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WO1998042667A1 - Composes hetero-tricycliques a activite inhibitrice du nos (monoxyde d'azote synthetase) - Google Patents

Composes hetero-tricycliques a activite inhibitrice du nos (monoxyde d'azote synthetase) Download PDF

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Publication number
WO1998042667A1
WO1998042667A1 PCT/JP1998/001257 JP9801257W WO9842667A1 WO 1998042667 A1 WO1998042667 A1 WO 1998042667A1 JP 9801257 W JP9801257 W JP 9801257W WO 9842667 A1 WO9842667 A1 WO 9842667A1
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group
therapeutic agent
compound according
active ingredient
formula
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PCT/JP1998/001257
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Japanese (ja)
Inventor
Nobuo Sekiguchi
Toshihiko Makino
Toru Esaki
Takashi Emura
Yasushi Kitoh
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Chugai Seiyaku Kabushiki Kaisha
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Priority to AU64219/98A priority Critical patent/AU6421998A/en
Publication of WO1998042667A1 publication Critical patent/WO1998042667A1/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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • 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
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/90—Benzo [c, d] indoles; Hydrogenated benzo [c, d] indoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/14—Aza-phenalenes, e.g. 1,8-naphthalimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention provides a tricyclic heterocyclic compound, more specifically a nitric oxide synthase (N 0 S) inhibitory action, and suppresses the production of nitric oxide (nitric oxide, N 0).
  • N 0 S nitric oxide synthase
  • Cerebrovascular disorders that are thought to involve excessive N0 or NO metabolites (cerebral hemorrhage, subarachnoid hemorrhage, cerebral infarction [atherothrombotic infarction, lacunar infarction, cardiogenic embolism], transient Cerebral ischemic attack, cerebral edema), head trauma, spinal injury, pain (headache [migraine, tension headache, cluster headache, chronic seizure headache]), Parkinson's disease, Alzheimer's disease, spasticity, morphine tolerance and Compounds useful for addiction, septic shock, rheumatoid arthritis, osteoarthritis, viral or non-viral infections, diabetes or possible tautomers, stereoiso
  • NOS non-neoplasmic senor
  • NNOS type 1
  • eNOS type 3
  • macrophages and others cytokines are induced and synthesized by the stimulation of cytokine II in vivo microlipin (lipopolysaccharide, LPS) and seem to be calcium-independent.
  • nNOS is calcium-dependent, it is considered that inhibiting abnormal activation of this type of NOS isoform exerts a protective effect on neurons by NOS inhibitors.
  • NOS inhibitors Daw soneta 1., Ann a 1 seurol. 32, 297—311, 1992.
  • the amount of nNOS mRNA and the number of nNOS-containing neurons began to increase early after rat regional cerebral ischemia, and their changes over time coincided with those of the appearance of infarct lesions (Zhangageta 1., Rain Res. 654, 85-95, 1994).
  • 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) (Mon cadaeta 1., Pharmaco l. Rev. 43, 109-142, 1991).
  • EDRF endothelium-derived relaxin factor
  • n NOS inhibitors include head trauma (0 uryeta 1., J. Bio 1. Chem. 268, 15394-15398, 1993; MacKenzieeta l., Neuroreport 6, 1789—1794, 19 5; Mesengeeta l., J. Neurotra uma. 13, 11-16, 1996; Wa lliseta l., Brain Res., 710, 169-177, 1996), headache and pain (Mo oreeta 1) , Br. J. Pharma Co., 102, 198—202, 1991; Olsen, Trends Pharmacol. 15, 149-153, 1994), No, 0 — Kinson's disease ( Yo ud imeta l., Adv aces Neuro 1.60.
  • iNOS inhibitors are useful for the treatment of rheumatoid arthritis and osteoarthritis (Farrelleta 1., Ann. Rheurn. Dis. 51, 1219—1222, 1992; Buy 1 manneta 1., FEBSL et t 352, 361-364, 1994; I slanteetal.. Br. J. Pharmacol. 110, 701-706, 1993), viral or non-viral infections (Zemb Vitzand Vane, Pro) USA 89. 2051— 2055, 1992; Ko prows kieta 1., Pro c. Natl. Ac ad. Sci. USA 90, 3024—3027 , 1993)-It has been suggested that it is useful as a therapeutic agent for diabetes (Ko lbeta 1., Life Sci. PL 213-PL 217, 1991).
