CN1079792C - 酶抑制剂 - Google Patents
酶抑制剂 Download PDFInfo
- Publication number
- CN1079792C CN1079792C CN94194782A CN94194782A CN1079792C CN 1079792 C CN1079792 C CN 1079792C CN 94194782 A CN94194782 A CN 94194782A CN 94194782 A CN94194782 A CN 94194782A CN 1079792 C CN1079792 C CN 1079792C
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- CN
- China
- Prior art keywords
- pyrrolidines
- glutaminyl
- group
- amino
- carbonyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 239000003001 serine protease inhibitor Substances 0.000 title 1
- 239000003112 inhibitor Substances 0.000 claims abstract description 24
- 150000001875 compounds Chemical class 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 17
- 230000001404 mediated effect Effects 0.000 claims abstract description 7
- 230000008569 process Effects 0.000 claims abstract description 7
- 125000000266 alpha-aminoacyl group Chemical group 0.000 claims abstract description 4
- 150000003235 pyrrolidines Chemical class 0.000 claims description 117
- -1 benzyloxycarbonyl-methyl Chemical group 0.000 claims description 37
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 21
- 239000004327 boric acid Substances 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- ZRALSGWEFCBTJO-UHFFFAOYSA-N anhydrous guanidine Natural products NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 6
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 125000001239 threonyl group Chemical group 0.000 claims description 6
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 claims description 3
- 229910006074 SO2NH2 Inorganic materials 0.000 claims description 3
- 125000001931 aliphatic group Chemical group 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 125000004429 atom Chemical group 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 125000003709 fluoroalkyl group Chemical group 0.000 claims description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 3
- 230000001629 suppression Effects 0.000 claims description 3
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 125000001939 glutaminyl group Chemical group 0.000 claims 46
- 235000015177 dried meat Nutrition 0.000 claims 29
- LAKXFMUJERKJJK-UHFFFAOYSA-N azane formonitrile Chemical compound N.N#C LAKXFMUJERKJJK-UHFFFAOYSA-N 0.000 claims 26
- 125000001288 lysyl group Chemical group 0.000 claims 25
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 17
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 13
- 241000534944 Thia Species 0.000 claims 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims 6
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 6
- 125000006309 butyl amino group Chemical group 0.000 claims 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 4
- 125000004894 pentylamino group Chemical group C(CCCC)N* 0.000 claims 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims 4
- 125000002072 seryl group Chemical group 0.000 claims 4
- 229910021529 ammonia Inorganic materials 0.000 claims 3
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 3
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 claims 3
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical group CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims 3
- 125000000143 2-carboxyethyl group Chemical group [H]OC(=O)C([H])([H])C([H])([H])* 0.000 claims 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 2
- AHLPHDHHMVZTML-BYPYZUCNSA-N ornithyl group Chemical group N[C@@H](CCCN)C(=O)O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 claims 2
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims 2
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 2
- NPDBDJFLKKQMCM-SCSAIBSYSA-N (2s)-2-amino-3,3-dimethylbutanoic acid Chemical compound CC(C)(C)[C@H](N)C(O)=O NPDBDJFLKKQMCM-SCSAIBSYSA-N 0.000 claims 1
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
- FFNVQNRYTPFDDP-UHFFFAOYSA-N 2-cyanopyridine Chemical compound N#CC1=CC=CC=N1 FFNVQNRYTPFDDP-UHFFFAOYSA-N 0.000 claims 1
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- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims 1
- GSYSFVSGPABNNL-UHFFFAOYSA-N methyl 2-dimethoxyphosphoryl-2-(phenylmethoxycarbonylamino)acetate Chemical group COC(=O)C(P(=O)(OC)OC)NC(=O)OCC1=CC=CC=C1 GSYSFVSGPABNNL-UHFFFAOYSA-N 0.000 claims 1
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims 1
- 150000003053 piperidines Chemical class 0.000 claims 1
- 229940124530 sulfonamide Drugs 0.000 claims 1
- 150000003456 sulfonamides Chemical class 0.000 claims 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N titanium dioxide Inorganic materials O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims 1
- 235000010215 titanium dioxide Nutrition 0.000 claims 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 79
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- 238000002143 fast-atom bombardment mass spectrum Methods 0.000 description 28
- 239000000243 solution Substances 0.000 description 28
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Abstract
选自下列通式的化合物为DP-Ⅳ介导过程抑制剂。
