CN1044249C - 基质金属蛋白酶抑制剂 - Google Patents
基质金属蛋白酶抑制剂 Download PDFInfo
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- CN1044249C CN1044249C CN94194001A CN94194001A CN1044249C CN 1044249 C CN1044249 C CN 1044249C CN 94194001 A CN94194001 A CN 94194001A CN 94194001 A CN94194001 A CN 94194001A CN 1044249 C CN1044249 C CN 1044249C
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- Prior art keywords
- compound
- alkyl
- methyl
- phenyl
- hydroxyl
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- 239000011159 matrix material Substances 0.000 title claims abstract description 11
- 239000003475 metalloproteinase inhibitor Substances 0.000 title 1
- -1 mercapto, acetylthio, carboxy, hydroxycarbamoyl Chemical group 0.000 claims abstract description 373
- 150000001875 compounds Chemical class 0.000 claims abstract description 300
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 23
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 22
- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 21
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 20
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 17
- 230000000694 effects Effects 0.000 claims abstract description 16
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- 125000003118 aryl group Chemical group 0.000 claims abstract description 13
- 241000124008 Mammalia Species 0.000 claims abstract description 11
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims abstract description 10
- 125000004414 alkyl thio group Chemical group 0.000 claims abstract description 10
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims abstract description 8
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims abstract description 6
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 5
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- 229910052751 metal Inorganic materials 0.000 claims description 6
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- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 claims description 3
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 3
- ZRALSGWEFCBTJO-UHFFFAOYSA-N anhydrous guanidine Natural products NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 3
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 2
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- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 abstract 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 abstract 1
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical class [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 12
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- 230000002123 temporal effect Effects 0.000 description 1
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- UZPGPVQCDJXSNM-UHFFFAOYSA-M tetrabutylazanium;iodate Chemical compound [O-]I(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC UZPGPVQCDJXSNM-UHFFFAOYSA-M 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000008354 tissue degradation Effects 0.000 description 1
- 230000007838 tissue remodeling Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000759 toxicological effect Toxicity 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- 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
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
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- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
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- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
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- C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
- C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
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- 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
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- C07C311/46—Y being a hydrogen or a carbon atom
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- C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C317/34—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring
- C07C317/38—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring with the nitrogen atom of at least one amino group being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfones
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Abstract
本发明公开了一种作为单一立体异构体或其混合物的式(I)的化合物或其可药用盐,其中R1为巯基、乙酰基硫基、羧基、羟基氨基甲酰基、烷氧羰基、芳氧羰基、芳烷氧羰基、苄氧基氨基甲酰基或如(i)(其中,R6为任意被取代的芳基,其中芳基为喹啉-2-基、萘-1-基、萘-2-基、吡啶基或苯基);R2为烷基、芳烷基或环烷基烷基;R3为环烷基、烷基(任意被环烷基、羟基、巯基、烷硫基、芳烷氧基、羧基、氨基、烷氨基、胍基、氨基甲酰基、吡啶基或吲哚基取代),或芳烷基(任意被羟基、羧基、烷基或烷氧基取代);R4为硝基、氨基、氰基、羟基、烷氧基、羧基、烷氧羰基、烷基磺酰基、卤代烷基、烷氧羰基烷基、四唑基、氨基甲酰基(任意被烷基或二烷基氨基烷基取代),或氨基磺酰基(任意被烷基取代);和R5为氢、卤原子或羟基。这些化合物可用于抑制哺乳动物中基质金属蛋白酶的活性。
Description
本发明涉及可抑制基质金属蛋白酶,特别是stromelysin(基质溶素)和matrilysin的化合物和其可药用盐,它们可用于治疗哺乳动物的由于该基质金属蛋白酶的被抑制而可减轻的疾病。
基质金属蛋白酶是一族与结缔组织降解和改型有关的蛋白酶。该族酶的成员有一系列性能,包括锌或钙依赖性,作为酶原的分泌作用,及有40-50%的氨基酸序列同源性。基质金属蛋白酶族包括间质胶原酶,它是由成纤维细胞/巨噬细胞和中性粒细胞衍生的,它催化天然胶原Ⅰ、Ⅱ、Ⅲ和Ⅹ型的初始与限速裂解。
胶原为哺乳动物的一种主要结构蛋白,它是许多组织如软骨、骨头、腱、皮肤基质的基本成分。间质胶原酶为特异性很强的基质金属蛋白酶,它裂解胶原以得到两个片断,它们同时在生理温度下变性,因而易于被较弱特异性的酶来裂解。由于通过胶原酶裂解导致目标组织的结构完整性的损失,它是一种基本上不可逆的过程,因而对治疗干涉作用为优良的对象。
除了间质胶原酶外,基质金属蛋白酶族包括两种特殊但高度相关的明胶酶:由成纤维细胞分泌的72-KD酶和由单核吞噬细胞释放的92-KD酶。这些明胶酶能够降解明胶(变性的胶原)、天然胶原Ⅳ型和Ⅴ型、纤维连接素和不溶性弹性硬蛋白。
基质金属蛋白酶族也包括stromelysin 1和2,它们能够使宽范围的基质底物包括:层粘连蛋白、纤维连接素、蛋白聚糖和胶原Ⅳ和Ⅸ型在其非螺区域(non-helical domains)裂解。
Matrilysin(相关的金属蛋白酶或PUMP)为一种近来描述的基质金属蛋白酶族的一员。Matrilysin能够降解宽范围的基质底物,包括蛋白聚糖、明胶、纤维连接素、弹性硬蛋白和层粘连蛋白。它的表达记载在单核吞噬细胞、大鼠子宫移植物,并偶尔发生在肿瘤中。
基质金属蛋白酶的抑制剂被认为提供了对关节疾病、骨吸收疾病(如骨质疏松症)、与糖尿病有关的增强性胶原损坏、牙周疾病、角膜溃疡、皮肤溃疡和肿瘤转移的有益治疗手段。例如,胶原酶抑制剂的设计与潜在的应用描述在J.Enzyme Inhibition(1987),vol.2,pp,1-22,和Drug News & Prospectives(1990),vol.3,No.8,pp.453-458。基质金属蛋白酶抑制剂也是各种专利及专利申请的主题,例如U.S.专利5,189,178(Galardy)和5,183,900(Galardy),EP-A-0438223(Beecham)和0276436(F.Hoffmann-La Roche),PCT国际申请92/21360(Merck),92/06966(Beecham)和92/09563(Glycomed)。
本发明提供了一种可用于抑制基质金属蛋白酶特别是stromel-ysin和matrilysin的新化合物,该化合物可有效地用于治疗以基质金属蛋白酶过量活性为特征的疾病。
本发明的一个方面是涉及一种作为单一立体异构体或其混合物的式(Ⅰ)化合物或其可药用盐:其中R1为巯基、乙酰基硫基、羧基、羟基氨基甲酰基、烷氧羰基、芳氧羰基、芳烷氧羰基、苄氧基氨基羰基或(其中,R6为任意被取代的芳基,其中芳基为喹啉-2-基、萘-1-基、萘-2-基、吡啶基或苯基);R2为烷基、芳烷基或环烷基烷基;R3为环烷基、烷基(任意被环烷基、羟基、巯基、烷硫基、芳烷氧基、羧基、氨基、烷氨基、胍基、氨基甲酰基、吡啶基或吲哚基取代),或芳烷基(任意被羟基、羧基、烷基或烷氧基取代);R4为硝基、氨基、氰基、羟基、烷氧基、羧基、烷氧羰基、烷基磺酰基、卤代烷基、烷氧羰基烷基、四唑基、氨基甲酰基(任意被烷基或二烷基氨基烷基取代)或氨基磺酰基(任意被烷基取代);和R5为氢、卤原子或羟基。