  • n NO as NO S inhibitors exhibit some selectivity for S, N G -.. Eyelopropyl- L- arginine (L- CPA) (L amb erteeta l, Eu r J. Ph a rma co l. 216, 131—134, 1992), L—NA (Furfineta 1., Bioche m. 32, 8512—8517, 1993), S—methy 1 _ L—thiocitru 1 1 ine (L— MIN) ( Narayananand G riffith, J. Med.Chem. 37, 885-887, 1994; Furfineetal., J. Biol. Chem.
  • N G -. Iminoet hy l-L- ornithine (L- NIO) M c C a 1 1 eta 1., B r J. Ph a rma col. 102, 234—238, 1991
  • aminogu anidine AG
  • nNOS which is constitutively present in nerve cells mainly in the brain and is calcium-dependent, or iNOS, which is inducible and apparently calcium-independent.
  • cerebrovascular disorder Cerebral hemorrhage, subarachnoid hemorrhage, cerebral infarction [atherothrombotic infarction, lacunar infarction, cardiogenic embolism], transient ischemic attack, cerebral edema), head injury, spinal injury, Pain (headache [migraine, tension headache, cluster headache, chronic seizure headache]), Parkinson's disease, Alzheimer's disease, convulsions, morphine tolerance and dependence, septic shock, rheumatoid arthritis, osteoarthritis, virus
  • Another object of the present invention is to provide a novel compound useful as a therapeutic agent for sexual or non-viral infections and diabetes.
  • R i represents a tricyclic heterocyclic group having at least one nitrogen atom which may be substituted at any position with a lower alkyl group and / or a halogen atom;
  • R 2 represents a phenyl group which may have a substituent, a pyridyl group which may have a substituent, a compound represented by the general formula (2)
  • R 3 represents a lower alkyl group which may be substituted with a halogen atom or a lower alkoxy group or a lower alkylthio group, or represents NHR 4 , SR 5 , OR 5 ;
  • R 4 represents a lower alkyl group or a nitro group
  • R 5 represents a lower alkyl group.
  • tautomers, stereoisomers, optically active forms and pharmaceutically acceptable salts thereof have an inhibitory effect on nNOS or iNOS.
  • the present inventors have found that they show a remarkable effect as a therapeutic agent for cerebrovascular disorders (particularly, a therapeutic agent for obstructive cerebrovascular disorders), and have completed the present invention.
  • the tricyclic heterocyclic group having one or more nitrogen atoms means any tricyclic heterocyclic group capable of achieving the object of the present invention, wherein the constituent ring is a single bond or Those linked by a double bond (linking type), those in which two or three of the constituent rings are fused together (condensed type), those in which two or three of the constituent rings are spiro bonded (spiro bond type), And the combination of these (composite type) And so on.
  • a condensed type is preferable, and examples thereof include those represented by the following general formulas (3) to (20).
  • n represents an integer of 0 to 2.
  • any atom forming a ring may be substituted with a nitrogen atom and / or an oxygen atom and a no or sulfur atom.
  • L may be formed by forming an unsaturated bond between the atoms to be formed.
  • the group represented by the general formula (4) includes a group represented by the following structure. —Examples of groups represented by general formula (4) (Part 1)
  • 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, and examples thereof include a methyl group, an ethyl group, an n-propyl group, and an n-butyl group.
  • n-pentyl group n-hexyl group, i-propyl group, i-butyl group, sec-butyl group, tert-butyl group, i-pentyl group, neopentyl group, tert-pentyl group, i- Xyl groups, cyclopropyl groups, cyclobutyl groups, cyclopentyl groups, cyclohexyl groups, cycloheptyl groups, cyclooctyl groups, and the like.
