JP2001335575A - Nitroethenamine derivative or its salt and medicine preparation containing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an MMP enzyme inhibitor suitable as a neovascularization inhibitor useful for treating or preventing cancers and inflammatory diseases, a carcinostatic agent, a cancerous infiltratus inhibitor, a metastasis inhibitor, a therapeutic agent and a prophylactic for a arthritis such as rheumatoid arthritis, arthrosis deformans, rheumatic arthritis, etc., and also suitable as a therapeutic agent and a prophylactic for various diseases such as gingivitis, glomerular nephritis, interstitial nephritis, cerebrospinal meningitis, arteriosclerosis, liver cirrhosis, blood vessel reocclusion/restenosis, retinopathy of diabetes mellitus, neovascular glaucoma, corneal ulcer, epidermolysis bullosa, hernia of intervertebral disk, bone absorption diseases such as osteoporosis, etc., multiple sclerosis, bronchial asthma, Alzheimer's dementia, autoimmune disease (Crohn disease, Sjogren's disease, etc.), etc. SOLUTION: This nitroethenamine derivative is represented by general formula (I) (R1 is a substitutable heterocyclic group; R2 is a substituted alkyl group) or its salt. The medicine preparation contains the derivative or its salt.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel nitroethenamine derivative having matrix metalloproteinase inhibitory activity or a salt thereof, and a pharmaceutical composition containing them.

[0002]

The connective tissue of higher organisms is composed of an extracellular matrix. The extracellular matrix maintains homeostasis of biological functions while repeating new formation and decomposition (reconstruction) according to the function and form of the target tissue. Matrix metalloproteinase (MMP) is a main enzyme involved in the degradation of extracellular matrix, and is characterized by having a divalent zinc ion at its active center. Approx. 20 to date, including secreted and membrane-bound
The existence of various types of MMPs has been elucidated, and the physiological functions and biodistribution of each molecule are being elucidated. MMP in a normal living body acts in a place where reconstitution of tissue is necessary, such as in fetal development and wound healing. However, a strict regulatory mechanism (expression regulation or feedback control) functions to prevent extracellular matrix from being destroyed more than necessary. That is, MMP is usually secreted as an inactive form by an external stimulus, and then converted to an active form by various proteases. On the other hand, the degradation activity by MMP
Its endogenous inhibitor, TIMP (tissue inhibitor)
of metalloproteinase). However, once the regulation mechanism becomes abnormal and the MMP becomes excessive, various tissue lesions are induced.

[0003] For example, IV which is a main component of basement membrane
MMP with strong degrading activity against type collagen
9 (gelatinase B / 92kDa type IV collagenase)
Usually, almost no expression is observed in epithelial cells in normal human tissues. On the other hand, overexpression is observed in many epithelial cancer cells including breast cancer and lung cancer and blood cancer cells. A positive correlation has been observed between MMP-9 expression levels and metastatic potential in colorectal cancer [M. Nakajima et al., Jo
urnal of National Cancer Institute, Vol. 82, 1890,
(1990)]. MMP-9 and MMP-2 (gelatinase A /
It has also been experimentally shown that various types of cancer cells have enhanced metastatic or invasive ability of cancer cells that highly express 72 kDa type IV collagenase) as compared to low-expressing cells [(DRWelch et al. , Proceedings of the National Acad
emy of Sciences of the UnitedStates of America, Vo
l. 87, 7687, (1990), S. Yamagata et al., Biochemical a
nd Biophysical Research Communication, Vol. 151, 1
86-162, (1988)]. MMP-13 (collagenase 3) is not expressed in normal tissues, but is highly expressed in breast cancer cells [JM Freije, M Nakajima et al., Journa
l of Biological Chemistry, Vol. 269, 16766-76773,
(1994)].

[0004] As described above, metastatic cancer cells having a high degree of malignancy have abnormal motility, adhesiveness, and tissue invasiveness in addition to the abnormal proliferative properties inherent to tumorigenic cells. One involves the overproduction of MMPs.

In addition, MMPs are involved in pseudolumen formation of cultured vascular endothelial cells [R. Montesano et al., Cell, Vol.
42, 469-477, (1985)] that MMPs act as one of angiogenic factors and promote tumor growth [T. Itoh et al., Canc.
er Research, Vol. 58, 1048-1051, (1998)], TIM
Melanoma cells overexpressing P-2 have reduced tissue wetting ability and angiogenesis-inducing ability [P. Valente et al., In
ternational Journal of cancer, Vol 75, 246-253 (1998)]
Is already known.

[0006] On the other hand, inflammatory cytokines are induced at the joint site for some reason, and MMP-
When 1 (interstitial collagenase) and MMP-3 (stromlysin 1) are excessively produced and stored in a large amount in synovial fluid, they act on articular cartilage to cause the destruction of the cartilage matrix, resulting in pain and range of motion of joints. A so-called arthritis-like disease typified by symptoms such as suppression, deformation and the like is caused.

[0007] Furthermore, in coronary artery disease, MMP promotes the migration of smooth muscle cells from the vessel wall to the intima, and promotes the formation of atherosclerotic plaques. In addition, it is involved in restenosis after angioplasty in the treatment of angina [DC Ce
lentano et al., Journal of Clinical Pharmacology, Vol.
37, 991-1000, (1997)].

In addition, in gingivitis, enhanced production of MMP-1 (interstitial collagenase) is observed.

[0009] As described above, MMP has a wide range of physiological actions in living organisms, and its overproduction disrupts the homeostasis of living organisms, and induces new diseases or worsens the pathological conditions.
Therefore, MMP enzyme inhibitors are used as angiogenesis inhibitors, anticancer agents, cancer invasion inhibitors, cancer metastasis inhibitors used for the treatment or prevention of cancer and inflammatory diseases; rheumatoid arthritis, osteoarthritis, rheumatoid arthritis, etc. For the treatment and prevention of arthritis of gingivitis, glomerulonephritis, interstitial nephritis, encephalomyelitis, arteriosclerosis,
Cirrhosis, vascular restenosis / restenosis, diabetic retinopathy, neovascular glaucoma, corneal ulcer, epidermolysis bullosa, herniated disc,
Bone resorption diseases such as osteoporosis, multiple sclerosis, bronchial asthma,
Alzheimer's disease, autoimmune diseases (Crohn's disease,
It is considered to be useful as an agent for treating or preventing various diseases such as Sjogren's disease.

[0010]

Many compounds having an MMP inhibitory action have been reported so far [RA Nigel
Et al., Current Opinion on Therapeutic Patents, Vol.
4, 7-16, (1994), RP Beckett et al., Drug Discovery To
day, Vol. 1, 16-26, (1996)], but many of them are MM
P is a peptide derivative designed based on the amino acid sequence of the enzyme cleavage site in the collagen molecule serving as a substrate for P,
Examples include hydroxamic acid type compounds; thiol type compounds; carboxylic acid type compounds; phosphonate type compounds; and phosphinate type compounds. Some of these compounds, mainly hydroxamic acid derivatives, have been subjected to clinical trials for diseases such as cancer and arthritis.

MMP having a peptide as a basic skeleton
Enzyme inhibitors have low oral absorption, especially hydroxamic acid type MMP enzyme inhibitors are said to have poor stability in plasma, and carboxylic acid type MMP enzyme inhibitors have high binding to plasma proteins, It is known that it is difficult to excrete. In order to overcome these problems, creation of new non-peptidic compounds has been attempted [A. Katrin et al.
Journal of Medicinal Chemistry, Vol. 41, 2194-220
0, (1998)]. Recently, an MMP inhibitor containing a flavone or anthocyanidin as an active ingredient described in JP-A-8-104628, a condensed thiophene derivative-based MMP inhibitor described in JP-A-10-130271, and the like have been disclosed. Are known. However, a pharmaceutical composition comprising a non-peptide nitroethenamine derivative or a salt thereof as an active ingredient as in the present invention has an MMP enzyme inhibitory activity, particularly, MMP-9 (gelatinase B / 92 kDa type IV collagenase). It is not known to have a potent and selective enzyme inhibitory activity.

