Tryptase inhibitor and novel guanidino derivatives

Details Tryptase inhibitor and novel guanidino derivatives Tryptase inhibitor and novel guanidino derivatives

1998-10-07

2002-05-14

Richter, Johann (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acid esters

C560S012000, C560S016000, C560S035000, C560S039000, C560S042000, C560S043000, C560S055000, C514S255010, C514S330000, C514S423000, C514S533000, C514S534000, C514S535000, C514S634000, C514S646000, C544S391000, C546S226000, C548S540000

Reexamination Certificate

active

06388122

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a tryptase inhibitor comprising, as an active ingredient, one or more kinds of substances selected from guanidinoaliphatic acid derivatives, guanidinobenzoic acid derivatives, guanidinophenol derivatives, amidinophenol derivatives, and nontoxic salts, acid addition salts or hydrates thereof, and to novel guanidinophenol derivatives and nontoxic salt, acid addition salt or hydrate thereof. More specifically, the present invention relates to a tryptase inhibitor comprising, as an active ingredient, one or more kinds of substances selected from guanidinoaliphatic acid derivatives, guanidinobenzoic acid derivatives, guanidinophenol derivatives and amidinophenol derivatives represented by the formulae (I) to (IV)
(in the formulae, all the symbols represent the same meanings as hereafter defined), or nontoxic salts, acid addition salts or hydrates thereof, and to pharmaceuticals comprising, as an active ingredient, novel guanidinophenol derivatives represented by the formula (V)
(in the formulae, all the symbols represent the same meanings as hereafter defined), or nontoxic salts, acid addition salts or hydrates thereof.
BACKGROUND ART
Tryptase is an intracellular trypsin-type protease that was isolated and purified from the human lung by Smith, et al. in 1984 (see T. J. Smith, M. W. Houglandi D. A. Johnson, J. Biol. Chem., 25, 11046 (1984)).
Tryptase is thought to belong to the trypsin-type protease since (1) tryptase cleaves the C-terminal of basic amino acids (especially arginine) as well as trypsin, (2) it decomposes common trypsin artificial substrates, and (3) its protease activity is inhibited by the trypsin inhibitors.
Tryptase is, however, categorized into a family having different properties from trypsin on the basis that (1) tryptase cannot decompose Arg-MCA (arginine-methylcoumarinamide) and Arg-bNA (arginine-&bgr;-naphthylamide) which are artificial substrates highly decomposed by trypsin, (2) it highly decomposes Boc-Ile-Gly-Arg-MCA(t-butoxycarbonyl-isoleucine-glycine-arginine-methylcoumarinamide) which is an artificial substrate of blood coagulation factor Xa that is hard to be decomposed by trypsin, and (3) it limitedly decomposes prothrombin to produce thrombin while trypsin nonlimitedly decomposes most prothrombin. Additionally, tryptase is completely different from the other protease (e.g., plasmin, thrombin, kallikrein, elastase. etc.) in the structure, localizing cells, physiological functions and so on.
Tryptase is known as it exists in the following cells, and however, the structure thereof varies depending upon the localizing cell.
(1) Tryptase in Mast Cell (Tryptase M)
Tryptase M localizes in the soluble state in the typical (connective tissue) mast cell, atypical (membrane) mast cell and the histamine granules of basocytes. Human tryptase M was isolated and purified by Schwartz, et al. (see L. B. Schwartz, R. A. Lewis, K. F. Ansten, J. Biol. Chem., 25, 11939 (1981)). This enzyme is a heterotetramer having a molecular weight of 144,000 composed of two molecules of subunit having a molecular weight of 37,000 and two having that of 35,000.
(2) Tryptase in T
4
Lymphocyte (Tryptases TL
1
, TL
2
and TL
3
)
Tryptases TL
1
, TL2 and TL
3
were isolated and purified from the bulk-cultured cells of the Molt 4 clone 8 strain, which is one of the T
4
lymphocytes, by Kido, Katunuma, et al. (see H. Kido, A. Fukutomi, N. Katunuma, J. Biol. Chem., 2, 21979 (1991)). Tryptases TL
1
and TL
2
were purified from the cell membrane, and Tryptase TL
3
was purified from the Golgi body.
(3) Tryptase in Clara Cells (Tryptase Clara)
