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WO1997046515A1 - Benzenes substitues ne presentant pas d'effets inhibiteurs - Google Patents

Benzenes substitues ne presentant pas d'effets inhibiteurs Download PDF

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WO1997046515A1
WO1997046515A1 PCT/JP1997/001881 JP9701881W WO9746515A1 WO 1997046515 A1 WO1997046515 A1 WO 1997046515A1 JP 9701881 W JP9701881 W JP 9701881W WO 9746515 A1 WO9746515 A1 WO 9746515A1
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group
substituent
lower alkyl
alkyl group
hydrogen atom
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PCT/JP1997/001881
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Japanese (ja)
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Takashi Emura
Nobuaki Kimura
Toshiaki Nagafuji
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Chugai Seiyaku Kabushiki Kaisha
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Priority to AU29781/97A priority Critical patent/AU2978197A/en
Publication of WO1997046515A1 publication Critical patent/WO1997046515A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
    • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
    • C07C257/18—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C07D211/28—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms to which a second hetero atom is attached
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/14—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/12—1,4-Dioxanes; Hydrogenated 1,4-dioxanes not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention has an inhibitory effect on substituted benzene, more specifically, nitric oxide synthase (NOS), and suppresses the production of nitric oxide (nitricoide, NO), thereby producing excess NO or NO metabolites.
  • NOS nitric oxide synthase
  • ischemic cerebrovascular disease especially ischemic cerebrovascular disease, including head trauma, spinal injury, headache and pain, Parkinson's disease, Alzheimer's disease, convulsions, For morphine tolerance and dependence, septic shock, rheumatoid arthritis, osteoarthritis, nephritis, nephritis, AIDS, viral or non-viral infections, organ transplant rejection, diabetes, autoimmune encephalomyelitis And useful tautomers, stereoisomers, optically active compounds and their pharmaceutically acceptable compounds represented by the general formula (1) And a prophylactic and therapeutic agent comprising these as an active ingredient.
  • stroke cerebrovascular disease
  • ischemic cerebrovascular disease including head trauma, spinal injury, headache and pain, Parkinson's disease, Alzheimer's disease, convulsions, For morphine tolerance and dependence, septic shock, rheumatoid arthritis, osteoarthritis, nephritis, nephritis, AIDS, viral or non-viral infections,
  • cerebral infarction In a cerebrovascular disorder (stroke), a state in which cerebral arteries or cervical arteries are occluded or perfusion pressure is reduced by some mechanism and ischemic necrosis of brain tissue is called cerebral infarction. Cerebral infarction is roughly classified into cerebral embolism and cerebral thrombosis according to the mechanism. In other words, cerebral embolism occurs when an intracardiac thrombus or, in rare cases, an arterial wall thrombus exfoliates and embolizes the cerebral artery, and an increase in blood viscosity or a decrease in perfusion pressure, mainly based on a sclerosing lesion of the cerebral artery.
  • cerebral thrombosis Tokyo Kakunabe and Teruo Omae, "Cerebrovascular disorders", Life Science Publishing, pp. 54-55, 1992.
  • cerebral tissue that has been subjected to ischemia is observed to develop edema with or in advance of the infarct lesion.
  • Vascular cerebral edema appears several hours after the onset of cerebral ischemia, and this condition continues until about one week after the onset. After that, brain edema gradually It is fixed as an infarct lesion between 1 and 3 months, depending on the extent of the infarct. Because the brain is covered by a hard skull, cerebral edema causes an increase in brain volume.
  • Excessive cerebral edema causes a rapid rise in tissue and intracranial pressure, often leading to fatal hernia, resulting in worse brain damage and determining the extent of subsequent infarct lesions ( Kenji Inamura, Akira Kuro, "Stroke Studies in the Age of CT and MR I, First Volume", Nihon Gakusha, pp. 231-239, 1993). Also, when a part of the brain becomes infarcted, the functions that the area was responsible for, such as cognition, sensation, and memory, are lost.
  • N 0 S isoforms there are at least three types of N 0 S isoforms is currently dominant from genetic analysis.
  • NNOS type 1
  • eNOS type 3
  • iNOS type 2
  • LPS cytokine ⁇ lipo- lysacchalide
  • N0S inhibitors As mentioned above, since nNOS is calcium-dependent, inhibiting abnormal activation of this type of N0S isoform exerts a protective effect on neurons by N0S inhibitors. (Daws 0 neta 1., Anals Neurol. 32.297-311, 1992).
  • iNOS is involved in the mechanism of progression of ischemic brain injury. That is, iNOS mRNA began to increase in the affected cerebral cortex 12 hours after rat regional cerebral ischemia, and peaked with iN ⁇ S activity 2 days later, and its origin was polynuclear leukocytes (I adecolaeta 1., J. Cere b. Blood Flow Metab. 15, 52-59, 1995; I adecolaeta 1., J. Cere b. Blood Flow Meta b. 15, 378 — 384, 1995).
  • am inioguanidi is considered to be a relatively specific inhibitor of iNOS
  • ne (AG) is administered 24 hours after ischemia, the volume of the infarct lesion is significantly reduced (I adec 01 aeta 1., Am. J. Physiol. R286-R292, 1995).
  • NO is considered to be involved in the regulation of vascular tension and blood flow because it is at least one body of endothelium-derived relaxin factor (EDRF) (Moncadaeta 1 , Pharmacol. Rev. 43, 109-142, 1991).
  • EDRF endothelium-derived relaxin factor
  • L-NA a known and known substance as an inhibitor of NOS
  • NOS nerve cell necrosis
  • relatively high doses of NOS inhibitors are ineffective or even exacerbate ischemic brain injury (I adeco l ae t a l., J. Cereb b. B i o
  • nNOS inhibitors include head trauma and spinal injury (Ouryetal., J. Biol. Chem. 268, 15394—15398, 1993; Mackenzieetal., Euroreport 6, 1789-1794. 1995), headache and pain (Mo oreetal., Br. J. Pharmaco 1.102, 198—202, 1991; 01 ese n., Trends Pharmacol. 15, 149—153, 1994) Parkinson's disease (Yo udimetal., Ad vaces Ne urol. 60, 25 9-266, 1993; Schul Z et al., J. Ne uroch em. 64, 936-939.
  • iNOS is induced and synthesized in immunocompetent cells such as macrophages and glial cells and other cells by certain types of cytokines and LPS, and the large amount of NO generated expands blood vessels and causes a fatal decrease in blood pressure. Therefore, iNOS inhibitors are thought to be effective in septic shock (Kilbournand G riffith, J. Natl. Cancer Inst. 84, 827-831, 1992; Cobbetal. , Crit. Care Med. 21, 1261-1263, 1993; Lorenteetal., Crit. Care Med. 21, 1287-1295, 1993).
  • iNOS inhibitors are used for the treatment of rheumatoid arthritis and osteoarthritis (Farre 11 eta 1., Ann. Rh eum. Dis. 51, 1219—1222, 19992; Buyl ma nneta 1. , FEBSL et t. 352, 361-364, 1994; I slanteetal., Br. J. Pharma co 1.110, 701—706, 1993), nephritis (Catte 1 eta 1., Kidney Intl) 38, 1056—1060, 1990), Flame (Kr O nckleeta 1., Biolch em. Biophy s. Res. Commun.
