WO2003040097A1 - Composes azotes, procede de production, et methode d'utilisation - Google Patents

Composes azotes, procede de production, et methode d'utilisation Download PDF

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WO2003040097A1
WO2003040097A1 PCT/JP2002/011449 JP0211449W WO03040097A1 WO 2003040097 A1 WO2003040097 A1 WO 2003040097A1 JP 0211449 W JP0211449 W JP 0211449W WO 03040097 A1 WO03040097 A1 WO 03040097A1
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compound
group
general formula
formula
medicament according
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Tadakazu Tamai
Masazumi Nishikawa
Junichi Kobayashi
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Maruha Corporation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen 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
    • 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
    • A61K31/13—Amines
    • A61K31/133—Amines having hydroxy groups, e.g. sphingosine
    • 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
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • Nitrogen-containing compounds are Nitrogen-containing compounds, production methods, and methods of using the same
  • the present invention provides a novel compound represented by the following formula I, wherein the optical configuration at the C3 position is a non-natural S-type, and a compound represented by the general formula ⁇ including its analogous compound: (endothelial differentiation gene, vascular endothelial cell differentiation gene) Drugs that antagonize receptors or cardiovascular diseases (eg, arteriosclerosis, vasospasm after subarachnoid hemorrhage, heart disease (myocardial infarction, arrhythmia, etc.)), respiration
  • cardiovascular diseases eg, arteriosclerosis, vasospasm after subarachnoid hemorrhage, heart disease (myocardial infarction, arrhythmia, etc.)
  • the present invention relates to a medicament for preventing or treating organ diseases (such as asthma), rheumatism, cancer, and diabetic retinopathy.
  • the present invention also relates to a drug acting on an Edg receptor containing a compound represented by the following general formula ',
  • AH0P 2-amino-1,3-dihydroxytactadecene monophosphate
  • ADP adenine nucleotide diphosphate
  • PDGF platelet derived growth factor
  • 5HT serotonin
  • AH0P is contained in a significant amount, and it is considered that AH0P plays a role in maintaining the homeostasis of living organisms.
  • Edg endothelial differentiation gene, JBC, 90, 265, p. 9308
  • the Edg receptor was cloned from vascular endothelial cells in 1990 (JBC, '90, 265, p. 9308) and is a seven-transmembrane receptor coupled to GTP (guanine triphosphate) -binding protein.
  • AH0P may be a specific ligand for the Edg receptor ('98 Science, 279, pp. 1552-1555).
  • three subspecies with AH0P as ligand Edg-1, Edg-3, Edg-5 (AGR16 / H218 ) It has been suggested that each of the receptors may exert physiological effects using specific intracellular signaling pathways.
  • AH0P cardiovascular diseases
  • AH0P like PDGF, promotes the migration of vascular smooth muscle cells and acts in the direction of narrowing blood vessels, but in the presence of PDGF, AH0P synergizes vascular smooth muscle cells with PDGF (, 01 Science, .291, pp. 1800-1803). Therefore, AH0P may have the potential to progress cardiovascular disease.
  • suramin a protozoan trypanosome inhibitor
  • Suramin has been shown to be curatively effective in atherosclerotic disease models (Circulation, '99, 100, p. 861, Cardiovascular Res., '94, 28, p. 1166). It is possible that Ed g antagonist 14 is involved in the mechanism.
  • SPC sphingosylphosphorylcholine
  • PTX GTP-binding protein inhibitor pertasystoxin
  • Basal artery spasm after subarachnoid hemorrhage is a serious problem that causes worse prognosis due to cerebral ischemia, but it is said that the mechanism of basilar artery spasm involves serotonin / thromboxane and endothelin. It is not clear. Also, no direct treatment for vasospasm after subarachnoid hemorrhage has been established. Tosaka et al.
  • AH0P was administered to the canine cerebellar medullary cistern, resulting in a decrease in basilar artery diameter of 25 nmol / kg (approximately 7 g / kg) and 50 nmol / kg (approximately ⁇ g / kg) in a dose-dependent manner, It was shown to be caused.
  • AH0P caused strong vasospasm for a long period of up to 2 days after AH0P administration, with the basilar artery diameter reduced to about 1 to 3 compared to the control group. Therefore, it is necessary to search for a drug that is suitable as a therapeutic agent for the above-mentioned diseases, using the antagonistic activity to the Edg receptor as an index.
  • AH OP may activate K + rectification toward muscarinic receptors and cause arrhythmias (, 99 Pfugers Arch-Eur J Phisiol, 438, pp. 642-648). Can respond to arrhythmias
  • the Edg-3 receptor is conjugated to the GTP-binding protein subtype G13Iq type ('99 Cell, pp. 301-312).
  • G13Iq GTP-binding protein subtype G13Iq type
  • inositol 3 is bound via the G13 / q protein.
  • Phosphoric acid (IP3) is produced.
