compound 3 was synthesized in the same manner as in example 1, except that ethyl 4-methylthiazole-5-carboxylate was replaced with ethyl 4-ethylthiazole-5-carboxylate.
LCMS(MS-ESI,m/z):(M+1)＝260.0
1 H NMR(400MHz,DMSO-d 6 ,ppm)：δ8.41(d,J＝5.7Hz,1H),7.99(d,J＝2.3Hz,1H),7.83(dd,J＝5.7,2.2Hz,1H),7.46(s,1H),3.01(q,J＝7.2Hz,2H),1.29(t,J＝7.2Hz,3H).
Example 4
Compound 4: synthesis of 2- (2-cyanopyridin-4-yl) -4- (trifluoromethyl) thiazole-5-carboxylic acid
(Compound 4)
Except that A1-1: compound 4 was synthesized according to the same procedure and method as in example 1, except for substituting ethyl 4-methylthiazole-5-carboxylate with ethyl 4- (trifluoromethyl) thiazole-5-carboxylate.
LCMS(MS-ESI,m/z):(M+1)＝300.0
1 H NMR(400MHz,DMSO-d 6 ,ppm)：δ8.49(d,J＝5.6Hz,1H),7.92(d,J＝2.3Hz,1H),7.78(dd,J＝5.7,2.2Hz,1H),7.50(s,1H).
Example 5
Compound 5: synthesis of 2- (2- (1H-imidazol-4-yl) pyridin-4-yl) -4-methylthiazole-5-carboxylic acid
(Compound 5)
Except that A1-2: replacement of 4-bromopyridine-2-carbonitrile with 4-bromo-2- (1H-imidazol-4-yl) pyridine
Except for this, compound 5 was synthesized in the same procedure and method as in example 1.
LCMS(MS-ESI,m/z):(M+1)＝287.1
1 H NMR(400MHz,DMSO-d6,ppm)：δ9.14(d,J＝5.7Hz,1H),8.06(dd,J＝21.5,2.3Hz,2H),7.86(d,J＝2.0Hz,1H),7.75(dd,J＝5.7,2.2Hz,1H),7.56(s,1H),2.56(s,3H).
Example 6
Compound 6: synthesis of 2- (2- (1H-imidazol-4-yl) pyridin-4-yl) thiazole-5-carboxylic acid
Except that A1-1: 4-methylthiazole-5-carboxylic acid ethyl ester was replaced with thiazole-5-carboxylic acid ethyl ester, A1-2: compound 6 was synthesized according to the same procedure and method as in example 1, except that 4-bromopyridine-2-carbonitrile was replaced with 4-bromo-2- (1H-imidazol-4-yl) pyridine.
LCMS(MS-ESI,m/z):(M+1)＝273.0
1 H NMR(400MHz,DMSO-d 6 ,ppm)：δ9.16(d,J＝5.7Hz,1H),8.65(s,1H),8.11(d,J＝2.2Hz,1H),8.05(d,J＝2.4Hz,1H),7.87–7.78(m,2H),7.56(s,1H).
Example 7
Compound 7: synthesis of 2- (2- (1H-imidazol-4-yl) pyridin-4-yl) -4-ethylthiazole-5-carboxylic acid
Except that A1-1: 4-methylthiazole-5-carboxylic acid ethyl ester was replaced with 4-ethylthiazole-5-carboxylic acid ethyl ester, A1-2: compound 7 was synthesized according to the same procedure and method as in example 1, except that 4-bromopyridine-2-carbonitrile was replaced with 4-bromo-2- (1H-imidazol-4-yl) pyridine.
LCMS(MS-ESI,m/z):(M+1)＝301.1
1 H NMR(400MHz,DMSO-d 6 ,ppm)：δ9.14(d,J＝5.7Hz,1H),8.14(d,J＝2.3Hz,1H),8.04(d,J＝2.4Hz,1H),7.86(d,J＝2.0Hz,1H),7.77(dd,J＝5.6,2.3Hz,1H),7.50(s,1H),2.99(q,J＝7.2Hz,2H),1.28(t,J＝7.2Hz,3H).
