CN1359900A - 新的金属蛋白酶抑制剂、其制备方法及含有其的药物组合物 - Google Patents
新的金属蛋白酶抑制剂、其制备方法及含有其的药物组合物 Download PDFInfo
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- CN1359900A CN1359900A CN01133859A CN01133859A CN1359900A CN 1359900 A CN1359900 A CN 1359900A CN 01133859 A CN01133859 A CN 01133859A CN 01133859 A CN01133859 A CN 01133859A CN 1359900 A CN1359900 A CN 1359900A
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
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Abstract
式(I)的化合物,其中:R1代表氢原子、卤原子、烷基或烷氧基,X代表氧原子、硫原子或NR基团,其中R代表氢原子或烷基,A代表说明书中所述的任一基团,它们的异构体,以及它们与药学上可接受的酸或碱的加成盐。药物。
Description
本发明涉及一种新的金属蛋白酶抑制剂,制备方法及含有其的药物组合物。
在生理学状态下,结缔组织的合成与细胞外基质的降解处于动态平衡。这种降解是由已有基质细胞分泌的锌蛋白酶(金属蛋白酶)引起的:不意味着任何限定,它们是胶原酶(MMP-1,MMP-8,MMP-13)、明胶酶或IV型胶原酶(MMP-2,MMP-9)和溶基质素(MMP-3)。
在正常状态下,由天然抑制剂,如与金属蛋白酶形成非活性配合物的α2-巨球蛋白或TIMPs(金属蛋白酶的组织抑制剂)调节这些分解代谢酶的合成和分泌,以及其细胞外酶活性。
病理学上常见的病因是其所涉及的酶在活化酶的活性和其天然抑制剂之间失衡,其结果是过度的组织降解。
由金属蛋白酶催化的细胞外基质的再吸收而引起的失控的和加速的膜降解是许多病的常见特征,如风湿性关节炎、关节病、肿瘤发病和生长,包括恶性扩散和肿瘤转移的形成、溃疡、动脉粥样硬化等等。
BB94,一种金属蛋白酶抑制剂,目前在临床应用中已表现出抗肿瘤活性,它被证实具有对卵巢癌的活性(Becket等人,DDT 19961(1),16)。
因此可以预期金属蛋白酶抑制剂将恢复蛋白酶和抑制剂之间的平衡,并因此利于改善这种病理的发展。
文献中已描述了某些金属蛋白酶抑制剂,更为具体而言,需要指出的是在以下专利说明书中所述的化合物:WO 95/35275、WO95/35276、EP 606 046、WO 96/00214、EP 803 505、WO 97/20824和EP 780 386。
本发明的化合物不仅是新的,而且已证明是比文献中所述的化合物更为有效的金属蛋白酶抑制剂,因而使其有可能应用于癌、风湿病如关节病和风湿性关节炎、动脉粥样硬化等的治疗。
其中:
R1代表氢原子、卤原子、直链或支链(C1-C6)烷基或直链或支链(C1-C6)烷氧基,
X代表氧原子、硫原子或NR基,其中R代表氢原子或者直链或支链(C1-C6)烷基,
其中,
其中Ra代表氢原子、卤原子、直链或支链(C1-C6)-烷基或直链或支链(C1-C6)烷氧基,
其中Rb和Rc,可以相同或不同,代表氢原子或直链或支链(C1-C6)烷基,而n为0、1或2,
它们的异构体、N-氧化物和其与药学上可接受的酸或碱的加成盐。
在这些药学上可接受的酸中,非限定性的举例有:盐酸、氢溴酸、硫酸、膦酸、磷酸、乙酸、三氟乙酸、乳酸、丙酮酸、丙二酸、琥珀酸、戊二酸、富马酸、酒石酸、马来酸、柠檬酸、抗坏血酸、草酸、甲烷磺酸、樟脑酸等等。
在这些药学上可接受的碱中,非限定性的举例有氢氧化钠、氢氧化钾、氢氧化锂、三乙胺、叔丁胺等等。
本发明优选的化合物为式(I)的化合物,其中X代表氧原子。
R1优选为氢原子。
时,该基团优选为基团:
本发明优选的化合物为:
-N-羟基-(5R)-6-{[2-(4-吡啶基)-1-苯并呋喃-5-基]磺酰基}-4,5,6,7-四氢-呋喃并[2,3-c]吡啶-5-甲酰胺,
-N-羟基-(3S)-2,2-二甲基-4-{[2-(4-吡啶基)-1-苯并呋喃-5-基]磺酰基}-3-硫代吗啉甲酰胺,
-N-羟基-4-{{[2-(4-吡啶基)-1-苯并呋喃-5-基]磺酰基}甲基}四氢-2H-吡喃-4-甲酰胺,
及其加成盐。
本发明还涉及制备式(I)的化合物的方法。
其中R1和X如式(I)所定义,而Hal代表卤原子,该化合物可以与以外消旋形式或特定异构体形式的化合物(IIIa)和(IIIb)之任一反应,
其中Rb、Rc和n如式(I)所定义,
其中,X、R1、Rb、Rc和n如式(I)所定义,
其中,X、R1、Rb、Rc和n如式(I)所定义,
使它们接受O-取代的羟基胺的作用,并在去保护异羟肟酸酯官能团后分别得到式(I/a)和(I/b)的化合物:
其中,X、R1、Rb、Rc和n如式(I)所定义,
式(I/a)和(I/b)的化合物:
-可任选地被转化为相应的N-氧化物,
-如果需要的话,根据常规的纯化技术将其纯化,
-如果合适的话,根据常规分离技术将其分离为它的异构体,
-如果需要的话,将其转化成其药学上可接受的酸或碱的加成盐。
其中Alk代表直链或支链(C1-C6)烷基,在酸水解后得到式(VIII)的化合物:
其中R1和X如式(I)所定义,
其中X和R1如式(I)所定义,
使该化合物接受O-取代的羟基胺的作用,并在去保护异羟肟酸酯官能团后得到式(I/c)的化合物,式(I)的化合物的特例:
其中R1和X如式(I)所定义,
可任选地将该化合物转化为对应的N-氧化物,
如果需要的话,根据常规的纯化技术将其纯化,
如果合适的话,根据常规分离技术将其分离为它的异构体,
如果需要的话,将其转化成其药学上可接受的酸或碱的加成盐。
其中Hal代表卤原子,而X如式(I)所定义,
其中Hal和X如上文定义,
其中R1为如式(I)定义,
得到式(VI)的化合物:
其中Hal、X和R1如上文定义,
然后在二氧化硫和正丁基锂的存在下将其转化为式(XIII)的化合物;
其中R1和X如上文定义,
其中Hal、X和R1如上文定义。
本发明还涉及包括与一或多种惰性、无毒的药学上可接受的赋形剂或载体组合的作为活性成分的至少一种式(I)的化合物的药物组合物。在本发明的药物组合物中,具体可提及的是适于口服、肠道外(静脉内或皮下)或鼻给药的片剂或糖衣丸、舌下片、明胶胶囊、锭剂、栓剂、乳膏、皮肤凝胶、注射剂、饮用悬浮物等等。
可以根据疾病的性质和严重性、给药途径和患者的年龄及重量来调节所用剂量。剂量范围为每天0.01-2g,一次或多次给药。
以下实施例例举本发明,但不是以任何方式对其限定。
所用的起始物质是已知的产品或根据已知的方法制备。
该制备产生用于制备本发明化合物的合成中间产物。
根据常规的分光光度技术(红外、NMR、质谱等)测定实施例和制备中所述的这些化合物的结构。
制备A:
4-(硫基甲基)四氢-2H-吡喃-4-羧酸乙酯
步骤A:4-[(乙酰基硫基)甲基]四氢-2H-吡喃-4-羧酸乙酯
氮气下将47g三苯基膦溶于350ml四氢呋喃(THF)。冷却至0℃,然后将34.9ml偶氮二羧酸二异丙酯(DIAD)加到该溶液。搅拌30分钟后,加入在300ml的THF中的含有89mmol 4-(羟基甲基)四氢-2H-吡喃-4-甲酸乙酯和12.8ml硫代乙酸的溶液。
室温下搅拌过夜并蒸发至干后,将残留物置于醚中。过滤后,蒸发滤液,得到期望的油状产物,在二氧化硅柱上,采用二氯甲烷/乙酸乙酯(90/10)的混合物作为洗脱剂进行色谱层析纯化。
步骤B:4-(硫基甲基)四氢-2H-吡喃-4-甲酸乙酯
将在乙醇中的92ml 2.2N盐酸溶液加到溶于50ml乙醇的67.4mmol的以上步骤得到的化合物。
搅拌过夜,然后将其全部蒸发至干得到期望的油状产物。
制备B:5-溴-2-(4-吡啶基)苯并呋喃
步骤A:(5-溴-2-羟基苄基)三苯基磷鎓溴化物
将169g溴化三苯膦加到悬浮在500ml的乙腈中的490mmol4-溴-2-(羟基甲基)酚。将其全部加热到100℃ 2小时。冷却后,滤去形成的沉淀并干燥得到期望的产物。
