CN1205328A - 磺酰氨基羧酸 - Google Patents

磺酰氨基羧酸 Download PDF

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CN1205328A
CN1205328A CN98115265A CN98115265A CN1205328A CN 1205328 A CN1205328 A CN 1205328A CN 98115265 A CN98115265 A CN 98115265A CN 98115265 A CN98115265 A CN 98115265A CN 1205328 A CN1205328 A CN 1205328A
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phenyl
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CN1280267C (zh
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W·索瓦特
W·施瓦博
M·舒多克
B·哈瑟
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Sanofi Aventis Deutschland GmbH
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Hoechst AG
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Abstract

式Ⅰ的化合物适用于制备用于预防和治疗在其过程中与基质降解金属蛋白酶的活性增加有关的疾病的药物。

Description

磺酰氨基羧酸
本发明是关于新的磺酰氨基羧酸，其制备方法和作为药物的用途。
专利申请EP 0606046，WO95／35276和WO96／27583描述了芳基磺酰氨基异羟肟酸和其作为基质金属蛋白酶抑制剂的作用。特定的芳磺酰氨基羧酸用作制备凝血酶抑制剂(EP0468231)和醛糖还原酶抑制剂的中间体(EP0305947)。专利申请EP0757037也描述了磺酰氨基羧酸衍生物作为金属蛋白酶抑制剂的作用。
此外，已证实芳基磺酰基可用作α-氨基羧酸氨基官能团的有效的保护基(R．Roemmele，H．Rapoport，有机化学杂志(J．Org．Chem．)53(1988)，2367-2371)。
在寻找治疗结缔组织疾病的有效化合物的努力中，已经发现根据本发明的磺酰氨基羧酸是基质金属蛋白酶的强抑制剂。其特殊的价值是抑制Stromelysin(基质金属蛋白酶3)和嗜中性白细胞胶原酶(MMP-8)，因为这两种酶都关键性地参与了作为软骨组织的重要组分的蛋白聚糖的降解(A．J．Fosang et al．临床研究杂志(J．Clin．Invest．)98(1996)，2292-2299)。
因此，本发明是关于式Ⅰ的化合物和／或其立体异构体和／或其生理上可容许的盐式中：
R1是1．苯基，
    2．被下列基团一或二取代的苯基：
      2．1．直链，支链或环状的(C1-C6)烷基，
      2．2．羟基，
      2．3．(C1-C6)烷基-C(O)-O-，
      2．4．(C1-C6)烷基-O-，
      2．5．(C1-C6)烷基-O-(C1-C4)烷基-O-，
      2．6．卤素，
      2．7．-CF3，
      2．8．-CN，
      2．9．-NO2，
      2．10．HO-C(O)-，
      2．11．(C1-C6)烷基-O-C(O)-，
      2．12．亚甲基二氧代(methylenedioxo)，
      2．13．R4-(R5)N-C(O)-，
      2．14．R4-(R5)N-，或
    3．选自3．1-3．15的杂芳基，其未取代或被2．1-2．14描述的基团取代：
      3．1．吡咯，
      3．2．吡唑，
      3．3．咪唑，
      3．4．三唑，
      3．5．噻吩，
      3．6．噻唑，
      3．7．噁唑，
      3．8．异噁唑，
      3．9．吡啶，
      3．10．嘧啶，
      3．11．吲哚，
      3．12．苯并噻吩，
      3．13．苯并咪唑，
      3．14．苯并噁唑，或
      3．15．苯并噻唑，
R2，R4和R5相同或不同，是
1．氢原子，
2．(C1-C6)烷基，
3．HO-C(O)-(C1-C6)烷基，
4．苯基-(CH2)n-，其中苯基未取代或被2．1-2．14描述的基团一或二取代，或被-NH-C(O)-(C1-C3)烷基取代，n是整数0，1或2，或
5．吡啶甲基，或
6．R4和R5与环上氨基一起形成4-7元环，其中一个碳原子任选被-O-、-S-或-NH-替换，或4-7元环的两个相邻的碳原子是苄基的一部分，
R3是1．氢原子，
    2．(C1-C10)烷基，其中烷基未取代和／或烷基的一个氢原子被-OH替代，
    3．直链或支链(C2-C10)链烯基，
    4．R2-O-(C1-C6)烷基，
    5．R2-S(O)n-(C1-C6)烷基，其中n具有上述含义，
    6．R2-S(O)(=NH)-(C1-C6)烷基
    7．
