CN1059519A - 磺酰胺衍生物 - Google Patents
磺酰胺衍生物 Download PDFInfo
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- CN1059519A CN1059519A CN91105827A CN91105827A CN1059519A CN 1059519 A CN1059519 A CN 1059519A CN 91105827 A CN91105827 A CN 91105827A CN 91105827 A CN91105827 A CN 91105827A CN 1059519 A CN1059519 A CN 1059519A
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 36
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 32
- 238000000034 method Methods 0.000 claims description 27
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 25
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 24
- 125000005843 halogen group Chemical group 0.000 claims description 20
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
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- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
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- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
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- FPWAUNJOQBHWTF-UHFFFAOYSA-N tert-butyl n-(2-imidazol-1-yl-2-oxoethyl)carbamate Chemical class CC(C)(C)OC(=O)NCC(=O)N1C=CN=C1 FPWAUNJOQBHWTF-UHFFFAOYSA-N 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
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- 231100000820 toxicity test Toxicity 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
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- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
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- 150000008505 β-D-glucopyranosides Chemical class 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
- C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
- C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
- C07C311/44—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/76—Nitrogen atoms to which a second hetero atom is attached
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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Abstract
公开了一类具有抗肿瘤活性和低毒性的磺酰胺
衍生物及其制备方法。所述衍生物具有以下通式
(I),其中各基团如说明书所示:
Description
本发明涉及新的磺酰胺衍生物及其制备方法,和含有这种衍生物作为活性成分的药物组合物。
以前,用于治疗癌症的化学治疗剂包括多种物质,举例来说有烷基化剂,如环磷酰胺,抗代谢产物,如氨甲喋呤和氟尿嘧啶;抗菌素,如亚德里亚霉素,丝裂霉素和搏来霉素(这些物质均由长春新碱之类的植物得到的),和金属配合物,如顺铂。
据报道,4-氨基苯磺酰胺衍生物(见日本专利公告3093/1968)、2-磺酰基酰胺/喹喔啉衍生物(见日本专利公开未决号426/1987)和m-AMSA衍生物(见J.Med Chem.,18,1110(1975))是具有磺酰胺基的抗肿瘤化合物。
这些抗肿瘤化合物中,大多数对人体肿瘤、特别是低速生长的实心肿瘤(如肺或癌或结肠癌)只具有很低的疗效,并显示出严重的付反应。在这些条件下,需要研制出一种具有很低的毒性和优良的抗肿瘤活性的新药。
本发明的一个目的是提供具有优良的抗肿瘤活性和低毒性的新的磺酰胺衍生物。本发明的另一个目的是提供一种制备这些化合物的方法和含有这种物质作为活性成分的药物组合物。
在本发明人对只具有低毒性的上述抗肿瘤化合物进行深入调查后,发现下述新的磺胺衍生物具有优良的抗肿瘤活性和很低的毒性。本发明正是基于这一发现完成的。
所以,本发明涉及以下通式(Ⅰ)的磺酰胺衍生物或其药用盐:
其中:
R1代表氢原子、卤原子、低级烷基、低级烷氧基、羟基、硝基、苯氧基、氰基、乙酰基或可保护的氨基,
R2和R3可相同或不同,分别代表氢原子、卤原子、低级烷基或低级烷氧基,
R4和R7可相同或不同,分别代表氢原子或低级烷基,
R5和R6可相同或不同,分别代表氢原子、卤原子、低级烷氧基或可取代的氨基,
A代表式=N-或=CH-基,
〔化学式12〕
E代表式-C-R11基,其中Q代表氧原子或硫原子,R11代表氢原子,低级烷基,可取代有低级烷基的氨基、低级烷氧基,2-噻吩基,2-呋喃基或下式的基团:
(D是式=N-或=CH-基,以及R12和R13可相同或不同,分别是氢原子、卤原子、硝基、可保护的羟基或低级烷基)〕;或可取代有1-3个取代基G的芳族6-元环基,其中取代基G可相同或不同,分别为卤原子,低级烷基,低级烷氧基,可保护的羟基,可酯化或酰胺化的羧基;低级烷硫基或苯氧基且该环基在环上可具有1或2个氮原子,条件是排除以下组合:
1)R1为氢原子、低级烷基、硝基或可保护的氨基,R2和R3分别是氢原子,A和B分别是=CH-且E是可取代有1-3个取代基G(取代基G可相同或不同)的苯基,以及
2)R1,R2和R3可相同或不同,分别为氢原子、低级烷基、硝基或卤素,A和B分别是=CH-,
〔化学式13〕
以下详细介绍本发明。
在上式(Ⅰ)中定义R1,R2,R3,R4,R7,R10,R11,R12,R13的低级烷基和定义E的可取代的取代基G包括直链和支链的C1-6烷基,如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、叔戊基、1-甲基丁基、2-甲基丁基、1,2-二甲基丙基、正己基、异己基、1-甲基戊基、2-甲基戊基、3-甲基戊基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、3,3-二甲基丁基、1-乙基丁基、2-乙基丁基、1,1,2-三甲基丙基、1,2,2-三甲基丙基、1-乙基-1-甲基丙基和1-乙基-2-甲基丙基。其中,优选甲基、乙基、丙基和异丙基,特别是甲基和乙基。
在R1,R2,R3,R5,R6,R11的定义中的低级烷氧基和E的定义中的可取代的取代基G是由上述低级烷基衍生的基团,例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基和叔丁氧基。其中,最理想的是甲氧基和乙氧基。卤原子包括氟,氯和溴原子。
R5和R6的定义中的取代的氨基包括取代有低级烷基的氨基(如甲氨基,乙氨基和二甲氨基)和取代有苯基的氨基。
在E的定义中,可取代的取代基G可保护的羟基包括羟基、甲氧基甲氧基、四氢吡喃氧基、苄氧基、磷酸酯、硫酸酯、磺酸酯(如,对甲氧基苯磺酸或甲磺酸的酯)、氨基酸酯(如,甘氨酸、亮氨酸、酪氨酸、天冬氨酸、谷氨酸、赖氨酸、精氨酸、腈氨酸、肌氨酸、β-丙氨酸或γ-氨基丁酸的酯)、苷(如,葡糖苷和葡糖苷酸)、可取代有低级烷基的氨基甲酰氧基(如,氨基甲酰氧基,甲基氨基甲酰氧基和二甲基氨基甲酰氧基)、低级酰氧基(具有1-5个碳原子,如甲酰氧基,乙酰氧基,丙酰氧基和新戊酰氧基)和苄酰氧基。
需要的话,苄酰氧基的芳环可取代有低级烷基,如甲基、乙基、正丙基或异丙基,低级烷氧基,如甲氧基、乙氧基、正丙氧基或异丙氧基,卤原子,如氟、氯或溴原子,或可取代有低级烷基的氨基。
在R1的定义中可保护的氨基包括未取代的氨基、低级酰氨基(具有1-4个碳原子,如甲酰氨基,乙酰氨基和丙酰氨基)和苄氧羰基氨基。
在E的定义中,取代基G的定义可酯化或酰胺化的羧基包括羧基,低级烷氧羰基(具有2-5个碳原子,如甲氧羰基,乙氧羰基和异丙氧羰基),未取代的氨基羰基,和取代了C1-4烷基的氨基羰基(如甲氨基羰基,乙氨基羰基和二甲氨基羰基)。
以上通式(Ⅰ)表示的磺酰胺衍生物可与酸或碱成盐。化合物(Ⅰ)的盐也包括在本发明之内。化合物(Ⅰ)与酸成盐的例子有无机酸盐,如盐酸盐、氢溴酸盐和硫酸盐;有机酸盐,如乙酸盐、乳酸盐、琥珀酸盐、富马酸盐、马来酸盐、柠檬酸盐、苯甲酸盐、甲磺酸盐和对甲苯磺酸盐。化合物(Ⅰ)与碱成盐的例子有无机盐,如钠、钾和钙盐,和有机碱盐,如三乙胺、精氨酸和赖氨酸。
当然,若存在的话,这些化合物的水合物和旋光异构体也包括在本发明之内。本发明的化合物显示出强有力的抗肿瘤活性。通过氧化、水解或体内配位之类的代射反应显示出抗肿瘤活性的化合物也包括在本发明之内。
本发明的化合物可通过不同方法制备。其中,典型方法如下:
(1)通式(Ⅱ)的磺酸或其反应性衍生物:
〔化学式14〕
(其中R2和R3定义如上,R1 0代表氢原子、卤原子或低级烷基、低级烷氧基保护的羟基、硝基、苯氧基、氰基、乙酰基或保护的氨基)与通式(Ⅲ)的化合物反应:
〔化学式15〕
(其中R4,R7,A,B和E分别定义如上,R5 a和R6 a可相同或不同,各代表氢原子或卤原子、低级烷氧基、或保护或取代的氨基)。
磺酸(Ⅱ)的反应性衍生物包括那些经常使用的物质,如磺酰卤、磺酸酐和N-磺酰基咪唑化物。其中,特别优选磺酰卤。当它们以化学计量等摩尔量使用时,反应便进行了。虽然反应用的溶剂不是特别关键,但优选的溶剂是那些起始物可溶且不易与起始物反应的溶剂。这样的溶剂的例子是吡啶、四氢呋喃、二噁烷、苯、乙醚、二氯甲烷、二甲基甲酰胺和其两种或多种物质的混合物。在使用磺酰卤,随着反应的进行释放出酸的情况下,反应在存在合适的酸结合剂下进行比较有利。所以,特别优选使用碱溶剂,如吡啶。当使用中性溶剂时,可加入一种碱金属碳酸盐或有机季胺之类的碱性溶剂。当然,这里使用的溶剂并不限于这里介绍的物质。反应一般在室温下进行,需要的话,也可在冷却或加热条件下进行。反应时间一般在10分钟-20小时之间。时间宜根据起始化合物和反应温度确定。
当所得磺酰胺衍生物(Ⅰ)中的氨基、羟基或羧基被保护时,可将其经过除去的保护基的普通方法,例如需要的话,用酸处理、碱处理或催化还原,以得到具有自由羟基、氨基或羧基的化合物(Ⅰ)。
(2)使通式(Ⅳ)的化合物
〔化学式16〕
(其中R1 a,R2,R3,R4,R5 a,R6 a,R7,A和B分别定义如上,Ea代表取代有1-3个取代基Ga的芳族6-元环基(环中可含有1或2个氮原子),取代基Ga可相同或不同,分别是卤原子、低级烷基、低级烷氧基、羟基、可酯化或酰胺化的羧基、低级烷硫基或苯氧基,条件是环上的至少一个Ga是羟基)与通式(Ⅴ)的化合物反应:
(其中X代表能与羟基的氧原子结合的基团,Y代表可除去基团)或与能和羟基反应的无机酸或有机酸酐反应。
X-Y包括芳族和脂族磺酸、芳族和脂族的羧酸、可保护的氨基酸、可保护的磷酸、可保护的硫酸、可取代有低级烷基的氨基甲酸和可保护的糖类的反应性衍生物。其例子有对甲氧基苯磺酰氯、甲磺酰氧、邻氯苯甲酰氯、乙酰氯、N-(叔丁氧基羰基氨基乙酰基)咪唑、磷酰氯、氯磺酸、N,N-二甲基氨基甲酰氯和1,2,3,4-四氧乙酰基-D-葡糖醛酸甲酯。酸酐的例子包括无机酸酐,如五氧化二磷和三氧化硫,以及有机酸酐,如α-氨基酸的N-羧基酸酐和靛红酸酐。
虽然反应用的溶剂不特别关键,但优选的溶剂是起始物不溶且不易与起始物反应的溶剂。这种溶剂的例子是吡啶,四氢呋喃,二噁烷,苯,乙醚,二氯甲烷,二甲基甲酰胺和它们中的两种或多种物质的混合物。当使用磷酰氯之类的液体起始化合物时,可不使用任何溶剂进行反应。
(3)在氢化钠之类的碱存在下,使通式(Ⅵ)的化合物
〔化学式17〕
(其中R1 a,R2,R3,R5 a,R6 a,R7,A,B和E分别定义如上)与以下通式
(其中R4 a代表低级烷基且L代表卤素)反应。
(4)使通式(Ⅶ)化合物
〔化学式18〕
(其中R1 a,R2,R3,R4,R5 a,R6 a,A和B分别定义如上)与以下通式(Ⅷ)化合物反应:
(其中R11定义如上,Z代表羧基或其它反应性衍生物),或当R11是低级烷氨基时,使其与异氰酸低级烷基酯反应。
这里可使用的羧酸的反应性衍生物的例子是酰卤、酸酐,活性酰胺化合物和活性酯。
这里可使用的酰卤的例子是酰氯和酰溴。这里可使用的酸酐的例子是混合的一烷基碳酸酐,含脂族羧酸(如乙酸,新戊酸,戊酸,异戊酸和三氯乙酸)混合酸酐,芳族羧酸(如苯甲酸)的混合酸酐和对称酸酐。这里可使用的活性酰胺化合物的例子是酸与咪唑、吡唑、4-取代的咪唑、二甲基吡咯、三唑、四唑和苯并四唑构成的酰胺。活性酯宜选自甲基酯,甲氧基甲酯,氰甲基酯,丙炔基酯,4-硝基苯基酯,2,4-二硝基苯基酯,三氯苯基酯,五氯苯基酯,甲磺酰基苯基酯,苯基偶氮苯基酯和1-羟基-1H-2-吡啶、N-羟基琥珀酰亚胺、N-羟基苯二酰亚胺或1-羟基苯并三唑的酯类。
在N,N′-二环己基碳化二乙胺(DCC)或N-环己基-N′-吗啉代乙基碳化二亚胺存在下,可使羧酸(Ⅷ)与胺(Ⅶ)反应。当R11是低级烷基取代的氨基时,胺(Ⅶ)可与异氰酸低级烷基酯反应。当R11是取代了低级烷基的氨基时,胺(Ⅶ)可与氰酸的碱金属盐反应。
这些反应可在有机叔胺(如三乙胺,N,N-二甲基苯胺或吡啶)、碱金属碳酸盐或碱金属碳酸氢盐之类的碱或酸(若需要)存在下进行。当各以化学计量等摩尔量使用反应物时,反应便进行了。虽然反应用的溶剂并不关键,但优选的溶剂是起始物可溶且不易与起始物反应的溶剂。这种溶剂的例子是吡啶,四氢呋喃,二噁烷,苯,乙醚,二氯甲烷,二甲基甲酰胺以及它们的两种或多种混合物。当使用难溶于有机溶剂的试剂(如氰酸盐)时,反应可在水化条件下进行。这里可使用溶剂并不限于上述溶剂。只要反应能进行,反应温度并不特别严格。一般是在室温下进行反应,需要的话,可在冷却或加热下进行反应。反应时间一般在5分钟-20小时。确定反应时间宜取决于起始化合物和反应温度的不同。当产物具有被保护的羟基或氨基时,可采用普通方法除去保护基,例如酸处理、碱处理或催化还原,以得到具有自由的羟基或氨基的化合物(Ⅰ)。当产物具有硝基时,该基团可转化成氨基,方法是采用普通的还原硝基的方法(如在钯/炭催化剂存在下进行催化还原),或采用锌粉和盐酸的方法。
以下介绍制备本发明用的起始化合物(Ⅸ)或其盐的方法:
〔化学式19〕
(其中R5 a,R6 a,R7,A,B和E分别定义如上)。
制法1
〔化学式20〕
其中L代表卤原子,R5 a,R6 a,R7,A,B和E分别定义如上。
通式(Ⅻ)化合物可通过以下文献介绍的不同方法合成(见例如J.Med.Chem.,Vol.21,p.965,J.Org.Chem.,Vol.28,p.3114,J.Chem.Soc.Perkin I.1974,1611,1974,1970和1979,135,Helv.Chim.Acta,Vol.,61,p.2452或类似方法)。也就是说,其制备方法是使通式(Ⅹ)化合物与通式(Ⅺ)化合物在存在或不存在的有机溶剂(如二甲基甲酰胺,乙醇或二噁烷)及室温或加热下反应。
当需要除去由此形成的氢卤化物时,加入三乙胺或吡啶之类的有机碱或碱金属碳酸盐作为酸结合剂,或者每当量化合物(Ⅹ)至少使用两当量的化合物(Ⅺ)进行反应。当产物(Ⅻ)在其芳环上具有高度活性的卤原子时,可将其进一步与烷氧化物或胺反应,使其转化为另一种化合物。通过采用还原硝基的普通方法还原上述制得的化合物(Ⅻ),可得到通式(Ⅸ)化合物。在还原法的某一优选例子中,是在钯/炭催化剂存在下进行催化还原,或使用锌粉和乙酸进行还原。催化还原反应一般是在有机溶剂(如甲醇,四氢呋喃或二甲基甲酰胺)及大气压或高压下进行的。
制法2
〔化学式21〕
其中R5 a,R6 a,R7,A,B,E和L分别定义如上。
通式(Ⅸ)表示的化合物可通过以下文献介绍的方法合成(见例如J.Org.Chem.,VOL.24,P.1314,介绍的方法,J.Heterocycl.Chem.,Vol.20,p.1339介绍的方法,或类似方法),也就是说,可通过使通式(Ⅷ)的化合物与通式(Ⅺ)化合物在盐酸或硫酸之类的酸催化剂存在下及水、乙醇或二甘醇之类的溶剂中进行反应来制备化合物(Ⅸ)。为了提高反应速率,最好加热反应混合物。
制法3
〔化学式22〕
(其中R5 a,R6 a,R7,A,B,E和L分别定义如上)。
通式(Ⅸ)表示的化合物可通过以下方法合成(例如,J.Chem.Soc.(C)(1970),p1355介绍的方法或类似方法)。也就是说,在存在或不存在二甲基甲酰胺或二噁烷之类的有机溶剂及室温或加热下,使通式(ⅩⅣ)化合物与通式(ⅩⅤ)化合物反应可制备这种化合物。
制法4
〔化学式23〕
(其中R5 a,R6 a,R7,A,B和Ea分别定义如上,Eb代表上述E,其中至少一个G是被保护的羟基)。
通式(ⅩⅦ)表示的化合物可通过使通式(ⅩⅥ)化合物与通式X-Y(Ⅴ)化合物(X和Y定义如上)反应或与能和羟基反应的无机酸或有机酸酐反应而制备。反应条件依X-Y(Ⅴ)和酸酐的不同而变化。反应溶剂通常最好是一种不与这些化合物反应的惰性溶剂,如二甲基甲酰胺,四氢呋喃或二噁烷。为了提高反应速度,可将氢化钠、碳酸钾或三乙胺之类的碱加到反应系统中,或者,可将反应系统加热。当R7是氢原子时,有时最好用普通氨基保护基(如苄氧羰基)在与X-Y(Ⅴ)或酸酐反应之前将其保护住,在反应完毕之后再除掉保护基。通式(ⅩⅧ)表示的化合物可通过普通还原硝基的方法还原上述制取的化合物(ⅩⅦ)而制备。
(其中R1 a,R2,R3,R4,R5 a,R6 a,A,B和L分别定义如上)。
