SG190243A1 - Hydroxamic acid derivatives and their use in the treatment of bacterial infections - Google Patents

Info

Publication number

SG190243A1

SG190243A1 SG2013036272A SG2013036272A SG190243A1 SG 190243 A1 SG190243 A1 SG 190243A1 SG 2013036272 A SG2013036272 A SG 2013036272A SG 2013036272 A SG2013036272 A SG 2013036272A SG 190243 A1 SG190243 A1 SG 190243A1

Authority

SG

Singapore

Prior art keywords

hydroxymethyl

buta

methyl

diynyl

hydroxyamino

Prior art date

2010-11-10

Links

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• Global Dossier
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• 208000035143 Bacterial infection Diseases 0.000 title claims abstract description 16
• 208000022362 bacterial infectious disease Diseases 0.000 title claims abstract description 16
• 238000011282 treatment Methods 0.000 title abstract description 19
• 239000002253 acid Substances 0.000 title description 6
• NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims abstract description 199
• 238000000034 method Methods 0.000 claims abstract description 46
• 150000003839 salts Chemical class 0.000 claims abstract description 28
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 24
• KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 135
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 46
• 239000003242 anti bacterial agent Substances 0.000 claims description 37
• 241000894006 Bacteria Species 0.000 claims description 35
• 125000000217 alkyl group Chemical group 0.000 claims description 26
• 230000002401 inhibitory effect Effects 0.000 claims description 23
• 229910052739 hydrogen Inorganic materials 0.000 claims description 22
• 239000001257 hydrogen Substances 0.000 claims description 21
• 125000000623 heterocyclic group Chemical group 0.000 claims description 18
• 108010059993 Vancomycin Proteins 0.000 claims description 17
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 17
• 229960003165 vancomycin Drugs 0.000 claims description 17
• MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 claims description 17
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
• 238000001727 in vivo Methods 0.000 claims description 15
• 125000006413 ring segment Chemical group 0.000 claims description 15
• 241000589517 Pseudomonas aeruginosa Species 0.000 claims description 14
• 229910052799 carbon Inorganic materials 0.000 claims description 14
• 125000001424 substituent group Chemical group 0.000 claims description 14
• 229910052717 sulfur Inorganic materials 0.000 claims description 14
• 241000588724 Escherichia coli Species 0.000 claims description 12
• HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 11
• 125000004432 carbon atom Chemical group C* 0.000 claims description 11
• 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 11
• 208000027096 gram-negative bacterial infections Diseases 0.000 claims description 11
• 229910052760 oxygen Inorganic materials 0.000 claims description 11
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
• JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 claims description 10
• 229960001225 rifampicin Drugs 0.000 claims description 10
• 239000003937 drug carrier Substances 0.000 claims description 9
• 241000588914 Enterobacter Species 0.000 claims description 8
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
• 150000003138 primary alcohols Chemical class 0.000 claims description 8
• 241001453380 Burkholderia Species 0.000 claims description 7
• 108090000790 Enzymes Proteins 0.000 claims description 7
• 102000004190 Enzymes Human genes 0.000 claims description 7
• 241000607734 Yersinia <bacteria> Species 0.000 claims description 7
• 239000003085 diluting agent Substances 0.000 claims description 7
• 230000005764 inhibitory process Effects 0.000 claims description 7
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 6
• LUQVCHRDAGWYMG-UHFFFAOYSA-N 4-phenylbenzamide Chemical compound C1=CC(C(=O)N)=CC=C1C1=CC=CC=C1 LUQVCHRDAGWYMG-UHFFFAOYSA-N 0.000 claims description 5
• 241000588923 Citrobacter Species 0.000 claims description 5
• 241000588748 Klebsiella Species 0.000 claims description 5
• 241000588769 Proteus <enterobacteria> Species 0.000 claims description 5
• 241000607142 Salmonella Species 0.000 claims description 5
• NDSRBKSYKYMKJX-LZJOCLMNSA-N n-[(2s)-3-amino-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl]-4-[4-[(1s,2r)-2-(hydroxymethyl)-2-methylcyclopropyl]buta-1,3-diynyl]benzamide Chemical compound C1=CC(C(=O)N[C@@H](C(C)(N)C)C(=O)NO)=CC=C1C#CC#C[C@H]1[C@@](CO)(C)C1 NDSRBKSYKYMKJX-LZJOCLMNSA-N 0.000 claims description 5
• 241000588921 Enterobacteriaceae Species 0.000 claims description 4
• 241000588771 Morganella <proteobacterium> Species 0.000 claims description 4
• 241000588768 Providencia Species 0.000 claims description 4
• 241000607720 Serratia Species 0.000 claims description 4