[0012]

BACKGROUND OF THE INVENTION Compounds similar to the nitroethenamine derivatives of the present invention have been used as analgesics (WO 97/179).
54). However, the compounds of the present invention are not known. Furthermore, Japanese Patent Publication No. 58-404956 describes a compound similar to the nitroethenamine 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 nitroethenamine derivative. Further, there is no description in this publication that this compound has an MMP enzyme inhibitory action.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION The present inventors have conducted intensive studies on the synthesis of compounds having an MMP enzyme inhibitory activity and their pharmacological activities. The nitroethenamine derivative of the present invention or a salt thereof has been found as a non-peptide compound having the compound.

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

Embedded image [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 them.

The salt of the nitroethenamine derivative represented by the formula (I) may be a pharmaceutically acceptable salt, for example, a mineral acid salt such as hydrochloride, sulfate, nitrate, etc .; Organic acid salts such as acid salts, propanesulfonic acid salts and methanesulfonic acid salts; alkali metal salts such as potassium salts and sodium salts; alkaline earth metal salts such as calcium salts; triethanolamine salts; Organic amine salts such as methyl) aminomethane salt and the like. 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 is a pyrrolyl group, a pyrrolinyl group, a pyrrolidinyl group, a furanyl group, a dihydrofuranyl group, a tetrahydrofuranyl group. , Thienyl group, dihydrothienyl group, tetrahydrothienyl group, pyrazolyl group, pyrazolinyl group, pyrazolidinyl group, imidazolyl group, imidazolinyl group, imidazolidinyl group, oxazolyl group, oxazolinyl group, oxazolidinyl group, isoxazolyl group, isoxazolinyl group, isoxa Zolidinyl group, thiazolyl group, thiazolinyl group, thiazolidinyl group, isothiazolyl group, isothiazolinyl group, isothiazolidinyl group, oxadiazolyl group, oxadiazolinyl group, oxadiazolidinyl group, thiadiazolyl group,
Thiadiazolinyl group, thiadiazolidinyl group, triazolyl group, triazolinyl group, triazolidinyl group, tetrazolyl group, tetrazolinyl group, tetrazolidinyl group,
Dioxolyl group, dioxolanyl group, dithiolyl group, dithiolanyl group, pyridyl group, dihydropyridyl group, tetrahydropyridyl group, piperidinyl group, pyrimidyl group,
Dihydropyrimidyl, tetrahydropyrimidyl, hexahydropyrimidyl, pyridazinyl, dihydropyridazinyl, tetrahydropyridazinyl, hexahydropyridazinyl, pyrazinyl, dihydropyrazini Monocyclic heterocyclic groups such as phenyl group, tetrahydropyrazinyl group, piperazinyl group, pyranyl group, dihydropyranyl group, tetrahydropyranyl group, dioxinyl group, dioxenyl group, dioxanyl group, dithianyl group, morpholinyl group; thienothienyl group , Dihydrocyclopentathienyl, indolyl, tetrahydroindolyl, isoindolyl, tetrahydroisoindolyl, benzothienyl, tetrahydrobenzothienyl, benzofuranyl, tetrahydrobenzofuranyl, benzoxazolyl, tetrahi Lobenzoxazolyl, benzoisoxazolyl, tetrahydrobenzoisoxazolyl, benzothiazolyl, tetrahydrobenzothiazolyl, benzoisothiazolyl, tetrahydrobenzoisothiazolyl, benzimidazolyl, tetrahydrobenzoimidazolyl Group, benzodioxolyl group, benzodithiolyl group, benzodioxanyl group, benzodithianyl group, quinolinyl group, isoquinolinyl group, quinazolinyl group, quinoxalinyl group, phthalazinyl group, naphthyridinyl group, condensed polycyclic heterocycle such as purinyl group A ring group; a cross-linked polycyclic heterocyclic group such as a quinuclidinyl group; Among them, furanyl group, tetrahydrofuranyl group, thienyl group, imidazolyl group,
Dioxolanyl group, pyridyl group, piperidinyl group, pyrazinyl group, piperazinyl group, tetrahydropyranyl group,
A dioxanyl, morphonyl, benzothiazolyl or quinolinyl group is preferred.

The alkyl moiety of the substituted alkyl group represented by R ² generally has 1 to 18 carbon atoms, for example, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group,
Examples include a hexyl group, an octyl group, a nonyl group, a decyl group, a nonadecyl group, and the like, including those having a linear or branched aliphatic chain with structural isomerism.

The substituent of the optionally substituted heterocyclic group represented by R ¹ includes a substituted alkyl group, a substituted alkenyl group, a substituted alkynyl group, a substituted cycloalkyl group, a substituted cycloalkenyl group. A substituted aryl group, a substituted heterocyclic group, a substituted alkoxy group, a substituted alkenyloxy group, a substituted alkynyloxy group, a substituted cycloalkoxy group, a substituted cycloalkenyloxy group, a substituted aryloxy group, a substituted Heterocyclic oxy group, substituted alkylthio group, substituted alkenylthio group, substituted alkynylthio group, substituted cycloalkylthio group, substituted cycloalkenylthio group, substituted arylthio group, substituted heterocyclic thio group, substituted alkyl Carbonyl group, substituted alkenylcarbonyl group, substituted alkynylcarbonyl group, substituted cycloalkyl Carbonyl group, substituted cycloalkenylcarbonyl group, substituted arylcarbonyl group, substituted heterocyclic carbonyl group, substituted alkoxycarbonyl group, substituted alkenyloxycarbonyl group, substituted alkynyloxycarbonyl group, substituted cycloalkyloxycarbonyl group , Substituted cycloalkenyloxycarbonyl group, substituted aryloxycarbonyl group, substituted heterocyclic oxycarbonyl group, substituted alkylcarbonyloxy group, substituted alkenylcarbonyloxy group, substituted alkynylcarbonyloxy group, substituted cycloalkylcarbonyl Oxy group, substituted cycloalkenylcarbonyloxy group, substituted arylcarbonyloxy group, substituted heterocyclic carbonyloxy group, substituted alkylsulfonyl group, substituted alkenylsulfonyl group, A substitutable alkynylsulfonyl group, a substitutable cycloalkylsulfonyl group,
Substituted cycloalkenylsulfonyl group, substituted arylsulfonyl group, substituted heterocyclic sulfonyl group, substituted alkyloxysulfonyl group, substituted alkenyloxysulfonyl group, substituted alkynyloxysulfonyl group, substituted cycloalkyloxysulfonyl group, substituted Cycloalkenyloxysulfonyl group, substituted aryloxysulfonyl group, substituted heterocyclic oxysulfonyl group, substituted alkylsulfonyloxy group, substituted alkenylsulfonyloxy group, substituted alkynylsulfonyloxy group,
Substituted cycloalkylsulfonyloxy group, substituted cycloalkenylsulfonyloxy group, substituted arylsulfonyloxy group, substituted heterocyclic sulfonyloxy group, substituted amino group, substituted aminocarbonyl group, substituted hydroxyaminocarbonyl group, halogen Atom, cyano group,
Examples include 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. The number of the substituents may be one or two or more. When the number of the substituents is two or more, they may be the same or different.