使通式(ⅩⅨ)化合物与通式(ⅩⅩ)化合物反应,可制备通式(Ⅶ)表示的化合物。反应条件依化合物的不同而变化。通常,每当量磺酰卤(ⅩⅨ)最好使用2-4当量化合物(ⅩⅩ)。反应溶剂最好是四氢呋喃,二噁烷,吡啶,二甲基甲酰胺等等。反应也可在水合条件下进行。一般是在室温下进行反应,需要的话,也可在冷却或加热条件下进行反应。
当本发明的化合物用作药物时,是通过口服或肠胃外给药。剂量不并严格,因为它可依症状,患者的年龄、姓别、体重和敏感度;给药方法;给药的时间和间格;制剂的配方和种类;以及活性成分的不同而变化。
依给药方式的不同而变化的剂量成人每天一般为10-6000mg,优选约50-4000mg,最佳100-3000mg。将上述化合物剂量分成每日1-3次给药。
在制备口服用的固体制剂时,将赋形剂和(若需要)粘合剂、崩解剂、润滑剂、着色剂、矫正药等等加到活性成分中,并将它们制成片剂涂覆的片剂、颗粒、细颗粒、粉末或颗粒。
赋形剂的例子有乳糖,玉米淀粉,白糖,葡萄糖,山梨糖,晶体纤维素和二氧化硅。粘合剂的例子有聚乙烯醇,聚乙烯醚,乙基纤维素,甲基纤维素,阿拉伯胶,黄蓍胶,明胶,紫胶,羟丙基纤维素,羟丙基甲基纤维基,柠檬酸钙,糖精和果胶。润滑剂的例子有硬脂酸镁,滑石,聚乙二醇,二氧化硅和硬化植物油。着色剂是允许加到药物中的物质。矫正药的例子有可可粉,甲醇,芳基化合物粉,薄荷油,冰片和肉桂粉。当然,这些片剂和颗粒可用糖、明胶等等合适地包衣。
在注射制剂中,将PH改进剂,缓冲剂、悬浮剂、增溶剂、稳定剂、等渗剂、防腐剂等等加到活性成分中,以通过普通方法形成静脉内、皮下或肌肉注射剂。需要的话,可将其冻干。
悬浮剂的例子有甲基纤维素,Polysorbate 80,羟乙基纤维素,阿拉伯胶,黄蓍胶粉,羧甲基纤维素钠和聚氧乙烯山梨糖-月桂酸酯。
增溶剂的例子有聚氧乙烯硬化的蓖麻油,Polysorbate 80,烟酰胺,聚氧乙烯山梨糖-月桂酸酯,大粒凝胶和蓖麻油脂肪酸的乙基酯。
稳定剂的例子有亚硫酸钠,焦亚硫酸钠和乙醚。防腐剂的例子有对甲氧基苯甲酸甲酯,对羟基苯甲酸乙酯,山梨酸,苯酚,甲酚和氯甲酚。
以下药理实验旨在说明本发明化合物的效果。
实施例1
KB细胞(人体鼻咽细胞)体外抗肿瘤试验:
将悬浮于RPMI 1640培养基(NissuiSeiyaku有限公司产,含20%牛胎血清、青酶素(100单位/毫升)、链霉素(100μg/ml)、巯基乙醇(5×10-5M)和丙酮酸钠(1mM)的1.25×103(0.1ml)KB细胞置于96孔平底小板的各孔中,并在一个含5%二氧化碳的恒温箱中于37℃保温1天。
将本发明的化合物溶于二甲亚砜,得到的20mg/ml溶液用0.1%牛胎血清/RPMI 1640培养液稀释到浓度为100μg/ml。该浓度为最大浓度,将其用0.1%牛胎血清RPMI 1640培养液(含0.5%二甲亚砜)依次两次稀释。将其以0.1ml的量加到上述培养板各孔中的KB细胞中,并在含5%二氧化碳的恒温箱中于37℃保温3天。
培养完毕后,往各孔中加入0.05mlMTT(3-(4,5-二甲基噻唑-2-基)-2,5-二苯基溴化四唑鎓)溶液(3.3mg/ml),并再培养1小时。通过吸滤的方法从各孔移出上清液,并将由此形成的甲腭溶于0.1ml二甲亚砜。采用小板读数计(microplate reader)确定540nm吸收度,用作存活指数。按照以下式子计算抑制百分数,并测定50%抑制率的试验化合物的浓度(IC50)。
(数式1)
抑制百分数(%)=(C-T)/C×100
T:含试验化合物的各孔吸收度
C:不含试验化合物的各孔吸收度
由此测定的IC50值列于表1。
实施例2
结肠38(鼠结肠癌)体内抗肿瘤试验:
将约7.5mg结肠38皮下移植到各7周龄BDF1雌鼠体内。将本发明的化合物悬浮在0.5%甲基纤维素中,第二天开始,口服预定量的悬浮液,每日一次,持续8天。对照组中口服0.5%甲基纤维素。对照组由10只鼠组成,而给药组由6只鼠组成。
移植21天后,取出肿瘤并称重,按照下式测定给药组与对照组肿瘤生长抑制率:
(数式2)
生长抑制率(%)=(C-T)/C×100
T:给药组中平均肿瘤重
C:对照组平均肿瘤重
表2给出了试验结果。
表2
化合物 剂量 生长抑制率 21天后存活率
(实施例号) (mg/kg/天)
1 100 80 100
2 100 69 100
3 100 98 100
4 100 99 100
6 100 98 100
7 50 61 100
70 50 63 100
实验例3:毒性试验
给一组五个7周龄BDF1雌鼠服用一次实施例3,4或6的化合物于甲基维维素中约0.5%悬浮液,并观察给药7天后的存活率。即使用1651mg/kg化合物也无鼠死亡。
从以上实验例可以明显看出,本发明的化合物具有非常优良的抗肿瘤作用,另外,本发明的化合物很高的安全性,使其可用于治疗恶性肿瘤,即用作抗肿瘤剂。
实施例
以下制备例旨在说明制备本发明化合物的起始化合物的方法,以下实施例旨在说明本发明的典型化合物,这些实施例不意味着限着本发明。
制备例1
2-苯氨基-3-硝基吡啶
(化学式25)
在100℃搅拌下,将11.21g(70mmol)2-氯-3-硝基吡啶和19.56g(210mmol)苯胺的混合物加热1小时。反应液冷却到室温,并溶于乙酸乙酯。将溶液用柠檬酸水溶液洗涤,然后水洗。硫酸镁干燥之后,减压蒸掉溶剂,残余物用乙酸乙酯/正己烷重结晶,得到13.7g标题化合物。
熔点:73-74℃
FAB质谱m/z:216(〔M+H〕+)
1H-NMR(CDCl3)δ(ppm):
6.84(1H,dd,J=8.4,4.4Hz),7.18-7.22(1H,m),7.37-7.43(2H,m),7.62-7.68(2H,m),8.49(1H,dd,J=4.4,2.0Hz),8.53(1H,dd,J=8.4,2.0Hz),10.12(1H,br-s)
元素分析C11H9N3O2:
C H N
计算值 61.39 4.22 19.53
实测值 61.49 4.34 19.23
制备例2
3-氨基-2-苯氨基吡啶
(化学式26)
将6.8g(31.6mmol)制备例1制得的化合物溶于40ml四氢呋喃和6ml甲醇的混合物中。将钯/炭加到溶液中,以在大气压及室温下进行氢化。滤除钯/炭,减压蒸掉溶剂,残余物用乙酸乙酯/正己烷重结晶,得到5.5g标题化合物。
熔点:143-144℃
FAB质谱m/z:186(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
4.95-5.10(2H,br),6.61(1H,dd,J=7.2,4.8Hz),6.80-6.86(1H,m),6.90(1H,dd,J=7.2,1.6Hz),7.18-7.24(2H,m),7.49(1H,dd,J=4.8,1.6Hz),7.60-7.65(2H,m),7.69(1H,s)
元素分析:C11H11N3:
C H N
计算值 71.33 5.99 22.69
实测值 71.49 6.04 22.59
制备例3
4-〔(3-硝基-2-吡啶基)氨基〕苯酚
(化学式27)
将8.17g(50mmol)2-氯-3-硝基吡啶和16.70g(150mmol)对氨基苯酚加到50ml二甲基甲酰胺中,混合物于100℃搅拌40分钟。减压蒸掉溶剂,重复制备例1的同样处理方法,产物用乙醇重结晶,得到9.4g标题化合物。
熔点:143-144℃
FAB质谱m/z:231(M+)
1H-NMR(CDCl3)δ(ppm):
5.23(1H,s),6.79(1H,dd,J=4.8,8.4Hz),6.84(2H,d,J=8.8Hz),7.41(2H,d,J=8.8Hz),8.44(1H,dd,J=1.6,4.8Hz),8.52(1H,dd,J=1.6,8.4Hz),9.94(1H,br-s)
元素分析C11H9N3O3:
C H N
计算值 57.14 3.92 18.18
实测值 57.15 3.97 18.14
制备例4
4-〔(3-氨基-2-吡啶基)氨基〕苯酚
(化学式28)
将9.25g(40mmol)制备例3制得的化合物催化还原,并用制备例2同样方式进行处理,产物用甲醇重结晶,得到7.8g标题化合物。
熔点:205-207℃
FAB质谱m/z:202(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
4.94(2H,br-s),6.50(1H,dd,J=4.8,7.6Hz),6.66(2H,d,J=8.8Hz),6.82(1H,dd,J=1.6,7.6Hz),7.38(1H,s),7.39(2H,d,J=8.8Hz),7.40(1H,dd,J=1.6,4.8Hz),8.85(1H,s)
元素分析C11H11N3O:
C H N
计算值65.66 5.51 20.88
实测值65.85 5.51 20.84
制备例5
3-〔(3-硝基-2-吡啶基)氨基〕苯酚
(化学式29)
熔点:148-149℃(用乙醇重结晶)
FAB质谱m/z:232(〔M+H〕+)
1H-NMR(CDCl3)δ(ppm):
5.31(1H,br-s),6.65(1H,dd,J=8.0,2.4Hz),6.85(1H,dd,J=8.4,4.8Hz),7.08(1H,dd,J=8.0,2.4Hz),7.24(1H,t,J=8.0Hz),7.37(1H,t,J=2.4Hz),8.49(1H,dd,J=4.8,1.6Hz),8.54(1H,dd,J=8.4,1.6Hz),10.11(1H,br-s)
元素分析C11H9N3O3:
C H N
计算值57.14 3.92 18.17
实测值57.33 4.03 18.18
制备例6
3-〔(3-氨基-2-吡啶基)氨基〕苯酚
(化学式30)
熔点:在198℃观察到逐渐分解(用乙醇重结晶)
FAB质谱m/z:202(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
5.04(2H,s),6.24-6.28(1H,m),6.60(1H,dd,J=7.6,4.8Hz),6.89(1H,dd,J=7.6,1.6Hz),6.97-6.99(2H,m),7.23(1H,br-s),7.50(1H,dd,J=4.8Hz,1.6Hz),7.57(1H,s),9.10(1H,s)
元素分析C11H11N3O:
C H N
计算值65.66 5.51 20.88
实测值65.92 5.58 20.86
制备例7
2-〔(4-甲氧基甲基氧苯基)氨基〕-3-硝基吡啶
(化学式31)
将8.4g(54.8mmol)4-甲氧基甲基氧苯胺和7.5g(49mmol)2-氯-3-硝基吡啶溶于35ml二甲基甲酰胺。7.6g(55mmol)无水碳酸钾加到溶液中。所得溶液100℃搅拌加热4小时。反应液冷却到室温,并滤除由此形成的不溶物。减压蒸掉溶剂,残余物溶于乙酸乙酯。溶液用柠檬酸水溶液洗涤,然后用水洗。硫酸镁干燥之后,减压蒸掉溶剂,残余物用乙醇重结晶,得到9.68g标题化合物。
熔点:80-81℃
FAB质谱 m/z:275(M+)
1H-NMR(CDCl3)δ(ppm):
3.50(3H,s),5.19(2H,s),6.79(1H,dd,J=4.4,8.4Hz),7.08(2H,d,J=8.8Hz),7.50(2H,d,J=8.8Hz),8.45(1H,dd,J=1.6,4.4Hz),8.51(1H,dd,J=1.6,8.4Hz),9.99(1H,br-s)
元素分析C13H13N3O4:
L H N
计算值:56.73 4.76 15.27
实测值:57.06 4.83 15.02
制备例8
2-〔N-苄氧羰基-N-(4-甲氧基甲基氧苯基)-氨基〕-3-硝基吡啶
(化学式32)
将4.0g(14.5mmol)制备例7得到的化合物溶于70ml二甲基甲酰胺。溶液中加入720mg(18mmol)氢化钠(60%)。在室温搅拌下,往里滴加3.2ml(22.4mmol)氯甲酸苄基酯。室温搅拌过夜后,减压蒸掉溶剂。残余物中加入乙酸乙酯和水,分离出乙酸乙酯层。水洗乙酸乙酯层、干燥(硫酸镁)、浓缩和硅胶柱色谱法纯化之后,得到4.5g油状标题化合物。
1H-NMR(CDCl3)δ(ppm):
3.47(3H,s),5.17(4H,s+s),7.06(2H,d,J=8.8Hz),7.22-7.26(2H,m),7.29-7.33(4H,m),7.37(2H,d,J=8.8Hz),8.29(1H,d,J=8.0Hz),8.56(1H,d,J=4.4Hz)
制备例9
4-〔N-苄氧羰基-N-(3-硝基-2-吡啶基)氨基〕苯酚
(化学式33)
将500mg(1.22mmol)制备例8得到的化合物溶于6ml四氢呋喃和1ml水的混合物中。溶液中加入2ml浓盐酸。混合物室温搅拌过夜之后,减压蒸掉溶剂。残余物中加入乙酸乙酯和饱和碳酸氢钠水溶液,并分离出由此形成的乙酸乙酯层。水洗分出的层、硫酸镁干燥和浓缩后,得到445mg标题化合物。
1H-NMR(DMSO-d6)δ(ppm):
5.11(2H,s),6.77(2H,d,J=8.8Hz),7.18-7.24(4H,m),7.31-7.34(3H,m),7.58(1H,dd,J=4.8,8.0Hz),8.51(1H,dd,J=1.6,8.0Hz),8.66(1H,dd,J=1.6,4.8Hz),9.64(1H,s)
制备例10
叔丁氧基羰基氨基乙酸4-〔(3-氨基-2-吡啶基)氨基〕苯酯
(化学式34)
将440mg(1.2mmol)制备例9制得的化合物、250mg(1.43mmol)N-(叔丁氧羰基)甘氨酸和25mg(0.2mmol)4-二甲基氨基吡啶溶于10ml吡啶中。溶液中加入290mg(1.41mmol)1,3-二环己基碳化二亚胺。室温搅拌过夜后,减压蒸掉溶剂。残余物中加入乙酸乙酯,滤除不溶物,并减压蒸掉溶剂。按照硅胶柱色谱法纯化残余物,并在钯/炭催化剂存在下通过普通方法催化还原所得化合物。滤除催化剂、浓缩之后,残余物用硅胶色谱法纯化,得到236mg标题化合物。
1H-NMR(DMSO-d6)δ(ppm):
1.41(9H,s),3.93(2H,d,J=6.0Hz),5.05(2H,br-s),6.62(1H,dd,J=4.8,7.2Hz),6.90(1H,dd,J=1.6,7.2Hz),6.96(2H,d,J=9.2Hz),7.37(1H,br-t,J=6.4Hz),7.49(1H,dd,J=1.6,4.8Hz),7.64(2H,d,J=9.2Hz),7.79(1H,s)
制备例11
4-〔〔(3-(4-甲氧基苯磺酰氨基)-2-吡啶基〕氨基〕苯基-2,3,4,6-四氧-乙酰基-β-D-吡喃葡萄糖苷
(化学式35)
将3.753g(10.10mmol)例6得到的化合物和3.959g(10.14mmol)β-D-葡萄糖五乙酸酯悬浮在200ml1,2-二氯乙烷中。在搅拌和冰冷却的氮气气氛下,往悬浮液中滴加30ml1.0M的四氯化锡的二氯甲烷溶液。冰冷搅拌2小时再于室温搅拌4天之后,将反应混合物加到含16g碳酸氢钠的冰/水中。减压蒸掉有机溶剂。往残余物中加入乙酸乙酯,并滤除由此形成的不溶物。分出乙酸乙酯层,水洗,干燥,浓缩,并用硅胶柱色谱法纯化,得到2.47g标题化合物。
1H-NMR(CDCl3)δ(ppm):
2.04(3H,s),2.05(3H,s),2.08(3H,s),2.10(3H,s),3.80-3.86(1H,m),3.84(3H,s),4.17(1H,dd,J=12.4,2.4Hz),4.30(1H,dd,J=12.4,5.6Hz),4.99(1H,d,J=7.6Hz),5.16(1H,t,J=9.6Hz),5.23-5.32(2H,m),6.37(1H,br-s),6.54(1H,dd,J=4.8,7.6Hz),6.84(1H,dd,J=1.6,7.6Hz),6.92(2H,d,J=8.8Hz),6.94(2H,d,J=8.8Hz),7.32(1H,br-s),7.38(2H,d,J=8.8Hz),7.69(2H,d,J=8.8Hz),8.07(1H,dd,J=1.6,4.8Hz)
制备例12
N-(2-氨基苯基)-4-甲氧基苯磺酰胺
(化学式36)
将33.1g(0.3mol)1,2-亚苯基二胺溶于200ml二噁烷。搅拌下,往里滴加20.87g(0.1mol)4-甲氧基苯磺酰氯的110ml二噁烷溶液。所得混合物室温搅拌过夜。往里加入12.1g(0.12mol)三乙胺。浓缩后加入柠檬酸水溶液和乙酸乙酯,分离出有机层,浓缩,并用硅胶柱色谱法纯化,得到27.1g标题化合物。
熔点:141-142℃(用乙醇重结晶)
FAB质谱m/z:279(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.81(3H,s),4.91(2H,br-s),6.37(1H,td,J=1.6,7.2,8.0Hz),6.60(1H,dd,J=1.6,8.0Hz),6.66(1H,dd,J=1.6,8.0Hz),6.86(1H,td,J=1.6,7.2,8.0Hz),7.03(2H,d,J=8.8Hz),7.61(2H,d,J=8.8Hz),9.07(1H,br-s)
元素分析C13H14N2O3S:
C H N
计算值56.10 5.07 10.07
实测值55.98 5.03 10.00
制备例13
N-(2-氨基苯基)-4-硝基苯磺酰胺
(化学式37)
按制备例12的同样方式制备标题化合物。
熔点:190-191℃(用苯重结晶)
FAB质谱m/z:294(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
4.90(2H,br-s),6.42(1H,dt,J=1.6,8.0Hz),6.61(1H,dd,J=1.6,8.0Hz),6.71(1H,dd,J=1.6,8.0Hz),6.91(1H,dt,J=1.6,8.0Hz),7.91(2H,d,J=8.8Hz),8.36(2H,d,J=8.8Hz)
元素分析C12H11N3O4S
C H N
计算值49.14 3.78 14.33
实测值49.38 3.82 14.13
制备例14
N-(2-氨基-3-甲基苯基)-4-甲氧基苯磺酰胺
(化学式38)
按制备例12的同样方式制备标题化合物。
熔点:177-178℃(用乙醇重结晶)
FAB质谱m/z:293(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
2.03(3H,s),3.81(3H,s),4.75(2H,br-s),6.30(1H,t,J=7.6Hz),6.44(1H,dd,J=1.2,7.6Hz),6.79(1H,dd,J=1.2,7.6Hz),7.04(2H,d,J=8.8Hz),7.61(2H,d,J=8.8Hz)
元素分析C14H16N2O3S:
C H N
计算值57.52 5.52 9.58
实测值57.76 5.51 9.57
实施例1
N-(2-苯胺基-3-吡啶基)-对甲基磺酰胺
(化学式39)
将3.7g(20mmol)制备例2得到的化合物溶于30ml吡啶。在室温和搅拌下,将30ml 3.81g(20mmol)对甲苯磺酰氯的四氢呋喃溶液分成若干份加到溶液中。搅拌过夜后,减压蒸掉溶剂,残余物溶于乙酸乙酯。溶液用水洗涤,并用硫酸镁干燥。减压蒸掉溶剂,残余物用乙醇重结晶,得到5.2g标题化合物。
熔点164-165℃
FAB质谱m/z:340(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