Example 8
Compound 8: synthesis of 2- (2-aminopyridin-4-yl) -4-methylthiazole-5-carboxylic acid
Except that in step one, A1-2: compound 8 was synthesized according to the same procedure and method as in example 1, except that 4-bromopyridine-2-carbonitrile was replaced with 2-amino-4-bromopyridine.
LCMS(MS-ESI,m/z):(M+1)＝236.0
1 H NMR(400MHz,DMSO-d 6 ,ppm)：δ8.17(d,J＝5.5Hz,1H),7.46(s,1H),7.34(dd,J＝5.7,2.2Hz,1H),6.91(d,J＝2.2Hz,1H),5.61(d,J＝6.0Hz,1H),5.44(d,J＝6.2Hz,1H),2.60(s,3H).
Example 9
Compound 9: synthesis of 2- (2-aminopyridin-4-yl) thiazole-5-carboxylic acid
Except that A1-1: 4-methylthiazole-5-carboxylic acid ethyl ester was replaced with thiazole-5-carboxylic acid ethyl ester, A1-2: compound 9 was synthesized according to the same procedure and method as in example 1, except that 4-bromopyridine-2-carbonitrile was replaced with 2-amino-4-bromopyridine.
LCMS(MS-ESI,m/z):(M+1)＝222.0
1 H NMR(400MHz,DMSO-d 6 ,ppm)：δ8.54(s,1H),8.19(d,J＝5.7Hz,1H),7.33(dd,J＝5.7,2.2Hz,1H),6.92(d,J＝2.2Hz,1H),5.63(d,J＝6.0Hz,1H),5.29(d,J＝6.2Hz,1H).
Example 10
Compound 10: synthesis of 2- (2-aminopyridin-4-yl) -4-ethylthiazole-5-carboxylic acid
Except that A1-1: 4-methylthiazole-5-carboxylic acid ethyl ester was replaced with 4-ethylthiazole-5-carboxylic acid ethyl ester, A1-2: compound 10 was synthesized according to the same procedure and method as in example 1, except for substituting 2-amino-4-bromopyridine for 4-bromopyridine-2-carbonitrile.
LCMS(MS-ESI,m/z):(M+1)＝250.1
1 H NMR(400MHz,DMSO-d 6 ,ppm)：δ8.21(d,J＝5.6Hz,1H),7.46(s,1H),7.37(dd,J＝5.6,2.3Hz,1H),6.94(d,J＝2.2Hz,1H),5.61(d,J＝6.0Hz,1H),5.44(d,J＝6.2Hz,1H),3.01(q,J＝7.3Hz,2H),1.30(t,J＝7.2Hz,3H).
Example 11
Compound 11: synthesis of 2- (2-cyano-6- (2H-tetrazol-5-yl) pyridin-4-yl) -4-methylthiazole-5-carboxylic acid
Except that A1-2: compound 11 was synthesized in the same manner as in example 1, except that 4-bromopyridine-2-carbonitrile was replaced with 4-bromo-6- (2H-tetrazolyl) -pyridine-2-carbonitrile.
LCMS(MS-ESI,m/z):(M+1)＝314.0
1 H NMR(400MHz,DMSO-d 6 ,ppm)：δ8.53(d,J＝2.2Hz,1H),8.13(d,J＝2.2Hz,1H),7.18(s,1H),2.52(s,3H).
Example 12
Compound 12: synthesis of 4- (4- (5-carboxy-4-methylthiazol-2-yl) -6-cyanopyridin-2-yl) thiazole-2-carboxylic acid
Except that in step one, A1-2: replacement of 4-bromopyridine-2-carbonitrile with
Except for this, compound 12 was synthesized in the same manner as in example 1.
LCMS(MS-ESI,m/z):(M+1)＝373.0
1 H NMR(400MHz,DMSO-d 6 ,ppm)：δ8.10(d,J＝2.2Hz,1H),7.81(d,J＝2.2Hz,1H),7.63(s,1H),7.00(s,1H),2.52(s,3H).
Example 13
Compound 13: synthesis of 2- (2-cyano-6- (2- (tetrahydrofuran-2-yl) -1H-imidazol-4-yl) pyridin-4-yl) -4-methylthiazole-5-carboxylic acid
Except that A1-2: replacement of 4-bromopyridine-2-carbonitrile with
Except for this, compound 13 was synthesized in the same manner as in example 1.