The substituent of the substituted alkyl group represented by R ² includes a substitutable alkenyl group, a substitutable alkynyl group, a substitutable cycloalkyl group, a substitutable cycloalkenyl group, a substitutable aryl group, and a substitutable 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 arylthio group, substituted heterocyclic thio group, substituted alkylcarbonyl group, substituted alkenylcarbonyl group, substituted Alkynylcarbonyl group, substitutable cycloalkylcarbonyl group, substitutable cycloal Nilcarbonyl group, substituted arylcarbonyl group, substituted heterocyclic carbonyl group, substituted alkoxycarbonyl group, substituted alkenyloxycarbonyl group, substituted alkynyloxycarbonyl group, substituted cycloalkyloxycarbonyl group, substituted cycloalkenyloxy group Carbonyl group, substituted aryloxycarbonyl group, substituted heterocyclic oxycarbonyl group, substituted alkylcarbonyloxy group, substituted alkenylcarbonyloxy group, substituted alkynylcarbonyloxy group,
Substituted cycloalkylcarbonyloxy group, substituted cycloalkenylcarbonyloxy group, substituted arylcarbonyloxy group, substituted heterocyclic carbonyloxy group, substituted alkylsulfinyl group, substituted alkylsulfonyl group, substituted alkenylsulfonyl group, substituted Alkynylsulfonyl group, substituted cycloalkylsulfonyl group,
Substituted cycloalkenylsulfonyl group, substituted arylsulfonyl group, substituted heterocyclic sulfonyl group, substituted alkyloxysulfonyl group, substituted alkenyloxysulfonyl group, substituted alkynyloxysulfonyl group, substituted cycloalkyloxysulfonyl group, substituted Cycloalkenyloxysulfonyl, substituted aryloxysulfonyl group, substituted heterocyclic oxysulfonyl group, substituted alkylsulfonyloxy group, substituted alkenylsulfonyloxy group, substituted alkynylsulfonyloxy group, substituted cycloalkylsulfonyloxy group, Substituted cycloalkenylsulfonyloxy group, substituted arylsulfonyloxy group, substituted heterocyclic sulfonyloxy group, substituted amino group, substituted aminocarbonyl group, substituted hydroxyaminocarbo Group, a halogen atom, a cyano 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 aminocarbonyl group or a hydroxyl group is desirable. The number of those 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 alkyl, alkenyl and alkynyl moieties of the secondary substituent are cycloalkyl, cycloalkenyl, aryl, heterocyclic, alkoxy, haloalkoxy, alkoxyalkoxy, alkylthioalkoxy, alkenyloxy, haloalkenyloxy, alkynyloxy , Haloalkynyloxy, cycloalkyloxy, cycloalkenyloxy, aryloxy, heterocyclic oxy, alkylthio, haloalkylthio, alkoxyalkylthio, alkylthioalkylthio, alkenylthio, haloalkenylthio, alkynylthio, haloalkynylthio, cycloalkylthio, cycloalkenyl Thio, arylthio, heterocyclic thio, alkylcarbonyl, haloalkylcarbonyl, alkoxyalkylcarbonyl, alkyl Oh alkylcarbonyl, alkenylcarbonyl, halo alkenylcarbonyl, alkynylcarbonyl, halo alkynylcarbonyl, cycloalkylcarbonyl, cycloalkenyl, arylcarbonyl, heterocyclic carbonyl, alkoxycarbonyl,
Haloalkoxycarbonyl, alkoxyalkoxycarbonyl, alkylthioalkoxycarbonyl, alkenyloxycarbonyl, haloalkenyloxycarbonyl, alkynyloxycarbonyl, haloalkynyloxycarbonyl, cycloalkyloxycarbonyl, cycloalkenyloxycarbonyl, aryloxycarbonyl, heterocyclic oxycarbonyl, alkyl Carbonyloxy, haloalkylcarbonyloxy, alkoxyalkylcarbonyloxy, alkylthioalkylcarbonyloxy, alkenylcarbonyloxy, haloalkenylcarbonyloxy, alkynylcarbonyloxy, haloalkynylcarbonyloxy, cycloalkylcarbonyloxy, cycloalkenylcarbonyloxy, arylcarbonyloxy , Heterocyclic carbonyloxy, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkylsulfonyl, alkylthioalkylsulfonyl, alkenylsulfonyl, haloalkenylsulfonyl, alkynylsulfonyl, haloalkynylsulfonyl, cycloalkylsulfonyl, cycloalkenylsulfonyl, arylsulfonyl, heterocyclesulfonyl, alkoxy Sulfonyl, haloalkoxysulfonyl, alkoxyalkoxysulfonyl, alkylthioalkoxysulfonyl, alkenyloxysulfonyl, haloalkenyloxysulfonyl, alkynyloxysulfonyl, haloalkynyloxysulfonyl, cycloalkyloxysulfonyl, cycloalkenyloxysulfonyl, aryloxysulfonyl, heterocyclic oxysulfonyl , Alkylsulfonyloxy, haloalkylsulfonyloxy, alkoxyalkylsulfonyloxy, alkylthioalkylsulfonyloxy, alkenylsulfonyloxy, haloalkenylsulfonyloxy, alkynylsulfonyloxy, haloalkynylsulfonyloxy, cycloalkylsulfonyloxy, cycloalkenylsulfonyloxy, arylsulfonyl Oxy, heterocyclic sulfonyloxy, amino, alkylamino, dialkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclic amino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkenylaminocarbonyl , Alkynylaminocarbonyl, cycloalkyl Aminocarbonyl, cycloalkenylaminocarbonyl, arylaminocarbonyl, heterocyclic aminocarbonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkenylaminosulfonyl, alkynylaminosulfonyl, cycloalkylaminosulfonyl, cycloalkenylaminosulfonyl, arylaminosulfonyl, Heterocyclic aminosulfonyl, alkylcarbonylamino, haloalkylcarbonylamino, alkoxyalkylcarbonylamino, alkylthioalkylcarbonylamino, alkenylcarbonylamino, haloalkenylcarbonylamino, alkynylcarbonylamino, haloalkynylcarbonylamino, cycloalkylcarbonylamino, cycloalkenylcarbonylamino The ant Le carbonylamino, heterocyclic carbonylamino, alkoxycarbonylamino,
Haloalkoxycarbonylamino, alkoxyalkoxycarbonylamino, alkylthioalkoxycarbonylamino, alkenyloxycarbonylamino, haloalkenyloxycarbonylamino, alkynyloxycarbonylamino, haloalkynyloxycarbonylamino, cycloalkyloxycarbonylamino, cycloalkenyloxycarbonylamino, aryl Oxycarbonylamino, heterocyclic oxycarbonylamino, alkylsulfonylamino, haloalkylsulfonylamino,
Alkoxyalkylsulfonylamino, alkylthioalkylsulfonylamino, alkenylsulfonylamino, haloalkenylsulfonylamino, alkynylsulfonylamino, haloalkynylsulfonylamino, cycloalkylsulfonylamino, cycloalkenylsulfonylamino, arylsulfonylamino, heterocyclesulfonylamino, hydroxyamino, It may be further substituted with a tertiary substituent such as alkoxyamino, hydroxyaminocarbonyl, alkoxyaminocarbonyl, halogen atom, cyano group, nitro group, hydroxyl group, thiol group, carboxyl group, sulfonic acid group and the like. 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, haloalkynyl, cycloalkyl, cycloalkenyl. , Aryl, heterocycle, alkoxy, haloalkoxy, alkoxyalkoxy, alkylthioalkoxy, alkenyloxy, haloalkenyloxy, alkynyloxy, haloalkynyloxy, cycloalkyloxy, cycloalkenyloxy, aryloxy, heterocycleoxy, alkylthio, haloalkylthio , Alkoxyalkylthio, alkylthioalkylthio, alkenylthio, haloalkenylthio, alkynylthio, haloalkynylthio, cyclo Alkylthio, cycloalkenylthio, arylthio, heterocyclic thio, alkylcarbonyl, haloalkylcarbonyl, alkoxyalkylcarbonyl, alkylthioalkylcarbonyl, alkenylcarbonyl, haloalkenylcarbonyl, alkynylcarbonyl, haloalkynylcarbonyl, cycloalkylcarbonyl, cycloalkenylcarbonyl, arylcarbonyl , Heterocyclic carbonyl, alkoxycarbonyl,
Haloalkoxycarbonyl, alkoxyalkoxycarbonyl, alkylthioalkoxycarbonyl, alkenyloxycarbonyl, haloalkenyloxycarbonyl, alkynyloxycarbonyl, haloalkynyloxycarbonyl, cycloalkyloxycarbonyl, cycloalkenyloxycarbonyl, aryloxycarbonyl, heterocyclic oxycarbonyl, alkyl Carbonyloxy, haloalkylcarbonyloxy, alkoxyalkylcarbonyloxy, alkylthioalkylcarbonyloxy, alkenylcarbonyloxy, haloalkenylcarbonyloxy, alkynylcarbonyloxy, haloalkynylcarbonyloxy, cycloalkylcarbonyloxy, cycloalkenylcarbonyloxy, arylcarbonyloxy , Heterocyclic carbonyloxy, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkylsulfonyl, alkylthioalkylsulfonyl, alkenylsulfonyl, haloalkenylsulfonyl, alkynylsulfonyl, haloalkynylsulfonyl, cycloalkylsulfonyl, cycloalkenylsulfonyl, arylsulfonyl, heterocyclesulfonyl, alkoxy Sulfonyl, haloalkoxysulfonyl, alkoxyalkoxysulfonyl, alkylthioalkoxysulfonyl, alkenyloxysulfonyl, haloalkenyloxysulfonyl, alkynyloxysulfonyl, haloalkynyloxysulfonyl, cycloalkyloxysulfonyl, cycloalkenyloxysulfonyl, aryloxysulfonyl, heterocyclic oxysulfonyl , Alkylsulfonyloxy, haloalkylsulfonyloxy, alkoxyalkylsulfonyloxy, alkylthioalkylsulfonyloxy, alkenylsulfonyloxy, haloalkenylsulfonyloxy, alkynylsulfonyloxy, haloalkynylsulfonyloxy, cycloalkylsulfonyloxy, cycloalkenylsulfonyloxy, arylsulfonyl Oxy, heterocyclic sulfonyloxy, amino, alkylamino, dialkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclic amino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkenylaminocarbonyl , Alkynylaminocarbonyl, cycloalkyl Aminocarbonyl, cycloalkenylaminocarbonyl, arylaminocarbonyl, heterocyclic aminocarbonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkenylaminosulfonyl, alkynylaminosulfonyl, cycloalkylaminosulfonyl, cycloalkenylaminosulfonyl, arylaminosulfonyl, Heterocyclic aminosulfonyl, alkylcarbonylamino, haloalkylcarbonylamino, alkoxyalkylcarbonylamino, alkylthioalkylcarbonylamino, alkenylcarbonylamino, haloalkenylcarbonylamino, alkynylcarbonylamino, haloalkynylcarbonylamino, cycloalkylcarbonylamino, cycloalkenylcarbonylamino The ant Le carbonylamino, heterocyclic carbonylamino, alkoxycarbonylamino,
Haloalkoxycarbonylamino, alkoxyalkoxycarbonylamino, alkylthioalkoxycarbonylamino, alkenyloxycarbonylamino, haloalkenyloxycarbonylamino, alkynyloxycarbonylamino, haloalkynyloxycarbonylamino, cycloalkyloxycarbonylamino, cycloalkenyloxycarbonylamino, aryl Oxycarbonylamino, heterocyclic oxycarbonylamino, alkylsulfonylamino, haloalkylsulfonylamino,
Alkoxyalkylsulfonylamino, alkylthioalkylsulfonylamino, alkenylsulfonylamino, haloalkenylsulfonylamino, alkynylsulfonylamino, haloalkynylsulfonylamino, cycloalkylsulfonylamino, cycloalkenylsulfonylamino, arylsulfonylamino, heterocyclesulfonylamino, hydroxyamino, It may be further substituted with a tertiary substituent such as alkoxyamino, hydroxyaminocarbonyl, alkoxyaminocarbonyl, halogen atom, cyano group, nitro group, hydroxyl group, thiol group, carboxyl group, sulfonic acid group and the like. Among them, alkyl or alkoxy is preferable. The number of the substituents may be one or two or more. When the number of the substituents is two or more, they may be the same or different.

