CN1069312C - 取代的亚胺基磺酰胺、其制法、用途、和含有它们的药物 - Google Patents
取代的亚胺基磺酰胺、其制法、用途、和含有它们的药物 Download PDFInfo
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- CN1069312C CN1069312C CN96122091A CN96122091A CN1069312C CN 1069312 C CN1069312 C CN 1069312C CN 96122091 A CN96122091 A CN 96122091A CN 96122091 A CN96122091 A CN 96122091A CN 1069312 C CN1069312 C CN 1069312C
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- FNXLCIKXHOPCKH-UHFFFAOYSA-N bromamine Chemical compound BrN FNXLCIKXHOPCKH-UHFFFAOYSA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
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- 230000001413 cellular effect Effects 0.000 description 1
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- 125000000259 cinnolinyl group Chemical class N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000006880 cross-coupling reaction Methods 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- 239000013530 defoamer Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- ONDPGJBEBGWAKI-UHFFFAOYSA-N diphenylphosphane;propane Chemical compound CCC.C=1C=CC=CC=1PC1=CC=CC=C1 ONDPGJBEBGWAKI-UHFFFAOYSA-N 0.000 description 1
- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- PJJJBBJSCAKJQF-UHFFFAOYSA-N guanidinium chloride Chemical compound [Cl-].NC(N)=[NH2+] PJJJBBJSCAKJQF-UHFFFAOYSA-N 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 230000012447 hatching Effects 0.000 description 1
- 238000005534 hematocrit Methods 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- HOBCFUWDNJPFHB-UHFFFAOYSA-N indolizine Chemical compound C1=CC=CN2C=CC=C21 HOBCFUWDNJPFHB-UHFFFAOYSA-N 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 229960001708 magnesium carbonate Drugs 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- 229960000869 magnesium oxide Drugs 0.000 description 1
- 235000012245 magnesium oxide Nutrition 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000035407 negative regulation of cell proliferation Effects 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- VWBWQOUWDOULQN-UHFFFAOYSA-N nmp n-methylpyrrolidone Chemical compound CN1CCCC1=O.CN1CCCC1=O VWBWQOUWDOULQN-UHFFFAOYSA-N 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
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- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
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- 239000011886 peripheral blood Substances 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