本发明的另一个方面涉及抑制哺乳动物中基质金属蛋白酶活性的方法,该方法包括以治疗有效量的如上所述的单一立体异构体或其混合物的式(Ⅰ)的化合物或其可药用盐向需要的哺乳动物给药。
本发明的另一个方面涉及一种药物组合物,它包含治疗有效量的如上定义的式(Ⅰ)化合物或其可药用盐,并含有一种或多种可药用的赋形剂。
在本说明书及附加的权利要求中,除非另有说明,下列术语具有如下含义:
“BOC”指叔丁氧羰基。
“CBZ”指苄氧羰基。
“DMAP”指N,N-二甲基氨基吡啶。
“DMF”指N,N-二甲基甲酰胺。
“EDCI”指N-乙基-N′-(3-二甲基氨基丙基)碳化二亚胺。
“HOBT”指1-羟基苯并三唑。
“羟基”指-OH。
“氨基”指-NH2。
“乙酰基硫基”指-SC(O)CH3。
“卤素”指溴、氯或氟。
“氨基甲酰基”指-C(O)NH20
“羧基”指-C(O)OH。
“羟基氨基”指-NHOH。
“羟基氨基甲酰基”指-C(O)NHOH。
“巯基”指-SH。
“苄氧基氨基甲酰基”指-C(O)N(H)CH2C6H50
“烷基”指直链或支链的仅由碳和氢组成的、不包含不饱和键、具有1-4个碳原子的一价基团,如甲基、乙基、正丙基、2-甲基丙基(异丁基)、1-甲基乙基(异丙基)、正丁基、1,1-二甲基乙基(叔丁基)等。
“烷氨基”指式-NHRa基团,其中Ra为如上定义的烷基,如甲氨基、乙氨基、异丙氨基、正丁氨基等。
“卤代烷基”指式-RaRd基团,其中Ra为被一个或多个如上定义的卤素基团(Rd)取代的如上定义的烷基,如,2-氯乙基、2-溴乙基、三氟甲基等。
“二烷氨基烷基”指式-RaN(Ra)2基团,其中每一个Ra独立为如上定义的烷基,如,二甲氨基乙基、二乙氨基正丙基、二甲氨基正丙基等。
“氨基磺酰基”指-S(O)2NH20
“烷基磺酰基”指式-S(O)2Ra基团,其中Ra为如上定义的烷基,如,甲磺酰基、乙磺酰基、异丙磺酰基等。
“烷硫基”指式-SRa的基团,其中Ra为如上定义的烷基,如甲硫基、乙硫基、异丙硫基、正丁硫基等。
“烷氧基”指式-ORa基团,Ra为如上定义的烷基,如甲氧基、乙氧基、正丙氧基、1-甲基乙氧基、正丁氧基、叔丁氧基等。
“烷氧羰基烷基”指式-RaC(O)Rb基团,其中Ra为如上定义的烷基,Rb为如上定义的烷氧基,如,甲氧羰基乙基、乙氧羰基乙基、甲氧羰基异丙基等。
“芳基”指喹啉-2-基、萘-1-基、萘-2-基或苯基。
“芳氧基”指式-ORb基团,其中Rb为如上定义的芳基,如苯氧基、喹啉-2-基氧基、萘-1-基氧基或萘-2-基氧基。
“芳烷基”指式-RaRb基团,其中Ra为如上定义的烷基,Rb为如上定义的芳基,如苄基、苯亚乙基、3-苯基丙基、2-喹啉-2-基乙基等。
“芳烷氧基”指式-ORaRb基团,其中Ra为如上定义的烷基,Rb为如上定义的芳基,如,苄氧基、2-喹啉-2-基乙氧基、3-萘-2-基丙氧基等。
“烷氧羰基”指式-C(O)Rb的基团,其中Rb为如上定义的烷氧基,如甲氧羰基、乙氧羰基、叔丁氧羰基等。
“芳氧羰基”指式-C(O)Rc,其中Rc为如上定义的芳氧基,如苄氧羰基、2-喹啉-2-基乙氧羰基等。
“环烷基”指仅由碳和氢原子组成、不包含不饱和键、具有5-7个碳原子的单价环基,如环戊基、环己基和环庚基。
“环烷基烷基”指式-ReRa基团,其中Ra为如上定义的烷基,Re为如上定义的环烷基,如环己基甲基、环己基乙基、环戊基甲基、环戊基甲基等。
“氧膦基”指式H2P(O)-基团,其中两个H原子可被其它基团取代。
“任选的(地)”指随后描述的事情可发生或不发生,还指某种描述包括了发生所述事情的情形或未发生所述事情的情形,如“任选地取代的喹啉-2-基”是指喹啉-2-基可被取代或未被取代,这种描述包括取代了的喹啉-2-基和无取代基的喹啉-2-基。
“任选取代的芳基”指被一个或多个选自如下基团取代或未取代的喹啉-2-基、萘-1-基、萘-2-基、吡啶基或苯基,取代基为:卤素、烷基、烷氧基、羟基和硝基,所说基团的实例为:6-硝基喹啉-2-基、6-氟喹啉-2-基、6-羟基喹啉-2-基、6-甲氧基喹啉-2-基、6-硝基萘-1-基、6-氯萘-1-基、6-羟基萘-1-基、6-甲氧基萘-1-基、6-硝基萘-2-基、6-氯萘-2-基、6-羟基萘-2-基、6-甲氧基萘-2-基、6-硝基苯基、6-氯苯基、6-羟基苯基、6-甲氧基苯基等。
“氨基保护基”指那些能保护氮原子在合成过程中不发生不需反应的基团,它们包括但不限于:苄基、酰基、乙酰基、苄氧羰基、对甲氧基苄氧羰基、对硝基苄氧羰基、叔丁氧羰基等。
“可药用盐”指保留游离酸或游离碱的生物活性和性能并且不是生理不可接受的那些盐。如果化合物以游离酸存在,所希望的盐可按公知技术制备,如用无机酸或有机酸处理化合物,无机酸的实例为:盐酸、氢溴酸、硫酸、硝酸、磷酸等;有机酸的实例为:乙酸、丙酸、乙醇酸、丙酮酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸、水杨酸等。如果化合物以游离碱存在,所希望的盐可按公知的技术制备,如用无机碱或有机碱进行处理。由无机碱得到的盐包括但不限于:钠、钾、锂、铵、钙、镁、铁、锌、铜、锰、铝盐等。由有机碱得到的盐包括但不限于以下化合物的盐:伯、仲、叔胺,包括天然存在的取代的胺在内的取代的胺,环胺和碱性离子交换树脂,如异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、2-甲基氨基乙醇、2-二乙基氨基乙醇、三甲胺、二环己基胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、羟胺(hydraba-mine)、胆碱、甜菜碱、乙二胺、葡糖胺、甲基葡糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。
“哺乳动物”包括人类和所有家养和野生动物,包括但不限于:牛、马、猪、绵羊、山羊、狗、猫等。
“治疗有效量”指当向需要的哺乳动物给药时,对由基质金属蛋白酶活性特别是stromelysin和matrilysin活性抑制可减轻的疾病足以进行有效治疗的式(Ⅰ)化合物的用量。构成“治疗有效量”的式(Ⅰ)化合物的用量随化合物、疾病状态及其严重程度、待治疗的哺乳动物的不同而变化,但本领域普通技术人员可根据其掌握的知识及本说明书作出决定。
“治疗”包括了对哺乳动物特别是人类的疾病进行治疗。所说的疾病是由于基质金属蛋白酶活性,特别是stromelysin和matril-ysin活性被抑制而减轻的;包括:
(1)当哺乳动物易受所述疾病的感染但还未诊断出已感染该疾病时,预防该哺乳动物发生疾病;
(2)抑制该疾病,即停止该疾病的发展;或
(3)减缓该疾病,即使该疾病得到消退。
“立体异构体”指化合物具有相同的分子式和键的种类或顺序,但它们的原子在空间的排列方式不同。
本文所用的命名法基本上为I.U.P.A.C命名法的改进方式,其中,本发明的化合物被命名为肽衍生物。式(Ⅰ)的化合物或其可药用盐在其结构中至少包含两个不对称碳原子,因而可能以单一立体异构体、外消旋物形式存在,及以对映体与非对映体的混合物存在。所有这些单一立体异构体、外消旋物及它们的混合物均属于本发明范围之内。
当命名式(Ⅰ)化合物的单一立体异构体时,可以按照Cahn、Ingold和Prelog的“顺序原则”对手性碳原子的绝对构型予以描述,如R或S。
此外,包括R3及邻近的氮原子和羰基的式(Ⅰ)化合物的那部分可定义为α-氨基酸残基并如是命名。
例如下式(Ⅰ)化合物:其中R1为羟基氨基甲酰基;R2为2-甲基丙基;R3为2-甲基丙基;R4为甲氧羰基;R5为氢;该化合物被命名为:N-(4-甲基-2-(N"-羟基氨基甲酰基)甲基戊酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺。实用性与给药
A.实用性
式(Ⅰ)的化合物用于抑制哺乳动物的基质金属蛋白酶,特别是stromelysin和matrilysin,因而可预防哺乳动物胶原的降解。因而,该化合物用于治疗与金属基质蛋白酶活性增加,特别是strom-elysin和matrilsin活性增加相关的疾病,如关节炎、骨关节病、瘤转移、牙周疾病和角膜溃疡。参见:如,Arthritis and Rheum-atism(1993),Vol.36,No.2,pp.181-189;Arthritis and Rheum-atism(1991),Vol.34,No.9,pp.1073-1075;Seminars in Arthri-tis and Rheumatism(1990),Vol.19,No.4,Supplement 1(Feb-ruary),pp.16-20;Drugs of the Future(1990),Vol.15,No.5,pp.495-508;和J.Emzyme Inhibition(1987),Vol.2,pp 1-22。
B.试验
按照各种本领域技术人员公知的不同的体内和体外试验方法,如在Anal.BioChem.(1985),Vol.147,p.437或其改进方法可表明式(Ⅰ)化合物在抑制基质金属蛋白酶活性,特别是stromelysin和matrilysin活性的能力。
C.给药
可以采用任何一种可接受的给药方式或类似效用的试剂实现以纯的形式或以适宜的药物组合物形式使式(Ⅰ)化合物或其可药用盐给药。因此,给药方式可以是,例如,口服、鼻给药、非肠道给药、表面给药、皮下给药、直肠给药,以固体形式、半固体形式、冻干粉、或液体制剂形式,如片剂、栓剂、丸剂、软塑料胶囊和硬明胶胶囊、粉剂、溶液剂、悬浮液剂或气溶胶剂,优选适用于准确剂量的简单给药的单位剂量方式。组合物将包括常规的药用载体或赋形剂和作为活性成分的式(Ⅰ)化合物,此外还可包括其它的医药试剂或制药试剂、载体、佐剂等。
通常,根据所采用的给药方式,可药用组合物包含约1%-99%(wt)的式(Ⅰ)化合物或其可药用盐,99-1%(wt)的适宜的药物赋形剂。优选地,组合物为约5%-75%(wt)的式(Ⅰ)化合物或其可药用盐,其余为适宜的药物赋形剂。
优选的给药途径是口服,使用常规的日常剂量制度,它可按照欲治疗疾病的严重程度调节。对这种口服给药形式,含式(Ⅰ)化合物或其可药用盐的药物组合物可通过掺入常规赋形剂的任一种而制成,赋形剂的实例是,药品级的甘露糖醇、乳糖、淀粉、预胶化淀粉、硬脂酸镁、糖精钠、滑石、纤维素醚衍生物、葡萄糖、明胶、蔗糖、柠檬酸酯、丙基gallate等。该组合物采用溶液剂、悬浮液剂、片剂、丸剂、胶囊剂、粉剂、缓释剂等形式。
该组合物优选采用胶囊剂、caplet或片剂,因而将包含稀释剂如乳糖、蔗糖、磷酸二钙等;崩解剂如croscarmellose sodium或其衍生物;润滑剂如硬脂酸镁等;粘合剂如淀粉、阿拉伯胶、聚乙烯基吡咯烷酮、明胶、纤维素醚衍生物等。
式(Ⅰ)的化合物或其可药用盐也可配制成栓剂,例如,使用约0.5%-50%的活性成分分散在载体中,载体可缓慢地在体内溶解,如聚氧乙烯乙二醇和聚乙二醇(PEG),如PEG 1000(96%)和PEG4000(4%)。
液体药物可给药的组合物可通过例如下述过程制备:将式(Ⅰ)的化合物(约0.5%-20%)或其可药用盐及任选的药用佐剂溶解、分散等在载体中以形成溶液或悬浮液,载体的实例为水、盐水、右旋糖液、甘油、乙醇等。
如果需要的话,本发明的药物组合物也可包含少量的辅助物,如润湿剂或乳化剂,pH缓冲剂、抗氧化剂等,如,柠檬酸、脱水山梨醇单月桂酸酯、三乙醇胺油酸酯、丁基化的羟基甲苯等。
该种剂型的制备方法是公知的,或对本领域的技术人员是明显的,如参见,Remington′s Pharmaceutical Sciences,18th Ed.,(Mack Publishing Company,Easton,Pennsylvania;1990)。按照本发明的技术,欲给药的组合物无论如何均包含一种治疗有效量的式(Ⅰ)化合物或其可药用盐,用于治疗由基质金属蛋白酶活性抑制而减轻的疾病。
式(Ⅰ)化合物或其可药用盐以治疗有效量给药,该量取决于如下的因素:所采用的具体化合物的活性、化合物作用的代谢稳定性和时间、病人年龄、体重、健康状况、性别、饮食、给药方式和时间、排泄率、联合用药、特定疾病的严重性及宿主承受治疗(host under-going therapy)。通常,每日的有效剂量为每天约0.14 mg-14.3mg式(Ⅰ)化合物或其可药用盐/kg体重,优选每天约0.7 mg-10 mg/kg体重,最优选每天约1.4 mg-7.2 mg/kg体重。例如,对70 kg的患者,式(Ⅰ)化合物或其可药用盐一天的剂量为约10 mg-1.0 g,优选约50 mg-700 mg,最优选约100 mg-500 mg。优选的实施方式
如上发明概述中所述的优选式(Ⅰ)化合物为R1为巯基或乙酰基硫基的那些化合物。
在该化合物组中,优选的亚组化合物为如下的化合物:其中,R2为烷基、芳烷基、环烷基烷基;R3为环烷基或烷基(任选被环烷基、羟基、芳烷氧基、烷硫基、吡啶基或吲哚基取代);R4为氰基、羧基、羟基、烷氧基、烷氧羰基、烷氧羰基烷基、氨基甲酰基(任选被芳烷基氨基烷基取代)或氨基磺酰基(任选被烷基取代);和R5为氢。
在该化合物亚组中,优选如下一类的化合物:其中,R2为烷基;R3为环己基、烷基(任选被环己基、羟基、苄氧基、甲硫基、吡啶基或吲哚基取代);R4为羧基、烷氧羰基或氨基磺酰基。
在该类化合物中,优选R2为2-甲基丙基的化合物。特别优选其中R3为2-甲基丙基的化合物。
如上发明概述中所述的式(Ⅰ)化合物优选R1为羧基的那些化合物。
在该化合物组中,优选的亚组化合物为如下的化合物:其中,R2为烷基、芳烷基、环烷基烷基;R3为环烷基或烷基(任选被环烷基、羟基、芳烷氧基、烷硫基、吡啶基或吲哚基取代);R4为氰基、羟基、烷氧基、羧基、烷氧羰基、烷氧羰基烷基、氨基甲酰基(任选被芳烷基氨基烷基取代)或氨基磺酰基(任选被烷基取代);和R5为氢。
在该化合物亚组中,优选如下一类的化合物:其中,R2为烷基;R3为环己基、烷基(任选被环己基、羟基、苄氧基、甲硫基、吡啶基或吲哚基取代);和R4为羧基、烷氧羰基或氨基磺酰基。
在该类化合物中,优选R2为2-甲基丙基的化合物。特别优选如下的化合物:其中R3为环己基、2-甲基丙基、吡啶-3-基甲基、1-苄氧基乙基、1-甲基丙基、1,1-二甲基乙基、1-羟基乙基和吲哚-2-基甲基;R4为甲氧羰基。
