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WO1997009982A1 - Inhibiteur de monoxyde d'azote synthetase qui contient des 2-aminopyridines en tant qu'ingredient actif - Google Patents

Inhibiteur de monoxyde d'azote synthetase qui contient des 2-aminopyridines en tant qu'ingredient actif Download PDF

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Publication number
WO1997009982A1
WO1997009982A1 PCT/JP1996/002637 JP9602637W WO9709982A1 WO 1997009982 A1 WO1997009982 A1 WO 1997009982A1 JP 9602637 W JP9602637 W JP 9602637W WO 9709982 A1 WO9709982 A1 WO 9709982A1
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Prior art keywords
group
amino
pyridine
methyl
pyridin
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PCT/JP1996/002637
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English (en)
Japanese (ja)
Inventor
Eiji Kawano
Masashi Nagai
Atsurou Inubushi
Keiichi Shimada
Hiroko Tobari
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Nippon Kayaku Kabushiki Kaisha
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Priority to AU69450/96A priority Critical patent/AU6945096A/en
Publication of WO1997009982A1 publication Critical patent/WO1997009982A1/fr

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    • 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

Definitions

  • the present invention relates to a medicament, particularly to a nitric oxide synthase inhibitor, and further relates to administration to a living body as an inhibitor of nitric oxide production.
  • nitroglycerin has been administered to humans as a vasodilator in the treatment of cardiovascular disease. Recently, it has been shown that such administered nitroglycerin converts in the body to nitric oxide, a pharmacologically active metabolite.
  • Nitric oxide was also found to be an important component of vascular endothelium-derived relaxing factors (EDRFs) and to be enzymatically formed from arginine as a normal metabolite.
  • EDRFs have been actively studied recently as being involved in regulating blood flow and vascular resistance.
  • macrophage and neuronal cells also produce nitric oxide in addition to vascular endothelium. It has been found that nitric oxide produced by macrophage has cytotoxicity and cell growth inhibitory effects, and that nitric oxide produced by neurons is involved in memory as an information transmitter. Was.
  • endothelial types enzymes that form nitric oxide from arginine or nitric oxide synthase have three distinct types, endothelial types, It was established that it consisted of neural type and induced type. Endothelial enzymes are constantly present in normal endothelial cells, and neural types are constantly present in neurons and the like. Nitric oxide formation by endothelial enzymes in endothelial cells is thought to play a role in normal blood pressure regulation. In addition, the formation of nitric oxide by neuronal enzymes in neurons plays a role in synaptic transmission plasticity, plays a role in memory and learning, and in cerebral ischemia due to cerebrovascular disorders, etc. May be involved in the development of the disease state.
  • the inducible enzyme is separated from activated macrophages, and endothelial cells or vascular smooth muscle cells also contain various cytokines or combinations of cytokines. It has been clarified that it is induced by In shocks induced by sepsis or site kinases, severe hypotension, often threatening to strike, is mainly due to overproduction of nitric oxide by inducible enzymes. Or all of them
  • these inhibitors of nitric oxide synthase when inhibiting inducible nitric oxide synthase, are particularly selective inhibitors of inducible nitric oxide synthase as described later.
  • diseases and symptoms such as septic shock (Lancet; 338, pp. 1555 and 1557, 1991) and arthritis (Ann. Rheum. Dis .; 51, 1219, 1992) are considered. Potential as a drug to improve.
  • neuronal nitric oxide synthase particularly when selectively inhibiting neuronal nitric oxide synthase as described later, cerebrovascular disorders (Eur. J.
  • NMMA in N 0 over main Chiru and one arginine (herein e.g., Lancet;.. 338, Vol 1555, pp, 15 57 p., 1991 .... a year), N G - d filtrated one said - abbreviated hereinafter as NNA is arginine (Honmyo Saisho e.g., Eur J. Pharmacol: 204 vol .339, pp, 1991 and neur os ci Le 11.; 147, 159, 1992).
  • NNA neuronal nitric oxide synthase inhibitor
  • nitric oxide synthase inhibitor II which belongs to a strain different from the conventional one in terms of chemical structure.
  • nitric oxide synthase inhibitors NMMA and NNA have a weaker and more potent inhibitory activity on inducible nitric oxide synthase than on endothelial nitric oxide synthase. was also unsatisfactory. For this reason, various studies have been conducted on derivatives and related compounds of NMMA and NNA, but no satisfactory results have been found. Thus, the present inventors have found that inducible nitric oxide synthase is more strongly inhibited than endothelial nitric oxide synthase, that is, nitric oxide synthase that is selective for inducible nitric oxide synthase. Investigations were conducted to find inhibitors.
