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WO2001070696A1 - Derives de nitroethenamine ou sels desdits composes, et compositions pharmaceutiques contenant ces derives ou ces sels - Google Patents

Derives de nitroethenamine ou sels desdits composes, et compositions pharmaceutiques contenant ces derives ou ces sels Download PDF

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Publication number
WO2001070696A1
WO2001070696A1 PCT/JP2001/002157 JP0102157W WO0170696A1 WO 2001070696 A1 WO2001070696 A1 WO 2001070696A1 JP 0102157 W JP0102157 W JP 0102157W WO 0170696 A1 WO0170696 A1 WO 0170696A1
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group
substituted
formula
compound
derivative
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Japanese (ja)
Inventor
Keizo Miyata
Hirohiko Kimura
Kazuhiro Yamamoto
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Ishihara Sangyo Kaisha Ltd
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Ishihara Sangyo Kaisha Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • 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.
  • 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.
  • MMPs matrix meta-oral proteinase
  • MMP is normally secreted as an inactive form by an external stimulus, and then is converted into an active form by various proteases.
  • the degradation activity of MMP is controlled by its intrinsic inhibitor TI-MP (ti ssue inhibitor of metal loproteinase).
  • TI-MP ti ssue inhibitor of metal loproteinase
  • MMP-9 gelatinase B / 92kDa type IV collagenase
  • type IV collagen a major component of the basement membrane
  • epithelial cells including breast cancer and lung cancer, and blood cancer cells.
  • metastatic potential M. Nakajima et al., Journal of Natal Cancer Instite, Vol.
  • 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.
  • 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)].
  • MMP-1 stromal collagenase
  • MMP-3 stromlysin 1
  • 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)].
  • MMP-1 interstitial collagenase
  • 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.
  • arthritis such as gingivitis, glomerulonephritis, interstitial n
  • 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.
  • 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.
  • 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.
  • the present invention provides a compound represented by the formula (I):
  • R 1 is an optionally substituted heterocyclic group
  • R 2 is a substituted alkyl group
  • 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.
  • 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, isothia
  • 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
  • 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.
  • 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, alkylalkylcarbon
  • 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, hal
  • the substituted amino group, substituted aminocarbonyl group or substituted hydroxyaminocarbonyl group is alkyl, haloalkyl, alkoxyalkyl, alkylthioalkyl, alkenyl, no, loalkenyl, alkynyl, no, loalkynyl, cycloalkyl, cycloalkenyl.
  • 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.
  • 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.
  • 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.
  • 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.
  • heterocyclic moiety in the above-mentioned secondary substituent and tertiary substituent examples 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.
  • 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)
  • 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.
  • 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.
  • ethers such as getyl ether, dipropyl ether, dibutyl ether, tetrahydrofuran, and dioxane
  • nitriles such as acetonitrile and propionitrile
  • 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.
  • 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).
  • the compound of the formula (111) is used in excess, the compound of the formula (IV) and the compound of the formula (VII):
  • 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).
  • the formula (V) is used in excess, the formula (V
  • 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
  • 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):
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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).
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • the reaction in the second step can be carried out in the presence of a suitable solvent.
  • 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 acet
  • 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.
  • 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).
  • 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.
  • a suitable solvent include the same solvents 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.
  • 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.
  • R 2 is as defined above, and a halogenating agent to obtain a compound of the formula (XI),
  • 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.
  • a suitable 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 ( ⁇ ). 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, ⁇ -methylmorpholine, 1,8-diazabicyclo [5 , 4,0] -7- ⁇ decene and ⁇ , ⁇ -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.
  • 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.
  • 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.
  • 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.
  • the reaction of Production Method 8 can be carried out in the presence of a suitable solvent.
  • a suitable solvent include the same solvents as those used in Production Methods 3 and 4.
  • 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.
  • 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
  • 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.
  • 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
  • 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.
  • a suitable solvent include the same solvents as those used in Production Methods 1 and 2.
  • Step 1 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.
  • nitromethane in the first step of Production Method 9, 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).
  • nitromethane in the first step of Production Method 10, 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 ( ⁇ ).
  • nitromethane 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
  • Production method 11 The first step can be carried out in the presence of a suitable solvent.
  • a suitable solvent include the same solvents as those used in Production Methods 1 and 2 described above.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • Table 1013 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).
  • 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.
  • MMP-1 MMP-2 MMP-3 MMP-7 MMP-9 inhibitory activity MMP-3 MMP 9 Inhibitory effect is particularly excellent, and MMP-9 inhibitory effect is the best.
  • 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.
  • 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.
  • 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.
  • compositions of the invention 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.
  • 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.
  • 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.
  • Test Example 1 Measurement of inhibitory activity on human ⁇ P-9 (gelatinase B)
  • 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.
  • 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.
  • Test Example 2 Inhibitory effect of Meth A / AD on tumor growth
  • 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 ⁇ g / 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.
  • 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].
  • Compound No. 21 and Compound No. 24 showed a statistically significant inhibition of tumor growth as compared with the vehicle control group.
  • Test Example 3 Inhibitory effect of Colon26 / AD on experimental lung metastasis
  • 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.
  • 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.