A选自特定的氨酰基化合物。
Description
背景:
DP-IV(EC3.4.14.5)是膜结合性丝氨酸蛋白酶,最初,由于它具有从某种肽的N-端裂解二肽的能力而从鼠的肾脏中鉴定出来(Hopsu-Havu,V.K.和Clenner G.G.,Histochemie,1966,7,197)。二肽必须是x-脯氨酸或x-丙氨酸型的,其中x为任何氨基酸。x-脯氨酸比x-丙氨酸更有效地被断裂。
DP-IV广泛地分布于哺乳动物组织中,并且发现在肾脏、肠上皮和胎盘中含量丰富(Yaron,A.and Naider,F.,Critical Reviews inBiochem.Mol.Biol.1993,28(1),31)。在人类免疫***中,这种酶几乎全部由激活的CD4+型T-淋巴细胞来表达,其中已显示该酶与细胞表面抗原CD26是同义的。
DP-IV在人类生理学中的确切作用还没有完全弄清楚,但最近的研究表明在人类生理学和病理生理学中,显然,该酶具有重要的作用,例如:
(a)免疫应答:在促***原或抗原刺激的T细胞中,DP-IV表达增加(Mattern,T.等,Scand.J.Immunol,1991,33,737)。曾有报道,DP-IV抑制剂或抗DP-IV抗体以剂量依赖方式抑制促***原或抗原刺激的T细胞的增殖(Sch_n,E等,Biol.Chem.Hopper-Seyler,1991,372,305和其中的参考文献)。
已表明T淋巴细胞的各种其它功能如产生细胞因子、IL-2介导的细胞增殖和B细胞辅助活性都依赖于DP-IV活性(Sch_n,E.等,Scand.J.Immunol,1989,29,127)。最近报道了基于硼脯氨酸(boroproline)的DP-IV抑制剂(Flentke,G.R.等人,Proc.Natl.A-cad.Sci.USA,1991,88,1556),该DP-IV抑制剂尽管不稳定,但能有效地抑制抗原诱导的淋巴细胞增殖和在鼠CD4+T辅助细胞中产生IL-2。已表明,这种硼酸抑制剂在小鼠体内可有效地抑制由免疫激发引起的抗体产生(Kubota,T.等,Clin.Exp.Immunol,1992,89,192)。近期的其它报道也提供证据表明免疫应答中涉及DP-IV(例如Tanaka,T等人,Proc.Natl.Acad.Sci.NY.1993,90,4586;Hegen,M.等人Cell Immun.1993,146,249;Subramanyan,M.等人J.Immunol.1993,150,25447)。
某些研究者认为DP-IV的重要性在于其细胞表面与跨膜磷酸酯酶CD45缔合(Torimoto,Y等人,J.Immunol,1991,147,2514)。CD45-DP-IV缔合可能被DP-IV抑制剂或非活性位点配体破坏。已知CD45是T细胞信号化的组成性成分。
(b)最近,据巴黎Pasteur Institute发表的报刊(并且接着由A.G.Hovanessian在8th Cent.Gardes Meeting,Paris,25-27th October1993中发表)报道。DP-IV是CD4+T细胞中HIV-1和HIV-2病毒的穿透和感染所必需的。该法国研究组认为DP-IV与病毒gp120外壳糖蛋白的V3环相互作用并且可能裂解V3环。他们也报道了DP-IV抑制剂或抗体有效地抑制病毒进入细胞。过去已知HIV-1感染个体的T细胞中,CD26表达选择性降低(Voll-Blazque,M等,J.Immunol.1992,149,3073),并且已知HIV-1 Tat蛋白与DP-IV结合(Subramaryam,M等人,J.Immunol,1993,150,2544)。
(c)最近已表明肺内皮DP—IV是肺转移型鼠乳腺和***癌细胞的粘连分子(Johnson,R.C等人,J.Cell,Biol,1993,121,1423)。已知DP-IV与粘连蛋白结合,并且已知某些转移的癌细胞在其表面上携带大量粘连蛋白。
(d)已表明DP-IV与T细胞表面的腺苷脱氨酶(ADA)相结合(Kameoka,J等人,Science,1993,261,466)。ADA缺乏引起人类严重联合免疫缺陷病(SCID)。ADA-CD26相互作用可为SCID的病理生理提供线索。
(e)在患牛皮癣、类风湿性关节炎(RA)和扁平苔癣的病人的人皮肤成纤维细胞中,已发现DP-IV表达水平高(Raynaud,F等,J,Cell.Physiol,1992,151,378)。
(f)在患良性***肥大病人的组织匀浆中和在***体(prostatosome)中,发现DP-IV活性高。这些是***衍化的细胞器,它们对促进***能动性是重要的(Vanhoof,G等人,Eur.J.Clin.Chem.Clin.Biochem,1992,30,333)。
(g)已表明,DP-IV引起在N-端具有次末端脯氨酸或丙氨酸的环状肽(例如P物质,生长激素释放因子和胰高血糖素/血管活性小肠肽族的成员)的降解和灭活(Menthein,R等人,Eur.J.Biochem,1993,214,829)。
(h)在患牙周炎病人的牙龈中,可见DP-IV水平增加(Cox,S.W.等人,Arch.Oral.Biol,1992,37,167)。
(i)也有许多其它的报道表明在各种病理条件下,DP-IV水平增加(或有时降低)。
由上述作用可知,有效的DP-IV抑制剂可作为药物来治疗人类的疾病。这种抑制剂可作为:
(a)免疫抑制剂,例如在器官移植中;细胞因子释放抑制剂,例如在各种自身免疫性疾病如炎症性肠病,多发性硬化病,RA中。
(b)抑制HIV进入T细胞的药物并且因此可用于预防和治疗AIDS。
(c)预防转移癌,尤其是乳腺癌和***癌向肺癌转移的药物。
(d)治疗皮肤病如牛皮癣,扁平苔癣的药物。
(e)抑制***能动力的药物并因此作为男性避孕药。
(f)治疗良性***肥大的药物。DP-IV抑制剂
迄今报道的DP-IV酶活性竞争性抑制剂只有上述提到的不稳定的硼酸衍生物(在PH7时t1/2为30-90分钟)(Bachovchin等,WO91/16339,October 1991)(其对DP-IV的Ki值在纳摩尔范围内)和简单的氨基酸吡咯酰胺(Pyrrolidides)或噻唑酰胺(thiazolides)(Neu-bert等人,DD296075 A5,November 1991)(它们只具有中等的功效(Ki>0.1μM))。在同一德国专利中公开的氨酰基脯氨酸醛由于易产生N端氨基与醛官能团的分子内缩合而不能被合成。
现在,我们公开高效竞争型DP-IV抑制剂(其Ki值为10-6-10-10),它们具有化学稳定性(t1/2>24小时)。它们属于三大组化合物(组I、II和III)。组I
设计了这些与DP-IV活性部位紧密结合并且抑制其蛋白分解活性,但不影响任何可以结合到DP-IV表面(即不在其活性部位)的辅助配位体结合的分子。该组I化合物可用作免疫抑制剂;抗HIV感染剂;抑制激活的T细胞释放某些细胞因子(例如IL-2,IL-6,γ-INF)的试剂。早期提到的硼酸衍生物和吡咯酰胺也属此类。组II
这些是由组I化合物发展而来的;然而它们在通式中称作A的氨基酸的侧链上包含延伸的长链。所得到的化合物紧紧结合到DP-IV的活性部位,但伸长的长链从酶的活性部位伸出并且抑制任何可以结合到DP-IV表面上的其它配位体的结合。该化合物可能具有组I化合物相同的作用,但另外可阻断DP-IV与(i)CD45(ii)HIV-1的gp120V3环(iii)癌细胞表面粘连蛋白(iv)任何对于T细胞激活,病毒进入T细胞或癌细胞粘连重要的其它配位体的相互作用。组III
该组包含新的二聚体,其中两个定向活性位点的DP-IV抑制剂通过通式中称作A的氨基酸残基的侧链结合成长链。该二聚体可同时抑制两种DP-IV分子并且也抑制辅助配位体结合到DP-IV表面,这些二聚体可能具有组II化合物相同的作用但可能是更有效的。
本发明提供DP-IV所介导过程的抑制剂,抑制剂通式为:A-B(细I和II)或
(组III)其中B为
n=1或2;m=0,1或2;X=CH2,O, S,SO,SO2,NH或NR1其中R1=低级烷基C1-C6);
A与Y接合;
-Y=-N,-CH或=C(当A的-CO基由CH=或CF=取代时);
R=H,CH,CHO,B(OH)2,C≡C-R7或CH=N-R8;
R7=H,F,低级烷基(C1-C6),CN,NO2,OR9,CO2R9或COR9;
R8=苯基,OH,OR9,OCOR9或OBn;
R9=低级烷基(C1-C6);并且可以不含ω或两个ε。
A的结构依赖于B部分中R的性质和化合物所属类别的性质。组I化合物
(a)R=H
A是由带有环状脂肪族侧链(例如C4-C10,单环或双环)的α-氨基酸衍变的α-氨酰基,其中所述环状脂肪族侧链的环可以含有一个或多个杂原子,例如L-环己基甘氨酸,L-环戊基甘氨酸,L-十氢化萘基甘氨酸,L-哌啶基甘氨酸;
(b)R=CN;C≡C-R7或CH=N-R8
A如上(a)中所定义,但另外可以从带有亲脂性侧链的L-α-氨基酸,例如Ile衍化得到。
(c)R=CHO或B(OH)2
A是上述(a)中所定义的β-氨酰基。得到的A-B化合物是稳定的,不象相同类型的α-氨酰基衍生物容易进行分子内环化。在化合物(c)中,B(OH)2可以以烷基硼酸酯的形式存在,例如
这些化合物在水中是不稳定的,可得到游离烷基硼酸。组II化合物
其中a=1-5;D=G-(CH2)b-(R4)q-R3;G=O,NH或NMe;
b=0-12;q=0-5;
D1=D(G≠O)
R4=Z-NH-(CH2)c-或NH-Z-(CH2)c-其中c=1-12并且Z=CO,CH2或SO2;并且
R3=CO2H或其酯[例如,任何低级烷基,氟烷基或环烷基(C1-C8)或芳族或杂芳族(5或6元环,单或双环)的酯];CONH2;CONHNH2;CONR5R6;CONHNR5R6;PO3H(或其酯,例如在CO2H下所定义的);SO3H;SO2NH2;SO2NR5R6;OH;OR5;芳基或杂芳基(例如5或6元环,单环或双环)[包括取代的芳基或杂芳基,其取代基优选选自F,Cl,I,Br,OH,OR5,NO2,SO3H,SO2NH2,SO2NR5R6,NH2,NR5R6,CO2R5,CF3,CN,CONH2,CONR5R6,NHCO2R5,CH(=NR5)NR5R6,NH-CH(=NR5)NR5R6和R5];NH2;NR5R6;NHCO2R5;NHSO2NR5R6;NHCOR5;NH-SO2R5;NH-CH(=NR5)NR5R6;NHCONR5R6;糖(可以通过醚键或糖苷键与其连接);CO-氨基糖(通过-NH2连接)例如葡糖胺或半乳糖胺;NHCO-氨基糖,或NHCS-氨基糖。
在上述R3的定义中,“糖”指任何糖类或低聚糖,并且R5和R6独立地选自H和烷基,氟烷基和环烷基(不超过8个原子),芳基,杂芳基和烷基杂芳基(不超过11个原子)或者R5和R6一起包含一个链(C3-C8)。
其中R1=H,Me;环也可以含多个杂原子;
其中R2=H或Me;环也可以含一个或多个杂原子;
L=(CH2)d-[CO]r-(CH2)b-(R4)q-R3或(CH2)e-NR1-(CH2)b-(R4)q-R3;
r=0或1;d=0-4;e=2-4;并且b,q,R3和R4如(i)下定义。组III
组III化合物由下列通式定义:
其中ω=CH2,O,NH,CO,S,SO2,苯基或NMe并且,独立地,
ε=CH2,O,NH,CO,S,SO2,苯基或NMe。
这些化合物是对称的二聚体。它们可能具有上述定义的任何B结构。A可选自任何组II结构[(i),(ii)或(iii)],但在这种情况下,每个A基中都缺少末端基R3并且由连接二聚体两半部分的共享对称基团[ε-ω-ε]代替,可以不含ω,此时,两个ε结合到一起构成连接两个A-B部分的链;或者,可以不含两个ε,此时,ω单独连接两个A-B部分。
