TW202246218A

TW202246218A - 抗菌化合物

抗菌化合物 Download PDF

Info

Publication number: TW202246218A
Authority: TW; Taiwan
Prior art keywords: alkyl; cycloalkyl; pharmaceutically acceptable; substituted; imidazol
Prior art date: 2021-02-11

Application number

TW111104618A

Other languages

English (en)

Chinese (zh)

Inventor

美商福吉醫療公司

Original Assignee

美商福吉醫療公司

Priority date

2021-02-11

Filing date

2022-02-08

Publication date

2022-12-01

2022-02-08 Application filed by 美商福吉醫療公司 filed Critical 美商福吉醫療公司

2022-12-01 Publication of TW202246218A publication Critical patent/TW202246218A/zh

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150000001875 compounds Chemical class 0.000 title claims abstract description 351
230000000844 anti-bacterial effect Effects 0.000 title 1
206010035664 Pneumonia Diseases 0.000 claims abstract description 33
239000008194 pharmaceutical composition Substances 0.000 claims abstract description 28
125000000592 heterocycloalkyl group Chemical group 0.000 claims description 305
229910052739 hydrogen Inorganic materials 0.000 claims description 231
239000001257 hydrogen Substances 0.000 claims description 231
125000000217 alkyl group Chemical group 0.000 claims description 159
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 143
150000003839 salts Chemical class 0.000 claims description 110
239000000243 solution Substances 0.000 claims description 109
-1 alkane Oxy Chemical group 0.000 claims description 108
125000000753 cycloalkyl group Chemical group 0.000 claims description 84
150000002431 hydrogen Chemical group 0.000 claims description 75
239000012453 solvate Substances 0.000 claims description 75
125000003545 alkoxy group Chemical group 0.000 claims description 68
238000000034 method Methods 0.000 claims description 56
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 49
125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 claims description 45
125000004404 heteroalkyl group Chemical group 0.000 claims description 43
125000006716 (C1-C6) heteroalkyl group Chemical group 0.000 claims description 40
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 40
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 39
125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims description 35
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 34
238000006467 substitution reaction Methods 0.000 claims description 34
229910052799 carbon Inorganic materials 0.000 claims description 33
125000001072 heteroaryl group Chemical group 0.000 claims description 33
208000027096 gram-negative bacterial infections Diseases 0.000 claims description 30
125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 29
238000002360 preparation method Methods 0.000 claims description 28
229940002612 prodrug Drugs 0.000 claims description 28
239000000651 prodrug Substances 0.000 claims description 28
239000003814 drug Substances 0.000 claims description 26
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 25
229910052731 fluorine Inorganic materials 0.000 claims description 25
239000011737 fluorine Substances 0.000 claims description 25
208000019693 Lung disease Diseases 0.000 claims description 21
229910052757 nitrogen Inorganic materials 0.000 claims description 21
125000002950 monocyclic group Chemical group 0.000 claims description 19
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
229910052736 halogen Inorganic materials 0.000 claims description 18
150000002367 halogens Chemical group 0.000 claims description 18
208000008745 Healthcare-Associated Pneumonia Diseases 0.000 claims description 17
125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 17
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 17
125000001715 oxadiazolyl group Chemical group 0.000 claims description 17
239000000546 pharmaceutical excipient Substances 0.000 claims description 15
241000589517 Pseudomonas aeruginosa Species 0.000 claims description 13
206010057190 Respiratory tract infections Diseases 0.000 claims description 11
239000000460 chlorine Substances 0.000 claims description 11
208000009470 Ventilator-Associated Pneumonia Diseases 0.000 claims description 10
208000015181 infectious disease Diseases 0.000 claims description 9
208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 8
230000001684 chronic effect Effects 0.000 claims description 8
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 8
125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 8
239000013543 active substance Substances 0.000 claims description 6
150000001412 amines Chemical class 0.000 claims description 6
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