2.23(3H,s),6.73(1H,dd,J=4.8,7.6Hz),6.86-6.92(1H,m),7.18-7.24(2H,m),7.24(2H,d,J=8.0Hz),7.27(1H,dd,J=7.6,1.6Hz),7.36-7.42(2H,m),7.54(2H,d,J=8.0Hz),7.86(1H,s),7.99(1H,dd,J=4.8,1.6Hz),9.62(1H,s)
元素分析C18H17N3O2S:
C H N
计算值63.70 5.05 12.38
实测值63.77 5.11 12.28
实施例2
N-(2-苯胺基-3-吡啶基)-4-乙基苯磺酰胺
(化学式40)
使3.11g(16.8mmol)制备例2得到的化合物与3.43g(16.9mmol)对乙基苯磺酰氯反应,产物用实施例1的同样方法处理,得到5.0g标题化合物。
熔点:138-139℃(用乙醇重结晶)
FAB质谱m/z:354(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
1.02(3H,t),2.50(2H,q),6.72(1H,dd,J=5.2,8.0Hz),6.83-6.89(1H,m),7.14-7.20(2H,m),7.24(2H,d,J=8.4Hz),7.29(1H,dd,J=8.0,1.8Hz),7.32-7.37(2H,m),7.54(2H,d,J=8.4Hz),7.80(1H,s),7.97(1H,dd,J=5.2,1.8Hz),9.60(1H,s)
元素分析C19H19N3O2S
C H N
计算值64.57 5.42 11.89
实测值64.89 5.33 12.00
实施例3
N-(2-苯胺基-3-吡啶基)-4-甲氧基苯磺酰胺
(化学式41)
使1.39g(7.5mmol)制备例2制得的化合物与1.55g(7.5mmol)对甲氧基苯磺酰氯反应,产物用实施例1同样方式处理,得到2.6g标题化合物。
熔点:172-173℃(用乙醇重结晶)
FAB质谱m/z:356(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.68(3H,s),6.71(1H,dd,J=7.6,5.0Hz),6.84-6.90(1H,m),6.92(2H,d,J=9.2Hz),7.15-7.22(2H,m),7.25(1H,dd,J=7.6,1.2Hz),7.36-7.42(2H,m),7.57(2H,d,J=9.2Hz),7.86(1H,s),7.97(1H,dd,J=5.0,1.2Hz),9.51(1H,s)
元素分析C18H17N3O3S:
C N H
计算值60.83 4.82 11.82
实测值61.02 4.69 11.86
实施例4
4-甲氧基-N-〔2-〔(4-甲氧基苯基)氨基〕-3-吡啶基〕苯磺酰胺
(化学式42)
按实施例1同样方式得到标题化合物。
熔点:145-147℃(用乙醇重结晶)
FAB质谱m/z:386(〔M+H〕+)
1H-NMR(CDCl3)δ(ppm):
3.79(3H,s),3.85(3H,s),6.16(1H,br-s),6.52(1H,dd,J=4.8,7.6Hz),6.85(3H,d,J=8.8Hz),6.93(2H,d,J=8.8Hz),7.12(1H,br-s),7.32(2H,d,J=8.8Hz),7.69(2H,d,J=8.8Hz),8.07(1H,dd,J=1.6,4.8Hz)
元素分析C19H19N3O4S:
C H N
计算值59.21 4.97 10.90
实测值59.26 5.05 10.75
实施例5
4-甲氧基-N-〔2-〔(4-甲氧基甲基氧苯基)氨基-3-吡啶基〕苯磺酰胺
(化学式43)
按实施例1同样方式制备标题化合物。
熔点:118-119℃(用乙醇重结晶)
FAB质谱m/z:416(〔M+H〕+)
1H-NMR(CDCl3)δ(ppm):
3.48(3H,s),3.83(3H,s),5.13(2H,s),6.45(1H,br-s),6.52(1H,dd,J=4.4,7.6Hz),6.87(1H,dd,J=1.6,7.6Hz),6.92(2H,d,J=8.8Hz),6.97(2H,d,J=8.8Hz),7.16(1H,br-s),7.31(2H,d,J=8.8Hz),7.69(2H,d,J=8.8Hz),8.07(1H,d)
元素分析C20H21N3O5S:
C H N
计算值57.82 5.09 10.11
实测值57.93 5.02 9.84
实施例6
N-〔2-〔(4-羟基苯基)氨基〕-3-吡啶基〕-4-甲氧基苯磺酰胺:
(化学式44)
使1.01g(5mmol)制备例4得到的化合物与1.05g(5mmol)对甲氧基苯磺酰氯反应,产物用实施例1的同样方式处理,得到1.43g标题化合物。
熔点:178-179℃(用乙醇重结晶)
FAB质谱m/z:372(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.75(3H,s),6.60(1H,dd,J=4.8,7.6Hz),6.63(2H,d,J=8.8Hz),6.98(2H,d,J=8.8Hz),7.14(2H,d,J=8.8Hz),7.18(1H,dd,J=1.6,7.6Hz),7.58(1H,br-s),7.60(2H,d,J=8.8Hz),7.88(1H,dd,J=1.6,4.8Hz),8.97(1H,s),9.44(1H,s)
元素分析C18H17N3O4S:
C H N
计算值58.21 4.61 11.31
实测值58.40 4.67 11.38
将2.0g标题化合物溶于50ml四氢呋喃。往溶液中加入0.5ml浓盐酸,并将所得溶液浓缩至干。残余物用甲醇重结晶,得到1.9g标题化合物的盐酸化物。
熔点:在225℃观察逐渐分解。
元素分析C18H17N3O4S·Hcl:
C H N
计算值53.01 4.45 10.30
实测值52.97 4.43 10.19
实施例7
4-甲氧基-N-〔2-〔(4-吡啶基)氨基〕-3-吡啶基〕-苯磺酰胺
(化学式45)
按实施例1同样的方式制备标题化合物。
熔点:172-173℃(用乙酸乙酯重结晶)
FAB质谱m/z:357(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.67(3H,s),6.86-6.91(3H,m),7.37(1H,dd,J=1.6,7.6Hz),7.48(2H,d,J=5.6Hz),7.54(2H,d,J=9.2Hz),8.04(1H,dd,J=1.6,4.8Hz),8.26(2H,d,J=5.6Hz),8.59(1H,br-s)
元素分析C17H16N3O3S:
C H N
计算值57.29 4.53 15.72
实测值57.37 4.56 15.66
实施例8
4-甲氧基-N-〔2-〔(4-甲基苯基)氨基〕-3-吡啶基〕苯磺酰胺
(化学式46)
按实施例1的同样方式制备标题化合物。
熔点:188-189℃(用乙醇重结晶)
FAB质谱m/z:370(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
2.21(3H,s),3.69(3H,s),6.66(1H,dd,J=6.4,2.4Hz),6.92(2H,d,J=7.2Hz),6.99(2H,d,J=7.6Hz),7.21(1H,dd,J=6.4,1.6Hz),7.27(2H,d,J=7.2Hz),7.56(2H,d,J=7.6Hz),7.75(1H,s),7.93(1H,dd,J=2.4,1.6Hz),9.48(1H,br-s)
元素分析C19H19N3O3S:
C H N
计算值61.77 5.18 11.38
实测值61.82 5.21 11.30
实施例9
N-〔2-〔(2-氟苯基)氨基〕-3-吡啶基〕-4-甲氧基苯磺酰胺
(化学式47)
按实施例1的同样方式制备标题化合物。
熔点:148-150℃(用乙醇重结晶)
FAB质谱m/z:374(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.72(3H,s),6.76(1H,dd,J=7.6,4.8Hz),6.90-6.98(3H,m),7.05(1H,td,J=8.0,0.8Hz),7.13-7.20(2H,m),7.57(2H,d,J=8.8Hz),7.82(1H,d,J=2.8Hz),7.95(1H,t,J=8.0Hz),8.01(1H,dd,J=4.8,1.6Hz),9.76(1H,s)
元素分析C18H16FN3O3S:
C H N
计算值57.90 4.32 11.25
实测值57.93 4.57 10.98
实施例10
N-〔2-〔(3-氟苯基)氨基〕-3-吡啶基〕-4-甲氧基苯磺酰胺
(化学式48)
按实施例1的同样方式制备标题化合物。
熔点:180-181℃(用乙醇重结晶)
FAB质谱m/z:374(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.69(3H,s),6.67(1H,td,J=8.4,2.0Hz),6.81(1H,dd,J=7.6,4.8Hz),6.92(2H,d,J=8.8Hz),7.09(1H,dd,J=8.4,2.0Hz),7.22(1H,dt,J=8.4,6.8Hz),7.31(1H,dd,J=7.6,1.6Hz),7.49(1H,dt,J=2.0,12.4Hz),7.56(2H,d,J=8.8Hz),8.05(1H,dd,J=4.8,1.6Hz),8.12(1H,s),9.52(1H,br-s)
元素分析C18H16FN3O3S:
C H N
计算值57.90 4.32 11.25
实测值57.89 4.42 11.16
实施例11
N-〔2-〔(4-氟苯基)氨基〕-3-吡啶基〕-4-甲氧基苯磺酰胺
(化学式49)
按实施例1的同样方式制备标题化合物。
熔点:196-197℃(用乙醇重结晶)
FAB质谱m/z:374(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.71(3H,s),6.72(1H,dd,J=4.8,7.6Hz),6.95(2H,d,J=8.8Hz),7.04(2H,t,J=8.8Hz),7.25(1H,dd,J=1.6,7.6Hz),7.42(2H,m),7.58(2H,d,J=8.8Hz),7.95(1H,br-s),7.98(1H,dd,J=1.6,4.8Hz),9.48(1H,br-s)
元素分析C18H16FN3O3S:
C H N
计算值57.90 4.32 11.25
实测值57.83 4.32 11.21
实施例12
N-(2-苯胺基-3-吡啶基)苯磺酰胺
(化学式50)
按实施例1的同样方式制备标题化合物。
熔点:148-150℃(用甲醇重结晶)
FAB质谱m/z:326(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
6.73(1H,dd,J=7.6,4.8Hz),6.87-6.93(1H,m),7.18-7.24(2H,m),7.25(1H,dd,J=7.6,1.6Hz),7.41-7.47(2H,m),7.47-7.51(2H,m),7.51-7.57(1H,m),7.67-7.72(2H,m),7.90(1H,s),7.99(1H,dd,J=4.8,1.6Hz),9.73(1H,s)
元素分析C17H15N3O2S:
C H N
计算值62.75 4.65 12.91
实测值63.03 4.74 12.67
实施例13
4-甲氧基-N-〔2-〔(3-甲氧基苯基)氨基〕-3-吡啶基〕苯磺酰胺
(化学式51)
按实施例1的同样方式制备标题化合物。
熔点:161-162℃(用乙醇重结晶)
FAB质谱m/z:386(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.67,3.70(3H×2),6.47(1H,dd,J=8.0,2.0Hz),6.73(1H,dd,J=8.0,4.8Hz),6.93(2H,d,J=8.8Hz),6.97(1H,dd,J=8.0,2.0Hz),7.10(1H,t,J=8.0Hz),7.13(1H,t,J=2.0Hz),7.29(1H,dd,J=8.0,1.6Hz),7.59(2H,d,J=8.8Hz),7.89(1H,s),8.01(1H,dd,J=4.8,1.6Hz),9.55(1H,s)
元素分析C19H19N3O4S:
C H N
计算值59.21 4.97 10.90
实测值59.14 4.96 10.74
实施例14
4-羟基-N-〔2-〔(4-羟苯基)氨基〕-3-吡啶基〕苯磺酰胺
(化学式52)
将实施例4制得的化合物溶于DMF,并往溶液中加5当量的甲烷硫羟酸钠。所得溶液于100℃加热和处理,得到标题化合物。
熔点:252-257℃(分解)(用乙醇/水重结晶)
FAB质谱m/z:358(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
6.60(1H,dd,J=7.6,4.8Hz),6.65(2H,d,J=8.8Hz),6.81(2H,d,J=8.8Hz),7.14(1H,dd,J=7.6,1.6Hz),7.19(2H,d,J=8.8Hz),7.52(2H,d,J=8.8Hz),7.61(1H,s),7.87(1H,dd,J=4.8,1.6Hz),9.01(1H,s),9.39(1H,s),10.42(1H,s)
实施例15
N-〔2-〔(3,4-二甲氧基苯基)氨基〕-3-吡啶基〕-4-甲氧基苯磺酰胺
(化学式53)
按实施例1同样方式制备标题化合物。
熔点:126-127℃(用乙醇重结晶)
FAB质谱m/z:415(M+)
1H-NMR(DMSO-d6)δ(ppm):
3.72,3.73(3H×3),6.66(1H,dd,J=8.0,3.6Hz),6.81(1H,d,J=8.8Hz),6.96-6.98(3H,m),7.02(1H,s),7.21(1H,dd,J=8.0,1.2Hz),7.60(2H,d,J=8.0Hz),7.73(1H,s),7.95(1H,dd,J=3.6,1.2Hz),9.45(1H,br-s)
元素分析C20H21N3O5S:
C H N
计算值57.82 5.10 10.12
实测值57.37 5.10 10.07
实施例16
4-甲氧基-N-〔2-〔(2-甲氧基苯基)氨基〕-3-吡啶基〕-苯磺酰胺
(化学式54)
按实施例1同样的方式制备标题化合物。
熔点:159-160℃(用乙醇重结晶)
FAB质谱m/z:386(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.78(3H,s),3.89(3H,s),6.69(1H,dd,J=7.6,4.8Hz),6.87-6.90(2H,m),6.96-7.01(2H,m),7.05(2H,d,J=8.8Hz),7.66(2H,d,J=8.8Hz),8.08(1H,dd,J=4.8,1.6Hz),8.10(1H,s),8.40(1H,dd,J=6.4,2.8Hz),9.78(1H,s)
元素分析C19H19N3O4S:
C H N
计算值59.21 4.97 10.90
实测值59.16 5.01 10.96
实施例17
4-甲氧基-N-〔2-〔(3-甲氧基苯基)氨基〕-3-吡啶基〕-苯磺酰胺
(化学式55)
按实施例1同样的方式制备标题化合物。
熔点:147-148℃(用乙醇重结晶)
FAB质谱m/z:370(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
2.26(3H,s),3.71(3H,s),6.71-6.73(2H,m),6.95(2H,d,J=7.6Hz),7.09(1H,t,J=7.6Hz),7.16(1H,s),7.25-7.27(2H,m),7.59(2H,d,J=7.6Hz),7.90(1H,s),8.00(1H.dd,J=2.8,1.6Hz),9.53(1H,br-s)
元素分析C19H19N3O3S:
C H N
计算值61.77 5.18 11.38
实测值61.79 5.18 11.46
实施例18
4-甲氧基-N-〔2-〔(2-甲基苯基)氨基〕-3-吡啶基〕-苯磺酰胺
(化学式56)
按实施例1同样的方式制备标题化合物。
熔点:147-148℃(用乙醇重结晶)
FAB质谱m/z:370(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
2.06(3H,s),3.77(3H,s),6.65(1H,dd,J=7.6,4.8Hz),6.92(1H,t,J=7.6Hz),7.03(2H,d,J=8.8Hz),7.09(1H,t,J=7.6Hz),7.11-7.15(2H,m),7.53(1H,s),7.55(1H,d,J=7.6Hz),7.63(2H,d,J=8.8Hz),7.91(1H,dd,J=4.8,1.6Hz),9.67(1H,s)
元素分析C19H19N3O3S:
C H N
计算值61.77 5.18 11.38
实测值61.80 5.17 11.40
实施例19
N-(2-苯胺基-3-吡啶基)-4-羟基苯磺酰胺
(化学式57)
按实施例14同样的方式处理实施例3的化合物,制备标题化合物。
熔点:226-228℃(用甲醇重结晶)
FAB质谱m/z:342(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
6.71(1H,dd,J=7.6,4.8Hz),6.79(2H,d,J=8.8Hz),6.88-6.94(1H,m),7.21(1H,dd,J=7.6,1.6Hz),7.21-7.27(2H,m),7.46-7.51(2H,m),7.52(2H,d,J=8.8Hz),7.92(1H,s),7.97(1H,dd,J=4.8,1.6Hz),9.50(1H,s),10.40(1H,s)
实施例20
N-(2-苯胺基-3-吡啶基)-4-硝基苯磺酰
(化学式58)
按实施例1同样的方式制备标题化合物。
熔点:191-192℃(用乙醇重结晶)
FAB质谱m/z:371(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
6.80-6.83(2H,m),7.12(2H,t,J=8.4Hz),7.25(2H,d,J=8.4Hz),7.40(1H,dd,J=1.6,7.6Hz),7.83(3H,d,J=8.8Hz),8.07(1H,br-s),8.19(2H,d,J=8.8Hz),9.91(1H,br-s)
元素分析C17H14N4O4S:
C H N
计算值55.13 3.81 15.13
实测值55.17 3.97 14.77
实施例21
4-氨基-N-(2-苯胺基-3-吡啶基)苯磺酰胺
(化学式59)
采用普通方法,在钯/炭催化剂存在下催化还原实施例20的化合物制备标题化合物。
熔点:228-230℃(用乙醇重结晶)
FAB质谱m/z:341(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