  • IP3 Phosphoric acid
  • angiotensin receptor mobilizes IP3 like Edg-3, but angiotensin receptor antagonist strongly suppresses cardiac hypertrophy. Therefore, it is possible to consider that an Edg receptor antagonist may respond to cardiac hypertrophy in the same way as an angiotensin receptor antagonist.
  • the effect of AH0P on vascular endothelial cells was examined using an angiogenesis animal model.
  • AH0P binds to Edg-1, Edg-3, angiogenesis by growth factors such as VEGF (vascular endothelial growth factor) and FGF-2 (fibroblast growth factor) It has been pointed out that Edg may be synergistically promoted, and that Edg may be involved in the progression of rheumatism, solid tumors and diabetic retinopathy (Cell, 99, p. 301).
  • VEGF vascular endothelial growth factor
  • FGF-2 fibroblast growth factor
  • the endothelial cell force Beriola expresses the Edg receptor, and it is considered that the generation and differentiation of vascular endothelial cells is performed normally by the action of the aliphatic such as AHOP on the Edg receptor (J Clin. Invest. 106, 8, p. 951, ⁇ 0).
  • the expression ability of endothelial NO synthase (eNOS) which has been reported to be involved in the health of vascular endothelium, is induced by AHOP (, 00 JBC, 275, p 32363).
  • a signal from the binding of AHOP and Edg receptor causes activation of G protein, which activates inositol tonole 3 -phosphate kinase and phosphorylates the protein kinase Akt.
  • ENOS was expressed via (.01 JBC, 276, p. 12420).
  • eNOS-induced NO inhibits platelet aggregation, maintains vascular endothelial cell homeostasis, or relaxes vascular smooth muscle cells, and plays an important role in vascular health (95 Prog. Cardiovasc. Dis. 38, p. 87).
  • Edg receptor-produced animal material is used as a NO production stimulus, it can be considered that it can be used as a preventive or therapeutic agent for cardiovascular diseases.
  • the present invention is based on these findings, and its purpose is to provide a general formula I compound, a method for producing the same, and a drug of the general formula compound including the compound of the general formula I and its analogs, and An object of the present invention is to provide a medicament of the compound of the formula I ′ ′′.
  • the compound of the general formula I, I ′ or ⁇ ′ is referred to as “the compound of the present invention.)
  • the present invention is characterized in that the optical configuration at the C3 position is a non-natural S type, and the general formula I:
  • R is CH 3 C n H ( 2n _ 2 m) -(n is an integer between 4 and 16, m is an unsaturated number and is between 0 and 2) Or an aryl group which may be substituted, and R ′ is hydrogen, an alkyl group or an alkylcarbonyl group].
  • Permissible salts are not limited to:
  • the present invention provides a compound represented by the general formula I ′ including a novel compound represented by the above general formula I and its analogous compound:
  • R is CH 3 C n H ( 2n _ 2 m )-(n is any number between 4 and 16) Is an integer, m is an unsaturated number and is any integer between 0 and 2), or an optionally substituted aryl group, and R ′ is hydrogen, alkyl A nitrogen-containing compound or a pharmaceutically acceptable salt thereof as an active ingredient, which antagonizes the Edg receptor.
  • the present invention provides a compound of the general formula ⁇ ':
  • R is CH 3 C n H ( 2n _ 2 m ) -which may be substituted, is any integer between 4 and 16, and m is an unsaturated number and is any number between 0 and 2. Or an aryl group which may be substituted, and R, is hydrogen, an alkyl group or an alkylcarbonyl group].
  • the present invention relates to a medicament acting on an Edg receptor containing a pharmaceutically acceptable salt as an active ingredient.
  • FIG. 1 is a graph showing that the compound of the present invention shows Edg antagonistic effect in a dose-dependent manner (suramin: control).
  • FIG. 2 shows the effect of AH0P on endothelial cell-neutrophil interaction.
  • FIG. 3A is a graph showing that the compound of the present invention (compound VI) suppresses neutrophil migration to vascular endothelial cells.
  • FIG. 3B is a graph showing that the compound of the present invention (compound V) acts to suppress the migration of neutrophils to vascular endothelial cells.
  • FIG. 4 is a graph showing the dose-dependent inhibitory effect of the compound of the present invention on vascular smooth muscle cell proliferation (suramin: control).
  • One is, for example, CH 3 C n H (H 2 O) substituted with at least one selected from the group consisting of a hydroxyl group, a halogen atom, and an alkyl group having 1 to 6 carbon atoms which may be linear or branched.
  • aryl group examples include a phenyl group, a 1-naphthyl group and a 2-naphthyl group.
  • the substituted aryl group of the “optionally substituted aryl group” is selected from the group consisting of, for example, an alkyl group having 1 to 10 carbon atoms, a nitro group, an alkoxy group having 1 to 10 carbon atoms and a halogen atom. Refers to an aryl group substituted by one or more. The substitution position is preferably para.
  • alkyl group is, for example, a lower alkyl group (an alkyl group having 1 to 6 carbon atoms), and specific examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, Isobutyl, tert-butyl, sec-butyl, n-pentyl, tert-aminole, 3-methylbutyl, neopentyl, n-hexyl, 3,3-dimethylbutyl, 2-ethylbutyl, etc. And a straight-chain or branched-chain alkyl group.