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- 239000010773 plant oil Substances 0.000 description 1
- 229940093916 potassium phosphate Drugs 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
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- 238000000746 purification Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical class [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
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- 239000000376 reactant Substances 0.000 description 1
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- 238000006722 reduction reaction Methods 0.000 description 1
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- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
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- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
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- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical class OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 150000003752 zinc compounds Chemical class 0.000 description 1
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Abstract
式Ⅰ的亚胺基磺酰胺
其中取代基R(1)，R(2)和R(3)中至少一个为胍基，其他取代基的定义如权利要求书所指，该化合物特别适用于心血管系统的药物；它可作为具有心血管保护作用的抗心律失常药，并可用于局部缺血引起的损害的治疗；它也可用外科手术如器官移植。
Description
本发明涉及式Ⅰ的亚胺基磺酰胺及其药用盐其中：R(1),R(2)和R(3)三个取代基中至少一个为苯甲酰胍
其中：其中苯基部分未取代或由1-4个选自如下的取代基取代：具有1,2,3,4,5,6,7或8个碳原子的烷基，具有2,3,4,5,6,7或8个碳原子的链烯基，-(CH)m-R(14),F,Cl,Br,I,-C≡N,CF3,R(22)SO2-,R(23)R(24)N-CO-,R(25)-CO-,R(26)R(27)N-SO2-,-OR(35),-SR(35)或-NR(35)R(36)；
m为0,1或2；R(14)为
-(C3-C8)-环烷基或苯基，
它可未被取代或由1-3个选自如下的基团取代：F和
Cl,-CF3,甲基，甲氧基和-NR(15)R(16)；
R(15)和R(16)各自独立地为氢或-CH3；R(22),R(23),R(25)和R(26)
各自独立地为具有1,2,3,4,5,6,7或8个碳原子的烷基，
具有2,3,4,5,6,7或8个碳原子的链烯基，(CH2)nR(29)
或-CF3；
n为0,1,2,3或4；
R(29)为-(C3-C7)-环烷基或苯基，
它可未取代或由1-3个选自F,Cl,-CF3，甲基，甲氧
基和-NR(30)R(31)的基团取代；
R(30)和R(31)
为氢或具有1,2,3或4个碳原子的烷基；或R(23),R(25)和R(26)为氢；R(24)和R(27)
各自为氢或具有1,2,3或4个碳原子的烷基；或R(23)和R(24)，以及R(26)和R(27)
一起为5或6个亚甲基，其中一个CH2可被氧，-S-,-
NH-,-NCH3或-N-苄基替代；
R(35)和R(36)
各自为氢或具有1,2,3,4,5或6个碳原子的烷基；或R(35)和R(36)
一起为4-7个亚甲基，其中一个CH2可被氧，-S-,-
NH-,-NCH3或-N-苄基替代；或R(35)
为苯基
它可被未取代或由1-3个选自F,Cl,-CF3，甲基，甲
氧基，SO2R(5),SO2NR(6)R(7)和-NR(32)R(33)的
基团取代；
R(5)为具有1,2,3,4,5或6个碳原子的烷基。
各自为氢或具有1,2,3或4个碳原子的烷基；
R(32)和R(33)
各自为氢或具有1,2,3或4个碳原子的烷基；
或R(35)
为C1-C9-杂芳基，
它可未被取代或由1-3个选自F,Cl,CF3,CH3，甲氧基，羟
基，氨基，甲氨基和二甲氨基的基团取代；其它的取代基R(1),R(2)和R(3)各自独立地为具有1,2,3,4,5,6,7或8个碳原子的烷基，(CH2)pR(10)p为0,1,2,3或4；R(10)为苯基，
它可未被取代或由1-3个选自F,Cl,-CF3，甲基，甲氧
基，SO2NR(17)R(8)和-SO2R(9)的基团取代；
R(17)和R(8)
各自为氢或具有1,2,3或4个碳原子的烷基；