LCMS(MS-ESI,m/z):(M+1)＝382.1
1 H NMR(400MHz,DMSO-d 6 ,ppm)：δ8.11(d,J＝2.0Hz,1H),7.94(d,J＝2.2Hz,1H),7.53(d,J＝2.6Hz,1H),7.00(s,1H),5.12(t,J＝5.1Hz,1H),3.91(t,J＝4.6Hz,2H),2.49(q,J＝5.2Hz,2H),2.44(s,3H),2.42–2.33(m,2H).
Example 14
Compound 14: synthesis of 2- (5 '-chloro-6-cyano- [2,2' -bipyridine ] -4-yl) -4-methylthiazole-5-carboxylic acid
Except that A1-2: replacement of 4-bromopyridine-2-carbonitrile with
Except for this, compound 14 was synthesized in the same manner as in example 1.
LCMS(MS-ESI,m/z):(M+1)＝357.0
1 H NMR(400MHz,DMSO-d 6 ,ppm)：δ8.61(d,J＝1.9Hz,1H),8.29–8.22(m,2H),7.90(d,J＝2.0Hz,1H),7.70(dd,J＝8.4,1.8Hz,1H),7.00(s,1H),2.52(s,3H).
Example 15
Compound 15: synthesis of 2- (2-cyano-6- (furan-2-yl) pyridin-4-yl) -4-methylthiazole-5-carboxylic acid
Except that A1-2: replacement of 4-bromopyridine-2-carbonitrile with
Except for this, compound 15 was synthesized in the same manner as in example 1.
LCMS(MS-ESI,m/z):(M+1)＝312.0
1 H NMR(400MHz,DMSO-d 6 ,ppm)：δ8.19(d,J＝2.2Hz,1H),7.77(dd,J＝9.1,1.8Hz,2H),7.32(d,J＝7.9Hz,1H),7.18(s,1H),6.68(dd,J＝7.9,1.4Hz,1H),2.57(s,3H).
Example 16
Compound 16: synthesis of 2- (2-cyano-6- (6-oxo-1, 6-dihydropyridazin-3-yl) pyridin-4-yl) -4-methylthiazole-5-carboxylic acid
Except that A1-2: replacement of 4-bromopyridine-2-carbonitrile with
Except for this, compound 16 was synthesized in the same manner as in example 1.
LCMS(MS-ESI,m/z):(M+1)＝340.0
1 H NMR(400MHz,DMSO-d 6 ,ppm)：δ8.02(d,J＝2.2Hz,1H),7.86–7.76(m,2H),7.00(s,1H),6.93(d,J＝9.7Hz,1H),2.52(s,3H).
Example (b): 17
Compound 17: synthesis of 2- (2-cyano-6-phenylpyridin-4-yl) -4-methylthiazole-5-carboxylic acid
Except that A1-2: compound 17 was synthesized according to the same procedure and method as in example 1, except for substituting 4-bromo-6-phenyl-pyridine-2-carbonitrile for 4-bromo-2-carbonitrile.
LCMS(MS-ESI,m/z):(M+1)＝322.1
1 H NMR(400MHz,DMSO-d 6 ,ppm)：δ8.22–8.14(m,3H),7.84(d,J＝2.0Hz,1H),7.56–7.48(m,3H),7.32(s,1H),2.52(s,3H).
Example 18
Compound 18: synthesis of 2- (2-carbamoylpyridin-4-yl) -4-methylthiazole-5-carboxylic acid
Adding 2- (2-cyanopyridin-4-yl) to the reaction flask-4-methylthiazole-5-carboxylic acid ethyl ester (A1-3) (0.2g, 0.73mmol), followed by addition of tetrahydrofuran (10.0 ml), stirring well, dropwise addition of a 20% aqueous sodium hydroxide solution (2.0 ml), stirring at room temperature, dissolution of the solid, reaction with continued stirring for 1 hour, pH adjustment of 4.0 with 1N hydrochloric acid, concentration under reduced pressure, and purification of the resulting crude product by reverse phase preparative liquid HPLC [ column: waters Sunfire C18,10 μm,
gradient elution: 5-95% of B (solvent A, water; solvent B, CH) 3 CN)]Purification gave 2- (2-carbamoylpyridin-4-yl) -4-methylthiazole-5-carboxylic acid (18) as a white solid (0.09g, 40.9%).
