IL312247A - Novel spiro compound - Google Patents
Novel spiro compoundInfo
- Publication number
- IL312247A IL312247A IL312247A IL31224724A IL312247A IL 312247 A IL312247 A IL 312247A IL 312247 A IL312247 A IL 312247A IL 31224724 A IL31224724 A IL 31224724A IL 312247 A IL312247 A IL 312247A
- Authority
- IL
- Israel
- Prior art keywords
- group
- substituted
- ring
- represented
- membered monocyclic
- Prior art date
Links
- 150000003413 spiro compounds Chemical class 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims description 610
- 125000001072 heteroaryl group Chemical group 0.000 claims description 336
- -1 azolidinyl Chemical group 0.000 claims description 305
- 125000003118 aryl group Chemical group 0.000 claims description 239
- 125000002950 monocyclic group Chemical group 0.000 claims description 227
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 226
- 125000000217 alkyl group Chemical group 0.000 claims description 205
- 125000005843 halogen group Chemical group 0.000 claims description 188
- 125000001424 substituent group Chemical group 0.000 claims description 177
- 125000000623 heterocyclic group Chemical group 0.000 claims description 165
- 125000001931 aliphatic group Chemical group 0.000 claims description 163
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 144
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 143
- 150000003839 salts Chemical class 0.000 claims description 139
- 125000003545 alkoxy group Chemical group 0.000 claims description 126
- 229910052757 nitrogen Inorganic materials 0.000 claims description 117
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 115
- 229910052760 oxygen Inorganic materials 0.000 claims description 115
- 239000001301 oxygen Substances 0.000 claims description 115
- 229910052717 sulfur Inorganic materials 0.000 claims description 114
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 113
- 125000005842 heteroatom Chemical group 0.000 claims description 113
- 239000011593 sulfur Substances 0.000 claims description 113
- 125000001188 haloalkyl group Chemical group 0.000 claims description 108
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 70
- 125000003277 amino group Chemical group 0.000 claims description 56
- 125000004043 oxo group Chemical group O=* 0.000 claims description 56
- 125000002947 alkylene group Chemical group 0.000 claims description 51
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 51
- 125000004414 alkyl thio group Chemical group 0.000 claims description 47
- 125000002252 acyl group Chemical group 0.000 claims description 45
- 208000002193 Pain Diseases 0.000 claims description 36
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 36
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 34
- 239000008194 pharmaceutical composition Substances 0.000 claims description 34
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 32
- 125000004076 pyridyl group Chemical group 0.000 claims description 31
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 30
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 29
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 25
- 125000003342 alkenyl group Chemical group 0.000 claims description 24
- 201000010099 disease Diseases 0.000 claims description 24
- 208000024891 symptom Diseases 0.000 claims description 24
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 23
- 125000000304 alkynyl group Chemical group 0.000 claims description 23
- 125000003725 azepanyl group Chemical group 0.000 claims description 23
- 125000005961 oxazepanyl group Chemical group 0.000 claims description 22
- 125000001544 thienyl group Chemical group 0.000 claims description 22
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 21
- 125000002883 imidazolyl group Chemical group 0.000 claims description 20
- 125000000335 thiazolyl group Chemical group 0.000 claims description 20
- 125000001425 triazolyl group Chemical group 0.000 claims description 20
- 125000005959 diazepanyl group Chemical group 0.000 claims description 19
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 18
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 18
- 125000002971 oxazolyl group Chemical group 0.000 claims description 18
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 18
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 18
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 18
- 208000019116 sleep disease Diseases 0.000 claims description 18
- 125000004104 aryloxy group Chemical group 0.000 claims description 16
