申请人:Ono Pharmaceutical Co., Ltd.
公开号:US06403644B1
公开(公告)日:2002-06-11
The present invention is related to:
(i) matrix metalloproteinase inhibitors containing sulfonylamino acid derivatives of the formula (Ia);
wherein R1 is hydrogen, C1-4 alkyl; R2 is hydrogen, C1-8 alkyl etc.; E is —CONR3—, in which R3 is hydrogen, C1-4 alkyl etc., —NR3CO—, —CO—O—, —O—CO— etc.; A is hydrogen, C1-8 alkyl, C3-7 cycloalkyl, or Ar; J is bond, C2-4 alkylene etc.; G is —
(CH2)m—, in which m is 2, 3 or 4, or
in which R6 and R7 is hydrogen, C1-8 alkyl etc.; and non-toxic salts thereof,
(ii) sulfonylamino acid derivatives of the formula (Ib):
wherein all the symbols are the same meaning as (i); and non-toxic salts thereof, and
(iii) process for the preparation of the compound of the formula (Ib).
The compounds of the formula (Ia) are useful for prevention and/or treatment of diseases induced by overexpression and excess activity of MMP. The diseases such as above, for example, are rheumatoid, arthrosteitis, unusual bone resorption, osteoporosis, periodontitis, interstitial nephritis, arteriosclerosis, pulmonary emphysema, cirrhosis, cornea injury, metastasis of, invasion of or growth of tumor cell, autoimmune disease (Crohn's disease, Sjogren's syndrome etc.), disease caused by vascular emigration or infiltration of leukocytes, arterialization.
本发明涉及以下内容:(i)含有式(Ia)的磺酰氨基酸衍生物的基质金属蛋白酶抑制剂;其中R1为氢、C1-4烷基;R2为氢、C1-8烷基等;E为—CONR3—,其中R3为氢、C1-4烷基等,—NR3CO—,—CO—O—,—O—CO—等;A为氢、C1-8烷基、C3-7环烷基或Ar;J为键、C2-4烷基等;G为—(CH2)m—,其中m为2、3或4,或其中R6和R7为氢、C1-8烷基等;以及其非毒性盐,(ii)式(Ib)的磺酰氨基酸衍生物:其中所有符号的含义与(i)相同;以及其非毒性盐,(iii)制备式(Ib)化合物的方法。式(Ia)的化合物对于预防和/或治疗由MMP过度表达和过度活性引起的疾病非常有用。例如,上述疾病包括类风湿性关节炎、关节炎、异常骨吸收、骨质疏松、牙周炎、间质性肾炎、动脉硬化、肺气肿、肝硬化、角膜损伤、肿瘤细胞的转移、侵袭或生长、自身免疫性疾病(Crohn病、Sjogren综合症等)、由白细胞的血管外渗或浸润引起的疾病、动脉化等。