5.99(2H,br-s),6.50(2H,d,J=8.8Hz),6.70(1H,dd,J=4.4,7.6Hz),6.91(1H,td,J=0.8,7.2Hz),7.18(1H,dd,J=1.6,7.6Hz),7.24(2H,t,J=7.6Hz),7.33(2H,d,J=8.8Hz),7.53(2H,dt,J=1.2,7.6Hz),7.95(2H,br-s),9.31(1H,s)
元素分析C17H16N4O2S:
C H N
计算值59.58 4.74 16.46
实测值60.08 4.67 16.23
实施例22
N-(2-苯胺基-3-吡啶基)-3,4-二甲氧基苯磺酰胺
(化学式60)
按实施例1同样的方式制备标题化合物。
熔点:171-172℃(用乙醇重结晶)
FAB质谱m/z:386(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.64(3H,s),3.69(3H,s),6.75(1H,dd,J=4.8,7.6Hz),6.88(1H,t,J=7.6Hz),6.93(1H,d,J=8.8Hz),7.10(1H,d,J=2.0Hz),7.17-7.22(3H,m),7.32(1H,d,J=7.6Hz),7.39(2H,d,J=8.0Hz),7.89(1H,br-s),8.00(1H,d,J=4.8Hz),9.48(1H,br-s)
元素分析C19H19N3O4S:
C H N
计算值59.21 4.97 10.90
实测值59.22 4.91 10.63
实施例23
4-羟基-N-〔2-〔(4-甲氧基)氨基〕-3-吡啶基〕苯磺酰胺
(化学式61)
按实施例14的同样处理方法制备标题化合物。
熔点:214-216℃(用乙醇/水重结晶)
FAB质谱m/z:372(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.71(3H,s),6.63(1H,dd,J=7.6,4.8Hz),6.80(2H,d,J=8.8Hz),6.82(2H,d,J=8.8Hz),7.16(1H,dd,J=7.6,1.6Hz),7.35(2H,d,J=8.8Hz),7.51(2H,d,J=8.8Hz),7.75(1H,s),7.90(1H,dd,J=4.8,1.6Hz),9.41(1H,s),10.42(1H,s)
元素分析C18H17N3O4S:
C H N
计算值58.21 4.61 11.31
实测值58.21 4.74 11.01
实施例24
N-(2-苯胺基-3-吡啶基)-4-氯苯磺酰胺
(化学式62)
按实施例1同样的方式制备标题化合物。
熔点:186-188℃(用乙醇重结晶)
FAB质谱m/z:360(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
6.77(1H,dd,J=7.6,4.8Hz),6.90(1H,dt,J=7.6,0.8Hz),7.22(2H,t,J=7.6Hz),7.30(1H,dd,J=7.6,1.2Hz),7.38(2H,dd,J=7.6,0.8Hz),7.51(2H,d,J=8.4Hz),7.64(2H,d,J=8.4Hz),7.89(1H,s),8.02(1H,dd,J=4.8,1.2Hz),9.76(1H,br-s)
元素分析C17H14clN3O2S:
C H N
计算值56.74 3.92 11.68
实测值56.79 4.03 11.67
实施例25
N-(2-苯胺基-3-吡啶基)-3-氯苯磺酰胺
(化学式63)
按照实施例1同样的方式制备标题化合物。
熔点:143-144℃(用乙醇重结晶)
FAB质谱m/z:360(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
6.77(1H,dd,J=7.6,4.8Hz),6.91(1H,dt,J=7.6,1.2Hz),7.21(2H,t,J=7.6Hz),7.32(1H,dd,J=7.6,1.6Hz),7.41(2H,dd,J=7.6,1.2Hz),7.46(1H,t,J=8.0Hz),7.54-7.61(2H,m),7.68(1H,br-s),7.92(1H,br-s),8.04(1H,dd,J=4.8,1.6Hz),9.80(1H,br-s)
元素分析C17H14clN3O2S:
C H N
计算值56.74 3.92 11.68
实测值56.73 4.09 11.68
实施例26
N-(2-苯胺基-3-吡啶基)-3-甲基苯磺酰胺
(化学式64)
按实施例1同样的方式制备标题化合物。
熔点:161-162℃(用乙醇重结晶)
FAB质谱m/z:340(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
2.22(3H,s),6.74(1H,dd,J=7.6,4.8Hz),6.90(1H,dt,J=7.2,1.2Hz),7.21(2H,t,J=7.2Hz),7.27-7.35(3H,m),7.42(2H,dd,J=7.2,1.2Hz),7.45(1H,td,J=7.2,2.0Hz),7.52(1H,br-s),7.92(1H,s),8.00(1H,dd,J=4.8,1.2Hz),9.68(1H,br-s)
元素分析C18H17N3O2S:
C H N
计算值63.70 5.05 12.38
实测值63.81 5.16 12.43
实施例27
N-(2-苯胺基-3-吡啶基)-4-乙氧基苯磺酰胺
(化学式65)
按照实施例1同样的方式制备标题化合物。
熔点:161-162℃(用乙醇重结晶)
FAB质谱m/z:370(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
1.26(3H,t,J=7.0Hz),3.94(2H,q,J=7.0Hz),6.74(1H,dd,J=7.6,4.8Hz),6.89(1H,tt,J=7.2,0.8Hz),6.92(2H,d,J=8.8Hz),7.21(2H,t,J=7.2Hz),7.27(1H,dd,J=7.6,1.6Hz),7.42(2H,dd,J=7.2,0.8Hz),7.57(2H,d,J=8.8Hz),7.88(1H,s),7.99(1H,dd,J=4.8,1.6Hz),9.53(1H,br-s)
元素分析C19H19N3O3S:
C H N
计算值61.77 5.18 11.37
实测值61.72 5.31 11.43
实施例28
4-乙酰氨基-N-(2-苯胺基-3-吡啶基)苯磺酰胺
(化学式66)
按实施例1同样的方式制备标题化合物。
熔点:234-236℃(用乙醇重结晶)
FAB质谱m/z:383(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
2.04(3H,s),6.72(1H,dd,J=7.6,4.8Hz),6.90(1H,tt,J=8.0,1.2Hz),7.19-7.24(3H,m),7.45(2H,dd,J=8.0,1.2Hz),7.60(2H,d,J=9.2Hz),7.65(2H,d,J=9.2Hz),7.91(1H,s),7.98(1H,dd,J=4.8,1.6Hz),9.60(1H,br-s),10.23(1H,br-s)
元素分析C19H18N4O3S:
C H N
计算值59.67 4.74 14.65
实测值59.69 4.82 14.38
实施例29
N-(2-苯胺基-3-吡啶基)-4-苯氧基苯磺酰胺
(化学式67)
按照实施例1同样的方式制备标题化合物。
熔点:164-166℃(用甲醇重结晶)
FAB质谱m/z:418(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
6.78(1H,dd,J=7.6,4.8Hz),6.84(2H,dd,J=7.6,1.2Hz),6.91-6.96(3H,m),7.19-7.27(3H,m),7.36-7.40(3H,m),7.44(2H,dd,J=7.6,1.2Hz),7.62(2H,d,J=9.2Hz),7.85(1H,s),8.02(1H,dd,J=4.8,1.6Hz),9.62(1H,br-s)
元素分析C23H19clN3O3S:
C H N
计算值66.17 4.59 10.06
实测值66.15 4.68 10.04
实施例30
N-(2-苯胺基-3-吡啶基)-4-氰基苯磺酰胺
(化学式68)
按实施例1同样的方式制备标题化合物。
熔点:155-157℃(用甲醇重结晶)
FAB质谱m/z:351(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
6.80(1H,dd,J=7.6,4.8Hz),6.90(1H,t,J=7.6Hz),7.20(2H,t,J=7.6Hz),7.31(2H,d,J=7.6Hz),7.36(1H,dd,J=7.6,1.6Hz),7.76(2H,d,J=7.6Hz),7.86-7.89(3H,m),8.05(1H,br),9.90(1H,br-s)
元素分析C18H14N4O2S:
C H N
计算值61.70 4.03 15.99
实测值61.73 4.14 15.35
实施例31
N-(2-苯胺基-3-吡啶基)-2,4-二甲氧基苯磺酰胺
(化学式69)
按照实施例1同样的方式制备标题化合物。
熔点:176-178℃(用乙醇重结晶)
FAB质谱m/z:386(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.76(3H,s),3.81(3H,s),6.53(1H,dd,J=8.8,2.4Hz),6.59(1H,d,J=2.4Hz),6.69(1H,dd,J=7.6,4.8Hz),6.92(1H,t,J=7.6Hz),7.25(2H,t,J=7.6Hz),7.33(1H,dd,J=7.6,1.6Hz),7.50(2H,d,J=7.6Hz),7.55(1H,d,J=8.8Hz),7.92(1H,dd,J=4.8,1.6Hz),8.07(1H,s)
元素分析C19H19N3O4S:
C H N
计算值59.21 4.97 10.90
实测值59.19 5.04 10.91
实施例32
N-(2-苯胺基-3-吡啶基)-2-氯苯磺酰胺
(化学式70)
按实施例1同样的方式制备标题化合物。
熔点:140-141℃(用乙醇重结晶)
FAB质谱m/z:360(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
6.72(1H,dd,J=7.6,4.8Hz),6.93(1H,t,J=7.6Hz),7.25(2H,t,J=7.6Hz),7.31(1H,dd,J=7.6,1.6Hz),7.42-7.46(1H,m),7.49(2H,d,J=7.6Hz),7.56-7.59(2H,m),7.87(1H,d,J=7.6Hz),7.95-8.01(2H,m),10.14(1H,br-s)
元素分析C17H14ClN3O2S:
C H N
计算值56.74 3.92 11.68
实测值56.86 4.06 11.62
实施例33
4-乙酰基-N-(2-苯胺基-3-吡啶基)苯磺酰胺
(化学式71)
按实施例1同样的方式制备标题化合物。
熔点:171-173℃(用乙醇重结晶)
FAB质谱m/z:368(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
2.46(3H,s),6.78(1H,dd,J=7.6,4.8Hz),6.85(1H,t,J=7.6Hz),7.15(2H,t,J=7.6Hz),7.31(2H,dd,J=7.6,1.2Hz),7.35(1H,dd,J=7.6,1.6Hz),7.74(2H,d,J=8.4Hz),7.85(1H,s),7.94(2H,d,J=8.4Hz),8.03(1H,dd,J=4.8,1.6Hz),9.83(1H,br-s)
元素分析C19H17N3O3S:
C H N
计算值62.11 4.66 11.44
实测值62.31 4.78 11.19
实施例34
N-〔2-〔(3-羟苯基)氨基〕-3-吡啶基〕-4-甲氧基苯磺酰胺
(化学式72)
使4.0g(19.9mmol)制备例6得到的化合物与4.11g(19.9mmol)对甲氧基苯磺酰氯反应,并按实施例1同样方式处理产物,得到5.0g标题化合物。
熔点:181-182℃(用甲苯重结晶)
FAB质谱m/z:372(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.72(3H,s),6.31(1H,dd,J=8.0,2.0Hz),6.72(1H,dd,J=7.6,4.8Hz),6.79(1H,d,J=8.0Hz),6.96(2H,d,J=8.8Hz),6.98(1H,t,J=8.0Hz),7.02(1H,t,J=2.0Hz),7.25(1H,dd,J=7.6,1.6Hz),7.59(2H,d,J=8.8Hz),7.77(1H,s),7.99(1H,dd,J=4.8,1.6Hz),9.18(1H,s),9.56(1H,br-s)
元素分析C18H17N3O4S:
C H N
计算值58.21 4.61 11.31
实测值58.26 4.67 10.99
实施例35
N-〔2-〔(4-乙氧基苯基)氨基〕-3-吡啶基〕-4-甲氧基苯磺酰胺
(化学式73)
按实施例1同样方式制备标题化合物。
熔点:144-146℃(用乙醇重结晶)
FAB质谱m/z:400(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
1.31(3H,t,J=2.8Hz),3.73(3H,s),3.97(2H,q,J=2.8Hz),6.65(1H,dd,J=4.8,7.6Hz),6.80(2H,d,J=8.8Hz),6.98(2H,d,J=8.8Hz),7.21(1H,dd,J=1.6,7.6Hz),7.28(2H,d,J=8.8Hz),7.60(2H,d,J=8.8Hz),7.72(1H,br-s),7.92(1H,dd,J=1.6,4.8Hz),9.47(1H,br-s)
元素分析C20H21N3O4S:
C H N
计算值60.13 5.30 10.52
实测值60.02 5.27 10.21
实施例36
N-〔2-〔(4-羟基-3-甲基苯基)氨基〕-3-吡啶基〕-4-甲氧基苯磺酰胺
(化学式74)
按实施例1同样方式制备标题化合物。
熔点:89-91℃(用甲苯重结晶)
FAB质谱m/z:386(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
2.07(3H,s),3.75(3H,s),6.60(1H,dd,J=4.8,7.6Hz),6.63(1H,d,J=8.4Hz),6.93(1H,d,J=2.8Hz),6.98-7.03(3H,m),7.18(1H,dd,J=1.6,7.6Hz),7.50(1H,br-s),7.60(2H,d,J=8.8Hz),7.88(1H,dd,J=1.6,4.8Hz),8.87(1H,s),9.44(1H,br-s)
元素分析C19H19N3O4S:
C H N
计算值59.21 4.97 10.90
实测值58.97 5.06 10.53
实施例37
4-〔〔3-(4-甲氧基苯磺酰胺基)-2-吡啶基〕氨基〕苯甲酸乙酯
(化学式75)
按实施例1同样方式制备标题化合物。
熔点:172-173℃(用乙醇重结晶)
FAB质谱m/z:428(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
1.31(3H,t,J=3.2Hz),3.63(3H,s),4.27(2H,q,J=3.2Hz),6.88(2H,d,J=8.8Hz),6.88(1H,dd,J=4.8,7.6Hz),7.38(1H,dd,J=1.6,7.6Hz),7.51(2H,d,J=8.8Hz),7.54(2H,d,J=8.8Hz),7.80(2H,d,J=8.8Hz),8.10(1H,dd,J=1.6,4.8Hz),8.34(1H,br-s),9.58(1H,br-s)
元素分析C21H21N3O5S:
C H N
计算值59.00 4.95 9.83
实测值58.98 4.91 9.63
实施例38
4-甲氧基-N-〔2-〔4-甲硫基苯基)〕-3-吡啶基〕苯磺酰胺
(化学式76)
按实施例1同样方式制备标题化合物。
熔点:148-149℃(用乙醇重结晶)
FAB质谱m/z:402(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
2.43(3H,s),3.70(3H,s),6.73(1H,dd,J=4.8,7.6Hz),6.94(2H,d,J=8.8Hz),7.17(2H,d,J=8.8Hz),7.26(1H,dd,J=1.6,7.6Hz),7.39(2H,d,J=8.8Hz),7.57(2H,d,J=8.8Hz),7.93(1H,br-s),7.98(1H,dd,J=1.6,4.8Hz),9.51(1H,br-s)
元素分析C19H19N3O3S2:
C H N
计算值56.84 4.77 10.47
实测值56.90 4.77 10.24
实施例39
4-〔〔3-(4-甲氧基苯磺酰胺基)-2-吡啶基〕氨基〕苯基硫酸钾
(化学式77)
将2.0g(5.38mmol)实施例6的化合物溶于20ml吡啶。于-15~-10℃,往里滴加800mg(6.87mmol)氯代磺酸(95%)。将温度缓慢升到室温,混合物搅拌3天。往反应混合物中加入1N碳酸钾水溶液以调节PH到8-9。减压蒸掉溶剂,往残余物中加水和乙酸乙酯,并分离出由此形成的乙酸乙酯层,浓缩,用硅胶柱色谱法纯化,并用甲醇/二氯甲烷沉淀,得到1.58g标题化合物。
熔点:165-166℃
FAB质谱m/z:528(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.73(3H,s),6.68(1H,dd,J=4.8,8.0Hz),6.98(2H,d,J=8.8Hz),7.02(2H,d,J=8.4Hz),7.25-7.27(3H,m),7.61(2H,d,J=8.8Hz),7.83(1H,s),7.94(1H,dd,J=1.2,4.8Hz),9.55(1H,s)
元素分析C18H16N3O7S2K.3/2H2O:
C H N
计算值41.85 3.71 8.13
实测值41.88 3.41 8.08
实例例40
4-甲氧基-N-〔2-〔(4-苯氧基苯基)氨基〕-3-吡啶基〕苯磺酰胺
(化学式78)
按实施例1同样方式制备标题化合物。
熔点:174-176℃(用乙醇重结晶)
FAB质谱m/z:448(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.75(3H,s),6.72(1H,dd,J=4.8,7.6Hz),6.92(2H,d,J=8.8Hz),6.91-6.97(2H,m),6.96(2H,d,J=8.8Hz),7.05-7.10(1H,m),7.27(1H,dd,J=1.6,7.6Hz),7.32-7.40(2H,m),7.43(2H,d,J=8.8Hz),7.59(2H,d,J=8.8Hz),7.92(1H,br-s),7.98(1H,dd,J=1.6,4.8Hz),9.44(1H,br-s)