如上发明概述中所述的式(Ⅰ)化合物另外优选R1为羟基氨基甲酰基的那些化合物。
在该化合物组中,优选的亚组化合物为如下的化合物:其中,R2为烷基、芳烷基、环烷基烷基;R3为环烷基或烷基(任选被环烷基、羟基、芳烷氧基、烷硫基、吡啶基或吲哚基取代);R4为氰基、羟基、烷氧基、羧基、烷氧羰基、烷氧羰基烷基、氨基甲酰基(任选被芳烷基氨基烷基取代)或氨基磺酰基(任选被烷基取代);和R5为氢。
在该化合物亚组中,优选如下一类的化合物:其中,R2为烷基;R3为环己基、烷基(任选被环己基、羟基、苄氧基、甲硫基、吡啶基或吲哚基取代);R4为羧基、烷氧羰基或氨基磺酰基。
在该类化合物中,优选R2为2-甲基丙基的化合物。特别优选如下的化合物:其中R3为环己基、2-甲基丙基、吡啶-3-基甲基、1-苄氧基乙基、1-甲基丙基、1,1-二甲基乙基、1-羟基乙基和吲哚-2-基甲基。
最优选的式(Ⅰ)化合物为:N-(4-甲基-2-(N"-羟基氨基甲酰基)甲基戊酰基)-L-色氨酸-N′(4-羧基苯基)甲酰胺;N-(4-甲基-2-(N"-羟基氨基甲酰基)甲基戊酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;N-(4-甲基-2-(N"-羟基氨基甲酰基)甲基戊酰基)-L-亮氨酸-N′-(4-羧基苯基)甲酰胺;N-(4-甲基-2-巯基甲基戊酰基)-L-亮氨酸-N′(4-甲氧羰基苯基)甲酰胺;N-(4-甲基-2-乙酰基硫基甲基戊酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;N-(4-甲基-2-羧基甲基戊酰基)-L-亮氨酸-N′(4-甲氧羰基苯基)甲酰胺;N-(4-甲基-2-(N"-羟基氨基甲酰基)甲基戊酰基)-L-环己基甘氨酸-N′-(4-甲氧羰基苯基)甲酰胺;N-(4-甲基-2-(N"-羟基氨基甲酰基)甲基戊酰基)-L-t-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺。式(Ⅰ)化合物的制备
单一立体异构体或其混合物的式(Ⅰ)化合物或其可药用盐为肽衍生物,它们可通过构分α-氨基酸衍生物制备。形成肽键的标准方法在如下文献中有述:M.Bodanszky等,The Practice of Pept-ide Synthesis(1984),Springer-Verlag;M.Bodanszky,Princ-iples of Peptide Synthesis(1984),Springer-Verlag;J.P.Greenstein等,Chemistry of the Amino Acids(1961),Vol.1-3,John Wiley and Sons Inc.;G.R.Pettit,Synthetic Peptid-es(1970),Vol.1-2,Van Nostrand Reinhold Company。
通常,在惰性溶剂如二甲基甲酰胺(DMF)中,在1-羟基苯并三唑(HOBT)存在下,采用试剂如二环己基碳化二亚胺或N′-乙基-N′-(3-二甲基氨基丙基)碳化二亚胺(EDCI)通过碳化二亚胺法实现用于形成式(Ⅰ)化合物的酰胺偶合。其它形成酰胺或肽键的方法包括但不限于经酰氯、酰基叠氮化物、混合酸酐或活性酯如硝基苯基酯的合成路径。通常,在有或没有肽片断存在下进行溶液相酰胺偶合。
用于制备式(Ⅰ)化合物的化合物的末端氨基或羧基基团的保护基的选择部分是由特定的酰胺或肽偶合条件决定,部分是由与偶合相关的氨基酸和/或肽成分决定。通常采用的氨基保护基包括众所周知的那些,例如,苄氧羰基、对甲氧基苄氧羰基、对硝基苄氧羰基、叔丁氧羰基(BOC)等。优选使用BOC或苄氧羰基(CBZ)作α-氨基的保护基,这是因为除去它只需要弱酸,如三氟乙酸(TFA),或乙酸乙酯中的盐酸;或通过催化氢化除去。
可以按照本领域普通技术人员公知的方法将式(Ⅰ)的各个立体异构体分开,例如通过选择结晶法或通过色谱法,和/或本文公开的方法。
式(Ⅰ)化合物和其中间体的取代基和/或变量的组合是允许的,只要这种组合导致稳定的化合物。A.式(E)化合物的制备
式(Ea)的化合物可以按照本领域普通技术人员公知的方法(如参见欧洲专利公开号0276436)或按照以下实施例1的方法制备。式(Ed)的化合物可商购,或按公知的方法制备。
通常,首先在非质子传递溶剂,优选四氢呋喃和二氯甲烷中,在0-15℃,优选0℃,在碱优选二异丙基乙基胺和双(三甲基甲硅烷基)乙酰胺存在下,用仲甲醛处理式(Ea)化合物来制备式(E)的化合物。将形成的溶液控温于25-37℃,优选37℃下18小时。然后通过标准方法分离出式(Eb)化合物,优选通过溶剂蒸发、萃取和过滤进行分离。
然后将于非质子传递溶剂优选二氯甲烷中的式(Eb)化合物冷却至-20℃~约0℃,优选冷却至-20℃。然后式(Ec)化合物通过标准方法进行酯化,该方法是采用至少化学计量量至100%过量的甲磺酰氯或甲苯磺酰氯在-20℃下处理该醇一段时间,优选约15分钟,然后在室温下处理一段时间,优选约3.5小时。随后按常规方法,优选通过萃取、过滤和蒸发从反应混合物中分离出式(Ec)化合物。
此后,于非质子传递溶剂,优选DMF中的式(Ec)化合物在开始温度为0℃,缓慢升温至室温的温度下,使其与式(Ed)化合物的盐(优选为钠盐,该盐是在非质子传递溶剂,优选DMF中由式(Ed)化合物与氢化钠反应形成的)反应约16~20小时,优选约18小时。此后通过常规的分离技术如萃取、蒸发和快速色谱从反应混合物中分离出式(Ee)化合物。
然后,在碱性条件下,优选在氢氧化钠存在下水解式(Ee)的化合物以形成式(E)的化合物,通过常规分离技术从反应混合物中将其分离出来。B.式(Ia)化合物的制备
式(Ia)化合物为其中R1为
R6为任选取代的芳基,其中芳基为喹啉-2-基、萘-1-基、萘-2-基、吡啶基或苯基;R2为烷基;R3如发明概述中所述;R4如发明概述中所述;R5为氢的式(Ⅰ)化合物。式(Ia)的化合物按下面的反应路线2所述进行制备,其中R2为烷基;R3如发明概述中所述;R4如发明概述中所述;R5为氢;R6为如上所述,BOC为叔丁氧羰基:
式(A)的N-保护氨基酸和式(B)的化合物可商购或按公知的方法制备。式(E)的化合物按如上A部分所述的方式制备。
通常,在常规酰胺偶合条件下,首先用式(B)的化合物偶合式(A)的化合物以形成式(C)的化合物来制备式(Ia)的化合物。例如,向冷(0-5℃)的式(A)化合物与过量摩尔量的HOBT的DMF溶液中加入过量摩尔量的EDCI。在0-5℃,优选0℃下,搅拌形成的溶液约1-2小时,优选约1小时。然后,在碱,优选DMAP存在下,向冷的溶液中加入等摩尔量的式(B)化合物。在室温,优选25℃下,搅拌形成的混合物12-24小时,优选24小时。然后,按照肽化学中的常规分离技术,如蒸发、萃取、柱色谱和/或HPLC从反应混合物中分离式(C)化合物。
随后,在弱酸性条件下,优选在三氟乙酸存在下除去式(C)化合物的氨基保护基,得到式(D)的化合物。
之后,在常规肽偶合条件下,用式(E)化合物偶合如此形成的式(D)化合物。例如,向惰性溶剂,优选THF中的冷(0-5℃,优选0℃)的式(D)化合物的溶液中加入1,1′-碳酰二咪唑(carbonyldiimidazo-le)。在0-5℃,优选0℃下搅拌形成的混合物60-90分钟,优选75分钟,然后与式(E)的化合物反应约12-17小时,优选约15小时。随后,采用肽化学中常规的技术,如萃取和反相HPLC从反应混合物中分离出式(Ia)化合物。C.式(F)化合物的制备
按照类似的方式,只是用D-(-)-2,10-樟脑磺内酰胺代替L-(+)-2,10-樟脑磺内酰胺,制得相应(S)构型的单一的立体异构体。
式(Fa)的化合物可商购,或按照公知技术制备,例如按实施例11的方法制得。L-(+)-2,10-樟脑磺内酰胺和D-(-)-2,10-樟脑磺内酰胺可商购,如从Aldrich Chemical Company(Milwauk-ee,Wisconsin,U.S.A.)购得。
通常,首先由式(Fa)化合物与L-(+)-2,10-樟脑磺内酰胺进行缩合反应形成式(Fb)化合物来制得式(F)化合物。使用NaHMDS以产生阴离子1小时,反应用溴乙酸叔丁酯骤冷结束,形成式(Q)化合物相应的酯。随后在碱性条件下除去樟脑基团以产生式(F)化合物的一种单一立体异构体,其中,与R2取代基相连的碳原子为(R)构型。D.式(Ib)、(Ic)、(Id)和(Ie)化合物的制备
式(Ib)化合物为式(Ⅰ)的化合物,其中R1为烷氧羰基或芳烷氧羰基;R2、R3、R4和R5如发明概述中定义。
式(Ic)化合物为式(Ⅰ)化合物,其中R1为羧基;R2、R3、R4和R5如发明概述中定义。
式(Id)化合物为式(Ⅰ)化合物,其中R1为苄氧基氨基甲酰基;R2、R3、R4和R5如发明概述中定义。
式(Ie)化合物为式(Ⅰ)化合物,其中R1为羟基氨基甲酰基;R2、R3、R4和R5如发明概述中定义。
式(Ib)、(Ic)、(Id)和(Ie)化合物按照如下的反应路线4制备,其中R2、R3、R4和R5如发明概述中定义;R8为叔丁基。
式(F)化合物如上述C部分制备。
式(D)化合物如上述B部分制备。
邻-苄基羟基胺可商购,如从Aldrich Chemical Co.以其盐酸盐购得。
通常,在常规的酰胺偶合条件下,首先使式(F)的化合物与式(D)的化合物偶合形成式(Ib)化合物而制备式(Ib)、(Ic)、(Id)和(Ie)化合物。例如,向含略为过量摩尔量的HOBT的式(F)化合物在非质子传递溶剂优选DMF中的溶液中加入过量摩尔量的EDCI。在0-5℃下,优选0℃下搅拌形成的混合物约1-2小时,优选1小时。然后,在碱优选DMAP存在下,向冷的溶液中加入等摩尔量的式(D)化合物。在室温,优选约25℃下,搅拌形成的混合物12-24小时,优选约24小时。之后,按照肽化学中常规的分离技术,如溶剂蒸发、萃取、快速色谱和/或HPLC从反应混合物中分离出式(Ib)化合物。
随后,在弱酸性条件下,优选采用三氟乙酸水解式(Ib)的化合物以得到式(Ic)的化合物。
随后,在常规的酰胺偶合条件下由邻-苄基羟基胺处理所得的式(Ic)化合物,形成了式(Id)化合物。例如,于惰性溶剂优选DMF中的式(Ic)化合物的冷(0-5℃)溶液用过量摩尔量的EDCI处理。在0-5℃,优选0℃下搅拌形成的混合物约30分钟~约1小时,再加入等摩尔量的邻-苄基羟基胺。使反应混合物过夜升温至室温。随后,按照常规分离技术,如通过萃取和快速色谱法从反应混合物中分离出式(Id)的化合物。
以后,在催化氢化(Pd/C)下除去式(Id)化合物的羟基保护基(苄基),得到式(Ie)化合物。E.式(G)化合物的制备
通常,首先用等摩尔量的碱如氢氧化钾水解式(Ga)的化合物以得到式(Gb)的化合物而制得式(G)化合物。然后,在碱性条件下,如在三乙胺存在下,在0-5℃,优选0℃下,对式(Gb)化合物进行去质子处理,然后,与甲醛反应,再用碱液,优选碳酸钾处理,得到式(Gc)化合物,再按常规分离方法从反应混合物中分离出式(Gc)化合物。
随后,在碱性条件下,优选在氢氧化锂存在下水解式(Gc)化合物以得到式(Gd)化合物。之后,在惰性气氛下,在90-100℃,优选95℃下,用过量摩尔量的硫代乙酸与式(Gd)化合物反应。然后,按照常规的分离技术如通过萃取和蒸发从反应混合物中分离出式(G)的化合物。F.式(If)和(Ig)化合物的制备
式(If)的化合物为式(Ⅰ)的化合物,其中R1为乙酰基硫基;R2、R3、R4和R5如发明概述中定义。
式(Ig)的化合物为式(Ⅰ)的化合物,其中R1为巯基;R2、R3、R4和R5如发明概述中定义。
式(If)和(Ig)的化合物按照如下的反应路线6制备,其中R2、R3、R4和R5如发明概述中定义:
反应路线6
式(D)化合物如上述B部分制备。
式(G)化合物如上述E部分制备。
通常,在酰胺偶合条件下,首先使式(G)化合物与式(D)化合物偶合得到式(If)化合物而制备式(If)和(Ie)化合物。例如,向非质子传递溶剂,优选DMF中的式(G)化合物和HOBT的溶液中加入过量摩尔量的EDCI。在室温下过夜搅拌形成的混合物。随后,按照常规分离技术,如通过溶剂蒸发、萃取和快速色谱从反应混合物中分离出所得式(If)化合物。之后,在碱性条件下,优选在氢氧化铵存在下在质子传递溶剂如甲醇中水解式(If)化合物以形成式(Ig)化合物。
此外,所有以游离酸或游离碱形式存在的式(Ⅰ)化合物可转化成它们的可药用盐,即分别用适宜的无机或有机碱或者用适宜的无机或有机酸进行处理。式(Ⅰ)化合物的盐也可转化成游离酸或游离碱形式或转化成另一种盐。
简而言之,式(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(If)和(Ig)的化合物(均为式(Ⅰ)的化合物)的制备过程如下:
1、使式(D)的化合物(其中R3和R4如发明概述中定义;R5为氢)与式(E)的化合物(其中R6为任选取代的芳基,芳基为喹啉-2-基、奈-1-基、萘-2-基、吡啶基或苯基;R2为烷基)反应形成式(Ia)的化合物(其中R1为:其中R6如式(E)化合物中的定义;R2、R3、R4和R5如式(D)或(E)化合物中的定义);或
2、式(F)的化合物(其中R2如发明概述中的定义;R8为烷基或苄基)与式(D)化合物(其中R3、R4和R5如发明概述中的定义)反应形成式(Ib)的化合物(其中R1为烷氧羰基或芳烷氧羰基;R2、R3、R4、R5和R8如式(F)或(D)化合物中的定义);或
3、处理式(Ib)化合物(其中R2、R3、R4和R5如发明概述中的定义;R8为烷基或苄基)形成式(Ic)的化合物(其中R1为羧基;R2、R3、R4和R5如发明概述中的定义);或
4、使式(Ic)化合物(其中R2、R3、R4和R5如发明概述中的定义)与邻-苄基羟基胺反应形成了式(Id)化合物(其中R1为苄氧基氨基甲酰基;R2、R3、R4和R5如发明概述中的定义);或
5、处理式(Id)的化合物(其中R2、R3、R4和R5如发明概述中的定义)形成式(Ie)的化合物(其中R1为羟基氨基甲酰基;R2、R3、R4和R5如发明概述中的定义);或
6、使式(G)的化合物(其中R2如发明概述中的定义)与式(D)的化合物(其中R3、R4和R5如发明概述中的定义)反应形成式(If)化合物(其中R1为乙酰基硫基;R2、R3、R4和R5如发明概述中的定义);或