当然ε-ω-ε结构必须是在化学上适宜的,例如NH-CO-NH,CO-NH-CO-,SO2-NMe-SO2;对于本领域技术人员而言,不适宜的结构是显然的,例如-NH-NH-NH-。可能的特定实例显示于表7中。
在组II和III所述的这些化合物中,在长链中存在的-CH2-基可以由已知的生物电子等排物,例如-O-代替,并不影响对DP-IV的抑制作用或结合活性。如-CONHCH2CH2NHCO类型的基团(如果存在)也可以由例如下式基团代替:
这些替代的实例见表8。生物化学
在体内对纯的人DP-IV(购于M&E,Copenhagen,DenmarK)测定所有的化合物。利用荧光底物Ala-Pro-AFC(Km0.8μM)测定对DP-IV的抑制,每种抑制剂在三种浓度下测定。典型的实验混合物(总体积0.4ml)包含Hepes Na 83.3mM,EDTA 1.67mM,BSA 1.5mg/ml,PH7.8,DP-IV 25μU/ml,抑制剂(在PH4.0的10mM醋酸盐中)。通过加底物开始反应并且每30秒记录一次读数计7.5分钟,激发波长395nm,发射波长450nm。利用Dixon作图法来测定Ki值。化学
表1-8中显示了152种合成化合物的实例,其后有每种不同结构类型制备方法流程式和实验细节。通过FAB质谱来确定所有最终产物的特性,并且通过反相HPLC来测定纯度;通过1HNMR来确定所有中间体的特性。
表9显示对于不同结构类型的抑制剂测定时所得到的对DP-IV的选择性Ki值。
计算值 FAB质谱No. A X R n 分子式
Mol.Wt. [M+H]+1
CH2 H 1 C11H20N2O 196.2 197.22
CH2 H 1 C12H22N2O 210.2 211.23
CH2 H 1 C10H20N2O 184.2 185.24
CH2 H 1 C12H20N2O 208.2 209.25cis
CH2 H 1 C11H20N2O 196.1 197.2
计算值 FAB质谱No. A X R n 分子式
Mol.Wt. [M+H]+6trans
CH2 H 1 C11H20N2O 196.1 197.27trans
CH2 H 1 C11H18N2O 194.1 195.28trans
CH2 H 1 C10H18N2O 182.1 183.29
CH2 H 1 C11H14N2O 190.1 191.210trans
CH2 H 1 C13H24N2O 224.2 225.2
表2组I(b)的实施例
计算值 FAB质谱No. A X n R1 R 分子式
Mol.Wt. [M+H]+11 H-Ile CH2 1 H CN C11H19N3O 209.3 210.212 H-Lys(Z) CH2 1 H CN C19H26N3O3 358.2 359.213 H-Pro CH2 1 H CN C10H15N3O 193.1 194.114
CH2 1 H CN C9H13N3OS 211.1 212.215
CH2 1 H CN C9H13N3OS 211.1 212.216
CH2 1 H CN C13H21N3O 235.2 236.317
CH2 1 H CN C12H19N3O 221.2 222.2
计算值 FAB质谱No. A X n R1 R 分子式
Mol.Wt. [M+H]+18
CH2 1 H CN C11H19N3O 209.2 210.219 H-lle S 1 H CN C10H17N3OS 227.1 228.120 H-lle S 1 CN H C10H17N3OS 227.1 228.121
S 1 H CN C12H19N3OS 253.1 254.122 H-Lys(Z) S 1 H CN C18H24N4O3S 376.2 377.223
S 1 H CN C11H17N3OS 239.1 240.224 H-lle O 1 H CN C10H17N3O2 211.1 212.225 H-lle CH2 2 H CN C12H21N3O 223.2 224.226 H-lle S 2 H CN C11H19N3OS 241.1 242.127 H-lle SO2 1 H CN C10H17N3O3S 259.1 260.128 H-lle
1 H CN C10H17N3O2S 243.1 244.129 H-lle
1 H CN C10H17N3O2S 243.1 244.2
计算值 FAB质谱No. A X n R1 R 分子式
Mol.Wt. [M+H]+30
CH2 1 H CN C12H19N3O 221.2 222.231
CH2 1 H CN C12H19N3O 221.2 222.232
CH2 1 H CN C11H17N3O 207.2 208.233
CH2 1 H CN C11H17N3O 207.2 208.234
CH2 1 H CN C12H17N3O 219.1 220.135
CH2 1 H CN C12H17N3O 219.1 220.1
计算值 FAB质谱No. A X n R1 R 分子式
计算值 FAB质谱No. A X R n 分子式
Mol.Wt. [M+H]+38
CH2 CHO 1 C12H20N2O2 224.2 225.239
CH2 CHO 1 C11H18N2O2 210.2 211.240
CH2 CHO 1 C11H18N2O2 210.2 211.241
CH2 B* 1 C20H33BN2O3 360.3 361.342
CH2 B* 1 C21H35BN2O3 374.3 375.143
CH2 B* 1 C21H35BN2O2 374.3 375.144
CH2 B* 1 C21H33BN2O3 372.3 373.3
计算值 FAB质谱No. A X R n 分子式
Mol.Wt. [M+H]+45
CH2 B* 1 C21H33BN2O3 372.3 373.3B*=
表4组II(i)的实施例
计算值 FAB质谱No. n Q X m R 分子式
Mol.Wt. [M+H]+46 1 -CONHCH2CO2Bn CH2 1 H C17H23N3O4 333.2 334.247 1 -CONHCH2CO2H CH2 1 H C10H17N3O4 243.1 244.248 1 -CONH(CH2)3CO2H CH2 1 H C12H21N3O4 271.2 272.249 1 -CONH(CH2)2CO2Bn CH2 1 H C18H25N3O4 347.2 348.250 1 -CONH(CH2)2CO2H CH2 1 H C11H19N3O4 257.1 258.251 1 -CONH(CH2)5CO2Bn CH2 1 H C21H31N3O4 389.3 390.352 1 -CONH(CH2)5CO2H CH2 1 H C14H25N3O4 299.2 300.253 1 -CONH(CH2)3CO2Bn CH2 1 H C19H27N3O4 361.2 362.254 2 -CONHCH2CO2Bn CH2 1 H C18H25N3O4 347.2 348.255 2 -CONHCH2CO2H CH2 1 H C11H19N3O4 257.1 258.156 2 -CONH(CH2)2CO2Bn CH2 1 H C19H27N3O4 361.2 362.357 2 -CONH(CH2)3CO2Bn CH2 1 H C20H29N3O4 375.2 376.358 2 -CONH(CH2)3CO2H CH2 1 H C13H23N3O4 285.2 286.2
计算值 FAB质谱No. n Q X m R 分子式
Mol.Wt. [M+H]+59 2 -CONH(CH2)5CO2Bn CH2 1 H C22H33N3O4 403.3 404.360 2 -CONH(CH2)5CO2H CH2 1 H C15H27N3O4 313.2 314.261 2 -CONH(CH2)2CO2H CH2 1 H C12H21N3O4 271.2 272.262 2 -CONH(CH2)7CO2Bn CH2 1 H C24H37N3O4 431.3 432.463 2 -CONH(CH2)7CO2H CH2 1 H C17H31N3O4 341.3 342.564 2 -CONH(CH2)7CONH- CH2 1 H C28H45N5O5 531.3 532.3
(CH2)3NHZ65 2 -CONH(CH2)6CONH- CH2 1 H C29H46N4O5 530.4 531.2
(CH2)5CO2Bn66 2 -CONH(CH2)6CONH- CH2 1 H C22H40N4O5 440.3 441.3
(CH2)5CO2H67 2 -CONH(CH2)7CONH- CH2 1 H C20H39N5O3 397.3 398.3
(CH2)3NH268 2 -CONH(CH2)11CO28n CH2 1 H C28H45N3O4 487.3 488.469 2 -CONH(CH2)11CO2H CH2 1 H C21H39N3O4 397.3 398.370 2 -CONH(CH2)6CO28n CH2 1 H C23H35N3O4 417.3 418.371 2 -CONH(CH2)6CO2H CH2 1 H C16H29N3O4 327.2 328.272 2 -CONH(CH2)5CONH- CH2 1 H C17H29F3N4O3 394.2 395.3
CH2CF3
计算值 FAB质谱No. n Q X m R 分子式
Mol.Wt. [M+H]+73 2 -CONH(CH2)5CONH- CH2 1 H C19H29F7N4O3 494.2 495.2
CH2(CF2)2CF374 2 -CONH(CH2)5CONH- CH2 1 H C21H40N4O4 412.3 413.2
(CH2)6OH75 2 -CONH(CH2)5CONH- CH2 1 H C24H38N4O3 430.3 431.2
(CH2)3Ph76 2 -CONH(CH2)5CONH- CH2 1 H C25H40N4O3 444.3 445.2
(CH2)4Ph77 2 -CONH(CH2)5CON- CH2 1 H C23H44N4O3 424.3 425.3
(nBu)278 2 -CONH(CH2)5CON- CH2 1 H C27H52N4O3 480.4 481.4
(nHx)279 2 -CONH(CH2)5CONH- CH2 1 H C22H34N4O3 402.3 403.4
CH2Ph80 2 -CONH(CH2)4CO2Bn CH2 1 H C21H31N3O4 389.2 390.381 2 -CONH(CH2)4CO2H CH2 1 H C14H25N3O4 299.2 300.382 2 -CONH(CH2)5CONH- CH2 1 H C17H32N4O3 340.3 341.3
CH2CH383 2 -CONH(CH2)6OH CH2 1 H C15H29N3O3 299.2 300.384 2 -CONH(CH2)5CO-1-Pip CH2 1 H C20H36N4O3 380.3 381.485 2 -CONH(CH2)5CONH2 CH2 1 H C15H28N4O3 312.2 313.3
计算值 FAB质谱No. n Q X m R 分子式
Mol.Wt. [M+H]+86 2 -CONH(CH2)5CONH- CH2 1 H C25H48N4O3 452.4 453.5
(CH2)9CH387 2 -CONH(CH2)5CONH- CH2 1 H C22H42N4O3 410.3 411.4
(CH2)6CH388 2 -CONH(CH2)5CONH- CH2 1 H C22H40N4O3 408.3 409.4