• RNQIBXQZXWCLEZ-VYXWTPOFSA-N n-[(1s)-1-(1-aminocyclobutyl)-2-(hydroxyamino)-2-oxoethyl]-4-[4-[(1r,2r)-2-(hydroxymethyl)cyclopropyl]buta-1,3-diynyl]benzamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.NC1([C@H](NC(=O)C=2C=CC(=CC=2)C#CC#C[C@H]2[C@@H](C2)CO)C(=O)NO)CCC1 RNQIBXQZXWCLEZ-VYXWTPOFSA-N 0.000 claims description 4
• GOCUUDXEOKIQRU-GVDBMIGSSA-N n-[(2s)-3-amino-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl]-4-[4-[(1s,2s)-2-(hydroxymethyl)cyclopropyl]buta-1,3-diynyl]benzamide Chemical compound C1=CC(C(=O)N[C@@H](C(C)(N)C)C(=O)NO)=CC=C1C#CC#C[C@@H]1[C@@H](CO)C1 GOCUUDXEOKIQRU-GVDBMIGSSA-N 0.000 claims description 3
• RNQIBXQZXWCLEZ-IIUXMCBISA-N n-[(1s)-1-(1-aminocyclobutyl)-2-(hydroxyamino)-2-oxoethyl]-4-[4-[(1r,2s)-2-(hydroxymethyl)cyclopropyl]buta-1,3-diynyl]benzamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.NC1([C@H](NC(=O)C=2C=CC(=CC=2)C#CC#C[C@H]2[C@H](C2)CO)C(=O)NO)CCC1 RNQIBXQZXWCLEZ-IIUXMCBISA-N 0.000 claims description 2
• MYPYJXKWCTUITO-LYRMYLQWSA-O vancomycin(1+) Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C([O-])=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)[NH2+]C)[C@H]1C[C@](C)([NH3+])[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-O 0.000 claims 1
• 230000000844 anti-bacterial effect Effects 0.000 abstract description 19
• 238000002360 preparation method Methods 0.000 abstract description 7
• 230000008569 process Effects 0.000 abstract description 2
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 175
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 150
• 239000000203 mixture Substances 0.000 description 124
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 123
• 239000000243 solution Substances 0.000 description 93
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 92
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 87
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 70
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 67
• 238000006243 chemical reaction Methods 0.000 description 67
• 235000019439 ethyl acetate Nutrition 0.000 description 64
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 57
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 55
• 238000003756 stirring Methods 0.000 description 51
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 50
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 47
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 45
• 239000011541 reaction mixture Substances 0.000 description 42
• 239000002904 solvent Substances 0.000 description 37
• 239000012044 organic layer Substances 0.000 description 35
• -1 methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy Chemical group 0.000 description 34
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 32
• 239000004698 Polyethylene Substances 0.000 description 31
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 30
• 230000015572 biosynthetic process Effects 0.000 description 30
• 239000003814 drug Substances 0.000 description 30
• 239000007787 solid Substances 0.000 description 30
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 27
• 239000000741 silica gel Substances 0.000 description 27
• 229910002027 silica gel Inorganic materials 0.000 description 27
• 229960001866 silicon dioxide Drugs 0.000 description 27
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
• 230000002829 reductive effect Effects 0.000 description 25
• 238000003786 synthesis reaction Methods 0.000 description 25
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 24
• 239000012267 brine Substances 0.000 description 24
• 208000015181 infectious disease Diseases 0.000 description 24
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 24
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
• 229940079593 drug Drugs 0.000 description 23
• MFJMYZLMFZMNSI-LQNKJABGSA-N methyl (2s)-3-amino-2-[[4-[4-[4-(hydroxymethyl)cyclohexyl]buta-1,3-diynyl]benzoyl]amino]-3-methylbutanoate;hydrochloride Chemical compound Cl.C1=CC(C(=O)N[C@H](C(=O)OC)C(C)(C)N)=CC=C1C#CC#CC1CCC(CO)CC1 MFJMYZLMFZMNSI-LQNKJABGSA-N 0.000 description 23
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 20
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 20
• 239000003826 tablet Substances 0.000 description 20
• 238000004809 thin layer chromatography Methods 0.000 description 20
• 239000002775 capsule Substances 0.000 description 19
• 239000012230 colorless oil Substances 0.000 description 19
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
• 239000007821 HATU Substances 0.000 description 18
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 18
• 238000004007 reversed phase HPLC Methods 0.000 description 18
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 17
• 239000003795 chemical substances by application Substances 0.000 description 17
• LXIWOWDRGZQTKE-LLAFXHEGSA-N methyl (2s)-2-[[4-[4-[4-(hydroxymethyl)cyclohexyl]buta-1,3-diynyl]benzoyl]amino]-3-methyl-3-[(2-methylpropan-2-yl)oxycarbonylamino]butanoate Chemical compound C1=CC(C(=O)N[C@H](C(=O)OC)C(C)(C)NC(=O)OC(C)(C)C)=CC=C1C#CC#CC1CCC(CO)CC1 LXIWOWDRGZQTKE-LLAFXHEGSA-N 0.000 description 17