R(9)为具有1,2,3或4个碳原子的烷基；或者其他的R(1)和R(3)基团为氢，R(4)为氢或具有1,2,3或4个碳原子的烷基。
优选的式Ⅰ化合物及其药用盐中：R(1),R(2)和R(3)中的一个为苯甲酰基胍
其中苯基部分可未取代或由1-3个选自如下的取代基取
代：具有1,2,3或4个碳原子的烷基；具有2,3或4个碳原
子的链烯基，-(CH2)mR(14),F,Cl,CF3,R(22)SO2-,R
(23)R(24)N-CO-,R(25)-CO-,R(26)R(27)N-
SO2,-OR(35),-SR(35)和-NR(35)R(36)；R(22)和R(25)
各自为甲基或-CF3；
R(23),R(24),R(26)和R(27)
各自为氢或甲基；
m为0,1或2；
R(14)为-(C3-C6)-环烷基或苯基，它可未取代或由1-
2个选自F和Cl,-CF3，甲基和甲氧基的基团取代；
R(35)和R(36)
各自为氢或具有1,2,3或4个碳原子的烷基；
或
R(35)和R(36)
一起为4-6个亚甲基；其中一个CH2可被氧，-S-,
-NH-或-NCH3替代；
或
R(35)为苯基，
它可未取代或由1-2个选自F,Cl,-CF3，甲基，甲氧
基，SO2R(5)和SO2NR(6)R(7)的基团取代；
R(5)为具有1,2,3或4个碳原子的烷基
R(6)和R(7)
各自为氢，甲基或乙基；
或
R(35)
为C1-C9-杂芳基
它可未取代或由1-2个选自F,Cl,CF3,CH3和甲氧
基的基团取代；其他的取代基R(1),R(2)和R(3)
各自独立为具有1,2,3,4,5或6个碳原子的烷基或(CH2)pR
(10)
p为0,1或2；
R(10)为苯基，
它可未取代或由1-2个选自F,Cl,CF3，甲基，甲氧基，
-SO2NR(17)R(8)和-SO2R(9)的基团取代；
R(17)和R(18)各自独立为氢，甲基或乙基；
R(9)为甲基或乙基；或其他的取代基R(1)和R(3)
为氢，R(4)
为氢或具有1,2,3或4个碳原子的烷基。
特别优选的式Ⅰ化合物及其药用盐中：取代基R(1),R(2)和R(3)之一为苯甲酰基胍其中苯基部分未取代或由1-2个选自如下的基团取代：具有1,2,3或4个碳原子的烷基，R(14),F,Cl,CF3,R(22)SO2-,R(23)R(24)N-CO-,R(25)-CO-,R(26)R(27)N-SO2-,-OR(35),-SR(35)和-NR(35)R(36)；R(22)和R(25)
各自独立为甲基或CF3；R(23),R(24),R(26)和R(27)
各自独立为氢或甲基；R(14)为-(C3-C6)-环烷基或苯基，
它可未取代或由一个选自F和Cl,-CF3，甲基和甲氧基
的基团取代；R(35)和R(36)
各自为氢或具有1,2,3或4个碳原子的烷基；或R(35)
为苯基，
它可未取代或由一个选自F,Cl,-CF3，甲基，甲氧基
SO2CH3和SO2NR(6)R(7)的基团取代；
SO2CH3和SO2NR(6)R(7)的基团取代；
R(6)和R(7)各自独立为氢，甲基或乙基；
或
R(35)
为C1-C9-杂芳基
它可未取代或由一个选自F,Cl,CF3,CH3和甲氧基的
基团取代；其他的取代基R(1),R(2)和R(3)
各自独立为具有1,2,3或4个碳原子的烷基或苯基，
它可未取代或由一个选自F,Cl,CF3，甲基，甲氧基，-
SO2NR(17)R(8)和-SO2CH3的基团取代；
R(17)和R(8)各自独立为氢，甲基或乙基；或R(1)为氢或具有1,2,3或4个碳原子的烷基；或R(3)为氢；R(4)为氢或具有1,2,3或4个碳原子的烷基。
所述的烷基可为直链的或支链的。
显然(C1-C9)-杂芳基为由苯基或萘基衍生的基团，其中一个或多个CH基被N替代，和/或其中至少两个相邻的CH基被S,NH或O替代(形成五元芳环)。另外，双环基(如中氮茚基)的缩合位置的一个或两个原子也可为N原子。
特别地，杂芳基为呋喃基，噻吩基，吡咯基，咪唑基，吡唑基，三唑基，四唑基，噁唑基，异噁唑基，噻唑基，异噻唑基，吡啶基，吡嗪基，嘧啶基，哒嗪基，吲哚基，吲唑基，喹啉基，异喹啉基，2,3-二氮杂萘基，喹喔啉基，喹唑啉基，噌啉基。
如果取代基R(1)到R(4)之一含有一个或多个不对称中心，它们会各自存在S或R构型。该化合物会存在光学异构体，非对映异构体，外消旋体或它们的混合物。
上述的烷基也可为直链的或支链的。
本发明进一步涉及制备化合物Ⅰ的方法，其中包括，使其中R
HS-R(2)′ Ⅱ与按已知方法就地制备的单氯-或单溴胺反应。该反应可在惰性溶剂如CH2Cl2,CHCl3或CCl4中，在室温至所用溶剂的熔点间的温度下，优选0°和-40℃间的温度下进行。在某些情况下，基于卤代胺的胺、或水也可用作溶剂。得到了其中R(1)′、R(2)′,R(3)′和R(4)′为暂时被任选地保护的或前述的R(1),R(2),R(3)和R(4)的式Ⅲ亚胺基磺酰胺。随后通过芳香亲核取代，引入基团R(3)，显然得到与式Ⅲ亚胺基磺酰胺相类似的磺酰胺。
苯甲酸的功能化是通过原则上已知的方法，在化合物Ⅳ上由胍基取代一个容易亲核除去的离去基团L而实现脒基化，
式Ⅳ中取代基R(1″),R(2″)或R(3″)中至少一个定义如R(1),R(2)和R(3)，但由易于除去的离去基团L代替胍基。
苯基部分由硫，氧或氮亲核试剂取代的苯甲酸衍生物的引入可按文献上已知的芳香亲核取代方法进行。已证明适用于该取代的苯甲酸衍生物离去基团为卤根和三氟甲磺酸根。反应在偶极非质子传递溶剂，如DMF或TMU中，在从0℃到溶剂沸点的温度下，优选从80℃到溶剂沸点的温度下进行较为有利。缚酸剂优优使用具有高碱性和低亲核性阴离子的碱金属和碱土金属盐，例如，K2CO3或CsCO3。