  • the lower alkoxy group refers to a linear alkoxy group having 1 to 6 carbon atoms, a branched or cyclic alkoxy group having 3 to 8 carbon atoms, and includes, for example, a methoxy group, an ethoxyquin group, an n-propoxy group, an n- Butoxy, n-pentoxy, n-hexoxy, i-propoxy, i-butoxy, sec-butoxy, tert-butoxy, i-pentoxy, neopentoxy, tert-pentoxy, i- Examples include a oxo group, a cyclopropoxy group, a cyclobutoxy group, a cyclopentoxy group, a cyclohexoxy group, a cycloheptoxy group, and a cycloethoxy group.
  • 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-propylthio group.
  • Substituents in the optionally substituted phenyl group and the optionally substituted pyridyl group include a halogen atom, a nitro group, a cyano group, a formyl group, a carboxyl group, a hydroxyl group, and a halogen atom.
  • a lower alkoxycarbonyl group is an alkoxy group in which the alkyl moiety is a straight-chain alkyl group having 1 to 6 carbon atoms, and an alkoxycarbo group in which the alkyl moiety is a branched or cyclic alkyl group having 3 to 8 carbon atoms.
  • Examples of the amino group optionally substituted with a lower alkyl group include an amino group, a methylamino group, an ethylamino group, a dimethylamino group, an ethylmethylamino group, a lipidinyl group, and a piperidino group.
  • the optionally substituted phenyl group means an optionally substituted phenyl group having 1 to 5 substituents, for example, a phenyl group, a 2-fluorophenyl group, a 3-nitro-4-cyanophenyl group.
  • the optionally substituted pyridyl group means a pyridyl group optionally having 1 to 4 substituents, for example, a 2-pyridyl group, a 2- (3-fluoropyridyl) group, a 2- (4-methylpyridyl), 2- (5-cyanopyridyl), 2- (6-formylpyridyl), 2- (3-carboquinyl 4-methoxypyridyl), 2- (3-amino-5-h Droxypyridyl) group, 2- (3-nitro-16-methoxypyridyl) group, 2- (4-methylthio-15-n-propylpyridyl) group, 2- (4-ethyl-6-methoxycarbonylpyridyl) group Group, 2- (5-trifluoromethyl-6-aminomethylpyridyl) group, 2- (3-trifluoromethyl-4-ethoxy-15-methylpyridyl) group, 2- (3-cyano-1-ethylthi
  • R 2 is preferably a group represented by the general formula (2), particularly preferably an S-ethylthioimidyl group.
  • NOS inhibitory activity refers to inhibiting the activity of nNOS or iNOS, and specifically refers to inhibiting NOS activity, for example, by the method described in Test Examples described later.
  • the IC 50 value concentration required for 50% activity inhibition
  • the compound of the present invention represented by the general formula (1) is commercially available, or a compound represented by the formula (21) described in the literature as a starting material, and the synthesis method depends on the type of R 2. No. For example, it can be synthesized as follows
  • R! Is a tricyclic heterocyclic group having at least one nitrogen atom which may be substituted at any position with a lower alkyl group and / or a halogen atom.
  • R 5 represents a lower alkyl group;
  • R 6 represents a phenyl group which may have a substituent;
  • a pyridyl group which may have a substituent; and
  • R 7 represents a halogen atom or a lower atom.
  • R 8 represents a tert-butyl group or a benzyl group
  • L represents a halogen atom, trifluoromethanesulfonyloxy group
  • p- It represents a leaving group such as a toluenesulfonyloxy group or a methanesulfonyloxy group.
  • the compound represented by the formula (23), wherein R 2 is R 6 is obtained by starting from the compound represented by the formula (21) and starting with the compound represented by the formula (22). It can be synthesized by reacting with the compound represented.
  • the compound represented by the formula (21) and the compound represented by the formula (22) are converted into copper, palladium, if necessary, in the presence of a base such as potassium carbonate, triethylamine, sodium-tert-butoxide, and potassium-tert-butoxide.
  • a metal catalyst such as methanol, ethanol, i-propanol, or dimethylformamide, tetrahydrofuran, acetate nitrile, toluene, dioxane
  • the reaction is carried out in a medium, preferably toluene, at a temperature from room temperature to the boiling point of the reaction mixture, preferably at 80 ° C, to obtain a compound represented by the formula (23).
  • R 2 is a compound represented by the formula (2)
  • R 3 represents a halogen atom or a lower alkyl group which may be substituted with a lower alkoxy group or a lower alkylthio group.