The above-mentioned substituted amino group, substituted aminocarbonyl group or substituted hydroxyaminocarbonyl group is
Alkyl, haloalkyl, alkoxyalkyl, alkylthioalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycle, alkylcarbonyl, haloalkylcarbonyl, alkoxyalkylcarbonyl, alkylthioalkylcarbonyl, alkenylcarbonyl, haloalkenyl Carbonyl, alkynylcarbonyl, haloalkynylcarbonyl, cycloalkylcarbonyl, cycloalkenylcarbonyl, arylcarbonyl, heterocyclic carbonyl, alkoxycarbonyl, haloalkoxycarbonyl, alkoxyalkoxycarbonyl, alkylthioalkoxycarbonyl, alkenyloxycarbonyl, haloalkenyloxycarbonyl, alkynyloxy Carboni , Halo alkynyloxycarbonyl, cycloalkyloxycarbonyl, cycloalkyl alkenyloxycarbonyl, aryloxycarbonyl,
Heterocycle oxycarbonyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkylsulfonyl, alkylthioalkylsulfonyl, alkenylsulfonyl, haloalkenylsulfonyl, alkynylsulfonyl, haloalkynylsulfonyl, cycloalkylsulfonyl, cycloalkenylsulfonyl, arylsulfonyl, heterocyclesulfonyl, aminocarbonyl , Alkylaminocarbonyl, dialkylaminocarbonyl, alkenylaminocarbonyl, alkynylaminocarbonyl,
Cycloalkylaminocarbonyl, cycloalkenylaminocarbonyl, arylaminocarbonyl, heterocyclic aminocarbonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkenylaminosulfonyl, alkynylaminosulfonyl, cycloalkylaminosulfonyl, cycloalkenylaminosulfonyl, arylamino It may be further substituted with a tertiary substituent such as sulfonyl, heterocyclic aminosulfonyl, cyano group and hydroxyl group. Among them, alkyl or alkylcarbonyl is desirable. 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.

As the alkyl moiety in the above-mentioned secondary and tertiary substituents, those similar to the alkyl defined as R ² can be mentioned.

The alkenyl moiety in the above-mentioned secondary and tertiary substituents generally has 2 to 18 carbon atoms,
Examples thereof include a vinyl group, a propenyl group, a butenyl group, a pentenyl group, a hexenyl group, a decenyl group, a nonadecenyl group and the like, and these include those having a linear or branched fatty chain with structural isomerism.

The alkynyl moiety in the above-mentioned secondary and tertiary substituents generally has 2 to 18 carbon atoms,
Examples thereof include an ethynyl group, a propynyl group, a butynyl group, a pentynyl group, a hexynyl group, a decynyl group, a nonadecynyl group, and the like, including those having a linear or branched fatty chain with structural isomerism.

The cycloalkyl moiety in the secondary and tertiary substituents generally has 3 to 10 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl and the like. A condensed polycyclic group; an adamantyl group;
Examples include a crosslinked polycyclic group such as a noradamantyl group, a norbornanyl group, and a norbornanyl group.

The cycloalkenyl moiety in the above-mentioned secondary and tertiary substituents 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.

The aryl moiety in the above-mentioned secondary and tertiary substituents includes, in addition to a phenyl group, a condensed polycyclic group such as a naphthyl group.

