WO2001070696A1 - Nitroethenamine derivatives or salts thereof and pharmaceutical compositions containing the derivatives or the salts - Google Patents

Abstract

Nitroethenamine derivatives of the general formula (I) or salts thereof; and pharmaceutical compositions containing the derivatives or the salts as the active ingredient, wherein R1 is an optionally substituted heterocyclic group; and R2 is substituted alkyl.

Description

 TECHNICAL FIELD The present invention relates to a tJ derivative or a salt thereof, and a pharmaceutical composition containing the same.

 The present invention relates to a novel ditrothetenamine derivative or its salt having matrix meta-oral proteinase inhibitory activity, and a pharmaceutical composition containing them.

Background art

The connective tissue of higher organisms is composed of an extracellular matrix. The extracellular matrix maintains the homeostasis of biological functions while repeatedly forming and decomposing (reconstructing) according to the function and morphology of the target tissue. Matrix meta-oral proteinase (MMP) is a major enzyme involved in the degradation of extracellular matrix, and is characterized by having a divalent zinc ion in the active center. To date, about 20 types of MMPs, including secreted and membrane-bound forms, have been identified, and the physiological functions and biodistribution of each molecule are being elucidated. MMPs in normal organisms act where fetal development and wound healing require tissue reconstitution. But force ^s et al, to prevent the extracellular Matrix is destroyed unnecessarily, and strict control mechanism (expression control or feedback control) force s function. That is, MMP is normally secreted as an inactive form by an external stimulus, and then is converted into an active form by various proteases. On the other hand, the degradation activity of MMP is controlled by its intrinsic inhibitor TI-MP (ti ssue inhibitor of metal loproteinase). However, once the regulatory mechanism becomes abnormal and MMPs become excessive, various tissue lesions are induced. For example, (1) MMP-9 (gelatinase B / 92kDa type IV collagenase), which has a strong degrading activity on type IV collagen, a major component of the basement membrane, is usually used in epithelial cells in normal human tissues. Almost no expression was observed. On the other hand, overexpression has been observed in many epithelial cancer cells, including breast cancer and lung cancer, and blood cancer cells. (2) In colorectal cancer, a positive correlation was observed between the expression level of MMP-9 and metastatic potential [M. Nakajima et al., Journal of Natal Cancer Instite, Vol. 82 , 1890, (1990)] o③ Cancer cells that express high levels of MMP-9 or MMP-2 (gelatinase A medium 72 kDa type IV collagenase) have higher metastatic or invasive ability than low-expressing cells. It has also been shown experimentally for various cancer cells to be enhanced [(DR Welch, Proceedings or the National Academy of sciences of the United States of America, Vol. 87, 7687, (1990), S. Yamagata Biochemical and Biophysical Research Communication, Vol. 151, 186-162, (1988)] ₀ ④ MMP-13 (collagenase 3) is not expressed in normal tissues but is highly expressed in breast cancer cells [ JM Freije, M Nakajima et al., Journal of Biological Chemistry, Vol. 269, 16766-76773, (1994)].

 As described above, metastatic cancer cells with high malignancy have abnormal motility, adhesiveness, and tissue invasiveness in addition to the abnormal proliferative properties inherent in tumorigenic cells. The overproduction of MMPs is involved.

 In addition, ① MMP is involved in pseudo-lumen formation of cultured vascular endothelial cells [R. ontesano et al., Cell, Vol. 42, 469-477, (1985)]. ② MMP is one of angiogenic factors. Acts to promote tumor growth [T. Itoh et al., Cancer Research, Vol. 58, 1048-1051, (1998)], [3] Melanoma cells overexpressing TIMP-2 have a tissue-wetting ability, It is already known that the ability to induce neogenesis is reduced [P. Valente et al., International Journal of Cancer, Vol 75, 246-253 (1998)].

 On the other hand, inflammatory cytokines are induced at the joint site for some reason, and MMP-1 (stromal collagenase) and MMP-3 (stromlysin 1) are excessively produced from synovial cells, and are produced in the synovial fluid. When stored in large quantities, it acts on the articular cartilage to destroy the cartilage matrix, causing so-called arthritis-like diseases represented by symptoms such as pain, reduced range of motion, and deformation.

 Furthermore, in coronary artery disease, MMPs promote smooth muscle cell migration from the vascular wall to the intima and promote the formation of atherosclerotic plaques. It is also known to be involved in restenosis after angioplasty in the treatment of angina [D.C. Celentano et al., Journal of Clinical Pharmacology, Vol. 37, 991-1000, (1997)].

In addition, increased production of MMP-1 (interstitial collagenase) is observed in gingivitis. Thus, MMPs are responsible for a wide range of physiological actions in living organisms, and their overproduction disrupts the homeostasis of the organism, leading to the induction of new diseases or worsening of the disease state. Therefore, MMP enzyme inhibitors are used in the treatment or prevention of cancer and inflammatory diseases, angiogenesis inhibitors, anticancer agents, cancer invasion inhibitors, cancer metastasis inhibitors; rheumatoid arthritis, osteoarthritis and rheumatoid arthritis Treatment and prevention of arthritis such as gingivitis, glomerulonephritis, interstitial nephritis, encephalomyelitis, arteriosclerosis, cirrhosis, vascular restenosis, restenosis, diabetic retinopathy, neovascular glaucoma, corneal ulcer, Treatment of various diseases such as epidermolysis bullosa, intervertebral disc herniation, osteoporosis and other 4 bone diseases, multiple sclerosis, bronchial asthma, Alzheimer's dementia, autoimmune diseases (Crohn's disease, Siggren's disease, etc.). Deemed useful.

 Many compounds having an MMP inhibitory action have been reported in the past [RA Nigel et al., Current Opinion on iherapeutic Patents, Vol. 4, 7-16, (1994), RP Beckett et al., Drug Discovery Today 1, 16-26, (1996)], but many of them are peptide derivatives designed based on the amino acid sequence of the enzyme cleavage site in the collagen molecule that serves as the substrate for MMP. Examples include hydroxamic acid type compounds; thiol type compounds; carboxylic acid type compounds; phosphonate type compounds; and phosphinate type compounds. Of these, some compounds, mainly hydroxamic acid derivatives, are undergoing clinical trials for diseases such as cancer and arthritis.

Generally, MMP enzyme inhibitors having a peptide as a basic skeleton have low oral absorbability, and especially hydroxamic acid type MMP enzyme inhibitors have poor plasma stability, and carboxylic acid type It is known that MMP enzyme inhibitors have high binding to plasma proteins and are not easily excreted. To overcome these problems, attempts have been made to create new non-peptide compounds [A. Katrm et al., Journal of Medicinal Chemistry, Vol. 41, 2194-2200, (1998)]. . Recently, MMP inhibitors containing a flavone or anthocyanidin as an active ingredient described in JP-A-8-104628, condensed thiophene derivative-based MMP inhibitors described in JP-A-10-130271, etc. It has been known. However, non-peptide systems such as the present invention A pharmaceutical composition comprising a nitroethenamine derivative or a salt thereof as an active ingredient has MMP enzyme inhibitory activity, in particular, it is potent against MMP-9 (gelatinase B / 92 kDa type IV collagenase). It is not known to have selective enzyme inhibitory activity.

 Compounds similar to the nitretheneamine derivatives of the present invention have been used as analgesics (W097 / 17954). However, the compounds of the present invention are not known. Furthermore, Japanese Patent Publication No. 58-404956 describes a compound similar to the ditrothetenamine derivative, which is the active ingredient of the pharmaceutical composition of the present invention, as an intermediate of the active ingredient compound of the pharmaceutical composition. And the above-mentioned nitroethenamine derivatives. Furthermore, there is no description in the publication that this substance has an MMP enzyme inhibitory action.

 The present inventors have conducted intensive studies on the synthesis of compounds having MMP enzyme inhibitory activity and on their pharmacological activities. As a result, the inventors have found that non-MMP-9 has a potent and selective enzyme inhibitory activity for MMP-9. The ditrothetenamine derivative of the present invention or a salt thereof has been found as a peptide-based compound.

Disclosure of the invention

 That is, the present invention provides a compound represented by the formula (I):

HR ¹

 N-N

0 ₂ N (H) C = QH

N—R ²

 H

[Wherein, R ¹ is an optionally substituted heterocyclic group; R ² is a substituted alkyl group] or a salt thereof, and a pharmaceutical composition containing the same.

The salt of the ditrothetenamine derivative represented by the formula (I) may be a pharmaceutically acceptable salt, and includes, for example, mineral salts such as hydrochloride, sulfate, and nitrate; P-toluenesulfonate, Organic acid salts such as propanesulfonic acid salt and methanesulfonic acid salt; alkaline metal salts such as potassium salt and sodium salt; alkaline earth metal salts such as calcium salt; triethanolamine salt; Droxymethyl) Aminomethane Organic amine salts such as salts are exemplified. Some of these salts have water of crystallization.