基团R(1)到R(4)中的可用作还原剂的功能基优选地在引入亚胺基磺酰胺基后被合成。在亚胺基磺酰胺官能团制备中，对保护基的需要取决于反应类型。在这种情况下，反应为使用强氧化剂的氧化反应。含氮杂芳基如吡啶基，可以相应的N-氧化物的形式被保护。
杂芳取代基中氮的氧化可使用原则上已知的方法，通过合适的中间体化合物如苯甲酸酯而进行。例如，已证明，间氯过苯甲酸在惰性溶剂如二氯甲烷中，在-30℃到溶剂沸点的温度下反应是合适的。杂芳基N-氧化物，例如，吡啶N-氧化物的还原反应方法同样在原则上是已知的。例如，与三苯膦或亚磷酸三甲酯的反应证明是合适的(C.Kaneko,A.Yamamoto,M.Gomi Heferocycles 12,227(1979))。
烷基或芳基取代基可通过文献中已知的方法、通过把一中介的芳基卤化物与，例如，有机锌化合物，有机锡，有机硼酸或有机硼烷的交叉偶合而导入。
通常，亚胺基磺酰胺为弱碱，可与酸结合形成盐。可能的酸加成盐为所有药用酸的盐，例如，卤化物，特别是盐酸盐，抗坏血酸盐，乳酸盐，硫酸盐，柠檬酸盐，酒石酸盐，乙酸盐，磷酸盐，甲磺酸盐和P-甲苯磺酸盐。
美国专利5091 394(HOE 89/F 288)和欧洲公开说明书0556674(HOE 92/F 034)公开了苯甲酰基胍，但是，取代基的定义与本发明所要求的不一样。无亚胺基苯磺酰胺衍生物的报导。另外，已知苯甲酰基胍的水溶性还需要改进。
由于其药理学性质，该化合物特别适用于具有心脏保护组分的抗心律失常药中，以用于梗塞的预防和梗塞的治疗以及心绞痛的治疗，它们也可预防性地抑制或大大减轻局部缺血诱导的损害的形成中，特别是局部缺血诱导的心律不齐的触发中的病理生理过程。由于其抗病理性缺氧和局部缺血的性质，按细胞Na+/H+交换抑制机理，本发明式Ⅰ化合物可用作治疗所有由局部缺血导致的急性或慢性损害或最初继发地由具诱导的疾病的药物。这涉及它们作为外科手术药剂的用途，例如，在器官移植中，该化合物既可用来保护摘除前和摘除中供体的器官，也可保护除去的器官，例如处理期间的或在生理溶液中储存的器官，并且也可在向受体移植的期间保护器官。该化合物也可用作在血管成型外科手术中，例如在心脏和外周血管中具有保护作用的药剂。根据其抗局部缺血诱导的损害的性质，该化合物也适用作治疗神经系统，特别是CNS的局部缺血的药剂，合适的话，它们可治疗例如，中风或大脑水肿。并且，本发明式Ⅰ化合物也适用作治疗休克状态，如过敏性，心原性，缺血性和细菌性休克。
本发明式Ⅰ化合物也具有强的抑制细胞增生，例如，成纤维细胞增生和血管平滑肌细胞增生的抑制作用。因而式Ⅰ化合物适用作其中细胞增生为首要的或第二位的原因的疾病的治疗剂，可也用作抗动脉粥样硬化剂，抗糖尿病晚期并发症药，抗癌药，抗纤维化疾病如肺纤维化，肝纤维化或肾纤维化药，抗器官肥大和增生，特别是前列腺增生或前列腺肥大药。
本发明化合物为细胞钠-质子反运输(Na+/H+交换)的有效抑制剂，该运输可引起多种疾病(原发性高血压，动脉粥样硬化，糖尿病等)，甚至在那些细胞中，该运输可易于测量，如在红细胞，血小板和白细胞中。因而本发明化合物适用作杰出的、简单的科学工具药，例如在它们作为诊断剂用于测定和鉴别某种形式的高血压，以及动脉粥样硬化，糖尿病，增生性疾病等中。式Ⅰ化合物更适用于高血压发生，例如原发性高血压的预防。
与已知化合物相比，本发明化合物具有很好的水溶性。因而它们更适于静脉注射用药。
与已知易溶于水的化合物相比，本发明化合物具有出色的生物利用度和药物动力学特性。
含化合物Ⅰ的药剂可口服，肠胃外用药，静脉用药，直肠用药或吸入法用药，优选的给药方式取决于特定的疾病的临床表现。化合物Ⅰ可单独使用或与药物学辅助剂，例如兽医和人类医学上使用的辅助剂一起使用。
根据其专业知识，本领域技术人员通晓适用于所需药剂的辅助剂。除溶剂外，可使用，例如，胶化剂，拴剂基质，片剂辅助剂和其他剂。除溶剂外，可使用，例如，胶化剂，拴剂基质，片剂辅助剂和其他活性化合物赋形剂，抗氧剂，分散剂，乳化剂，消泡剂，矫味剂，防腐剂，增溶剂或加色剂。
对于口服给药剂型，活性化合物与适用的添加剂，如赋形剂，稳定剂或惰性稀释剂混合，并按常规方法制成适于服用的剂型，如片剂，包膜片剂，硬胶囊，水溶液，醇溶液或油溶液。可使用的惰性赋形剂有例如，阿拉伯胶，氧化镁，碳酸镁，磷酸钾，乳糖，葡萄糖或淀粉，特别是玉米淀粉。其制备既可以干法进行，也可由湿颗粒进行。合适的油性赋形剂或溶剂为例如，植物或动物油，如葵花油或鱼肝油。
对于皮下给药或静脉给药，可将活性化合物，如果需要，与该剂型常用物质，如增溶剂，乳化剂或其他辅助剂一起制备成溶液，悬浮液，或乳剂。合适的溶剂为，例如：水，生理盐水或醇，例如乙醇，丙醇，甘油，另外还有糖溶液如葡萄糖或甘露醇溶液，或选择性地包括上述各种溶剂的混合物。
适用于气雾剂或喷雾剂的药剂为，例如，式Ⅰ活性化合物在药学上可接受的溶剂，如，乙醇或水、或这些溶剂的混合物中形成的溶液，悬浮液或乳剂。如果需要，该剂型也可含有其他的药物辅助剂如表面活性剂。乳化剂和稳定剂，以及推进剂。这样的制剂通常含大约0.1到10，优选约0.3到3重量％浓度的活性化合物。
式Ⅰ活性化合物的给药剂量和给药频率取决于使用化合物的功效和作用周期；另外也取决于所治疗疾病的性质和严重程度，以及被治疗的哺乳动物的性别，年龄，体重和个体反应性。
平均说来，体重约75kg的患者的式Ⅰ化合物日剂量至少为0.001mg/kg体重，优选至少0.01mg/kg体重，至多为10mg/kg体重，优选至多1mg/kg体重。对于急性病症，例如心肌梗塞后，必须使用更大的剂量以及提高给药的频率，例如每天给药4次。特别地当静脉内给药时，例如特别护理的梗塞病人，至多可每天使用100mg。
缩写表：
AIBN α,α-偶氮双异丁腈
Bn 苄基
CH2Cl2 二氯甲烷
DCl 解析化学离子化
DIP 二异丙醚
DMA 二甲基乙酰胺
DME 二甲氧基乙烷
DMF N,N-二甲基甲酰胺
EE 乙酸乙酯(EtOAc)
