CN101687851A - 有机化合物 - Google Patents
有机化合物 Download PDFInfo
- Publication number
- CN101687851A CN101687851A CN200880022681A CN200880022681A CN101687851A CN 101687851 A CN101687851 A CN 101687851A CN 200880022681 A CN200880022681 A CN 200880022681A CN 200880022681 A CN200880022681 A CN 200880022681A CN 101687851 A CN101687851 A CN 101687851A
- Authority
- CN
- China
- Prior art keywords
- bases
- group
- alkyl
- azane
- carbon ring
- Prior art date
- 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.)
- Granted
Links
- 150000002894 organic compounds Chemical class 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 138
- 150000003839 salts Chemical class 0.000 claims abstract description 36
- 238000011282 treatment Methods 0.000 claims abstract description 22
- 210000000981 epithelium Anatomy 0.000 claims abstract description 17
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 15
- 108010052164 Sodium Channels Proteins 0.000 claims abstract description 10
- 102000018674 Sodium Channels Human genes 0.000 claims abstract description 10
- 239000012453 solvate Substances 0.000 claims abstract description 9
- 239000002585 base Substances 0.000 claims description 251
- 229910052757 nitrogen Inorganic materials 0.000 claims description 128
- -1 amino (hydroxyl) Chemical group 0.000 claims description 95
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 93
- 229910000062 azane Inorganic materials 0.000 claims description 91
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 65
- 125000000623 heterocyclic group Chemical group 0.000 claims description 60
- 125000003118 aryl group Chemical group 0.000 claims description 47
- 238000000034 method Methods 0.000 claims description 44
- 239000000203 mixture Substances 0.000 claims description 39
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Natural products O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 36
- 229910052736 halogen Inorganic materials 0.000 claims description 26
- 150000002367 halogens Chemical class 0.000 claims description 26
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 26
- 239000003814 drug Substances 0.000 claims description 25
- 208000006673 asthma Diseases 0.000 claims description 22
- 229910052799 carbon Inorganic materials 0.000 claims description 22
- 239000002253 acid Substances 0.000 claims description 21
- 238000002360 preparation method Methods 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 15
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 13
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 13
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 11
- 206010006451 bronchitis Diseases 0.000 claims description 10
- 201000003883 Cystic fibrosis Diseases 0.000 claims description 9
- CKMXBZGNNVIXHC-UHFFFAOYSA-L ammonium magnesium phosphate hexahydrate Chemical compound [NH4+].O.O.O.O.O.O.[Mg+2].[O-]P([O-])([O-])=O CKMXBZGNNVIXHC-UHFFFAOYSA-L 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 229910052567 struvite Inorganic materials 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 7
- 208000023504 respiratory system disease Diseases 0.000 claims description 7
- PIGFYZPCRLYGLF-UHFFFAOYSA-N Aluminum nitride Chemical compound [Al]#N PIGFYZPCRLYGLF-UHFFFAOYSA-N 0.000 claims description 6
- 229940124630 bronchodilator Drugs 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 230000000414 obstructive effect Effects 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 5
- 239000000739 antihistaminic agent Substances 0.000 claims description 5
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 5
- 206010006458 Bronchitis chronic Diseases 0.000 claims description 4
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 4
- ZRALSGWEFCBTJO-UHFFFAOYSA-N anhydrous guanidine Natural products NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 4
- 208000007451 chronic bronchitis Diseases 0.000 claims description 4
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 4
- 206010013781 dry mouth Diseases 0.000 claims description 4
- 206010023332 keratitis Diseases 0.000 claims description 4
- 201000010666 keratoconjunctivitis Diseases 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 125000004043 oxo group Chemical group O=* 0.000 claims description 4
- 208000025678 Ciliary Motility disease Diseases 0.000 claims description 3
- 206010011224 Cough Diseases 0.000 claims description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
- 206010057190 Respiratory tract infections Diseases 0.000 claims description 3
- 208000005946 Xerostomia Diseases 0.000 claims description 3
- 125000001118 alkylidene group Chemical group 0.000 claims description 3
- 229940125715 antihistaminic agent Drugs 0.000 claims description 3
- 201000005202 lung cancer Diseases 0.000 claims description 3
- 208000020816 lung neoplasm Diseases 0.000 claims description 3
- 201000009266 primary ciliary dyskinesia Diseases 0.000 claims description 3
- 238000010572 single replacement reaction Methods 0.000 claims description 3
- 150000007530 organic bases Chemical class 0.000 claims description 2
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical group [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 claims 6
- 201000010099 disease Diseases 0.000 abstract description 9
- 210000004400 mucous membrane Anatomy 0.000 abstract description 5
- 230000008901 benefit Effects 0.000 abstract description 4
- 230000036571 hydration Effects 0.000 abstract description 2
- 238000006703 hydration reaction Methods 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- 239000000243 solution Substances 0.000 description 43
- 239000000543 intermediate Substances 0.000 description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 38
- 239000007787 solid Substances 0.000 description 36
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 28
- 238000003756 stirring Methods 0.000 description 27
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- 239000000725 suspension Substances 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 16