7、处理式(If)化合物(其中R2、R3、R4和R5如发明概述中的定义)形成式(Ig)的化合物(其中R1为巯基;R2、R3、R4和R5如发明概述中的定义)。
以下给出具体的制备过程和实施例,它们用来帮助实施本发明,但它们并不作为对本发明范围的限定。
实施例1
式(Ea)的化合物
A.在室温下,将细晶次膦酸(8.4 g,0.13 mol)在纯原甲酸三乙酯(22 ml,0.20 mL)中搅拌90分钟。然后经套管转移至搅拌中的异丁基丙烯酸乙酯(ethylisobutylacrylate)(8 g,0.036 mol)和四甲基胍(4.5 ml,0.036 mol)的溶液中,该溶液已冷却至0℃ 10分钟。去除冰浴,反应物再搅拌4小时。混合物用200 ml乙醚稀释,溶液用1N HCl(100 ml)洗涤,水洗(4×100ml),盐水洗(100ml),用硫酸镁干燥。经旋转蒸发,得到8.15 g的2-(乙氧基)氧膦基甲基-4-甲基戊酸乙酯,浅黄色油,MS:349(M-H2O)+。
B.按照类似的方法,制备下述式(Ea)的化合物:
2-(乙氧基)氧膦基甲基-5-苯基戊酸乙酯;
2-(乙氧基)氧膦基甲基-4-苯基丁酸乙酯;
2-(乙氧基)氧膦基甲基-3-苯基丙酸乙酯;
2-(乙氧基)氧膦基甲基-3-环己基丙酸乙酯;
2-((乙氧基)氧膦基甲基)戊酸乙酯。
实施例2
式(Eb)的化合物
A.将粗产物2-(乙氧基)氧膦基甲基-4-甲基戊酸乙酯(26 g)溶解于600 ml THF/CH2Cl2(50/50)中,并冷却至0℃。向溶液中加入N,N-二异丙基乙基胺(32 ml)和90.8 ml的双-(三甲基甲硅烷基)乙酰胺,形成的混合物搅拌20分钟,然后加入仲甲醛(5.5 g)。将溶液加温至室温,并在37℃下加热18小时。通过蒸发除去溶剂,形成的油溶解于200 ml的乙酸乙酯中。溶液用50 ml的1N HCl(2次)、50 ml的盐水(2次)洗涤,经MgSO4干燥,过滤及蒸发后,得到19.3g的2-(乙氧基)(羟甲基)氧膦基甲基-4-甲基戊酸乙酯,淡黄色油,MS:281.2(MH+)。
B.按照类似的方法,制备下述式(Eb)的化合物:
2-(乙氧基)(羟甲基)氧膦基甲基-5-苯基戊酸乙酯;
2-(乙氧基)(羟甲基)氧膦基甲基-4-苯基丁酸乙酯;
2-(乙氧基)(羟甲基)氧膦基甲基-3-苯基丙酸乙酯;
2-(乙氧基)(羟甲基)氧膦基甲基-3-环己基丙酸乙酯;
2-((乙氧基)(羟甲基)氧膦基甲基)戊酸乙酯。
实施例3
式(Ec)的化合物
A.将2-(乙氧基)(羟甲基)氧膦基甲基-4-甲基戊酸乙酯(5 g)溶解于20 ml CH2Cl2中并冷却至-20℃(两份)。向溶液中滴加甲磺酰氯(1.5 ml)和三乙胺(3.0 ml)。15分钟后,撤去冰浴,在室温下使反应进行3.5小时。每一份溶液用10 ml冷的2%HCl、10 mlNaHCO3(饱和)、10 ml盐水洗涤,经MgSO4干燥,过滤及蒸发后,得到12.8 g(合并产生)的2-(乙氧基)(甲磺酰基氧基甲基)氧膦基甲基-4-甲基戊酸乙酯。
B.按照类似的方法,只是用对甲苯磺酰氯代替甲磺酰氯,制备2-(乙氧基)-(对甲苯磺酰氧基甲基)氧膦基甲基-4-甲基戊酸乙酯。
C.按照类似的方法,制备下述式(Ec)的化合物:
2-(乙氧基)(甲磺酰氧基甲基)氧膦基甲基-5-苯基戊酸乙酯;
2-(乙氧基)(甲磺酰氧基甲基)氧膦基甲基-4-苯基丁酸乙酯;
2-(乙氧基)(甲磺酰氧基甲基)氧膦基甲基-3-苯基丙酸乙酯;
2-(乙氧基)(甲磺酰氧基甲基)氧膦基甲基-3-环己基丙酸乙酯;
2-((乙氧基)(甲磺酰氧基甲基)氧膦基甲基)戊酸乙酯;
2-(乙氧基)(对甲苯磺酰氧基甲基)氧膦基甲基-5-苯基戊酸乙酯;
2-(乙氧基)(对甲苯磺酰氧基甲基)氧膦基甲基-4-苯基丁酸乙酯;
2-(乙氧基)(对甲苯磺酰氧基甲基)氧膦基甲基-3-苯基丙酸乙酯;
2-(乙氧基)(对甲苯磺酰氧基甲基)氧膦基甲基-3-环己基丙酸乙酯;和
2-((乙氧基)(对甲苯磺酰氧基甲基)氧膦基甲基)戊酸乙酯。
实施例4
式(Ee)的化合物
在0℃下,将氢化钠(1.52 g(60%))和2-喹啉硫醇(6 g)在50ml DMF中一起搅拌。在最初的H2释放平息后,混合物在室温下搅拌2.5小时。然后,将混合物冷却至0℃,经套管加入于10 ml DMF中的2-(乙氧基)(甲磺酰基氧基甲基)氧膦基甲基-4-甲基戊酸乙酯(12.8g)。形成的混合物搅拌18小时后,缓慢升温至室温。蒸发除去DMF后,残余物溶于50 ml乙酸乙酯并用50 ml水(2次)、盐水(50 ml)洗涤,经MgSO4干燥,蒸发,得到黄色的半固体。使用10%的乙酸乙酯/己烷-80%的乙酸乙酯/己烷洗脱进行的快速色谱纯化后,得到10 g的2-(乙氧基)(喹啉-2-基硫甲基)氧膦基甲基-4-甲基戊酸乙酯(Rf0.35 80%乙酸乙酯/己烷),MS:424.1(MH+)。
B.按照类似的方法,只是用1-萘硫醇、2-萘硫醇或苯硫酚代替2-喹啉硫醇,制备下述式(Ee)的化合物:
2-(乙氧基)(萘-1-基硫甲基)氧膦基甲基-4-甲基戊酸乙酯;
2-(乙氧基)(萘-2-基硫甲基)氧膦基甲基-4-甲基戊酸乙酯:和
2-(乙氧基)(苯基硫甲基)氧膦基甲基-4-甲基戊酸乙酯。
C.按照类似的方法,制备下述式(Ee)的化合物:
2-(乙氧基)(喹啉-2-基硫甲基)氧膦基甲基-5-苯基戊酸乙酯;
2-(乙氧基)(喹啉-2-基硫甲基)氧膦基甲基-4-苯基丁酸乙酯;
2-(乙氧基)(喹啉-2-基硫甲基)氧膦基甲基-3-苯基丙酸乙酯;
2-(乙氧基)(喹啉-2-基硫甲基)氧膦基甲基-3-环己基丙酸乙酯;
2-((乙氧基)(喹啉-2-基硫甲基)氧膦基甲基)戊酸乙酯;
2-(乙氧基)(萘-1-基硫甲基)氧膦基甲基-5-苯基戊酸乙酯;
2-(乙氧基)(萘-1-基硫甲基)氧膦基甲基-4-苯基丁酸乙酯;
2-(乙氧基)(萘-1-基硫甲基)氧膦基甲基-3-苯基丙酸乙酯;
2-(乙氧基)(萘-1-基硫甲基)氧膦基甲基-3-环己基丙酸乙酯;
2-((乙氧基)(萘-1-基硫甲基)氧膦基甲基)戊酸乙酯;
2-(乙氧基)(萘-2-基硫甲基)氧膦基甲基-5-苯基戊酸乙酯;
2-(乙氧基)(萘-2-基硫甲基)氧膦基甲基-4-苯基丁酸乙酯;
2-(乙氧基)(萘-2-基硫甲基)氧膦基甲基-3-苯基丙酸乙酯;
2-(乙氧基)(萘-2-基硫甲基)氧膦基甲基-3-环己基丙酸乙酯;
2-((乙氧基)(萘-2-基硫甲基)氧膦基甲基)戊酸乙酯;
2-(乙氧基)(苯基硫甲基)氧膦基甲基-5-苯基戊酸乙酯;
2-(乙氧基)(苯基硫甲基)氧膦基甲基-4-苯基丁酸乙酯;
2-(乙氧基)(苯基硫甲基)氧膦基甲基-3-苯基丙酸乙酯;
2-(乙氧基)(苯基硫甲基)氧膦基甲基-3-环己基丙酸乙酯;
2-((乙氧基)(苯基硫甲基)氧膦基甲基)戊酸乙酯。
实施例5
式(E)的化合物
A.将2-(乙氧基)(喹啉-2-基硫甲基)氧膦基甲基-4-甲基戊酸乙酯(4.5 g)溶于100 ml THF中,向其中一起加入12.5 ml的2NNaOH和足量的甲醇,使溶液均匀。18小时后,经蒸发除去THF。残余物用50 ml H2O稀释,用50 ml乙酸乙酯洗涤。水相酸化至pH为4,产物用50 ml乙酸乙酯萃取(2次)。乙酸乙酯用20 ml盐水洗涤,经MgSO4干燥,蒸发,得到3.8 g的2-(羟基)(喹啉-2-基硫甲基)氧膦基甲基-4-甲基戊酸,黄色油,MS:368(MH+)。
B.按照类似的方法,制备下述式(E)的化合物:
2-(羟基)(萘-1-基硫甲基)氧膦基甲基-4-甲基戊酸;
2-(羟基)(萘-2-基硫甲基)氧膦基甲基-4-甲基戊酸;
2-(羟基)(苯基硫甲基)氧膦基甲基-4-甲基戊酸。
C.按照类似的方法,制备下述式(E)的化合物:
2-(羟基)(喹啉-2-基硫甲基)氧膦基甲基-5-苯基戊酸;
2-(羟基)(喹啉-2-基硫甲基)氧膦基甲基-4-苯基丁酸;
2-(羟基)(喹啉-2-基硫甲基)氧膦基甲基-3-苯基丙酸;
2-(羟基)(喹啉-2-基硫甲基)氧膦基甲基-3-环己基丙酸;
2-((羟基)(喹啉-2-基硫甲基)氧膦基甲基)戊酸;
2-(羟基)(萘-1-基硫甲基)氧膦基甲基-5-苯基戊酸;
2-(羟基)(萘-1-基硫甲基)氧膦基甲基-4-苯基丁酸;
2-(羟基)(萘-1-基硫甲基)氧膦基甲基-3-苯基丙酸;
2-(羟基)(萘-1-基硫甲基)氧膦基甲基-3-环己基丙酸;
2-((羟基)(萘-1-基硫甲基)氧膦基甲基)戊酸;
2-(羟基)(萘-2-基硫甲基)氧膦基甲基-5-苯基戊酸;
2-(羟基)(萘-2-基硫甲基)氧膦基甲基-4-苯基丁酸;
2-(羟基)(萘-2-基硫甲基)氧膦基甲基-3-苯基丙酸;
2-(羟基)(萘-2-基硫甲基)氧膦基甲基-3-环己基丙酸;
2-((羟基)(萘-2-基硫甲基)氧膦基甲基)戊酸;
2-(羟基)(苯基硫甲基)氧膦基甲基-5-苯基戊酸;
2-(羟基)(苯基硫甲基)氧膦基甲基-4-苯基丁酸;
2-(羟基)(苯基硫甲基)氧膦基甲基-3-苯基丙酸;
2-(羟基)(苯基硫甲基)氧膦基甲基-3-环己基丙酸;
2-((羟基)(苯基硫甲基)氧膦基甲基)戊酸。
实施例6式(E)化合物的拆分
将2-(羟基)(喹啉-2-基硫甲基)氧膦基-甲基-4-甲基戊
酸(5.3 g)溶解于50 ml热的乙醇(无水)中,加入4.2 g(-)-辛可尼定。室温下30分钟后,盐开始沉淀出来。用薄片盖住烧瓶使其静置2天。随后,通过抽滤除去盐,将滤液蒸发至黄色泡沫。将盐和滤液分别溶解于100 ml乙酸乙酯,连接用1%HCl洗涤以除去辛可尼定,同时保持pH在4以上。两份溶液分别经MgSO4干燥,蒸发得到2.4 g的单一立体异构体,[α]D 24=+10.68°(9.73 mg于甲醇中(2 ml))和2.5 g的另一单一立体异构体,[α]D 24=-8.70°(9.88mg于甲醇中(2 ml))。
实施例7
式(B)的化合物
A.向CH2Cl2(40 ml)中的4-乙酰氨基苯磺酰氯(4.0 g,17 mmol)的冷(0℃)悬浮液中加入吡啶(1.7 ml,20 mmol)和DMAP(209 mg,1.7 mmol)。形成澄清的溶液。在0℃下1小时内鼓泡加入无水甲胺,然后使溶液在25℃下搅拌2小时。溶液用1M NaOH(3×15 ml)萃取,合并后的萃取液在0℃下用3M HCl调节pH至6。以松散的白色结晶沉淀出的产物滤出后,用冷水洗涤,得到3.2 g(82%)的4-乙酰氨基-N-甲基苯磺酰胺;1H NMR(300 MHz,MeOH)δ2.35(s,3H),2.70(s,3H),7.96(s,4H)。
B.在氢气氛下,将4-乙酰氨基-N-甲基苯磺酰胺(3.2 g,14mmol)和100 ml 1M的HCl的混合物回流3小时。冷却至25℃后,加入CH2Cl2(10 ml),水相在0℃下用1M NaOH中和。分离水相,并用CH2Cl2(2×25ml)萃取。合并后的有机相用盐水(10ml)洗涤,干燥(Na2SO4),浓缩,得到1.5 g(58%)的式(B)化合物,其中R4为N-甲基磺酰胺,为无色固体;1H NMR(300 MHz,MeOH)δ2.46(s,3H),6.67-6.72(AA1XX1的部分AA1,2H),7.48-7.52(AA1XX1的部分XX1,2H)。
实施例8
式(C)的化合物
A.分批向DMF(30 ml)中的N-叔丁氧羰基-L-亮氨酸(1.4 g,6.3 mmol)与HOBT(1.5 g,9.8 mmol)的冷(0℃)溶液中加入EDCI(2.5 g,14 mmol)。在0℃下搅拌1小时后,形成的溶液用4-氨基苯甲酸甲酯(1.09 ml,6.8 mmol)和DMAP(0.32 g,2.6 mmol)处理。在25℃下搅拌24小时后,真空除去DMF。将残余物溶解于CH2Cl2中,用饱和NaHCO3溶液、1M HCl(两次)和盐水洗涤。经Na2SO4干燥后,真空浓缩,得到粗产物,该产物经SiO2快速色谱(20%乙酸乙酯/己烷洗脱液)纯化。得到1.0 g(85%)的N-叔丁氧羰基-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺,为泡沫状固体,MS(FAB)363(M-H)-。
B.按照类似的方法,制备下述式(C)的化合物:
N-叔丁氧羰基-L-色氨酸-N′-苯基甲基甲酰胺;
N-叔丁氧羰基-L-色氨酸-N′-苯基甲酰胺;
N-叔丁氧羰基-L-色氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-叔丁氧羰基-L-色氨酸-N′-(4-乙氧羰基苯基)甲酰胺;
N-叔丁氧羰基-L-亮氨酸-N′-(4-(N"-甲氨基磺酰基)苯基)甲酰胺;
N-叔丁氧羰基-L-丙氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-叔丁氧羰基-L-蛋氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-叔丁氧羰基-L-亮氨酸-N′-(3-乙氧羰基苯基)甲酰胺;
N-叔丁氧羰基-L-亮氨酸-N′-(2-甲氧羰基苯基)甲酰胺;
N-叔丁氧羰基-L-亮氨酸-N′-(4-(1-甲基乙氧)羰基)苯基)甲酰胺;
N-叔丁氧羰基-L-亮氨酸-N′-(氨基磺酰基苯基)甲酰胺;
N-叔丁氧羰基-L-亮氨酸-N′-(4-甲氧羰基甲基苯基)甲酰胺;
N-叔丁氧羰基-L-吡啶-3-基丙氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-叔丁氧羰基-L-环己基甘氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-叔丁氧羰基-L-异亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-叔丁氧羰基-L-O-苄基苏氨酸-N′(4-甲氧羰基苯基)甲酰胺;
N-叔丁氧羰基-L-t-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-叔丁氧羰基-L-亮氨酸-N′-(4-氰基苯基)甲酰胺;
N-叔丁氧羰基-L-亮氨酸-N′-(4-(N"-(2-二甲基氨基乙基氨基甲酰基)苯基)甲酰胺;
N-叔丁氧羰基-L-亮氨酸-N′-(4-(N"-(3-二甲基氨基丙基氨基甲酰基)苯基)甲酰胺。
C.按照类似的方法,制备下述式(C)的化合物:
N-叔丁氧羰基-L-色氨酸-N′-(4-硝基苯基)甲酰胺;