EI 电子轰击
eq 当量
ES 电喷雾离子化
Et 乙基
FAB 快原子轰击
HEP 正庚烷
HOAc 乙酸
Me 甲基
MeOH 甲醇
mp 熔点
MTB 甲基叔丁基醚
NBS N-溴丁二酰亚胺
NMP N-甲基吡咯烷酮
RT 室温
THF 四氢呋喃
TMU N,N,N′,N′-四甲基脲
ToI 甲基
CNS 中枢神经系统
实验部分制备苯甲酰基胍(Ⅰ)的一般步骤变通方案A：由苯甲酸开始(Ⅱ,L=OH)将0.01M式Ⅱ苯甲酸衍生物溶于或悬浮于60ml无水THF中，然后用1.78g(0.011M)羰基二咪唑处理。在RT下搅拌2小时后，将2.95g(0.05M)胍导入反应溶液。搅拌过夜后，减压(旋转蒸发器)蒸除THF，用水处理残留物，用2N HCl将混合物调至PH6到7，并将相应的苯甲酸基胍(式Ⅰ)滤出。通过用盐酸水溶液，甲醇溶液或乙醚溶液或其他药用酸处理，将所得到的苯甲酰基胍转变成相应的盐。
制备苯甲酰基胍(Ⅰ)的一般步骤
变通方案B：由苯甲酸烷基酯开始(Ⅱ,L=O-烷基)
将5mmol式Ⅱ苯甲酸烷基酯和25mmol胍(游离碱)溶于15ml异丙醇或悬浮于15ml THF中，并将其回流沸腾(典型的反应时间为2到5小时)直到转化完全(薄层检测)。减压(旋转蒸发器)蒸除溶剂，将残留物转入300ml EE，并将该溶液每次用50ml NaHCO3溶液洗涤3次。将其用Na2SO4干燥，真空蒸除溶剂，使用合适的洗脱剂，例如EE/MeOH 5∶1，将残留物经色谱法纯化。(按变通方案A制备盐)实施例1：4-(4-氟苯基-N,N′-二乙基亚胺磺酰氨基)-3-甲基磺酰基苯甲酰基胍，二盐酸盐。
a．4-氟苯基亚胺基磺酰N,N′-二乙基胺
在-30℃用30.8ml溴处理146ml 70％乙胺水溶液。将该混合物温热到-5℃，然后滴入19.2ml 4-氟硫代苯酚，然后将该混合物在RT下搅拌5小时。将反应溶液首先用100ml饱和Na2SO3水溶液处理，然后用200ml饱和Na2CO3水溶液处理，并且每次用200mlEE萃取5次。将有机相用Na2SO4干燥，真空除去溶剂，使用EE/Tol/MeOH 5∶5∶2作为洗脱剂将残留物经硅胶色谱纯化。得到1.8gTol/MeOH 5∶5∶2作为洗脱剂将残留物经硅胶色谱纯化。得到1.8g无色物。Rf(EE/ToL/MeOH 5∶5∶2)=0.68MS(ES):231(M+H)+b．5-羧基-2-氟苯亚磺酸
在70℃将15.6g(0.124mol)亚硫酸钠溶于120ml水。恒温下，同时并分批加入23.8g(0.1mol)4-氟-3-氯磺酰基苯甲酸和10NNaOH，使PH保持在9和10之间(放热反应)。将该反应物在70℃再搅拌3小时，与活性炭搅拌15分钟，然后过滤。在外部冷却下，用浓盐酸将滤液PH调至0-1，滤出结晶的5-羧基-2-氟苯亚磺酸。为无色结晶，m.p.:167-170℃。c．5-羧基-2-氟苯亚磺酸二钠：
将17.2g(0.084mol)5-羧基-2-氟苯亚磺酸导入搅拌着的6.72g(0.168mol)NaOH在150ml甲醇和30ml水的混合物中的溶液中，以悬浮方式过滤后，蒸除溶剂，并将残留物用丙酮结晶。无色结晶物质，m.p.:＞320℃。d．4-氟-3-甲基磺酰基苯甲酸甲酯：
将30g(0.21mol)甲基碘加入15g(0.06mol)5-羧基-2-氟苯亚磺酸二钠在80ml无水DMF中的悬浮液中，将该混合物在60℃搅拌6小时，蒸除溶剂，用水处理残留物。冰冷却下将混合物搅拌30分钟并将沉淀滤出。无色结晶物质，m.p.:102-105℃。e．4-(4-氟苯基-N,N′-二乙基亚胺磺酰氨基)-3-甲基磺酰基苯甲酸甲酯
将461mg 4-氟苯基亚胺基磺酰N,N′-二乙基胺和464mg4-氟-3-三氟甲基苯甲酸甲酯溶于10ml NMP，加入2.0g Cs2CO3，并将混合物在100℃搅拌3小时，冷却后，将反应混合物用300ml EE烯释，并且每次用100ml水洗涤。将其用Na2SO4干燥，并使用DIP将残留物进行硅胶色谱纯化。得到440mg无色油。Rf(DIP)=0.27MS(FAB):443(M+H)+f．4-(4-氟苯基-N,N′-二乙基亚胺磺酰氨基)-3-甲基磺酰基苯甲酰基胍，二盐酸盐
按制备苯甲酰基胍(Ⅰ)的一般步骤，变通方案B的方法，使用180mg 4-(4-氟苯基-N,N′-二甲基亚胺磺酰氨基)-3-甲基磺酰基苯甲酸甲酯反应。得到140mg无色油，使用HCl水溶液将其转化成二盐酸盐。m.p.(二盐酸盐)=193℃(分解)Rf(EE)=0.31MS(ES):470(M+H)+实施例2的标题化合物可按与实施例1类似的方法，由4-氟-3-三氟甲基苯甲酸甲酯制备：实施例2：4-(4-氟苯基-N,N′-二乙基亚胺磺酰氨基)-3-三
氟甲基苯甲酰基胍，二盐酸盐无定形固体，无确定的熔点。Rf(EE)=0.51MS(ES):460(M+H)+a)4-氟-3-三氟甲基苯甲酸甲酯
在60℃将5g 4-氟-3-三氟甲基苯甲酸和9ml SOCl2在50mlMeOH中搅拌8小时。然后真空除去挥发性组分，得到5.1g无色油，无需纯化便可继续使用。Rf(EE/MeOH 10∶1)=0.74MS(DCl):223(M+H+)实施例3：3-甲基磺酰基-4-(4-氟苯基亚胺基磺酰氨基)苯甲
a)4-氟苯基亚胺基磺酰-N,N′-二-叔丁基胺
将100ml叔丁胺和30ml水冷却至-30℃，并在该温度下滴加6.2ml溴。将该混合物在该温度下搅拌30分钟。然后将其温热至-5℃并滴加4.6g4-氟硫代苯酚。将该混合物温热至RT并在该温度下搅拌10小时。将反应混合物搅拌入200ml饱和Na2SO3水溶液中，加入200ml饱和Na2CO3水溶液，并将该混合物搅拌30分钟。每次用150mlEE萃取4次，将有机相用Na2SO4干燥，真空除去溶剂。将残留物转入200ml 1NHCl水溶液，将该溶液搅拌1小时，然后用Na2CO3将PH调至9，并每次用150ml EE萃取3次。将其用Na2SO4干燥，真空除去溶剂。使用EE/HEP 1∶2将残留物进行色谱纯化。得到3.2g无色油。Rf(DIP)=0.40MS(ES):287(M+M+)b)4-氟苯基亚胺基磺酰胺