  • alkylcarbonyl group is, for example, an alkyl group having 2 to 5 carbon atoms, and specific examples thereof include an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a paleryl group, an isopararyl group and a pivaloyl group.
  • Groups Preferred embodiments include the following:
  • the present invention relates to a compound of the formula I, wherein the compound of the formula I is:
  • the present invention relates to a compound of the formula I:
  • the present invention relates to a compound of the formula I, wherein the compound of the formula V:
  • the present invention provides a compound of the formula ⁇ , wherein
  • the present invention provides the above medicine, which is a 2R, 3S-2-amino-1,1,3-dihydroxy-14-ene compound represented by the following formula:
  • the present invention provides a compound of formula I ′ wherein
  • R preferably has ⁇ of 4 to 12, and more preferably 5 to 11.
  • R ′ are a methyl group, an ethyl group, and an acetyl group.
  • these compounds can be synthesized via Boc-protected aldehydes using serine as a starting material (Tetrahedron '98, 54, p. 3141-3150, Liebigs Ann., 1996, 1083, part 18, J. Chem. Soc., Perkin Trans. 1'97 p. 97) Q
  • the salt of the compound of the present invention is not particularly limited as long as it is pharmaceutically acceptable.
  • Hydrochloride, hydrobromide, hydroiodide, etc. inorganic acid salts such as hydrohalide, nitrate, perchlorate, lead sulfate, phosphate, carbonate, methanesulfonate , Lower alkyl sulfonates such as trifluoromethane sulfonate and ethane sulfonate, aryl sulfonates such as benzene sulfonate and p-toluene sulfonate, acetate, fumarate, glycine salt, Alanine, glutamate, asparagine Amino acid salts, sodium salts, such as salts, such as alkali metal salts, such as force Riumu salts.
  • inorganic acid salts such as hydrohalide, nitrate, perchlorate, lead sulfate, phosphate, carbonate, methanesulfonate , Lower alkyl sulfonates
  • Solvates of the compound of the present invention are also encompassed in the present invention.
  • examples of the solvates include acetone, 2-butanol, 2-pronoxanol, ethanol, ethyl acetate tetrahydrofuran, and jetinole ether. Solvates.
  • the compound of the present invention exhibits endothelial differentiation gene (E dg) receptor antagonism and antagonizes the binding of Edg receptor agonists such as AHOP and sphingosylphosphorylcholine to the Edg receptor. These can block the intracellular signal transduction system.
  • Edg receptor agonists such as AHOP and sphingosylphosphorylcholine
  • the compound of formula (I) of the present invention exhibits about 30 times stronger action strength than the positive control suramin as seen in the following examples. Therefore, the present invention provides a medicament for antagonizing an endothelial differentiation gene (Edg) receptor, which comprises the compound of the present invention as an active ingredient.
  • a drug containing the compound of formula (I) of the present invention as an active ingredient is useful for inflammatory cell activation, vascular smooth muscle proliferation, hemodynamic deterioration, and diseases caused by angiogenesis, such as circulatory diseases (eg, arteriosclerosis). , Vasospasm after subarachnoid hemorrhage, heart disease (eg, myocardial infarction, arrhythmia)), rheumatism (eg, rheumatoid arthritis), cancer, diabetic retinopathy, respiratory disease (eg, pneumonia, chronic obstruction) It is effective in preventing or treating sexual respiratory tract disease and respiratory hypertension).
  • circulatory diseases eg, arteriosclerosis
  • rheumatism eg, rheumatoid arthritis
  • cancer eg, diabetic retinopathy
  • respiratory disease eg, pneumonia, chronic obstruction
  • the term “circulatory system disease” refers to a disease in which the circulatory state of blood, lymph, etc. is impaired, causing damage to tissues and cells.
  • arteriosclerotic diseases for example, atherosclerosis
  • atherosclerosis Porous sclerosis
  • vasospasm after subarachnoid hemorrhage heart disease (eg, myocardial infarction, arrhythmia).
  • the term “respiratory disease” refers to a disease in which the respiratory tract, such as the trachea, bronchi, and lungs, is impaired and symptoms related thereto.
  • the disease include asthma (immediate type, delayed type, allergy type). ), Bronchial asthma, allergic rhinitis, eosinophil infiltration, bronchitis (chronic bronchitis, etc.), airway inflammation, emphysema, pneumonia, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome, respiratory system If you have systemic hypertension, dyspnea, pain, cough, sputum, vomiting, or shortness of breath.
  • COPD chronic obstructive pulmonary disease
  • the compound of formula I ′′ ′ of the present invention exerts an effect on the Edg receptor, stimulates NO production, and can maintain normal development and differentiation of vascular endothelial cells or inhibit fibrosis of organs. it can.
  • a medicament containing the compound of formula (I) of the present invention as an active ingredient is effective for preventing or treating cardiovascular diseases, fibrotic diseases and the like.