熔点:260℃
步骤B:5-溴-2-(4-吡啶基)苯并呋喃
在90.1g的异烟酰氯的存在下将6ml三乙胺加到在2升甲苯中的243g的前一步骤得到的产物。在100℃下将其全部加热24小时。冷却后,滤去形成的沉淀,并在乙酸乙酯中重结晶后得到期望产物。
熔点:160℃
制备C:2-(4-吡啶基)-1-苯并呋喃-磺酰氯
步骤A:{[2-(4-吡啶基)4-苯并呋喃-5-基]磺酰基}锂
-72℃下将正丁基锂为加到悬浮在四氢呋喃中的60.2mmol在制备B中得到的化合物。72℃下经90分钟后,使SO2气流经过该混合物1小时。室温下两天后,滤去已形成的固体并用醚洗涤得到期望的产物。
步骤B:2-(4-吡啶基)-1-苯并呋喃-5-磺酰氯
将59mmol在前一步骤中得到的产物悬浮在80ml的二氯甲烷。冷却至0℃后,滴加5.7ml磺酰氯。室温下过夜后,去已形成的沉淀并用醚洗涤得到期望的产物。
熔点:210℃
实施例1:N-羟基-(5R)-6-{[2-(4-吡啶基-1-苯并呋喃-5-基]磺酰基}-4,5,6,7-四氢呋喃并[2,3-c]吡啶-5-羧酰胺-盐酸盐
步骤A:(5R)-6-{2-(4-吡啶基)-1-苯并呋喃-5-基]磺酰基}-4,5,6,7-四氢呋喃并[2,3-c]吡啶-5-甲酸四丁基酯
将30mmol(5R)-4,5,6,7-四氢呋喃[2,3-c]吡啶-5-甲酸四丁基酯置于150ml吡啶。然后室温下加入30mmol在制备C中所述的2-(4-吡啶基)-1-苯并呋喃-5-磺酰氯。60℃下将其全部加热过夜。
蒸发除去吡啶,然后将残留物置于二氯甲烷,用水洗涤,干燥并蒸发,得到油状的期望产物,在二氧化硅上采用二氯甲烷/乙醇(98/2)的混合物作为洗脱剂进行色谱层析纯化。
步骤B:(5R)-6-{(2-(4-吡啶基)4-(苯并呋喃-5-基]磺酰基-4,5,6,7-四氢呋喃并[2,3-c]吡啶-5-甲酸
将2.4ml茴香醚加到在250ml二氯甲烷中的22mmol在前一步骤中得到的酯。将其全部冷却至0℃并加入17ml三氟乙酸。室温下其全部保持。蒸发至干后,在二氧化硅上采用二氯甲烷/甲醇(85/15)的混合物作为洗脱剂进行色谱层析纯化得到期望产物。
步骤C:N-烯丙氧基-(5R)-6{[2-4-吡啶基)-1-苯并呋喃-5-基]磺酰基}-4,5,6,7-四氢呋喃并[2.3-c]吡啶-5-甲酰胺
往冷却至0℃,含有在150ml二氯甲烷中的12mmol在前一步骤中得到的酸的溶液中加入10.3ml二异丙基乙胺、1.65g 1-羟基苯并三唑、含有在50ml甲酰胺中的1.6g的O-烯丙基羟基胺盐酸盐的溶液、和4.65g的O-苯并三唑基-四甲基异尿鎓四氟硼酸盐(TBTU)。室温下将其全体保持过夜。蒸发至干,将残留物置于二氯甲烷。用水洗涤后,干燥并蒸发,得到残留物,在二氧化硅柱上采用二氯甲烷/乙醇/氨(98/2/0.2)的混合物作为洗脱剂进行纯化后得到期望产物。
步骤D:N-羟基-(5R)-6-{[2-(4-吡啶基)-1-苯并呋喃-5-基]磺酰基}-4,5,6,7-四氢呋喃并[2,3-c]-吡啶-5-甲酰胺盐酸盐
将300mg的Pd催化剂(PPh3)2Cl2和1.5ml乙酸加到在150ml二氯甲烷中的8.55mmol在前一步骤中得到的产物,5分钟后,加入4.9ml氢三丁基锡。室温下将其全部保持30小时,然后蒸发。将残留物置于乙腈中,加入20ml 1N盐酸。用水稀释全部。用醚洗涤含水相,然后冻干得到期望的产物。
元素微量分析:
C% H% N% Cl% S%计算 53.00 3.81 8.83 7.45 6.74实测 52.94 3.81 8.70 7.30 6.65
实施例2:N-羟基-(3S)-2,2-二甲基4-{[2-(4-吡啶基)-1-苯并呋喃-5-基]磺酰基}-3-硫代吗啉甲酰胺
步骤A:4-{[2-4-(氨基苯基)4-苯并呋喃-5-基磺酰基}-2.2-二甲基-3-硫代吗啉甲酸叔丁基(二甲基)甲硅烷基酯
将58.7mmol 2,2-二甲基-3-硫吗啉甲酸四丁基(二甲基)甲硅烷基酯溶于500ml无水二氯甲烷。-20℃下,加入16ml的N-甲基吗啉,然后加入57.5mmol在制备C中所述的2-(4-吡啶基)-1-苯并呋喃-5-磺酰氯。室温下将其全部搅拌48小时,然后倾入300ml的水中。倾泻后,用水洗涤,干燥并蒸发,得到期望的油状产物。
