WO2004106312A1 - Nouveau derive de 2-aminoselenazoline et son utilisation - Google Patents

Nouveau derive de 2-aminoselenazoline et son utilisation Download PDF

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WO2004106312A1
WO2004106312A1 PCT/JP2004/007547 JP2004007547W WO2004106312A1 WO 2004106312 A1 WO2004106312 A1 WO 2004106312A1 JP 2004007547 W JP2004007547 W JP 2004007547W WO 2004106312 A1 WO2004106312 A1 WO 2004106312A1
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compound
aminoselenazoline
physiologically acceptable
acid addition
dihydro
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PCT/JP2004/007547
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Japanese (ja)
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Shigeo Ueda
Hideo Terauchi
Akihiro Yano
Masashi Matsumoto
Taeko Kubo
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Dainippon Pharmaceutical Co., Ltd.
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Publication of WO2004106312A1 publication Critical patent/WO2004106312A1/fr

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    • C07D293/04—Five-membered rings
    • C07D293/06—Selenazoles; Hydrogenated selenazoles
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Definitions

  • the present invention relates to 2-aminoselenazoline derivatives useful as nitric oxide synthase inhibitors and uses thereof.
  • nitric oxide is an endothelium-derived vasorelaxant in the vascular system (see Moncada, S., et al., Pharmacological Reviews, 1991, 43, 109), and nervous system in the nervous system. Natl. Acad. Sci., USA., 1992, 89, 11651 as a transmitter (see Edelman, GM, et al., Proc. Natl. Acad. Sci., 1992, 89, 11651). It is considered that NO plays a role as a biological defense factor by bactericidal action, etc. (see Curr. Opin.
  • NOS Nitric Oxide Synthase
  • L-arginine L-arginine
  • nNOS neuroneuronal N0S: hereinafter abbreviated as “nNOS”), all of which are constantly expressed and depend on intracellular calcium that rises due to physiological stimulation. Produces small amounts of NO.
  • the other is called inducible NOS (abbreviated as “iNOS”), and its expression is induced in various cells including macrophages by stimulation with endotoxin and various cytokines.
  • iNOS inducible NOS
  • iNOS unlike cNOS, produces a sustained amount of NO, independent of intracellular calcium. Therefore, it has been reported that NO produced by iNOS causes various cell damages. For example, in septic endotoxinemia, excessive NO produced by iNOS can cause hypotensive shock.
  • N 2 O produced by iNOS during cerebral ischemia-reperfusion may cause neuronal cell death (Parmentier-Batteur S., et al., J. Cereb.
  • a compound represented by the following formula (A) has been reported as a compound having NOS inhibitory activity (see Le Sciences, 1996, 58, 1139).
  • R 1 is a hydrogen atom or an alkyl group
  • R 2 denotes an alkyl group, one alkyl Le one NH 2, etc.
  • an object of the present invention is to treat and / or prevent diseases caused by excessive NO production of iNOS, and to obtain a NO inhibitor having a strong inhibitory activity and / or high selectivity for iNOS.
  • the present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have found a compound having extremely strong inhibitory activity against iNOS and Z or high selectivity.
  • the present invention relates to a novel 2-aminoselenazoline derivative represented by the following general formula (I) or a physiologically acceptable acid addition salt thereof (hereinafter, also referred to as “the compound of the present invention”), and the compound:
  • the present invention relates to a NOS inhibitor which is useful for treating and / or preventing a disease caused by iNOS overproduction, comprising as an active ingredient.
  • the present invention provides the following various aspects of the invention.
  • R 1 and R 2 are the same or different and each represent a hydrogen atom or an alkyl group having 1 to 10 carbon atoms; and R 1 and R 2 are not hydrogen atoms at the same time)
  • Amino selenazoline derivatives or physiologically acceptable acid addition salts thereof are the same or different and each represent a hydrogen atom or an alkyl group having 1 to 10 carbon atoms; and R 1 and R 2 are not hydrogen atoms at the same time.
  • R 1 and R 2 are the same or different and each represent a hydrogen atom or an alkyl group having 1 to 10 carbon atoms, and when R 1 or R 2 is not a hydrogen atom, ⁇ * '' indicates an asymmetric carbon atom. Means an atom. And R 1 and R 2 are not hydrogen at the same time)