  • organ transplant rejection (Lancastereta 1., J. Biol. Chem. 267 (16), 10994—10998, 1992; Langrehreta 1., Abst. Of 1st Int '1 C ongress FK506 (ed. Lawr enceeta 1) No 87, 1992; Visseretal., Clin. Chem., 37 (7), 1303. 1991), diabetes (Ko lbeta 1., Life Sci. PL 213-PL 217, 1991), autoimmune encephalomyelitis (Mac Mickingeta 1., J. Ex. Med. 176, 303- 307, 1992).
  • N c - cyclopropyl- L- arginine (L- CPA;.. (L amb erteeta 1., Eu r J. P ha rma col 216, 131 — 134, 1992), L—NA (Furfineeta 1., Bioche m. 32, 8512-8517, 1993), S-methyl-L-thiocitruine (L-MIN) (arayananand G riffith, J. Chem. 37, 885—887, 1994; Furfineeta 1., J. Biol. Chem. 37, 885-887. 1994; Furfineetal., J. Biol. Chem.
  • N G -.. Iminoethyl -Lo rnithine (LN IO) Mc C a 1 1 eta 1., B r J. P ha rma col 102, 234- 238, 1991
  • AG Griffitheta 1., Br. J. Pharma col. 110, 963-968, 1993; Hasaneta 1., Eur. J. Pharma co 1.249, 101-106, 1993; Zh angeta 1., J. Cere b. Blood Flow Me ta b. 16. 599—604, 1 996) has been reported. Disclosure of the invention
  • An object of the present invention is to selectively inhibit calcium-dependent nNOS, which is constitutively present in the brain, particularly in nerve cells, or iNOS, which is inducible and apparently calcium-independent. Acting, cerebrovascular disorder treatment, head trauma treatment, spinal cord injury treatment, analgesic, Parkinson's disease treatment, Alzheimer's disease treatment, convulsion treatment, morphine resistance or dependence, sepsis Shock, rheumatoid arthritis, osteoarthritis, nephritis, AIDS, AIDS, viral or non-viral infections, organ transplant rejection To provide novel compounds useful as therapeutic agents for diabetes and autoimmune encephalomyelitis.
  • R 2 represents a hydrogen atom, a lower alkyl group which may have a substituent, or may form a 3- to 8-membered ring together with R 3 or R 4 ;
  • R 3 represents a hydrogen atom, a lower alkyl group which may have a substituent, or may form a 3- to 8-membered ring together with R 2 ;
  • R 4 represents a hydrogen atom, a lower alkyl group which may have a substituent, or
  • R 2 or R 5 may together form a 3 to 8 membered ring
  • R 5 represents a hydrogen atom, a lower alkyl group which may have a substituent, or And R 4 may form a 3- to 8-membered ring;
  • ⁇ . ⁇ 2 , ⁇ 3 , ⁇ 4 may be the same or different, and each is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group, or a lower alkyl group which may have a substituent.
  • ⁇ 5 and ⁇ ⁇ may be the same or different, and each is a hydrogen atom, a lower alkyl group which may have a substituent, an acyl group, or a lower group which may have a substituent.
  • Upsilon 7 is a hydrogen atom, hydroxyl, optionally substituted lower alkyl group, optionally substituted lower alkoxy group, a ⁇ 8 ⁇ 9;
  • ⁇ 8 and ⁇ 9 may be the same or different and represent a hydrogen atom, a lower alkyl group which may have a substituent, or 3 to 8 May form a ring;
  • n and m each represent an integer of 0 or 1.
  • R 2 represents a hydrogen atom, a lower alkyl group which may have a substituent, or may form a 3- to 8-membered ring together with R 3 ;
  • R 3 represents a hydrogen atom, a lower alkyl group which may have a substituent, or may form a 3- to 8-membered ring together with R 2 ;
  • R 4 represents a hydrogen atom, a lower alkyl group which may have a substituent, a tert-butoxycarbonyl group, a benzyloxycarbonyl group, or 3 to 8 together with R 5 May form a membered ring;
  • R 5 represents a hydrogen atom, a lower alkyl group which may have a substituent, a tert-butoxycarbonyl group, a benzyloxycarbonyl group, or 3 to 8 together with R 4 May form a membered ring;
  • R 6 represents a tert-butyl group or a benzyl group
  • Yi, ⁇ 2, ⁇ 3, ⁇ 4 may be the same or different, are each a hydrogen atom, a halo gen atom, a halogen atom and / or lower alkyl optionally substituted Fuweniru group group, a hydroxyl group, a substituted A lower alkyl group which may have a group, a lower alkenyl group, a lower alkynyl group, a lower alkoxy group which may have a substituent, a lower alkylthio group which may have a substituent, NY 5 Y 6 , representing COY 7 ;
  • ⁇ 5 and ⁇ 6 may be the same or different and are each a hydrogen atom, a lower alkyl group which may have a substituent, an acyl group, or a lower group which may have a substituent.
  • Upsilon 7 represents a hydroxyl group, a lower alkoxy group which may have a substituent, wherein represents ⁇ 8 ⁇ 9, ⁇ 8, ⁇ 9 may be the same or different, are each a hydrogen atom, a substituent Represents a lower alkyl group which may have, or may form a 3- to 8-membered ring together;
  • n represents an integer of 0 or 1.
  • R 2 represents a hydrogen atom, a lower alkyl group which may have a substituent, or may form a 3- to 8-membered ring together with R 3 ;
  • R 3 represents a hydrogen atom, a lower alkyl group which may have a substituent, or may form a 3- to 8-membered ring together with R 2 ;
  • R 4 represents a hydrogen atom, a lower alkyl group which may have a substituent, a tert-butoxycarbonyl group, a benzyloxycarbonyl group, or 3 to 8 together with R 5 May form a membered ring;
  • R 5 represents a hydrogen atom, a lower alkyl group which may have a substituent, a tert-butoxycarbonyl group, a benzyloxycarbonyl group, or together with R 4 And may form a 3- to 8-membered ring:
  • ⁇ , ⁇ 2 , ⁇ 3 , and ⁇ 4 may be the same or different, and each is a hydrogen group, a halogen atom, a halogen atom, and a phenyl group, a hydroxyl group,
  • a lower alkyl group which may have a group, a lower alkenyl group, a lower alkynyl group, a lower alkoxy group which may have a substituent, a lower alkylthio group which may have a substituent, NY 5 Y 6 , representing COY 7 ;
  • Upsilon 5 Upsilon beta may be the same or different, are each a hydrogen atom, an optionally substituted lower alkyl group, Ashiru group, optionally low grade may have a substituent Represents an alkoxycarbonyl group, or may be joined together to form a 3- to 8-membered ring;
  • Upsilon 7 represents a hydroxyl group, a lower alkoxy group which may have a substituent, wherein represents ⁇ 8 ⁇ 9, ⁇ 8, ⁇ 9 may be the same or different, are each a hydrogen atom, a substituent Represents a lower alkyl group which may have, or may be taken together to form a 3- to 8-membered ring;
  • n an integer of 0 or 1;
  • n an integer of 0 or 1.
  • the substituent in the optionally substituted lower alkyl group is a halogen atom, a phenyl group, a nitro group, a cyano group, a cyclic alkyl group having 3 to 8 carbon atoms, a halogen atom or a phenyl group.
  • optionally substituted lower alkoxy group, a halo gen atom or Fuweniru lower alkylthio group which may be substituted with a group, a lower ⁇ alkoxycarbonyl group, a NY 8 Y 9:
  • ⁇ 8 and ⁇ 9 may be the same or different and each represents a halogen atom or a lower alkyl group which may be substituted by a phenyl group, or May form a 3- to 8-membered ring;
  • R 6 represents a tert-butyl group or a benzyl group.