  • fibrotic disease includes pulmonary fibrosis, interstitial pneumonia, chronic hepatitis, cirrhosis, chronic renal failure or glomerulosclerosis.
  • Each compound in the present invention can be administered orally or parenterally (injection, external preparation, suppository, etc.).
  • the dose is preferably in the range of about 0.0001 to about 1 g / kg body weight / day, once or more times a day, but this dose depends on the type of disease, patient's age, weight, and symptoms. Can be increased or decreased.
  • the compound of the present invention in order to use the compound of the present invention as a medicament, it may be in any form of a solid composition, a liquid composition, and other compositions, and an optimum one is selected as necessary.
  • the pharmaceutical composition is obtained by adding a pharmaceutically acceptable carrier, that is, a commonly used excipient, a bulking agent, a binder, a disintegrant, a PH regulator, a solubilizer, and the like to the compound of the present invention
  • a pharmaceutically acceptable carrier that is, a commonly used excipient, a bulking agent, a binder, a disintegrant, a PH regulator, a solubilizer, and the like
  • Tablets, pills, capsules, granules, powders, solutions, powders, suspensions, injections, etc. can be prepared by conventional formulation techniques.
  • Excipients and bulking agents include, for example, lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame oil, cocoa pattern, ethylene glycol, and others. I can give things.
  • an antioxidant tocopherol or the like
  • the preparation can be encapsulated with an inclusion agent such as cyclodextrin, or the preparation can be encapsulated with a film such as gelatin.
  • the compound can be prepared as an OZW type preparation using a phospholipid or a nonionic surfactant as an emulsifier, as described in JP-A-6-289642.
  • Emulsifiers can be used alone or in combination of two or more. The addition amount may be appropriately determined, but is preferably 0.01 to 10% (W / V), preferably 0.01 to 5% (W / V). ).
  • soybean-derived phospholipids soybean-derived phospholipids, egg yolk-derived phospholipids, lysolecithin, phosphatidylcholine (lecithin), phosphatidylserine, and the like can be used alone or in combination.
  • non-surfactant include a polyoxyethylene-polyoxypropylene block copolymer having a molecular weight of 500 to 1500 (for example, Punorelonic F-68), and a molecular weight of 100 to 1000.
  • Polyoxyalkylene glycol, polyoxyalkylene copolymer having a molecular weight of 1000 to 2000, hydrogenated castor oil polyoxyalkylene derivative, castor oil polyoxyalkylene derivative, glycerin fatty acid ester, poly A glycerin fatty acid ester, a sorbitan fatty acid ester, a polyoxyethylene castor oil, a hydrogenated castor oil, a polyoxyethylene alkyl ether, a sucrose fatty acid ester or the like is preferably used alone or in combination, but is not limited thereto.
  • the compound of the present invention can be produced by the following production methods.
  • the methods for producing the compounds of the formulas I and I are described below, including examples of the preparation of the reaction raw materials.
  • N-protected (R) -formyloxazolidine derivatives of the following formula can be synthesized by conventional methods, for example, from (R) -serine to the method of Mori et al. (Tetrahedr on 1985, 41, 2379-2386) ).
  • A is a protecting group for N, and B and C are alkyl groups (eg, methyl groups)
  • protecting group A for N for example, benzyloxycarbonyl (Z), t-butoxycarbonyl (Bo c), t-aminooxycarbonyl (Ao c), isobonyloxycarbonyl, p— Groups such as methoxybenzyloxycarbonyl, 2-hydroxylbenzyloxycarbonyl, adamantyloxycarbonyl, trifluoroacetinole, phthaloynole, honoleminole, o_nitropheninolesnolefeninole, diphenylphosphinochioyl, etc. Is mentioned.
  • Boc is used.
  • the HC ⁇ CR (R is as defined above) is reacted with the N-protected (R) -formyloxazolidine derivative obtained in (1) above.
  • the reaction of the first step is carried out under about 0.5-3.0 equivalents of a base (for example, n-butyllithium) per 1 equivalent of (R) -formyloxazolidine derivative in an inert solvent (for example, n-butyllithium). , THF) under ice-cooling (for example, about 20 ° C) for about 5 to about 20 hours.
  • the triple bond of the product of the first step is reduced to a double bond, and at the same time, deprotection is carried out while opening oxazolidine to give the following compound having an NH 2 group and an OH group (where R and are hydrogens in the general formula II). Is obtained. Further, in the general formula II, a compound in which R ′ is other than hydrogen can be obtained by a general method of substituting the NH 2 group with R ,.
  • the reaction of the second step can be carried out with an alkali metal and an amine (eg, lithium in the presence of ethylamine) in an inert solvent (eg, THF) at a temperature of about 150 ° C. or less for about 2 hours.
  • an alkali metal and an amine eg, lithium in the presence of ethylamine
  • an inert solvent eg, THF
  • the product of the second step can also be synthesized by a usual method through a Wittig-Olefinification reaction using cyclohexane cis-diol as a starting material ('98 J. Org. Chem. 63 , p.510-520).