将3.1g 4-氟苯基亚胺基磺酰N,N′-二叔丁基胺溶于55ml33％HBr在冰醋酸中的溶液，并将该溶液在RT下搅拌10小时。将反应混合物慢慢搅拌入400ml饱和Na2CO3水溶液中，并用150mlEE萃取4次。将有机相用Na2SO4干燥，真空除去溶剂。用MTB进行硅胶色谱纯化，得到1.4g无色结晶，m.p.:111℃Rf(EE/MeOH 10∶1)=0.44MS(ES):175(M+H)+c)3-甲基磺酰基-4-(4-氟苯基亚胺基磺酰氨基)苯甲酸甲酯
将350mg 4-氟苯基亚胺基磺酰胺，460mg 4-氟-3-甲基磺酰基苯甲酸甲酯和1.96g Cs2CO3溶于10ml NMP，并将该溶液在100℃搅拌4小时。然后将反应混合物搅拌入100ml饱和NaHCO3水溶液，每次用100ml EE萃取3次，并将有机相每次用50ml水洗涤3次。将其用Na2SO4干燥，真空除去溶剂。用MTB进行硅胶色谱纯化，得到130mg无色油。Rf(MTB)=0.58MS(ES):387(M+H)+d)3-甲基磺酰基-4-(4-氟苯基亚胺磺酰氨基)苯甲酰基胍
使用90mg在1ml异丙醇中的胍、按制备苯甲酰基胍的一般步骤、变通方案B的方法脒化120mg 3-甲基磺酰基-4-(4-氟苯基亚胺磺酰氨基)苯甲酸甲酯。回流下反应3小时。使用EE/MeOH 5∶1进行硅胶色谱纯化，得到70mg无色油。二盐酸盐的熔点：240℃。Rf(EE/MeOH 5∶1)=0.14MS(ES):414(M+H)+实施例4：2-异丙基-5-胍基甲酰基苯基亚胺基磺酰N,N′-二甲基胺a)2-异丙基苯基亚胺基磺酰N,N′-二甲基胺
在-30℃用5.7ml溴处理110ml 40％甲胺水溶液。将该混合物在该温度下搅拌30分钟，然后将其温热至-5℃，并滴加5.0ml 2-异丙基硫代苯酚。将反应混合物在RT下搅拌5小时，然后将其搅拌入200ml饱和Na2SO3水溶液。加入200ml饱和Na2CO3水溶液，并将该混合物在RT下搅拌1小时。然后每次使用150ml EE萃取3次。将有机相用Na2SO4干燥，真空蒸除溶剂。使用EE进行硅胶色谱纯化，得到2.8g无色固体，m.p.84-85℃Rf(EE)=0.48MS(ES):227(M+H+)b)2-异丙基-5-碘苯基亚胺基磺酰N,N′-二甲基胺
将2.7g 2-异丙基苯基亚胺基磺酰N,N′-二甲基胺溶于10mlCF3SO3H，然后加入N-碘丁二酰亚胺，将该溶液在RT下搅拌4小时。将反应混合物慢慢滴加入150ml饱和NaHCO3水溶液和150ml饱和Na2CO3水溶液的混合物中。将其每次用150ml EE萃取3次，将有机相用Na2SO4干燥，真空除去溶剂。使用MTB进行硅胶色谱纯化，得到3.6g无色油。Rf(MTB)=0.51MS(ES):353(M+H)+c)2-异丙基-5-正丁氧羰基苯基亚胺基磺酰N,N′-二甲基胺
将3.6g 2-异丙基-5-碘苯基亚胺基磺酰N,N′-二甲基胺，37.6mg乙酸钯(Pd(Ⅱ)),69.2mg 1,3-双(二苯膦基)丙烷和5.1ml三-正丁基胺溶于11ml正丁醇和22ml DMF，并将该溶液在100℃搅拌6小时。将反应混合物转入250ml饱和NaHCO3水溶液，加入100ml水，每次使用150ml EE萃取三次。有机相用Na2SO4干燥，真空除去溶剂。使用EE/HEP 1∶1进行硅胶色谱纯化，得到340mg无色油。Rf(EE/HEP 1∶1)=0.21MS(ES):327(M+H)+d)2-异丙基-5-胍基甲酰基苯基亚胺基磺胺N,N′-二甲基胺
将177mg盐酸胍溶于2.5ml DMF中并加入190mg叔丁醇钾在2.5ml DMF中的溶液。将该混合物在RT下搅拌1小时。然后加入110mg 2-异丙基-5-叔丁氧羰基苯基亚胺基磺酰N,N′-二甲基胺在5ml DMF中的溶液。将反应混合物在RT下搅拌2小时。搅拌入100ml饱和NaHCO3水溶液，每次用100ml EE萃取三次，将有机相用Na2SO4干燥，真空除去溶剂。用EE/MeOH 1∶8进行硅胶色谱纯化，得到32mg白色固体，m.p.:148℃(分解)。Rf(EE/MeOH 1∶8)=0.21MS(ES):312(M+H)+药理数据兔子红细胞Na+/H+交换的抑制
用含2％胆固醇的标准饲料喂养白新西兰兔(Ivanovas)六周，以活化Na+/H+交换，因而能通过闪光光度计测定Na+经Na+/H+交换流入红细胞的量。将血液从耳动脉取出，并以25IE肝素钾抗凝。将一部分样品用来离心，进行血细胞比容的重复测定。每份100μl的样品用来测量红细胞的Na+初始浓度。
为了测定amiloride-敏感的钠流入量，将每份100μl的血样在5ml高渗盐-蔗糖介质中(mmol/l:140 NaCl,3KCl,150蔗糖，0.1哇巴因，20 tris-羟甲基氨基甲烷)在PH7.4和37℃下孵育。然后用冰冷却的MgCl2哇巴因溶液(mmol/l:1 12MgCl2,0.1哇巴因)将红细胞洗涤三次，并在2.0ml蒸留水中溶血。通过闪光光度计测定细胞内钠的含量。
纯的Na+流入量由开始时的钠的值和孵育后钠的含量的差来计算。amiloride抑制的钠流入由未使用和使用3×10-4mol/lamiloride孵育的差异而得到。该方法也适用于本发明化合物。结果Na+/H+交换的抑制：
| 实 施 例 | IC50(mmol/l) |
| 1 | 0.68 |
| 2 | 0.053 |
| 3 | 2 |
| 4 | 6 |
Claims (14)
1．式Ⅰ的亚胺基磺酰胺或其药用盐其中
