AU2021282039A1 - Arylformamide compound and preparation method and medical use thereof - Google Patents

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Publication number

AU2021282039A1

AU2021282039A1 AU2021282039A AU2021282039A AU2021282039A1 AU 2021282039 A1 AU2021282039 A1 AU 2021282039A1 AU 2021282039 A AU2021282039 A AU 2021282039A AU 2021282039 A AU2021282039 A AU 2021282039A AU 2021282039 A1 AU2021282039 A1 AU 2021282039A1

Authority

AU

Australia

Prior art keywords

group

alkyl

cycloalkyl

heterocyclyl

compound

Prior art date

2020-05-25

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.)

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• 150000001875 compounds Chemical class 0.000 title claims abstract description 173
• 238000002360 preparation method Methods 0.000 title claims abstract description 35
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• 206010011224 Cough Diseases 0.000 claims abstract description 24
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• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 21
• 230000000694 effects Effects 0.000 claims abstract description 17
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• 230000036407 pain Effects 0.000 claims abstract description 8
• 206010020853 Hypertonic bladder Diseases 0.000 claims abstract description 7
• 208000009722 Overactive Urinary Bladder Diseases 0.000 claims abstract description 6
• 208000013116 chronic cough Diseases 0.000 claims abstract description 6
• 208000020629 overactive bladder Diseases 0.000 claims abstract description 6
• 201000009273 Endometriosis Diseases 0.000 claims abstract description 5
• 125000000623 heterocyclic group Chemical group 0.000 claims description 122
• -1 cyano, hydroxy Chemical group 0.000 claims description 90
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 87
• 125000000217 alkyl group Chemical group 0.000 claims description 73
• 125000003118 aryl group Chemical group 0.000 claims description 57
• 229910052736 halogen Inorganic materials 0.000 claims description 57
• 150000002367 halogens Chemical group 0.000 claims description 57
• 239000000203 mixture Substances 0.000 claims description 56
• 125000001072 heteroaryl group Chemical group 0.000 claims description 55
• 125000003545 alkoxy group Chemical group 0.000 claims description 53
• 150000003839 salts Chemical class 0.000 claims description 49
• 125000001424 substituent group Chemical group 0.000 claims description 47
• 239000003513 alkali Substances 0.000 claims description 42
• 125000003342 alkenyl group Chemical group 0.000 claims description 34
• 125000000304 alkynyl group Chemical group 0.000 claims description 34
• 229910052739 hydrogen Inorganic materials 0.000 claims description 33
• 239000001257 hydrogen Substances 0.000 claims description 33
• 125000004185 ester group Chemical group 0.000 claims description 27
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 27
• 150000003573 thiols Chemical group 0.000 claims description 27
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 26
• 229910003827 NRaRb Inorganic materials 0.000 claims description 24
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 23
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 23
• 125000004043 oxo group Chemical group O=* 0.000 claims description 22
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 20
• 125000004438 haloalkoxy group Chemical group 0.000 claims description 19
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 18
• 238000000034 method Methods 0.000 claims description 17
• 125000002757 morpholinyl group Chemical group 0.000 claims description 16
• 125000004193 piperazinyl group Chemical group 0.000 claims description 15
• 125000003386 piperidinyl group Chemical group 0.000 claims description 15
• 229910052757 nitrogen Inorganic materials 0.000 claims description 14
• 125000003554 tetrahydropyrrolyl group Chemical group 0.000 claims description 14
• 239000003795 chemical substances by application Substances 0.000 claims description 13
• 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 13
• 125000004429 atom Chemical group 0.000 claims description 12
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 11
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 11
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 11
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 11
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 11
• 239000007821 HATU Substances 0.000 claims description 10
• 125000002393 azetidinyl group Chemical group 0.000 claims description 10
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• 125000003566 oxetanyl group Chemical group 0.000 claims description 10
• 125000000335 thiazolyl group Chemical group 0.000 claims description 10
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
• 125000001188 haloalkyl group Chemical group 0.000 claims description 7
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 7
• 229910052799 carbon Inorganic materials 0.000 claims description 6
• 238000006482 condensation reaction Methods 0.000 claims description 6
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 6
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• 239000005557 antagonist Substances 0.000 claims description 5
• 125000002883 imidazolyl group Chemical group 0.000 claims description 5
• 125000002971 oxazolyl group Chemical group 0.000 claims description 5
• 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 claims description 4
• 206010013935 Dysmenorrhoea Diseases 0.000 claims description 4
• 239000003937 drug carrier Substances 0.000 claims description 4
• 208000002551 irritable bowel syndrome Diseases 0.000 claims description 4
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
• 238000011282 treatment Methods 0.000 claims description 4
• 206010004446 Benign prostatic hyperplasia Diseases 0.000 claims description 3