In the formula (I), the heterocyclic moiety of the optionally substituted heterocyclic group represented by R ¹ includes a pyrrolyl group, a pyrrolinyl group, a pyrrolidinyl group, a furanyl group, a dihydrofuranyl group, a tetrahydrofuranyl group, a phenyl group Group, dihydrophenyl, tetrahydrophenyl, pyrazolyl, pyrazolidinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolinyl, oxazolidinyl, isoxazolyl, isoxazolyl Group, isooxazolizinyl group, thiazolyl group, thiazolinyl group, thiazolidinyl group; urea group, isothiazolyl group, isothiazolinyl group, isothiazolidinyl group, oxaziazolyl group, oxaziazolinyl group, oxaziazolidinyl group, Thiaziazolyl group, Diazolidinyl, thiadiazolidinyl, triazolyl, triazolidinyl, triazolidinyl, tetrazolyl, tetrazolinyl, tetrazolidinyl, dioxolyl, dioxolanyl, dithiolyl, dithiolanyl, pyridyl, dihydro Pyridyl group, tetrahydropyridyl group, piperidinyl group, pyrimidyl group, dihydropyrimidyl group, tetrahydropyrimidyl group, hexahydropyrimidyl group, pyridazinyl group, dihydropyridazinyl group, tetrahydropyridazinyl group, hexahydropyridazinyl Group, pyrazinyl group, dihydrovirazinyl group, tetrahydrovirazinyl group, piperazinyl group, vilanil group, dihydroviranyl group, tetrahydrovinylil group, dioxinyl group, dioxenyl group, Monocyclic heterocyclic groups such as sanyl, dithianyl, and morpholinyl; thienothienyl, dihydrocyclopentaphenyl, indolyl, tetrahydroindolyl, isoindolyl, tetrahydroisoindolyl, benzoceyl Nyl group, tetrahydrobenzozozenyl group, benzofuranyl group, tetrahydrobenzozofuranyl group, benzoxazolyl group, tetrahydrobenzozoxazolyl group, benzisoxazolyl group, tetrahydrobenzozoisoxazolyl group, benzothiazolyl group, Tetrahydrobenzothiazolyl group, benzoisothiazolyl group, tetrahydrobenzoisothiazolyl group, benzoimidazolyl group, tetrahydrobenzoimidazolyl group, benzodiamine Condensed polycyclic heterocyclic groups such as xolyl, benzodithiolyl, benzodioxanyl, benzodithianyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl; And a crosslinked polycyclic heterocyclic group such as a quinuclidinyl group. Among them, furanyl group, tetrahydrofuranyl group, chenyl group, imidazolyl group, dioxolanyl group, pyridyl group, piperidinyl group, vilazinyl group, piperazinyl group, tetrahydrovinylanyl group, dioxanyl group, morphonyl group, benzothiazolyl group or quinolinyl Groups are preferred.

The alkyl moiety of the substituted alkyl groups represented by R ^2, generally those having 1-18 carbon atoms, such as methyl group, Echiru group, propyl group, butyl group, a pentyl group, a carboxy group, Okuchiru group, nonyl group Decyl group, nonadecyl group and the like, which include those having linear or branched aliphatic chains with structural isomerism.

Examples of the substituent of the optionally substituted heterocyclic group represented by R ¹ include a substitutable alkyl group, a substitutable alkenyl group, a substitutable alkynyl group, a substitutable cycloalkyl group, a substitutable cycloalkenyl group, Substituted aryl group, substituted heterocyclic group, substituted alkoxy group, substituted alkenyloxy group, substituted alkynyloxy group, substituted cycloalkoxy group, substituted cycloalkenyloxy group, substituted aryloxy group, Substituted heterocyclic oxy group, substituted alkylthio group, substituted alkenylthio group, substituted alkynylthio group, substituted cycloalkylthio group, substituted cycloalkenylthio group, substituted arylaryl thio group, substituted heterocyclic thio group, Substitutable alkylcarbonyl group, Substitutable alkenylcarbonyl group, Substitutable alkynylcarbonyl group, Substitutable cycle Alkylcarbonyl group, substitutable cycloalkenylcarbonyl group, substitutable arylcarbonyl group, substitutable heterocyclic carbonyl group, substitutable alkoxycarbonyl group, substitutable alkenyloxycarbonyl group, substitutable alkynyloxycarbonyl group, substitutable Cycloalkyloxycarbonyl group, substituted cycloalkenyloxycarbonyl group, substituted aryloxycarbonyl group, substituted heterocyclicoxycarbonyl group, substituted alkylcarbonyloxy group, substituted alkenylcarbonyloxy group , A substitutable alkynylcarbonyloxy group, a substitutable cycloalkylcarbonyloxy Group, substituted cycloalkenylcarbonyl group, substituted arylcarbonyl group, substituted heterocyclylcarbonyl group, substituted alkylsulfonyl group, substituted alkenylsulfonyl group, substituted alkynylsulfonyl group, substituted Cycloalkylsulfonyl group, Cycloalkenylsulfonyl group, Awarsulfonyl group, Heterocyclic sulfonyl group, Alkoxysulfonyl group, Alkenyloxysulfonyl group, Alkynyloxysulfonyl group Group, substituted cycloalkyloxysulfonyl group, substituted cycloalkenyloxysulfonyl group, substituted arylalkylsulfonyl group, substituted heterocyclic oxysulfonyl group, substituted alkylsulfonyloxy group, substituted alkenyl Sulfonyloxy group, Substitutable alkynylsulfonyl group, substitutable cycloalkylsulfonyloxy group, substitutable cycloalkenylsulfonyloxy group, substitutable arylsulfonyloxy group, substitutable heterocyclic sulfonyloxy group, substitutable amino group, substitutable Examples thereof include an aminocarbonyl group, a substituted hydroxyaminocarbonyl group, a halogen atom, a cyano group, a nitro group, a hydroxyl group, a thiol group, a carboxyl group, and a sulfonic acid group. Among them, a substitutable alkyl group, a substitutable alkoxy group, a substitutable alkenyloxy group or a halogen atom is preferable. Even if the number of those substituents is one

It may be two or more, and when the number of substituents is two or more, they may be the same or different.

Examples of the substituent of the substituted alkyl group represented by R ² include a substitutable alkenyl group, a substitutable alkynyl group, a substitutable cycloalkyl group, a substitutable cycloalkenyl group, a substitutable aryl group, a substitutable heterocyclic group, and a substitutable heterocyclic group. Substitutable alkenyloxy, substitutable alkynyloxy, substitutable cycloalkoxy, substitutable cycloalkenyl, substitutable aryloxy, substitutable heterocyclic oxy, substitutable alkylthio, substitutable Alkenylthio group, substituted alkynylthio group, substituted cycloalkylthio group, substituted cycloalkenylthio group, substituted arylarylthio group, substituted heterocyclic thio group, substituted alkylcarbonyl group, substituted alkenylcarbonyl group, Alkynylcarbonyl group, cycloalkylcarbonyl group, Roaruke two Rukarupo group, a substitutable § reel carbonyl group, a substitutable heterocyclic force Rubo Nyl group, substituted alkoxycarbonyl group, substituted alkenyloxycarbonyl group, substituted alkynyloxycarbonyl group, substituted cycloalkyl group, substituted cycloalkenyloxycarbonyl group, substituted cycloalkenyloxycarbonyl group, substituted arylcarbonyl group Group, substituted heterocyclic oxycarbonyl group, substituted alkylcarbonyl group; reoxy group, substituted alkenylcarbonyloxy group, substituted alkynylcarbonyloxy group, substituted cycloalkylcarbonyl group, substituted cycloalkenylcarbonyl group Nyloxy group, substituted arylcarbonyl group, substituted heterocyclic carbonyl group, substituted alkylsulfinyl group, substituted alkylsulfonyl group, substituted alkenylsulfonyl group, substituted alkynylsulfonyl group, substituted cycloalkyl Rusulfonyl group, substituted cycloalkenylsulfonyl group, substituted arylarylsulfonyl group, substituted heterocyclic sulfonyl group, substituted alkyloxysulfonyl group, substituted alkenyloxysulfonyl group, substituted alkynyloxysulfonyl group, substituted Cycloalkyloxysulfonyl group, cycloalkenyloxysulfonyl group, aryloxysulfonyl group, heterocyclic oxysulfonyl group, alkylsulfonyl group, alkenylsulfonyloxy group Group, substituted alkynylsulfonyloxy group, substituted cycloalkylsulfonyloxy group, substituted cycloalkenylsulfonyloxy group, substituted arylarylsulfonyloxy group, substituted heterocyclic sulfonyloxy group, substituted amino group , Substitutable aminocarbo Group, optionally substituted hydroxyl § amino group, a halogen atom, Shiano group, a nitro group, a hydroxyl group, a thiol group, a carboxyl group, a sulfonic acid group. Among them, a substituted heterocyclic group, a substituted alkoxy group, a substituted heterocyclic oxy group, a substituted alkylthio group, a substituted alkylsulfinyl group, a substituted alkylsulfonyl group, a substituted amino group, a substituted amino group A minocarbonyl group or a hydroxyl group is desirable. The number of those substituents may be one or more than two. When the number of the substituents is two or more, they may be the same or different.