  • a nitric oxide synthase inhibitor comprising, as an active ingredient, the 2-aminoselenazoline derivative or the physiologically acceptable acid addition salt thereof according to any one of (1) to (4).
  • the 2-aminoselenazoline derivative may be referred to as a 4,5-dihydro-1,3-selenazole-2-ylamine derivative.
  • the compound of the present invention is a compound represented by the above formula (I), preferably R 1 or R 2 in the formula (I) is an alkyl group having 1 to 6 carbon atoms.
  • the compound of the present invention represented by the general formula (I) or () is a physiologically acceptable caro salt with acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, oxalic acid, fumaric acid, and maleic acid Salts with organic acids such as acids, malonic acid, lactic acid, malic acid, succinic acid,
  • an alkyl group having 1 to carbon atoms: L 0 refers to a linear or branched alkyl group.
  • Means alkyl group specific examples include methyl, ethyl, n-propyl, isopropylinole, n-butynole, isoptinole, sec-butinole, tert-butinole, n-pentyl, hexyl, heptyl, octyl, noel, decyl And the like.
  • the compound of the present invention represented by the general formula (I) has one or two asymmetric carbon atoms on the selenazoline ring, and its configuration is R-type, S-type, RR-type, and RS-type. , SR type or SS type, and these optical isomers are also included in the compounds of the present invention. Further, a mixture of these optical isomers is also included in the compound of the present invention.
  • the 2-aminoselenazolyne derivative represented by the general formula (I) or () is an imino tautomer (2-1) represented by the following formula (I-1) or (I'-11). (Imino-1,3-selenazolidine derivative), and these tautomers are also included in the compounds of the present invention.
  • the compound represented by the general formula (I) or a physiologically acceptable acid addition salt thereof may be present as a hydrate or a solvate, and these compounds are also compounds of the present invention. include.
  • the compound of the present invention represented by the general formula (I) can be produced by the following production methods 1 to 3.
  • the compound of the present invention represented by the general formula (I) can be produced according to the following reaction formula.
  • compound (I) of the present invention is produced by reacting compound (II) with selenocyanate in the presence of a solvent according to the method described in the literature (Chem. Ber., 1890, 23, 1003). can do.
  • the compound (I) of the present invention can be produced by reacting the compound (III) with selenourea.
  • the above reaction is usually performed in a suitable solvent that does not affect the reaction.
  • suitable solvent examples include water, methanol, ethanol and the like, and these solvents may be used alone or as a mixed solvent of two or more kinds.
  • the reaction temperature varies depending on the type of the starting compound used, but is usually 0 ° C to 120 ° C, preferably 20 ° C to 120 ° C.
  • the reaction time is usually about 30 minutes to 24 hours, preferably about 1 to 8 hours.
  • the compound (I) of the present invention can be produced by reacting the isoselenocyanate derivative (IV) with liquid ammonia, ammonia gas, an aqueous ammonia solution or an ammoniacal alcohol solution.
  • the above reaction is usually performed in a suitable solvent that does not affect the reaction.
  • suitable solvent examples include water, methanol, ethanol, dioxane, tetrahydrofuran and the like, and these solvents may be used alone or as a mixed solvent of two or more kinds.
  • the reaction temperature varies depending on the type of the starting compound used and the like, but is usually from 140 ° C to 150 ° C, preferably from 20 ° C to 120 ° C.
  • the reaction time is generally about 30 minutes to 24 hours, preferably about 1 hour to 10 hours.
  • Compound (II) used in Production Method 1 can be produced, for example, according to the method shown in the following reaction formula.
  • R represents a methyl group, a tolyl group, etc.
  • I 1 , R 2 , X and Y are as defined above.
  • the compound (II) is produced according to the method described in the literature (J. Org. Chem., 1996, 61, 4210; Angew. Chem., Int. Ed. Engl., 1987, 26, 1M1).
  • the compound (V) was reacted with di-tert-butyl dicarbonate (Boc 20 ) according to a conventional method to obtain a compound (VI) in which an amino group was protected.
  • the hydroxy group of the compound (VI) was converted to ( i) Sulfonylation according to a conventional method using a tosyl or methanesulfoneuryl chloride, or (ii) halogenation using a conventional method with a triphenylphosphine dihalogenide to obtain a compound (VII).