  • R 4 represents a hydrogen atom, a lower alkyl group which may have a substituent, or may form a 3- to 8-membered ring together with R 5 :
  • R 5 represents a hydrogen atom, a lower alkyl group which may have a substituent, or may form a 3- to 8-membered ring together with R 4 )
  • 1 ⁇ represents a lower alkyl group, a lower alkenyl group or a lower alkynyl group which may have a substituent.
  • the substituent in the optionally substituted lower alkyl group refers to a halogen atom, a phenyl group, a hydroxyl group, a cyclic alkyl group having 3 to 8 carbon atoms, a halogen atom or a funilyl group.
  • ⁇ 8 and ⁇ 9 may be the same or different and each represent a hydrogen atom, a halogen atom or a lower alkyl group which may be substituted with a funyl group, or A 3- to 8-membered ring may be formed.
  • the method for synthesizing the compound represented by the general formula (1) is a method for producing the compound represented by the general formula (1) or a possible tautomer, stereoisomer, optically active substance and a pharmaceutically acceptable salt thereof. , Found to be useful.
  • the lower alkyl group means a linear alkyl group having 1 to 6 carbon atoms, a branched or cyclic alkyl group having 3 to 8 carbon atoms, for example, a methyl group, an ethyl group, an n-propynole group , N-butyl, n-pentyl, n-hexyl, i-propyl, i-butyl, sec-butyl, tert-butyl, i-pentyl, neopentyl, tert-pentyl And i-hexyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexinole group, cycloheptinole group, cyclooctyl group and the like.
  • the lower alkenyl group means a straight-chain alkenyl group having 2 to 6 carbon atoms or a branched alkenyl group having 3 to 6 carbon atoms, such as vinyl group, aryl group, 1-butenyl group, 1-pentenyl group, and 1-pentenyl group.
  • Examples include a 1-hexenyl group, a 2-butenyl group, a 2-pentenyl group, a 2-hexenyl group, an isopropenyl group, a 2-butenyl group, a 1-methyl-11-propenyl group, and the like.
  • the lower alkynyl group means a straight-chain alkynyl group having 2 to 6 carbon atoms or a branched alkynyl group having 3 to 6 carbon atoms, for example, ethynyl group, 1-propynyl group, 1-butynyl group, 1-pentynyl group.
  • 1 C lower alkoxy group means a linear alkoxy group having 1 to 6 carbon atoms, a branched or cyclic alkoxy group having 3 to 8 carbon atoms, such as methoxy group, ethoxy group, etc.
  • n-propoxy group n-butoxy group, n-pentoxy group, n-hexoquine group, i-ep Mouth oxy group, i-butoxy group, sec-butoxy group, tert-butoxy group, i-pentoxy group, neopentoxy group, tert-pentoxy group, i-hexoxy group, cyclopropoxy group, cyclobutoxy group, cyclopen Examples include a methoxy group, a cyclohexoxy group, a cycloheptoxy group, a cyclohexoxy group, and the like.
  • the lower alkylthio group means a straight-chain alkylthio group having 1 to 6 carbon atoms, a branched or cyclic alkylthio group having 3 to 8 carbon atoms, and examples thereof include a methylthio group, an ethylthio group, an n-propylthio group, and an n-butylthio group.
  • n-pentylthio group n-hexylthio group, i-propylthio group, i-butylthio group, sec-butylthio group, tert-butylthio group, i-pentylthio group, neopentylthio group, tert-pentylthio group, i Examples include a heminylthio group, a cyclopropylthio group, a cyclobutylthio group, a cyclopentylthio group, a cyclohexylthio group, a cycloheptylthio group, and a cyclooctylthio group.
  • An acyl group is an alkylcarbonyl group having 1 to 8 carbon atoms in which the alkyl portion is a linear alkyl group, an alkylcarbonyl group having 4 to 8 carbon atoms in which the alkyl portion is a branched or cyclic alkyl group, or arylcarbonyl. And represents, for example, formyl group, acetyl group, propionyl group, butyryl group, valeryl group, isobutyryl group, isovaleryl group, bivaloyl group, benzoyl group, phthaloyl group, and toluoyl group.
  • a lower alkoxy group is an alkoxycarbonyl group in which the alkyl moiety is a linear alkyl group having 1 to 6 carbon atoms, and an alkoxycarbonyl group in which the alkyl moiety is a branched or cyclic alkyl group having 3 to 8 carbon atoms.
  • the 3- to 6-membered saturated heterocyclic group is a monocyclic group containing at least one nitrogen atom and / or oxygen atom and / or sulfur atom. Examples thereof include an aziridine-2-yl group and an oxylane group. 2-yl, thiirane-2-yl, azetidine-12-yl, oxetane-12-yl, chetan-12-yl, azetidine-13-yl, oxetane-13 —Yl, Chetan-3-yl, pyrrolidine-12-yl, tetrahydrofuran-12-yl, tetrahydrodrochofen-12-yl, 1,3-dithiolan-1-yl Group, pyrrolidine-13-yl group, tetrahydrofuran-13-yl group, tetrahydrothiophene-13-yl group, piperidine-12-yl group, tetrahydrodropyrane-12-yl group , Thi
  • the substituent in the lower alkyl group which may have a substituent in R t includes a halogen atom, a phenyl group, a hydroxyl group, a nitro group, a cyano group, a cyclic alkyl group having 3 to 8 carbon atoms, a halogen atom or a phenyl group.
  • ⁇ 8 and ⁇ 9 may be the same or different and each represents a hydrogen atom, a halogen atom or a lower alkyl group which may be substituted by a phenyl group, or It may form a to 8-membered ring.
  • R 2 , R 3 , R 4 , R 5 , Y i, Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 may have a substituent
  • the substituent in the lower alkyl group, the lower alkoxy group which may have a substituent, the lower alkylthio group which may have a substituent, and the lower alkoxycarbonyl group which may have a substituent are halogen. Atom, halogen atom or phenyl group optionally substituted with lower alkyl group, cyclic carbon And an alkyl group having a prime number of 3 to 8.
  • the lower alkyl group which may have a substituent in the above is, for example, a methyl group, a benzyl group, a nitromethyl group, a cyclopropylmethyl group, a methoxymethyl group, an ethoxyquinmethyl group, a trifluoromethoxymethyl group, a benzyloquinmethyl group, Methylthiomethyl, ethylthiomethyl, methoxycarbonylmethyl, dimethylaminomethyl, methylaminomethyl, ethylaminomethyl, ethyl,
  • Examples thereof include a 2-fluoroethyl group, a 2-methoxyethyl group, a 2-methylaminoethyl group, an n-propyl group, an i-propyl group, a 1-methylthiopropyl group, an n-butyl group, and an i-butyl group.
  • R 2 , R 3 , R 4 , R 5 , ⁇ ,. Y 2 , ⁇ 3 , ⁇ 4 , ⁇ 5 , ⁇ 6 , ⁇ 7 , ⁇ 8 , and ⁇ ⁇ 9 may have a substituent.
  • the lower alkyl group include a methyl group, a benzyl group, a cyclopropylmethyl group, an ethyl group, a 2-fluoroethyl group, a 2-phenylethyl group, and an ⁇ -propyl group.
  • ⁇ ,, ⁇ 2, ⁇ 3, ⁇ 4 and represents a lower alkoxy group which may have a substituent in Upsilon 7, for example, main butoxy group, Torifuruorome Bok Kin group, Benjiruokishi group, shea Kuropuropirume butoxy group, Etokin A ⁇ -propoxy group.