Figure 98115265001378
其中n是整数0，1或2，W是氮、氧或硫原子，
    8、苯基-(CH2)m，其中m是整数0，1，2，3，4，5或6和／或-(CH2)m链的一个氢原子被-OH替代和苯基未取代或被下列基团一或二取代：
    8．1 2．1-2．14描述的基团，
    8．2-O-(CH2)m-苯基，其中苯基未取代或被2．1-2．14描述的基团一或二取代，m是整数0，1，2，3，4，5或6，
    8．3-C(O)-(CH2)m-苯基，其中苯基同8．2定义，
    9．杂芳基-(CH2)m-，其中杂芳基同3．1-3．15定义，m同上述定义和／或-(CH2)m-链的一个氢原子被-OH替代和杂芳基未取代或被下列基团一或二取代：
    9．1 2．1-2．14描述的基团，
    9．2  -CH(O)，
    9．3  -SO2-苯基，其中苯基未取代或同8．2或8．3的定义，
    9．4  -O-(CH2)m-苯基，
    10．-(CH2)m-P(O)(OH)-(C1-C3)烷基，其中m同上述定义，或
    11．R6-C(O)-(C1-C6)烷基，其中
R6是1．氢原子，
    2．(C1-C6)烷基，其中烷基是直链、支链或环状的，
    3．苯基，其未取代或被2．1-2．14描述的基团取代，
    4．杂芳基，其同3．1-3．15定义和／或被2．1-2．14描述的基团取代或被-(C1-C4)烷基-COOH取代，
    5．HO-，
    6．R2O-，其中R2具有上述定义，
    7．R4-(R5)N-，其中R4和R5同上述定义，
    8．杂芳基-(CH2)m-NH-，其中杂芳基同3．1-3．15定义和／或被2．1-2．14描述的基团取代，m同上述定义，
    9．R4-(R5)N-NH-，其中R4和R5同上述定义，或
    10．HO-C(O)-CH(R3)-NH-，其中R3同上述定义，或
R2和R3一起形成亚式(Ⅱ)的具有环上羧基的环，
Figure 98115265001479
其中r是整数0，1，2或3和／或环中的一个碳原子被-O-、-S-或-(R7)N-替换，其中：
R7是1．氢原子，
    2．(C1-C6)烷基，
    3．苯基，其未取代或被2．1-2．14描述的基团取代，
    4．苄基，其未取代或被2．1-2．14描述的基团取代，或
    5．R2N-C(=NH)-，其中R2具有上述含义，和／或亚式Ⅱ环中的碳原子被(C1-C6)烷基、苯基、苯基-(CH2)m-或HO-一或多取代，
A是a)共价键，
    b)-O-，
    c)-CH=CH-或
    d)-C≡C-，
B是a)-(CH2)m-，其中m具有上述含义，
    b)-O-(CH2)p，其中p是整数1-5，或
    c)-CH=CH-和
X是-CH=CH-，氧原子或硫原子。
优选式Ⅰ化合物，式中：
R1是1．苯基，或
    2．被下列基团一取代的苯基：
      2．1．(C1-C6)烷基，其中烷基是直链，支链或环状的，
      2．2．-OH，
      2．3．(C1-C6)烷基-C(O)-O-，
      2．4．(C1-C6)烷基-O-，
      2．5．(C1-C6)烷基-O-(C1-C4)烷基-O-，
      2．6．卤素
      2．7．-CF3，或
      2．8．R4-(R5)N-，
R2，R4和R5相同或不同，是
1．氢原子，或
2．(C1-C6)烷基，
R3是1．(C1-C10)烷基，其中烷基是直链，支链或环状的，和／或烷基的氢原子被-OH替代，
2．R2-S(O)n-(C1-C6)烷基，其中R2是(C1-C6)烷基或苯基-(CH2)n-，n是整数0或1，
3．苯基-(CH2)m-，其中苯基未取代或被2．1-2．14描述的基团一或二取代和／或-(CH2)m-链的一个氢原子被-OH替代，m是整数1，2，3，4或5，
4．杂芳基-(CH2)m-，其中杂芳基具有3．3，3．5，3．6，3．9或3．11描述的含义和／或被2．1-2．14描述的基团取代和／或-(CH2)m-链的一个氢原子被-OH替代，m是整数1，2，3或4，
5．R6-C(O)-(C1-C6)烷基，其中：
R6是1．-OH
    2．R2O-，其中R2同上述定义，
    3．R4-(R5)N-，其中R4和R5同上述定义，或
    4．R4和R5与环上氨基一起形成5-6元环，其中一个碳原子任选被-O-，-S-或-NH-替换，或5-6元环的两个相邻的碳原子是苄基的一部分，
6．R2和R3一起形成亚式Ⅱ的含有环上羧基的环，其中n是整数1或2和／或环中的一个碳原子被-O-或-(R7)N-替换，和
R7是1．氢原子，
    2．(C1-C6)烷基，
    3．苯基，其未取代或被2．1-2．14描述的基团取代，
    4．苄基，其未取代或被2．1-2．14描述的基团取代，或
    5．R2N-C(=NH)-，其中R2同上述定义，
和／或亚式Ⅱ的环中的碳原子被苯基或-OH单取代，
A是a)共价键，或
    b)-O-，
B是a)-(CH2)m-，其中m是整数0，1或2，或
    b)-O-(CH2)p，其中p是整数1或2，和
X是-CH=CH-。
特别优选式Ⅰ化合物，式中：
R1是1．苯基，或
    2．被下列基团一取代的苯基：
    2．1．卤素，特别是氯或氟，或
    2．2．R4-(R5)N-，其中R4和R5相同或不同，是