The alkyl, alkenyl and alkynyl moieties of the secondary substituent may be cycloalkyl, cycloalkenyl, aryl, heterocycle, alkoxy, haloalkoxy, alkoxyalkoxy, alkylthioalkoxy, alkenyloxy, Alkenyloxy, alkynyloxy, haloalkynyloxy, cycloalkyloxy, cycloalkenyloxy, aryloxy, heterocyclicoxy, alkylthio, haloalkylthio, alkoxyalkylthio, alkylthioalkylthio, alkenylthio, haloalkenylthio , Alkynylthio, haloalkynylthio, cycloalkylthio, cycloalkenylthio, arylthio, heterocyclic thio, alkenylcarbonyl, benzoyl, alkylalkylcarbonyl, alkoxyalkyl carbonyl, alkenylcarbonyl, alkenylcarbonyl, Noloalkenylcarbonyl, alkynylcarbo, nil, no, alkynylcarbonyl, cycloalkylcarbonyl, cycloalkenylcarbonyl, arylcarbonyl Heterocyclic carboxy, alkoxycarbonyl, noroalkoxycarbonyl, alkoxyalkoxycarbonyl, alkylthioalkoxycarbonyl, alkenyloxycarbonyl, no, alkenyloxycarbonyl, alkynyloxycarbonyl, nodolo Alkynyloxycarbonyl, cycloalkyloxycarbonyl, cycloalkenyloxycarbonyl, aryloxycarbonyl, heterocyclic oxycarbonyl, alkylcarbonylcarbonyl, no, mouth alkylcarbonyloxy, alkoxyalkyl Carbonyloxy, alkylthioalkyl alkenyloxy, alkenylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyl, haloalkynylcarbonyl, cycloalkoxy Carbonyl, cycloalkenylcarbonyl, arylcarbonyl, heterocyclic carbonyl, alkylsulfonyl, amino, alkylsulfonyl, alkoxyalkylsulfonyl, alkylthioalkylsulfonyl, alkenylsulfonyl, haloalkenylsulfonyl, Alkynylsulfonyl, no, loalkynylsulfonyl, cycloalkylsulfonyl, cycloalkenylsulfonyl, arylsulfonyl, heterocyclicsulfonyl, alkoxysulfonyl, haloalkoxysulfonyl, alkoxyalkoxysulfonyl, alkylthioalkoxysulfonyl, alkenyloxysulfonyl, Haloalkenyloxysulfonyl, alkynyloxysulfonyl, haloalkynyloxysulfonyl, cycloa Kill O carboxymethyl sulfonyl, cycloalkenyl Okishisuruhoniru, Ariru old Kishisuruhoniru, heterocyclic Okishisuruhoniru, Al Resulfuryloxy, alkylthioalkylsulfonyloxy, arylechenylsulfonyloxy, haloalkenylsulfonyloxy, alkynylsulfonyloxy, haloalkynylsulfonyloxy, haloalkylsulfonyloxy, haloalkylsulfonyloxy, alkoxyl; Cycloalkylsulfonyloxy, cycloalkenylsulfonyloxy, arylsulfonyloxy, heterocyclic sulfonyl, amino, alkylamino, dialkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, Arylamino, complex ring amino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkenylaminocarbonyl, alkynylamino Nyl, cycloalkylaminocarbonyl, cycloalkenylaminocarbonyl, arylaminocarbonyl, heterocyclicaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkenylaminosulfonyl, alkynylaminosulfonyl, cycloalkylaminosulfonyl, cyclo Alkenyl aminosulfonyl, arylaminosulfonyl, heterocyclic aminosulfonyl, alkylcarbonylamino, haloalkylcarbonylamino, alkoxyalkyl force carbonyloxyamino, alkylthioalkylcarbonylamino, alkenylcarboxyamino, nonoalkenylcarbonylamino, alkynylcarbonyl Amino, alkynylcarbonylamino, cycloalkylcarbonyl Mino, cycloalkenylcarbonylamino, arylcarbonylamino, heterocyclic carbonylamino, alkoxycarbonylamino, haloalkoxycarbonylamino, alkoxyalkoxycarbonylamino, alkylthioalkoxycarbonylamino, alkenyloxycarbonylamino Mino, haloalkenyloxycarbonylamino, alkynyloxycarbonylamino, haloalkynyloxycarbonylamino, cycloalkyloxycarbonylamino, cycloalkenyloxycarbonylamino, aryloxycarbonylamino, complex Alkoxycarbonylamino, alkylsulfonylamino, haloalkylsulfonylamino, alkoxyalkylsulfonylamino, alkylthioalkylsulfonylamino, Nirusuruhonirua Mino, Nono b alkenylsulfonyl § Mino, alkynylsulfonyl § Mino, Haroa Lucinylsulfonylamino, cycloalkylsulfonylamino, cycloalkenylsulfonylamino, arylsulfonylamino, heterocyclic sulfonylamino, hydroxyamino, alkoxyamino, hydroxyaminocarbonyl, alkoxyaminocarbonyl, halogen It may be further substituted with a tertiary substituent such as an atom, a cyano group, a nitro group, a hydroxyl group, a thiol group, a carboxyl group and a sulfonic acid group. Among them, alkoxy, alkoxyalkoxy, heterocyclic oxy, halogen atom or hydroxyl group is preferable. The number of such substituents may be one or two or more. When the number of substituents is two or more, they may be the same or different.

The cycloalkyl portion, cycloalkenyl portion, aryl portion and heterocyclic portion of the secondary substituent are alkyl, haloalkyl, alkoxyalkyl, alkylthioalkyl, alkenyl, haloalkenyl, alkynyl, amino, loalkynyl, cycloalkyl, cycloalkenyl, Aryl, heterocycle, alkoxy, haloalkoxy, alkoxyalkoxy, alkylthioalkoxy, alkenyloxy, noloalkenyloxy, alkynyloxy, haloalkynoxy, cycloalkyloxy, cycloalkenyloxy, aryloxy, heterocyclic, alkyl Thio, haloalkylthio, alkoxyalkylthio, alkylthioalkylthio, alkenylthio, haloalkenylthio, alkynylthio, halo Ruquinylthio, cycloalkylthio, cycloalkenylthio, arylthio, heterocyclicthio, alkylcarbonyl, haloalkylcarbonyl, alkoxyalkylcarbonyl, alkylthioalkylcarbonyl, alkenylcarbonyl, haloalkenylcarbonyl, alkynylcarbonyl, haloalkynylcarbonyl, cycloalkyl Force carbonyl, cycloalkenylcarbonyl, arylcarbonyl, heterocyclic carbonyl, alkoxycarbonyl, haloalkoxycarbonyl, alkoxyalkoxycarbonyl, alkylthioalkoxycarbonyl, alkenyloxycarbonyl, haloalkenyloxycarbonyl, alkynyloxycarbonyl, haloalkynyl Oxycarbonyl, cycloalkyloxycarbonyl, Kuroarukeniru old alkoxycarbonyl, § reel O alkoxycarbonyl, heterocycle O alkoxycarbonyl, alkyl Rucarbonyloxy, haloalkylcarbonyloxy, alkoxyalkylcarbonyloxy, alkylthioalkylcarbonyloxy, alkenylcarbonyloxy, amino, loalkenylcarbonyloxy, alkynylcarbonyloxy, haloalkynylcarbonyloxy, cycloalkylcarbonyloxy, Cycloalkenylcarbonyloxy, arylcarbonyloxy, heterocyclic carbonyloxy, alkylsulfonyl, no, mouth alkylsulfonyl, alkoxyalkylsulfonyl, alkylthioalkylsulfonyl, alkenylsulfonyl, haloalkenylsulfonyl, alkynylsulfonyl, no, Roalkynylsulfonyl, cycloalkylsulfonyl, cycloalkenylsulfonyl, arylsulfonyl, complex Sulfonyl, alkoxysulfonyl, noloalkoxysulfonyl, alkoxyalkoxysulfonyl, alkylthioalkoxysulfonyl, alkenyloxysulfonyl, no, loalkenyloxysulfonyl, alkynicleoxysulfonyl, // alkynyloxysulfonyl, cycloalkyl Oxysulfonyl, cycloalkenyloxysulfonyl, aryloxysulfonyl, heterocyclic oxysulfonyl, alkylsulfonyloxy, haloalkylsulfonyloxy, alkoxyalkylsulfonyloxy, alkylthioalkylsulfonyloxy, alkenylsulfonyloxy , Noloalkenylsulfonyloxy, alkynylsulfonyloxy, noroalkynylsulfonyloxy, cycloalkylsulfo Roxy, cycloalkenylsulfonyloxy, arylsulfonyl, heterocyclic sulfonyl, amino, alkylamino, dialkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, multiple Elementary ring amino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkenylaminocarbonyl, alkynylaminocarbonyl, cycloalkylaminocarbonyl, cycloalkenylaminocarbonyl, arylaminocarbonyl, heterocyclic aminocarbonyl, aminosulfonyl , Alkylamino sulfonyl, dialkylaminosulfonyl, alkenylaminosulfonyl, alkynylaminosulfonyl, cycloalkylamino Ruhoniru, cycloalkenyl aminosulfonyl, § reel aminosulfonyl, heterocyclic aminosulfonyl, Al Killcarbonylamino, haloalkylcarbonylamino, alkoxyalkyl force rubonylamino, alkylthioalkylcarbonylamino, alkenylcarbonylamino, haloalkenylcarbonylamino, alkynylcarbonylamino, alkynylcarbonylamino, cycloalkylcarbonyl Amino, cycloalkenylcarbonylamino, arylcarbonylamino, heterocyclic carbonylamino, alkoxycarbonylamino, haloalkoxycarbonylamino, alkoxyalkoxycarbonylamino, alkylthioalkoxycarbonylamino, alkenyl Roxycarbonylamino, haloalkenyloxycarbonylamino, alkynyloxycarbonylamino, haloalkynyloxycarbonylamino , Consequent opening alkyl O alkoxycarbonylamino, cycloalkenyl O butoxycarbonyl amino

, Aryloxycarbonylamino, heterocyclicoxycarbonylamino, alkylsulfonylamino, haloalkylsulfonylamino, alkoxyalkylsulfonylamino, alkylthioalkylsulfonylamino, alkenylsulfonylamino, haloalkenylsulfonyl Amino, alkynylsulfonylamino, no, lower alkynylsulfonylamino, cycloalkylsulfonylamino, cycloalkenylsulfonylamino, arylsulfonylamino, heterocyclic sulfonylamino, hydroxyamine, alkoxyamino, hydroxyamine Even if it is further substituted with a tertiary substituent such as cyanocarbonyl, alkoxyaminocarbonyl, halogen atom, cyano group, nitro group, hydroxyl group, thiol group, carboxyl group or sulfonic acid group There. Among them, alkyl or alkoxy is preferable. The number of such substituents may be one or two or more. When the number of substituents is two or more, they may be the same or different.