R(1)为H或C1-C4-烷基；
R(2)和R(3)之一为苯甲酰胍基；
其中苯基部分是未取代的或由1个选自C1-C8-烷基，CF3和R(22)SO2的取代基取代，其中R(22)为C1-C8-烷基；
R(2)和R(3)中的另一个基团互相独立地为C1-C8-烷基或苯基；该苯基是未取代的或被1-3个选自F和Cl的取代基取代；
当R(2)为苯甲酰胍基时，R(3)还可为氢；
R(4)为氢或具有1-4个碳原子的烷基。
2．制备按权利要求1的化合物Ⅰ的方法，其中在化合物Ⅳ中
取代基R(1″),R(2″)和R(3″)的定义分别对应于R(1),R(2)和R(3)的定义，不同的是，胍基换成带有易除去的离去基团L，该方法包括，由胍基取代易于亲核取代除去的基团L。
3．权利要求1的化合物Ⅰ的用途，用于制备治疗心律失常药物。
4．权利要求1的化合物Ⅰ的应用，用于制备治疗或预防心肌梗塞药物。
5．权利要求1的化合物Ⅰ的应用，用于制备治疗或预防心绞痛药物。
6．权利要求1的化合物Ⅰ的应用，用于制备治疗或预防心肌局部缺血药物。
7．权利要求1的化合物Ⅰ的应用，用于制备治疗或预防外周和中枢神经系统局部缺血以及中风药物。
8．权利要求1的化合物Ⅰ的应用，用于制备治疗或预防外周器官和肢体局部缺血药物。
9．权利要求1的化合物Ⅰ的应用，用于制备治疗休克药物。
10．权利要求1的化合物Ⅰ的应用，用于制备用于外科手术和器官移植的药物。
11．权利要求1的化合物Ⅰ的应用，用于制备用来保存和储藏外科措施中移植器官的药物。
12．权利要求1的化合物Ⅰ的应用，用于制备治疗细胞增生为其首要或次要原因的疾病的药物，以及它们用于制备抗动脉粥样硬化剂，抗糖尿病晚期并发症药，抗癌药，抗纤维化疾病药以及抗前列腺增生药。
13．权利要求1的化合物Ⅰ的应用，用于制备抑制Na+/H+交换的科学工具药，以及用于诊断高血压和增生疾病。
14．含有有效量的、一种或多种如权利要求1中定义的式Ⅰ化合物的药物。
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| DE19540995A DE19540995A1 (de) | 1995-11-03 | 1995-11-03 | Substituierte Sulfonimidamide, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
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| DE4344550A1 (de) * | 1993-12-24 | 1995-06-29 | Hoechst Ag | Substituierte 1-Oxo-1,2-dihydro-isochinolinoyl- und 1,1-Dioxo-2H-1,2-benzothiazinoylguanidine, Verfahrenzu ihrer Herstellung, ihre Verwendung als Medikamentt oder Diagnostikum sowie sie enthaltendes Medikamen |
| TW415937B (en) * | 1994-01-25 | 2000-12-21 | Hoechst Ag | Phenyl-substituted alkylcarboxylic acid guanidides bearing perfluoroalkyl groups, process for their preparation, their use as a medicament or diagnostic, and medicament containing them |
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| DE4417004A1 (de) * | 1994-05-13 | 1995-11-16 | Hoechst Ag | Perfluoralkyl-substituierte Benzoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
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| IL114670A0 (en) * | 1994-08-05 | 1995-11-27 | Fujisawa Pharmaceutical Co | Guanidine derivatives pharmaceutical compositions containing the same and processes for the preparation thereof |
| DE4432105A1 (de) * | 1994-09-09 | 1996-03-14 | Hoechst Ag | Fluoro-alkyl/alkenyl-substituierte Benzoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
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-
1995
- 1995-11-03 DE DE19540995A patent/DE19540995A1/de not_active Withdrawn
-
1996
- 1996-10-08 PL PL96316440A patent/PL184570B1/pl unknown
- 1996-10-22 ES ES96116938T patent/ES2143122T3/es not_active Expired - Lifetime