CH2Ch89 2 -CONH(CH2)5CONH- CH2 1 H C26H41N5O5 503.3 504.4
(CH2)3NHZ90 2 -CONH(CH2)5CONH- CH2 1 H C18H35N5O3 369.3 370.3
(CH2)3NH291 2 -CONH(CH2)5CONH- CH2 1 H C19H37N7O3 411.3 412.4
(CH2)3-Gua92 2 -CONH(CH2)5CONH- CH2 1 H C21H32N4O6S 468.2 469.2
Ph(4-SO3H)93 2 -CONH(CH2)5CONH-4- CH2 1 H C27H43N5O3 485.3 486.3
Pip(1-Bn)94 2 -CONH(CH2)5CONH- CH2 1 H C20H37N5O3 395.3 396.3
4-Pip95 2 -CONH(CH2)4N(Z)- CH2 1 H C32H45N5O6 595.3 596.3
(CH2)3NHZ96 2 -CONH(CH2)4NH- CH2 1 H C16H33N5O2 327.2 328.2
(CH2)3NH2
计算值 FAB质谱No. n Q X m R 分子式
Mol.Wt. [M+H]+97 2 -CONH(CH2)5CO2Bn CH2 1 CN C23H32N4O4 428.3 429.398 3 -CONH(CH2)6CONH- CH2 1 H C30H48N4O5 544.4 545.2
(CH2)5CO2Bn99 3 -CONH(CH2)6CONH- CH2 1 H C23H42N4O5 454.3 455.3
(CH2)5CO2H100 3 -CONH(CH2)5CO2Bn CH2 1 H C23H35N3O4 417.3 418.2101 3 -CONH(CH2)5CO2H CH2 1 H C16H29N3O4 327.2 328.2102 2 -SO2NH(CH2)5CO2H CH2 1 H C14H27N3O5S 349.2 350.2103 2 -CONH(CH2)8NH-G CH2 1 H C24H45N5O7S 547.4 548.5
表5组II(ii)的实施例
计算值 FAB质谱No. n Q X m R 分子式
Mol.Wt. [M+H]+104 1 -CO(CH2)6CO2H CH2 1 H C15H27N3O4 313.2 314.3105 1 -CO(CH2)6CO2Bn CH2 1 H C22H33N3O4 403.3 404.3106 3 -CO(CH2)4CO2H CH2 1 H C15H27N3O4 313.2 314.3107 3 -CO(CH2)4CO2Me CH2 1 H C16H29N3O4 327.2 328.3108 4 -CO(CH2)5NH2 CH2 1 H C16H32N4O2 312.3 313.3109 4 -CO(CH2)3NH2 CH2 1 H C14H28N4O2 284.2 285.2110 1 -CO(CH2)3NHSO2Pfp CH2 1 H C20H27F5N4O4S 514.2 515.2111 4 -CO(CH2)3NHCOPfp CH2 1 H C21H27F5N4O3 478.2 479.2112 4 -CO(CH2)3NHSO2- CH2 1 H C16H29F3N4O4S 430.2 431.3
CH2CF3113 4 -CO(CH2)11NHCO- CH2 1 H C37H63N5O5 657.5 658.6
(CH2)6NHZ114 4 -CO(CH2)11NH- CH2 1 H C29H57N5O3 523.4 524.4
CO(CH2)6NH2
计算值 FAB质谱No. n Q X m R 分子式
Mol.Wt. [M+H]+115 4 -CO(CH2)5NHCO- CH2 1 H C35H60N5O5 672.5 673.6
(CH2)5NHCO(CH2)5-
NHZ116 4 -CO(CH2)5NHCO- CH2 1 H C28H54N5O4 538.4 539.4
(CH2)5NHCO(CH2)5-
NH2117 4 -CO(CH2)3CO2H CH2 1 H C15H27N3O4 313.2 314.3118 4 -CO(CH2)3CO2Bn CH2 1 H C22H33N3O4 403.3 404.3119 4 -CO(CH2)6NH2 CH2 1 H C17H34N4O2 326.3 327.3120 4 -CO(CH2)7NH2 CH2 1 H C18H36N4O2 340.3 341.3121 4 -CO(CH2)16Me CH2 1 H C28H55N3O2 465.4 466.4122 4 -CO(CH2)6-Gua CH2 1 H C18H36N5O2 368.3 369.3123 4 -SO2(CH2)7CH3 CH2 1 H C18H37N3O3S 375.3 376.3124 4 -CO(CH2)11NH2 CH2 1 H C22H44N4O2 396.4 397.4125 4 -COCH2NHZ CH2 1 H C20H30N4O4 390.2 391.3126 4 -CO(CH2)2NHZ CH2 1 H C21H32N4O4 404.2 405.3127 4 -CO(CH2)3NHZ CH2 1 H C22H34N4O4 418.3 419.3128 4 -CO(CH2)2NH2 CH2 1 H C12H24N4O2 256.2 257.2
计算值 FAB质谱No. n Q X m R 分子式
Mol.Wt. [M+H]+129 4 -CO(CH2)5NHZ CH2 1 H C24H38N4O4 446.3 447.4130 4 -COCH2-Gua CH2 1 H C13H25N6O2 298.2 299.3131 4 -CO(CH2)2NH2 CH2 1 H C13H25N4O2 270.2 271.3132 4 -CO(CH2)2-Gua CH2 1 H C14H28N6O2 312.2 313.3133 4 -CO(CH2)3-Gua CH2 1 H C15H30N6O2 326.3 327.3134 4 -CO(CH2)5-Gua CH2 1 H C17H34N5O2 354.3 355.3135 4 -CO(CH2)6NH2 CH2 1 CN C18H33N5O2 351.3 352.4136 4 -CO(CH2)7NH2 CH2 1 CN C19H35N5O2 365.3 366.3
表6 组II(iii)的实施例
计算值 FAB质谱No. R R1 X n Y 分子式
Mol.Wt. [M+H]+137 H -OCH2CONH(CH2)5- CH2 1 H C15H27N3O5 329.2 330.3
CO2H138 H -OCH2CONH(CH2)5- CH2 1 H C22H33N3O5 419.3 420.3
CO2Bn139 H -OCH2CONH(CH2)4- CH2 1 H C21H31N3O5 405.2 406.3
CO2Bn140 H -OCH2CONH(CH2)4- CH2 1 H C14H25N3O5 315.2 316.3
CO2H141 CH3 -OCH3 CH2 1 H C9H18N2O2 186.1 187.2142 CH3 -OC2H5 CH2 1 H C10H20N2O2 200.1 201.2143 CH3 -O(CH2)5CH3 CH2 1 H C14H28N2O2 256.2 257.3144 CH3 -OCH2CONH(CH2)5- CH2 1 H C23H35N3O5 433.3 434.3
CO2Bn145 CH3 -OCH2CONH(CH2)5- CH2 1 H C16H29N3O5 343.2 344.3
CO2H
计算值 FAB质谱No. R R1 X n Y 分子式
Mol.Wt. [M+H]+146 CH3 -OCH2CONH(CH2)4- CH2 1 H C22H33N3O5 419.2 420.3
CO2Bn147 CH3 -OCH2CONH(CH2)4- CH2 1 H C15H27N3O5 329.2 330.3
CO2H
表7 组III的实施例
计算值 FAB质谱No. 结构 分子式
表8含酰胺键生物电子等排体的化合物A—B的特定实施例
计算值 FAB质谱No. A-B 分子式
Mol.Wt. [M+H]+149
C11H21N 167.2 168.2150
C12H20N2 192.2 193 2151
C12H20N2 192.2 193.2152
C10H20N2S 200.1 201.2
表9 对DP-IV的选择性Ki值
No. Ki(M)
2 6.4×10-8
7 7.6×10-6
11 2.2×10-9
20 1.7×10-9
23 5.0×10-10
35 3.7×10-8
38 9.8×10-9
44 2.0×10-9
59 1.5×10-7
66 1.8×10-7
97 5.0×10-10
110 2.5×10-7
136 1.7×10-8
143 9.4×10-7
150 1.7×10-6图解表示各类化合物的一般制备方法表1按E.Sch_n等人在Biol.Chem.Hoppe—Seylar,1991,372,305-311中所描述的一般途径,可以制备这些化合物。表2(a)R:-CN 表3按W.W.Bachovchin等人在J.Biol.Chem.,1990,265,3738-3743中所描述的方法制备。(b)R=CHO表4(W,P=保护基;P1,P2=在相应的表中所述的基团)(a)R=CN按照G.Luisi等人在Tet.Lett.,1993,34,2391-2392中的方法制备(IV)。(c)R=H,按表1实施例所述对上述方法修改。表5(a)R=CN(b)R=H,按表1实施例所述对上述方法修改。表6按照表5实施例所描述的方法,由(V)制备(VI)表7类似于上述图解的标准偶合,脱水和脱保护系列操作表8按照K.Clausen等人在Tetrahedron 1981,37,3635-3639中所描述的方法制备硫代酰胺。按照文献先例,可以制备其它酰胺生物电子等排体(A.F.Spatola in“Chemistry and biochemistry of Amino Acids,Pep-tides and proteins”,Vol.III,B.Weinstein Ed.,Marcal Dekker,NewYork,1983,P.267)
将二异丙基乙胺加到H-ProNH2·HCl(225mg,1.5mmol)在无水CH2Cl2(15cm3)的溶液中直到将PH调至9。在氮气氛下,一次加入BocIleONSu并将混合物搅拌16小时。将溶剂蒸发并按标准方法来处理残余物,即将残余物在乙酸乙酯(60cm3)和0.3N KHSO4溶液(10cm3)之间分配。用饱和NaCHO3溶液(10cm3),水(10cm3)和盐水(5cm3)进一步洗涤有机层。将溶液干燥(Na2SO4)并在减压下蒸发。将粗品经过短的硅胶柱,用己烷∶乙酸乙酯(10∶90-0∶100)洗脱,得到301mg(92%)BocIleProNH2的无色泡沫。1H NMR(CDCl3),δ(ppm);6.90(1H,br.s);5.51(1H,br.s);5.18(1H,d,J=9.6Hz);4.62(1H,dd,J=2.6,7.0Hz);4.29(1H,dd,J=8.4,9.2Hz);3.79-3.58(2H,m);2.36(1H,m);2.09-1.57(5H,m);1.43(9H,s);1.17(1H,m);0.95(3H,d,J=6.6Hz);0.90(3H,t,J=7.3Hz).