  • a hydroxyl-protecting agent for example, tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf) can be used, and this reaction is carried out in the presence of a base (eg, 2,6-lutidine). It can be carried out in an inert solvent (for example, dichloromethane).
  • a base eg, 2,6-lutidine
  • an inert solvent for example, dichloromethane
  • TsCl p-toluenesulfoninole chloride
  • the epoxidation reaction is carried out in an inert solvent (eg, hexane) under alkaline (pH 8-11) (eg, sodium bicarbonate) conditions, with about 2-5 equivalents of 1 equivalent of (2) product.
  • an oxidizing agent eg, m-chloroperbenzoic acid (MCPBA) (for example, 70%), osmium, hydrogen peroxide and the like are used.
  • an epoxy having a desired optical configuration is separated by a common fractionation method such as silica gel column chromatography.
  • a common fractionation method such as silica gel column chromatography.
  • the optical configuration at the C4 position of the final product is S
  • the epoxy of the syn is separated from the hydroxyl group at the C3 position (this is shown in the scheme).
  • the optical configuration at the C 4 position of the final product is R
  • the anti-epoxy is separated from the hydroxyl group at the C 3 position.
  • the compound having a hydroxyl group at the 4-position is obtained by opening the epoxy ring of the product of the third step.
  • an inert solvent for example, toluene
  • an alkaline condition pH 8-10
  • a metal hydride for example, diisobutylaluminum hydride (DI BAL-H)
  • DI BAL-H diisobutylaluminum hydride
  • MsC 1 methanesulfonyl chloride
  • a base eg, pyridine
  • a ring is formed between the nitrogen of the amine at the 2-position and the carbon at the 4-position.
  • This reaction is carried out in an inert solvent (eg, tetrahydrofuran (THF)) in the presence of about 0.5-3 equivalents of a metal hydride (eg, NaH) for 1 equivalent of the fourth step product.
  • THF tetrahydrofuran
  • a metal hydride eg, NaH
  • the protecting group for OH and the protecting group for nitrogen on the ring are deprotected to obtain a compound of formula I (a compound of formula I in which R 'is hydrogen).
  • a compound in which R ′ is other than hydrogen can be obtained by a general method of substituting an NH 2 group with R ′.
  • Deprotection of the nitrogen protecting group on the ring is carried out using sodium naphthalenide in an inert solvent (eg, 1,2-dimethoxetane (DME)), and deprotection of the OH protecting group is not carried out.
  • the reaction can be carried out using a weak acid (eg, hydrofluoric acid) in an active solvent (eg, acetonitrile).
  • the compound of the present invention can be isolated and purified according to a conventional method (filtration, solvent extraction, recrystallization, reprecipitation, or chromatography), if necessary.
  • the reaction in the first step is performed in the same manner as in Synthesis Example 1.
  • the optical configuration of the hydroxyl group at the C 3 position of the product of the second step is inverted from R to S.
  • the compound of the formula I ′′ can be synthesized by a reaction similar to the above Synthesis Examples 1 and 2, using a compound having a desired optical configuration.
  • the general formula I ′ compound of the present invention characterized in that the optical configuration at the C3 position is a non-natural S type, antagonizes the Edg (endothelial differentiation gene) receptor, Prevention of cardiovascular diseases (eg, arteriosclerosis, vasospasm after subarachnoid hemorrhage, heart disease (myocardial infarction, arrhythmia, etc.)), respiratory disease (such as asthma), rheumatism, cancer, diabetic retinopathy Or it has an excellent effect on treatment.
  • cardiovascular diseases eg, arteriosclerosis, vasospasm after subarachnoid hemorrhage, heart disease (myocardial infarction, arrhythmia, etc.)
  • respiratory disease such as asthma
  • rheumatism cancer
  • diabetic retinopathy Or it has an excellent effect on treatment.
  • the compound of the present invention represented by the general formula ⁇ ′, in which the optical configuration at the C3 position is a natural R-type with respect to the compound of the formula, acts on the Edg receptor to normalize the development and differentiation of vascular endothelial cells. It is effective in preventing or treating cardiovascular and fibrotic diseases.
  • compound (2) (5.5 g, 21.1 mmol) dissolved in dry toluene (50 ml) was added to a 300 mil-necked flask, and 1.0 M-toluene of diisobutylaluminum hydride was added at -70 ° C.
  • the solution (36.5 ml, 36.5 mmol, 1.7 equivalents) was added dropwise, and the reaction solution was stirred at -70 ° C or lower for 2 hours. 3 ml of methanol was added to terminate the reaction.
  • the reaction solution was poured into 1M-HC1 ice water, stirred for 15 minutes, and extracted three times with ethyl acetate.
  • reaction solution was diluted with water, added a small amount of sodium thiosulfate, and extracted three times with ethyl acetate.
  • the obtained compound (10) was dissolved in dry THF (8 ral), 60% sodium hydride (94 mg, 2.35 mmol, 3 equivalents) was added under ice cooling, and the mixture was stirred at room temperature for 15 hours.