  • R 7 is the same as R 3 described above.
  • the compound represented by the formula (21) and the compound represented by the formula (24) are converted into a solvent having no influence on the reaction in the presence or absence of 4-dimethylaminopyridine, for example, methanol, ethanol, i— Alcohols such as propanol, or in chloroform, methylene chloride, 1,2-dichloroethane, toluene, dimethylformamide, preferably in methylene chloride, at a temperature from 0 ° C to the boiling point of the reaction mixture, preferably at room temperature
  • the reaction is performed to obtain a compound represented by the formula (25).
  • the deprotection reaction of the amidino group is carried out in a solvent that does not affect the reaction, for example, in methanol, ethanol, 1,4-dioxane or without solvent at 0 ° C. It is preferably carried out from C to room temperature using a deprotecting agent such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid or the like, and particularly preferably trifluoroacetic acid at room temperature under anhydrous conditions.
  • a deprotecting agent such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid or the like, and particularly preferably trifluoroacetic acid at room temperature under anhydrous conditions.
  • 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
  • a solvent that does not affect the reaction
  • the reaction can be performed in methanol, in a hydrogen atmosphere, or in the presence of a hydrogen source such as ammonium formate or sodium borohydride, at a temperature from room temperature to the boiling point of the reaction mixture, preferably room temperature.
  • R 2 is a compound represented by the formula (2) H
  • R 3 represents NHR 5 ;
  • R 5 represents a lower alkyl group.
  • the compound represented by the formula (30) is obtained by using the compound represented by the formula (21) as a starting material, via a compound represented by the formula (27) or the formula (28), It can be synthesized via the compound represented by the formula (32).
  • the compound represented by the formula (21) is prepared by adding chloroform, potassium carbonate, or another inorganic base or an organic base, such as triethylamine or 4-dimethylaminopyridine, to chloroform, methylene chloride, water, or dimethylformamide.
  • the compound represented by the formula (27) can be prepared by converting the compound represented by the formula (21) into a solvent that does not affect the reaction, for example, acetone, benzoyl chloride and ammonium thiocyanate from room temperature to the boiling point of the reaction mixture. At the same temperature, preferably at room temperature, followed by heating to reflux with a 10% aqueous sodium hydroxide solution.
  • the compound represented by the formula (27) is represented by the formula (28) according to the method of A. Maryan 0ff et al. (J. Org. Chem. 51, 1882—1884, 1986). After conversion into a compound, the compound is reacted with an amine represented by the formula (29) to obtain a compound represented by the formula (30).
  • the compound represented by the formula (21) is reacted with the compound represented by the formula (31) according to the method of MA P oss et al. (T etrahedron L et t. 33, 5933-5936, 1992), After obtaining the compound represented by 32), Deprotection of the tert-butoxycarbonyl protecting group gives the compound of the formula (30).
  • R 2 is a compound represented by the formula (2)
  • R 3 represents a NHN0 2.
  • the compound represented by the formula (33) can be synthesized as follows using the compound represented by the formula (21) as a starting material.
  • the compound represented by the formula (21) is converted into a solvent such as acetonitrile, ethanol, methanol, and water which does not affect the reaction, preferably in acetonitrile, at a temperature from room temperature to the boiling point of the reaction mixture, preferably at room temperature.
  • the compound represented by the formula (33) is obtained by adding triethylamine-acetic acid according to the above reaction and reacting with N-methyl-N'-ditro N-ditrosoguanidine.
  • R 2 is a compound represented by the formula (2)
  • R 3 represents SR 5 ;
  • R 5 represents a lower alkyl group.
  • the compound represented by the formula (35) can be synthesized by reacting the compound represented by the formula (27) with the formula (34) using the compound represented by the formula (27) as a starting material.
  • the compound represented by the formula (21) can be synthesized as a starting material via the compound represented by the formula (37).
  • the compound represented by the formula (27) is affected by the reaction of the compound represented by the formula (34) with acetonitrile, acetone, 1,4-dioxane, methanol, ethanol, etc. Heating the reaction mixture to reflux in a solvent that does not affect the reaction mixture at a temperature from room temperature to the boiling point of the reaction mixture, preferably in acetonitrile to obtain the compound represented by the formula (35).