The substituted amino group, substituted aminocarbonyl group or substituted hydroxyaminocarbonyl group is alkyl, haloalkyl, alkoxyalkyl, alkylthioalkyl, alkenyl, no, loalkenyl, alkynyl, no, loalkynyl, cycloalkyl, cycloalkenyl. , Aryl, heterocycle, alkylcarbonyl, haloalkylcarbonyl, alkoxyalkylcarbonyl, alkylthioalkyl force, alkenylcarpo'nyl, alkenylcarpo'nil, alkenylcarpo-nil, alkynylcar Po'nyl, amino, alkynylcarbonyl, cycloalkylcafleponyl, cycloalkenylcarbonyl, arylcarbonyl, heterocyclic carbonyl, alkoxycarbonyl, haloalkoxycarbonyl, alkoxyalkoxycarbonyl, alkylthioalkoxycarbonyl, alkenylo Xyloxycarbonyl, haloalkenyloxycarbonyl, alkynyloxycarbonyl, no, alkynyloxycarbo, nil, cycloalkyloxycarbonyl, cycloalkenyloxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkylsulfonyl, Haloalkylsulfonyl, alkoxyalkylsulfonyl, alkylthioalkylsulfonyl, alkenylsulfonyl, no, alkenylsulfonyl, a Quinylsulfonyl, amino, loalkynylsulfonyl, cycloalkylsulfonyl, cycloalkenylsulfonyl, arylsulfonyl, heterocyclicsulfonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkenylaminocarbonyl, alkynylaminocarbonyl, cyclo Alkylaminocarbonyl, cycloalkenylaminocarbonyl, arylaminocarbonyl, heterocyclicaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkenylaminosulfonyl, alkynylaminosulfonyl, cycloalkylaminosulfonyl, cycloalkenylamino Sulfonyl, arylaminosulfonyl, heterocyclic aminosulfonyl, cyano group, hydroxyl group It may be further substituted with a tertiary substituent such as. Among them, alkyl or alkyl carbonyl is preferable. The number of such substituents may be one or two or more. When the number of substituents is two or more, they may be the same or different.

Examples of the alkyl moiety in the aforementioned secondary and tertiary substituents include the same alkyl groups as defined for R ² .

 The alkenyl moiety in the above-mentioned secondary and tertiary substituents generally has 2 to 18 carbon atoms, such as vinyl, propenyl, butenyl, pentenyl, hexenyl, decenyl, nonadecenyl. And the like, and they also include those having a structural isomer of a straight-chain or branched aliphatic chain.

The alkynyl moiety in the secondary and tertiary substituents described above is generally carbon A prime number 2 to L8, for example, ethynyl group, propynyl group, butynyl group, pentynyl group, hexynyl group, decynyl group, nonadecynyl group and the like. Including things.

 The cycloalkyl moiety in the above-mentioned secondary substituent and tertiary substituent generally has 3 to 10 carbon atoms, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cyclooctyl group And condensed polycyclic groups; and crosslinked polycyclic groups such as adamantyl, noradamantyl, norbornanyl and norbornanoyl groups.

 The cycloalkenyl moiety in the secondary and tertiary substituents described above generally has 3 to 10 carbon atoms, for example, a monocyclic group such as a cyclopentenyl group, a cyclohexenyl group, or a cyclooctenyl group. Other examples include a condensed polycyclic group and a crosslinked polycyclic group.

 Examples of the aryl moiety in the above-mentioned secondary and tertiary substituents include a fused polycyclic group such as a naphthyl group in addition to a fuunyl group.

 Examples of the heterocyclic moiety in the above-mentioned secondary substituent and tertiary substituent include those similar to the heterocycle defined as R]. Among them, furanyl group, tetrahydrofuranyl group, chenyl group, imidazolyl group, dioxolanyl group, pyridyl group, piperidinyl group, vilazinyl group, piperazinyl group, tetrahydrovinylanyl group, dioxanyl group, morphonyl group, benzothiazolyl group or quinolinyl group are preferred. Good.

 The compound of the formula (I) or a salt thereof can be produced by a method for producing a known analogous compound (for example, the method described in JP-A-2-171) or a method analogous thereto. The following production methods 1 to 11 are exemplified.

 Manufacturing method 1

Formula (II):

One ^two

0 ₂ N (H) C = Q

 S—Z

[Wherein, Z is an alkyl group or an arylalkyl group] , Formula (III):

R ²

 /

 Y—

 \

 H

[Wherein Y is a hydrogen atom or an alkali metal atom, and R ² is as described above], and a compound represented by the formula (IV):

 S-Z

 /

0 ₂ N (H) C = Q

 N-R 2

 I

 H

[Wherein Z and R ² are as defined above], a compound of the formula (IV) obtained in the first step and a compound of the formula (V):

N— N

 / \

Y H

Wherein Y is a hydrogen atom or an alkali metal atom, and R ¹ is as described above, to obtain a ditrothetenamine derivative of the formula (I)

A method for producing a nitretheneamine derivative of the formula (I), comprising:

 Manufacturing method 2

The compound of the formula (II) is reacted with the compound of the formula (V) to obtain a compound of the formula (VI):

Wherein Ζ and R ¹ are as described above.

Reacting the compound of the formula (VI) obtained in the first step with the compound of the formula (III) to obtain a nitroethenamine derivative of the formula (I),

A method for producing a nitretheneamine derivative of the formula (I), comprising:

In addition, the compound of formula (II), the compound of formula (III) and formula (V) Can be produced by a known method or a method analogous thereto. Each reaction of Production Method 1 and Production Method 2 can be performed in the presence of a suitable solvent. Specific examples of solvents used include alcohols such as methanol, ethanol, propanol, and butanol; aromatic hydrocarbons such as benzene, toluene, and xylene; pentane, hexane, heptane, petroleum ether, and rig ports. Aliphatic hydrocarbons such as petroleum benzene, petroleum benzene; ethers such as getyl ether, dipropyl ether, dibutyl ether, tetrahydrofuran, and dioxane; nitriles such as acetonitrile and propionitrile; dimethylformamide Acid amides such as dimethylacetamide; sulfoxides such as dimethyl sulfoxide; sulfones such as sulfolane; phosphoric acid amides such as hexamethylphosphoramide; chloroform, dichloromethane, carbon tetrachloride , 1,2-dichloroeta Halogenated hydrocarbons such as and it may be mixtures of these solvents.

 In Production Methods 1 and 2, in order to carry out each reaction efficiently, it is desirable to carry out the reaction in the presence of a base. Specific examples of the base used include organic bases such as triethylamine, pyridine, N-methylmorpholine, 1,8-diazabicyclo [5,4,0] -7-indene, N, N-dimethylaniline; Alkali metals such as lithium, sodium and potassium; alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; alkali metal carbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate Hydrogen salts; hydrides of alkali metals such as lithium hydride, hydrogen hydride and potassium hydride; alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide. The compound of formula (III) and the compound of Z or formula (V) also act as a base.

 Each reaction of Production Method 1 and Production Method 2 is carried out at a reaction temperature of -30 to 150 ° C, preferably at a reaction temperature of 0 to 100 ° C. The reaction time is between 0.1 and 48 hours.

Production Method 1 In the first step, the compound of the formula (III) can be used in a proportion of 1 to 1.2 equivalents per 1 mol of the compound of the formula (II). When the compound of the formula (111) is used in excess, the compound of the formula (IV) and the compound of the formula (VII):

[Wherein R ² is as defined above]. Further, in the production method 1 second step, 1 mol of the compound of the formula (IV), the compound of formula (V) is 1 ^to;? Force that can be used in a proportion of L. 5 equivalents, excess There is no particular disadvantage even if used.

 Production Method 2 In the first step, the compound of the formula (V) can be used in a proportion of 1 to 1.2 equivalents per 1 mol of the compound of the formula (II). When the compound of formula (V) is used in excess, the formula (V

In addition to the compound of VI), formula (VIII):

HR ¹

 , N—N,

 / H

0 ₂ N (H) C = C, _H

I, 1

H ^R

[Wherein R ¹ is as defined above]. In the second step of the production method 2, the compound of the formula (III) is used in an excess of 1 to 1.5 equivalents per mole of the compound of the formula (VI). There is no particular problem.

 The compound of the formula (IV) obtained in the production method 1 and the compound of the formula (VI) obtained in the production method 2 can be separated or purified by known means such as concentration, concentration under reduced pressure, solvent extraction, recrystallization, chromatography and the like. The reaction mixture may be subjected to the next reaction for producing the compound of the formula (I) as it is.