元素分析C24H21N3O4S:
C H N
计算值64.41 4.73 9.39
实测值64.71 4.96 9.30
实例例41
4-〔〔3-(4-甲氧基苯磺酰胺基)-2-吡啶基〕氨基〕苯磺酸
(化学式79)
按普通方式碱解实施例37的化合物来制备标题化合物。
熔点:248-250℃(用乙醇重结晶)
FAB质谱m/z:400(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.64(3H,s),6.87(1H,dd,J=4.8,7.6Hz),6.89(2H,d,J=8.8Hz),7.37(1H,dd,J=1.6,7.6Hz),7.49(2H,d,J=8.8Hz),7.54(2H,d,J=8.8Hz),7.78(2H,d,J=8.8Hz),8.09(1H,dd,J=1.6,4.8Hz),8.29(1H,br-s),9.58(1H,br-s),12.44(1H,br)
元素分析C19H17N3O5S:
C H N
计算值57.13 4.29 10.52
实测值57.10 4.42 10.35
实例例42
N-〔2-〔(4-氯苯基)氨基)-3-吡啶基〕-4-甲氧基苯磺酰胺
(化学式80)
按实施例1同样方式制备标题化合物。
熔点:205-207℃(分解)(用乙醇重结晶)
FAB质谱m/z:390(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.70(3H,s),6.78(1H,dd,J=7.6,4.8Hz),6.93(2H,d,J=8.8Hz),7.24(2H,d,J=8.8Hz),7.30(1H,dd,J=7.6,2.0Hz),7.45(2H,d,J=8.8Hz),7.56(2H,d,J=8.8Hz),8.02(1H,dd,J=4.8,2.0Hz),8.05(1H,s),9.51(1H,br-s)
元素分析C18H16ClN3O3S:
C H N
计算值55.46 4.14 10.78
实测值55.44 4.32 10.71
实例例43
N-〔2-〔(2-羟基苯基)氨基〕-3-吡啶基〕-4-甲氧基苯磺酰胺
(化学式81)
按实施例1同样方式制备标题化合物。
熔点:154-155℃(用甲苯重结晶)
FAB质谱m/z:372(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.81(3H,s),6.63(1H,dd,J=8.0,5.2Hz),6.72-6.79(2H,m),6.82-6.86(2H,m),7.07(2H,d,J=8.8Hz),7.66(2H,d,J=8.8Hz),8.05(1H,dd,J=5.2,1.6Hz),8.15(1H,s),8.29(1H,dd,J=7.6,2.0Hz),9.70(1H,s),9.94(1H,s)
元素分析C18H17N3O4S:
C H N
计算值58.22 4.61 11.32
实测值58.39 4.60 11.20
实施例44
N-(2-苯胺基-3-吡啶基)-2,4,6-三甲基苯磺酰胺
(化学式82)
按实施例1同样方式制备标题化合物。
熔点:140-142℃(用乙醇重结晶)
FAB质谱m/z:368(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
2.16(3H,s),2.41(6H,s),6.70(1H,dd,J=7.6,4.8Hz),6.89-6.94(3H,m),7.08(1H,dd,J=7.6,1.6Hz),7.24(2H,t,J=7.6Hz),7.43(2H,d,J=7.6Hz),7.89(1H,s),8.01(1H,dd,J=4.8,1.6Hz),9.58(1H,s)
元素分析C20H21N3O2S:
C H N
计算值65.37 5.76 11.43
实测值65.45 5.67 11.34
实施例45
N-(2-苯胺基-3-吡啶基)-4-氯-2,5-二甲基苯磺酰胺
(化学式83)
按实施例1同样方式制备标题化合物。
熔点:153-154℃(用乙醇重结晶)
FAB质谱m/z:388(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
2.20(3H,s),2.41(3H,s),6.75(1H,dd,J=7.6,4.8Hz),6.91(1H,t,J=7.6Hz),7.23(2H,t,J=7.6Hz),7.26(1H,dd,J=7.6,1.6Hz),7.33(1H,s),7.38(2H,d,J=7.6Hz),7.63(1H,s),7.93(1H,s),8.02(1H,dd,J=4.8,1.6Hz),9.76(1H,s)
元素分析C19H18ClN3O2S:
C H N
计算值58.83 4.68 10.83
实测值58.97 4.64 10.85
实例例46
4-甲氧基-N-〔(2-〔(2-甲氧基-5-吡啶基)氨基〕-3-吡啶基〕苯磺酰胺
(化学式84)
按实施例1同样方式制备标题化合物。
熔点:159-160℃(用乙醇重结晶)
FAB质谱m/z:387(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.73(3H,s),3.81(3H,s),6.68-6.73(2H,m),6.98(2H,d,J=8.8Hz),7.25(1H,dd,J=7.6,1.2Hz),7.60(2H,d,J=8.8Hz),7.72(1H,dd,J=8.8,2.8Hz),7.90(1H,s),7.93(1H,dd,J=4.8,1.2Hz),8.13(1H,d,J=2.8Hz),9.44(1H,br-s)
元素分析C18H18N4O4S:
C H N
计算值55.95 4.69 14.50
实测值55.95 4.72 14.46
实施例47
N-(4-苯胺基-6-甲氧基-5-嘧啶基)-4-甲氧基苯磺酰胺
(化学式85)
按实施例1同样方式制备标题化合物。
熔点:159-160℃(用乙醇重结晶)
FAB质谱m/z:387(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.38(3H,s),3.80(3H,s),7.01-7.07(3H,m),7.30(2H,t,J=8.0Hz),7.57(2H,dd,J=8.0,0.8Hz),7.63(2H,d,J=8.8Hz),8.20(1H,s),8.33(1H,s),9.29(1H,s)
元素分析C18H18N4O4S:
C H N
计算值55.95 4.70 14.50
实测值55.95 4.71 14.49
实施例48
N-(4-苯胺基-6-氯-5-嘧啶基)-4-甲氧基苯磺酰胺
(化学式86)
按实施例1同样方式制备标题化合物。
熔点:174-175℃(用乙醇重结晶)
FAB质谱m/z:391(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.75(3H,s),7.03(2H,d,J=8.8Hz),7.09(1H,t,J=7.6Hz),7.32(2H,t,J=7.6Hz),7.46(2H,d,J=7.6Hz),7.65(2H,d,J=8.8Hz),8.29(1H,s),8.63(1H,s),9.74(1H,br-s)
元素分析C17H15N4O3Scl:
C H N
计算值52.24 3.87 14.33
实测值52.29 3.85 14.27
实施例49
N-(2-苯胺基-6-二甲氧基-3-吡啶基)-4-甲氧基苯磺酰胺
(化学式87)
按实施例1同样方式制备标题化合物。
熔点:152-153℃(用乙酸乙酯/正己烷重结晶)
FAB质谱m/z:399(〔M+H〕+)
1H-NMR(CDCl3)δ(ppm):
3.04(6H,s),3.83(3H,s),5.71(1H,d,J=8.8Hz),5.75(1H,s),6.59(1H,d,J=8.8Hz),6.91-6.96(3H,m),7.24-7.28(3H,m),7.53(2H,d,J=7.6Hz),7.72(2H,d,J=9.2Hz)
元素分析C20H32N4O3S:
C H N
计算值60.28 5.56 14.06
实测值60.21 5.47 13.92
实施例50
N-(2-苯胺基-6-氯-3-吡啶基)-4-甲氧基苯磺酰胺
(化学式88)
按实施例1同样方式制备标题化合物。
熔点:206-208℃(用乙醇重结晶)
FAB质谱m/z:390(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.71(3H,s),6.79(1H,d,J=8.0Hz),6.93-6.99(3H,m),7.26(3H,t,J=8.0Hz),7.38(2H,d,J=8.0Hz),7.61(2H,d,J=9.2Hz),8.15(1H,s),9.56(1H,s)
元素分析C18H16ClN3O3S:
C H N
计算值55.46 4.14 10.78
实测值55.49 4.04 10.62
实施例51
N-(4-苯胺基-3-吡啶基)-4-甲氧基苯磺酰胺
(化学式89)
按实施例1同样方式制备标题化合物。
熔点:201-202℃(用乙醇重结晶)
FAB质谱m/z:356(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.75(3H,s),6.92(1H,d,J=6.4Hz),6.95(2H,d,J=8.8Hz),7.13-7.20(3H,m),7.39(2H,t,J=8.0Hz),7.67(2H,d,J=8.8Hz),7.78(1H,s),7.82(1H,d,J=5.6Hz)
元素分析C18H17N3O3S:
C H N
计算值60.83 4.82 11.82
实测值60.78 4.77 11.84
实例例52
N-〔2-〔(4-二甲基氨基甲酰氧苯基)氨基〕-3-吡啶基〕-4-甲氧基苯磺酰胺
(化学式90)
按实施例1同样方式制备标题化合物。
熔点:202-203℃(用乙醇重结晶)
FAB质谱m/z:443(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
2.90(3H,s),3.03(3H,s),3.72(3H,s),6.72(1H,dd,J=7.6,4.8Hz),6.96(2H,d,J=8.8Hz),6.97(2H,d,J=8.8Hz),7.26(1H,dd,J=7.6,1.6Hz),7.41(2H,d,J=8.8Hz),7.60(2H,d,J=8.8Hz),7.94(1H,s),7.97(1H,dd,J=4.8,1.6Hz),9.52(1H,br-s)
元素分析C21H22N4O5S:
C H N
计算值57.00 5.01 12.66
实测值57.35 4.98 12.55
实施例53
N-(4-苯胺基-5-嘧啶基)-4-甲氧基苯磺酰胺
(化学式91)
采用普通方法,在钯/炭催化剂存在下催化还原实施例48的化合物来制备标题化合物。
熔点:189-190℃(用乙醇重结晶)
FAB质谱m/z:357(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.73(3H,s),7.01(2H,d,J=8.8Hz),7.05(1H,t,J=8.0Hz),7.30(2H,t,J=8.0Hz),7.50(2H,d,J=8.0Hz),7.64(2H,d,J=8.8Hz),7.87(1H,s),8.40(1H,s),8.57(1H,br-s)
元素分析C17H16N4O3S:
C H N
计算值57.29 4.53 15.72
实测值57.25 4.68 15.36
实施例54
N-(2-苯胺基-6-甲氧基-3-吡啶基)-4-甲氧基苯磺酰胺
(化学式92)
按实施例1同样方式制备标题化合物。
熔点:187-188℃(用乙醇重结晶)
FAB质谱m/z:386(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.70(3H,s),3.77(3H,s),6.11(1H,d,J=8.0Hz),6.89(1H,t,J=7.6Hz),6.95(2H,d,J=9.2Hz),7.07(1H,d,J=8.0Hz),7.22(2H,t,J=7.6Hz),7.43(2H,d,J=7.6Hz),7.52(2H,d,J=9.2Hz),7.83(1H,br-s),9.23(1H,br-s)
元素分析C19H19N3O4S:
C H N
计算值59.21 4.97 10.90
实测值59.32 4.97 10.76
实施例55
N-(4,6-二苯胺基-5-嘧啶基)-4-甲氧基苯磺酰胺
(化学式93)
按实施例1同样方式制备标题化合物。
熔点:149-151℃(用二氯甲烷/正己烷重结晶)
FAB质谱m/z:448(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.53(3H,s),6.82(2H,d,J=8.8Hz),6.96(2H,t,J=7.6Hz),7.23(4H,t,J=7.6Hz),7.40(4H,d,J=7.6Hz),7.62(2H,d,J=8.8Hz),8.05(2H,s),8.11(1H,s),8.90(1H,s)
元素分析C23H21N5O3S:
C H N
计算值61.73 4.73 15.65
实测值61.91 4.72 15.74
实施例56
4-甲氧基-N-〔2-(甲基苯基)氨基-3-吡啶基〕苯磺酰胺
(化学式94)
按实施例1同样方式制备标题化合物。
熔点:80-81℃(用二异丙基醚重结晶)
FAB质谱m/z:370(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.01(3H,s),3.82(3H,s),6.46-6.51(2H,m),6.78-6.84(1H,m),7.04(2H,d,J=8.8Hz),7.11-7.17(2H,m),7.17(1H,dd,J=4.8,8.0Hz),7.65(1H,dd,J=1.6,8.0Hz),7.68(2H,d,J=8.8Hz),8.14(1H,dd,J=1.6,4.8Hz),9.30(1H,br-s)
元素分析C19H19N3O3S:
C H N
计算值61.77 5.18 11.38
实测值61.85 5.28 11.36
实施例57
4-甲氧基-N-〔2-〔(2-嘧啶基)氨基〕苯基苯磺酰胺
(化学式95)
按实施例1同样方式制备标题化合物。
熔点:193-195℃(用乙醇重结晶)
FAB质谱m/z:357(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.70(3H,s),6.79-6.83(3H,m),6.96(1H,dt,J=1.6,8.4Hz),7.01(1H,dd,J=1.6,8.4Hz),7.19(1H,dt,J=1.6,8.4Hz),7.47(2H,d,J=8.8Hz),7.87(1H,dd,J=1.6,8.4Hz),8.38(2H,dd,J=1.6,4.8Hz),8.54(1H,br-s),9.53(1H,br-s)
元素分析C17H16N4O3S:
C H N
计算值57.29 4.53 15.72
实测值57.18 4.57 15.80
实施例58
N-(2-苯胺基苯基-4-甲氧基苯磺酰胺
(化学式96)
按实施例1同样方式制备标题化合物。
熔点:140-142℃(用乙醇重结晶)
FAB质谱m/z:354(M+)
1H-NMR(DMSO-d6)δ(ppm):
3.69(3H,s),6.66-6.72(2H,m),6.81(2H,d,J=8.8Hz),6.76-6.87(2H,m),7.04-7.17(5H,m),7.24(1H,br-s),7.52(2H,d,J=8.8Hz),9.30(1H,br-s)
元素分析C19H18N4O3S:
C H N
计算值64.39 5.12 7.90
实测值64.49 5.17 7.77
实施例59
N-〔2-〔(4-苄氧苯基)氨基〕-3-吡啶基〕-4-甲氧基苯磺酰胺
(化学式97)
按实施例1同样方式制备标题化合物。
熔点:208-210℃(用甲醇重结晶)
FAB质谱m/z:476(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.73(3H,s),6.75(1H,d,J=4.8,7.6Hz),6.98(2H,d,J=8.8Hz),7.13(2H,d,J=8.8Hz),7.28(1H,dd,J=1.6,7.6Hz),7.51(2H,d,J=8.8Hz),7.61(2H,d,J=8.8Hz),7.58-7.65(2H,m),7.72-7.78(1H,m),8.00(1H,dd,J=1.6,4.8Hz),8.04(1H,br-s),8.11-8.16(2H,m),9.54(1H,br-s)
元素分析C25H21N3O5S:
C H N
计算值63.15 4.45 8.84
实测值62.95 4.57 8.76
实施例60
N-〔2-〔(4-叔丁氧基羰基氨基乙酰氧基)苯基〕氨基〕-3-吡啶基〕-4-甲氧基苯磺酰胺
(化学式98)
按实施例1同样方式制备标题化合物。
1H-NMR(CDCl3)δ(ppm):
1.47(9H,s),3.82(3H,s),4.18(2H,d,J=5.6Hz),5.17(1H,br-s),6.58(2H,dd,J=7.6,4.8Hz),6.89(1H,dd,J=7.6,1.6Hz),6.90(2H,d,J=8.8Hz),7.00(2H,d,J=8.8Hz),7.35(1H,br-s),7.47(2H,d,J=8.8Hz),7.68(2H,d,J=8.8Hz),8.10(1H,dd,J=4.8,1.6Hz)
实施例61
N-〔2-〔(4-(氨基乙酰氧基)苯基〕氨基〕-3-吡啶基〕-4-甲氧基苯磺酰胺二盐酸化物
(化学式99)
将272mg(0.515mmol)实施例60的化合物加到10ml四氢呋喃中。往混合物中加入2ml浓盐酸,并于室温搅拌3小时。减压蒸掉溶剂,残余物用乙醇重结晶,得到159mg标题化合物。
熔点:196-199℃(分解)
FAB质谱m/z:429(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.71(3H,s),4.08-4.11(2H,m),6.78(1H,dd,J=4.8,7.6Hz),6.94(2H,d,J=8.8Hz),7.04(2H,d,J=8.8Hz),7.32(1H,dd,J=1.6,7.6Hz),7.48-7.51(2H,m),7.61(2H,d,J=8.8Hz),7.97(1H,dd,J=1.6,4.8Hz),8.48(3H,br-s),9.84(1H,br-s)
元素分析C20H20N4O5S·2HCl·1/2H2O:
C H N
计算值47.07 4.54 10.98
实测值47.38 4.45 10.78
实施例62