Examples of the heterocyclic moiety in the above-mentioned secondary and tertiary substituents include those similar to the heterocycle defined as R ¹ . Among them, furanyl group,
Tetrahydrofuranyl group, thienyl group, imidazolyl group, dioxolanyl group, pyridyl group, piperidinyl group,
Pyrazinyl, piperazinyl, tetrahydropyranyl, dioxanyl, morphonyl, benzothiazolyl or quinolinyl are preferred.

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

Production method 1 Formula (II):

Embedded image Wherein Z is an alkyl group or an arylalkyl group, and a compound represented by the formula (III):

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

Embedded image [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):

Embedded image Wherein Y is a hydrogen atom or an alkali metal atom;
R ¹ is as defined above), and a second step of obtaining a nitroethenamine derivative of the formula (I) by reacting the compound with a compound represented by the formula (I): Production method.

Process 2 The compound of the formula (II) is reacted with the compound of the formula (V) to give a compound of the formula (VI):

Embedded image Wherein Z and R ¹ are as defined above, by reacting the compound of the formula (VI) obtained in the first step with the compound of the formula (III) And a second step of obtaining a nitroethenamine derivative of the formula (I).

It should be noted that the starting material used in Production Method 1 and Production Method 2
The compound of the formula (II) and the compounds of the formulas (III) and (V) can be produced by a known method or a method analogous thereto.

Each of the reactions of Production Method 1 and Production Method 2 can be carried out in the presence of a suitable solvent. Specific solvents used include methanol, ethanol, propanol,
Alcohols such as butanol; benzene, toluene,
Aromatic hydrocarbons such as xylene; aliphatic hydrocarbons such as pentane, hexane, heptane, petroleum ether, ligroin, petroleum benzine; ethers such as diethyl ether, dipropyl ether, dibutyl ether, tetrahydrofuran, dioxane; acetonitrile; Nitriles such as propionitrile; acid amides such as dimethylformamide and dimethylacetamide; sulfoxides such as dimethylsulfoxide; sulfones such as sulfolane; phosphoric amides such as hexamethylphosphoramide; chloroform, dichloromethane and tetrachloride Examples thereof include halogenated hydrocarbons such as carbon and 1,2-dichloroethane, and a mixed solvent thereof.

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-undecene and N, N-dimethylaniline; lithium, sodium Alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; lithium hydride and sodium hydride Hydrides of alkali metals, such as potassium hydride;
Alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide and the like can be mentioned. The compound of formula (III) and / or
The compound (V) also acts as a base.

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

In the first step of the production method 1, 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 an excess of the compound of formula (III) is used, in addition to the compound of formula (IV), the compound of formula (VII):

Embedded image [Wherein R ² is as defined above], which is not desirable because it is by-produced. In the second step of the production method 1, the compound of the formula (V) can be used in a proportion of 1 to 1.5 equivalents relative to 1 mol of the compound of the formula (IV). No inconvenience.

In the first step of the production method 2, 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 an excess of the compound of formula (V) is used, in addition to the compound of formula (VI), the compound of formula (VIII):

Embedded image [Wherein R ¹ is as defined above], which is undesirable because it is by-produced. In the second step of the production method 2, the compound of the formula (III) can be used in a proportion of 1 to 1.5 equivalents relative to 1 mol of the compound of the formula (VI),
There is no particular problem even if it is used in excess.

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

The various reaction conditions in Production Method 1 can be appropriately combined with each other.

The various reaction conditions in Production Method 2 can be appropriately combined with each other.

Formula 3 (IX):

Embedded image Wherein X is a halogen atom, and / or a compound represented by the formula (X): O ₂ N—CH ₂ CX _{3 wherein} X is as defined above. Reacting the compound of formula (III) with a compound of formula (XI):

Embedded image Wherein X and R ² are as defined above, and reacting the compound of the formula (XI) obtained in the first step with the compound of the formula (V) By letting
A method for producing a nitroethenamine derivative of the formula (I), comprising a second step of obtaining a nitroethenamine derivative of the formula (I).

Production Method 4 The compound of the formula (IX) and / or the compound of the formula (X) is reacted with the compound of the formula (V) to obtain a compound of the formula (XII):

Embedded image Wherein X and R ¹ are as defined above, and reacting the compound of the formula (XII) obtained in the first step with the compound of the formula (III) A method for producing a nitroethenamine derivative of the formula (I), which comprises a second step of obtaining a nitroethenamine derivative of the formula (I).

It should be noted that the starting material used in Production Method 3 and Production Method 4
Compounds of formula (IX) and compounds of formula (X) are, for example, Journal
f Organic compounds can be produced by a known method described in Organic Chemistry. Vol 25.1312 (1960) or a method analogous thereto.

Each reaction of Production Method 3 and Production Method 4 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, ligroin, petroleum benzine; diethyl ether and dipropyl ether Ethers such as, dibutyl ether, tetrahydrofuran and dioxane; nitriles such as acetonitrile and propionitrile; acid amides such as dimethylformamide and dimethylacetamide; sulfoxides such as dimethyl sulfoxide; sulfones such as sulfolane; hexamethylphosphor Examples thereof include phosphoric amides such as amides; halogenated hydrocarbons such as chloroform, dichloromethane, carbon tetrachloride, and 1,2-dichloroethane, and mixed solvents thereof.

In Production Methods 3 and 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 as those used in Production Methods 1 and 2. The compound of the formula (III) and / or the compound of the formula (V) also acts as a base.

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

In the first step of Process 3, 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) can be used in a proportion of 1 to 1.5 equivalents relative to 1 mol of the compound of the formula (XI). Absent.

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 proportion of 1 to 1.5 equivalents relative to 1 mol of the compound of the formula (XII). Absent.

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 can be separated and purified by known means such as concentration, concentration under reduced pressure, solvent extraction, recrystallization, chromatography and the like. After or as a reaction mixture, it may be subjected to the reaction of the next step for producing the compound of the formula (I).

The various reaction conditions in Production Method 3 can be appropriately combined with each other.

The various reaction conditions in Production Method 4 can be appropriately combined with each other.

Process 5 A compound represented by the formula (V) and a compound represented by the formula (XIII): R ² -NCS
Wherein R ² is as defined above, and reacted with a compound of the formula (XIV):

Embedded image Wherein R ¹ and R ² are as defined above, a compound of the formula (XIV) obtained in the first step, a compound of the formula (XV): ZX Wherein Z and X are as defined above, and reacted with a compound of the formula (XV
I):

Embedded image [Wherein Z, R ¹ and R ² are as defined above], a second step for obtaining a compound represented by the formula (XV
By reacting the compound of I) with nitromethane, the formula
A method for producing a nitroethenamine derivative of the formula (I), comprising a third step of obtaining a nitroethenamine derivative of the formula (I).

The reaction in the first 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 first step of Production method 5, 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 the base used include organic bases such as triethylamine, pyridine, N-methylmorpholine, 1,8-diazabicyclo [5,4,0] -7-undecene and N, N-dimethylaniline; lithium carbonate, Carbonates of alkali metals such as sodium carbonate and potassium carbonate; lithium hydrogen carbonate,
Examples include alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate. The compound of the formula (V) also acts as a base.

The reaction in the first step of Production Method 5 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.

In the first step of Process 5, 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) is separated by a known means, for example, concentration, concentration under reduced pressure, solvent extraction, recrystallization, chromatography and the like.
It may be subjected to the reaction of the step.

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

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

The reaction in the second step of Production Method 5 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.

In the reaction of the second step of Production method 5, the compound of the formula (XIV)
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 (I). Various compounds can be used as the compound of the formula (XV). For example, benzyl bromide, methyl iodide and the like can be used. The obtained compound of the formula (XVI) may be subjected to the reaction in the third step after separation and purification by a known means such as concentration, concentration under reduced pressure, solvent extraction, recrystallization, chromatography or the like or the reaction mixture as it is.

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

The reaction in the third step of Production Method 5 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.