- 1996-10-22 DK DK96116938T patent/DK0771788T3/da active
- 1996-10-22 SI SI9630136T patent/SI0771788T1/xx unknown
- 1996-10-22 EP EP96116938A patent/EP0771788B1/de not_active Expired - Lifetime
- 1996-10-22 AT AT96116938T patent/ATE188688T1/de not_active IP Right Cessation
- 1996-10-22 PT PT96116938T patent/PT771788E/pt unknown
- 1996-10-22 DE DE59604165T patent/DE59604165D1/de not_active Expired - Lifetime
- 1996-10-28 HR HR960496A patent/HRP960496B1/xx not_active IP Right Cessation
- 1996-10-30 CZ CZ19963184A patent/CZ290811B6/cs not_active IP Right Cessation
- 1996-10-30 TW TW085113224A patent/TW352382B/zh active
- 1996-10-30 CA CA002189221A patent/CA2189221C/en not_active Expired - Fee Related
- 1996-10-30 CN CN96122091A patent/CN1069312C/zh not_active Expired - Fee Related
- 1996-10-31 AR ARP960104995A patent/AR004253A1/es unknown
- 1996-10-31 US US08/740,634 patent/US5708034A/en not_active Expired - Lifetime
- 1996-10-31 RU RU96121572/04A patent/RU2180658C2/ru not_active IP Right Cessation
- 1996-10-31 SK SK1418-96A patent/SK281766B6/sk unknown
- 1996-11-01 AU AU70608/96A patent/AU707256B2/en not_active Ceased
- 1996-11-01 TR TR96/00873A patent/TR199600873A2/xx unknown
- 1996-11-01 NO NO964639A patent/NO306550B1/no not_active IP Right Cessation
- 1996-11-01 ZA ZA969211A patent/ZA969211B/xx unknown
- 1996-11-01 NZ NZ299682A patent/NZ299682A/en unknown
- 1996-11-01 HU HU9603023A patent/HUP9603023A3/hu unknown
- 1996-11-01 KR KR1019960051506A patent/KR970025611A/ko not_active Ceased
- 1996-11-01 JP JP29139696A patent/JP3924028B2/ja not_active Expired - Fee Related
- 1996-11-01 MY MYPI96004552A patent/MY132862A/en unknown
- 1996-11-01 MX MX9605317A patent/MX9605317A/es not_active IP Right Cessation
- 1996-11-03 IL IL11955296A patent/IL119552A/xx not_active IP Right Cessation
- 1996-11-04 BR BR9605417A patent/BR9605417A/pt not_active Application Discontinuation
-
2000
- 2000-02-18 GR GR20000400387T patent/GR3032689T3/el not_active IP Right Cessation
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5091394A (en) * | 1989-09-06 | 1992-02-25 | Hoechst Aktiengesellschaft | Benzoylguanidines, a process for their preparation, their use as medicaments and medicaments containing them |
| EP0556674A1 (de) * | 1992-02-15 | 1993-08-25 | Hoechst Aktiengesellschaft | 3,5-Substituierte Benzoylguanidine, mit antiarrythmischer Wirkung und inhibierender Wirkung auf die Proliferationen von Zellen |
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