- UYWQUFXKFGHYNT-UHFFFAOYSA-N Benzylformate Chemical compound O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 13
- 239000000126 substance Substances 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 125000003368 amide group Chemical group 0.000 description 12
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 10
- 238000005406 washing Methods 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- 230000008569 process Effects 0.000 description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 7
- 150000001412 amines Chemical class 0.000 description 7
- 150000001721 carbon Chemical group 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical group CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 125000000524 functional group Chemical group 0.000 description 6
- 125000006239 protecting group Chemical group 0.000 description 6
- 239000003195 sodium channel blocking agent Substances 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 108010067396 dornase alfa Proteins 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical compound CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 5
- RNFZNFKJNXAOPP-UHFFFAOYSA-N 3,5-diamino-6-chloropyrazine-2-carboxamide;hydrochloride Chemical compound Cl.NC(=O)C1=NC(Cl)=C(N)N=C1N RNFZNFKJNXAOPP-UHFFFAOYSA-N 0.000 description 4
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 4
- XSDQTOBWRPYKKA-UHFFFAOYSA-N amiloride Chemical compound NC(=N)NC(=O)C1=NC(Cl)=C(N)N=C1N XSDQTOBWRPYKKA-UHFFFAOYSA-N 0.000 description 4
- 239000005557 antagonist Substances 0.000 description 4
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- 239000012043 crude product Substances 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
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- 230000006870 function Effects 0.000 description 4
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000012545 processing Methods 0.000 description 4
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 4
- 230000009466 transformation Effects 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- 108091006146 Channels Proteins 0.000 description 3
- 108010053770 Deoxyribonucleases Proteins 0.000 description 3
- 102000016911 Deoxyribonucleases Human genes 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000000443 aerosol Substances 0.000 description 3
- 230000036428 airway hyperreactivity Effects 0.000 description 3
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 3
- 238000011914 asymmetric synthesis Methods 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- MZLADHZLVUEJTC-UHFFFAOYSA-N bis(4-aminopiperidin-1-yl)methanone Chemical class C1CC(N)CCN1C(=O)N1CCC(N)CC1 MZLADHZLVUEJTC-UHFFFAOYSA-N 0.000 description 3
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- SMDGVPQREIZILS-UHFFFAOYSA-N $l^{1}-oxidanylmethylbenzene Chemical compound [O]CC1=CC=CC=C1 SMDGVPQREIZILS-UHFFFAOYSA-N 0.000 description 2
- SFWLDKQAUHFCBS-AOEYGKNYSA-N (1S,4S,13S,16S,19S,22S,25S,28R,31S,37S,40S,41S,44R,47S,50S,53S,56R,65S,70S)-44-amino-47-(4-aminobutyl)-4,16,22-tribenzyl-31-[(R)-carboxy(hydroxy)methyl]-2,5,14,17,20,23,26,29,32,35,38,45,48,51,54,57,67-heptadecahydroxy-37-(2-hydroxy-2-iminoethyl)-50-(3-hydroxy-3-iminopropyl)-41,70-dimethyl-8-oxo-25-propan-2-yl-42,69,72-trithia-3,6,9,15,18,21,24,27,30,33,36,39,46,49,52,55,58,60,66-nonadecazapentacyclo[38.18.9.319,56.328,53.09,13]triheptaconta-2,5,14,17,20,23,26,29,32,35,38,45,48,51,54,57,66-heptadecaene-65-carboxylic acid Chemical compound CC(C)[C@@H]1\N=C(O)/[C@H](Cc2ccccc2)\N=C(O)/[C@@H]2\N=C(O)/[C@H](Cc3ccccc3)\N=C(O)/[C@@H]3CCCN3C(=O)C\N=C(O)/[C@H](Cc3ccccc3)\N=C(O)/[C@@H]3CNCCCC[C@H](\N=C(O)\[C@@H]4\N=C(O)\[C@H](CC(O)=N)\N=C(O)\C\N=C(O)/[C@@H](\N=C(O)\[C@H](CSC[C@@H](N=C(O)[C@H](CCC(O)=N)N=C(O)[C@H](CCCCN)N=C(O)[C@@H](N)CS[C@H]4C)C(O)=N[C@@H](CS[C@H]2C)C(O)=N3)\N=C1\O)[C@@H](O)C(O)=O)C(O)=O SFWLDKQAUHFCBS-AOEYGKNYSA-N 0.000 description 2
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 2
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- 239000013543 active substance Substances 0.000 description 2
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Abstract
式(I)化合物或者其互变异构体或立体异构体或溶剂化物或药学上可接受的盐,其中M1、M2、L1、L2、W1、W2、X1、X2、Y1、Y2、A、R5和R5a与本文中所定义,其用于治疗通过阻断上皮钠通道能够治疗的病症,特别是受益于粘膜水化作用的疾病。
Description
本发明涉及有机化合物、它们的制备及作为药物的用途。
一方面,本发明提供式(I)化合物或者其互变异构体或立体异构体或溶剂化物或药学上可接受的盐:
其中,
R1、R2、R3和R4独立地选自H、C1-C8-烷基、C1-C8-烷基-羧基、C1-C8-卤代烷基、C3-C15碳环基团、C1-C8-烷基羰基、C1-C8-烷氧基羰基、C6-C15-元芳香族碳环基团、4-至14-元杂环基团、被4-至14-元杂环基团取代的C1-C8-烷基和被C6-C15-元芳香族碳环基团取代的C1-C8-烷基,或
R1和R2与它们所连接的氮原子形成任选地被R14取代的C3-C14-元杂环基团,或
R3和R4与它们所连接的氮原子形成任选地被R14取代的C3-C14-元杂环基团;
L1和L2独立地选自:
R6、R5和R5a独立地选自H、C1-C8-烷基、C1-C8-烷基-羧基、C1-C8-烷基-烷氧基、C1-C8-卤代烷基、C3-C15-碳环基团、C1-C8-烷基羰基、C1-C8-烷氧基羰基、硝基、氰基、C6-C15-元芳香族碳环基团、4-至14-元杂环基团、被4-至14-元杂环基团取代的C1-C8-烷基和被C6-C15-元芳香族碳环基团取代的C1-C8-烷基;
W1和W2独立地选自C0-C8-亚烷基;
X1和X2独立地选自4-至14-元杂环基团;
Y1和Y2独立地是-C0-C8-亚烷基-或C1-C8-烷基氨基;
A选自C6-C15-元芳香族碳环基团、-CONR11a-(C1-C8-亚烷基)-NR11aCO-、-CO-(C1-C8-亚烷基)-CO-、-CO-(C1-C8-亚烯基)-CO-、-(C=O)、-CO-(C0-C8-亚烷基)-Z-(C0-C8-亚烷基)-CO-、-CO NR11a-(C0-C8-亚烷基)-Z-(C0-C8-亚烷基)-NR11aCO-、C3-C15-碳环基团和4-至14-元杂环基团;
Z选自C6-C15-元芳香族碳环基团、C3-C15-碳环基团和4-至14-元杂环基团;
T选自H、卤素、C1-C8-烷基、C1-C8-卤代烷基、C1-C8-卤代烷氧基、C3-C15-碳环基团、硝基、氰基、C6-C15-元芳香族碳环基团和被C6-C15-元芳香族碳环基团取代的C1-C8-烷基;
其中,除非文中另外说明,每个C6-C15-元芳香族碳环基团和每个4-至14-元杂环基团或5-至14-元杂环基团独立地任选地被一个或多个基团取代,所述基团选自OH、C1-C8-烷氧基、C1-C8-烷基、卤素、SO2NR11R12、任选地被羟基取代的羟基C1-C8-烷氧基、(C0-C4-亚烷基)CONR11R12、(C0-C4-亚烷基)-N=C(NR11R12)2、-O-(C1-C4-亚烷基)-N=C(NR11R12)2、-O-(C1-C4-亚烷基)-CONR11R12、C7-C10-芳烷氧基、C7-C10-芳烷基、SH、S(C1-C8-亚烷基)、SO2(C1-C8-亚烷基)、SO(C1-C8-亚烷基)、NR11R12、其中碳环基团任选地被卤素或C1-C8-烷基取代的NR11(C3-C12-碳环基团)、R15、被R15取代的C1-C8-烷基、R16、被R16取代的C1-C8-烷基、O(C1-C8-亚烷基)-NR11-(C=O)O-(C0-C4-亚烷基)-R15、氰基、氧代、羧基、硝基、C1-C8-烷基羰基、羟基-C1-C8-烷基、C1-C8-卤代烷基、氨基-C1-C8-烷基、氨基(羟基)C1-C8-烷基和任选地被氨基羰基取代的C1-C8-烷氧基,其中R15是任选地被OH、C1-C8-烷氧基、C1-C8-烷基、卤素和C1-C8-卤代烷基取代的C6-C15-元芳香族碳环基团,R16是任选地被OH、C1-C8-烷氧基、C1-C8-烷基、C6-C15-元芳香族碳环基团、CO2H、(C=O)-3至14-元杂环基团、卤素和C1-C8-卤代烷基取代的4-至14-元杂环基团,
并且其中,除非文中另有说明,每个亚烷基基团任选地被以下基团取代:C1-C8-烷基、卤素、C1-C8-烷氧基、羧基、C1-C8-烷基-羧基、C1-C8-卤代烷基、C1-C8-卤代烷氧基、C3-C15-碳环基团、C1-C8-烷基羰基、C1-C8-烷氧基羰基、硝基、氰基、R15、被R15取代的C1-C8-烷基、R16或被R16取代的C1-C8-烷基;