XDPCNPCKDGQBAN-UHFFFAOYSA-N 3-hydroxytetrahydrofuran Chemical compound OC1CCOC1 XDPCNPCKDGQBAN-UHFFFAOYSA-N 0.000 claims description 5
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
201000003883 Cystic fibrosis Diseases 0.000 claims description 5
206010014561 Emphysema Diseases 0.000 claims description 5
201000009267 bronchiectasis Diseases 0.000 claims description 5
229910052801 chlorine Inorganic materials 0.000 claims description 5
HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 claims description 5
125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 5
YPFDHNVEDLHUCE-UHFFFAOYSA-N propane-1,3-diol Chemical compound OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 claims description 4
FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims description 4
150000003254 radicals Chemical class 0.000 claims description 4
208000032536 Pseudomonas Infections Diseases 0.000 claims description 3
KQNPFQTWMSNSAP-UHFFFAOYSA-N alpha-isobutyric acid Natural products CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 claims description 3
230000001066 destructive effect Effects 0.000 claims description 3
238000011321 prophylaxis Methods 0.000 claims description 3
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RLFMLLBZDXYHRH-BIOCXDLKSA-N C[C@@H](C1=NC=CN1CC#CC(C=C1)=CC=C1C1=CC=C(C(C2)CC2NCC(N)=N)C=C1)O Chemical compound C[C@@H](C1=NC=CN1CC#CC(C=C1)=CC=C1C1=CC=C(C(C2)CC2NCC(N)=N)C=C1)O RLFMLLBZDXYHRH-BIOCXDLKSA-N 0.000 claims description 2
XGMTWQAOAMMZQU-BULFRSBZSA-N C[C@@H](C1=NC=CN1[C@@H](CO)C#CC(C=C1)=CC=C1C(C=C1)=CC=C1OC[C@H](CO)N)O Chemical compound C[C@@H](C1=NC=CN1[C@@H](CO)C#CC(C=C1)=CC=C1C(C=C1)=CC=C1OC[C@H](CO)N)O XGMTWQAOAMMZQU-BULFRSBZSA-N 0.000 claims description 2
WXZKHGDKHCVARA-VSGQMKJSSA-N C[C@@H](C1=NC=CN1[C@H](CO)C#CC(C=C1)=CC=C1C(C=C1)=CC=C1OCC1OCCOC1)O Chemical compound C[C@@H](C1=NC=CN1[C@H](CO)C#CC(C=C1)=CC=C1C(C=C1)=CC=C1OCC1OCCOC1)O WXZKHGDKHCVARA-VSGQMKJSSA-N 0.000 claims description 2
YCSACJFGWHXQEL-OFAXGOBFSA-N C[C@@H](C1=NC=CN1[C@H](CO)C#CC(C=C1)=CC=C1C(C=C1)=CC=C1OC[C@@H](COC)O)O Chemical compound C[C@@H](C1=NC=CN1[C@H](CO)C#CC(C=C1)=CC=C1C(C=C1)=CC=C1OC[C@@H](COC)O)O YCSACJFGWHXQEL-OFAXGOBFSA-N 0.000 claims description 2
NDIKSDAEXFJMPW-ZOGZYCIHSA-N C[C@@H](C1=NC=CN1[C@H](CO)C#CC(C=C1)=CC=C1C(C=C1)=CC=C1O[C@H](C1)[C@@H]1N)O Chemical compound C[C@@H](C1=NC=CN1[C@H](CO)C#CC(C=C1)=CC=C1C(C=C1)=CC=C1O[C@H](C1)[C@@H]1N)O NDIKSDAEXFJMPW-ZOGZYCIHSA-N 0.000 claims description 2
COIMHHZPSDAPNT-REJOCVHCSA-N C[C@@H](C1=NC=CN1[C@H](CO)C#CC(C=C1)=CC=C1C1=CC=C(C(C2)CC2NCC(CO)(F)F)C=C1)O Chemical compound C[C@@H](C1=NC=CN1[C@H](CO)C#CC(C=C1)=CC=C1C1=CC=C(C(C2)CC2NCC(CO)(F)F)C=C1)O COIMHHZPSDAPNT-REJOCVHCSA-N 0.000 claims description 2
ZRDWOXMUOKJSIN-NUIDASMPSA-N C[C@@H](C1=NC=CN1[C@H](CO)C#CC(C=C1)=CC=C1C1=CC=C(C(C2)CC2NCC(F)F)C=C1)O Chemical compound C[C@@H](C1=NC=CN1[C@H](CO)C#CC(C=C1)=CC=C1C1=CC=C(C(C2)CC2NCC(F)F)C=C1)O ZRDWOXMUOKJSIN-NUIDASMPSA-N 0.000 claims description 2
RBCULSFXVINMTN-SULVSCTJSA-N C[C@@H](C1=NC=CN1[C@H](CO)C#CC(C=C1)=CC=C1C1=CC=C(C(C2)CC2N[C@@H](COC2)[C@H]2O)C=C1)O Chemical compound C[C@@H](C1=NC=CN1[C@H](CO)C#CC(C=C1)=CC=C1C1=CC=C(C(C2)CC2N[C@@H](COC2)[C@H]2O)C=C1)O RBCULSFXVINMTN-SULVSCTJSA-N 0.000 claims description 2
VWAQMOKAUTVFAH-WOPGWRJJSA-N C[C@@H](C1=NC=CN1[C@H](CO)C#CC(C=C1)=CC=C1C1=CC=C(COCC(CO)N)C=C1)O Chemical compound C[C@@H](C1=NC=CN1[C@H](CO)C#CC(C=C1)=CC=C1C1=CC=C(COCC(CO)N)C=C1)O VWAQMOKAUTVFAH-WOPGWRJJSA-N 0.000 claims description 2
IAQZLSAAXBTFOC-UYGLSEIWSA-N C[C@@H](C1=NC=CN1[C@H](CO)C#CC(C=C1)=CC=C1C1=CC=C(CO[C@H](C2)[C@@H]2N)C=C1)O Chemical compound C[C@@H](C1=NC=CN1[C@H](CO)C#CC(C=C1)=CC=C1C1=CC=C(CO[C@H](C2)[C@@H]2N)C=C1)O IAQZLSAAXBTFOC-UYGLSEIWSA-N 0.000 claims description 2
239000007928 intraperitoneal injection Substances 0.000 claims description 2
238000010253 intravenous injection Methods 0.000 claims description 2
230000002685 pulmonary effect Effects 0.000 claims description 2
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 6
LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims 2
DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims 2
DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims 2
OTJZCIYGRUNXTP-UHFFFAOYSA-N but-3-yn-1-ol Chemical compound OCCC#C OTJZCIYGRUNXTP-UHFFFAOYSA-N 0.000 claims 2
ZVQAVWAHRUNNPG-VPENINKCSA-N (2r,4s,5r)-oxane-2,4,5-triol Chemical compound O[C@H]1C[C@H](O)[C@H](O)CO1 ZVQAVWAHRUNNPG-VPENINKCSA-N 0.000 claims 1
ROANNWMBUUFWQV-RTMPEQEDSA-N C[C@@H](C1=NC=CN1[C@H](CCO)C#CC(C=C1)=CC=C1C(C=C1)=CC=C1O[C@H](COC1)[C@@H]1O)O Chemical compound C[C@@H](C1=NC=CN1[C@H](CCO)C#CC(C=C1)=CC=C1C(C=C1)=CC=C1O[C@H](COC1)[C@@H]1O)O ROANNWMBUUFWQV-RTMPEQEDSA-N 0.000 claims 1