• 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 3
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• 125000002541 furyl group Chemical group 0.000 claims description 3
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• 230000007823 neuropathy Effects 0.000 claims description 3
• 208000033808 peripheral neuropathy Diseases 0.000 claims description 3
• 201000007094 prostatitis Diseases 0.000 claims description 3
• 125000003373 pyrazinyl group Chemical group 0.000 claims description 3
• 125000004076 pyridyl group Chemical group 0.000 claims description 3
• 125000000168 pyrrolyl group Chemical group 0.000 claims description 3
• 125000003831 tetrazolyl group Chemical group 0.000 claims description 3
• 125000001544 thienyl group Chemical group 0.000 claims description 3
• 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 claims description 2
• 125000004514 1,2,4-thiadiazolyl group Chemical group 0.000 claims description 2
• 125000004520 1,3,4-thiadiazolyl group Chemical group 0.000 claims description 2
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• 206010002556 Ankylosing Spondylitis Diseases 0.000 claims description 2
• 206010004663 Biliary colic Diseases 0.000 claims description 2
• 201000006474 Brain Ischemia Diseases 0.000 claims description 2
• 208000009079 Bronchial Spasm Diseases 0.000 claims description 2
• 208000014181 Bronchial disease Diseases 0.000 claims description 2
• 206010006482 Bronchospasm Diseases 0.000 claims description 2
• 206010008120 Cerebral ischaemia Diseases 0.000 claims description 2
• 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 2
• 208000011231 Crohn disease Diseases 0.000 claims description 2
• 208000005171 Dysmenorrhea Diseases 0.000 claims description 2
• 208000004483 Dyspareunia Diseases 0.000 claims description 2
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• 208000018737 Parkinson disease Diseases 0.000 claims description 2
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• 206010008118 cerebral infarction Diseases 0.000 claims description 2
• 201000003146 cystitis Diseases 0.000 claims description 2
• 208000021302 gastroesophageal reflux disease Diseases 0.000 claims description 2
• 125000001786 isothiazolyl group Chemical group 0.000 claims description 2
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 2
• 208000010125 myocardial infarction Diseases 0.000 claims description 2
• 201000005737 orchitis Diseases 0.000 claims description 2
• 201000008482 osteoarthritis Diseases 0.000 claims description 2
• 230000002265 prevention Effects 0.000 claims description 2
• 208000005069 pulmonary fibrosis Diseases 0.000 claims description 2
• 125000002098 pyridazinyl group Chemical group 0.000 claims description 2
• 206010039073 rheumatoid arthritis Diseases 0.000 claims description 2
• 229910052701 rubidium Inorganic materials 0.000 claims description 2
• 230000009529 traumatic brain injury Effects 0.000 claims description 2
• 125000001425 triazolyl group Chemical group 0.000 claims description 2
• 208000000143 urethritis Diseases 0.000 claims description 2
• 150000002431 hydrogen Chemical group 0.000 claims 12
• 208000012902 Nervous system disease Diseases 0.000 claims 2
• 208000010643 digestive system disease Diseases 0.000 claims 2
• 208000017445 musculoskeletal system disease Diseases 0.000 claims 2
• 210000002229 urogenital system Anatomy 0.000 claims 2
• 206010009900 Colitis ulcerative Diseases 0.000 claims 1
• 206010014561 Emphysema Diseases 0.000 claims 1
• 208000029082 Pelvic Inflammatory Disease Diseases 0.000 claims 1
• 201000006704 Ulcerative Colitis Diseases 0.000 claims 1
• 206010046798 Uterine leiomyoma Diseases 0.000 claims 1
• 230000000112 colonic effect Effects 0.000 claims 1
• 206010015037 epilepsy Diseases 0.000 claims 1
• 201000010260 leiomyoma Diseases 0.000 claims 1
• 210000003932 urinary bladder Anatomy 0.000 claims 1
• 229940126202 P2X3 receptor antagonist Drugs 0.000 abstract description 3
• 238000006243 chemical reaction Methods 0.000 description 87
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 69
• 239000000243 solution Substances 0.000 description 52
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 37
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical group [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 28
• 230000015572 biosynthetic process Effects 0.000 description 28
• 238000003786 synthesis reaction Methods 0.000 description 28
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
• 239000000047 product Substances 0.000 description 25
• 230000002829 reductive effect Effects 0.000 description 24
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
• 239000000706 filtrate Substances 0.000 description 20
• KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 18
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 18
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
• 239000003054 catalyst Substances 0.000 description 18
• 239000007787 solid Substances 0.000 description 18
• 125000004432 carbon atom Chemical group C* 0.000 description 17
• 239000003480 eluent Substances 0.000 description 17
• 125000004435 hydrogen atom Chemical group [H]* 0.000 description 16
• QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
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• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
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• 101710189968 P2X purinoceptor 2 Proteins 0.000 description 14
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
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• KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 12
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• SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical group [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 12
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