  • the reaction solution was diluted with water and saturated aqueous ammonia and extracted three times with ethyl acetate. The combined organic layers were washed with saturated aqueous ammonium chloride and saturated saline, and dried over anhydrous sodium sulfate.
  • the sodium naphthalenide used here was prepared by dissolving naphthalene (883 mg, 6.89 mol, 10 equivalents) in dry 1,2-dimethoxetane (8 ml) in a 30 ml 1-neck flask under a nitrogen atmosphere, It was prepared by adding sodium (127 rag, 5.51 mol, 8 equivalents) at room temperature and stirring at room temperature for 3 hours.
  • HL60 cells were obtained from a cell bank, and were passaged for 50 years using RPMI-1640 medium (Gibco) containing 10% fetal calf serum according to the method described in BBRC '98, 263, p. 253.
  • RPMI-1640 medium Gibco
  • fetal calf serum 10% fetal calf serum
  • Pre- and post-culture was performed to prepare a promyeloblastoma cell line HL60 expressing the Edg receptor on the cell surface.
  • This Ed g receptor on the cell surface Using the expressed promyeloblastoma cell line HL60, the cell responsiveness of the test substance was examined. As an indicator of the cellular response, an increase in intracellular Ca 2+ concentration was measured.
  • the Ca 2+ chelating agent Fura-2 AM was incorporated into HL 60 cells.
  • a test substance compound V or compound VI at a final concentration of 30 microM each using a microsyringe
  • the fluorescence intensity was followed to examine whether Ca 2+ increased.
  • AH0P It was confirmed whether Ca 2+ increased when a final concentration of 1 microM was added, and the AH0P antagonism of each substance was examined.
  • Promyeloblastoma cell line HL expressing the same Edg receptor on the cell surface as in Example 3 60 was used.
  • HL60 cells were collected by centrifugation, suspended in F-12 medium (stored at 4 ° C, 10 ml), and transported to the RI laboratory. 200 microl of cell suspension (1 x 106 cells / ml F-12) was added to 1 nM final concentration of 3 H-AH0P (10 microCi / 1 mM) and 100 nM final concentration of unlabeled compound (compound V, VI) were added and the binding test was performed at 4 ° C for 30 minutes (with occasional stirring).
  • Exposed collagen is targeted as an injury signal at the site of injury in the body, and platelets aggregate, but inflammatory substances such as PDGF released from aggregated and activated platelets are released. Cytokines are thought to promote inflammation, and severe inflammation disrupts cardiovascular homeostasis and promotes atherosclerosis. A HOP is also believed to have a similar effect as PDGF.
  • AH0P as an inflammation-inducing agent, a pseudo-vascular in vitro model was established, and using this model, whether the compound of the present invention exhibited an anti-inflammatory action, thereby maintaining circulatory homeostasis and maintaining the disease state Whether there is a possibility of acting in a direction to improve Debated.
  • one layer of endothelial cells is cultured on the pore membrane at the bottom of the upper chamber of the translucent cell, and the fluorescence is applied to the upper chamber of the transwell.
  • a labeled (BCECF-AM (Dojindo)) neutrophil suspension was added, and AH0P was suspended in the lower chamber to a final concentration of 0.1 to;
  • the upper and lower chambers of the transwell are separated by an endothelial layer, and the upper chamber is a simulated blood vessel in w'iro inflammation model in which the lower chamber corresponds to an inflamed area outside the blood vessel.
  • the number of neutrophils that penetrated into the lower chamber from the upper chamber by penetrating the ⁇ skin layer and the number of neutrophils adhering to the endothelial layer were measured.
  • the number of neutrophils that passed through the endothelial layer and penetrated into the lower chamber and the number of neutrophils adhered to the endothelial layer were measured, and the relative neutrophil number% was calculated by the following equation.
  • Relative neutrophil number% [neutrophil (permeate and adherence) number in experimental group] [neutrophil (permeate and adherence) number in control] X 100
  • the control is the case without the addition of AHOP.
  • AH0P was considered to be acting as an inflammation-inducing substance.
  • the number of neutrophils adhered to the endothelial layer or the number of neutrophils that passed through the endothelial layer and penetrated into the lower chamber were measured at a fluorescence intensity of 530 nm, and the relative neutrophil number% was calculated in the same manner as above. .
  • test substance The effect of the test substance on vascular smooth muscle cell proliferation was examined.
  • Rat carotid intima was scraped by ballooning, and two weeks later, vascular smooth muscle cells prepared by the explant culture were cultured in DMEM medium (Gibco) containing 10% fetal bovine serum, and several times. After passage and stabilization, the cells were seeded at a cell density of 5 ⁇ 1 ⁇ cells / cm 2 and used for experiments. Compound V or suramin is added to the above cells together with the growth factor SPC (10 ⁇ ), and 24 hours later, BrdU atssay (Science '82, 218, p. 474, Cytometry '85, 6, p. 584) The cell density was measured by As a control, the cell density in the absence of the drug was measured.