  • the lower alkylthio group which may have a substituent in ⁇ . ⁇ 2 , ⁇ 3 , and ⁇ 4 is, for example, a methylthio group, a benzylthio group, a cyclopropylmethylthio group, an ethylthio group, a 2-fluoroethylthio group Group, ⁇ -propylthio group and the like.
  • gamma 5 Upsilon and represents a lower alkoxycarbonyl group which may have a substituent in beta, for example, main butoxycarbonyl group, a benzyl O Kin carbonyl group, cyclopropyl main butoxycarbonyl group, ethoxy Kin carbonyl group, .eta. propoxy Carbonyl group, tert-butyne carbonyl group and the like.
  • ⁇ 5 ⁇ 6 is represented by ⁇ 5 ⁇ 6, as the ⁇ 5 ⁇ 6, for example, an amino group, Mechiruamino group, Benjiruamino group, Echiruamino group, dimethylaminopyridine cyano group, Echirumechiru Amino group, pyrrolidinyl group, piperidino group, morpholino group, acetoamide group, benzamide group, ⁇ -methylacetoamide group, benzamide group, tert-butoxycarbonylamino, N-methyl-tert-butoxycal And a bonylamino group.
  • COY 7 is represented by COY 7, as the COY 7, for example, a formyl group, a carboxyl group, Asechiru group, a propionyl group, Shikuropuchiriru group, main butoxycarbonyl group, an ethoxycarbonyl Group, tert-butoxycarbonyl group, carbamoyl group, N-methylcarbamoyl group, N-ethylcarbamoyl group, N, N-dimethylcarbamoyl group, N-ethyl-N-methylcarbamoyl group, 1-pyrrolidinecarbonyl group, 1 —Piperidinecarbonyl group, 4-morpholinecarbonyl group and the like.
  • a 3- to 8-membered ring which may be formed together with R 2 and R 3 represents a saturated ring having 3 to 8 carbon atoms, wherein any position is substituted with a nitrogen atom, an oxygen atom, or a sulfur atom.
  • R 2 and R 3 represents a saturated ring having 3 to 8 carbon atoms, wherein any position is substituted with a nitrogen atom, an oxygen atom, or a sulfur atom.
  • R 2 and R 4 , or, R 4 and R 5 may be formed together to form a 3- to 8-membered ring,
  • a ring in which Y 5 and Y 6 may together form a 3 to 8 membered ring, or a ring in which ⁇ 8 and ⁇ 9 may be joined together to form a 3 to 8 membered ring is carbon
  • an aziridine ring, an azetidine ring, a pyrrolidine ring, a piperidine ring, a piperazine ring , A morpholine ring and a thiomorpholine ring is an aziridine ring, an azetidine ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, A morpholine ring and a thiomorpholine ring.
  • An amino group optionally substituted with a lower alkyl group refers to a linear alkyl group having 1 to 6 carbon atoms or an amino group optionally substituted with a branched or cyclic alkyl group having 3 to 8 carbon atoms.
  • R 2 is preferably a hydrogen atom or a lower alkyl group, particularly preferably a hydrogen atom or a methyl group.
  • R 3 is preferably a hydrogen atom or a lower alkyl group, particularly preferably a hydrogen atom or a methyl group.
  • R 4 is preferably a hydrogen atom.
  • R 5 is preferably a hydrogen atom.
  • n, Y i, Y 2 in the general formula (1) is Upsilon 3, when benzene nucleus substitution position of Upsilon 4 other substituents m- substitutions, both is preferably 0.
  • ⁇ !, ⁇ 2, ⁇ 3 , ⁇ 4 may be the same or different, are each a hydrogen atom, C androgenic atom, a nitro group, Shiano group, hydroxyl group, optionally substituted lower Al kill may have a substituent Group, lower alkenyl group, lower alkynyl group, lower alkoxy group optionally having substituent (s), lower alkylthio group optionally having substituent (s), halogen atom and / or lower alkyl group Preferred are phenyl, methylamino, ethylamino, dimethylamino, ethylmethylamino, 1-pyrrolidinyl and piperidino, and further optionally substituted with a hydrogen atom, a halogen atom or a halogen atom.
  • the compound of the present invention represented by the general formula (1) can be synthesized, for example, as follows. 97/46515
  • the compound represented by the formula (2) is synthesized from the compound represented by the formula (2) as a starting material, via the compound represented by the formula (4), or directly by the compound represented by the formula (2). Can be synthesized by reacting the compound represented by
  • R 2 represents a hydrogen atom, a lower alkyl group which may have a substituent, or may form a 3- to 8-membered ring together with R 3 ;
  • R 3 represents a hydrogen atom, a lower alkyl group which may have a substituent, or may form a 3- to 8-membered ring together with R 2 ;
  • R 4 represents a hydrogen atom, a lower alkyl group which may have a substituent, a tert-butoxycarbonyl group, a benzyloquincarbonyl group, or 3 to 8 together with R 5 May form a membered ring;
  • R 5 represents a hydrogen atom, a lower alkyl group which may have a substituent, a tert-butoxycarbonyl group, a benzyloquincarbonyl group, or 3 to 8 together with R 4 May form a membered ring;
  • ⁇ ,. ⁇ 2 , ⁇ 3 , ⁇ 4 may be the same or different, and each may be substituted with a hydrogen atom, a halogen atom, a halogen atom and / or a lower alkyl group
  • ⁇ 5 and ⁇ 6 may be the same or different and are each a hydrogen atom, a lower alkyl group which may have a substituent, an acyl group, or a lower group which may have a substituent.
  • Upsilon 7 represents a hydroxyl group, an optionally substituted lower alkoxy group, wherein represents a ⁇ 8 ⁇ 9, ⁇ 8, ⁇ 9 may be the same or different, are each a hydrogen atom, a substituent Represents a lower alkyl group which may have, or may be taken together to form a 3- to 8-membered ring;
  • n an integer of 0 or 1;
  • n an integer of 0 or 1.
  • the substituent in the lower alkyl group which may have a substituent is a halogen atom, a phenyl group, a nitro group, a cyano group, a cyclic alkyl group having 3 to 8 carbon atoms, a halogen atom or a phenyl group.
  • I may be substituted, it represents a lower alkoxy group, a halo gen atom or Fuweniru lower alkylthio group which may be substituted with a group, a lower ⁇ alkoxycarbonyl group, a NY 8 Y 9;
  • ⁇ 8 and ⁇ 9 may be the same or different and each represent a halogen atom or a lower alkyl group which may be substituted with a phenyl group, or together form a 3- to 8-membered ring May be formed;
  • Re represents a tert-butyl group or a benzyl group.
  • Reaction of the compound represented by the formula in the presence or absence of 4-dimethylaminopyridine Alcohols such as methanol, ethanol, i-propanol, or in chloroform, methylene chloride, 1,2-dichloromethane, toluene, dimethylformamide, or without solvent
  • the reaction is carried out at a temperature from 0 ° C. to the boiling point of the reaction mixture, preferably at room temperature, preferably in methylene chloride or without solvent, to obtain a compound represented by the formula (4).
  • those having a primary or secondary amino group are subjected to this reaction after protecting the amino group with a commonly used protecting group. .
  • the protecting group for an amino group include a tert-butoxycarbonyl group and a benzyloxycarbonyl group.
  • the reaction for protecting the amino group is, for example, the reaction with tert-butyl carbamate is performed in a solvent that does not affect the reaction, for example, alcohols such as methanol, ethanol, and i-propanol, or methylene chloride, dimethylformamide,
  • a solvent that does not affect the reaction for example, alcohols such as methanol, ethanol, and i-propanol, or methylene chloride, dimethylformamide
  • the reaction can be carried out by reacting di-tert-butyl dicarbonate at 0 ° C. to room temperature in the presence of an organic base such as triethylamine or 4-dimethylaminopyridine in 4-dioxane.