- 208000010112 Spinocerebellar Degenerations Diseases 0.000 claims description 15
- 206010008025 Cerebellar ataxia Diseases 0.000 claims description 14
- 208000007590 Disorders of Excessive Somnolence Diseases 0.000 claims description 13
- 206010020765 hypersomnia Diseases 0.000 claims description 13
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 13
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 13
- 125000006407 thiazinanyl group Chemical group 0.000 claims description 13
- 125000004305 thiazinyl group Chemical group S1NC(=CC=C1)* 0.000 claims description 13
- 125000004306 triazinyl group Chemical group 0.000 claims description 13
- 125000002541 furyl group Chemical group 0.000 claims description 12
- 208000020685 sleep-wake disease Diseases 0.000 claims description 12
- 125000006310 cycloalkyl amino group Chemical group 0.000 claims description 11
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 11
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 11
- 125000003282 alkyl amino group Chemical group 0.000 claims description 10
- 230000001668 ameliorated effect Effects 0.000 claims description 10
- 125000005844 heterocyclyloxy group Chemical group 0.000 claims description 10
- 208000004296 neuralgia Diseases 0.000 claims description 10
- 125000000160 oxazolidinyl group Chemical group 0.000 claims description 8
- 125000001984 thiazolidinyl group Chemical group 0.000 claims description 8
- 208000000094 Chronic Pain Diseases 0.000 claims description 7
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 7
- 125000002393 azetidinyl group Chemical group 0.000 claims description 7
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 7
- 208000021722 neuropathic pain Diseases 0.000 claims description 7
- 230000029058 respiratory gaseous exchange Effects 0.000 claims description 7
- 208000017164 Chronobiology disease Diseases 0.000 claims description 6
- 208000019888 Circadian rhythm sleep disease Diseases 0.000 claims description 6
- 208000028389 Nerve injury Diseases 0.000 claims description 6
- 208000001294 Nociceptive Pain Diseases 0.000 claims description 6
- 125000000532 dioxanyl group Chemical group 0.000 claims description 6
- 230000004064 dysfunction Effects 0.000 claims description 6
- 125000005945 imidazopyridyl group Chemical group 0.000 claims description 6
- 230000008764 nerve damage Effects 0.000 claims description 6
- 125000003551 oxepanyl group Chemical group 0.000 claims description 6
- 125000003566 oxetanyl group Chemical group 0.000 claims description 6
- 125000005475 oxolanyl group Chemical group 0.000 claims description 6
- 208000020431 spinal cord injury Diseases 0.000 claims description 6
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 6
- 125000005458 thianyl group Chemical group 0.000 claims description 6
- 125000001583 thiepanyl group Chemical group 0.000 claims description 6
- 125000001166 thiolanyl group Chemical group 0.000 claims description 6
- 208000024827 Alzheimer disease Diseases 0.000 claims description 4
- 208000020925 Bipolar disease Diseases 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 4
- 125000005334 azaindolyl group Chemical group N1N=C(C2=CC=CC=C12)* 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 238000004393 prognosis Methods 0.000 claims description 4
- 208000002320 spinal muscular atrophy Diseases 0.000 claims description 4
- 208000011580 syndromic disease Diseases 0.000 claims description 4
- 206010000117 Abnormal behaviour Diseases 0.000 claims description 3
- 206010008874 Chronic Fatigue Syndrome Diseases 0.000 claims description 3
- 208000023890 Complex Regional Pain Syndromes Diseases 0.000 claims description 3
- 208000022540 Consciousness disease Diseases 0.000 claims description 3
- 208000032131 Diabetic Neuropathies Diseases 0.000 claims description 3
- 206010019196 Head injury Diseases 0.000 claims description 3
- 208000016588 Idiopathic hypersomnia Diseases 0.000 claims description 3
- 208000001456 Jet Lag Syndrome Diseases 0.000 claims description 3
- 208000012902 Nervous system disease Diseases 0.000 claims description 3
- 208000008705 Nocturnal Myoclonus Syndrome Diseases 0.000 claims description 3
- 208000018737 Parkinson disease Diseases 0.000 claims description 3
- 206010036376 Postherpetic Neuralgia Diseases 0.000 claims description 3
- 208000004550 Postoperative Pain Diseases 0.000 claims description 3
- 208000005793 Restless legs syndrome Diseases 0.000 claims description 3