在氮气氛下,将咪唑(84mg,1.24mmol)加入BocIleProNH2在无水吡啶(10cm3)的溶液中。在滴加POCl3(0.25cm3,2.48mmol)之前,将溶液冷却至-35℃。在-30℃-20℃之间,将反应搅拌60分钟。然后将溶液蒸发并将粗品残渣进行柱层析(硅胶),得到180mg(94%)2-(s)-氰基-1-[N-(叔丁氧基羰基)异亮氨酰基]吡咯烷的无色油状物。1H NMR(CDCl3),δ(ppm);5.14(1H,d,J=9.2Hz);4.80(1H,dd,J=2.6,7.1Hz);4.22(1H,dd,J=7.9,9.1Hz);3.81(1H,m),3.71(1H,m),2.30-2.12(4H,m);1.75(1H,m);1.60(1H,m);1.42(9H,s);1.19(1H,m);0.97(3H,d,J=6.9Hz);0.91(3H,t,J=7.3Hz).13C NMR(CDCl3),δ(ppm);171.7,155.6,118.0,79.6,56.0,46.5,46.0,37.8,29.6,28.1,25.0,24.2,15.2,10.9.
通过与三氟乙酸一起搅拌60分钟进行脱保护。从水中蒸发并冷冻干燥,得到60mg 2-(s)-氰基-1-异亮氨酰基吡咯烷(11)的白色蓬松固体。
FAB质谱:计算值209.3,实测值(M+H)+=210.2。1H NMR(D2O),δ(ppm);4.3(1H,m);3.64(1H,d,J=5.6Hz);3.16(2H,m);1.86-1.48(5H,m);0.98(1H,m);0.68(1H,m);0.51(3H,d,J=6.9Hz);0.38(3H,t,J=7.3Hz).13NMR(D2O),δ(ppm);1697,119.7,57.3,48.6,48.1,36.9,30.2,25.8,24.5,15.4,11.5.实施例2 H-Glu[NH(CH2)7CONH(CH2)3NHZ]吡咯烷酰胺(64)
将二异丙基乙胺加入BocGlu(OH)吡咯烷酰胺(Pyrrolidide)(193mg,0.64mmol)和PyBop(500mg,0.96mmol)在CH2Cl2(6cm3)的溶液中,将混合物的PH调至9。搅拌5分钟后,加入8-氨基-辛酸苄酯(220mg,0.77mmol)在CH2Cl2(5cm3)中的溶液。在室温下,将混合物搅拌16小时。按实施例1所述的标准方法处理反应混合物。将粗品残渣进行柱层析(1%-3%甲醇/乙酸乙酯),得到344mg(99%)BocGlu[NH(CH2)7CO2Bn]吡咯烷酰胺的无色固体。1H NMR(CDCl3),δ(ppm);7.35(5H,s);6.63(1H,br.t,J=6.7Hz);5.65(1H,d,J=8.3Hz);5.11(2H,s);4.36(1H,dt,J=2.6,8.9Hz);3.55-3.20(6H,m);2.34(2H,t,J=7.3Hz);2.26(2H,dd,J=5.6,7.3Hz);2.11-1.48(10H,m);1.43(9H,s);1.32-
1.27(6H,m).
将氢气泡通入BocGlu[NH(CH2)7CO2Bn]吡咯烷酰胺(230mg,0.43mmol)在含10%钯/碳(50mg)的乙酸乙酯(10cm3)中的溶液中。90分钟后,用氮气冲洗反应容器,将溶液通过硅藻土层过滤并将溶剂蒸发,得到187mg(98%)的BocGlu[NH(CH2)7CO2H]吡咯烷酰胺的无色油状物。
将二异丙基乙胺加入BocGlu[NH(CH2)7CO2H]吡咯烷酰胺(125mg,0.28mmol)和PyBop(221mg,0.43mmol)在CH2Cl2(10cm3)的溶液中,将溶液PH调至9。搅拌5分钟后,一次加入ZNH(CH2)3NH2·HCl(90mg,0.37mmol)和二异丙基乙胺(38mg,0.37mmol)的溶液。将溶液搅拌18小时,然后按照实施例1所述的标准方法处理。将粗品残渣进行柱层析(2%-15%甲醇/乙酸乙酯),得到151mg(85%)BocGlu[NH(CH2)7CONH(CH2)3NHZ]吡咯烷酰胺的无色油状物。1H NMR(CDCl3),δ(ppm);7.35(5H,s);6.60(1H,br,t,J=7 2Hz);6.14(1H,br.t,J=7.2Hz);5.63(1H,d,J=8.3Hz);5.39(1H,br.t,J=5.6Hz);5.10(2H,s);4.38(1H,dt,J=2.3,9.2Hz);3.52-3.13(10H,m);2.26(2H,t,J=6.9Hz);2.17(2H,t,J=7.6Hz);1.98-1.48(12H,m);1.44(9H,s);1.38-1.23(6H,m).
将BocGlu[NH(CH2)7CONH(CH2)3NHZ]吡咯烷酰胺(14mg,0.022mmol)在4N HCl/二噁烷中的溶液搅拌45分钟。将溶剂蒸发并将残渣溶解在水中,过滤并冷冻干燥,得到13mg H-Glu[NH(CH2)7CONH(CH2)3NHZ]吡咯烷酰胺(64)的无色油状物。
将ZNH(CH2)3CO2NSu(570mg,1.7mmol)一次加入1-[N-(叔丁氧基羰基)赖氨酰基]吡咯烷(745mg,2.2mmol)在无水CH2Cl2的溶液中。用二异丙基乙胺将PH调至9并将混合物搅拌60分钟。将溶剂蒸发并按实施例1所述的标准方法将残渣处理。柱层析(100%乙酸乙酯-15%甲醇/乙酸乙酯),得到620mg(68%)BocLys[CO(CH2)3NHZ]吡咯烷酰胺。1H NMR(CDCl3),δ(ppm);7.42(5H,s);6.31(1H,br.t,J=6.5Hz);5.58(1H,d,J=8.9Hz);5.39(1H,br.t,J=6.9Hz);5.17(2H,s);4.44(1H,m);3.72-3.20(8H,m);2.29(2H,t,J=7.3Hz);2.14-1.83(8H,m);1.78-1.41(4H,m);1.43(9H,s).