  • benzyl carbamate formation is carried out in a solvent that does not affect the reaction, for example, in methylene chloride, in the presence of an organic base such as triethylamine, 4-dimethylaminopyridine, etc., with benzyl chloroformate at 0 ° C to room temperature. It can be carried out.
  • R, R 2 , R 3 , R 4 , R 5 , R 6 , Y, Y 2 , Y 3 , Y 4 , m and n represent the same as described above.
  • the deprotection reaction of the urethane protecting group of the amino group and the amidino group can be performed in a solvent that does not affect the reaction, for example, in methanol, ethanol, 1,4-dioxane, or Perform at 0 ° C to room temperature using a deprotecting agent such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, or methanesulfonic acid.
  • a deprotecting agent such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, or methanesulfonic acid.
  • trifluoroacetic acid is used at room temperature.
  • the protecting group is a benzyloxycarbonyl group
  • the compound is subjected to a catalytic reduction reaction to perform deprotection.
  • the catalytic reduction reaction uses palladium monocarbon, Raney nickel or platinum oxide as a catalyst in a solvent that does not affect the reaction, for example, ethanol, methanol, ethyl acetate, acetic acid, 1,4-dioxane, preferably ethanol or
  • a solvent that does not affect the reaction for example, ethanol, methanol, ethyl acetate, acetic acid, 1,4-dioxane, preferably ethanol or
  • the reaction can be carried out in methanol, under a hydrogen atmosphere, at a temperature from room temperature to the boiling point of the reaction mixture, preferably at room temperature.
  • R 4 may have a hydrogen atom or a substituent. Represents a lower alkyl group, or may form a 3- to 8-membered ring together with R 5 ;
  • R 5 represents a hydrogen atom or a lower alkyl group which may have a substituent, or may form a 3- to 8-membered ring together with R 4 .
  • the compound represented by is an alkyl metal such as methyllithium, n-butyllithium, sec-butyllithium, tert-butyllithium, ethylmagnesium bromide, lithium diisopropylamide, lithium hexamethyldisilazide, Reaction of tetrahydrofuran, ethyl ether, 1,4-dioxane, dimethoxetane, etc. in the presence of a metal amide such as potassium hexamethyldisilazide, preferably in the presence of n-butyllithium or lithium diisopropylamide At a temperature from 178 ° C. to the boiling point of the reaction mixture, preferably at room temperature, in a solvent which does not affect the reaction, preferably in tetrahydrofuran,
  • the substituent in the lower alkyl group which may have a substituent means a halogen atom, a phenyl group, a hydroxyl group, a cyclic alkyl group having 3 to 8 carbon atoms, a halogen atom or a phenyl group.
  • ⁇ 8 and ⁇ 9 may be the same or different and each represents a hydrogen atom, a halo Or a force representing a lower alkyl group which may be substituted by a phenyl atom or a phenyl group, or may be taken together to form a 3- to 8-membered ring.
  • ⁇ 2 , ⁇ 3 and ⁇ 4 may be the same or different, and each may be substituted with a hydrogen atom, a halogen atom, a hydroxyl group, a halogen atom and / or a lower alkyl group
  • Phenyl group, lower alkyl group which may have a substituent, lower alkenyl group, lower alkynyl group, lower alkoxy group which may have a substituent, lower alkylthio group which may have a substituent represents ⁇ 5 ⁇ 6, wherein, Upsilon 5, Upsilon or 6, which may be the same or different, each a hydrogen atom, an optionally substituted lower alkyl group, or, together It is preferable to form a three- to eight-membered ring.
  • those in which R 4 is a hydrogen atom can also be synthesized as follows. That is, among the compounds represented by the formula (2), those in which R 4 is a hydrogen atom are used as starting materials, and after the above reaction is completed, the amino group represented by NHR 5 is converted into tert-butylcarbamate to form a simple compound. After separation, the obtained tert-butyl carbamate is treated with a deprotecting agent to deprotect the compound, and among the compounds represented by the formula (1), those in which R 4 is a hydrogen atom are obtained.
  • the compound represented by the formula (2) which is a raw material for producing the compound represented by the formula (1), can be produced, for example, as follows.
  • the compound represented by the formula (2) can be synthesized using the compound represented by the formula (6) as a starting material.
  • R 2 represents a hydrogen atom, a lower alkyl group which may have a substituent, or may form a 38-membered ring together with R 3 ;
  • R 3 represents a hydrogen atom, a lower alkyl group which may have a substituent, or may form a 38-membered ring together with R 2 ;
  • R 4 represents a hydrogen atom, a lower alkyl group which may have a substituent, a tert-butoxycarbonyl group, a benzyloxycarbonyl group, or a 38 member together with R 5 May form a ring;
  • R 5 represents a hydrogen atom, a lower alkyl group which may have a substituent, a tert-butoxycarbonyl group, a benzyloxycarbonyl group, or 38 members together with R 4 May form a ring;
  • Y, o> Y s ⁇ 12 ⁇ 13 may be the same or different, and each represents a hydrogen atom, A halogen atom, a halogen atom and a phenyl group which may be substituted with a halogen or lower alkyl group, a hydroxyl group, a lower alkyl group which may have a substituent, a lower alkoxy group which may have a substituent, optionally substituted lower alkylthio O group, an NY 5 Y 6, COY 7;
  • ⁇ 5 and ⁇ ⁇ may be the same or different, and each is a hydrogen atom, a lower alkyl group which may have a substituent, an acyl group, or a lower group which may have a substituent.
  • Upsilon 7 is hydroxyl, optionally substituted lower alkoxy group, ⁇ 8 ⁇
  • ⁇ 8 and ⁇ 9 may be the same or different and each represent a hydrogen atom or a lower alkyl group which may have a substituent, or together form a 3- to 8-membered ring May be formed;
  • n an integer of 0 or 1;
  • n an integer of 0 or 1.
  • a reduction reaction is performed at room temperature at room temperature to reduce the nitro group to obtain a compound represented by the formula (2).
  • R 4 and / or R 5 , Y 5 and / or Y 6 are benzyloxycarbonyl groups, they are replaced by hydrogen atoms by this catalytic reduction reaction.
  • R 2 , R 3 , R 4 , and R 5 are all hydrogen atoms, and ⁇ 2 , ⁇ 3 , and ⁇ 4 are ⁇ 14 , ⁇ 15 , ⁇ 16 , and ⁇ , respectively. 17 , a compound in which m is 1 and ⁇ is 0, that is, a compound represented by the formula (11)
  • ⁇ 14, ⁇ 15, ⁇ > ⁇ 17 may be the same or different, are each a hydrogen atom, a halogen atom, a halogen atom and / or a lower alkyl optionally off alkylsulfonyl group optionally substituted with a group, the substituent Optionally having a lower alkyl group or a substituent A lower alkoxy group which may be substituted, and a lower alkylthio group which may have a substituent. )
  • the compound represented by the formula (7) can be synthesized as follows using the compound represented by the formula (7) as a starting material.
  • Y 14 , ⁇ 15 , ⁇ 16 , and ⁇ 17 in the following formulas (7), (8), (9), and (10) represent the same as described above.
  • R 7 in the following formulas (7), (8), and (9) represents an amino group protected with a tert-butynecarbonyl group, a benzyloxycarbonyl group, and the like
  • X in the following formula (8) represents Represents a chlorine atom or a bromine atom.