  • NMMA and NNA did not provide a satisfactory balance between the inhibitory activity of neuronal nitric oxide synthase and the inhibitory activity of endothelial nitric oxide synthase. Therefore, NMMA and NNA Various studies have been conducted on derivatives and related compounds, but no satisfactory results have been found. Therefore, the present inventors conducted an investigation to find a nitric oxide synthase inhibitor that is selective for neuronal nitric oxide synthase.
  • 2-aminobinidines or a pharmaceutically acceptable salt thereof has an inhibitory effect on nitric oxide synthase.
  • 2-amino pyridines or pharmaceutically acceptable salts thereof have a stronger inhibitory effect on inducible nitric oxide synthase than endothelial nitric oxide synthase. It was found that it has.
  • 2-aminobinidines or their pharmaceutically acceptable salts have a stronger inhibitory effect on neuronal nitric oxide synthase than endothelial nitric oxide synthase. It was found that it has.
  • there has been no report that a compound having a 2-amino pyridine as a skeleton has the enzyme inhibitory activity, and a new strain of the inhibitor has been pioneered by the present invention. .
  • the present invention firstly provides a nitric oxide synthase inhibitory activity having a 50% nitric oxide synthase inhibitory concentration (IC 5 ) of 10 to 2 M or less.
  • IC 5 50% nitric oxide synthase inhibitory concentration
  • the present invention relates to a nitric oxide synthase inhibitor comprising, as an active ingredient, an aminoviridine or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a method for producing an active ingredient comprising a 2-aminophenol or a pharmaceutically acceptable salt thereof having a molecular weight of 350 or less and having a nitric oxide synthase inhibitory activity. Nitric oxide synthesis inhibitor About harm
  • R ′, R 2 , R 3 and R 4 are the same or independent substituents, and each represents a hydrogen atom, a nitrogen atom, a nitro group, a straight-chain or branched-chain.
  • Carbon number! 1-7 lower alkyl group [unsubstituted or halo gain down atom, having 3 to 8 sheets click lower alkyl group having a carbon ⁇ Li Lumpur group, OR 5 group ⁇ is R 5 in here hydrogen atom, a straight Represents a chain or branched lower alkyl group having 1 to 4 carbon atoms (which may be unsubstituted or substituted with one or more hydrogen atoms by an aryl group), NR 6 R 7 group (Where R 6 and R 7 are a hydrogen atom, a linear or branched lower alkyl group having 1 to 4 carbon atoms, a linear or branched lower alkyl group having 1 to 4 carbon atoms.
  • R 6 and R 7 are the same or independent substituents), unsubstituted or substituted with one or more hydrogen atoms by an amino group.
  • One or more hydrogen atoms may be substituted with any of a molybdenum or pyridyl group], a straight-chain or branched lower alkenyl group having 2 to 5 carbon atoms, carbon Having 3 to 8 sheets click Roarukiru group, ⁇ rie group, ⁇ R S group (in here!? 8 is a hydrogen atom, a linear or branched lower alkyl group having 1 to 4 carbon atoms Indicate), NR 9 R '.
  • R 9 R IG is a hydrogen atom, a straight-chain or branched-chain lower alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, a straight-chain or branched carbon number 1 Represents up to 4 lower acyl groups or aryl groups, and R 9 and R 1 ° are the same, or each is an independent substituent, or COR ′ ′ group (here, R ′ 1 represents a hydroxyl group, a linear or branched lower alkoxy group having 1 to 4 carbon atoms), or R ′ and R 2 , R 2 and R 3 or R 3 And R 4 together form an unsubstituted or substituted benzene ring which may be substituted with one or more halogen atoms or lower alkyl groups, or one or more unsubstituted or substituted with halogen atoms or lower alkyl groups.
  • R ′ and R 2 or R 2 and R 3 or R 3 and R 4 together do not form a ring, at least one of R ′, R 2 , R 3 and R 4 One is a hydrogen atom.
  • a nitric oxide synthase inhibitor comprising, as an active ingredient, a 2-amino pyridine or a pharmaceutically acceptable salt thereof represented by
  • R 1 is a hydrogen atom, a halogen atom, a linear or branched lower alkyl group having 1 to 7 carbon atoms [unsubstituted or a cycloalkyl group having 3 to 8 carbon atoms, aryl Group, ⁇ R 5 group ⁇ wherein R 5 is a hydrogen atom, a linear or branched lower alkyl group having 1 to 4 carbon atoms (unsubstituted or one or more hydrogen atoms such as aryl group) Indicates that the atom may be substituted)), NR 6 R 7 group (here, R 6 and R 7 are a hydrogen atom, a straight-chain or branched-chain low alkyl group having 1 to 4 carbon atoms, a straight-chain or branched-chain carbon number!