 The reaction conditions in Production Method 1 can be appropriately combined with each other. The reaction conditions in Production Method 2 can be appropriately combined with each other. Manufacturing method 3

Equation (IX): X

 /

0 ₂ N (H) C = C ヽ

 X

Wherein X is a halogen atom; and / or a compound represented by the formula (X): 0 ₂ N-CH ₂ CX _{3 wherein} X is as defined above. Reacting the compound of formula (II I) with a compound of formula (XI):

Wherein X and R ² are the same as defined above, wherein a compound of the formula (XI) obtained in the first step is reacted with a compound of the formula (V) A second step of obtaining the ditrothetenamine derivative of formula (I),

 A method for producing a nitroethenamine derivative of the formula (I), comprising:

 Manufacturing method 4

The compound of the formula (Π) and Z or the compound of the formula (X) are reacted with the compound of the formula (V) to obtain a compound of the formula (XII):

1

Wherein X and R ¹ are the same as defined above, and reacting the compound of the formula (III) obtained in the first step with the compound of the formula (III) A second step of obtaining a ditrothetenamine derivative of formula (I),

A method for producing a nitretheneamine derivative of the formula (I), comprising:

 The compound of the formula (IX) and the compound of the formula (X), which are the raw materials of the production method 3 and the production method 4, can be obtained by a known method described in, for example, Journal of Organic Chemistry. Vol 25. 1312 (1960) or the like. It can be manufactured by a method according to the above.

Each reaction of Production Method 3 and Production Method 4 can be performed in the presence of a suitable solvent. Specific examples of solvents used include aromatic hydrocarbons such as benzene, toluene, and xylene; pentane, hexane, heptane, petroleum ether, rig-in, petroleum base. Aliphatic hydrocarbons such as benzene; ethers such as getyl ether, dipropyl ether; le, dibutyl ether, tetrahydrofuran, and dioxane; nitriles such as acetonitrile and propionitrile; dimethylformamide and dimethylacetamide Acid amides such as dimethyl sulfoxide; sulfones such as sulfolane; phosphoric acid amides such as hexamethylphosphoramide; chloroform, dichloromethane, carbon tetrachloride, 1,2- Examples thereof include halogenated hydrocarbons such as dichloroethane and a mixed solvent thereof.

In Production Method 3 and Production Method 4, in order to carry out each reaction efficiently, it is desirable to carry out the reaction in the presence of a base. Specific examples include the same bases ⁵ ′ as the bases used in Production Methods 1 and 2. The compound of formula (ΠΙ) and the compound of Z or formula ':: V) also act as bases.

 Each reaction of Production Method 3 and Production Method 4 is performed at a reaction temperature of −30 to 150 ° C., preferably at a reaction temperature of 0 to 80 ° C. The reaction time is between 0.1 and 48 hours.

 Process 3 In the first step, the compound of the formula (III) can be used in a ratio of 0.8 to 2 equivalents, preferably 1 to 1.2 equivalents, per 1 mol of the compound of the formula (IX). In the second step of the production method 3, the compound of the formula (III) is used in an amount of 1 to 1.5 equivalents per 1 mol of the compound of the formula (XI). No inconvenience. In the first step of the production method 4, the compound of the formula (V) can be used in a proportion of 1 to 2 equivalents, preferably 1 to 1.2 equivalents, per 1 mol of the compound of the formula (IX). In the second step of the production method 4, the compound of the formula (III) can be used in a ratio of 1 to 1.5 equivalents relative to 1 mol of the compound of the formula (XII). .

 The compound of the formula (XI) obtained by the production method 3 and the compound of the formula (XII) obtained by the production method 4 are separated and purified by a known means such as concentration, concentration under reduced pressure, solvent extraction, recrystallization, chromatography, etc. After or as a reaction mixture, it may be subjected to the next reaction for producing the compound of the formula (I).

The reaction conditions in Production Method 3 can be appropriately combined with each other. The reaction conditions in Production Method 4 can be combined with each other as appropriate. C Production Method 5 A compound represented by the formula (V) is reacted with a compound represented by the formula (XIII): R ² — NCS wherein R ² is as defined above, to obtain a compound represented by the formula (XIV):

Wherein R ¹ and R ² are as described above; a compound of the formula (XIV) obtained in the first step, a compound of the formula (XV): Z—X Wherein Z and X are the same as defined above, by reacting a compound represented by the formula (XVI):

Wherein Z, R ¹ and R ² are as defined above, to obtain a compound represented by the following formula:

By reacting the compound of the formula (XVI) obtained in the second step with nitromethane, the formula (XVI)

A third step of obtaining a ditrothetenamine derivative of I),

A method for producing a nitretheneamine derivative of the formula (I), comprising:

 Production Method 5 The reaction in the first step can be carried out in the presence of a suitable solvent. Specific examples include the same solvents as those used in Production Methods 1 and 2.

 In the first step of Production method 5, it is desirable to carry out the reaction in the presence of a base in order to carry out the reaction efficiently. Specific examples of the base used include organic bases such as triethylamine, pyridine, N-methylmorpholine, 1,8-diazabicyclo [5,4,0] -7-pandene, N, N-dimethylaniline; Examples thereof include alkali metal carbonates such as lithium, sodium carbonate and carbonated carbonate; and alkali metal bicarbonates such as lithium hydrogencarbonate, sodium hydrogencarbonate and potassium hydrogencarbonate. Note that the compound of the formula (V) also acts as a base.

Process 5 The reaction of the first step is carried out at a reaction temperature of -30 to 200 ° C, preferably at a reaction temperature of 0 to 150 ° C. The reaction time is between 0.1 and 48 hours. Process 5 In the first step, the compound of the formula (XIII) can be used in a ratio of 0.8 to 2 equivalents, preferably 1 to 1.2 equivalents, per 1 mol of the compound of the formula (V). The obtained compound of the formula (XIV) may be subjected to the reaction in the second step after separation or purification by a known means such as concentration, concentration under reduced pressure, solvent extraction, recrystallization, and mouth chromatography, or as a reaction mixture. Good.

 Production Method 5 The reaction in the second step can be carried out in the presence of a suitable solvent. Specific examples of solvents used include alcohols such as methanol, ethanol, propanol, and butanol; ketones such as acetone, methylethyl ketone, dimethyl ketone, and ethyl ketone; methyl acetate, ethyl acetate, butyl acetate, methyl formate, Esters such as ethyl formate, butyl formate, and ethyl propionate; aromatic hydrocarbons such as benzene, toluene, and xylene; aliphatics such as pentane, hexane, heptane, petroleum ether, rigoin, petroleum benzene Hydrocarbons; ethers such as getyl ether, dipropyl ether, dibutyl ether, tetrahydrofuran, and dioxane; nitriles such as acetonitrile and propionitrile; acids such as dimethylformamide and dimethylacetamide A Sulfoxides such as dimethyl sulfoxide; sulfones such as sulfolane; phosphoric acid amides such as hexamethylphosphoramide; halogenated carbons such as chloroform, dichloromethane, carbon tetrachloride and 1,2-dichloroethane. Hydrogens and their mixed solvents can be mentioned.

 In the second step of Production method 5, it is desirable to carry out the reaction in the presence of a base in order to carry out the reaction efficiently. Specifically, the same force as the base used in Production Methods 1 and 2 can be used.

 Process 5 The reaction in the second step is carried out at a reaction temperature of -30 to 150 ° C, preferably at a reaction temperature of 0 to 100 I :. The reaction time is between 0.1 and 48 hours.

In the reaction of the second step of Production Method 5, the compound of the formula (XV) can be used in an amount of 1 equivalent or more per 1 mol of the compound of the formula (XIV). As the compound of the formula (XV), various powers, for example, benzyl bromide, methyl iodide and the like can be used. The obtained compound of the formula (XVI) can be obtained by a known method such as concentration and concentration under reduced pressure. It may be subjected to the reaction in the third step after separation and purification by condensation, solvent extraction, recrystallization, chromatography or the like or as a reaction mixture.

 The reaction in the third step of Production Method 5 can be carried out in the presence of a suitable solvent. Specific examples include the same solvents as those used in Production Methods 1 and 2.

 In the third step of Production Method 5, it is desirable to carry out the reaction in the presence of a base in order to carry out the reaction efficiently. Specific examples include the same bases as those used in Production Methods 1 and 2.

 Process 5 The reaction of the third step is carried out at a reaction temperature of -30 to 200 ° C, preferably at a reaction temperature of 0 to 150. The reaction time is between 0.1 and 48 hours.

 Process 5 In the reaction of the third step, dinitromethane is used in an amount of 0.8 to 2 equivalents, preferably 1 to 1.5 equivalents, per mole of the compound of the formula (XVI). Can also be used as a solvent. In this case, there is no particular problem even if it is used in excess.

 The reaction conditions in Production Method 5 can be appropriately combined with each other. Manufacturing method 6

Equation νπ):

^Η 2 II

0 ₂ N— CC— Ν

 H

Wherein R ² is as defined above, and a halogenating agent to obtain a compound of the formula (XI),

Reacting the compound of the formula (XI) obtained in the first step with the compound of the formula (V) to obtain a compound of the formula (I),

A method for producing a nitretheneamine derivative of the formula (I), comprising:

 Manufacturing method 7

The formula νιπ):

Wherein R ¹ is as defined above, and a halogenating agent. A first step of obtaining a compound of formula (XII)

A second step of obtaining a compound of the formula (I) by reacting the compound of the formula (XII) obtained in the first step with the compound of the formula (III),

 A method for producing a nitretheneamine derivative of the formula (I), comprising:

 In addition, the compound of the formula (XVII) and the compound of the formula (XVIII), which are the raw materials of the production methods 6 and 7, can be produced by a known method or a method analogous thereto.