  • the compound represented by the formula (8) is obtained by substituting the primary hydroxyl group of the compound represented by the formula (7) with a chlorine atom or a bromine atom under ordinary reaction conditions.
  • the substitution reaction of a primary hydroxyl group with a chlorine atom or a bromine atom can be performed, for example, when X is a chlorine atom in a solvent that does not affect the reaction, for example, in benzene, in the presence of a suitable base group, for example, pyridine.
  • the reaction can be performed at 0 ° C. to room temperature using thionyl chloride.
  • X is a bromine atom
  • the reaction can be carried out at 0 ° C. to room temperature in a solvent that does not affect the reaction, for example, methylene chloride, using carbon tetrabromide and triphenylphosphine. .
  • the compound represented by the formula (8) is reacted with sodium cyanide / potassium cyanide to obtain a compound represented by the formula (9).
  • the resulting compound represented by the formula (9) is subjected to a deprotection reaction to give a compound represented by the formula (10), and then a hydride reducing agent, preferably lithium aluminum hydride is added.
  • the reaction is carried out in a solvent that does not affect the reaction of ether, tetrahydrofuran or the like in the presence of sulfuric acid, preferably in ether, at a temperature from room temperature to the boiling point of the reaction mixture, preferably under reflux with heating to reduce the cyano group.
  • a compound represented by the formula (11) is obtained.
  • the compound represented by the formula (6) which is a raw material for producing the compound represented by the formula (2), can be produced, for example, as follows.
  • a is R 2
  • R 3 are hydrogen atoms
  • ⁇ ⁇ , ⁇ , ⁇ 13 are each, ⁇ 14, ⁇ 15, ⁇ 16, in Upsilon
  • m is 0, that is, a compound represented by the formula (16)
  • R 4 represents a hydrogen atom, a lower alkyl group which may have a substituent, or may form a 3- to 8-membered ring together with R 5 ;
  • R 5 represents a hydrogen atom, a lower alkyl group which may have a substituent, or may form a 3- to 8-membered ring together with R 4 ;
  • the compound represented by the formula (12) can be synthesized from the compound represented by the formula (12) as a starting material, via the compounds represented by the formulas (13) and (14).
  • the following equation (12), (13), 14 Upsilon in (14), ⁇ 15, ⁇ 16, ⁇ 17, ⁇ , and, what R 4, R 5 are the same as the in the following equation (15)
  • X in the following formula (14) represents a bromine atom or a chlorine atom.
  • the carboxyl group of the compound represented by the formula (12) is represented by the formula (13) by heating and refluxing in a solvent that does not affect the reaction, for example, tetrahydrofuran using a hydride reducing agent, preferably diborane. Obtain the compound.
  • the compound represented by the formula (14) is obtained by substituting the primary hydroxyl group of the compound represented by the formula (13) with a chlorine atom or a bromine atom.
  • the obtained compound represented by the formula (14) is combined with the amine represented by the formula (15) in a solvent that does not affect the reaction, for example, in dimethylformamide, an organic base such as triethylamine or 4-dimethylaminopyridine.
  • the reaction is carried out at 0 ° C. to room temperature in the presence or absence of an inorganic base such as sodium hydrogen carbonate, lithium carbonate or the like to obtain a compound represented by the formula (16).
  • the compound represented by the formula (17) is combined with the compound represented by the formula (18) in a solvent that does not affect the reaction, for example, in dimethylformamide, at 0 ° C. At room temperature to obtain a compound represented by the formula (19).
  • R 5 represents a hydrogen atom or a lower alkyl group which may have a substituent:
  • the compound represented by the formula (20) can be synthesized from the compound represented by the formula (20) as a starting material, via the compound represented by the formula (22).
  • the following equation (20), 1 Upsilon in (22) (), ⁇ , ⁇ ⁇ 12, ⁇ 13, ⁇ represents the same as above
  • a compound represented by the formula (22) is obtained by subjecting the compound represented by the formula (20) to a reductive amination reaction with an amine represented by the formula (21).
  • the reductive amination reaction can be carried out in a solvent that does not affect the reaction, for example, in ethanol or methanol, using a suitable reducing agent, for example, sodium cyanoborohydride, at 0 ° C. to room temperature.
  • a suitable reducing agent for example, sodium cyanoborohydride
  • the compound represented by the formula (23) is obtained by converting the amino group of the compound represented by the formula (22) into a tert-butyl carbamate or a benzyl carbamate.
  • R 2 Of the compounds represented by Formula (6), it is R 2, R 3, R 5 , are both hydrogen, R 4 is C_ ⁇ _OR 6, Y 8, ⁇ 9, ⁇ 10, ⁇ Chikaraku And ⁇ 18 , ⁇ ⁇ 9 , ⁇ 20 , and ⁇ 21 , respectively, and a compound wherein m is 0, (Where
  • ⁇ 18, ⁇ 19, ⁇ 2 ⁇ , ⁇ 21 which may be identical or different, are each a hydrogen atom, a lower alkyl optionally Fuweniru group optionally substituted with a group, optionally substituted lower An alkyl group, a lower alkoxy group which may have a substituent, a lower alkylthio group which may have a substituent, NY 5 Y 6 , COY 7 ;
  • ⁇ 5 and ⁇ ⁇ may be the same or different, and each is a hydrogen atom, a lower alkyl group which may have a substituent, an acyl group, or a lower group which may have a substituent.
  • Upsilon 7 is optionally substituted lower alkoxy group, wherein represents a ⁇ 8 ⁇ 9, ⁇ 8, ⁇ 9 may be the same or different, are each a hydrogen atom, a substituent Represents a lower alkyl group which may have, or may form a 3- to 8-membered ring together;
  • R 6 and n represent the same as described above.
  • the compound represented by the formula (26) can be obtained by subjecting the compound represented by the formula (24) to phthalimid reaction or subjecting the compound represented by the formula (25) to phthalimid potassium to affect the reaction. It can be obtained by performing the reaction in a solvent that is not present, for example, in dimethylformamide at room temperature.
  • the phthalimid protecting group of the compound represented by the formula (26) is subjected to a deprotection reaction using hydrazine, followed by tert-butyl carbamate or benzyl carbamate to form the compound represented by the formula (27).
  • the compound represented is obtained.
  • R 4 is COOR 6
  • Ri Oh R 5 is a hydrogen atom
  • ⁇ 8, ⁇ 9, ⁇ each, ⁇ ", ⁇ 15, ⁇ 1 ⁇ , at Upsilon 17 Yes, m and ⁇ are A compound which is already 0, ie, formula (29)
  • R 2 represents a hydrogen atom, a lower alkyl group which may have a substituent, or may form a 3- to 8-membered ring together with R 3 ;
  • R 3 represents a hydrogen atom, a lower alkyl group which may have a substituent, or
  • Crutius rearrangement reaction and the addition reaction of alcohol are carried out in a solvent that does not affect the reaction, for example, in methylene chloride, in the presence of an organic base such as triethylamine, 4-dimethylaminopyridine, or the like.
  • reagent a compound represented by, for generating an acid azide from a carboxylic acid, for example Jifue After reacting with nylphosphoryl azide at room temperature, this can be carried out by reacting with tert-butanol and benzyl alcohol while heating under reflux.
  • a reaction for generating an acid azide from a carboxylic acid for example, diphenylphosphoryl azide in tert-butanol or benzyl alcohol in the presence of an organic base such as triethylamine or 4-dimethylaminopyridine under heating to reflux. You can also do this.