4-甲氧基-N-〔2-〔(4-甲氧基苯基)氨基〕-3-吡啶基〕-N-甲基苯磺酰胺
(化学式100)
将500mg(1.3mmol)实施例4的化合物溶于5ml二甲基甲酰胺。往溶液中加入60mg(1.5mmol)氢化钠(60%)。所得溶液于室温搅拌30分钟,并往里加入90μl(1.5mmol)甲基碘。
搅拌过夜后,减压蒸掉溶剂。所得残余物溶于乙酸乙酯,并水洗溶液。硫酸镁干燥后,将其浓缩,并用硅胶柱色谱法纯化,得到290mg标题化合物。
FAB质谱m/z:400(〔M+H〕+)
1H-NMR(CDCl3)δ(ppm):
3.15(3H,s),3.80(3H,s),3.88(3H,s),6.50(1H,dd,J=4.8,7.6Hz),6.67(1H,dd,J=1.6,7.6Hz),6.89(2H,d,J=8.8Hz),6.98(2H,d,J=8.8Hz),7.29(1H,br-s),7.47(2H,d,J=8.8Hz),7.65(2H,d,J=8.8Hz),8.09(1H,dd,J=1.6,4.8Hz)
元素分析C20H21N3O3S:
C H N
计算值60.14 5.30 10.52
实测值60.08 5.39 10.29
实施例63
N-〔2-〔〔4-(2-氨基苯甲酰氧)苯基〕氨基〕-3-吡啶基〕-4-甲氧基苯磺酰胺:
(化学式101)
将500mg(1.35mmol)实施例6的化合物、260mg(1.59mmol)靛红酸酐和170mg(1.39mmol)4-二甲基氨基吡啶溶于5ml二甲基甲酰胺,溶液于80℃搅拌5小时。减压蒸掉溶剂,并往残余物中加入乙酸乙酯。用乙醇重结晶形成的沉淀,得到500mg标题化合物。
熔点:221-225℃(分解)
FAB质谱m/z:491(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.74(3H,s),6.60(1H,td,J=1.6,8.4Hz),6.73(2H,br-s),6.74(1H,dd,J=4.8,8.0Hz),6.83(1H,dd,J=0.8,8.4Hz),6.98(2H,d,J=8.8Hz),7.08(2H,d,J=9.2Hz),7.27(1H,dd,J=2.0,8.0Hz),7.33(1H,td,J=1.6,7.2Hz),7.49(1H,d,J=9.2Hz),7.61(2H,d,J=8.8Hz),7.92(1H,dd,J=1.6,8.4Hz),7.99(1H,dd,J=2.0,4.8Hz),8.02(1H,s),9.60(1H,br-s)
元素分析C25H22N4O5S:
C H N
计算值61.21 4.52 11.42
实测值60.98 4.52 11.24
实施例64
4-〔〔3-(4-甲氧基苯磺酰胺基)-2-吡啶基〕氨基〕苯基磷酸二氢酯
(化学式102)
将7.44g(20mmol)实施例6的化合物悬浮于100ml磷酰氯中,并将悬浮液加热回流直至得到均相溶液。减压蒸掉磷酰氯,然后往残余物中加入二异丙醚,形成固体。将该固体通过过滤进行分离,并悬浮于四氢呋喃(100ml)。冰冷下往悬浮液中加50ml水,并搅拌,直至得到均相溶液。减压蒸掉溶剂后,将100ml甲醇和100ml水加到残余物中,得到的溶液减压浓缩,直至形成不溶物。除掉不溶物,残余物进一步减压浓缩,通过过滤移出所得沉淀,得到4.27g标题化合物。
熔点:215-216℃
FAB质谱m/z:452(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.73(3H,s),6.70(1H,dd,J=7.6,4.8Hz),6.98(2H,d,J=8.8Hz),7.02(2H,d,J=8.8Hz),7.24(1H,dd,J=7.6,1.6Hz),7.35(2H,d,J=8.8Hz),7.60(2H,d,J=8.8Hz),7.88(1H,s),7.95(1H,dd,J=4.8,1.6Hz),9.50(1H,br-s)
元素分析C18H18N3O7PS:
C H N
计算值47.90 4.02 9.31
实测值47.72 4.00 9.39
实施例65
3-〔(3-(4-甲氧基苯磺酰胺基)-2-吡啶基〕氨基〕苯基磷酸二氢酯
(化学式103)
使1.00g(2.7mmol)实施例34的化合物与10ml磷酰氯反应,产物用实施例64的同样方式处理,由此得到120mg标题化合物。
熔点:166-168℃
FAB质谱m/z:452(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.70(3H,s),6.73(1H,d,J=7.6Hz),6.77(1H,dd,J=7.6,4.8Hz),6.95(2H,d,J=8.8Hz),7.15(1H,t,J=7.6Hz),7.21(1H,d,J=7.6Hz),7.30(1H,dd,J=7.6,1.6Hz),7.37(1H,s),7.59(2H,d,J=8.8Hz),8.01(1H,dd,J=4.8,1.6Hz),8.10(1H,s),9.61(1H,br-s)
元素分析C18H18N3O7PS·H2O:
C H N
计算值46.06 4.29 8.95
实测值46.16 4.13 8.83
实施例66
4-甲氧基-N-〔2-〔〔4-(4-甲氧基苯磺酰胺基)苯基〕氨基〕-3-吡啶基〕苯磺酰胺
(化学式104)
使制备例4得到的化合物与4-甲氧基苯磺酰氯以1∶2的当量比反应,得到标题化合物。
熔点:122-123℃(用乙醇重结晶)
FAB质谱m/z:542(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.71(3H,s),3.88(3H,s),6.76(1H,dd,J=7.6,4.8Hz),6.84(2H,d,J=8.8Hz),6.94(2H,d,J=8.8Hz),7.17(2H,d,J=8.8Hz),7.25(1H,dd,J=7.6,1.2Hz),7.42(2H,d,J=8.8Hz),7.56(2H,d,J=8.8Hz),7.76(2H,d,J=8.8Hz),7.98(1H,dd,J=4.8,1.2Hz),8.06(1H,s),9.51(1H,br-s)
元素分析C25H23N3O7S2:
C H N
计算值55.40 4.28 7.76
实测值55.57 4.26 7.61
实施例67
N-〔2-〔(4-羟苯基)氨基〕苯基〕-4-甲氧基苯磺酰胺:
(化学式105)
按实施例1同样方式制备标题化合物。
熔点:163-164℃(用乙醇重结晶)
FAB质谱m/z:370(M+)
1H-NMR(DMSO-d6)δ(ppm):
3.76(3H,s),6.58-6.67(5H,m),6.77(1H,br-s),6.80(1H,dd,J=1.6,8.0Hz),6.90-7.00(4H,m),7.56(2H,d,J=8.8Hz),9.05(1H,s),9.23(1H,br-s)
元素分析C19H48N2O4S:
C H N
计算值61.61 4.90 7.56
实测值61.86 4.90 7.39
实施例68
4-甲氧基-N-〔2-〔(4-新戊酰氧苯基)氨基〕-3-吡啶基〕苯磺酰胺
(化学式106)
按实施例1同样方式制备标题化合物。
熔点:188-189℃(用甲苯重结晶)
FAB质谱m/z:456(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
1.30(9H,s),3.72(3H,s),6.73(1H,dd,J=7.6,4.8Hz),6.94(2H,d,J=8.8Hz),6.97(2H,d,J=8.8Hz),7.25(1H,dd,J=7.6,1.6Hz),7.45(2H,d,J=8.8Hz),7.60(2H,d,J=8.8Hz),7.97-8.00(2H,m),9.52(1H,br-s)
元素分析C23H25N3O5S:
C H N
计算值60.64 5.53 7.22
实测值60.57 5.43 8.95
实施例69
4-甲氧基-N-〔2-〔(4-吡啶基)氨基〕苯基〕苯磺酰胺
(化学式107)
按实施例1同样方式制备标题化合物。
熔点:185-187℃(用乙醇重结晶)
FAB质谱m/z:356(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.67(3H,s),6.45(2H,d,J=6.0Hz),6.73(2H,d,J=8.8Hz),7.07(1H,dt,J=7.6,1.2Hz),7.16(1H,dt,J=7.6,1.2Hz),7.22(1H,dd,J=7.6,1.2Hz),7.28(1H,dd,J=7.6,1.2Hz),7.45(2H,d,J=8.8Hz),7.90(1H,br-s),8.05(2H,d,J=6.0Hz)
元素分析C18H17N3O3S:
C H N
计算值60.83 4.82 11.82
实测值61.08 4.86 11.87
实施例70
N-〔2-(4-甲氧基苯磺酰胺基)苯基〕-2-甲基烟酰胺
(化学式108)
将0.97g(7mmol)2-甲基烟酸悬浮于4.5ml二氯甲烷中。将1.33g(16.8mmol)吡啶和(然后)硫酰氯加到溶液中。混合物室温搅拌30分钟,然后往里加入1.77g(6.36mmol)制备例12得到的化合物于7ml二氯甲烷溶液。搅拌过夜后,往里加入碳酸氢钠水溶液,产物用二氯甲烷萃取。浓缩后,将乙醇加到浓缩液中,过滤分离出形成的晶体,并用乙醇重结晶,得到0.80g标题化合物。
熔点:148-149℃
FAB质谱m/z:398(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
2.56(3H,s),3.80(3H,s),7.02(2H,d,J=8.8Hz),7.08(1H,dd,J=2.0,8.4Hz),7.11(1H,dt,J=1.6,4.4Hz),7.18-7.27(1H,m),7.37(1H,dd,J=4.8,7.6Hz),7.57(2H,d,J=8.8Hz),7.71-7.84(2H,m),8.58(1H,dd,J=1.6,4.8Hz),9.37(1H,br-s),9.60(1H,br-s)
元素分析C20H19N3O4S:
C H N
计算值60.44 4.82 10.57
实测值60.37 4.90 10.41
实施例71
N-〔2-(4-甲氧基苯磺酰胺基)苯基〕-4-甲基烟酰胺
(化学式109)
按实施例70的同样方式制备标题化合物。
熔点:199-200℃(用甲醇重结晶)
FAB质谱m/z:398(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
2.58(39,s),3.81(3H,s),7.00-7.07(3H,m),7.09-7.18(1H,m),7.19-7.27(1H,m),7.62(2H,d,J=8.4Hz),7.74-7.80(1H,m),7.82(1H,d,J=5.6Hz),8.80(1H,d,J=5.6Hz),8.87(1H,s),9.62(1H,br-s),10.16(1H,br-s)
实施例72
N-〔2-(4-甲氧基苯磺酰胺基)苯基〕-3-甲基异烟酰胺
(化学式110)
按实施例70的同样方式制备标题化合物。
熔点:194-195℃(用乙醇重结晶)
FAB质谱m/z:398(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
2.36(3H,s),3.81(3H,s),7.03(2H,d,J=8.8Hz),7.07(1H,dd,J=1.6,8.0Hz),7.12(1H,dt,J=1.6,8.0Hz),7.20-7.27(1H,m),7.36(1H,d,J=4.8Hz),7.58(2H,d,J=8.8Hz),7.76-7.83(1H,m),8.55-8.61(2H,m),9.39(1H,br-s),9.65(1H,br-s)
元素分析C20H19N3O4S:
C H N
计算值60.44 4.82 10.57
实测值60.29 4.83 10.49
实施例73
4-〔〔3-(4-甲氧基苯磺酰胺基)-2-吡啶基〕氨基〕苯基β-D-吡喃葡萄糖苷
(化学式111)
将637mg(0.908mmol)制备例11得到的化合物溶于7ml 1N氢氧化钠和20ml乙醇的混合物中,并回流溶液3小时。冷却后,往溶液中加4ml 1N盐酸,并浓缩混合物。往浓缩液中加入乙酸乙酯和水,分离出形成的乙酸乙酯层,干燥,浓缩,和硅胶柱色谱法纯化,得到270mg标题化合物。
1H-NMR(DMSO-d6)δ(ppm):
3.15-3.33(4H,m),3.49(1H,dd,J=5.6,11.6Hz),3.70-3.73(4H,s+dd),4.75(1H,d,J=7.6Hz),6.68(1H,dd,J=4.8,8.0Hz),6.93(2H,d,J=9.2Hz),6.97(2H,d,J=9.2Hz),7.23(1H,dd,J=2.0,7.6Hz),7.29(2H,d,J=9.2Hz),7.60(2H,d,J=9.2Hz),7.95(1H,dd,J=2.0,4.8Hz)
实施例74
β-D-吡喃葡萄糖苷糖醛酸4-〔〔3-(4-甲氧基苯磺酰胺基)-2-吡啶基〕氨基〕苯酯
(化学式112)
按制备例11和实施例73的同样方式制备标题化合物。
1H-NMR(DMSO-d6)δ(ppm):
3.27(1H,t,J=8.8Hz),3.33(1H,t,J=8.8Hz),3.42(1H,t,J=8.8Hz),3.71(3H,s),3.86(1H,d,J=9.6Hz),4.92(1H,d,J=7.6Hz),6.70(1H,dd,J=5.2,7.6Hz),6.90(2H,d,J=8.8Hz),6.96(2H,d,J=8.8Hz),7.25(1H,dd,J=1.6,7.6Hz),7.29(2H,d,J=8.8Hz),7.59(2H,d,J=8.8Hz),7.95(1H,dd,J=1.6,5.2Hz)
实施例75
4-甲氧基-N-〔2-〔(3,4,5-三甲氧基苯基)氨基〕-3-吡啶基〕苯磺酰胺
(化学式113)
按实施例1同样方式制备标题化合物。
FAB质谱m/z:445(M+)
1H-NMR(DMSO-d6)δ(ppm):
3.61(3H,s),3.71(3H,s),3.74(6H,s),6.72(1H,dd,J=4.8,7.6Hz),6.79,6.80(2H,s+s),6.98(2H,d,J=8.8Hz),7.24(1H,dd,J=1.6,7.6Hz),7.59(2H,d,J=8.8Hz),7.81(1H,br-s),8.00(1H,dd,J=1.6,4.8Hz),9.47(1H,br-s)
元素分析C21H23N3O6S:
C H N
计算值56.62 5.20 9.43
实测值56.42 5.22 9.14
实施例76
4-甲氧基-N-〔2-〔(2-吡啶基)氨基〕苯基〕苯磺酰胺
(化学式114)
按实施例1同样方式制备标题化合物。
熔点:113-116℃(用环己烷重结晶)
FAB质谱m/z:356(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.70(3H,s),6.53-6.59(1H,m),6.70-6.75(1H,m),6.71(2H,d,J=8.8Hz),6.95(1H,dt,J=1.2,8.0Hz),7.11(1H,dd,J=1.2,8.0Hz),7.14(1H,dt,J=1.6,8.0Hz),7.41-7.52(3H,m),7.61-7.66(1H,m),8.05(1H,dd,J=1.2,4.8Hz),8.06(1H,br-s),9.59(1H,br-s)
元素分析C18H17N3O3S:
C H N
计算值60.83 4.82 11.82
实测值61.11 4.82 11.85
实施例77
N-(2-苯胺基-4-氟苯基)-4-甲氧基苯磺酰胺
(化学式115)
按实施例1同样方式制备标题化合物。
熔点:173-174℃(用乙醇重结晶)
FAB质谱m/z:372(M+)
1H-NMR(DMSO-d6)δ(ppm):
3.69(3H,s),6.57(1H,dt,J=2.8,8.8Hz),6.73-6.91(6H,m),7.00(1H,dd,J=6.4,8.8Hz),7.19(2H,t,J=7.6Hz),7.37(1H,br-s),7.50(2H,d,J=8.8Hz),9.33(1H,br-s)
元素分析C19H17FN2O3S:
C H N
计算值61.28 4.60 7.52
实测值61.39 4.62 7.25
实施例78
N-〔2-〔(4-氯苯基)氨基〕苯基〕-4-甲氧基苯磺酰胺
(化学式116)
按实施例1同样方式制备标题化合物。
熔点:127-128℃(用乙醇重结晶)
FAB质谱m/z:388(M+)
1H-NMR(DMSO-d6)δ(ppm):
3.69(3H,s),6.61(2H,d,J=8.8Hz),6.77(2H,d,J=9.2Hz),6.88-6.94(1H,m),7.07-7.14(4H,m),7.18(1H,dd,J=1.2,8.0Hz),7.36(1H,br-s),7.47(2H,d,J=9.2Hz),9.28(1H,br-s)
元素分析C19H17ClN2O3S:
C H N
计算值58.68 4.41 7.20
实测值58.85 4.39 7.04
实施例79
N-〔2-〔(4-羟苯基)氨基〕苯基〕-4-甲氧基苯磺酰胺
(化学式117)
按实施例1同样方式制备标题化合物。
熔点:165-166℃(用乙醇重结晶)
FAB质谱m/z:370(M+)
1H-NMR(DMSO-d6)δ(ppm):
3.71(3H,s),6.12-6.17(2H,m),6.19-6.24(1H,m),6.79-6.86(3H,m),6.91(1H,t,J=8.4Hz),7.07(1H,dt,J=1.2,8.0Hz),7.08(1H,dd,J=1.2,8.0Hz),7.13(1H,dd,J=1.2,8.0Hz),7.14(1H,br-s),7.52(2H,d,J=8.8Hz),9.16(1H,s),9.28(1H,br-s)
元素分析C19H18N2O4S:
C H N
计算值61.61 4.90 7.56
实测值61.62 4.91 7.42
实施例80
4-苄氧基-N-〔2-(4-甲氧基苯磺酰胺基)苯基〕苯甲酰胺
(化学式118)
按实施例70同样方式制备标题化合物。
熔点:148-149℃(用乙醇重结晶)
FAB质谱m/z:489(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.74(3H,s),5.23(2H,s),6.89(2H,d,J=8.8Hz),7.07(1H,dd,J=2.0,8.0Hz),7.10(1H,dt,J=1.2,8.0Hz),7.17(2H,d,J=8.8Hz),7.23(1H,dt,J=2.0,8.0Hz),7.33-7.39(1H,m),7.42(2H,t,J=7.6Hz),7.47-7.52(4H,m),7.74(1H,dd,J=1.2,8.0Hz),7.81(2H,d,J=8.8Hz),9.44(1H,br-s),9.47(1H,br-s)
元素分析C27H24N2O5S:
C H N