N-叔丁氧羰基-L-色氨酸-N′-(4-氨基苯基)甲酰胺;
N-叔丁氧羰基-L-亮氨酸-N′-(4-甲基磺酰基苯基)甲酰胺;
N-叔丁氧羰基-L-亮氨酸-N′-(4-乙基磺酰基苯基)甲酰胺;
N-叔丁氧羰基-L-亮氨酸-N′-(4-四唑基苯基)甲酰胺。
实施例9
式(D)的化合物
A.向无水CH2Cl2(10 ml)中的N-叔丁氧羰基-L-亮氨酸-N′-苯基甲酰胺(3.4 g,11 mmol)的冷(0℃)溶液中加入TFA(2 ml)。溶液在25℃下搅拌6小时,随后进行真空浓缩。用CH2Cl2和H2O使残余物分层,水层在0℃下用饱和K2CO3溶液碱化。分离出有机相,水层用CH2Cl2萃取3次。合并后的有机层用盐水洗涤,Na2SO4干燥。浓缩后得到L-亮氨酸-N′-苯基甲酰胺。
B.按照类似的方法,制备下述化合物:
L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
L-色氨酸-N′-苯基甲基甲酰胺;
L-色氨酸-N′-苯基甲酰胺;
L-色氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
L-色氨酸-N′-(4-乙氧羰基苯基)甲酰胺;
L-亮氨酸-N′-(4-(N"-甲氨基磺酰基)苯基)甲酰胺;
L-丙氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
L-蛋氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
L-亮氨酸-N′-(3-乙氧羰基苯基)甲酰胺;
L-亮氨酸-N′-(2-甲氧羰基苯基)甲酰胺;
L-亮氨酸-N′-(4-(1-甲基乙氧羰基)苯基)甲酰胺;
L-亮氨酸-N′-(氨基磺酰基苯基)甲酰胺;
L-亮氨酸-N′-(4-甲氧羰基甲基苯基)甲酰胺;
L-吡啶-3-基丙氨基-N′-(4-甲氧羰基苯基)甲酰胺;
L-螺环戊基甘氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
L-环己基甘氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
L-异亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
L-O-苄基苏氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
L-t-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
L-亮氨酸-N′-(4-氰基苯基)甲酰胺;
L-亮氨酸-N′-(4-(N"-(2-二甲基氨基乙基)氨基甲酰基)苯基)甲酰胺;
L-亮氨酸-N′-(4-(N"-(3-二甲基氨基丙基)氨基甲酰基)苯基)甲酰胺。
C.按照类似的方法,制备下述式(D)的化合物:
L-色氨酸-N′-(4-硝基苯基)甲酰胺;
L-色氨酸-N′-(4-氨基苯基)甲酰胺;
L-亮氨酸-N′-(4-甲基磺酰基苯基)甲酰胺;
L-亮氨酸-N′-(4-乙基磺酰基苯基)甲酰胺;
L-亮氨酸-N′-(4-四唑基苯基)甲酰胺。
实施例10
式(Ia)的化合物
A.向THF(6 ml)中的2-(羟基)(喹啉-2-基硫甲基)氧膦基甲基-4-甲基戊酸(0.20 g,0.54 mmol)的冷(0℃)溶液中加入1,1′-羰基二咪唑(0.12 g,0.7 mmol)。在0℃下搅拌混合物75分钟,然后,用L-色氨酸-N′-(4-乙氧羰基苯基)甲酰胺(0.22 g,0.62 mmol),在25℃下搅拌15小时。蒸出THF,将残余物溶解于乙酸乙酯(60 ml)中。溶液用H2O(10 ml)、盐水(10 ml)洗涤,用MgSO4干燥。随后,使用乙腈和50 mM NH4OAc缓冲液梯度(gradient)经反相HPLC浓缩,得到30 mg的N-(2-(羟基)(喹啉-2-基硫甲基)氧膦基甲基-4-甲基戊酰基)-L-色氨酸-N′-(4-乙氧羰基苯基)甲酰胺,为灰白色固体,MS(FAB)701(M-H)+(非对映体的混合物)。
B.按照类似的方法,制备下述式(Ia)化合物:
N-(2-(羟基)(喹啉-2-基硫甲基)氧膦基甲基-4-甲基戊酰基)-L-色氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
MS(FAB)687(M+H)+;
N-(2-(羟基)(喹啉-2-基硫甲基)氧膦基甲基-4-甲基戊酰基)-L-丙氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
MS(FAB)572(M+H)+;
N-(2-(羟基)(喹啉-2-基硫甲基)氧膦基甲基-4-甲基戊酰基)-L-蛋氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
MS(FAB)632(M+H)+;化合物1
N-(2-(羟基)(喹啉-2-基硫甲基)氧膦基甲基-4-甲基戊酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
MS(FAB)614(M+H)+;
N-(2-(羟基)(喹啉-2-基硫甲基)氧膦基甲基-4-甲基戊酰基)-L-亮氨酸-N′-(3-乙氧羰基苯基)甲酰胺,
1H NMR(300 MHz,MeOH),δ0.73-1.01(m,12H),1.28-2.00(m,14H),2.4-3.61(m,2H),4.27-4.45(m,3H),7.23-7.44(m,3H),7.65-7.98(m,6H),8.29(s,0.5H),8.50(s,0.5H);
N-(2-(羟基)(喹啉-2-基硫甲基)氧膦基甲基-4-甲基戊酰基)-L-亮氨酸-N′-(2-甲氧羰基苯基)甲酰胺;
1H NMR(300 MHz,MeOH),δ0.78-0.99(m,13H),1.3-2.4(m,7H),2.90-3.05(m,1H),3.5-3.75(m,2H),3.89,3.90,3.94(3s,3H总和),4.35-3.50(m,1H),7.05-8.10(m,11H),8.32,8.55 8.60(3d,J=8.7,1H);
N-(2-(羟基)(喹啉-2-基硫甲基)氧膦基甲基-4-甲基戊酰基)-L-亮氨酸-N′-(4-(1,1-二甲基乙氧羰基)苯基)甲酰胺,MS(FAB)642(MH)+;
N-(2-(羟基)(喹啉-2-基硫甲基)氧膦基甲基-4-甲基戊酰基)-L-亮氨酸-N′-(4-氨基磺酰基苯基)甲酰胺;
1H NMR(300 MHz,MeOH),δ0.76(d,J=6.5,3H),0.81(d,J=6.5,3H),0.85-1.1(m,7H),1.2-2.1(m,7H),2.92-2.95(m,1H),3.45-3.70(m,2H),4.35-4.45(m,1H),7.28(d,J=8.7,1H),7.45(t,J=8.7,1H),7.68(t,J=8.7,1H),7.7-7.8(m,3H),7.87(d,J=8.7,1H),7.95-8.1(m,3H);
N-(2-(羟基)(喹啉-2-基硫甲基)氧膦基甲基-4-甲基戊酰基)-L-亮氨酸-N′-(4-甲氧羰基甲基苯基)甲酰胺,
MS(FAB)628(MH)+。
C.按照类似的方法,制备下述式(Ia)的化合物:
N-(2-(羟基)(喹啉-2-基硫甲基)氧膦基甲基-5-苯基戊酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(2-(羟基)(喹啉-2-基硫甲基)氧膦基甲基-4-苯基丁酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(2-(羟基)(喹啉-2-基硫甲基)氧膦基甲基-3-苯基丙酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(2-(羟基)(喹啉-2-基硫甲基)氧膦基甲基-3-环己基丙酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(2-((羟基)(喹啉-2-基硫甲基)氧膦基甲基)戊酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(2-(羟基)(萘-1-基硫甲基)氧膦基甲基-5-苯基戊酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(2-(羟基)(萘-1-基硫甲基)氧膦基甲基-4-苯基丁酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(2-(羟基)(萘-1-基硫甲基)氧膦基甲基-3-苯基丙酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(2-(羟基)(萘-1-基硫甲基)氧膦基甲基-3-环己基丙酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(2-((羟基)(萘-1-基硫甲基)氧膦基甲基)戊酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(2-(羟基)(萘-2-基硫甲基)氧膦基甲基-5-苯基戊酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(2-(羟基)(萘-2-基硫甲基)氧膦基甲基-4-苯基丁酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(2-(羟基)(萘-2-基硫甲基)氧膦基甲基-3-苯基丙酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(2-(羟基)(萘-2-基硫甲基)氧膦基甲基-3-环己基丙酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(2-((羟基)(萘-2-基硫甲基)氧膦基甲基)戊酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(2-(羟基)(苯基硫甲基)氧膦基甲基-5-苯基戊酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(2-(羟基)(苯基硫甲基)氧膦基甲基-4-苯基丁酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(2-(羟基)(苯基硫甲基)氧膦基甲基-3-苯基丙酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(2-(羟基)(苯基硫甲基)氧膦基甲基-3-环己基丙酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(2-((羟基)(苯基硫甲基)氧膦基甲基)戊酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺。
D.在25℃下,将THF(2 ml)和1M NaOH(1 ml)中的N-(2-(羟基)喹啉-2-基硫甲基)氧膦基甲基-4-甲基戊酰基)-L-色氨酸-N′-(4-甲氧羰基苯基)甲酰胺的溶液搅拌24小时。蒸出有机溶剂后,将残余物溶解于乙酸乙酯/H2O中。水相用1M HCl酸化,分离出的水相用乙酸乙酯萃取两次。合并后的有机层用盐水洗涤,干燥(MgSO4),浓缩至27 mg的N-(2-(羟基)(喹啉-2-基硫甲基)-氧膦基甲基-4-甲基戊酰基)-L-色氨酸-N′-(4-羧基苯基)甲酰胺,为黄色粉末。
E.用类似的方法,只是开始用N-(2-(羟基)(喹啉-2-基硫甲基)氧膦基甲基-4-甲基戊酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺(30 mg,0.048 mmol),在用乙酸乙酯研制后,得到10 mg的N-(2-(羟基)(喹啉-2-基硫甲基)氧膦基甲基-4-甲基戊酰基)-L-亮氨酸-N′-(4-羧基苯基)甲酰胺,为半固体;
1H NMR1(300 MHz,MeOH)0.81-1.02(m,12H),1.1-2.3(m,10H),2.82-3.00(m,1H),3.49-3.56(2s,2H),3.5-3.8(m,2H),4.45-4.55(m,1H),7.09(d,J=8.2,1H),7.19(d,J=8.2,1H),7.45(t,J=8.2,1H),7.45-7.6(m,3H),7.65-7.80(m,1H),7.82-7.98(m,2H),8.10-8.20(m,1H)。
实施例11
式(Fa)的化合物
A.在25℃水浴中的4-甲基戊酸(25 g,0.215 mmol)中缓慢地加入亚硫酰氯(20.4 ml,1.3 g)。在氩气氛下在50℃下加热混合物3小时(直至气体释出停止)。在大气压下蒸馏粗反应混合物得到4-甲基戊酰氯(25.3 g,87.3%),b.p.143℃。
B.以类似的方法,只是用5-苯基戊酸(5 g)代替4-甲基戊酸,得到5-苯基戊酰氯(4.4 g),为无色液体,b.p.91-93℃。
实施例12
式(Fb)的化合物
A.在室温及氩气氛下,向甲苯(200 ml)中的60%NaH(836 mg,1.5当量)的悬浮液中分批加入L-(+)-2,10-樟脑磺内酰胺(3.0g,3.9 mmol)。室温下剧烈搅拌混合物1小时。随后,在0℃下向溶液中小心滴加4-甲基戊酰氯。在室温下搅拌反应3小时后,用10ml水使反应停止,加入70 ml乙醚。反应混合物依次用0.5N HCl(2×50 ml)、5% K2CO3(3×50 ml)及盐水(1×50 ml)洗涤。有机层用MgSO4干燥,过滤,蒸发至干。经柱色谱(1∶6乙酸乙酯/石油醚作洗脱液)纯化,得到N-4-甲基戊酰基-L-(+)-2,10-樟脑磺内酰胺(3.39 g,78%)。
B.以类似的方法,只是用相应的氯化物代替4-甲基戊酰氯,得到下式(Fb)的化合物:
N-3-苯基丙酰基-L-(+)-2,10-樟脑磺内酰胺,MS:347(M+);
N-5-苯基戊酰基-L-(+)-2,10-樟脑磺内酰胺;
MS:375 M+;
N-戊酰基-L-(+)-2,10-樟脑磺内酰胺,MS:300(M+H)+。