In the reaction of the third step of Production Method 5, the compound of the formula (XVI)
Nitromethane can be used in a ratio of 0.8 to 2 equivalents, preferably 1 to 1.5 equivalents to 1 mol of the compound of the formula (I), but nitromethane can also be used as a solvent. There is no.

The various reaction conditions in Production Method 5 can be combined with one another as appropriate.

Production Method 6 Formula (XVII):

Embedded image Wherein R ² is as defined above and a halogenating agent to obtain a compound of the formula (XI), a first step, and a compound represented by the formula (XI ) And a compound of the above formula
A method for producing a nitroethenamine derivative of the formula (I), comprising a second step of obtaining a compound of the formula (I) by reacting the compound with the compound of the formula (V).

Production method 7 Formula (XVIII):

Embedded image Wherein R ¹ is as defined above, and a halogenating agent to obtain a compound of the formula (XII). ) And
By reacting the compound of the formula (III), the compound of the formula (I)
A method for producing a nitroethenamine derivative of the formula (I), which comprises a second step of obtaining a compound of the formula (I).

It should be noted that the starting materials of the production methods 6 and 7
The compound of the formula (XVII) and the compound of the formula (XVIII) can be produced by a known method or a method analogous thereto.

The reaction in the first step of Production Method 6 and the first step of 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, ligroin, petroleum benzine; diethyl ether and dipropyl ether And ethers such as dibutyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform, dichloromethane, carbon tetrachloride and 1,2-dichloroethane, and mixed solvents thereof. The reaction is desirably performed in a system without water.

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 includes, for example, phosphorus pentachloride, phosphorus oxychloride, phosphorus trichloride, thionyl chloride, oxalyl chloride and the like. 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 (XVIII). Further, it is desirable that a base coexist in order to capture hydrogen chloride generated in this reaction.Examples of such a base include triethylamine, pyridine, N-methylmorpholine, 1,8-diazabicyclo [5,4,0 -7-undecene,
Organic bases such as N, N-dimethylaniline can be mentioned.

The reaction in 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 200 ° C.
The reaction is performed at a reaction temperature of 150 ° C. The reaction time is between 0.1 and 48 hours.

The compound of the formula (XI) obtained in the first step of the production method 6 and the compound of the formula (XII) obtained in the first step of the production method 7 can be obtained by a known method such as concentration, concentration under reduced pressure, solvent extraction, and recrystallization. After the separation and purification by chromatography or the like, or as a reaction mixture, the reaction of the second step of the production method 6 which is the same reaction as the second step of the production method 3, and the second step of the production method 7 which is the same reaction as the second step of the production method 4 May be subjected to the reaction.

The reaction conditions in Production Method 6 can be combined with one another as appropriate.

The reaction conditions in Production Method 7 can be appropriately combined with each other.

Production method 8 Formula (XIX):

Embedded image 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. By reacting
A method for producing a nitroethenamine of the formula (I).

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 the base used include triethylamine, pyridine, N-methylmorpholine, 1,8-diazabicyclo [5,4,
0] Organic bases such as -7-undecene and N, N-dimethylaniline; alkali metals such as lithium, sodium and potassium; alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; lithium hydrogen carbonate and hydrogen carbonate Alkali metal bicarbonates such as sodium and potassium bicarbonate; alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; n-butyllithium, lithium diisopropylamide, sodium amide and the like. .

The reaction of the production method 8 is carried out at a reaction temperature of -70 to 150 ° 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 various reaction conditions in Production Method 8 can be appropriately combined with each other.

Production method 9 Formula (XXI):

Embedded image Wherein R ² and Z are as defined above, and nitromethane are reacted to obtain a compound of the formula (IV) in the first step, and the compound represented by the formula ( By reacting the compound of IV) with the compound of formula (V),
A method for producing a nitroethenamine derivative of the formula (I), comprising a second step of obtaining a nitroethenamine derivative of the formula (I).

Production method 10 Formula (XXII):

Embedded image (Wherein R ¹ and Z are as defined above) and nitromethane are reacted to obtain a compound of the formula (VI) in the first step, and the compound obtained in the first step ( By reacting the compound of VI) with the compound of formula (III),
A method for producing a nitroethenamine derivative of the formula (I), comprising a second step of obtaining a nitroethenamine derivative of the formula (I).

It should be noted that the starting material used in production method 9 and production method 10
The compound of (XXI) and the compound of formula (XXII) can be produced by a known method or a method analogous thereto.

The reaction in the first step of Production method 9 and the first step of 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. Specifically, the production methods 1 and 2
And the same bases as those used in the above.

Each reaction of the first step of the production method 9 and the first step of the production method 10 is carried out at a reaction temperature of -30 to 150 ° C.
The reaction is performed at a reaction temperature of 8080 ° C. The reaction time is between 0.1 and 48 hours.

In the first step of Production Method 9, the compound of the formula (XXII)
0.8 to 2 equivalents of nitromethane to 1 mol of the compound
Desirably, it can be used at a ratio of 1 to 1.5 equivalents. 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 (XXIII). 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 disadvantage even if it is used in excess.

The compound of the formula (IV) obtained in the first step of the production method 9 and the compound of the formula (VI) obtained in the first step of the production method 10 are:
Separation and purification by known means, for example, concentration, concentration under reduced pressure, solvent extraction, recrystallization, chromatography, etc. After the reaction, the reaction mixture is the same reaction as the first step in the first step and the reaction in the second step, respectively. It may be subjected to the reaction of the second step of Production Method 10, which is the same reaction as the second step.

The reaction conditions in Production Method 9 can be appropriately combined with each other.

The various reaction conditions in Production Method 10 can be appropriately combined with each other.

Production method 11 The compound represented by the formula (XIII) is reacted with nitromethane, and then the compound represented by the formula (XV) is reacted.
A first step of obtaining a compound of formula (IV), and a compound of formula (I) obtained in the first step
A process for producing a nitroethenamine derivative of the formula (I) comprising a second step of reacting the compound of the formula (V) with the compound of the formula (V) to obtain a nitroethenamine derivative of the formula (I) .

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.

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.

The reaction in the first step of Process 11 is carried out 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.

In the first step of 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 (XIII). In this step, nitromethane can also be used as a solvent, and in this case, there is no particular disadvantage even if it is used in excess.

The compound of the formula (XXII) obtained in the first step of the production method 11 can be obtained by a known method such as concentration, concentration under reduced pressure, solvent extraction,
After separation and purification by recrystallization, chromatography, or the like, or as a reaction mixture, the reaction may be subjected to the reaction of the second step of the production method 11, which is the same reaction as the second step of the production method 1.

The reaction conditions in Production Method 11 can be appropriately combined with each other.

The compounds of the formula (I) obtained by the methods described in the above-mentioned production methods 1 to 11 can be prepared by known methods, for example,
It can be isolated and purified by concentration, concentration under reduced pressure, distillation, fractional distillation, phase transfer, solvent extraction, crystallization, 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 conventional method. Also, the formula
The compound (I) may form an inner salt in some cases. The compound of formula (I), its stereoisomers and tautomers each independently exhibit a matrix metalloproteinase inhibitory action in any state of a mixture.

[0101]

EXAMPLES Specific examples of the synthesis of nitroethenamine derivatives represented by the formula (I) and intermediates for producing the same will now be described.

Synthesis Example 1: N-2,2-dimethoxyethyl-1-
(2- (5-chloro-2-pyridyl) hydrazino) -2-nitroe
Synthesis of Tenamine (Compound No. 13) (1) 1,1-bis (methylthio) -2-nitroethene 3.0 g, 2,2
-1.9 g of dimethoxyethylamine and 20 ml of chloroform
Is stirred under reflux for about 4.5 hours, then cooled to room temperature,
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-dimethoxyethyl-1-methylthio-2-nitroethenamine (intermediate No. 1) having a melting point of 64 ° C. (2) N-2,2-dimethoxyethyl-1-methylthio-2-nitroethenamine 500 mg, 5-chloro-2-pyridylhydrazine 33
After stirring 0 mg and 10 ml of ethanol for about 13.5 hours while heating under reflux, the mixture was cooled to room temperature, and the precipitated crystals were collected by filtration. The crystals collected by filtration are washed with ethanol and then dried to a melting point of 19
340 mg of the desired product (compound No. 13) was obtained at 5 ° C. (decomposition).