  • those having an asymmetric carbon in the structure thereof are those pure stereoisomers and optically active isomers known in the art, for example, It can be obtained by applying a chromatographic method using an optical isomer separation column or fractional crystallization.
  • the pharmaceutically acceptable salt of the compound of the present invention represented by the general formula (1) is not particularly limited as long as it is a pharmaceutically acceptable salt.
  • examples thereof include hydrochloric acid, sulfuric acid, usic acid, and hydrobromic acid. , Inorganic acid salts with hydroiodic acid, etc., organic acid salts with formic acid, acetic acid, fumaric acid, tartaric acid, etc., alkali metal salts with sodium, potassium, etc., alkaline earth metal salts with calcium, magnesium, etc. Is mentioned.
  • the compound of the present invention or a salt thereof may be a suitable excipient, auxiliary agent, lubricant, preservative, disintegrant, buffer, binder, stabilizer, wetting agent, emulsifier, coloring agent, flavoring agent, flavoring agent, etc.
  • auxiliary agent e.g., talc, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, etc.
  • the dose of the compound of the present invention or a salt thereof can be appropriately selected depending on the patient's body type, age, physical condition, the degree of the disease, the time elapsed after the onset of the disease, and the like. Expected to be O mg / body. In general, even if the same dose is administered, the blood concentration may vary greatly from patient to patient, so it is ideal to determine the optimal dose of the drug for each patient while monitoring the blood concentration of the drug. It is.
  • lactose When formulated as an internal preparation, for example, lactose, sucrose, sorbite, mannite, potato starch, corn starch, or other starches such as lactose, starch derivatives, cellulose derivatives, or gelatin can be used as pharmaceutical carriers.
  • lubricants such as, for example, magnesium stearate, carbowax or polyethylene glycol can be added, and these mixtures can be converted into granules, tablets, capsules, etc. by conventional methods. can do.
  • an effective amount of the main component is dissolved in distilled water for injection, and an antioxidant, a stabilizer, a solubilizer, a buffer, a preservative, etc. are added as necessary. After complete dissolution, it can be filtered, filled, sealed by a conventional method, and sterilized by a high-pressure steam sterilization method, a dry heat sterilization method or the like to prepare an injection.
  • an aqueous solution in which the main component is dissolved in distilled water for injection may be freeze-dried by a conventional method, and if necessary, freeze-drying is easy.
  • the excipient can be prepared by adding a sugar such as mannitol, inositol, lactose, maltose, sucrose, or a sugar alcohol, or glycine, followed by freeze-drying in a conventional manner.
  • Tables 1 to 5 show the chemical structural formulas of the example compounds.
  • Example 112 Example 113
  • Example 114
  • Example 116 Example U7
  • Example 118 Example 118
  • Example 121 Example 122 Example 123
  • Example 125 Example 126 7
  • Example 128 The Example, c indicating a list of example compounds in Tables 6 to 14 3 ⁇ 46
  • ⁇ ⁇ Z — (03 ⁇ 4) -0 2 (0 ⁇ ) ⁇ - ⁇
  • R is benzene. I: represents;!? ⁇ ! 5.
  • Example 5a Using the compound obtained in Example 5a as a starting material, the title compound was quantitatively obtained in the same manner as in Example lb.
  • Example 5a A mixture of the compound (215.9 mg) obtained in Example 5a, 5% palladium on carbon (10 Omg) and methanol (30 ml) was stirred at room temperature for 5 hours under a hydrogen atmosphere. The reaction mixture was filtered to remove palladium-carbon, and the obtained filtrate was concentrated under reduced pressure to quantitatively obtain 163.Omg of the title compound.
  • Example 9b A mixture of the compound (5.16 g) obtained in Example 9b and trifluoroacetic acid (20 ml) was left at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, an aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to quantitatively obtain 2.09 g of the title compound.
  • Example 9c Using the compound obtained in Example 9c as a starting material, the title compound was obtained in the same manner as in Example 1 (yield: 25%).
  • Example 10a Using the compound obtained in Example 10a as a starting material, the title compound was quantitatively obtained in the same manner as in Example 6a.
  • Example 11b Using the compound obtained in Example 11b as a starting material, the title was performed in the same manner as in Example 1b. Compound 22.4 mg was obtained quantitatively.
  • Example 18a Using the compound obtained in Example 18a as a starting material, the title compound was obtained in the same manner as in Examples 6a and 1b (96% yield).
  • Example 11a The compound obtained in Example 11a was used as a starting material, and 3- (N- (tert-butoxycarbonyl) aminomethyl) -14-methoxyxylene was used as a reactant in the same manner as in Example 18. The title compound was obtained (yield 65%).
  • Example 11a Using the compound obtained in Example 11a as a starting material and di-tert-butyl N- (5-amino-12-chlorophenylphenylmethyl) iminodicarboxylate as a reactant, in the same manner as in Example 18 The title compound was obtained (yield 68%).
  • Example 11a Using the compound obtained in Example 11a as a starting material and tert-butyl N- (3-amino-2-cyclophenylphenylmethyl) carbamate as a reactant, the title compound was prepared in the same manner as in Example 18 Obtained (64% yield).
  • a crude enzyme preparation of nNOS was prepared by the following procedure.
  • An untreated male Sprague Dawley (SD) rat (body weight 300-400 g) was decapitated, the whole brain was quickly removed, and the cerebral cortex was collected on ice.
  • a 5-fold amount of a 50 mM Tris-HC1, ImM DTT (pH 7.4) solution was added, homogenized for 3 minutes, and centrifuged at 1,000 ⁇ g for 10 minutes. The obtained supernatant was centrifuged at 100,00 Oxg for 60 minutes, and the soluble cytoplasmic fraction of the finally obtained supernatant was used as a crude enzyme sample of nNOS.
  • a crude enzyme sample of eN0S was prepared by the following procedure. ⁇ Pulmonary artery endothelial cell line (CPAE) was cultured in MEM medium containing 20% FBS. A few days later, this was detached from the flask with a 0.25 trypsin, ImMEDTA solution, added with an appropriate amount of FBS, and centrifuged at 1,000 rpm for 10 minutes. An appropriate amount of calcium buffer and magnesium-free phosphate buffer solution (pH 7.4) was added to the sedimented cells, and centrifuged at 1,000 rpm for 10 minutes.
  • CPAE Pulmonary artery endothelial cell line
  • a crude enzyme preparation of iNOS was prepared by the following procedure.
  • LPS l Omg / kg
  • the rats were intraperitoneally administered to the rats, and after 6 hours, they were perfused transcardially with 1 OU / ml of heparin-containing saline, and the lungs were removed.
  • a 5-fold volume of a 50 mM Tris-HC1, 1 mM DTT (pH 7.4) solution was added, homogenized for 3 minutes, and centrifuged at 1,000 ⁇ g for 10 minutes. The obtained supernatant was centrifuged at 100,000 ⁇ g for 60 minutes, and the soluble cytoplasmic fraction of the finally obtained supernatant was used as a crude enzyme preparation of iNOS.
  • NO S activity is one of the substrate L - [3 H] arginine from a certain one of the reaction product L- [3 H] citru 1 1 to ine (Nagafujieta 1., in Brain Edema IX (I toeta 1.ed s.) 60, pp. 285-288, 1994; Nagafujieta 1., Neuroreport 6, 1541-1545, 1995).