实施例13
式(Fc)的化合物
A.向在氩气氛及-78℃下,75 ml无水THF中的N-4-甲基戊酰基-L-(+)-2,10-樟脑磺内酰胺(3.39 g,10.8 mmol)的溶液中在5分钟内滴加NaN(TMS)2(1.0M的THF溶液,11.34 ml,1.05当量)。于-78℃搅拌1小时后,向混合物中加入六甲基磷酰胺(5 ml),随后加入溴乙酸叔丁酯(5.2 ml,3当量),再一次加入400 mg的碘化四正丁基铵。形成的溶液在-78℃氩气氛下过夜放置。第二天早上,用水(100 ml)停止反应,然后用乙醚(3×100 ml)萃取。合并后的乙醚层用盐水洗涤,用Na2SO4干燥,过滤,浓缩。经柱色谱(5∶95乙酸乙酯/石油醚-10∶90乙酸乙酯/石油醚作洗脱液)纯化,得到N-(4-甲基-2-叔丁氧羰基甲基)戊酰基-L-(+)-2,10-樟脑磺内酰胺(4 g,86.5%)。
B.以类似的方法,只是用合适的式(Fb)化合物代替N-4-甲基戊酰基-L-(+)-2,10-樟脑磺内酰胺,得到如下式(Fc)的化合物:
N-(3-苯基-2-叔丁氧羰基甲基)丙酰基-L-(+)-2,10-樟脑磺内酰胺,MS:461(M+);
N-(5-苯基-2-叔丁氧羰基甲基)戊酰基-L-(+)-2,10-樟脑磺内酰胺;MS:490.1(M+H)+;
N-(2-叔丁氧羰基甲基)戊酰基-L-(+)-樟脑磺内酰胺,MS:414(M+H)+。
实施例14
式(F)的化合物
A.在0℃,氩气氛下,向于50%含水THF(150 ml)中的N-(4-甲基-2-叔丁氧羰基甲基)戊酰基-L-(+)-2,10-樟脑磺内酰胺(5.45 g,12.7 mmol)的搅拌溶液中加入LiOH·H2O晶体(2.14 g,4当量),再加入30%的H2O2(11.5 ml)。除去冰浴,在形成的乳液变得澄清之前,搅拌3小时。在35℃下减压除去大部分THF。加入CH2Cl2(150 ml),搅拌下加入4N HCl至pH=2。加入NaCl后,水层用CH2Cl2(3×150 ml)萃取。35℃减压除去CH2Cl2后,将残余物吸收入乙酸乙酯(150 ml)中。该溶液用5% K2CO3(3×50 ml)萃取,合并后的萃取液用乙醚(50 ml)洗涤。向水层中加入CH2Cl2,搅拌下再加入NaCl。水层用CH2Cl2(3×70 ml)萃取,合并后的萃取液用Na2SO4干燥,过滤,浓缩,得到(2R)-4-甲基-2-叔丁氧羰基甲基戊酸,为无色油(2.95 g,定量产出)。
B.以类似的方法,只是用合适的式(Fc)的化合物代替N-(4-甲基-2-叔丁氧羰基甲基)戊酰基-L-(+)-2,10樟脑磺内酰胺,制备下式(F)的化合物:
(2R)-3-苯基-2-叔丁氧羰基甲基丙酸,MS:265(M+H)+;
(2R)-5-苯基-2-叔丁氧羰基甲基戊酸,MS:293.1(M+H)+;
(2R)-2-叔丁氧羰基甲基戊酸,(无色油,1.09 g)。
C.将(2R)-3-苯基-2-叔丁氧羰基甲基丙酸(55 mg)吸收于冰醋酸(20 ml)中,PtO2(25 mg)加在乙酸中。将烧杯放置在帕尔弹(Parr bomb)中,将其抽空,充入100 psi的H2。搅拌3天后,通过1 cm的硅藻土(Celite)床抽滤混合物。将滤液浓缩至黄色油,(2R)-3-环己基-2-叔丁氧羰基甲基丙酸(56 mg),MS:269.5(M-H)-。
实施例15
A.向含HOBT(0.22 g,1.8 mmol)于DMF(5 ml)中的4-甲基-2-叔丁氧羰基甲基戊酸(0.28 g,1.2 mmol)的溶液中加入EDCI(0.31 g,1.8 mmol)。在0℃下搅拌混合物1小时,然后用L-环己基甘氨酸-N′-(4-甲氧羰基苯基)甲酰胺(1.2 mmol)和DMAP(27mg,0.24 mmol)处理。继续在25℃下搅拌24小时,然后蒸出DMF。将残余物溶于CH2Cl2(20 ml)中,溶液用1 M HCl(10 ml)、饱和NaHCO3(10 ml)、盐水(10 ml)洗涤,经Na2SO4干燥,真空浓缩得到一种油,它经SiO2快速色谱(20%乙酸乙酯/己烷作洗脱液)纯化,得到0.22 g(22%)的N-(4-甲基-2-叔丁氧羰基甲基戊酰基)-L-环己基甘氨酸-N′-(4-甲氧羰基苯基)甲酰胺,为固体,MS(FAB)503(MH)+。
B.按照类似的方法,制备下述化合物:
N-(4-甲基-2-叔丁氧羰基甲基戊酰基)-L-吡啶-3-基丙氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(4-甲基-2-叔丁氧羰基甲基戊酰基)-L-邻-苄基苏氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(4-甲基-2-叔丁氧羰基甲基戊酰基)-L-异亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(4-甲基-2-叔丁氧羰基甲基戊酰基)-L-亮氨酸-N′-(4-甲氧羰基甲基苯基)甲酰胺;
N-(4-甲基-2-叔丁氧羰基甲基戊酰基)-L-t-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(4-甲基-2-叔丁氧羰基甲基戊酰基)-L-亮氨酸-N′-(4-氰基苯基)甲酰胺;
N-(4-甲基-2-叔丁氧羰基甲基戊酰基)-L-亮氨酸-N′-(4-(N"-(3-二甲基氨基丙基)氨基甲酰基)苯基)甲酰胺;
N-(4-甲基-2-叔丁氧羰基甲基戊酰基)-L-亮氨酸-N′-(4-(N"-(2-二甲基氨基乙基)氨基甲酰基)苯基)甲酰胺;
N-(4-甲基-2-叔丁氧羰基甲基戊酰基)-L-亮氨酸-N′-(4-氨基磺酰基苯基)甲酰胺;
N-(4-甲基-2-叔丁氧羰基甲基戊酰基)-L-亮氨酸-N′-(4-甲基氨基磺酰基苯基)甲酰胺;
N-(2-叔丁氧羰基甲基戊酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(3-苯基-2-叔丁氧羰基甲基戊酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(3-环己基-2-叔丁氧羰基甲基戊酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(4-苯基-2-叔丁氧羰基甲基戊酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(5-苯基-2-叔丁氧羰基甲基戊酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺。
实施例16
式(Ic)的化合物
A.向CH2Cl2(2 ml)中的N-(4-甲基-2-叔丁氧羰基甲基戊酰基)-L-环己基甘氨酸-N′-(4-甲氧羰基苯基)甲酰胺(70 mg,0.14 mmol)的冷(0℃)溶液中加入TFA(0.5 ml)。在25℃下搅拌5小时后,真空浓缩该溶液,产物用反相HPLC(乙腈和50 mM NH4OAc缓冲液梯度)纯化,得到44 mg(71%)的N-(4-甲基-2-羧基甲基戊酰基)-L-环己基甘氨酸-N′-(4-甲氧羰基苯基)甲酰胺,为白色固体,MS(FAB)445(M-H)+。
B.按照类似的方法,制备下述化合物:
N-(4-甲基-2-羧甲基戊酰基)-L-异亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺,MS(FAB)419(M-H)-;
N-(4-甲基-2-羧甲基戊酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺,MS(FAB)419(M-H)-;
N-(4-甲基-2-羧甲基戊酰基)-L-t-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(4-甲基-2-羧甲基戊酰基)-L-亮氨酸-N′-(4-氰基苯基)甲酰胺,
1H NMR1(300 MHz,MeOH)δ0.84-0.99(m,12H),1.15-1.82(m,6H),2.36-2.41(m,1H),2.52-2.65(m,1H),2.8-2.95(m,1H),4.49-4.54(m,1H),7.4-7.9(m,4H);
N-(4-甲基-2-羧甲基戊酰基)-L-亮氨酸-N′-(4-氨基磺酰基苯基)甲酰胺,
1H NMR1(300 MHz,MeOH)δ0.85-1.00(m,12H),1.1-1.3(m,2H),1.52-1.85(m,4H),2.31-2.95(m,3H),4.49-4.55(m,1H),7.75-7.91(m,4H);
N-(4-甲基-2-羧甲基戊酰基)-L-亮氨酸-N′-(4-甲基氨基磺酰基苯基)甲酰胺,MS(FAB)459(M-H)-;
N-(2-羧甲基戊酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺,MS(FAB)405(M-H)-;
N-(3-苯基-2-羧甲基丙酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺,MS(FAB)455(M+H)+;
N-(3-环己基-2-羧甲基丙酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺,MS(FAB)459(M-H)-;
N-(4-苯基-2-羧甲基丁酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺,MS(FAB)467(M-H)-;
N-(4-苯基-2-羧甲基丁酰基)-L-环己基甘氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(4-苯基-2-羧甲基丁酰基)-L-t-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(5-苯基-2-羧甲基戊酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺,MS(FAB)481(M-H)-;
N-(4-甲基-2-羧甲基戊酰基)-L-邻-苄基苏氨酸-N′-(4-甲氧羰基苯基)甲酰胺,MS(FAB)497(M-H)-。
C.按照类似的方法,只是用乙醚研制粗产物,然后滗析出乙醚,得到下列作为TFA盐的化合物:
N-(4-甲基-2-羧甲基戊酰基)-L-吡啶-3-基丙氨酸-N′-(4-甲氧羰基苯基)甲酰胺,MS(FAB)456(M+H)+;
N-(4-甲基-2-羧甲基戊酰基)-L-亮氨酸-N′-(4-(N"-(3-二甲基氨基丙基)氨基甲酰基)苯基)甲酰胺,MS(FAB)491(M+H)+;
N-(4-甲基-2-羧甲基戊酰基)-L-亮氨酸-N′-(4-(N"-(2-二甲基氨基乙基)氨基甲酰基)苯基)甲酰胺,MS(FAB)491(M+H)+。
D.在1 atm下,过夜氢化N-(4-甲基-2-叔丁氧羰基甲基戊酰基)-L-邻-苄基苏氨酸-N′-(4-甲氧羰基苯基)甲酰胺(60 mg)与Pd/C在乙酸乙酯/THF(1∶1,25 ml)中的混合物。通过硅藻土过滤,浓缩滤液,残余物用乙醚/己烯研制,得到N-(4-甲基-2-叔丁氧羰基甲基-戊酰基)-L-苏氨酸-N′-(4-甲氧羰基苯基)甲酰胺,MS(FAB)407(M-H)-。
实施例17
式(Id)的化合物
A.将无水DMF(20 ml)中的N-(4-甲基-2-羧甲基戊酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺(0.28 g,0.66 mmol)与HOBT(0.12 g)的溶液冷却至0℃,用EDCI(0.32 g)处理。在0℃搅拌0.5小时后,加入邻-苄基羟基胺(0.30 ml),反应物加温至25℃过夜。真空除去DMF,残余物吸收于CH2Cl2中,用5%HCl/5%NaHCO3及盐水洗涤,用Na2SO4干燥。浓缩后,经快速色谱(SiO2,Rf=0.6,10%MeOH/CH2Cl2)纯化。含产物的馏分进一步用CH2Cl2研制而纯化,得到N-(4-甲基-2-(N"-苄氧基氨基甲酰基)甲基戊酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺,为固体,mp198-199℃。
B.按照类似的方法,制备下述化合物:
N-(2-(N"-苄氧基氨基甲酰基)甲基戊酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(4-苯基-2-(N"-苄氧基氨基甲酰基)甲基戊酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(4-甲基-2-(N"-苄氧基氨基甲酰基)甲基戊酰基)-L-色氨酸-N′-(4-甲氧羰基苯基)甲酰胺。
C.用1M NaOH(1.4 ml)在50-60℃下,于THF(20 ml)和MeOH(5 ml)中水解N-(4-甲基-2-(N"-苄氧基氨基甲酰基)甲基戊酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺(210 mg)。蒸出有机溶剂,残余物吸收于10 ml H2O中,用乙醚(2×10 ml)洗涤。水相用10%HCl酸化至pH为2,用乙酸乙酯(3×10 ml)萃取。合并后的萃取液用盐水洗涤、经Na2SO4干燥,浓缩,得到N-(4-甲基-2-(N"-苄氧基氨基甲酰基)甲基戊酰基)-L-亮氨酸-N′-(4-羧基苯基)甲酰胺(110 mg)。
实施例18
式(Ie)的化合物
A.向于20 ml MeOH和10 ml THF中的N-(4-苯基-2-(N"-苄氧基氨基甲酰基)甲基丁酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺(25 mg)的溶液中加入10%Pd/C(20 mg)。悬浮液被氢化1小时,然后通过硅藻土抽滤。浓缩,得到的产物用硅胶(2.5%MeOH/CH2Cl2)纯化,得到8 mg的N-(4-苯基-2-(N"-羟基氨基甲酰基)甲基丁酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺,MS(FAB)482(M-H)-。
B.按照类似的方法,制备下述化合物:
N-(4-甲基-2-(N"-羟基氨基甲酰基)甲基戊酰基)-L-亮氨酸-N′-(4-羧基苯基)甲酰胺;
N-(4-甲基-2-(N"-羟基氨基甲酰基)甲基戊酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺,MS(FAB)436(M+H)-;化合物2
N-(2-(N"-羟基氨基甲酰基)甲基戊酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺,MS(FAB)420(M-H)-;
N-(4-苯基-2-(N"-羟基氨基甲酰基)甲基丁酰基)-L-t-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(4-苯基-2-(N"-羟基氨基甲酰基)甲基丁酰基)-L-环己基甘氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(4-苯基-2-(N"-羟基氨基甲酰基)甲基戊酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(4-甲基-2-(N"-羟基氨基甲酰基)甲基戊酰基)-L-t亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(4-甲基-2-(N"-羟基氨基甲酰基)甲基戊酰基)-L-色氨酸-N′-(4-甲氧羰基苯基)甲酰胺,MS(FAB)507(M-H)-;
化合物3(2R);化合物4(2S);和
N-(4-苯基-2-(N"-羟基氨基甲酰基)甲基丁酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺。
C.按照类似的方法,制备下述化合物:
N-(3-苯基-2-(N"-羟基氨基甲酰基)甲基丙酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(5-苯基-2-(N"-羟基氨基甲酰基)甲基戊酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(3-环己基-2-(N″-羟基氨基甲酰基)甲基丙酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺。
实施例19
式(Gb)的化合物
A.在30分钟内,向150 ml乙醇中的异丁基丙二酸二乙酯(21.6 g,0.1 mol)的冷(0℃)溶液中,缓慢加入KOH溶液(5.89 g,0.1 mol)。在25℃下搅拌该澄清溶液60小时。减压除去乙醇,将固体残余物溶解于50 ml H2O中。用4 M HCl酸化该水溶液至pH为2,用乙醚(2×50 ml)萃取。合并后的萃取液用MgSO4干燥,蒸发以得到19.0 g(100%)的异丁基丙二酸乙酯,为无色油。
B.以类似的方法,制备下式(Gb)的化合物:
叔丁基丙二酸乙酯;
丙基丙二酸乙酯;
苄基丙二酸乙酯;和
环己基甲基丙二酸乙酯。
实施例20
式(Gc)和(Gd)的化合物
A.向0℃下纯的异丁基丙二酸乙酯(25 g,0.13 mol)中缓慢地加入冰冷的二乙胺(15.1 ml,0.15 mol)。搅拌15分钟后,滴加福尔马林(11.1 ml的37%甲醛水溶液),混合物在25℃下搅拌3天。反应物用20 g K2CO3在40 ml H2O中的溶液处理,用乙醚萃取(2×100ml)。合并后的乙醚层用盐水洗涤,用MgSO4干燥,在旋转蒸发器20℃下蒸发。将粗产物4-甲基-2-亚甲基戊酸乙酯(含有一些醚)溶解于250 ml无水乙醇中,用乙腈(250 ml)、1M LiOH(9.7 g在250 ml H2O中,0.23 mol)处理。搅拌过夜后,蒸出有机溶剂,含水残余物用乙酸乙酯萃取(2×150 ml)。合并后的萃取液用盐水洗涤、干燥(MgSO4),蒸发,得到10.5g的4-甲基-2-亚甲基戊酸,为无色油。
B.以类似的方法,制备下式(Gd)的化合物:
4-苯基-2-亚甲基丁酸;
3-环己基-2-亚甲基丙酸;
5-苯基-2-亚甲基戊酸;
2-亚甲基戊酸;和
3,3-二甲基-2-亚甲基丁酸。
实施例21
式(G)的化合物
A.在氩气氛下将4-甲基-2-亚甲基戊酸(5.0 g)和硫代乙酸(25 ml)的混合物在95℃下加热3天。蒸出过量的硫代乙酸,将残余的油溶于乙酸乙酯(40 ml)中,用饱和NaHCO3(3×40 ml)萃取。合并后的NaHCO3萃取液用1M HCl在0℃下酸化至pH为2。水层用CH2Cl2(3×40 ml)萃取,合并后的有机相经MgSO4干燥,最后进行蒸发,得到3.0 g的4-甲基-2-乙酰硫基甲基戊酸;1H NMR(80 MHz,CDCl3)δ0.95(d,J=8.0,6H),1.20-1.90(m,4H),2.35(s,3H),2.50-3.20(m,3H),6.7(br s,1H)。
实施例22
式(If)的化合物
A.向无水DMF(15 ml)中含HOBT(92 mg,0.6 mmol)和L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺(0.6 mmol)的4-甲基-2-乙酰硫基甲基戊酸(204 mg,1.0 mmol)的溶液中,加入EDCI(345 mg,1.8 mmol)。溶液在25℃下过夜搅拌,随后真空除去DMF。将残余物溶解于乙酸乙酯(35 ml)中,用1M HCl、1M NaOH和盐水洗涤。经MgSO4干燥及蒸发后,得到一种半固体,将其在硅胶(乙酸乙酯1:石油醚2)上快速色谱纯化,得到N-(4-甲基-2-乙酰硫基-甲基戊酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺(190mg),为白色固体。
B.按照类似的方法,制备下述式(If)的化合物:
N-(5-苯基-2-乙酰基硫基甲基戊酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(4-苯基-2-乙酰基硫基甲基丁酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(3-苯基-2-乙酰基硫基甲基丙酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(3-环己基-2-乙酰基硫基甲基丙酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(2-乙酰基硫基甲基戊酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(5-苯基-2-乙酰基硫基甲基戊酰基)-L-亮氨酸-N′-(4-氨基羰基苯基)甲酰胺;
N-(4-苯基-2-乙酰基硫基甲基丁酰基)-L-亮氨酸-N′-(4-羧基苯基)甲酰胺;
N-(3-苯基-2-乙酰基硫基甲基丙酰基)-L-亮氨酸-N′-(4-甲磺酰基苯基)甲酰胺;
N-(3-环己基-2-乙酰基硫基甲基丙酰基)-L-亮氨酸-N′-(4-氨基甲酰基苯基)甲酰胺;
N-(2-乙酰基硫基甲基戊酰基)-L-亮氨酸-N′-(4-氰基苯基)甲酰胺;
N-(5-苯基-2-乙酰基硫基甲基戊酰基)-L-色氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(4-苯基-2-乙酰基硫基甲基丁酰基)-L-色氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(3-苯基-2-乙酰基硫基甲基丙酰基)-L-色氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(3-环己基-2-乙酰基硫基甲基丙酰基)-L-色氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(2-乙酰基硫基甲基戊酰基)-L-色氨酸-N′-(4-甲氧羰基苯基)甲酰胺。
实施例23
式(Ig)的化合物
A.在0℃下向于MeOH(8 ml)中的N-(4-甲基-2-乙酰硫基甲基戊酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺(85 mg,0.19 mmol)的溶液中加入浓NH4OH(0.4 ml)。在0℃下搅拌5小时后,蒸出甲醇,加入乙醚(30 ml)。乙醚溶液用0.5 M HCl、盐水洗涤,用MgSO4干燥。浓缩后,得到定量产出的N-(4-甲基-2-巯基甲基戊酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺,为白色泡沫,MS(FAB)407(M-H)-。
B.按照类似的方法,制备下述式(Ig)的化合物:
N-(5-苯基-2-巯基甲基戊酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(4-苯基-2-巯基甲基丁酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(3-苯基-2-巯基甲基丙酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(3-环己基-2-巯基甲基丙酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(2-巯基甲基戊酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(5-苯基-2-巯基甲基戊酰基)-L-亮氨酸-N′-(4-氨基羰基苯基)甲酰胺;
N-(4-苯基-2-巯基甲基丁酰基)-L-亮氨酸-N′-(4-羧基苯基)甲酰胺;
N-(3-苯基-2-巯基甲基丙酰基)-L-亮氨酸-N′-(4-甲磺酰基苯基)甲酰胺;
N-(3-环己基-2-巯基甲基丙酰基)-L-亮氨酸-N′-(4-氨基甲酰基苯基)甲酰胺;
N-(2-巯基甲基戊酰基)-L-亮氨酸-N′-(4-氰基苯基)甲酰胺;
N-(5-苯基-2-巯基甲基戊酰基)-L-色氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(4-苯基-2-巯基甲基丁酰基)-L-色氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(3-苯基-2-巯基甲基丙酰基)-L-色氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(3-环己基-2-巯基甲基丙酰基)-L-色氨酸-N′-(4-甲氧羰基苯基)甲酰胺;
N-(2-巯基甲基戊酰基)-L-色氨酸-N′-(4-甲氧羰基苯基)甲酰胺。
实施例24
本实施例表明代表性口服给药形式的药用组合物的制备方法,该组合物包含式(Ⅰ)的化合物或其可药用盐,如,N-(4-甲基-2-(N″-羟基氨基甲酰基)甲基戊酰基)-L-亮氨酸-N′-(4-羧基羰基苯基)甲酰胺:
A.组分 %wt./wt.
式(Ⅰ)的化合物 20.0%
乳糖 79.5%
硬脂酸镁 0.5%
将上述组分混合,并分配入硬壳的明胶胶囊中,每个包含100mg,一个胶囊大约为一天的剂量。
B.组分 % wt./wt.
式(Ⅰ)的化合物 20.0%
硬脂酸镁 0.9%
淀粉 8.6%
乳糖 69.6%
PVP(聚乙烯基吡咯烷酮) 0.9%
将上述除硬脂酸镁外的组分合并,用水作为造粒液体进行造粒。将制剂干燥,与硬脂酸镁混合,用适宜的压片机进行压片。
C.组分
式(Ⅰ)的化合物 0.1g
丙二醇 20.0g
聚乙二醇400 20.0g
多乙氧基醚 1.0g
0.9%水 足量至100ml
将式(Ⅰ)化合物溶解于丙二醇、聚乙二醇400和多乙氧基醚中。然后搅拌下加入足量的水以得到100ml的溶液,将其过滤,装瓶。
D.组分 %wt./wt.
式(Ⅰ)的化合物 20.0%
花生油 78.0%
山梨糖醇酯类(span 60) 2.0%
将上述组分熔化、混合后,装入软塑料胶囊中。
实施例25
本实施例表明代表性胃肠外给药形式的药用组合物的制备方法,该组合物包含式(Ⅰ)的化合物或其可药用盐,如,N-(4-甲基-2-(N"-羟基氨基甲酰基)甲基戊酰基)-L-色氨酸-N′-(4-羧基苯基)甲酰胺:
组分
式(Ⅰ)的化合物 0.02g
丙二醇 20.0g
聚乙二醇400 20.0g
多乙氧基醚 1.0g
0.9%盐水溶液 足量至100ml
将式(Ⅰ)化合物溶解于丙二醇、聚乙二醇400和多乙氧基醚中。然后搅拌下加入足量的0.9%盐水溶液以得到100 ml的静脉注射溶液,将其通过0.2μ的膜过滤,在无菌条件下包装。
实施例26
本实施例表明代表性栓剂形式的药用组合物的制备方法,该组合物包含式(Ⅰ)的化合物或其可药用盐,如N-(4-甲基-2-(N"-羟基氨基甲酰基)甲基戊酰基)-L-亮氨酸-N′-(4-羰基苯基)甲酰胺:
组分 %wt./wt.
式(Ⅰ)的化合物 1.0%
聚乙二醇1000 74.5%
聚乙二醇4000 24.5%
将上述组分在蒸气浴上熔化、混合,然后将其倒入塑模(molds)中,每个包含2.5g(总量)。
实施例27
本实施例表明代表性吹入剂形式的药用组合物的制备方法,该组合物包含式(Ⅰ)的化合物或其可药用盐,如,N-(4-甲基-2-(N"-羟基氨基甲酰基)甲基戊酰基)-L-环己基甘氨酸-N′-(4-甲氧羰基苯基)甲酰胺:
组分 %wt./wt.
细微化的式(Ⅰ)的化合物 1.0%
细微化的乳糖 99.0%
将上述组分粉碎、混合,将其装入备有剂量泵的吹入器中。
实施例28
本实施例表明代表性喷雾剂形式的药用组合物的制备方法,该组合物包含式(Ⅰ)的化合物或其可药用盐,如,N-(4-甲基-2-(N"-羟基氨基甲酰基)甲基戊酰基)-L-t-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺:
组分 %wt./wt.
式(Ⅰ)的化合物 0.005%
水 89.995%
乙醇 10.000%
将式(Ⅰ)化合物溶解于乙醇并与水混和。然后将制剂装入备有剂量泵的喷雾器中。
实施例29
本实施例表明代表性气溶胶形式的药用组合物的制备方法,该组合物包含式(Ⅰ)的化合物或其可药用盐,如,N-(4-甲基-2-巯基甲基戊酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺:
组分 %wt./wt.