    2．2．1．(C1-C3)烷基，或
      2．2．2．R4和R5与环上氨基一起形成5-6元环，其中一个碳原子任选被-O-或-N-替换，
R2是氢原子，
R3是1．杂芳基-(CH2)m-，其中杂芳基同3．5，3．11或3．13定义，其未取代或被2．1-2．14描述的基团单取代，m是整数1或2，或
    2．R6-C(O)-(C2-C3)烷基，其中：
R6是1．-OH，
    2．R2-O-，其中R2同上述定义，或
    3．R4-(R5)N-，其中R4和R5相同或不同，是
    3．1．氢原子，
    3．2．(C1-C3)烷基，
    3．3．苯基-(CH2)-，其中苯基未取代或被2．1-2．14描述的基团单取代或双取代，n是整数0，1或2，
    3．4．R4和R5与环上氨基一起形成5-6元环，其中一个碳原子任选被-O-或-NH-替换，或形成二氢吲哚基，或
    3．5．HO-C(O)-CH(R3)-NH-，其中R3同上述定义，
A是共价键，
B是-(CH2)O-，其中O是0，和
X是-CH=CH-。
语句“R4和R5与环上氨基一起形成4-7元环和／或一个碳原子被-O-，-S-或-NH-替换”应理解为是指例如由下列化合物衍生的基团：氮杂环丁烷、吡咯、吡咯啉、吡啶、吖庚因、哌啶、噁唑、异噁唑、咪唑、二氢吲哚、吡唑、噻唑、异噻唑、二氮杂_、硫代吗啉、嘧啶或吡嗪。术语“卤素”应理解为是指氟、氯、溴或碘。术语“烷基”或“链烯基”应理解为是指其碳链是直链或支链的烃基。环烷基是例如3-6元单环系，例如环丙基、环丁基、环戊基或环己基。此外，链烯基也可以含有几个双键。
本发明中的化学反应的原料是已知的或可容易地用文献中的已知方法制备。
本发明还涉及式Ⅰ化合物和／或其立体异构体和／或其生理上可容许的盐的制备方法，包括：
a)在碱或任选脱水剂存在下，式Ⅲ的氨基羧酸式中R2和R3同式Ⅰ中定义，与式Ⅳ的磺酸衍生物反应，
Figure 98115265001881
式中R1、A和B同式Ⅰ中定义，Y是卤原子、咪唑基或-OR8，其中R8是氢原子、(C1-C6)烷基、苯基或苄基，任选被取代，得到式Ⅰ化合物；或
b)在上述条件下，式Ⅴ的氨基羧酸酯式中R2、R3和R8具有上述含义，与式Ⅳ的磺酸衍生物反应，得到式Ⅵ的化合物，
Figure 98115265001883
和优选在碱或酸存在下除去R8将式Ⅵ的化合物转化为式Ⅰ的化合物；或
C)式Ⅶ的化合物
Figure 98115265001884
式中n是整数0、1或2，与保护基E反应，得到式Ⅷ的化合物，
Figure 98115265001985
在上述条件下用式Ⅳ的磺酸衍生物将式Ⅷ的化合物转化为式Ⅸ的化合物，
Figure 98115265001986
然后用合适的解离试剂除去保护基E和R8基，将式Ⅸ的化合物转化为式Ⅰ的化合物；
d)将由方法a)、b)和c)制备的基于其化学结构以对映体形式出现的式Ⅰ化合物拆解为纯的对映体，拆解方法包括使其与对映异构纯的酸或碱形成盐，用手性固定相进行色谱分离，或用手性对映异构纯的化合物如氨基酸形成衍生物，分离得到的非对映体，除去手性辅助基团；或
e)分离由方法a)、b)、c)或d)制备的游离形式的式Ⅰ化合物，或者在存在酸或碱基团的情况下将式Ⅰ的游离形式的化合物转化成生理上可容许的盐。
用于此目的的合适的保护基E优选在肽化学中通用的N-保护基，例如脲烷型保护基、苄氧羰基(Z)、叔丁氧羰基(Boc)、9-芴氧羰基(Fmoc)、烯丙氧羰基(Aloc)，或酰胺型保护基，特别是甲酰基、乙酰基或三氟乙酰基，和烷基型的，例如苄基。
使用的其中R2是氢原子和R3是天然α-氨基酸的特征基团的式Ⅲ化合物优选甘氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、苯丙氨酸、酪氨酸、色氨酸、丝氨酸、苏氨酸、胱氨酸、蛋氨酸、天冬酰胺、谷氨酰胺、赖氨酸、组氨酸、精氨酸、谷氨酸和天冬氨酸。在天然的也有非天然α-氨基酸的情况下，所述α-氨基酸在其侧链R3中有官能团，例如氨基、羟基、羧基、巯基、胍基、咪唑基或吲哚基，该基团也可以被保护。
在R3有咪唑基的情况下，例如用于生成磺酰胺的式Ⅳ的磺酸衍生物用作咪唑氮的保护基，特别在碱如氢氧化钠溶液存在下该保护基可以再除去。
为了制备其中R2和R3一起形成亚式Ⅱ的环的式Ⅰ化合物，使用的式Ⅲ的原料是例如脯氨酸、3-或4-羟基脯氨酸、哌啶-2-羧酸、哌嗪-2-羧酸和六氢哒嗪-3-羧酸，特别是哌嗪-2-羧酸4-位上的氮可能被方法C)中描述的保护基Z，例如苄氧羰基或叔丁氧羰基，或被R7基取代。
制备式Ⅳ的磺酸衍生物使用的原料优选式Ⅹ的磺酸或其盐，例如
Figure 98115265002087
Figure 98115265002188
式中R9是2．1-2．14描述的基团。
为了制备式Ⅹa和Ⅹb的芳基磺酸，优选使用Houben-Weyl在有机化学方法“Methoden der Organischen Chemie”[Methods of OrganicChemistry]．，Volume9，PP．450-546中描述的使用浓硫酸的磺化方法，该方法任选存在催化剂，三氧化硫和其加合物或卤磺酸，例如氯磺酸。特别在式Ⅹb的二苯醚的情况下，已证明使用浓硫酸和乙酸酐溶剂(参见C．M．Suter，美国化学会志(J．Am．Chem．Soc．)53(1931)，1114)或与过量氯磺酸的反应(J．P．Bassin，R．Cremlyn and F．Swinbourne，磷、硫、硅(Phosphorus，Sulfur and Silicon)72(1992)，157)是合适的。式Ⅹc、Ⅹd或Ⅹe的磺酸可以用已知方法制备，包括在水溶液或水／醇溶液中合适的芳烷基卤与亚硫酸盐如亚硫酸钠或亚硫酸铵反应，在有机季铵盐如氯化四丁基铵存在下可能加速反应。