 The reaction in the first step of the production method 6 and the first step of the production method 7 can be carried out in the presence of a suitable solvent. Specific examples of the solvent include aromatic hydrocarbons such as benzene, toluene, and xylene; aliphatic hydrocarbons such as pentane, hexane, heptane, petroleum ether, lignin, petroleum benzine; Ethers such as ether, dibutyl ether, dibutyl ether, tetrahydrofuran, and dioxane; halogenated hydrocarbons such as chloroform, dichloromethane, carbon tetrachloride, 1,2-dichloroethane, and mixtures thereof. Can be mentioned. The reaction is desirably performed in a water-free system.

 Examples of the halogenating agent used in the reaction of the first step of the production method 6 and the first step of the production method 7 include, for example, phosphorus pentachloride, oxychloride phosphorus, phosphorus trichloride, thionyl chloride, and oxalyl chloride. The use amount thereof is 1 to 10 equivalents, preferably 1 to 5 equivalents, per 1 mol of the compound of the formula (XVII) or the compound of the formula (ΠΙΙΙ). It is also desirable to allow a base to coexist in order to capture the hydrogen chloride generated in this reaction. Examples of such a base include triethylamine, pyridine, Ν-methylmorpholine, 1,8-diazabicyclo [5 , 4,0] -7- ゥ decene and Ν, Ν-dimethylaniline.

 The reaction of the first step of the production method 6 and the first step of the production method 7 is carried out at a reaction temperature of −30 to 200 ° C., preferably 0 to L50 ° C. The reaction time is 0.1 to 48 hours.

Preparation 6 The compound of formula (XI) obtained in the first step and the compound of formula (XII) obtained in the first step of the manufacturing method 7 can be obtained by a known method such as concentration, concentration under reduced pressure, solvent extraction, recrystallization, and Separation and purification by chromatography, etc. (3) Production method which is the same reaction as the second step (6) Reaction of the second step and production method (4) Production method which is the same reaction as the second step (7) The reaction may be carried out in the second step.

 The reaction conditions in Production Method 6 can be appropriately combined with each other. The reaction conditions in Production Method 7 can be appropriately combined with each other. Manufacturing method 8

Formula (XIX):

 H H

 N-N

0 ₂ N (H) C = Q ^H

NR ²

 I

 H

Wherein R ² is as defined above, and a compound represented by the formula (XX): X-R ^{1 wherein} R ¹ and X are as defined above. A method for producing a nitroethenamine of the formula (I) by reacting

 The reaction of Production Method 8 can be carried out in the presence of a suitable solvent. Specific examples include the same solvents as those used in Production Methods 3 and 4.

 In production method 8, in order to carry out the reaction efficiently, it is desirable to carry out the reaction in the presence of a base. Specific examples of bases used include organic bases such as triethylamine, pyridine, N-methylmorpholine, 1,8-diazabicyclo [5,4,0] -7-pandene, N, N_dimethylylaniline; lithium, Alkali metals such as sodium and potassium; alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; carbonates; alkali metal bicarbonates such as lithium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; hydrogen Hydrides of alkali metals such as lithium hydride, sodium hydride, and lithium hydride; and n-butyllithium, lithium diisopropylamide, and sodium amide.

 The reaction of Production Method 8 is carried out at a reaction temperature of -70 to; L50 ° C, preferably at a reaction temperature of -50 to 100 ° C. The reaction time is between 0.1 and 48 hours.

In Production Method 8, the compound of the formula (XX) can be used in a ratio of 0.8 to 2 equivalents, preferably 1 to 1.5 equivalents, per 1 mol of the compound of the formula (XIX). The reaction conditions in Production Method 8 can be appropriately combined with each other. Manufacturing method 9

Formula (XXI):

Wherein R ² and Z are as defined above, and nitromethane, to obtain a compound of formula (IV),

A second step of reacting the compound of the formula (IV) obtained in the first step with the compound of the formula (V) to obtain a ditrothetenamine derivative of the formula (I),

A method for producing a ditrothetenamine derivative of the formula (I), comprising:

 Manufacturing method 10

Formula (XXII):

Wherein R ¹ and Z are as defined above, and nitromethane, to obtain a compound of the formula (VI),

Reacting the compound of the formula (VI) obtained in the first step with the compound of the formula (III) to obtain a ditrothetenamine derivative of the formula (I) in a second step,

A method for producing a nitretheneamine derivative of the formula (I), comprising:

The compounds of the formula (XXI) and the compound of the formula (XXII), which are the starting materials for the production methods 9 and 10, can be produced by a known method or a method analogous thereto.

 The reaction of the first step of the production method 9 and the first step of the production method 10 can be carried out in the presence of a suitable solvent. Specific examples include the same solvents as those used in Production Methods 1 and 2.

 In the first step of the production method 9 and the first step of the production method 10, it is desirable to carry out the reaction in the presence of a base in order to carry out the reaction efficiently. Specific examples include the same bases as those used in Production Methods 1 and 2.

Process 9 Step 1 and Process 10 Each reaction in Step 1 is carried out at a reaction temperature of -30 to 150 ° C. The reaction is preferably performed at a reaction temperature of 0 to 80 ° C. The reaction time is 0.1 to 48 hours.

 In the first step of Production Method 9, nitromethane can be used in a ratio of 0.8 to 2 equivalents, preferably 1 to 1.5 equivalents, per 1 mol of the compound of the formula (II). In the first step of Production Method 10, nitromethane can be used in a ratio of 0.8 to 2 equivalents, preferably 1 to 1.5 equivalents, per 1 mol of the compound of the formula (ΧΧΙΠ). In the first step of the production method 9 and the first step of the production method 10, nitromethane can also be used as a solvent. In this case, there is no particular problem even if it is used in excess.

 Preparation 9 The compound of the formula (IV) obtained in the first step and the compound of the formula (VI) obtained in the first step can be obtained by a known method such as concentration, concentration under reduced pressure, solvent extraction, recrystallization, and chromatography. Separation and purification by chromatography, etc., or the reaction mixture as they are, respectively.Production method 1 Production method that is the same reaction as the second step 9 Reaction of the second step and production method 2 Production method that is the same reaction as the second step 10 Production method 2 It may be used for the reaction.

 The reaction conditions in Production Method 9 can be appropriately combined with each other. The reaction conditions in Production Method 10 can be appropriately combined with each other. Manufacturing method 11

A first step of reacting the compound of the formula (XIII) with nitromethane and then reacting the compound of the formula (XV) to obtain the compound of the formula (IV),

Reacting the compound of the formula (IV) obtained in the first step with the compound of the formula (V) to obtain a nitroethenamine derivative of the formula (I),

A method for producing a ditrothetenamine derivative of the formula (I), comprising:

 Production method 11 The first step can be carried out in the presence of a suitable solvent. Specific examples include the same solvents as those used in Production Methods 1 and 2 described above.

 In the first step of Production method 11, it is desirable to carry out the reaction in the presence of a base in order to carry out the reaction efficiently. Specific examples include the same bases as those used in Production Methods 1 and 2. In the second step of Production Method 11, the compound of formula (V) also acts as a base.

Production method 11 The reaction in the first step is carried out at a reaction temperature of -30 to 150 ° C, preferably 0 to 80 The reaction is performed at a reaction temperature of ° C. The reaction time is between 0.1 and 48 hours.

 In the first step of the production method 11, nitromethane and the compound of the formula (XV) can be used in an amount of 0.8 to 2 equivalents, preferably 1 to 1.5 equivalents, per 1 mol of the compound of the formula (II). In this step, nitromethane can also be used as a solvent, and in this case, there is no particular problem even if it is used in excess.

 Production method 11 The compound of formula (XXII) obtained in the first step can be separated by known means such as enrichment, decompression concentration, solvent extraction, recrystallization, chromatography, etc., purified or purified as a reaction mixture. (1) Production method which is the same reaction as in the second step 1) The reaction may be performed in the second step.

 The reaction conditions in Production Method 11 can be appropriately combined with each other. Compounds of formula (I) obtained by the methods described in the above-mentioned production methods 1 to 11 can be obtained by known methods, for example, concentration, concentration under reduced pressure, distillation, fractional distillation, phase transfer, solvent extraction, and crystal crystallization. It can be isolated and purified by recrystallization, chromatography and the like.

 When the compound of the formula (I) is obtained in a free form, a salt may be formed by a usual method. Further, the compound of the formula (I) may form an inner salt. The compound of the formula (I), its stereoisomer and tautomer alone each exhibit a matrix metalloproteinase inhibitory action in any state of a mixture.

Example

 Next, specific synthetic examples of the nitretheneamine derivative represented by the formula (I) and an intermediate for producing the same will be described.

 Synthesis Example 1: Synthesis of N-2,2-Dimethoxethyl-1- (2- (5-chloro-2-pyridyl) hydrazino) -2--2-trothetenamine (Compound No. 13)

 (1) After stirring 1,3-bis (methylthio) -2-nitroethene 3.0g, 2,2-dimethoxshetylamine 1.9g and kuguchiguchi form 20ml under reflux for about 4.5 hours, room temperature Then, the solvent was distilled off under reduced pressure. The concentrated residue was purified by silica gel column chromatography to obtain 2.5 g of N-2,2-dimethoxethyl-1-methylthio-2-nitroethenamine (intermediate No. 1) having a melting point of 64 ° C.

(2) N-2,2-Dimethoxethyl-1 -methylthio-2-nitroethenamine 500 mg, 5-k 330 mg of roro-2-pyridylhydrazine and ethanol lOral were stirred under reflux for about 13.5 hours, then cooled to room temperature, and the precipitated crystals were collected by filtration. The crystals collected by filtration were washed with ethanol and dried to obtain 340 mg of the desired product (Compound No. 13) having a melting point of 195 ° C (decomposition).