  • the compound (VII) can be produced by subjecting the compound (VII) to a deprotection treatment under acidic conditions such as trifluoroacetic acid or hydrochloric acid.
  • the compound (III) used in the production method 2 can be produced, for example, according to the method shown in the following reaction formula.
  • the compound (III) can be converted to the compound (VII 1) in an inert solvent such as carbon tetrachloride according to the method described in the literature (Tetrahedron, 1985, 41, 4717). It can be produced by reacting dic acid getyl ester and trifluoroborane etherate.
  • Compound (IV) used in Production Method 3 can be produced, for example, according to the method shown in the following reaction formula.
  • compound (IV) is produced according to the method described in the literature (J. Org. Chem., 1996, 61, 4210; Angew. Chera., Int. Ed. Engl., 1987, 26, 1141).
  • Compound (V) was prepared according to the method described in the literature (J. Chera. Soc. Perk in Trans. 1, 1990, 61, 2255; Angew. Chem., Int. Ed. Engl., 1987, 26, 1141).
  • R a represents an alkyl group having 1 to 8 carbon atoms
  • B n represents a benzyl group
  • RR 2 and X are the same as described above.
  • compound (V) is reacted with compound (XI) produced according to the method described in the literature (J. Am. Chera. So, 1999, 121, 7509) using normal butyl lithium and an aldehyde according to a conventional method. , compounds which are Orefin body and (XII), then after hydrogenation the compound (XII) according to a conventional method, and di one tert- Petit / cashier force Ruponeto (Bo c 2 0) and allowed to react compound (XIII) Next, the compound (XIII) is ring-opened using a base catalyst to give a compound (XIV).
  • Benzylated compound (XV) can be produced from compound (XV) according to the method described in the literature (Angew. Chem., Int. Ed. Engl., 1987, 26, 1141).
  • the compound (I) of the present invention which is a specific optical isomer, uses the starting compounds (I1), (III) and (IV) of the predetermined optical isomer in the above-mentioned Production Methods 1 to 3. Thus, it can be manufactured.
  • the compound (I) of the present invention can be obtained in the form of a free base or an acid addition salt. Both compounds can be converted into each other by a usual method.
  • the NOS inhibitor of the present invention is a disease caused by NO, for example, a neurodegenerative disease such as Alzheimer's disease and Parkinson's disease; a disease of central or peripheral nerves such as depression, anxiety, and schizophrenia; Heart disease; hepatitis; nephritis; chronic or acute lung disease; shock such as septic shock, hypotensive shock, or hemorrhagic shock; inflammatory gastrointestinal diseases such as ulcerative colitis or Crohn's disease; Complications; autoimmune diseases; chronic or acute transplant rejection; erectile or reproductive disorders; allergic diseases; skin diseases such as topotopic skin disease and psoriasis; cutaneous pruritus; hyperalgesia; pain; Diseases caused by irradiation, the sun, etc .; viral infections; trauma from various diseases, for example, a neurodegenerative disease such as Alzheimer's disease and Parkinson's disease; a disease of central or peripheral nerves such as depression, anxiety, and schizophrenia; Heart disease; hepatitis; nep
  • the administration route of the compound of the present invention may be any of oral administration, parenteral administration and rectal administration.
  • the daily dose varies depending on the type of the compound, the administration method, the symptom of the patient and the age.
  • oral administration usually, about 0.01 to 1 mg / kg of human or mammal body weight: L 0.00 mg, more preferably about 0.01 to 50 mg is divided into 1 to several times.
  • parenteral administration such as intravenous injection, usually, for example, about 1 / X g to 1 mg / kg body weight of human or mammal; L 0 mg, more preferably about 1 ⁇ g to 5 mg Can be.
  • the compound of the present invention When the compound of the present invention is used for pharmaceutical applications as described above, it is usually administered in the form of a preparation prepared by mixing with a carrier for preparation.
  • a carrier for preparations non-toxic substances which do not react with the compound of the present invention are commonly used in the field of pharmaceutical preparations.
  • Dosage forms include tablets, capsules, granules, powders, syrups, suspensions, injections, suppositories, eye drops, ointments, liniments, inhalants and the like. These preparations can be prepared according to a conventional method. When used, liquid preparations may be in the form of solutions or suspensions in water or other suitable media. Tablets and granules may be coated by a well-known method.