使用的式Ⅳ的磺酸衍生物特别是磺酰氯。为了制备所述衍生物，相应的磺酸或其盐，例如钠盐、铵盐或吡啶鎓盐与五氯化磷或亚硫酰氯用已知方法反应，反应一般在反应温度20℃至使用的反应介质的沸点下在无或有溶剂如磷酰氯或惰性溶剂如二氯甲烷、环己烷或氯仿存在下进行。
根据方法a)、b)或c)，或Ⅳ的磺酸衍生物和式Ⅲ、Ⅴ或Ⅶ的氨基酸的反应用Schotten-Baumann反应的方法便利地进行。为此目的合适的碱特别是碱金属氢氧化物，例如氢氧化钠，也可以是碱金属乙酸盐、碳酸氢盐、碳酸盐和胺。反应在水或水溶混的或水不溶混的溶剂如四氢呋喃(THF)、丙酮、二噁烷或乙腈中进行，反应温度一般保持-10℃-50℃。在反应在无水介质的情况下进行时，尤其使用四氢呋喃或二氯甲烷、乙腈或二噁烷，在碱，例如三乙胺、N-甲基吗啉、N-乙基或二异丙基乙胺存在下，可能的话在N，N-二甲基氨基吡啶催化剂存在下进行。
在另一种情况下，式Ⅲ、Ⅳ或Ⅶ的氨基羧酸可以用甲硅烷基化剂如双-三甲基甲硅烷基三氟乙酰胺(BSTFA)首先转化成其甲硅烷基化物形式，然后与磺酸衍生物反应，得到式Ⅰ的化合物。
可生成盐的式Ⅰ化合物的生理上可容许的盐，包括其立体异构体，用本身已知的方法制备。用碱性试剂，例如氢氧化物、碳酸盐、碳酸氢盐、醇化物和氨或有机碱，例如三甲胺、三乙胺、乙醇胺或三乙醇胺，或另外的碱性氨基酸，例如赖氨酸、鸟氨酸或精氨酸，与羧酸形成稳定的碱金属盐、碱土金属盐或任选取代的铵盐。如果式Ⅰ的化合物具有碱性基团，稳定的酸加成盐也可以用强酸制备。适合于此目的酸是无机酸和有机酸，例如盐酸、氢溴酸、硫酸、磷酸、甲磺酸、苯磺酸、对甲苯磺酸、4-溴苯磺酸、环己基酰氨基磺酸、三氟甲磺酸、乙酸、草酸、酒石酸、琥珀酸或三氟乙酸。
本发明还涉及药物组合物，包括有效量的至少一种式Ⅰ的化合物和／或其生理上可容许的盐和／或其任选的立体异构体和药物学上合适的和生理上可容许的赋形剂、添加剂，和／或其他活性组分和助剂。
基于药物学性质，根据本发明的化合物适合于预防和治疗在其过程中与基质降解金属蛋白酶活性提高有关的所有疾病。所述疾病包括退行性关节疾病，例如骨关节病、脊椎病、关节损伤后的或半月板或髌骨损伤后的相对长时间的固定后的软骨溶解或韧带撕裂。另外，所述疾病还包括结缔组织的疾病，例如胶原病、牙周疾病、创伤愈合疾病和运动器官的慢性疾病，例如与发炎，免疫或代谢有关的急性和慢性关节炎、关节病、肌痛和骨代谢疾病。式Ⅰ的化合物还适合于治疗溃疡、动脉粥样硬化和狭窄。式Ⅰ的化合物还适合于治疗炎症、癌症、肿瘤转移形成、恶质病、厌食和败血性休克。本发明的药物一般口服给药或肠胃外给药。也可以直肠或透皮给药。
本发明还涉及药物的生产方法，该方法包括使用制药学上适用的和生理上可接受的赋形剂，适当的时候还使用其它合适的活性化合物、添加剂或助剂，将至少一种式Ⅰ化合物配制成合适的给药剂型。
适当的固体或药物剂型是，例如，粒剂、粉剂、包衣片剂、片剂、(微)胶囊、栓剂、糖浆剂、汁剂、悬浮剂、乳剂、滴剂、注射液及活性化合物缓释的制剂，在所述制剂中使用普通的助剂，例如，赋形剂、崩解剂、粘结剂、包衣剂、溶胀剂、脱模剂或润滑剂、香料、增甜剂和增溶剂。可能提到的常用助剂是碳酸镁、二氧化钛、乳糖、甘露糖醇以及其它糖类、滑石、乳蛋白质、明胶、淀粉、纤维素及其衍生物、动物油和植物油，例如，鱼肝油、葵花籽油、花生油或芝麻油、聚乙二醇和溶剂，例如，灭菌水和一元醇或多元醇如甘油。
药物制剂优选以剂量单位进行制备和给药，作为活性组分，每个单位含有本发明式Ⅰ化合物的特定剂量。在固体剂量单位如片剂、胶囊、包衣片剂或栓剂中该剂量高达大约1000毫克，但优选大约50-300毫克，在针剂注射液中该剂量高达大约300毫克，但优选大约10-100毫克。
根据式Ⅰ化合物的效力，为体重大约70千克的成年病人进行治疗，建议日剂量为大约20-1000毫克，优选大约100-500毫克。然而，在某些情况下，较高或较低的日剂量也是适合的。日剂量可以以单独的剂量单位形式或几个较小的剂量单位形式进行一次性给药也可以在特定的时间间隔以分开的剂量进行多次给药。
在室温下(RT)按惯例使用四甲硅烷(TMS)为内标物，在200MHz瓦里安公司(Varian)的仪器上记录1H-NMR谱。在各种情况下标明所用溶剂。按惯例，用质谱法(FAB-，ESI-MS)测定最终产物。温度数值是指摄氏温度，RT指室温(22-26℃)。所用缩写或已进行解释或是与常规用法相一致。
    实施例1：N-(苯氧基苯磺酰基)高丝氨酸(根据方法a制备)
在冰冷却下10g(54．9mmol)D，L-高丝氨酸内酯用50ml 1N NaOH和50ml四氢呋喃(THF)处理。在5℃和搅拌下滴加16．0g(59．5mmol)苯氧基苯磺酰氯在50ml THF中的溶液。加入一半后反应混合物用7．1g(54．9mmol)二异丙基乙基胺处理。在搅拌一夜后混合物用2NHCl调至PH=5．5，用乙酸乙酯萃取几次。过滤合并的有机相，用硫酸钠干燥后，过滤并在减压下蒸发。从冰乙酸／石油醚中重结晶，得到上述化合物。
产量：18．3g(理论量的73％)    熔点：134℃
1H-NMR(DMSO-d6)：1．6-1．85(m，2H)；3．2-3．45(m，3H)；3．75-3．95(m，1H)；7．0-8．1(m，9H)