  • One or more hydrogen atoms may be substituted with any of the pyridyl groups whose atoms may be substituted.
  • a linear or branched lower alkenyl group having 2 to 5 carbon atoms A cycloalkyl group, an aryl group, or a 0R "group having 3 to 8 carbon atoms (where R represents a linear or branched lower alkyl group having 1 to 4 carbon atoms)
  • NR 9 R 10 groups (where R 9 and R 1 are a hydrogen atom, a linear or branched lower alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms) group, a straight-chain or branched-chain C 1-4 lower ⁇ sill group carbon, indicates ⁇ Li one luer
  • R ′′ represents a linear or branched lower alkoxy group having 1 to 4 carbon atoms
  • R 3 represents a hydrogen atom; halogen atom, a linear or branched carbon atoms 1-4 lower alkyl group (unsubstituted or or one or more hydrogen atoms in the hydroxyl group may be substituted), ⁇ R 8 groups (this Where R 8 is a linear or branched C 1 -C 4 A NR 9 R 1 ° group (where R 9 and R 1 ° represent a straight-chain or branched ft′i-like lower alkyl group having 1 to 4 carbon atoms; R 9 , R 1 (1 is the same or each is an independent substituent) or C 0 R 11 (where R ′ ′′ is a hydroxyl group, a linear or branched carbon number I to R 4 represents a hydrogen atom, a nit ⁇ group, a linear or branched lower alkyl group having 1 to
  • a hydrogen atom may be substituted), a hydroxyl group, an amino group or a C 0 R ′ 1 group (where R 11 is a hydroxyl group, a linear or branched lower alkoxy having 1 to 4 carbon atoms) shows a shows a group), or further R 1 and R 2 or R 3 and R 4 together such connexion unsubstituted or halogen atoms, one or more optionally substituted benzene ring with a lower alkyl group, also The nitric oxide synthase inhibitor as described above, which is unsubstituted or can form a pyridin ring which may be substituted with one or more halogen atoms or lower alkyl groups. About.
  • R ' is a hydrogen atom, methyl group, ethyl group, vinyl group, ⁇ - ⁇ - ⁇ -propyl group, isopropyl group, ⁇ -butyl group, isobutyl group, ⁇ -pentynole group, cyclobutylmethylinole group, and Lopentyl methyl group, cyclohexyl group, cyclohexylmethyl group, 5 — (6—amino pyridine 1 2 — yl) Pentyl group, 7 1 (6 — amino butyl) Lysine 1 2 — yl) heptyl group, hydroxymethyl group, 2 — hydroxy ⁇ -xethyl group, 3 — hydroxy group Propyl group, 4—hydroquinbutyl group, 3—aminopropyl group, 41-aminobutyl group, amino group, methylamino group, t-butyl
  • R 2 is a hydrogen atom, methyl
  • the present invention relates to 2-amino pyridine, 2-amino 4-black pyridine, 2-amino 3-methyl pyridine, 2-.
  • Amino 4 methinopyridine, 2 — Amino 4 — ethynoleviridine, 2 — amino 6 — methyl pyridine, 2 — amino 1 6 — Ethyl pyridine, 2 — amino 6 — n — propyl pyridin, 2 — amino 6 — n — butyl pyridine, 2 — amino — 6 — isobutyl Pyridines, 2—Amino 4, 6—Dimethyl viridine, 2—Amino 4—Methyl 1 6—Ethyno pyridine, 1, 5— Screw (6—Aminobilizin 1—2—yl) pendant, 2—Amino4, 6—Dimethylyl5—Nitropyridine, 2—Amino One 4-methyl pyridine, 2, 6—diaminobilizin
  • An inducible nitric oxide synthase inhibitor comprising, as an active ingredient, 2-ryminopyridines or a pharmaceutically acceptable salt thereof as described in the above item 1, 2 or 3. About.
  • the present invention relates to a selective inducible nitric oxide synthase inhibitor comprising, as an active ingredient, a 2-amino pyridine or a pharmaceutically acceptable salt thereof according to the above item 2 or 3. there is, the selectivity is IC 5.
  • the present invention relates to a neuronal nitric oxide synthase inhibitor comprising, as an active ingredient, a 2-aminobinidine or a pharmaceutically acceptable salt thereof according to the above 1, 2, or 3. .
  • the present invention relates to a selective neuronal nitric oxide synthase inhibitor comprising, as an active ingredient, the 2-amino pyridine or the pharmaceutically acceptable salt thereof described in 1, 2, or 3.
