Organic compounds -- part of the class 532-570 series – Organic compounds – Chalcogen in the nitrogen containing substituent
Patent
1991-11-27
1993-04-20
Shah, Mukund J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Chalcogen in the nitrogen containing substituent
548568, 530331, 530332, C07D26512, C07D20708, C07D20746, C07D 502
Patent
active
052044629
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a novel 4H-3,1-benzoxazin-4-one derivative and, more particularly, to 4H-3,1-benzoxazin-4-one derivatives having a serine protease inhibiting effect.
BACKGROUND ART
Proteases (proteolytic enzymes) present in a living body play a role in the decomposition of extrinsic foreign materials such as bacteria and in removal of decay products of cells. On the other hand, when secretion of proteases, especially serine proteases, is excessively accelerated, degradation and deterioration of tissues are induced in a body. It is, therefore assumed that, in the steady state, proteases maintain a good balance with various intrinsic protease inhibiting substances to maintain homeostasis in a living body. Serine proteases provide a serine residue at their active center for proteolytic activity, and include elastase, chymotrypsin, trypsin, and many other enzymes of individual systems in blood. Particularly, elastase sustains an effect of degrading elastin that exists in and functions to maintain the elasticity of connective tissues such as that of lung, cartilage, tendon, walls of blood vessels, or the skin of higher animals. For example, negative effects have been observed such as pancreatic dysfunction in vivo with pancreatic elastase and other elastases.
Recently, the etiological relation between elastase released from neutrophiles (LE) and the degradation of the extracellular matrix and tissues in inflammatory regions has become clarified. Accordingly, an LE inhibitor is a promising agent for preventing and curing various diseases such as pneumonia, pulmonary emphysema, lung fibrosis, bronchitis, arthritis, pancreatitis, nephritis, shock, sepsis, and arteriosclerosis caused by excessive degradation and deterioration of tissue occurring when LE is excessively produced.
Several compounds have already been reported as serine protease inhibitors such as LE inhibitors. For example, various types of derivatives of a 4H-3,1-benzoxazin-4-one compound are described or disclosed in "Journal of the Biological Chemistry", Vol. 257, pp. 5,085 to 5,091 (1982), "Biochemistry", Vol. 23, pp. 1,753 to 1,759 (1984), "Biochemical and Biophysical Research Communications", Vol. 140, pp. 928 to 933 (1986), Published Unexamined Japanese Patent Application Nos. 60-169469 and 62-30770, and Republication WO 9790/88.
DISCLOSURE OF INVENTION
It is an object of the present invention to provide novel 4H-3,1-benzoxazin-4-one derivatives having a serine protease inhibiting effect and intermediate compounds useful in the manufacture of the same.
The present inventors have conducted extensive studies on various types of derivatives of a 4H-3,1-benzoxazin-4-one compound and found that novel 4H-3,1-benzoxazin-4-one derivatives having a proline residue-containing substituent at its 2-position have an excellent effect in inhibiting serine protease, particularly, elastase, thereby establishing the present invention.
That is, the novel 4H-3,1-benzoxazin-4-one derivatives of the present invention are compounds represented by formula (I) below: ##STR2## wherein R.sup.1 represents a lower alkyl group, R.sup.2 represents a lower alkyl group, a lower alkylthioalkyl group, or a lower alkanesulfinylalkyl group, R.sup.3 represents a hydrogen atom, a hydroxyl group, a lower alkoxy group, or a lower acyloxy group, X represents an amino acid residue selected from the group consisting of alanine, valine, and phenylalanine, n represents an integer of 0, 1, or 2, and Y represents a substituent selected from the group consisting of an alkanoyl group having 2 to 6 carbon atoms which may be substituted by a phenyl group, a benzyloxycarbonyl group, a lower alkoxycarbonyl group, a cinnamoyl group, and a methoxysuccinyl group.
Intermediate compounds of the present invention are compounds represented by formula (F) below: ##STR3## wherein R.sup.1 represents a lower alkyl group, R.sup.2 represents a lower alkyl group, a lower alkylthioalkyl group, or a lower alkanesulfinylalkyl group, R.sup.3 represents a hydrogen atom, a hydro
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Kobayashi Koji
Ozawa Koichi
Sasabuchi Masashi
Uchida Itsuo
Grumbling Matthew V.
Japan Tobacco Inc.
Shah Mukund J.
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