  • the compound represented by the formula (21) in a solvent that does not affect the reaction such as acetonitrile, dimethylformamide, etc., preferably in acetonitrile, at a temperature from 0 ° C. to room temperature, preferably at room temperature, A compound represented by the formula (36) in the presence of a suitable condensing agent such as hydrochloride of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide or 2-methyl-1-methylpyridinium chloride And a compound represented by the formula (37) is obtained.
  • a suitable condensing agent such as hydrochloride of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide or 2-methyl-1-methylpyridinium chloride
  • the protecting group for the isothiourea group represented by COOR 8 of the resulting compound represented by the formula (37) is deprotected under the same conditions as the deprotection reaction for the protecting group for the amidino group. Is obtained.
  • R 2 is a compound represented by the formula (2)
  • R 5 represents a lower alkyl group.
  • the compound represented by the formula (39) can be synthesized as follows using the compound represented by the formula (21) as a starting material.
  • the compound represented by the formula (21) is reacted with cyanogen bromide and various alcohols represented by the formula (38) at a temperature from 0 ° C. to the boiling point of the reaction mixture, preferably at room temperature.
  • the compound represented is obtained.
  • the compound represented by the formula (1) is obtained by first constructing a partial structure (NHR 2 ) of the compound represented by the formula (1), and then forming a tricyclic heterocycle corresponding to , Can be synthesized.
  • the substituent requiring a protecting group is a primary or secondary amino group
  • examples of the protecting group include a tert-butoxycarbonyl group, a benzyloxycarbonyl group, and a trifluoroacetyl group.
  • amino group protection reaction! Ert Monobutylcarbonylation is carried out in a solvent that does not affect the reaction, for example, alcohols such as methanol, ethanol and i-propanol, or methylene chloride, dimethylformamide, 1,4-dioxane, triethylamine,
  • 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 4-dimethylaminopyridine.
  • benzyloquine carbonylation 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, and the like. It can be performed at room temperature.
  • trifluoroacetylation is carried out by reacting trifluoroacetic anhydride with trifluoroacetic anhydride at 0 ° C to room temperature in a solvent that does not affect the reaction, for example, in methylene chloride in the presence of an organic base such as triethylamine or pyridine. be able to.
  • the deprotection reaction of the amino group can be carried out under the same conditions as the deprotection reaction of the amidino group when the protecting group is, for example, t tert -butynecarbonyl group ⁇ benzyloxycarbonyl group.
  • the deprotection reaction can be carried out by reacting with potassium carbonate in methanol at room temperature or by heating and reacting in hydrochloric acid at 60 ° C.
  • those having an asymmetric carbon in the structure are those pure stereoisomers and optically active isomers known in the art, for example, Apply chromatographic method and fractional crystallization with optical isomer separation column Can be obtained.
  • 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.
  • a pharmaceutically acceptable salt for example, hydrochloric acid, sulfuric acid, nitric acid, 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, degree of disease, elapsed time after onset, etc., and is 0.1 to 1 Omg / day. Expected to be 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 sucrose, sorbite, mannite, potato starch, corn starch, or other starches such as lactose, starch derivatives, cellulose derivatives, or gelatin
  • lubricants such as, for example, magnesium stearate, carbowax or polyethylene glycol can be added, and these mixtures can be prepared in the usual manner in granules, tablets, capsules And so on.
  • 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, filter, fill, and seal using standard methods, high-pressure steam sterilization, dry heat sterilization An injection can be prepared by sterilization by a method or the like.
  • an aqueous solution in which the main component is dissolved in distilled water for injection may be lyophilized by a conventional method.
  • a mannitol as a lyophilizable excipient may be used. It can be prepared by adding a sugar such as cellulose, inositol, lactose, maltose, sucrose or sugar alcohols or glycine and freeze-drying as usual.
  • the compounds included in the present invention include the compounds exemplified in Tables 1 to 3.
  • test results on the inhibitory effect of the compound represented by the general formula (1) on various NOS are shown in Test Examples.