LCMS(MS-ESI,m/z):(M+1)＝264.0
1 H NMR(400MHz,DMSO-d 6 ,ppm)：δ8.80(d,J＝5.5Hz,1H),8.36–8.28(m,2H),7.97(d,J＝7.9Hz,1H),7.65(dd,J＝5.6,2.3Hz,1H),7.46(s,1H),2.68(s,3H).
Example 19
Compound 19: synthesis of 2- (2- (2H-tetrazol-5-yl) pyridin-4-yl) -4-methylthiazole-5-carboxylic acid
The method comprises the following steps: ethyl 2- (2-cyanopyridin-4-yl) -4-methylthiazole-5-carboxylate (A1-3) (1.0g, 3.1mmol), sodium azide (1.0g, 15.5 mmol) and ammonium chloride (1.0g, 18.6 mmol) were charged into a reaction flask, N' -dimethylformamide (5 ml) was further added, the mixture was heated to 120 ℃ to react for 16 hours, the reaction mixture was filtered, and water (100 ml) was added to the filtrate with stirring to precipitate a large amount of solid, which was then filtered and dried to obtain ethyl 2- (2- (2H-tetrazol-5-yl) pyridin-4-yl) -4-methylthiazole-5-carboxylate (A1-4) (0.6g, 45.5%) as a white solid.
Step two: to a reaction flask was added ethyl 2- (2- (2H-tetrazol-5-yl) pyridin-4-yl) -4-methylthiazole-5-carboxylate (A1-4) (0.6 g,1.9 mmol), followed by addition of methanol (100 ml), stirring well, dropwise addition of 20% aqueous sodium hydroxide solution (10 ml), stirring at room temperature to dissolve the solid, further stirring for 1 hour, cooling to 0 ℃ and reaction with 1N saltThe pH was adjusted to 4.0 with acid, concentrated under reduced pressure and the resulting crude product purified by reverse phase preparative liquid HPLC [ column: waters Sunfire C18,10 μm,
gradient secondary desorption: 10-95% of B (solvent A, water; solvent B, CH) 3 CN)]Purification gave 2- (2- (2H-tetrazol-5-yl) pyridin-4-yl) -4-methylthiazole-5-carboxylic acid (10) (250mg, 40.6%) as a white solid.
LCMS(MS-ESI,m/z):(M+1)＝289.0
1 H NMR(400MHz,DMSO-d 6 ,ppm)：δ9.27(d,J＝5.7Hz,1H),8.47(d,J＝2.3Hz,1H),7.91(dd,J＝5.7,2.2Hz,1H),7.50(s,1H),2.59(s,3H).
Example 20
Synthesis of 2- (2- (2H-tetrazol-5-yl) pyridin-4-yl) thiazole-5-carboxylic acid (20)
Compound 20 was synthesized in the same manner as in example 19, except for replacing ethyl 2- (2- (2H-tetrazol-5-yl) pyridin-4-yl) -4-methylthiazole-5-carboxylate (A1-4) with ethyl 2- (2- (2H-tetrazol-5-yl) pyridin-4-yl) thiazole-5-carboxylate.
LCMS(MS-ESI,m/z):(M+1)＝275.0
1 H NMR(400MHz,DMSO-d 6 ,ppm)：δ9.30(d,J＝5.6Hz,1H),8.63(s,1H),8.48(d,J＝2.2Hz,1H),7.97(dd,J＝5.7,2.2Hz,1H),7.56(s,1H).
Example 21
Compound 21: synthesis of 2- (2- (2H-tetrazol-5-yl) pyridin-4-yl) -4-ethylthiazole-5-carboxylic acid
Compound 21 was synthesized in the same manner as in example 19, except that ethyl 2- (2- (2H-tetrazol-5-yl) pyridin-4-yl) -4-methylthiazole-5-carboxylate (A1-4) was replaced with ethyl 2- (2- (2H-tetrazol-5-yl) pyridin-4-yl) -4-ethylthiazole-5-carboxylate.