  • a is, its selectivity is ⁇ C 5.
  • IC 50 [endothelial type] / 1 C 50 [nerve type]) 1.
  • a selective neuronal nitric oxide synthase inhibitor which is 0 or more, preferably 5 or more, particularly preferably 10 or more.
  • the present invention relates to the 2—amino pyridines or pharmaceutically acceptable salts thereof according to 1, 2, or 3, which selectively inhibits inducible nitric oxide synthase.
  • IC 5 of selectivity Value ratio (IC 5 0 [endothelial] Z 1 C. 5.
  • the present invention relates to a medicament for treating septic shock, comprising [inducible] 2.0 or more as an active ingredient.
  • the present invention also relates to a therapeutic agent for arthritis or arregii, comprising as an active ingredient the 2-aminopyridin or the pharmaceutically acceptable salt thereof described in the above item 1, 2 or 3. Regarding treatment II.
  • the present invention relates to a therapeutic agent for cerebrovascular disorders comprising a 2-aminopyridin or a pharmaceutically acceptable salt thereof according to the above item 1, 2 or 3 as an active ingredient. II for anti-kinson disease, analgesic or obesity treatment.
  • the present invention relates to 2 -amino-4, methylpyridin, 2-rymino 4, 6 -dimethyl which strongly showed an inducible nitric oxide synthase inhibitory activity.
  • an inducible nitric oxide synthase inhibitor comprising a pharmaceutically acceptable salt as an active ingredient
  • the present invention provides 2-amino-4-methylpyridin, 2-amino-4, 6-dimethyl bi, which has a strong inhibitory effect on neuronal nitric oxide synthase.
  • the present invention relates to ⁇ transformation-type nitric oxide synthase inhibitor ⁇ which is pyrimidine or a pharmaceutically acceptable salt active ingredient thereof.
  • the present invention relates to 2-amino 6-cyclohexylmethylpyridin, which has strongly shown a selective inducible nitric oxide synthase inhibitory action.
  • Amino 6 Cycloheptyl methyl pyridin, 2 — Amino 1 3 — Nitro pyridin, 2 — Amino — 4 — Methyl 1 3 — 2-Tropyridin, 2—Amino 1-, 4-, 6-Methyl Methanol 3 — Nitro-pyridin, 2—Amino 1-6—Cyclic mouth Bilydin, 2—Amino 6— (4—Aminobutyl) pyridin, 2—Amino 1-4-methyl—6— (4-Aminobutyl) pyri 11.
  • the present invention provides 2_amino-4-ethyl pyridine, 2-amino-6-n-, which strongly exhibited a selective inhibitory action on neuronal nitric oxide synthase.
  • R ' is a vinyl group, a cyclobutylmethyl group, an n-hexyl group, a cyclopentylmethyl group, or a cyclohexyl group.
  • 2-aminopyridines are not 2—Aminopyridines having 1 to 3 substituents at positions other than the 2-position of the aminopyridin or pyridin skeleton, When having two or three substituents, adjacent substituents may be bonded to form a ring. There is no particular limitation on the substituent on the amino pyridine skeleton, as long as it does not harm the nitric oxide synthase inhibitory Sakugawa.
  • Atom nitro group, alkyl group, halogeno anoalkyl group, cycloanolekyanoloxy group, arylanoloxy group, hydroxyalkyl group, alkoxyalkyl group, arylalkoxy group ) Alkyl group, aminoalkyl group, mono- or dialkyl-substituted aminoalkyl group, mono- or bis- (alkoxy-canoleponyl) -substituted aminoalkyl group, pyridylalkyl group, (aminovinylidyl) Alkyl group, alkenyl group, cycloalkyl group, aryl group, hydroxy group, alkoxy group, amino group, mono- or dialkyl-substituted amino group, mono or di Cycloalkyl-substituted amino group, mono- or di-substituted amino group, mono- or bis- (arylalkyl) -substituted amino group or carboxyl group, al
  • a 5- to 6-membered ring sharing one side with the pyridin ring of 2-aminophenol is used.
  • examples thereof include a quinoline ring and an isoquinoline together with the pyridine ring.
  • a ring or a naphthyridine ring may be substituted with the above substituents and the like.
  • alkyl group in the present invention a lower alkyl group is preferable.
  • examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and are preferably a fluorine atom and a chlorine atom.
  • examples of the linear or branched lower alkyl having 1 to 7 carbon atoms include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an ⁇ -butyl group, and an i-butyl group.