  • N- (2-Fluoro-5-nitrophenylmethyl) carbamic acid tert-butyl ester (2.27 g) and dimethylformamide (2.0 ml) were added to a mixture of 4-aminobutyl aldehyde at room temperature.
  • Dimethyl acetal (5.9 ml) was added.
  • the reaction mixture was stirred at 80 ° C for 1 hour, cooled to room temperature, added with a saturated aqueous solution of ammonium chloride, and extracted with ethyl acetate.
  • the organic layer was washed with a saturated aqueous solution of ammonium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the obtained residue was purified by silica gel gel column chromatography to obtain 1.87 g of the title compound (yield: 58%).
  • Example 2 To the compound (750 mg) obtained in Example 1, a saturated aqueous solution of sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was subjected to column chromatography using an optical isomer separation column (Daicel Chiral Cell OD 2 cm x 25 cm) to perform optical resolution. 85.7 mg and (+) form 82.3 mg were obtained, respectively.
  • 6-Amino-1 _ (N— (tert—butoxycarbonylaminoethyl)) —3,
  • Example 6b Using the compound (125 mg) obtained in Example 6b as a starting material, 34 mg of the title compound was obtained in the same manner as in Example 1b (yield 31%).
  • Example 24 The compound obtained in d (9 Omg) and trifluoroacetic acid (2 Oml) was stirred at room temperature for 1 hour, concentrated under reduced pressure, and then added with a solution of hydrogen chloride in 1,4-dioxane (4N, 10 ml) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain the title compound (yield: 72%).
  • Example 24e A mixture of the compound (10 mg) obtained in Example 24e and concentrated hydrochloric acid (2 ml) was stirred at 95 ° C for 14 hours, and then concentrated under reduced pressure to quantitatively obtain the title compound.
  • 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 X 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 sample of nNOS.
  • a crude enzyme preparation of iNOS was prepared by the following procedure.
  • LPS (1 Omg / kg) was intraperitoneally administered to the rats, and after 6 hours, the rats were perfused transcardially with 1 OUZni 1 of saline containing heparin, and the lungs were removed.
  • a 5-fold volume 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 100,000 ⁇ g for 60 minutes, and the soluble cytoplasmic fraction of the finally obtained supernatant was used as a crude enzyme preparation of iNOS.
  • a crude enzyme sample of eNOS was prepared by the following procedure.
  • Pulmonary artery vascular 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 a phosphate buffer solution (pH 7.4) without calcium and magnesium was added to the cells in the sediment, and the mixture was centrifuged at 1,000 rpm for 10 minutes. After the same procedure was repeated to wash the cells, 50 mM Tris-HC1 (pH 7.4) containing 1% TritonX-100 and ImM DTT was added, and the mixture was left on ice for 1 hour.
  • CPAE Pulmonary artery vascular endothelial cell line
  • NO S activity in accordance with essentially the method which the present inventors have reported, 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. eds.) 60, pp. 285-288, 1994; Naga) fujietal., N euroreport 6, 1541—1545, 1995).
  • the reaction solution 100 nM L- [3 H] arginine, a crude enzyme preparation (1 0_30 / g / m 1 protein), 1. 25mM C a C 1 2, 1 mM EDTA, 10 ug / 1 cal mo dulin, Consists of 1 mM NAD PH, 100 zM 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 is added. added.
  • the reaction was initiated L- [3 H] was added to A rginine, 37 ° after fin incubation for 10 minutes at C, 50 mM T ris- HC 1 (pH5. 5), a ImM EDTA 2m l was added, the ice To stop the reaction.
  • the reaction solution is passed through a cation exchange resin column (Dow X AG50WX-8, Na + form, 3.2m 1), and the unreacted remaining substrate L— [ 3 H] arginine and the reaction product L— [ 3 H] citru 1 1 i ⁇ e was separated. And eluate this, further an amount eluate Distilled water was obtained through column placed in Minibai Al was recovered L_ [3 H] citru 1 1 ine. Then, added Singh Chireta, the radioactivity was measured by liquid scintillation counter to quantify L one [3 H] citru 1 1 ine .
  • activity of nNOS and eNOS was determined by subtracting the C a C l 2 and cal mo C a from activity detected in the presence of Dulin C l 2 and cal mo activity detected in the absence of Dulin.