  • 7W raw solvent eg, distilled water, physiological saline, Ringer's solution, etc.
  • tonicity agent eg, pudose sugar, D-sorbitol, D-mannitol, Sodium chloride, etc.
  • stabilizers eg, human serum albumin
  • preservatives eg, benzyl alcohol, chlorobutanol, methyl noroxybenzoate, propyl parahydroxybenzoate, phenol
  • buffers eg, : Phosphate buffer, sodium acetate buffer, etc.
  • soothing agents eg, benzalcoium chloride, proforce hydrochloride, etc.
  • Me is a methyl group
  • Et is an ethyl group
  • n-Pr is a normal propyl group
  • i-Pr is an isopropyl group
  • n_Bu is a normal butyl group
  • recrystallization solvents include ET for ethanol, HX for n-hexane and IP for isopropanol.
  • Example 1 The same reaction and treatment as in Example 1 were carried out in the same manner as in Example 1 except that (2R) -2-aminopropyl methylsulfonate monohydrochloride in Example 1 was replaced with the corresponding starting material obtained in Reference Example 2.
  • reaction solution was washed with water, dried over sodium sulfate, concentrated, and the residue was subjected to silica gel column chromatography, eluting with ethyl acetate-n-hexane (1: 1) and purified to obtain the following two compounds.
  • silica gel column chromatography eluting with ethyl acetate-n-hexane (1: 1) and purified to obtain the following two compounds.
  • N_ (4S, 5S) _ (4-ethylen-5-methinole-1,4,5-dihydro-1,3-selenazolone obtained in step 2 above 0.21 g of (4S, 5S) -4-ethyl-5-methyl-4,5-dihydro-1,3-selenazole-12-ylamine was obtained as an oil from 0.50 g of (2-inole) -oxamic acid methyl ester.
  • Step 2 A solution of 0.15 g of (2R, 3S) -N-formyl-1-amino-3-pentanomono obtained in Step 1 above and 0.16 ml of triethylamine in a methylene chloride solution To 10 ml, a solution of 0.13 g of methanesulfoyl chloride in 2 ml of methylene chloride was added under ice-cooling and stirring, and the mixture was stirred at the same temperature for 1 hour.
  • Step 3 0.21 g of (1S, 2R) -1-ethyl-2-formylaminopropyl methylsulfonate obtained in the above step 2 and 28 ml of triethylamine 2.5 ml and methylene chloride solution 2.5 ml and dimethyl ether 5 m 0.15 g of triphosgene was added to 1 under ice-cooled stirring, and the mixture was stirred at the same temperature for 10 minutes. Hexane (15 ml) was added to the reaction solution, and the mixture was filtered through celite and concentrated to obtain (1S, 2R) -1-ethyl-2-isocyanopropyl methylsulfonate.
  • Step 5 Without further purification, the dioxane 5 ml solution of (1S, 2R) -1-ethylenoleate 2-isoselenocyanatopropynole methinolesnorefonate obtained in Step 4 above was added to After adding 3 ml of water, the mixture was heated to 60 ° C. and stirred for 1 hour. After dioxane is distilled off under reduced pressure, 25% sodium hydroxide 2 ml of an aqueous solution was added, and the mixture was extracted three times with 10 ml of a mouth mouth form.
  • Test Example 1 Inhibitory activity on inducible NO synthase (iNOS)
  • a crude enzyme preparation of iNOS was prepared by the following procedure.
  • Mouse macrophage cell line RAW 264.7 (3-4 x 10 6 plates per culture dish) containing 10% FBS (fetal calf serum) in D-MEM (Dalbecco-Minimum)
  • Test Example 2 Inhibitory activity on constitutive NO synthase (nNOS) derived from rat brain A crude enzyme sample of nNOS was prepared by the following procedure.
  • nNOS activity have been conducted under measurement to quantify L one [3 H] amount of conversion to single citrulline from L- [3 H] one arginine.
  • the compound of the present invention is considered to have few NO side effects because of its excellent NOS inhibitory activity and high selectivity for Z or iNOS.
  • Neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease; central or peripheral nerve diseases such as depression, anxiety and schizophrenia; heart diseases such as myocarditis; hepatitis; nephritis; chronic or acute lung disease; Shock, hypotensive shock, hemorrhagic shock, etc .; inflammatory gastrointestinal diseases such as ulcerative colitis, Kuhn's disease; diabetes or its complications; autoimmune diseases; chronic or acute transplantation beta rejection Erectile or reproductive disorders; allergic diseases; atopic skin diseases, skin diseases such as psoriasis; cutaneous pruritus; hyperalgesia; pain; cancer; Diseases caused by irradiation, etc .; viral infections; trauma due to various causes; rheumatoid arthritis, osteoarthritis; prevention of poisoning by alcohol, chemicals, etc.,