• IHVCFWXDQZYDTB-UHFFFAOYSA-N 4-[4-[4-(hydroxymethyl)cyclohexyl]buta-1,3-diynyl]benzoic acid Chemical compound C1CC(CO)CCC1C#CC#CC1=CC=C(C(O)=O)C=C1 IHVCFWXDQZYDTB-UHFFFAOYSA-N 0.000 description 16
• 239000003921 oil Substances 0.000 description 16
• 235000019198 oils Nutrition 0.000 description 16
• MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 16
• 238000005160 1H NMR spectroscopy Methods 0.000 description 15
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
• 230000001580 bacterial effect Effects 0.000 description 15
• WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 15
• 239000010410 layer Substances 0.000 description 15
• XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 14
• KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 14
• 238000009472 formulation Methods 0.000 description 14
• 239000003112 inhibitor Substances 0.000 description 14
• PPEFLTCNYXTIJX-UHFFFAOYSA-N methyl 4-[4-[4-(hydroxymethyl)cyclohexyl]buta-1,3-diynyl]benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1C#CC#CC1CCC(CO)CC1 PPEFLTCNYXTIJX-UHFFFAOYSA-N 0.000 description 14
• KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
• 239000000047 product Substances 0.000 description 14
• 239000000725 suspension Substances 0.000 description 14
• KUNQEGGHYAYAQI-KGLIPLIRSA-N 4-[4-[(1r,2r)-2-(hydroxymethyl)cyclopropyl]buta-1,3-diynyl]benzoic acid Chemical compound OC[C@@H]1C[C@H]1C#CC#CC1=CC=C(C(O)=O)C=C1 KUNQEGGHYAYAQI-KGLIPLIRSA-N 0.000 description 13
• AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 13
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 13
• 241001465754 Metazoa Species 0.000 description 13
• NETVGNKAFWGXPK-BQBZGAKWSA-N [(1r,2r)-2-formylcyclopropyl]methyl acetate Chemical compound CC(=O)OC[C@@H]1C[C@H]1C=O NETVGNKAFWGXPK-BQBZGAKWSA-N 0.000 description 13
• 229960000583 acetic acid Drugs 0.000 description 13
• 230000000694 effects Effects 0.000 description 13
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 13
• 238000000746 purification Methods 0.000 description 13
• 238000010898 silica gel chromatography Methods 0.000 description 13
• 229940086542 triethylamine Drugs 0.000 description 13
• 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 13
• 241000699670 Mus sp. Species 0.000 description 12
• 229910052786 argon Inorganic materials 0.000 description 12
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 12
• 238000004128 high performance liquid chromatography Methods 0.000 description 12
• WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Inorganic materials [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 12
• 239000000463 material Substances 0.000 description 11
• 239000000126 substance Substances 0.000 description 11
• GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 10
• 238000005481 NMR spectroscopy Methods 0.000 description 10
• WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 10
• 239000002552 dosage form Substances 0.000 description 10
• VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 description 10
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 10
• 235000019341 magnesium sulphate Nutrition 0.000 description 10
• 229910052757 nitrogen Inorganic materials 0.000 description 10
• 239000000546 pharmaceutical excipient Substances 0.000 description 10
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
• 239000000843 powder Substances 0.000 description 10
• SQHSJJGGWYIFCD-UHFFFAOYSA-N (e)-1-diazonio-1-dimethoxyphosphorylprop-1-en-2-olate Chemical compound COP(=O)(OC)C(\[N+]#N)=C(\C)[O-] SQHSJJGGWYIFCD-UHFFFAOYSA-N 0.000 description 9
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
• 238000004949 mass spectrometry Methods 0.000 description 9
• 239000012528 membrane Substances 0.000 description 9
• RUZLIIJDZBWWSA-INIZCTEOSA-N methyl 2-[[(1s)-1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoate Chemical group COC(=O)C1=CC=CC=C1N[C@@H](C)C1=CC(C)=CN2C(=O)C=C(N3CCOCC3)N=C12 RUZLIIJDZBWWSA-INIZCTEOSA-N 0.000 description 9
• 229910000104 sodium hydride Inorganic materials 0.000 description 9
• LHNVWCNLKADYSZ-UHFFFAOYSA-N (4-ethynylcyclohexyl)methanol Chemical compound OCC1CCC(C#C)CC1 LHNVWCNLKADYSZ-UHFFFAOYSA-N 0.000 description 8
• ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 8
• 150000001721 carbon Chemical group 0.000 description 8
• 229940125782 compound 2 Drugs 0.000 description 8
• 229940126214 compound 3 Drugs 0.000 description 8
• 239000002158 endotoxin Substances 0.000 description 8
• UTWVEOUYCGZORL-SSDOTTSWSA-N methyl (2s)-2-amino-3-methyl-3-[(2-methylpropan-2-yl)oxycarbonylamino]butanoate Chemical compound COC(=O)[C@@H](N)C(C)(C)NC(=O)OC(C)(C)C UTWVEOUYCGZORL-SSDOTTSWSA-N 0.000 description 8
• 229910052938 sodium sulfate Inorganic materials 0.000 description 8
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