每个R11和R12独立地选自H、C1-C8-烷基、C1-C8-卤代烷基、C3-C15-碳环基团、C6-C15-芳香族碳环基团和任选地被-COOH或C1-C8-烷基取代的4-至14-元杂环基团,或R11和R12与它们所连接的氮一起形成任选地被CO2H、C1-C8-烷基、(C=O)-4-至14-元杂环基团或C6-C15-元芳香族碳环基团取代的5-至14-元杂环基团,当R11或R12是C1-C8-烷基时,它们可任选地被下列基团单取代或双取代:C6-C15-芳香族碳环基团、5-至14-元杂环基团、任选地被OH取代的C1-C8-烷基氨基或任选地被OH取代的二(C1-C8-烷基)氨基;
R11a选自H和C1-C8-烷基;并且
R14选自H、卤素、C1-C8-烷基、OH、C6-C15-元芳香族碳环基团、C7-C14-芳烷基和O-C7-C14-芳烷基。
定义
本说明书中使用的术语具有以下含义:
“任选取代的”意指所述基团可以在一个或多个位置上被其后列出的基团中的任意一个或其任意组合取代。
本文中使用的“卤代”或“卤素”可以是氟、氯、溴或碘。
本文中使用的“C1-C8-烷基”表示具有1-8个碳原子的直链或支链烷基。
本文中使用的“C1-C8-烷氧基”表示具有1-8个碳原子的直链或支链烷氧基。
术语“亚烷基”表示直链或支链的饱和烃链。
术语“亚烯基”表示含有一个或多个碳-碳双键的直链或支链的部分不饱和的烃链。
“氨基-C1-C8-烷基”和“氨基-C1-C8-烷氧基”表示氨基通过氮原子与C1-C8-烷基相连,例如,NH2-(C1-C8)-,或与C1-C8-烷氧基相连,例如,NH2-(C1-C8)-O-。
“C1-C8-烷基氨基”和“二(C1-C8-烷基)氨基”表示如上文中所定义的C1-C8-烷基通过碳原子与氨基相连。在二(C1-C8-烷基)氨基中的C1-C8-烷基可以是相同的或不同的。
“氨基-(羟基)-C1-C8-烷基”表示氨基通过氮原子与C1-C8-烷基相连,且羟基通过氧原子与同一个C1-C8-烷基相连。
本文中使用的“C1-C8-烷基羰基”和“C1-C8-烷氧基羰基”分别表示如上文中所定义的C1-C8-烷基或C1-C8-烷氧基通过碳原子与羰基相连。
本文中使用的“C3-C8-环烷基羰基”表示如上文中所定义的C3-C8-环烷基通过碳原子与羰基相连。
本文中使用的“C7-C14-芳烷基”表示被本文中所定义的C6-C10-芳香族碳环基团取代的如上文中所定义的烷基(例如,C1-C4-烷基)。
本文中使用的“C3-C15-碳环基团”表示具有3-15个环碳原子的饱和的或者部分饱和的碳环基团,例如C3-C8-环烷基。C3-C15-碳环基团的实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基或环辛基,或双环基诸如二环辛基、包括茚满基和茚基的二环壬基及二环癸基。
本文中使用的“C6-C15-芳香族碳环基团”表示具有6-15个环碳原子的芳香族基团。C6-C15-芳香族碳环基团的实例包括但不限于苯基、亚苯基、次苯基(benzenetriyl)、萘基、亚萘基、次萘基(naphthylenetriyl)或亚蒽基。
“4-至8-元杂环基团”、“3-至14-元杂环基团”、“4-至-14-元杂环基团”和“5-至14-元杂环基团”分别指含有至少一个环杂原子的4-至8-元、3-至14-元、4-至-14-元和5-至14-元杂环,其中所述环杂原子选自氮、氧和硫,所述杂环可以是饱和的、部分饱和的或不饱和的(芳香族)。这样的杂环基团的实例包括但不限于呋喃、吡咯、吡咯烷、吡唑、咪唑、三唑、异三唑、四唑、噻二唑、异噻唑、噁二唑、吡啶、哌啶、吡嗪、噁唑、异噁唑、吡嗪、哒嗪、嘧啶、哌嗪、吡咯烷、吡咯烷酮、吗啉、三嗪、噁嗪、四氢呋喃、四氢噻吩、四氢噻喃、四氢吡喃、1,4-二氧六环、1,4-噁噻烷、吲唑、喹啉、吲唑、吲哚或噻唑。
本发明的另一个实施方案提供了式(I)化合物或其互变异构体或立体异构体或药学上可接受的盐:
其中
R1、R2、R3、R4、R5、R5a和R6是H;
W1和W2独立地选自C0-C8-亚烷基;
X1和X2独立地选自4-至14-元杂环基团;
Y1和Y2独立地是-C0-C8-亚烷基-或C1-C8-烷基氨基-;
A选自C6-C15-元芳香族碳环基团、-CONR11a-(C1-C8-亚烷基)-NR11aCO-、-(C=O)、-CO-(C1-C8-亚烷基)-CO-、-CO-(C1-C8-亚烯基)-CO-、-CO-(C0-C8-亚烷基)-Z-(C0-C8-亚烷基)-CO-、-CO NR11a-(C0-C8-亚烷基)-Z-(C0-C8-亚烷基)-NR11aCO-、C3-C15-碳环基团和4-至14-元杂环基团;
Z选自C6-C15-元芳香族碳环基团、C3-C15-碳环基团和4-至14-元杂环基团;
T选自H、卤素、C1-C8-烷基、C1-C8-卤代烷基、C1-C8-卤代烷氧基、C3-C15-碳环基团、硝基、氰基、C6-C15-元芳香族碳环基团和被C6-C15-元芳香族碳环基团取代的C1-C8-烷基;
其中,除非文中另有说明,每个C6-C15-元芳香族碳环基团和每个4-至14-元杂环基团独立地任选地被一个或多个基团取代,所述基团选自OH、C1-C8-烷氧基、C1-C8-烷基、卤素、SO2NR11R12、羟基C1-C8-烷氧基,其任选地被羟基取代,(C0-C4-亚烷基)CONR11R12、(C0-C4-亚烷基)-N=C(NR11R12)2、-O-(C1-C4-亚烷基)-N=C(NR11R12)2、-O-(C1-C4-亚烷基)-CONR11R12、C7-C10-芳烷氧基、C7-C10-芳烷基、SH、S(C1-C8-亚烷基)、SO2(C1-C8-亚烷基)SO(C1-C8-亚烷基)、NR11R12、其中碳环基团任选地被卤素或C1-C8-烷基取代的NR11(C3-C12-碳环基团)、R15、被R15取代的C1-C8-烷基、R16、被R16取代的C1-C8-烷基、O(C1-C8-亚烷基)-NR11C(C=O)O-(C0-C4-亚烷基)-R15、氰基、氧代、羧基、硝基、C1-C8-烷基羰基、羟基-C1-C8-烷基、C1-C8-卤代烷基、氨基-C1-C8-烷基、氨基(羟基)C1-C8-烷基和任选地被氨基羰基取代的C1-C8-烷氧基,其中R15是C6-C15-元芳香族碳环基团,其任选地被OH、C1-C8-烷氧基、C1-C8-烷基、卤素和C1-C8-卤代烷基取代,R16是3-至14-元杂环基团,其任选地被OH、C1-C8-烷氧基、C1-C8-烷基、C6-C15-元芳香族碳环基团、CO2H、(C=O)-3-至14-元杂环基团、卤素和C1-C8-卤代烷基取代;
每个R11和R12独立地选自H、C1-C8-烷基、C3-C15-碳环基团、C6-C15-芳香族碳环基团,或R11和R12与它们所连接的氮一起形成4-至8-元杂环基团,其任选地被CO2H、C1-C4-烷基、(C=O)-4-至8-元杂环基团或C6-C10-元芳香族碳环基团取代,当R11或R12是C1-C8-烷基时,它们可任选地被下列基团单取代或双取代:C6-C10-芳香族碳环基团、C3-C8-元杂环基团或任选地被OH取代的二(C1-C8-烷基)氨基;并且
R11a选自H和C1-C8-烷基。
在式(I)化合物中,独立地、共同地或任意组合地优选以下含义:
根据式(I),R1合适地是H。
根据式(I),R2合适地是H。
根据式(I),R3合适地是H。
根据式(I),R4合适地是H。
M1和M2合适地是
根据式(I),W1和W2合适地是C0亚烷基。
根据式(I),X1和X2合适地是哌啶。
根据式(I),Y1和Y2合适地是C0亚烷基。
根据式(I),R5和R5a合适地是H。
根据式(I),R6合适地是H。
A合适地选自C6-C15-元芳香族碳环基团、-CONH-(C1-C8-亚烷基)-NHCO-、-CO-(C1-C8-亚烷基)-CO-、-CO-(C1-C8-亚烯基)-CO-、-(C=O)、-CO-(C0-C8-亚烷基)-Z-(C0-C8-亚烷基)-CO-、-CONH-(C0-C8-亚烷基)-Z-(C0-C8-亚烷基)-NHCO-、C3-C15-碳环基团和4-至14-元杂环基团,例如,
本发明的另一方面提供了式(Ia)化合物或其互变异构体或立体异构体或药学上可接受的盐:
其中A选自:
在另一个实施方案中,本发明提供了游离形式或药学上可接受的盐形式的上述任何实施方案中的式(I)化合物在制备治疗炎症性或过敏性病症、特别是炎症性或阻塞性气道疾病或粘膜水化(mucosal hydration)的药物中的用途。
本发明的优选实施方案提供了游离形式或药学上可接受的盐形式的上述任何实施方案中的式(I)化合物在制备治疗炎症性或过敏性病症的药物中的用途,所述的炎症性或过敏性病症选自囊性纤维化、原发性纤毛运动障碍、慢性支气管炎、慢性阻塞性肺病、哮喘、呼吸道感染、肺癌、口腔干燥症和角膜结膜炎。
应当理解,可以将本发明任何的和所有的实施方案与任何其它实施方案结合从而描述本发明的额外实施方案。此外,将实施方案中的任何要素与来自任何实施方案的任何和所有的其它要素结合来描述额外的实施方案。本领域技术人员应当理解在不可能的取代基组合并非本发明的方面。
除非上下文中另有要求,否则在本说明书和随后的权利要求中出现的术语“包含”或其变化形式例如“包括”,应当理解为是指包括所述的总体或步骤、或总体或步骤的组,但不排除任何其它的总体或步骤、或总体或步骤的组。
特别优选的式(I)的具体化合物是下文实施例中所述的那些化合物。
式(I)表示的化合物能够形成酸加成盐,特别是药学上可接受的酸加成盐。式(I)化合物的药学上可接受的酸加成盐包括无机酸和有机酸的盐,所述的无机酸例如氢卤酸,如氢氟酸、盐酸、氢溴酸或氢碘酸;硝酸;硫酸;磷酸;所述的有机酸例如脂肪族一元羧酸,如甲酸、乙酸、三氟乙酸、丙酸和丁酸;脂肪族羟酸,如乳酸、柠檬酸、酒石酸或苹果酸;二元羧酸,如马来酸或琥珀酸;芳香族羧酸,如苯甲酸、对-氯苯甲酸、二苯基乙酸,对-联苯基苯甲酸或三苯基乙酸;芳香族羟酸,如邻-羟基苯甲酸、对-羟基苯甲酸、1-羟基萘-2-甲酸或3-羟基萘-2-甲酸;肉桂酸类,如3-(2-萘基)丙烯酸、对-甲氧基肉桂酸或对-甲基肉桂酸;以及磺酸,如甲磺酸或苯磺酸。可以通过已知的成盐方法从式(I)的化合物制备这些盐。
可能包含酸性基团如羧基的式(I)化合物还能够与碱,特别是药学上可接受的碱,例如本领域众所周知的那些碱成盐;合适的这类盐包括金属盐,特别是碱金属或碱土金属盐,如钠、钾、镁或钙盐;或者与氨或药学上可接受的有机胺类或杂环碱类如乙醇胺类、苄胺类或吡啶形成的盐。可以通过已知的成盐方法从式(I)的化合物制备这些盐。
根据本发明的药学上可接受的溶剂化物包括其中结晶化溶剂可以被同位素替代(例如D2O、d6-丙酮或d6-DMSO)的那些。
可以用常规方法将游离形式的式(I)的化合物转化为盐的形式,反之亦然。游离或盐形式的化合物可以以水合物或含有用于结晶的溶剂的溶剂化物的形式获得。式(I)化合物可从反应混合物中回收并且用常用方法纯化。异构体例如对映体可以用常用方法获得,例如通过分步结晶或从相应的不对称取代的(例如光学活性的)原料通过不对称合成而获得。
本发明的一些化合物含有至少一个不对称碳原子,并且因而它们以单一的光学活性异构体或其混合物如外消旋混合物的形式存在。在有另外的不对称中心存在的情况下,本发明还包括单一的光学活性异构体及其混合物(例如,非对映体混合物)。
本发明包括所有此类形式,特别是纯的异构体形式。可以通过常规方法使这些不同的异构体形式互相分离或拆分开,或任何给出的异构体可以通过常规的合成方法或通过立体特异性或不对称合成获得。由于预期将本发明的化合物应用于药物组合物中,因此很容易理解,优选以基本纯的形式提供它们,例如至少60%的纯度,更合适的是至少75%的纯度,并优选至少85%,特别是至少98%纯度(%是重量百分比)。化合物的不纯的制备物可以用于制备用于药物组合物的更纯形式;化合物的这些较不纯的制备物应当含有至少1%、更合适地至少5%并优选10-59%的本发明化合物。
本发明包括所有药学上可接受的同位素标记的式(I)所示化合物,其中一个或多个原子被具有同样原子序数但是原子质量或质量数与自然界中通常见到的原子质量或质量数不同的原子替代。适合包含在本发明的化合物中的同位素的实例包括:氢的同位素,例如2H和3H;碳的同位素,例如11C、13C和14C;氯的同位素,例如36Cl;氟的同位素,例如18F;碘的同位素,例如123I和125I;氮的同位素,例如13N和15N;氧的同位素,例如15O、17O和18O;和硫的同位素,例如35S。
某些同位素标记的式(I)化合物(例如那些含有放射性同位素的化合物)在药物和/或底物组织分布研究中非常有用。因为放射性同位素氚(3H)和碳14(14C)很容易被引入且很容易被检测,所以它们对于上述目的而言是特别有用的。用较重的同位素诸如氘(2H)替代可以提供某些治疗优点,因为其具有较高的代谢稳定性,例如增加在体内的半衰期或减少剂量需求,并且因此在一些情况中是优选的。用正电子发射同位素诸如11C、18F、15O和13N的替代在用于测试底物受体占据的正电子放射层扫描术(PET)中可能是有用的。
通常可通过本领域技术人员已知的常规技术,或通过与在所附实施例中描述的方法相类似的方法采用一种合适的同位素标记试剂代替先前使用的非同位素标记试剂,制备同位素标记的式(I)化合物。
互变异构体是存在于平衡中的并且容易从一种异构体形式转化为另一种的两个或多个结构异构体之一。
互变异构体的例子包括但是不限于权利要求中所描述的那些,并且还包括式(II)化合物:
其中
M1、M2、W1、W2、X1、X2、Y1、Y2和A如上文所述;并且
L1和L2是其中Rx、R6和R6a独立地选自H、C1-C8烷基、C1-C8-烷基-羧基、C1-C8-烷基-烷氧基、C1-C8-卤代烷基、C3-C15-碳环基团、C1-C8-烷基羰基、C1-C8-烷氧基羰基、硝基、氰基、C6-C15-元芳香族碳环基团、4-至14-元杂环基团、被4-至14-元杂环基团取代的C1-C8-烷基和被C6-C15-元芳香族碳环基团取代的C1-C8-烷基。
本发明的化合物可以以非溶剂化和溶剂化形式存在。本文使用的术语“溶剂化物”描述了含有本发明的化合物和一种或多种药学上可接受的溶剂分子的分子复合物,所述溶剂例如是乙醇。当所述溶剂是水时,使用术语“水合物”。
合成
本发明的实施方案提供了制备式(I)的化合物或其互变异构体或立体异构体或药学上可接受的盐的方法:
其中
M1、M2、L1、L2、NR5、NR5a、W1、W2、X1、X2、Y1、Y2和A如上文中所定义,所述方法包括以下步骤:
(i)使式(IV)化合物
其中
M*是M1或M2;
L*是L1或L2;并且
M1、M2、L1、L2和T如上文所定义,
与式(V)化合物任选地在碱例如有机碱的存在下,在有机溶剂例如非质子偶极溶剂中进行反应,
其中R5、R5a、W1、W2、X1、X2、Y1、Y2和A如上文所定义,和
(ii)回收得到的游离或药学上可接受的盐形式的式(I)化合物。
例如可以使用下面和实施例中描述的反应和技术制备式(I)化合物。反应可以在对于所使用的试剂和物质适宜的并且适于进行有效转化的溶剂中进行。有机合成领域的技术人员应当了解,分子中存在的官能团应当符合预期的转化。有时这需要判断改变合成步骤的顺序或选择某种特定的不同反应流程,以得到预期的本发明化合物。
在以下反应流程所示的合成中间体和终产物上的各种取代基,在本领域技术人员认为需要的情况下,可以使用保护基以其充分被加工的形式存在,或者以前体形式存在,所述前体可以随后通过本领域技术人员熟悉的方法被加工成其最终形式。这些取代基也可以在合成过程的各种阶段或在合成过程完成后加入。在很多情况下,通常使用的官能团操作可以用于将一种中间体转化为另一种中间体,或者将一种式(I)化合物转化为另一种式(I)化合物。这类操作的实例包括将酯或酮转化为醇;将酯转化为酮;酯、酸和酰胺的互相转换;醇和胺的烷化、酰化和磺酰化反应;以及许多其他反应。也可以使用普通的反应,如烷化、酰化、卤化或氧化反应来加入取代基。这类操作在本领域内是众所周知的,许多参考著作概述了用于这类操作的步骤和方法。一些参考著作给出了用于许多官能团操作和常用于有机合成领域其他转化反应的有机合成原始文献的实例和参考,例如March’s Organic Chemistry,第5版,Wiley和Chichester编辑,(2001);Comprehensive Organic Transformations,Larock编辑,VCH(1989);Comprehensive Organic Functional Group Transformations,Katritzky等人(系列编辑),Pergamon(1995);和Comprehensive Organic Synthesis,Trost和Fleming(系列编辑),Pergamon(1991)。还应当了解,在该领域内设计任何合成路线的另一项主要考虑是明智地选择用于保护本发明所述化合物中存在的反应性官能团的保护基。在同一分子中可以选择多种保护基,以便这些保护基各自可以在不脱去该分子中其它保护基的情况下脱去,或者使用同一反应步骤脱去多个保护基,这取决于所需要的结果。Greene和Wuts的权威性著作Protective Groups in Organic Synthesis,Wiley and Sons(1999)为技术人员描述了许多供选方法。
一般地,在本专利申请范围内描述的化合物可以通过流程1和流程2以及实施例所述的路线进行合成。
在流程1中,式(Ib)的化合物可以根据Cragoe等人在《药物化学》(JMed Chem),第10卷,第66-73页,1967;和欧洲专利EP 0 017 152和美国专利号3,544,571中描述的方法制备。例如,中间体1(R=H)可以与中体间2(其中A如上文定义)在三乙胺的存在下、在有机溶剂中进行反应,以提供作为游离碱的化合物(Ib)。然后可通过用合适的酸处理而将该游离碱转化为盐形式。或者,偶联反应可以在BoC或CBz保护基团存在下进行。中间体可通过本领域技术人员已知的方法制备,或是商业可获得的。
流程1
其中R=H或BoC或CBz基团 (Ib)
式(Ic)的化合物也能够根据流程2(其中中间体2中的Y1或X1含有被基团P保护的伯胺或仲胺)如下制备:使中间体1与单保护的二胺(中间体2)在三乙胺的存在下、在有机溶剂中反应制备中间体3。随后使用常规的脱保护技术使中间体3脱保护得到中间体4。可使中间体4与AJ1J2(J3)n和中间体4a反应,其中中间体4a中的Y2或X2含有伯胺或仲胺,从而得到化合物(Ic)。当n=1时,A可以被额外取代,从而得到化合物(Ic)。A、Y2、X2、W2、L2、R5和M2如上文定义。P表示标准的胺保护基团,例如,Boc、CBz、醋酸盐/酯并且可以用标准方法脱保护。与基团A结合的J1、J2和J3独立地提供可以与胺反应的官能团,例如,卤素、硫醚、羧酸、异氰酸酯、磺酰氯、醛和酮。在任一情况下,还可应用文献中已知及本领域技术人员已知的方法通过适当的N保护基团(例如,Boc、CBz)对中间体1进行保护。
流程2
可以用本领域技术人员公知的常规方法将游离形式的式(I)化合物转化为盐形式,反之亦然。游离或盐形式的化合物能够以水合物或含有用于结晶的溶剂的溶剂化物的形式获得。可通过常规的方法从反应混合物中回收式(I)化合物并进行纯化。异构体诸如立体异构体可以通过常规的方法获得,例如,通过分步结晶或从相应的不对称取代的(例如光学活性的)起始原料通过不对称合成获得。
药理学活性
由于其对上皮钠通道(ENaC)的阻断作用,游离或药学上可接受的盐形式的式(I)化合物(或者在下文中称为“本发明的物质”)可用于治疗对上皮钠通道的阻断有响应的病症,特别是受益于粘膜水化的病症。
通过阻断上皮钠通道可治疗的疾病包括与调节通过上皮膜的流体体积相关的疾病。例如,气道表面液体的体积是粘膜纤毛清除和保持肺健康的关键调节因素。阻断上皮钠通道会促进气道上皮粘膜一侧的流体蓄积,由此促进粘液清除和防止粘液和痰在呼吸组织(包括肺气道)中的蓄积。这类疾病包括:呼吸疾病,如囊性纤维化、原发性纤毛运动障碍、慢性支气管炎、慢性阻塞性肺病(COPD)、哮喘、呼吸道感染(急性和慢性;病毒性和细菌性)和肺癌。受上皮钠通道的阻断影响的疾病除了呼吸疾病,还包括与异常的通过上皮的流体调节相关的疾病,可能涉及其表面上的保护性表面液体的异常生理学,例如口腔干燥症(口干燥)或男性角膜结膜炎(keratoconjunctivitis sire)(干眼)。此外,阻断肾的上皮钠通道可以用于促进利尿并由此引起降血压作用。
根据本发明的治疗可以是对症治疗或预防性治疗。
囊性纤维化包括肺部的疾病,包括非典型的、轻度、中度和重度的囊性纤维化肺疾病,以及因其它药物治疗特别是其它的吸入药物治疗而导致的气道高反应性的恶化。囊性纤维化还包括受囊性纤维化影响的其它器官系统(例如鼻窦、胃肠道和生殖管道)的疾病。
慢性阻塞性肺病包括慢性支气管炎或与此相关的呼吸困难、肺气肿,以及因其它药物治疗特别是其它的吸入药物治疗而导致的气道高反应性的恶化。本发明也适用于治疗任何类型或起源的支气管炎,包括例如急性支气管炎、花生仁吸入性支气管炎、卡他性支气管炎、格鲁布性(croupus)支气管炎、慢性或结核性支气管炎。
哮喘包括内源性(非过敏性)哮喘和外源性(过敏性)哮喘、轻度哮喘、中度哮喘、重度哮喘、支气管哮喘、运动诱发的哮喘、职业性哮喘和由细菌感染诱发的哮喘。哮喘的治疗还应理解为包括对于例如不足4或5岁的、显示出哮鸣症状和已诊断或可被诊断为“喘鸣婴儿”(一种确立的主要医疗关注的患者类型,并且现在经常鉴定为初期或早期哮喘)的个体的治疗。(为了方便,将这种特定的哮喘病症称为“喘鸣婴儿综合征”。)
治疗哮喘的预防性功效将通过降低例如急性哮喘或支气管收缩的症状发作的频率或严重度、改善肺功能或改善气道高反应性来证实。还可以通过减少对其它的对症治疗(即当症状发生时用于或试图用来限制或中止症状发作的治疗)例如抗炎(如皮质类固醇)或支气管扩张的需求来证明。哮喘的预防益处对于易发生“晨降”的患者特别明显。“晨降”是已经识别的哮喘综合征,常见于很大比例的哮喘患者,其特征在于例如上午约4-6点的时间内哮喘发作,即通常在基本远离任何预先施用的哮喘对症疗法的时间内发作。
上皮钠通道阻断剂作为治疗受益于粘膜水化的疾病的适用性可以通过在合适的基于细胞的测试法中测定通道阻断剂对ENaC的抑制效果来测试。例如,应用电生理学技术或离子流研究,内源性表达或改造以过表达ENaC的单细胞或融合的上皮细胞可以用于评估通道功能。参见Hirsh等人,J Pharm Exp Ther(2004)和Moody等人,Am J Physiol Cell Physiol(2005)中描述的方法。
包括式(I)化合物的上皮钠通道阻断剂还可用作与其它药物联合使用的共治疗剂,所述其它药物诸如抗炎药、支气管扩张药、抗感染药、氯化物-促分泌剂、选择性祛痰剂(alternative mucokinetic)、抗组胺剂或止咳药物,特别是用于治疗囊性纤维化、哮喘或阻塞性或炎症性气道疾病,诸如上面提到的那些,例如作为所述药物治疗活性的增效剂或作为减少所述药物的所需剂量或潜在副作用的手段。
上皮钠通道阻断剂可以与其它药物混合在固定的药物组合物中,或其可以在另一种药物之前、同时或之后单独施用。
因此,作为另一方面,本发明还包括上皮钠通道阻断剂与吸入渗透剂(例如,高渗的盐水、葡聚糖、甘露醇、木糖醇)的组合。此外,本发明包括与囊性纤维化跨膜传导调节蛋白(CFTR)功能的调节剂的组合。CFTR包括正常的或“野生型”CFTR并且还包括突变的CFTR(例如ΔF508CFTR、G551DCFTR)。CFTR功能的调节剂是指CFTR通道功能的增效剂,以及矫正在CFTR 3类突变观察到的错误折叠及传输缺陷的化合物,例如,在以下文献中描述的那些:WO 2007/021982、WO 2006/099256、WO2006/127588、WO 2004/080972、WO 2005/026137、WO 2005/035514、WO 2005/075435、WO 2004/111014、WO 2006/101740、WO 2004/110352、WO 2005/120497和US 2005/0176761。
此外,本发明包括与具有不同作用模式的合适的祛痰剂的组合,所述祛痰剂诸如嘌呤能P2-受体激动剂(例如INS 37217)、选择性(alternative)氯通道活化剂(例如Moli-1901[耐久霉素],SPI-8811)、基底外侧钾传导活化剂诸如HiK1(例如EBIO、DCEBIO)。
与合适的抗感染药诸如大环内酯抗生素(例如,妥布霉素、阿奇霉素)和抗炎药、支气管扩张剂、抗组胺剂、止咳剂、抗生素或脱氧核糖核酸酶(DNase)药物的组合,所述的上皮钠通道阻断剂和所述的药物在相同的或不同的药物组合物中。合适的脱氧核糖核酸酶药物包括阿法链道酶(PulmozymeTM),其为选择性裂解DNA的重组人类脱氧核糖核酸酶I(rhDNase)的高纯度溶液。阿法链道酶用于治疗囊性纤维化。
上皮钠通道阻断剂与抗炎药的其它有用的组合是与趋化因子受体拮抗剂联合的那些组合,趋化因子受体拮抗剂例如CCR-1、CCR-2、CCR-3、CCR-4、CCR-5、CCR-6、CCR-7、CCR-8、CCR-9和CCR10、CXCR1、CXCR2、CXCR3、CXCR4、CXCR5、特别是CCR-5拮抗剂,诸如先灵-葆雅公司(Schering-Plough)拮抗剂SC-351125、SCH-55700和SCH-D;日本武田公司(Takeda)拮抗剂,诸如N-[[4-[[[6,7-二氢-2-(4-甲基-苯基)-5H-苯并-环庚烯-8-基]羰基]氨基]苯基]-甲基]四氢-N,N-二甲基-2H-吡喃-4-铵氯化物(TAK-770);和在美国专利6,166,037(特别是权利要求18和19)、WO00/66558(特别是权利要求8)、WO 00/66559(特别是权利要求9)、WO04/018425和WO 04/026873中描述的CCR-5拮抗剂。
合适的抗炎药包括:甾类,特别是糖皮质激素,如布地奈德、丙酸倍氯米松、丙酸氟替卡松、环索奈德或糠酸莫米松;或描述于下列文献中的甾类:WO 02/88167、WO 02/12266、WO 02/100879、WO 02/00679(尤其是实施例3、11、14、17、19、26、34、37、39、51、60、67、72、73、90、99和101中的那些化合物)、WO 03/35668、WO 03/48181、WO03/62259、WO 03/64445、WO 03/72592、WO 04/39827和WO 04/66920;非甾类糖皮质激素受体激动剂,如下列文献所述的化合物:DE 10261874、WO 00/00531、WO 02/10143、WO 03/82280、WO 03/82787、WO 03/86294、WO 03/104195、WO 03/101932、WO 04/05229、WO 04/18429、WO 04/19935和WO 04/26248;LTD4拮抗剂,如孟鲁司特和扎鲁司特;PDE4抑制剂,如西洛司特(葛兰素史克公司(GlaxoSmithKline))、罗氟司特(BykGulden)、V-11294A(Napp)、BAY19-8004(拜尔公司(Bayer))、SCH-351591(先灵-葆雅公司(Schering-Plough))、阿罗茶碱(Almirall Prodesfarma)、PD189659/PD168787(Parke-Davis)、AWD-12-281(Asta Medica)、CDC-801(Celgene)、SelCID(TM)CC-10004(Celgene)、VM554/UM565(Vernalis)、T-440(Tanabe)、KW-4490(Kyowa Hakko Kogyo)和下列文献所述的那些化合物:WO 92/19594、WO 93/19749、WO 93/19750、WO93/19751、WO 98/18796、WO 99/16766、WO 01/13953、WO 03/104204、WO 03/104205、WO 03/39544、WO 04/000814、WO 04/000839、WO04/005258、WO 04/018450、WO 04/018451、WO 04/018457、WO 04/018465、WO 04/018431、WO 04/018449、WO 04/018450、WO 04/018451、WO 04/018457、WO 04/018465、WO 04/019944、WO 04/019945、WO04/045607和WO 04/037805;腺苷A2B受体拮抗剂,如WO 02/42298中所述的那些;和β-2肾上腺素受体激动剂,如沙丁胺醇(舒喘灵)、奥西那林、特布他林、沙美特罗、非诺特罗、丙卡特罗,并且尤其是福莫特罗、卡莫特罗,及其药学上可接受的盐,和WO 0075114中的式(I)化合物(游离形式或盐或溶剂化物形式),该文献引入本文作为参考,优选其实施例中的化合物,尤其是对应于茚达特罗(indacaterol)的下式的化合物及其药学可接受的盐:
和WO 04/16601中的式(I)化合物(游离形式或盐或溶剂合物形式),以及下列文献中的化合物:EP 1440966,JP 05025045,WO 93/18007,WO99/64035,USP 2002/0055651,WO 01/42193,WO 01/83462,WO 02/66422,WO 02/70490,WO 02/76933,WO 03/24439,WO 03/42160,WO 03/42164,WO 03/72539,WO 03/91204,WO 03/99764,WO 04/16578,WO 04/22547,WO 04/32921,WO 04/33412,WO 04/37768,WO 04/37773,WO 04/37807,WO 04/39762,WO 04/39766,WO 04/45618,WO 04/46083,WO 04/80964,WO 04/108765和WO 04/108676。
合适的支气管扩张药包括抗胆碱能药或抗毒蕈碱药,特别是异丙托溴铵、氧托溴铵、噻托溴铵盐和CHF 4226(凯西公司(Chiesi))和格隆溴铵,还有描述在下列文献中的化合物:EP 424021、USP 3,714,357、USP5,171,744、WO 01/04118、WO 02/00652、WO 02/51841、WO 02/53564、WO 03/00840、WO 03/33495、WO 03/53966、WO 03/87094、WO 04/018422和WO 04/05285。
合适的双重抗炎和支气管扩张药包括双重β-2肾上腺素受体激动剂/毒蕈碱拮抗剂,例如在USP 2004/0167167、WO 04/74246和WO 04/74812中公开的那些化合物。
合适的抗组胺药物包括盐酸西替利嗪、对乙酰氨基酚、富马酸氯马斯汀、异丙嗪、氯雷他定、地氯雷他定、苯海拉明和盐酸非索非那定、阿伐斯汀(activastine)、阿司咪唑、氮卓斯汀、依巴斯汀、依匹斯汀、咪唑斯汀和特芬那定(tefenadine),以及JP 2004107299、WO 03/099807和WO04/026841中公开的那些化合物。
根据前述,另一方面,本发明还提供了治疗对上皮钠通道的阻断有响应的病症的方法,所述病症例如是与通过上皮膜的流体体积的调节相关的疾病,特别是阻塞性气道疾病,所述方法包括向有其需要的个体、特别是人类个体施用游离形式或药学上可接受的盐形式的式(I)化合物。
另一个方面,本发明提供了游离形式或药学上可接受的盐形式的(I)化合物在制备治疗对上皮钠通道的阻断有响应的病症的药物中的用途,所述病症特别是阻塞性气道疾病,例如囊性纤维化和COPD。
可以通过任何适宜的途经施用本发明的物质,例如,以片剂或胶囊的形式口服给药;例如,通过例如静脉内,胃肠外给药;通过吸入给药,例如用于治疗阻塞性气道疾病;通过鼻内给药,例如用于治疗过敏性鼻炎;皮肤局部给药;或通过直肠给药。本发明另一方面还提供了药物组合物,其包含游离形式或药学上可接受的盐形式的式(I)化合物以及任选的药学上可接受的稀释剂或载体。该组合物可以包含共治疗剂,例如上文所述的抗炎药、支气管扩张药、抗组胺药或镇咳药。可以使用常规稀释剂或赋形剂以及盖伦制剂(galenic)领域中已知的技术制备这类组合物。因此,口服剂型可以包括片剂和胶囊剂。用于局部给药的制剂可以采用霜剂、软膏剂、凝胶剂或透皮递送系统如贴剂的形式。用于吸入的组合物可以包括气雾剂或其它可雾化的制剂或干粉制剂。
当组合物包括气雾剂制剂时,它优选包含例如氢-氟-烷(HFA)抛射剂,如HFA134a或HFA227或它们的混合物,并且可以包含一种或多种本领域内已知的共溶剂,如乙醇(最多达20重量%),和/或一种或多种表面活性剂,如油酸或三油酸山梨坦,和/或一种或多种填充剂,如乳糖。当组合物包括干粉制剂时,它优选包含例如粒径最多10微米的式(I)化合物以及任选的所需粒径分布的稀释剂或载体如乳糖,和帮助防止因湿度而使产品性能变质的化合物,例如硬脂酸镁。当组合物包括喷雾制剂时,它优选包含例如溶解于或悬浮于溶媒中的式(I)化合物,所述的溶媒包含水、共溶剂如乙醇或丙二醇和稳定剂,所述稳定剂可以是表面活性剂。
本发明的其它方面包括:
(a)可吸入形式的式(I)化合物,所述的可吸入形式例如是气雾剂或其它可雾化的组合物或可吸入微粒,例如微粉化的形式;
(b)包含可吸入形式的式(I)化合物的可吸入药物;
(c)包含可吸入形式的式(I)化合物与吸入装置的药物产品;和
(d)包含可吸入形式的式I化合物的吸入装置。
当然,用于实施本发明的式(I)化合物的剂量根据例如所治疗的特定病症、所需效果和给药方式不同而改变。一般而言,用于吸入给药的合适的日剂量为0.005-10mg,而用于口服给药的合适的日剂量为0.05-100mg。
药物用途和试验
式(I)化合物及其药学上可接受的盐(或者在下文称作“本发明的物质”)可用作药物。具体来说,这些化合物具有良好的ENaC阻断剂的活性,并且可以在下述试验中进行测试。
细胞培养
在气-液界面条件下培养人支气管上皮细胞(HBEC)(Cambrex公司)以提供分化良好的粘膜纤毛表型。
使用Gray和同事(Gray等,1996)所述方法的改进方法培养HBEC。将细胞接种在塑料的T-162培养瓶中,并在支气管上皮细胞生长培养基(BEGM;Cambrex)中培养,所述培养基添加了牛垂体提取物(52μg/ml)、氢化可的松(0.5μg/ml)、人重组表皮生长因子(0.5ng/ml)、肾上腺素(0.5μg/ml)、转铁蛋白(10μg/ml)、胰岛素(5μg/ml)、视黄酸(0.1μg/ml)、三碘甲状腺原氨酸(6.5μg/ml)、庆大霉素(50μg/ml)和两性霉素B(50ng/ml)。每48小时更换一次培养基,直到细胞达到90%汇合。然后将细胞传代并接种(8.25×104个细胞/插入物)在分化培养基中的聚碳酸酯Snapwell插入物(Costar公司)上,所述的分化培养基包含50%的溶在BEGM中的DMEM和如上所述的相同添加物,但不含三碘甲状腺原氨酸,并且视黄酸最终浓度为50nM(全反式视黄酸)。将细胞最初7天在培养基中浸没培养,此后在剩余的培养期中使其暴露于顶层气体界面。此时,将培养基换成用于剩余培养期的包含2%(v/v)Ultroser G的DMEM:F12培养基。在用于尤斯灌流室(Ussing chamber)之前,从所有培养基的3种接种物中除去两性霉素B。在建立顶层气体界面后第7-21天内使用细胞。在所有培养阶段,将细胞维持在37℃、5%CO2的空气培养箱内。
短路电流(ISC)测定
将Snapwell插入物固定在立式扩散室(Costar公司)中,并浸泡在维持于37℃下的持续通气的林格溶液(5%CO2,在O2中;pH 7.4)中,所述林格溶液包含(以mM计):120NaCl、25NaHCO3、3.3KH2PO4、0.8K2HPO4、1.2CaCl2、1.2MgCl2和10葡萄糖。所有使用的生理盐溶液的溶液渗透度在280到300mOsmol/kg H2O之间。将细胞电压钳调到0mV(EVC4000型;WPI)。通过以30秒的间隔施加1-或2-mV脉冲并通过欧姆定律计算RT来测定RT。使用PowerLab工作站(AD Instruments公司)记录数据。
将测试化合物制备为在DMSO中的10mM储备液(95%)。用合适的溶媒(蒸馏水或林格溶液)新鲜制备3-倍的系列稀释液。将在5μL中的1000×浓缩液加入到顶室中作为初始浓度,得到尤斯灌流室的5ml体积的最终1×浓度。随后以3.3μL体积的1000×的系列稀释储备液加入化合物。在完成浓度-响应实验时,将阿米洛利(10μM)加入到顶室中以便能够测定总的阿米洛利-敏感电流。在每次实验开始时建立阿米洛利对照的IC50。
将结果表示为抑制阿米洛利-敏感ISC的平均百分比(%)。绘制浓度-响应曲线并且使用GraphPad Prism 3.02得到IC50值。通常按两份重复来使用细胞插入物和根据平均抑制%的数据计算IC50。
本文以下实施例中的化合物在用上述描述的数据测试中通常具有低于10μM的IC50值。例如,实施例2、4、7、13和23化合物分别具有0.0015、0.010、0.006、0.001和0.0016μM的IC50值。
通过以下实施例举例说明本发明。
实施例
还为式(X)化合物的式(I)化合物:
显示在下表1中,其制备方法描述在下文中。
表1
一般条件
使用电喷雾离子化在开放存取(open access)的Waters 600/ZQ HPLC/质谱仪系统上采集质谱。[M+H]+和[M+2H]2+是指单同位素分子量。
DCM 二氯甲烷
DIPEA 二异丙基乙胺
DMF 二甲基甲酰胺
DMSO 二甲基亚砜
EtOAc 乙酸乙酯
EtOH 乙醇
HATU 二甲基氨基-([1,2,3]三唑并[4,5-b]吡啶-3-基氧基)-亚甲基]-
二甲基-铵;六氟磷酸盐
IPA 异丙醇
MeCN 乙腈
MeOH 甲醇
NMP N-甲基吡咯烷酮
TEA 三乙胺
TFA 三氟乙酸
THF 四氢呋喃
在提及化合物的盐形式时,省略了平衡离子的化学计量。本领域技术人员将能理解所述化合物不限于单盐形式,并且其可作为二盐、三盐或其它的化合物:平衡离子化学计量。
实施例1 N,N′-(1,1′-(1,4-亚苯基双(亚甲基))双(氮烷二基)双(氧代亚甲基)双(哌啶-4,1-二基))双(氮烷二基)双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺)氢溴酸盐
步骤1 (1,1′-(1,4-亚苯基双(亚甲基))双(氮烷二基)双(氧代亚甲基)双(哌啶-4,1-二基))双(氮烷二基)双((3,5-二氨基-6-氯吡嗪-2-甲酰氨基)甲-1-基-1-亚基)二氨基甲酸苄基酯
在惰性的氮气气氛下,向(4-羧基甲基-苯基)-乙酸(0.5g,2.57mmol)的干燥DCM(10mL)悬浮液中加入TEA(0.7mL,5.14mmol),随后加入二苯基磷酰基叠氮化物(1.1mL,5.14mmol)。搅拌回流2小时后,将混合物用(3,5-二氨基-6-氯吡嗪-2-甲酰氨基)(哌啶-4-基氨基)亚甲基氨基甲酸苄基酯(中间体C)(1.72g,3.9mmol)和TEA(0.7mL,5.14mmol)的DCM/DMF(10mL)溶液处理。将得到的混合物在38℃加热过夜,并随后冷却至室温。在真空中除去溶剂,用硅胶柱色谱纯化粗产物(用9∶1DCM/MeOH洗脱),得到标题化合物。
步骤2 N,N′-(1,1′-(1,4-亚苯基双(亚甲基))双(氮烷二基)双(氧代亚甲基)双(哌啶-4,1-二基))双(氮烷二基)双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺)氢溴酸盐
在45℃加热(1,1′-(1,4-亚苯基双(亚甲基))双(氮烷二基)双(氧代亚甲基)双(哌啶-4,1-二基))双(氮烷二基)双((3,5-二氨基-6-氯吡嗪-2-甲酰氨基)甲-1-基-1-亚基)二氨基甲酸苄基酯(步骤1)(0.2g,0.18mmol)在33%HBr的乙酸溶液(5ml)中的悬浮液,加热5小时。冷至室温后,在真空中除去溶剂,用水(约20mL)缓慢处理粗产物,直至固体沉淀。过滤收集固体并用水、甲醇和乙醚洗涤,得到标题所述化合物。[M+H]+813
实施例2 N,N′-(1,1′-(1,4-亚苯基双(氮烷二基))双(氧代亚甲基)双(哌啶-4,1-二基))双(氮烷二基)双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺)氢溴酸盐
该化合物用与实施例1相似的方法通过采用1,4-亚苯基二异氰酸酯代替1,4-双-异氰酸基(isocyanato)甲基-苯(原位制备)进行制备。[M+H]+785
实施例3 N,N′-(1,1′-(环己烷-1,3-二基双(亚甲基))双(氮烷二基)双(氧代亚甲基)双(哌啶-4,1-二基))双(氮烷二基)双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺)三氟乙酸盐
该化合物用与实施例1相似的方法、采用1,3-双-异氰酸基甲基-环己基代替1,4-双-异氰酸基甲基-苯(原位制备)进行制备。[M+H]+819
实施例4 N,N′-(1,1′-(1,4-亚苯基)双(氧代亚甲基)双(哌啶-4,1-二基))双(氮烷二基)双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺)盐酸盐
步骤1:(1,1′-(1,4-亚苯基)双(氧代亚甲基)双(哌啶-4,1-二基))双(氮烷二基)双((3,5-二氨基-6-氯吡嗪-2-甲酰氨基)甲-1-基-1-亚基)二氨基甲酸叔丁基酯
用TEA(8.5ml)处理搅拌的[4-(4-氨基-哌啶-1-羰基)-苯基]-(4-氨基-哌啶-1-基)-甲酮二盐酸盐(中间体D)(1.1g,3.32mmol)在DMF(27.5ml)中的悬浮液,然后在室温下搅拌。加入中间体A(2.5g,6.99mmol),并将所得混合物在60℃加热2天。然后在真空条件下趁热过滤反应混合物,并在真空下干燥所得固体,得到为白色固体的产物。[M+H]+955
步骤2:将步骤1的产物悬浮在4.0HCl的1,4-二氧六环溶液(2.15mL,8.6mmol)和1,4二氧六环(1mL)中。在室温下反应2天。真空除去溶剂,将固体冷冻干燥,得到标题化合物。[M+H]+755
实施例5 N,N′-(1,1′-(6-氯-1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺)