计算值66.38 4.95 5.73
实测值66.34 4.92 5.73
实施例81
4-羟基-N-〔2-(4-甲氧基苯磺酰胺基)苯基〕苯甲酰胺
(化学式119)
以普通方式催化还原实施例80得到的化合物来制备标题化合物。
熔点:205-207℃(用乙酸乙酯重结晶)
FAB质谱m/z:399(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.76(3H,s),6.89(2H,d,J=8.8Hz),6.91(2H,d,J=8.8Hz),7.04(1H,dd,J=1.6,8.0Hz),7.09(1H,dt,J=1.6,8.0Hz),7.20-7.25(1H,m),7.50(2H,d,J=8.8Hz),7.68-7.76(3H,m),9.38(1H,s),9.47(1H,s),10.20(1H,s)
元素分析C20H18N2O5S:
C H N
计算值60.29 4.55 7.03
实测值60.38 4.58 6.75
实施例82
4-氟-N-〔2-(4-甲氧基苯磺酰胺基)苯基〕苯甲酰胺
(化学式120)
按实施例70的同样方式制备标题化合物。
熔点:169-170℃(用乙醇重结晶)
FAB质谱m/z:401(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.75(3H,s),6.90(2H,d),7.07-7.16(2H,m),7.19-7.26(1H,m),7.39(2H,t,J=8.8Hz),7.50(2H,d,J=8.8Hz),7.66-7.73(1H,m),7.91(2H,dd,J=5.6,8.8Hz),9.38(1H,br-s),9.54(1H,br-s)
元素分析C20H17FN2O4S:
C H N
计算值59.99 4.28 7.00
实测值60.00 4.31 6.70
实施例83
3-羟基-N-〔2-(4-甲氧基苯磺酰胺基)苯基〕苯甲酰胺
(化学式121)
按实施例81同样方式制备标题化合物。
熔点:191-192℃(用乙醇重结晶)
FAB质谱m/z:399(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.77(3H,s),6.92(2H,d,J=8.8Hz),6.99-7.06(2H,m),7.09(1H,dt,J=1.6,8.0Hz),7.20-7.27(3H,m),7.34(1H,t,J=8.0Hz),7.51(2H,d,J=8.8Hz),7.75-7.81(1H,m),9.46(1H,s),9.51(1H,s),9.81(1H,s)
元素分析C20H18N2O5S:
C H N
计算值60.29 4.55 7.03
实测值60.41 4.55 6.71
实施例84
N-〔2-(4-甲氧基苯磺酰胺基)苯基〕-2-噻吩甲酰胺
(化学式122)
按实施例70同样方式制备标题化合物。
熔点:136-137℃(用乙醇重结晶)
FAB质谱m/z:389(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.75(3H,s),6.85(2H,d,J=8.8Hz),7.05-7.13(2H,m),7.17-7.26(2H,m),7.49(2H,d,J=8.8Hz),7.60-7.70(1H,m),7.77(1H,dd,J=1.6,4.0Hz),7.87(1H,dd,J=1.6,5.2Hz),9.50(2H,br-s)
元素分析C20H16N2O5S2:
C H N
计算值55.65 4.15 7.21
实测值55.80 4.27 7.24
实施例85
N-〔2-(4-甲氧基苯磺酰胺基)苯基〕-2-呋喃甲酰胺
(化学式123)
按实施例70同样方式制备标题化合物。
熔点:158-159℃(用乙醇重结晶)
FAB质谱m/z:373(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.76(3H,s),6.73(1H,dd,J=1.6,3.6Hz),6.91(2H,d,J=8.8Hz),6.98(1H,dd,J=1.6,8.0Hz),7.08(1H,dt,J=1.6,8.0Hz),7.21(1H,dd,J=0.8,3.6Hz),7.24(1H,dt,J=1.6,8.0Hz),7.53(2H,d,J=8.8Hz),7.84(1H,dd,J=1.6,8.0Hz),7.99(1H,dd,J=0.8,1.6Hz),9.42(1H,br-s),9.62(1H,br-s)
元素分析C18H16N2O4S:
C H N
计算值58.05 4.33 7.52
实测值58.08 4.39 7.44
实施例86
N-〔2-(4-甲氧基苯磺酰胺基)苯基〕-2-吡啶甲酰胺
(化学式124)
按实施例70同样方式制备标题化合物。
熔点:174-175℃(用乙醇重结晶)
FAB质谱m/z:384(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.75(3H,s),6.82(1H,dd,J=1.6,8.0Hz),6.92(2H,d,J=8.8Hz),7.03(1H,dt,J=1.6,8.0Hz),7.30(1H,dt,J=1.6,8.0Hz),7.57(2H,d,J=8.8Hz),7.70(1H,td,J=1.6,4.8,7.6Hz),8.08(1H,dt,J=1.6,7.6Hz),8.12-8.17(1H,m),8.24(1H,dd,J=1.6,7.6Hz),8.77(1H,dd,J=1.6,4.8Hz),9.73(1H,br-s),10.67(1H,br-s)
元素分析C19H17N3O4S:
C H N
计算值59.52 4.47 10.96
实测值59.73 4.54 10.92
实施例87
N-〔2-(4-甲氧基苯磺酰胺基)苯基〕-烟酰胺
(化学式125)
按实施例70同样方式制备标题化合物。
熔点:179-180℃(用乙醇重结晶)
FAB质谱m/z:384(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.74(3H,s),6.89(2H,d,J=8.8Hz),7.12-7.19(2H,m),7.19-7.27(1H,m),7.51(2H,d,J=8.8Hz),7.59(1H,dd,J=4.8,8.0Hz),7.63-7.71(1H,m),8.17(1H,dd,J=1.2,8.0Hz),8.79(1H,dd,J=1.2,4.8Hz),8.99(1H,d,J=1.2Hz),9.49(1H,br-s),9.68(1H,br-s)
元素分析C19H17N3O4S:
C H N
计算值59.52 4.47 10.96
实测值59.61 4.57 10.84
实施例88
N-〔2-(4-甲氧基苯磺酰胺基)苯基〕-异烟酰胺
(化学式126)
按实施例70同样方式制备标题化合物。
熔点:162-163℃(用乙醇重结晶)
FAB质谱m/z:384(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.75(3H,s),6.90(2H,d,J=8.8Hz),7.11-7.27(3H,m),7.53(2H,d,J=8.8Hz),7.64-7.71(1H,m),7.75(2H,d,J=4.8Hz),8.81(2H,d,J=4.8Hz),9.52(1H,br-s),9.73(1H,br-s)
元素分析C19H17N3O4S:
C H N
计算值59.52 4.47 10.96
实测值59.59 4.52 10.96
实施例89
4-氟-N-〔2-(4-甲氧基苯磺酰胺基)-6-甲基苯基〕苯甲酰胺
(化学式127)
按实施例70同样方式制备标题化合物
熔点:204-206℃(用乙醇重结晶)
FAB质谱m/z:415(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
2.10(3H,s),3.80(3H,s),6.97(2H,d,J=8.8Hz),7.00-7.12(3H,m),7.37(2H,t,J=8.8Hz),7.65(2H,d,J=8.8Hz),8.03(2H,dd,J=5.6,8.8Hz),9.46(1H,br-s),9.48(1H,br-s)
元素分析C21H19FN2O4S:
C H N
计算值60.86 4.62 6.76
实测值60.74 4.56 6.65
实施例90
N-〔2-(4-甲氧基苯磺酰胺基)-6-甲基苯基〕烟酰胺
(化学式128)
按实施例70同样方式制备标题化合物。
熔点:207-209℃(用乙醇重结晶)
FAB质谱m/z:398(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
2.11(3H,s),3.79(3H,s),6.98(2H,d,J=8.8Hz),7.02(1H,dd,J=1.6,7.6Hz),7.05-7.14(2H,m),7.58(1H,dd,J=4.8,8.0Hz),7.66(2H,d,J=8.8Hz),8.29(1H,dt,J=1.6,8.0Hz),8.77(1H,dd,J=1.6,4.8Hz),9.13(1H,d,J=1.6Hz),9.53(1H,br),9.64(1H,br-s)
元素分析C20H19N3O4S:
C H N
计算值60.44 4.82 10.57
实测值60.55 4.90 10.53
实施例91
N-〔2-(4-甲氧基苯磺酰胺基)-6-甲基苯基〕异烟酰胺
(化学式129)
按实施例70同样方式制备标题化合物。
熔点:213-217℃(用乙醇重结晶)
FAB质谱m/z:398(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
2.10(3H,s),3.80(3H,s),6.99(2H,d,J=8.8Hz),7.02(1H,dd,J=1.6,7.6Hz),7.04-7.14(2H,m),7.67(2H,d,J=8.8Hz),7.87(2H,dd,J=1.6,8.4Hz),8.80(2H,dd,J=1.6,8.4Hz),9.56(1H,br-s),9.73(1H,br-s)
元素分析C20H19N3O4S:
C H N
计算值60.44 4.82 10.57
实测值60.60 4.85 10.53
实施例92
N-〔2-(4-甲氧基苯磺酰胺基)-6-甲基苯基〕-2-吡啶甲酰胺
(化学式130)
按实施例70同样方式制备标题化合物。
熔点:180-182℃(用乙醇重结晶)
FAB质谱m/z:398(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
2.12(3H,s),3.78(3H,s),6.90(2H,d,J=8.8Hz),6.93(1H,t,J=4.8Hz),7.11(2H,d,J=4.8Hz),7.54(2H,d,J=8.8Hz),7.65-7.72(1H,m),8.03-8.08(2H,m),8.75(1H,dd,J=1.2,5.2Hz),9.53(1H,br-s),10.11(1H,br-s)
元素分析C20H19N3O4S:
C H N
计算值60.44 4.89 10.57
实测值60.43 4.92 10.45
实施例93
N-〔2-(4-甲氧基苯磺酰胺基)苯基〕-2-硝基苯甲酰胺
(化学式131)
按实施例70同样方式制备标题化合物。
熔点:168-170℃(用乙醇重结晶)
FAB质谱m/z:428(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.80(3H,s),7.05(2H,d,J=8.8Hz),7.07-7.16(2H,m),7.19-7.26(1H,m),7.62(2H,d,J=8.8Hz),7.66(1H,d,J=8.0Hz),7.73(1H,d,J=8.0Hz),7.79(1H,t,J=8.0Hz),7.92(1H,t,J=8.0Hz),8.16(1H,d,J=8.0Hz),9.23(1H,br-s),9.93(1H,br-s)
元素分析C20H17N3O6S:
C H N
计算值56.20 4.01 9.83
实测值56.21 4.05 9.77
实施例94
2-氯-4-氟-N-〔2-(4-甲氧基苯磺酰胺基)苯基〕苯甲酰胺
(化学式132)
按实施例70同样方式制备标题化合物。
熔点:160-162℃(用乙醇重结晶)
FAB质谱m/z:435(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.81(3H,s),6.97-7.18(4H,m),7.19-7.28(1H,m),7.34-7.44(1H,m),7.51-7.64(4H,m),6.74-7.82(1H,m),9.33(1H,br-s),9.69(1H,s)
元素分析C20H16clN2O4S:
C H N
计算值55.24 3.71 6.44
实测值55.42 3.90 6.20
实施例95
N-〔2-(4-甲氧基苯磺酰胺基)苯基〕-2-甲基苯甲酰胺
(化学式133)
按实施例70同样方式制备标题化合物。
熔点:129-130℃(用乙醇重结晶)
FAB质谱m/z:397(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
2.38(3H,s),3.81(3H,s),7.03(2H,d,J=8.8Hz),7.07(1H,dd,J=2.0,8.0Hz),7.10(1H,dt,J=1.2,8.0Hz),7.19-7.27(1H,m),7.27-7.39(3H,m),7.42(1H,dt,J=2.0,7.2Hz),7.56(2H,d,J=8.8Hz),7.80-7.87 (1H,m),9.40(1H,br-s),9.46(1H,br-s)
元素分析C21H20cl
C H N
计算值63.62 5.09 7.07
实测值63.64 5.09 7.03
实施例96
2-氯-4-N-〔2-(4-甲氧基苯磺酰胺基)苯基〕烟酰胺
(化学式134)
按实施例70同样方式制备标题化合物。
熔点:133-135℃(用乙醇重结晶)
FAB质谱m/z:418(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.81(3H,s),7.04(2H,d,J=8.8Hz),7.07-7.15 (2H,m),7.18-7.22(1H,m),7.60(2H,d)(J=8.8Hz),7.61(1H,dd,J=4.8,7.6HZ,7.78(1H,d,J=7.6Hz),7.98(1H,dd,J=2.0,7.6Hz),8.56(1H,dd,J=2.0,4.8Hz),9.29(1H,br-s),9.87(1H,s)
元素分析C19H16clN3O4S:
C H N
计算值54.61 3.86 10.06
实测值54.71 3.87 9.90
实施例97
2-氟-N-〔2-(4-甲氧基苯磺酰胺基)苯基〕苯硫酰胺
(化学式135)
在100℃下,将549mg(1.371mmol)实施例82得到的化合物、333mg(0.823mmol)Lawesson试剂和10ml甲苯的混合物加热。浓缩后,残余物用硅胶柱色谱法纯化,得到506mg标题化合物。
熔点:155-156℃(用正丁醇重结晶)
FAB质谱m/z:417(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.80(3H,s),7.02(2H,d,J=8.8Hz),7.10-7.25,(3H,m),7.33(2H,t,J=8.8Hz),7.47-7.58(1H,m),7.63(2H,d,J=8.8Hz),7.98(2H,dd,J=5.6,8.8Hz),9.45(1H,br),11.13(1H,br)
元素分析C20H17FN2O3S:
C H N
计算值57.68 4.11 6.73
实测值57.63 4.12 6.58
实施例98
N-〔5-氟-2-(4-甲氧基苯磺酰胺基)苯基〕苯甲酰胺
(化学式136)
按实施例70同样方式制备标题化合物。
熔点:153-154℃(用乙醇重结晶)
FAB质谱m/z:401(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.75(3H,s),6.88(2H,d,J=8.8Hz),6.94(1H,dt,J=3.2,8.8Hz),7.00(1H,dd,J=6.0,8.8Hz),7.47(2H,d,J=8.8Hz),7.55(2H,t,J=7.6Hz),7.59-7.66(1H,m),7.74-7.83(3H,m),9.45(1H,br-s),9.55(1H,br-s)
元素分析C20H17clN2O4S:
C H N
计算值59.55 4.28 7.00
实测值59.97 4.32 6.79
实施例99
4-氯-N-〔2-(4-硝基苯磺酰胺基)苯基〕苯甲酰胺
(化学式137)
按实施例70同样方式制备标题化合物。
熔点:265-266℃(用乙酸乙酯重结晶)
FAB质谱m/z:416(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
7.21(1H,dt,J=1.6,8.0Hz),7.25(1H,dd,J=2.0,8.0Hz),7.30(1H,dt,J=2.0,8.0Hz),7.35(2H,t,J=8.8Hz),7.55-7.60(1H,m),7.76(2H,d,J=8.8Hz),7.83(2H,dd,J=5.6,8.8Hz),8.22(2H,d,J=8.8Hz),9.42(1H,s),9.89(1H,s)
元素分析C19H14FN3O5S:
C H N
计算值54.94 3.40 10.12
实测值54.90 3.36 9.93
实施例100
2-氯-6-甲基-N-〔2-(4-甲氧基苯磺酰胺基)苯基〕烟酰胺
(化学式138)
按实施例70同样方式制备标题化合物。
熔点:150-151℃(用乙醇重结晶)
FAB质谱m/z:432(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
2.58(3H,s),3.76(3H,s),6.90(2H,d,J=8.8Hz),7.15-7.26(3H,m),7.52(2H,d,J=8.8Hz),7.54-7.63(3H,m),9.44(1H,br-s),9.73(1H,br-s)
元素分析C20H18ClN3O4S:
C H N
计算值55.62 4.20 9.73
实测值55.80 4.26 9.75
实施例101
N-〔2-(4-甲氧基苯磺酰胺基)苯基〕乙酰胺
(化学式139)
按实施例70同样方式制备标题化合物。
熔点:160-161℃(用乙醇重结晶)
FAB质谱m/z:321(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
1.96(3H,s),3.80(3H,s),6.99-7.17(5H,m),7.48(1H,d,J=8.0Hz),7.53(2H,d,J=8.8Hz),9.23(2H,br-s)
元素分析C15H16N2O4S:
C H N