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Abstract

L'invention a trait à un nouveau dérivé de 2-aminosélénazoline, représenté par la formule générale (I), qui présente une excellente activité inhibitrice de l'oxyde nitrique synthase (NOS), ou un sel d'addition d'acide physiologiquement acceptable dudit dérivé. Dans ladite formule, R1 et R2 sont identiques ou différents et représentent chacun hydrogène ou alkyle C1-10, sous réserve que R1 et R2 ne représentent pas tous deux hydrogène. Le composé selon l'invention présente une très forte activité inhibitrice de la NOS inductible (iNOS) et/ou une forte sélectivité pour cette dernière, et est donc utile en tant qu'inhibiteur de la NOS présentant des effets indésirables réduits.
PCT/JP2004/007547 2003-05-29 2004-05-26 Nouveau derive de 2-aminoselenazoline et son utilisation WO2004106312A1 (fr)

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JP2003152028A JP2006232671A (ja) 2003-05-29 2003-05-29 新規セレナゾリン誘導体

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103483291A (zh) * 2012-06-14 2014-01-01 沈阳药科大学 4,5-二芳基-1,3-硒唑类化合物及其制备方法和用途
WO2022010328A1 (fr) * 2020-07-10 2022-01-13 덕성여자대학교 산학협력단 1-alkyl-5-arylidène-2-sélénooxoimidazolidine-4-one et son dérivé, son procédé de préparation et composition le comprenant pour prévenir, soulager ou traiter des maladies neurodégénératives
WO2023132681A1 (fr) * 2022-01-10 2023-07-13 덕성여자대학교 산학협력단 Composition pharmaceutique et composition alimentaire comprenant de la 1-alkyl-5-arylidène-2-sélénoxoimidazolidin-4-one et un dérivé de celle-ci pour la prévention, le soulagement ou le traitement d'une maladie inflammatoire

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JPH10186563A (ja) * 1996-12-17 1998-07-14 Agfa Gevaert Ag 写真用ハロゲン化銀乳剤
JP2003192678A (ja) * 2001-12-25 2003-07-09 Gifu Univ 新規な１，３−セレナゾリン誘導体及びその製造方法

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JPH10186563A (ja) * 1996-12-17 1998-07-14 Agfa Gevaert Ag 写真用ハロゲン化銀乳剤
JP2003192678A (ja) * 2001-12-25 2003-07-09 Gifu Univ 新規な１，３−セレナゾリン誘導体及びその製造方法

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ATTANASI O.A. ET AL: "1,2-Diaza-1,3-Butadienes: A New Approach to the Synthesis of Selenoheterocycles", EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, vol. 14, 2002, pages 2323 - 2330, XP002981335 *
SOUTHAN G.J. ET AL: "Potent inhibitation of the inducible isoform of nitric oxide synthase by aminoethylisoselenourea and related compounds", LIFE SCIENCES, vol. 58, no. 14, 1996, pages 1139 - 1148, XP002981334 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103483291A (zh) * 2012-06-14 2014-01-01 沈阳药科大学 4,5-二芳基-1,3-硒唑类化合物及其制备方法和用途
CN103483291B (zh) * 2012-06-14 2015-08-12 沈阳药科大学 4,5-二芳基-1,3-硒唑类化合物及其制备方法和用途
WO2022010328A1 (fr) * 2020-07-10 2022-01-13 덕성여자대학교 산학협력단 1-alkyl-5-arylidène-2-sélénooxoimidazolidine-4-one et son dérivé, son procédé de préparation et composition le comprenant pour prévenir, soulager ou traiter des maladies neurodégénératives
KR20220123180A (ko) * 2020-07-10 2022-09-06 덕성여자대학교 산학협력단 1-알킬-5-아릴리덴-2-셀레녹소이미다졸리딘-4-온 및 그 유도체, 이의 제조방법 및 이를 포함하는 신경퇴행성 질환의 예방, 개선 또는 치료용 조성물
KR102475361B1 (ko) 2020-07-10 2022-12-07 덕성여자대학교 산학협력단 1-알킬-5-아릴리덴-2-셀레녹소이미다졸리딘-4-온 및 그 유도체, 이의 제조방법 및 이를 포함하는 신경퇴행성 질환의 예방, 개선 또는 치료용 조성물
WO2023132681A1 (fr) * 2022-01-10 2023-07-13 덕성여자대학교 산학협력단 Composition pharmaceutique et composition alimentaire comprenant de la 1-alkyl-5-arylidène-2-sélénoxoimidazolidin-4-one et un dérivé de celle-ci pour la prévention, le soulagement ou le traitement d'une maladie inflammatoire

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