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 claims description 3
- 208000006011 Stroke Diseases 0.000 claims description 3
- 201000004810 Vascular dementia Diseases 0.000 claims description 3
- 201000007034 advanced sleep phase syndrome Diseases 0.000 claims description 3
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 3
- 206010008118 cerebral infarction Diseases 0.000 claims description 3
- 208000026106 cerebrovascular disease Diseases 0.000 claims description 3
- 238000002512 chemotherapy Methods 0.000 claims description 3
- 201000001098 delayed sleep phase syndrome Diseases 0.000 claims description 3
- 208000033921 delayed sleep phase type circadian rhythm sleep disease Diseases 0.000 claims description 3
- 206010016256 fatigue Diseases 0.000 claims description 3
- 206010022437 insomnia Diseases 0.000 claims description 3
- 208000033923 irregular sleep wake type circadian rhythm sleep disease Diseases 0.000 claims description 3
- 208000011977 language disease Diseases 0.000 claims description 3
- 208000029766 myalgic encephalomeyelitis/chronic fatigue syndrome Diseases 0.000 claims description 3
- 201000003631 narcolepsy Diseases 0.000 claims description 3
- 208000013651 non-24-hour sleep-wake syndrome Diseases 0.000 claims description 3
- 201000008482 osteoarthritis Diseases 0.000 claims description 3
- 208000023515 periodic limb movement disease Diseases 0.000 claims description 3
- 208000033808 peripheral neuropathy Diseases 0.000 claims description 3
- 208000020016 psychiatric disease Diseases 0.000 claims description 3
- 230000036385 rapid eye movement (rem) sleep Effects 0.000 claims description 3
- 230000003252 repetitive effect Effects 0.000 claims description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 3
- 201000002859 sleep apnea Diseases 0.000 claims description 3
- 238000001356 surgical procedure Methods 0.000 claims description 3
- 206010044652 trigeminal neuralgia Diseases 0.000 claims description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 169
- 238000006243 chemical reaction Methods 0.000 description 159
- 239000002904 solvent Substances 0.000 description 142
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 120
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 104
- 239000000203 mixture Substances 0.000 description 102
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 99
- 238000001308 synthesis method Methods 0.000 description 73
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 66
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 54
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 54
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 48
- 238000000034 method Methods 0.000 description 46
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- 239000002585 base Substances 0.000 description 45
- 239000011541 reaction mixture Substances 0.000 description 45
- 230000002829 reductive effect Effects 0.000 description 43
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 42
- 238000004519 manufacturing process Methods 0.000 description 38
- 239000007864 aqueous solution Substances 0.000 description 37
- 239000000047 product Substances 0.000 description 36
- 239000012044 organic layer Substances 0.000 description 35
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 32
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 32
- 239000000243 solution Substances 0.000 description 30
- 238000010898 silica gel chromatography Methods 0.000 description 29
- 102400000336 Thyrotropin-releasing hormone Human genes 0.000 description 26
- 101800004623 Thyrotropin-releasing hormone Proteins 0.000 description 26
- XNSAINXGIQZQOO-SRVKXCTJSA-N protirelin Chemical compound NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H]1NC(=O)CC1)CC1=CN=CN1 XNSAINXGIQZQOO-SRVKXCTJSA-N 0.000 description 26
- 229940034199 thyrotropin-releasing hormone Drugs 0.000 description 26
- 239000000843 powder Substances 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 23
- 239000012267 brine Substances 0.000 description 23
- 238000010511 deprotection reaction Methods 0.000 description 23
- 150000002170 ethers Chemical class 0.000 description 23
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 23
- 239000012043 crude product Substances 0.000 description 21
- 239000007787 solid Substances 0.000 description 21
- 239000003795 chemical substances by application Substances 0.000 description 20
- 238000000605 extraction Methods 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 18