将氢气泡通入BocLys[CO(CH2)3NHZ]吡咯烷酰胺(620mg,1.16mmol)和含1分子当量2NHCl的10%钯/碳的甲醇液(10cm3)的混合物中。60分钟后,用氮气冲洗反应混合物并通过硅藻土过滤。将溶剂蒸发得到282mg(49%)BocLys[CO(CH2)3NH2,HCl]吡咯烷酰胺。在氮气氛下,将该产物溶解在CH2Cl2(10cm3)中并搅拌。在引入全氟苯磺酰氯(45mg,0.17mmol)之前,加入二异丙基乙胺,将PH调至9。将该混合物搅拌16小时。蒸发溶剂并按实施例1所述的标准方法将粗品处理。柱层析(100%乙酸乙酯-10%甲醇/乙酸乙酯),得到33mg(31%)BocLys[CO(CH2)3NHSO2Pfp]吡咯烷酰胺的无色油状物。1H NMR(CDCl3);δ(ppm);7.19(1H,br.t,J=6.3Hz);6.18(1H,br.t,J=6.6Hz);5.50(1H,d,J=8.4Hz);4.38(1H,m);3.65-3.16(8H,m);2.36(2H,t,J=6.8Hz);2.01-1.82(8H,m);1.69-1.41(4H,m);1.43(9H,s).
用三氟乙酸(10cm3)将该产品搅拌30分钟。将溶剂蒸发并将粗品溶解在水中,过滤并冷冻干燥,得到30mg H-Lys[CO(CH2)3NHSO2Pfp]Prl(110)的无色油状物。
FAB质谱:计算值514.2;实测值(M+H)+=515.2。实施例4 H-Thr[(CH2)5CH3]吡咯烷酰胺(143)在氮气氛下,将吡咯烷(0.88g,12.4mmol)加入BocThrONSu(3.0g,9.5mmol)在无水CH2Cl2(30cm3)的溶液中。在室温下,将反应物搅拌60分钟。将溶剂蒸发并按实施例1所述的标准方法将残渣处理。将残渣进行柱层析(己烷∶乙酸乙酯,30∶70),得到2.50g(96%)1-[N-(叔丁氧基羰基)苏氨酰基]吡咯烷的无色油状物。1H NMR(CDCl3),δ(ppm);5.52(1H,d,J=6.5Hz);4.30(1H,d,J=7.4Hz);4.16(2H,m);3.72(1H,m);3.46(3H,m);1.98-1.82(4H,m);1.43(9H,s);1.19(3H,d,J=7.1Hz).
在0℃、氮气氛下,将氢化钠(17mg,0.70mmol)加入1-[N-(叔丁氧基羰基)苏氨酰基]吡咯烷在无水THF的溶液中。在引入正己基碘(200mg,0.94mmol)之前,在0℃下将混合物搅拌15分钟。然后在室温下,将反应物搅拌16小时。将溶剂蒸发并按实施例1所述的标准方法将残渣处理。将粗品进行柱层析(己烷∶乙酸乙酯,40∶60),得到25mg(10%)BocThr[CH2)5CH3]吡咯烷酰胺(143)。1H NMR(CDCl3),δ(ppm);5.50(1H,d,J=6.9Hz);4.48(1H,m);3.70-3.32(7H,m);1.92-1.80(6H,m);1.52(2H,m);1.42(9H,s);1.30(6H,m);1.22(8H,d,J=6.9Hz);0.83(3H,t,J=7.9Hz).
将BocThr[(CH2)5CH3]吡咯烷酰胺(20mg,0.06mmol)在4NHCl/二噁烷(5cm3)中搅拌60分钟。将溶剂蒸发,将残渣溶解在水中,过滤并冷冻干燥,得到H-Thr[(CH2)5CH3]吡咯烷酰胺(20mg)的橙色油状物。通过反相HPLC将产物纯化,得到15mg(143)的无色油状物。
FAB质谱:计算值:256.2,实测值(M+H)+=257.3。实施例5 H-Ile-_[CH=CH]吡咯烷酰胺(149)
在氮气氛下,保持温度在-30℃下,将1.6N正丁基锂(0.50cm3,0.76mmol)加到搅拌的环戊基三苯基溴化鏻(287mg,0.69mmol)在无水THF(6cm3)的溶液中。搅拌60分钟后,将溶液进一步冷却至-50℃,然后滴加N-(叔丁氧基羰基)-L-异亮氨醛(isoleucinal)(125mg,0.58mmol,按Fehrentz and Castro,Synthe-sis,1983,676中的方法制备)在无水THF(4cm3)中的溶液。滴加结束后,反应物经过3.5小时慢慢升至室温。
用饱和氯化铵溶液(2cm3)终止反应。用水(10cm3)将反应物稀释并用***(3×20cm3)萃取。将合并的***层用水(10cm3)洗涤,干燥(Na2SO4)并蒸发,得到187mg(>100%)粗品,柱层析(90∶10,己烷∶Et2O)得到53mg(34%)Boc-ILe-_[CH=CH]吡咯烷酰胺的无色油状物。1H NMR(CDCl3),δ(ppm);0.84(3H,t,J=6.9Hz);0.91(3H,d,J=7.3Hz);1.08(1H,m);1.44(9H,s);1.48(1H,m);1.64(5H,m);2.24-2.45(4H,m);4.08(1H,br,s);4.41(1H,br,s);5.12(1H,dt,J=2.3,8.9Hz).13C NMR(CDC13)δ(ppm);155.8,147.4,119.1,79.2,54.8,40.1,34.2,29.6,28.9,26.8,26.6,26.1,15.0,12.1.
用4N HCl/二噁烷将该产物处理35分钟,除去Boc-保护基。将反应物蒸发,将残渣溶解在水中,过滤并冷冻干燥,得到24mg(63%)H-ILe-_[CH=CH]吡咯烷酰胺(149)的泡沫状固体。
FAB质谱:计算值:167.2,实测值(M+H)+=168.2。
实施例6和7:
H-ILe[(2R)-氰基-_(CH=CH)吡咯烷酰胺(150)
H-ILe[(2S)-氰基-_(CH=CH)吡咯烷酰胺(151)
在氮气氛下,在甲苯中将N-(叔-丁氧基羧基)-L-异亮氨醛(2.40g,11.2mmol)和2-氧-1-三苯基正膦环戊烷(4.61g,13.4mmol,按H.O.House and H.Babed,J.Org.Chem.,1963,28,90中所述的方法制备)加热回流。15小时后,将混合物冷却,并将溶剂蒸发。将粗品残渣进行柱层析(80∶20,己烷∶乙酸乙酯),得到2.33g(74%)BocIle-_[CH=CH]吡咯烷-2-酮的无色油状物。1H NMR(CDCl3),δ(ppm);6.29(1H,dt,J=2.6,9.2Hz);4.59(1H,br,d);4.17(1H,m),2.82(1H,m);2.66-2.50(2H,m);2.34(2H,t,J=7.8Hz);1.96(2H,q,J=7.6Hz);1.44(1H,m);1.43(9H,s);1.12(1H,m),0.89(3H,d,J=5.3Hz);0.88(3H,t,J=6.9Hz).
在氮气氛下,将二乙基氰基膦酰基乙酸酯(0.30cm3,1.92mmol)加入BocIle-_[CH=CH]吡咯烷-2-酮(180mg,0.64mmol)和LiCN(0.5M DMF液,3.84cm3,1.92mmol)在无水DMF(2cm3)的溶液中。在室温下将反应物搅拌30分钟。用水(20cm3)将混合物稀释,然后用乙酸乙酯(2×30cm3)萃取。用水(5×10cm3)洗涤合并的有机层,干燥(Na2SO4)并蒸发,得到360mg(>100%)粗品。将部分该粗品氰基膦酸酯(284mg,0.64mmol)溶解在无水THF中,并在氮气下搅拌。加入叔丁醇(47mg,0.64mmol)再滴加碘化钐(II)(0.1M的THF液,19.2cm3,1.92mmol)。滴加结束后,在加入2N HCl(20cm3)之前,再进一步将反应物搅拌30分钟。用***(3×30cm3)萃取混合物。用10%Na2S2O3溶液(10cm3)、水(2×10cm3)和盐水(2×10cm3)洗涤合并的***层。将溶液干燥(Na2So4),蒸发并将粗品残渣进行柱层析(90∶10,己烷∶乙酸己脂),得到122mg(66%)BocILe[2-(RS)-氰基-_(CH=CH)吡咯烷]非对映体混合物的无色油状物。
1H NMR(CDCl3),δ(ppm);5.52(1H,d,J=9.6Hz);4.5(1H,br.s);4.12(1H,m);
3.35(1H,m);2.57(1H,m);2.38(1H,m);2.17(1H,m);1.91(2H,m);1.69(2H,m);
1.53(1H,m);1.43(9H,s);1.12(1H,m);0.92(1.5H,d,J=7.3Hz);0.91(1.5H,d,J
=7.3Hz);0.89(1.5H.d,J=6.6Hz);0.86(1.5H,t,J=6.9Hz).