步骤B:4-{[2-(4-氨基苯基)-1-苯并呋喃-5-基}-2,2-二甲基-3-硫代吗啉基甲酸
将33g在前一步骤中得到的化合物溶于400ml无水甲醇。将其全部回流2小时,然后蒸发。从醚中重结晶残留物得到期望的产物。
步骤C:N-(烯丙氧基)-4-{[2-(4-氨基苯基)-1-苯并呋喃-5-基]磺酰基}-2,2-二甲基-3-硫代吗啉甲酰胺
根据在实施例1的步骤C中所述方法,从前一步步骤所述的产物开始得到期望的产物。
步骤D:N-羟基-(35)-2,2-二甲基-4-{[2-(4-吡啶基)4-苯并呋喃-5-基]-磺酰基}-3-硫代吗啉甲酰胺
将10.2mmol在前一步骤中所述的化合的溶于70ml二氯甲烷,加入360mg Pd催化剂(PPh3)2Cl2和1.75ml乙酸,5分钟后加入5.8ml氢化三丁基锡。搅拌20分钟,然后加入70的醚。滤去不溶物并用醚洗涤,将其置于乙腈/水(50/50)的混合物中,冻干后得到期望产物。
元素微量分析:
C% H% N% S%计算 53.68 4.73 9.39 14.33实测 53.38 4.81 9.08 13.91
实施例3:N-羟基-4-{{[2-(4-吡啶基)-1-苯并呋喃-5-基]磺酰基}-甲基}-四氢-2H-吡喃-4-甲酰胺
步骤A:4{{[2-(4-吡啶基)-1-苯并呋喃-5-基]硫基}甲基}四氢-2H-吡喃-4-甲酸乙酯
将23.9mmol在制备B中所述的5-溴-2-(4-吡啶基)苯并呋喃、7.32g在制备A中所述的化合物、431mg三-(二亚苄基丙酮)二钯和1.05g的1,1’-双(二苯基)膦二茂铁置于75ml的N-甲基-吡咯烷酮。将其全体加热到100℃,持续48小时。蒸发,然后将残留物置于乙酸乙酯中并蒸发,在二氧化硅柱上采用二氯甲烷/乙酸乙酯(9/1)混合物作为洗脱剂将残留物色谱法纯化。然后结晶出期望的产物。
熔点:92℃
步骤B:4-{{[2-(4-吡啶基)4-苯并呋喃-5-基]硫基}甲基}四氢-2H-吡喃-4-甲酸
将7.5g在前一步骤中得以的酯置于200ml的6N盐酸。将其全体回流过夜。冷却后,加入氢氧化钠将溶液的PH调节至7。滤去形成的沉淀,并用水洗涤得到期望的产物。
熔点:227℃
步骤C:4-{{[2-(4-吡啶基)-1-苯并呋喃-5-基]磺酰基}甲基}四氢-2H-吡喃-4-甲酸
将18mmol在前一步骤中得到的化合物置于116ml水和140ml乙腈中。在冰浴上将其全体冷却并分部分加入17.65g。室温下旋转混合48小时。蒸发后,将PH调节至7并沉淀期望产物。
熔点:217℃
步骤D:4-{{[2-(4-吡啶基)-1-苯并呋喃-5-基]磺酰基}甲基}-N-(烯丙氧基)-四氢-2H-吡喃-4-甲酰胺
根据实施例1的步骤C中所述的方法,从前一步骤所述的化合物开始得到期望的产物。
步骤E:N-羟基4-{{[2-(4-吡啶基)-1-苯并呋喃-5-基]磺酰基}甲基}四氢-2H-吡喃-4-甲酰胺
根据实施例1的步骤D中所述的方法,从前一步骤所述的化合物开始得到期望的产物。
元素微量分析:
C% H% N% S%计算 57.68 4.84 6.73 7.70实测 57.71 4.90 6.19 7.23
实施例4:N-羟基-(3S)-2,2-二甲基-4-{[2-(4-吡啶基)-1-苯并呋喃-5-基]磺酰基}-3-硫代吗啉甲酰胺1-氧化物
根据实施例2的步骤A中所述的方法,用2,2-二甲基-3-硫吗啉甲酸1-氧化物代替2,2-二甲基-3-硫代吗啉甲酸而得到期望的产物。
实施例5:N-羟基-(3S)-2,2-二甲基-4-{[2-(4-吡啶基)-1-苯并呋喃-5-基]磺酰基}-3-硫代吗啉甲酰胺1,1-二氧化物
根据实施例2的步骤A中所述的方法,用2,2-二甲基-3-硫吗啉甲酸1,1-二氧化物代替2,2-二甲基-3-硫代吗啉甲酸而得到期望的产物。
实施例6:N-羟基-(3S)-2,2-二甲基-4-{[2-(4-吡啶基氧化物(4-pyridyl oxide))-1-苯并呋喃-5-基]磺酰基}-3-硫代吗啉甲酰胺