- 239000003054 catalyst Substances 0.000 description 18
- 239000002994 raw material Substances 0.000 description 18
- 102100028088 Thyrotropin-releasing hormone-degrading ectoenzyme Human genes 0.000 description 17
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 16
- 101710181597 Thyrotropin-releasing hormone-degrading ectoenzyme Proteins 0.000 description 16
- 238000007112 amidation reaction Methods 0.000 description 16
- 235000012501 ammonium carbonate Nutrition 0.000 description 16
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 15
- 239000001099 ammonium carbonate Substances 0.000 description 15
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 15
- 239000000706 filtrate Substances 0.000 description 15
- 229910000104 sodium hydride Inorganic materials 0.000 description 15
- 239000012312 sodium hydride Substances 0.000 description 15
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 15
- 125000004432 carbon atom Chemical group C* 0.000 description 14
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 14
- 238000004007 reversed phase HPLC Methods 0.000 description 13
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 12
- 150000001408 amides Chemical class 0.000 description 12
- 208000035475 disorder Diseases 0.000 description 12
- 238000007363 ring formation reaction Methods 0.000 description 12
- 239000002841 Lewis acid Substances 0.000 description 11
- 235000002597 Solanum melongena Nutrition 0.000 description 11
- 238000001816 cooling Methods 0.000 description 11
- 238000001914 filtration Methods 0.000 description 11
- 150000007517 lewis acids Chemical class 0.000 description 11
- 229910052763 palladium Inorganic materials 0.000 description 11
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- 150000001412 amines Chemical class 0.000 description 10
- 229910052799 carbon Inorganic materials 0.000 description 10
- 230000002401 inhibitory effect Effects 0.000 description 10
- 229910052938 sodium sulfate Inorganic materials 0.000 description 10
- 235000011152 sodium sulphate Nutrition 0.000 description 10
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 10
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 10
- 239000002253 acid Substances 0.000 description 9
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 9
- 235000019341 magnesium sulphate Nutrition 0.000 description 9
- 125000006239 protecting group Chemical group 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 238000007126 N-alkylation reaction Methods 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 208000009415 Spinocerebellar Ataxias Diseases 0.000 description 8
- 239000003638 chemical reducing agent Substances 0.000 description 8
- 238000006268 reductive amination reaction Methods 0.000 description 8
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- 150000008064 anhydrides Chemical class 0.000 description 7
- 230000015556 catabolic process Effects 0.000 description 7
- 238000006731 degradation reaction Methods 0.000 description 7
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 7
- USVVENVKYJZFMW-ONEGZZNKSA-N (e)-carboxyiminocarbamic acid Chemical class OC(=O)\N=N\C(O)=O USVVENVKYJZFMW-ONEGZZNKSA-N 0.000 description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 6
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- 238000006751 Mitsunobu reaction Methods 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- 150000001298 alcohols Chemical class 0.000 description 6
- 238000006482 condensation reaction Methods 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 150000002430 hydrocarbons Chemical group 0.000 description 6
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 6
- 229910052740 iodine Inorganic materials 0.000 description 6
- 239000011630 iodine Substances 0.000 description 6
- 239000003446 ligand Substances 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 230000003287 optical effect Effects 0.000 description 6
- 150000003003 phosphines Chemical class 0.000 description 6
- XYFCBTPGUUZFHI-UHFFFAOYSA-O phosphonium Chemical compound [PH4+] XYFCBTPGUUZFHI-UHFFFAOYSA-O 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 238000005932 reductive alkylation reaction Methods 0.000 description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- 239000007821 HATU Substances 0.000 description 5
- 230000009435 amidation Effects 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 5
- 230000002265 prevention Effects 0.000 description 5