用4N HCl/二噁烷处理该非对映体混合物,除掉保护基。蒸发溶剂并接着将粗品进行反相HPLC得到两种纯的非对映体。
(150),(47mg,60%)FAB质谱:计算值192.2,实测值(M+H)+=193.2
(151),(28mg,36%)FAB质谱:计算值192.2,实测值(M+H)+=193.2
本文参照表1-8和实施例1-7所描述的制备方法构成本发明的一部分。
缩写
Boc 叔丁氧基羰基
Bn 苄基
BSA 牛血清白蛋白
nBu 正丁基
Ch 环己基
DMF 二甲基甲酰胺
DMP Dess-Martin Periodane
EDTA 乙二胺四乙酸
FAB 快速原子轰击
Gua 胍基
HPLC 高效液相色谱
nHx 正己基
Mass Spec 质谱
mCPBA 间氯过苯甲酸
Mol Wt 分子量
ONSu N-O-琥珀酰亚胺
Pfp 五氟苯基
Ph 苯基
Pip 哌啶基Prl 吡咯烷酰胺Py 吡淀PyBop 苯并***-1-基-氧基-三-
吡咯烷基-鏻的六氟磷酸盐WSCD 水溶性碳化二亚胺Z 苄氧基羰基
Claims (7)
2.权利要求1的抑制剂,其中B为5元环,n为1;X为CH2或S;并且R为CN。
3.选自下列通式的DP-IV介导过程的抑制剂,A-B(组II)
n=1或2;
m=0,1或2;
X=CH2,O,S,SO或SO2;
-Y=-N,
其中a=1-5;
D=-G-(CH2)b-(R4)q-R3;
G=NH或NMe;
b=1-12;q=0或1;
R4=Z-NH-(CH2)c-或NH-Z-(CH2)c-,其中c=1-12,并且Z=CO或CH2;R3=CO2H或其酯,CONH2,CONR5R6,SO2NH2,SO2NR5R6,OH,OR5,最多1 1个原子的芳基,NH2,NR5R6,-NHCOR5,NH-SO2R5,NH-CH(:NR5)NR5R6,并且R5和R6独立地选自H和1-6个碳原子的低级烷基和氟烷基或者R5和R6可与它们连结的氮原子一起包含一个链(C3-C8);或者A为(ii)其中R1=H或Me,E=J-(CH2)b-(R4)q-R3,J=CO,并且a,b,q,R3和R4如(i)中定义;或者A为(iii)其中R2=H或Me,L为(CH2)d-[CO]r-(CH2)b-(R4)q-R3,其中r为1,d=1-4,并且b,q,R3和R4如(i)中定义。
4.根据权利要求1的DP-IV介导过程的抑制剂,其选自:N-(环戊基甘氨酰)吡咯烷,N-(L-环己基甘氨酰)吡咯烷,N-(L-环己-3-烯基甘氨酰)吡咯烷,N-(顺-2-氨基环己基羰基)吡咯烷,N-(反-2-氨基环己基羰基)吡咯烷,N-(反-2-氨基环己-4-烯基羰基)吡咯烷,N-(反-2-氨基环戊基羰基)吡咯烷,N-(反-2-氨基环辛基羰基)吡咯烷,N-异亮氨酰-L-脯氨甲腈,L-(N-苄氧羰基赖氨酰)-L-脯氨甲腈,L-脯氨酰-L-脯氨甲腈,L-4-硫杂脯氨酰-L-脯氨甲腈,3-硫杂脯氨酰-L-脯氨甲腈,L-环己基甘氨酰-L-脯氨甲腈,L-环戊基甘氨酰-L-脯氨甲腈,L-叔丁基甘氨酰-L-脯氨甲腈,L-异亮氨酰-L-4-硫杂脯氨甲腈,L-异亮氨酰-3-硫杂脯氨甲腈,L-环己基甘氨酰-L-4-硫杂脯氨甲腈,L-(N-苄氧羰基赖氨酰)-L-4-硫杂脯氨甲腈,L-异亮氨酰-L-4-氧杂脯氨甲腈,N-(L-异亮氨酰)吡啶甲腈,N-(L-异亮氨酰)-5-硫杂吡啶甲腈,L-异亮氨酰-L-4-硫杂脯氨甲腈-S,S-二氧化,L-异亮氨酰-L-4-硫杂脯氨甲腈-S-氧化,N-(1S,2S-2-氨基环己基羰基)-L-脯氨甲腈,N-(1R,2R-2-氨基环己基羰基)-L-脯氨甲腈,N-(1S,2S-2-氨基环戊基羰基)-L-脯氨甲腈,N-(1R,2R-2-氨基环戊基羰基)-L-脯氨甲腈,N-(1S,2S-2-氨基环己-4-烯基羰基)-L-脯氨甲腈,N-(1R,2R-2-氨基环己-4-烯基羰基)-L-脯氨甲腈,N-(1S,2R-2-氨基环己基羰基)-L-脯氨甲腈,N-(1S,2R-2-氨基环己-4-烯基羰基)-L-脯氨甲腈,N-(反-2-氨基环己基羰基)-L-脯氨甲醛,N-(1S,2S-2-氨基环戊基羰基)-L-脯氨甲醛,N-(1R,2R-2-氨基环戊基羰基)-L-脯氨甲醛,N-(反-2-氨基环戊基羰基)吡咯烷-2-硼酸,N-(1S,2S-2-氨基环己基羰基)吡咯烷-2-硼酸,N-(1R,2R-2-氨基环己基羰基)吡咯烷-2-硼酸,N-(1S,2S-2-氨基环己-4-烯基羰基)吡咯烷-2-硼酸,N-(1R,2R-2-氨基环己-4-烯基羰基)吡咯烷-2-硼酸,及其立体异构体。
5.根据权利要求3的DP-IV介导过程的抑制剂,其选自:N-(Nω-(苄氧羰基甲基)天冬酰胺酰)吡咯烷,N-(Nω-(羧甲基)天冬酰胺酰)吡咯烷,N-(Nω-(3-羧丙基)天冬酰胺酰)吡咯烷,N-(Nω-(2-(苄氧羰基)乙基)天冬酰胺酰)吡咯烷,N-(Nω-(2-羧乙基)天冬酰胺酰)吡咯烷,N-(Nω-(5-(苄氧羰基)戊基)天冬酰胺酰)吡咯烷,N-(Nω-(5-(羧戊基)天冬酰胺酰)吡咯烷,N-(Nω-(3-(苄氧羰基)丙基)天冬酰胺酰)吡咯烷,N-(Nω-(苄氧羰基甲基)谷氨酰胺酰)吡咯烷,N-(Nω-(羧甲基)谷氨酰胺酰)吡咯烷,N-(Nω-(2-(苄氧羰基)乙基)谷氨酰胺酰)吡咯烷,N-(Nω-(3-(苄氧羰基)丙基)谷氨酰胺酰)吡咯烷,N-(Nω-(3-羧丙基)谷氨酰胺酰)吡咯烷,N-(Nω-(5-(苄氧羰基)戊基)谷氨酰胺酰)吡咯烷,N-(Nω-(5-羧戊基)谷氨酰胺酰)吡咯烷,N-(Nω-(2-羧乙基)谷氨酰胺酰)吡咯烷,N-(Nω-(7-(苄氧羰基)庚基)谷氨酰胺酰)吡咯烷,N-(Nω-(7-羧庚基)谷氨酰胺酰)吡咯烷,N-(Nω-(7-(3-(苄氧羰基氨基)丙基氨基羰基)庚基)谷氨酰胺酰)吡咯烷,N-(Nω-(6-(5-(苄氧羰基)戊基氨基羰基)己基)谷氨酰胺酰)吡咯烷,N-(Nω-(6-(5-羧戊基氨基羰基)己基)谷氨酰胺酰)吡咯烷,N-(Nω-(7-(3-氨基丙基氨基羰基)庚基)谷氨酰胺酰)吡咯烷,N-(Nω-(11-(苄氧羰基)十一烷基)谷氨酰胺酰)吡咯烷,N-(Nω-(11-羧基十一烷基)谷氨酰胺酰)吡咯烷,N-(Nω-(6-(苄氧羰基)己基)谷氨酰胺酰)吡咯烷,N-(Nω-(6-羧己基)谷氨酰胺酰)吡咯烷,N-(Nω-(5-(2,2,2-三氟乙基氨基羰基)戊基)谷氨酰胺酰)吡咯烷,N-(Nω-(5-(2,2,3,3,4,4,4-七氟丁基氨基羰基)戊基)谷氨酰胺酰)吡咯烷,N-(Nω-(5-(6-羟基己基氨基羰基)戊基)谷氨酰胺酰)吡咯烷,N-(Nω-(5-(3-苯基丙基氨基羰基)戊基)谷氨酰胺酰)吡咯烷,N-(Nω-(5-(4-苯基丁基氨基羰基)戊基)谷氨酰胺酰)吡咯烷,N-(Nω-(5-(二丁基氨基羰基)戊基)谷氨酰胺酰)吡咯烷,N-(Nω-(5-(二己基氨基羰基)戊基)谷氨酰胺酰)吡咯烷,N-(Nω-(5-(二苄基氨基羰基)戊基)谷氨酰胺酰)吡咯烷,N-(Nω-(4-(苄氧羰基)丁基)谷氨酰胺酰)吡咯烷,N-(Nω-(4-羧丁基)谷氨酰胺酰)吡咯烷,N-(Nω-(5-(乙基氨基羰基)戊基)谷氨酰胺酰)吡