  • Examples include a sobutyl group, an s-butyl group, a t-butyl group, an n-pentylene group, an n-hexynole group, an n-heptyl group, and a 4-heptyl group, preferably a methyl group, Ethyl group, n-butyl group, isopropyl group, n-butyl group, isobutyl group, n-pentyl group or n-heptyl group.
  • Examples of the cycloalkyl group having 3 to 8 carbon atoms include a cyclopropyl group, a cyclopentyl group, a cyclopentyl group, a cyclohexyl group, a cyclo ⁇ heptyl group, Examples thereof include a cyclooctyl group and the like, preferably a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.
  • Examples of the aryl group include an unsubstituted or benzene ring which may be substituted with one or more halogen atoms or lower alkyl groups.
  • the linear or branched lower alkyl group having 1 to 4 carbon atoms include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, and an isobutyl group.
  • a s-butyl group, a t-butyl group and the like preferably a methyl group, an ethyl group or an isopropyl group.
  • the straight-chain or branched lower alkoxycarbonyl group having 1 to 4 carbon atoms include methoxycarbonyl, ethoxyquinone, t-butoxycarbonyl and the like.
  • the group is an extended group, and is preferably a t-butoxy group.
  • Examples of the linear or branched lower alkenyl group having 2 to 5 carbon atoms include a vinyl group, an aryl group, a butenyl group, and an isobutenyl group, and a vinyl group is preferable. It is.
  • Examples of the straight-chain or branched lower acyl group having 1 to 4 carbon atoms include an acetyl group, a propionyl group, an n-butylinole group and an alkylcarbonyl group such as an isobutyl group. And the like, preferably an acetyl group or a propionyl group.
  • Examples of the aryloxy group include a benzoyl group and a benzoyl group which may have a substituent such as a 0, m or p-cyclobenzoyl group. And preferably a benzyl group.
  • Examples of the linear or branched lower alkoxy group having 1 to 4 carbon atoms include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, and an n-butyl group.
  • Examples include a toxic group, an ethoxy group, an s-butoxy group, and a t-butoxy group, and are preferably a methoxy group and an ethoxy group.
  • Unsubstituted or substituted by one or more halogen atoms or lower alkyl groups As a benzene ring or pyridin ring that may be substituted, one or more methyl, methyl, propyl, chloronole, and fluorine atoms are introduced at the non-substituted, o, m, and p positions. Benzene ring and pyridin ring are obtained. Preference is given to unsubstituted or chloro, fluorine or methyl-substituted benzenes at the m- or 0- and p-positions. More preferably, there is no substitution holiday.
  • Preferred compounds in the present invention are the following compounds
  • R ′, R 2 , R 3 and R 4 are the same or independent substituents
  • R ′ is a hydrogen atom, a halogen atom, a linear or branched having 1-7 carbon lower alkyl group [unsubstituted or carbon 3-8 shea click Roarukiru group, ⁇ rie group
  • the R 5 in ⁇ R 5 groups ⁇ here Represents a hydrogen atom, a linear or branched lower alkyl group having 1 to 4 carbon atoms (unsubstituted or one or more hydrogen atoms may be substituted with an aryl group) ⁇ NR 6 R 7 groups (where R 6 and R 7 are a hydrogen atom, a linear or branched lower alkyl group having 1 to 4 carbon atoms, a linear or branched chain carbon number having 1 to 4 carbon atoms) four lower alkoxycarbonyl two Le group indicates, R beta, R 7 are the same or, alternatively each independent substituents),
  • Up to 4 lower alkyl groups (which may be unsubstituted or one or more of which may be substituted with a halogen atom or a hydroxyl group), an amino group or a COR 1 'group (where RI 1 is a linear Or a branched chain lower alkoxy group having 1 to 4 carbon atoms), but R 3 is a hydrogen atom, a halogen atom, a linear or branched chain carbon number of 1 to 4
  • a lower alkyl group (which may be unsubstituted or one or more hydrogen atoms may be substituted with a hydroxyl group);
  • ⁇ R 8 group (where R 8 is a straight-chain or branched-chain carbon atom having 1 to shows four lower alkyl group), NR 9 R 'groups (here in R s, R' ⁇ is shown a straight or branched carbon atoms 1-4 lower alkyl groups, R 9 , Are the same or each are independent substituents) or C ⁇ R
  • a hydroxyl group, an amino group or a COR 1 'group (here, R 1 'represents a hydroxyl group, a linear or branched carbon atoms to four lower ⁇ Rukoki shea group) is correct preferable, further R' and R 2 or R 3 and I Do to R 4 gar cord It is also preferable to form a benzene ring or a pyridin ring. However, when R ′ and R 2 or R 3 and R ′ do not form a ring, at least one of the four substituents represents a hydrogen atom.