将3,5-二氨基-6-氯-N-(N-哌啶-4-基甲脒基)吡嗪-2-甲酰胺盐酸盐(中间体E)(8.0g,20.7mmol)和干燥的DIPEA(25mL)的DMF(80mL)溶液冷却至0℃,并用三氯三嗪(1.9g,10.4mmol)的DMF(20mL)溶液处理。在0℃搅拌1小时后,使反应混合物升温至室温过夜。历经1小时、在剧烈搅拌下,用滴加加入的MeCN(500mL)处理混合物。通过真空过滤收集得到的微细的悬浮物,用MeCN(2x250mL)洗涤。然后将固体在0℃、MeCN中超声处理,过滤并在真空下干燥,得到标题化合物。[M+H]+739
实施例6 N,N′-(1,1′-羰基双(哌啶-4,1-二基)双(氮烷二基))双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺)盐酸盐
步骤1:(1,1′-羰基双(哌啶-4,1-二基)双(氮烷二基))双((3,5-二氨基-6-氯吡嗪-2-甲酰氨基)甲-1-基-1-亚基)二氨基甲酸叔丁基酯盐酸盐
将双(4-氨基哌啶-1-基)甲酮(中间体F)(43mg,0.11mmol)和中间体A(90mg,0.25mmol)的DMF(1.5mL)悬浮液用TEA(100mg,1.0mmol)处理,并在70℃加热48小时。用反相柱色谱(IsoluteTM C18,0-100%乙腈水溶液-0.1%HCl)纯化反应混合物,得到在30ml的洗脱剂(乙腈水溶液-0.1%HCl)中的标题化合物。[M+H]+850
步骤2:N,N′-(1,1′-羰基双(哌啶-4,1-二基)双(氮烷二基))双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺)盐酸盐
用TFA(4mL)处理在30ml洗脱剂(乙腈水溶液-0.1%HCl)中的(1,1′-羰基双(哌啶-4,1-二基)双(氮烷二基))双((3,5-二氨基-6-氯吡嗪-2-甲酰氨基)甲-1-基-1-亚基)二氨基甲酸叔丁基酯盐酸盐(0.25mmol),并且在室温下将混合物搅拌3天,真空中除去溶剂,通过反相柱色谱(IsoluteTM C18,0-100%乙腈水溶液-0.1%HCl)纯化,得到标题化合物。[M+H]+651
实施例7 N,N′-(1,1′-(1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺)盐酸盐
该化合物用与实施例6相似的方法、采用1,1′-(1,3,5-三嗪-2,4-二基)二哌啶-4-胺.4HCl代替双(4-氨基哌啶-1-基)甲酮.4HCl(中间体F)进行制备。[M+H]+701
实施例8 N,N′-(1,1′-(6-(4-苯基哌嗪-1-基)-1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺)乙酸盐
用N-苯基哌嗪(0.275g,1.70mmol)处理N,N′-(1,1′-(6-氯-1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺)(实施例5)(0.25g,0.34mmol)的DMF(2mL)溶液,在30℃搅拌过夜。将MeCN(3mL)滴加加入至搅拌的混合物中,过滤收集得到的黄色沉淀物。将沉淀物溶于MeOH,并干法上载至硅胶上。在硅胶上用快速色谱法纯化(采用1:MeOH/DCM-4%NH3洗脱),得到固体,将其从乙酸/EtOH中重结晶进一步纯化,得到标题化合物。[M+2H]2+432
实施例9 N,N′-(1,1′-(6-吗啉代-1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺)
该化合物用与实施例8相似的方法、采用吗啉代替N-苯基哌嗪进行制备。[M+H]+787
实施例10 N,N′-(1,1′-(6-(3-吗啉代丙基氨基)-1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺)三氟乙酸盐
用3-(N-吗啉代)丙胺(29mg,0.2mmol)处理N,N′-(1,1′-(6-氯-1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺)(实施例5)(0.15mg,20μmol)的NMP(0.5mL)溶液,并随后在50℃搅拌过夜。通过基于质量的(mass directed)半制备HPLC纯化,得到标题化合物。[M+H]+846
实施例11-12
这些化合物即,
·N,N′-(1,1′-(6-(2-(双(2-羟基乙基)氨基)乙基氨基)-1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺)三氟乙酸盐(实施例11);
·N,N′-(1,1′-(6-(4-(氮杂环庚烷-1-羰基)哌啶-1-基)-1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺)三氟乙酸盐(实施例12);
·N,N′-(1,1′-(6-(3-(二丁基氨基)丙基氨基)-1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺)三氟乙酸盐(实施例13);
·N,N′-(1,1′-(6-(2-(吡啶-4-基)乙基氨基)-1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺)三氟乙酸盐(实施例14);
·N,N′-(1,1′-(6-(己基氨基)-1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺)三氟乙酸盐(实施例15);
·1-(4,6-双(4-(3-(3,5-二氨基-6-氯吡嗪-2-羰基)胍基)哌啶-1-基)-1,3,5-三嗪-2-基)哌啶-4-甲酸三氟乙酸盐(实施例16);
·N,N′-(1,1′-(6-(4-甲基哌嗪-1-基)-1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺)三氟乙酸盐(实施例17);
·N,N′-(1,1′-(6-(二丙基氨基)-1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺)三氟乙酸盐(实施例18);
·N,N′-(1,1′-(6-(环己基氨基)-1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺)三氟乙酸盐(实施例19);
·N,N′-(1,1′-(6-(氮杂环庚烷-1-基)-1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺)三氟乙酸盐(实施例20);
·N,N′-(1,1′-(6-(环己基氨基)-1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺))三氟乙酸盐(实施例21);和
·N,N′-(1,1′-(6-(环辛基氨基)-1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺)(实施例22),
以上化合物用与实施例10相似的方法、采用合适的胺代替3-(N-吗啉代)丙胺制备。
实施例23 N,N′-(1,1′-(丁烷-1,4-二基双(氮烷二基))双(氧代亚甲基)双(哌啶-4,1-二基))双(氮烷二基)双(氨基甲-1-基-1-亚基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺)氢溴酸盐
步骤1:N,N′-(1,1′-(丁烷-1,4-二基双(氮烷二基))双(氧代亚甲基)双(哌啶-4,1-二基))双(氮烷二基)双((苄基氧基羰基氨基)甲-1-基-1-亚基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺)
将包含在DMF(420mL)中的(3,5-二氨基-6-氯吡嗪-2-甲酰氨基)(甲硫基)亚甲基氨基甲酸苄基酯(中间体B)(18.6g,45.0mmol)和N,N′-(丁烷-1,4-二基)双(4-氨基哌啶-1-甲酰胺)(中间体F)(6.3g,15.4mmol)的混合物在氮气惰性气氛下在50℃搅拌三天。趁热过滤反应混合物,加入氨甲基聚苯乙烯(清除树脂),在50℃将混合物搅拌过夜。过滤除去树脂,用DMF洗涤,然后在真空中浓缩滤液,得到固体残留物,将其在最小量的DMF中再溶解,并在室温下逐滴加入到搅拌的MeCN溶液中,得到固体。过滤所述固体,用MeCN洗涤,得到为固体的标题化合物。[M+H]+1033
步骤2:N,N′-(1,1′-(丁烷-1,4-二基双(氮烷二基))双(氧代亚甲基)双(哌啶-4,1-二基))双(氮烷二基)双(氨基甲-1-基-1-亚基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺)氢溴酸盐
将N,N′-(1,1′-(丁烷-1,4-二基双(氮烷二基))双(氧代亚甲基)双(哌啶-4,1-二基))双(氮烷二基)双((苄基氧基羰基氨基)甲-1-基-1-亚基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺)(646mg)和33%HBr的乙酸溶液(6mL)的水(1.5mL)溶液在50℃下搅拌过夜。在真空中除去溶剂,通过从MeOH/IPA中重结晶,纯化得到的粗残余物。通过用MeOH/EtOH、随后用MeOH/IPA研磨将残余物进一步纯化,得到标题化合物。[M+H]+765
实施例24 N,N′-(1,1′-(6-(苯基氨基)-1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺)三氟乙酸盐
将3,5-二氨基-6-氯-N-(N-哌啶-4-基甲脒基)吡嗪-2-甲酰胺盐酸盐(中间体E)(200mg,0.52mmol)、(4,6-二氯-[1,3,5]三嗪-2-基)-苯基-胺(60mg,0.25mmol)和DIPEA(205mg,1.6mmol)的NMP(4mL)溶液在35℃搅拌过夜。然后将反应混合物滴加加入到MeCN中,并通过过滤收集得到的白色固体。将固体溶于1∶1 MeCN∶水(0.1%TFA)(60mL)中,冷却并放置4天。过滤得到的悬浮液,得到为固体的标题化合物。
实施例25 N,N′-(1,1′-(6-(5,6-二乙基-2,3-二氢-1H-茚-2-基氨基)-1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(氨基甲-1-基-1-亚基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺)
在一个0.5-2.0ml的Biotage微波小瓶中,将N,N′-(1,1′-(6-氯-1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺)(实施例5)(250mg,0.34mmol)和5,6-二乙基茚满-2-基胺盐酸盐(225mg,1.00mmol;参见Prashad等人,Org Process ResDev,第10卷,第1期,第135-141页(2006))悬浮于含有DIPEA(350μl,260mg,2.00mmol)的DMF(1ml)中。密封小瓶,并用微波辐射在60℃将反应加热24小时,随后在70℃加热22.5小时。将反应混合物加入乙腈(50ml)中进行沉淀,得到标题化合物和N,N′-(1,1′-(6-(二甲基氨基)-1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(氨基甲-1-基-1-亚基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺)的混合物,为灰色固体。用基于质量的制备HPLC纯化,接着用乙醚研磨,得到标题化合物,其为浅黄色粉末。[M+H]+890
实施例26 N,N′-(1,1′-(6-(二甲基氨基)-1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(氨基甲-1-基-1-亚基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺)
该化合物作为实施例25的合成的副产物制备。[M+H]+745
实施例27-29
即:
·N,N′-(1,1′-(6-(2,3-二氢-1H-茚-2-基氨基)-1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(氨基甲-1-基-1-亚基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺)(实施例27);
·N,N′-(1,1′-(6-(2,2-二苯基乙基氨基)-1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(氨基甲-1-基-1-亚基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺)(实施例28);和
·N,N′-(1,1′-(6-(环十二烷基氨基)-1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(氨基甲-1-基-1-亚基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺)(实施例29),
这些化合物用类似于实施例25的方法从N,N′-(1,1′-(6-氯-1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺)(实施例5)起始、并用合适的胺代替5,6-二乙基茚满-2-基胺盐酸盐进行制备。
实施例30 (1,1′-(Z)-丁-2-烯-1,4-二基双(氮烷二基)双(氧代亚甲基)双(哌啶-4,1-二基))双(氮烷二基)双((3,5-二氨基-6-氯吡嗪-2-甲酰氨基)甲-1-基-1-亚基)二氨基甲酸苄基酯