VKGCGBTYIFPKIY-CMIZEVDMSA-N C[C@@H](C1=NC=CN1[C@H](CN)C#CC(C=C1)=CC=C1C(C=C1)=CC=C1O[C@H](COC1)[C@@H]1O)O Chemical compound C[C@@H](C1=NC=CN1[C@H](CN)C#CC(C=C1)=CC=C1C(C=C1)=CC=C1O[C@H](COC1)[C@@H]1O)O VKGCGBTYIFPKIY-CMIZEVDMSA-N 0.000 claims 1
239000004146 Propane-1,2-diol Substances 0.000 claims 1
230000000414 obstructive effect Effects 0.000 claims 1
229960004063 propylene glycol Drugs 0.000 claims 1
235000013772 propylene glycol Nutrition 0.000 claims 1
239000000203 mixture Substances 0.000 abstract description 44
230000002401 inhibitory effect Effects 0.000 abstract description 17
238000011282 treatment Methods 0.000 abstract description 14
241000894006 Bacteria Species 0.000 abstract description 10
230000012010 growth Effects 0.000 abstract description 6
208000035143 Bacterial infection Diseases 0.000 abstract description 5
208000022362 bacterial infectious disease Diseases 0.000 abstract description 5
150000002391 heterocyclic compounds Chemical class 0.000 abstract description 2
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 258
239000011541 reaction mixture Substances 0.000 description 126
238000006243 chemical reaction Methods 0.000 description 93
230000002829 reductive effect Effects 0.000 description 86
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 78
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 76
125000004093 cyano group Chemical group *C#N 0.000 description 70
239000012043 crude product Substances 0.000 description 61
239000012044 organic layer Substances 0.000 description 59
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 54
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 53
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 51
238000004895 liquid chromatography mass spectrometry Methods 0.000 description 49
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 45
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 42
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 38
238000004809 thin layer chromatography Methods 0.000 description 36
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 35
239000012267 brine Substances 0.000 description 33
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 33
239000007787 solid Substances 0.000 description 30
125000003118 aryl group Chemical group 0.000 description 29
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 28
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
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201000010099 disease Diseases 0.000 description 26
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239000007858 starting material Substances 0.000 description 24
239000003208 petroleum Substances 0.000 description 22
239000011734 sodium Substances 0.000 description 22
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
238000000746 purification Methods 0.000 description 21
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 19
125000000623 heterocyclic group Chemical group 0.000 description 19
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 19
229910004298 SiO 2 Inorganic materials 0.000 description 18
125000001309 chloro group Chemical group Cl* 0.000 description 18
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 18
229910052938 sodium sulfate Inorganic materials 0.000 description 18
235000011152 sodium sulphate Nutrition 0.000 description 18
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
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125000004429 atom Chemical group 0.000 description 14
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
239000000741 silica gel Substances 0.000 description 14
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RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 12
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230000008901 benefit Effects 0.000 description 12
125000004432 carbon atom Chemical group C* 0.000 description 12
239000002158 endotoxin Substances 0.000 description 12
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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
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
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VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
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DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
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DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 8
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KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 6
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