计算值56.24 5.03 8.75
实测值56.26 5.03 8.72
实施例102
N-〔2-(4-甲氧基苯磺酰胺基)苯基〕甲酰胺
(化学式140)
按实施例70同样方式制备标题化合物。
熔点:143-144℃(用乙醇重结晶)
FAB质谱m/z:307(〔M+H〕+)
元素分析C14H14N2O4S:
C H N
计算值54.89 4.61 9.14
实测值55.05 4.65 9.09
实施例103
N-〔2-〔(乙氧基羰基)氨基〕苯基〕-4-甲氧基苯磺酰胺
(化学式141)
按实施例70同样方式制备标题化合物。
熔点:118-119℃(用乙醇重结晶)
FAB质谱m/z:351(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
1.22(3H,t,J=7.2Hz),3.79(3H,s),4.03(2H,q,J=7.2Hz),6.98-7.03(4H,m),7.17(1H,t,J=8.0Hz),7.52(2H,d,J=8.8Hz),7.57(1H,d,J=8.0Hz),8.43(1H,s),9.35(1H,s)
元素分析C16H18N2O5S:
C H N
计算值54.84 5.18 7.99
实测值54.78 5.19 7.86
实施例104
N-〔2-〔(乙基氨基羰基)氨基〕苯基〕-4-甲氧基苯磺酰胺
(化学式142)
使制备例12得到的化合物与异氰酸乙酯反应并按普通方式处理产物制备标题化合物。
熔点:152-154℃(用乙醇重结晶)
FAB质谱m/z:350(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
1.08(3H,t,J=7.2Hz),3.10(2H,dq,J=5.6,7.2Hz),3.82(3H,s),6.61(1H,dd,J=1.6,8.0Hz),6.77(1H,dt,J=1.2,8.0Hz),6.89(1H,t,J=5.6Hz),7.04(2H,d,J=8.8Hz),7.05-7.12(1H,m),7.57(2H,d,J=8.8Hz),7.78(1H,dd,J=1.2,8.4Hz),7.94(1H,s),9.41(1H,s)
元素分析C16H19N3O4S:
C H N
计算值55.00 5.48 12.03
实测值55.08 5.47 11.88
实施例105
N-〔3-(4-甲氧基苯磺酰胺基)-2-吡啶基〕-2-甲基苯甲酰胺
(化学式143)
按实施例70同样方式制备标题化合物。
熔点:160-162℃(用乙醇重结晶)
FAB质谱m/z:398(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
2.37(3H,s),3.81(3H,s),7.05(2H,d,J=8.8Hz),7.22-7.33(4H,m),7.36-7.43(1H,m),7.59(2H,d,J=8.8Hz),7.71(1H,dd,J=1.6,8.0Hz),8.25(1H,dd,J=1.6,4.8Hz),9.24(1H,br-s),10.47(1H,br-s)
元素分析C20H19N3O4S:
C H N
计算值60.44 4.82 10.57
实测值60.53 4.84 10.67
实施例106
N-〔2-(4-氨基苯磺酰胺基)苯基〕-4-氟苯甲酰胺
(化学式144)
用锌/盐酸还原实施例99制得的化合物制备标题化合物。
熔点:203-205℃(用乙醇重结晶)
FAB质谱m/z:386(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
5.98(2H,br-s),6.45(2H,d,J=8.8HZ,7.05(1H,dd,J=1.6,8.0Hz),7.09(1H,dt,J=1.6,8.0Hz),7.20(1H,dt,J=1.6,8.0Hz),7.23(2H,d,J=8.8Hz),7.39(2H,t,J=8.8Hz),7.74-7.80(1H,m),7.93(2H,dd,J=5.6,8.8Hz),9.20(1H,br-s),9.63(1H,br-s)
元素分析C19H16FN3O3S:
C H N
计算值59.21 4.18 10.90
实测值59.36 4.21 10.80
实施例107
N-〔2-(4-氯苯磺酰胺基)苯基〕苯甲酰胺
(化学式145)
按实施例70同样方式制备标题化合物。
熔点:191-192℃(用乙醇重结晶)
FAB质谱m/z:387(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
7.13-7.20(2H,m),7.24-7.30(1H,m),7.42(2H,d,J=8.8Hz),7.54(2H,d,J=8.8Hz),7.55(2H,t,J=8.8Hz),7.60-7.66(1H,m),7.68-7.72(1H,m),7.78-7.83(2H,m),9.52(1H,s),9.71(1H,s)
元素分析C19H15clN2O3S:
C H N
计算值58.99 3.91 7.24
实测值59.25 4.02 7.29
实施例108
N-〔2-(3,4-二甲氧基苯磺酰胺基)苯基〕苯甲酰胺
(化学式146)
按实施例70同样方式制备标题化合物。
熔点:183-184℃(用乙醇重结晶)
FAB质谱m/z:413(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.53(3H,s),3.75(3H,s),6.90(1H,d,J=8.4Hz),6.95(1H,d,J=2.0Hz),7.13(1H,dd,J=2.0,8.4Hz),7.13-7.18(2H,m),7.23-7.29(1H,m),7.54(2H,t,J=7.6Hz),7.59-7.65(1H,m),7.71-7.76(1H,m),7.76-7.82(2H,m),9.43(1H,br-s),9.53(1H,br-s)
元素分析C21H20N2O5S:
C H N
计算值61.15 4.89 6.78
实测值61.16 4.90 6.82
实施例109
N-〔2-(4-甲氧基苯磺酰胺基)苯基〕苯甲酰胺
(化学式147)
按实施例70同样方式制备标题化合物。
熔点:167-168℃(用乙醇重结晶)
FAB质谱m/z:383(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
3.75(3H,s),6.91(2H,d,J=8.8Hz),7.08(1H,dd,J=1.6,8.0Hz),7.12(1H,dt,J=1.6,8.0Hz),7.24(1H,dt,J=1.6,8.0Hz),7.51(2H,d,J=8.8Hz),7.52-7.59(2H,m),7.60-7.66(1H,m),7.76(1H,dd,J=1.6,8.0Hz),7.81-7.86(2H,m),9.50(1H,br-s),9.55(1H,br-s)
元素分析C20H19N2O4S:
C H N
计算值62.81 4.74 7.33
实测值63.06 4.77 7.32
实施例110
4-乙氧基-N-〔2-((4-羟苯基)氨基-3-吡啶基〕苯甲酰胺
熔点:194-195℃(用乙醇重结晶)
FAB质谱m/z:386(〔M+H〕+)
1H-NMR(DMSO-d6)δ(ppm):
1.27(3H,t,J=7.2Hz),3.98(2H,g,J=7.2Hz),6.59(1H,dd,J=4.8,7.6Hz),6.61(2H,d,J=8.8Hz),6.95(2H,d,J=9.2Hz),7.12(2H,d,J=8.8Hz),7.17(1H,dd,J=1.6,7.6Hz),7.55(1H,br-s),7.56(2H,d,J=9.2Hz),7.87(1H,dd,J=1.6,4.8Hz),8.97(1H,s),9.41(1H,br-s)
元素分析C19H19N3O3S:
C H N
计算值59.21 4.97 10.90
实测值59.12 4.93 10.66
Claims (11)
1、通式(Ⅰ)的磺酰胺衍生物或其药用盐:
[化学式1]
其中:
R1代表氢原子,卤原子,低级烷基,低级烷氧基,羟基,硝基,苯氧基,氰基,乙酰基或可保护的氨基,
R2和R3可相同或不同,分别代表氢原子,卤原子,低级烷基或低级烷氧基,
R4和R7可相同或不同,分别代表氢原子或低级烷基,
R5和R6可相同或不同,分别代表氢原子,卤原子,低级烷氧基或可取代的氨基,
A代表式=N-或=CH-基,
[化学式2]
E代表式 基,其中Q代表氧原子或硫原子,R11代表氢原子,低级烷基,可取代有低级烷基的氨基,低级烷氧基、2-噻吩基、2-呋喃基或式 基(D是=N-或=CH-,R12和R13可相同或不同,各代表氢原子,卤原子,硝基,可保护的羟基或低级烷基);或者可取代有1-3个取代基G的6元环基,其中取代基G彼此可相同或不同且环基在环上可具有1或2个氮原子(G是卤原子,低级烷基,低级烷氧基,可保护的羟基,可酯化或酰胺化的羧基或苯基),条件是排除以下组合:
1)R1是氢原子、低级烷基、硝基或可保护的氨基,R2和R3分别是氢原子,A和B分别是=CH-且R是可取代有1-3个可相同或不同的取代基G的苯基,和
2)R1,R2和R3可相同或不同,分别代表氢原子、低级烷基、硝基或卤原子,A和B分别是=CH-,
[化学式3]
2、按照权利要求1的磺酰胺衍生物或其药用盐,其中R1代表低级烷氧基。
3、按照权利要求1的磺酰胺衍生物或其药用盐,其中A代表式=CH-基且B代表式=N-基。
4、按照权利要求1~3的磺酰胺衍生物或其药用盐,其中E代表可取代有1-3个相同或不同取代基G(G按权利要求1定义)的苯基、吡啶基或嘧啶基。
5、按照权利要求1~3的磺酰胺衍生物或其药用盐,其中E代表取代的可保护的羟基的苯基。
8、一种制备权利要求1的磺酰胺衍生物或其药用盐的方法,包括下述(a)~(d)中任意一种方法:
a)使通式(Ⅱ)的磺酸或其反应性衍生物
〔化学式6〕
(其中R1 a代表氢原子,卤原子,低级烷基,低级烷氧基,保护的羟基,硝基,苯氧基,氰基,乙酰基或保护的氨基,R2和R3按权利要求1定义)
与通式(Ⅲ)的化合物反应:
〔化学式7〕
(其中R4,R7,A,B和E按权利要求1定义,R5 a和R6 a可相同或不同,分别代表氢原子,低级烷基,低级烷氧基或保护或取代的氨基),而且当所得化合物具有保护基时,需要的话,将所述保护基除掉;
b)使通式(Ⅳ)化合物
〔化学式8〕
〔其中R1 a,R2,R3,R4,R5 a,R6 a,R7,A和B定义如上,Ea代表可取代了1-3个取代基Ga的芳族6元环基(环上可含有1或2个氮原子),取代基Ga彼此可相同或不同,为卤原子,低级烷基,低级烷氧基,羟基,可酯化或酰胺化的羧基,低级烷硫基或苯氧基,条件是环上至少一个Ga基是羟基〕
与通式(Ⅴ)的化合物反应:
(其中X代表能与羟基的氧原子结合的基团,Y代表可除去基团),或与能和羟基反应的无机酸或有机酸酐反应,而且当所得化合物具有保护基时,需要的话,除去所述保护基;
c)使通式(Ⅵ)化合物
〔化学式9〕
(其中R1 a,R2,R3,R5 a,R6 a,R7,A,B和E分别定义如上)与烷基化剂反应,当所得化合物具有保护基时,需要的话,除掉所述保护基;以及
(d)使通式(Ⅶ)化合物
〔化学式10〕
(其中R1 a,R2,R3,R4,R5 a,R6 a,A和B分别定义如上)与通式(Ⅷ)化合物反应:
(其中R11定义如上,Z代表羧基或其反应性衍生物),或当R11是低级烷氨基时,与低级异氰酸烷基酯反应。
9、一种抗肿瘤剂,它含有按照权利要求1所述的磺酰胺衍生物或其药用盐作为活性成分。
10、按照权利要求1的磺酰胺衍生物或其药用盐,其中所述化合物选自以下磺酰胺衍生物:
1)N-(2-苯胺基-3-吡啶基)-对甲苯磺酰胺,
2)N-(2-苯胺基-3-吡啶基)-4-乙基苯磺酰胺,
3)N-(2-苯胺基-3-吡啶基)-4-甲氧基苯磺酰胺,
4)4-甲氧基-N-〔2-〔(4-甲氧基苯基)氨基〕-3-吡啶基〕苯磺酰胺,
5)N-〔2-〔(4-羟基苯基)氨基〕-3-吡啶基〕-4-甲氧基苯磺酰胺,
6)4-甲氧基-N-〔2-〔(4-吡啶基)氨基〕-3-吡啶基〕苯磺酰胺,
7)4-〔〔3-(4-甲氧基苯磺酰胺基)-2-吡啶基〕氨基苯基磷酸二氢酯,
8)N-(2-苯胺基苯基)-4-甲氧基苯磺酰胺,
9)N-〔2-(4-甲氧基苯磺酰胺基)苯基〕-2-甲基烟酰胺,和
10)N-〔2-(4-甲氧基苯磺酰胺基)苯基〕-3-甲基异烟酰胺。
11、一种药物组合物,它含有药用有效量的权利要求1定义的衍生物和药用载体。
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1991
- 1991-08-07 DE DE69129611T patent/DE69129611T2/de not_active Expired - Lifetime
- 1991-08-07 EP EP91113256A patent/EP0472053B1/en not_active Expired - Lifetime
- 1991-08-07 AT AT91113256T patent/ATE167473T1/de not_active IP Right Cessation
- 1991-08-08 US US07/742,618 patent/US5250549A/en not_active Expired - Lifetime
- 1991-08-12 HU HU912676A patent/HUT59663A/hu unknown
- 1991-08-12 FI FI913815A patent/FI913815A/fi not_active Application Discontinuation
- 1991-08-14 TW TW080106438A patent/TW206208B/zh active
- 1991-08-16 AU AU82493/91A patent/AU636239B2/en not_active Ceased
- 1991-08-16 NZ NZ239425A patent/NZ239425A/xx unknown
- 1991-08-16 NO NO913207A patent/NO178695C/no unknown
- 1991-08-16 KR KR1019910014156A patent/KR950001686B1/ko not_active IP Right Cessation
- 1991-08-19 CA CA002049496A patent/CA2049496C/en not_active Expired - Fee Related
- 1991-08-19 CN CN91105827A patent/CN1036650C/zh not_active Expired - Fee Related
- 1991-08-19 IE IE293691A patent/IE912936A1/en not_active Application Discontinuation
- 1991-08-20 RU SU915001370A patent/RU2059615C1/ru active
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1992
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1994
- 1994-04-22 US US08/231,272 patent/US5434172A/en not_active Expired - Fee Related
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1995
- 1995-03-17 CN CN95103522A patent/CN1136036A/zh active Pending
- 1995-05-26 US US08/450,138 patent/US5610320A/en not_active Expired - Fee Related
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109331868A (zh) * | 2018-09-29 | 2019-02-15 | 广东工业大学 | 一种苯甘氨酸类双官能团催化剂及其制备方法和应用 |
CN109331868B (zh) * | 2018-09-29 | 2021-03-26 | 广东工业大学 | 一种苯甘氨酸类双官能团催化剂及其制备方法和应用 |
Also Published As
Publication number | Publication date |
---|---|
ATE167473T1 (de) | 1998-07-15 |
KR950001686B1 (ko) | 1995-02-28 |
EP0472053A2 (en) | 1992-02-26 |
NO178695B (no) | 1996-02-05 |
CA2049496A1 (en) | 1992-02-21 |
AU8249391A (en) | 1992-02-27 |
KR920004341A (ko) | 1992-03-27 |
DE69129611T2 (de) | 1998-12-17 |
EP0472053B1 (en) | 1998-06-17 |
US5610304A (en) | 1997-03-11 |
NO913207L (no) | 1992-02-21 |
CN1036650C (zh) | 1997-12-10 |
NO913207D0 (no) | 1991-08-16 |
HUT59663A (en) | 1992-06-29 |
FI913815A0 (fi) | 1991-08-12 |
US5250549A (en) | 1993-10-05 |
NZ239425A (en) | 1993-10-26 |
CN1136036A (zh) | 1996-11-20 |
US5332751A (en) | 1994-07-26 |
NO178695C (no) | 1996-05-15 |
US5610320A (en) | 1997-03-11 |
FI913815A (fi) | 1992-02-21 |
TW206208B (zh) | 1993-05-21 |
US5434172A (en) | 1995-07-18 |
RU2059615C1 (ru) | 1996-05-10 |
AU636239B2 (en) | 1993-04-22 |
CA2049496C (en) | 1997-02-04 |
IE912936A1 (en) | 1992-02-26 |
HU912676D0 (en) | 1992-01-28 |
US5292758A (en) | 1994-03-08 |
EP0472053A3 (en) | 1994-08-10 |
DE69129611D1 (de) | 1998-07-23 |
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