Tryptase Clara was isolated and purified from the bronchial membrane secretory cell (Clara cell) by Kido, Katsunuma, et al. (see H. Kido, Y. Yokogoshi, K. Sakai, M. Tashiro, Y. Kishino, A. Fukutomi, N. Katunuma, J. Biol. Chem., 267, 13573 (1992)). The molecular weight of this enzyme is 30,000 by means of SDS-PAGE (SDS-polyacrylamide gel electrophoresis) in the presence of a reducing agent, or 180,000 by gel filtration.
The physiological functions of the above-mentioned tryptase have been reported as follows:
(1) decomposition of fibrinogen (see J. Immunol., 135, 2762 (1985)),
(2) decomposition of polymer kininogen and fibrin (see J. Immunol., 135, 2762 (1985)),
(3) activation of single-stranded urokinase type plasminogen activator (see J. Biol. Chem., 269, 9416 (1994)),
(4) formation of complement C3a from C3 (see J. Immunol., 130, 1891 (1983)),
(5) decomposition of VIP (vaso active intestinal peptide) and CGRP (calcitonin gene-related peptide) (see Allergy, 27, 90 (1990), J. Pharmacol. Exp. Ther., 244, 133 (1988), and J. Pharmac. and Exp. Ther., 248, 947 (1989)),
(6) release of IL-8 from the bronchial epithelial cell and stimulation to express ICAM-1 (see J. Immunol., 15, 275 (1996)),
(7) decomposition of fibronectin (see J. Cell. Biochem., 50, 337 (1992)).
(8) stimulation to proliferate fibroblast (see J. Crin. Invest., 88, 493 (1991)),
(9) decomposition of collagen IV,
(10) activation of promatrix metalloprotease 3 (proMMP-3) (J. Crin. Invest., 84, 1657 (1989)),
(11) activation of stromelysin, and
(12) decomposition of 72 kD gelatomase.
Studies on the relation of tryptase to condition of disorder have been reported as follows.
(1) Tryptase at high level exists in the washing water of the bronchus of asthma patients.
(2) The tryptase released from the mast cell in the site of pulmonary fibrosis induces inflammation reaction mediated by various mediators.
(3) The tryptase released from the mast cell in the site of chronic rheumatism enhances collagenase activity.
(4) The tryptase in the process of infection of Sendai virus elevates the ability of membrane fusion and infection of the virus.
Tryptase inhibitors are thought to be useful for prevention and/or treatment of various diseases caused by tryptase. In consideration of the relation between the physiological function of tryptase and condition of disorder, the diseases are exemplified by asthma, pulmonary fibrosis, interstitial pneumonitis, nephritis, hepatic fibrosis, hepatitis, cirrhosis, scleroderma, psoriasis, atopic dermatitis, chronic rheumatism, influenza, Crohn's disease, inflammatory intestinal diseases, ulcerative colitis, nasal allergy, atherosclerosis, etc.
Recently, some studies on the tryptase inhibitors of nonpeptide compounds having an amidino or guanidino group have been reported (see J. Stuerzebecher, et. al., Biol. Chem. Hoppe-Seyler, 37, 1025 (1992), G. H. Caughey, et. al., J. Pharmacol. Exp. Ther. 2, 676 (1993), C. H. Kam, et al., Arch. Biochem. Biophys., 316, 808 (1995), U.S. Pat. No. 4,845,242, U.S. Pat. No. 5,089,634, U.S. Pat. No. 5,324,648, and PCT Publication No. 9,427,958).
Disclosure of the Invention
In order to find tryptase inhibitors from the points of view above, the present inventors intensively studied to find that guanidinoaliphatic acid derivatives represented by the formula (I), guanidinobenzoic acid derivatives represented by the formula (II), guanidinophenol derivatives represented by the formula (III) and amidinophenol derivatives represented by the formula (IV) have potent tryptase inhibitory activity. Thus, the present invention is completed.
Further, it was found that novel guanidinophenol derivatives represented by the formula (V) have potent tryptase inhibitory activity.
Moreover, it was found that the novel guanidinophenol derivatives represented by the formula (V) have potent antagonistic inhibitory activity on a variety of proteinases (e.g., trypsin, plasmin, thrombin and kallikrein), phospholipase A
2
(PLA
2
) and/or leukotriene B
4
(LTB
4
).
That is, the present invention relates to
(1) a tryptase inhibitor comprising, as an active ingredient, guanidinoaliphatic acid derivatives represented by the formula (I)
 (in the formula, R
1
represents a hydrogen atom, a halogen atom, a nitro group, an alkyl group, an alkoxyl group, a carboxyl group or an alkoxycarbonyl group, and n represents an integer of 3 to 6), or nontoxic salts, acid addition salts or hydrates thereof;
(2) a tryptase in

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