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Abstract

L'invention concerne des dérivés de nitroéthènamine de formule générale (I) ou des sels desdits composés, ainsi que des compositions pharmaceutiques contenant ces dérivés ou ces sels en tant qu'ingrédient actif. Dans ladite formule, R1 est un groupe hétérocyclique éventuellement substitué et R2 est alkyle substitué.
PCT/JP2001/002157 2000-03-21 2001-03-19 Derives de nitroethenamine ou sels desdits composes, et compositions pharmaceutiques contenant ces derives ou ces sels Ceased WO2001070696A1 (fr)

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AU2001241194A AU2001241194A1 (en) 2000-03-21 2001-03-19 Nitroethenamine derivatives or salts thereof and pharmaceutical compositions containing the derivatives or the salts

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8202897B2 (en) 2007-04-18 2012-06-19 Probiodrug Ag Inhibitors of glutaminyl cyclases
US8772508B2 (en) 2007-04-18 2014-07-08 Probiodrug Ag Inhibitors of glutaminyl cyclase

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0930067A2 (fr) * 1997-12-19 1999-07-21 Pfizer Products Inc. Inhibiteurs de mmp dans le traitement de l'angiogenese oculaire
EP0935963A2 (fr) * 1997-10-24 1999-08-18 Pfizer Products Inc. Utilisation des inhibiteurs selectifs de MMP-13 pour le traitement de l'osteoarthrite et autres maladies mediées par le matrix metalloproteinase
WO2000016766A1 (fr) * 1998-09-22 2000-03-30 Ishihara Sangyo Kaisha Ltd. Composition medicale contenant des derives de nitroetheneamine ou des sels de ces derives comme constituants actifs

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0935963A2 (fr) * 1997-10-24 1999-08-18 Pfizer Products Inc. Utilisation des inhibiteurs selectifs de MMP-13 pour le traitement de l'osteoarthrite et autres maladies mediées par le matrix metalloproteinase
EP0930067A2 (fr) * 1997-12-19 1999-07-21 Pfizer Products Inc. Inhibiteurs de mmp dans le traitement de l'angiogenese oculaire
WO2000016766A1 (fr) * 1998-09-22 2000-03-30 Ishihara Sangyo Kaisha Ltd. Composition medicale contenant des derives de nitroetheneamine ou des sels de ces derives comme constituants actifs

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8202897B2 (en) 2007-04-18 2012-06-19 Probiodrug Ag Inhibitors of glutaminyl cyclases
US8772508B2 (en) 2007-04-18 2014-07-08 Probiodrug Ag Inhibitors of glutaminyl cyclase

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