 Synthetic Example 2: N-2- (2-Hydroxyshetyloxy) ethyl-1- (2- (5-chloro-2-pyridyl) hydrazino) —2-nitroethenamine (Compound No. 19) Synthesis of

 (1) 1,1-Bis (methylthio) -2-nitroethene 5.0g, 2- (2-hydroxyshethyloxy) ethylamine 3.2g and 50 ml of porcine form are heated and stirred under reflux for about 5 hours. After cooling to room temperature, the solvent was removed under reduced pressure. The concentrated residue was purified by silica gel column chromatography to give N-2- (2-hydroxyxyloxy) ethyl-1-methylthio-2-nitroethenamine with a melting point of 59 ° C (intermediate No. 3). 2.8 g was obtained.

 (2) N-2- (2-Hydroxyshetyloxy) ethyl-1-methylthio-2-nitroethenamine 2.0 g, 5-chloro-2-pyridylhydrazine 1.3 g and ethanol 25 ml are heated under reflux. After stirring for about 17 hours, the mixture was cooled to room temperature, and the precipitated crystals were collected by filtration. The crystals collected by filtration were washed with ethanol and dried to obtain 860 mg of the desired product (Compound No. 19) having a melting point of 166 ° C.

 Synthesis Example 3: Synthesis of (R) -N-tetrahydrofurfuryl-1- (2- (5-chloro-2-pyridyl) hydrazino) -2-nitroethenamine (Compound No. 21)

 (1) 1.9 g of 1,1-bis (methylthio) -2-nitroethene, 1.2 g of (R)-(-)-tetrahydrofurfurylamine and 12 ml of chloroform were stirred under reflux for about 2 hours and then allowed to reach room temperature. After cooling, the solvent was distilled off under reduced pressure. The concentrated residue was purified by silica gel column chromatography to obtain 1.4 g of (R) -N-tetrahydrofurfuryl-1-methylthio-1-nitronitroenamine (intermediate No. 5) having a melting point of 59 ° C.

(2) (R) -N-tetrahydrofurfurfuryl-1-700-methylthio-2-ditrothenamine, 460 mg of 5-chloro-2-pyridylhydrazine and 10 ml of ethanol are heated under reflux for about 17.5 hours. After stirring, the mixture was cooled to room temperature, and the precipitated crystals were collected by filtration. The crystals collected by filtration were washed with ethanol and then dried to obtain 490 mg of the desired product (compound No. 21) having a melting point of 201 ° C (decomposition). The compounds of the formula (I) produced by the methods according to Synthesis Example 13 and the above-mentioned Production Method 111 are shown in Table 19 below.

 table 1

表 2

Table 2

表 3

Table 3

表 4

Table 4

表 6

Table 6

表 7

Table 7

表 8

Table 8

前記製法 1 9および 11に準じた方法で製造した式（IV)の化合物の製造例を以 下の表 10 13に示す。 これら化合物は、 式（I )の化合物を製造するための中間体と して使用される。 表 10

Table 1013 below shows production examples of the compound of the formula (IV) produced by a method according to the above Production Methods 19 and 11. These compounds are used as intermediates for producing the compounds of the formula (I). Table 10

表 12

Table 12

表 13

Table 13

式（I)の二トロェテンアミン誘導体またはその塩は、 マトリックスメタロプロテ イナーゼ阻害作用、 中でも MMP— 1 MMP— 2 MMP— 3 MMP— 7 MMP— 9阻害作用を有し、 それらの中でも MMP— 3 MMP— 9阻害作用が 特に優れており、 MMP— 9阻害作用が最も優れている。 また、 式 (I)の化合物ま たはその塩に限らず、 式 （IV) の化合物またはその塩もマトリックスメタ口プロ ティナーゼ阻害作用を有する。 従って、 それらを有効成分とし、 必要により後述 の担体等を組合せることにより、 本発明の医薬組成物が提供される。 本発明の医 薬組成物を、 例えば癌や炎症性疾患の治療または予防に用いられる血管新生阻害 剤、 制癌剤、 癌浸潤抑制剤、 癌転移抑制剤、 リウマチ関節炎治療 ·予防剤として 臨床に適応するに際しては、 前記有効成分と製薬的に許容される担体とから成る 医薬組成物にさらに必要に応じて希釈剤、 賦形剤、 安定剤などの添加剤を含んだ 製剤とするのが望ましい。

The ditrothetenamine derivative of the formula (I) or a salt thereof has a matrix metalloproteinase inhibitory activity, in particular, an MMP-1 MMP-2 MMP-3 MMP-7 MMP-9 inhibitory activity, and among them, MMP-3 MMP 9 Inhibitory effect is particularly excellent, and MMP-9 inhibitory effect is the best. Not only the compound of formula (I) or a salt thereof, but also the compound of formula (IV) or a salt thereof has a matrix meta-oral proteinase inhibitory action. Therefore, use them as active ingredients and, if necessary, The pharmaceutical composition of the present invention is provided by combining the above carrier and the like. The pharmaceutical composition of the present invention is clinically applied as, for example, an angiogenesis inhibitor, an anticancer agent, a cancer invasion inhibitor, a cancer metastasis inhibitor, a rheumatoid arthritis treatment or prevention agent used for treatment or prevention of cancer or inflammatory diseases. At this time, it is desirable to prepare a pharmaceutical composition comprising the above-mentioned active ingredient and a pharmaceutically acceptable carrier, and further containing, if necessary, additives such as a diluent, an excipient and a stabilizer.

 In the pharmaceutical composition of the present invention, the mixing ratio of the above active ingredient to the carrier component is generally 1.0 to 906 W / W. The therapeutically effective dose is generally 0.1 to 1000 mg / day / person for adults, depending on the method of administration, the sex, weight, age and target disease of the patient. Dosage forms and administration forms include granules, fine granules, pills, tablets, capsules and liquids, and may be administered orally as raw powders, suppositories, air Parenteral administration may be made in the form of oral sols or topical preparations such as nasal drops. Injection may be administered intravenously, intramuscularly, subcutaneously, or intraarticularly. It may also be prepared as a powder for injection at the time of use.

 Pharmaceutical organic or inorganic, solid or liquid carriers or diluents suitable for oral, enteral or parenteral administration can be used to formulate the pharmaceutical compositions of the invention. Representative carriers or diluents that can be incorporated in tablets, capsules, and the like include acacia, disintegrants such as corn starch and arginic acid, lubricants such as magnesium stearate, and sweeteners such as sucrose and lactose. it can. When the dosage form is a capsule, it may contain, in addition to the above substances, a liquid carrier such as a fatty oil. Various other materials may be used as coatings or as agents to improve the physical form of the dosage unit. For example, it is desirable to dissolve or suspend the active ingredient in an excipient such as water and natural vegetable oils and in a synthetic fat excipient such as ethyl oleate. Buffers such as citrate, acetate, phosphate and the like, and antioxidants such as ascorbic acid can be incorporated according to accepted pharmaceutical methods.

 Next, specific test examples will be described.

 Test Example 1: Measurement of inhibitory activity on human 丽 P-9 (gelatinase B)

Inhibitory activity of each compound on human MMP-9 purified enzyme (Chemicon, Code No. CC079) Sex, fluorescent base peptide substrate (7- methoxycoumarin- 4-yl) Acetyl -Pro- Leu- Gly- Leu- (3 - [2,4- dinitrophenyl] - Ala- Arg-NH 2, Inc. Bae flop de Research Using Code.3163-VC), the method of G. Knight et al. [FEBS Letters, Vol. 296, No. 3, 263-266 (1992)] was partially modified and measured. That is, a P-9 enzyme solution 180 ^ 1 in a fluoro Nunc plate (96C) white (No. 437842), a sample dissolved in DMS0 (compound of the present invention) {μ}, and a 100 ^ Μ dissolved in DMS0 Of fluorescent peptide substrate 101 (maximum concentration 5Μ) was added and reacted at 37 ° C for 3 hours in the dark. After completion of the reaction, the fluorescence intensity was measured (excitation wavelength: 327 nm, fluorescence wavelength: 400 nm) using a wavelength variable type fluorescence plate reader, Sectron FL-2575 (manufactured by Towa Kagaku Co., Ltd.). The MMP-9 enzyme activity is determined by measuring the amount of degradation products after the reaction based on the change in relative fluorescence intensity.The inhibitory rate of the enzyme activity by the inhibitor is determined by the relative amount of the inhibitor-added group and the non-added group after the reaction. It was calculated by comparing the fluorescence intensities.

In addition, since MMP-9 exists as an inactive precursor, 150 mM 4_aminophenylmercuric acetate (APMA, Tokyo No. A0395, Code No. A0395) was added to 1 / g / ml enzyme solution 1490 1 beforehand. After addition (final concentration: lraM), the mixture was allowed to stand at 37 ° C for 4 hours to convert to an active form, and then tested for enzyme inhibitory activity. The enzyme was diluted with 50 mM Tris-HCl (pH 7.5) containing 0.1 M NaCK, 10 mM CaCl ₂ , 0.05% Brij 35 and 0.02% NaN ₃ .

The MP-9 inhibitory activity was measured once or twice each, and the results are shown in Tables 14 and 15.