  • the reaction solution 100 nM L- [3 H] arginine, a crude enzyme preparation (10- 30 gZm 1 protein), 1. 25mM C a C 1 2, 1 mM EDTA, 10 g / m 1 cal mo dulin, 1 It consists of mM NADPH, 100 M tetrahydrobiopterine, 10 M FAD, 10 M FMN, 5 OmM Tris-HC1 (pH 7.4), to which the compound of the present invention or a control compound was added.
  • the protein concentration in the crude enzyme preparation was determined using a BioRad microassay kit. All experiments were performed in duplicate. Table 15 shows the ratio of the IC 50 value (concentration required for 50% activity inhibition) of the test compound to each NOS isoform, and the IC 5 o value as an index indicating selectivity.
  • Table 15 shows the following four points.
  • the compounds of Examples 32 and 129 have stronger inhibitory activities than L-MIN, which showed the strongest nNOS inhibitory activity among existing NOS inhibitors.
  • the compounds of Examples 7, 8, 30, 54, 124, 125, 126, and 128 have the best nNOS selectivity among existing NOS inhibitors in selectivity with eNOS. It has nNOS selective inhibitory activity superior to L-EIN which showed inhibitory activity.
  • the compound of Example 1 has stronger inhibitory activity than L-MIN which showed the strongest iNOS inhibitory activity among existing NOS inhibitors.
  • the compound of the present invention exhibits stronger nNOS inhibitory activity or iNOS inhibitory activity than existing NOS inhibitors, or has a selective inhibitory effect on nNOS or iNOS, especially among isoforms of NOS.
  • Cerebrovascular disorders especially ischemic cerebrovascular disorders, head trauma, spinal cord injury, headache and pain, Parkinson's disease, Alzheimer's disease, spasticity, morphine tolerance and dependence, septic shock, chronic joint It is useful as a treatment for rheumatism, osteoarthritis, nephritis, nephritis, AIDS, viral or non-viral infections, organ transplant rejection, diabetes, and autoimmune encephalomyelitis.

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Abstract

Composés représentés par la formule suivante (1), ses tautomères éventuels, ses stéréoisomères et ses isomères optiques, ainsi que ses sels acceptables sur le plan pharmaceutique, exerçant des effets inhibiteurs puissants sur les synthétases de monoxyde d'azote. Ces composés sont utiles en tant que médicaments contre des maladies, telles que des troubles cérébro-vasculaires et des lésions crâniennes; (1) dans laquelle R1 représente alkyle inférieur éventuellement substitué; R2, R3, R4 et R5 représentent chacun hydrogène ou alkyle inférieur éventuellement substitué; Y1, Y2, Y3 et Y4 représentent chacun hydrogène, halogéno ou alkyle inférieur éventuellement substitué; n et m sont chacun un entier égal à 0 ou 1.
PCT/JP1997/001881 1996-06-04 1997-06-03 Benzenes substitues ne presentant pas d'effets inhibiteurs WO1997046515A1 (fr)

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AU29781/97A AU2978197A (en) 1996-06-04 1997-06-03 Substituted benzenes having nos inhibitory effects

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JP8/178402 1996-06-04
JP17840296 1996-06-04
JP23574796 1996-08-02
JP8/235747 1996-08-02

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0949242A1 (fr) * 1996-12-24 1999-10-13 Chugai Seiyaku Kabushiki Kaisha Derives d'amine aromatiques ayant une action inhibitrice a l'egard des nos
EP1043312A1 (fr) * 1997-11-04 2000-10-11 Chugai Seiyaku Kabushiki Kaisha Composes heterocycliques a activites inhibant nos
FR2801053A1 (fr) * 1999-11-16 2001-05-18 Sod Conseils Rech Applic Nouveaux derives d'amidines, leur preparation et leur application a titre de medicaments

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JPS5865276A (ja) * 1981-07-16 1983-04-18 ブリストル−マイア−ズ・コムパニ− 不整脈抑制性フエネチルピペリジン化合物
JPH02229148A (ja) * 1989-02-16 1990-09-11 Boots Co Plc:The 血糖低下活性アミジン化合物およびグアニジン化合物
WO1995000505A1 (fr) * 1993-06-21 1995-01-05 The Wellcome Foundation Limited Derives d'acides amines servant d'inhibiteurs de no synthase
WO1995005363A1 (fr) * 1993-08-12 1995-02-23 Astra Aktiebolag Derives de l'amidine ayant des activites de synthetase de l'oxyde nitrique
WO1995024382A1 (fr) * 1994-03-10 1995-09-14 G.D. Searle & Co. Derives de la l-n6-(1-iminoethyl)lysine utiles comme inhibiteurs de la synthetase generant de l'oxyde nitrique
WO1996019440A1 (fr) * 1994-12-20 1996-06-27 The Wellcome Foundation Limited Derives d'acetamidine et leur utilisation comme inhibiteurs de no synthetase

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JPS5865276A (ja) * 1981-07-16 1983-04-18 ブリストル−マイア−ズ・コムパニ− 不整脈抑制性フエネチルピペリジン化合物
JPH02229148A (ja) * 1989-02-16 1990-09-11 Boots Co Plc:The 血糖低下活性アミジン化合物およびグアニジン化合物
WO1995000505A1 (fr) * 1993-06-21 1995-01-05 The Wellcome Foundation Limited Derives d'acides amines servant d'inhibiteurs de no synthase
WO1995005363A1 (fr) * 1993-08-12 1995-02-23 Astra Aktiebolag Derives de l'amidine ayant des activites de synthetase de l'oxyde nitrique
WO1995024382A1 (fr) * 1994-03-10 1995-09-14 G.D. Searle & Co. Derives de la l-n6-(1-iminoethyl)lysine utiles comme inhibiteurs de la synthetase generant de l'oxyde nitrique
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 (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0949242A1 (fr) * 1996-12-24 1999-10-13 Chugai Seiyaku Kabushiki Kaisha Derives d'amine aromatiques ayant une action inhibitrice a l'egard des nos
EP0949242A4 (fr) * 1996-12-24 2004-09-08 Chugai Seiyakukabushiki Kaisha Derives d'amine aromatiques ayant une action inhibitrice a l'egard des nos
EP1043312A1 (fr) * 1997-11-04 2000-10-11 Chugai Seiyaku Kabushiki Kaisha Composes heterocycliques a activites inhibant nos
EP1043312A4 (fr) * 1997-11-04 2001-01-17 Chugai Pharmaceutical Co Ltd Composes heterocycliques a activites inhibant nos
US6414005B1 (en) 1997-11-04 2002-07-02 Chugai Seiyaku Kabushiki Kaisha Heterocyclic compounds having nos inhibitory activities
FR2801053A1 (fr) * 1999-11-16 2001-05-18 Sod Conseils Rech Applic Nouveaux derives d'amidines, leur preparation et leur application a titre de medicaments
WO2001036407A1 (fr) * 1999-11-16 2001-05-25 Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) Nouveaux derives d'amidines, leur preparation et leur application a titre de medicaments
JP2003514811A (ja) * 1999-11-16 2003-04-22 ソシエテ・ド・コンセイユ・ド・ルシエルシエ・エ・ダアツプリカーション・シヤンテイフイツク・（エス．セー．エール．アー．エス） 新規なアミジン誘導体、その調製及びその医薬としての使用
US6770669B1 (en) 1999-11-16 2004-08-03 Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) Amidine derivatives, preparation and use thereof as medicines
RU2272807C2 (ru) * 1999-11-16 2006-03-27 Сосьете Де Консей Де Решерш Э Д`Аппликасьон Сьентифик (С.К.Р.А.С.) Новые производные амидинов, их получение и их использование в качестве лекарственных средств

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