  • activity of the i NOS is, Ji 3 Ji 1 2. Detected in the absence of & 1 mo du 1 in. The protein concentration in the crude enzyme preparation was determined using a Bio-Arad microassay kit. All experiments were performed in duplicate.
  • Table 4 as an indicator IC 50 values and selectivity for the NOS ⁇ isoform of the test compound was expressed the ratio of each IC 5 () value.
  • the compound of the present invention shows excellent nNOS inhibitory activity or iNOS inhibitory activity, and exhibits cerebrovascular disorders (cerebral hemorrhage, subarachnoid hemorrhage, cerebral infarction [atherothrombotic infarction, lacunar infarction, cardiogenic embolism], transient Cerebral ischemic attack, cerebral edema), head trauma, spinal injury, pain (headache [migraine, tension-type headache, cluster headache, chronic seizure headache]), Parkinson's disease, Alzheimer's disease, convulsions, morphine It is useful as a treatment for resistance and dependence, septic shock, rheumatoid arthritis, osteoarthritis, viral or non-viral infections, and diabetes.
  • cerebrovascular disorders cerebral hemorrhage, subarachnoid hemorrhage, cerebral infarction [atherothrombotic infarction, lacunar infarction, cardiogenic embolism], transient Cerebral ischemic attack

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Abstract

La présente invention concerne des composés de formule générale (1), les tautomères, les stéréo-isomères et les isomères optiques de ces derniers, et leurs sels médicalement acceptables, qui déploient une excellente activité inhibitrice du nNOS et de l'iNOS et qui peuvent par conséquent être utilisés comme remèdes de plusieurs maladies dans lesquelles intervient un excès de NO ou de métabolite NO. Dans ladite formule, R1 est un groupe hétéro-tricyclique azoté pouvant être substitué par un alkyle inférieur et/ou un halogéno dans une position arbitraire, et R2 est un phényle facultativement substitué, un pyridyle facultativement substitué, ou un groupe de formule générale (2), dans laquelle R3 est un alkyle inférieur facultativement substitué par un halogéno, un alcoxy inférieur ou un thioalkyle inférieur, ou, dans un autre mode de réalisation, par NHR4, SR5 ou OR5, R4 étant un alkyle inférieur ou un nitro, et R5 étant un alkyle inférieur.
PCT/JP1998/001257 1997-03-24 1998-03-24 Composes hetero-tricycliques a activite inhibitrice du nos (monoxyde d'azote synthetase) WO1998042667A1 (fr)

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Cited By (4)

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Publication number Priority date Publication date Assignee Title
WO2000066118A1 (fr) * 1999-04-28 2000-11-09 Ajinomoto Co., Inc. Compositions pour le traitement de l'infarctus cerebral
WO2008097707A1 (fr) * 2007-02-07 2008-08-14 Cytec Technology Corp. Nouveaux collecteurs de dithiocarbamate et leur utilisation pour bonifier des corps de minerai
US7718671B2 (en) 2003-07-10 2010-05-18 Achillion Pharmaceuticals, Inc. Substituted arylthiourea derivatives useful as inhibitors of viral replication
US11168068B2 (en) 2016-07-18 2021-11-09 Janssen Pharmaceutica Nv Tau PET imaging ligands

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000066118A1 (fr) * 1999-04-28 2000-11-09 Ajinomoto Co., Inc. Compositions pour le traitement de l'infarctus cerebral
US7718671B2 (en) 2003-07-10 2010-05-18 Achillion Pharmaceuticals, Inc. Substituted arylthiourea derivatives useful as inhibitors of viral replication
WO2008097707A1 (fr) * 2007-02-07 2008-08-14 Cytec Technology Corp. Nouveaux collecteurs de dithiocarbamate et leur utilisation pour bonifier des corps de minerai
US8376142B2 (en) 2007-02-07 2013-02-19 Cytec Technology Corp. Dithiocarbamate collectors and their use in the beneficiation of mineral ore bodies
US11168068B2 (en) 2016-07-18 2021-11-09 Janssen Pharmaceutica Nv Tau PET imaging ligands

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