将((Z)-4-苯氧基羰基氨基-丁-2-烯基)-氨基甲酸苯基酯(中间体J)(325mg,1.0mmol)、(3,5-二氨基-6-氯吡嗪-2-甲酰氨基)(哌啶-4-基氨基)亚甲基氨基甲酸苄基酯(中间体C)(1.25g,2.2mmol)和TEA(0.6mL,4.4mmol)的DMF(4ml)溶液在60℃加热过夜。用水处理混合物,并在室温下放置10分钟。将IPA(20ml)加入得到的固体中,过滤混合物,得到为固体的标题化合物。[M+H]+1031
中间体的制备
中间体A(3,5-二氨基-6-氯吡嗪-2-甲酰氨基)(甲硫基)亚甲基氨基甲酸叔丁基酯
步骤1:3,5-二氨基-6-氯-吡嗪-2-甲酸锂
将5-10℃(冰浴)的搅拌的3,5-二氨基-6-氯-吡嗪-2-甲酸甲酯(110g,542.9mmol)的MeOH(500mL)悬浮液通过滴加加入氢氧化锂(46.6g,1111mmol)的水(500mL)悬浮液进行处理。将反应混合物加热至50℃反应5小时,然后冷至室温,并搅拌过夜。过滤收集得到的沉淀物,在真空烘箱中干燥,得到为锂盐(二水合物)的标题化合物。[M-Li]-187
步骤2:氨基(甲硫基)亚甲基氨基甲酸叔丁基酯
在室温下用4M NaOH(15mL)处理搅拌的S-甲基-异-硫脲硫酸盐(10g,35.9mmol)的甲苯(75mL)悬浮液。向该两相混合物中一次性加入二碳酸二叔丁基酯(3.27g,15mmol)。将反应混合物在室温下搅拌1小时,然后加热至60℃过夜。分离有机部分,用盐水洗涤,然后用Na2SO4干燥,过滤并在真空中浓缩至成为粘稠油状物,该油状物在高真空下结晶,得到标题化合物,为无色固体。
步骤3:(3,5-二氨基-6-氯吡嗪-2-甲酰氨基)(甲硫基)亚甲基氨基甲酸叔丁基酯
在氮气惰性气氛下,用HATU(41g,107.83mmol)分次处理搅拌着的3,5-二氨基-6-氯-吡嗪-2-甲酸锂(22.6g,98.03mmol)的DMF(400mL)悬浮液。将反应混合物在室温下搅拌2小时,然后在10分钟内分批加入氨基(甲硫基)亚甲基氨基甲酸叔丁基酯(20.5g,107.83mmol)。将反应混合物室温下再搅拌1.5小时,然后加热至50℃并搅拌过夜。热过滤得到的沉淀,用水洗涤,并在真空烘箱(40℃)中干燥过夜,得到标题化合物。[M+H]+361
中间体B(3,5-二氨基-6-氯吡嗪-2-甲酰氨基)(甲硫基)亚甲基氨基甲酸苄基酯
向搅拌的1-(3,5-二氨基-6-氯-吡嗪-2-羰基)-2-甲基-异硫脲氢碘酸盐(中间体I)(50g,0.129mol)的干燥THF(1L)溶液中加入TEA(18mL,0.129mol),接着加入N-(苄氧基羰基氧基)-琥珀酰亚胺(32.1g,0.129mol)。然后将反应混合物加热回流(66℃)6小时。将反应物冷却至室温,然后在真空中浓缩至成为黄色固体。将粗产物悬浮于EtOAc(500mL)和水(500mL)中,并剧烈研磨30分钟。将得到的悬浮液过滤,在真空烘箱(40℃)中经P2O5干燥,得到为浅黄色固体的产物。[M+H]+395
中间体C(3,5-二氨基-6-氯吡嗪-2-甲酰氨基)(哌啶-4-基氨基)亚甲基氨基甲酸苄基酯
步骤1:4-(2-(苄基氧基羰基)-3-(3,5-二氨基-6-氯吡嗪-2-羰基)胍基)哌啶-1-甲酸叔丁基酯
将(3,5-二氨基-6-氯吡嗪-2-甲酰氨基)(甲硫基)亚甲基氨基甲酸苄基酯(中间体B)(6.7g,17mmol)和4-氨基-1-Boc-哌啶(4.1g,20.4mmol)的干燥THF(150mL)悬浮液加热回流过夜。在真空中除去溶剂,浓缩后形成固体。分离该固体并保留,将剩余的母液浓缩至形成固体。将该固体在EtOAc和水之间分配,干燥(MgSO4)有机部分,并在真空中部分浓缩,然后使其结晶。过滤晶体并与保留的固体合并,得到标题产物。[M+H]+547
步骤2:(3,5-二氨基-6-氯吡嗪-2-甲酰氨基)(哌啶-4-基氨基)亚甲基氨基甲酸苄基酯
用4M HCl的二氧六环溶液(40mL)处理4-(2-(苄基氧基羰基)-3-(3,5-二氨基-6-氯吡嗪-2-羰基)胍基)哌啶-1-甲酸叔丁基酯(步骤1)(6.3g,11.5mmol)的二氧六环(250mL)和MeOH(小体积)悬浮液,并在40℃搅拌过夜。过滤得到的悬浮液,并将得到的固体在水(800mL)和EtOAc(800mL)之间分配。加入1M NaOH调节pH至pH 8并分离有机部分,干燥(MgSO4)并在真空中浓缩,得到标题化合物。[M+H]+447
中间体D[4-(4-氨基-哌啶-1-羰基)-苯基]-(4-氨基-哌啶-1-基)-甲酮
步骤1:
在惰性的氮气气氛下,将对苯二甲酰氯(50.7g,0.249mol)的DMF(200mL)溶液缓慢加入到4-(N-Boc-氨基)哌啶(100g,0.499mol)和三乙胺(104mL,0.749mol)的DMF(800mL)混合物中。将反应混合物在室温下搅拌过夜。形成白色悬浮液,并且用饱和NaHCO3溶液(500mL)和水(500mL)缓慢地将得到的混合物淬灭。将得到的悬浮液搅拌30分钟,并在真空下过滤,得到白色固体。在45℃、真空下干燥该固体,得到所需的产物。[M+H]+531
步骤2:[4-(4-氨基-哌啶-1-羰基)-苯基]-(4-氨基-哌啶-1-基)-甲酮二盐酸盐
用4M HCl的二氧六环溶液(236mL)处理含有在1,4-二氧六环(236ml)中的步骤1的产物(50g,0.09mol)的混合物。将得到的悬浮液在室温下搅拌过夜。在真空下过滤得到的悬浮液并用乙醚(3x200ml)洗涤,得到所需要的产物。将回收的固体在真空下干燥两天,得到标题化合物。[M+H]+331
或者,步骤2可以在室温下、在TMSI存在下、在DCM中完成,得到[4-(4-氨基-哌啶-1-羰基)-苯基]-(4-氨基-哌啶-1-基)-甲酮。
中间体D-备选的合成路线
[4-(4-氨基-哌啶-1-羰基)-苯基]-(4-氨基-哌啶-1-基)-甲酮
步骤1:
在氩气惰性气氛下,将对苯二甲酰氯(1.02g,5.0mmol)的DMF(10mL)溶液通过滴加4-(N-Boc-氨基)哌啶(2.00g,10.0mmol)溶液处理20分钟。将反应混合物在室温下搅拌40分钟,然后滴加加入TEA(2.09mL,15.0mmol)。形成白色的悬浮液,并继续搅拌2小时。用饱和NaHCO3溶液(50mL)和水(100mL)洗涤得到的混合物。使用相分离纸在真空下过滤得到的混合物,得到白色固体。在真空、45℃下干燥该固体,得到所需的产物。[M+H]+531
步骤2:[4-(4-氨基-哌啶-1-羰基)-苯基]-(4-氨基-哌啶-1-基)-甲酮二氢溴酸盐
室温下将包含在33%的HBr的乙酸溶液(13.4mL,25.3mmol)中的步骤1的产物(1.34g,2.53mmol)的混合物搅拌过夜。用DCM(10-20mL)稀释得到的悬浮液并在真空下过滤。将回收的固体在真空下干燥2天,得到标题化合物。[MH+331.16]
或者,步骤2可以在4M HCl的二氧六环溶液存在下进行,以得到[4-(4-氨基-哌啶-1-羰基)-苯基]-(4-氨基-哌啶-1-基)-甲酮二盐酸盐。
中间体E 3,5-二氨基-6-氯-N-(N-哌啶-4-基甲脒基)吡嗪-2-甲酰胺盐酸盐
将1-(3,5-二氨基-6-氯-吡嗪-2-羰基)-2-甲基-异硫脲氢碘酸盐(7.2g,18.4mmol)和4-氨基-1-Boc-哌啶(5.5g,27.5mmol)的DMF(40mL)溶液搅拌并在50℃加热4小时。用水(150mL)稀释混合物并超声处理2小时。通过过滤收集得到的悬浮物,并悬浮在4M HCl的二氧六环溶液(40mL)中。加入MeOH(20mL),在室温下将混合物搅拌过夜并过滤。用EtOH(2x10mL)洗涤固体,并干燥,得到标题化合物。[M+H]+313
中间体F 双(4-氨基哌啶-1-基)甲酮盐酸盐
步骤1:1,1′-羰基双(哌啶-4,1-二基)二氨基甲酸叔丁基酯
通过滴加三光气(0.503g,1.7mmol)的DCM(8mL)溶液,处理冷的(0℃)、搅拌的4-N-Boc-氨基-哌啶(2.0g,10.2mmol)的DCM(8mL)溶液。使混合物升温至室温,然后继续搅拌2小时,然后在DCM和1M NaOH之间分配混合物。分离有机部分,用1M HCl、水、饱和NaHCO3洗涤,干燥,并在真空中浓缩,得到标题化合物。MH+427
步骤2:双(4-氨基哌啶-1-基)甲酮
在室温下,将1,1′-羰基双(哌啶-4,1-二基)二氨基甲酸叔丁基酯(1.0g,2.3mmol)在4M HCl的二氧六环溶液(3mL)及MeOH(5mL)中的溶液搅拌过夜。真空中除去溶剂,得到标题化合物,为白色固体。[M+H]+227
中间体G 1,1′-(1,3,5-三嗪-2,4-二基)二哌啶-4-胺盐酸盐
该化合物通过用2,4-二氯-1,3,5-三嗪代替三光气、采用与制备中间体F相似的方法制备。步骤1在THF中进行。
中间体H N,N′-(丁烷-1,4-二基)双(4-氨基哌啶-1-甲酰胺)
步骤1:1,1′-(丁烷-1,4-二基双(氮烷二基))双(氧代亚甲基)双(哌啶-4,1-二基)二氨基甲酸叔丁基酯
用1,4-二异氰酸基丁烷(317μL,2.49mmol)处理4-N-Boc-氨基哌啶(1.0g,4.99mmol)和干燥的DCM(20mL)的溶液,并在室温下搅拌过夜。将得到的悬浮液过滤并用DCM洗涤,得到标题化合物。[M+H]+541
步骤2:N,N′-(丁烷-1,4-二基)双(4-氨基哌啶-1-甲酰胺)
将1,1′-(丁烷-1,4-二基双(氮烷二基))双(氧代亚甲基)双(哌啶-4,1-二基)二氨基甲酸叔丁基酯(1.26g,2.33mmol)的MeOH(10mL)悬浮液用TFA(25mL)处理,随后用水(催化量)处理,将得到的溶液在室温下搅拌5天。在真空中除去DCM、MeOH和TFA,将残留物用小体积的水稀释并通过加入4M NaOH中和。使混合物在凉的环境(冰箱)中结晶过夜,过滤得到的晶体并在真空中干燥,得到标题化合物。[M+H]+341
中间体I 1-(3,5-二氨基-6-氯-吡嗪-2-羰基)-2-甲基-异硫脲
通过滴加溶于DCM(5mL)的TFA(0.412mL,5.543mmol),处理搅拌着的(3,5-二氨基-6-氯吡嗪-2-甲酰氨基)(甲硫基)亚甲基氨基甲酸叔丁基酯(中间体A)(200mg,0.554mmol)的DCM(10mL)悬浮液,得到黄色溶液。将反应混合物在室温下搅拌4小时,在真空中除去溶剂,得到含有少量固体的黄色油状物。将油状物溶于水并通过过滤除去不溶的固体。将含水的滤液用NaHCO3碱化至pH 9,通过过滤收集得到的沉淀,并在真空烘箱(40℃)中干燥过夜,得到标题化合物。[M+H]+261
中间体J((Z)-4-苯氧基羰基氨基-丁-2-烯基)-氨基甲酸苯基酯
通过滴加吡啶(1.9g,24mmol)的DCM(10ml)溶液,处理搅拌的氯甲酸苯基酯(3.4g,22mmol)的DCM(70ml)溶液。历时15分钟,向该混合物中滴加加入(Z)-丁-2-烯-1,4-二胺(根据Fabiano等人,Synthesis,(2),190(2);1987的方法制备)的DCM(20ml)溶液。将得到的混合物在室温下搅拌4小时并在DCM和水之间分配。分离有机部分并用水、0.5M HCl(2x)、NaHCO3(水溶液)(2x)洗涤,干燥(MgSO4)并在真空中浓缩。将粗产物用硅胶色谱法(采用0-1% MeOH的DCM溶液洗脱)纯化,得到标题化合物;[M+H]+327。
Claims (12)
1.式(I)化合物或者其互变异构体或立体异构体或溶剂化物或药学上可接受的盐:
其中,
M1和M2独立地是
R1、R2、R3和R4独立地选自H、C1-C8-烷基、C1-C8-烷基-羧基、C1-C8-卤代烷基、C3-C15碳环基团、C1-C8-烷基羰基、C1-C8-烷氧基羰基、C6-C15-元芳香族碳环基团、4-至14-元杂环基团、被4-至14-元杂环基团取代的C1-C8-烷基和被C6-C15-元芳香族碳环基团取代的C1-C8-烷基,或
R1和R2与它们所连接的氮原子形成任选地被R14取代的C3-C14-元杂环基团,或
R3和R4与它们所连接的氮原子形成任选地被R14取代的C3-C14-元杂环基团;
R6、R5和R5a独立地选自H、C1-C8-烷基、C1-C8-烷基-羧基、C1-C8-烷基-烷氧基、C1-C8-卤代烷基、C3-C15-碳环基团、C1-C8-烷基羰基、C1-C8-烷氧基羰基、硝基、氰基、C6-C15-元芳香族碳环基团、4-至14-元杂环基团、被4-至14-元杂环基团取代的C1-C8-烷基和被C6-C15-元芳香族碳环基团取代的C1-C8-烷基;
W1和W2独立地选自C0-C8-亚烷基;
X1和X2独立地选自4-至14-元杂环基团;
Y1和Y2独立地是-C0-C8-亚烷基-或C1-C8-烷基氨基;
A选自C6-C15-元芳香族碳环基团、-CONR11a-(C1-C8-亚烷基)-NR11aCO-、-CO-(C1-C8-亚烷基)-CO-、-CO-(C1-C8-亚烯基)-CO-、-(C=O)、-CO-(C0-C8-亚烷基)-Z-(C0-C8-亚烷基)-CO-、-CO NR11a-(C0-C8-亚烷基)-Z-(C0-C8-亚烷基)-NR11aCO-、C3-C15-碳环基团和4-至14-元杂环基团;
Z选自C6-C15-元芳香族碳环基团、C3-C15-碳环基团和4-至14-元杂环基团;
T选自H、卤素、C1-C8-烷基、C1-C8-卤代烷基、C1-C8-卤代烷氧基、C3-C15-碳环基团、硝基、氰基、C6-C15-元芳香族碳环基团和被C6-C15-元芳香族碳环基团取代的C1-C8-烷基;
其中,除非文中另外说明,每个C6-C15-元芳香族碳环基团和每个4-至14-元杂环基团或5-至14-元杂环基团独立地任选地被一个或多个基团取代,所述基团选自OH、C1-C8-烷氧基、C1-C8-烷基、卤素、SO2NR11R12、任选地被羟基取代的羟基C1-C8-烷氧基、(C0-C4-亚烷基)CONR11R12、(C0-C4-亚烷基)-N=C(NR11R12)2、-O-(C1-C4-亚烷基)-N=C(NR11R12)2、-O-(C1-C4-亚烷基)-CONR11R12、C7-C10-芳烷氧基、C7-C10-芳烷基、SH、S(C1-C8-亚烷基)、SO2(C1-C8-亚烷基)、SO(C1-C8-亚烷基)、NR11R12、其中碳环基团任选地被卤素或C1-C8-烷基取代的NR11(C3-C12-碳环基团)、R15、被R15取代的C1-C8-烷基、R16、被R16取代的C1-C8-烷基、O(C1-C8-亚烷基)-NR11-(C=O)O-(C0-C4-亚烷基)-R15、氰基、氧代、羧基、硝基、C1-C8-烷基羰基、羟基-C1-C8-烷基、C1-C8-卤代烷基、氨基-C1-C8-烷基、氨基(羟基)C1-C8-烷基和任选地被氨基羰基取代的C1-C8-烷氧基,其中R15是任选地被OH、C1-C8-烷氧基、C1-C8-烷基、卤素和C1-C8-卤代烷基取代的C6-C15-元芳香族碳环基团,R16是任选地被OH、C1-C8-烷氧基、C1-C8-烷基、C6-C15-元芳香族碳环基团、CO2H、(C=O)-3至14-元杂环基团、卤素和C1-C8-卤代烷基取代的4-至14-元杂环基团,并且