    实施例2：(2R)-1-(4-氯联苯磺酰基)-4-cis-羟脯氨酸(根据方法a制备)
将2g(15．2mmol)D-cis-羟脯氨酸溶于无水乙腈中，与12．1ml(46．7mmol，3．1当量)BSTFA(双-三甲基甲硅烷基三氟乙酰胺)一起在回流下加热2小时。然后，混合物用4．4g(15．2mmol)4-氯联苯磺酰氯在15ml乙腈中的溶液处理，在回流下放置4小时，生成O-甲硅烷基化的-N-磺化的化合物的稠的白色沉淀。在悬浮液冷却和完全沉淀后，分离沉淀物，在减压下干燥，反应产量是定量的。
为了进行二甲硅烷基化，将100mg O-甲硅烷基化的化合物溶于10ml甲醇(MeOH)中，加入100mg KF，与10ml 1NHCl一起在室温下搅拌2小时。用抽吸滤器过滤沉淀物，在减压下干燥，得到上述产物。
产量：61mg(是理论量的84％)
1H-NMR(DMSO-d6)：1．8-2．2(m，2H)；3．15(m，1H)；3．3(dd，2H)；4．0(m，1H)；4．3(dd，1H)；7．6；7．8(2d，4H)；7．9(s，4H)
实施例29：(R)-N-(4-氯联苯磺酰基)色氨酸(根据方法b制备)
29a)(R)-N-(4-氯联苯磺酰基)色氨酸甲酯
将5．1g(20mmol)D-色氨酸甲酯盐酸盐悬浮于50ml无水乙腈中，用2．0g(20mmol)三乙胺处理，在室温下搅拌。在加入6．2ml(24mmol)BSTFA后，混合物在80℃搅拌2小时，然后滴加5．75g(20mmol)4-氯联苯磺酰氯在50ml乙腈中的溶液和2．0g TEA，混合物在80℃保持2小时。冷却至室温后，在搅拌下向反应混合物中加入100ml 1NHCl，沉淀出结晶的沉淀。从甲醇／水中重结晶，得到上述甲酯。
产量：6．8g(是理论量的92％)  熔点：189℃
29b)(R)-N-(4-氯联苯磺酰基)色氨酸
将2．34g(5mmol)上述甲酯溶于30ml甲醇中，在加入10ml 1N NaOH后，在40℃搅拌6小时。用1NHCl调节溶液的PH至6，得到上述的结晶的羧酸。
产量：1．8g(理论量的81％)  熔点：138°-140℃
1H-NMR(DMSO-d6)：2．8-2．92(m，1H)，3．0-3．12(m，1H)，3．83-3．97(m，1H)，6．85-7．8(m，13H)，8．3(d，1H)，10．75(s，1H)，12．4(s，1H)
下面表1中记述的实施例的化合物用与实施例1，2和29类似的方法制备。
表1
Figure 9811526500291
Figure 9811526500308
Figure 98115265003194
Figure 98115265003295
Figure 98115265003611
Figure 98115265003712
Figure 981152650038101
Figure 981152650040103
Figure 981152650041104
Figure 98115265004213
Figure 981152650043106
Figure 981152650047110
Figure 981152650048111
药物实施例
人体Stromelysin和嗜中性白细胞胶原酶的制备及其催化结构域的酶催化活性的测定。
根据Ye等人的方法制备Stromelysin(MMP-3)和嗜中性白细胞胶原酶(MMP-8)两种酶(生物化学(Biochemistry)；31(1992)，11231-11235页)。为测定酶活性或酶抑制剂作用，将70μl缓冲溶液和10μl酶溶液与任选含有酶抑制剂的10μl浓度10％(V／V)二甲基亚砜水溶液一起恒温15分钟。在加入含有1mmol／l基质的10μl浓度10％(V／V)二甲基亚砜水溶液之后，用荧光光谱(328nm(ex)／393nm(em))监测酶反应。
酶活性以消光增加值／分表示。测定以抑制剂浓度表示的表2中所列的IC50值，在各种情况下该抑制剂浓度导致50％酶抑制。
缓冲溶液含有0．05％ Brij(Sigma，Deisenhofen，德国)和0．1mol／ltris／HCl，0．1mol／l NaCl，0．01mol／l CaCl2和0．1mol／l哌嗪-N，N’-二[2-乙磺酸](PH=6．5)。
酶溶液含有5μg／ml根据Ye等人的方法制备的一种酶结构域。基质溶液含有1mmol／L荧光基质(7-甲氧基香豆素-4-基)乙酰基-Pro-Leu-Gly-Leu-3-(2’，4’-二硝基苯基)-L-2，3-二氨基丙酰基-Ala-Arg-NH2(Bachem，Heidelberg，德国)。
表2
  实施例号   Stromelysin IC50(M)   嗜中性白细胞胶原酶IC50(M)
    1     4*10-7     1*10-8
    2     1*10-7     9*10-8
    3     2*10-5     2*10-7
    6     2*10-7     2*10-8
    7     2*10-7     4*10-8
    8     3*10-7     1*10-8
    9     3*10-7     2*10-8
    10     9*10-8     1*10-8
    11     9*10-8     3*10-9
    15     1*10-7     1*10-8
    16     7*10-8     7*10-9