LCMS(MS-ESI,m/z):(M+1)＝303.1
1 H NMR(400MHz,DMSO-d 6 ,ppm)：δ9.32(d,J＝5.7Hz,1H),8.53(d,J＝2.3Hz,1H),7.94(dd,J＝5.7,2.2Hz,1H),7.50(s,1H),2.99(q,J＝7.3Hz,2H),1.31(t,J＝7.2Hz,3H).
Example 22
Compound 22: synthesis of 2- (2- (1H-tetrazol-1-yl) pyridin-4-yl) -4-methylthiazole-5-carboxylic acid
The method comprises the following steps: under nitrogen protection, 2- (2-aminopyridin-4-yl) -4-methylthiazole-5-carboxylic acid (8) (0.50g, 1.8mmol) and glacial acetic acid (10 ml) were charged to a reaction flask, triethyl orthoformate (1.36g, 9.0mmol) and trimethylsilyl azide (0.41g, 3.6 mmol) were added with stirring, the reaction was stirred at an elevated temperature to 70 ℃ for 3 hours, most of the solvent was removed by concentration under reduced pressure, the temperature was lowered to room temperature, water (30 ml) was added, the pH was adjusted to 10 with a 10% aqueous solution of sodium carbonate, extraction was performed with ethyl acetate (30ml _:. Sup.3), the organic phases were combined, the solvent was concentrated under reduced pressure, and column purification (ethyl acetate: petroleum ether =1 5) was carried out to obtain ethyl 2- (2- (1H-tetrazol-1-yl) pyridin-4-yl) -4-methylthiazole-5-carboxylate (A1-5) (0.26g, 44.8%)
Step two: to a reaction flask was added ethyl 2- (2- (1H-tetrazol-1-yl) pyridin-4-yl) -4-methylthiazole-5-carboxylate (A1-5) (0.25g, 0.79mmol), followed by addition of methanol (50 ml), stirring well, dropwise addition of 20% aqueous sodium hydroxide (5 ml), stirring at room temperature to dissolve the solid, further stirring for 1 hour, cooling to 0 ℃, adjusting pH 4.0 with 1N hydrochloric acid, concentrating under reduced pressure to give a crude product, which was purified by reverse phase preparative liquid phase HPLC [ column: waters Sunfire C18,10 μm,
gradient elution: 10-90% of B (solvent A, water; solvent B, CH) 3 CN)]Purification to give 2- (2- (1H-tetrazol-1-yl) pyridin-4-yl) -4-methyl as a white solidThiazole-5-carboxylic acid (22) (0.15g, 58.6%).
LCMS(MS-ESI,m/z):(M+1)＝289.0
1 H NMR(400MHz,DMSO-d 6 ,ppm)：δ9.83(s,1H),8.71(d,J＝5.7Hz,1H),8.55(d,J＝2.2Hz,1H),7.72(dd,J＝5.6,2.3Hz,1H),7.50(s,1H),2.37(s,3H).
Example 23
Compound 23: synthesis of 2- (2- (1H-tetrazol-1-yl) pyridin-4-yl) thiazole-5-carboxylic acid
Compound 23 was synthesized in the same manner as in example 22, except that 2- (2-aminopyridin-4-yl) -4-methylthiazole-5-carboxylic acid was replaced with 2- (2-aminopyridin-4-yl) thiazole-5-carboxylic acid.
LCMS(MS-ESI,m/z):(M+1)＝275.0
1 H NMR(400MHz,DMSO-d 6 ,ppm)：δ9.82(s,1H),8.83(d,J＝5.7Hz,1H),8.59(s,1H),8.54(d,J＝2.2Hz,1H),7.75(dd,J＝5.7,2.2Hz,1H),7.56(s,1H).
Example 24
Compound 24: synthesis of 2- (2- (1H-tetrazol-1-yl) pyridin-4-yl) -4-ethylthiazole-5-carboxylic acid
Compound 24 was synthesized in the same manner as in example 22, except that 2- (2-aminopyridin-4-yl) -4-methylthiazole-5-carboxylic acid was replaced with 2- (2-aminopyridin-4-yl) -4-ethylthiazole-5-carboxylic acid.