其中,除非另有说明,每个亚烷基基团任选地被以下基团取代:C1-C8-烷基、卤素、C1-C8-烷氧基、羧基、C1-C8-烷基-羧基、C1-C8-卤代烷基、C1-C8-卤代烷氧基、C3-C15-碳环基团、C1-C8-烷基羰基、C1-C8-烷氧基羰基、硝基、氰基、R15、被R15取代的C1-C8-烷基、R16或被R16取代的C1-C8-烷基;
每个R11和R12独立地选自H、C1-C8-烷基、C1-C8-卤代烷基、C3-C15-碳环基团、C6-C15-芳香族碳环基团和任选地被-COOH或C1-C8-烷基取代的4-至14-元杂环基团,或R11和R12与它们所连接的氮一起形成任选地被CO2H、C1-C8-烷基、(C=O)-4-至14-元杂环基团或C6-C15-元芳香族碳环基团取代的5-至14-元杂环基团,当R11或R12是C1-C8-烷基时,它们可任选地被下列基团单取代或双取代:C6-C15-芳香族碳环基团、5-至14-元杂环基团、任选地被OH取代的C1-C8-烷基氨基或任选地被OH取代的二(C1-C8-烷基)氨基;
R11a选自H和C1-C8-烷基;并且
R14选自H、卤素、C1-C8-烷基、OH、C6-C15-元芳香族碳环基团、C7-C14-芳烷基和O-C7-C14-芳烷基。
2.权利要求1的式(I)化合物或者其互变异构体或立体异构体或药学上可接受的盐:
其中
M1和M2是
R1、R2、R3、R4、R5和R5a是H;
R6是H;
W1和W2独立地选自C0-C8-亚烷基;
X1和X2独立地选自4-至14-元杂环基团;
Y1和Y2独立地是-C0-C8-亚烷基或C1-C8-烷基氨基;
A选自C6-C15-元芳香族碳环基团、-CONR11a-(C1-C8-亚烷基)-NR11aCO-、-(C=O)、-CO-(C1-C8-亚烷基)-CO-、-CO-(C1-C8-亚烯基)-CO-、-CO-(C0-C8-亚烷基)-Z-(C0-C8-亚烷基)-CO-、-CONR11a-(C0-C8-亚烷基)-Z-(C0-C8-亚烷基)-NR11a-CO-、C3-C15-碳环基团和4-至14-元杂环基团;
Z选自C6-C15-元芳香族碳环基团、C3-C15-碳环基团和4-至14-元杂环基团;
每个R11和R12独立地选自H、C1-C8-烷基、C3-C15-碳环基团、C6-C15-芳香族碳环基,或
R11和R12与它们所连接的氮一起形成任选地被CO2H、C1-C4-烷基、(C=O)-4至8-元杂环基或C6-C10-元芳香族碳环基团取代的4-至8-元杂环基团,当R11或R12是C1-C8-烷基时,它们可任选地被以下基团单取代或双取代:C6-C10-芳香族碳环基团、C3-C8-元杂环基或任选地被OH取代的二(C1-C8-烷基)氨基;
T选自H、卤素、C1-C8-烷基、C1-C8-卤代烷基、C1-C8-卤代烷氧基、C3-C15-碳环基团、硝基、氰基、C6-C15-元芳香族碳环基团和被C6-C15-元芳香族碳环基团取代的C1-C8-烷基;
其中,除非另有说明,每个C6-C15-元芳香族碳环基团和每个4-至14-元杂环基独立地任选地被一个或多个基团取代,所述基团选自OH、C1-C8-烷氧基、C1-C8-烷基、卤素、SO2NR11R12、羟基C1-C8-烷氧基,其任选地被羟基取代、(C0-C4-亚烷基)CONR11R12、(C0-C4-亚烷基)-N=C(NR11R12)2、-O-(C1-C4-亚烷基)-N=C(NR11R12)2、-O-(C1-C4-亚烷基)-CONR11R12、C7-C10-芳烷氧基、C7-C10-芳烷基、SH、S(C1-C8-亚烷基)、SO2(C1-C8-亚烷基)、SO(C1-C8-亚烷基)、NR11R12、其中碳环基团任选地被卤素或C1-C8-烷基取代的NR11(C3-C12-碳环基团)、R15、被R15取代的C1-C8-烷基、R16、被R16取代的C1-C8-烷基、O(C1-C8-亚烷基)-NR11C(C=O)O-(C0-C4-亚烷基)-R15、氰基、氧代、羧基、硝基、C1-C8-烷基羰基、羟基-C1-C8-烷基、C1-C8-卤代烷基、氨基-C1-C8-烷基、氨基(羟基)C1-C8-烷基和任选地被氨基羰基取代的C1-C8-烷氧基,其中R15是C6-C15-元芳香族碳环基团,其任选地被OH、C1-C8-烷氧基、C1-C8-烷基、卤素和C1-C8-卤代烷基取代,R16是3-至14-元杂环基团,其任选地被OH、C1-C8-烷氧基、C1-C8-烷基、C6-C15-元芳香族碳环基团、CO2H、(C=O)-3-至14-元杂环基团、卤素和C1-C8-卤代烷基取代;并且
R11a是H。
5.根据权利要求1的化合物,其选自
N,N′-(1,1′-(1,4-亚苯基双(亚甲基))双(氮烷二基)双(氧代亚甲基)双(哌啶-4,1-二基))双(氮烷二基)双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺);
N,N′-(1,1′-(1,4-亚苯基双(氮烷二基))双(氧代亚甲基)双(哌啶-4,1-二基))双(氮烷二基)双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺);
N,N′-(1,1′-(环己烷-1,3-二基双(亚甲基))双(氮烷二基)双(氧代亚甲基)双(哌啶-4,1-二基))双(氮烷二基)双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺);
N,N′-(1,1′-(1,4-亚苯基)双(氧代亚甲基)双(哌啶-4,1-二基))双(氮烷二基)双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺);
N,N′-(1,1′-(6-氯-1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺);
N,N′-(1,1′-羰基双(哌啶-4,1-二基)双(氮烷二基))双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺);
N,N′-(1,1′-(1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺);
N,N′-(1,1′-(6-(4-苯基哌嗪-1-基)-1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺);
N,N′-(1,1′-(6-吗啉代-1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺);
N,N′-(1,1′-(6-(3-吗啉代丙基氨基)-1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺);
N,N′-(1,1′-(6-(2-(双(2-羟基乙基)氨基)乙基氨基)-1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺);
N,N′-(1,1′-(6-(4-(氮杂环庚烷-1-羰基)哌啶-1-基)-1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺);
N,N′-(1,1′-(6-(3-(二丁基氨基)丙基氨基)-1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺);
N,N′-(1,1′-(6-(2-(吡啶-4-基)乙基氨基)-1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺);
N,N′-(1,1′-(6-(己基氨基)-1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺);
1-(4,6-双(4-(3-(3,5-二氨基-6-氯吡嗪-2-羰基)胍基)哌啶-1-基)-1,3,5-三嗪-2-基)哌啶-4-甲酸;
N,N′-(1,1′-(6-(4-甲基哌嗪-1-基)-1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺);
N,N ′-(1,1′-(6-(二丙基氨基)-1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺);
N,N′-(1,1′-(6-(环己基氨基)-1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺);
N,N′-(1,1′-(6-(氮杂环庚烷-1-基)-1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺);
N,N ′-(1,1′-(6-(环己基氨基)-1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰氨基));
N,N′-(1,1′-(6-(环辛基氨基)-1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺);
N,N′-(1,1′-(丁烷-1,4-二基双(氮烷二基))双(氧代亚甲基)双(哌啶-4,1-二基))双(氮烷二基)双(氨基甲-1-基-1-亚基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺);
N,N′-(1,1′-(6-(苯基氨基)-1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(亚氨基亚甲基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺);
N,N′-(1,1′-(6-(5,6-二乙基-2,3-二氢-1H-茚-2-基氨基)-1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(氨基甲-1-基-1-亚基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺);
N,N′-(1,1′-(6-(二甲基氨基)-1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(氨基甲-1-基-1-亚基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺);
N,N′-(1,1′-(6-(2,3-二氢-1H-茚-2-基氨基)-1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(氨基甲-1-基-1-亚基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺);
N,N′-(1,1′-(6-(2,2-二苯基乙基氨基)-1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(氨基甲-1-基-1-亚基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺);
N,N′-(1,1′-(6-(环十二烷基氨基)-1,3,5-三嗪-2,4-二基)双(哌啶-4,1-二基))双(氮烷二基)双(氨基甲-1-基-1-亚基)双(3,5-二氨基-6-氯吡嗪-2-甲酰胺);和
(1,1′-(Z)-丁-2-烯-1,4-二基双(氮烷二基)双(氧代亚甲基)双(哌啶-4,1-二基))双(氮烷二基)双((3,5-二氨基-6-氯吡嗪-2-甲酰氨基)甲-1-基-1-亚基)二氨基甲酸苄基酯。
6.根据权利要求1-5中任一项所述的化合物,其用作药物。
7.药物组合物,其包含权利要求1-5中任一项所述的化合物。
8.权利要求1-5中任一项所述的化合物在制备治疗病症的药物中的用途,所述病症是通过阻断上皮钠通道能够治疗的病症。
9.权利要求1-5中任一项所述的化合物在制备治疗炎症性或过敏性病症、特别是炎症性或阻塞性气道疾病的药物中的用途。
10.权利要求1-5中任一项所述的化合物在制备用于治疗炎症性或过敏性病症的药物中的用途,其中所述炎症性或过敏性病症选自囊性纤维化、原发性纤毛运动障碍、慢性支气管炎、慢性阻塞性肺病、哮喘、呼吸道感染、肺癌、口腔干燥症和角膜结膜炎。
11.权利要求1-5中任一项所述的化合物与抗炎药、支气管扩张药、抗组胺剂或止咳药物的组合。
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CN105440032B (zh) * | 2010-09-17 | 2017-12-08 | 诺华股份有限公司 | 作为enac阻断剂的吡嗪衍生物 |
CN105518000A (zh) * | 2013-07-02 | 2016-04-20 | 加州生物医学研究所 | 用于治疗囊性纤维化的化合物 |
CN105518000B (zh) * | 2013-07-02 | 2018-09-14 | 加州生物医学研究所 | 用于治疗囊性纤维化的化合物 |
CN107405505A (zh) * | 2015-01-07 | 2017-11-28 | 加州生物医学研究所 | 用于治疗囊性纤维化的化合物 |
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