    17     1*10-7     2*10-8
    19     5*10-7     5*10-8
    20     4*10-7     2*10-8
    23     1*10-6     6*10-7
    25     2*10-7     4*10-8
    26     4*10-7     4*10-8
    27     2*10-7     1*10-8
    28     3*10-7     6*10-8
    29     8*10-8     9*10-9
    31     1*10-6     5*10-8
    32     2*10-7     4*10-8
    34     2*10-7     2*10-8
    35     1*10-7     1*10-8
    36     2*10-7     1*10-8
    40     7*10-8     2*10-9
    41     2*10-7     3*10-8
    42     4*10-7     3*10-8
    44     9*10-8     1*10-8
    51     5*10-8     5*10-9
    55     8*10-7     4*10-8
    56     3*10-8     5*10-9
    58     4*10-8     6*10-9
    60     6*10-7     2*10-8
    61     4*10-7     2*10-8
    62     7*10-9     2*10-9
    63     3*10-6     6*10-7
    65     1*10-7     3*10-9
    66     2*10-8     2*10-9
    67     1*10-6     2*10-7
    68     4*10-7     1*10-7
    69     1*10-8     4*10-9
    70     1*10-7     3*10-9
    71     1*10-8     2*10-9
    72     6*10-7     2*10-8
    73     3*10-7     2*10-8
    74     1*10-7     1*10-8
    75     3*10-7     2*10-8
    76     5*10-9     3*10-9
    77     4*10-9     4*10-9
    78     2*10-8     2*10-9
    79     2*10-8     4*10-9
    80     7*10-9     2*10-9
    81     1*10-8     2*10-9
    82     1*10-7     1*10-8
    83     1*10-6     2*10-8
    84     5*10-6     2*10-9
    85     3*10-6     3*10-8
    86     3*10-7     1*10-8
    87     3*10-8     5*10-9
    88     1*10-7     7*10-9
    89     3*10-7     2*10-8
    90     1*10-8     2*10-9
    91     3*10-7     1*10-8
    92     3*10-8     4*10-9
    93     2*10-7     2*10-8
    94     2*10-7     3*10-8
    95     3*10-7     2*10-8
    96     6*10-7     2*10-8
    97     1*10-6     3*10-8
    98     4*1 0-7     3*10-8
    99     7*10-7     5*10-8
    100     5*10-7     2*10-8
    101     4*10-8     4*10-9
    104     4*10-8     5*10-9
    105     3*10-8     1*10-8
    107     4*10-8     1*10-8

Claims (9)

1、式Ⅰ的化合物和／或其立体异构体和／或其生理上可容许的盐，
Figure 981152650002130
式中：
R1是1．苯基，
    2．被下列基团一或二取代的苯基：
      2．1．直链，支链或环状的(C1-C6)烷基，
      2．2．羟基，
      2．3．(C1-C6)烷基-C(O)-O-，
      2．4．(C1-C6)烷基-O-，
      2．5．(C1-C6)烷基-O-(C1-C4)烷基-O-，
      2．6．卤素，
      2．7．-CF3，
      2．8．-CN，
      2．9．-NO2，
      2．10．HO-C(O)-，
      2．11．(C1-C6)烷基-O-C(O)-，
      2．12．亚甲基二氧代，
      2．13．R4-(R5)N-C(O)-，
      2．14．R4-(R5)N-，或