  • Promyeloblastoma cell line HL expressing the same Edg receptor on the cell surface as in Example 3 60 was used.
  • HL 60 cells IX 10 6 cells / ml were loaded with Fura-2AM and mounted on a fluorometer (Perkin Elmer LS 50 B). Excitation was performed at 340 nm and 380 nm, and the fluorescence intensity was measured at 510 nm.
  • the intracellular Ca 2+ increasing concentration was calculated from the increase in the fluorescence ratio after addition.
  • the intracellular Ca 2+ increasing concentration was calculated from the proportionality between the previously confirmed fluorescence intensity and the Ca 2+ concentration.
  • compound 101 is Edg receptor agonist is acting as N0 2 stimulants, compound 101 platelet aggregation inhibition, homeostasis of vascular endothelial cells, or vascular smooth muscle cells It was suggested that the drug may be effective in circulatory disease while showing the effect of relaxation.
  • Egret NZW male (weight 2.83-3.20 kg) from Kitayama Labes Purchased, reared at room temperature 20-26 ° C, humidity 40-70%, lighting time 12 hours / day (7-19 o'clock), and have free access to feed and water, After quarantine and acclimatized breeding for 2 weeks or more, those with good health were used.
  • Compound VI showed a tendency to suppress the decrease in pulse due to ligation and to reduce the number of arrhythmias in the egret arrhythmia model. Effect of compound VI on pulse (time Z)
  • the basilar artery was removed from a 13 kg beagle dog, a 4 mm ring specimen was prepared, and suspended in a Magnus tube. After equilibration for 1 hour while exchanging the Krebs-ringer nutrient solution, nonspecific contraction was induced with 40 mM KCl, which was used as a standard for the contractile force of each ring specimen. After the nutrient solution was exchanged again and equilibrated, AH0P was cumulatively administered to 1 to 10 ⁇ l and the contractile force was measured.

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Abstract

L'invention concerne un médicament contenant un composé de formule générale (I'), caractérisé en ce que la configuration optique du carbone en position 3 est de type S, non naturelle, et possédant un effet antagoniste sur un récepteur Edg. L'invention concerne aussi un médicament contenant un composé de formule générale (II'), formule représentant la formule générale (I') dans laquelle la configuration optique du carbone en position 3 est de type R, naturelle, ce composé agissant sur un récepteur Edg.
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004074297A1 (fr) 2003-02-18 2004-09-02 Kyorin Pharmaceutical Co., Ltd. Derives d'acide aminophosphonique, leurs sels d'addition et des modulateurs de recepteurs s1p
WO2005063704A1 (fr) 2003-12-25 2005-07-14 Ono Pharmaceutical Co., Ltd. Composes cycliques d'azetidine et medicaments les renfermant
WO2006093352A1 (fr) * 2005-03-04 2006-09-08 Riken Compose a structure cyclique et son utilisation
WO2008018427A1 (fr) 2006-08-08 2008-02-14 Kyorin Pharmaceutical Co., Ltd. Dérivé d'ester de l'acide aminophosphorique et modulateur du récepteur s1p contenant ledit dérivé en tant que principe actif
WO2008018447A1 (fr) 2006-08-08 2008-02-14 Kyorin Pharmaceutical Co., Ltd. Dérivé d'aminoalcool et immunodépresseur le contenant en tant que principe actif
US7482491B2 (en) 2002-09-19 2009-01-27 Kyorin Pharmaceutical Co., Ltd. Amino alcohol derivative, addition salt thereof, and immunosuppressant
US8546452B2 (en) 2005-10-12 2013-10-01 Toa Eiyo Ltd. S1P3 receptor antagonist

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995003039A1 (fr) * 1993-07-23 1995-02-02 The Biomembrane Institute Derives de n,n,n-trimethylsphingosine
WO1999046277A1 (fr) * 1998-03-09 1999-09-16 Smithkline Beecham Corporation POLYNUCLEOTIDES ET POLYPEPTIDES D'EDG-1c HUMAIN ET LEURS PROCEDES D'UTILISATION
WO2001069252A1 (fr) * 2000-03-13 2001-09-20 The General Hospital Corporation Methodes et compositions de regulation de la vasoconstriction

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995003039A1 (fr) * 1993-07-23 1995-02-02 The Biomembrane Institute Derives de n,n,n-trimethylsphingosine
WO1999046277A1 (fr) * 1998-03-09 1999-09-16 Smithkline Beecham Corporation POLYNUCLEOTIDES ET POLYPEPTIDES D'EDG-1c HUMAIN ET LEURS PROCEDES D'UTILISATION