LCMS(MS-ESI,m/z):(M+1)＝303.1
1 H NMR(400MHz,DMSO-d 6 ,ppm)：δ9.83(s,1H),8.86(d,J＝5.7Hz,1H),8.62(d,J＝2.2Hz,1H),7.71(dd,J＝5.7,2.2Hz,1H),7.50(s,1H),3.00(q,J＝7.3Hz,2H),1.29(t,J＝7.2Hz,3H).
Xanthine oxidase activity inhibition assay
The test compound was dissolved in DMSO (D2650 Sigma-Aldrich) to a concentration of 20mM, and a phosphate buffered saline (hereinafter referred to as "PBS") was added to adjust the target concentration at the time of use. A xanthine solution prepared in advance to 10mM with 20mM sodium hydroxide was diluted to a final concentration of 150uM with PBS, 2mL of the xanthine solution was taken, 2.5mL of PBS was added, and 0.4mL of 0.05U/mL xanthine oxidase (Solarbio) and 0.1mL of a test substance at different concentrations were added. After mixing, the absorbance change at 305nm was rapidly measured using an ultraviolet spectrophotometer (Agilent Cary 60) for 5 minutes. Simultaneously detecting the inhibition rate of the compound without adding test compound, and calculating the Inhibition Concentration (IC) of the compound on the oxidase type xanthine oxidoreductase by using the reaction rate 50 )。
The results are shown in Table 1, wherein the symbols (+, ++, +++) indicate the inhibitory activity values described below.
20.0nM≤IC 50 ：+；
10.0nM≤IC 50 ＜20.0nM：++；
1.0nM≤IC 50 ＜10.0nM：+++。
Xanthine oxidase inhibitor activity IC of the Compounds of Table 1 50 (n＝2)
As seen from the results in table 1, the compounds of the present invention showed excellent xanthine oxidase inhibitory effects in vitro pharmacological tests.
Claims (7)
1. A compound of the general formula (I) or a pharmaceutically acceptable salt thereof:
wherein the content of the first and second substances,
R 1 is-OH;
R 2 selected from H, C1-C5 alkyl, C1-C5 haloalkyl;
R 3 and R 4 One is selected from-CN, heterocyclic aromatic hydrocarbon radical with 5-membered ring, the other is selected from H, C1-C6 alkyl,
the 5-membered heterocyclic aromatic hydrocarbon group is selected from
2. A compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R 3 And R 4 At least one of which is selected from-CN,
3. a compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from:
2- (2-cyanopyridin-4-yl) -4-methylthiazole-5-carboxylic acid,
2- (2-cyanopyridin-4-yl) -4- (trifluoromethyl) thiazole-5-carboxylic acid,
2- (2-cyano-6- (furan-2-yl) pyridin-4-yl) -4-methylthiazole-5-carboxylic acid,
2- (2- (2H-tetrazol-5-yl) pyridin-4-yl) -4-methylthiazole-5-carboxylic acid,
2- (2- (1H-tetrazol-1-yl) pyridin-4-yl) -4-methylthiazole-5-carboxylic acid.
4. A pharmaceutical composition comprising a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, as an active ingredient, and a pharmaceutically acceptable carrier.
5. Use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a xanthine oxidase inhibitor.
6. A xanthine oxidase inhibitor containing the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient.
7. Use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention and/or treatment of hyperuricemia, gout.
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| CN101928259A (en) * | 2009-06-18 | 2010-12-29 | 南京海辰药业有限公司 | 2-arylthiazole derivative and medicament composition thereof |
| CN103980267A (en) * | 2013-02-08 | 2014-08-13 | 镇江新元素医药科技有限公司 | New xanthine oxidase inhibitor compound and pharmaceutical composition thereof |
| WO2016017699A1 (en) * | 2014-07-30 | 2016-02-04 | 帝人ファーマ株式会社 | Azole carboxylic acid derivative |
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| CN101928259A (en) * | 2009-06-18 | 2010-12-29 | 南京海辰药业有限公司 | 2-arylthiazole derivative and medicament composition thereof |
| CN103980267A (en) * | 2013-02-08 | 2014-08-13 | 镇江新元素医药科技有限公司 | New xanthine oxidase inhibitor compound and pharmaceutical composition thereof |
| WO2016017699A1 (en) * | 2014-07-30 | 2016-02-04 | 帝人ファーマ株式会社 | Azole carboxylic acid derivative |
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