  • R ′, R 2 , R 3 and R 4 are the same or each independently a substituent, and R ′ is a hydrogen atom, a methyl group, an ethyl group, Vinyl group, n — propyl group, isopropyl group, n — butyl group, isobutyl group, n — pentyl group, cyclobutylmethyl group, cyclopentylmethyl group, cyclohexyl group , Cyclohexylmethyl group, 5-(6-amino viridine 1-2-yl) pentyl group, 7-1 (6-amino viridine 12-yl) heptyl group , Hydroxymethyl group, 2-hydroxyethyl group, 3-hydroxypropyl group, 4-hydroxybutyl group, 3-aminopropyl group, 41-aminobutyl group, amino Group, methylamino group, t-butoxycarbonylaminomethyl Or Ca carboxy
  • 2-aminopyridines of the present invention include, for example, 2-aminopyridin, 2-amino4-pyridinyl pyridine, and 2— Amino 5 — Black mouth pyridine, 2 — Amino 5 — Bromo pyridine, 2 — Amino 6 — Bromo pyridine, 2 — Amino 1-3-methine pyridin, 2-amino 14-1 methyl pyridin, 2-amino 1-4-ethynolepyridin, 2-amino 4-n-pro Pilpyridine, 2—Amino 41-isopropylpyridine, 2—Amino 41-t-butynolepyridine, 2—Amino 5—Metylpi Lysine, 2—Amino 5—Ethyl pyridine, 2—Amino 5—n—Propyl pyridine, 2—Amino 5—Isopropyl pyridine , 2 — Mino 5 —
  • 6-Amino pyridine-2-dinole) Pen 1, 7-screw (6-aminopyridin 1-2-yl) No. 312 ⁇ -pyridin, 21 Amino 5 — Nitrogen pyridin, 2-Amino 14-methyl 1-3-2 D pyridine, 2 — Amino 1-4-methyl pyridin, 2-Amino 4-ethyl-3-1 2 D-pyridin, 2 — Amino 1-41 D-Pyridine, 2-Amino 4- ⁇ -Propyl
  • the 50% nitric oxide synthase inhibitory concentration (IC 5 ) in the present invention can be determined by the method described in the experimental method described below in Experimental Examples.
  • the nitric oxide synthase inhibitor of the present invention is used for suppressing the synthesis of nitric oxide, and is used as a therapeutic agent for patients who need to inhibit nitric oxide synthesis.
  • 2-aminopyridine forms a salt with an acid, for example, hydrochloride, sulfate, nitrate, phosphate, paratoluene sulfo. And the like.
  • an acid for example, hydrochloride, sulfate, nitrate, phosphate, paratoluene sulfo.
  • they are hydrochloride and sulfate.
  • 2-aminopyridins of the present invention are known compounds (for example, described in Chemical Abstracts), and also include some novel compounds.
  • Some known compounds are e.g. Compound sold by Doritsu Co., Ltd.
  • Other known compounds and novel compounds can be obtained from readily available raw materials, for example, titibabin reaction, kultiuse transfer reaction, esterification reaction, alkylation reaction, acylation reaction, nitration reaction. It can be easily manufactured using well-known techniques such as, amination reaction, oxidation reaction, reduction reaction, and ester hydrolysis reaction.
  • the 2-aminopyridines or a pharmaceutically acceptable salt thereof of the present invention may be used alone or in suspension, or in the form of a solid. Injection, infusion, granules, tablets, granules, powders, capsules, inhalants, suppositories, eye drops by mixing with pharmaceutically acceptable excipients such as It can be safely orally or parenterally (systemically administered, topically administered, etc.) and administered to mammals in the form of preparations such as patches, ointments, sprays and the like.
  • pharmaceutically acceptable excipients such as It can be safely orally or parenterally (systemically administered, topically administered, etc.) and administered to mammals in the form of preparations such as patches, ointments, sprays and the like.
  • the content of the compound of the present invention or a pharmaceutically acceptable salt thereof during production varies depending on the preparation, but is usually preferably 0.1 to 100% by weight.
  • the dosage is determined according to the age, body weight, symptoms, treatment purpose, etc. of the patient, but the dosage is about 0.001 to 300 mg / kg / day.
  • the selective inducible nitric oxide synthase inhibitor II comprising 2-amino pyridines or a pharmaceutically acceptable salt thereof as an active ingredient has a selectivity of 1 C5.
  • 2 - A Mi Bruno bi Li di emissions acids or selective inhibitors of neuronal nitric oxide synthase to a pharmaceutically acceptable salt thereof as an active ingredient, its selectivity is 1C 5.