    3．选自3．1-3．15的杂芳基，其未取代或被2．1-2．14描述的基团取代：
      3．1．吡咯，
      3．2．吡唑，
      3．3．咪唑，
      3．4．三唑，
      3．5．噻吩，
      3．6．噻唑，
      3．7．噁唑，
      3．8．异噁唑，
      3．9．吡啶，
      3．10．嘧啶，
      3．11．吲哚，
      3．12．苯并噻吩，
      3．13．苯并咪唑，
      3．14．苯并噁唑，或
      3．15．苯并噻唑，
R2，R4和R5相同或不同，是
1．氢原子，
2．(C1-C6)烷基，
3．HO-C(O)-(C1-C6)烷基，
4．苯基-(CH2)n-，其中苯基未取代或被2．1-2．14描述的基团一或二取代，或被-NH-C(O)-(C1-C3)烷基取代，n是整数0，1或2，或
5．吡啶甲基，或
6．R4和R5与环上氨基一起形成4-7元环，其中一个碳原子任选被-O-、-S-或-NH-替换，或4-7元环的两个相邻的碳原子是苄基的一部分，
R3是1．氢原子，
    2．(C1-C10)烷基，其中烷基未取代和／或烷基的一个氢原子被-OH替代，
    3．直链或支链(C2-C10)链烯基，
    4．R2-O-(C1-C6)烷基，
    5．R2-S(O)n-(C1-C6)烷基，其中n具有上述含义，
    6．R2-S(O)(=NH)-(C1-C6)-烷基，
    7．
Figure 981152650004131
    其中n是整数0，1或2，W是氮、氧或硫原子，
8．苯基-(CH2)-m，其中m是整数0，1，2，3，4，5或6和／或-(CH2)m链的一个氢原子被-OH替代和苯基未取代或被下列基团一或二取代：
8．1  2．1-2．14描述的基团，
8．2-O-(CH2)m-苯基，其中苯基未取代或被2．1-2．14描述的基团一或二取代，m是整数0，1，2，3，4，5或6，
8．3-C(O)-(CH2)m-苯基，其中苯基同8．2定义，
9．杂芳基-(CH2)m-，其中杂芳基同3．1-3．15定义，m同上述定义和／或-(CH2)m-链的一个氢原子被-OH替代和杂芳基未取代或被下列基团一或二取代：
9．1  2．1-2．14描述的基团，
9．2  -CH(O)，
9．3  -SO2-苯基，其中苯基未取代或同8．2或8．3的定义，
9．4  -O-(CH2)m-苯基，
10．-(CH2)m-P(O)(OH)-(C1-C3)烷基，其中m同上述定义，或
11．R6-C(O)-(C1-C6)烷基，其中
R6是1．氢原子
    2．(C1-C6)烷基，
    3．苯基，其未取代或被2．1-2．14描述的基团取代，
    4．杂芳基，其同3．1-3．15定义和／或被2．1-2．14描述的基团取代或被-(C1-C4)烷基-COOH取代，
    5．HO-，
    6．R2O-，其中R2具有上述定义，
    7．R4-(R5)N-，其中R4和R5同上述定义，
    8．杂芳基-(CH2)m-NH-，其中杂芳基同3．1-3．15定义和／或被2．1-2．14描述的基团取代，m同上述定义，或被-(C1-C4)烷基-COOH取代，
    9．R4-(R5)N-NH-，其中R4和R5同上述定义，或
    10．HO-C(O)-CH(R3)-NH-，其中R3同上述定义，或
R2和R3一起形成亚式(Ⅱ)的具有环上羧基的环，
Figure 981152650005132
其中r是整数0，1，2或3和／或环中的一个碳原子被-O-、-S-或-(R7)N-替换，其中：
R7是1．氢原子，
    2．(C1-C6)烷基，
    3．苯基，其未取代或被2．1-2．14描述的基团取代，
    4．苄基，其未取代或被2．1-2．14描述的基团取代，或
    5．R2N-C(=NH)-，其中R2具有上述含义，和／或亚式Ⅱ环中的碳原子被(C1-C6)烷基、苯基、苯基-(CH2)m-或HO-一或多取代，
A是a)共价键
    b)-O-，
    c)-CH=CH-或
    d)-C≡C-，
B是a)-(CH2)m-，其中m具有上述含义，
    b)-O-(CH2)p，其中p是整数1-5，或
    c)-CH=CH-和
X是-CH=CH-，氧原子或硫原子。
2、根据权利要求1要求保护的式Ⅰ的化合物，其中：
R1是1．苯基，或
    2．被下列基团一取代的苯基：
      2．1．(C1-C6)烷基，其中烷基是直链，支链或环状，
      2．2．-OH，
      2．3．(C1-C6)烷基-C(O)-O-，
      2．4．(C1-C6)烷基-O-，
      2．5．(C1-C6)烷基-O-(C1-C4)烷基-O-，
      2．6．卤素，
      2．7．-CF3，或
      2．8．R4-(R5)N-，
R2，R4和R5相同或不同，是
1．氢原子，或
2．(C1-C6)烷基，
R3是1．(C1-C10)烷基，其中烷基是直链，支链或环状的，和／或烷基的一个氢原子被-OH替代，
2．R2-S(O)n-(C1-C6)烷基，其中R2是(C1-C6)烷基或苯基-(CH2)n-，n是整数0或1，
3．苯基-(CH2)m-，其中苯基未取代或被2．1-2．14描述的基团一或二取代和／或-(CH2)m-链的一个氢原子被-OH替代，m是整数1，2，3，4或5，