Table 14

表 15

Table 15

Awake P-9 inhibitory activity of the compound of formula (I)

Compound IC ₅₀ value mol / 1) Compound IC / \)

Object No. 1st 2nd average Material No. 1st 2nd average

 4 2 0 .9 1 .0 1 .0 6 0 6 .0 9 .6 7 .8

4 3 2 .9 2 • 7 2 .8 6 3 6 .3 6. 3

4 4 5 .6 5 .7 5 .7 7 0 5 .5 3 .9 4 .7

4 5 0 .9 1 .3 1 .1 7 1 1 .0 1 .0 1 .0

4 6 1 .3 1 .5 1 .4 7 2 1 .2 1 .4 1 .3

4 7 0 .8 1 .2 1 .0 7 3 0 .4 9 0 .3 3 0 .4 1

480.50.80.0.77 40.7.30.0.560.6.5

5 2 5 .8 4 .5 5 .2 7 5 1 .3 1 .0 1 .2

 S

 5 3 9 .9 8 .9 9 .4 7 6 1 .01 1 .1 1 .1

5 5 0 .9 1-1 1 .0 7 7 3 .9 5 .0 4 .5

5 6 4. 0 3 • 5 3 .8 7 8 0 .9 1 .5 1 .2

59.9.49.4.790.0.9 Test Example 2: Inhibitory effect of Meth A / AD on tumor growth

(l) Preparation of Meth A / AD strain showing adhesive growth in vitro

An In vi Meth A mouse fibrosarcoma cell (given test from Sasaki Institute) showing a floating proliferative in tro a 39 ° C, 5% C0 ₂ under a 10-day culture [10% © shea fetal serum-containing RPMI medium (Fl ow Laboratories), and then inoculated subcutaneously into BALB / c mice. The tumor 30 days after growth was excised, excised into a single cell by passing through a metal mesh, returned to in vitro again, and cultured (37 ° C). When the subculture was repeated for about one month, a Meth A / AD cell line that adhered to the culture dish and grew stably was obtained. The Meth A / AD strain showed almost the same doubling time and cell growth in vitro as the parent strain, but the subcutaneous or intradermal growth rate in vivo was slower, 1/2 to 1/3 of that of the parent strain. In addition, the Meth A / AD strain did not show the intraperitoneal growth of mice found in the parent strain. On the other hand, Meth A / AD The strain always produces and secretes MMP-2 in the in vitro culture supernatant, but when TNF- (50 ηg / ml) is added to the culture solution, solid P-9 is remarkably produced, and the strain is clearly identified as the parent strain. It showed different traits.

(2) Inhibitory effect of Meth A / AD strain on tumor growth in vivo

5 weeks old, back intradermally, in vi IX 10 ⁶ pieces of Meth A / AD cells (0.1 Hanks balanced salt 05ml cultured in tro of male BALB / c AnNCrj mice (purchased from Japan Chiya one Rusuriba I) (Suspension in the solution) was transplanted (Day 0). Two hours after cell inoculation and Oayl-4, Day7-; L1 was intraperitoneally administered with the test agent once a day (10 times in total) (in a volume of 10 ml / kg). Compounds were administered suspended in 1% Tween 80 / saline. In the vehicle control group, only the vehicle containing no test drug was similarly administered.

Body weight measurement and general symptom observation were performed daily until Day 22 or 24, and tumor diameters (long and short diameters) were measured every other day with calipers to evaluate the difference in tumor volume between the solvent control group and the drug-treated group. The tumor volume was calculated according to the formula of [(major axis) X (minor axis) ² X 1/2].

(3) Results

 Compound No. 21 and Compound No. 24 showed a statistically significant inhibition of tumor growth as compared with the vehicle control group.

 Table 16

試験例 3 ： Colon26/ADの実験的肺転移に対する抑制効果

Test Example 3: Inhibitory effect of Colon26 / AD on experimental lung metastasis

 (1) Preparation of [01011 26 / AD cell line that highly expresses? -9

Colon 26 mouse colon cancer cells (distributed from the Cancer Research Institute Cancer Institute) were implanted subcutaneously in BALB / c mice, and 10 days later, the proliferating tumor was removed. Single cells obtained by chopping in Hanks' balanced salt solution and passing through a metal mesh are in vitro (37 ° C, 5 ° C). C0 ₂₎ in culture [10% © Shea fetal serum-containing Dulbecco's Modified Eagle Medium (Sigma Co., No.D-5648) used] was. After several subcultures, a Co Ion 26 / AD cell line that adhered to the culture dish and grew stably was obtained. The cell line constantly produces and secretes MMP-2 in the culture supernatant in vitro, but when TNF- "(50 ng / ml) is added to the culture and cultured, MMP-9 is significantly produced. However, the trait was clearly different from that of the parent strain.

 (2) Effect of Col on 26 / AD on experimental lung metastasis

From the tail vein of a 6-week-old male BALB / c AnNCrj mouse (purchased from Nippon Charls River), 3X10 ⁴ Colon 26 / AD cells cultured in vitro [0.2 ml of Minimum Essential Medium (Nissi (Made by Pharmaceutical Co.) was transplanted (Day 0). The test substance is suspended in 1% Tween 80 / physiological diet immediately before cell transplantation (within 2 minutes), 2 hours later, and once a day each on ay 1-4 and Day 7-11 (total 11 times). (Administered in a volume of 10 ml / kg). In the solvent control group, only the solvent containing no test drug was similarly administered. On Day 14 or 15, the lungs of each mouse were excised and weighed, and the metastasis inhibition rate was calculated according to the following equation.

Suppression rate {1-( _a — b) Z (c-b)} X100

a: Lung weight of drug treated group (g)

b: Average lung weight of normal group (g)

c: Average lung weight of vehicle control group (g)

 (3) Results

Compound No. 13, Compound No. 19 and Compound No. 21 showed a statistically significant suppression of lung metastasis as compared with the vehicle control group.

Table 17

 Inhibitory effect of compounds No.13, No.19 and o.21 on experimental lung metastasis of Colon 26 / AD (ip injection) Note) * p <0.05 (t-test)

 Dosage Dose to vehicle control group

 (mg / kgX 1 time) Number of animals Lung metastasis suppression rate (%) Compound No. 13 50 6 43 * Compound No. 19 50 6 35,

Compound No. 21 50 6 56 *

Claims

The scope of the claims  1. Formula (I): _H ,  N-N 0 ₂ N (H) C = QH NR ²  H [Wherein, R ¹ is an optionally substituted heterocyclic group; R ² is a substituted alkyl group] or a ditrothetenamine derivative represented by the following formula: 2. The substituent of the optionally substituted heterocyclic group represented by R ¹ may be substituted with an alkoxy, an alkoxyalkoxy, a heterocyclic oxy, a halogen atom or a hydroxyl group; an alkyl group; an alkoxy, an alkoxyalkoxy, A heterocyclic group, an alkoxy group optionally substituted with a halogen atom or a hydroxyl group; an alkoxy group, an alkoxyalkoxy group, a heterocyclic oxy group, an alkenyloxy group optionally substituted with a halogen atom or a hydroxyl group; or a halogen atom. (1) Nitroethenamine derivative or a salt thereof. 3. A heterocyclic group in which the substituent of the substituted alkyl group represented by R ² may be substituted with alkyl or alkoxy; alkoxy, alkoxyalkoxy, heterocyclic oxy, alkoxy which may be substituted with a halogen atom or a hydroxyl group A heterocyclic oxy group which may be substituted with alkyl or alkoxy; an alkoxy, alkoxyalkoxy, heterocyclic group, an alkylthio group which may be substituted with a halogen atom or a hydroxyl group; alkoxy, alkoxyalkoxy, heterocyclic An alkylsulfyl group which may be substituted with an oxy, halogen atom or hydroxyl group; an alkoxy, an alkoxyalkoxy, a heterocyclic oxy, an alkylsulfonyl group which may be substituted with a halogen atom or a hydroxyl group;て もAmino group; two Toroeten'amin derivative or salt thereof according to Claim 1 which is or a hydroxyl group; Yoi Amino force Ruponiru group optionally substituted by alkyl or alkylcarbonyl. 4. The compound of formula (I) is (R) -N-tetrahydrofurfuryl-1- (2- (5-chloro-2-pi Lysyl) hydrazino) -2-nitroethenamine or (S) -N-tetrahydrofurofurfuryl_1— (2- (5-chloro-2-pyridyl) hydrazino) -2-nitroethenamine A nitrothethenamine derivative or a salt thereof according to range 1.  5. A pharmaceutical composition comprising the nitretheneamine derivative of claim 1 or a salt thereof as an active ingredient.  6. A matrix metalloproteinase enzyme inhibitor comprising the nitretheneamine derivative of claim 1 or a salt thereof as an active ingredient.  7. The matrix according to claim 6, wherein the matrix inhibits at least one matrix metalloproteinase selected from MMP-1, MMP-2, MMP-3, MMP-7 and MMP-9. Metalloproteinase enzyme inhibitors.  8. The enzyme inhibitor of matrix meta-oral proteinase according to claim 7, which inhibits MMP-9.  9. An angiogenesis inhibitor comprising the nitretheneamine derivative of claim 1 or a salt thereof as an active ingredient.  10. A carcinostatic agent comprising the nitroethenamine derivative of claim 1 or a salt thereof as an active ingredient.  11. A cancer invasion inhibitor comprising the nitroethenamine derivative of claim 1 or a salt thereof as an active ingredient.  12. A cancer metastasis inhibitor comprising the nitroethenamine derivative of claim 1 or a salt thereof as an active ingredient.  13. A therapeutic or prophylactic agent for rheumatoid arthritis, comprising the nitrotrothenamine derivative of claim 1 or a salt thereof as an active ingredient.