  • the ratio of the values (IC 50 [endothelial] Bruno [C 5. [Neuronal]) 1. Than zero or more Monodea, favored by rather is 5 or more of, particularly preferred and rather one 0 or more of Is preferred.
  • Neuronal nitric oxide synthesis was prepared by partially modifying the method of David S. Bredt et al. (Proc. Natl. Acad. Sci. USA; 87, 682, 1990).
  • the cerebellum obtained from the slaughterhouse was mixed with 5 volumes of 50 mM Tris-HCl, ImM EDTA (pH 7, 4) buffer, homogenized, and centrifuged at 1,000 X g.
  • the obtained supernatant was centrifuged at 100,000 X g for 60 minutes, and the obtained supernatant was used as a crude enzyme solution of neuronal nitric oxide synthase.
  • the activity of neuronal nitric oxide synthase was determined by the method of David S. Bred et al.
  • Endothelial nitric oxide synthase was prepared by a partial modification of the method of Jennifer S. Pollock et al. (Proc. Natl. Acad. Sci. USA; 88, 10480, 1991). Endothelial cells were isolated from the slaughterhouse obtained from the slaughterhouse according to a standard method. The isolated endothelial cells were mixed with 5 volumes of 50 mM Tris-HCl, 0. ImM EDTA, 0. ImM E GTA, 0.1% 2-Mercaptoethanol buffer, homogenized, and centrifuged at 100.000 X g for 60 minutes.
  • the obtained precipitate was washed with a buffer containing 1 M KC1, and then endothelial nitric oxide synthase was extracted in a buffer containing 20 mM CHAPS.
  • the extract was centrifuged at 100,000 X g for 30 minutes, and the obtained supernatant was used as a crude enzyme solution of endothelial nitric oxide synthase.
  • the measurement of the activity of endothelial nitric oxide synthase and the evaluation of the results were performed in the same manner as in the case of neuronal nitric oxide synthase.
  • Inducible nitric oxide synthase was prepared by the following method.
  • the method of Richard G. Knowles et al. was partially modified to obtain liver fli of endotoxin-administered rats.
  • the obtained liver was purified from the inducible enzyme by a partial modification of the method of Dennis J. Stuehr et al. (Proc, Nat. And Acad. Sc USA: 88, 7773, 1991).
  • a substrate and a test drug were added to the enzyme solution thus obtained, and the mixture was incubated at 37 ° C. to measure the amount of nitric oxide produced.
  • the production of nitric oxide was measured by the method of aura Green et al. (Anal. Biochem .; 126, 131, 1982), which produced NO 2- , a metabolite of nitric oxide produced. And quantified.
  • the pressor response due to nitric oxide synthase inhibition was examined using a rat endotoxin shock model.
  • 2,6-Diaminopyridine 2.18 g of methylene chloride (160 ml) solution was cooled on ice with 0.29 ml of acetyl chloride, 0.29 ml of methylene chloride (4%). 0 ml) Add the solution dropwise (40 minutes). Raise the temperature gradually and react at room temperature for 2 hours. The reaction was stopped by adding ice water to the reaction mixture, the crude product was extracted with methylene chloride, the organic layer was concentrated under reduced pressure, and the resulting crude product was purified by silica gel chromatography. The residue is purified by chromatography to obtain 0.52 g of 6-acetylamino-21-aminopyridine.
  • 2-amino pyridines and pharmaceutically acceptable salts thereof have strong nitric oxide synthase inhibitory activity. This was found. That is, a pharmaceutical composition containing 2-amino pyridine or a pharmaceutically acceptable salt thereof as an active ingredient may be useful as a nitric oxide production inhibitor. Was found.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pyridine Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Inhibiteur de monoxyde d'azote synthétase qui contient en tant qu'ingredient actif des 2-aminopyridines ou des sels pharmaceutiquement acceptables desdites substances. On a trouvé que des 2-aminopyridines et des sels pharmaceutiquement acceptables desdites substances ont de puissants effets d'inhibition de la monoxyde d'azote synthétase. On a trouvé, en particulier, qu'une composition médicinale contenant des 2-aminopyridines et des sels pharmaceutiquement acceptables de ces substances sont utiles en tant qu'inhibiteurs de la formation de monoxyde d'azote.