- 238000006722 reduction reaction Methods 0.000 description 5
- 238000006798 ring closing metathesis reaction Methods 0.000 description 5
- 235000009518 sodium iodide Nutrition 0.000 description 5
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 5
- MWKJTNBSKNUMFN-UHFFFAOYSA-N trifluoromethyltrimethylsilane Chemical compound C[Si](C)(C)C(F)(F)F MWKJTNBSKNUMFN-UHFFFAOYSA-N 0.000 description 5
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- 208000001089 Multiple system atrophy Diseases 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000002168 alkylating agent Substances 0.000 description 4
- 229940100198 alkylating agent Drugs 0.000 description 4
- RROBIDXNTUAHFW-UHFFFAOYSA-N benzotriazol-1-yloxy-tris(dimethylamino)phosphanium Chemical compound C1=CC=C2N(O[P+](N(C)C)(N(C)C)N(C)C)N=NC2=C1 RROBIDXNTUAHFW-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 230000002140 halogenating effect Effects 0.000 description 4
- 150000002429 hydrazines Chemical class 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 229910000160 potassium phosphate Inorganic materials 0.000 description 4
- 235000011009 potassium phosphates Nutrition 0.000 description 4
- 229930195734 saturated hydrocarbon Natural products 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 125000005942 tetrahydropyridyl group Chemical group 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
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- C07D513/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2021177933 | 2021-10-29 | ||
| PCT/JP2022/040370 WO2023074847A1 (ja) | 2021-10-29 | 2022-10-28 | 新規スピロ化合物 |
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| IL312247A true IL312247A (en) | 2024-06-01 |
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| IL312247A IL312247A (en) | 2021-10-29 | 2022-10-28 | Novel spiro compound |
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| EP4558481A1 (en) * | 2022-07-22 | 2025-05-28 | Biogen MA Inc. | Emopamil-binding protein inhibitors and uses thereof |
| CN117603226B (zh) * | 2023-11-27 | 2025-08-01 | 成都大学 | 一种吡唑并氮氧双杂卓类化合物及其制备方法和用途 |
| CN120398919B (zh) * | 2024-02-01 | 2026-04-07 | 福石生物科技(合肥)有限公司 | 作为wrn抑制剂的螺环衍生物及其应用 |
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| IE20000240A1 (en) | 2000-02-17 | 2003-03-05 | Trinity College Dublin | TRH-like peptide derivatives |
| KR100557268B1 (ko) | 2000-08-31 | 2006-03-07 | 시오노기세이야쿠가부시키가이샤 | 파킨슨씨병 치료제 |
| US7713935B2 (en) | 2004-10-01 | 2010-05-11 | The Provost, Fellows And Scholars Of The College Of The Holy And Undivided Trinity Of Queen Elizabeth Near Dublin | Compounds that modulate TRH actions |
| IE20060253A1 (en) | 2006-03-31 | 2007-11-14 | Trinity College Dublin | Methods for modulating the levels and effects of thyrotropin-releasing hormone(trh)and trh-related peptides |
| TW202204333A (zh) * | 2020-04-08 | 2022-02-01 | 美商阿吉歐斯製藥公司 | Menin抑制劑及治療癌症之使用方法 |
| AU2021333760A1 (en) * | 2020-08-26 | 2023-04-06 | Nalo Therapeutics | Modulators of Myc family proto-oncogene protein |
| WO2022140472A1 (en) * | 2020-12-22 | 2022-06-30 | Nikang Therapeutics, Inc. | Compounds for degrading cyclin-dependent kinase 2 via ubiquitin proteosome pathway |
| US20220363662A1 (en) * | 2021-04-20 | 2022-11-17 | Integral Biosciences Privated Limited | Compounds as lxr agonists |
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- 2022-10-28 JP JP2023556670A patent/JPWO2023074847A1/ja active Pending
- 2022-10-28 KR KR1020247017508A patent/KR20240091009A/ko active Pending
- 2022-10-28 CN CN202280072520.6A patent/CN118176179A/zh active Pending
- 2022-10-28 AR ARP220102936A patent/AR127489A1/es not_active Application Discontinuation
- 2022-10-28 WO PCT/JP2022/040370 patent/WO2023074847A1/ja not_active Ceased
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- 2022-10-28 CA CA3236538A patent/CA3236538A1/en active Pending
- 2022-10-28 EP EP22887172.9A patent/EP4438594A1/en not_active Withdrawn
- 2022-10-28 AU AU2022379243A patent/AU2022379243A1/en active Pending
- 2022-10-28 TW TW111141195A patent/TW202325272A/zh unknown
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| CA3236538A1 (en) | 2023-05-04 |
| EP4438594A1 (en) | 2024-10-02 |
| MX2024005187A (es) | 2024-07-19 |
| WO2023074847A1 (ja) | 2023-05-04 |
| JPWO2023074847A1 (https=) | 2023-05-04 |
| AR127489A1 (es) | 2024-01-31 |
| AU2022379243A1 (en) | 2024-05-02 |
| TW202325272A (zh) | 2023-07-01 |
| KR20240091009A (ko) | 2024-06-21 |
| CN118176179A (zh) | 2024-06-11 |
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