Synthesis Example 2: N-2- (2-hydroxyethylthio)
Xy) ethyl-1- (2- (5-chloro-2-pyridyl) hydrazide
No) Synthesis of 2-nitroetheneamine (Compound No. 19) (1) 5.0 g of 1,1-bis (methylthio) -2-nitroethene, 2-g
3.2 g of (2-hydroxyethyloxy) ethylamine and 50 ml of chloroform were stirred under reflux for about 5 hours, cooled to room temperature, and the solvent was distilled off under reduced pressure. The concentrated residue was purified by silica gel column chromatography to give a melting point of 59.
2.8 g of N-2- (2-hydroxyethyloxy) ethyl-1-methylthio-2-nitroethenamine (intermediate No. 3) was obtained at ℃. (2) 2.0 g of N-2- (2-hydroxyethyloxy) ethyl-1-methylthio-2-nitroethenamine, 1.3 g of 5-chloro-2-pyridylhydrazine and 25 ml of ethanol were stirred for about 17 hours while heating under reflux. After cooling to room temperature, 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: (R) -N-tetrahydrofurfurfury
1- (2- (5-chloro-2-pyridyl) hydrazino) -2-d
Synthesis of Troetheneamine (Compound No. 21) (1) 1.9 g of 1,1-bis (methylthio) -2-nitroethene, (R)
1.2 g of-(-)-tetrahydrofurfurylamine and 12 ml of chloroform were stirred under reflux for about 2 hours, then cooled to room temperature, and the solvent was distilled off under reduced pressure. The concentrated residue was purified by silica gel column chromatography, and had a melting point of 59 ° C.
1.4 g of (R) -N-tetrahydrofurfuryl-1-methylthio-2-nitroethenamine (intermediate No. 5) were obtained. (2) (R) -N-tetrahydrofurfuryl-1-methylthio-2-
700 mg of nitroethenamine, 460 mg of 5-chloro-2-pyridylhydrazine and 10 ml of ethanol were heated to reflux for about 17.5.
After stirring for an hour, the mixture was cooled to room temperature, and the precipitated crystals were collected by filtration. The collected crystals are washed with ethanol and then dried,
490 mg of the desired product (compound No. 21) having a melting point of 201 ° C. (decomposition) was obtained.

The compounds of the formula (I) produced by the methods according to Synthesis Examples 1 to 3 and the above Production Methods 1 to 11 are shown in Tables 1 to 9 below.

[0106]

[Table 1]

[0107]

[Table 2]

[0108]

[Table 3]

[0109]

[Table 4]

[0110]

[Table 5]

[0111]

[Table 6]

[0112]

[Table 7]

[0113]

[Table 8]

[0114]

[Table 9] Formula (IV) produced by a method according to the above-mentioned production methods 1, 9 and 11
The production examples of the compound are shown in Tables 10 to 13 below. These compounds are used as intermediates for producing compounds of formula (I).

[0115]

[Table 10]

[0116]

[Table 11]

[0117]

[Table 12]

[0118]

[Table 13]

The nitroethenamine derivative of the formula (I) or a salt thereof has a matrix metalloproteinase inhibitory action, in particular, MMP-1, MMP-2, MMP-3, MM
P-7 has MMP-9 inhibitory action, and among them, M
MP-3 and MMP-9 inhibitory effects are particularly excellent, and MM
The P-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 metalloproteinase inhibitory action. Therefore, the pharmaceutical composition of the present invention is provided by combining them as active ingredients and, if necessary, combining the carriers described below. When 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, or a therapeutic / prophylactic agent for rheumatoid arthritis, which is used for treating or preventing cancer or inflammatory diseases It is preferable to prepare a pharmaceutical composition comprising the above-mentioned active ingredient and a pharmaceutically acceptable carrier and further containing additives such as diluents, excipients and stabilizers, if necessary.

In the pharmaceutical composition of the present invention, the compounding ratio of the above active ingredient to the carrier component is generally 1.0 to 90% W / W. The therapeutically effective dose depends on the method of administration, the sex, weight,
Depending on age, target disease, etc., it is generally 0 for adults.
1-1000 mg / day / person.

The dosage form and administration form may be in the form of granules, fine granules, pills, tablets, capsules or liquids, and may be administered orally as it is in bulk, suppositories, Parenteral administration may be made in the form of aerosols or topical preparations such as nasal drops. The 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 present invention. Representative carriers or diluents that can be incorporated into tablets, capsules, and the like include acacia, disintegrants such as corn starch and alginic acid, lubricants such as magnesium stearate, and sweeteners such as sucrose and lactose. 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 or natural vegetable oil or a synthetic fat excipient such as ethyl oleate. Buffers such as citrate, acetate, phosphate,
Antioxidants such as ascorbic acid can be incorporated according to accepted pharmaceutical methods.

Next, specific test examples will be described. Test Example 1: Inhibitory activity on human MMP-9 (gelatinase B)
The inhibitory activity of each compound on human MMP-9 purified enzyme (manufactured by Chemicon, Code No.CC079) was measured using a fluorescent peptide substrate (7-met
hoxycoumarin-4-yl) Acetyl-Pro-Leu-Gly-Leu- (3- [2,4-d
initrophenyl] -Ala-Arg-NH ₂ , manufactured by Pepdo Laboratories,
Code.3163-VC) using the method of CG Knight et al. [FEBS Le
tters, Vol.296, No. 3, 263-266 (1992)]. That is, a fluoro Nunc plate (96C) white (Nunc No. 437842) MMP-9 enzyme solution 180μl, DMSO
10 μl of a sample (compound of the present invention) dissolved in water and 10 μl of a 100 μM fluorescent peptide substrate dissolved in DMSO (maximum concentration 5 μl)
M) was added and reacted at 37 ° C. for 3 hours in the dark. After the reaction is completed, tunable fluorescent plate reader Spectron
The fluorescence intensity was measured using FL-2575 (manufactured by Towa Kagaku KK) (excitation wavelength: 327 nm, fluorescence wavelength: 400 nm). MMP-9 enzyme activity is determined by measuring the amount of degradation products after the reaction based on the change in relative fluorescence intensity, and the inhibitory rate of enzyme activity by the inhibitor is determined by the relative fluorescence intensity of the group with and without the inhibitor after the reaction. Was calculated by comparing. Since MMP-9 is present as an inactive precursor, 15 μl was previously added to 1490 μl of a 1 μg / ml enzyme solution.
10 μl of 0 mM 4-aminophenylmercuric acetate (APMA, Tokyo Chemical Industry, Code No.A0395) was added (final concentration 1 mM), and at 37 ° C.
After being allowed to stand for 4 hours to be converted into an active form, it was subjected to a test for enzyme inhibitory activity. The dilution of the enzyme was 0.1 M NaCl, 10 mM Ca.
50 mM Tris with Cl ₂ , 0.05% Brij 35 and 0.02% NaN ₃
Performed using -HCl (pH 7.5). MMP-9 inhibitory activity was measured once or twice each, and the results are shown in Tables 14 and 15.