通过氧化实施例2中所述的化合物得到期望产物。
本发明化合物的药理学研究
实施例A:金属蛋白酶的酶抑制作用
用APMA(4-氨基苯基汞乙酸盐)活化六种人类重组酶,MMP-1(间质胶原酶)、MMP-2(明胶酶A)、MMP-3(溶基质素1)、MMP-8(嗜中性胶原酶)、MMP-9(明胶酶B)和MMP-13(胶原酶3)。采用以下肽模拟底物进行MMP-1、-2、-8、-9和-13的酶试验:
DnpProGhaGlyCys(Me)HisAlaLys(Nma)NH2,
在甘氨酸和半胱氨酸之间将其裂解得到D.M.BICKETT等人(分析生物化学(Anal.Biochem.),212,58-64,1993)所述的荧光产物。
采用以下肽模拟底物进行MMP-3的酶试验:
McaArgproLysProTyrAlaNvaTrpMetLys(Dnp)NH2,
在丙氨酸和正缬氨酸之间将其裂解得到H.NAGASE等人(生化杂志(J.Biol.Chem.),269,20952-20957,1994)所述的荧光产物。
在pH为7.7的50mM Tris、200mM NaCl、5mM CaCl2、0.1%Brij 35的缓冲液中进行的反应初始采用37℃下总体积为100μl的20μM反应物。
在同时配备用于激发和发射的360μm和460μm滤波器的荧光计的96孔平板上读取6小时后得到的荧光。
本发明化合物中除了MMP-1以外所有的MMP的IC50值为10-10-10-8M。胶原酶MMP-13和MMP-8与胶原酶MMP-1相比表现出1000倍的特异性。
实施例B:软骨基质的体外降解
在由IL-1β诱发的软骨基质损坏模型中研究本发明化合物。该试验在兔软骨上进行,涉及:
-一方面,胶原的降解:由与IL-1β(10ng/ml)和胞质素(0.1U/ml)接触2天后的组织释放的OH-脯氨酸片断的比色试验,根据Grant(GRANT R.A. Estimation of OH-proline by theautoanalyser,J.Clin.Path.,17,685,1964)技术;
-另一方面,蛋白聚糖的降解:在与APMA(5×104M)接触的24小时期间用35SO4预标记的组织,在用IL-1β(10ng/ml)刺激的24小时后释放出的葡萄糖氨基聚糖片断的放射性同位素测定。
在测试的3天将本发明的化合物加到培养基上对其进行研究。对于10-9-10-6M的浓度,它们有力地抑制胶原和蛋白聚糖的降解。
实施例C:体外血管生成
根据Nicosia和Ottinetti(Lab.Invest.,63,115,1990)的方法,将8-12周龄的雌性Fischer 344大鼠的胸主动脉的部分浸泡在I型胶原凝胶中。在无血清的培养基中培养5天后,在显微镜下检查制品并在数字化和成像分析之后对假性血管形成进行血管密度定量。
10-9-10-6M浓度的本发明的化合物选择性地阻断内皮细胞的假性血管形成,同时不影响成纤维细胞
实施例D:药物组合物
制备1000片每片含100mg活性成分的片剂的配方:实施例1的化合物---------------------------------100g羟丙基纤维素--------------------------------------2g小麦淀粉-----------------------------------------10g乳糖--------------------------------------------100g硬脂酸镁------------------------------------------3g滑石----------------------------------------------3g
Claims (12)
6.根据权利要求1或2的式(I)的化合物,其为N-羟基-(5R)-6-{[2-(4-吡啶基)-1-苯并呋喃-5-基]磺酰基}-4,5,6,7-四氢[2,3-c]-吡啶-5-甲酰胺,其异构体,和其与药学上可接受的酸或碱的加成盐。