咯烷,N-(Nω-(6-羟基己基)谷氨酰胺酰)吡咯烷,N-(Nω-(5-(哌啶-1-羰基)戊基)谷氨酰胺酰)吡咯烷,N-(Nω-(5-氨基甲酰基戊基)谷氨酰胺酰)吡咯烷,N-(Nω-(5-(癸基氨基羰基)戊基)谷氨酰胺酰)吡咯烷,N-(Nω-(5-(庚基氨基羰基)戊基)谷氨酰胺酰)吡咯烷,N-(Nω-(5-(环己基甲基氨基羰基)戊基)谷氨酰胺酰)吡咯烷,N-(Nω-(5-(3-(苄氧羰基氨基)丙基氨基羰基)戊基)谷氨酰胺酰)吡咯烷,N-(Nω-(5-(3-氨基丙基氨基羰基)戊基)谷氨酰胺酰)吡咯烷,N-(Nω-(5-(3-胍基丙基氨基羰基)戊基)谷氨酰胺酰)吡咯烷,N-(Nω-(5-(4-磺基苯基氨基羰基)戊基)谷氨酰胺酰)吡咯烷,N-(Nω-(5-(1-苄基哌啶-4-基氨基羰基)戊基)谷氨酰胺酰)吡咯烷,N-(Nω-(5-(哌啶-4-基氨基羰基)戊基)谷氨酰胺酰)吡咯烷,N-(Nω-(4-(N-苄氧羰基-N-(3-苄氧羰基氨基丙基)氨基羰基)丁基)谷氨酰胺酰)吡咯烷,N-(Nω-(4-(3-氨基丙基氨基羰基)丁基)谷氨酰胺酰)吡咯烷,N-(Nω-(5-(苄氧羰基)戊基)谷氨酰胺酰)脯氨甲腈,N-(Nω-(6-(5-(苄氧羰基)戊基氨基羰基)己基)高谷氨酰胺酰)吡咯烷,N-(Nω-(6-(5-羧戊基氨基羰基)己基)高谷氨酰胺酰)吡咯烷,N-(Nω-(5-(苄氧羰基)戊基)高谷氨酰胺酰)吡咯烷,N-(Nω-(5-羧戊基)高谷氨酰胺酰)吡咯烷,(3S)-3-氨基-N-(5-羧戊基)-4-氧代-4-(1-吡咯烷基)丁磺酰胺,N-(Nω-(8-(葡糖胺基硫代羰基氨基)辛基)谷氨酰胺酰)吡咯烷,N-((2S)-2-氨基-3-(7-羧庚酰基氨基)丙酰基)吡咯烷,N-((2S)-2-氨基-3-(7-(苄氧羰基)庚酰基氨基)丙酰基)吡咯烷,N-(Nω-(5-羧戊酰基)鸟氨酰)吡咯烷,N-(Nω-(5-(甲氧羰基)戊酰基)鸟氨酰)吡咯烷,N-(Nω-(6-氨基己酰基)赖氨酰)吡咯烷,N-(Nω-(4-氨基丁酰基)赖氨酰)吡咯烷,N-(Nω-(4-(五氟苯磺酰氨基)丁酰基)赖氨酰)吡咯烷,N-(Nω-(4-(五氟苯甲酰氨基)丁酰基)赖氨酰)吡咯烷,N-(Nω-(4-(2,2,2-三氟乙磺酰氨基)丁酰基)赖氨酰)吡咯烷,N-(Nω-(12-(7-(苄氧羰基氨基)庚酰氨基)十二烷酰基)赖氨酰)吡咯烷,N-(Nω-(12-(7-氨基庚酰氨基)十二烷酰基)赖氨酰)吡咯烷,N-(Nω-(6-(6-(6-(苄氧羰基氨基)己酰氨基)己酰氨基)己酰基)赖氨酰)吡咯烷,N-(Nω-(6-(6-(6-氨基己酰氨基)己酰氨基)己酰基)赖氨酰)吡咯烷,N-(Nω-(4-羧丁酰基)赖氨酰)吡咯烷,N-(Nω-(4-(苄氧羰基)丁酰基)赖氨酰)吡咯烷,N-(Nω-(7-氨基庚酰基)赖氨酰)吡咯烷,N-(Nω-(8-氨基辛酰基)赖氨酰)吡咯烷,N-(Nω-十八烷酰基赖氨酰)吡咯烷,N-(Nω-(7-胍基庚酰基)赖氨酰)吡咯烷,N-(Nω-辛磺酰基赖氨酰)吡咯烷,N-(Nω-(12-氨基十二烷酰基)赖氨酰)吡咯烷,N-(Nω-(2-(苄氧羰基氨基)乙酰基)赖氨酰)吡咯烷,N-(Nω-(3-(苄氧羰基氨基)丙酰基)赖氨酰)吡咯烷,N-(Nω-(4-(苄氧羰基氨基)丁酰基)赖氨酰)吡咯烷,N-(Nω-(3-氨基丙酰基)赖氨酰)吡咯烷,N-(Nω-(6-(苄氧羰基氨基)己酰基)赖氨酰)吡咯烷,N-(Nω-(2-胍基乙酰基)赖氨酰)吡咯烷,N-(Nω-(3-氨基丙酰基)赖氨酰)吡咯烷,N-(Nω-(3-胍基丙酰基)赖氨酰)吡咯烷,N-(Nω-(4-胍基丁酰基)赖氨酰)吡咯烷,N-(Nω-(6-胍基己酰基)赖氨酰)吡咯烷,N-(Nω-(7-氨基庚酰基)赖氨酰)脯氨甲腈,N-(Nω-(8-氨基辛酰基)赖氨酰)脯氨甲腈,N-(O-(2-(5-羧戊基氨基)-2-氧代乙基)丝氨酰)吡咯烷,N-(O-(2-(5-(苄氧羰基)戊基氨基)-2-氧代乙基)丝氨酰)吡咯烷,N-(O-(2-(4-(苄氧羰基)丁基氨基)-2-氧代乙基)丝氨酰)吡咯烷,N-(O-(2-(4-羧丁基氨基)-2-氧代乙基)丝氨酰)吡咯烷,N-(O-甲基苏氨酰)吡咯烷,N-(O-乙基苏氨酰)吡咯烷,N-(O-己基苏氨酰)吡咯烷,N-(O-(2-(5-羧戊基氨基)-2-氧代乙基)苏氨酰)吡咯烷,N-(O-(2-(5-(苄氧羰基)戊基氨基)-2-氧代乙基)苏氨酰)吡咯烷,N-(O-(2-(4-(苄氧羰基)丁基氨基)-2-氧代乙基)苏氨酰)吡咯烷,和N-(O-(2-(4-羧丁基氨基)-2-氧代乙基)苏氨酰)吡咯烷。
6.权利要求1-5中任一项的化合物在制备抑制DP-IV介导过程的药物中的应用。
7.含DP-IV抑制量的权利要求1-5中任何一项化合物的药物组合物。
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IL (1) | IL111785A0 (zh) |
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PL (1) | PL182723B1 (zh) |
WO (1) | WO1995015309A1 (zh) |
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JPH09509921A (ja) | 1997-10-07 |
NO962269D0 (no) | 1996-05-31 |
EP0731789A1 (en) | 1996-09-18 |
US5939560A (en) | 1999-08-17 |
FI962315A0 (fi) | 1996-06-03 |
HU9601508D0 (en) | 1996-07-29 |
US6201132B1 (en) | 2001-03-13 |
WO1995015309A1 (en) | 1995-06-08 |
NO962269L (no) | 1996-07-30 |
JP3970317B2 (ja) | 2007-09-05 |
FI962315A (fi) | 1996-08-05 |
CN1141033A (zh) | 1997-01-22 |
HUT76274A (en) | 1997-07-28 |
CZ289931B6 (cs) | 2002-04-17 |
KR100347828B1 (ko) | 2003-01-06 |
NO306458B1 (no) | 1999-11-08 |
PL182723B1 (pl) | 2002-02-28 |
CZ159596A3 (en) | 1997-01-15 |
FI115629B (fi) | 2005-06-15 |
AU1113395A (en) | 1995-06-19 |
CA2178066A1 (en) | 1995-06-08 |
PL314838A1 (en) | 1996-09-30 |
IL111785A0 (en) | 1995-01-24 |
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