WO2001069252A1 (fr) * 2000-03-13 2001-09-20 The General Hospital Corporation Methodes et compositions de regulation de la vasoconstriction

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
BEAUHAIRE J. AND DUCROT P.: "Nouvelle methodologie de synthese d'alcaloides azetidiniques polyhydroxyles", COMPTES RENDUS DE L'ACADEMIE DES SCIENCES, SERIE IIC: CHIMIE, vol. 2, no. 9-10, 1999, pages 477 - 482, XP002904787 *
CHEMICAL ABSTRACTS, vol. 128, Columbus, Ohio, US; abstract no. 270754, LIN G. AND LIU D.: "Stereoselective synthesis of 2-epi-penaresidin A and its (15R,16R)-stereoisomer" XP002904788 *
HIRAKI T. ET AL: "Synthesis of a Straight Chain Analog of Penaresidins, Azetidine Alkaloids from Marine Sponge Penares SP", TETRAHEDRON LETTERS, vol. 36, no. 27, 1995, pages 4841 - 4844, XP004027782 *
KNAPP S. AND DONG Y.: "Stereoselective Synthesis of Penaresidin A and Related Azetidine Alkaloids", TETRAHEDRON LETTERS, vol. 38, no. 22, 1997, pages 3813 - 3816, XP002234076 *
KOBAYASHI J. ET AL: "Absolute Stereochemistry of Penaresidins A and B", TETRAHEDRON LETTERS, vol. 37, no. 37, 1996, pages 6775 - 6776, XP004088091 *
KOBAYASHI J. ET AL: "Penaresidin A and B, Two Novel Azetidine Alkaloids with Potent Actomyosin ATPase-Activating Activity from the Okinawan Marine Sponge Penares SP", J. CHEM. SOC. PERKIN TRANS. 1, no. 5, 1991, pages 1135 - 1137, XP002904789 *
LIU D. AND LIN G.: "Novel Enantioselective Synthesis of Penaresidin A and Allo-penaresidin A via the Construction of a Highly Functionalized Azetidine", TETRAHEDRON LETTERS, vol. 40, no. 2, 1999, pages 337 - 340, XP004152546 *
TAKIKAWA H. ET AL: "Synthesis of Penaresidin A, an Azetidine Alkaloid with Actomyosin ATPase-Activating Property", TETRAHEDRON LETTERS, vol. 36, no. 42, 1995, pages 7689 - 7692, XP004027117 *
TAKIKAWA H. ET AL: "Synthesis of sphingosine relatives. Part 19. Synthesis of penaresidin A and B, azetidine alkaloids with actomyosin ATPase-activating properties", J. CHEM. SOC., PERKIN TRANS. 1, no. 2, 1997, pages 97 - 111, XP002961092 *

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7763752B2 (en) 2002-09-19 2010-07-27 Kyorin Pharmaceutical Co., Ltd. Amino alcohol derivatives, salts thereof and immunosuppresive agents
US7482491B2 (en) 2002-09-19 2009-01-27 Kyorin Pharmaceutical Co., Ltd. Amino alcohol derivative, addition salt thereof, and immunosuppressant
US7456157B2 (en) 2003-02-18 2008-11-25 Kyorin Pharmaceutical Co., Ltd. Aminophosphonic acid derivatives, addition salts thereof and S1P receptor modulators
WO2004074297A1 (fr) 2003-02-18 2004-09-02 Kyorin Pharmaceutical Co., Ltd. Derives d'acide aminophosphonique, leurs sels d'addition et des modulateurs de recepteurs s1p
US7759326B2 (en) 2003-02-18 2010-07-20 Kyorin Pharmaceutical Co., Ltd. Aminophosphonic acid derivative, salt thereof, and modulator of S1P receptor
EP2308562A2 (fr) 2003-12-25 2011-04-13 Ono Pharmaceutical Co., Ltd. Composes cycliques d'azetidine et medicaments les renfermant
WO2005063704A1 (fr) 2003-12-25 2005-07-14 Ono Pharmaceutical Co., Ltd. Composes cycliques d'azetidine et medicaments les renfermant
WO2006093352A1 (fr) * 2005-03-04 2006-09-08 Riken Compose a structure cyclique et son utilisation
US8173608B2 (en) 2005-03-04 2012-05-08 Riken Compound having cyclic structure and use thereof
JP5099343B2 (ja) * 2005-03-04 2012-12-19 独立行政法人理化学研究所 環状構造を有する化合物及びその用途
US8546452B2 (en) 2005-10-12 2013-10-01 Toa Eiyo Ltd. S1P3 receptor antagonist
WO2008018447A1 (fr) 2006-08-08 2008-02-14 Kyorin Pharmaceutical Co., Ltd. Dérivé d'aminoalcool et immunodépresseur le contenant en tant que principe actif
WO2008018427A1 (fr) 2006-08-08 2008-02-14 Kyorin Pharmaceutical Co., Ltd. Dérivé d'ester de l'acide aminophosphorique et modulateur du récepteur s1p contenant ledit dérivé en tant que principe actif
US8232319B2 (en) 2006-08-08 2012-07-31 Kyorin Pharmaceutical Co., Ltd. Amino phosphate derivative and S1P receptor modulator having same as an active ingredient
US8273748B2 (en) 2006-08-08 2012-09-25 Kyorin Pharmaceutical Co., Ltd. Amino alcohol derivative and immunosuppresive agent having same as an active ingredient

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