式(Ⅰ)的化合物 0.10%
推进剂11/12 98.90%
油酸 1.00%
将式(Ⅰ)化合物分散于油酸和推进剂中。将形成的混合物倒入备有计量阀的气溶胶容器中。
实施例30
体外测定
Matrilysin是通过蓝琼脂糖(Blue-Sepharose)和锌-鏊合琼脂糖柱由克隆哺乳动物细胞培养基纯化,并随之在MONO S柱上由快速蛋白质液相色谱纯化。该酶通过用1 mmol APMA在35-37℃下培养1小时活化。
将式(Ⅰ)的化合物溶解于DMSO中,并被加至-个包含0.4μg ma-trilysin于1 ml TC缓冲液(20 mM Tris,5 mM CaCl2,pH 7.5)(2%DMSO最终浓度)的小池中。选择式(Ⅰ)化合物的浓度使每20%活性变化时有一个数据点。酶与化合物允许在37℃下预培养3分钟。为了起动该反应,分别加入N-(7-二甲基氨基-4-甲基)香豆素(coumarinyl)(“DACM”)(Sigma)和硫肽(Ac-Pro-Leu-Gly-S“Leu”-Leu-Gly-OEt,Bachem Bioscience Inc.)至20μM。分别用395和485 nm激发与发射波长记录荧光的增加。每一个数据点为两次单行实验的平均值。使用Enzfitter程序的IC50 Fit来分析对化合物浓度的每分钟荧光变化来表示的至少六个数据点。
本测定中试验表明式(Ⅰ)化合物抑制matrilysin的能力。
IC50(nM)
HFC PUMP HNG STROM.化合物2 8.4 K1=140fM 1.4
实施例31
体外测定
本次测定确定式(Ⅰ)的化合物是否抑制来自软骨移植物的35S标记的葡糖氨基聚糖(GAG′s)的释放。
小的软骨移植物(直径3 mm)由通过新杀的牛膝关节制备的,并用35SO4标记。35S标记的葡糖氨基聚糖(GAG′s)被释放入培养基中以响应rhIL-1-alpha的加入,它引导软骨细胞基质金属蛋白酶(MMP′s)包括stromelysin和胶原酶的表达。标记的GAG′s的抑制百分数在不存在rhIL-1-alpha时对自发释放进行校正。每组的结果对五个移植物表示平均±S.E.M.。
在该测定中,式(Ⅰ)化合物显示出抑制由软骨移植物35S标记的GAG′s的释放的能力。
EC50(摩尔)
化合物2 3.5×10-6
实施例31体外测定
体外鼠胎儿长骨模型被用于研究式(Ⅰ)化合物的抗骨吸收效果。牛PTH用于诱导体外的骨吸收。骨吸收效果通过由45Ca预标记的鼠胎儿长骨释放的进入培养基的45Ca量来表示。式(Ⅰ)化合物对牛PTH诱导骨吸收的抑制效果由平均百分抑制率±sem表示。
由45Ca预标记的鼠胎儿长骨(来自前臂)被分割开,在37℃下于补充有1 mg/ml BSA的BGJb培养基中,在Linbro皿中过夜培养。在每组中包含有五对骨头。式(Ⅰ)化合物先溶解于乙醇中,然后稀释至各种浓度,在第一天同时加入1×10-8M的牛PTH(1-34)。在化合物溶液中的乙醇浓度小于0.05%不会干扰该测定。该测定在第6天终止,一个培养基在第3天改变。
在每一培养基改变终了时,对存在于培养基中的45Ca量进行计数。其余的骨头用0.1N HCl蒸煮,同时对蒸煮的骨头中存在的45Ca量进行计数。结果以总的由每对骨头释放的45Ca的%表示。1×10-8M的牛PTH引起骨吸收至最大量,该值设定为100%,该浓度用作标准。存在培养基时骨吸收的基线仅设定为0%。所有经化合物处理的组与1×10-8M的牛PTH(1-34)比较。在化合物抑制骨吸收率为50%的浓度被定义为IC50。
在本次测定中,式(Ⅰ)的化合物显示出抑制由牛PTH吸引的骨吸收的能力。
IC50(摩尔)
化合物1 ≥5×10-6
化合物2 2.7×10-7
化合物3 5×10-8
化合物4 ≥5×10-6
毒性
在上述测定中未观察到严重的毒理作用。
Claims (16)
1、一种单一立体异构体或其混合物的式(Ⅰ)的化合物或其可药用盐:其中R1为巯基、乙酰基硫基、羧基、羟基氨基甲酰基、烷氧羰基、芳氧羰基、芳烷氧羰基、苄氧基氨基甲酰基或其中,R6为任意被取代的芳基,其中芳基为喹啉-2-基、萘-1-基、萘-2-基、吡啶基或苯基;R2为烷基、芳烷基或环烷基烷基;R3为环烷基、烷基,该烷基任意被环烷基、羟基、巯基、烷硫基、芳烷氧基、羧基、氨基、烷氨基、胍基、氨基甲酰基、吡啶基或吲哚基取代,或芳烷基,该芳烷基任意被羟基、羧基、烷基或烷氧基取代;R4为硝基、氨基、氰基、羟基、烷氧基、羧基、烷氧羰基、烷基磺酰基、卤代烷基、烷氧羰基烷基、四唑基、任意被烷基或二烷基氨基取代的氨基甲酰基或任意被烷基取代的氨基磺酰基;和R5为氢、卤原子或羟基。
2、根据权利要求1的化合物,其中R1为巯基或乙酰基硫基。
3、根据权利要求2的化合物,其中:R3为环烷基或烷基,该烷基任意被环烷基、羟基、芳烷氧基、烷硫基、吡啶基或吲哚基取代;R4为氰基、羟基、烷氧基、羧基、烷氧羰基、烷氧羰基烷基、任意被芳烷基氨基烷基取代的氨基甲酰基或任意被烷基取代的氨基磺酰基;和R5为氢。
4、根据权利要求3的化合物,其中R2为烷基;R3为环己基或烷基,该烷基任意被环己基、羟基、苄氧基、甲硫基、吡啶基或吲哚基取代;和R4为羧基、烷氧羰基或氨基磺酰基。
5、根据权利要求4的化合物,其中R2和R3为2-甲基丙基。
6、根据权利要求5的化合物,其中R1为巯基或乙酰基硫基,R4为甲氧羰基。
7、根据权利要求6的化合物的单一立体异构体或其可药用盐,即N-(4-甲基-2-巯基甲基戊酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;或N-(4-甲基-2-乙酰基硫基甲基戊酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺。
8、根据权利要求1的化合物,其中R1为羧基或羟基氨基甲酰基。
9、根据权利要求8的化合物,其中:R3为环烷基或烷基,该烷基任意被环烷基、羟基、芳烷氧基、烷硫基、吡啶基或吲哚基取代;R4为氰基、羟基、烷氧基、羧基、烷氧羰基、烷氧羰基烷基、任意被芳烷基氨基烷基取代的氨基甲酰基或任意被烷基取代的氨基磺酰基;和R5为氢。
10、根据权利要求9的化合物,其中:R2为烷基;R3为环己基或烷基,该烷基任意被环己基、羟基、苄氧基、甲硫基、吡啶基或吲哚基取代;R4为羧基、烷氧羰基或氨基磺酰基。
11、根据权利要求10的化合物,其中R2为2-甲基丙基。
12、根据权利要求11的化合物,其中R3为环己基、2-甲基丙基、吡啶-3-基甲基、1-苄氧乙基、1-甲基丙基、1,1-二甲基乙基、1-羟基乙基和吲哚-2-基甲基。
13、根据权利要求12的化合物,其中R3为2-甲基丙基,R4为羧基或甲氧羰基。
14、根据权利要求13的化合物的单一立体异构体或其可药用盐,即N-(4-甲基-2-羧基甲基戊酰基)-L-亮氨酸-N′(4-甲氧羰基苯基)甲酰胺;N-(4-甲基-2-(N"-羟基氨基甲酰基)甲基戊酰基)-L-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺;N-(4-甲基-2-(N"-羟基氨基甲酰基)甲基戊酰基)-L-亮氨酸-N′-(4-羧基苯基)甲酰胺;N-(4-甲基-2-(N"-羟基氨基甲酰基)甲基戊酰基)-L-色氨酸-N′-(4-羧基苯基)甲酰胺;N-(4-甲基-2-(N"-羟基氨基甲酰基)甲基戊酰基)-L-环己基甘氨酸-N′(4-甲氧羰基苯基)甲酰胺;或N-(4-甲基-2-(N″-羟基氨基甲酰基)甲基戊酰基)-L-t-亮氨酸-N′-(4-甲氧羰基苯基)甲酰胺。
15、一种药物组合物,它包含治疗有效量的权利要求1的化合物或其可药用盐,并含有一种或多种可药用的赋形剂。
16、单一立体异构体或其混合物的下式(Ⅰ)的化合物或其可药用盐在制造用于抑制哺乳动物基质金属蛋白酶活性的药物中的应用,其中,R1为巯基、乙酰基硫基、羧基、羟基氨基甲酰基、烷氧羰基、芳氧羰基、芳烷氧羰基、苄氧基氨基甲酰基或其中,R6为任意被取代的芳基,其中芳基为喹啉-2-基、萘-1-基、萘-2-基、吡啶基或苯基;R2为烷基、芳烷基或环烷基烷基;R3为环烷基、烷基,该烷基任意被环烷基、羟基、巯基、烷硫基、芳烷氧基、羧基、氨基、烷氨基、胍基、氨基甲酰基、吡啶基或吲哚基取代,或芳烷基,该芳烷基任意被羟基、羧基、烷基或烷氧基取代;R4为硝基、氨基、氰基、羟基、烷氧基、羧基、烷氧羰基、烷基磺酰基、卤代烷基、烷氧羰基烷基、四唑基、任意被烷基或二烷基氨基烷基取代的氨基甲酰基或任意被烷基取代的氨基磺酰基;和,R5为氢、卤原子或羟基。
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US14781193A | 1993-11-04 | 1993-11-04 | |
US08/147,811 | 1993-11-04 |
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DE (1) | DE69404324T2 (zh) |
DK (1) | DK0726903T3 (zh) |
ES (1) | ES2105783T3 (zh) |
FI (1) | FI961857A (zh) |
GR (1) | GR3024248T3 (zh) |
HU (1) | HUT74730A (zh) |
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PL (1) | PL178326B1 (zh) |
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UA (1) | UA48121C2 (zh) |
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GB9601042D0 (en) * | 1996-01-17 | 1996-03-20 | Smithkline Beecham Plc | Medical use |
US5831004A (en) * | 1994-10-27 | 1998-11-03 | Affymax Technologies N.V. | Inhibitors of metalloproteases, pharmaceutical compositions comprising same and methods of their use |
US5840698A (en) * | 1994-10-27 | 1998-11-24 | Affymax Technologies N.V. | Inhibitors of collagenase-1 and stormelysin-I metalloproteases, pharmaceutical compositions comprising same and methods of their use |
HUP9903863A3 (en) | 1995-11-23 | 2000-11-28 | British Biotech Pharm | Metalloproteinase inhibitors |
DE69633947T2 (de) * | 1995-12-08 | 2005-12-01 | Agouron Pharmaceuticals, Inc., San Diego | Zwischenprodukte zur Herstellung von Metallproteinasehemmern |
US6500948B1 (en) | 1995-12-08 | 2002-12-31 | Agouron Pharmaceuticals, Inc. | Metalloproteinase inhibitors-compositions, uses preparation and intermediates thereof |
EP0923585B1 (en) * | 1996-07-18 | 2002-05-08 | Pfizer Inc. | Phosphinate based inhibitors of matrix metalloproteases |
CN1228773A (zh) * | 1996-08-28 | 1999-09-15 | 普罗克特和甘保尔公司 | 杂环金属蛋白酶抑制剂 |
IL128337A0 (en) | 1996-09-10 | 2000-01-31 | British Biotech Pharm | Cytostatic hydroxamic acid derivatives |
US6462023B1 (en) | 1996-09-10 | 2002-10-08 | British Biotech Pharmaceuticals, Ltd. | Cytostatic agents |
US6008243A (en) * | 1996-10-24 | 1999-12-28 | Agouron Pharmaceuticals, Inc. | Metalloproteinase inhibitors, pharmaceutical compositions containing them, and their use |
US6174915B1 (en) | 1997-03-25 | 2001-01-16 | Agouron Pharmaceuticals, Inc. | Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses |
US6034136A (en) | 1997-03-20 | 2000-03-07 | Novartis Ag | Certain cyclic thio substituted acylaminoacid amide derivatives |
US5985900A (en) * | 1997-04-01 | 1999-11-16 | Agouron Pharmaceuticals, Inc. | Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses |
US6420427B1 (en) * | 1997-10-09 | 2002-07-16 | Ono Pharmaceutical Co., Ltd. | Aminobutyric acid derivatives |
CN1284942A (zh) | 1998-01-09 | 2001-02-21 | 辉瑞大药厂 | 基质金属蛋白酶抑制剂 |
US6329418B1 (en) | 1998-04-14 | 2001-12-11 | The Procter & Gamble Company | Substituted pyrrolidine hydroxamate metalloprotease inhibitors |
US6329400B1 (en) | 1998-08-26 | 2001-12-11 | Glaxo Wellcome Inc. | Formamide compounds as therapeutic agents |
US6172064B1 (en) | 1998-08-26 | 2001-01-09 | Glaxo Wellcome Inc. | Formamides as therapeutic agents |
GB9818605D0 (en) | 1998-08-26 | 1998-10-21 | Glaxo Group Ltd | Formamide compounds as therepeutic agents |
US6696456B1 (en) | 1999-10-14 | 2004-02-24 | The Procter & Gamble Company | Beta disubstituted metalloprotease inhibitors |
PL365444A1 (en) | 2000-03-21 | 2005-01-10 | The Procter & Gamble Company | Heterocyclic side chain containing, n-substituted metalloprotease inhibitors |
AU2001245862A1 (en) | 2000-03-21 | 2001-10-03 | The Procter & Gamble Company | Difluorobutyric acid metalloprotease inhibitors |
GB0818907D0 (en) * | 2008-10-15 | 2008-11-19 | Isis Innovation | Histone lysine demethylase inhibitors |
CN108218918A (zh) * | 2018-03-01 | 2018-06-29 | 四川大学 | 芳基偕二磷酸衍生物制备方法和用途 |
TW202039473A (zh) | 2018-12-19 | 2020-11-01 | 丹麥商理奧藥品公司 | Il-17的小分子調節劑 |
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ES2105783T3 (es) | 1997-10-16 |
PL314134A1 (en) | 1996-08-19 |
CZ287642B6 (en) | 2001-01-17 |
WO1995012603A1 (en) | 1995-05-11 |
DK0726903T3 (da) | 1997-10-13 |
JPH09505038A (ja) | 1997-05-20 |
ATE155471T1 (de) | 1997-08-15 |
ZA948691B (en) | 1996-05-03 |
AU683317B2 (en) | 1997-11-06 |
UA48121C2 (uk) | 2002-08-15 |
HUT74730A (en) | 1997-02-28 |
CN1134153A (zh) | 1996-10-23 |
FI961857A (fi) | 1996-07-01 |
FI961857A0 (fi) | 1996-05-02 |
GR3024248T3 (en) | 1997-10-31 |
BR9407960A (pt) | 1996-11-26 |
PL178326B1 (pl) | 2000-04-28 |
DE69404324D1 (de) | 1997-08-21 |
AU8089794A (en) | 1995-05-23 |
NO961780D0 (no) | 1996-05-02 |
KR100352199B1 (ko) | 2002-11-11 |
NO306726B1 (no) | 1999-12-13 |
NZ275315A (en) | 1997-07-27 |
RU2132327C1 (ru) | 1999-06-27 |
EP0726903B1 (en) | 1997-07-16 |
HU9601154D0 (en) | 1996-07-29 |
KR960705830A (ko) | 1996-11-08 |
EP0726903A1 (en) | 1996-08-21 |
DE69404324T2 (de) | 1998-01-08 |
CZ126096A3 (en) | 1996-11-13 |
NO961780L (no) | 1996-07-03 |
CA2175667A1 (en) | 1995-05-11 |
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