4．杂芳基-(CH2)m-，其中杂芳基具有3．3，3．5，3．6，3．9或3．11描述的含义和／或被2．1-2．14描述的基团取代和／或-(CH2)m-链的一个氢原子被-OH替代，m是整数1，2，3或4，
5．R6-C(O)-(C1-C6)烷基，其中：
R6是1．-OH
    2．R2O-，其中R2同上述定义，
    3．R4-(R5)N-，其中R4和R5同上述定义，或
    4．R4和R5与环上氨基一起形成5-6元环，其中一个碳原子任选被-O-，-S-或-NH-替换，或5-6元环的两个相邻的碳原子是苄基的一部分，
6．R2和R3一起形成亚式Ⅱ的含有环上羧基的环，其中n是整数1或2和／或环中的一个碳原子被-O-或-(R7)N-替换，和
R7是1．氢原子，
    2．(C1-C6)烷基，
    3．苯基，其未取代或被2．1-2．14描述的基团取代，
    4．苄基，其未取代或被2．1-2．14描述的基团取代，或
    5．R2N-C(=NH)-，其中R2同上述定义，
和／或亚式Ⅱ的环中的碳原子被苯基或-OH单取代，
A是a)共价键，或
    b)-O-，
B是a)-(CH2)m-，其中m是整数0，1或2，或
    b)-O-(CH2)p，其中p是整数1或2，和
X是-CH=CH-。
3、根据权利要求1要求保护的式Ⅰ的化合物，其中：
R1是1．苯基，或
    2．被下列基团一取代的苯基：
    2．1．卤素，特别是氯或氟，或
    2．2．R4-(R5)N-，其中R4和R5相同或不同，是
    2．2．1．(C1-C3)烷基，或
    2．2．2．R4和R5与环上氨基一起形成5-6元环，其中一个碳原子任选被-O-或-N-替换，
R2是氢原子，
R3是1．杂芳基-(CH2)m-，其中杂芳基同3．5，3．11或3．13定义，其未取代或被2．1-2．14描述的基团单取代，m是整数1或2，或
2．R6-C(O)-(C2-C3)烷基，其中：
R6是1．-OH，
    2．R2-O-，其中R2同上述定义，或
    3．R4-(R5)N-，其中R4和R5相同或不同，是
    3．1．氢原子，
    3．2．(C1-C3)烷基，
    3．3．苯基-(CH2)-，其中苯基未取代或被2．1-2．14描述的基团单取代或双取代，n是整数0，1或2，
    3．4．R4和R5与环上氨基一起形成5-6元环，其中一个碳原子任选被-O-或-NH-替换，或形成二氢吲哚基，或
    3．5．HO-C(O)-CH(R3)-NH-，其中R3同上述定义，
A是共价键，
B是-(CH2)O-，其中O是0，和
X是-CH=CH-。
4、式Ⅵ的化合物和／或其立体异构体和／或其生理上可容许的盐，
Figure 981152650008133
式中R1、A、X、B、R2、R3和R8具有权利要求1中要求保护的式Ⅰ的化合物中说明的含义。
5、制备权利要求1-4中一项或多项中要求保护的式Ⅰ的化合物的方法，包括：
a)在碱或任选脱水剂存在下，式Ⅲ的氨基羧酸式中R2和R3同式Ⅰ中定义，与式Ⅳ的磺酸衍生物反应，
Figure 981152650008135
式中R1、A和B同式Ⅰ中定义，Y是卤原子、咪唑基或-OR8，其中R8是氢原子、(C1-C6)烷基、苯基或苄基，任选被取代，得到式Ⅰ化合物；或
b)在上述条件下，式Ⅴ的氨基羧酸酯式中R2、R3和R8具有上述含义，与式Ⅳ的磺酸衍生物反应，得到式Ⅵ的化合物，和优选在碱或酸存在下除去R8将式Ⅵ的化合物转化为式Ⅰ的化合物；或
C)式Ⅶ的化合物
Figure 981152650009142
式中n是整数0、1或2，与保护基E反应，得到式Ⅷ的化合物，
Figure 981152650009143
在上述条件下用式Ⅳ的磺酸衍生物将式Ⅷ的化合物转化为式Ⅸ的化合物，
Figure 981152650009144
然后用合适的解离试剂除去保护基E和R8基，将式Ⅸ的化合物转化为式Ⅰ的化合物；
d)将按照方法a)、b)和c)制备的、基于其化学结构以对映体形式出现的式Ⅰ化合物拆解为纯的对映体，拆解方法包括使其与对映异构纯的酸或碱形成盐，用手性固定相进行色谱分离，或用手性对映异构纯的化合物如氨基酸形成衍生物，分离得到的非对映体，除去手性辅助基团；或
e)分离由方法a)、b)、c)或d)制备的游离形式的式Ⅰ化合物，或者在存在酸或碱性基团的情况下将式Ⅰ的游离形式的化合物转化成生理上可容许的盐。
6、药物，包括有效量的至少一种权利要求1-4中一项和多项要求保护的式Ⅰ的化合物和药物学上合适的和生理上可容许的赋形剂、添加剂和／或其他活性化合物和助剂。
7、权利要求1-4中一项或多项要求保护的至少一种式Ⅰ的化合物用于制备预防和治疗在其过程中与基质降解金属蛋白酶活性提高有关的疾病的药物用途。
8、根据权利要求7要求保护的用途，用于治疗退行性关节疾病，例如骨关节病、脊椎病、关节损伤后的或半月板或髌骨损伤后相当长时间的固定之后的软骨溶解或韧带撕裂，结缔组织疾病，例如胶原病、牙周疾病、创伤愈合疾病和运动器官的慢性疾病，例如与发炎、免疫或代谢有关的急性和慢性关节炎、关节病、肌痛和骨代谢疾病，溃疡、动脉粥样硬化和狭窄，还用于治疗炎症、癌症、肿瘤转移形成、恶质病、厌食和败血性休克。
9、制备药物的方法，包括用药物学上适用的和生理上可容许的赋形剂，和适当时候用其他合适的活性化合物、添加剂或助剂，将至少一种权利要求1-4中一项或多项要求保护的式Ⅰ的化合物配制成合适的给药剂型。
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