[0124]

[Table 14]

[0125]

[Table 15]

Test Example 2: Meth A / AD against tumor growth
Inhibitory effect (1) Preparation of Meth A / AD strain showing adhesive growth in vitro Meth A mouse fibrosarcoma cells showing floating growth in vitro
(Provided by Sasaki Laboratory) at 39 ° C, 5% CO ₂ for 10 days
After using 10% fetal bovine serum-containing RPMI medium (manufactured by Flow Laboratories), BALB / c mice were inoculated subcutaneously. The tumor 30 days after growth is removed, excised and passed through a metal mesh to make a single cell, returned to in vitro and cultured (37
° C). Meth A / A that adheres to the culture dish and grows stably when subculture is repeated for about one month
D cell line was obtained. The Meth A / AD strain shows almost the same doubling time and cell proliferation as the parent strain in vitro, but in vivo
Subcutaneous or intradermal growth rate was 1/2 to 1/3 that of the parent strain. In addition, the Meth A / AD strain did not show the intraperitoneal growth of the mouse seen in the parent strain. On the other hand, the Meth A / AD strain always produces and secretes MMP-2 in the in vitro culture supernatant, but when TNF-α (50 ng / ml) is added to the culture solution, MMP-9 is significantly produced, The trait was clearly different from that of the parent strain. (2) Inhibitory effect on in vivo tumor growth of Meth A / AD strain 5 weeks old, 1 × 10 5 cultured in vitro in the back skin of male BALB / c AnNCrj mice (purchased from Japan Charles River)
^Six Meth A / AD cells (suspended in 0.05 ml of Hanks balanced salt solution) were transplanted (Day 0). 2 hours after cell inoculation and Day 1
Each of the test drugs was administered intraperitoneally once a day (total of 10 times) on days 4 to 7 and on days 7 to 11 (administration at a volume of 10 ml / kg). Compound is 1% Tween
The suspension was administered in 80 / saline. In the solvent control group, only the solvent containing no test drug was similarly administered. Daily weight measurement and general symptom observation until Day 22 or 24, 1
The tumor diameter (major axis and minor axis) was measured with calipers every other day, and the difference in tumor volume between the solvent control group and the drug-treated group was evaluated. The tumor volume was calculated according to the formula [(major axis) × (minor axis) ² × 1/2]. (3) Results Compound No. 21 and compound No. 24 showed a statistically significant inhibition of tumor growth as compared with the solvent control group.

[0127]

[Table 16]

Test Example 3: Against experimental lung metastasis of Colon26 / AD
Inhibiting effect (1) Preparation Colon 26 mouse colon cancer cells Colon 26 / AD cell lines with high expression of MMP-9 (dispensing from Foundation Cancer Research Cancer Institute) were implanted subcutaneously into BALB / c mice After 10 days, the tumor that grew was removed. Shred in Hanks balanced salt solution,
Inject single cells obtained by passing through a metal mesh
Cultured in vitro (37 ° C, 5% CO ₂ ) (Dul containing 10% fetal bovine serum)
becco's Modified Eagle Medium (Sigma, No.D-564
8) Use]. After several subcultures, a Colon 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-α (50 ng / ml) is added to the culture and cultured, MMP-9 is significantly produced, The trait was clearly different from that of the parent strain. (2) Control effect on experimental lung metastasis of Colon 26 / AD 6 weeks old, 3 × 10 cultured in vitro from the tail vein of male BALB / c AnNCrj mouse (purchased from Japan Charles River)
⁴ Colon 26 / AD cells (0.2 ml of Minimum Essential Me
dium (manufactured by Nissui Pharmaceutical Co., Ltd.)]
0). The test substance is administered immediately before cell transplantation (within 2 minutes), 2 hours later, and once a day on each of Day 1-4 and Day 7-11 (total 11 times), 1% Tw
een 80 / suspended in saline and administered intraperitoneally (10 ml /
kg dose). In the solvent control group, only a solvent containing no test drug was similarly administered. On Day 14 or 15, the lungs of each mouse were removed and weighed, and the metastasis inhibition rate was calculated according to the following equation. Inhibition rate (%) = {1− (ab) / (c−b)} × 100 a: Lung weight of drug-treated group (g) b: Average lung weight of normal group (g) c: Solvent control group (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.

[0129]

[Table 17]

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61K 31/4433 A61K 31/4433 31/4436 31/4436 31/4439 31/4439 31/4523 31/4523 31 / 496 31/496 31/497 31/497 31/5377 31/5377 A61P 29/00 101 A61P 29/00 101 35/00 35/00 35/04 35/04 43/00 111 43/00 111 C07D 213 / 77 C07D 213/77 403/12 403/12 409/12 409/12 417/12 417/12 F term (reference) 4C055 AA01 BA02 BA03 BA39 BA42 BA52 BB08 BB17 CA02 CA39 DA01 DA13 DB14 4C063 AA01 BB07 BB09 CC25 CC34 CC73 CC75 CC78 CC81 CC82 CC92 DD12 DD14 EE01 4C086 AA01 AA02 AA03 BC17 BC21 BC28 BC38 BC48 BC50 BC84 GA02 GA04 GA08 GA10 GA12 MA01 MA04 NA14 ZB11 ZB15 ZB26 ZC20

Claims (13)

[Claims] (1) Formula (I): [Wherein, R ¹ is an optionally substituted heterocyclic group; R ² is a substituted alkyl group] or a salt thereof. 2. The substituent of the optionally substituted heterocyclic group represented by R ¹ is an alkoxy group, an alkoxyalkoxy, a heterocyclic oxy, an alkyl group optionally substituted by a halogen atom or a hydroxyl group; alkoxy, alkoxyalkoxy A heterocyclic oxy, an alkoxy group optionally substituted with a halogen atom or a hydroxyl group; an alkoxy, an alkoxyalkoxy, a heterocyclic oxy, an alkenyloxy group optionally substituted with a halogen atom or a hydroxyl group, or a halogen atom. Nitroethenamine derivatives or salts 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; even when the substituent is substituted with an alkoxy, alkoxyalkoxy, heterocyclic oxy, halogen atom or hydroxyl group. Good alkoxy group; heterocyclic oxy group optionally substituted by alkyl or alkoxy; alkoxy, alkoxyalkoxy, heterocyclic oxy, alkylthio group optionally substituted by halogen atom or hydroxyl group; alkoxy, alkoxyalkoxy, heterocyclic oxy, halogen An alkylsulfyl group optionally substituted with an atom or a hydroxyl group; alkoxy, alkoxyalkoxy, heterocyclic oxy, an alkylsulfonyl group optionally substituted with a halogen atom or a hydroxyl group; an amino optionally substituted with an alkyl or an alkylcarbonyl ; Nitro ethene derivative or its salt according to claim 1 which is or a hydroxyl, alkyl or an amino carbonyl group optionally substituted with alkylcarbonyl. 4. A compound of formula (I) wherein (R) -N-tetrahydrofurfuryl-1- (2- (5-chloro-2-pyridyl) hydrazino) -2-nitroethenamine or (S)- N-tetrahydrofurfuryl-1- (2- (5-chloro-2-pyridyl) hydrazino)
2. The nitroethenamine derivative according to claim 1, which is 2-nitroethenamine, or a salt thereof. 5. A pharmaceutical composition comprising the nitroethenamine derivative of claim 1 or a salt thereof as an active ingredient. 6. A matrix metalloproteinase enzyme inhibitor comprising the nitroethenamine derivative or a salt thereof according to claim 1 as an active ingredient. 7. MMP-1, MMP-2, MMP-3,
At least one selected from MMP-7 and MMP-9
7. The matrix metalloproteinase enzyme inhibitor according to claim 6, which inhibits two matrix metalloproteinases. 8. The matrix metalloproteinase enzyme inhibitor according to claim 7, which inhibits MMP-9. 9. An angiogenesis inhibitor comprising the nitroethenamine derivative of claim 1 or a salt thereof as an active ingredient. 10. An anticancer 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 nitroethenamine derivative of claim 1 or a salt thereof as an active ingredient.