PCT/JP1996/002637 1995-09-14 1996-09-13 Inhibiteur de monoxyde d'azote synthetase qui contient des 2-aminopyridines en tant qu'ingredient actif WO1997009982A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU69450/96A AU6945096A (en) 1995-09-14 1996-09-13 Nitrogen monoxide synthetase inhibitor comprising 2-aminopyridines as active ingredient

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP7/261006 1995-09-14
JP26100695 1995-09-14
JP11819396 1996-04-17
JP8/118193 1996-04-17

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WO1997009982A1 true WO1997009982A1 (fr) 1997-03-20

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19806348A1 (de) * 1998-02-12 1999-08-19 Schering Ag 3,4-Dihydrochinolin-Derivate und ihre Verwendung in Arzneimitteln
DE19845830A1 (de) * 1998-09-24 2000-03-30 Schering Ag Aminoalkyl-3,4-dihydrochinolin-Derivate und ihre Verwendung in Arzneimitteln
US6579883B1 (en) 1998-11-13 2003-06-17 Schering Aktiengesellschaft Fluorinated 3,4-dihydroquinoline derivatives used as NOS inhibitors
WO2012097869A1 (fr) * 2011-01-19 2012-07-26 Universita' Degli Studi Di Parma Dérivés du n-oxyde d'acide nicotinique, leur préparation et leur utilisation en tant qu'inhibiteurs de l'enzyme 3-hydroxyanthranilate-3,4-dioxygénase
US8629182B2 (en) 2003-08-11 2014-01-14 Hill's Pet Nutrition, Inc. Method for decreasing cartilage damage in dogs
US8633246B2 (en) 2003-08-11 2014-01-21 Hill's Pet Nutrition, Inc. Omega-3 fatty acids for osteoarthritis
JP2015518865A (ja) * 2012-05-30 2015-07-06 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ ピロリジノ複素環

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995005363A1 (fr) * 1993-08-12 1995-02-23 Astra Aktiebolag Derives de l'amidine ayant des activites de synthetase de l'oxyde nitrique
WO1995011231A1 (fr) * 1993-10-21 1995-04-27 G. D. Searle & Co. Derives amidino utiles en tant qu'inhibiteurs de la synthase de l'oxyde nitrique
WO1996018616A1 (fr) * 1994-12-12 1996-06-20 Merck & Co., Inc. 2-aminopyridines substituees utilisees comme inhibiteurs de synthase d'oxyde d'azote
WO1996019440A1 (fr) * 1994-12-20 1996-06-27 The Wellcome Foundation Limited Derives d'acetamidine et leur utilisation comme inhibiteurs de no synthetase

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995005363A1 (fr) * 1993-08-12 1995-02-23 Astra Aktiebolag Derives de l'amidine ayant des activites de synthetase de l'oxyde nitrique
WO1995011231A1 (fr) * 1993-10-21 1995-04-27 G. D. Searle & Co. Derives amidino utiles en tant qu'inhibiteurs de la synthase de l'oxyde nitrique
WO1996018616A1 (fr) * 1994-12-12 1996-06-20 Merck & Co., Inc. 2-aminopyridines substituees utilisees comme inhibiteurs de synthase d'oxyde d'azote
WO1996019440A1 (fr) * 1994-12-20 1996-06-27 The Wellcome Foundation Limited Derives d'acetamidine et leur utilisation comme inhibiteurs de no synthetase

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19806348A1 (de) * 1998-02-12 1999-08-19 Schering Ag 3,4-Dihydrochinolin-Derivate und ihre Verwendung in Arzneimitteln
DE19845830A1 (de) * 1998-09-24 2000-03-30 Schering Ag Aminoalkyl-3,4-dihydrochinolin-Derivate und ihre Verwendung in Arzneimitteln
US6579883B1 (en) 1998-11-13 2003-06-17 Schering Aktiengesellschaft Fluorinated 3,4-dihydroquinoline derivatives used as NOS inhibitors
US8629182B2 (en) 2003-08-11 2014-01-14 Hill's Pet Nutrition, Inc. Method for decreasing cartilage damage in dogs
US8629183B2 (en) 2003-08-11 2014-01-14 Hill's Pet Nutrition, Inc. Methods for decreasing cartilage damage in dogs
US8633246B2 (en) 2003-08-11 2014-01-21 Hill's Pet Nutrition, Inc. Omega-3 fatty acids for osteoarthritis
US8633247B2 (en) 2003-08-11 2014-01-21 Hill's Pet Nutrition, Inc. Method for decreasing cartilage damage in dogs
WO2012097869A1 (fr) * 2011-01-19 2012-07-26 Universita' Degli Studi Di Parma Dérivés du n-oxyde d'acide nicotinique, leur préparation et leur utilisation en tant qu'inhibiteurs de l'enzyme 3-hydroxyanthranilate-3,4-dioxygénase
JP2015518865A (ja) * 2012-05-30 2015-07-06 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ ピロリジノ複素環

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