7.根据权利要求1、3或5的式(I)的化合物,其为N-羟基-(3S)-2,2-二甲基-4-{[2-(4-吡啶基)-1-苯并呋喃-5-基]磺酰基}-3-硫代吗啉-甲酰胺,其异构体,和其与药学上可接受的酸或碱的加成盐。
8.根据权利要求1或4的式(I)的化合物,其为N-羟基-4-{{[2-(4-吡啶基)-1-苯并呋喃-5-基]磺酰基}甲基}四氢-2H-吡喃-4-甲酰胺,其异构体,和其与药学上可接受的酸或碱的加成盐。
9.根据权利要求1的式(I)的化合物的制备方法,其特征在于,当式(I)的化合物中的A代表以下任一基团时:和
其中R1和X如式(I)所定义,而Hal代表卤原子,该化合物可以与以外消旋形式或特定异构体形式的化合物(IIIa)和(IIIb)之任一反应,
其中Rb、Rc和n如式(I)所定义,
其中,X、R1、Rb、Rc和n如式(I)所定义,
其中,X、R1、Rb、Rc和n如式(I)所定义,
其中,X、R1、Rb、Rc和n如式(I)所定义,
式(I/a)和(I/b)的化合物:
-可任选地被转化为相应的N-氧化物,
-如果需要的话,根据常规的纯化技术将其纯化,
-如果合适的话,根据常规分离技术将其分离为它的异构体,
-如果需要的话,将其转化成其药学上可接受的酸或碱的加成盐。
该方法的其特征在于存在一个用作起始物质的式(VI)的化合物:
其中R1和X如式(I)所定义,
其中X和R1如式(I)所定义,
其中R1和X如式(I)所定义,
可任选地将该化合物转化为相应的N-氧化物,
如果需要的话,根据常规的纯化技术将其纯化,
如果合适的话,根据常规分离技术将其分离为它的异构体,
如果需要的话,将其转化成其药学上可接受的酸或碱的加成盐。
11.包括单独的或与一或多种惰性、无毒的药学上可接受的赋形剂或载体组合的作为活性成分的至少一种根据权利要求1-8之任一的化合物的药物组合物。
12.根据权利要求11的药物组合物,包括至少一种根据权利要求1-8之任一的活性成分,用作金属蛋白酶抑制剂。
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DE102005002500A1 (de) * | 2005-01-19 | 2006-07-27 | Sanofi-Aventis Deutschland Gmbh | Tetrahydrofuranderivate als Inhibitoren von Matrix-Metalloproteinasen |
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US8761860B2 (en) | 2009-10-14 | 2014-06-24 | Nocimed, Llc | MR spectroscopy system and method for diagnosing painful and non-painful intervertebral discs |
US8825131B2 (en) | 2009-10-14 | 2014-09-02 | Nocimed, Llc | MR spectroscopy system and method for diagnosing painful and non-painful intervertebral discs |
US9280718B2 (en) | 2010-11-24 | 2016-03-08 | Nocimed, Llc | Systems and methods for automated voxelation of regions of interest for magnetic resonance spectroscopy |
US8965094B2 (en) | 2012-04-14 | 2015-02-24 | Nocimed, Llc | Magnetic resonance spectroscopy pulse sequence, acquisition, and processing system and method |
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